Decitabine and Venetoclax Treatment as Maintenance Therapy in Patients Post Allograft Stem Cell Transplant

Acute myeloid leukemia (AML) is the most common acute leukemia in adults. While 60-80% patients can achieve remission, a high rate of relapse mandates consolidative treatment. Unfortunately, 40% of AML patients and 30% of myelodysplastic syndrome patients will relapse after alloSCT, and those who relapse after transplant exhibit poor outcomes. As such, prevention of post-transplant relapse remains a key interest. Maintenance therapy with low-intensity chemotherapy and/or targeted therapy is one strategy that holds promise to reduce post-transplant relapse, controlling residual subclinical disease before frank relapse. As post-transplant maintenance strategies yield mixed results, standard of care maintenance therapy remains an unmet clinical need. The combination of hypomethylating agents (HMAs), such as decitabine or 5-azacytidine, and the B-cell lymphoma 2 (BCL2) inhibitor venetoclax combination has transformed the management of transplant-ineligible AML patient improving median overall survival (OS) to 14.7 months compared to 9.6 months with azacytidine and placebo at the cost of more pronounced cytopenias (Grade 3 and 4 thrombocytopenia and neutropenia occurring in 45%/38% and 42%/28% respectively). Recent work has demonstrated a mechanism by which HMAs cooperate with venetoclax, via priming AML cells for death via the integrated stress response (ISR). The ISR transcription factor activating transcription factor-4 (ATF4) is upregulated in a matter of hours after HMA treatment, and in turn activates Phorbol-12-myristate-13-acetate-induced protein 1 (PMAIP1) (NOXA) that degrades the BCL2-family member myeloid cell leukemia sequence 1 (MCL1), thus creating greater dependence in HMA-exposed malignant cells on BCL2 to avoid BAX/BAK mediated mitochondrial outer membrane permeabilization (MOMP), caspase release, and subsequent apoptosis. An irreversible step toward apoptosis is mitochondrial outer membrane permeabilization (MOMP) by BAX/BAK oligomers, which releases caspase proteases into the cells, a commitment into apoptosis that is fundamentally counteracted by BCL2-family antiapoptotic proteins, e.g., BCL2, the target of venetoclax inhibition. This mechanism primes AML blasts for venetoclax-mediated toxicity. Through rigorous pharmacological optimization, it has been shown that the decitabine 5 mg/m2 weekly with a single dose of venetoclax 6 hours after the decitabine can control disease with limited effects normal hematopoietic cells.9 This novel dosing regimen may maximize decitabine/venetoclax anti-leukemic activity while minimizing hematologic toxicity and represents an attractive regimen for post-alloSCT maintenance therapy.