scholarly journals Clinical Outcomes of Ruxolitinib in the Salvage Treatment of Chronic Graft-Versus-Host Disease

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5677-5677
Author(s):  
Yanping Ji ◽  
Baolin Tang ◽  
Xiaoyu Zhu ◽  
Huilan Liu ◽  
Kaidi Song ◽  
...  
Keyword(s):  
Body Weight ◽  
Adverse Effects ◽  
Median Time ◽  
Graft Versus Host Disease ◽  
Salvage Treatment ◽  
Second Line ◽  
First Line ◽  
Host Disease ◽  
Graft Versus Host ◽  
Jak2 Inhibitor

Introduction Allogeneic hematopoietic stem cell transplantation (HSCT) is an effective therapy for malignant and non-malignant hematological diseases. Chronic Graft-versus-Host Disease (cGVHD) is a major contributor to late morbidity and mortality, significantly affects patients' quality of life.The first-line systemic therapy is corticosteroid,but 40%-60% patients need second-line or additional treatments. Available second-line therapies such as cyclosporine, mycophenolate mofetil, methotrexate, tacrolimus and sirolimus are less than ideal. Ruxolitinib is is an orally selective JAK1 and JAK2 inhibitor that has been approved by the FDA for the treatment of myelofibrosis. Prospective phase II and III trials using Ruxolitinib have demonstrated that it's effective and safe in the treatment of cGVHD. In this report, we share the clinical outcomes of using Ruxolitinib as salvage treatment of cGVHD. Method s This is a retrospective study of 39 patients with cGVHD who received Ruxolitinib as salvage treatment after failure of first-line or second-line therapies given at least one week.All patients were informed of the off-label use of Ruxolitinib and provided informed consent. Patients were treated with Ruxolitinib orally as an add-on immunosuppressive therapy(5mg twice daily if body weight ≥ 25kg and 2.5mg twice daily if body weight <25kg).If their cGVHD improved,2.5 mg was reduced weekly until withdrawal.Patients were monitored weekly for blood test and cytomegalovirus (CMV) DNA. Results Among the 39 patients,19 were male (48.7%) and 20 were female(51.3%). According to the 2015 NIH cGVHD diagnosis and staging criteria, 10 patients had mild,14 patients had moderate and 15 patients had severe cGVHD.The median time of cGVHD was 112 days (range 38-2000 days),the median time of Ruxolitinib taken was 56 (7-154) days,the median follow-up time was 221 (33-312) days,and the median time of Ruxolitinib taking effect was 14 (7-28) days.All patients tolerated Ruxolitinib well.According to the 2015 NIH cGVHD therapeutic response criteria,the overall response rate was 84.6%, including complete remission (CR) in 24 (59% )and partial response (PR) in 10 (25.6%). However,four patients (10.3%) had no response (NR) and two patients (5.1%) had disease progression. The organ responses (CR+PR) were as follows: skin 19/21 (90.5%),gastrointestinal tract 5/6 (83.3%),liver 5/6 (83.3%),lung 8/11(72.7%),hematologic 1/1(100%),mouth 3/5(60%),eyes 4/8 (50%),genitourinary tract 0/2 (0%),and musculoskeletal 0/1(0%).Among the adverse effects,eight cases (20.5%) had CMV reactivation and was controlled with antiviral therapy,ten cases (25.6%)had cytopenia, six cases (15.4%)had cGVHD relapse after Ruxolitinib was discontinued,two cases (5.1%) developed relapse of primary disease, and three cases (8%) died of pulmonary infection. Conclusions Low-dose of Ruxolitinib was effective to refractory cGVHD with good drug tolerance and controllable adverse effects. Ruxolitinib is expected to be a first- or second-line treatment for cGVHD but requires a randomized controlled trial. OffLabel Disclosure: Ruxolitinib,an orally selective JAK1 and JAK2 inhibitor,has been approved by the FDA for the treatment of myelofibrosis.We applied Ruxolitinib as a salvage treatment of chronic Graft-Versus-Host Disease after failure of the first or second-line therapies.

Predictors for Steroid Tapering in Patients with Acute Graft-Versus-Host Disease and Their Impact on Graft-Versus-Host Disease Response and Non-Relapse Mortality: Older Age and Co-Morbidities Are Associated with Quicker Tapering and Worse Outcomes

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3424-3424
Author(s):  
LaQuisa Hill ◽  
Rima M Saliba ◽  
Julianne Chen ◽  
Gabriela Rondon ◽  
Muzaffar H. Qazilbash ◽  
...  
Keyword(s):  
Median Time ◽  
Graft Versus Host Disease ◽  
Second Line ◽  
Second Line Therapy ◽  
Host Disease ◽  
Graft Versus Host ◽  
Steroid Dose ◽  
Line Therapy ◽  
Initiation Of Therapy ◽  
Grade 3

