martes, 16 de abril de 2019

Childhood Acute Myeloid Leukemia Treatment (PDQ®) 3/3 —Health Professional Version - National Cancer Institute

Childhood Acute Myeloid Leukemia Treatment (PDQ®)—Health Professional Version - National Cancer Institute

National Cancer Institute



Childhood Acute Myeloid Leukemia/Other Myeloid Malignancies Treatment (PDQ®)–Health Professional Version


Acute Promyelocytic Leukemia (APL)

Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia (AML) because of several factors, including the following:
  • Clinical presentation of universal coagulopathy (disseminated intravascular coagulation) and unique morphologic characteristics (French-American-British [FAB] M3 or its variants).
  • Unique molecular etiology as a result of the involvement of the RARA oncogene.
  • Unique sensitivity to the differentiating agent all-trans retinoic acid (ATRA) and to the proapoptotic agent arsenic trioxide.[1]
These unique features of APL mandate a high index of suspicion at diagnosis so as to initiate proper supportive care measures to avoid coagulopathic complications during the first days of therapy. It is also critical to institute a different induction regimen of therapy to minimize the risk of coagulopathic complications and to provide a much improved long-term relapse-free survival and overall survival (OS) than with past approaches to APL and compared with outcomes for patients with the other forms of AML.[2,3]

Molecular Abnormality

The characteristic chromosomal abnormality associated with APL is t(15;17). This translocation involves a breakpoint that includes the retinoic acid receptor and leads to production of the promyelocytic leukemia (PML)–retinoic acid receptor alpha (RARA) fusion protein.[1]
Patients with a suspected diagnosis of APL can have their diagnosis confirmed by detection of the PML-RARA fusion (e.g., through fluorescence in situ hybridization [FISH], reverse transcriptase–polymerase chain reaction [RT-PCR], or conventional cytogenetics). An immunofluorescence method using an anti-PML monoclonal antibody can rapidly establish the presence of the PML-RARA fusion protein based on the characteristic distribution pattern of PML that occurs in the presence of the fusion protein.[4-6]

Clinical Presentation

Clinically, APL is characterized by severe coagulopathy that is often present at the time of diagnosis.[7] This is typically manifested with thrombocytopenia, prolonged prothrombin time, partial thromboplastin time, elevated d-dimers, and hypofibrinogenemia.[8] Mortality during induction (particularly with cytotoxic agents used alone) caused by bleeding complications is more common in this subtype than in other FAB or World Health Organization (WHO) classifications.[9,10] A multicooperative group analysis of children with APL who were treated with ATRA and chemotherapy reported that early induction coagulopathic deaths occurred in 25 of 683 children (3.7%); 23 deaths resulted from hemorrhage (19 CNS, 4 pulmonary), and 2 resulted from CNS thrombosis.[11] A lumbar puncture at diagnosis should not be performed until evidence of coagulopathy has resolved.
ATRA therapy is initiated as soon as APL is suspected on the basis of morphological and clinical presentation,[2,12] because ATRA has been shown to ameliorate bleeding risk for patients with APL.[13] A retrospective analysis identified an increase in early death resulting from hemorrhage in patients with APL in whom ATRA introduction was delayed.[8] Additionally, initiation of supportive measures such as replacement transfusions directed at correction of the coagulopathy is critical during these initial days of diagnosis and therapy. Patients at greatest risk of coagulopathic complications are those presenting with high white blood cell (WBC) counts, high body mass index, hypofibrinogenemia, molecular variants of APL, and the presence of FLT3-ITD mutations.[8,11]
APL in children is generally similar to APL in adults, although children have a higher incidence of hyperleukocytosis (defined as WBC count higher than 10 × 109/L) and a higher incidence of the microgranular morphologic subtype.[14-17] As in adults, children with WBC counts less than 10 × 109/L at diagnosis have significantly better outcomes than do patients with higher WBC counts.[15,16,18]

Risk Classification for Treatment Stratification

The prognostic significance of WBC count is used to define high-risk and low-risk patient populations and to assign postinduction treatment, with high-risk patients most commonly defined by WBC count of 10 × 109/L or greater.[19,20] FLT3 mutations (either internal tandem duplications or kinase domain mutations) are observed in 40% to 50% of APL cases, with the presence of FLT3 mutations correlating with higher WBC counts and the microgranular variant (M3v) subtype.[21-25] The FLT3 mutation has been associated with an increased risk of induction death and, in some reports, an increased risk of treatment failure.[21-27]
In the COG AAML0631 (NCT00866918) trial, which included treatment with chemotherapy, ATRA, and arsenic trioxide, risk classification primarily defined early death risk rather than relapse risk (standard risk, 0 of 66 patients vs. high risk, 4 of 35 patients). Relapse risk after remission induction was 4% overall, with one relapse in a standard-risk child and two relapses in high-risk children. High-risk patients on this trial had earlier initiation of idarubicin, with first dose on day 1 rather than day 3 to reduce leukemic burden more rapidly, and one additional consolidation chemotherapy (high-dose cytarabine and idarubicin) and ATRA cycle.[28]

The Central Nervous System (CNS) and APL

CNS involvement at the time of diagnosis is not ascertained in most patients with APL because of the presence of disseminated intravascular coagulation. The COG AAML0631 (NCT00866918) trial identified 28 patients out of 101 enrolled children who had CSF exams at diagnosis, and in 7 of these children, blasts were identified in atraumatic taps.[28] None of the patients experienced a CNS relapse with intrathecal treatment during induction and prophylactic doses during therapy.
Overall, CNS relapse is uncommon for patients with APL, particularly for those with WBC counts of less than 10 × 109/L.[29,30] In two clinical trials enrolling over 1,400 adults with APL in which CNS prophylaxis was not administered, the cumulative incidence of CNS relapse was less than 1% for patients with WBC counts of less than 10 × 109/L, while it was approximately 5% for those with WBC counts of 10 × 109/L or greater.[29,30] In addition to high WBC counts at diagnosis, CNS hemorrhage during induction is also a risk factor for CNS relapse.[30] A review of published cases of pediatric APL also observed low rates of CNS relapse. Because of the low incidence of CNS relapse among children with APL presenting with WBC counts of less than 10 × 109/L, CNS surveillance and prophylactic CNS therapy may not be needed for this group of patients,[31] although there is no consensus on this topic.[32]

Treatment of APL

Modern treatment programs for APL are based on the sensitivity of leukemia cells from APL patients to the differentiation-inducing and apoptotic effects of ATRA and arsenic trioxide. APL therapy first diverged from the therapy of other non-APL subtypes of AML with the addition of ATRA to chemotherapy.
Treatment options for children with APL may include the following:
  1. Chemotherapy.
  2. ATRA.
  3. Arsenic trioxide.
  4. Supportive care.
The standard approach to treating children with APL builds upon adult clinical trial results; the approach begins with induction therapy using ATRA given in combination with an anthracycline administered with or without cytarabine. The dramatic efficacy of ATRA against APL results from the ability of pharmacologic doses of ATRA to overcome the repression of signaling caused by the PML-RARA fusion protein at physiologic ATRA concentrations. Restoration of signaling leads to differentiation of APL cells and then to postmaturation apoptosis.[33] Most patients with APL achieve a complete remission (CR) when treated with ATRA, although single-agent ATRA is generally not curative.[34,35]
A series of randomized clinical trials defined the benefit of combining ATRA with chemotherapy during induction therapy and the utility of using ATRA as maintenance therapy.[36-38] One regimen uses ATRA in conjunction with standard-dose cytarabine and daunorubicin,[14,39] while another uses idarubicin and ATRA without cytarabine for remission induction.[15,16] Almost all children with APL treated with one of these approaches achieves CR in the absence of coagulopathy-related mortality.[15,16,39-41]
Assessment of response to induction therapy in the first month of treatment using morphologic and molecular criteria may provide misleading results because delayed persistence of differentiating leukemia cells can occur in patients who will ultimately achieve CR.[2,3] Alterations in planned treatment based on these early observations are not appropriate because resistance of APL to ATRA plus anthracycline-containing regimens is extremely rare.[20,42]
Consolidation therapy has typically included ATRA given with an anthracycline with or without cytarabine. The role of cytarabine in consolidation therapy regimens is controversial. While a randomized study addressing the contribution of cytarabine to a daunorubicin-plus-ATRA regimen in adults with low-risk APL showed a benefit for the addition of cytarabine,[43] regimens using a high-dose anthracycline appear to produce as good as or better results in low-risk patients.[44] For high-risk patients (WBC ≥10 × 109/L), a historical comparison of the Programa para el Tratamiento de Hemopatías Malignas (PETHEMA) LPA 2005 (NCT00408278) trial with the preceding LPA 99 (NCT00465933) trial suggested that the addition of cytarabine to anthracycline-ATRA combinations can lower the relapse rate.[42] The results of the AIDA 2000 (NCT00180128) trial confirmed that the cumulative incidence of relapse for adult patients with high-risk disease can be reduced to approximately 10% with consolidation regimens that contain ATRA, anthracyclines, and cytarabine.[20] Studies using arsenic trioxide–based consolidation have demonstrated excellent survival without cytarabine consolidation.[26,45,46]
Maintenance therapy includes ATRA plus mercaptopurine and methotrexate; this combination has shown conflicting benefit, with some randomized trials in adults with APL showing an advantage over ATRA alone [36,47] and other studies showing no benefit.[46,48,49] However, the utility of maintenance therapy in APL may be dependent on multiple factors (e.g., risk group, the anthracycline used during induction, the use of arsenic trioxide, and the intensity of induction and consolidation therapy).
At this time, maintenance therapy remains standard for children with APL. Because of the favorable outcomes observed with chemotherapy plus ATRA and arsenic trioxide (event-free survival [EFS] rates of 70%–90%), hematopoietic stem cell transplantation is not recommended in first CR.
Arsenic trioxide is the most active agent in the treatment of APL, and while initially used in relapsed APL, it has been incorporated into the treatment of newly diagnosed patients. Data supporting the use of arsenic trioxide initially came from trials that included adult patients only, but more recently, its efficacy has been seen on trials that included both pediatric and adult patients and pediatric patients alone.
Evidence (arsenic trioxide therapy):
  1. In adults with newly diagnosed APL treated on the CALGB-C9710 (NCT00003934) trial, the addition of two consolidation courses of arsenic trioxide to a standard APL treatment regimen resulted in the following:[45]
    • A significant improvement in EFS (80% vs. 63% at 3 years; P < .0001) and disease-free survival (DFS) (90% vs. 70% at 3 years; P < .0001), although the outcome of patients who did not receive arsenic trioxide was inferior to the results obtained in the Gruppo Italiano Malattie EMatologiche dell’Adulto (GIMEMA) or PETHEMA trials.
  2. In children and adolescents with newly diagnosed APL treated on the COG AAML0631 (NCT00866918) trial, two consolidation cycles of arsenic trioxide were incorporated into a chemotherapy regimen with lower cumulative anthracycline doses compared with historical controls.[28]
    • The 3-year OS was 94%, and EFS was 91%.
    • Patients with standard-risk APL had an OS of 98% and EFS of 95%.
    • High-risk patients had an OS of 86% and EFS of 83%. This lower survival compared with standard-risk patients was primarily caused by early death events.
    • The relapse risk after arsenic trioxide consolidation was 4% and was similar for standard-risk and high-risk APL.
  3. The concurrent use of arsenic trioxide and ATRA in newly diagnosed patients with APL results in high rates of CR.[50-52] Early experience in children with newly diagnosed APL also shows high rates of CR to arsenic trioxide, either as a single agent or given with ATRA.[53][Level of evidence: 3iiA]
    • Results of a meta-analysis of seven published studies in adult APL patients suggest that the combination of arsenic trioxide and ATRA may be more effective than arsenic trioxide alone in inducing CR.[54]
    • The impact of arsenic induction (either alone or with ATRA) on EFS and OS has not been well characterized in children, although early results appear promising.[53,55,56]
  4. Arsenic trioxide was evaluated as a component of induction therapy with idarubicin and ATRA in the APML4 clinical trial, which enrolled both children and adults (N = 124 evaluable patients).[26] Patients received two courses of consolidation therapy with arsenic trioxide and ATRA (but no anthracycline) and maintenance therapy with ATRA, mercaptopurine, and methotrexate.[57]
    • The 2-year rate for freedom from relapse was 97.5%, failure-free survival (FFS) was 88.1%, and OS was 93.2%.
    • These results are superior for freedom from relapse, DFS, EFS, and OS when compared with the predecessor clinical trial (APML3) that did not use arsenic trioxide.
  5. A German and Italian phase III clinical trial (APL0406 [NCT00482833]) compared ATRA plus chemotherapy with ATRA plus arsenic trioxide in adults with APL classified as low to intermediate risk (WBC ≤10 × 109/L).[46] Patients were randomly assigned to receive either ATRA plus arsenic trioxide for induction and consolidation therapy or standard ATRA-idarubicin induction therapy followed by three cycles of consolidation therapy with ATRA plus chemotherapy and maintenance therapy with low-dose chemotherapy and ATRA.
    • All patients who received ATRA plus arsenic trioxide (n = 77) achieved CR at the end of induction therapy, while 95% of patients who received ATRA plus chemotherapy (n = 79) achieved CR.
    • EFS rates were 97% in the ATRA-arsenic trioxide group compared with 86% in the ATRA-chemotherapy group (P = .02).
    • Two-year OS probability was 99% (95% confidence interval [CI], 96%–100%) in the ATRA-arsenic trioxide group and 91% (95% CI, 85%–97%) in the ATRA-chemotherapy group (P = .02).
    • An updated longer-term analysis demonstrated that at 50 months, the ATRA-arsenic trioxide arm showed even greater superiority, with OS rates of 97% versus 80% (P < .001).[46,58]
    • These results indicate that low-risk to intermediate-risk APL is curable for a high percentage of patients without conventional chemotherapy.
Numerous trials showed that for children with APL, survival rates exceeding 80% are now achievable using treatment programs that prescribe the rapid initiation of ATRA with appropriate supportive care measures;[2,14-16,19,20,40,41] a rate exceeding 90% was demonstrated in a single trial that added arsenic trioxide to the treatment regimen.[28] For patients in CR for more than 5 years, relapse is extremely rare.[59][Level of evidence: 1iiDi]

Treatment options under clinical evaluation

Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.
The following is an example of a national and/or institutional clinical trial that is currently being conducted:
  1. COG AAML1331 (NCT02339740) (Tretinoin and Arsenic Trioxide in Treating Patients with Untreated APL): This is a single-arm trial that risk stratifies therapy to either ATRA plus arsenic trioxide alone for those with standard-risk APL (WBC <10,000/µl) or to the same induction with brief additional doses of idarubicin during induction for high-risk APL (WBC ≥10,000/µl). This builds upon the adult APL trials that eliminated traditional chemotherapy and which saw no decline in outcomes. Additionally, this trial eliminates maintenance therapy and thus reduces the overall length of therapy from 30 months to 8 months. Results will be compared historically to the COG-AAML0631trial.

Complications unique to APL therapy

In addition to the previously mentioned universal presence of coagulopathy in patients newly diagnosed with APL, several other unique complications occur in patients with APL for which the clinician should be aware. These include two ATRA-related conditions, pseudotumor cerebri and differentiation syndrome (also called retinoic acid syndrome), and an arsenic trioxide–related complication, QT interval prolongation.
  • Pseudotumor cerebri. Pseudotumor cerebri is typically manifested by headache, papilledema, sixth nerve palsy, visual field cuts, and normal intracranial imaging in the face of an elevated opening lumbar puncture pressure (not often obtained in APL patients). Pseudotumor cerebri is known to be associated with the use of ATRA, presumably by the same mechanism of vitamin A toxicity that leads to increased production of cerebrospinal fluid.
    The incidence of pseudotumor cerebri has been reported to be as low as 1.7% with very strict definitions of the complication and as high as 6% to 16% in three pediatric trials.[14,15,28,60] Pseudotumor cerebri is thought to be more prevalent in children receiving ATRA, leading to lower dosing in contemporary pediatric APL clinical trials.[14] Pseudotumor cerebri most typically occurs during induction at a median of 15 days (range, 1–35 days) after starting ATRA, but is known to occur in other phases of therapy as well.[60] Pseudotumor cerebri incidence and severity may be exacerbated with the concurrent use of azoles via inhibition of cytochrome P450 metabolism of ATRA.
    When a diagnosis of pseudotumor cerebri is suspected, ATRA is held until symptoms abate and then is slowly escalated to full dose as tolerated.[60]
  • Differentiation syndrome. Differentiation syndrome (also known as retinoic acid syndrome or ATRA syndrome) is a life-threatening syndrome thought to be an inflammatory response–mediated syndrome manifested by weight gain, fever, edema, pulmonary infiltrates, pleuro-pericardial effusions, hypotension, and, in the most severe cases, acute renal failure.[61] In the contemporary COG AAML0631 (NCT00866918) study, it was present in 20% of patients during induction and was more prevalent in high-risk children (31%) than in low-risk children (13%), a risk factor also seen in adults with APL.[28,62] There is a bimodal peak with this syndrome seen in the first and third weeks of induction therapy.
    Because of the increased incidence in high-risk patients, dexamethasone is given with ATRA and/or arsenic therapy to prevent this complication in this subset of patients.[61] Prophylaxis with dexamethasone and hydroxyurea (for cytoreduction) is also administered to standard-risk patients if their WBC count rises to greater than 10,000/uL after the start of ATRA or arsenic. If differentiation syndrome still occurs, the dexamethasone dose may be escalated first, rather than stopping ATRA or arsenic. If this fails to resolve the symptoms or if the symptoms are life-threatening, then ATRA or arsenic should be held and, similar to pseudotumor cerebri, restarted at a lower dose with plans to escalate as tolerated.
  • QT interval prolongation. Arsenic trioxide is associated with QT interval prolongation that can lead to life-threatening arrhythmias (e.g., torsades de pointes).[63] It is essential to monitor electrolytes closely in patients receiving arsenic trioxide and to maintain potassium and magnesium values at midnormal ranges, as well as to be cognizant of other agents known to prolong the QT interval.[64]

Minimal disease monitoring

The induction and consolidation therapies currently employed result in molecular remission, as measured by RT-PCR for PML-RARA, in most APL patients, with 1% or fewer showing molecular evidence of disease at the end of consolidation therapy.[20,42] While two negative RT-PCR assays after completion of therapy are associated with long-term remission,[65] conversion from negative to positive RT-PCR is highly predictive of subsequent hematologic relapse.[66]
Patients with persistent or relapsing disease on the basis of PML-RARA RT-PCR measurement may benefit from intervention with relapse therapies [67,68] (refer to the Recurrent Acute Promyelocytic Leukemia (APL) subsection of the Recurrent Childhood Acute Myeloid Leukemia and Other Myeloid Malignancies section of this summary for more information).

Molecular Variants of APL Other Than PML-RARA and Therapeutic Impact

Uncommon molecular variants of APL produce fusion proteins that join distinctive gene partners (e.g., PLZF, NPM, STAT5B, and NuMA) to RARA.[69,70] Recognition of these rare variants is important because they differ in their sensitivity to ATRA and to arsenic trioxide.[71]
  • PLZF-RARA variant. The PLZF-RARA variant, characterized by t(11;17)(q23;q21), represents about 0.8% of APL, expresses surface CD56, and has very fine granules compared with t(15;17) APL.[72-74] APL with PLZF-RARA has been associated with a poor prognosis and does not usually respond to ATRA or arsenic trioxide.[71-74]
  • NPM-RARA or NuMA-RARA variant. The rare APL variants with NPM-RARA (t(5;17)(q35;q21)) or NuMA-RARA (t(11;17)(q13;q21)) translocations may still be responsive to ATRA.[71,75-78]

Treatment of Recurrent APL

Historically, 10% to 20% of patients with APL relapse; however, more current studies that incorporated arsenic trioxide therapy showed cumulative incidence of relapse of less than 5%.[28,58]
In patients initially receiving chemotherapy-based treatments, the duration of first remission is prognostic in APL, with patients who relapse within 12 to 18 months of initial diagnosis having a worse outcome.[79-81]
An important issue in children who relapse is the previous exposure to anthracyclines, which can range from 400 mg/m2 to 750 mg/m2.[2] Thus, regimens containing anthracyclines are often not optimal for children with APL who suffer relapse.
Treatment options for children with recurrent APL may include the following:
  1. Arsenic trioxide or ATRA.
  2. Gemtuzumab ozogamicin.
  3. Hematopoietic stem cell transplantation (HSCT).

