Treatment Of Steroid Refractory Acute GVHD Research Articles

Sequential Umbilical Cord Derived Mesenchymal Stromal Cells (MSCs) for the Third-Line Salvage Treatment of Steroid-Refractory Acute GvHD: A Multicenter, Open Label, Phase 1b/2 Trial

Background and Aim: Acute graft-versus-host disease (aGVHD) is a life-threatening complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT), particularly if treatment is refractory. Human mesenchymal stromal cells (MSCs) have demonstrated safety and efficacy in steroid refractory acute graft versus host disease, due to their well-described immunosuppressive properties, however, clinical trials have resulted in variable success and an optimal source of MSC has yet to be defined. Based on the importance of maternal-fetal interface immune tolerance, the umbilical cord may provide a superior tissue source of MSC to mediate immunomodulation in aGVHD (SR-aGVHD). This study aimed to investigate the safety and efficacy of MSCs delivered as third-line salvage therapy for SR-aGVHD who had received at least two-lines of steroid-containing immunosuppressive therapy. Method: This phase1b/2, multicenter, open-label clinical trial of a third-party, off-the-shelf preparation of human umbilical cord derived mesenchymal stromal cells (hUC-MSCs) (ChiCTR2200061603) enrolled grades II to IV steroid-refractory aGVHD patients who had been treated with at least two-lines of steroid-containing immunosuppressive therapy. This trial consist of 2 parts：a phase Ib dose escalation part using a standard 3+3 design, which planed biweekly i.v. infusions of hUC-MSCs, at 0.5× 10 6 per kg, 1.0× 10 6per kg and 2.0× 10 6 per kg for 3 weeks, to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). Phase II of this work is an expansion cohort study of hUC-MSCs at RP2D 1.0×10 6 per kg with 15 patients. The primary endpoint of the study was safety and RP2D. The key secondary endpoints were efficacy of the overall response rate (ORR) at Day 28 and Day 56 defined per the 2014 NIH consensus criteria. Results: From June 23, 2022, through June 12, 2023, a total of 25 patients were enrolled with the median follow up period of 106 (10,210) days. Of the included 25 cases 11 patients (44.0%) were grade III/IV and 14 patients (56.0%) were grade II aGVHD at enrollment. Median patient age was 37.0 (range:24.5-47.0) years, 44.0% male. hUC-MSCs was well tolerated without dose-limiting toxicities in aforementioned three dosages. The reported adverse events (AEs) potentially associated with hUC-MSCs were hypofibrinogenemia (12.0%), upper respiratory tract infection (4.0%), leukopenia (4.0%) and anemia (8.0%) within the median follow-up period of 106 (10, 210) days. Grade 3 or higher AEs were reported in 6 patients (6/25, 24%) with 11 events, all of them were supposed uncorrelated with hUC-MSC. Three patients unfinished the administration:1 was due to withdrawn ICF; 1 was SAE and 1 was due to participate another trial. Up to date of June 12, 2023, twenty of the initial included 25 patients were still in group. And the RP2D of this trial was identified as 1.0× 10 6 per kg. At Day 28, 20 patients (80.0%, 95% CI:59.3%-93.2%) had an overall response, including 10 (40.0%) with complete responses. And at day 56, only one patient loss response, while another non-response patient at day 28 in the dose of 1.0× 10 6 per kg achieved late responses at day 56 ( Table 1). Responses were observed across skin (19/19, 100%), gastrointestinal tract (7/11,72.7%), and liver (2/2, 100.0%) at day 28. Durable overall response at day 56 was 76% (19/25), Figure 1. The median follow-up time after the initiation of hUC-MSC treatment was 106 (10,210) days with the cutoff date of 180 days after recruitment. The probability of 180-day overall survival (OS) and non-relapse mortality was 88.0% (95% CI, 68.8-97.5%) and 8.0% (95% CI, 1.0-26.0%), respectively. The 180-day cumulative incidence of relapse of primary hematologic disease was 8.0% (95%CI,1.0-26.0%). The percentage of total T lymphocyte, neutrophil, cytokine IL-10, IP-10 were statistically decreased in CR group, while CD8+central memory T cell was significantly increased compared to non-CR groups 24h or 96h after hUC-MSC administration (P<0.05）. Conclusion: Collectively, our results support hUC-MSCs as an effective salvage treatment for SR-aGVHD with safe profile. Key words: Acute graft-versus-host disease; allogeneic hematopoietic stem cell transplantation; mesenchymal stromal cells