Abstract Introduction The hematopoietic cell transplantation comorbidity index (HCT-CMI) at the time of transplant has previously been shown to predict the development of grade 3/4 acute GVHD (aGHVD) and higher non-relapse mortality (NRM) for patients with a high CMI (≥3). It has been postulated that inflammatory cytokines associated with many of the conditions accounted for in the CMI may contribute to GVHD development, severity, and ultimately mortality. Because of concerns for corticosteroid toxicities in frail or elderly patients, some clinicians will attempt to rapidly taper steroid doses. We hypothesized that patients with a high CMI and/or advanced age (>60 yo) are treated differently with respect to systemic steroids, and this results in a higher likelihood of progression to more severe aGVHD, increases the need for second-line GVHD therapy, and increases NRM. In order to test this hypothesis, we examined steroid tapering patterns in patients who received systemic steroids for aGVHD in order to determine the influence of age and/or CMI on the rate of taper, and whether this impacted treatment outcome. Methods Patients who underwent a first allogeneic HCT at MD Anderson Cancer Center between January 2010 and 2015 were retrospectively identified in our HCT database. All patients ≥18 years old that developed aGVHD in the first 100 days and required systemic therapy were evaluated. Detailed information on GVHD therapy, steroid tapering, indication for taper, response, and outcomes were collected retrospectively from the medical records using standard criteria. Competing risks analyses were used to estimate the incidence of second line therapy and NRM, and to evaluate predictors of early (≤5 days) taper, need for second line therapy, and non-relapse mortality. Incidence of second line therapy and NRM were estimated in landmark analysis starting on the date of initial taper. Results A total of 417 patients met the eligibility criteria for this analysis (Table 1). Median age of patients was 53 (range 18-75; 28% >60 yo), median CMI was 1 (0-10). Grade of aGVHD at the initiation of therapy was ≤ 2 in 87% of patients and grade 3/4 in 13% of patients with a median time to initiation of therapy of 2 days (0-58). The time from aGVHD diagnosis to initiation of therapy, initial aGVHD grade, and median starting steroid dose, (mg/kg/day) in methylpred equivalents, were comparable in patients ≤60 yo vs >60 yo (Table 1). However CMI>3 was higher in patients >60 yo as would be expected. The median time to initial taper was 5 days (1-26). Predictors for early taper (≤ 5 days) on multivariate analysis included CMI>3 in patients older than 60 yo (HR=1.6, p=0.02) and starting steroid dose >1.5 mg/kg/day (HR=1.5, p=0.001). In the subset of patients with grade 2-4 aGVHD (N=276) who were initially tapered for response, the median steroid dose on day 14 was significantly lower in patients >60 yo with a CMI>3 (0.4 [range 0.05-1.5] vs 0.7 [range 0-9]; p= 0.02) in all other patients. In responding patients, early taper was significantly predictive for cumulative incidence of second line therapy within the first month from the time of first taper (14% vs 6%, HR=2.5, p=0.04). The highest incidence of second line therapy (29%) was in patients >60 yo with CMI>3 who were tapered within the first 5 days (HR 2.8, CI 1.03-7.5, p=0.04). Importantly, none of the patients >60 yo with CMI>3 (n=8) who were tapered after 5 days required second line therapy (n=8). In patients >60 yo with CMI>3, those who were tapered early had a 6-month NRM of 47% vs 25% in those tapered after 5 days (p= 0.1). Conclusions These results confirm earlier reports implicating the impact of a high CMI at the time of transplant on aGVHD-related mortality. Our data offers evidence that tapering practices differ according to age and CMI and that this directly impacts GVHD outcomes. Investigating alternative (steroid sparing) strategies to prevent under-treatment of aGVHD is thus essential to improving survival outcomes in these patients. Disclosures Ciurea: Spectrum Pharmaceuticals: Other: Advisory Board; Cyto-Sen Therapeutics: Equity Ownership.

scholarly journals Ruxolitinib Is an Effective Salvage Treatment for Multidrug-Resistant Graft-Versus-Host Disease after Allogeneic Hematopoietic Transplantation

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5670-5670 ◽  
Author(s):  
Sining Liu ◽  
Jiaoyu Zhao ◽  
Lanping Xu ◽  
Xiaohui Zhang ◽  
Yu Wang ◽  
...  
Keyword(s):  
Overall Survival ◽  
Median Time ◽  
Graft Versus Host Disease ◽  
Conflicts Of Interest ◽  
Multidrug Resistant ◽  
Salvage Treatment ◽  
Health Improvement ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host