Arsenic trioxide

For children with recurrent APL, the use of arsenic trioxide as a single agent or in regimens including ATRA should be considered, depending on the therapy given during first remission. Arsenic trioxide is an active agent in patients with recurrent APL, with approximately 85% of patients achieving remission after treatment with this agent.[48,50,82-84] Arsenic trioxide is even capable of inducing remissions in patients who relapse after having received arsenic trioxide during initial therapy.[85] APL cells, however, may become resistant to arsenic trioxide through mechanisms including mutation of the PML domain of the PML-RARA fusion oncogene.[86]
For adults with relapsed APL, approximately 85% achieve morphologic remission after treatment with arsenic trioxide.[83,84,87] Data are limited on the use of arsenic trioxide in children, although published reports suggest that children with relapsed APL have a response to arsenic trioxide similar to that of adults.[82,84,88] Arsenic trioxide is well tolerated in children with relapsed APL. The toxicity profile and response rates in children are similar to that observed in adults.[82]
Because arsenic trioxide causes QT-interval prolongation that can lead to life-threatening arrhythmias,[63] it is essential to monitor electrolytes closely in patients receiving arsenic trioxide and to maintain potassium and magnesium values at midnormal ranges.[64]

Gemtuzumab ozogamicin

The use of gemtuzumab ozogamicin, an anti-CD33/calicheamicin monoclonal antibody, as a single agent resulted in a 91% (9 of 11 patients) molecular remission after two doses and a 100% (13 of 13 patients) molecular remission after three doses, thus demonstrating excellent activity of this agent in relapsed APL.[89]

HSCT

Retrospective pediatric studies have reported 5-year EFS rates after either autologous or allogeneic transplantation approaches to be similar, at approximately 70%.[90,91]
Evidence (autologous HSCT):
  1. When considering autologous transplantation, a study in adult patients demonstrated improved 7-year EFS (77% vs. 50%) when both the patient and the stem cell product had negative promyelocytic leukemia/retinoic acid receptor alpha fusion transcript by polymerase chain reaction (molecular remission) before transplant.[92]
  2. Another study demonstrated that among seven patients undergoing autologous HSCT and whose cells were minimal residual disease (MRD)-positive, all relapsed in less than 9 months after transplantation; however, only one of eight patients whose autologous donor cells were MRD-negative relapsed.[93]
  3. Another report demonstrated that the 5-year EFS was 83.3% for patients who underwent autologous HSCT in second molecular remission and was 34.5% for patients who received only maintenance therapy.[94]
Such data support the use of autologous transplantation in patients who are MRD-negative in second CR who have poorly matched allogeneic donors.
Because of the rarity of APL in children and the favorable outcome for this disease, clinical trials in relapsed APL to compare treatment approaches are likely not feasible. However, an international expert panel provided recommendations for the treatment of relapsed APL on the basis of the reported pediatric and adult experience.[95]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
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  28. Kutny MA, Alonzo TA, Gerbing RB, et al.: Arsenic Trioxide Consolidation Allows Anthracycline Dose Reduction for Pediatric Patients With Acute Promyelocytic Leukemia: Report From the Children's Oncology Group Phase III Historically Controlled Trial AAML0631. J Clin Oncol 35 (26): 3021-3029, 2017. [PUBMED Abstract]
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  34. Huang ME, Ye YC, Chen SR, et al.: Use of all-trans retinoic acid in the treatment of acute promyelocytic leukemia. Blood 72 (2): 567-72, 1988. [PUBMED Abstract]
  35. Castaigne S, Chomienne C, Daniel MT, et al.: All-trans retinoic acid as a differentiation therapy for acute promyelocytic leukemia. I. Clinical results. Blood 76 (9): 1704-9, 1990. [PUBMED Abstract]
  36. Fenaux P, Chastang C, Chevret S, et al.: A randomized comparison of all transretinoic acid (ATRA) followed by chemotherapy and ATRA plus chemotherapy and the role of maintenance therapy in newly diagnosed acute promyelocytic leukemia. The European APL Group. Blood 94 (4): 1192-200, 1999. [PUBMED Abstract]
  37. Fenaux P, Chevret S, Guerci A, et al.: Long-term follow-up confirms the benefit of all-trans retinoic acid in acute promyelocytic leukemia. European APL group. Leukemia 14 (8): 1371-7, 2000. [PUBMED Abstract]
  38. Tallman MS, Andersen JW, Schiffer CA, et al.: All-trans-retinoic acid in acute promyelocytic leukemia. N Engl J Med 337 (15): 1021-8, 1997. [PUBMED Abstract]
  39. Gregory J, Kim H, Alonzo T, et al.: Treatment of children with acute promyelocytic leukemia: results of the first North American Intergroup trial INT0129. Pediatr Blood Cancer 53 (6): 1005-10, 2009. [PUBMED Abstract]
  40. Imaizumi M, Tawa A, Hanada R, et al.: Prospective study of a therapeutic regimen with all-trans retinoic acid and anthracyclines in combination of cytarabine in children with acute promyelocytic leukaemia: the Japanese childhood acute myeloid leukaemia cooperative study. Br J Haematol 152 (1): 89-98, 2011. [PUBMED Abstract]
  41. Testi AM, Pession A, Diverio D, et al.: Risk-adapted treatment of acute promyelocytic leukemia: results from International Consortium for Childhood APL. Blood : , 2018. [PUBMED Abstract]
  42. Sanz MA, Montesinos P, Rayón C, et al.: Risk-adapted treatment of acute promyelocytic leukemia based on all-trans retinoic acid and anthracycline with addition of cytarabine in consolidation therapy for high-risk patients: further improvements in treatment outcome. Blood 115 (25): 5137-46, 2010. [PUBMED Abstract]
  43. Adès L, Chevret S, Raffoux E, et al.: Is cytarabine useful in the treatment of acute promyelocytic leukemia? Results of a randomized trial from the European Acute Promyelocytic Leukemia Group. J Clin Oncol 24 (36): 5703-10, 2006. [PUBMED Abstract]
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  46. Lo-Coco F, Avvisati G, Vignetti M, et al.: Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med 369 (2): 111-21, 2013. [PUBMED Abstract]
  47. Sanz M, Martínez JA, Barragán E, et al.: All-trans retinoic acid and low-dose chemotherapy for acute promyelocytic leukaemia. Br J Haematol 109 (4): 896-7, 2000. [PUBMED Abstract]
  48. Avvisati G, Lo-Coco F, Paoloni FP, et al.: AIDA 0493 protocol for newly diagnosed acute promyelocytic leukemia: very long-term results and role of maintenance. Blood 117 (18): 4716-25, 2011. [PUBMED Abstract]
  49. Powell BL, Moser BK, Stock W, et al.: Adding mercaptopurine and methotrexate to alternate week ATRA maintenance therapy does not improve the outcome for adults with acute promyelocytic leukemia (APL) in first remission: results from North American Leukemia Intergroup Trial C9710. [Abstract] Blood 118 (21): A-258, 2011. Also available online. Last accessed April 11, 2019.
  50. Shen ZX, Shi ZZ, Fang J, et al.: All-trans retinoic acid/As2O3 combination yields a high quality remission and survival in newly diagnosed acute promyelocytic leukemia. Proc Natl Acad Sci U S A 101 (15): 5328-35, 2004. [PUBMED Abstract]
  51. Ravandi F, Estey E, Jones D, et al.: Effective treatment of acute promyelocytic leukemia with all-trans-retinoic acid, arsenic trioxide, and gemtuzumab ozogamicin. J Clin Oncol 27 (4): 504-10, 2009. [PUBMED Abstract]
  52. Hu J, Liu YF, Wu CF, et al.: Long-term efficacy and safety of all-trans retinoic acid/arsenic trioxide-based therapy in newly diagnosed acute promyelocytic leukemia. Proc Natl Acad Sci U S A 106 (9): 3342-7, 2009. [PUBMED Abstract]
  53. Cheng Y, Zhang L, Wu J, et al.: Long-term prognosis of childhood acute promyelocytic leukaemia with arsenic trioxide administration in induction and consolidation chemotherapy phases: a single-centre experience. Eur J Haematol 91 (6): 483-9, 2013. [PUBMED Abstract]
  54. Wang H, Chen XY, Wang BS, et al.: The efficacy and safety of arsenic trioxide with or without all-trans retinoic acid for the treatment of acute promyelocytic leukemia: a meta-analysis. Leuk Res 35 (9): 1170-7, 2011. [PUBMED Abstract]
  55. Zhang L, Zhao H, Zhu X, et al.: Retrospective analysis of 65 Chinese children with acute promyelocytic leukemia: a single center experience. Pediatr Blood Cancer 51 (2): 210-5, 2008. [PUBMED Abstract]
  56. Zhou J, Zhang Y, Li J, et al.: Single-agent arsenic trioxide in the treatment of children with newly diagnosed acute promyelocytic leukemia. Blood 115 (9): 1697-702, 2010. [PUBMED Abstract]
  57. Iland HJ, Collins M, Bradstock K, et al.: Use of arsenic trioxide in remission induction and consolidation therapy for acute promyelocytic leukaemia in the Australasian Leukaemia and Lymphoma Group (ALLG) APML4 study: a non-randomised phase 2 trial. Lancet Haematol 2 (9): e357-66, 2015. [PUBMED Abstract]
  58. Platzbecker U, Avvisati G, Cicconi L, et al.: Improved Outcomes With Retinoic Acid and Arsenic Trioxide Compared With Retinoic Acid and Chemotherapy in Non-High-Risk Acute Promyelocytic Leukemia: Final Results of the Randomized Italian-German APL0406 Trial. J Clin Oncol 35 (6): 605-612, 2017. [PUBMED Abstract]
  59. Douer D, Zickl LN, Schiffer CA, et al.: All-trans retinoic acid and late relapses in acute promyelocytic leukemia: very long-term follow-up of the North American Intergroup Study I0129. Leuk Res 37 (7): 795-801, 2013. [PUBMED Abstract]
  60. Coombs CC, DeAngelis LM, Feusner JH, et al.: Pseudotumor Cerebri in Acute Promyelocytic Leukemia Patients on Intergroup Protocol 0129: Clinical Description and Recommendations for New Diagnostic Criteria. Clin Lymphoma Myeloma Leuk 16 (3): 146-51, 2016. [PUBMED Abstract]
  61. Sanz MA, Montesinos P: How we prevent and treat differentiation syndrome in patients with acute promyelocytic leukemia. Blood 123 (18): 2777-82, 2014. [PUBMED Abstract]
  62. Montesinos P, Bergua JM, Vellenga E, et al.: Differentiation syndrome in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and anthracycline chemotherapy: characteristics, outcome, and prognostic factors. Blood 113 (4): 775-83, 2009. [PUBMED Abstract]
  63. Unnikrishnan D, Dutcher JP, Varshneya N, et al.: Torsades de pointes in 3 patients with leukemia treated with arsenic trioxide. Blood 97 (5): 1514-6, 2001. [PUBMED Abstract]
  64. Barbey JT: Cardiac toxicity of arsenic trioxide. Blood 98 (5): 1632; discussion 1633-4, 2001. [PUBMED Abstract]
  65. Jurcic JG, Nimer SD, Scheinberg DA, et al.: Prognostic significance of minimal residual disease detection and PML/RAR-alpha isoform type: long-term follow-up in acute promyelocytic leukemia. Blood 98 (9): 2651-6, 2001. [PUBMED Abstract]
  66. Diverio D, Rossi V, Avvisati G, et al.: Early detection of relapse by prospective reverse transcriptase-polymerase chain reaction analysis of the PML/RARalpha fusion gene in patients with acute promyelocytic leukemia enrolled in the GIMEMA-AIEOP multicenter "AIDA" trial. GIMEMA-AIEOP Multicenter "AIDA" Trial. Blood 92 (3): 784-9, 1998. [PUBMED Abstract]
  67. Lo Coco F, Diverio D, Avvisati G, et al.: Therapy of molecular relapse in acute promyelocytic leukemia. Blood 94 (7): 2225-9, 1999. [PUBMED Abstract]
  68. Esteve J, Escoda L, Martín G, et al.: Outcome of patients with acute promyelocytic leukemia failing to front-line treatment with all-trans retinoic acid and anthracycline-based chemotherapy (PETHEMA protocols LPA96 and LPA99): benefit of an early intervention. Leukemia 21 (3): 446-52, 2007. [PUBMED Abstract]
  69. Zelent A, Guidez F, Melnick A, et al.: Translocations of the RARalpha gene in acute promyelocytic leukemia. Oncogene 20 (49): 7186-203, 2001. [PUBMED Abstract]
  70. Yan W, Zhang G: Molecular Characteristics and Clinical Significance of 12 Fusion Genes in Acute Promyelocytic Leukemia: A Systematic Review. Acta Haematol 136 (1): 1-15, 2016. [PUBMED Abstract]
  71. Rego EM, Ruggero D, Tribioli C, et al.: Leukemia with distinct phenotypes in transgenic mice expressing PML/RAR alpha, PLZF/RAR alpha or NPM/RAR alpha. Oncogene 25 (13): 1974-9, 2006. [PUBMED Abstract]
  72. Licht JD, Chomienne C, Goy A, et al.: Clinical and molecular characterization of a rare syndrome of acute promyelocytic leukemia associated with translocation (11;17). Blood 85 (4): 1083-94, 1995. [PUBMED Abstract]
  73. Guidez F, Ivins S, Zhu J, et al.: Reduced retinoic acid-sensitivities of nuclear receptor corepressor binding to PML- and PLZF-RARalpha underlie molecular pathogenesis and treatment of acute promyelocytic leukemia. Blood 91 (8): 2634-42, 1998. [PUBMED Abstract]
  74. Grimwade D, Biondi A, Mozziconacci MJ, et al.: Characterization of acute promyelocytic leukemia cases lacking the classic t(15;17): results of the European Working Party. Groupe Français de Cytogénétique Hématologique, Groupe de Français d'Hematologie Cellulaire, UK Cancer Cytogenetics Group and BIOMED 1 European Community-Concerted Action "Molecular Cytogenetic Diagnosis in Haematological Malignancies". Blood 96 (4): 1297-308, 2000. [PUBMED Abstract]
  75. Sukhai MA, Wu X, Xuan Y, et al.: Myeloid leukemia with promyelocytic features in transgenic mice expressing hCG-NuMA-RARalpha. Oncogene 23 (3): 665-78, 2004. [PUBMED Abstract]
  76. Redner RL, Corey SJ, Rush EA: Differentiation of t(5;17) variant acute promyelocytic leukemic blasts by all-trans retinoic acid. Leukemia 11 (7): 1014-6, 1997. [PUBMED Abstract]
  77. Wells RA, Catzavelos C, Kamel-Reid S: Fusion of retinoic acid receptor alpha to NuMA, the nuclear mitotic apparatus protein, by a variant translocation in acute promyelocytic leukaemia. Nat Genet 17 (1): 109-13, 1997. [PUBMED Abstract]
  78. Wells RA, Hummel JL, De Koven A, et al.: A new variant translocation in acute promyelocytic leukaemia: molecular characterization and clinical correlation. Leukemia 10 (4): 735-40, 1996. [PUBMED Abstract]
  79. Marjerrison S, Antillon F, Bonilla M, et al.: Outcome of children treated for relapsed acute myeloid leukemia in Central America. Pediatr Blood Cancer 61 (7): 1222-6, 2014. [PUBMED Abstract]
  80. Lengfelder E, Lo-Coco F, Ades L, et al.: Arsenic trioxide-based therapy of relapsed acute promyelocytic leukemia: registry results from the European LeukemiaNet. Leukemia 29 (5): 1084-91, 2015. [PUBMED Abstract]
  81. Holter Chakrabarty JL, Rubinger M, Le-Rademacher J, et al.: Autologous is superior to allogeneic hematopoietic cell transplantation for acute promyelocytic leukemia in second complete remission. Biol Blood Marrow Transplant 20 (7): 1021-5, 2014. [PUBMED Abstract]
  82. Fox E, Razzouk BI, Widemann BC, et al.: Phase 1 trial and pharmacokinetic study of arsenic trioxide in children and adolescents with refractory or relapsed acute leukemia, including acute promyelocytic leukemia or lymphoma. Blood 111 (2): 566-73, 2008. [PUBMED Abstract]
  83. Niu C, Yan H, Yu T, et al.: Studies on treatment of acute promyelocytic leukemia with arsenic trioxide: remission induction, follow-up, and molecular monitoring in 11 newly diagnosed and 47 relapsed acute promyelocytic leukemia patients. Blood 94 (10): 3315-24, 1999. [PUBMED Abstract]
  84. Shen ZX, Chen GQ, Ni JH, et al.: Use of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia (APL): II. Clinical efficacy and pharmacokinetics in relapsed patients. Blood 89 (9): 3354-60, 1997. [PUBMED Abstract]
  85. Lu J, Huang X, Bao L, et al.: Treatment outcomes in relapsed acute promyelocytic leukemia patients initially treated with all-trans retinoic acid and arsenic compound-based combined therapies. Oncol Lett 7 (1): 177-182, 2014. [PUBMED Abstract]
  86. Zhu HH, Qin YZ, Huang XJ: Resistance to arsenic therapy in acute promyelocytic leukemia. N Engl J Med 370 (19): 1864-6, 2014. [PUBMED Abstract]
  87. Soignet SL, Maslak P, Wang ZG, et al.: Complete remission after treatment of acute promyelocytic leukemia with arsenic trioxide. N Engl J Med 339 (19): 1341-8, 1998. [PUBMED Abstract]
  88. Zhang P: The use of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia. J Biol Regul Homeost Agents 13 (4): 195-200, 1999 Oct-Dec. [PUBMED Abstract]
  89. Lo-Coco F, Cimino G, Breccia M, et al.: Gemtuzumab ozogamicin (Mylotarg) as a single agent for molecularly relapsed acute promyelocytic leukemia. Blood 104 (7): 1995-9, 2004. [PUBMED Abstract]
  90. Dvorak CC, Agarwal R, Dahl GV, et al.: Hematopoietic stem cell transplant for pediatric acute promyelocytic leukemia. Biol Blood Marrow Transplant 14 (7): 824-30, 2008. [PUBMED Abstract]
  91. Bourquin JP, Thornley I, Neuberg D, et al.: Favorable outcome of allogeneic hematopoietic stem cell transplantation for relapsed or refractory acute promyelocytic leukemia in childhood. Bone Marrow Transplant 34 (9): 795-8, 2004. [PUBMED Abstract]
  92. de Botton S, Fawaz A, Chevret S, et al.: Autologous and allogeneic stem-cell transplantation as salvage treatment of acute promyelocytic leukemia initially treated with all-trans-retinoic acid: a retrospective analysis of the European acute promyelocytic leukemia group. J Clin Oncol 23 (1): 120-6, 2005. [PUBMED Abstract]
  93. Meloni G, Diverio D, Vignetti M, et al.: Autologous bone marrow transplantation for acute promyelocytic leukemia in second remission: prognostic relevance of pretransplant minimal residual disease assessment by reverse-transcription polymerase chain reaction of the PML/RAR alpha fusion gene. Blood 90 (3): 1321-5, 1997. [PUBMED Abstract]
  94. Thirugnanam R, George B, Chendamarai E, et al.: Comparison of clinical outcomes of patients with relapsed acute promyelocytic leukemia induced with arsenic trioxide and consolidated with either an autologous stem cell transplant or an arsenic trioxide-based regimen. Biol Blood Marrow Transplant 15 (11): 1479-84, 2009. [PUBMED Abstract]
  95. Abla O, Kutny MA, Testi AM, et al.: Management of relapsed and refractory childhood acute promyelocytic leukaemia: recommendations from an international expert panel. Br J Haematol 175 (4): 588-601, 2016. [PUBMED Abstract]

