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Childhood Acute Myeloid Leukemia/Other Myeloid Malignancies Treatment (PDQ®)

Acute Promyelocytic Leukemia

Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia (AML) and is treated differently than other types of AML. Optimal treatment requires rapid initiation of treatment with all-trans retinoic acid (ATRA) and supportive care measures.[1,2] The characteristic chromosomal abnormality associated with APL is t(15;17). This translocation involves a breakpoint that includes the retinoic acid receptor and leads to production of the promyelocytic leukemia (PML)-retinoic acid receptor alpha (RARA) fusion protein.[3] Patients with a suspected diagnosis of APL can have their diagnosis confirmed by detection of the PML-RARA fusion (e.g., through fluorescence in situ hybridization [FISH], reverse transcriptase–polymerase chain reaction [RT–PCR], or conventional cytogenetics). An immunofluorescence method using an anti-PML monoclonal antibody can rapidly establish the presence of the PML-RARA fusion protein based on the characteristic distribution pattern of PML that occurs in the presence of the fusion protein.[4-6]

Clinically, APL is characterized by severe coagulopathy that is often present at the time of diagnosis.[7] Mortality during induction (particularly with cytotoxic agents used alone) caused by bleeding complications is more common in this subtype than in other French-American-British classifications.[8,9] A lumbar puncture at diagnosis should not be performed until evidence of coagulopathy has resolved. Initiation of ATRA therapy is strongly recommended as soon as APL is suspected based on morphological and clinical presentation,[1,10] because ATRA has been shown to ameliorate bleeding risk for patients with APL.[11] A retrospective analysis identified an increase in early death resulting from hemorrhage in patients with APL in whom ATRA introduction was delayed.[12]

APL in children is generally similar to APL in adults, though children have a higher incidence of hyperleukocytosis (defined as white blood cell [WBC] count higher than 10 × 109/L) and a higher incidence of the microgranular morphologic subtype.[13-16] Similar to adults, children with WBC counts less than 10 × 109/L at diagnosis have significantly better outcome than patients with higher WBC counts.[14,15,17] The prognostic significance of WBC count is used to define high-risk and low-risk patient populations and to assign postinduction treatment, with high-risk patients most commonly defined by WBC of 10 × 109/L or greater.[18,19] FLT3 mutations (either internal tandem duplications or kinase domain mutations) are observed in 40% to 50% of APL cases, with the presence of FLT3 mutations correlating with higher WBC counts and the microgranular variant (M3v) subtype.[20-24] FLT3 mutation has been associated with an increased risk of induction death, and in some reports, an increased risk of treatment failure.[20-26] Data from a combined analysis of two European trials demonstrated that children younger than 4 years with APL presented with higher WBC counts, had an increased incidence of the M3v subtype, and had a higher cumulative incidence of relapse and fatal cardiac toxicity during remission than did adolescents and adults; however, overall survival (OS) was similar.[27][Level of evidence: 3iiA]

The basis for current treatment programs for APL is the sensitivity of leukemia cells from patients with APL to the differentiation-inducing effects of ATRA. The dramatic efficacy of ATRA against APL results from the ability of pharmacologic doses of ATRA to overcome the repression of signaling caused by the PML-RARA fusion protein at physiologic ATRA concentrations. Restoration of signaling leads to differentiation of APL cells and then to postmaturation apoptosis.[28] Most patients with APL achieve a complete remission (CR) when treated with ATRA, though single-agent ATRA is generally not curative.[29,30] A series of randomized clinical trials defined the benefit of combining ATRA with chemotherapy during induction therapy and also the utility of using ATRA as maintenance therapy.[31-33] ATRA is also commonly used as a component of postinduction consolidation therapy, with treatment regimens that include several additional courses of ATRA given with an anthracycline with or without cytarabine.[15,18,19,34] Evidence for the benefit of giving ATRA with consolidation chemotherapy is derived from historical comparisons of results from adult APL clinical trials showing significant improvements in outcome for patients receiving ATRA given in conjunction with chemotherapy compared with chemotherapy alone.[18,19] For children with APL, survival rates exceeding 80% are now achievable using treatment programs that prescribe the rapid initiation of ATRA and appropriate supportive care measures.[1,13-15,18,19,34] For patients in CR for more than 5 years, relapse is extremely rare.[35][Level of evidence: 1iiDi]

