Progress in risk-adapted acute GVHD therapy

In this issue of Blood, Etra et al report that itacitinib, a selective JAK1 inhibitor, has activity as the primary treatment of acute graft-versus-host disease (GVHD). The use of itacitinib spared steroid exposure and was associated with decreased infectious complications compared with a matched control population.¹ 

Advances are needed to improve the safety and efficacy of acute GVHD treatment. Systemic corticosteroids (commonly, prednisone at 1 to 2 mg/kg/day starting dose) are the long-standing standard initial therapy for acute GVHD. Limitations of this practice include incomplete efficacy with subsequent steroid-refractory GVHD and associated mortality, morbidity, and complications of prolonged steroid therapy. As important, the universal application of high-intensity treatment does not respect individual disease risk. Important prior research has defined clinically based and biomarker-based tools to provide risk stratification of acute GVHD,^2,3 and the field has begun to test novel interventions in acute GVHD risk subgroups. These new strategies may hold promise to personalize GVHD therapy, in which the right intensity of therapy is delivered to the right patient.

In this current report, the investigators describe notable results of a multicenter phase 2 trial testing steroid-free initial therapy with itacitinib among patients with clinical and biomarker-defined low-risk acute GVHD. Although ruxolitinib has been studied in steroid-refractory acute GVHD (and is now approved for this indication),⁴ the investigators chose to test itacitinib in this setting for potential advantage in hematologic toxicities. As well, itacitinib has been tested in combination with corticosteroids for acute GVHD treatment.⁵ A total of 70 patients with low-risk (Minnesota standard risk, biomarker AA score 1) acute GVHD were treated with itacitinib and compared with a matched control population (140 patients from a prospectively assembled multicenter consortium) meeting the same eligibility criteria and treated with at least 0.5 mg/kg/day prednisone therapy. The results support that this steroid-free therapy achieved a high response rate (overall response rate [ORR] of 89% at day 28). There was no signal of inferior outcomes compared with the steroid control group considering day 28 ORR, response according to subgroups of GVHD organ involvement and severity, time to initial response, durability of response, or risk for treatment failure or GVHD flare. Importantly, the itacitinib-treated participants had significant reduction in cumulative prednisone exposure through days 28 and 56 of therapy compared with control participants and significant reduction in risk of infectious complications. Itacitinib discontinuation occurred for lack of efficacy (10% of participants), treatment-emergent (most commonly hematologic) adverse events (AEs) (29%), or relapse of malignancy (3%). A total of 30% of itacitinib-treated participants had other (nonhematologic, noninfectious) treatment-emergent ≥ grade 3 AEs, with the highest frequency events being alanine aminotransferase increase and hypertension. There was no evidence of worsened long-term outcomes, including chronic GVHD, relapse, and nonrelapse mortality. Potential limitations (nonrandomized control group, not standardized infectious prophylaxis, limitation to AA biomarker score 1 participants, possibility that topical therapy alone could be sufficient) of this work were well described.

Additional progress in the field will require selection of priority interventions and allied trial designs for risk-adapted therapy. A national Blood and Marrow Transplant Clinical Trials Network randomized trial is currently underway in high-risk acute GVHD (NCT04167514). For lower-risk acute GVHD (the majority of acute GVHD cases), at least 3 (lower-dose prednisone,⁶ sirolimus,⁷ itacitinib) steroid-minimizing or steroid-free primary therapy approaches have now been tested, albeit with variation in the definition of standard or lower-risk acute GVHD. These and other agents should be considered in development of randomized trials, and such investigation should capture a full extent of treatment benefit and risks, including steroid exposure, infectious complications, and patient-reported outcome measures. Taken together, there is significant promise to advance the field toward personalized therapy of acute GVHD.

Conflict-of-interest disclosure: J.P. reports consulting and advisory board membership (Syndax, CTI Biopharma, Amgen, Regeneron, Incyte) and clinical trial support (Novartis, Amgen, Takeda, Janssen, Johnson and Johnson, Pharmacyclics, CTI Biopharma, BMS).