Transient Abnormal Myelopoiesis (TAM) or Children With Down Syndrome and AML

TAM Associated With Down Syndrome

In addition to increased risk of AML during the first 3 years of life, about 10% of neonates with Down syndrome develop a TAM (also termed transient myeloproliferative disorder[TMD]).[1] This disorder mimics congenital AML but typically improves spontaneously within the first 3 months of life (median, 49 days), although TAM has been reported to remit as late as 20 months.[2] The late remissions likely reflect a persistent hepatomegaly from TAM-associated hepatic fibrosis rather than active disease.[3]
Although TAM is usually a self-resolving condition, it can be associated with significant morbidity and may be fatal in 10% to 17% of affected infants.[2-6] Infants with progressive organomegaly, visceral effusions, preterm delivery (less than 37 weeks of gestation), bleeding diatheses, failure of spontaneous remission, laboratory evidence of progressive liver dysfunction (elevated direct bilirubin), renal failure, and very high white blood cell (WBC) count are at particularly high risk of early mortality.[3,4,6] Death has been reported to occur in 21% of these patients with high-risk TAM, although only 10% were attributable to TAM and the remaining deaths were caused by coexisting conditions known to be more prominent in neonates with Down syndrome.[3]
The following three risk groups have been identified on the basis of the diagnostic clinical findings of hepatomegaly with or without life-threatening symptoms:[3]
  • Low risk includes those with neither hepatomegaly nor life-threatening symptoms (38% of patients and 92% ± 8% overall survival [OS]).
  • Intermediate risk includes those with hepatomegaly alone (40% of patients and 77% ± 12% OS).
  • High risk includes those with hepatomegaly and life-threatening symptoms (21% of patients and 51% ± 19% OS).
Therapeutic intervention is warranted in patients with apparent severe hydrops or organ failure. Because TAM eventually spontaneously remits, treatment is short in duration and primarily aimed at the reduction of leukemic burden and resolution of immediate symptoms. Several treatment approaches have been used, including the following:[7]
  • Exchange transfusion.
  • Leukapheresis.
  • Low-dose cytarabine. Of these approaches, only cytarabine was found to be consistently beneficial.[3,6] Dosing has varied between 0.4 to 1.5mg/kg per dose given intravenously or subcutaneously twice a day for 4 to 12 days [6] or 3.3 mg/kg per day given as a continuous infusion for 5 days.[3] While both were equally effective, the higher continuous dose was associated with severe pancytopenia. The use of the lower dose approach reduced early cumulative death from 72% to 24% (P = .001).[6]
The mean time for the development of AML in the 10% to 30% of children who have a spontaneous remission of TAM but then develop AML has been reported to be approximately 16 months, with a range of 1 to 30 months.[2,3,8] Thus, most infants with Down syndrome and TAM who later develop AML will do so within the first 3 years of life.
Patients with Down syndrome who develop AML with an antecedent TAM have superior event-free survival (EFS) (91% ± 5%) compared with such children without TAM (70% ± 4%) at 5 years,[6] although this was not observed in other studies.[9,10] While TAM is generally not characterized by cytogenetic abnormalities other than trisomy 21, the presence of additional cytogenetic findings may connote an increased risk of developing subsequent AML.[4]

Myeloid Leukemia Associated With Down Syndrome

Children with Down syndrome have a tenfold to twentyfold increased risk of leukemia compared with children without Down syndrome; however, the ratio of acute lymphoblastic leukemia to acute myeloid leukemia (AML) is typical for childhood acute leukemia. The exception is during the first 3 years of life, when AML, particularly the megakaryoblastic subtype, predominates and exhibits a distinctive biology characterized by GATA1 mutations and increased sensitivity to cytarabine.[11-19] Importantly, these risks appear to be similar whether a child has phenotypic characteristics of Down syndrome or whether a child has only genetic bone marrow mosaicism.[20]

Prognosis and Treatment of Children With Down Syndrome and AML

Outcome is generally favorable for children with Down syndrome who develop AML (called myeloid leukemia associated with Down syndrome in the World Health Organization classification).[9,10,21]
Prognostic factors for children with Down syndrome and AML include the following:
  • Age. The prognosis is particularly good (EFS exceeding 85%) in children aged 4 years or younger at diagnosis; this age group accounts for the vast majority of Down syndrome patients with AML.[9,10,22,23] Children with Down syndrome who are older than 4 years have a significantly worse prognosis.[24]
  • White blood cell count. A large international Berlin-Frankfurt-Münster (BFM) retrospective study of 451 children with AML and Down syndrome (aged >6 months and <5 years) observed a 7-year EFS of 78% and 7-year OS of 79%. In multivariate analyses, WBC count (≥20 × 109/L) and age (>3 years) were independent predictors of lower EFS. The 7-year EFS for the older population (>3 years) and for the higher WBC-count population still exceeded 60%.[25]
  • AML karyotype. Normal karyotypic AML (other than trisomy 21), which was observed in 29% of patients, independently predicted for inferior OS and EFS (7-year EFS of 65% compared with 82% for patients with aberrant karyotypes).[25] However, this was not seen in a later trial.[23] In this same trial, the presence of trisomy 8 was shown to adversely impact prognosis.
  • Minimal residual disease (MRD). MRD at the end of induction 1 was found to be a strong prognostic factor;[10] this was consistent with the BFM finding that early response correlated with improved OS.[23]
Approximately 29% to 47% of Down syndrome patients present with myelodysplastic syndromes (MDS) (<20% blasts) but their outcomes are similar to those with AML.[9,10,23]
Treatment options for newly diagnosed children with Down syndrome and AML include the following:
  1. Chemotherapy.
Appropriate therapy for younger children (aged ≤4 years) with Down syndrome and AML is less intensive than current standard childhood AML therapy. Hematopoietic stem cell transplant is not indicated in first remission.[8-10,13,21-24,26-28]
Evidence (chemotherapy):
  1. In a Children's Oncology Group (COG) trial for newly diagnosed children with Down syndrome and AML (AAML0431 [NCT00369317]), 204 children were enrolled on a regimen that substituted high-dose cytarabine for the second of four induction cycles (thereby reducing cumulative anthracycline exposure from 320 mg to 240 mg), moving this cycle from intensification where it was used in the previous COG A2971 (NCT00003593) trial.[9,10] Intrathecal doses were reduced from seven to two total injections and intensification included two cycles of cytarabine/etoposide.
    • When compared with the previous trial, these changes resulted in an overall improvement of approximately 10%.
    • EFS was 89.9%, and OS was 93%.
    • Relapse occurred in 14 patients and there were two treatment-related deaths, both related to pneumonia, neither of which occurred during induction 2.
    • No patient had central nervous system (CNS) involvement on this trial or the preceding COG A2971 (NCT00003593) trial.[9]
    • The only prognostic factor identified was MRD using flow cytometry on day 28 of induction 1. Among those who were MRD negative (≤0.01%), DFS was 92.7%; in the 14.4% of patients who were MRD positive, DFS was 76.2% (P = .011).
  2. In a joint trial (ML-DS 2006) from the BFM, Dutch Childhood Oncology Group (DCOG), and Nordic Society of Pediatric Hematology and Oncology (NOPHO), 170 children with Down syndrome were enrolled in a trial that focused on reducing therapy by eliminating etoposide during consolidation, reducing the number of intrathecal doses from 11 to 4, and the elimination of maintenance from the reduced therapy Down syndrome arm of AML-BFM 98.[23] As in the COG trials, no patient had CNS disease at diagnosis.
    • Outcomes were no worse despite reduction in chemotherapy. OS was 89% ± 3% and EFS was 87% ± 3%, similar to that observed in AML-BFM 98 (OS, 90% ± 4% [P = NS]; EFS, 89% ± 4% [P = NS]). Cumulative incidence of relapse (CIR) was 6% in both trials.
    • Nine patients relapsed, and seven of those patients died.
    • Patients with a good early response (<5% blasts by morphology before induction cycle 2, n = 123 [72%]) had better outcomes (OS, 92% ± 3% vs. 57% ± 16%, P < .0001; EFS, 88% ± 3% vs. 58% ± 16%, P = .0008; and CIR, 3% ± 2% vs. 27% ± 18%, P = .003).
    • Less toxicity was seen in this new trial, and treatment-related mortality remained low (2.9% vs. 5%, P = .276).
    The following two prognostic factors were identified:[23]
    • Trisomy 8 was an adverse factor (n = 37; OS, 77% vs. 95%, P = .07; EFS, 73% ± 8% vs. 91% ± 4%, P = .018; CIR, 16% ± 7% vs. 3% ± 2%, P = .02).
    • This was confirmed in multivariate analysis, where lack of good early response and trisomy 8 maintained their adverse impact on relapse, with relative risks of 8.55 (95% confidence interval [CI], 1.96–37.29, P = .004) and 4.36 (1.24–15.39, P = .022), respectively.
Children with mosaicism for trisomy 21 are treated similarly to those children with clinically evident Down syndrome.[3,9,20] Although an optimal treatment for these children has not been defined, they are usually treated on AML regimens designed for children without Down syndrome.

Treatment options under clinical evaluation

Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.
The following is an example of a national and/or institutional clinical trial that is currently being conducted:
  1. COG AAML1531 (NCT02521493) (Response-Based Chemotherapy in Treating Newly Diagnosed AML or Myelodysplastic Syndrome in Younger Patients With Down Syndrome): This is a phase III, single-arm trial for newly diagnosed children with Down syndrome–associated AML which uses response to induction therapy to stratify patients to less intensive therapy if they have no MRD and more intensive therapy if they do have MRD at the end of induction cycle one.

Refractory Disease or Relapse in Children With Down Syndrome

A small number of publications address outcomes in children with Down syndrome who relapse after initial therapy or who have refractory AML. All of these retrospective analyses with varying approaches to therapy found that for these children who relapse or have refractory outcomes, the outlook is poor. Thus, these children are treated similarly to children without Down syndrome, with an intensive reinduction chemotherapy regimen, and if a remission is achieved, therapy is followed by an allogeneic hematopoietic stem cell transplant (HSCT).
Treatment options for children with Down syndrome with refractory or relapsed AML include the following:
  1. Chemotherapy, which may be followed by an allogeneic HSCT.
Evidence (treatment of children with Down syndrome with refractory or relapsed AML):
  1. The Japanese Pediatric Leukemia/Lymphoma Study Group reported the outcomes of 29 Down syndrome patients with relapsed (n = 26) or refractory (n = 3) AML. As expected with Down syndrome, the children in this cohort were very young (median age, 2 years); relapses were almost all early (median, 8.6 months; 80% <12 months from diagnosis); and 89% had M7 French-American-British classification.[29][Level of evidence: 3iiA]
    • In contrast to the excellent outcomes achieved after initial therapy, only 50% of the children attained a second remission, and the 3-year OS rate was 26%.
    • Approximately one-half of the children underwent allogeneic transplant, and no advantage was noted with transplant compared with chemotherapy, but the number of patients was small.
  2. A Center for International Blood and Marrow Transplant Research study of children with Down syndrome and AML who underwent HSCT reported a similarly poor outcome, with a 3-year OS of 19%.[30][Level of evidence: 3iiA] The main cause of failure after transplant was relapse, which exceeded 60%; transplant-related mortality was approximately 20%.
  3. A Japanese registry study reported better survival after transplant of children with Down Syndrome using reduced-intensity conditioning regimens compared with myeloablative approaches, but the number of patients was very small (n = 5) and the efficacy of reduced-intensity approaches in children with Down syndrome and AML requires further study.[31][Level of evidence 3iDi]
References
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  2. Homans AC, Verissimo AM, Vlacha V: Transient abnormal myelopoiesis of infancy associated with trisomy 21. Am J Pediatr Hematol Oncol 15 (4): 392-9, 1993. [PUBMED Abstract]
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  5. Muramatsu H, Kato K, Watanabe N, et al.: Risk factors for early death in neonates with Down syndrome and transient leukaemia. Br J Haematol 142 (4): 610-5, 2008. [PUBMED Abstract]
  6. Klusmann JH, Creutzig U, Zimmermann M, et al.: Treatment and prognostic impact of transient leukemia in neonates with Down syndrome. Blood 111 (6): 2991-8, 2008. [PUBMED Abstract]
  7. Al-Kasim F, Doyle JJ, Massey GV, et al.: Incidence and treatment of potentially lethal diseases in transient leukemia of Down syndrome: Pediatric Oncology Group Study. J Pediatr Hematol Oncol 24 (1): 9-13, 2002. [PUBMED Abstract]
  8. Ravindranath Y, Abella E, Krischer JP, et al.: Acute myeloid leukemia (AML) in Down's syndrome is highly responsive to chemotherapy: experience on Pediatric Oncology Group AML Study 8498. Blood 80 (9): 2210-4, 1992. [PUBMED Abstract]
  9. Sorrell AD, Alonzo TA, Hilden JM, et al.: Favorable survival maintained in children who have myeloid leukemia associated with Down syndrome using reduced-dose chemotherapy on Children's Oncology Group trial A2971: a report from the Children's Oncology Group. Cancer 118 (19): 4806-14, 2012. [PUBMED Abstract]
  10. Taub JW, Berman JN, Hitzler JK, et al.: Improved outcomes for myeloid leukemia of Down syndrome: a report from the Children's Oncology Group AAML0431 trial. Blood 129 (25): 3304-3313, 2017. [PUBMED Abstract]
  11. Ravindranath Y: Down syndrome and leukemia: new insights into the epidemiology, pathogenesis, and treatment. Pediatr Blood Cancer 44 (1): 1-7, 2005. [PUBMED Abstract]
  12. Ross JA, Spector LG, Robison LL, et al.: Epidemiology of leukemia in children with Down syndrome. Pediatr Blood Cancer 44 (1): 8-12, 2005. [PUBMED Abstract]
  13. Gamis AS: Acute myeloid leukemia and Down syndrome evolution of modern therapy--state of the art review. Pediatr Blood Cancer 44 (1): 13-20, 2005. [PUBMED Abstract]
  14. Bassal M, La MK, Whitlock JA, et al.: Lymphoblast biology and outcome among children with Down syndrome and ALL treated on CCG-1952. Pediatr Blood Cancer 44 (1): 21-8, 2005. [PUBMED Abstract]
  15. Massey GV: Transient leukemia in newborns with Down syndrome. Pediatr Blood Cancer 44 (1): 29-32, 2005. [PUBMED Abstract]
  16. Taub JW, Ge Y: Down syndrome, drug metabolism and chromosome 21. Pediatr Blood Cancer 44 (1): 33-9, 2005. [PUBMED Abstract]
  17. Crispino JD: GATA1 mutations in Down syndrome: implications for biology and diagnosis of children with transient myeloproliferative disorder and acute megakaryoblastic leukemia. Pediatr Blood Cancer 44 (1): 40-4, 2005. [PUBMED Abstract]
  18. Jubinsky PT: Megakaryopoiesis and thrombocytosis. Pediatr Blood Cancer 44 (1): 45-6, 2005. [PUBMED Abstract]
  19. Ge Y, Stout ML, Tatman DA, et al.: GATA1, cytidine deaminase, and the high cure rate of Down syndrome children with acute megakaryocytic leukemia. J Natl Cancer Inst 97 (3): 226-31, 2005. [PUBMED Abstract]
  20. Kudo K, Hama A, Kojima S, et al.: Mosaic Down syndrome-associated acute myeloid leukemia does not require high-dose cytarabine treatment for induction and consolidation therapy. Int J Hematol 91 (4): 630-5, 2010. [PUBMED Abstract]
  21. Lange BJ, Kobrinsky N, Barnard DR, et al.: Distinctive demography, biology, and outcome of acute myeloid leukemia and myelodysplastic syndrome in children with Down syndrome: Children's Cancer Group Studies 2861 and 2891. Blood 91 (2): 608-15, 1998. [PUBMED Abstract]
  22. Creutzig U, Reinhardt D, Diekamp S, et al.: AML patients with Down syndrome have a high cure rate with AML-BFM therapy with reduced dose intensity. Leukemia 19 (8): 1355-60, 2005. [PUBMED Abstract]
  23. Uffmann M, Rasche M, Zimmermann M, et al.: Therapy reduction in patients with Down syndrome and myeloid leukemia: the international ML-DS 2006 trial. Blood 129 (25): 3314-3321, 2017. [PUBMED Abstract]
  24. Gamis AS, Woods WG, Alonzo TA, et al.: Increased age at diagnosis has a significantly negative effect on outcome in children with Down syndrome and acute myeloid leukemia: a report from the Children's Cancer Group Study 2891. J Clin Oncol 21 (18): 3415-22, 2003. [PUBMED Abstract]
  25. Blink M, Zimmermann M, von Neuhoff C, et al.: Normal karyotype is a poor prognostic factor in myeloid leukemia of Down syndrome: a retrospective, international study. Haematologica 99 (2): 299-307, 2014. [PUBMED Abstract]
  26. Craze JL, Harrison G, Wheatley K, et al.: Improved outcome of acute myeloid leukaemia in Down's syndrome. Arch Dis Child 81 (1): 32-7, 1999. [PUBMED Abstract]
  27. Zeller B, Gustafsson G, Forestier E, et al.: Acute leukaemia in children with Down syndrome: a population-based Nordic study. Br J Haematol 128 (6): 797-804, 2005. [PUBMED Abstract]
  28. Taga T, Shimomura Y, Horikoshi Y, et al.: Continuous and high-dose cytarabine combined chemotherapy in children with down syndrome and acute myeloid leukemia: Report from the Japanese children's cancer and leukemia study group (JCCLSG) AML 9805 down study. Pediatr Blood Cancer 57 (1): 36-40, 2011. [PUBMED Abstract]
  29. Taga T, Saito AM, Kudo K, et al.: Clinical characteristics and outcome of refractory/relapsed myeloid leukemia in children with Down syndrome. Blood 120 (9): 1810-5, 2012. [PUBMED Abstract]
  30. Hitzler JK, He W, Doyle J, et al.: Outcome of transplantation for acute myelogenous leukemia in children with Down syndrome. Biol Blood Marrow Transplant 19 (6): 893-7, 2013. [PUBMED Abstract]
  31. Muramatsu H, Sakaguchi H, Taga T, et al.: Reduced intensity conditioning in allogeneic stem cell transplantation for AML with Down syndrome. Pediatr Blood Cancer 61 (5): 925-7, 2014. [PUBMED Abstract]

Myelodysplastic Syndromes (MDS)

The myelodysplastic syndromes (MDS) and myeloproliferative syndromes (MPS) represent between 5% and 10% of all myeloid malignancies in children. They are a heterogeneous group of disorders, with MDS usually presenting with cytopenias and MPS presenting with increased peripheral white blood cell, red blood cell, or platelet counts. MDS is characterized by ineffective hematopoiesis and increased cell death, while MPS is associated with increased progenitor proliferation and survival. Because they both represent disorders of very primitive, multipotential hematopoietic stem cells, curative therapeutic approaches nearly always require allogeneic hematopoietic stem cell transplantation (HSCT).