Ruxolitinib-corticosteroid as first-line therapy for newly diagnosed high-risk acute graft versus host disease: study protocol for a multicenter, randomized, phase II controlled trial

BackgroundThe response rate of the first-line therapy with corticosteroid for acute graft versus host disease (aGVHD) is about 50%, and steroid-refractory disease is associated with high mortality. The improved response rate to the first-line therapy of newly diagnosed aGVHD patients would result in therapeutic benefits. Ruxolitinib, a selective Janus kinase (JAK) 1/2 inhibitor, has been approved for the treatment of steroid-refractory acute GVHD. The addition of ruxolitinib to the first-line therapy may improve the efficacy of corticosteroids.MethodsThis investigator-initiated, open-label, multicenter, prospective randomized, and controlled two-arm phase II study compares the efficacy and safety of ruxolitinib combined with 1 mg/kg methylprednisolone versus 2 mg/kg methylprednisolone alone in newly diagnosed aGVHD patients. Patients with intermediate or high-risk aGVHD, as defined by the Minnesota aGVHD high-risk score and biomarker algorithm, are eligible for this study. A total of 198 patients will be randomized at a 1:1 ratio and assigned a GVHD risk (intermediate versus high risk) and disease status before transplantation (complete remission versus no complete remission). The primary endpoint is the overall response rate on day 28, which is defined as an improvement of at least one stage in the severity of aGVHD in one organ without deterioration in any other organ or disappearance of any GVHD signs from all organs without requiring new systemic immunosuppressive treatment. The secondary objectives consist of response time, response duration, overall survival, disease-free survival, non-relapse mortality, failure-free survival, and changes in serum levels of proinflammatory cytokines and GVHD-related biomarkers.DiscussionThis open-label, multicenter, two-arm randomized trial will evaluate whether the addition of ruxolitinib combined with corticosteroid is superior to corticosteroid alone in newly diagnosed high-risk aGVHD.Trial registrationClinicalTrials.gov NCT04061876 (version number: 2019.5.18). Registered on July 16, 2019

A Phase I/II Study on the Anti-CD3/CD7 Immunotoxin Combination (T-GuardTM) for the Treatment of Steroid-Refractory Acute Gvhd

