scholarly journals Efficiency and Toxicity of Ruxolitinib as a Salvage Treatment for Steroid-Refractory Chronic Graft-Versus-Host Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Dong Wang ◽  
Yin Liu ◽  
Xiaoxuan Lai ◽  
Jia Chen ◽  
Qiao Cheng ◽  
...  
Keyword(s):  
Overall Survival ◽  
Survival Rate ◽  
Graft Versus Host Disease ◽  
Overall Survival Rate ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
One Year ◽  
Steroid Refractory

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.

scholarly journals Successful and Safe Treatment of Intestinal Graft-Versus-Host Disease (GvHD) with Pooled-Donor Full Ecosystem Microbiota Biotherapeutics

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1993-1993
Author(s):  
Florent Malard ◽  
Faezeh Legrand ◽  
Jérôme Cornillon ◽  
Amandine Le Bourgeois ◽  
Jean-Baptiste Mear ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Graft Versus Host Disease ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
Steroid Dependent ◽  
Gi Symptoms ◽  
Microbiota Diversity ◽  
Steroid Refractory

Introduction Intestinal Graft-versus-Host Disease (GvHD), following allogeneic Hematopoietic Stem Cell Transplantation (allo-HSCT), comes with a high mortality rate and a reduced life-expectancy. In this context, failure to respond to steroid therapy is associated with an absence of further therapeutic options, thereby representing an unmet medical need. A marked reduction in gut microbiota diversity leading to loss of functions was strongly associated with reduced overall survival in GvHD, while a high gut microbiota diversity appears to be protective. Aiming at restoring microbiome functions, Fecal Microbiota Transfer proved to be a promising treatment modality in this challenging clinical situation, with recent studies reporting favorable results in steroid refractory-acute GVHD (SR-aGvHD) patients. Here we report on the use of "MaaT013", a standardized, pooled-donor, high-richness microbiota biotherapeutic, used to treat 8 patients with intestinal-predominant aGvHD. Patients and methods Eight allo-HSCT recipients with steroid-dependent or steroid-refractory gastrointestinal GvHD (classical aGVHD n=3, late-onset aGVHD n=2; aGvHD with overlap syndrome n=3) were treated with the MaaT013 biotherapeutic as part of a compassionate use program. These patients had previously received and failed 1 to 5 lines (median 2.5) of GvHD systemic treatments. MaaT013 microbiota biotherapeutics were provided as a pharmaceutical preparation to hospitals by the developer, "MaaT Pharma". Each patient received 1 to 3 doses (median: 3; total doses administered: 21) of MaaT013, a 150 mL bag, by enema (n=7) or nasogastric tube (n=1). GvHD response was evaluated 7 days after each administration and 28 days after the first dose. Prepared under Good Manufacturing Practices, MaaT013 biotherapeutics are characterized by a highly consistent richness of 455 +/- 3% Operational Taxonomic Units (OTUs) and an Inverse Simpson index greater than 20. Batch release specifications are based on potency (viability), identity (diversity), and purity (microbiological safety testing following regulatory guidelines and proportion of proinflammatory species), ensuring the desired consistency between batches. Results We observed 6/8 positive responses at D28 after first dosing, including 3 Complete Responses (CR), one Very Good Partial Response (VGPR), and 2 Partial Responses (PR). Considering the best GI response achieved, all (8/8) patients experienced at least a PR, with 3 CRs, 2 VGPRs and 3 PRs. The 3 patients with CR were still alive at last follow-up (60 to 192 days after last dosing; median: 115 days) and were able to taper and stop steroids and immunosuppressants without relapse of GI symptoms. Of note, among these 3 patients, mild mouth chronic GvHD symptoms persisted in one patient, and relapse of hematologic malignancy was observed in another patient. Among the 8 treated patients, 5 were still alive at last follow-up (60 to 232 days after last dosing; median: 125 days). The safety of the MaaT013 microbiota biotherapeutic was satisfactory in all patients. One patient developed a possibly related sepsis one day after the third MaaT013 administration. In the latter case, no pathogen was identified in blood cultures, and the patient recovered after a course of antibiotics. Conclusions We herein report for the first time the treatment of 8 patients with steroid-dependent or steroid-refractory intestinal aGvHD using a full ecosystem, standardized, pooled-donor, high-richness biotherapeutic. Overall, 3/8 patients attained a complete response following treatment with the off-the-shelf MaaT013 product, shown to be safe and effective in these immunocompromised patients with severe conditions, warranting further exploration of the full ecosystem microbiota restoration approach. Disclosures Malard: Sanofi: Honoraria; JAZZ pharmaceutical: Honoraria; Astellas: Honoraria; Therakos/Mallinckrodt: Honoraria; Keocyte: Honoraria; Janssen: Honoraria. Plantamura:MaaT Pharma: Employment. Carter:MaaT Pharma: Employment. Chevallier:Jazz Pharmaceuticals: Honoraria; Incyte: Consultancy, Honoraria; Daiichi Sankyo: Honoraria. Blaise:Pierre Fabre medicaments: Honoraria; Molmed: Consultancy, Honoraria; Jazz Pharmaceuticals: Honoraria; Sanofi: Honoraria. Mohty:Jazz Pharmaceuticals: Honoraria, Research Funding.

