PROTEOSOME INHIBITOR FOR GVHD

A proteasome drug used for the treatment of multiple myeloma could be a treatment option for patients with advanced chronic graft versus host disease (GVHD).

Ixazomib (Ninlaro, Takeda) achieved a significant improvement in treatment failure rate when compared to historical controls, according to the results of a US phase II trial.

Specifically, among 50 patients who had failed multiple immunosuppressive agents and were treated with ixazomib, there was a 6-month treatment failure rate of only 28% vs 44% seen in historical data (P = 0.01).

The majority of the patients had acute leukemia.

Ixazomib was approved in 2015 by the US Food and Drug Administration as a second-line therapy for multiple myeloma in combination with lenalidomide and dexamethasone.

The results were presented here at the Transplantation and Cellular Therapy (TCT) 2019 Meetings.

Presenter Joseph A. Pidala, MD, PhD, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, said that the reduction in treatment failure rate vs benchmark data was "notable" given that the historical data came from patients who had received fewer prior treatments.

He also underscored that the partial response rate of 40% at 6 months seen with ixazomib, as well as the "modest" reduction in prednisone doses required, indicated that the drug has "activity" in advanced GVHD.

Session co-chair John Koreth, MD, DPhil, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, told Medscape Medical News that he was not "overwhelmed" by the findings, but they showed that ixazomib was a "reasonable option."

"We’ve previously tried using bortezomib [Velcade, Takeda] in a similar setting, maybe earlier in the course of disease, and had fairly similar results," said Koreth, who was not involved with the current research.

Koreth believes that there’s "some activity" but added the caveat that ixazomib was tested with steroids and not alone. Noting "a huge convenience" that ixazomib is an oral medication, Koreth said that "it’s a glass half-full story, that’s my sense; I’m not thinking of it as a game changer".

Nevertheless, he said that it’s not entirely surprising that a drug approved for use in the treatment of myeloma could have activity against chronic GVHD.

He explained: "It was obviously developed for myeloma and there’s clearly story about how it impacts B cells."

"But we know chronic GVHD is a story of both T and B cells," continued Koreth, "and there’s a lot of preliminary data in animal models saying proteasome inhibition, NF-κB inhibition, does affect T-cell activation as well."

Study Details

The participants had to have failed on at least one systemic immune suppressive therapy for chronic GHVD but not have started a new agent within the previous 2 weeks.

Ixazomib was given at a 4 mg oral weekly dose on days 1, 8, and 15 of a 28-day cycle for up to six cycles.

After amending the protocol, it was permitted that patients with responsive GVHD could continue receiving treatment beyond the six cycles, and patients were followed up for a total of 1 year.

Pidala underscored that the vast majority of treatment failures are 6 months, and for the rest of the study these treatment failures occurred because of changes in treatment, as opposed to nonrelated mortality or relapse.

Further analysis revealed that the 6-month treatment failure was not associated with any patient, transplant, or chronic GVHD variables. Using the NIH response criteria for chronic GVHD, the team determined that the overall response rate at 6 months was 40%.

Moreover, ixazomib was found to have a better failure-free survival rate than that seen in the historical data, at 72% vs 56% at 6 months and 57% vs 45% at 12 months.

The researchers also found that the median dose of prednisone used by the patients declined during the course of the study, from 0.14 mg/kg at enrollment to 0.07 mg/kg at 6 months, and 0.01 mg/kg at 12 months.

During the post-presentation discussion, Pidala said that seven patients "elected to continue on cycles beyond six because they had ongoing responses."

He added that, based on individual patient trajectories, some of the patients who responded to ixazomib but came off the drug did not require another line of therapy, although the overall picture was "mixed."

Consequently, the researchers are planning on further study to identify biomarkers associated with treatment response.

The median age of the patients was 58 years, and 76% were male. The majority (52%) had acute leukemia, 18% had lymphoma, and 12% had chronic leukemia.

In 90% of the cases, the source of the graft was peripheral blood. The median time from transplant to study enrollment was 3.6 years; the time from the onset of chronic GVHD to enrollment was 2.8 years.

The vast majority (84%) of patients had severe GVHD on the National Institutes of Health (NIH) criteria, and it was classic type GVHD in 80%.

In addition, 52% of patients had at least four organs involved, and 78% had received at least three prior lines of therapy.

Investigator Pidala showed that 52% of patients completed six cycles of treatment with ixazomib. The reasons for not completing six cycles were unresolved toxicity (16%), treatment failure (10%), and study withdrawal (8%).

The most common reasons for dose reduction were thrombocytopenia, fatigue, diarrhea, and infection.

Thirty-eight percent of patients experienced a serious adverse event, and there were five deaths (two of which were deemed possibly related to ixazomib).

Pidala and Koreth have disclosed no relevant financial relationships; other study authors disclosed consultancy with Pfizer, CSL Behring, Agios, and Takeda, as well as research funding from Incyte, Genentech, and Pfizer.

Transplantation and Cellular Therapy (TCT) 2019 Meetings: Abstract 35. Presented February 21, 2019.