Venetoclax in Combination with Decitabine for Relapsed T-Cell Acute Lymphoblastic Leukemia after Allogeneic Hematopoietic Cell Transplant

Abstract

Long-term disease-free survival in adults with T-cell acute lymphoblastic leukemia (T-ALL) remains poor, particularly after relapse, with few available salvage options. Preclinical data suggest that inhibition of the antiapoptotic protein BCL-2 (B-cell lymphoma 2) either alone or in combination with other agents, may be a unique therapeutic approach for the treatment of T-ALL. We present a case of a young male with T-ALL, relapsed after allogeneic hematopoietic stem cell transplant, who achieved a second complete remission following salvage therapy with combined venetoclax and decitabine. Assessment of measurable residual disease by next generation sequencing showed no evidence of residual disease of a sensitivity of 1 × 10−6. While the combination of venetoclax and hypomethylating agents has shown promise in the treatment of relapsed/refractory AML, and to our knowledge, this is the first report of this combination demonstrating clinical activity in relapsed/refractory T-ALL.

Aging of Preleukemic Thymocytes Drives CpG Island Hypermethylation in T-cell Acute Lymphoblastic Leukemia

“…inhibitor Venetoclax (35,36). The largely perturbed DNA methylation profile observed in T-ALL further supports the rationale of using DNA hypomethylating agents for the treatment of this disease.…”

Gilteritinib: a novel FLT3 inhibitor for acute myeloid leukemia

“…Epigenetic dysregulation plays a major role in leukemogenesis [36][37][38][39]. Hypomethylating agents have been shown to be active in AML as a single agent as well as in combination regimens [40][41][42][43][44][45][46]. A multicenter, openlabel, 3-arm study is being done to compare gilteritinib, gilteritinib plus azacitidine (AZA), or azacitidine alone in newly diagnosed FLT3 mutated (FLT3 mut+) AML patients who are unfit for intensive induction chemotherapy (NCT02752035).…”

Venetoclax in association with decitabine as effective bridge to transplant in a case of relapsed early T‐cell lymphoblastic leukemia

“…Despite the role demonstrated in lymphoproliferative disease such as CLL and MCL, the employment of venetoclax in ALL is reported in only three published cases. 8,10 Maturation stage of T-ALL cells determines BCL-2 vs BCL-XL dependence and sensitivity to BCL-2 inhibition. 12 Venetoclax use is supported by in vitro studies on T-ALL-derived cell lines and ex vivo patients derived blasts, suggesting a rationale for a novel therapeutic strategy.…”

“…Initial early T-ALL phenotype was confirmed by flow cytometry. According to promising preclinical data and pivotal case reports about venetoclax efficacy in T-ALL, 7,8,10 we decided to test BCL-2 expression on the leukemic blasts, and we found a high expression ( Figure 1). This finding encouraged us to start salvage treatment with standard-dose decitabine, 20 mg/m 2 for 5 days every 28 days in combination with venetoclax, daily dose 400mg, after a brief rump up of 6 days (initial daily dose 100 mg).…”

“…9 According to this background, venetoclax in combination with decitabine was successfully used to treat a patient who experienced T-ALL relapse after allo-SCT. 10…”