Ibrutinib for Therapy of Steroid-Refractory Chronic Graft Vs. Host Disease: A Multicenter Real-World Analysis
Year: 2024
Type: article
Study design: Observational Study
Abstract: Ibrutinib has been studied in steroid-refractory chronic graft vs. host disease (SR-cGVHD), yet the phase II trial that led to FDA approval contained 42 subjects, had restricted organ involvement, and median 2 prior lines of therapy. To expand on this evidence base, we conducted a multi-center real-world study. Eligible subjects had SR-cGVHD, did not have relapsed malignancy post-transplant, and were treated with ibrutinib after the FDA approval date (8/2017 onward). No other restrictions were placed for cGVHD organ sites/features, or prior lines of cGVHD therapy. The NIH 2014 Consensus Response Measures were used to compute responses using serial cGVHD organ scores. Time-to-event outcomes were assessed from ibrutinib start date. Failure-free survival (FFS) was a composite outcome including death, relapse, or new line of cGVHD therapy. 270 subjects from 19 centers were studied. Median age was 57 (range 4-77). The majority had previously received PBSC grafts with non-PTCY GVHD prophylaxis. Involved organs at ibrutinib start included skin (59%), eye (50%), mouth (45%), joint/fascia (40%), GI (24%), lung (22%), liver (15%), genital (6.3%), other (4.4%). Overall NIH severity was mild in 5.7%, moderate 42%, severe 53%. 61% had overlap subtype. KPS was ≥ 80% in 79% of subjects. Median prednisone (mg/kg) was 0.21 (0-2.27). Ibrutinib was started at median of 18.2 months after cGVHD onset most commonly at 420mg dose (66% of subjects; reductions in others for drug interaction or clinician discretion) and largely in earlier lines of therapy (2nd line: 26%, 3rd: 30%, 4th: 21%, 5th: 9.6%, 6th/beyond: remainder). Among evaluable subjects, the 6 month overall response rate (CR/PR) was 45% (PR 42%, CR 3%), with others having lack of response (unchanged/mixed/progression). Median duration of response was 13 months (range 1-46). Most cGVHD features (overlap status, PLT, KPS, prednisone dose, NIH overall severity, time from cGVHD, prior lines of therapy) did not have significant association with 6 month CR/PR, except liver involvement (multivariate (MVA) OR 5.49 (95% CI 2.3-14.2, p <0.001) had greater response. The best overall response (CR/PR) was 56%, with the majority (86%) achieving best response by 1-3 months after start. With median follow up time for survivors of 30.5 months, FFS was 59% (53-65%) at 6 months and 41% (36-48%) at 12 months (Fig 1). On final MVA, increased age (HR 1.01, 95% CI 1.0-1.02, p=0.033), higher baseline prednisone dose (HR 1.92, 1.09-3.38, p=0.032), and lung involvement (HR 1.58, 1.1-2.28, p=0.016) were associated with worse FFS. OS at 6 and 12 months was 93% (90-97%) and 87% (83-91%), respectively. Toxicities (hold/stop ibrutinib) are in Fig 2-3). These multicenter real-world data support that ibrutinib has activity in SR-cGVHD, provide new insight into factors associated with response and FFS, and demonstrate the toxicity profile associated with dose reduction or discontinuation.
Authors: Joseph A. Pidala, Mary E.D. Flowers, Zachariah DeFilipp, Dr. Iskra Pusic, Muna Qayed, Anthony D Sung, Helen Tang, Hemalatha G. Rangarajan, Aaron Etra, Najla El Jurdi, Betty K. Hamilton, Mehdi Hamadani, Gulrayz Ahmed, Nosha Farhadfar, Dr. Corey Cutler, Kuo-Kai Chin, Carrie L. Kitko, Marcello Rotta, Eneida Nemecek, Doris M. Ponce, William J. Hogan, Samantha Jaglowski
Institutions: Moffitt Cancer Center, Fred Hutch Cancer Center, Massachusetts General Hospital, Washington University in St. Louis, Emory University, Duke University, Duke Medical Center, Hospital of the University of Pennsylvania, Nationwide Children's Hospital, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, University of Minnesota, Cleveland Clinic, Medical College of Wisconsin, University of Florida, Dana-Farber Cancer Institute, Memorial Sloan Kettering Cancer Center, Vanderbilt University Medical Center, Colorado Blood Cancer Institute, Oregon Health & Science University, OHSU Knight Cancer Institute
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $3,650
OpenAlex ID: W4391603643