scholarly journals Effectiveness of Subcutaneous Low-Dose Alemtuzumab and Rituximab Combination Therapy for Steroid-Resistant Chronic Graft-Versus-Host Disease

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4703-4703
Author(s):  
Cesar H Gutiérrez-Aguirre ◽  
Juan A. Flores-Jiménez ◽  
Olga Cantú-Rodríguez ◽  
Jorge Cuervo-Sierra ◽  
Adrián A. Ceballos-López ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Graft Versus Host Disease ◽  
Conflicts Of Interest ◽  
Late Complication ◽  
Low Doses ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
Steroid Refractory

Abstract Abstract 4703 Background: Chronic graft-versus-host disease (cGVHD) is a common late complication of allogeneic hematopoietic stem cell transplantation. Corticosteroids are the standard initial treatment for cGVHD. A second-line treatment is not well defined. We prospectively evaluated the effectiveness and safety of low doses of alemtuzumab and low doses of rituximab as treatment steroid-refractory cGVHD. Materials and Methods: Ten men and 5 women with cGVHD refractory to steroids and CSA were included. All patients received subcutaneous Alemtuzumab 10 mg/day/3 days and intravenous Rituximab 100 mg on days +1, +7, +14 and +21. Results: The median age was 41 years. The main organ involved were oral mucosa (86.7%), eyes (66.7%), liver (60%), skin (53%), lungs (13.3%) and intestinal tract (6.7%). The overall response was 100% at 30-day evaluation; 10 patients (67%) had partial remission (PR), and 5 patients (33%) had complete remission (CR). At 90-day evaluation, 7 (50%) patients had PR, 4 (28%) had CR; three (21%) relapsed and 1 patient not reached evaluation. Currently, 5 patients have reached the 365-day follow-up evaluation, 2 (40%) had PR, 2 had CR and 1 showed progression. The adverse effects were mainly infectious and one patient died from pneumonia. Conclusion: This combination therapy appears to be an efficacious and safe as treatment for steroid-refractory cGVHD. Disclosures: No relevant conflicts of interest to declare.

Early Intervention with Mesenchymal Stromal Cells for Refractory Grade III-IV Graft Versus Host Disease In Children Results In Excellent Long Term Outcome

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2336-2336
Author(s):  
Lynne Margaret Ball ◽  
Maria E. Bernardo ◽  
Jaap Jan Zwaginga ◽  
Maarten van Tol ◽  
Angela Cometa ◽  
...  
Keyword(s):  
Overall Survival ◽  
Graft Versus Host Disease ◽  
Immune Suppression ◽  
Term Survival ◽  
Long Term Survival ◽  
Host Disease ◽  
Graft Versus Host ◽  
Steroid Refractory

