Conference Coverage

Ixazomib targets treatment failure in chronic GVHD



HOUSTON – Ixazomib may reduce treatment failure in patients with advanced chronic graft-versus-host disease (cGVHD), findings from a phase 2 trial suggest.

Patients who received ixazomib in this trial had a lower rate of treatment failure – a composite endpoint of death, relapse, and need for additional systemic immunosuppressive therapy – than that of historical controls.

Joseph Pidala, MD, PhD, of Moffitt Cancer Center in Tampa, Fla., presented this finding at the Transplantation & Cellular Therapy Meetings.

The trial (NCT02513498) included 50 patients with a median age of 58 years (range, 44-65). Patients had acute leukemia (52%), lymphoma (18%), chronic leukemia (12%), myelodysplastic syndromes/myeloproliferative neoplasms (8%), and myeloma (4%).

Most patients (90%) received peripheral blood transplants, but 10% received bone marrow. Patients had matched unrelated donors (48%), matched related donors (44%), mismatched unrelated donors (6%), and mismatched related donors (2%).

Most patients (84%) had severe cGVHD, but 16% had moderate cGVHD. About half of patients (52%) had four or more organs involved, and 78% received three or more prior lines of systemic therapy for cGVHD. The median time from cGVHD onset to trial enrollment was 33.5 months.

“[I]t was an advanced population that was highly treatment experienced,” Dr. Pidala said.

Initially, patients received ixazomib at 4 mg on days 1, 8, and 15 of a 28-day cycle for up to six cycles. However, the protocol was amended to allow additional cycles for responders.

Fifty-two percent of patients (n = 26) completed at least six cycles of therapy. The remaining patients stopped treatment because of unresolved toxicity, treatment failure, withdrawal, noncompliance, and death.

“Seven patients, in total, did continue therapy beyond six cycles,” Dr. Pidala said. “Six of these had partial response at 6 months, and one had stable disease.”

The overall response rate at 6 months was 40%. All 20 responders had partial responses.

The 6-month treatment failure rate was significantly lower in this trial than in historical controls (Blood 2013 121:2340-6). The rates of treatment failure were 28% and 44%, respectively (P = .01).

Treatment failure was largely due to the need for additional treatment, Dr. Pidala noted. Relapse and nonrelapse mortality were “uncommon” in this trial.

The investigators did not find any patient, transplant, or cGVHD-related factors significantly associated with 6-month treatment failure.

The failure-free survival rate at 6 months was 72% in this trial and 56% in historical controls. The failure-free survival rate at 12 months was 57% and 45%, respectively.

Serious adverse events occurred in 38% of patients on this trial. Patients required ixazomib dose reductions due to thrombocytopenia, fatigue, diarrhea, and infection.

There were five deaths, and two of them were considered possibly related to ixazomib.

“This was driven by the proximity of the death events to the last dose of ixazomib, specifically, within 1 month,” Dr. Pidala said. “One of these death events was a case of respiratory failure. The other was a case of sudden, unexplained death.”

The meeting was held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research. At the meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).

Dr. Pidala reported having nothing to disclose. Other investigators reported relationships with Pfizer, CSL Behring, Agios, Incyte, Genentech, and Takeda. The trial was sponsored by the Fred Hutchinson Cancer Research Center in collaboration with the National Cancer Institute.

SOURCE: Pidala J et al. TCT 2019, Abstract 35.

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