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Next-generation hypomethylating agent shows promise for intermediate-, high-risk myelodysplastic syndrome
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Guadecitabine demonstrated clinical activity with acceptable toxicity among patients with intermediate- and high-risk myelodysplastic syndrome, according to randomized phase 2 trial results published in The Lancet Haematology.
Moreover, the next-generation hypomethylating agent yielded promising rates of response and OS in a subset of patients with relapsed or refractory disease.
“Guadecitabine (SGI-110, Astex Pharmaceuticals) is a dinucleotide comprising decitabine and deoxyguanosine,” Guillermo Garcia-Manero, MD, chief of the section of myelodysplastic syndromes in the division of cancer medicine at The University of Texas MD Anderson Cancer Center, and colleagues wrote. “Unlike decitabine, guadecitabine is relatively resistant to degradation by cytidine deaminase. Guadecitabine slowly releases its active metabolite decitabine following subcutaneous administration. This attribute results in prolonged exposure time and a reduced maximum plasma concentration of decitabine.”
In the phase 2 portion of the randomized, open-label, dose-ranging phase 1/phase 2 study, Garcia-Manero and colleagues evaluated 105 patients (median age, 72 years; range, 18-89) with intermediate- or high-risk myelodysplastic syndromes or chronic myelomonocytic leukemia who had not been treated previously with a hypomethylating agent (n = 51) or had relapsed or refractory disease after receiving a hypomethylating agent (n = 54).
Study participants, enrolled at 14 North American medical centers, had ECOG performance statuses of 0 to 2 and adequate renal and hepatic function, and had not undergone major surgery within the previous month.
The researchers randomly assigned participants 1:1 to subcutaneous guadecitabine doses of 60 mg/m² (52%; treatment-naive, n = 28; relapsed or refractory, n = 27) or 90 mg/m² (48%; treatment-naive, n = 23; relapsed or refractory, n = 27) on days 1 to 5 of a 28-day treatment cycle. They stratified treatment based on prior treatment with hypomethylating agents. Patients and investigators were not masked.
The analyses omitted three patients who did not receive study treatment.
Overall response, assessed by local investigators as a composite of complete response, partial response, marrow complete response and hematological improvement, served as the study’s primary outcome. Secondary endpoints included OS, blood transfusion and platelet transfusion independence at 8 weeks and 16 weeks and safety.
Median follow-up was 3.2 years (interquartile range, 2.8-3.5).
Results showed an overall response rate among all patients of 47% (95% CI, 37-57), with similar proportion of patients achieving this outcome in the 60 mg/m² group (40%; 95% CI, 27-54) and the 90 mg/m²group (55%; 95% CI, 40-69). Twenty-five of the 49 treatment-naive patients (51%; 95% CI, 36-66) and 23 of the 53 patients with relapsed or refractory disease (43%; 95% CI, 30-58) attained an overall response.
The lower-dose and higher-dose groups had similar rates of complete response (11% vs. 14%).
More patients in the higher-dose group had a marrow complete response compared with the lower-dose group (33% vs. 11%), perhaps owing to a greater percentage of patients in the higher-dose group with baseline bone marrow blast percentages of more than 5% that could qualify for a marrow complete response or more potent effects of the larger dose in the bone marrow, according to researchers.
Fifteen of the 58 patients dependent on red blood cell transfusions at baseline became transfusion-independent for at least 8 weeks, and nine remained transfusion-independent for at least 16 weeks. These rates appeared similar between the dose groups.
Median OS was 460 days (95% CI, 384-663) among all patients, 611 days (95% CI, 408-771) for the 60 mg/m² group and 399 days (95% CI, 303-663) for the 90 mg/m² group. Researchers noted the relatively long median OS among patients with relapsed or refractory disease (352 days; 95% CI, 262-505), who typically survive about 4 to 6 months and for whom no approved therapies exist. Median OS among hypomethylating agent treatment-naive patients was 703 days (95% CI, 458-920).