Abstract Abstract 2336 Mesenchymal stromal cell (MSC) infusions have been reported to be effective in patients with severe, steroid-refractory, acute graft-versus-host disease (aGVHD). However, long term comprehensive follow up data on pediatric patients is limited. We analyzed the outcome of 37 children receiving MSC for steroid-refractory aGvHD in two centers between January 2005 and December 2009 (characteristics see Table 1). A median of 2 infusions (range 1–13) were administered, with a median cell dose of 2×106/kg (range 0.9–3.0). MSC were from 3rd party HLA-mismatched donors (n=31), haploidentical relative (n=3) or both (n=3). (see Table 2) Fifteen children had either no (n=6) or partial (n=9) response to MSC. In this group, transplantation-related mortality (TRM) was 60%. Complete response (CR) was observed in 22 children, TRM being 14%. (p=0.005). Among the 28 patients with hematological malignancies, 5 relapsed, three with CR and two with PR. With a median follow-up of 2.3 years (range 7 months–4.7 years), overall survival was 62% with 87% versus 27% in patients who did or did not achieve CR after MSC respectively (p value <0.001). MSC after 2009 given at the time of steroid failure (median 8 days range 4 to 24) compared to pre 2009 (median 24 days range 5 to 85) (Maan-Whitney U = 65.5 two tailed p= 0.002) reduced fatal infections and was associated with a trend to better overall survival at 2 years post MSC infusion (p = 0.07). Although infections were evident at the time of immune suppression and mortality was high in NR/PR, response to MSC allows for reduction and eventual discontinuation of pharmacological immune suppression. Long term survival in responders is associated with eventual immune recovery, no late infections and persistent remission status. Treatment of steroid refractory aGVHD should aim to induce rapid stable control and early reduction of steroids to reduce TRM from viral reactivations. We conclude that MSC are ideal candidates for this purpose. Our results show that children responding to MSC treatment for severe steroid refractory GvHD have an excellent long term survival. Legend: ALL = acute lymphoblastic leukemia; AML = acute myeloid leukemia; MDS = myelodysplastic syndrome; jMML = juvenile myelomonocytic leukemia; HLH = hemophagocytic lymphohistiocytosis; MSD = matched sibling donor; (m) MUD (mis) Matched unrelated donor; PBSC = peripheral blood stem cells; TBI = total body irradiation; CSA = Cyclosporine A; MTX = short course methrotrexate; ATG = anti-thymocyte globulin; HSCT = hematopoietic stem cell transplantation; DLI = donor lymphocyte infusion; GvHD = graft versus host disease; M=Male; F=Female. Disclosures: No relevant conflicts of interest to declare.

scholarly journals ROCK2 Inhibition With Belumosudil (KD025) for the Treatment of Chronic Graft-Versus-Host Disease

2021 ◽  
pp. JCO.20.02754
Author(s):  
Madan Jagasia ◽  
Aleksandr Lazaryan ◽  
Carlos R. Bachier ◽  
Amandeep Salhotra ◽  
Daniel J. Weisdorf ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Overall Survival ◽  
Survival Rate ◽  
Graft Versus Host Disease ◽  
Overall Survival Rate ◽  
Once Daily ◽  
Host Disease ◽  
Graft Versus Host ◽  
Dose Reductions

PURPOSE The rho-associated coiled-coil–containing protein kinase-2 (ROCK2) signaling pathway regulates the Th17/regulatory T cells balance and controls profibrotic pathways. Selective ROCK2 inhibition with belumosudil (KD025) may offer a novel approach to the management of chronic graft-versus-host disease (cGVHD). PATIENTS AND METHODS A phase IIa, open-label, dose-finding study of belumosudil enrolled 54 patients with cGVHD who had received one to three prior lines of therapy (LOTs). The primary end point was overall response rate (ORR). RESULTS The median time from cGVHD diagnosis to enrollment was 20 months. Seventy-eight percent of patients had severe cGVHD, 50% had ≥ 4 organs involved, 73% had cGVHD refractory to their last LOT, and 50% had received ≥ 3 prior LOTs. With an overall median follow-up of 29 months, the ORR (95% CI) with belumosudil 200 mg once daily, 200 mg twice daily, and 400 mg once daily was 65% (38% to 86%), 69% (41% to 89%), and 62% (38% to 82%), respectively. Responses were clinically meaningful, with a median duration of response of 35 weeks, and were associated with quality-of-life improvements and corticosteroid (CS) dose reductions. CS treatment was discontinued in 19% of patients. The failure-free survival rate was 76% (62% to 85%) and 47% (33% to 60%) at 6 and 12 months, respectively. The 2-year overall survival rate was 82% (69% to 90%). Belumosudil was well-tolerated, with low rates of cytopenia. There were no unexpected adverse events and no apparent increased risk of infection, including cytomegalovirus infection and reactivation. CONCLUSION Belumosudil treatment resulted in a high ORR and overall survival rate and demonstrated quality-of-life improvements, CS dose reductions, and limited toxicity. Data from the study indicated that belumosudil may prove to be an effective therapy for patients with treatment-refractory cGVHD.