The standard approach to treating children with APL builds upon adult clinical trial results and begins with induction therapy using ATRA given in combination with an anthracycline administered with or without cytarabine. One regimen uses ATRA in conjunction with standard-dose cytarabine and daunorubicin,[13,36] while another utilizes idarubicin and ATRA without cytarabine for remission induction.[14,15] Almost all children with APL treated with one of these approaches achieves CR in the absence of coagulopathy-related mortality.[14,15,34,36] Assessment of response to induction therapy in the first month of treatment using morphologic and molecular criteria may provide misleading results as delayed persistence of differentiating leukemia cells can occur in patients who will ultimately achieve CR.[1,2] Alterations in planned treatment based on these early observations are not appropriate as resistance of APL to ATRA plus anthracycline-containing regimens is extremely rare.[19,37]

Consolidation therapy has typically included ATRA given with an anthracycline with or without cytarabine. The role of cytarabine in consolidation therapy regimens is controversial. While a randomized study addressing the contribution of cytarabine to a daunorubicin plus ATRA regimen in adults with low-risk APL showed a benefit for the addition of cytarabine,[38] regimens using high-dose anthracycline appear to produce as good or better results for low-risk patients.[39] For high-risk patients (WBC ≥10 × 109/L), a historical comparison of the LPA2005 trial to the preceding PETHEMA LPA99 trial suggested that the addition of cytarabine to anthracycline-ATRA combinations can lower the relapse rate.[37] The results of the AIDA-2000 trial confirmed that the cumulative incidence of relapse for adult patients with high-risk disease can be reduced to approximately 10% with consolidation regimens containing ATRA, anthracyclines, and cytarabine.[19]

Maintenance therapy includes ATRA plus 6-mercaptopurine and methotrexate; this combination showed an advantage over ATRA alone in randomized trials in adults with APL.[31,40] A randomized study in adults has reported that maintenance therapy does not improve event-free survival (EFS) for patients with APL who achieve a complete molecular remission at the end of consolidation.[41] However, the utility of maintenance therapy in APL may be dependent on multiple factors (e.g., risk group, the anthracycline used during induction, the intensity of induction and consolidation therapy, etc.), and at this time maintenance therapy remains standard for children with APL. Because of the favorable outcomes observed with chemotherapy plus ATRA (EFS rates of 70%–80%), hematopoietic stem cell transplantation is not recommended in first CR.

Central nervous system (CNS) relapse is uncommon for patients with APL, particularly for those with WBC count less than 10 × 109/L.[42,43] In two clinical trials enrolling over 1,400 adults with APL in which CNS prophylaxis was not administered, the cumulative incidence of CNS relapse was less than 1% for patients with WBC less than 10 × 109/L, while it was approximately 5% for those with WBC of 10 × 109/L or greater.[42,43] In addition to high WBC at diagnosis, CNS hemorrhage during induction is also a risk factor for CNS relapse.[43] A review of published cases of pediatric APL also observed low rates of CNS relapse. Because of the low incidence of CNS relapse among children with APL presenting with WBC less than 10 × 109/L, CNS surveillance and prophylactic CNS therapy may not be needed for this group of patients,[44] although there is no consensus on this topic.[45]

Arsenic trioxide has also been identified as an active agent in patients with APL, and there are now data for its use as induction therapy, consolidation therapy, and in the treatment of patients with relapsed APL:

