Ruxolitinib Resistance or Intolerance in Steroid-Refractory Chronic Graft-Versus-Host Disease - a Real-World Single Center Analysis
Authors: Ahmed Gulrayz , Al Homssi Amer , Ahmed Ramsha , Longo Walter , Shah Nirav N. , Runaas Lyndsey , Pasquini Marcelo C. , Fenske Timothy S. , Rein Lisa E , Szabo Aniko , Hamadani Mehdi , Abedin Sameem 
Published: December 2024

Background: Chronic graft-versus-host disease (cGVHD) is a cause of significant morbidity and mortality in allogeneic hematopoietic cell transplant (alloHCT) recipients. For cGVHD requiring immunosuppression, steroids remain frontline therapy, followed by ruxolitinib as second line. There are limited real-world data for patients who fail ruxolitinib as second line treatment in cGVHD. We assessed patterns of ruxolitinib failure and/or intolerance and responses to 3rd line treatments in patients with cGVHD.
Methods:This is a single center retrospective study to identify and characterize ruxolitinib failure in steroid refractory cGVHD (SR-cGVHD). AlloHCT recipients aged ≥18 years for any hematological malignancy, receiving ruxolitinib for SR-cGVHD between January 2016 and February 2024 were included. Baseline demographics, alloHCT related variables and treatment modalities for cGVHD utilized prior and after ruxolitinib were collected. Grading and response to cGVHD treatment were defined as per 2014 NIH criteria. Ruxolitinib failure was defined as, (i) Failure to achieve a complete response (CR) or partial response (PR) after ≥90 days of use, (Iii) Loss of response and/or development of cGVHD in another organ leading to initiation of additional systemic immunosuppressive therapy and (iii)discontinuation of ruxolitinib due to intolerance.
Results: Forty-seven patients with cGVHD were included who met the above ruxolitinib failure/intolerance criteria. Median age at ruxolitinib failure/intolerance was 56 (range: 22 - 82) years with 55% (n = 26) being male. AML was the most common transplant indication (n = 24), 68% patients underwent marrow ablative conditioning and 96% (n = 45) patients received tacrolimus and methotrexate for GVHD prophylaxis. 57% (n = 27) patients had history of prior acute GVHD. Median time for cGVHD onset post alloHCT was 264 (IQR 76 - 1337) days. 18, 26 and 3 patients had mild, moderate and severe cGVHD respectively at onset, with 24, 11, 9 and 3 patients having 1, 2, 3 and 4 organs involved respectively. Oral (47%), liver (36%) and skin (32%) were the most common organs involved. Lungs were involved in 19% (n = 9). 30 (64%) patients were on immunosuppressive at that time. Median time to ruxolitinib initiation post alloHCT was 411 (IQR: 304 - 1174) days. Median number of prior treatments for cGVHD was 1 (range 1 - 5). 10 mg BID was the most common starting dose for ruxolitinib. 6 (13%), 29 (62%) and 12 (26%) of patients had mild, moderate and severe cGVHD at initiation of ruxolitinib. No patients had life threatening cGVHD. Best overall response rate (ORR) to ruxolitinib was 51% with a median time of 79 days. After ruxolitinib failure/intolerance, the three most common next line agents used were belumsoudil (51%), ECP (30%) and on trial axatilimab (4.5%). Concurrent ruxolitinib was continued in 11 patients along with third line therapy. At ruxlotinib failure/intolerance 2 (4.3%), 20 (43%), 24 (51%) and 1 (2.1%) patient had mild, moderate, severe and life threatening cGVHD, with skin (n = 22), lung (n = 20), and oral (n = 15) being the most common involved organs, respectively. ORR to 3rd line therapy was 38.6% (n = 17) with 4.5% achieving CR. ORR to 3rd line therapy for patients who failed ruxolitinib versus intolerant to ruxolitinib was 41% and 20% respectively.
Belumosudil was initiated at a median of 1477 (range 172 - 4845) days post-alloHCT. Median duration on belumosudil was 356 (95% CI: [153, 627]) days. Patients who initiated belumosudil (n = 24), ORR was 33% (n = 8) with none achieving CR. ORR in patients with belumosudil initiation before and after 2 years of alloHCT were 14% (n = 1) and 41% (n = 7) respectively. Among patients that initiated ECP alone or in combination with another agent, ORR was 71% (n = 10) with 2 patients achieving CR. ECP was initiated at a median of 508.5 (range 232 - 1749) days post-alloHCT. Median duration on ECP was 466.5 (95% CI: [167, Not reached]) days.
11 (25.6%) patients continued ruxolitinib while initiating 3rd line therapy of which 6 were concurrently on ECP (ORR 67%, 1 CR, 3 PR, 1 Stable disease [SD], 1 PD) while 3 were on belumosudil (ORR 67%, 2 PR, 1 SD).
Conclusion: cGVHD remains a significant problem, with patients requiring therapy after ruxolitinib. Third line therapy provides modest benefit with responses in 38.5% of patients, creating potential for new drug development or utilizing current drugs as combinations for improved outcomes.