martes, 16 de abril de 2019

Childhood Acute Myeloid Leukemia Treatment (PDQ®) 2/3 —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


Treatment Option Overview for Childhood AML

Leukemia is considered to be disseminated in the hematopoietic system at diagnosis, even in children with acute myeloid leukemia (AML) who present with isolated chloromas (also called granulocytic or myeloid sarcomas). If these children do not receive systemic chemotherapy, they invariably develop AML in months or years. AML may invade nonhematopoietic (extramedullary) tissue such as meninges, brain parenchyma, testes or ovaries, or skin (leukemia cutis). Extramedullary leukemia is more common in infants than in older children with AML.[1]
Childhood AML is diagnosed when bone marrow has 20% or greater blasts. The blasts have the morphologic and histochemical characteristics of one of the French-American-British (FAB) subtypes of AML. It can also be diagnosed by biopsy of a chloroma. For treatment purposes, patients with clonal cytogenetic abnormalities typically associated with AML, such as t(8;21)(RUNX1-RUNX1T1), inv(16)(CBFB-MYH11), t(9;11)(MLLT3-KMT2A) or t(15;17)(PML-RARA) and who have less than 20% bone marrow blasts, are considered to have AML rather than a myelodysplastic syndrome.[2]
Complete remission (CR) has traditionally been defined in the United States using morphologic criteria such as the following:
  • Peripheral blood counts (white blood cell [WBC] count, differential [absolute neutrophil count >1,000/μL], and platelet count >100,000/μL) rising toward normal.
  • Mildly hypocellular to normal cellular marrow with fewer than 5% blasts.
  • No clinical signs or symptoms of the disease, including in the central nervous system (CNS) or at other extramedullary sites.[3]
Alternative definitions of remission using morphology are used in AML because of the prolonged myelosuppression caused by intensive chemotherapy and include CR with incomplete platelet recovery and CR with incomplete marrow recovery (typically absolute neutrophil count). Whereas the use of incomplete platelet recovery provides a clinically meaningful response, the traditional CR definition remains the gold standard because patients in CR were found to be more likely to survive longer than those in incomplete platelet recovery.[4]
Achieving a hypoplastic bone marrow (using morphology) is usually the first step in obtaining remission in AML with the exception of the M3 subtype (acute promyelocytic leukemia [APL]); a hypoplastic marrow phase is often not necessary before the achievement of remission in APL. Additionally, early recovery marrows in any of the subtypes of AML may be difficult to distinguish from persistent leukemia, although the application of flow cytometric immunophenotyping and cytogenetic/molecular testing have made this less problematic. Correlation with blood cell counts and clinical status is imperative in passing final judgment on the results of early bone marrow findings in AML.[5] If the findings are in doubt, the bone marrow aspirate should be repeated in 1 to 2 weeks.[1]
In addition to morphology, more precise methodology (e.g., multiparameter flow cytometry or quantitative reverse transcriptase–polymerase chain reaction [RT-PCR]) is used to assess response and has been shown to be of greater prognostic significance than morphology. (Refer to the Prognostic Factors in Childhood AML section of this summary for more information about these methodologies.)

Treatment Approach

The mainstay of the therapeutic approach is systemically administered combination chemotherapy.[6] Approaches involving risk-group stratification and biologically targeted therapies are being tested to improve antileukemic treatment while sparing normal tissue.[7] Optimal treatment of AML requires control of bone marrow and systemic disease. Treatment of the CNS, usually with intrathecal medication, is a component of most pediatric AML protocols but has not yet been shown to contribute directly to an improvement in survival. CNS irradiation is not necessary in patients, either as prophylaxis or for those presenting with cerebrospinal fluid leukemia that clears with intrathecal and systemic chemotherapy.
Treatment is ordinarily divided into the following two phases:
  • Induction (to induce remission).
  • Postremission consolidation/intensification (to reduce the risk of relapse).
Postremission therapy may consist of varying numbers of courses of intensive chemotherapy and/or allogeneic hematopoietic stem cell transplantation (HSCT). For example, ongoing trials of the Children’s Oncology Group (COG) and the United Kingdom Medical Research Council (MRC) use similar chemotherapy regimens consisting of two courses of induction chemotherapy followed by two to three additional courses of intensification chemotherapy.[8,9]
Maintenance therapy is not part of most pediatric AML protocols because two randomized clinical trials failed to show a benefit for maintenance therapy when given after modern intensive chemotherapy.[10,11] The exception to this generalization is made for APL, because maintenance therapy was shown to improve event-free survival (EFS) and overall survival (OS) when all-trans retinoic acid (ATRA) was combined with chemotherapy.[12] Some studies of adult APL patients, including studies incorporating arsenic trioxide treatment, have shown no benefit to maintenance.[13,14]
Attention to both acute and long-term complications is critical in children with AML. Modern AML treatment approaches are usually associated with severe, protracted myelosuppression with related complications. Children with AML should receive care under the direction of pediatric oncologists in cancer centers or hospitals with appropriate supportive care facilities (e.g., specialized blood products; pediatric intensive care; provision of emotional and developmental support). With improved supportive care, toxic death constitutes a smaller proportion of initial therapy failures than in the past.[8] The most recent COG trials reported an 11% to 13% incidence of remission failure because of resistant disease and only 2% to 3% resulted from toxic death during the two induction courses.[15,16]
Children treated for AML are living longer and require close monitoring for cancer therapy side effects that may persist or develop months or years after treatment. The high cumulative doses of anthracyclines require long-term monitoring of cardiac function. The use of some modalities have declined, including total-body irradiation with HSCT because of its increased risk of growth failure, gonadal and thyroid dysfunction, cataract formation, and second malignancies.[17] (Refer to the Survivorship and Adverse Late Sequelae section of this summary or to the PDQ summary on Late Effects of Treatment for Childhood Cancerfor more information.)

Prognostic Factors in Childhood AML

Prognostic factors in childhood AML can be categorized as follows:

Host risk factors

  • Age: Several reports published since 2000 have identified older age as an adverse prognostic factor.[9,18-22] The age effect is not large with regard to overall survival, but there is consistency in the observation that any adverse outcomes seen in adolescents compared with younger children are primarily caused by increases in toxic mortality.[23]
    While outcome for infants with ALL remains inferior to that of older children, outcome for infants with AML is similar to that of older children when they are treated with standard AML regimens.[18,24-26] Infants have been reported to have a 5-year survival of 60% to 70%, although with increased treatment-associated toxicity, particularly during induction.[18,24-27]
  • Race/Ethnicity: In both the Children's Cancer Group (CCG) CCG-2891 and COG-2961 (NCT00002798) studies, Caucasian children had higher OS rates than African American and Hispanic children.[20,28] A trend for lower survival rates for African American children compared with Caucasian children was also observed in children treated on St. Jude Children’s Research Hospital AML clinical trials.[29]
  • Down syndrome: For children with Down syndrome who develop AML, survival is generally favorable.[30-32] The prognosis is particularly good (event-free survival exceeding 80%) for children younger than 4 years at diagnosis, the age group that accounts for the vast majority of Down syndrome patients with AML.[33-35]
  • Body mass index: In the COG-2961 (NCT00002798) study, obesity (body mass index more than 95th percentile for age) was predictive of inferior survival.[20,36] Inferior survival was attributable to early treatment-related mortality that was primarily caused by infectious complications.[36] Obesity has been associated with inferior survival in children with AML, primarily caused by a higher rate of fatal infections during the early phases of treatment.[37]