BackgroundMore effective therapies for steroid-refractory acute graft-versus-host disease (SR-aGVHD) are urgently needed. Because infections and relapse of the hematological malignancy contribute to the dismal overall survival (OS) therapies that limit the duration of immune suppression after achieving a remission might be preferred. The immunotoxin (IT)-combination (T-GuardTM) consists of two antibody-drug conjugates (i.e. Ricin A) that target CD3 and CD7 on activated T lymphocytes and has shown efficacy as third-line therapy in SR-aGVHD while allowing fast immune reconstitution.ObjectivesWe conducted a prospective phase I/II multicenter trial on the safety and efficacy of T-GuardTM for the treatment of SR-aGVHD (NCT02027805).MethodsAdult patients with grade II-IV SR-aGVHD were eligible for inclusion. Exclusion criteria consisted of the presence of uncontrolled infections, signs of chronic GVHD, severe renal impairment and severe hypoalbuminemia. T-Guard was given as 4-hour intravenous infusions every 48 hours for a total of 4 doses of each 4 mg/m2. The primary efficacy endpoint was defined as overall clinical response (ORR) on day 28. The main secondary endpoints were the 6-month OS and the safety and tolerability.ResultsBetween June 2014 and September 2016 the planned 20 adult patients were included in two European centers. Patients, 11 female and 9 male, with a median age of 53 years (range 18-74) all had received an allogeneic stem cell transplantation for myeloid and lymphoid malignancies. All but two completed the planned 8 days of treatment with T-Guard. SR-aGVHD was grade II in 3 patients (15%), III in 11 (55%), and IV in 7 (35%). In most patients 2 organs were involved (16/20, 80%), with gastro-intestinal (GI) and liver involvement in 18 and 5 cases, respectively. Baseline albumin levels were median 23 gr/L (range:16-34; N 35-50 gr/L) and based on the 2-biomarker model (ST2 and REG3α) no patients were classified as low-risk (p̂ < 0.08), and 50% as high-risk (p̂ ≥ 0.32).On day 28, 12 patients had achieved a clinical response (ORR: 12/20, 60%), with 10 (50%) achieving a complete remission (CR), Figure 1. In those with a high-risk biomarker profile a CR was achieved in 50%. With a minimum follow-up of 6 months 12 patients were alive (6-month OS 60%), Figure 1. The cause of death in the other eight patients was refractory aGVHD (N=4), refractory GVHD and infection (N=3) and pseudomembranous colitis (N=1). Of those receiving the planned treatment the ORR, CR rate and 6-month OS were 67%, 56%, and 67% respectively. The outcomes compared favorably with historical controls receiving either infliximab (N=21) or inolimomab/etanercept (N=21) were the ORR was 52% and the 6-month OS 29% (Figure 1 and 2).No significant infusion reactions were recorded, although two patients experienced chills on their first infusion, and after introduction of clemastine pre-infusion no infusion reactions were seen. As expected, the rate of overall infection and adverse events was high. However, there was a limited number of potentially attributable adverse events that occurred in more than one patient, and consisted of hypoalbuminemia, microangiopathy, and thrombocytopenia. Vascular leak syndrome occurred in only one patient, with edema requiring treatment with diuretics (grade 2). Early (< 3 months) EBV and CMV infections were recorded in 3 patients each, but no CMV disease or PTLD occurred. Whilst only 40% received mould-active antifungal prophylaxis no IFD were seen.While the one-week treatment course was associated with an immediate depletion of T and NK cells, IT-combination's short half-life (~9 hrs) allowed for a swift immune reconstitution accompanied by a diverse T cell receptor repertoire and without a negative effect on the fraction of anti-viral EBV and CMV-specific clones.ConclusionTreatment of SR-aGVHD with a short course of the T-GuardTM proved to be safe and well tolerated, and resulted in a high rate of CR and a promising 6-month OS of 60%, especially considering the high-risk setting (90% GI involvement, 50% high-risk biomarker profile). A pivotal multicentre international controlled trial, comparing T-GuardTM with best-available therapy for SR-aGVHD is scheduled for the end of 2017. [Display omitted] Disclosuresvan Hooren:xenikos: Employment, Equity Ownership. van Oosterhout:Xenikos: Employment, Equity Ownership. Levine:Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees.

Safety Analysis of Patients Who Received Ruxolitinib for the Treatment of Steroid-Refractory Chronic Graft-Versus-Host Disease in an Expanded Access Program

Safety Analysis of Patients Who Received Ruxolitinib for the Treatment of Steroid-Refractory Chronic Graft-Versus-Host Disease in an Expanded Access Program

Ruxolitinib for the treatment of steroid-refractory acute GVHD (REACH1): a multicenter, open-label phase 2 trial