  • For adults with relapsed APL, approximately 85% achieve morphologic remission after treatment with this agent.[46-48] Arsenic trioxide is well tolerated in children with relapsed APL. The toxicity profile and response rates in children are similar to that observed in adults.[49]
  • In adults with newly diagnosed APL, the addition of two consolidation courses of arsenic trioxide to a standard APL treatment regimen resulted in a significant improvement in EFS (80% vs. 63% at 3 years; P < .0001) and disease-free survival (90% vs. 70% at 3 years; P < .0001), although the outcome of patients who did not receive arsenic trioxide was inferior to the results obtained in the GIMEMA or PETHEMA trials.[50]
  • The concurrent use of arsenic trioxide and ATRA in newly diagnosed patients with APL results in high rates of CR.[51-53] Early experience in children with newly diagnosed APL also shows high rates of CR to arsenic trioxide, either as a single agent or given with ATRA.[54][Level of evidence: 3iiA] Results of a meta-analysis of seven published studies in adult APL patients suggest that the combination of arsenic trioxide and ATRA may be more effective than arsenic trioxide alone in inducing CR.[55] The impact of arsenic induction (either alone or with ATRA) on EFS and OS has not been well characterized in children, although early results appear promising.[54,56,57]
  • Arsenic trioxide was evaluated as a component of induction therapy with idarubicin and ATRA in the APML4 clinical trial, which enrolled both children and adults (N = 124 evaluable patients).[25] Patients received two courses of consolidation therapy with arsenic trioxide and ATRA (but no anthracycline) and maintenance therapy with ATRA, 6-mercaptopurine, and methotrexate. The 2-year rate for freedom from relapse was 97.5%, failure-free survival (FFS) was 88.1%, and OS was 93.2%. These results are superior for FFS and freedom from relapse when compared with the predecessor clinical trial (APML3) that did not use arsenic trioxide.
  • A German and Italian phase III clinical trial compared ATRA plus chemotherapy with ATRA plus arsenic trioxide in adults with APL classified as low to intermediate risk (WBC ≤ 10 × 109/L).[58] Patients were randomly assigned to receive either ATRA plus arsenic trioxide for induction and consolidation therapy or standard ATRA-idarubicin induction therapy followed by three cycles of consolidation therapy with ATRA plus chemotherapy and maintenance therapy with low-dose chemotherapy and ATRA.

    All patients receiving ATRA plus arsenic trioxide (n = 77) achieved CR at the end of induction therapy, while 95% of patients receiving ATRA plus chemotherapy (n = 79) achieved CR. EFS rates were 97% in the ATRA-arsenic trioxide group compared with 86% in the ATRA-chemotherapy group (P = .02). Two-year OS probability was 99% (95% confidence interval [CI], 96–100) in the ATRA-arsenic trioxide group and 91% (95% CI, 85–97) in the ATRA-chemotherapy group (P = .02). These results indicate that low- to intermediate-risk APL is curable for a high percentage of patients without conventional chemotherapy.

Because arsenic trioxide causes QT interval prolongation that can lead to life-threatening arrhythmias (e.g., torsades de pointes),[59] it is essential to monitor electrolytes closely in patients receiving arsenic trioxide and to maintain potassium and magnesium values at midnormal ranges.[60]

The induction and consolidation therapies currently employed result in molecular remission as measured by reverse transcriptase–polymerase chain reaction (RT–PCR) for PML-RARA in the large majority of APL patients, with 1% or fewer showing molecular evidence of disease at the end of consolidation therapy.[19,37] While two negative RT-PCR assays after completion of therapy are associated with long-term remission,[61] conversion from negative to RT-PCR positivity is highly predictive of subsequent hematologic relapse.[62] Patients with persistent or relapsing disease based upon PML-RARA RT-PCR measurement may benefit from intervention with relapse therapies (refer to the Recurrent Acute Promyelocytic Leukemia (APL) subsection of the Recurrent Childhood Acute Myeloid Leukemia and Other Myeloid Malignancies section of this summary for more information).

Molecular Variants of APL Other than PML-RARA

Uncommon molecular variants of APL produce fusion proteins that join distinctive gene partners (e.g., PLZF, NPM, STAT5B, and NuMA) to RARA.[63] Recognition of these rare variants is important as they differ in their sensitivity to ATRA and to arsenic trioxide.[64] The PLZF-RARA variant, characterized by t(11;17)(q23;q21), represents about 0.8% of APL, expresses surface CD56, and has very fine granules compared with t(15;17) APL.[65-67] APL with PLZF-RARA has been associated with a poor prognosis and does not usually respond to ATRA or to arsenic trioxide.[64-67] The rare APL variants with NPM-RARA (t(5;17)(q35;q21)) or with NuMA-RARA (t(11;17)(q13;q21)) translocations may still be responsive to ATRA.[64,68-71]

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with childhood acute promyelocytic leukemia (M3). The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.


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  • Updated: April 9, 2015