Use of ruxolitinib before, during, and after allogeneic stem cell transplant was associated with low rates of GVHD in myelofibrosis.
Treatment with ruxolitinib (Jakafi) before, during, and after administration of allogeneic hematopoietic stem cell transplant (allo-HSCT) led to low rates of graft-vs-host disease (GVHD) in patients with myelofibrosis, according to data from a phase 2 trial (NCT04384692) presented at the
Findings demonstrated that among patients treated with peri-transplant ruxolitinib (n = 45), no instances of primary graft failure were reported; 1 patient experienced secondary graft failure. Grade 2 to 4 acute GVHD occurred in 26.7% of patients; notably, the rate of grade 3 or 4 acute GHVD was 8.9%. At 1 year, chronic GVHD was reported in 22.2% of patients, including 6.6% who had moderate to severe chronic GVHD.
The 1- and 2-year overall survival (OS) rates were 95.3% and 86.2%, respectively. The nonrelapse mortality (NRM) rate at 1 year was 2.5%. Additionally, 6.9% of patients experienced disease relapse at 1 year. Grade 3 and grade 4 infections were reported in 15 patients and 4 patients, respectively.
“Compared [with] patients given standard GVHD prophylaxis with a calcineurin inhibitor and methotrexate, the incidence of acute and chronic GVHD was markedly reduced,” lead study author Rachel B. Salit, MD, said in a presentation of the data. “However, NRM, relapse, and OS were not compromised.”
Salit is an assistant professor in the Clinical Research Division and an affiliate investigator in the Translational Science and Therapeutics Division at Fred Hutch Cancer Center, as well as an associate professor at the University of Washington School of Medicine in Seattle.
JAK inhibitors such as ruxolitinib are integral parts of the treatment paradigm for myelofibrosis, where activation of the JAK-STAT pathway drives the malignancy. Additionally, this pathway has been implicated in GVHD pathogenesis, with JAK signaling playing a key role in inflammation and tissue damage.
As such, investigators sought to evaluate the use of ruxolitinib as GVHD prophylaxis for patients undergoing allo-HSCT. After a previous portion of the study evaluated pre-transplant ruxolitinib use, this portion of the phase 2 trial looked at peri-transplant use of the JAK inhibitor.1,2
In this portion of the trial, investigators enrolled patients aged at least 18 years with primary or secondary myelofibrosis who had intermediate-1–, intermediate-2–, or high-risk disease per Dynamic International Prognostic Scoring System (DIPSS) or DIPSS-plus criteria.1 Other key inclusion criteria comprised a carbon monoxide diffusion capacity higher than 60, a creatinine clearance above 60, an ejection fraction of more than 40%, no liver cirrhosis, and an HSCT comorbidity index of 5 or less. Permitted donor types included HLA-matched sibling donors, 10/10 HLA-matched unrelated donors, 1 allele mismatched unrelated donors, and umbilical cord blood units. Notably, peripheral blood was preferred over bone marrow.
Patients enrolled in this portion of the study received ruxolitinib at a dose determined by platelet count for at least 8 weeks prior to transplant, with tapering starting on day –14 ahead of conditioning; patients were tapered with the goal of reaching 5 mg twice per day by day –4, and this dose was continued through engraftment.
For patients who underwent myeloablative conditioning, it started on day –7 with cytoxan at 120 mg/kg and 4-day busulfan. Reduced-intensity conditioning started on day –5 with fludarabine at 150 mg/kg and melphalan at 140 mg/kg. Donor cells were infused on day 0, and patients also received tacrolimus from day –1 to 220 and methotrexate on days 1, 3, 6, and 11. Ruxolitinib was continued through donor cell infusion and then for 9 to 12 months following transplant.
The dose of ruxolitinib could be increased to 10 mg twice per day at day 28 if they underwent successful engraftment and tolerated the 5-mg dosing. Decreasing to 5 mg once per day was permitted at any time if 5 mg twice per day was not tolerated. For patients who developed grade 2 or higher GVHD, ruxolitinib could be continued or tapered/stopped at clinician discretion. If patients required only topical therapy, ruxolitinib was continued.
The incidence of grade 2 to 4 GVHD at day 100 served as the primary end point. A secondary end point was to determine if the addition of ruxolitinib to GVHD prophylaxis could reduce the incidence of chronic GVHD without compromising relapse, NRM, and OS.
All enrolled patients were receiving ruxolitinib at 5 mg twice per day by day –4, and from days 0 to 100, 11 patients received an increased dose of ruxolitinib at 10 mg twice per day; 10 of these patients were reduced back to 5 mg twice per day due to cytopenias or other adverse effects. Additionally, 10 patients had ruxolitinib reduced to 5 mg once per day due to cytopenias between days 0 and 100. Ruxolitinib was held for 3 patients due to treatment with systemic prednisone (n = 1) and bleeding (n = 2); all 3 patients eventually resumed treatment with ruxolitinib.
At the time of transplant, patients had a median age of 63 years (range, 42-71). Most patients were male (58%), had primary myelofibrosis (56%), had 10/10 HLA matched unrelated donors (62%), received donor cells derived from peripheral blood stem cells (95%), and received RIC (67%). Reported JAK-STAT pathway alterations included JAK2 (60%), CALR (24%), and MPL (13%); 2% of patients harbored none of these alterations. DIPSS scores included low risk (2%), intermediate-1 risk (22%), intermediate-2 risk (64%), and high risk (11%). The median time on ruxolitinib at the time of allo-HSCT was 5 months (range, 2.6-22.6).
Although this was not a randomized study, Salit and colleagues compared outcomes for patients treated with peri-transplant ruxolitinib vs those given pre-transplant ruxolitinib (n = 61). In the pre-ruxolitinib arm, 1 patient had primary graft failure, and 2 experienced secondary graft failure. The rates of grade 2 to 4 acute GVHD and grade 3 to 4 acute GVHD were 71% and 19%, respectively. The 1-year chronic GVHD rate was 25%, including 17% with moderate to severe chronic GVHD. The 2-year OS rate was 79%, and the 1-year relapse rate was 9%. NRM at 1 year was reported in 13% of patients. Grade 3 infections occurred in 58% of patients, and 2% had grade 4 infections.
“The [patient] demographics were similar, with a higher age in the [peri-transplant] group,” Salit said. “[Incidence of grade 2 to 4] acute GVHD had decreased from 71% in the [pre-transplant ruxolitinib] cohort to 27% in the more recent cohort…[rate] of chronic GVHD was approximately the same, but the [rate of] moderate to severe [chronic GVHD] was 7% [with peri-transplant ruxolitinib] vs 17% [with pre-transplant ruxolitinib.]”
Disclosures: Salit reported receiving clinical trial funding from Incyte.