Risk Factors

Patients with the following germline mutations or inherited disorders have a significantly increased risk of developing MDS:
  • Fanconi anemia: Caused by germline mutations in DNA repair genes.
  • Dyskeratosis congenita: Resulting from mutations in genes regulating telomere length. Genes mutated in dyskeratosis congenital include ACD, CTC1, DKC1, NHP2, NOP10, PARN, RTEL1, TERC, TERT, TINF2, and WRAP53.
  • Shwachman-Diamond syndrome, Diamond-Blackfan anemia, and other bone marrow failure syndromes: Resulting from mutations in genes encoding ribosome-associated proteins.[1,2] GATA1 mutations have been linked to Diamond-Blackfan anemia and MDS predisposition.[3]
  • Severe congenital neutropenia: Caused by mutations in the gene encoding elastase. The 15-year cumulative risk of MDS in patients with severe congenital neutropenia, also known as Kostmann syndrome, has been estimated to be 15%, with an annual risk of MDS/acute myeloid leukemia (AML) of 2% to 3%. It is unclear how mutations affecting this protein and how the chronic exposure of granulocyte colony-stimulating factor (G-CSF) contribute to the development of MDS.[4]
  • Trisomy 21 syndrome: GATA1 mutations are nearly always present in the transient leukemia associated with Trisomy 21 and MDS in Down syndrome children younger than 3 years.[5]
  • Congenital amegakaryocytic thrombocytopenia (CAMT): Inherited mutations in the RUNX1 or CEPBA genes are associated with CAMT.[6,7] Mutations in the c-MPL gene are the underlying genetic cause of CAMT; there is a less than 10% risk of developing MDS/AML in patients with CAMT.[8]
  • GATA2 mutations: Germline mutations of GATA2 have been reported in patients with MDS/AML in conjunction with monocytopenia, B cell and natural killer cell deficiency, pulmonary alveolar proteinosis, and susceptibility to opportunistic infections.[9,10]
  • RUNX1 or CEPBA mutations: Inherited mutations in the RUNX1 or CEPBA genes are associated with familial MDS/AML.[6,7]
A retrospective analysis that used a capture assay to target mutations known to predispose to marrow failure and MDS was performed on genomic DNA from peripheral blood mononuclear cell samples from patients undergoing stem cell transplant for MDS and aplastic anemia. Among the 46 children aged 18 years and younger with MDS, 10 patients (22%) harbored constitutional predisposition genetic mutations (5 GATA2, 1 each of MPL, RTEL1, SBDS, TINF2, and TP53), of which only 2 were suspected before transplant. This is considered a high incidence of genetic mutations compared with only 8% (4 of 64) in patients aged 18 to 40 years.[11]

Clinical Presentation

Patients usually present with signs of cytopenias, including pallor, infection, or bruising.
The bone marrow is usually characterized by hypercellularity and dysplastic changes in myeloid precursors. Clonal evolution can eventually lead to the development of AML. The percentage of abnormal blasts is less than 20% and lack common AML recurrent cytogenetic abnormalities (t(8;21), inv(16), t(15;17), or KMT2A [MLL] translocations).
The less common hypocellular MDS can be distinguished from aplastic anemia in part by its marked dysplasia, clonal nature, and higher percentage of CD34-positive precursors.[12,13]

Molecular Abnormalities

Pediatric myelodysplastic syndromes (MDS) are associated with a distinctive constellation of genetic alterations compared with MDS arising in adults. In adults, MDS often evolves from clonal hematopoiesis and is characterized by mutations in TET2, DNMT3A, and TP53. In contrast, mutations in these genes are rare in pediatric MDS, while mutations in GATA2, SAMD9/SAMD9L, SETBP1, ASXL1, and Ras/MAPK pathway genes are observed in subsets of pediatric MDS cases.[14,15]
A report of the genomic landscape of pediatric MDS described the results of whole-exome sequencing for 32 pediatric primary MDS patients and targeted sequencing for another 14 cases.[14] These 46 cases were equally divided between refractory cytopenia of childhood and MDS with excess blasts (MDS-EB). The results from the report include the following:
  • Mutations in Ras/MAPK pathway genes were observed in 43% of primary MDS cases, with mutations most commonly involving PTPN11 and NRAS but with mutations also observed in other pathway members (e.g., BRAF [non–BRAF V600E], CBL, and KRAS). Ras/MAPK mutations were more common in patients with MDS-EB (65%) than in patients with refractory cytopenia of childhood (17%).
  • Germline variants in SAMD9 (n = 4) or SAMD9L (n = 4) were observed in 17% of patients with primary MDS, with seven of eight mutations occurring in patients with refractory cytopenia of childhood. These cases all showed loss of material on chromosome 7. Approximately 40% of patients with deletions of part or all of chromosome 7 had germline SAMD9 or SAMD9L variants.
  • GATA2 mutations were observed in three cases (7%), and all cases were confirmed or presumed to be germline.
  • Deletions involving chromosome 7 were the most common copy number alteration and were observed in 41% of cases. Loss of part or all of chromosome 7 was most commonly observed in SAMD9/SAMD9L cases (100%) and in MDS-EB patients with a Ras/MAPK mutation (71%).
  • Other genes that were mutated in more than 1 of the 46 cases studied included SETBP1, ETV6, and TP53.
A second report described the application of a targeted sequencing panel of 105 genes to 50 pediatric patients with MDS (refractory cytopenia of childhood = 31 and MDS-EB = 19) and was enriched for cases with monosomy 7 (48%).[14,15] SAMD9 and SAMD9L were not included in the gene panel. The second report described the following results:
  • Germline GATA2 mutations were observed in 30% of patients, and RUNX1 mutations were observed in 6% of patients.
  • Somatic mutations were observed in 34% of patients and were more common in patients with MDS-EB than in patients with refractory cytopenia of childhood (68% vs. 13%).
  • The most commonly mutated gene was SETBP1 (18%); less commonly mutated genes included ASXL1, RUNX1, and Ras/MAPK pathway genes (PTPN11, NRAS, KRAS, NF1). Twelve percent of cases showed mutations in Ras/MAPK pathway genes.
Patients with germline GATA2 mutations, in addition to MDS, show a wide range of hematopoietic and immune defects as well as nonhematopoietic manifestations.[16] The former defects include monocytopenia with susceptibility to atypical mycobacterial infection and DCML deficiency (loss of dendritic cells, monocytes, and B and natural killer lymphoid cells). The resulting immunodeficiency leads to increased susceptibility to warts, severe viral infections, mycobacterial infections, fungal infections, and human papillomavirus–related cancers. The nonhematopoietic manifestations include deafness and lymphedema. Germline GATA2 mutations were studied in 426 pediatric patients with primary MDS and 82 cases with secondary MDS who were enrolled in consecutive studies of the European Working Group of MDS in Childhood (EWOG-MDS).[17] The study had the following results:
  • Germline GATA2 mutations were identified in 7% of pediatric patients with primary MDS. While the median age of patients presenting with GATA2 mutations was 12.3 years in the EWOG-MDS pediatric population, most cases of germline GATA2-related myeloid neoplasms occur during adulthood.[18]
  • GATA2 mutations were more common in patients with MDS-EB (15%) than in patients with refractory cytopenia of childhood (4%).
  • Among patients with GATA2 mutations, 46% presented with MDS-EB and 70% showed monosomy 7.
  • Familial MDS/AML was identified in 12 of 53 GATA2-mutated patients for whom detailed family histories were available.
  • Nonhematologic phenotypes of GATA2 deficiency were present in 51% of GATA2-mutated patients with MDS and included deafness (9%), lymphedema/hydrocele (23%), and immunodeficiency (39%).
SAMD9 and SAMD9L germline mutations are both associated with pediatric MDS cases in which there is an additional loss of all or part of chromosome 7.[19] In 2016, SAMD9 was identified as the cause of the MIRAGE syndrome (myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy), which is associated with early-onset MDS with monosomy 7.[20] Subsequently, mutations in SAMD9L were identified in patients with ataxia pancytopenia syndrome (ATXPC; OMIM 159550). SAMD9and SAMD9L mutations were also identified as the cause of myelodysplasia and leukemia syndrome with monosomy 7 (MLSM7; OMIM 252270),[21] a syndrome first identified in phenotypically normal siblings who developed MDS or AML associated with monosomy 7 during childhood.[22]
  • Causative mutations in both SAMD9 and SAMD9L are gain-of-function mutations and enhance the growth-suppressing activity of SAMD9/SAMD9L.[20,22]
  • Both SAMD9 and SAMD9L are located at chromosome 7q21.2. Cases of MDS in patients with SAMD9 or SAMD9L mutations often show monosomy 7, with the remaining chromosome 7 having wild-type SAMD9/SAMD9L. This results in the loss of the enhanced growth-suppressing activity of the mutated gene.
  • Phenotypically normal patients with SAMD9/SAMD9L mutations and monosomy 7 may progress to MDS or AML or, alternatively, may show loss of their monosomy 7 with a return of normal hematopoiesis.[22] The former outcome is associated with the acquisition of mutations in genes associated with MDS/AML (e.g., ETV6 or SETBP1), while the latter is associated with genetic alterations (e.g., revertant mutations or copy-neutral loss of heterozygosity with retention of the wild-type allele) that result in normalization of SAMD9/SAMD9L activity. These observations suggest that monitoring of patients with SAMD9/SAMD9L-related monosomy 7 using clinical sequencing for acquired mutations in genes associated with progression to AML may identify patients at high risk of leukemic transformation who may benefit most from hematopoietic stem cell transplantation.[22]
(Refer to the WHO Classification of Bone Marrow and Peripheral Blood Findings for Myelodysplastic Syndromes section of this summary for more information about the WHO classification of MDS.)

Classification of MDS

The French-American-British (FAB) and World Health Organization (WHO) classification systems of MDS and MPS have been difficult to apply to pediatric patients. Alternative classification systems for children have been proposed, but none have been uniformly adopted, with the exception of the modified 2008 WHO classification system.[23-27] The WHO system [28] has been modified for pediatrics.[26] Refer to Table 3 and Table 4 for the WHO classification schema and diagnostic criteria. The 2016 revision to the WHO MDS classification did not affect classification in children.[29]
The refractory cytopenia subtype represents approximately 50% of all childhood cases of MDS. The presence of an isolated monosomy 7 is the most common cytogenetic abnormality, although it does not appear to portend a poor prognosis compared with its presence in overt AML. However, the presence of monosomy 7 in combination with other cytogenetic abnormalities is associated with a poor prognosis.[30,31] The relatively common abnormalities of -Y, 20q-, and 5q- in adults with MDS are rare in childhood MDS. The presence of cytogenetic abnormalities that are found in AML defines disease that should be treated as AML and not MDS.[32]
The International Prognostic Scoring System can help to distinguish low-risk from high-risk MDS, although its utility in children with MDS is more limited than in adults because many characteristics differ between children and adults.[33,34] The median survival for children with high-risk MDS remains substantially better than adults, and the presence of monosomy 7 in children has not had the same adverse prognostic impact as does the presence in adults with MDS.[35]

Treatment of Childhood MDS

Treatment options for children with MDS include the following:
  1. HSCT.
  2. Other therapies.

HSCT

MDS and associated disorders usually involve a primitive hematopoietic stem cell. Thus, allogeneic HSCT is considered to be the optimal approach to treatment for pediatric patients with MDS. Although matched sibling transplantation is preferred, similar survival has been noted with well-matched, unrelated cord blood and haploidentical approaches.[36-40]
When making treatment decisions, some data should be considered. For example, survival as high as 80% has been reported for patients with early-stage MDS proceeding to transplant within a few months of diagnosis. Additionally, early transplant and not receiving pretransplant chemotherapy have been associated with improved survival in children with MDS.[41][Level of evidence: 3iiA] Disease-free survival (DFS) has been estimated to be between 50% to 70% for pediatric patients with advanced MDS using myeloablative transplant preparative regimens.[39,42-45] While nonmyeloablative preparative transplant regimens are being tested in patients with MDS and AML, such regimens are still investigational for children with these disorders, but may be reasonable in the setting of a clinical trial or when a patient’s organ function is compromised in such a way that they would not tolerate a myeloablative regimen.[46-49]; [50][Level of evidence: 3iiiA]
The question of whether chemotherapy should be used in high-risk MDS has been examined.
Evidence (HSCT):
  1. An analysis of 37 children with MDS treated on Berlin-Frankfurt-Münster AML protocols 83, 87, and 93 confirmed the induction response of 74% for patients with refractory anemia with excess blasts in transformation and suggested that transplantation was beneficial.[51]
  2. Another study by the same group showed that with current approaches to HSCT, survival occurred in more than 60% of children with advanced MDS, and outcomes for patients receiving unrelated donor cells were similar to those for patients who received matched-family donor (MFD) cells.[52]
  3. The Children's Cancer Group 2891 trial accrued patients between 1989 and 1995, including children with MDS.[42] There were 77 patients with refractory anemia (n = 2), refractory anemia with excess blasts (n = 33), refractory anemia with excess blasts in transformation (n = 26), or AML with antecedent MDS (n = 16) who were enrolled and randomly assigned to standard or intensively timed induction. Subsequently, patients were allocated to allogeneic HSCT if there was a suitable family donor, or randomly assigned to either autologous HSCT or chemotherapy.
    • Patients with refractory anemia or refractory anemia with excess blasts had a poor remission rate (45%), and those with refractory anemia with excess blasts in transformation (69%) or AML with history of MDS (81%) had similar remission rates compared with de novo AML (77%).
    • Six-year survival was poor for those with refractory anemia or refractory anemia with excess blasts (28%) and refractory anemia with excess blasts in transformation (30%).
    • Patients with AML and antecedent MDS had a similar outcome to those with de novo AML (50% survival compared with 45%).
    • Allogeneic HSCT appeared to improve survival (P = .08).
When analyzing these results, it is important to consider that the subtype refractory anemia with excess blasts in transformation is likely to represent patients with overt AML, while refractory anemia and refractory anemia with excess blasts represents MDS. The WHO classification has now omitted the category of refractory anemia with excess blasts in transformation, concluding that this entity was essentially AML.
Because survival after HSCT is improved in children with early forms of MDS (refractory anemia), transplantation before progression to late MDS or AML should be considered. HSCT should especially be considered when transfusions or other treatment are required, as is usually the case in patients with severe symptomatic cytopenias.[39,45] The 8-year disease-free survival (DFS) for children with various stages of MDS has been reported to be 65% for those treated with HLA matched donor transplants and 40% for those treated with mismatched unrelated donor transplants.[45][Level of evidence: 3iiiDii] A 3-year DFS of 50% was reported with the use of unrelated cord blood donor transplants for children with MDS, when the transplants were done after the year 2001.[53][Level of evidence: 3iiiDiii]
Because MDS in children is often associated with inherited predisposition syndromes, reports of transplantation in small numbers of patients with these disorders have been documented. For example, in patients with Fanconi anemia and AML or advanced MDS, the 5-year overall survival (OS) has been reported to be 33% to 55%.[54,55][Level of evidence: 3iiiA] Second transplants have also been used in pediatric patients with MDS/MPD who relapse or suffer graft failure. The 3-year OS was 33% for those retransplanted after relapse and 57% for those transplanted after initial graft failure.[56][Level of evidence: 3iiiA]
For patients with clinically significant cytopenias, supportive care that includes transfusions and prophylactic antibiotics are considered standard of care. The use of hematopoietic growth factors can improve the hematopoietic status, but concerns remain that such treatment could accelerate conversion to AML.[57]

Other therapies

Other supportive therapies that have been studied include the following:
  • Steroid therapy, including glucocorticoids and androgens, have been tried with mixed results.[58]
  • Treatments directed toward scavenging free oxygen radicals with amifostine [59,60] or the use of differentiation-promoting retinoids,[61] DNA methylation inhibitors (e.g., azacytidine and decitabine), and histone deacetylase inhibitors have all shown some response, but no definitive trials in children with MDS have been reported. Azacytidine has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of MDS in adults on the basis of randomized studies.[62] (Refer to the Disease-Modifying Agents section in the PDQ summary on Myelodysplastic Syndromes Treatment for more information.)
  • Agents such as lenalidomide an analog of thalidomide, have been tested based on findings that demonstrated increased activity in the bone marrow of patients with MDS. Lenalidomide has shown the most efficacy in patients with 5q- syndrome, especially those with thrombocytosis, and is now FDA-approved for use in adults with this finding.[63]
  • Immunosuppression with antithymocyte globulin and/or cyclosporine has also been reported in adults.[63,64]

Treatment Options Under Clinical Evaluation

The use of a variety of DNA methylation inhibitors and histone deacetylase inhibitors, as well as other therapies designed to induce differentiation, are being studied in both young and older adults with MDS.[65-67]
Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
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  25. Niemeyer CM, Kratz CP: Paediatric myelodysplastic syndromes and juvenile myelomonocytic leukaemia: molecular classification and treatment options. Br J Haematol 140 (6): 610-24, 2008. [PUBMED Abstract]
  26. Hasle H: Myelodysplastic and myeloproliferative disorders in children. Curr Opin Pediatr 19 (1): 1-8, 2007. [PUBMED Abstract]
  27. Mandel K, Dror Y, Poon A, et al.: A practical, comprehensive classification for pediatric myelodysplastic syndromes: the CCC system. J Pediatr Hematol Oncol 24 (7): 596-605, 2002. [PUBMED Abstract]
  28. Nösslinger T, Reisner R, Koller E, et al.: Myelodysplastic syndromes, from French-American-British to World Health Organization: comparison of classifications on 431 unselected patients from a single institution. Blood 98 (10): 2935-41, 2001. [PUBMED Abstract]
  29. Arber DA, Orazi A, Hasserjian R, et al.: The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 127 (20): 2391-405, 2016. [PUBMED Abstract]
  30. Göhring G, Michalova K, Beverloo HB, et al.: Complex karyotype newly defined: the strongest prognostic factor in advanced childhood myelodysplastic syndrome. Blood 116 (19): 3766-9, 2010. [PUBMED Abstract]
  31. Haase D, Germing U, Schanz J, et al.: New insights into the prognostic impact of the karyotype in MDS and correlation with subtypes: evidence from a core dataset of 2124 patients. Blood 110 (13): 4385-95, 2007. [PUBMED Abstract]
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  33. Cutler CS, Lee SJ, Greenberg P, et al.: A decision analysis of allogeneic bone marrow transplantation for the myelodysplastic syndromes: delayed transplantation for low-risk myelodysplasia is associated with improved outcome. Blood 104 (2): 579-85, 2004. [PUBMED Abstract]
  34. Hasle H, Baumann I, Bergsträsser E, et al.: The International Prognostic Scoring System (IPSS) for childhood myelodysplastic syndrome (MDS) and juvenile myelomonocytic leukemia (JMML). Leukemia 18 (12): 2008-14, 2004. [PUBMED Abstract]
  35. Hasle H, Niemeyer CM: Advances in the prognostication and management of advanced MDS in children. Br J Haematol 154 (2): 185-95, 2011. [PUBMED Abstract]
  36. Uberti JP, Agovi MA, Tarima S, et al.: Comparative analysis of BU and CY versus CY and TBI in full intensity unrelated marrow donor transplantation for AML, CML and myelodysplasia. Bone Marrow Transplant 46 (1): 34-43, 2011. [PUBMED Abstract]
  37. Nemecek ER, Guthrie KA, Sorror ML, et al.: Conditioning with treosulfan and fludarabine followed by allogeneic hematopoietic cell transplantation for high-risk hematologic malignancies. Biol Blood Marrow Transplant 17 (3): 341-50, 2011. [PUBMED Abstract]
  38. Shaw PJ, Kan F, Woo Ahn K, et al.: Outcomes of pediatric bone marrow transplantation for leukemia and myelodysplasia using matched sibling, mismatched related, or matched unrelated donors. Blood 116 (19): 4007-15, 2010. [PUBMED Abstract]
  39. Parikh SH, Mendizabal A, Martin PL, et al.: Unrelated donor umbilical cord blood transplantation in pediatric myelodysplastic syndrome: a single-center experience. Biol Blood Marrow Transplant 15 (8): 948-55, 2009. [PUBMED Abstract]
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  41. Smith AR, Christiansen EC, Wagner JE, et al.: Early hematopoietic stem cell transplant is associated with favorable outcomes in children with MDS. Pediatr Blood Cancer 60 (4): 705-10, 2013. [PUBMED Abstract]
  42. Woods WG, Barnard DR, Alonzo TA, et al.: Prospective study of 90 children requiring treatment for juvenile myelomonocytic leukemia or myelodysplastic syndrome: a report from the Children's Cancer Group. J Clin Oncol 20 (2): 434-40, 2002. [PUBMED Abstract]
  43. Andolina JR, Kletzel M, Tse WT, et al.: Allogeneic hematopoetic stem cell transplantation in pediatric myelodysplastic syndromes: improved outcomes for de novo disease. Pediatr Transplant 15 (3): 334-43, 2011. [PUBMED Abstract]
  44. Al-Seraihy A, Ayas M, Al-Nounou R, et al.: Outcome of allogeneic stem cell transplantation with a conditioning regimen of busulfan, cyclophosphamide and low-dose etoposide for children with myelodysplastic syndrome. Hematol Oncol Stem Cell Ther 4 (3): 121-5, 2011. [PUBMED Abstract]
  45. Woodard P, Carpenter PA, Davies SM, et al.: Unrelated donor bone marrow transplantation for myelodysplastic syndrome in children. Biol Blood Marrow Transplant 17 (5): 723-8, 2011. [PUBMED Abstract]
  46. Champlin R: Hematopoietic stem cell transplantation for treatment of myleodysplastic syndromes. Biol Blood Marrow Transplant 17 (1 Suppl): S6-8, 2011. [PUBMED Abstract]
  47. Nelson RP Jr, Yu M, Schwartz JE, et al.: Long-term disease-free survival after nonmyeloablative cyclophosphamide/fludarabine conditioning and related/unrelated allotransplantation for acute myeloid leukemia/myelodysplasia. Bone Marrow Transplant 45 (8): 1300-8, 2010. [PUBMED Abstract]
  48. Warlick ED: Optimizing stem cell transplantation in myelodysplastic syndromes: unresolved questions. Curr Opin Oncol 22 (2): 150-4, 2010. [PUBMED Abstract]
  49. Pulsipher MA, Boucher KM, Wall D, et al.: Reduced-intensity allogeneic transplantation in pediatric patients ineligible for myeloablative therapy: results of the Pediatric Blood and Marrow Transplant Consortium Study ONC0313. Blood 114 (7): 1429-36, 2009. [PUBMED Abstract]
  50. Gao L, Gao L, Gong Y, et al.: Reduced-intensity conditioning therapy with fludarabine, idarubicin, busulfan and cytarabine for allogeneic hematopoietic stem cell transplantation in acute myeloid leukemia and myelodysplastic syndrome. Leuk Res 37 (11): 1482-7, 2013. [PUBMED Abstract]
  51. Creutzig U, Bender-Götze C, Ritter J, et al.: The role of intensive AML-specific therapy in treatment of children with RAEB and RAEB-t. Leukemia 12 (5): 652-9, 1998. [PUBMED Abstract]
  52. Strahm B, Nöllke P, Zecca M, et al.: Hematopoietic stem cell transplantation for advanced myelodysplastic syndrome in children: results of the EWOG-MDS 98 study. Leukemia 25 (3): 455-62, 2011. [PUBMED Abstract]
  53. Madureira AB, Eapen M, Locatelli F, et al.: Analysis of risk factors influencing outcome in children with myelodysplastic syndrome after unrelated cord blood transplantation. Leukemia 25 (3): 449-54, 2011. [PUBMED Abstract]
  54. Mitchell R, Wagner JE, Hirsch B, et al.: Haematopoietic cell transplantation for acute leukaemia and advanced myelodysplastic syndrome in Fanconi anaemia. Br J Haematol 164 (3): 384-95, 2014. [PUBMED Abstract]
  55. Ayas M, Saber W, Davies SM, et al.: Allogeneic hematopoietic cell transplantation for fanconi anemia in patients with pretransplantation cytogenetic abnormalities, myelodysplastic syndrome, or acute leukemia. J Clin Oncol 31 (13): 1669-76, 2013. [PUBMED Abstract]
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  58. Chan G, DiVenuti G, Miller K: Danazol for the treatment of thrombocytopenia in patients with myelodysplastic syndrome. Am J Hematol 71 (3): 166-71, 2002. [PUBMED Abstract]
  59. Mathew P, Gerbing R, Alonzo TA, et al.: A phase II study of amifostine in children with myelodysplastic syndrome: a report from the Children's Oncology Group study (AAML0121). Pediatr Blood Cancer 57 (7): 1230-2, 2011. [PUBMED Abstract]
  60. Schanz J, Jung H, Wörmann B, et al.: Amifostine has the potential to induce haematologic responses and decelerate disease progression in individual patients with low- and intermediate-1-risk myelodysplastic syndromes. Leuk Res 33 (9): 1183-8, 2009. [PUBMED Abstract]
  61. Sadek I, Zayed E, Hayne O, et al.: Prolonged complete remission of myelodysplastic syndrome treated with danazol, retinoic acid and low-dose prednisone. Am J Hematol 64 (4): 306-10, 2000. [PUBMED Abstract]
  62. Silverman LR, Demakos EP, Peterson BL, et al.: Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B. J Clin Oncol 20 (10): 2429-40, 2002. [PUBMED Abstract]
  63. Yazji S, Giles FJ, Tsimberidou AM, et al.: Antithymocyte globulin (ATG)-based therapy in patients with myelodysplastic syndromes. Leukemia 17 (11): 2101-6, 2003. [PUBMED Abstract]
  64. Yoshimi A, Baumann I, Führer M, et al.: Immunosuppressive therapy with anti-thymocyte globulin and cyclosporine A in selected children with hypoplastic refractory cytopenia. Haematologica 92 (3): 397-400, 2007. [PUBMED Abstract]
  65. Mufti G, List AF, Gore SD, et al.: Myelodysplastic syndrome. Hematology (Am Soc Hematol Educ Program) : 176-99, 2003. [PUBMED Abstract]
  66. Esteller M: DNA methylation and cancer therapy: new developments and expectations. Curr Opin Oncol 17 (1): 55-60, 2005. [PUBMED Abstract]
  67. Bhalla K, List A: Histone deacetylase inhibitors in myelodysplastic syndrome. Best Pract Res Clin Haematol 17 (4): 595-611, 2004. [PUBMED Abstract]

