A diagnostic pitfall: Therapy-related acute promyelocytic leukemia mimicking mixed-phenotype acute leukemia Free

Acute myeloid leukemia (AML) is a heterogeneous group of diseases characterized by distinct genetic alterations. The acute promyelocytic leukemia (APL) is defined by the translocation t(15;17), which results in the formation of the PML::RARA fusion gene. Therapy-related APL (t-APL) occurs as a complication of chemotherapy and/or radiation therapy that usually arises years after the initial cancer treatment. A high proportion of t-APL cases have been observed following treatment for breast cancer (BC). Topoisomerase-II inhibitors (TI) are considered possible causative agents in the pathogenesis of t-APL as they can induce chromosomal aberrations involving the PML::RARA fusion gene. Specific hotspots within the breakpoint regions of the PML and RARA genes that coincide with TI-binding sites have been identified. Despite of the rare incidence, t-APL shows no inferior outcome compared to de novo APL. Mixed-phenotype acute leukemias (MPAL) are a complex subgroup of acute leukemias which are defined by the World Health Organization (WHO) according to the co-expression of myeloid and lymphoid (B- or T-cell) markers. Cases presenting an APL that mimic a MPAL by fulfilling the MPAL criteria are rarely reported.

We present a rare and unusual case of t-APL in a 51-year-old woman who suffered from a locally advanced BC three years prior to the diagnosis of the leukemia. The BC was treated according to national guidelines with surgery, radiation therapy, chemotherapy (4 cycles of etoposide and cyclophosphamide and 12 cycles of paclitaxel), and endocrine maintenance therapy and has been in remission ever since. When the patient was referred to the hospital, peripheral blood analysis showed decreased thrombocytes (platelets: 7x10⁹/l), normal leukocytes (leukocytes: 4.9x10⁹/l), and anemia (hemoglobin: 8.8 g/dl). A blood smear revealed the presence of 85% blasts. The patient had signs of diffuse cutaneous bruising and developed a large hematoma after the bone marrow puncture, despite having normal global coagulation parameters. Since the bone marrow puncture was a dry tap, a biopsy was performed and imprint smears were prepared. Initial cytological assessments of the bone marrow imprint smears and the peripheral blood obscured the diagnosis of APL due to an atypical immunophenotype. No definitive Auer rods were observed in the initial evaluation. The bone marrow biopsy revealed acute leukemia with a high blast count of 91%. Subsequent immunophenotypic analysis of the blood using multicolor flow cytometry revealed that the blasts met the diagnostic criteria for MPAL (t/myeloid), as defined by both the WHO classification and the European Group for the Immunological Classification of Leukemias (EGIL). Therefore, an acute lymphoblastic leukemia (ALL)-based therapy regimen was initiated with the administration of corticosteroids for two days until obtaining molecular diagnostics. These diagnostics revealed the PML::RARA fusion gene, which was confirmed by conventional genetic testing. Following the identification of the t(15;17) translocation, one faggot cell was recognized retrospectively by microscopic examination. Induction therapy was immediately initiated according to the current APL treatment standard with tretinoin (ATRA) and arsenic trioxide (ATO) plus a single dose of idarubicin based on the APOLLO study for cytoreduction because the patient developed hyperleukocytosis mainly due to administration of corticosteroids. The patient achieved complete remission after 58 days of treatment with one episode of moderate differentiation syndrome with interruption of treatment and administration of corticosteroids. Measurable residual disease diagnostics, determined by the detection of PML::RARA, were negative. The patient has continued with maintenance therapy.

Since both subtypes of acute leukemia ((t)-APL and MPAL) – and especially their simultaneous occurrence – are extremely rare, reporting this case is of significant clinical relevance for guidance in similar cases. (I.) It underscores the importance of timely accurate molecular testing of leukemias. (II.) Even in the context of previous chemotherapy, genetic testing is mandatory as t-APL is treated specifically and shows a better prognosis than other forms of therapy-related AML. (III.) It highlights the importance of careful integrated diagnostics for acute leukemias that incorporate morphology, flow cytometry, and genetic results to guide therapeutic decision-making.