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Ruxolitinib mitigates steroid-refractory CRS during CAR T therapy.

ABSTRACT: Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity are two major CAR T related toxicities. With the interventions of Tocilizumab and steroids, many patients can recover from severe CRS. However, some patients are refractory to steroids and develop life-threatening consequences. Ruxolitinib is an oral JAKs inhibitor and promising drug in inflammatory diseases. In this pilot study, we evaluate the efficacy of Ruxolitinib in CRS. Of 14 r/r B-ALL children who received CD19 or CD22 CAR T cell therapies, 4 patients developed severe (?grade 3) CRS with symptoms that were not alleviated with high-dose steroids and thus received ruxolitinib. Rapid resolution of CRS symptoms was observed in 4 patients after ruxolitinib treatment. Serum cytokines significantly decreased after ruxolitinib intervention. All patients achieved complete remission on day 30 after infusion, and we could still detect CAR T expansion in vivo despite usage of ruxolitinib. There were no obvious adverse events related to ruxolitinib. In vitro assays revealed that ruxolitinib could dampen CAR T expansion and cytotoxicity, suggesting that the timing and dosage of ruxolitinib should be carefully considered to avoid dampening anti-leukaemia response. Our results suggest that ruxolitinib is active and well tolerated in steroid-refractory and even life-threatening CRS.

SUBMITTER: Pan J

PROVIDER: S-EPMC7812291 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Ruxolitinib mitigates steroid-refractory CRS during CAR T therapy.

Pan Jing J Deng Biping B Ling Zhuojun Z Song Weiliang W Xu Jinlong J Duan Jiajia J Wang Zelin Z Chang Alex H AH Feng Xiaoming X Tan Yue Y

Journal of cellular and molecular medicine 20201212 2

Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity are two major CAR T related toxicities. With the interventions of Tocilizumab and steroids, many patients can recover from severe CRS. However, some patients are refractory to steroids and develop life-threatening consequences. Ruxolitinib is an oral JAKs inhibitor and promising drug in inflammatory diseases. In this pilot study, we evaluate the efficacy of Ruxolitinib in CRS. Of 14 r/r B-ALL children who received ...[more]

PMID: 33314568

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Project description:Graft-versus-host disease (GVHD), especially steroid-refractory GVHD, remains a life-threatening complication after hematopoietic stem cell transplantation (HSCT). The effect of the JAK1/2 kinase inhibitor ruxolitinib on treating steroid-refractory acute GVHD has been verified by the REACH1/2 study; however, its safety and efficacy in patients with steroid-refractory chronic GVHD (SR-cGVHD) remain unclear. In this retrospective study, 70 patients received ruxolitinib as a salvage therapy for SR-cGVHD. Twenty-four weeks after ruxolitinib treatment, the overall response rate (ORR) was 74.3% (52/70), including 34 patients who achieved complete remission (CR) and 18 who achieved partial remission (PR). The main adverse event was cytopenia, which occurred in 51.4% (36/70) of patients. After ruxolitinib treatment, the percentage of CD4 cells increased from 18.20% to 23.22% (P<0.001), while the percentages of NK (CD16+CD56+) cells and regulatory T cells (CD4+CD127 ± CD25+) decreased (P<0.001, P<0.001). Among the B cell subsets, the proportion of total B cells approximately tripled from 3.69% to 11.16% (P<0.001). Moreover, we observed a significant increase in IL-10 levels after ruxolitinib treatment (P=0.025) and a remarkable decrease in levels of suppression of tumorigenicity 2 (ST2) from 229.90 ng/ml to 72.65 ng/ml. The median follow-up after the initiation of ruxolitinib treatment was 401 (6-1076) days. The estimated one-year overall survival rate of the whole group was 66.0% (54.4-77.6%, 95% CI), and the one-year overall survival rate of patients with mild and moderate cGVHD was 69.6% (57.4-81.8%, 95% CI), which was better than that of patients with severe cGVHD (31.3%, 0.0-66.2%, 95% CI) (P=0.002). Patients who achieved a CR and PR achieved better survival outcomes (84.5%, 73.9-95.1%, 95% CI) than those who showed NR to ruxolitinib treatments (16.7%, 0-34.3%, 95% CI) (P<0.001). At the final follow-up, cGVHD relapse occurred in six patients after they reduced or continued their ruxolitinib doses. Collectively, our results suggest that ruxolitinib is potentially a safe and effective treatment for SR-cGVHD.

Project description:ImportanceRuxolitinib, a selective inhibitor of the Janus kinases 1/2 signaling pathway, has shown a significant response in steroid-refractory chronic graft-vs-host disease (SR-cGVHD), a major cause of morbidity and mortality in individuals who have undergone allogeneic hematopoietic stem cell transplantation (HSCT).ObjectivesTo investigate the clinical response to ruxolitinib in patients with SR-cGVHD after allogeneic HSCT and to evaluate its safety profile during the treatment course.Design, setting, and participantsThis single-center case series included 41 consecutive patients who were treated with ruxolitinib for SR-cGVHD after allogeneic HSCT between August 2017 and December 2019. Data were collected from each patient's medical record at the First Affiliated Hospital of Zhejiang University School of Medicine. Data analysis was conducted from March to May 2020.ExposureRuxolitinib.Main outcomes and measuresTreatment responses, factors associated with response, and adverse effects during ruxolitinib administration.FindingsOverall, 41 patients (median [range] age, 31 [17-56] years; 14 [34.1%] women) were treated with ruxolitinib and included in this study. A total of 15 patients (36.6%) had a complete remission, and 14 (34.1%) had a partial remission, with an overall response rate of 70.7% (29 patients; 95% CI, 56.2%-85.3%). Lung involvement (odds ratio, 0.112; 95% CI, 0.020-0.639; P = .01) and matched related donors (odds ratio, 0.149; 95% CI, 0.022-0.981; P = .048) were associated with less favorable treatment response. Major adverse events associated with ruxolitinib were cytopenias and infectious complications. The median (range) follow-up for this cohort was 14.9 (1.4-32.5) months. Prolonged survival was observed in patients with a male donor (P = .006), complete remission before transplantation (P = .02), baseline moderate cGVHD (P = .02), and skin cGVHD (P = .001).Conclusions and relevanceIn this small, single-site case series, ruxolitinib demonstrated a significant response in heavily pretreated patients with SR-cGVHD and a reasonably well-tolerated safety profile. The results add to the body of literature suggesting ruxolitinib as a promising treatment option in SR-cGVHD.

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Ruxolitinib mitigates steroid-refractory CRS during CAR T therapy.

Publications

Ruxolitinib mitigates steroid-refractory CRS during CAR T therapy.

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