Childhood Acute Myeloid Leukemia/Other Myeloid Malignancies Treatment (PDQ®): Treatment - Health Professional Information [NCI] - 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. 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.[4,5,6]
Clinically, APL is characterized by a severe coagulopathy that is often present at the time of diagnosis. Mortality during induction (particularly with cytotoxic agents used alone) due to bleeding complications is more common in this subtype than in other French-American-British classifications. A lumbar puncture at diagnosis should not be performed until evidence of coagulopathy has resolved.
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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.[8,9,10,11] Similar to adults, children with WBC counts less than 10 × 109 /L at diagnosis have significantly better outcome than patients with higher WBC counts.[9,10,12] The prognostic significance of WBC count is used in defining high-risk and low-risk patient populations for assigning postinduction treatment, with high-risk patients most commonly defined by WBC of 10 × 109 /L or greater.[13,14]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.[15,16,17,18,19]FLT3 mutation has been associated with an increased risk of induction death, and in some reports, an increased risk of treatment failure.[15,16,17,18,19,20,21] 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.[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. Most patients with APL achieve a complete remission (CR) when treated with ATRA, though single-agent ATRA is generally not curative.[24,25] A series of randomized clinical trials has defined the benefit of combining ATRA with chemotherapy during induction therapy and also the utility of using ATRA as maintenance therapy.[26,27,28] 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.[10,13,14,29] 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.[13,14] 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.[1,8,9,10,13,14,29]