scholarly journals Ruxolutinib in Steroid Refractory Graft Versus Host Disease (SR-GVHD): Systemic Literature Review

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5682-5682
Author(s):  
Mostafa F. Mohammed Saleh ◽  
Shahrukh K. Hashmi
Keyword(s):  
Adverse Events ◽  
Graft Versus Host Disease ◽  
Chronic Gvhd ◽  
Infectious Complications ◽  
Systemic Review ◽  
Close Monitoring ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
Steroid Refractory

Background: Graft versus host disease (GVHD) is a main cause of morbidity and mortality in patients having undergone allogeneic hematopoietic stem cell transplantation (HSCT). About 30-40% of patients have steroid‐refractory GVHD (SR‐GVHD) after the first‐line use of high doses of corticosteroids with a poor prognosis .Ruxolitinib is a promising treatment for SR-GVHD. However, data regarding optimum dosing, response rates and associated adverse events are scarce. Herein, we provide the first systemic review of literature for the use ruxolutinib in GVHD. Methods: A Medline (PubMed), google scholar, OVID and Cochrane Database of Systematic Reviews search using key words "Ruxolutinib and GVHD", "Ruxolutinib and SR-GVHD" was undertaken in June 2019. Only peer reviewed databases were searched and search was restricted to human studies of acute and chronic GVHD only. Results: 16 publications, as listed in Table 1. Only one was a prospective trial, all others were retrospective studies, case series (5), and case reports (2). Overall response, ranged 45% - 100%, complete response was noted in 5.2% -80% patients. Time to response was variable from 1-12 weeks. Cytopenias and infectious complications were frequently reported with dose reduction or interruptions needed in most studies. Maintained responses were reported in a small proportion after ruxolutinib discontinuation. Conclusion Ruxolutinib has promising efficacy in SR-GVHD , however cytopenias and infectious complications reported frequently mandate close monitoring. Results of ongoing prospective trials could provide answers for optimum dosing and response assessment, and management of related adverse events. Table Disclosures No relevant conflicts of interest to declare.

Safety and efficacy of denileukin diftitox in patients with steroid-refractory acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation

Blood ◽  
2004 ◽  
Vol 104 (4) ◽  
pp. 1224-1226 ◽  
Author(s):  
Vincent T. Ho ◽  
David Zahrieh ◽  
Ephraim Hochberg ◽  
Eileen Micale ◽  
Jesse Levin ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Phase 1 ◽  
Interleukin 2 ◽  
Maximum Tolerated Dose ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
Denileukin Diftitox ◽  
Steroid Refractory ◽  
Acute Graft

Abstract Denileukin diftitox (Ontak), a recombinant protein composed of human interleukin 2 (IL-2) fused to diphtheria toxin, has selective cytotoxicity against activated lymphocytes expressing the high-affinity IL-2 receptor. We conducted a phase 1 study of denileukin diftitox in 30 patients with steroid refractory acute graft-versus-host disease (GVHD). Seven patients received 9 μg/kg intravenously on days 1 and 15; 18 received 9 μg/kg intravenously on days 1, 3, 5, 15, 17, and 19; and 5 received 9 μg/kg intravenously on days 1 to 5 and 15 to 19. Hepatic transaminase elevation was the dose-limiting toxicity (DLT), and dose level 2 was the maximum tolerated dose (MTD). Overall, 71% of patients responded with complete resolution (12 of 24; 50%) or partial resolution (5 of 24; 21%) of GVHD. Eight of 24 patients (33%) are alive at 6.3 to 24.6 months (median, 7.2 months). Denileukin diftitox is tolerable and has promising activity in steroid-refractory acute GVHD. (Blood. 2004;104:1224-1226)

Diverting Enterostomy Improves Overall Survival of Patients with Severe Steroid-Refractory Gastrointestinal Acute Graft-versus-host Disease

2021 ◽  
Vol Publish Ahead of Print ◽  
Author(s):  
Justine Khodr ◽  
Philippe Zerbib ◽  
Moshe Rogosnitzky ◽  
Leonardo Magro ◽  
Stéphanie Truant ◽  
...  
Keyword(s):  
Overall Survival ◽  
Graft Versus Host Disease ◽  
Host Disease ◽  
Graft Versus Host ◽  
Steroid Refractory ◽  
Acute Graft

