ZBTB16::RARA variant acute promyelocytic leukemia (vAPL) treated with gemtuzumab ozogamicin (GO) with unique pathology and genetic findings

A 38-year-old male patient presented with clinical symptoms of shortness of breath, chest pain and scattered bruising. Initial workup showed elevated D-dimer (14 137 ng/mL) and LDH (388 U/L). CT angiography of the chest showed bilateral pulmonary embolisms and left pleural effusion that was negative for malignant cells on cytological examination. Full blood count demonstrated leukocytes (10.5 × 109/L), hemoglobin (88 g/L), and platelets (115 × 109/L). Coagulation screening was abnormal with a prolonged prothrombin time (PT), activated partial thromboplastin time (APTT) and low level of fibrinogen. A peripheral blood smear showed 65% promyelocytes. Bone marrow aspirate showed 50.5% promyelocytes with hypergranular cytoplasm (upper left panel), round non-lobulated nuclei, no Auer rods, and some containing non-crystalline intracytoplasmic inclusions (upper middle and right panels, inclusions indicated by yellow arrows). These differed in appearance from crystalline inclusions previously reported by others.1, 2 Immunophenotyping was consistent with promyelocytic origin of the primitive cells. Fluorescence in situ hybridisation (middle row of panels as labelled) using a PML::RARA probe did not identify t(15;17) but showed three green signals for RARA. A RARA break-apart probe confirmed RARA rearrangement. Chromosome analysis showed 46,XY,add(9)(q13),t(11;17)(q23;q21)[12]/46,XY[8 (lower left panel)]. The ZBTB16::RARA probe was used to confirm the ZBTB16::RARA fusion. Chromosomal SNP microarray identified chromothripsis at 11p13p14.1 and an interstitial 9q deletion breakpoints that was called an add(9) on the karyotype (lower right panel). A pathogenic variant in NRAS (NM_002524 c.35G > A) p.G12D was detected with a variant allele frequency (VAF) of 9%. All authors have no conflicts of interest to declare except TBM. TBM received honaria from BMS, consulting fees from chimerics. All co-authors have seen and agree with the contents of the manuscript and there is no financial interest to report except TBM. KAM was funded for an educational scholarship by the Egyptian Embassy and Cultural Bureau. This report is anonymised to protect the patient described. This study was approved by the institution review board (STUDY20221317). Patient is deceased and no photographs of the patient or any parts will be published. No material was reproduced, and all information was appropriately cited. Not a clinical trial.