Decadine Demonstrates Therapeutic Potential for the Treatment of Myelofibrosis

Low-dose subcutaneous decitabine (Dacogen; MGI Pharma Inc) demonstrated clinically meaningful overall response rates (ORR) in a small trial of patients with myelofibrosis (MF). The results, published in Blood Advances, supports further investigation into the use of hypomethylating agents as monotherapies or combination therapies for treatment of this challenging disease.¹

The treatment showed favorable safety with low frequency of non-hematologic toxicities. Image Credit: © Formoney - stock.adobe.com

MF is an uncommon myeloproliferative neoplasm (MPN) that results in increasingly reduced blood cell production caused by the proliferation of hematopoietic stem cells. Despite increased knowledge of the genomic landscape of MPNs, there is little understanding of the mechanisms underlying MF; however, studies have shown that the dysfunctional interaction between abnormal megakaryocytes and stromal cells contribute to the excessive buildup of fibrous tissues and scarring within the bone marrow. This interaction leads to severe anemia, weakness, and fatigue.²

Decitabine is a chemotherapy agent approved by the FDA as a monotherapy in 2006 and as a combination therapy with cedazuridine (Inqovi; Astex Pharmaceuticals) for the treatment of myelodysplastic syndromes. In vitro and in vivo studies show that decitabine enters cancer cells and incorporates itself into the cells’ DNA. Once inside, decitabine inhibits DNA methylation to reactivate previously silenced tumor suppressor genes. Additional studies also found that decitabine induces differentiation of bone marrow cells, resulting in the normalization of bone marrow in some patients.^3,4

In the prospective, multicenter, phase II study of decitabine in MF (NCT00095784), researchers evaluated the safety and efficacy of subcutaneous decitabine in 21 patients with chronic- (n=18), accelerated- (n=2), and blast-phase (n=1) MF. The primary end points were response rates including complete and partial responses and hematological improvement, as well as the treatment’s overall safety. As secondary end points, the researchers aimed to identify the effects of decitabine on specific epigenetic changes, hemoglobin F levels, and on the absolute numbers of circulating CD34+ progenitor cells.^1,5

The patients were treated on days 1-5 and 8-12 with subcutaneous decitabine at 0.3 mg/kg/day, repeating every 42 days until disease progression or unacceptable toxicity. According to the results, there was an ORR of 33% (95% CI, 15-57), which primarily manifested as an improvement in cytopenias. There was a median duration of response of 7 months (range, 3-44). The researchers also reported a high IPSS risk score, high baseline fetal hemoglobin level, and sustained decreases in circulating CD34+ cell counts associated with decitabine treatment.¹

The treatment showed favorable safety with low frequency of non-hematologic toxicities such as fatigue, anorexia, and hypocalcemia being the most common. All the patients experienced at least 1 grade 3 or 4 cytopenia.¹

The results suggest the need for further research into decitabine as a potential therapeutic option for patients with MF, who are often limited to fewer therapeutic options focused on symptom palliation. Decitabine may pave the pathway towards advancements in therapies beyond symptom palliation therapies that can effectively treat MF.

REFERENCES

1. Lin C, Patel A, Huo D, et al. A multicenter phase ii clinical trial of low-dose subcutaneous decitabine in myelofibrosis. Blood Adv. September 9, 2024. doi:10.1182/bloodadvances.2024013215

2. Study finds ruxolitinib may slow fibrosis progression in myelofibrosis. Pharmacy Times. September 24, 2024. Accessed October 2, 2024. https://www.pharmacytimes.com/view/study-finds-ruxolitinib-may-slow-fibrosis-progression-in-myelofibrosis

3. Decitabine. National Library of Medicine. July 27, 2024. Accessed October 2, 2024. https://www.ncbi.nlm.nih.gov/books/NBK548668/

4. Fda approves oral combination of decitabine and cedazuridine for myelodysplastic syndromes. FDA. July 7, 2020. Accessed October 2, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-oral-combination-decitabine-and-cedazuridine-myelodysplastic-syndromes

5. Decitabine in treating patients with myelofibrosis. ClinicalTrials.gov Identifier: NCT00095784. Updated August 27, 2024. Accessed October 2, 2024. https://clinicaltrials.gov/study/NCT00095784