Lenalidomide Maintenance Therapy After Toxicity-Reduced Myeloablative Allograft As Salvage Therapy for Efractory/Relapsed Myeloma Patients

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3024-3024
Author(s):  
Nicolaus Kröger ◽  
Evgeny Klyuchnikov ◽  
Thomas Stübig ◽  
Christine Wolschke ◽  
Francis Ayuk ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Maintenance Therapy ◽  
Graft Versus Host Disease ◽  
Cumulative Incidence ◽  
Myeloablative Conditioning ◽  
Host Disease ◽  
Graft Versus Host ◽  
Grade Iii

Abstract Abstract 3024FN2 Reduced-intensity conditioning (RIC) regimen followed by allogeneic stem cell transplantation (SCT) has become a reasonable treatment option for patients with multiple myeloma who are refractory or have relapse to an autograft. However, in comparison to standard myeloablative conditioning RIC resulted in higher risk of relapse. Maintenance therapy after autologous transplantation has shown to improve survival while after allogeneic SCT data are lacking so far. We here report the results of myeloablative toxicity-reduced allograft consisting of intravenous busulfan (12.2 mg/kg) and cyclophosphamide (120 mg/kg) followed by lenalidomide maintenance in 33 patients with multiple myeloma who relapsed to an autograft. A total of 32 patients had received one (n=16), two (n=15), or even three (n=1) autografts, and 1 patient was refractory to 2 induction therapies and failed to collect autologous stem cells. The median duration of remission after the autograft was 12 months. The primary endpoint of the study was non-relapse mortality at 1 year and secondary objectives were evaluation of response, incidence of acute and chronic graft-versus-host disease as well as progression and overall survival. To prevent graft-versus-host disease antithymocyte globulin (ATG Fresenius®) was given at a median dose of 20 mg/kg on day -3, -2, and -1. Lenalidomide was started earliest at day 120 after transplantation if there were no signs of infection or graft-versus-host disease. The median time between last autograft and allogeneic transplantation was 20 months. 19 patients were treated with fully HLA-matched unrelated donor, 8 patients had a mismatch donor, and 6 patients were transplanted from an HLA-identical sibling. 2 patients died of treatment-related complications resulting in a cumulative incidence of non-relapse mortality at 1 year of 6% (95% CI: 0–14%). After transplantation 27% developed grade II graft-versus-host disease, and severe grade III graft-versus-host disease was seen in 6% of the patients. Complete remission was noted in 46% of the patients, partial remission was seen in 48% and stable disease in 3%. The median interval between allogeneic transplant and start of lenalidomide was 168 days. The median starting dose was 5 mg (range 5–15 mg) without dexamethasone for 21 day followed by 1 week rest. 9 patients did not receive lenalidomide maintenance due to ongoing graft-versus-host disease, cytopenia or patient's wish. The median number of lenalidomide cycles was 6 (range 1–30). During follow-up 13 patients discontinued lenalidomide treatment due to progressive disease (n=6), GvHD (n=3), thrombocytopenia (n=2), or fatigue (n=2). In 10 patients lenalidomide dose could be increased to 10 or 15 mg, respectively. The major toxicities of lenalidomide were acute graft-versus-host disease grade I – III (21%), viral reactivation (12%), thrombocytopenia grade III-IV (12%), neutropenia grade III-IV (6%), peripheral neuropathy grade I-II (12%), or other infectious complications (6%). During follow-up 9 patients experienced relapse resulting in a cumulative incidence of relapse at 3 years of 42% (95% CI: 18–66%). The 3 year estimated probability of progression-free and overall survival was 52 % (95% CI: 28–76%) and 79 % (95% CI: 63–95%), respectively. In the current trial neither the deletion 13q14 nor the use of mismatch donor nor the chemosensitivity prior allogeneic SCT could be identified as risk factor for survival. This study showed that toxicity-reduced myeloablative conditioning regimen is feasible and highly effective in relapsed patients with multiple myeloma resulting in an acceptable treatment-related mortality. Lenalidomide as maintenance therapy is feasible early after transplantation but toxicity especially the induction of graft-versus-host disease should be considered. Disclosures: Kröger: Celgene: Research Funding. Kropff:Janssen-Cilag: Consultancy, Honoraria; Celgene: Consultancy, Honoraria.

