sábado, 8 de junio de 2019

Childhood Acute Myeloid Leukemia Treatment (PDQ®) 4/12 —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.
      cNPM1CEBPA, 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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