Initial Results of KD025-208: A Phase 2a Open-Label Clinical Trial of KD025 for Steroid-Dependent Chronic Graft Versus Host Disease (cGVHD)

Abstract Treatment for steroid-resistant acute graft-versus-host disease (GVHD) has had limited success. ABX-CBL is a hybridoma-generated murine IgM monoclonal antibody against the CD147 antigen, weakly expressed on human leukocytes and up-regulated on activated lymphocytes. A prospective, multicenter, open-label, randomized clinical trial comparing ABX-CBL to antithymocyte globulin (ATG) for treatment of steroid-resistant acute GVHD was conducted in 95 patients at 21 centers. Forty-eight patients received ABX-CBL daily for 14 consecutive days followed by up to 6 weeks of ABX-CBL twice weekly. Forty-seven patients received equine ATG, 30 mg/kg every other day for a total of 6 doses with additional courses as needed. By day 180, overall improvement was similar in the patients receiving ABX-CBL and in those receiving ATG (56% versus 57%, P = .91). Patient survival at 18 months was less favorable on ABX-CBL than on ATG (35% versus 45%), with the 95% confidence interval ruling out that ABX-CBL provides at least a 10.4% improvement. Data from this trial suggest that ABX-CBL does not offer an improvement over ATG in the treatment of acute steroid-resistant GVHD. This prospective, multicenter, randomized clinical trial for steroid-resistant acute GVHD serves as a model for future evaluation of new agents.

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Chronic Graft-Versus-Host Disease Responds to Imatinib and Pre Transplant/Donor Anti-PDGFRA Antibodies Predict for Chronic Graft-Versus-Host Disease Development

Blood ◽

10.1182/blood.v116.21.2320.2320 ◽

2010 ◽

Vol 116 (21) ◽

pp. 2320-2320

Author(s):

George L. Chen ◽

Sally Arai ◽

Mary E.D. Flowers ◽

Joanne M Otani ◽

Marc Coram ◽

...

Keyword(s):