Leukemia risk factors

  • White blood cell (WBC) count: WBC count at diagnosis has been consistently noted to be inversely related to survival.[9,38-40] Patients with high presenting leukocyte counts have a higher risk of developing pulmonary and CNS complications and have a higher risk of induction death.[41]
    In APL, WBC at initial diagnosis alone is used to distinguish standard-risk and high-risk APL. A WBC count of 10,000 cells/μL or more denotes high risk, and these patients have an increased risk of both early death and relapse.[42]
  • FAB subtype: Associations between FAB subtype and prognosis have been more variable.
    • M3 subtype. The M3 (APL) subtype has a favorable outcome in studies using ATRA in combination with chemotherapy and arsenic trioxide consolidation.[42-45]
    • M7 subtype. Some studies have indicated a relatively poor outcome for M7 (megakaryocytic leukemia) in patients without Down syndrome,[30,46] although reports suggest an intermediate prognosis for this group of patients when contemporary treatment approaches are used.[8,47,48]
      In a retrospective study of non–Down syndrome M7 patients with samples available for molecular analysis, the presence of specific genetic abnormalities (CBFA2T3-GLIS2 [cryptic inv(16)(p13q24)], NUP98-KDM5A4 [JARIDIA], t(11;12)(p15;p13), KMT2A [MLL] rearrangements, monosomy 7) was associated with a significantly worse outcome than for other M7 patients.[49,50] By contrast, the 10% of non–Down syndrome AMKL patients with GATA1 mutations appeared to have a favorable outcome if there were no prognostically unfavorable fusion genes also present, as did patients with HOX-rearrangement.[50]
    • M0 subtype. The M0, or minimally differentiated subtype, has been associated with a poor outcome.[51]
  • CNS disease: CNS involvement at diagnosis is categorized on the basis of the presence or absence of blasts in cerebrospinal fluid (CSF), as follows:
    • CNS1: CSF negative for blasts on cytospin, regardless of CSF WBC count.
    • CNS2: CSF with fewer than five WBC/μL and cytospin positive for blasts.
    • CNS3: CSF with five or more WBC/μL and cytospin positive for blasts in an atraumatic (<100 RBC/μL) or a traumatic tap in which the WBC/RBC ratio in the CSF is more than or equal to twice the ratio in the peripheral blood. CNS3 disease also includes patients with clinical signs of CNS leukemia (e.g., cranial nerve palsy, brain/eye involvement, or radiographic evidence of an intracranial, intradural chloroma).
      CNS2 disease has been observed in approximately 13% to 16% of children with AML and CNS3 disease in 11% to 17% of children with AML.[52,53] Studies have variably shown that patients with CNS2/CNS3 were younger, more often had hyperleukocytosis, and had higher incidences of t(9;11), t(8;21), or inv(16).[52,53]
      While CNS involvement (CNS2 or CNS3) at diagnosis has not been shown to be correlated with OS in most studies, a COG analysis of children with AML enrolled from 2003 to 2010 on two consecutive and identical backbone trials found that CNS involvement, especially CNS3 status, was associated with inferior outcomes, including complete remission rate, EFS, disease-free survival, and an increased risk of relapse involving the CNS.[53] Another trial showed it to be associated with an increased risk of isolated CNS relapse.[54] Finally, the COG study did not find an adverse impact of traumatic lumbar punctures at diagnosis upon eventual outcome.[53]
  • Cytogenetic and molecular characteristics: Cytogenetic and molecular characteristics are also associated with prognosis. (Refer to the Molecular Evaluationsubsection in the Histochemical, Immunophenotypic, and Molecular Evaluation for Childhood AML section of this summary for detailed information.) Cytogenetic and molecular characteristics that are currently used in the COG clinical trials for treatment assignment include the following:
    • Favorable: inv(16)/t(16;16) and t(8;21), t(15;17), biallelic CEBPA mutations, and NPM1mutations.
    • Unfavorable: monosomy 7, monosomy 5/del(5q), 3q abnormalities, and FLT3-ITDwith high-allelic ratio.[55,56]

Therapeutic response risk factors

  • Response to therapy/minimal residual disease (MRD): Early response to therapy, generally measured after the first course of induction therapy, is predictive of outcome and can be assessed by standard morphologic examination of bone marrow,[38,57] cytogenetic analysis,[58] fluorescence in situ hybridization, or more sophisticated techniques to identify MRD (e.g., multiparameter flow cytometry, quantitative RT-PCR).[59-63] Multiple groups have shown that the level of MRD after one course of induction therapy is an independent predictor of prognosis.[59,61-65]
    Molecular approaches to assessing MRD in AML (e.g., using quantitative RT-PCR) have been challenging to apply because of the genomic heterogeneity of pediatric AML and the instability of some genomic alterations. Quantitative RT-PCR detection of RUNX1-RUNX1T1 (AML1-ETO) fusion transcripts can effectively predict higher risk of relapse for patients in clinical remission.[66-69] Other molecular alterations such as NPM1mutations [70] and CBFB-MYH11 fusion transcripts [71] have also been successfully employed as leukemia-specific molecular markers in MRD assays, and for these alterations, the level of MRD has shown prognostic significance. The presence of FLT3-ITD has been shown to be discordant between diagnosis and relapse, although when its presence persists (usually associated with a high-allelic ratio at diagnosis), it can be useful in detecting residual leukemia.[72]
    For APL, MRD detection at the end of induction therapy lacks prognostic significance, likely related to the delayed clearance of differentiating leukemic cells destined to eventually die.[73,74] However, the kinetics of molecular remission after completion of induction therapy is prognostic, with the persistence of minimal disease after three courses of therapy portending increased risk of relapse.[74-76]
    Flow cytometric methods have been used for MRD detection and can detect leukemic blasts based on the expression of aberrant surface antigens that differ from the pattern observed in normal progenitors. A CCG study of 252 pediatric patients with AML in morphologic remission demonstrated that MRD as assessed by flow cytometry was the strongest prognostic factor predicting outcome in a multivariate analysis.[59] Other reports have confirmed both the utility of flow cytometric methods for MRD detection in the pediatric AML setting and the prognostic significance of MRD at various time points after treatment initiation.[61,62,64]