AbstractPatients who develop steroid-refractory acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic cell transplantation have poor prognosis, highlighting an unmet therapeutic need. In this open-label phase 2 study (ClinicalTrials.gov identifier: NCT02953678), patients aged at least 12 years with grades II to IV steroid-refractory aGVHD were eligible to receive ruxolitinib orally, starting at 5 mg twice daily plus corticosteroids, until treatment failure, unacceptable toxicity, or death. The primary end point was overall response rate (ORR) at day 28; the key secondary end point was duration of response (DOR) at 6 months. As of 2 July 2018, 71 patients received at least 1 dose of ruxolitinib. Forty-eight of those patients (67.6%) had grade III/IV aGVHD at enrollment. At day 28, 39 patients (54.9%; 95% confidence interval, 42.7%-66.8%) had an overall response, including 19 (26.8%) with complete responses. Best ORR at any time was 73.2% (complete response, 56.3%). Responses were observed across skin (61.1%), upper (45.5%) and lower (46.0%) gastrointestinal tract, and liver (26.7%). Median DOR was 345 days. Overall survival estimate at 6 months was 51.0%. At day 28, 24 (55.8%) of 43 patients receiving ruxolitinib and corticosteroids had a 50% or greater corticosteroid dose reduction from baseline. The most common treatment-emergent adverse events were anemia (64.8%), thrombocytopenia (62.0%), hypokalemia (49.3%), neutropenia (47.9%), and peripheral edema (45.1%). Ruxolitinib produced durable responses and encouraging survival compared with historical data in patients with steroid-refractory aGVHD who otherwise have dismal outcomes. The safety profile was consistent with expectations for ruxolitinib and this patient population.

Results from an Expanded Access Program of Anti-CD3/CD7 Immunotoxin Combination (T-Guard®) for the Treatment of Steroid-Refractory Acute Gvhd

Background More effective therapies for treating steroid-refractory acute GVHD (SR-aGVHD) are urgently needed. In our recent phase I/II study, we showed that anti-CD3/anti-CD7 immunotoxin (IT) therapy T-Guard was both safe and well tolerated, and yielded both a high rate of CR and high 6-month OS in high-risk patients (Groth et al. BBMT 2019). Following this study, patients with SR-aGVHD were offered T-Guard via an expanded access treatment program (EAP). Objectives We evaluated patients' outcome after receiving T-Guard for SR-aGVHD. In addition, we examined the relationship between plasma citrulline levels (a biomarker of enterocyte mass) and the response to T-Guard in a subset of patients with SR-aGVHD of the gut, combining 16 patients from the phase I/II trial and 9 patients in the EAP group. Methods An EAP was started after completion of the phase I/II trial. This program was approved by the local ethics committee and the Health and Youth Care Inspectorate of the Dutch government. Adult patients with grade II-IV SR-aGVHD were eligible to receive T-Guard as their second- or third-line treatment for aGVHD. Patients with an uncontrolled infection, signs of moderate-severe chronic GVHD, and/or severe renal impairment were not eligible to receive T-Guard. Eligible patients received four 4-hour i.v. infusions of 4 mg/m2 T-Guard delivered at 48-hour intervals. In addition, plasma citrulline levels were measured at baseline and every 7 days after the start of T-Guard therapy using HPLC with mass spectrometry. A plasma citrulline level &lt;10 µmol/L was considered to indicate severe GI-GVHD. Results From Jan. 2017 through Dec. 2018, 12 patients (8 male, 4 female; median age: 54 yr, range: 20-70 yr) who had received an allogeneic stem cell transplantation for myeloid or lymphoid malignancy were treated with T-Guard. T-Guard was given as the second-line therapy to 10 patients; the remaining 2 patients received T-Guard as the third-line therapy after receiving ruxolitinib (N=1) or cyclosporin-UVB (N=1). The median time between aGVHD onset and the start of T-Guard therapy was 7 days (range: 3-55 days). SR-aGVHD was classified as grade II, III, or IV in 1, 7, and 4 patients, respectively. Nine patients (75%) had GI involvement, and the skin and liver were involved in 6 and 2 cases, respectively. All 12 patients were classified as high-risk in accordance with MacMillan et al. (BJH 2012), and the median albumin level at baseline was 23 g/L (range: 13-32 g/L). By treatment day 28, 9 patients (75%) had achieved a clinical response, with 5 achieving complete remission. After a median follow-up of 16 months, 7 patients were alive; the 6-month and 1-year OS rate was 75% and 58%, respectively, which was significantly higher than historical controls; Figure 1. The cause of death in the other five patients was refractory aGVHD (N=3), relapse AML (N=1), and GVHD after undergoing a second stem cell transplantation for relapse AML (N=1). No significant infusion-related reactions were recorded. As expected, the overall rate of infection was high, but was comparable to other cohorts; 1 and 2 patients developed an EBV or CMV infection, respectively, but these were manageable. The most common potentially treatment-related adverse events were transient worsening of hypoalbuminemia and thrombocytopenia. One patient developed grade 2 vascular leak syndrome, but this was easily managed. One patient developed severe thrombotic microangiopathy with renal insufficiency, but several contributing factors other than the use of T-Guard were present in this patient, including calcineurin toxicity, severe GI-GVHD, and CMV disease. Our preliminary analysis of citrulline levels in 16 patients with GI-GVHD showed that mean baseline levels were extremely low (4.3 µmol/L; range: 2.9-17.9 µmol/L); 28 days after the start of T-guard, citrulline levels had increased significantly in the 9 patients who achieved complete remission; Figure 2. Conclusion Consistent with our recent phase I/II trial, our expanded access program in which 12 patients with high-risk SR-aGVHD received T-guard confirms that this treatment is safe and significantly improves patient outcome. A multicenter phase III study is planned to start in 2019 (BMT-CTN 1802). Disclosures Hooren: Xenikos BV: Employment. van Oosterhout:Xenikos BV: Employment.