Therapy-Related AML/Myelodysplastic Syndromes

Pathogenesis

The development of acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) after treatment with ionizing radiation or chemotherapy, particularly alkylating agents and topoisomerase inhibitors, is termed therapy-related AML (t-AML) or therapy-related MDS (t-MDS). In addition to genotoxic exposures, genetic predisposition susceptibilities (such as polymorphisms in drug detoxification and DNA repair pathway components) may contribute to the occurrence of secondary AML/MDS.[1-4]
The risk of t-AML/t-MDS is regimen-dependent and often related to the cumulative doses of chemotherapy agents received and the dose and field of radiation administered.[5] Regimens previously used that employed high cumulative doses of either epipodophyllotoxins (e.g., etoposide or teniposide) or alkylating agents (e.g., mechlorethamine, melphalan, busulfan, and cyclophosphamide) induced excessively high rates of t-AML/t-MDS that exceeded 10% in some cases.[5,6] However, most current chemotherapy regimens that are used to treat childhood cancers have a cumulative incidence of t-AML/t-MDS no greater than 1% to 2%.
t-AML/t-MDS resulting from epipodophyllotoxins and other topoisomerase II inhibitors (e.g., anthracyclines) usually occur within 2 years of exposure and are commonly associated with chromosome 11q23 abnormalities,[7] although other subtypes of AML (e.g., acute promyelocytic leukemia) have been reported.[8,9] t-AML that occurs after exposure to alkylating agents or ionizing radiation often presents 5 to 7 years later and is commonly associated with monosomies or deletions of chromosomes 5 and 7.[1,7]

Treatment of Therapy-Related AML/MDS

Treatment options for therapy-related AML/MDS include the following:
  1. HSCT.
The goal of treatment is to achieve an initial complete remission (CR) using AML-directed regimens and then, usually, to proceed directly to hematopoietic stem cell transplantation (HSCT) with the best available donor. However, treatment is challenging because of the following:[10]
  1. Increased rates of adverse cytogenetics and subsequent failure to obtain remission with chemotherapy.
  2. Comorbidities or limitations related to chemotherapy for the previous malignancy.
Accordingly, CR rates and overall survival (OS) rates are usually lower for patients with t-AML compared with patients with de novo AML.[10-12] Also, survival for pediatric patients with t-MDS is worse than survival for pediatric patients with MDS not related to previous therapy.[13]
Patients with t-MDS-refractory anemia usually have not needed induction chemotherapy before transplant; the role of induction therapy before transplant is controversial in patients with refractory anemia with excess blasts-1.
Only a few reports describe the outcome of children undergoing HSCT for t-AML.
Evidence (HSCT for t-AML/t-MDS):
  1. One study described the outcomes of 27 children with t-AML who received related and unrelated donor HSCT.[14]
    • Three-year OS rates were 18.5% ± 7.5% and event-free survival (EFS) rates were 18.7% ± 7.5%.
    • Poor survival was mainly the result of very high transplant-related mortality (59.6% ± 8.4%).
  2. Another study reported a second retrospective single-center experience of 14 patients with t-AML/t-MDS who were transplanted between 1975 and 2007.[11]
    • Survival was 29%, but in this review, only 63% of patients diagnosed with t-AML/t-MDS underwent HSCT.
  3. A multicenter study (CCG-2891) examined outcomes of 24 children with t-AML/t-MDS compared with other children enrolled on the study with de novo AML (n = 898) or MDS (n = 62). Children with t-AML/t-MDS were older and low-risk cytogenetics rarely occurred.[15]
    • Although rates of achieving CR and OS at 3 years were worse in the t-AML/t-MDS group (CR, 50% vs. 72%; P = .016; OS, 26% vs. 47%; P = .007), survival was similar (OS, 45% vs. 53%; P = .87) if patients achieved a CR.
  4. The importance of remission to survival in these patients is further illustrated by another single-center report of 21 children who underwent HSCT for t-AML/t-MDS between 1994 and 2009. Of the 21 children, 12 had t-AML (11 in CR at the time of transplant), seven had refractory anemia (for whom induction was not done), and two had refractory anemia with excess blasts.[16]
    • Survival of the entire cohort was 61%; patients in remission or with refractory anemia had a disease-free survival of 66%, and for the three patients with more than 5% blasts at the time of HSCT, survival was 0% (P = .015).
Because t-AML is rare in children, it is not known whether the significant decrease in transplant-related mortality after unrelated donor HSCT noted over the past several years will translate to improved survival in this population. Patients should be carefully assessed for pre-HSCT morbidities caused by earlier therapies, and treatment approaches should be adapted to give adequate intensity while minimizing transplant-related mortality.
References
  1. Leone G, Fianchi L, Voso MT: Therapy-related myeloid neoplasms. Curr Opin Oncol 23 (6): 672-80, 2011. [PUBMED Abstract]
  2. Bolufer P, Collado M, Barragan E, et al.: Profile of polymorphisms of drug-metabolising enzymes and the risk of therapy-related leukaemia. Br J Haematol 136 (4): 590-6, 2007. [PUBMED Abstract]
  3. Ezoe S: Secondary leukemia associated with the anti-cancer agent, etoposide, a topoisomerase II inhibitor. Int J Environ Res Public Health 9 (7): 2444-53, 2012. [PUBMED Abstract]
  4. Ding Y, Sun CL, Li L, et al.: Genetic susceptibility to therapy-related leukemia after Hodgkin lymphoma or non-Hodgkin lymphoma: role of drug metabolism, apoptosis and DNA repair. Blood Cancer J 2 (3): e58, 2012. [PUBMED Abstract]
  5. Leone G, Mele L, Pulsoni A, et al.: The incidence of secondary leukemias. Haematologica 84 (10): 937-45, 1999. [PUBMED Abstract]
  6. Pui CH, Ribeiro RC, Hancock ML, et al.: Acute myeloid leukemia in children treated with epipodophyllotoxins for acute lymphoblastic leukemia. N Engl J Med 325 (24): 1682-7, 1991. [PUBMED Abstract]
  7. Andersen MK, Johansson B, Larsen SO, et al.: Chromosomal abnormalities in secondary MDS and AML. Relationship to drugs and radiation with specific emphasis on the balanced rearrangements. Haematologica 83 (6): 483-8, 1998. [PUBMED Abstract]
  8. Ogami A, Morimoto A, Hibi S, et al.: Secondary acute promyelocytic leukemia following chemotherapy for non-Hodgkin's lymphoma in a child. J Pediatr Hematol Oncol 26 (7): 427-30, 2004. [PUBMED Abstract]
  9. Okamoto T, Okada M, Wakae T, et al.: Secondary acute promyelocytic leukemia in a patient with non-Hodgkin's lymphoma treated with VP-16 and MST-16. Int J Hematol 75 (1): 107-8, 2002. [PUBMED Abstract]
  10. Larson RA: Etiology and management of therapy-related myeloid leukemia. Hematology Am Soc Hematol Educ Program : 453-9, 2007. [PUBMED Abstract]
  11. Aguilera DG, Vaklavas C, Tsimberidou AM, et al.: Pediatric therapy-related myelodysplastic syndrome/acute myeloid leukemia: the MD Anderson Cancer Center experience. J Pediatr Hematol Oncol 31 (11): 803-11, 2009. [PUBMED Abstract]
  12. Yokoyama H, Mori S, Kobayashi Y, et al.: Hematopoietic stem cell transplantation for therapy-related myelodysplastic syndrome and acute leukemia: a single-center analysis of 47 patients. Int J Hematol 92 (2): 334-41, 2010. [PUBMED Abstract]
  13. Xavier AC, Kutny M, Costa LJ: Incidence and outcomes of paediatric myelodysplastic syndrome in the United States. Br J Haematol 180 (6): 898-901, 2018. [PUBMED Abstract]
  14. Woodard P, Barfield R, Hale G, et al.: Outcome of hematopoietic stem cell transplantation for pediatric patients with therapy-related acute myeloid leukemia or myelodysplastic syndrome. Pediatr Blood Cancer 47 (7): 931-5, 2006. [PUBMED Abstract]
  15. Barnard DR, Lange B, Alonzo TA, et al.: Acute myeloid leukemia and myelodysplastic syndrome in children treated for cancer: comparison with primary presentation. Blood 100 (2): 427-34, 2002. [PUBMED Abstract]
  16. Kobos R, Steinherz PG, Kernan NA, et al.: Allogeneic hematopoietic stem cell transplantation for pediatric patients with treatment-related myelodysplastic syndrome or acute myelogenous leukemia. Biol Blood Marrow Transplant 18 (3): 473-80, 2012. [PUBMED Abstract]

Juvenile Myelomonocytic Leukemia (JMML)

Incidence

Juvenile myelomonocytic leukemia (JMML) is a rare leukemia that occurs approximately ten times less frequently than acute myeloid leukemia (AML) in children, with an annual incidence of about 1 to 2 cases per 1 million people.[1] JMML typically presents in young children (median age, approximately 1.8 years) and occurs more commonly in boys (male to female ratio, approximately 2.5:1).

Clinical Presentation and Diagnostic Criteria

Common clinical features at diagnosis include the following:[2]
  • Hepatosplenomegaly (97%).
  • Lymphadenopathy (76%).
  • Pallor (64%).
  • Fever (54%).
  • Skin rash (36%).
In children presenting with clinical features suggestive of JMML, current criteria used for a definitive diagnosis are described in Table 8.[3]
Table 8. Diagnostic Criteria for Juvenile Myelomonocytic Leukemia (JMML) Per the 2016 Revision to World Health Organization Classification
Category 1 (All are Required)Category 2 (One is Sufficient)aCategory 3 (Patients Without Genetic Features Must Have the Following in Addition to Category 1b)
Clinical and Hematologic FeaturesGenetic StudiesOther Features
GM-CSF = granulocyte-macrophage colony-stimulating factor; NF1 = neurofibromatosis type 1.
aPatients who are found to have a category 2 lesion need to meet the criteria in category 1 but do not need to meet the category 3 criteria. Patients who are not found to have a category 2 lesion must meet the category 1 and 3 criteria.
bNote that only 7% of patients with JMML will NOT present with splenomegaly, but virtually all patients develop splenomegaly within several weeks to months of initial presentation.
Absence of the BCR-ABL1fusion geneSomatic mutation in KRAS, NRAS, or PTPN11 (germline mutations need to be excluded)Monosomy 7 or other chromosomal abnormality, or at least 2 of the criteria listed below:
>1 × 109/L circulating monocytesClinical diagnosis of NF1 or NF1 gene mutation— Circulating myeloid or erythroid precursors
<20% blasts in the peripheral blood and bone marrowGermline CBL mutation and loss of heterozygosity of CBL— Increased hemoglobin F for age
Splenomegaly — Hyperphosphorylation of STAT5
  — GM-CSF hypersensitivity

Pathogenesis and Related Syndromes

The pathogenesis of JMML has been closely linked to activation of the RAS oncogene pathway, along with related syndromes (refer to Figure 1).[4,5] In addition, distinctive RNA expression and DNA methylation patterns have been reported; they are correlated with clinical factors such as age and appear to be associated with prognosis.[6,7]
ENLARGESchematic diagram showing ligand-stimulated Ras activation, the Ras-Erk pathway, and gene mutations contributing to the neuro-cardio-facio-cutaneous congenital disorders and JMML.
Figure 1. Schematic diagram showing ligand-stimulated Ras activation, the Ras-Erk pathway, and the gene mutations found to date contributing to the neuro-cardio-facio-cutaneous congenital disorders and JMML. NL/MGCL: Noonan-like/multiple giant cell lesion; CFC: cardia-facio-cutaneous; JMML: juvenile myelomonocytic leukemia. Reprinted from Leukemia Research, 33 (3), Rebecca J. Chan, Todd Cooper, Christian P. Kratz, Brian Weiss, Mignon L. Loh, Juvenile myelomonocytic leukemia: A report from the 2nd International JMML Symposium, Pages 355-62, Copyright 2009, with permission from Elsevier.
Children with neurofibromatosis type 1 (NF1) and Noonan syndrome are at increased risk of developing JMML:[8,9]
  • NF1. Up to 14% of cases of JMML occur in children with NF1.[2]
  • Noonan syndrome. Noonan syndrome is usually inherited as an autosomal dominant condition, but can also arise spontaneously. It is characterized by facial dysmorphism, short stature, webbed neck, neurocognitive abnormalities, and cardiac abnormalities. Germline mutations in PTPN11 are observed in children with Noonan syndrome and in children with JMML.[10-12]
    Importantly, some children with Noonan syndrome have a hematologic picture indistinguishable from JMML that self-resolves during infancy, similar to what happens in children with Down syndrome and transient myeloproliferative disorder.[5,12]
    Within a large prospective cohort of 641 patients with Noonan syndrome and a germline PTPN11 mutation, 36 patients (~6%) showed myeloproliferative features, with 20 patients (~3%) meeting the consensus diagnostic criteria for JMML.[12] Of the 20 patients meeting the criteria for JMML, 12 patients had severe neonatal manifestations (e.g., life-threatening complications related to congenital heart defects, pleural effusion, leukemia infiltrates, and/or thrombocytopenia), and 10 of 20 patients died during the first month of life. Among the remaining eight patients, none required intensive therapy at diagnosis or during follow-up. All 16 patients with myeloproliferative features not meeting JMML criteria were alive, with a median follow-up of 3 years, and none of the patients received chemotherapy.
Mutations in the CBL gene, an E3 ubiquitin-protein ligase that is involved in targeting proteins, particularly tyrosine kinases, for proteasomal degradation occur in 10% to 15% of JMML cases,[13,14] with many of these cases occurring in children with germline CBLmutations.[15,16] CBL germline mutations result in an autosomal dominant developmental disorder that is characterized by impaired growth, developmental delay, cryptorchidism, and a predisposition to JMML.[15] Some individuals with CBL germline mutations experience spontaneous regression of their JMML but develop vasculitis later in life.[15]CBL mutations are nearly always mutually exclusive of RAS and PTPN11 mutations.[13]

Genomics of JMML

The genomic landscape of JMML is characterized by mutations in one of five genes of the Ras pathway: NF1, NRAS, KRAS, PTPN11, and CBL.[17-19] In a series of 118 consecutively diagnosed JMML cases with Ras pathway–activating mutations, PTPN11 was the most commonly mutated gene, accounting for 51% of cases (19% germline and 32% somatic) (refer to Figure 2).[17] Patients with mutated NRAS accounted for 19% of cases, and patients with mutated KRAS accounted for 15% of cases. NF1 mutations accounted for 8% of cases and CBL mutations accounted for 11% of cases. Although mutations among these five genes are generally mutually exclusive, 4% to 17% of cases have mutations in two of these Ras pathway genes,[17-19] a finding that is associated with poorer prognosis.[17,19]
The mutation rate in JMML leukemia cells is very low, but additional mutations beyond those of the five Ras pathway genes described above are observed.[17-19] Secondary genomic alterations are observed for genes of the transcriptional repressor complex PRC2 (e.g., ASXL1 was mutated in 7%–8% of cases). Some genes associated with myeloproliferative neoplasms in adults are also mutated at low rates in JMML (e.g., SETBP1was mutated in 6%–9% of cases).[17-20] JAK3 mutations are also observed in a small percentage (4%–12%) of JMML cases.[17-20] Cases with germline PTPN11 and germline CBLmutations showed low rates of additional mutations (refer to Figure 2).[17] The presence of mutations beyond disease-defining Ras pathway mutations is associated with an inferior prognosis.[17,18]
A report describing the genomic landscape of JMML found that 16 of 150 patients (11%) lacked canonical Ras pathway mutations. Among these 16 patients, 3 were observed to have in-frame fusions involving receptor tyrosine kinases (DCTN1-ALK, RANBP2-ALK, and TBL1XR1-ROS1). These patients all had monosomy 7 and were aged 56 months or older. One patient with an ALK fusion was treated with crizotinib plus conventional chemotherapy and achieved a complete molecular remission and proceeded to allogeneic bone marrow transplantation.[19]
ENLARGEChart showing alteration profiles in individual JMML cases.
Figure 2. Alteration profiles in individual JMML cases. Germline and somatically acquired alterations with recurring hits in the RAS pathway and PRC2 network are shown for 118 patients with JMML who underwent detailed genetic analysis. Blast excess was defined as a blast count ≥10% but <20% of nucleated cells in the bone marrow at diagnosis. Blast crisis was defined as a blast count ≥20% of nucleated cells in the bone marrow. NS, Noonan syndrome. Reprinted by permission from Macmillan Publishers Ltd: Nature Genetics (Caye A, Strullu M, Guidez F, et al.: Juvenile myelomonocytic leukemia displays mutations in components of the RAS pathway and the PRC2 network. Nat Genet 47 [11]: 1334-40, 2015), copyright (2015).
General characteristics of leukemia cells provide both prognostic information and guidance regarding therapeutic opportunities for JMML:
  • Number of non-RAS pathway mutations. A strong predictor of prognosis for children with JMML is the number of mutations beyond the disease-defining RAS-pathway mutations.[17,18] Of 64 patients (65.3%) at diagnosis, zero or one somatic alteration (pathogenic mutation or monosomy 7) was identified, whereas two or more alterations were identified in 34 (34.7%) patients.[18] In multivariate analysis, mutation number (two or more vs. zero or one) maintained significance as a predictor of inferior event-free survival and overall survival. A higher proportion of patients diagnosed with two or more alterations were older and male, and these patients also demonstrated a higher rate of monosomy 7 or somatic NF1 mutation.[18] Similar findings and observations reported that patients with RAS-pathway double mutations (15 of 96 patients) were at the highest risk of treatment failure.[17]
  • RAS-MAPK pathway inhibitors. Because JMML is a disease defined by mutations in the RAS-MAPK pathway, one might speculate that inhibitors of this pathway (e.g., MEK inhibitors) may have clinical utility in the treatment of JMML. However, preclinical data to support this hypothesis are inconsistent,[21,22] and there are no clinical data available.