Risk Classification Systems

Risk classification for treatment assignment has been used by several cooperative groups performing clinical trials in children with AML. In the COG, stratifying therapeutic choices on the basis of risk factors is a relatively recent approach for the non-APL, non–Down syndrome patient. Classification is most directly derived from the observations of the MRC AML 10 trial for EFS and OS [57] and further applied based on the ability of the pediatric patient to undergo reinduction and obtain a second complete remission and their subsequent OS after first relapse.[77]
The following COG trials have used a risk classification system to stratify treatment choices:
  1. In COG AAML0531 (NCT00372593), the first COG trial to stratify therapy by risk group, patients were stratified into three risk groups on the basis of diagnostic cytogenetics and response after induction 1.[16]
    • Low-risk patients included those diagnosed with a core-binding factor AML (either t(8;21) or inv(16)).
    • High-risk patients had either monosomy 7, monosomy 5 or del5q, chromosome 3 abnormalities, or a poor response to induction 1 therapy with morphologic marrow leukemic blasts (>15%).
    • All other patients fell into the intermediate-risk category.
    • This resulted in a risk distribution of 24% low risk, 59% intermediate risk, and 17% high risk.
  2. In the subsequent COG trial COG-AAML1031 (NCT01371981), the risk groups were reduced to two on the basis of the finding that those in the intermediate category could be more specifically and prognostically defined by adding the use of MRD by multiparameter flow cytometry.[78]
    • Patients whose cytogenetics and/or molecular genetics were noninformative (i.e., traditional intermediate risk) and were negative for MRD (<0.1%) were placed in the low-risk category.
    • Patients who were positive for MRD (≥0.1%) were placed in the high-risk category.
  3. In COG-AAML1031, the study stratification was further based on cytogenetics, molecular markers, and MRD at bone marrow recovery postinduction 1, with patients being divided into a low-risk or high-risk group as follows:
    1. The low-risk group represents about 73% of patients, has a predicted OS of approximately 75%, and is defined by the following:
      • Inv(16), t(8;21), nucleophosmin (NPM) mutations, or CEBPA mutations regardless of MRD and other cytogenetics.
      • Intermediate-risk cytogenetics (defined by the absence of either low-risk or high-risk cytogenetic characteristics) with negative MRD (<0.1% by flow cytometry) at end of induction 1.
    2. The high-risk group represents the remaining 27% of patients, has a predicted OS less than 35%, and is defined by the following:
      • High-allelic ratio FLT3-ITD-positive with any MRD status.
      • Monosomy 7 with any MRD status.
      • Monosomy 5/del(5q) with any MRD status.
      • Intermediate-risk cytogenetics with positive MRD at end of induction 1.
      Where risk factors contradict each other, the following evidence-based table is used (refer to Table 7).
      Table 7. Risk Assignment in AAML1031a,b
      ENLARGE
      Risk Assignment:Low RiskHigh Risk
       Low-Risk Group 1Low-Risk Group 2High-Risk Group 1High-Risk Group 2High-Risk Group 3
      aGroups are based on combinations of risk factors, which may be found in any individual patient.
      bBold indicates the overriding risk factor in risk-group assignment.
      cNPM1, CEBPA, t(8;21), inv(16).
      dMonosomy 7, monosomy 5, del(5q).
      FLT3-ITDallelic ratioLow/negativeLow/negativeHighLow/negativeLow/negative
      Good-risk molecular markerscPresentAbsentAnyAbsentAbsent
      Poor-risk cytogenetic markersdAnyAbsentAnyPresentAbsent
      Minimal residual diseaseAnyNegativeAnyAnyPositive
The high-risk group of patients are guided to transplantation in first remission with the most appropriate available donor. Patients in the low-risk group are instructed to pursue transplantation if they relapse. Validation of this approach awaits analysis.[62,79]
Risk factors used for stratification vary by pediatric and adult cooperative clinical trial groups and the prognostic impact of a given risk factor may vary in their significance depending on the backbone of therapy used. Other pediatric cooperative groups use some or all of these same factors, generally choosing risk factors that have been reproducible across numerous trials and sometimes including additional risk factors previously used in their risk group stratification approach.
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  52. Abbott BL, Rubnitz JE, Tong X, et al.: Clinical significance of central nervous system involvement at diagnosis of pediatric acute myeloid leukemia: a single institution's experience. Leukemia 17 (11): 2090-6, 2003. [PUBMED Abstract]
  53. Johnston DL, Alonzo TA, Gerbing RB, et al.: Central nervous system disease in pediatric acute myeloid leukemia: A report from the Children's Oncology Group. Pediatr Blood Cancer 64 (12): , 2017. [PUBMED Abstract]
  54. Johnston DL, Alonzo TA, Gerbing RB, et al.: The presence of central nervous system disease at diagnosis in pediatric acute myeloid leukemia does not affect survival: a Children's Oncology Group study. Pediatr Blood Cancer 55 (3): 414-20, 2010. [PUBMED Abstract]
  55. Lugthart S, Gröschel S, Beverloo HB, et al.: Clinical, molecular, and prognostic significance of WHO type inv(3)(q21q26.2)/t(3;3)(q21;q26.2) and various other 3q abnormalities in acute myeloid leukemia. J Clin Oncol 28 (24): 3890-8, 2010. [PUBMED Abstract]
  56. Creutzig U, van den Heuvel-Eibrink MM, Gibson B, et al.: Diagnosis and management of acute myeloid leukemia in children and adolescents: recommendations from an international expert panel. Blood 120 (16): 3187-205, 2012. [PUBMED Abstract]
  57. Wheatley K, Burnett AK, Goldstone AH, et al.: A simple, robust, validated and highly predictive index for the determination of risk-directed therapy in acute myeloid leukaemia derived from the MRC AML 10 trial. United Kingdom Medical Research Council's Adult and Childhood Leukaemia Working Parties. Br J Haematol 107 (1): 69-79, 1999. [PUBMED Abstract]
  58. Marcucci G, Mrózek K, Ruppert AS, et al.: Abnormal cytogenetics at date of morphologic complete remission predicts short overall and disease-free survival, and higher relapse rate in adult acute myeloid leukemia: results from Cancer and Leukemia Group B study 8461. J Clin Oncol 22 (12): 2410-8, 2004. [PUBMED Abstract]
  59. Sievers EL, Lange BJ, Alonzo TA, et al.: Immunophenotypic evidence of leukemia after induction therapy predicts relapse: results from a prospective Children's Cancer Group study of 252 patients with acute myeloid leukemia. Blood 101 (9): 3398-406, 2003. [PUBMED Abstract]
  60. Weisser M, Kern W, Rauhut S, et al.: Prognostic impact of RT-PCR-based quantification of WT1 gene expression during MRD monitoring of acute myeloid leukemia. Leukemia 19 (8): 1416-23, 2005. [PUBMED Abstract]
  61. van der Velden VH, van der Sluijs-Geling A, Gibson BE, et al.: Clinical significance of flowcytometric minimal residual disease detection in pediatric acute myeloid leukemia patients treated according to the DCOG ANLL97/MRC AML12 protocol. Leukemia 24 (9): 1599-606, 2010. [PUBMED Abstract]
  62. Loken MR, Alonzo TA, Pardo L, et al.: Residual disease detected by multidimensional flow cytometry signifies high relapse risk in patients with de novo acute myeloid leukemia: a report from Children's Oncology Group. Blood 120 (8): 1581-8, 2012. [PUBMED Abstract]
  63. Buldini B, Rizzati F, Masetti R, et al.: Prognostic significance of flow-cytometry evaluation of minimal residual disease in children with acute myeloid leukaemia treated according to the AIEOP-AML 2002/01 study protocol. Br J Haematol 177 (1): 116-126, 2017. [PUBMED Abstract]
  64. Rubnitz JE, Inaba H, Dahl G, et al.: Minimal residual disease-directed therapy for childhood acute myeloid leukaemia: results of the AML02 multicentre trial. Lancet Oncol 11 (6): 543-52, 2010. [PUBMED Abstract]
  65. Tierens A, Bjørklund E, Siitonen S, et al.: Residual disease detected by flow cytometry is an independent predictor of survival in childhood acute myeloid leukaemia; results of the NOPHO-AML 2004 study. Br J Haematol 174 (4): 600-9, 2016. [PUBMED Abstract]
  66. Buonamici S, Ottaviani E, Testoni N, et al.: Real-time quantitation of minimal residual disease in inv(16)-positive acute myeloid leukemia may indicate risk for clinical relapse and may identify patients in a curable state. Blood 99 (2): 443-9, 2002. [PUBMED Abstract]
  67. Viehmann S, Teigler-Schlegel A, Bruch J, et al.: Monitoring of minimal residual disease (MRD) by real-time quantitative reverse transcription PCR (RQ-RT-PCR) in childhood acute myeloid leukemia with AML1/ETO rearrangement. Leukemia 17 (6): 1130-6, 2003. [PUBMED Abstract]
  68. Weisser M, Haferlach C, Hiddemann W, et al.: The quality of molecular response to chemotherapy is predictive for the outcome of AML1-ETO-positive AML and is independent of pretreatment risk factors. Leukemia 21 (6): 1177-82, 2007. [PUBMED Abstract]
  69. Zhang L, Cao Z, Ruan M, et al.: Monitoring the AML1/ETO fusion transcript to predict outcome in childhood acute myeloid leukemia. Pediatr Blood Cancer 61 (10): 1761-6, 2014. [PUBMED Abstract]
  70. Krönke J, Schlenk RF, Jensen KO, et al.: Monitoring of minimal residual disease in NPM1-mutated acute myeloid leukemia: a study from the German-Austrian acute myeloid leukemia study group. J Clin Oncol 29 (19): 2709-16, 2011. [PUBMED Abstract]
  71. Corbacioglu A, Scholl C, Schlenk RF, et al.: Prognostic impact of minimal residual disease in CBFB-MYH11-positive acute myeloid leukemia. J Clin Oncol 28 (23): 3724-9, 2010. [PUBMED Abstract]
  72. Cloos J, Goemans BF, Hess CJ, et al.: Stability and prognostic influence of FLT3 mutations in paired initial and relapsed AML samples. Leukemia 20 (7): 1217-20, 2006. [PUBMED Abstract]
  73. Mandelli F, Diverio D, Avvisati G, et al.: Molecular remission in PML/RAR alpha-positive acute promyelocytic leukemia by combined all-trans retinoic acid and idarubicin (AIDA) therapy. Gruppo Italiano-Malattie Ematologiche Maligne dell'Adulto and Associazione Italiana di Ematologia ed Oncologia Pediatrica Cooperative Groups. Blood 90 (3): 1014-21, 1997. [PUBMED Abstract]
  74. Burnett AK, Grimwade D, Solomon E, et al.: Presenting white blood cell count and kinetics of molecular remission predict prognosis in acute promyelocytic leukemia treated with all-trans retinoic acid: result of the Randomized MRC Trial. Blood 93 (12): 4131-43, 1999. [PUBMED Abstract]
  75. 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]
  76. Martinelli G, Ottaviani E, Testoni N, et al.: Disappearance of PML/RAR alpha acute promyelocytic leukemia-associated transcript during consolidation chemotherapy. Haematologica 83 (11): 985-8, 1998. [PUBMED Abstract]
  77. Webb DK, Wheatley K, Harrison G, et al.: Outcome for children with relapsed acute myeloid leukaemia following initial therapy in the Medical Research Council (MRC) AML 10 trial. MRC Childhood Leukaemia Working Party. Leukemia 13 (1): 25-31, 1999. [PUBMED Abstract]
  78. Tarlock K, Meshinchi S: Pediatric acute myeloid leukemia: biology and therapeutic implications of genomic variants. Pediatr Clin North Am 62 (1): 75-93, 2015. [PUBMED Abstract]
  79. Pui CH, Carroll WL, Meshinchi S, et al.: Biology, risk stratification, and therapy of pediatric acute leukemias: an update. J Clin Oncol 29 (5): 551-65, 2011. [PUBMED Abstract]

Treatment of Childhood AML

The general principles of therapy for children and adolescents with acute myeloid leukemia (AML) are discussed below, followed by a more specific discussion of the treatment of children with Down syndrome and acute promyelocytic leukemia (APL).
Overall survival (OS) rates have improved over the past three decades for children with AML, with 5-year survival rates now in the 55% to 65% range.[1-5] Overall remission-induction rates are approximately 85% to 90%, and event-free survival (EFS) rates from the time of diagnosis are in the 45% to 55% range.[2-5] There is, however, a wide range in outcome for different biological subtypes of AML (refer to the Molecular Evaluation and Risk Classification Systems sections of this summary for more information); after taking specific biological factors of their leukemia into account, the predicted outcome for any individual patient may be much better or much worse than the overall outcome for the general population of children with AML.

