martes, 27 de agosto de 2019

Childhood Acute Myeloid Leukemia/Other Myeloid Malignancies Treatment (PDQ®)–Health Professional Version - National Cancer Institute 11/11

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


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
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  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]
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  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]
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  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]
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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 CancersExit Disclaimer and the National Comprehensive Cancer Network's Guidelines for Acute Myeloid LeukemiaExit Disclaimer. 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 (08/20/2019)

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.
Transient Abnormal Myelopoiesis (TAM) or Children With Down Syndrome and AML
Revised text about the use of low-dose cytarabine to consistently reduce TAM complications and related mortality (cited Flasinski et al. as reference 8 and level of evidence 2Di).
Added text about the risks and prevention of the subsequent development of myeloid leukemia associated with Down syndrome in children who have a spontaneous remission of TAM.
Juvenile Myelomonocytic Leukemia (JMML)
The Genomics of JMML subsection was reformatted.
The Prognosis (Clinical Factors) subsection was reformatted.
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, FACR (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]
Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.

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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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