Prognosis

Several factors affect prognosis in JMML, including the following:
  1. Number of non–Ras pathway mutations. A predictor of prognosis for children with JMML is the number of mutations beyond the disease-defining Ras pathway mutations.[17,18]
    • One study observed that zero or one somatic alteration (pathogenic mutation or monosomy 7) was identified in 64 patients (65.3%) at diagnosis, whereas two or more alterations were identified in 34 patients (34.7%).[18] In multivariate analysis, mutation number (2 or more vs. 0 or 1) maintained significance as a predictor of inferior event-free survival (EFS) and overall survival (OS). A higher proportion of patients diagnosed with two or more alterations were older and male, and these patients also demonstrated a higher rate of monosomy 7 or somatic NF1 mutations.[18]
    • Another study observed that approximately 60% of patients had one or more additional mutations beyond their disease-defining Ras pathway mutation. These patients had an inferior OS compared with patients who had no additional mutations (3-year OS, 61% vs. 85%, respectively).[17]
    • A third study observed a trend for an inferior OS for patients with two or more mutations compared with patients with zero or one mutation.[19]
  2. Ras pathway double mutations. Although mutations in the five canonical Ras pathway genes associated with JMML (NF1, NRAS, KRAS, PTPN11, and CBL) are generally mutually exclusive, 4% to 17% of cases have mutations in two of these Ras pathway genes,[17,18] a finding that has been associated with a poorer prognosis.[17,18]
    • Two Ras pathway mutations were identified in 11% of JMML patients in one report, and these patients had significantly inferior EFS (14%) compared with patients who had a single Ras pathway mutation (62%). Patients with Noonan syndrome were excluded from the analyses.[18]
    • Similar findings for Ras pathway mutations were reported in a second study that observed that patients with Ras pathway double mutations (15 of 96 patients) had lower survival rates than did patients with either no additional mutations or with additional mutations beyond the Ras pathway mutation.[17]
  3. Age, platelet count, and fetal hemoglobin level after any treatment. Historically, more than 90% of patients with JMML died despite the use of chemotherapy,[23] but with the application of hematopoietic stem cell transplantation (HSCT), survival rates of approximately 50% are now observed.[24] Patients appeared to follow three distinct clinical courses:
    • Rapidly progressive disease and early demise.
    • Transiently stable disease followed by progression and death.
    • Clinical improvement that lasted up to 9 years before progression or, rarely, long-term survival.
    Favorable prognostic factors for survival after any therapy include age younger than 2 years, platelet count greater than 33 × 109/L, and low age-adjusted fetal hemoglobin levels.[1,2] In contrast, being older than 2 years and having high blood fetal hemoglobin levels at diagnosis are predictors of poor outcome.[1,2]
  4. DNA methylation profile. One study applied DNA methylation profiling to a discovery cohort of 39 patients with JMML and to a validation cohort of 40 patients. Distinctive subsets of JMML with either high, intermediate, or low methylation levels were observed in both cohorts. Patients with the lowest methylation levels had the highest survival rates, and all but 1 of 15 patients experienced spontaneous resolution in the low methylation cohort. High methylation status was associated with lower EFS rates.[25]
    Another study applied DNA methylation profiling to a cohort of 106 patients with JMML and observed one subgroup of patients with a hypermethylation profile and one subgroup of patients with a hypomethylation profile. Patients in the hypermethylation group had a significantly lower OS rate than did patients in the hypomethylation group (5-year OS, 46% vs. 73%, respectively). Patients in the hypermethylation group also had a significantly poorer 5-year transplant-free survival rate than did patients in the hypomethylation group (2.2%; 95% CI, 0.2%–10.1% vs. 41.2%; 95% CI, 27.1%–54.8%). Hypermethylation status was associated with two or more mutations, higher fetal hemoglobin levels, older age, and lower platelet count at diagnosis. All patients with Noonan syndrome were in the hypomethylation group.[19]
  5. LIN28B overexpression. LIN28B overexpression is present in approximately one-half of children with JMML and identifies a biologically distinctive subset of JMML. LIN28B is an RNA-binding protein that regulates stem cell renewal. LIN28B overexpression was positively correlated with high blood fetal hemoglobin level and age (both of which are associated with poor prognosis), and it was negatively correlated with presence of monosomy 7 (also associated with inferior prognosis). Although LIN28Boverexpression identifies a subset of patients with increased risk of treatment failure, it was not found to be an independent prognostic factor when other factors such as age and monosomy 7 status are considered.[26] Another study also observed a subset of JMML patients with elevated LIN28B expression and identified LIN28B as the gene for which expression was most strongly associated with hypermethylation status.[19]

Treatment of JMML

Treatment options for JMML include the following:
  • Hematopoietic stem cell transplant (HSCT).
The role of conventional antileukemia therapy in the treatment of JMML is not defined. The absence of consensus response criteria for JMML complicates determination of the role of specific agents in the treatment of JMML.[27] Some agents that have shown antileukemia activity against JMML include etoposide, cytarabine, thiopurines (thioguanine and mercaptopurine), isotretinoin, and farnesyl inhibitors, but none of these have been shown to improve outcome.[27-31]; [32][Level of evidence: 2B]
HSCT currently offers the best chance of cure for JMML.[24,33-36]
Evidence (HSCT):
  1. A report from the European Working Group on Childhood Myelodysplastic Syndromes included 100 transplant recipients at multiple centers treated with a common preparative regimen of busulfan, cyclophosphamide, and melphalan, with or without antithymocyte globulin. Recipients had been treated with varying degrees of pretransplant chemotherapy or differentiating agents, and some patients had splenectomy performed.[24]
    • The 5-year EFS rate was 55% for children with JMML transplanted with HLA-identical matched family donor cells and 49% for children with JMML transplanted with unrelated donor cells.
    • The multivariate analysis showed no effect on survival of previous AML-like chemotherapy versus low-dose chemotherapy or no chemotherapy.
    • No effect on survival was observed for splenectomy pretransplant or difference in spleen size.
    • Comparison of outcomes based on related versus unrelated donors also found no difference.
    • Only age older than 4 years and sex were shown to be poor prognostic factors for outcome and increased risk of relapse (relative risk [RR], 2.24 [1.07–4.69]; P= .032 for older age; RR, 2.22 [1.09–4.50]; P = .028 for females).[24]
  2. Cord blood transplantation results in a 5-year disease-free survival rate of 44%, with improved outcome in children younger than 1.4 years at diagnosis, those with nonmonosomy 7 karyotype, and those receiving 5/6 to 6/6 HLA-matched cord units.[37][Level of evidence: 3iiDii] This suggests that cord blood can provide an additional donor pool for this group of children.
  3. The use of reduced-intensity preparative regimens to decrease the adverse side effects of transplantation have also been reported in small numbers of patients, generally for patients ineligible for myeloablative HSCT.[38,39]
    COG conducted a randomized trial in children with JMML that compared a standard-intensity preparative regimen (busulfan/cyclophosphamide/melphalan) with a reduced-intensity regimen (busulfan/fludarabine).[40]
    • The trial closed to enrollment early when an interim analysis revealed a higher frequency of relapse/disease persistence (7 of 9 patients) in children who received the reduced-intensity regimen than in children who received the standard-intensity regimen (1 of 6 patients).
Disease recurrence is the primary cause of treatment failure for children with JMML after HSCT and occurs in 30% to 40% of cases.[24,33,34] While the role of donor lymphocyte infusions is uncertain,[41] reports indicate that approximately 50% of patients with relapsed JMML can be successfully treated with a second HSCT.[42]

Treatment Options Under Clinical Evaluation

Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.
The following is an example of a national and/or institutional clinical trial that is currently being conducted:
  • COG-ADVL1521 (NCT03190915) (Trametinib in Treating Patients With Relapsed or Refractory JMML): This trial is evaluating the activity of trametinib (inhibitor of MEK1/2, which is downstream of RAS/MAPK signaling) in pediatric patients with relapsed or refractory JMML. The rationale for studying this agent is based on the finding that nearly all genetic mutations found in JMML lead to aberrant RAS pathway signaling. Eligible patients are those who have relapsed or have persistent disease after intravenous chemotherapy (such as fludarabine or cytarabine) and/or hematopoietic stem cell transplant, but not after low-dose oral chemotherapy (such as mercaptopurine). The primary objective is to determine the response rate of trametinib administered orally once daily in 28-day cycles.
References
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  11. Kratz CP, Niemeyer CM, Castleberry RP, et al.: The mutational spectrum of PTPN11 in juvenile myelomonocytic leukemia and Noonan syndrome/myeloproliferative disease. Blood 106 (6): 2183-5, 2005. [PUBMED Abstract]
  12. Strullu M, Caye A, Lachenaud J, et al.: Juvenile myelomonocytic leukaemia and Noonan syndrome. J Med Genet 51 (10): 689-97, 2014. [PUBMED Abstract]
  13. Loh ML, Sakai DS, Flotho C, et al.: Mutations in CBL occur frequently in juvenile myelomonocytic leukemia. Blood 114 (9): 1859-63, 2009. [PUBMED Abstract]
  14. Muramatsu H, Makishima H, Jankowska AM, et al.: Mutations of an E3 ubiquitin ligase c-Cbl but not TET2 mutations are pathogenic in juvenile myelomonocytic leukemia. Blood 115 (10): 1969-75, 2010. [PUBMED Abstract]
  15. Niemeyer CM, Kang MW, Shin DH, et al.: Germline CBL mutations cause developmental abnormalities and predispose to juvenile myelomonocytic leukemia. Nat Genet 42 (9): 794-800, 2010. [PUBMED Abstract]
  16. Pérez B, Mechinaud F, Galambrun C, et al.: Germline mutations of the CBL gene define a new genetic syndrome with predisposition to juvenile myelomonocytic leukaemia. J Med Genet 47 (10): 686-91, 2010. [PUBMED Abstract]
  17. Caye A, Strullu M, Guidez F, et al.: Juvenile myelomonocytic leukemia displays mutations in components of the RAS pathway and the PRC2 network. Nat Genet 47 (11): 1334-40, 2015. [PUBMED Abstract]
  18. Stieglitz E, Taylor-Weiner AN, Chang TY, et al.: The genomic landscape of juvenile myelomonocytic leukemia. Nat Genet 47 (11): 1326-33, 2015. [PUBMED Abstract]
  19. Murakami N, Okuno Y, Yoshida K, et al.: Integrated molecular profiling of juvenile myelomonocytic leukemia. Blood 131 (14): 1576-1586, 2018. [PUBMED Abstract]
  20. Sakaguchi H, Okuno Y, Muramatsu H, et al.: Exome sequencing identifies secondary mutations of SETBP1 and JAK3 in juvenile myelomonocytic leukemia. Nat Genet 45 (8): 937-41, 2013. [PUBMED Abstract]
  21. Hernández-Porras I, Fabbiano S, Schuhmacher AJ, et al.: K-RasV14I recapitulates Noonan syndrome in mice. Proc Natl Acad Sci U S A 111 (46): 16395-400, 2014. [PUBMED Abstract]
  22. Chang T, Krisman K, Theobald EH, et al.: Sustained MEK inhibition abrogates myeloproliferative disease in Nf1 mutant mice. J Clin Invest 123 (1): 335-9, 2013. [PUBMED Abstract]
  23. Freedman MH, Estrov Z, Chan HS: Juvenile chronic myelogenous leukemia. Am J Pediatr Hematol Oncol 10 (3): 261-7, 1988 Fall. [PUBMED Abstract]
  24. Locatelli F, Nöllke P, Zecca M, et al.: Hematopoietic stem cell transplantation (HSCT) in children with juvenile myelomonocytic leukemia (JMML): results of the EWOG-MDS/EBMT trial. Blood 105 (1): 410-9, 2005. [PUBMED Abstract]
  25. Stieglitz E, Mazor T, Olshen AB, et al.: Genome-wide DNA methylation is predictive of outcome in juvenile myelomonocytic leukemia. Nat Commun 8 (1): 2127, 2017. [PUBMED Abstract]
  26. Helsmoortel HH, Bresolin S, Lammens T, et al.: LIN28B overexpression defines a novel fetal-like subgroup of juvenile myelomonocytic leukemia. Blood 127 (9): 1163-72, 2016. [PUBMED Abstract]
  27. Bergstraesser E, Hasle H, Rogge T, et al.: Non-hematopoietic stem cell transplantation treatment of juvenile myelomonocytic leukemia: a retrospective analysis and definition of response criteria. Pediatr Blood Cancer 49 (5): 629-33, 2007. [PUBMED Abstract]
  28. Castleberry RP, Emanuel PD, Zuckerman KS, et al.: A pilot study of isotretinoin in the treatment of juvenile chronic myelogenous leukemia. N Engl J Med 331 (25): 1680-4, 1994. [PUBMED Abstract]
  29. Woods WG, Barnard DR, Alonzo TA, et al.: Prospective study of 90 children requiring treatment for juvenile myelomonocytic leukemia or myelodysplastic syndrome: a report from the Children's Cancer Group. J Clin Oncol 20 (2): 434-40, 2002. [PUBMED Abstract]
  30. Loh ML: Childhood myelodysplastic syndrome: focus on the approach to diagnosis and treatment of juvenile myelomonocytic leukemia. Hematology Am Soc Hematol Educ Program 2010: 357-62, 2010. [PUBMED Abstract]
  31. Hasle H: Myelodysplastic and myeloproliferative disorders in children. Curr Opin Pediatr 19 (1): 1-8, 2007. [PUBMED Abstract]
  32. Stieglitz E, Ward AF, Gerbing RB, et al.: Phase II/III trial of a pre-transplant farnesyl transferase inhibitor in juvenile myelomonocytic leukemia: a report from the Children's Oncology Group. Pediatr Blood Cancer 62 (4): 629-36, 2015. [PUBMED Abstract]
  33. Smith FO, King R, Nelson G, et al.: Unrelated donor bone marrow transplantation for children with juvenile myelomonocytic leukaemia. Br J Haematol 116 (3): 716-24, 2002. [PUBMED Abstract]
  34. Yusuf U, Frangoul HA, Gooley TA, et al.: Allogeneic bone marrow transplantation in children with myelodysplastic syndrome or juvenile myelomonocytic leukemia: the Seattle experience. Bone Marrow Transplant 33 (8): 805-14, 2004. [PUBMED Abstract]
  35. Baker D, Cole C, Price J, et al.: Allogeneic bone marrow transplantation in juvenile myelomonocytic leukemia without total body irradiation. J Pediatr Hematol Oncol 26 (3): 200-3, 2004. [PUBMED Abstract]
  36. Locatelli F, Niemeyer CM: How I treat juvenile myelomonocytic leukemia. Blood 125 (7): 1083-90, 2015. [PUBMED Abstract]
  37. Locatelli F, Crotta A, Ruggeri A, et al.: Analysis of risk factors influencing outcomes after cord blood transplantation in children with juvenile myelomonocytic leukemia: a EUROCORD, EBMT, EWOG-MDS, CIBMTR study. Blood 122 (12): 2135-41, 2013. [PUBMED Abstract]
  38. Yabe M, Sako M, Yabe H, et al.: A conditioning regimen of busulfan, fludarabine, and melphalan for allogeneic stem cell transplantation in children with juvenile myelomonocytic leukemia. Pediatr Transplant 12 (8): 862-7, 2008. [PUBMED Abstract]
  39. Koyama M, Nakano T, Takeshita Y, et al.: Successful treatment of JMML with related bone marrow transplantation after reduced-intensity conditioning. Bone Marrow Transplant 36 (5): 453-4; author reply 454, 2005. [PUBMED Abstract]
  40. Dvorak CC, Satwani P, Stieglitz E, et al.: Disease burden and conditioning regimens in ASCT1221, a randomized phase II trial in children with juvenile myelomonocytic leukemia: A Children's Oncology Group study. Pediatr Blood Cancer 65 (7): e27034, 2018. [PUBMED Abstract]
  41. Yoshimi A, Bader P, Matthes-Martin S, et al.: Donor leukocyte infusion after hematopoietic stem cell transplantation in patients with juvenile myelomonocytic leukemia. Leukemia 19 (6): 971-7, 2005. [PUBMED Abstract]
  42. Yoshimi A, Mohamed M, Bierings M, et al.: Second allogeneic hematopoietic stem cell transplantation (HSCT) results in outcome similar to that of first HSCT for patients with juvenile myelomonocytic leukemia. Leukemia 21 (3): 556-60, 2007. [PUBMED Abstract]

Chronic Myelogenous Leukemia (CML)

Incidence

Chronic myelogenous leukemia (CML) accounts for less than 5% of all childhood leukemia, and in the pediatric age range, occurs most commonly in older adolescents.[1]

Molecular Abnormality

The cytogenetic abnormality most characteristic of CML is the Philadelphia chromosome (Ph), which represents a translocation of chromosomes 9 and 22 (t(9;22)) resulting in a BCR-ABL1 fusion protein.[2]

Clinical Presentation

CML is characterized by a marked leukocytosis and is often associated with thrombocytosis, sometimes with abnormal platelet function. Bone marrow aspiration or biopsy reveals hypercellularity with relatively normal granulocytic maturation and no significant increase in leukemic blasts. Although reduced leukocyte alkaline phosphatase activity is seen in CML, this is not a specific finding.
CML has the following three clinical phases:
  • Chronic phase. Chronic phase, which lasts for approximately 3 years if untreated, usually presents with symptoms secondary to hyperleukocytosis such as weakness, fever, night sweats, bone pain, respiratory distress, priapism, left upper quadrant pain (splenomegaly), and, rarely, hearing loss and visual disturbances.
  • Accelerated phase. The accelerated phase is characterized by progressive splenomegaly, thrombocytopenia, and increased percentage of peripheral and bone marrow blasts, along with accumulation of karyotypic abnormalities in addition to the Ph chromosome.
  • Blast crisis phase. Blast crisis is notable for the bone marrow, showing greater than 20% blasts or chloromatous lesions and a clinical picture that is indistinguishable from acute leukemia. Approximately two-thirds of blast crisis is myeloid, and the remainder is lymphoid, usually of B lineage. Patients in blast crisis will die within a few months.[3]

Treatment of CML: Historical Perspective

Before the tyrosine kinase inhibitor (TKI) era, allogeneic hematopoietic stem cell transplantation (HSCT) was the primary treatment for children with CML. Published reports from this period described survival rates of 70% to 80% when an HLA–matched-family donor (MFD) was used in the treatment of children in early chronic phase, with lower survival rates when HLA–matched-unrelated donors were used.[4-6]
Relapse rates were low (less than 20%) when transplant was performed in chronic phase.[4,5] The primary cause of death was treatment-related mortality, which was increased with HLA–matched-unrelated donors compared with HLA-MFDs in most reports.[4,5] High-resolution DNA matching for HLA alleles appeared to reduce rates of treatment-related mortality, leading to improved outcome for HSCT using unrelated donors.[7]
Compared with transplantation in chronic phase, transplantation in accelerated phase or blast crisis and in second-chronic phase resulted in significantly reduced survival.[4-6] The use of T-lymphocyte depletion to avoid graft-versus-host disease resulted in a higher relapse rate and decreased overall survival (OS),[8] supporting the contribution of a graft-versus-leukemia effect to favorable outcome after allogeneic HSCT.
The introduction of the TKI imatinib as a therapeutic drug targeted at inhibiting the BCR-ABL fusion kinase revolutionized the treatment of patients with CML, for both children and adults.[9] As most data on the use of TKIs for CML is from adult clinical trials, the adult experience is initially described, followed by a description of the more limited experience in children.