Induction Therapy

Contemporary pediatric AML protocols result in 85% to 90% complete remission (CR) rates.[6-8] Approximately 2% to 3% of patients die during the induction phase, most often caused by treatment-related complications.[6-9] To achieve a CR, inducing profound bone marrow aplasia (with the exception of the M3 APL subtype) is usually necessary with currently used combination-chemotherapy regimens. Because induction chemotherapy produces severe myelosuppression, morbidity and mortality from infection or hemorrhage during the induction period may be significant.
Treatment options for children with AML during the induction phase may include the following:
  1. Chemotherapy.
  2. Gemtuzumab ozogamicin.
  3. Supportive care.

Chemotherapy

The two most effective and essential drugs used to induce remission in children with AML are cytarabine and an anthracycline. Commonly used pediatric induction therapy regimens use cytarabine and an anthracycline in combination with other agents such as etoposide and/or thioguanine.[3,10,11]
Evidence (induction chemotherapy regimen):
  1. The United Kingdom Medical Research Council (MRC) AML10 trial compared induction with cytarabine, daunorubicin, and etoposide (ADE) versus cytarabine and daunorubicin administered with thioguanine (DAT).[12]
    • The results showed no difference between the thioguanine and etoposide arms in remission rate or disease-free survival (DFS), although the thioguanine-containing regimen was associated with increased toxicity.
  2. The MRC AML15 trial demonstrated that induction with daunorubicin and cytarabine (DA) resulted in equivalent survival rates when compared with ADE induction.[13]
The anthracycline that has been most used in induction regimens for children with AML is daunorubicin,[3,10,11] although idarubicin and the anthracenedione mitoxantrone have also been used.[6,14,15] Randomized trials have attempted to determine whether any other anthracycline or anthracenedione is superior to daunorubicin as a component of induction therapy for children with AML. In the absence of convincing data that another anthracycline or mitoxantrone produces superior outcome over daunorubicin when given at an equitoxic dose, daunorubicin remains the anthracycline most commonly used during induction therapy for children with AML in the United States.
Evidence (anthracycline):
  1. The German Berlin-Frankfurt-Münster (BFM) Group AML-BFM 93 study evaluated cytarabine plus etoposide with either daunorubicin or idarubicin (ADE or AIE).[11,14]
    • Similar EFS and OS were observed for both induction treatments.
  2. The MRC-LEUK-AML12 (NCT00002658) clinical trial studied induction with cytarabine, mitoxantrone, and etoposide (MAE) in children and adults with AML compared with a similar regimen using daunorubicin (ADE).[6,16]
    • For all patients, MAE showed a reduction in relapse risk, but the increased rate of treatment-related mortality observed for patients receiving MAE led to no significant difference in DFS or OS when compared with ADE.[16]
    • Similar results were noted when analyses were restricted to pediatric patients.[6]
  3. The AML-BFM 2004 (NCT00111345) clinical trial compared liposomal daunorubicin (L-DNR) to idarubicin at a higher-than-equivalent dose (80 mg/m2 vs. 12 mg/m2 per day for 3 days) during induction.[17]
    • Five-year OS and EFS rates were similar in both treatment arms.
    • Treatment-related mortality was significantly lower with L-DNR than with idarubicin (2 of 257 patients vs. 10 of 264 patients).
The intensity of induction therapy influences the overall outcome of therapy. The CCG-2891 study demonstrated that intensively timed induction therapy (4-day treatment courses separated by only 6 days) produced better EFS than standard-timing induction therapy (4-day treatment courses separated by 2 weeks or longer).[18] The MRC has intensified induction therapy by prolonging the duration of cytarabine treatment to 10 days.[10]
In adults, another method of intensifying induction therapy is to use high-dose cytarabine. While studies in nonelderly adults suggest an advantage for intensifying induction therapy with high-dose cytarabine (2–3 g/m2/dose) compared with standard-dose cytarabine,[19,20] a benefit for the use of high-dose cytarabine compared with standard-dose cytarabine in children was not observed using a cytarabine dose of 1 g/m2 given twice daily for 7 days with daunorubicin and thioguanine.[21] A second pediatric study also failed to detect a benefit for high-dose cytarabine over standard-dose cytarabine when used during induction therapy.[22]

Gemtuzumab ozogamicin

Because further intensification of induction regimens has increased toxicity with little improvement in EFS or OS, alternative approaches, such as the use of gemtuzumab ozogamicin, have been examined.
Evidence (gemtuzumab ozogamicin):
  1. The Children's Oncology Group (COG) has completed a series of trials—AAML03P1 (NCT00070174), a pilot study, and AAML0531 (NCT00372593), a randomized trial—that examined the incorporation of the anti-CD33 conjugated antibody gemtuzumab ozogamicin into induction therapy.[8,9]
    • With the use of gemtuzumab ozogamicin during induction cycle one, dosed at 3 mg/m2 on day 6, the randomized trial identified an improved EFS but not OS; this was because of a reduction in postremission relapse overall and specifically in distinct subsets of patients. These subsets included patients with low-risk cytogenetics, patients with intermediate-risk AML who went on to receive stem cell transplantation (SCT) from a matched-related donor, and patients with high-risk AML (FLT3-ITD high-allelic ratio, >0.4) who then received a SCT from any donor.[23]
    • The expression intensity of CD33 on leukemic cells appeared to predict which patients benefited from gemtuzumab ozogamicin on the COG AAML0531 clinical trial.[24][Level of evidence: 1iiD] Patients whose CD33 intensity fell into the highest three population quartiles benefited from gemtuzumab ozogamicin (improved relapse risk, DFS, and EFS), whereas those in the lowest quartile had no reduction in relapse risk, EFS, or OS. This impact was seen for low-, intermediate-, and high-risk patients.
  2. In a retrospective analysis of the ALFA-0701 (NCT00927498) trial of older adults, higher CD33 expression corresponded with greater benefit from treatment with gemtuzumab ozogamicin.[25]
  3. The CD33 receptor on AML cells exhibited architectural variability (polymorphism) that resulted in 51% of patients expressing the single nucleotide polymorphism (SNP) rs12459419 (designated CC), for whom there was a significant reduction in relapse with the use of gemtuzumab ozogamicin compared with patients who did not use gemtuzumab ozogamicin (26% vs. 49%; P < .001). The alteration of this SNP resulted in a CD33 isoform lacking the CD33 IgV domain to which gemtuzumab ozogamicin binds and that is used in diagnostic immunophenotyping.[26]
    • For patients with either a one or two allele C>T mutation (CT and TT phenotypes, respectively) at this SNP, there was no reduction in relapse when adding gemtuzumab ozogamicin therapy (5-year cumulative incidence of relapse [CIR], 39% vs. 40%; P = .85).
  4. A meta-analysis of five randomized clinical trials that evaluated gemtuzumab ozogamicin for adults with AML observed the following:[27]
    • The greatest OS benefit was for patients with low-risk cytogenetics (t(8;21)(q22;q22) and inv(16)(p13;q22)/t(16;16)(p13;q22)).
    • Adult AML patients with intermediate-risk cytogenetics who received gemtuzumab ozogamicin had a significant but more modest improvement in OS.
    • There was no evidence of benefit for patients with adverse cytogenetics.
    • The evidence for a benefit in patients with FLT3-ITD mutations was mixed; the French ALFA-0701 (NCT00927498) trial showed a trend towards a benefit, whereas the five-trial meta-analysis study did not find a benefit.[27,28] These trials did not examine the outcomes specifically for the combination of gemtuzumab ozogamicin followed by stem cell transplant, as was reported by the COG.[23]

