medwireNews: Findings from a proof-of-principle study indicate that use of the Janus kinase (JAK)1 inhibitor itacitinib alongside a calcineurin inhibitor (CNI) may help prevent graft-versus-host disease (GvHD) after allogeneic hematopoietic cell transplantation (alloHCT).

The phase 1 GRAVITAS-119 study results were presented at the virtual 62nd American Society of Hematology Annual Meeting and Exposition by Hannah Choe, from The Ohio State University in Columbus, USA.

She explained that the study was open to adults with hematologic malignancy, such as acute myeloid leukemia or myelodysplastic syndrome, undergoing peripheral blood stem cell transplant who were candidates for reduced-intensity conditioning, and had a Karnofsky score of at least 70% or an ECOG performance status of 0–2. The majority of patients had an intermediate disease risk index.

In all, 65 patients were given itacitinib 200 mg/day from 3 days before alloHCT up to day 90 after transplantation, followed by a dose reduction to 100 mg/day up to day 180.  

Forty-one of the patients were given itacitinib in combination with the CNI tacrolimus plus methotrexate alone (n=33) or alongside antithymocyte globulin (ATG; n=8), while 24 patients instead were given the CNI cyclosporine A plus mycophenolate mofetil alone (n=8) or alongside ATG (n=16).

Of the patients in the tacrolimus and cyclosporine A groups, a respective 26.8% and 50.0% completed treatment at day 180, with a median itacitinib exposure of 140 days; the majority (73.8%) of study participants received itacitinib for more than 90 days, Choe said.

Discontinuation in the tacrolimus–methotrexate arm occurred following adverse events (AEs; 24.4%), relapse (19.5%), nonspecified causes (14.6%), acute GvHD (7.3%), and chronic GvHD (7.3%), while for the cyclosporine A–mycophenolate mofetil arm, treatment was discontinued because of AEs (16.7%), death from infection or intracranial hemorrhage (12.5%), relapse (12.5%), and acute GvHD (4.2%). 

The primary endpoint of hematologic recovery – defined as recovery of both absolute neutrophil count and platelet level by day 28 – was achieved by 98.5% of patients; one patient who achieved only platelet recovery within the target period subsequently achieved neutrophil recovery on day 31.

Graft failure occurred in 3.1% of patients, one patient on day 65 of itacitinib treatment and one patient on day 182, around 4 months after they had ended treatment. Both patients subsequently underwent a second alloHCT.

Choe said that the rates of the secondary endpoint of cumulative incidence of acute GvHD at 180 days were “low” and “compared favorably with historical data for CNI-based regimens,” with grade II–IV rates of 10.2–13.0% and grade III–IV rates of 4.3–5.1% depending on ATG use. 

The cumulative incidence of chronic GvHD at 1 year ranged from 43.6% to 44.6% for any-grade events and was 10.4–31.3% for moderate or severe events, with a lower rate of the latter found for patients given ATG.

“However, these results must be interpreted with caution because of the small sample size and possible confounding factors,” the presenter said, such as use of concomitant use of rituximab for Epstein-Barr virus infection.

The estimated 1-year GvHD and relapse-free survival rate (GRFS) was 23.1% for itacitinib plus CNI, rising to 60.9% with additional ATG, with estimated 1-year overall survival rates of 74.3% and 82.6%, respectively. 

The most common grade 3 and more severe hematologic AE was thrombocytopenia (49.3%), with 29.2% of patients each experiencing anemia or decreased levels of white blood cells, neutrophils, and lymphocytes, respectively. The most common nonhematologic AEs at this severity were diarrhea (15.4%), hypertension (13.8%), and hypertriglyceridemia (12.3%).

Of note, AEs resulted in itacitinib dose reduction or discontinuation in 23.1% of patients, most commonly due to thrombocytopenia (9.2%) or mixed chimerism (6.2%).

Grade 3 or more severe infections occurred in 26.8% of patients given itacitinib plus CNI and 33.3% of those who also received ATG; bacterial infections were more common in the former group (14.6 vs 4.2%) and viral infections less common (7.3 vs 25.0%).

In patients given itacitinib plus CNI, there was one death from infection during treatment and 11 deaths during follow-up, from malignancy relapse (n=5), infection (n=3), pulmonary failure (n=2), and ischemic stroke (n=1). Among patients who also received ATG, there were two deaths on treatment from infection and intracranial hemorrhage, respectively, followed by two deaths after treatment from acute GvHD.

Choe summarized that the use of itacitinib plus a CNI-based regimen both “permitted timely hematopoietic engraftment” and did not “appear to increase the risk of graft failure, relapse/progression, or infections.”

Nor did addition of itacitinib to regimens including ATG “appear to increase rates of infection or relapse,” and also “yielded encouraging GRFS.”

The investigator concluded that use of itacitinib should be evaluated “for efficacy in a larger, more homogenous population” and that the use of the JAK1 inhibitor is now being studied in the GRAVITAS-119 study as an additive to post-transplantation cyclophosphamide.

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62nd ASH Annual Meeting and Exposition; 5–8 December 2020