088 A phase I/II study on the anti-CD3/CD7 immunotoxin combination for the treatment of steroid-refractory acute GVHD

Effective therapies for treating patients with steroid-refractory acute graft-versus-host-disease (SR-aGVHD) are urgently needed. aGvHD affects mostly the skin and gut, and is a leading cause of morbidity and mortality. We conducted a phase I/II trial in 20 patients with SR-aGVHD, to examine the safety and efficacy of a mixture of anti-CD3 and anti-CD7 antibodies separately conjugated to recombinant ricin A (CD3/CD7-IT). On day 28 after the start of CD3/CD7-IT therapy, the overall response rate was 60%, with 50% complete remissions. The 6-month overall survival rate was 60%. Using flow cytometric analysis and T cell receptor (TCR) sequencing, we show CD3/CD7-IT caused profound but transient depletion of T cells and NK cells, followed by rapid recovery of the immune system with a diverse TCR Vβ repertoire, and preservation of Epstein-Barr virus- and cytomegalovirus-specific T cell clones. Different characteristics of responders (Rs) versus non-responders (NR) were noticed. Rs had a more swift recovery of T cells in the blood after treatment, and CD4 and CD8 subsets reconstitute differently between groups. Before treatment, Rs had significantly higher amounts of regulatory T cells (Tregs), CD4:CD8 ratios and higher clonal T cell diversity. While T cells reconstitution is not associated with disease severity, there seems to be an inverse relationship between disease severity and response rate. We further noticed a correlation between the conditioning regimen and amount Tregs, CD4:CD8 ratio and T cell diversity. These results suggest CD3/CD7-IT is safe and well tolerated, with a relatively low prevalence of reversible adverse events. It can be effective in all aGvHD grades and in patients with different conditioning regimens. Determining the Treg counts, CD4:CD8 ratio and T cell repertoire diversity before CD3/CD7-IT may predict response and select patients that benefit from CD3/CD7-IT therapy.

A monocentric study of steroid-refractory acute graft-versus-host disease treatment with tacrolimus and mTOR inhibitor.