Treatment of Adult CML With TKIs

Imatinib is a potent inhibitor of the ABL tyrosine kinase, platelet-derived growth factor (PDGF) receptors (alpha and beta), and KIT. Imatinib treatment achieves clinical, cytogenetic, and molecular remissions (as defined by the absence of BCR-ABL fusion transcripts) in a high proportion of CML patients treated in chronic phase.[10]
Evidence (imatinib for adults):
  1. Imatinib replaced the use of recombinant interferon alfa in the initial treatment of CML based on the results of a large phase III trial comparing imatinib with interferon plus cytarabine (IRIS).[11,12]
    • Patients receiving imatinib had higher complete cytogenetic response rates (76% vs. 14% at 18 months).[11] The rate of treatment failure diminished over time, from 3.3% and 7.5% in the first and second years of imatinib treatment, respectively, to less than 1% by the fifth year of treatment.[12]
    • After censoring for patients who died from causes unrelated to CML or transplantation, the overall estimated survival rate for patients randomly assigned to imatinib was 95% at 60 months.[12]
Guidelines for imatinib treatment have been developed for adults with CML on the basis of patient response to treatment, including the timing of achieving complete hematologic response, complete cytogenetic response, and major molecular response (defined as attainment of a 3-log reduction in BCR-ABL1/control gene ratio).[13-16]
Poor adherence is a major reason for loss of complete cytogenetic response and imatinib failure for adult CML patients on long-term therapy.[17] The identification of BCR-ABL1kinase domain mutations at the time of failure or of suboptimal response to imatinib treatment also has clinical implications,[18] because there are alternative BCR-ABL kinase inhibitors (e.g., dasatinib and nilotinib) that maintain their activity against some (but not all) mutations that confer resistance to imatinib.[13,19,20]
Two TKIs, dasatinib and nilotinib, have been shown to be effective in patients who have an inadequate response to imatinib, although not in patients with the T315I mutation. Both dasatinib and nilotinib have also received regulatory approval for the treatment of newly diagnosed chronic-phase CML in adults, on the basis of the following studies:
  • Dasatinib. Dasatinib was approved on the basis of a phase III trial that compared dasatinib (100 mg daily) with imatinib (400 mg daily).[21] There was no significant difference in progression-free survival (PFS) or OS. However, after 12 months of treatment, dasatinib was associated with a higher rate of complete cytogenetic response (83% vs. 72%, P = .001) and major molecular response (46% vs. 28%, P < .0001). Responses were achieved in a shorter time with dasatinib (P < .0001).
  • Nilotinib. Nilotinib (at a dose of either 300 mg or 400 mg twice daily) was compared with imatinib (400 mg daily) in a phase III trial.[22] At 12 months, the rates of complete cytogenetic response were significantly higher for nilotinib (80% for the 300-mg dose and 78% for the 400-mg dose) than were the rates for imatinib (65%) (P < .001 for both comparisons). Also, nilotinib was associated with higher rates of major molecular response (44% for the 300-mg dose and 43% for the 400-mg dose compared with 22% for imatinib, P < .001 for both comparisons). The 300-mg twice-daily dose of nilotinib was associated with a more favorable safety profile compared with the 400-mg dose.
Because of the superiority over imatinib in terms of complete cytogenetic response rate and major molecular response rate, both dasatinib and nilotinib are extensively used as first-line therapy in adults with CML. However, despite more rapid responses with dasatinib and nilotinib than with imatinib when used as frontline therapy, PFS and OS appear to be similar for all three agents.[23,24] Additional follow-up will be required to better define the impact of these agents on long-term PFS and OS.
Bosutinib is another TKI that targets the BCR-ABL fusion and has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of all phases of CML in adults who show intolerance to or whose disease shows resistance to previous therapy with another TKI. Bosutinib has not been studied in the pediatric population.
Ponatinib is a BCR-ABL inhibitor that is effective against the T315I mutation.[25] Ponatinib induced objective responses in approximately 70% of heavily pretreated adults with chronic-phase CML, with responses observed regardless of the baseline BCR-ABL kinase domain mutation.[26] Development of ponatinib has been complicated by the high rate of vascular occlusion observed in patients receiving the agent, with arterial and venous thrombosis and occlusions (including myocardial infarction and stroke) occurring in more than 20% of treated patients.[27] Ponatinib has not been studied in the pediatric population.
For adult CML patients who proceed to allogeneic HSCT, there is no evidence that pretransplant imatinib adversely impacts outcome.
Evidence (imatinib followed by HSCT in adults):
  1. A retrospective study that compared 145 patients who received imatinib before transplant with a historical cohort of 231 patients showed no difference in early hepatic toxic effects or engraftment delay.[28]
    • In addition, OS, disease-free survival, relapse, and nonrelapse mortality were similar between the two cohorts.
    • The only factor associated with poor outcome in the cohort that received imatinib was a poor initial response to imatinib.
  2. Further evidence for a lack of effect of pretransplant imatinib on posttransplant outcomes was supplied by a report from the Center for International Blood and Marrow Transplant Research; this report compared outcomes of 181 pediatric and adult subjects with CML in first chronic phase treated with imatinib before HSCT with that of 657 subjects who did not receive imatinib before HSCT.[29]
    • Among the patients in first chronic phase, imatinib therapy before HSCT was associated with better OS.
  3. A third report of imatinib followed by allogeneic HSCT supports the efficacy of this transplantation strategy in patients with imatinib failure in first chronic phase.[13]
    • The 3-year OS rate was 94% for this group (n = 37), with approximately 90% achieving a complete molecular remission after HSCT.
For adult patients treated with a TKI alone (without HSCT), the optimal duration of therapy remains unknown and most patients continue TKI treatment indefinitely.
Evidence (length of imatinib therapy in adults):
  1. In an attempt to answer the question of length of treatment, a prospective study reported on 69 adults treated with imatinib for more than 2 years who had been in a cytogenetic major response for more than 2 years. The patients were monitored monthly and restarted on imatinib if there was evidence of molecular relapse.[30]
    • Of this group, 61% experienced disease relapse, with about 38% still in cytogenetic major response at 24 months.
    • Of note, all of the patients who had disease recurrence responded again to the reinitiation of imatinib.
  2. Another study reported on 40 chronic-phase CML patients who stopped treatment with imatinib after at least 2 years of sustained undetectable minimal residual disease (MRD) by polymerase chain reaction (PCR).[31]
    • At 24 months, the probability of sustained molecular remission for patients no longer receiving imatinib was 47.1%.
    • Most relapses occurred within 4 months of stopping treatment with imatinib, and no relapses beyond 27 months were observed.
    • All patients with molecular relapse demonstrated a favorable response when imatinib was restarted; with a median follow-up of 42 months, no patients had progressive disease or developed the BCR-ABL fusion.
Additional research is required before cessation of imatinib or other BCR-ABL targeted therapy for selected patients with CML in molecular remission can be recommended as a standard clinical practice.

Treatment of Childhood CML

Treatment options for children with CML may include the following:
  1. Tyrosine kinase inhibitor, such as imatinib.
Imatinib has shown a high level of activity in children with CML that is comparable with the activity observed in adults.[32-36]
Evidence (imatinib in children):
  1. In a prospective trial, 44 pediatric patients with newly diagnosed CML were treated with imatinib (260 mg/day).[36]
    • The PFS rate at 36 months was 98%.
    • A complete hematologic response was achieved in 98% of the patients.
    • The rate of complete cytogenetic response was 61% and the rate of major molecular response was 31% at 12 months, similar to the rates seen in adult chronic-phase CML patients treated with imatinib.
As a result of this high level of activity, it is common to initiate imatinib treatment in children with CML rather than proceeding immediately to allogeneic stem cell transplantation.[37] The pharmacokinetics of imatinib in children appears consistent with previous results in adults.[38]
Doses of imatinib used in phase II trials for children with CML have ranged from 260 mg/m2 to 340 mg/m2, which provide comparable drug exposures as the adult flat-doses of 400 mg to 600 mg.[34-36]
Evidence (imatinib dose in children):
  1. In an Italian study of 47 pediatric chronic-phase CML patients treated with 340 mg/m2per day of imatinib, complete cytogenetic response was achieved in 91.5% of patients at a median time of 6 months, and the rate of major molecular response at 12 months was 66.6%.[36]
    Thus, it appears that starting with the higher dose of 340 mg/m2 has superior efficacy and is typically tolerable, with dose adjustment as needed for toxicity.[35,36]
  2. Early molecular responses, such as PCR-based MRD measurement at 3 months of therapy showing up to 10% BCR-ABL1/ABL, have been reported to be associated with improved PFS, similar to early molecular response data in adults.[39]
The monitoring guidelines described above for adults with CML are reasonable to use in children.
Imatinib is generally well tolerated in children, with adverse effects generally being mild to moderate and reversible with treatment discontinuation or dose reduction.[34,35] Growth retardation occurs in most prepubertal children receiving imatinib.[40] Children receiving imatinib and experiencing growth impairment may show some catch-up growth during their pubertal growth spurts, but they are at risk of having lower-than-expected adult height, as most patients do not achieve midparental height.[40,41]
There are fewer published data regarding the efficacy and toxicities of the two other TKIs approved by the FDA for use in children with CML—dasatinib and nilotinib.
Evidence (dasatinib in children):
  1. A phase I trial of dasatinib in children showed that drug disposition, tolerability, and efficacy of this agent was similar to that observed in adults.[42,43]
  2. A phase II trial of dasatinib, which included 84 children with newly diagnosed CML in chronic phase, utilized a dose of 60 mg/m2 (tablets) or 72 mg/m2 (oral solution) given to patients once daily.[44]
    • Complete cytogenetic response and major molecular response (≥3-log reduction or ≤0.1% on the International Scale) were achieved in 92% and 52% of patients, respectively, after 12 months of therapy, with a 4-year PFS of 93%.
    • Dasatinib was well tolerated, with very few grade 3 or grade 4 adverse events. No pleural or pericardial effusions or pulmonary complications were observed.
Evidence (nilotinib in children):
  1. The approval of nilotinib by the FDA in March 2018 for the treatment of children with CML was based on two sponsored trials.[45,46] An initial study (NCT01077544[CAMN107A2120]) of 11 patients evaluated pharmacokinetic, safety, and preliminary efficacy data; a second study (NCT01844765 [CAMN107A2203; AAML1321]) of 58 patients evaluated efficacy and safety. Data from both studies were combined for a pooled-data analysis of 69 patients, which included 25 patients with newly diagnosed CML and 44 patients with resistant or intolerant CML. Both studies utilized a dose of 230 mg/m2 given twice daily (rounded to the nearest 50 mg; maximum dose, 400 mg).[45]
    • Sixty percent of patients with newly diagnosed CML achieved a major molecular response at 1 year, with one patient experiencing progression.
    • The tolerability of nilotinib in children was similar to that observed in adults. Primary side effects affecting more than 30% of children included headache, fever, and hyperbilirubinemia.
    • Prolongation of QTc interval (defined in this trial as an increase of >30 msec over baseline) is a recognized side effect of nilotinib, and it was observed in 25% of children in these trials. The investigators recommend obtaining an electrocardiogram at baseline, 1 week, periodically afterward, and after dose adjustments.
A safe pediatric dose has not yet been established for other TKIs (e.g., bosutinib and ponatinib).

Treatment of Recurrent or Refractory Childhood CML

Treatment options for children with recurrent or refractory CML may include the following:
  1. Alternative kinase inhibitors such as dasatinib or nilotinib.
  2. Allogeneic HSCT.
In children who develop a hematologic or cytogenetic relapse during treatment with imatinib or who have an inadequate initial response to imatinib, determination of BCR-ABLkinase domain mutation status should be considered to help guide subsequent therapy. Depending on the patient’s mutation status, alternative kinase inhibitors such as dasatinib or nilotinib can be considered on the basis of the adult and pediatric experience with these agents.[21,22,44,47-49]
Evidence (dasatinib in children with resistant or intolerant CML):
  1. In 14 children with resistant or intolerant CML, 76% of patients were in complete cytogenetic remission, and 41% of patients had a major molecular response after 12 months of dasatinib therapy. PFS was 78% at 48 months.[44]
Evidence (nilotinib in children with resistant or intolerant CML):
  1. In 44 children with CML who were resistant or intolerant to imatinib or dasatinib, 40.7% of patients achieved a major molecular response after 12 months of nilotinib therapy. After a median of 11.3 months, no patients had experienced disease progression.[45]
Dasatinib and nilotinib are active against many BCR-ABL mutations that confer resistance to imatinib, although the agents are ineffective in patients with the T315I mutation. In the presence of the T315I mutation, which is resistant to all FDA-approved kinase inhibitors, an allogeneic transplant should be considered.
The question of whether a pediatric patient with CML should receive an allogeneic transplant when multiple TKIs are available remains unanswered; however, reports suggest that PFS does not improve when using HSCT, compared with the sustained use of imatinib.[36] The potential advantages and disadvantages need to be discussed with the patient and family. While HSCT is currently the only known definitive curative therapy for CML, patients discontinuing treatment with TKIs after sustained molecular remissions, who remained in molecular remission, have been reported.[31]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
References
  1. Ries LA, Smith MA, Gurney JG, et al., eds.: Cancer incidence and survival among children and adolescents: United States SEER Program 1975-1995. Bethesda, Md: National Cancer Institute, SEER Program, 1999. NIH Pub.No. 99-4649. Also available online. Last accessed February 07, 2019.
  2. Quintás-Cardama A, Cortes J: Molecular biology of bcr-abl1-positive chronic myeloid leukemia. Blood 113 (8): 1619-30, 2009. [PUBMED Abstract]
  3. O'Dwyer ME, Mauro MJ, Kurilik G, et al.: The impact of clonal evolution on response to imatinib mesylate (STI571) in accelerated phase CML. Blood 100 (5): 1628-33, 2002. [PUBMED Abstract]
  4. Millot F, Esperou H, Bordigoni P, et al.: Allogeneic bone marrow transplantation for chronic myeloid leukemia in childhood: a report from the Société Française de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC). Bone Marrow Transplant 32 (10): 993-9, 2003. [PUBMED Abstract]
  5. Cwynarski K, Roberts IA, Iacobelli S, et al.: Stem cell transplantation for chronic myeloid leukemia in children. Blood 102 (4): 1224-31, 2003. [PUBMED Abstract]
  6. Weisdorf DJ, Anasetti C, Antin JH, et al.: Allogeneic bone marrow transplantation for chronic myelogenous leukemia: comparative analysis of unrelated versus matched sibling donor transplantation. Blood 99 (6): 1971-7, 2002. [PUBMED Abstract]
  7. Lee SJ, Klein J, Haagenson M, et al.: High-resolution donor-recipient HLA matching contributes to the success of unrelated donor marrow transplantation. Blood 110 (13): 4576-83, 2007. [PUBMED Abstract]
  8. Horowitz MM, Gale RP, Sondel PM, et al.: Graft-versus-leukemia reactions after bone marrow transplantation. Blood 75 (3): 555-62, 1990. [PUBMED Abstract]
  9. Druker BJ: Translation of the Philadelphia chromosome into therapy for CML. Blood 112 (13): 4808-17, 2008. [PUBMED Abstract]
  10. Kantarjian H, Sawyers C, Hochhaus A, et al.: Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N Engl J Med 346 (9): 645-52, 2002. [PUBMED Abstract]
  11. O'Brien SG, Guilhot F, Larson RA, et al.: Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 348 (11): 994-1004, 2003. [PUBMED Abstract]
  12. Druker BJ, Guilhot F, O'Brien SG, et al.: Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med 355 (23): 2408-17, 2006. [PUBMED Abstract]
  13. Saussele S, Lauseker M, Gratwohl A, et al.: Allogeneic hematopoietic stem cell transplantation (allo SCT) for chronic myeloid leukemia in the imatinib era: evaluation of its impact within a subgroup of the randomized German CML Study IV. Blood 115 (10): 1880-5, 2010. [PUBMED Abstract]
  14. Hughes TP, Hochhaus A, Branford S, et al.: Long-term prognostic significance of early molecular response to imatinib in newly diagnosed chronic myeloid leukemia: an analysis from the International Randomized Study of Interferon and STI571 (IRIS). Blood 116 (19): 3758-65, 2010. [PUBMED Abstract]
  15. Kantarjian H, Cortes J: Considerations in the management of patients with Philadelphia chromosome-positive chronic myeloid leukemia receiving tyrosine kinase inhibitor therapy. J Clin Oncol 29 (12): 1512-6, 2011. [PUBMED Abstract]
  16. Bisen A, Claxton DF: Tyrosine kinase targeted treatment of chronic myelogenous leukemia and other myeloproliferative neoplasms. Adv Exp Med Biol 779: 179-96, 2013. [PUBMED Abstract]
  17. Ibrahim AR, Eliasson L, Apperley JF, et al.: Poor adherence is the main reason for loss of CCyR and imatinib failure for chronic myeloid leukemia patients on long-term therapy. Blood 117 (14): 3733-6, 2011. [PUBMED Abstract]
  18. Soverini S, Hochhaus A, Nicolini FE, et al.: BCR-ABL kinase domain mutation analysis in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors: recommendations from an expert panel on behalf of European LeukemiaNet. Blood 118 (5): 1208-15, 2011. [PUBMED Abstract]
  19. Hazarika M, Jiang X, Liu Q, et al.: Tasigna for chronic and accelerated phase Philadelphia chromosome--positive chronic myelogenous leukemia resistant to or intolerant of imatinib. Clin Cancer Res 14 (17): 5325-31, 2008. [PUBMED Abstract]
  20. Brave M, Goodman V, Kaminskas E, et al.: Sprycel for chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia resistant to or intolerant of imatinib mesylate. Clin Cancer Res 14 (2): 352-9, 2008. [PUBMED Abstract]
  21. Kantarjian H, Shah NP, Hochhaus A, et al.: Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 362 (24): 2260-70, 2010. [PUBMED Abstract]
  22. Saglio G, Kim DW, Issaragrisil S, et al.: Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med 362 (24): 2251-9, 2010. [PUBMED Abstract]
  23. Jabbour E, Kantarjian HM, Saglio G, et al.: Early response with dasatinib or imatinib in chronic myeloid leukemia: 3-year follow-up from a randomized phase 3 trial (DASISION). Blood 123 (4): 494-500, 2014. [PUBMED Abstract]
  24. Hochhaus A, Saglio G, Hughes TP, et al.: Long-term benefits and risks of frontline nilotinib vs imatinib for chronic myeloid leukemia in chronic phase: 5-year update of the randomized ENESTnd trial. Leukemia 30 (5): 1044-54, 2016. [PUBMED Abstract]
  25. O'Hare T, Shakespeare WC, Zhu X, et al.: AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance. Cancer Cell 16 (5): 401-12, 2009. [PUBMED Abstract]
  26. Cortes JE, Kim DW, Pinilla-Ibarz J, et al.: A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias. N Engl J Med 369 (19): 1783-96, 2013. [PUBMED Abstract]
  27. Prasad V, Mailankody S: The accelerated approval of oncologic drugs: lessons from ponatinib. JAMA 311 (4): 353-4, 2014 Jan 22-29. [PUBMED Abstract]
  28. Oehler VG, Gooley T, Snyder DS, et al.: The effects of imatinib mesylate treatment before allogeneic transplantation for chronic myeloid leukemia. Blood 109 (4): 1782-9, 2007. [PUBMED Abstract]
  29. Lee SJ, Kukreja M, Wang T, et al.: Impact of prior imatinib mesylate on the outcome of hematopoietic cell transplantation for chronic myeloid leukemia. Blood 112 (8): 3500-7, 2008. [PUBMED Abstract]
  30. Mahon FX, Réa D, Guilhot J, et al.: Discontinuation of imatinib in patients with chronic myeloid leukaemia who have maintained complete molecular remission for at least 2 years: the prospective, multicentre Stop Imatinib (STIM) trial. Lancet Oncol 11 (11): 1029-35, 2010. [PUBMED Abstract]
  31. Ross DM, Branford S, Seymour JF, et al.: Safety and efficacy of imatinib cessation for CML patients with stable undetectable minimal residual disease: results from the TWISTER study. Blood 122 (4): 515-22, 2013. [PUBMED Abstract]
  32. Champagne MA, Capdeville R, Krailo M, et al.: Imatinib mesylate (STI571) for treatment of children with Philadelphia chromosome-positive leukemia: results from a Children's Oncology Group phase 1 study. Blood 104 (9): 2655-60, 2004. [PUBMED Abstract]
  33. Millot F, Guilhot J, Nelken B, et al.: Imatinib mesylate is effective in children with chronic myelogenous leukemia in late chronic and advanced phase and in relapse after stem cell transplantation. Leukemia 20 (2): 187-92, 2006. [PUBMED Abstract]
  34. Millot F, Baruchel A, Guilhot J, et al.: Imatinib is effective in children with previously untreated chronic myelogenous leukemia in early chronic phase: results of the French national phase IV trial. J Clin Oncol 29 (20): 2827-32, 2011. [PUBMED Abstract]
  35. Champagne MA, Fu CH, Chang M, et al.: Higher dose imatinib for children with de novo chronic phase chronic myelogenous leukemia: a report from the Children's Oncology Group. Pediatr Blood Cancer 57 (1): 56-62, 2011. [PUBMED Abstract]
  36. Giona F, Putti MC, Micalizzi C, et al.: Long-term results of high-dose imatinib in children and adolescents with chronic myeloid leukaemia in chronic phase: the Italian experience. Br J Haematol 170 (3): 398-407, 2015. [PUBMED Abstract]
  37. Andolina JR, Neudorf SM, Corey SJ: How I treat childhood CML. Blood 119 (8): 1821-30, 2012. [PUBMED Abstract]
  38. Menon-Andersen D, Mondick JT, Jayaraman B, et al.: Population pharmacokinetics of imatinib mesylate and its metabolite in children and young adults. Cancer Chemother Pharmacol 63 (2): 229-38, 2009. [PUBMED Abstract]
  39. Millot F, Guilhot J, Baruchel A, et al.: Impact of early molecular response in children with chronic myeloid leukemia treated in the French Glivec phase 4 study. Blood 124 (15): 2408-10, 2014. [PUBMED Abstract]
  40. Shima H, Tokuyama M, Tanizawa A, et al.: Distinct impact of imatinib on growth at prepubertal and pubertal ages of children with chronic myeloid leukemia. J Pediatr 159 (4): 676-81, 2011. [PUBMED Abstract]
  41. Millot F, Guilhot J, Baruchel A, et al.: Growth deceleration in children treated with imatinib for chronic myeloid leukaemia. Eur J Cancer 50 (18): 3206-11, 2014. [PUBMED Abstract]
  42. Aplenc R, Blaney SM, Strauss LC, et al.: Pediatric phase I trial and pharmacokinetic study of dasatinib: a report from the children's oncology group phase I consortium. J Clin Oncol 29 (7): 839-44, 2011. [PUBMED Abstract]
  43. Zwaan CM, Rizzari C, Mechinaud F, et al.: Dasatinib in children and adolescents with relapsed or refractory leukemia: results of the CA180-018 phase I dose-escalation study of the Innovative Therapies for Children with Cancer Consortium. J Clin Oncol 31 (19): 2460-8, 2013. [PUBMED Abstract]
  44. Gore L, Kearns PR, de Martino ML, et al.: Dasatinib in Pediatric Patients With Chronic Myeloid Leukemia in Chronic Phase: Results From a Phase II Trial. J Clin Oncol 36 (13): 1330-1338, 2018. [PUBMED Abstract]
  45. Novartis Pharmaceuticals Corporation: TASIGNA (nilotinib): Prescribing Information. East Hanover, NJ: Novartis, 2018. Available online. Last accessed April 11, 2019.
  46. Hijiya N, Maschan A, Rizzari C, et al.: Efficacy and safety of nilotinib in pediatric patients with Philadelphia chromosome–positive (PH+) chronic myeloid leukemia (CML): results from a PHASE 2 trial. [Abstract] Pediatr Blood Cancer 64 (Suppl 3): A-O-032, 2017. Also available online. Last accessed April 11, 2019.
  47. Hochhaus A, Baccarani M, Deininger M, et al.: Dasatinib induces durable cytogenetic responses in patients with chronic myelogenous leukemia in chronic phase with resistance or intolerance to imatinib. Leukemia 22 (6): 1200-6, 2008. [PUBMED Abstract]
  48. le Coutre P, Ottmann OG, Giles F, et al.: Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is active in patients with imatinib-resistant or -intolerant accelerated-phase chronic myelogenous leukemia. Blood 111 (4): 1834-9, 2008. [PUBMED Abstract]
  49. Kantarjian H, O'Brien S, Talpaz M, et al.: Outcome of patients with Philadelphia chromosome-positive chronic myelogenous leukemia post-imatinib mesylate failure. Cancer 109 (8): 1556-60, 2007. [PUBMED Abstract]