Supportive care

In children with AML receiving modern intensive therapy, the estimated incidence of severe bacterial infections is 50% to 60%, and the estimated incidence of invasive fungal infections is 7.0% to 12.5%.[29-31] Several approaches have been examined in terms of reducing the morbidity and mortality from infection in children with AML.
Hematopoietic growth factors
Hematopoietic growth factors such as granulocyte-macrophage colony-stimulating factor (GM-CSF) or granulocyte colony-stimulating factor (G-CSF) during AML induction therapy have been evaluated in multiple placebo-controlled studies in adults with AML in attempts to reduce the toxicity associated with prolonged myelosuppression.[7,32] These studies have generally shown a reduction in the duration of neutropenia of several days with the use of either G-CSF or GM-CSF [32] but have not shown significant effects on treatment-related mortality or OS.[32] (Refer to the Treatment Option Overview for AML section in the PDQ summary on Adult Acute Myeloid Leukemia Treatment for more information.)
Routine prophylactic use of hematopoietic growth factors is not recommended for children with AML.
Evidence (hematopoietic growth factors):
  1. A randomized study in children with AML that evaluated G-CSF administered after induction chemotherapy showed a reduction in duration of neutropenia but no difference in infectious complications or mortality.[33]
  2. A higher relapse rate has been reported for children with AML expressing the differentiation defective G-CSF receptor isoform IV.[34]
Antimicrobial prophylaxis
The use of antibacterial prophylaxis in children undergoing treatment for AML has been supported by several studies. Studies, including one prospective randomized trial, suggest a benefit to the use of antibiotic prophylaxis.
Evidence (antimicrobial prophylaxis):
  1. A retrospective study from St. Jude Children's Research Hospital (SJCRH) in patients with AML reported that the use of intravenous (IV) cefepime or vancomycin in conjunction with oral ciprofloxacin or a cephalosporin significantly reduced the incidence of bacterial infection and sepsis compared with patients receiving only oral or no antibiotic prophylaxis.[35]
  2. The SJCRH results were confirmed in a subsequent study.[36]
  3. A retrospective report from the COG AAML0531 (NCT00372593) trial demonstrated significant reductions in sterile-site bacterial infection and particularly gram-positive, sterile-site infections with the use of antibacterial prophylaxis.[37] This study also reported that prophylactic use of G-CSF reduced bacterial and Clostridium difficileinfections.[37]
  4. In a study that compared the percentage of bloodstream infections or invasive fungal infections in children with acute lymphoblastic leukemia (ALL) or AML who underwent chemotherapy and received antibacterial and antifungal prophylaxis, a significant reduction in both variables was observed when compared with a historical control group that did not receive any prophylaxis.[38]
  5. In the prospective COG ACCL0934 trial for children receiving intensive chemotherapy, patients were enrolled in two separate groups—patients with acute leukemia (consisting of AML or relapsed ALL) and patients undergoing stem cell transplant. Patients with acute leukemia were randomly assigned to receive levofloxacin (n = 96) or no prophylactic antibiotic (n = 99) during the period of neutropenia in one to two cycles of chemotherapy.[39]
    • Analysis of the 195 children with acute leukemia revealed a significant reduction in bacteremia (43.4% to 21.9%, P = .001) and neutropenic fever (82.1% to 71.2%, P = .002) in the levofloxacin prophylaxis group compared with the control group, without increases in fungal infections, C. difficile–associated diarrhea, or musculoskeletal toxicities.
    • There was no significant decrease in severe infections (3.6% vs. 5.9%, P = .20), and no bacterial infection–related deaths occurred in either group.
    • Levofloxacin prophylaxis is consistent with the guidelines published by the American Society of Clinical Oncology and Infectious Diseases Society of America in 2018 for adult cancer patients considered at high risk of infection by virtue of neutropenia (<100 neutrophils/µl) in excess of 7 days.[40]
Antifungal prophylaxis
The role of antifungal prophylaxis has not been studied in children with AML using randomized, prospective studies.
Evidence (antifungal prophylaxis):
  1. Two meta-analysis reports have suggested that antifungal prophylaxis in pediatric patients with AML during treatment-induced neutropenia or during bone marrow transplantation does reduce the frequency of invasive fungal infections and, in some instances, nonrelapse mortality.[41,42]
  2. Another study that analyzed 1,024 patients with AML treated on the COG AAML0531 (NCT00372593) clinical trial reported no benefit of antifungal prophylaxis on fungal infections or nonrelapse mortality.[37]
  3. Several randomized trials in adults with AML, however, have reported significant benefit in reducing invasive fungal infection with the use of antifungal prophylaxis. Such studies have also balanced cost with adverse side effects; when effectiveness at reducing invasive fungal infection is balanced with these other factors, posaconazole, voriconazole, caspofungin, and micafungin are considered reasonable choices.[38,43-47]
Cardiac monitoring
Bacteremia or sepsis and anthracycline use have been identified as significant risk factors in the development of cardiotoxicity, manifested as reduced left ventricular function.[48,49] Monitoring of cardiac function through the use of serial exams during therapy is an effective method for detecting cardiotoxicity and adjusting therapy as indicated. The use of dexrazoxane in conjunction with bolus dosing of anthracyclines can be an effective method of reducing the risk of cardiac dysfunction during therapy.[50]
Evidence (cardiac monitoring):
  1. In the COG AAML0531 (NCT00372593) trial, 8.6% of enrolled patients experienced a reduction in left ventricular function during protocol therapy, with a cumulative incidence of left ventricular dysfunction of 12% within 5 years of completing therapy.[48]
    • Risk factors for left ventricular dysfunction during therapy included black race, older age, underweight body mass, and bacteremia.
    • The occurrence of left ventricular dysfunction adversely impacted 5-year EFS (hazard ratio [HR], 1.57; 95% confidence interval [CI], 1.16–2.14; P = .004) and OS (HR, 1.59; 95% CI, 1.15–2.19; P = .005), which was primarily a result of nonrelapse mortality.
    • In patients who experienced left ventricular dysfunction during therapy, there was a 12-fold greater risk of left ventricular dysfunction in the 5 years after the completion of therapy.
  2. The use of dexrazoxane was assessed in patients enrolled on the COG AAML1031 (NCT01371981) trial.[50]
    • Among the approximately 10% of children (96 of 1,014) who received dexrazoxane with each dose of anthracycline, there was significantly less decline in ejection fraction (range of course-specific median absolute change in ejection fraction from baseline: 0 to -4.0 versus 0 to -6.4; all P < .05) and an overall lower risk of early left ventricular systolic dysfunction (6.3% vs. 19.2%; relative risk [RR], 0.33; 95% CI, 0.15–0.72; P = .005).
    • Patients who received dexrazoxane had a nonsignificantly improved 3-year EFS (54.4% vs. 44.2%, P = .070) and OS (71.9% vs. 63.0%, P = .093) compared with patients who did not receive dexrazoxane.
Hospitalization
Hospitalization until adequate granulocyte (absolute neutrophil or phagocyte count) recovery has been used to reduce treatment-related mortality. The COG-2961 (NCT00002798) trial was the first to note a significant reduction in treatment-related mortality (19% before mandatory hospitalization was instituted in the trial along with other supportive care changes vs. 12% afterward); OS was also improved in this trial (P <.001).[3] Another analysis of the impact of hospitalization using a survey of institutional routine practice found that those who mandated hospitalization had nonsignificant reduction in patients' treatment-related mortality (adjusted HR, 0.60 [0.26–1.36, P = .22]) compared with institutions who had no set policy.[37] Although there was no significant benefit seen in this study, the authors noted the limitations, including its methodology (survey), an inability to validate cases, and limited power to detect differences in treatment-related mortality. To avoid prolonged hospitalizations until count recovery, some institutions have used outpatient IV antibiotic prophylaxis effectively.[36]

Induction failure (refractory AML)

Induction failure (the morphologic presence of 5% or greater marrow blasts at the end of all induction courses) is seen in 10% to 15% of children with AML. Subsequent outcomes for patients with induction failure are similar to those for patients with AML who relapse early (<12 months after remission).[51,52]

Granulocytic sarcoma/chloroma

Granulocytic sarcoma (chloroma) describes extramedullary collections of leukemia cells. These collections can occur, albeit rarely, as the sole evidence of leukemia. In a review of three AML studies conducted by the former Children's Cancer Group, fewer than 1% of patients had isolated granulocytic sarcoma, and 11% had granulocytic sarcoma along with marrow disease at the time of diagnosis.[53] This incidence was also seen in the NOPHO-AML 2004 (NCT00476541) trial.[54]
Importantly, the patient who presents with an isolated tumor, without evidence of marrow involvement, must be treated as if there is systemic disease. Patients with isolated granulocytic sarcoma have a good prognosis if treated with current AML therapy.[53]
In a study of 1,459 children with newly diagnosed AML, patients with orbital granulocytic sarcoma and central nervous system (CNS) granulocytic sarcoma had better survival than did patients with marrow disease and granulocytic sarcoma at other sites and AML patients without any extramedullary disease.[54,55] Most patients with orbital granulocytic sarcoma have a t(8;21) abnormality, which has been associated with a favorable prognosis. The use of radiation therapy does not improve survival in patients with granulocytic sarcoma who have a complete response to chemotherapy, but may be necessary if the site(s) of granulocytic sarcoma do not show complete response to chemotherapy or for disease that recurs locally.[53]

