Novel JAK inhibitor may improve safety of certain stem cell transplants
Key takeaways:
- Adding itacitinib to standard prophylaxis may reduce GVHD incidence for patients who undergo haploidentical stem cell transplantation.
- Itacitinib also may reduce incidence of severe cytokine release syndrome.
The addition of itacitinib to standard graft-versus-host-disease prophylaxis may reduce severe toxicities following haploidentical hematopoietic stem cell transplantation, according to results of a single-arm study.
Researchers observed no cases of grade 3 or grade 4 acute graft-versus-host disease, and no cases of grade 2 to grade 5 cytokine release syndrome, among study participants.
“The results were much more dramatic than we expected,” John F. DiPersio, MD, PhD, Virginia E. and Sam J. Golman professor and section director of cellular therapy at Washington University School of Medicine in St. Louis, told Healio. “We think that this is the way to give these JAK inhibitors — upfront and not after patients have developed acute graft-versus-host disease.”
Background
Haploidentical HSCT, which involves a half-match donor such as a parent, child or sometimes a sibling, has become more widely used for people with hematologic malignancies due to improved treatments for GVHD.
“This is the new wave of transplantation,” DiPersio said.
However, 40% to 50% of recipients develop acute GVHD, and 10% to 15% develop life-threatening acute GVHD, according to study background. Patients also develop CRS. Grade 1 to grade 2 CRS actually is associated with longer survival; however, only 25% of those who develop grade 3 to grade 5 CRS survive long term.
DiPersio and colleagues conducted previous research that showed JAK inhibitors, such as ruxolitinib (Jakafi, Incyte), reduced GVHD. However, that research included patients who already developed the condition.
“We wanted to give this early after transplant, but for a number of years the company that owned ruxolitinib would not let us test it early on because it’s a known inhibitor of signaling for some of the cytokine receptors,” DiPersio said. “They thought it might cause too much in the way of decreasing blood counts.”
Itacitinib (INCB039110, Incyte) is a JAK1 inhibitor that blocks the interferon-gamma pathway, but not as much through the cytokine receptors.
“The thought was that itacitinib might cause less decrease in the blood counts but the same protection against graft-versus-host disease,” DiPersio said.
Methods
DiPersio and colleagues evaluated itacitinib for 42 adults (median age at transplant, 59 years; range, 19-72; 57% men) with hematologic cancers who underwent haploidentical transplantation as part of a study that included a pilot and expansion phase.
More than half (60%) of study participants had acute myeloid leukemia.
Participants in the pilot study (n = 20) received 200 mg itacitinib every day from 3 days before transplant to 100 days after, then a taper. Those in the expansion cohort (n = 22) received 200 mg itacitinib through day 180 after transplant, then a taper.
The taper period consisted of 100 mg itacitinib daily for a month, then every other day for another month.
All participants received standard GVHD prophylaxis, which included tacrolimus, mycophenolate mofetil and post-transplant cyclophosphamide.
Incidence of primary graft failure and grade 3 to grade 4 acute GVHD served as the primary endpoints. Incidence and severity of CRS and nonrelapse mortality served as secondary endpoints.
Results
Median follow-up was 453 days (range, 142-1,259).
No participants had primary graft failure.
None developed grade 3 to grade 4 acute GVHD in either phase. The expected rate exceeded 15%, researchers wrote.
In all, 21.9% developed grade 2 acute GVHD after day 100.
In the pilot phase, two patients developed grade 2 skin acute GVHD during taper, but both cases resolved after restarting the regular dose of itacitinib and topical steroids.
Researchers reported cumulative incidence of relapse of 10% at 1 year and 14% at 2 years.
The cohort had a GVHD-free RFS of 85% at 180 days and 79% at 1 year. Historically, rates have been between 36% and 43%.
Participants who got to day 100 without relapse had a 1-year cumulative incidence of moderate or severe chronic GVHD of 5%. After 1 year, 89% had no chronic GVHD, 7% had mild GVHD, and 5% had moderate or severe GVHD.
Results showed nonrelapse mortality rates of 8% at 180 days and 11% at 1 year.
No patients developed grade 2 to grade 5 CRS. Researchers expected a grade 2 CRS rate of 28% and a grade 3 to grade 5 rate of 17%.
Grade 3 febrile neutropenia occurred among 83% of participants.
“The toxicity profile is very well tolerated,” DiPersio said.
Researchers acknowledged study limitations, including it the single-arm design with no control group, and the fact it focused solely on haploidentical transplantation.
“The results may not extend to other donor types and transplant platforms,” they wrote.
‘Future is bright’
DiPersio and colleagues are conducting the same study with ruxolitinib. They also are looking at drug combinations with ruxolitinib to further reduce GVHD.
“I think we’ve developed some reasonable data to support the use of a second drug with ruxolitinib to further limit the amount of graft-versus-host disease, which is already reduced significantly compared with standard of care,” DiPersio said.
However, randomized trials are needed to show prophylaxis with JAK inhibitors should be the new standard of care. DiPersio said he is uncertain those will occur due to funding and interest.
DiPersio emphasized research is needed into JAK inhibitors as prophylaxis in chimeric antigen receptor T-cell therapy for CRS, as well.
“The future is bright — other people will repeat in some fashion the work we’ve done,” he said. “I don’t know if we can show that one JAK inhibitor is going to be better than another. That requires a huge study and a lot of money. I’m not sure if any of these companies really have the desire to do that.
“Five years from now, it’s very possible that JAK inhibitors will be standard prophylaxis for two conditions: haploidentical transplants the way we do them now, and CAR T-cell prophylaxis,” DiPersio added.
For more information:
John F. DiPersio, MD, PhD, can be reached at jdipersi@wustl.edu.
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