Acute graft-versus-host disease (aGVHD) remains one of the leading causes of morbidity and mortality after allogeneic hematopoietic stem cell transplantation. No consensus exists on the best second-line treatment of steroid-refractory acute GVHD (SR-aGVHD). Previously published smaller studies on the use of sirolimus in SR-aGVHD treatment report a response rate of 57 to 86%, with 40% overall survival. The association of tacrolimus and mTOR inhibitor is supported by pre-clinical data and has been used as GVHD prophylaxis. We report 42 patients who received tacrolimus and mTOR inhibitor as a second- or third-line treatment of SR-aGVHD. Thirty-one patients were treated in second-line, with an overall response rate of 48.5% (complete response: 42%). Eleven patients were treated in third-line, with an overall response rate of 27%. Thirty-eight patients had at least one episode of infection, due to bacteria, viruses, fungi and parasites in 61, 42, 12 and two episodes, respectively. For patients treated in second-line, six-month and one-year survival were 61% and 42%, respectively. None of the patients treated in third-line survived. These results were not promising enough to initiate a phase three randomized clinical trial, but tacrolimus and mTOR inhibitor can be discussed among other options for patients with SR-aGVHD.

Phase I Multicenter Trial of Brentuximab Vedotin for Steroid Refractory Acute Graft-Vs.-Host Disease (GVHD)

Background: Outcomes for patients with steroid-refractory acute GVHD remain poor with no standard therapeutic approach. Pre-clinical data demonstrate increased CD30 expression on activated CD8+ T-cells at diagnosis of acute GVHD. Brentuximab vedotin (BV) is an antibody-drug conjugate comprised of an anti-CD30 monoclonal antibody linked to MMAE (mono-methyl aurastatin E). We hypothesized that targeting CD30+ /CD8+ T cells could lead to control of steroid-refractory acute GVHD.Methods: The primary endpoint of this multicenter phase I trial is to establish the maximum tolerated dose (MTD) of BV for the treatment of steroid-refractory acute GVHD. A 3+3 cohort design was conducted initially with BV given weekly x 3 doses followed by maintenance dosing with a DLT period of 4 weeks (initial dose 0.6 mg/kg IV weekly). After the first 6 patients, the trial was revised to escalating cohorts of 5 patients treated every 2 weeks x 4 doses with a DLT period of 8 weeks. The revised initial starting dose was 0.6 mg/kg IV given every 2 weeks, with planned dose escalation to 0.8 mg/kg, 1.0 mg/kg and 1.2 mg/kg.Results: A total of 24 patients have been treated at four centers. Eighteen patients had progressive acute GVHD on initial corticosteroid therapy, while six patients experienced a flare of symptoms upon tapering of steroids. Six patients were treated with the initial weekly dosing scheme and two of these patients died from complications of neutropenic sepsis. Eighteen patients were treated with every two week dosing (n=10 at 0.6 mg/kg and n=8 at 0.8 mg/kg). The MTD was defined at 0.8 mg/kg with one DLT being observed (neutropenia). Other attributable adverse events included thrombocytopenia (grade 3, n=1), fatigue (grade 3, n=1) and ileus (grade 3, n=1). At day 28, the overall response rate was 37.5% (9 of 24 patients) with 3 complete responses (CR, 12.5%) and 6 very good partial responses (VGPR, 25%). Another 4 patients had stable disease and remained on trial with one each achieving CR and VGPR after day 28. Nine of 24 patients are currently alive with a median follow-up of 12.9 months (range, 4.7-31.5 months). Analysis of free MMAE levels showed lack of clearance with weekly dosing and this was thought to contribute to the observed cases of neutropenia. With every other week dosing, there was no significant accumulation of free MMAE.Conclusion: Brentuximab vedotin given at 0.8 mg/kg IV every two weeks x 4 doses was established as the MTD. BV is tolerable and has promising activity in steroid-refractory acute GVHD. An additional 10 patients will be treated at the MTD and ongoing analysis is investigating if CD30 expression on lymphocyte subsets or soluble CD30 levels are associated with response. DisclosuresChen:Bayer: Consultancy, Research Funding. Off Label Use: Use of brentuximab vedotin for the treatment of acute GVHD will be discussed.. Soiffer:Gentium SpA/Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Perales:Incyte: Honoraria; Amgen: Honoraria; Merck: Honoraria; Takeda: Honoraria; Astellas: Honoraria; SOBI: Research Funding.