Central Nervous System (CNS) Prophylaxis for AML

CNS involvement by AML and its impact on prognosis has been discussed above in the Prognostic Factors in Childhood AML section of this summary. Therapy with either radiation or intrathecal chemotherapy has been used to treat CNS leukemia present at diagnosis and to prevent later development of CNS leukemia. The use of radiation has essentially been abandoned as a means of prophylaxis because of the lack of documented benefit and long-term sequelae.[56] The COG has used single-agent cytarabine for both CNS prophylaxis and therapy. Other groups have attempted to prevent CNS relapse by using additional intrathecal agents.
Evidence (CNS prophylaxis):
  1. The COG AAML0531 (NCT00372593) trial used single-agent cytarabine for prophylaxis.[57]
    • The results of this approach found a total CNS relapse incidence of 3.9% in the 71% of enrolled patients who had no evidence of CNS leukemia at diagnosis (CNS1).
    • Patients who had minimal evidence of CNS leukemia at diagnosis (CNS2 or blasts present when CSF WBC was <5 cells/HPF; 16% of newly diagnosed patients) were given twice-weekly intrathecal cytarabine until the CSF cleared. For the CNS2 patients who initially cleared their CSF (95.8%) of leukemic blasts, 11.7% had later evidence of CNS relapse.
    • Among those with CNS3 involvement at diagnosis (13%), using the same approach of additional twice-weekly intrathecal cytarabine until clear (which had a 90.7% success rate), 17.7% later experienced a CNS relapse. For these CNS3 patients, even with multivariate analysis, their risk of isolated CNS relapse was significantly worse (HR, 7.82; P = .0003).
  2. Another methodology uses additional intrathecal agents, including triples, a combination of intrathecal cytarabine, hydrocortisone, and methotrexate.[58]
    • SJCRH reported that after switching from triples (their previous standard treatment) to single-agent cytarabine, the incidence of isolated CNS relapse increased from 0% (0 of 131 patients) to 9% (3 of 33 patients), prompting them to return to triples, which then reproduced a 0% (0 of 79 patients) CNS relapse rate.

Postremission Therapy for AML

A major challenge in the treatment of children with AML is to prolong the duration of the initial remission with additional chemotherapy or hematopoietic stem cell transplantation (HSCT).
Treatment options for children with AML in postremission may include the following:
  1. Chemotherapy.
  2. HSCT.

Chemotherapy

Postremission chemotherapy includes some of the drugs used in induction while also introducing non–cross-resistant drugs and, commonly, high-dose cytarabine. Studies in adults with AML have demonstrated that consolidation with a high-dose cytarabine regimen improves outcome compared with consolidation with a standard-dose cytarabine regimen, particularly in patients with inv(16) and t(8;21) AML subtypes.[59,60] (Refer to the Adult AML in Remission section in the PDQ summary on Adult Acute Myeloid Leukemia Treatment for more information.) Randomized studies evaluating the contribution of high-dose cytarabine to postremission therapy have not been conducted in children, but studies employing historical controls suggest that consolidation with a high-dose cytarabine regimen improves outcome compared with less intensive consolidation therapies.[11,61,62]
The optimal number of postremission courses of therapy remains unclear, but appears to require at least three courses of intensive therapy inclusive of the induction course.[3]
Evidence (number of postremission courses of chemotherapy):
  1. A United Kingdom Medical Research Council (MRC) study randomly assigned adult and pediatric patients to either four or five courses of intensive therapy. Five courses did not show an advantage in relapse-free survival and OS.[6,16][Level of evidence: 1iiA]
  2. Based on this MRC data, in the COG AAML1031 (NCT01371981) trial, non–high-risk patients treated without HSCT in first CR (73% of all patients) received four cycles of chemotherapy (two induction cycles and two consolidation cycles) rather than five cycles (two induction cycles and three consolidation cycles); nontransplanted patients had received five cycles of chemotherapy on the previous COG AAML0531 (NCT00372593) and AAML03P1 (NCT00070174) trials.[63]
    • In a retrospective analysis, patients treated without HSCT on the COG AAML1031 trial (four chemotherapy cycles) had significantly worse outcomes than did those who had received five cycles of chemotherapy on the AAML0531 or AAML03P1 trials; outcomes included inferior OS (HR, 1.83; 95% CI, 1.22–2.74; P = .003), inferior DFS (HR, 1.49; 95% CI, 1.13–1.97; P = .005), and higher cumulative risk of relapse (HR, 1.42; 95% CI, 1.08–1.88; P = .013).
    • An exception was found in the low-risk subgroup defined by favorable cytogenetics or molecular genetics who were minimal residual disease (MRD) negative at the end of induction cycle 1. This subset of patients had similar outcomes regardless of whether they received four chemotherapy cycles (AAML1031) or five chemotherapy cycles (AAML0531 or AAML03P1).
    Additional study of the number of intensification courses and specific agents used will better address this issue, but these data suggest that four chemotherapy courses should only be administered to the favorable group described above, and that all other nontransplanted patients should receive five chemotherapy courses.

