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Abstract
It has been suggested that 1–2% of acute promyelocytic leukemia (APL) patients present variant rearrangements of retinoic acid receptor alpha (RARα) fusion gene, with the promyelocytic leukaemia zinc finger (PLZF)/RARα being the most frequent. Resistance to all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO) has been suggested in PLZF/RARα and other variant APLs. Herein, we analyze the incidence, characteristics, and outcomes of variant APLs reported to the multinational PETHEMA (Programa para el Tratamiento de Hemopatias Malignas) registry, and we perform a systematic review in order to shed light on strategies to improve management of these extremely rare diseases. Of 2895 patients with genetically confirmed APL in the PETHEMA registry, 11 had variant APL (0.4%) (9 PLZF-RARα and 2 NPM1-RARα), 9 were men, with median age of 44.6 years (3 months to 76 years), median leucocytes (WBC) 16.8 × 109/L, and frequent coagulopathy. Eight patients were treated with ATRA plus chemotherapy-based regimens, and 3 with chemotherapy-based. As compared to previous reports, complete remission and survival was slightly better in our cohort, with 73% complete remission (CR) and 73% survival despite a high relapse rate (43%). After analyzing our series and performing a comprehensive and critical review of the literature, strong recommendations on appropriate management of variant APL are not possible due to the low number and heterogeneity of patients reported so far.
Highlights
Acute promyelocytic leukemia (APL) is a relatively rare hematologic malignancy accounting for ~10% of acute myeloid leukemia (AML) cases [1]
This study shows that variant acute promyelocytic leukemia (APL) is probably less frequent (0.4%) than previously reported
Our systematic literature search found 60 manuscripts on this topic (58 original reports and 2 reviews), almost equaling the number of patients with variant APL reported to date (n = 79)
Summary
Acute promyelocytic leukemia (APL) is a relatively rare hematologic malignancy accounting for ~10% of acute myeloid leukemia (AML) cases [1]. APL is characterized by M3 morphological subclassification, t(15;17)(q22;q21) chromosomal translocation, and promyelocytic leukemia protein (PML)—retinoic acid receptor alpha (RARα ) gene fusion, showing high rates of complete remission (CR) and cure using front-line schedules with all-trans-retinoic acid (ATRA) and/or arsenic trioxide (ATO). Apart from the classical PML-RARα cases, some APL patients are diagnosed with rare APL variants, characterized by a different rearrangement involving RARα plus another partner gene. These APL genetic variants account for ~1–2% of APL cases, but the real frequency remains unknown [2,3,4,5]. Some authors have suggested resistance to ATO and ATRA for the PLZF-RARα APL, which is probably the most frequent form of rare APL forms
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