Aim: Graft-versus-host disease (GVHD), particularly the multidrug-resistant (MDR) GVHD, is one of the most important complications for allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients. The purpose of our study is to identify the efficacy of ruxolitinib in allo-HSCT recipients with MDR-GVHD. Methods: A total of 44 patients who received ruxolitinib treatment for MDR-GVHD after allo-HSCT between 2017 and 2019 were enrolled in this study (HLA-identical sibling donors: n=10; HLA-haploidentical related donors: n=34). MDR-GVHD was defined as GVHD showing no improvement after at least 3 types of treatments. Patients were treated with ruxolitinib as an add-on immunosuppression therapy at a dose of 5 mg orally twice daily, and it could be increased to 10mg twice daily if hematologic parameters were stable and no treatment-related toxicities were observed after the first 7 days of treatment. This work was supported by the Capital's Funds for Health Improvement and Research (grant number 2018-4-4089). Results: The median number of previous GVHD-therapies was 4 for both MDR-aGVHD and MDR-cGVHD. For MDR-aGVHD (n=16), the median time to response was 10 days (range, 2 to 65), and the overall response rate (ORR) was 62.5% (10/16) in, including 37.5% (6/16) complete response (CR) and 25.0% (4/16) partial response (PR). Patients with 3 organs involvement had a lower ORR compared to that of those with 1-2 organs involvements (88.9% vs 28.6%, P=0.035). The 1-year probability of overall survival after ruxolitinib was 62.1%. The rates of hematologic and infectious toxicities were 75.0% and 50.0% after ruxolitinib treatment. For MDR-cGVHD (n=28), the median time to response was 30 days (range, 6 to 270), and the ORR was 78.6% (22/28), including 28.6% (8/28) CR and 50% (14/28) PR. The 1-year probability of overall survival after ruxolitinib was 90.0%. The rates of hematologic and infectious toxicities were 46.4% and 42.9% after ruxolitinib treatment. Conclusions: Ruxolitinib is an effective and safe salvage treatment for both MDR-aGVHD and MDR-cGVHD in allo-HSCT recipients. Disclosures No relevant conflicts of interest to declare.

scholarly journals Therapeutic efficacy of azathioprine in addition to prednisone-based regimens as first-line chronic graft-versus-host disease treatment

2017 ◽  
Vol 53 (3) ◽  
pp. 334-338
Author(s):  
Jieun Uhm ◽  
Elizabeth Shin ◽  
Fotios V. Michelis ◽  
Santhosh Thyagu ◽  
Auro Viswabandya ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Therapeutic Efficacy ◽  
First Line ◽  
Disease Treatment ◽  
Host Disease ◽  
Graft Versus Host

Salvage Therapy with Everolimus Reduces the Severity of Treatment-Refractory Chronic Graft-Versus-Host Disease without Impairing Disease Control: A Dual Center Experience

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4173-4173
Author(s):  
Stephan Mielke ◽  
Mathias Lutz ◽  
Judith Schmidhuber ◽  
Markus Kapp ◽  
Julia Ammer ◽  
...  
Keyword(s):  
Disease Control ◽  
Graft Versus Host Disease ◽  
Severity Score ◽  
Infectious Complications ◽  
Salvage Treatment ◽  
Line Treatment ◽  
Host Disease ◽  
Graft Versus Host ◽  
Off Label ◽  
Severity Scores