HSCT

The use of HSCT in first remission has been under evaluation since the late 1970s, and evidence-based appraisals concerning indications for autologous and allogeneic HSCT have been published.[64] Prospective trials of transplantation in children with AML suggest that overall, 60% to 70% of children with HLA-matched donors available who undergo allogeneic HSCT during their first remission experience long-term remissions,[10,65] with the caveat that outcome after allogeneic HSCT is dependent on risk-classification status.[66]
In prospective trials of allogeneic HSCT compared with chemotherapy and/or autologous HSCT, a superior DFS has been observed for patients who were assigned to allogeneic transplantation based on availability of a family 6/6 or 5/6 HLA-matched donor in adults and children.[10,65,67-71] However, the superiority of allogeneic HSCT over chemotherapy has not always been observed.[72] Several large cooperative group clinical trials for children with AML have found no benefit for autologous HSCT over intensive chemotherapy.[10,65,67,69]
Current application of allogeneic HSCT involves incorporation of risk classification to determine whether transplantation should be pursued in first remission. Because of the improved outcome in patients with favorable prognostic features (low-risk cytogenetic or molecular mutations) receiving contemporary chemotherapy regimens and the lack of demonstrable superiority for HSCT in this patient population, this group of patients typically receives matched-family donor (MFD) HSCT only after first relapse and the achievement of a second CR.[64,66,73,74]
There is conflicting evidence regarding the role of allogeneic HSCT in first remission for patients with intermediate-risk characteristics (neither low-risk or high-risk cytogenetics or molecular mutations):
Evidence (allogeneic HSCT in first remission for patients with intermediate-risk AML):
  1. A study combining the results of the POG-8821, CCG-2891, COG-2961 (NCT00002798), and MRC AML10 studies identified a DFS and OS advantage for allogeneic HSCT in patients with intermediate-risk AML but not favorable-risk (inv(16) and t(8;21)) or poor-risk AML (del(5q), monosomy 5 or 7, or more than 15% blasts after first induction for POG/CCG studies); the MRC study included patients with 3q abnormalities and complex cytogenetics in the high-risk category.[66] Weaknesses of this study include the large percentage of patients not assigned to a risk group and the relatively low EFS and OS rates for patients with intermediate-risk AML assigned to chemotherapy, as compared with results observed in more recent clinical trials.[6,17]
  2. The AML99 clinical trial from the Japanese Childhood AML Cooperative Study Group observed a significant difference in DFS for intermediate-risk patients assigned to MFD HSCT, but there was not a significant difference in OS.[75]
  3. The AML-BFM 99 clinical trial demonstrated no significant difference in either DFS or OS for intermediate-risk patients assigned to MFD HSCT versus those assigned to chemotherapy.[72]
Given the improved outcome for patients with intermediate-risk AML in recent clinical trials and the burden of acute and chronic toxicities associated with allogeneic transplantation, many childhood AML treatment groups (including the COG) employ chemotherapy for intermediate-risk patients in first remission and reserve allogeneic HSCT for use after potential relapse.[6,75,76]
There are conflicting data regarding the role of allogeneic HSCT in first remission for patients with high-risk disease, complicated by the differing definitions of high risk used by different study groups.
Evidence (allogeneic HSCT in first remission for patients with high-risk AML):
  1. A retrospective analysis from the COG and Center for International Blood and Marrow Transplant Research (CIBMTR) compared chemotherapy only with matched-related donor and matched-unrelated donor HSCT for patients with AML and high-risk cytogenetics, defined as monosomy 7/del(7q), monosomy 5/del(5q), abnormalities of 3q, t(6;9), or complex karyotypes.[77]
    • The analysis demonstrated no difference in the 5-year OS among the three treatment groups.
  2. A Nordic Society for Pediatric Hematology and Oncology study reported that time-intensive reinduction therapy followed by transplant with best available donor for patients whose AML did not respond to induction therapy resulted in 70% survival at a median follow-up of 2.6 years.[78][Level of evidence: 2A]
  3. A single-institution retrospective study of 36 consecutive patients (aged 0–30 years) with high-risk AML (FLT3-ITD, 11q23 KMT2A [MLL] rearrangements, presence of chromosome 5 or 7 abnormalities, induction failure, persistent disease), who were in a morphologic first remission before allogeneic transplant.[79]
    • The investigators reported a 5-year 72% OS and a 69% leukemia-free survival (from the time of transplant) with the use of a myeloablative conditioning regimen.
    • They also reported a 17% treatment-related mortality.
    • These outcomes were similar to 14 standard-risk AML patients transplanted during the same time period.
  4. A subgroup analysis from the AML-BFM 98 clinical trial demonstrated improved survival rates for patients with 11q23 aberrations allocated to allogeneic HSCT, but not for patients without 11q23 aberrations.[72]
  5. For children with FLT3-ITD (high-allelic ratio), patients who received MFD HSCT (n = 6) had higher OS than did patients who received standard chemotherapy (n = 28); however, the number of cases studied limited the ability to draw conclusions.[80]
  6. A subsequent retrospective report from three consecutive trials in young adults with AML found that patients with FLT3-ITD high-allelic ratio did benefit from allogeneic HSCT (P =.03), whereas patients with low-allelic ratio did not (P = .64).[81]
  7. A subset analysis of the COG phase 3 trial evaluated gemtuzumab ozogamicin during induction therapy in children with newly diagnosed AML.[23]
    • For patients with FLT3-ITD high-allelic ratio who received HSCT, a lower relapse rate was observed for those who also received gemtuzumab ozogamicin (15% vs. 53%, P = .007).
    • Conversely, patients receiving gemtuzumab ozogamicin showed higher treatment-related mortality (19% vs. 7%, P = .08), resulting in overall improved DFS (65% vs. 40%, P = .08).
Many, but not all, pediatric clinical trial groups prescribe allogeneic HSCT for high-risk patients in first remission.[74] For example, the COG frontline AML clinical trial (COG-AAML1031) prescribes allogeneic HSCT in first remission only for patients with predicted high risk of treatment failure based on unfavorable cytogenetic and molecular characteristics and elevated end-of-induction MRD levels. On the other hand, the AML-BFM trials restrict allogeneic HSCT to patients in second CR and to refractory AML. This was based on results from their AML-BFM 98 study, which found no improvement in DFS or OS for high-risk patients receiving allogeneic HSCT in first CR, as well as the successful treatment using HSCT for a substantial proportion of patients who achieved a second CR.[72,82] Additionally, late sequelae (e.g., cardiomyopathy, skeletal anomalies, and liver dysfunction or cirrhosis) were increased for children undergoing allogeneic HSCT in first remission on the AML-BFM 98 study.[72]
Because definitions of high-, intermediate-, and low-risk AML are evolving because of the ongoing association of molecular characteristics of the tumor with outcome (e.g., FLT3internal tandem duplications, WT1 mutations, and NPM1 mutations) and response to therapy (e.g., MRD assessments postinduction therapy), further analysis of subpopulations of patients treated with allogeneic HSCT will be an ongoing need in current and future clinical trials.
If transplant is chosen in first CR, the optimal preparative regimen and source of donor cells has not been determined, although alternative donor sources, including haploidentical donors, are being studied.[71,83,84] There are no data that suggest total-body irradiation (TBI) is superior to busulfan-based myeloablative regimens.[72,73]
Evidence (myeloablative regimen):
  1. A randomized trial that compared busulfan plus fludarabine with busulfan plus cyclophosphamide as a preparative regimen for AML in first CR demonstrated that the former regimen was associated with less toxicity and comparable DFS and OS.[85]
  2. In addition, a large prospective CIBMTR cohort study of children and adults with AML, myelodysplastic syndromes (MDS), and chronic myelogenous leukemia (CML) showed superior survival of patients with early-stage disease (chronic-phase CML, first CR AML, and MDS-refractory anemia) with busulfan-based regimens compared with TBI.[86]
Other than the APL subtype, there are no data that demonstrate that maintenance therapy given after intensive postremission therapy significantly prolongs remission duration. Maintenance chemotherapy failed to show benefit in two randomized studies that used modern intensive consolidation therapy,[61,87] and maintenance therapy with interleukin-2 also proved ineffective.[3]

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.

Recurrent or Refractory Childhood AML and Other Myeloid Malignancies

The diagnosis of recurrent or relapsed AML according to COG criteria is essentially the same as the criteria for making the diagnosis of AML. Usually this is defined as patients having more than 5% bone marrow blasts who were in previous remission after therapy for a diagnosis of AML according to World Health Organization (WHO) classification criteria.[88,89]
Despite second remission induction in over one-half of children with AML treated with drugs similar to drugs used in initial induction therapy, the prognosis for a child with recurrent or progressive AML is generally poor.[51,90]

