Ibrutinib Plus Prednisone Improves Patient-Reported Outcomes in cGVHD

Ibrutinib when given in combination with prednisone has been shown to improve patient-reported outcomes in chronic graft-versus-host disease (cGVHD), according to study findings presented at the EHA2021 Virtual Congress.

About 34% of patients with cGVHD require systemic treatment after hematopoietic cell transplant, according to Dr David Miklos, Stanford University School of Medicine, Stanford, California, and colleagues.

“Many patients experience recurrent cGVHD or become refractory to standard of care first-line corticosteroids. Ibrutinib has demonstrated sustained efficacy and safety in cGVHD and is currently the only therapy approved in the United States for adults with cGVHD after failure of ≥1 line of systemic therapy,” said Dr Miklos.

Thus, Dr Miklos et al developed the phase 3, randomized, double-blind iNTEGRATE study to determine the efficacy and safety of ibrutinib plus corticosteroids in previously untreated patients with cGVHD.

Patients were eligible for the study if they had newly diagnosed moderate/severe cGVHD, required systemic corticosteroid therapy, and had no prior systemic treatment for cGVHD.

The primary end point was complete or partial response rate at 48 weeks per the 2014 NIH Consensus Development Project Criteria. Other endpoints included event-free survival, duration of response (DOR), time to withdrawal of corticosteroids and immunosuppressants (except ibrutinib/placebo), improvement of Lee cGVHD Symptom Scale score, overall survival (OS), and safety.

Overall, 95 patients received 420mg of ibrutinib plus prednisone, starting at 1 mg/kg/d, and 98 patients received placebo plus prednisone. Both arms had balanced baseline characteristics.

The median time patients were on treatment was 5.4 months and 6.4 for the ibrutinib/prednisone and placebo/prednisone arms, respectively. The median follow-up was 25 months for both. At the time of the primary analysis, 41% (39) of patients treated with ibrutinib/prednisone had a response at 48 weeks compared to 37% (36) of patients receiving placebo/prednisone (p=0.54).

Although the primary end point did not meet statistical significant, ibrutinib/prednisone had clinically meaningful improvements in several other end points. Researchers suggested that those endpoints be evaluated further.

With extended follow up, the median DOR was 16 months for the ibrutinib/prednisone arm compared to 10 months for the placebo/prednisone arm. The median EFS was 15 months for ibrutinib/prednisone and 8 months for placebo/prednisone (hazard ratio [HR] 0.75, 95% CI: 0.53-1.1; p=0.1).

Corticosteroids were withdrawn by 48% (ibrutinib/prednisone) and 39% (placebo/prednisone) of patients, and 38% versus 28% (p=0.08) withdrew immunosuppressants, respectively. Improvements in the overall Lee cGVHD Symptom Scale score were experienced by 40% of patients in the ibrutinib/prednisone arm, and 29% of patients in the placebo/prednisone arm (p=0.09). The median overall survival was not met by either arm.

The most common grade ≥3 serious adverse events (AEs) were experienced in 49% (46) of patients in the ibrutinib/prednisone arm and 46% (44) in the placebo/prednisone arm. Also, 22% (21) and 25% (24), respectively, experienced an AE leading to discontinuation of the study drug, while 22% (21) and 19% (19), respectively, died from any cause.

“Numerical trends of improved clinical outcomes in the ibrutinib-prednisone arm were noted, including longer DOR and EFS and improved patient-reported outcomes. Safety was consistent with the known profiles of ibrutinib and prednisone and was similar between treatment arms. The positive trends observed in other important clinical endpoints along with no additional safety trends and concerns suggest that ibrutinib may have value in some previously untreated patients with cGVHD,” Dr Miklos concluded.

Miklos D, Zaid MA, Cooney JP, et al. Ibrutinib vs placebo in combination with corticosteroids in patients with new-onset chronic graft-versus-host disease (cgvhd): results from the randomized, double-blind phase 3 integrate study. Presented at: the EHA2021 Virtual Congress; June 9-17, 2021; virtual. Abstract S235.