Atypical Rearrangements in APL-Like Acute Myeloid Leukemias: Molecular Characterization and Prognosis

Abstract

Acute promyelocytic leukemia (APL) accounts for 10–15% of newly diagnosed acute myeloid leukemias (AML) and is typically caused by the fusion of promyelocytic leukemia with retinoic acid receptor α (RARA) gene. The prognosis is excellent, thanks to the all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) combination therapy. A small percentage of APLs (around 2%) is caused by atypical transcripts, most of which involve RARA or other members of retinoic acid receptors (RARB or RARG). The diagnosis of these forms is difficult, and clinical management is still a challenge for the physician due to variable response rates to ATRA and ATO. Herein we review variant APL cases reported in literature, including genetic landscape, incidence of coagulopathy and differentiation syndrome, frequent causes of morbidity and mortality in these patients, sensitivity to ATRA, ATO, and chemotherapy, and outcome. We also focus on non-RAR rearrangements, complex rearrangements (involving more than two chromosomes), and NPM1-mutated AML, an entity that can, in some cases, morphologically mimic APL.

Case Report: Successful therapy with all-trans retinoic acid combined with chemotherapy followed by hematopoietic stem cell transplantation for acute promyelocytic leukemia carrying the BCOR-RARA fusion gene

“…The detailed treatment and outcome of the 3 patients are shown in Table 1. Transplantation was rarely used as a modality for vAPL, given the short-term followup and small number of the cases, but the benefit has been discussed in some variants with the high relapse rate, like STAT5B-RARA (9) and very young cases, like TTMV-RARA (7). Our patient had even stronger indications for transplantation due to complicated chromosome karyotype and poorly prognostic mutated genes.…”

“…Still, fusions, such as NPM1-RARA and FIP1L1-RARA, are sensitive to ATRA, and fusions, such as TTMV-RARA, are sensitive to both ATRA and ATO combination therapy (4,7). Generally, these variants should be treated with a combination of ATRA and chemotherapy (anthracyclines), with the possible use of AML protocols in known resistant variants (4,8,9). APL with BCOR-RARA is quite rare among vAPL.…”

Pharmaceutical/Clinical Strategies in the Treatment of Acute Promyelocytic Leukemia: All-Trans Retinoic Acid Encapsulation by Spray-Drying Technology as an Innovative Approach–Comprehensive Overview

“…The immunophenotype of blast cells in APL can be also evaluated for the diagnosis [ 23 , 24 ]. A more accurate approach can be performed at genetic level considering the cytogenetic characterization of APL, fluorescence in situ hybridization (FISH), reverse transcription polymerase chain reaction (RT-PCR) and immunofluorescence with anti-PML antibodies [ 19 , 25 , 26 , 27 ].…”

The treatment of acute promyelocytic leukemia in 2023: Paradigm, advances, and future directions

“…Similarly, RARG rearrangements, including NUP98-RARG, PML-RARG, CPSF6-RARG, NPM1-RARG-NPM1, and HNRNPC-RARG, have been identified and also show resistance to standard ATRA-based therapy. Very rarely, morphological and immunophenotypic APL with non-RAR rearrangements can occur involving fusion of MLL with partners such as ELL, AF1Q, and RPRD2; only three such cases have been reported, with successful induction with AML-directed intensive chemotherapy and discontinuation of ATRA as ATRA-sensitive RAR mutations were not detected ( 43 , 44 ). Overall, atypical variants of APL are important to identify by cytogenetic analysis, as they may be resistant to conventional APL-directed therapy and may require modification of treatment ( 42 ).…”