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Guadecitabine shows promise in high-risk myelodysplastic syndrome, CMML
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SAN DIEGO — Patients with higher-risk myelodysplastic syndromes and chronic myelomonocytic leukemia responded favorably to guadecitabine, according to findings presented at the ASH Annual Meeting and Exposition.
Guadecitabine (SGI-110, Astex Pharmaceuticals) — a next-generation hypomethylating agent — demonstrated activity even in patients with adverse biological features such as high frequency of complex karyotype, therapy-related disease and TP53 mutations.
The agent is formulated as a dinucleotide of decitabine and deoxyguanosine. It has an increased length of exposure compared with decitabine because of reduced metabolism by cytidine deaminase.
Phase 1 and phase 2 clinical trials of guadecitabine demonstrated clinical activity and safety in untreated and previously treated patients with myelodysplastic syndrome.
Guillermo Montalban-Bravo, MD, fellow in leukemia at The University of Texas MD Anderson Cancer Center, and colleagues conducted a single-arm, nonrandomized, phase 2 trial to evaluate the clinical activity of guadecitabine in a cohort of 40 patients with newly diagnosed, higher-risk MDS and chronic myelomonocytic leukemia (CMML).
“Therapeutic options in higher-risk myelodysplastic syndrome and CMML are limited,” Montalban-Bravo said. “Response rates are still low and there are poor outcomes with hypomethylating agent failure.”
Patients received 60mg/m2 guadecitabine subcutaneously daily on days 1 through 5 every 28 days. Complete response served as the primary outcome measure. Overall response rate, EFS, OS and transfusion independence served as secondary endpoints.
The study included 43 patients with MDS and seven patients with CMML. Nine percent were classified as high-risk by International Prognostic Scoring System (IPSS) standards. However, using the revised IPSS criteria, 42% fell into the very high–risk category.
After a median follow-up of 4 months (range, 0-19 months), patients had received a median of six (range, 1-17) treatment cycles.
Among 44 patients evaluable for response, 32% had a complete response and the ORR was 71%. The complete response rate was 32% among patients with myelodysplastic syndrome and 33% for patients with CMML. The ORR rates were 68% for myelodysplastic syndrome and 83% for CMML.
The median OS for the entire cohort was 14 months, and median EFS was 8.4 months.
TP53 was the most commonly reported mutation. However, TP53 mutation did not impact survival outcomes, according to Montalban-Bravo.
“Only RUNX1 predicted response,” he said.
Twenty patients remain on the study, five of whom are on their first cycle. Of that group, seven have had a complete response, five have had a microscopic complete response and four have had no response. Ten patients have been scheduled to undergo allogeneic stem cell transplantation.
Grade 1 to grade 2 nausea and neutropenia were the most common adverse events. Grade 3 febrile neutropenia occurred in 32 patients, and 26 patients experienced infections.
“These data suggest that guadecitabine has activity in patients with higher-risk myelodysplastic syndrome and CMML,” Montalban-Bravo concluded. “Guadecitabine was active in the presence of high-risk mutations. The regimen was well tolerated. – by Rob Volansky
For more information:
Montalban-Bravo G, et al. Abstract 346. Presented at: The ASH Annual Meeting and Exposition; Dec. 3-6, 2016; San Diego.
Disclosures: Montalban-Bravo reports no relevant financial disclosures. Please see the abstract for a list of all other researchers’ relevant financial disclosures.
Perspective
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Henry Chi Hang Fung, MD
This is the first time guadecitabine (SGI-110, Astex Pharmaceuticals) has been administered subcutaneously rather than intravenously, which can be an advantage for some patients. The standout result is that there was a response even in patients with the TP53 mutation, which usually means a very severe disease. This may be the area where this drug will benefit the most. It is also important that we saw a response at the molecular level.
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