Response to JAK 1/2 Inhibition in Patients with Corticosteroid-Refractory Acute Graft-Versus-Host Disease

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3934-3934 ◽  
Author(s):  
Silvia Spoerl ◽  
Kristina Maas-Bauer ◽  
Mareike Verbeek ◽  
Petya Apostolova ◽  
Anna Lena Illert ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Chronic Gvhd ◽  
Complete Response ◽  
Serum Levels ◽  
Salvage Treatment ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
Number Of Patients

Abstract Acute corticosteroid-refractory graft-versus-host-disease (GvHD) is a life-threatening complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT) with reported mortality rates of 40-60%. Our previous study (Spoerl S et al. Blood 2014) had shown the induction of tolerogenic regulatory T cells after ruxolitinib treatment in the mouse and clinical responses in six patients with corticosteroid-refractory GvHD. Here we report the outcome of 14 patients with GvHD refractory to steroids and at least two other lines of treatment who received ruxolitinib as a salvage treatment. Ten patients were classified as acute and four as chronic GvHD involving the skin, intestinal tract and liver as detailed in Table 1. Patients were treated with ruxolitinib at a starting dose of 5 mg orally twice daily with a dose increase to 10 mg orally twice daily. Clinical and histopathological grading of skin, intestinal and liver GvHD was performed according to established criteria. Of 14 patients, 13 responded with respect to clinical GvHD symptoms and serum levels of pro-inflammatory cytokines. Three patients with histologically proven acute skin or intestinal GvHD grade I, achieved a complete response. One non-responder discontinued ruxolitinib after one week because of lack of efficacy. In all other patients corticosteroids could be reduced after a median treatment of 1.5 weeks. Serum levels of IL-6 and soluble IL-2R were measured prior and after the start of ruxolitinib and declined in the majority of the analyzed patients (n=11). CMV reactivation was observed in four out of 14 patients and responded well to antiviral therapy. Two out of 14 patients developed cytopenia during ruxolitinib treatment that was mild and did not require dose reduction or transfusion. Our results indicate that treatment of corticosteroid-refractory GvHD with ruxolitinib is safe and well tolerated. Despite the low number of patients treated so far, our results demonstrate that ruxolitinib reduces the severity of corticosteroid-refractory GvHD and support further development of therapeutic JAK1/2 inhibition as a salvage treatment in GvHD. Table 1: GvHD and response to ruxolitinib Pt. no. 1 GvHD: organ/grade 2 Reduction of cortico-steroids after ruxolitinib Clinical response (PR / CR) 3 Time to response (weeks) Duration of response 4 / Current follow up (weeks) 5 01 Intestines / IV (acute) Yes CR 1 42 / 43 02 Skin / III (acute) Yes PR 1.5 46.5 / 48 03 Skin / IV liver / III (acute) Yes CR 1 57 / 58 04 Skin / III intestines / IV (acute) Yes PR 1.5 24.5 / 26 05 Skin / III (chronic) Yes PR 1 64 / 65 06 intestine/III-IV (acute) Yes PR 1 15 / 16 07 Skin/ III (chronic) Yes Response 1 46 / 47 08 Skin/ III (acute) Yes Response 1 2 / 3 09 Skin/ II intestine/II (chronic) Yes No response stopped after 1 week N/A N/A 10 Skin/ III liver/III (acute) Yes PR 1 1 / 2 11 intestines IV (acute) Yes PR 2 6 / 8 12 Skin/III (chronic) Yes Response 1 8 / 9 13 intestines/IV Skin/ II (late onset acute) Yes CR 1 17 / 18 14 intestines/IV Skin/ II (acute) Yes PR 1,5 3 / 4 1Pt.: patient, no: individual patient number, 2Acute and chronic GvHD were defined according to NIH criteria, 3PR: partial response, CR: complete response; 4Until last follow up, none of the patients experienced a relapse of GvHD. 5Follow up was calculated from the time of initiation of ruxolitinib treatment. In patient 01, ruxolitinib was discontinued at week 16 because of complete resolution of all GvHD signs. The patient did not develop any signs of GvHD after discontinuation of ruxolitinib until last follow up. Disclosures Off Label Use: Ruxolitinib in GvHD.

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