David Sallman, MD, an assistant member of the Malignant Hematology Department of Moffitt Cancer Center and Research Institute, Tampa, Florida, commented on the IMerge and QUAZAR studies for The ASCO Post. As background, he noted the “predominant struggle” of patients with lower-risk myelodysplastic syndromes (MDS) is symptomatic anemia and transfusion dependence. “Thus, therapies are predominantly focused on restoring normal hematopoiesis,” he noted.
Following failure of erythropoiesis stimulating agents, therapeutic options in the United States include lenalidomide (approved solely for deletion 5q MDS) and hypomethylating agents. Additionally, in April 2020, luspatercept received approval in the above patient population with increased ringed sideroblasts based on the phase III MEDALIST trial, which found 38% more patients in the luspatercept arm achieved transfusion independence for at least 8 weeks.1
David Sallman, MD
In the phase II IMerge trial, imetelstat, a first-in-class telomerase inhibitor, resulted in a high percentage of patients achieving 8-week transfusion independence (42%). “Most notably,” he observed, “these responses were durable, with a median duration of response of 20 months and nearly one-third of responses lasting more than 1 year.”
“Future investigation is required to further evaluate whether there is disease-modifying activity and, importantly, whether there are clinical or genetic factors that predict response, particularly given the overlap in patient populations with luspatercept,” Dr. Sallman added. “Together, these data are encouraging and support the ongoing placebo-controlled phase III portion of the IMerge trial, which would support approval if the primary endpoint is met.”
Comments on QUAZAR Trial
Also commenting on the phase III QUAZAR study of CC-486, Dr. Sallman noted that although the hypomethylating agents (ie, azacitidine and decitabine) have improved outcomes in patients with higher-risk MDS, the data are more unclear in patients with lower-risk disease. “Despite the lack of disease-modifying activity, however, they are extensively utilized in lower-risk patients in the United States, with transfusion independence rates ranging from 15% to 50%.”
Dr. Sallman added: “Notably, these agents can only be administered via subcutaneous or intravenous routes, and thus oral hypomethylating options would be of value to decrease the significant clinical burden on monthly schedules of hypomethylating agents in this patient population.”
The QUAZAR trial did meet its primary endpoint of transfusion independence (31%) but was closed early secondary to a nonsignificant rate of higher early deaths in the CC-486 arm. Overall, this response rate is within the range of transfusion independence rates with standard hypomethylating agents, although not superior to their historical counterparts,” he pointed out.
Dr. Sallman further noted that the study used a 21-day schedule of CC-486 to potentially maximize efficacy, but recent studies in lower-risk MDS have suggested similar response rates can be achieved with a reduced schedule of a hypomethylating agent. In a study by Jabbour et al,2 intravenous decitabine for 3 consecutive days per 28-day cycle resulted in a 32% transfusion independence rate and was well tolerated (0% mortality at 6 weeks). Future investigation is required to evaluate the optimal schedule of CC-486 in patients with lower-risk MDS, he said.
DISCLOSURE: Dr. Sallman has served as a consultant or advisor to Agios, BMS, Celyad, Incyte, Kite Phamra, Novartis, and Syndax; has participated in a speakers bureau for AbbVie, Agios, Incyte, and Novartis; has received institutional research funding from Celgene and Jazz; and holds a patent for LB-100.
REFERENCES
1. Fenaux P, Platzbecker U, Mufti GJ, et al: Luspatercept in patients with lower-risk myelodysplastic syndromes. N Engl J Med 382:140-151, 2020.
2. Jabbour E, Short NJ, Montalban-Bravo G, et al: Randomized phase 2 study of low-dose decitabine vs low-dose azacitidine in lower-risk MDS and MDS/MPN. Blood 130:1514-1522, 2017.
