Update of Multicenter, Retrospective Evaluation of Overall Response and Failure Free Survival Following Ruxolitinib Therapy for Heavily Pre-Treated Chronic Gvhd Patients with Steroid-Failure: A Proposal of Risk Score Model for Failure-Free Survival

Abstract Background The REACH3 trial evaluating Ruxolitinib (RUX) treatment for steroid-refractory chronic GVHD concluded that RUX leads to significantly greater overall response and failure-free survival (FFS) than best available therapies (NEJM 2021). We reported a real-world experience of RUX in 47 chronic GVHD (cGVHD) patients, with 36% overall response rate (ORR) at 6 months (ASH 2020). The present study expanded this to 115 pts, evaluating ORR, FFS and overall survival (OS), and explored prognostic factors associated with clinical outcomes. Patients and methods A total of 115 patients treated with RUX for cGVHD from 2016 to 2021 at 5 sites were evaluated retrospectively. Patients and disease characteristics are as follows: median age 57.5 years; males 67 (60%); organ involvement at the time of RUX: skin 75.7%, mouth 51.3%, eye 42.6%, gastrointestinal 19.1%, liver 39.1%, lung 31.3%, and musculoskeletal 38.3%. Out of 108 pts with available HCT-CI prior to HCT, 29 pts (26.9%) had HCT-CI score 3 or higher, while 79 (73.1%) had HCT-CI score 0-2. The ORR were assessed at months 3, 6 and 12, retrospectively. Treatment failure was defined as 1) resistance requiring treatment switch, 2) non-relapse mortality (NRM), 3) relapse, 4) intolerance to treatment. FFS and OS were calculated from the day of starting RUX therapy for cGVHD treatment. For risk factor analysis, logistic regression was adopted for ORR at 6 months, while Cox's proportional hazard model was implemented for FFS and OS at 12 months. The following variables were evaluated for risk factor analysis: GVHD-related factors (cGVHD severity, no. of organ involvement, prednisone dose or RUX dose at start, previous history of acute GVHD); host factors (age or performance status at RUX starts, sex, HCT-CI comorbidity score pre-HCT); transplant factors (conditioning intensity; donor type, HLA match, T-cell depletion). From those variables identified as significant in the multivariate analysis, a prognostic risk score was generated as the sum of adverse risk factor scores. Results A total of 115 pts had severe (n=69, 60%) or moderate grade (n=44, 38.3%) cGVHD except 2 (1.7%) who had mild grade cGVHD with high-risk features. The median number of organ involvement was 3 (range 1-7). 96 pts (84.2%) received RUX as 4 th line or beyond for cGVHD treatment. The previous treatments included mycophenolate mofetil (n=46, 40.0%), extracorporeal photopheres (n=45, 39.1%), Imatinib (n=13, 11.3%), and Ibrutinib (n=9, 7.8%). RUX was started at 10-20 mg daily as the initial dose, then maintained at 20mg daily in two divided doses on months 3, 6 and 12. With a median follow-up duration of 12 months, ORR was attained in 46.8%, 61.8% and 62.3% at 3, 6 and 12 months, similar to 49.7% ORR rate at 6 months in the REACH3 study. ORR in the range of 48.1-64.5% at 6 months was observed across all the organs involved. No difference in ORR was noted between steroid-resistant vs steroid-dependent cGVHD, or according to previous treatment with TKI drug for GVHD. For ORR, severe grade cGVHD showed a lower ORR rate at 46.8% at 6 months compared to those with moderate/mild grade cGVHD at 81.1% (p=0.001). In terms of prednisone dose reduction, by 12 months, more than half of pts (63.8%) could taper prednisone doses below 0.1mg/kg/day, while the proportion of pts on prednisone dose below 0.1mg/kg/day was 14.83%, 33.6%, 47.6%, and 63.8% at month 0, 3, 6 and 12, respectively. A total of 39 failures (33.4%) were noted, including resistance requiring switch to other therapy (n=17), NRM (n=14), relapse of primary disease (n=3) and intolerance (n=5). The FFS rate in the overall population was 64.6% (54.1-73.2), while the OS rate was 83.3% (74.4-89.4%) at 12 months. For FFS, two risk factors were identified for FFS (Figure): 1) Severe grade cGVHD at RUX start (p=0.008, HR 2.496 [1.229-5.072]); 2) HCT-CI comorbidity 3 or higher (p=0.001, HR 2.802 [1.493-5.259]). When a risk score model was generated, it stratified pts according to the FFS at 12 months (p=0.0001): 85.8% in score 0 (n=32); 58.7% in score 1 (n=57); and 36.8% in score 2 (n=19). Conclusion: Updated results confirm that RUX is an effective treatment option for cGVHD pts, even including heavily treated pts. Also, favorable response was observed across all organs involved with GVHD. Failure of RUX is associated with cGVHD severity and HCT-CI score. Figure 1 Figure 1. Disclosures White: Novartis: Honoraria. Elemary: Jazz, BMS, Abbvie, Novartis, Pfiz: Membership on an entity's Board of Directors or advisory committees; Pfizer, Janssen: Membership on an entity's Board of Directors or advisory committees. Hamad: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Law: Novartis: Consultancy; Actinium Pharmaceuticals: Research Funding. Mattsson: MattssonAB medical: Current Employment, Current holder of individual stocks in a privately-held company. Kim: Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria; Paladin: Consultancy, Honoraria, Research Funding; Bristol-Meier Squibb: Research Funding. OffLabel Disclosure: This presentation discusses the use of ruxolitinib for chronic GVHD. This indication is under FDA review.

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