Inhibiting JAK1: lowering CRS, CAR stays on track Free

In this issue of Blood, Frigault et al¹ report results of a phase 2 study demonstrating that itacitinib, a selective JAK1 inhibitor, reduced rates of cytokine release syndrome (CRS) in patients with hematologic malignancies undergoing chimeric antigen receptor T-cell (CAR-T) therapy. Most patients in the study had relapsed/refractory large B-cell lymphoma (LBCL) and received axicabtagene-ciloleucel (axi-cel).

CD19-directed CAR-T therapies, including axi-cel, have demonstrated impressive efficacy in relapsed/refractory LBCL,² but toxicities have limited its broader application in patients with significant comorbidities, especially in older patients.³ Axi-cel is associated with 6.5% to 16% rates of grade 3 to 5 CRS and 21% to 35% grade 3 to 5 immune effector cell–associated neurologic toxicity (ICANS).⁴ In a real-world comparison, axi-cel showed superior progression-free survival compared with lisocabtagene-maraleucel, but with higher frequency of CRS and ICANS.⁵ Improving safety is crucial for broader use and improved outcomes in relapsed LBCL when using CAR-T.

CRS is an inflammatory syndrome that arises from complex interactions between CAR-T cells and tumor antigens, leading to an initial release of effector cytokines. These cytokines then activate stromal cells, including macrophages, monocytes, and dendritic cells, which further amplify the cytokine release, including interleukin (IL)-2, IL-6, interferon-γ, C-reactive protein, granulocyte-macrophage colony-stimulating factor, and IL-2.⁴ High peak CAR-T cell blood levels have been linked to both improved clinical responses and increased rates of CRS, indicating that CAR-T expansion and toxicity may be interconnected.^1,4 Consequently, there are concerns that attempts to reduce toxicity and CRS may hinder efficacy.

Several professional societies have established consensus guidelines for CRS treatment based on severity. First-line treatment involves tocilizumab, an IL-6 receptor antagonist, which is generally recommended for fevers persisting for >3 days or for fever accompanied by hypotension and hypoxia. Dexamethasone is recommended for higher grade CRS or in cases that do not respond to initial treatments. Tocilizumab is preferred before steroids due to concerns that steroids may be directly toxic to CAR-T cells and could potentially decrease treatment efficacy. Although the data are conflicting, a retrospective study of axi-cel–treated patients showed that earlier steroid use, higher cumulative doses, and prolonged steroid exposure were associated with shorter overall survival.⁶ In recent years, interest has shifted from mitigation to CRS prevention. Early data raised concerns that prophylactic tocilizumab may increase ICANS, but later studies did not support this idea. Various strategies for preventing and treating CRS and ICANS are being explored and have been summarized in a recent review.⁴ 

As Janus kinase (JAK) mediates downstream signaling from cytokine receptors implicated in CRS, JAK inhibition offers a promising approach to mitigate this toxicity. Treatment with ruxolitinib, a JAK1/2 inhibitor, resulted in a significant decline in serum cytokines in refractory CRS. However, as CAR-T cells had already peaked before ruxolitinib use and continued their decline, coupled with in vitro experiments demonstrating that ruxolitinib inhibits CAR-T expansion, there are concerns ruxolitinib may reduce efficacy.⁷ 

Itacitinib, a selective JAK1 inhibitor, demonstrated in preclinical models a dose-dependent reduction in cytokines without significantly inhibiting CAR-T proliferation.⁸ Therefore, it has the potential to reduce CAR-T–related CRS without compromising efficacy.

In their study, Frigault et al report results of a 2-part, phase 2 study of itacitinib for the prevention of CRS. Phase 1 was a single-arm study evaluating itacitinib 200 mg/day, starting 3 days prior to immune effector cell infusion and continuing through day 26. Patients in phase 1 could be treated with either axi-cel, tisagenlecleucel, or brexucabtagene autoleucel, at the investigator's discretion. Phase 2 enrolled patients ≥18 years of age with relapsed or refractory diffuse LBCL or follicular lymphoma eligible to receive axi-cel. Patients were randomized to receive itacitinib 200 mg twice daily or placebo over the same period. The primary endpoint was the incidence of grade ≥2 CRS by day 14.

Among 63 part 1 patients and 47 part 2 patients, any-grade CRS was observed in 85.7% (200 mg/day), 65.2% (200 mg twice daily), and 87.0% (placebo) of patients. By day 14, grade ≥2 CRS occurred in 22.2% of those in the group given itacitinib 200 mg/day. In part 2, grade ≥2 CRS was significantly reduced in the itacitinib group (17.4%) compared with placebo (56.4%).

Itacitinib use was associated with reduced tocilizumab use. Dexamethasone use was low overall, with 3 patients receiving steroids in the placebo group and none in the group given itacitinib 200 mg twice daily. Rates of ICANS were numerically lower in the prophylactic itacitinib-treated group as well.

Given the broad toxicity profile of CAR-T therapy, assessing safety in the nonrandomized portion of the study is challenging. There were 4 fatal adverse events (6.3%) in part 1, which is numerically higher than seen in the registrational trials.² However, the randomized portion was reassuring, with similar rates of toxicities in both arms. Investigator-assessed itacitinib-related adverse events were approximately 10% higher in the group given itacitinib 200 mg twice daily compared with the placebo group.

Exploratory analyses revealed significant reductions in tumor necrosis factor-α, IL-6, and IL-2 receptor subunit alpha with itacitinib vs placebo, without significant differences in CAR-T expansion. Progression-free survival and response rates appeared similar between arms, although the study was not powered for efficacy comparisons.

These results suggest that itacitinib may prevent severe CRS without compromising efficacy. In this study, 4.7% of patients treated with itacitinib had a fatal adverse event (including 1 case each of acute kidney injury, sepsis, atrial fibrillation and hypotension, and pneumonia and sepsis in part 1, but none among patients receiving itacitinib 200 mg twice daily or placebo). No CRS-related deaths occurred when axi-cel was given as second-line treatment for LBCL.² Efforts to mitigate CRS, a severe but manageable complication, must avoid introducing new harms. Larger studies are needed to define its safety profile and compare itacitinib with other preventive strategies.

Itacitinib has also been shown to reduce severe CRS and graft-versus-host disease in allogeneic transplant recipients without impairing engraftment.⁹ Frigault et al's findings extend application of this treatment to CAR-T therapy, illustrating the convergence of strategies to prevent graft-versus-host disease and CRS. As T-cell therapies continue to expand, optimizing CRS prevention and management will be critical to broadening access and improving outcomes. In-depth mechanistic studies of how CRS prevention strategies work, as well as the cytokine pathways and single-cell dynamics of breakthrough toxicities, are critically needed.¹⁰ 

Conflict-of-interest disclosure: The authors declare no competing financial interests.