Torque teno mini virus as a cause of childhood acute promyelocytic leukemia lacking PML/RARA fusion

A 6-year-old girl was admitted to the emergency department with a 3-day history of shoulder pain and fever. On physical examination, she presented with pallor and ecchymosis of the lower limbs. A full blood count showed a hemoglobin concentration of 9.7 g/dL, and leukocyte and platelet counts of 2.8 × 103/μL and 101 × 103/μL, respectively. Coagulation tests showed consumptive coagulopathy with slightly prolonged prothrombin and activated partial thromboplastin times, an increased D-dimer concentration, and hypofibrinogenemia. A peripheral blood smear showed atypical promyelocytes packed with numerous azurophilic granules (Figure 1A), whereas analysis of the bone marrow aspirate demonstrated markedly hypercellular marrow containing 85% abnormal promyelocytes with Auer rods (CD33+, CD13+, CD38+, CD99+, HLA-DRlow), with strong and diffuse reactivity to myeloperoxidase staining. Molecular analysis was negative for PML/RARA fusions, and karyotype analysis did not show t(15;17)(q24;q21). Fluorescence in situ hybridization with RARA break-apart probe confirmed the negativity of all RARA rearrangements and of the cryptic RARA gene insertion. Based on the characteristic morphologic features, the review of the peripheral blood and bone marrow was consistent with a diagnosis of hypergranular (or typical) APL, and therapy with ATRA was immediately started. The patient received treatment combining standard induction acute myeloid leukemia therapy and ATRA, followed by 3 high-dose cytarabine-based courses of consolidation therapy. Complete remission was achieved after the first induction cycle and persisted until the end of treatment.