Acute promyelocytic leukemia with torque teno mini virus (TTMV)::RARAfusion: an approach to screening and diagnosis

Abstract

Acute promyelocytic leukemia (APL) with variant RARA translocation is linked to over 15 partner genes. Recent publications encompassing six cases have expanded the spectrum of RARA partners to torque teno mini virus (TTMV). This entity is likely under-recognized due to lack of clinician and pathologist familiarity, inability to detect the fusion using routine testing modalities, and informatic challenges in its recognition within next-generation sequencing (NGS) data. We describe a clinicopathologic approach and provide necessary tools to screen and diagnose APL with TTMV::RARA using existing clinical DNA or RNA-based NGS assays, which led to identification of four cases, all without other known cytogenetic/molecular drivers. One was identified prospectively and three retrospectively, including two from custom automated screening of multiple data sets (50,257 cases of hematopoietic malignancy, including 4809 acute myeloid leukemia (AML)/myeloid sarcoma/APL cases). Two cases presented as myeloid sarcoma, including one with multiple relapses after AML-type chemotherapy and hematopoietic stem cell transplant (HSCT). Two cases presented as leukemia, had a poor response to induction chemotherapy, but achieved remission upon re-induction (including all-trans retinoic acid (ATRA) in one case) and subsequent HSCT. Neoplastic cells demonstrated features of APL including frequent azurophilic granules and dim/absent CD34 and HLA-DR expression. RARA rearrangement was not detected by karyotype or FISH. Custom analysis of NGS fusion panel data identified TTMV::RARA rearrangements, and in the prospectively identified case, facilitated monitoring in sequential bone marrow samples. APL with TTMV::RARA is a rare leukemia with a high rate of treatment failure in described cases. The diagnosis should be considered in leukemias with features of APL that lack detectable RARA fusions and other drivers, and may be confirmed by appropriate NGS tests with custom informatics. Incorporation of ATRA may have a role in treatment but requires accurate recognition of the fusion for appropriate classification as APL.