A multicenter phase 2 clinical trial has provided promising evidence for the use of low-dose subcutaneous decitabine in patients with myelofibrosis (MF). The study, published on November 26, 2024 in the journal Blood Advances, was conducted across multiple centers in the United States and funded by the National Cancer Institute.
The primary objective of this prospective trial was to assess the efficacy and safety profile of low-dose decitabine in patients with MF. The study enrolled 21 patients, including 18 with chronic phase MF, 2 with accelerated phase MF, and 1 with blast phase MF. Eligible patients were adults aged 18 or older who met the Italian Consensus Criteria for MF diagnosis and had either palpable splenomegaly or hemoglobin levels below 11 g/dL. Key exclusion criteria included prior treatment with decitabine, known central nervous system disease, and inadequate organ function.
The demographic data revealed a median age of 67 years (range 40-89), with 57% of participants being male. The majority of patients (76%) had primary myelofibrosis, while 19% had post-polycythemia vera MF and 5% had post-essential thrombocythemia MF. Notably, 81% of patients had intermediate or high-risk disease according to the Lille scoring system, and 76% had either intermediate-2 or high-risk disease by the International Prognostic Scoring System model.
Treatment consisted of subcutaneous decitabine administered at a dose of 0.3 mg/kg per day on days 1-5 and 8-12 of 42-day cycles. The study reported an overall response rate of 33% (95% confidence interval, 14.6-57.0), with responses primarily manifesting as improvements in cytopenias. The median time to response was 2 months, with a median duration of response of 7 months. Notably, all 7 responders demonstrated improvements in pre-existing cytopenias after treatment.
The study also revealed interesting correlative findings. Patients with high-risk prognosis indicated by a Lille score of ≥2 were more likely to respond to decitabine. Additionally, a sustained early decline in circulating CD34+ cells was associated with response to therapy. Higher baseline levels of fetal hemoglobin were also observed in responders compared to non-responders.
Regarding safety, the most common adverse events were hematologic toxicities, with 71% of patients experiencing grade 3/4 neutropenia, 76% experiencing grade 3/4 anemia, and 62% experiencing grade 3/4 thrombocytopenia. Febrile neutropenia was noted in 48% of patients. Non-hematologic adverse events were less frequent, with fatigue, hypocalcemia, and anorexia being the most common.
The study had several limitations, including its small sample size and single-arm design, which precluded robust multivariable analyses to determine predictors of response. Additionally, the lack of standardized patient-reported outcome measures at the time of study design limited the assessment of symptom burden and quality of life improvements.
Despite these limitations, the authors concluded that the results demonstrate the potential of this 10-day schedule of low-dose subcutaneous decitabine therapy to treat cytopenias associated with MF. They emphasized the low rates of non-hematologic toxicities but acknowledged that myelosuppression was a common side effect, suggesting the need for future investigation of alternative doses and schedules of administration.
The potential clinical impact of this study is significant, particularly for patients with MF who have severe cytopenias. Given the limited treatment options for MF, especially for those with cytopenias, this study supports further investigation into the use of hypomethylating agents as single agents or in combination therapies. The observed benefits in improving anemia and transfusion dependence address a significant unmet need in the field.
Furthermore, the study's findings on potential biomarkers, such as the association between response and sustained decrease in circulating CD34+ cells, as well as higher baseline fetal hemoglobin levels, may help guide future patient selection and response prediction in clinical practice.
The results also open avenues for further research, including the exploration of combinatorial approaches using hypomethylating agents with novel JAK inhibitors. The availability of an oral decitabine-cedazuridine preparation may facilitate future trials in this regard, potentially leading to more convenient treatment options for patients with MF.
In conclusion, this phase 2 trial provides valuable insights into the use of low-dose subcutaneous decitabine in myelofibrosis, offering a potential new treatment strategy for managing cytopenias in this challenging disease. While larger randomized controlled studies are needed to confirm these findings, the results represent a promising step forward in expanding the therapeutic arsenal for myelofibrosis patients, particularly those with severe cytopenias who have limited treatment options.
References
Lin C, Patel AA, Huo D, et al. A multicenter phase 2 clinical trial of low-dose subcutaneous decitabine in myelofibrosis. Blood Adv. 2024;8(22):5735-5743. doi:10.1182/bloodadvances.2024013215