Infliximab Versus Rabbit Anti-Thymocyte Globulin As a Salvage Treatment For Steroid-Refractory Acute Graft-Versus-Host Disease After Reduced-Intensity Cord Blood Transplantation In Adults

Introduction In reduced intensity cord blood transplantation (CBT) post transplant immune disorders, including early immune reactions (PIR) and acute GVHD, are potential complications following CBT in adult patients. Such reactions might increase the risk of organ dysfunction, leading to high rates of transplantation-related mortality, particularly in patients who do not respond to primary therapy, which usually consists of steroids. There is no consensus on the optimal salvage treatment of steroid-refractory acute GVHD. Patients and Methods We retrospectively reviewed 388 patients who underwent single-unit reduced intensity cord blood transplantation consecutively from June 2008 to October 2012 at Toranomon Hospital. Patients who were in poor performance status (ECOG PS &gt;3), had active bacterial or fungal infections at the time of conditioning were excluded. The most frequently used conditioning regimens were fludarabine, alkylating agent (melphalan or busulfan) with total body irradination (TBI), tacrolimus plus mycophenolate mofetil for GVHD prophylaxis. Patients in whom acute GVHD developed received methylpredonisolone 1-2 mg/kg per day. If no partial or complete resolution of symptoms occurred, they were considered steroid-refractory and proceeded to salvage treatment with infliximab or ATG. The dose of infliximab was 5 mg/kg/day once weekly for at least 1 course. ATG was given at 1mg/kg/day once weekly for at least 1 course. An observational study compared response and survival rates in all consecutive patients receiving 1 of these 2 treatments. Results 52 patients among this group developed steroid refractory acute GVHD. Infliximab group (n=31) had a higher proportion of patients with grade III-IV GVHD (69% VS 59%, p=0.18). ATG group (n=21) had a higher proportion of patients with stage 3-4 liver GVHD (28% VS 5%, p&lt;0.01). Infliximab or ATG therapy was initiated after a median of 12 days (range, 2 to 85 days; 10 days for infliximab group VS 22 days for ATG group; p&lt;0.01) of steroids for primary therapy for GVHD. Both overall response (PR+CR) were significantly higher in the infliximab group compared with the ATG group (54.8% VS 33.3%, p=0.015 ). In multivariate analysis, time from first-line therapy (days&lt;10) was an independent predictor of response (HR, 3.91; 95%CI, 1.10-13.8; p=0.034), infliximab therapy was not significant, (HR, 1.30; 95%CI, 0.42-3.99; p=0.18). Median follow-up of surviving patients from the date of initiation of salvage treatment was 21.6 months (range, 5.5-57.9 months).Overall, median survival was 2 months after salvage treatment (95% CI, 1-3), with 25% of patients surviving at 12 months (95%CI, 11-20). Patients who achieved a CR have better survival rates. GVHD was the main cause of death (50%). When comparing survival according to salvage treatment, better OS with infliximab (33.9% VS 22.8, p=0.08) in univariate analysis was not confirmed in multivariate analysis. In multivariate analysis, grade IV GVHD at steroid refractory GVHD onset (HR,7.1; 95% CI, 1.29-38.7; P=0.021), and gut involvement with bleeding (HR, 7.65; 95% CI, 1.35-43.2; P=0.024) were significantly associated with worse survival. Conclusion We conclude that infliximab has more activity than ATG in the treatment of severe steroid-refractory GVHD, and earlier initiation of salvage therapy may give better response. But outcomes remain poor. New methods to prevent and treat GVHD are needed. Disclosures: No relevant conflicts of interest to declare.

Alemtuzumab for Treatment of Acute Gvhd In Steroid-Refractory Patients.