Recurrent childhood AML

Approximately 50% to 60% of relapses occur within the first year after diagnosis, with most relapses occurring by 4 years from diagnosis.[90] The vast majority of relapses occur in the bone marrow, and CNS relapse is very uncommon.[90]
Prognosis and prognostic factors
Factors affecting the ability to attain a second remission include the following:
  • Length of first remission. Length of first remission is an important factor affecting the ability to attain a second remission; children with a first remission of less than 1 year have substantially lower rates of second remission (50%–60%) than children whose first remission is greater than 1 year (70%–90%).[51,91,92] Survival for children with shorter first remissions is also substantially lower (approximately 10%) than that for children with first remissions exceeding 1 year (approximately 40%).[51,91-93] The Therapeutic Advances in Childhood Leukemia and Lymphoma Consortium also identified duration of previous remission as a powerful prognostic factor, with 5-year OS rates of 54% ± 10% for patients with greater than 12 months first remission duration and 19% ± 6% for patients with shorter periods of first remission.[94] In this same analysis, outcomes, primarily in early relapsing patients, declined with each attempt to reinduce remission (56% ± 5%, 25% ± 8%, and 17% ± 7% for each consecutive attempt).
  • Molecular alterations. In addition, specific molecular alterations at the time of relapse have been reported to impact subsequent survival. For instance, the presence of either WT1 or FLT3-ITD mutations at first relapse were associated, as independent risk factors, with worse OS in patients achieving a second remission.[95]
Additional prognostic factors were identified in the following studies:
  • In a report of 379 children with AML who relapsed after initial treatment on the German BFM group protocols, a second complete remission rate was 63% and OS was 23%.[96][Level of evidence: 3iiiA] The most significant prognostic factors associated with a favorable outcome after relapse included achieving second complete remission, a relapse greater than 12 months from initial diagnosis, no allogeneic bone marrow transplant in first remission, and favorable cytogenetics (t(8;21), t(15;17), and inv(16)).
  • The international Relapsed AML 2001/01 (NCT00186966) trial also found that early response to salvage therapy was highly prognostic.[97][Level of evidence: 3iiD]
  • A retrospective study of 71 patients with relapsed AML from Japan reported a 5-year OS rate of 37%. Patients who had an early relapse had a 27% second remission rate compared with 88% for patients who had a late relapse. The 5-year OS rate was higher in patients who underwent HSCT after achieving a second complete remission (66%) than in patients not in remission (17%).[93]
  • Patients who relapsed on two consecutive Nordic Society of Pediatric Hematology and Oncology (NOPHO) AML trials between 1993 to 2012 were analyzed for survival (208 patients relapsed of 543 children initially treated). Second remissions were achieved in 146 children (70%) with a variety of reinduction regimens. Five-year OS was 39%. Favorable prognostic factors included late relapse (≥1 year from diagnosis), no HSCT in first remission, and a core-binding factor AML subtype. For the children in second remission who underwent HSCT, the 5-year OS was 61%, as opposed to a 5-year OS of 18% for those who did not include HSCT in their therapy (P < .001).[98]
Treatment of recurrent AML
Treatment options for children with recurrent AML may include the following:
  1. Chemotherapy.
  2. HSCT.
Regimens that have been successfully used to induce remission in children with recurrent AML have commonly included high-dose cytarabine given in combination with the following agents:
  • Mitoxantrone.[51]
  • Fludarabine and idarubicin.[99-101]
  • L-asparaginase.[102]
  • Etoposide.
  • Liposomal daunorubicin. A study by the international BFM group compared fludarabine, cytarabine, and G-CSF (FLAG) with FLAG plus liposomal daunorubicin. Four-year OS was 38%, with no difference in survival for the total group; however, the addition of liposomal daunorubicin increased the likelihood of obtaining a remission and led to significant improvement in OS in patients with core-binding factor mutations (82%, FLAG plus liposomal daunorubicin vs. 58%, FLAG; P = .04).[103][Level of evidence: 1iiA]
Regimens built upon clofarabine have also been used;[104-106][Level of evidence: 2Div] as have regimens of 2-chloroadenosine.[107] The COG AAML0523 (NCT00372619) trial evaluated the combination of clofarabine plus high-dose cytarabine in patients with relapsed AML; the response rate was 48% and the OS rate, with 21 of 23 responders undergoing HSCT, was 46%. MRD before HSCT was a strong predictor of survival.[108][Level of evidence: 2Di]
The standard-dose cytarabine regimens used in the United Kingdom MRC AML10 study for newly diagnosed children with AML (cytarabine and daunorubicin plus either etoposide or thioguanine) have, when used in the setting of relapse, produced remission rates similar to those achieved with high-dose cytarabine regimens.[92] In a COG phase II study, the addition of bortezomib to idarubicin plus low-dose cytarabine resulted in an overall CR rate of 57%, and the addition of bortezomib to etoposide and high-dose cytarabine resulted in an overall CR rate of 48%.[109]
The selection of additional treatment after the achievement of a second complete remission depends on previous treatment and individual considerations. Consolidation chemotherapy followed by HSCT is conventionally recommended, although there are no controlled prospective data regarding the contribution of additional courses of therapy once a second complete remission is obtained.[90]
Evidence (HSCT after second complete remission):
  1. Unrelated donor HSCT has been reported to result in 5-year probabilities of leukemia-free survival of 45%, 20%, and 12% for patients with AML transplanted in second complete remission, overt relapse, and primary induction failure, respectively.[110][Level of evidence: 3iiA]
  2. A number of studies, including a large, prospective CIBMTR cohort study of children and adults with myeloid diseases, have shown similar or superior survival with busulfan-based regimens compared with TBI.[86,111,112]
  3. Matched-sibling donor transplantation has generally led to the best outcomes, but use of single-antigen mismatched related or matched unrelated donors results in very similar survival at the cost of increased rates of GVHD and nonrelapse mortality.[113] Umbilical cord outcomes are similar to other unrelated donor outcomes, but matching patients at a minimum of 7/8 alleles (HLA A, B, C, DRB1) leads to less nonrelapse mortality.[114] Haploidentical approaches are being used with increasing frequency and have shown comparable outcomes to other stem cell sources in pediatrics.[115] Direct comparison of haploidentical and other unrelated donor sources has not been performed in pediatrics, but studies in adults have shown similar outcomes.[116]
  4. Reduced-intensity approaches have been used successfully in pediatrics, but mainly in children unable to undergo myeloablative approaches.[117] A randomized trial in adults showed superior outcomes with myeloablative approaches compared with reduced-intensity regimens.[118]
There is evidence that long-term survival can be achieved in a portion of pediatric patients who undergo a second transplant subsequent to relapse after a first myeloablative transplant. Survival was associated with late relapse (>6 months from first transplant), achievement of complete response before the second procedure, and use of a TBI-based regimen (after receiving a non-TBI regimen for the first procedure).[119,120] A large prospective cohort study that included children and adults with myeloid diseases showed comparable or superior outcome with busulfan-based regimens compared with TBI.[86]
CNS relapse
Isolated CNS relapse occurs in 3% to 6% of pediatric AML patients.[57,121,122] Factors associated with an increased risk of isolated CNS relapse include the following:[121]
  • Age younger than 2 years at initial diagnosis.
  • M5 leukemia.
  • 11q23 abnormalities.
  • CNS2 or CNS3 involvement at initial diagnosis.[57]
The risk of CNS relapse increases with increasing CNS leukemic involvement at initial AML diagnosis (CNS1: 0.6%, CNS2: 2.6%, CNS3: 5.8% incidence of isolated CNS relapse, P < .001; multivariate HR for CNS3: 7.82, P = .0003).[57] The outcome of isolated CNS relapse when treated as a systemic relapse is similar to that of bone marrow relapse. In one study, the 8-year OS for a cohort of children with an isolated CNS relapse was 26% ± 16%.[121] CNS relapse may also occur in the setting of bone marrow relapse and its likelihood increases with CNS involvement at diagnosis (CNS1: 2.7%, CNS2: 8.5%, CNS3: 9.2% incidence of concurrent CNS relapse, P < .001).[57]

Refractory childhood AML (induction failure)

Treatment options for children with refractory AML may include the following:
  1. Chemotherapy.
  2. Gemtuzumab ozogamicin.
Like patients with relapsed AML, induction failure patients are typically directed towards HSCT once they attain a remission, because studies suggest a better EFS than in patients treated with chemotherapy only (31.2% vs. 5%, P < .0001). Attainment of morphologic CR for these patients is a significant prognostic factor for DFS after HSCT (46% vs. 0%; P = .02), with failure primarily resulting from relapse (relapse risk, 53.9% vs. 88.9%; P = .02).[123]
Evidence (treatment of refractory childhood AML with gemtuzumab ozogamicin):
  1. In the SJCRH trial AML02 (NCT00136084), gemtuzumab ozogamicin was given alone (n = 17), typically where MRD was low but still detectable (0.1%–5.6%), or in combination with chemotherapy (n = 29) to those patients with high residual MRD (1%–97%) after the first induction cycle.[124]
    • When given alone, 13 of 17 patients became MRD negative.
    • When given in combination with chemotherapy, 13 of 29 patients became MRD negative and 28 of 29 patients had reductions in MRD.
    • Compared with a nonrandomized cohort of patients with 1%–25% MRD after induction 1, addition of gemtuzumab ozogamicin to chemotherapy versus chemotherapy alone resulted in significant differences in MRD (P = .03); MRD was eliminated or reduced in all patients who received gemtuzumab ozogamicin versus in only 82% of patients who did not receive gemtuzumab ozogamicin. This was seen despite higher postinduction 1 MRD levels in the cohort receiving gemtuzumab ozogamicin (median, 9.5% vs. 2.9% in the no gemtuzumab ozogamicin group, P < .01). There was a nonstatistically significant improvement in 5-year OS (55% ± 13.9% vs. 36.4% ± 9.7%, P = .28) and EFS (50% ± 9.3% vs. 31.8% ± 13.4%, P = .28).
    • No impact upon HSCT treatment-related mortality was seen.
  2. In a phase II trial of gemtuzumab ozogamicin alone for children with relapsed/refractory AML failing previous reinduction attempts, 11 of 30 patients achieved a CR or partial CR, with a 27% versus 0% (P = .001) 3-year OS for responders versus nonresponders.[125]
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 are examples of national and/or institutional clinical trials that are currently being conducted:
  1. NCT03071276 (Selinexor, Fludarabine Phosphate, and Cytarabine in Treating Younger Patients with Refractory or Relapsed AML, ALL, or MDS): SJCRH-sponsored, single-arm, open label, phase II trial examining whether the addition of the selective inhibitor of nuclear export, selinexor, when added to a common AML reinduction backbone improves the study endpoint, complete response.
  2. NCT02538965 (A Study of Lenalidomide in Pediatric Subjects With Relapsed or Refractory AML): This joint industry/COG study, AAML1522, is a single-arm, open label, phase II trial to evaluate the activity, safety, and pharmacokinetics of lenalidomide as a single agent for children with relapsed or refractory AML with complete response within a maximum of four cycles as the primary outcome.
  3. NCT02642965 (Liposomal Cytarabine-Daunorubicin CPX-351, Fludarabine Phosphate, Cytarabine, and Filgrastim in Treating Younger Patients with Relapsed or Refractory AML): This phase I/II COG trial, AAML1421, for children in first relapse of their AML, uses a novel liposomal preparation of the two agents, cytarabine and daunomycin in a fixed 5:1 molar concentration in cycle 1, that exams whether this method of formulation of these two traditional AML agents is less toxic and more effective determined by the primary outcomes of toxicity and overall response.

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.

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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