Addition of venetoclax to myeloablative conditioning regimens for allogeneic hematopoietic stem cell transplantation in high-risk AML

Abstract

Background Venetoclax monotherapy is an effective option for patients with acute myeloid leukemia (AML). Venetoclax has also been used in non-myeloablative conditioning allogeneic hematopoietic stem cell transplantation (allo-HSCT) for high-risk AML with a tolerable toxicity profile. However, the efficacy and safety of a venetoclax-containing myeloablative conditioning (MAC) allo-HSCT regimen for high-risk AML have not been evaluated. Objective To evaluate the safety and efficacy of a MAC regimen containing venetoclax for high-risk AML. Study design From 25 February 2021 to 4 September 2022, a total of 31 patients with high-risk AML who underwent allo-HSCT and a MAC regimen with venetoclax were analyzed. Results At the time of transplantation, 21 patients were in first complete remission (CR1), 4 were in a second complete remission (CR2), and 6 in non-remission (NR). Twenty-four patients (77.4%) were minimal residual disease (MRD)-positive before transplant. The FLT3-ITD gene mutation was present in 51.6% of patients. NUP98 rearrangement, MLL rearrangement or MLL-PTD and DEK::CAN fusion genes were found in 5 (16.1%), 7(22.6%) and 2 (6.5%) patients, respectively. Twenty-nine (93.6%) patients underwent haploidentical allo-HSCT. The median follow-up time was 278 days (range: 52–632 days). The 100-day cumulative incidence of grade 3 to 4 acute graft-versus-host disease (aGVHD) was 16.1% (95%CI, 7.2–36.0%). The 180-day cumulative incidence of moderate to severe chronic graft-versus-host disease (cGVHD) was 7.1% (95%CI, 1.9–26.9%). Cumulative incidence of 100-day cytomegalovirus (CMV) viraemia and 100-day Epstein-Barr virus (EBV) viraemia was 61.6% (95%CI, 46.5–81.4%) and 3.2% (95%CI, 0.4–22.2%), respectively. The 600-day overall survival (OS) and leukemia-free survival (LFS) were 80.9% (95%CI, 63.5–93.6%) and 81.3% (95%CI, 64.2–93.7%), respectively. The 600-day relapse incidence (RI) and non-relapse mortality (NRM) was 6.9% (95%CI, 1.8–26.3%) and 11.7% (95%CI, 3.9–35.0%). Conclusion Our study shows that the addition of venetoclax to a MAC allo-HSCT was feasible, safe and effective for high-risk AML patients.

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“…In addition, Handgretinger [22] estimates that more than half of all HLA haplotype-mismatched transplants will be performed worldwide following similar protocols. Previous studies at our center demonstrated that conditioning regimens based on GIAC achieved favorable engraftment, OS, and an acceptable morbidity of GVHD among allo-HSCT patients [23][24][25][26][27][28][29].…”

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“…Venetoclax with azacitidine is a new first-line therapeutic option for patients with AML ineligible for intensive chemotherapy based on the VIALE-A trial and it has also been studied in combination with low-dose ara-C and IDH inhibitors in the up-front setting ( 56 , 168 , 169 ). In the transplant setting, venetoclax has been studied in combination with RIC and MAC chemotherapy regimens in patients with high-risk myeloid malignancies ( 65 , 170 ). The VIALE-T study is recruiting patients to study venetoclax with azacitidine maintenance versus standard best supportive care after alloHSCT (NCT04161885).…”

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“…The 1-year OS was 84%, with relapse incidence (RI) of 13% and NRM of 10%. Another study in younger patients (median age 25) reported outcomes of venetoclax with MAC in 31 high-risk AML patients who underwent their first alloHCT with low 600-day RI and NRM, 6.9% and 11.7%, respectively [ 44 ]. Of note, most patients received haploidentical transplant and high-risk AML was defined as refractory or relapsed AML, MRD-positive at transplantation, or adverse ELN risk.…”