Thrombocytopenia was the most prevalent grade 3 or higher adverse event, occurring in 41% of patients in the lower-dose group and 57% of patients in the higher-dose group. Other grade 3 or higher adverse events included neutropenia (40% of lower-dose group vs. 51% of higher-dose group), anemia (47% vs. 49%), febrile neutropenia (32% vs. 43%) and pneumonia (25% vs. 31%). Seven patients, all but one of whom had relapsed or refractory disease, died of adverse events, including four in the lower-dose group and three in the higher-dose group. Two treatment-related deaths occurred, one of septic shock in the lower-dose group and one of pneumonia in the higher-dose group.
Based on the results, researchers recommended a guadecitabine dose of 60 mg/m² on a 5-day schedule for patients with myelodysplastic syndromes.
The researchers acknowledged several study limitations, including the small sample size, lack of another treatment comparator, and lack of evaluable data on potential clearance of some mutations among patients who attained prolonged response.
Guadecitabine could hold promise as a future frontline treatment for patients who have failed treatment with other hypomethylating agents, according to a related editorial by Lionel Adés, PhD, Marie Sebert, MD, and Pierre Fanaux, MD, PhD, of Hôpital Saint-Louis and INSERM U944 in Paris.
“The outcome of higher-risk myelodysplastic syndromes might also change based on the very promising effect of newer drugs in people with acute myeloid leukemia, including venetoclax [Venclexta; AbbVie, Genentech] in combination with hypomethylating agents, IDH1 or IDH2 inhibitors (when the respective mutations are present), and chemotherapy with CPX-351 [Vyxeos, Jazz Pharmaceuticals], if results in AML can be reproduced in higher-risk myelodysplastic syndromes,” the researchers wrote. “Nevertheless, irrespective of the drugs evaluated, given the great heterogeneity of myelodysplastic syndromes, a better understanding of the mechanism driving disease occurrence, progression and drug resistance is warranted.” – by Jennifer Byrne
Disclosures: Garcia-Manero reports honoraria and research funding from Astex/Otsuka. Please see the study for all other authors’ relevant financial disclosures. Ades, Sebert and Fanaux report no relevant financial disclosures.
Perspective
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Ruben A. Mesa, MD
Myelodysplastic syndrome remains a challenging chronic myeloid neoplasm that leads to patient morbidity and/or mortality largely through progressive cytopenias and their resulting complications. Progression of myelodysplastic syndromes to AML usually accelerates mortality by worsening those cytopenias. Our current range of commercially available treatment options has been stagnant for over a decade and includes lenalidomide (Revlimid, Celgene), an immunomodulatory drug most active in patients with the del5q cytogenetic change, and the hypomethylating agents azacitidine and decitabine. The hypomethylating agents have had a favorable impact for patients with myelodysplastic syndrome by improving cytopenias, delaying progression to acute leukemia and, undoubtedly for some patients, prolonging survival.
Patients who fail a hypomethylating agent have poor survival outcomes and rarely viable treatment options outside of the clinical trial setting.
Guadecitabine is a second-generation hypomethylating agent, given subcutaneously, whose active metabolite is decitabine but which is more resistant than direct decitabine (given IV) to degradation by cytidine deaminase, leading to longer exposure and reduced peak plasma concentration levels, which might decrease toxicities.
The results of this study are important in demonstrating very substantial rates of meaningful efficacy and tolerability, most importantly among patients who previously failed a hypomethylating agent. There are limitations to the study, which include a variable standard for having “failed” a hypomethylating agent, and no randomization between the study drug and a therapeutic (or supportive care) comparator. Despite these limitations, guadecitabine appears to be a potentially important option for patients with myelodysplastic syndromes who have failed a hypomethylating agent, and those benefits might extend to patients with myeloproliferative neoplasm-myelodysplastic syndrome overlap or even myelofibrosis.
Whether guadecitabine should be considered as frontline therapy ahead of commercially available hypomethylating agents would require a randomized trial, however, the results from this trial would suggest at least equivalent — if not superior — results with this newer agent.
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