Abstract Abstract 4173 Introduction: Chronic graft-versus-host disease (cGVHD) following allogeneic hematopoietic stem cell transplantation remains the most important cause of late non-relapse mortality. While first-line treatment of cGVHD can be based on controlled data evidence for second-line treatment remains challenging with no single agent having been approved for salvage treatment yet. Here, we report a dual center retrospective cross-sectional analysis on salvage treatment of refractory cGVHD with everolimus, an inhibitor of the mammalian target of rapamycin (mTOR). Patients and Methods: A total of 78 consecutive patients (51 males, 27 females) with a median age of 53 years (range: 20 – 71 years) who received everolimus for off-label treatment of refractory cGVHD were considered eligible for this analysis. Potential toxicities according to Common Terminology Criteria for Adverse Events (CTCAE) were assessed in a retrospective manner using patients' records. Response to treatment was assessed using the cGVHD Global Severity Score according to NIH Consensus Criteria (NIH Severity Score). Possible response rates included complete remission (CR), partial remission (PR), mixed response (MR), stable disease (SD) and progressive disease (PD). Results: Out of 78 total patients 14 (18%) suffered from mild, 38 (49%) from moderate, and 26 (33%) from severe cGVHD before being commenced on an everolimus-based salvage regimen. Concomitant immunosupression included steroids, calcineurin inhibitors, inosine monophosphate dehydrogenase inhibitors, methotrexate and/or rituximab. Patients received daily oral doses of everolimus ranging from 0.125 to 6 mg resulting in median plasma levels of 4.1 ng/mL (range: 1.1 – 7.4 ng/mL). At time of analysis median follow-up after introduction of everolimus was 731 days (range: 14 – 2205 days). Median treatment duration with everolimus was 484 days ranging from 12 to 1250 days. Everolimus-based treatment was discontinued in 49 patients due to toxicity (n=14), CR (n=12), PR (n=6), MR (n=6), death (n=6), refractory cGVHD (n=3), relapse of underlying disease (n=1) or patient's request (n=1) while 29 patients (37%) were continued on everolimus. Most frequent grade 3/4 toxicities included infections (n=29) and thrombocytopenia (n=15). Infectious complications were the main cause of death. There was a single case of relapse of the underlying malignancy in the entire treatment series. NIH Severity Score improved in 34 patients (44%), remained stable in 36 patients (46%), and worsened in 8 patients (10%) resulting in a 21% CR and 31% PR rate of cGVHD. The total sum of NIH Severity Scores in all patients assessable was significantly reduced after treatment with everolimus (168 vs. 125; p<0.0001 [Wilcoxon signed-rank test]). The different levels of response are presented in [Figure 1]. Conclusions: Everolimus-based salvage treatment of refractory cGVHD results in significant improvement of the NIH Severity Score even including complete remissions. The observed toxicity profile highlights infectious complications and myelotoxicity while control of the malignant disease was not impaired in this series. However, disease control could be either contributable to enhanced graft-versus-malignancy effects in association with cGVHD and/or the beneficial anti-malignancy effects of everolimus itself. Finally, these promising results demand verification in a prospective clinical trial. Disclosures: Mielke: Novartis, Germany: Honoraria. Off Label Use: Everolimus for off-label treatment of refractory cGVHD. Wolff:Novartis, Germany: Research Funding.

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.

Myelofibrosis and Reduced Intensity Allogeneic Hematopoietic Stem Cell Transplantation (RISCT).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3062-3062
Author(s):  
Uday R. Popat ◽  
Gabriela Rondon ◽  
Amin M. Alousi ◽  
Paolo Anderlini ◽  
Borje S. Andersson ◽  
...  
Keyword(s):  
High Risk ◽  
Median Time ◽  
Graft Versus Host Disease ◽  
Peripheral Blood ◽  
Older Patients ◽  
Unrelated Donor ◽  
Molecular Remission ◽  
Host Disease ◽  
Graft Versus Host ◽  
Reduced Intensity

Background: Reduced intensity allogeneic transplantation was developed to harness graft versus leukemia immune effect to treat older patients and patients with comorbidities who are not eligible for conventional myeloablative transplant. Limited but encouraging data are available on outcome of patients with myelofibrosis undergoing this therapy. We therefore sought to prospectively study the safety and efficacy of reduced intensity HCT in patients with myelofibrosis. Methods: Patients with intermediate or high risk MF were eligible if they had adequate organ function and at least 9/10 matched related or unrelated donor. Patients were conditioned with Fludarabine 40mg/m2 × 4 (days −5, −4, −3 −2) and Busulfan 130mg/m2 × 2 (day −3,−2). Thymoglobulin 2.5 mg/kg × 3 (day −3,−2 and −1) was additionally given to patients receiving unrelated donor graft. Tacrolimus and mini Methotrexate were used as graft versus host disease prophylaxis. All patients received standard supportive care. Results: Twelve consecutive patients with myelofibrosis were enrolled between 1/2006 and 7/2007. There were 6 males and 6 female with a median age of 59 (range 40–65). Four patients had primary MF, 3 post PV MF and 5 Post ET MF. Based on Lile criteria, 8 patients had intermediate risk disease and 4 had high risk disease. Eight patients had circulating blasts (1%-8%). Six patients had splenectomy prior to transplant; median spleen size was 15 cms (range 5–28cms) below the costal margin in the remaining 6 patients. Seven patients had mutated Jak 2. Median peripheral blood CD 34 count was 77/μl (range 2–3770/μl). Karyotype was abnormal in 6 patients and diploid in 6. Donors were siblings for 3 patients, matched unrelated for 6, and one antigen or allele mismatched unrelated for 3 patient. All but 1 patient received peripheral blood stem cells. All patients engrafted with a median time to neutrophil engraftment of 13 days (0–27) days) and a median time to platelet engraftment of 14 (0–74) days. Day 100 non relapse mortality was 0%. One patient developed grade 3 acute graft versus host disease (GVHD) and died. One patient developed limited chronic GVHD. All Jak 2 positive patients achieved molecular remission post transplant with negative JaK 2. Three patients relapsed: 2 in blast phase and 1 in chronic phase. With a median follow up of 177 (29–563) days, six month overall survival is 87%. Conclusion: RISCT induces molecular remission with very low non relapse mortality in older patients with myelofibrosis.

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