Special Considerations for the Treatment of Children With Cancer

Cancer in children and adolescents is rare, although the overall incidence of childhood cancer has been slowly increasing since 1975.[1] Children and adolescents with cancer should be referred to medical centers that have a multidisciplinary team of cancer specialists with experience treating the cancers that occur during childhood and adolescence.[2] This multidisciplinary team approach incorporates the skills of the following pediatric specialists and others to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life.
  • Primary care physicians.
  • Pediatric surgical subspecialists.
  • Radiation oncologists.
  • Pediatric medical oncologists/hematologists.
  • Rehabilitation specialists.
  • Pediatric nurse specialists.
  • Social workers.
(Refer to the PDQ Supportive and Palliative Care summaries for specific information about supportive care for children and adolescents with cancer.)
Guidelines for pediatric cancer centers and their role in the treatment of children with cancer have been outlined by the American Academy of Pediatrics.[3] At these pediatric cancer centers, clinical trials are available for most types of cancer that occur in children and adolescents, and the opportunity to participate in these trials is offered to most patients and their families. Clinical trials for children and adolescents with cancer are generally designed to compare potentially better therapy with therapy that is currently accepted as standard. Most of the progress made in identifying curative therapies for childhood cancers has been achieved through clinical trials. Information about ongoing clinical trials is available from the NCI website.
References
  1. Smith MA, Altekruse SF, Adamson PC, et al.: Declining childhood and adolescent cancer mortality. Cancer 120 (16): 2497-506, 2014. [PUBMED Abstract]
  2. Wolfson J, Sun CL, Wyatt L, et al.: Adolescents and Young Adults with Acute Lymphoblastic Leukemia and Acute Myeloid Leukemia: Impact of Care at Specialized Cancer Centers on Survival Outcome. Cancer Epidemiol Biomarkers Prev 26 (3): 312-320, 2017. [PUBMED Abstract]
  3. Corrigan JJ, Feig SA; American Academy of Pediatrics: Guidelines for pediatric cancer centers. Pediatrics 113 (6): 1833-5, 2004. [PUBMED Abstract]

Survivorship and Adverse Late Sequelae

While the issues of long-term complications of cancer and its treatment cross many disease categories, several important issues related to the treatment of myeloid malignancies are worth emphasizing. (Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for more information.)
Selected studies of the late effects of AML therapy in adult survivors who were not treated with hematopoietic stem cell transplant (HSCT) include the following:
  1. Cardiac.
    1. The Children’s Cancer Survivor Study examined 272 survivors of childhood acute myeloid leukemia (AML) who did not undergo a HSCT.[1]
      • This study identified second malignancies (cumulative incidence, 1.7%) and cardiac toxic effects (cumulative incidence, 4.7%) as significant long-term risks.
      • Cardiomyopathy has been reported in 4.3% of survivors of AML based on Berlin-Frankfurt-Münster studies. Of these, 2.5% showed clinical symptoms.[2]
    2. A retrospective study of cardiac function of children treated with United Kingdom Medical Research Council–based regimens at a median of 13 months after treatment reported a mean detrimental change in left ventricular stroke volume of 8.4% compared with baseline values.[3]
    3. For pediatric patients, the risk of developing early toxicity was 13.7%, and the risk of developing late cardiac toxic effects (defined as 1 year after completing first-line therapy) was 17.4%. Early cardiac toxic effects was a significant predictor of late cardiac toxic effects and the development of clinical cardiomyopathy requiring long-term therapy.[4]
    4. Retrospective analysis of a single study suggests cardiac risk may be increased in children with Down syndrome,[5] but prospective studies are required to confirm this finding.
  2. Psychosocial.
    1. A Nordic Society for Pediatric Hematology and Oncology retrospective trial of children with AML treated with chemotherapy only at a median follow-up of 11 years, based on self-reported uses of health care services, demonstrated similar health care usage and marital status as their siblings.[6]
    2. A population-based study of survivors of childhood AML who had not undergone an HSCT reported equivalent rates of educational achievement, employment, and marital status compared with siblings. AML survivors were, however, significantly more likely to be receiving prescription drugs, especially for asthma, than were siblings (23% vs. 9%; P = .03). Chronic fatigue has also been demonstrated to be a significantly more likely adverse late effect in survivors of childhood AML than in survivors of other malignancies.[7]
Renal, gastrointestinal, and hepatic late adverse effects have been reported to be rare for children undergoing chemotherapy only for treatment of AML.[8]
Selected studies of the late effects of AML therapy in adult survivors who were treated with HSCT include the following:
  1. In a review from one institution, the highest frequency of adverse long-term sequelae for children treated for AML included the following incidence rates: growth abnormalities (51%), neurocognitive abnormalities (30%), transfusion-acquired hepatitis (28%), infertility (25%), endocrinopathies (16%), restrictive lung disease (20%), chronic graft-versus-host disease (20%), secondary malignancies (14%), and cataracts (12%).[9]
    • Most of these adverse sequelae are the consequence of myeloablative, allogeneic HSCT. Although cardiac abnormalities were reported in 8% of patients, this is an issue that may be particularly relevant with the current use of increased anthracyclines in clinical trials for children with newly diagnosed AML.
  2. Another study examined outcomes for children younger than 3 years with AML or acute lymphoblastic leukemia (ALL) who underwent HSCT.[10]
    • The toxicities reported include growth hormone deficiency (59%), dyslipidemias (59%), hypothyroidism (35%), osteochondromas (24%), and decreased bone mineral density (24%).
    • Two of the 33 patients developed secondary malignancies
    • Survivors had average intelligence but frequent attention-deficit problems and fine-movement abnormalities, compared with population controls.
  3. In contrast, The Bone Marrow Transplant Survivor Study compared childhood AML or ALL survivors with siblings using a self-reporting questionnaire.[11] The median follow-up was 8.4 years, and 86% of patients received total-body irradiation (TBI) as part of their preparative transplant regimen.
    • Survivors of leukemia who received an HSCT had significantly higher frequencies of several adverse effects, including diabetes, hypothyroidism, osteoporosis, cataracts, osteonecrosis, exercise-induced shortness of breath, neurosensory impairments, and problems with balance, tremor, and weakness than did siblings.
    • The overall assessment of health was significantly decreased in survivors compared with siblings (odds ratio, 2.2; P = .03).
    • Significant differences were not observed between regimens using TBI compared with chemotherapy only, which mostly included busulfan.
    • The outcomes were similar for patients with AML and ALL, suggesting that the primary cause underlying the adverse late effects was undergoing an HSCT.
  4. A Children's Oncology Group (COG) study using a health-related, quality-of-life comparison reported an overall 21% of 5-year survivors having a severe or life-threatening chronic health condition; when compared by type of treatment, this percentage was 16% for the chemotherapy-only treated group, 21% for the autologous HSCT treated group, and 33% for those who received an allogeneic HSCT.[12]
New therapeutic approaches to reduce long-term adverse sequelae are needed, especially for reducing the late sequelae associated with myeloablative HSCT.
Important resources for details on follow-up and risks for survivors of cancer have been developed, including the COG’s Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers and the National Comprehensive Cancer Network's Guidelines for Acute Myeloid Leukemia. Furthermore, having access to past medical history that can be shared with subsequent medical providers has become increasingly recognized as important for cancer survivors.
References
  1. Mulrooney DA, Dover DC, Li S, et al.: Twenty years of follow-up among survivors of childhood and young adult acute myeloid leukemia: a report from the Childhood Cancer Survivor Study. Cancer 112 (9): 2071-9, 2008. [PUBMED Abstract]
  2. Creutzig U, Diekamp S, Zimmermann M, et al.: Longitudinal evaluation of early and late anthracycline cardiotoxicity in children with AML. Pediatr Blood Cancer 48 (7): 651-62, 2007. [PUBMED Abstract]
  3. Orgel E, Zung L, Ji L, et al.: Early cardiac outcomes following contemporary treatment for childhood acute myeloid leukemia: a North American perspective. Pediatr Blood Cancer 60 (9): 1528-33, 2013. [PUBMED Abstract]
  4. Temming P, Qureshi A, Hardt J, et al.: Prevalence and predictors of anthracycline cardiotoxicity in children treated for acute myeloid leukaemia: retrospective cohort study in a single centre in the United Kingdom. Pediatr Blood Cancer 56 (4): 625-30, 2011. [PUBMED Abstract]
  5. O'Brien MM, Taub JW, Chang MN, et al.: Cardiomyopathy in children with Down syndrome treated for acute myeloid leukemia: a report from the Children's Oncology Group Study POG 9421. J Clin Oncol 26 (3): 414-20, 2008. [PUBMED Abstract]
  6. Molgaard-Hansen L, Glosli H, Jahnukainen K, et al.: Quality of health in survivors of childhood acute myeloid leukemia treated with chemotherapy only: a NOPHO-AML study. Pediatr Blood Cancer 57 (7): 1222-9, 2011. [PUBMED Abstract]
  7. Jóhannsdóttir IM, Hjermstad MJ, Moum T, et al.: Increased prevalence of chronic fatigue among survivors of childhood cancers: a population-based study. Pediatr Blood Cancer 58 (3): 415-20, 2012. [PUBMED Abstract]
  8. Skou AS, Glosli H, Jahnukainen K, et al.: Renal, gastrointestinal, and hepatic late effects in survivors of childhood acute myeloid leukemia treated with chemotherapy only--a NOPHO-AML study. Pediatr Blood Cancer 61 (9): 1638-43, 2014. [PUBMED Abstract]
  9. Leung W, Hudson MM, Strickland DK, et al.: Late effects of treatment in survivors of childhood acute myeloid leukemia. J Clin Oncol 18 (18): 3273-9, 2000. [PUBMED Abstract]
  10. Perkins JL, Kunin-Batson AS, Youngren NM, et al.: Long-term follow-up of children who underwent hematopoeitic cell transplant (HCT) for AML or ALL at less than 3 years of age. Pediatr Blood Cancer 49 (7): 958-63, 2007. [PUBMED Abstract]
  11. Baker KS, Ness KK, Weisdorf D, et al.: Late effects in survivors of acute leukemia treated with hematopoietic cell transplantation: a report from the Bone Marrow Transplant Survivor Study. Leukemia 24 (12): 2039-47, 2010. [PUBMED Abstract]
  12. Schultz KA, Chen L, Chen Z, et al.: Health conditions and quality of life in survivors of childhood acute myeloid leukemia comparing post remission chemotherapy to BMT: a report from the children's oncology group. Pediatr Blood Cancer 61 (4): 729-36, 2014. [PUBMED Abstract]

Changes to This Summary (04/12/2019)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
Classification of Pediatric Myeloid Malignancies
The WHO Classification of Bone Marrow and Peripheral Blood Findings for Myelodysplastic Syndromes subsection was extensively revised.
Histochemical, Immunophenotypic, and Molecular Evaluation for Childhood Acute Myeloid Leukemia (AML)
Revised text to state that comprehensive molecular profiling of pediatric and adult AML has shown that AML is a disease demonstrating both commonalities and differences across the age spectrum.
Added text about the genomic differences between pediatric and adult AML.
Added text about RUNX1 mutations in AML patients, including the results of a study of children with AML and RUNX1 mutations (cited Yamato et al. as reference 153).
Treatment of Childhood AML
Added text about the results of the prospective COG ACCL0934 trial for children with acute leukemia receiving intensive chemotherapy who were randomly assigned to receive levofloxacin or no prophylactic antibiotic during the period of neutropenia in one to two cycles of chemotherapy (cited Alexander et al. and Taplitz et al. as references 39 and 40, respectively).
Added Cardiac monitoring as a new subsection.
Myelodysplastic Syndromes (MDS)
The Molecular Abnormalities subsection was extensively revised.
Juvenile Myelomonocytic Leukemia (JMML)
Revised text to state that although mutations among five genes are generally mutually exclusive, 4% to 17% of cases have mutations in two of these Ras pathway genes, a finding that is associated with poorer prognosis (cited Murakami et al. as reference 19).
Added text to state that the presence of mutations beyond disease-defining Ras pathway mutations is associated with an inferior prognosis.
Added text about a report that described the genomic landscape of JMML and found that 16 of 150 patients lacked canonical Ras pathway mutations.
Added text to state that a study observed that approximately 60% of patients had one or more additional mutations beyond their disease-defining Ras pathway mutation. These patients had an inferior overall survival (OS) compared with patients who had no additional mutations. Also added text to state that a third study observed a trend for an inferior OS for patients with two or more mutations compared with patients with zero or one mutation.
Added text about Ras pathway double mutations, including the outcome results of two studies that identified Ras pathway double mutations in patients with JMML.
Added text about DNA methylation profiling, including the results of two studies that investigated the methylation statuses in cohorts of patients with JMML (cited Stieglitz et al. as reference 25).
Added text to state that a study also observed a subset of JMML patients with elevated LIN28B expression and identified LIN28B as the gene for which expression was most strongly associated with hypermethylation status.
This summary is written and maintained by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood acute myeloid leukemia and other myeloid malignancies. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
  • be discussed at a meeting,
  • be cited with text, or
  • replace or update an existing article that is already cited.
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewers for Childhood Acute Myeloid Leukemia/Other Myeloid Malignancies Treatment are:
  • Alan Scott Gamis, MD, MPH (Children's Mercy Hospital)
  • Karen J. Marcus, MD (Dana-Farber Cancer Institute/Boston Children's Hospital)
  • Michael A. Pulsipher, MD (Children's Hospital Los Angeles)
  • Lewis B. Silverman, MD (Dana-Farber Cancer Institute/Boston Children's Hospital)
  • Malcolm A. Smith, MD, PhD (National Cancer Institute)
Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

Permission to Use This Summary

PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”
The preferred citation for this PDQ summary is:
PDQ® Pediatric Treatment Editorial Board. PDQ Childhood Acute Myeloid Leukemia/Other Myeloid Malignancies Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/leukemia/hp/child-aml-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389454]
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Based on the strength of the available evidence, treatment options may be described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.

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  • Updated: April 12, 2019
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