martes, 8 de octubre de 2019

Childhood Acute Myeloid Leukemia/Other Myeloid Malignancies Treatment (PDQ®)–Health Professional Version - National Cancer Institute 5/8

Childhood Acute Myeloid Leukemia/Other Myeloid Malignancies 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-AAML0631 trial.

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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