Venetoclax with chemotherapy in relapse/refractory early T-cell precursor acute lymphoblastic leukemia

Early T-cell precursor acute lymphoblastic leukemia (ETPALL) is a clinically distinct and highly aggressive subset of T-cell ALL [1]. It is characterized by an immunophenotype with reduced or absent expression of CD1a, CD5 and CD8 and presence of at least one hematopoietic stem cell and/or myeloid antigen [2,3]. ETP-ALL comprises around 10%–35% of all T-cell ALL cases in adults and is associated with poor outcomes due to intrinsic resistance to conventional chemotherapy resulting in high rates of relapse/refractory (r/r) disease [2–4]. Allogeneic stem cell transplant (allo-sct) has shown to improve survival in patients with ETP-ALL [5]. The challenge lies in identifying novel agents to be used as a bridge to transplant. Recent reports have highlighted that whereas T-ALL cell lines are dependent upon BCLXL, the ETP-ALL phenotype, in particular, is BCL-2 dependent, leading to the investigation of the BCL-2 inhibitor, venetoclax, as a potential therapeutic agent [2–4,6–8]. In this context, we describe retrospective outcomes of five consecutive patients (Table 1) with r/r ETPALL treated with venetoclax in combination with chemotherapy. Patient 1: A 37-year-old male was diagnosed with ETPALL in August 2016. A karyotype was unsuccessful, and FISH testing revealed 9% of cells with one copy of chromosome 17. The patient achieved complete remission (CR) after 3 cycles (1A–2B) of hyper-fractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone alternating with high-dose methotrexate and cytarabine (Hyper-CVAD/MA). The patient completed hyper-CVAD/MA 3A–4B. An allo-sct was not pursued due to socioeconomic barriers. Maintenance with 6-mercaptopurine, vincristine, methotrexate, and prednisone (POMP) was started in June 2017. The patient experienced first relapse in November 2017 and was treated with nelarabine for 5 cycles resulting in second CR in March 2018. A second relapse occurred in June 2018 and was refractory to liposomal vincristine (4 doses). A third CR was achieved with methotrexate, vincristine, pegylatedasparaginase, and dexamethasone (MOpAD) in August 2018. A third relapse occurred in November 2018 and was refractory to fludarabine, cytarabine, g-csf and idarubicin (FLAG-Ida). The patient was started on attenuated doses of Hyper-CVAD (minus doxorubicin) alternating with methotrexate and cytarabine (mini-CVD/MA) plus venetoclax (100mg starting on day 8, concomitant voriconazole) in February 2019. The patient achieved fourth CR after 2 cycles and went on to receive 4 more cycles of mini-CVD plus venetoclax. The duration of cytopenia ranged from 16–21 days per cycle. There was one hospital admission for febrile neutropenia due to pneumonia (radiographic diagnosis) after the fourth cycle. The patient remained in morphological CR with 1% disease detected by flow cytometry. Maintenance was started with venetoclax, vincristine and prednisone in June 2019. Delayed neutrophil and platelet recovery were observed after the second cycle of maintenance therapy. Treatment was held and subsequently resumed 2weeks later once blood counts recovered. The patient remained in remission till November 2019 at which point he experienced a fourth relapse. The patient was then treated with daratumumab but could only tolerate 3 doses due to vision changes and concerns for transient ischemic attack. The patient then transitioned to hospice care. Patient 2: A 62-year-old female was diagnosed with ETP-ALL in August 2019. Cytogenetics revealed deletion 5q and a molecular panel identified aberrations in NRAS, BCOR, RUNX1 and ASXL1. She was refractory to HyperCVAD/MA 1A and 1B. Second line treatment was started with nelarabine. She had residual disease (10–15% blasts) after 2 cycles. Venetoclax was added to the 3 cycle at a dose of 200mg daily (with isavuconazole) for 3weeks. A bone marrow biopsy after the 3 cycle revealed CR with minimum residual disease (MRD) negativity by flow cytometry. She received a 4 cycle of the same combination and remained in MRD-negative CR prior to proceeding with a reduced intensity allo-sct from a matched unrelated donor (MUD). She experienced transient