Azacitidine regimens failed to improve high-risk myelodysplastic syndromes

SAN FRANCISCO — The addition of lenalidomide or vorinostat to azacitidine did not improve response rates in patients with high-risk myelodysplastic syndromes and chronic myelomonocytic leukemia, according to phase 2 study results presented at the ASH Annual Meeting and Exposition.

“While response rates were similar across study arms, a study like this makes us wonder if response rate should be a clinically meaningful endpoint in MDS studies, or if we should routinely be focusing on response duration and OS,” Mikkael A. Sekeres, MD, MS, of the department of hematology and medical oncology at Cleveland Clinic, told HemOnc Today. “That responses appeared to be deeper in combination arms should also make us wonder if we are doing a great disservice to our patients by removing them from therapy too early.”

Mikkael A. Sekeres

Researchers have tried to improve outcomes by combining azacitidine (Vidaza, Celgene) — the

standard upfront therapy for patients with higher-risk myelodysplastic syndromes (MDS) — with other therapies.

“Vorinostat is a histone deacetylase inhibitor that acts synergistically with hypomethylating agents such as azacitidine on epigenetic modification,” Sekeres said during his presentation. “Lenalidomide has also been added to azacitidine, as the two drugs have non-overlapping mechanisms of action.”

A phase 3, prospective study of azacitidine in higher-risk patients with MDS demonstrated an overall response rate of 35%, Sekeres said. However, a previous phase 1/2 study evaluating the combination of azacitidine plus vorinostat (Zolinza, Merck) demonstrated a 70% response rate in 33 patients, and a phase 2 study evaluating azacitidine plus lenalidomide (Revlimid, Celgene) demonstrated a 72% response rate in 36 patients.

In the current analysis, Sekeres and colleagues evaluated data from 276 patients who had higher-risk MDS (82%) — defined as an International Prognostic Scoring System classification of intermediate-2 or high and/or bone marrow blasts ≥5% — or chronic myelomonocytic leukemia (CMML; 18%) with bone marrow blasts <20%. The median age of patients was 70 years (range, 28-93), and 31% were female.

Seven percent of the MDS cases were therapy-related.

Researchers randomly assigned patients 75 mg/m² daily azacitidine on days 1 to 7 of a 28-day cycle (n=92), azacitidine plus 10 mg daily lenalidomide on days 1 to 21 (n=93) or azacitidine plus 300 mg twice daily vorinostat on days 3 to 9 (n=91).

Patients received treatment for a median of 23 weeks. Median follow-up was 9 months (range, 0-26).

The median time to best response was 15 weeks in the azacitidine monotherapy arm and 16 weeks in each the combination arms.

Thirty-seven percent of patients who received azacitidine monotherapy responded to treatment, which was comparable to the 39% response rate in the azacitidine plus lenalidomide arm (P=1) and the 24% response rate in the azacitidine plus vorinostat arm (P=.07).

Complete response rates were slightly higher with azacitidine monotherapy (24%) compared with rates in the lenalidomide (18%) and vorinostat (15%) arms.

“Patients coming off of study early [in the combination arms] may have affected complete response rates, as many could not go on to have a confirmatory bone marrow biopsy to assess complete response,” Sekeres said.

The rate for hematologic improvement was slightly higher in the lenalidomide arm (19%) than in the monotherapy (13%) and vorinostat (7%) arms. Significantly more patients who received lenalidomide achieved neutrophil hematologic improvement than those who received azacitidine alone (P=.05); however, all other rates for neutrophil, erythroid and platelet hematologic improvement were comparable across the arms.

Among patients with CMML, 33% of those on the azacitidine arm responded to treatment, which was not statistically significantly different from the 59% response rate on the lenalidomide arm (P=.15) and the 12% response rate on the vorinostat arm (P=.41).

Median RFS was 7 months in the azacitidine monotherapy arm, 8 months in the lenalidomide arm and 11 months in the vorinostat arm (P=.3 for combinations vs. monotherapy).

Among patients who were on treatment for longer than 6 months, median RFS was 7 months on the azacitidine monotherapy arm, 7.5 months on the lenalidomide arm (P=.74) and 13 months on the vorinostat arm (P=.11).

“We recognize there are biases that go into this type of analysis, but we were trying to account for patients who came off of study drug early,” Sekeres said. “If patients remained on study drug for 6 months or greater … [RFS for] vorinostat did appear to be higher than for patients who received azacitidine monotherapy, but this was not statistically different.”

The most common grade 3 or worse adverse events in the entire cohort were febrile neutropenia (azacitidine, n=10; lenalidomide, n=13; vorinostat, n=13), gastrointestinal disorders (azacitidine, n=4; lenalidomide, n=11; vorinostat, n=23), infections (azacitidine, n=2; lenalidomide, n=3; vorinostat, n=3) and rash (azacitidine, n=2; lenalidomide, n=12; vorinostat, n=1). More patients in the combination arms discontinued treatment due to toxicities, side effects or complications, and these patients were more likely to have non-protocol defined dose modifications. These data may have affected response rates, Sekeres said.

“We have to wonder if combination regimens in MDS are too toxic, and if we need to manage toxicities better,” Sekeres said. “There are provocative data in which both patients and their physicians were questioned on the tolerability of therapy. In those studies, it turns out that doctors were twice as likely to report that their patients had unacceptable toxicities compared to what their patients themselves were reporting. Are the combination therapies too toxic, or do we think that they’re too toxic, and actually our patients may be able to tolerate them for a longer period of time?”

For more information:

Sekeres MA. Abstract #LBA-5. Presented at: ASH Annual Meeting and Exposition; Dec. 6-9, 2014; San Francisco.

Disclosure: Researchers report board of directors, consultant, speakers’ bureau or advisory roles with; and research funding or honoraria from Amgen, Celgene, Incyte, Novartis, Seattle Genetics and Takeda Pharmaceuticals.