Chimeric antigen receptor (CAR) T-cell therapy can induce long-term remission in patients with relapsed or refractory hematologic malignancies; however, its therapeutic benefit can be hampered by the associated cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). The INCB 39110-211 study, published in Blood, demonstrated that itacitinib, a JAK1 inhibitor, can effectively reduce the incidence and severity of these toxicities when used prophylactically in CD19-directed CAR T-cell therapy.
“Blockade of JAK1/JAK2 and gamma interferon signaling is a well-defined, logical, clinically supported way of mitigating CRS,” said corresponding author John DiPersio, MD, PhD, professor of immunology and pathology at Washington University School of Medicine in Missouri. “We think that gamma interferon is involved in an endogenous loop of activating T cells, that it can secondarily activate myeloid cells to produce the cytokines that cause many of the symptoms of CRS, and it may potentially contribute to ICANS.” Dr. DiPersio and colleagues sought to interrupt this endogenous loop.
The phase II INCB 39110-211 study consisted of two parts. In part one, patients received 200 mg of prophylactic itacitinib once daily (qd) three days before immune effector cell (IEC) therapy through day 26 after receiving any one of three CD19-directed therapies, alongside other CRS and ICANS interventions.
In the double-blinded randomized part two, researchers aimed to optimize target coverage with a higher dose of itacitinib: patients were randomized to receive either 200 mg of itacitinib twice daily (bid) or placebo starting three days before IEC therapy with axicabtagene ciloleucel only and continued through day 26.
The study included 63 and 47 patients in parts one and two, respectively. The primary endpoint was incidence of grade 2 or greater CRS by day 14 of treatment. Secondary endpoints included CRS and ICANS incidence, severity, and therapeutic interventions.
Compared with placebo, itacitinib 200 mg bid significantly reduced the incidence of grade 2 or greater CRS by day 14 (56.5% vs. 17.4%, respectively; p=0.003) and showed lower rates of grade 2 or greater ICANS by day 28 (21.7% vs. 8.7%).
Moreover, objective response rates at six months for patients receiving itacitinib 200 mg bid were similar compared with placebo (39.1% vs. 26.1%, respectively). “There was no obvious signal for lack of efficacy,” Dr. DiPersio said, suggesting that itacitinib does not compromise CAR T-cell efficacy, but he emphasized that “to confirm these findings would take a much larger study.”
Overall, itacitinib was well tolerated, and toxicity was limited and reversible. Patients receiving itacitinib bid had a higher incidence of persistent grade 3-4 cytopenias at day 28 compared with qd or placebo, “which is not surprising,” Dr. DiPersio said, “because itacitinib blocks JAK1 but also secondarily JAK1/JAK2 signaling, so it's going to affect cytokine signaling.” Differences in counts did not lead to meaningful differences in severe infections or the need for platelet transfusions after day 28.
Nevertheless, inhibition of JAK1 may help manage the toxicities associated with CAR-T therapy. Itacitinib prophylaxis resulted in reduced systemic cytokine production associated with CRS and ICANS of tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, and IL-2RA over time.
Researchers cite the small sample size and lack of direct comparisons with other therapies as limitations to their ability to generalize study results. Further studies with larger, more diverse patient populations are needed to confirm these findings.
Prospectively, Dr. DiPersio pointed to the potential role of “incorporating itacitinib into the treatment of patients receiving CAR-T ... who may be at the highest risk for the worst CRS toxicity, such as patients coming to CAR-T with high disease burden, elevated LDH, or a highly proliferative tumor.
“We don’t clearly know the mechanisms of CRS yet, and when we do, we can more powerfully block CRS without altering CAR T-cell function, but this is a big step forward.”
Any conflicts of interest declared by the authors can be found in the original article.
Reference
Frigault MJ, Maziarz RT, Park JH, et al. Itacitinib for the prevention of IEC therapy-associated CRS: results from the two-part phase 2 INCB 39110-211 study. [published online ahead of print, 2025 March 16]. Blood. doi: 10.1182/blood.2024026586.