Clinical Trial ◽

Relative Risk ◽

Graft Versus Host Disease ◽

Stable Disease ◽

Progressive Disease ◽

Plasma Samples ◽

Minor Response ◽

Host Disease ◽

Graft Versus Host ◽

Steroid Dependent

Abstract Abstract 2320 The therapeutic potential of imatinib in chronic graft-versus-host disease (cGVHD) is thought to derive from abrogation of the agonistic effects of anti-PDGFRA antibodies (APA) previously identified in patients with extensive cGVHD. Here, we update outcomes from a 15 subject phase 1 dose escalation trial of imatinib for steroid dependent cGVHD and provide correlation with APA measurements. We also determine the prevalence of APA in 120 allo-HCT patients and their donors demonstrating that donor and pre transplant plasma sample APA measurements predict for cGVHD. Methods. All trial subjects had extensive steroid dependent cGVHD previously treated with ≥2 agents. Steroid dependence was defined as progressive cGVHD refractory to prednisone ≥0.5 mg/kg/d for ≥ 1 month or cGVHD requiring prednisone ≥0.25 mg/kg/d for ≥ 3 months. Subjects were treated with imatinib for ≥ 6 months starting at 200 mg daily with dose escalation to 400 mg after 4 weeks as tolerated and if a complete response did not occur. Steroids and one other immunosuppressant were allowed. Steroids were tapered as tolerated and other immunosuppressant dosing remained constant. The primary endpoint was safety and tolerability measured by CTCAE v. 3.0 criteria through 6 months. Secondary endpoints were graded according to the Hopkins' scale for cGVHD assessment, change in daily prednisone requirement, and change in symptom burden measured by the Lee cGVHD scale. APA in pre-imatinib plasma samples were detected by immunoblot with the extracellular PDGFRA domain (56 kDa) and confirmed by ELISA. Subsequently, 120 consecutive allo-HCT patients with available donor, pre- and 1 year post transplant plasma samples were tested for APA by ELISA. Results. Median age was 46 years (20-68). Mean time to study enrollment from transplant was 5.1 years and from cGVHD diagnosis 4.1 years. The clinical trial completed accrual on 8/4/09. Imatinib was escalated in 12/15 subjects. Grade 2–3 adverse events (AEs) possibly or probably related to imatinib occurred in 8/12 subjects receiving imatinib 400 mg daily; 5 of these subjects were subsequently dose reduced. Grade 2–3 AEs possibly or probably related to imatinib occurred in 4/15 subjects receiving imatinib 200 mg daily; we concluded this dose to be well tolerated. Subjects were evaluable for clinical responses after 6 months of therapy. Four subjects were non-evaluable: one subject died secondary to H1N1 infection induced respiratory failure, one subject experienced grade 3 vascular thrombosis and was removed from the study, and two subjects withdrew consent before 6 months. Of 11 clinically evaluable subjects, 3 experienced a major response, 4 experienced a minor response, 2 had stable disease, and 2 experienced progressive disease. Median follow-up was 56.6 weeks (19.1-76.1). We measured APA in order to directly assess PDGFRA as a relevant imatinib target. APA were detected by immunoblotting in 7/11 evaluable subjects: 4 experienced a major or minor response, 2 had stable disease, and 1 experienced progressive disease. APA were not detected in 4/11 evaluable subjects: 2 experienced a major or minor response, 1 had stable disease, and 1 experienced progressive disease. The small sample size precluded interpretation of the significance of APA relative to clinical outcome. Therefore, we extended our APA analysis and measured donor, pre, and 1 year post transplant plasma samples from 120 consecutive allo-HCT patients to determine the clinically relevant APA frequency. Pre transplant and donor APA ELISA measurements ≥ OD 2.0 (absorption at 405 nm) were associated with development of extensive cGVHD (see figure, relative risk=2.23, CI=1.71-2.90). Positive and negative predictive value of this assay for extensive cGVHD was 93% and 58%. Sensitivity and specificity were 24% and 98%. APA measurements in samples 1 year after transplant did not associate with extensive cGVHD (relative risk=0.51, CI=0.09-2.8) explaining the inability of APA to predict response to imatinib in our clinical trial. Conclusions. 1) The response rate of cGVHD to imatinib was 64% warranting further phase 2 studies using 200 mg daily. 2) Pre transplant and donor APA measurements predict for the development of extensive cGVHD. Our APA ELISA may be utilized to improve patient selection in cGVHD prophylaxis trials and to improve donor selection. Disclosures: Off Label Use: imatinib for cGVHD. Miklos: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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An Open-label, Single-arm, Multicenter Study of Ibrutinib in Japanese Patients With Steroid-dependent/Refractory Chronic Graft-Versus-Host Disease

Transplantation and Cellular Therapy ◽

10.1016/j.jtct.2021.05.019 ◽

2021 ◽

Author(s):

Noriko Doki ◽

Masako Toyosaki ◽

Souichi Shiratori ◽

Tomoo Osumi ◽

Masaya Okada ◽

...

Keyword(s):

Graft Versus Host Disease ◽

Multicenter Study ◽

Japanese Patients ◽

Open Label ◽

Host Disease ◽

Graft Versus Host ◽

Steroid Dependent

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

Blood ◽

10.1182/blood-2019-125540 ◽

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.

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Narrowband ultraviolet B phototherapy for the treatment of steroid-refractory and steroid-dependent acute graft-versus-host disease of the skin

Journal of the American Academy of Dermatology ◽

10.1016/j.jaad.2010.08.006 ◽

2011 ◽

Vol 65 (4) ◽

pp. 733-738 ◽

Cited By ~ 20

Author(s):

Jonathan V. Feldstein ◽

Javier Bolaños-Meade ◽

Viki L. Anders ◽

Rachel Abuav

Keyword(s):

Graft Versus Host Disease ◽

Ultraviolet B ◽

Host Disease ◽

Graft Versus Host ◽

Steroid Dependent ◽

Steroid Refractory ◽

Acute Graft

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Topical Corticosteroids a Viable Solution for Oral Graft versus Host Disease? A Systematic Insight on Randomized Clinical Trials