AbstractAbstract 4545Acute GVHD is associated with high-mortality. Alemtuzumab is a humanized monoclonal antibody against CD52 and although alemtuzumab has been used in the treatment of steroid-refractory acute GVHD, there is limited data. The severe immunosuppresion caused by alemtuzumab nonetheless is worrisome. We used lower dose of alemtuzumab subcutaneously to reduce the degree of immunosuppresion.Between August 2008 and April 2010, ten patients underwent allo-BMT from matched related donors (7) and unrelated donors (3) developed grade ≥ III, steroid-refractory acute GVHD. Their underlying diagnoses were SAA (3), Hodgkin's lymphoma (3), CML (1), AML (2) and non-Hodgkin's lymphoma (1). Median age was 30 years (range 6 to 45 years), 8 were males and 2 females. Four patients received myeloablative conditioning regimen with busulfan (Bu) and cyclophosphamde and 6 patients received reduced intensity conditioning with Bu and fludarabine/GVHD prophylaxis consisted of cyclosporine A and mycofenolate mofetil. Five patients received bone marrow harvest stem cells from either related donor (4) or unrelated donor (1), 4 received PBSC (3 related and one unrelated) and one received umbilical cord stem cells.All patients developed grade ≥ III acute GVHD. They were initially treated with 2mg of methylprednisolone daily for 5 consecutive days without response. They were then treated with alemtuzumab 10mg/day SQ for 5 consecutive days. The methylprednisolone was reduced to 1mg/kg/day in alternating days.Complete response was considered complete resolution of all manifestation by day 28; partial response if at least one organ target resolved and non response if no regression was seen till D+14.All patients received antibiotics, antifungal treatment and PCP prophylaxis with sulfamethoxazole and anti-CMV/HSV prophylaxis with gancyclovir and acyclovir.The treatment with alemtuzumab SQ was well tolerated. Five patients developed significant hematological toxicities: 4 developed neutropenia (ANC <500/mm3), median duration 6 days (3 to 11 days) and thrombocytopenia (PLT < 20,000) median duration 8 days (5 to 12 days). They recovered their cell count without any specific intervention. They all had complete chimerism by VNTR.Nine patients (90%) responded to treatment. Seven patients (70%) had complete resolution of GVHD. One patient did not respond and died of GVHD and Pseudomonas aeruginosa infection. One CR case had recurrence of GVHD 9 months later and died from sepsis and four others responsive patients died from infectious complications. Four patients remain free of GVHD for 4, 9, 15 and 16 months, their underlying diseases were AML (1), CML (1), SAA (2). One of these patients developed chronic GVHD six months later involving the lungs and responded to budesonide and systemic steroids. Three patients remain well and two with moderated thrombocytopenia.Viral infectious reactivations were frequent, nonetheless, they were non-fatal: 2 cases of BK-virus associated hemorrhagic cystitis treated with leflunomide and 3 cases with CMV positive antigenemia treated with gancyclovir. Disclosures:No relevant conflicts of interest to declare.

Pentostatin for treatment of steroid-refractory acute GVHD: a retrospective single-center analysis

Acute GVHD (aGVHD) remains a major cause of mortality in patients undergoing allo-SCT. In particular, the outcome of those patients who fail first-line therapy with glucocorticosteroids is poor. Preliminary reports suggested that the purine analogue pentostatin might be effective for treatment of steroid-refractory aGVHD. Here, we report on our single-center experience with pentostatin in this condition. From 2005 to 2008, a total of 24 consecutive patients, who had undergone first-line salvage treatment for steroid-refractory aGVHD of the gastrointestinal tract with pentostatin, were identified from 301 patients allografted during that period and retrospectively analyzed. Response to treatment, defined as CR or very good PR (VGPR), was observed in nine patients (38%), with a median time to response of 10 days. Although pentostatin was associated with only moderate myelosuppressive toxicity, if any, 2-year survival was only 17% with five of the nine responders dying from infection (four patients) or recurrent GVHD (one patient). We conclude that pentostatin is a moderately effective therapy for steroid-refractory aGVHD, showing response and outcome rates similar to other clinically used regimens.