Overcoming High-Risk MDS/AML Post-Allogeneic HSCT: Venetoclax and Azacitidine As Maintenance Therapy
Authors: Ohga Shintaro , Yamauchi Takuji , Yoshimoto Goichi , Kato Koji , Akashi Koichi 
Published: December 2024

Myelodysplastic syndromes (MDS) and Acute myeloid leukemia (AML) are hematologic malignancies with poor prognoses. Although recent advancements in genetic mutation analysis and the development of molecular targeted therapies have improved treatment outcomes, only a limited number of patients benefit from these targeted therapies. Hematopoietic stem cell transplantation (HSCT) is a well-established curative treatment, but the prognosis for patients who relapse after transplantation remains miserable. While the efficacy of post-transplant maintenance therapy with FLT3 inhibitors has been demonstrated, it is not applicable to AML patients without FLT3 mutations. Then, it is urgent needed that developing post-transplant therapies to prevent relapse for high risk MDS/AML patients without druggable targeted mutation.
Venetoclax is a novel drug that inhibits the anti-apoptotic molecule BCL2 and has been designated as a breakthrough therapy by the FDA. The combination therapy of Venetoclax and Azacitidine, a hypomethylating agent, has been reported to significantly improve treatment outcomes compared to Azacitidine monotherapy (DiNardo, NEJM, 2020). This combination therapy, although highly effective, has a lower treatment intensity compared to intensive chemotherapy such as 3+7 and high-dose cytarabine and is widely used in elderly patients with MDS/AML. Given that Venetoclax plus Azacitidine therapy is considered tolerable even for frail patients after allogeneic HSCT, we performed Venetoclax plus Azacitidine after allogeneic HSCT in 14 high-risk MDS/AML patients to assess efficacy and safety of the maintenance therapy.
The median age of the patient cohort was 60 years. The AML subtypes included AML-NOS (not otherwise specified) (6 cases), therapy-related AML (1 case), AML-MRC (with myelodysplasia-related changes) (5 cases), and MDS/AML (2 cases). Among the 12 AML cases, the ELN risk classification was favorable in 1 case, intermediate in 5 cases, and adverse in 6 cases. The pre-transplant disease status was CR (complete response) in 11 cases and non-CR in 3 cases. All 14 patients were in hematologic remission at the start of maintenance therapy, with only one patient in a mixed chimerism state. Seven out of the 14 patients had a history of Venetoclax administration prior to transplantation.
The median observation period was 817 days (range 12-1439 days), with the median post-transplant overall survival (OS) not yet reached and a 1-year OS rate of 91.7%. The median cumulative relapse time was not reached, with a 1-year cumulative relapse rate of 25.0%. The cumulative incidence of moderate-to-severe chronic graft-versus-host disease (cGVHD) was 3 out of 14 patients (21.4%). The most common grade 3-4 adverse events during maintenance therapy were leukopenia, neutropenia, and thrombocytopenia, all of which were transient and manageable. Three patients had TP53 gene mutations, which are considered one of the most adverse prognostic factors in AML. Of these, two patients achieved long-term remission. This suggests that post-transplant Venetoclax plus Azacitidine maintenance therapy may overcome the poor prognosis associated with TP53-mutated AML clones. However, one patient developed progressive multifocal leukoencephalopathy caused by the JC virus as a non-hematologic toxicity. There are concerns that inhibition of BCL2 signaling might induce immunosuppression, potentially leading to viral infections. Nonetheless, as these observations are based on a small cohort, further careful monitoring and investigation are warranted.
This study suggests that post-transplant Venetoclax plus Azacitidine maintenance therapy is tolerable and may reduce relapse rates while improving survival outcomes. Although concerns such as viral infections exist, the therapy also shows potential in overcoming high risk MDS/AML such as TP53-mutated clones. Further accumulation of cases and detailed reporting are needed for more comprehensive evaluation.