A metronomic, low-dose schedule of decitabine and venetoclax was deemed to be a safe and effective treatment for patients with myeloid malignancies. Patients with acute myeloid leukemia (AML) who received the combination experienced a median overall survival (OS) of 16.1 months, and patients with TP53-mutated disease had an OS of 11.3 months. Mendel Goldfinger, MD, of Montefiore Medical Center in Bronx, New York, and colleagues published their evaluation of metronomic dosing in an older, racially diverse population of patients in Blood.
Dr. Goldfinger described the low-dose result as “more than a signal at this point. We are clearly seeing much less toxicity with metronomic dosing, and in this small trial, the efficacy seems similar, but it needs fine-tuning to understand which patients may benefit most from metronomic low dose versus standard dosing.”
Dr. Goldfinger explained that the U.S. Food and Drug Administration (FDA) approved hypomethylating agents (HMA) decitabine or azacitidine combination with venetoclax dosing schedule based on the pivotal phase III VIALE-A clinical trial that showed a clear survival advantage for the combination of azacitidine and venetoclax over single-agent azacitidine. However, this trial did not address the optimal dosing of these drugs.
The pivotal clinical trial, like most clinical trials, was designed based on the maximum tolerated dose. In contrast, Dr. Goldfinger and his colleagues created their trial to identify the optimal dosing schedule with the lowest dose that achieves efficacy while sparing functioning hematopoietic cells and thereby minimizing toxicity from myelosuppression. The phase II trial enrolled 31 patients (21 with AML; six with high-risk myelodysplastic syndromes [MDS]; two with MDS/myeloproliferative neoplasms [MPN]; and two with chronic myelomonocytic leukemia) between April 2022 and September 2023 in a single academic center. Six of the patients with AML and all six patients with high-risk MDS had TP53-mutated disease. Patients received a once-weekly dose of decitabine (0.2 mg/kg SQ) and one dose of venetoclax (400 mg PO) on days 1, 8, 15, and 22 of a 28-day cycle. In this study, 90% of patients were able to receive continuous therapy without dose reductions or delays. There were no treatment-related mortalities, with a 100% 60-day survival. The overall response rate was 57%.
The results indicated that precision dose scheduling decreased toxicity and delivered a similar efficacy to that seen with the higher dose. This regimen was first adopted by the group at Montefiore during the COVID-19 pandemic. Dr. Goldfinger explained that when the pandemic hit, the team had a limited ability to treat their patients. As a result, they “quickly adopted this regimen to try to keep patients out of the hospital.” They found that the patients had similar survival to that seen with the FDA-approved dosing regimen but much less toxicity. He said that, because of the findings, the weekly low-dose regimen was studied in this prospective clinical trial.
“The FDA now mandates that drugs be dosed in a smarter way,” Dr. Goldfinger said, describing the FDA’s Project Optimus that is intended to reform the dose optimization and dose selection paradigm in oncology. “It’s clear that it’s time to revisit our approach to dosing … Our drugs are much more targeted and smarter.”
Dr. Goldfinger explained that toxicity reduction benefits patients treated today and paves the way for advancements in hematology treatments. “Even though the addition of venetoclax has had a dramatic benefit, we still don’t cure most older patients with MDS and AML who can’t tolerate chemotherapy and stem cell transplants,” he said. There is thus a need to add a third agent to the combination of HMA with venetoclax, but until the toxicity from the two existing agents can be reduced to a tolerable level, it will be difficult to add to the current regimen. If more extensive trials confirm that lower dosing is as effective as approved dosing, then drug developers have a path toward adding a third drug. “Our next step is to find that triplet to drive the field forward,” he said.
While Dr. Goldfinger acknowledged that the results still need to be repeated in a larger trial, the current findings are particularly interesting for patients with TP53-mutated disease. He pointed out that patients without an intact TP53 gene have difficulty repairing their DNA. Unfortunately, for patients with AML and TP53 mutations, the addition of venetoclax has not improved long-term outcomes. “With this regimen, it seems unique in this population. There is an added benefit,” he said.
Any conflicts of interest declared by the authors can be found in the original article.
Reference
Goldfinger M, Mantzaris I, Shastri A, et al. Weekly low-dose regimen of decitabine and venetoclax is efficacious and less myelotoxic in a racially diverse cohort [published online ahead of print 2024 Sept. 24]. Blood. doi: 10.1182/blood.2024025834.
