LAUSR

Dear Editor, Venetoclax is an oral drug that is BH3-mimetic and a selective B-cell lymphoma 2 (BCL-2) inhibitor. Inhibition of BCL-2 induces apoptosis in hematological malignancies [1]. Venetoclax has shown activity in patients with acute myeloid leukemia (AML) [2, 3] and chronic lymphocytic leukemia [4]. The approval of venetoclax is suggested to expand the treatment options for hematological malignancies. Herein, we report a patient with therapy-related myelodysplastic syndrome/acute myeloid leukemia (t-MDS/AML) with concomitant Waldenström’s macroglobulinemia (WM) who was treated with venetoclax and azacitidine (Ven/Aza). A 74-year-old male diagnosed as having WM more than 20 years previously had been administered several cytotoxic agents including MP (melphalan, prednisolone, every 3 weeks) at a previous hospital, R-ICE (rituximab 375 mg/ m2, day 1, ifosfamide 1.7 g/m2, days 2–3, 1.6 g/m2, day 4, carboplatin 5 × AUC, day 2, and etoposide 100 mg/m2, days 2–4, for 3 cycles), and rituximab (375 mg/m2, 13 times for 2 years). The IgM level decreased from 3270 to 2020 mg/dL after these treatments. We assessed him as a minor response according to the International Workshops for WM (IWWM) criteria [5]. After that, he was followed by observation via watch-and-wait for about 2.5 years. As his WM progressed, he received tirabrutinib, a novel Bruton’s tyrosine kinase (BTK) inhibitor that has been approved in Japan for WM [6]. For the first month, he was treated with tirabrutinib 600 mg once daily, but due to developing of pneumonia, dosage was reduced to 160 mg once daily. After administration of tirabrutinib, the symptoms of WM, such as fever and fatigue, improved and serum IgM levels decreased. The level of IgM in the pre-treatment was 4018 mg/dL; after treatment, the IgM level decreased to 548 mg/dL. The response was assessed as partial response according to the IWWM criteria [5]. However, after 5.5 years of starting tirabrutinib, blast cells appeared in the peripheral blood (PB) and bone marrow examination revealed that t-MDS arose (blast 14.4%) and there was infiltration of lymphoplasmacytoid cells (Fig. 1). Karyotypic G-banding showed complex karyotype abnormalities such as 46,XY,del(20)(q11.2q13) [13/20]/48,idem,add(1)(p34),del(2)(q?),-5,del(5),del(5) (q?), + add(7)(q11.2), + 8,-11,-15, + 19, + r1, + mar1[7/20]. None of the specific chimeric genes was found. One week later, blast cells in PB exceeded 20% and his t-MDS developed overt t-AML. The complete blood count in PB, white blood cells (WBC), neutrophil (Neu), hemoglobin (Hgb), and platelet (Plt) were 10,300/μL, 1030/μL, 10.7 g/dL, and 79,000/μL, respectively. He was AML with myelodysplasiarelated changes as WHO classification, and AML M2 as FAB classification. The patient has adverse risk according to European LeukemiaNet stratification for the reason that he had complex karyotype. Tirabrutinib was discontinued and CA (cytarabine 10 mg/m2, days 1–14, and aclarubicin 14 mg/m2, days 1–4, for 1 cycle) was administered for t-AML. Although complete remission with incomplete * Dai Maruyama [email protected]