Medicina ◽

10.3390/medicina56070349 ◽

2020 ◽

Vol 56 (7) ◽

pp. 349

Author(s):

Arin Sava ◽

Andra Piciu ◽

Sergiu Pasca ◽

Alexandru Mester ◽

Ciprian Tomuleasa

Keyword(s):

Clinical Trials ◽

Graft Versus Host Disease ◽

Randomized Clinical Trials ◽

Open Label ◽

Double Blind ◽

Host Disease ◽

Graft Versus Host ◽

Overall Response ◽

Topical Corticosteroids ◽

Oral Gvhd

Background and Objectives: This research attempts to provide a clear view of the literature on randomized clinical trials (RCTs) concerning the efficacy of topical dexamethasone, clobetasol and budesonide in oral graft versus host disease (GVHD). Materials and Methods: An electronic search of the PubMed, Web of Science and Scopus databases was carried out for eligible RCTs. Studies were included if they had adult patients with oral GVHD treatment with topical corticosteroids, and if the RCT study was published in English. The Cochrane Risk of Bias tool was used to assess the quality of these studies. Overall, three RCTs were included (an Open, Randomized, Multicenter Trial; a Randomized Double-Blind Clinical Trial; and an Open-Label Phase II Randomized Trial). Results: The trials involved 76 patients, of which 44 patients received topical dexamethasone, 14 patients received topical clobetasol and 18 patients received topical budesonide. Topical agents were most frequently used when oral tissues were the sole site of involvement. It appears that the best overall response is present for budesonide with no difference between the four arms, followed by clobetasol, and then by dexamethasone. The limitation of the current study is mainly represented by the fact that overall response was derived in two of the studies from other parameters. Moreover, both budesonide and clobetasol were used in only one study each, while two assessed dexamethasone. Conclusions: Based on the clinical trials, all three agents seem to be effective in treating oral GVHD and had a satisfactory safety profile. There is still a need for assessing high quality RCTs to assess the efficacy of these therapies on a larger cohort.

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Donor fecal microbiota transplantation ameliorates intestinal graft-versus-host disease in allogeneic hematopoietic cell transplant recipients

Science Translational Medicine ◽

10.1126/scitranslmed.aaz8926 ◽

2020 ◽

Vol 12 (556) ◽

pp. eaaz8926 ◽

Cited By ~ 5

Author(s):

Yannouck F. van Lier ◽

Mark Davids ◽

Nienke J. E. Haverkate ◽

Pieter F. de Groot ◽

Marjolein L. Donker ◽

...

Keyword(s):

Graft Versus Host Disease ◽

Fecal Microbiota Transplantation ◽

Fecal Microbiota ◽

Hematopoietic Cell ◽

Cell Transplant ◽

Host Disease ◽

Graft Versus Host ◽

Steroid Dependent ◽

Study Participants ◽

Steroid Refractory

Disruption of the intestinal microbiota occurs frequently in allogeneic hematopoietic cell transplantation (allo-HCT) recipients and predisposes them to development of graft-versus-host disease (GvHD). In a prospective, single-center, single-arm study, we investigated the effect of donor fecal microbiota transplantation (FMT) on symptoms of steroid-refractory or steroid-dependent, acute or late-onset acute intestinal GvHD in 15 individuals who had undergone allo-HCT. Study participants received a fecal suspension from an unrelated healthy donor via nasoduodenal infusion. Donor FMT was well tolerated, and infection-related adverse events did not seem to be related to the FMT procedure. In 10 of 15 study participants, a complete clinical response was observed within 1 month after FMT, without additional interventions to alleviate GvHD symptoms. This response was accompanied by an increase in gut microbial α-diversity, a partial engraftment of donor bacterial species, and increased abundance of butyrate-producing bacteria, including Clostridiales and Blautia species. In 6 of the 10 responding donor FMT recipients, immunosuppressant drug therapy was successfully tapered. Durable remission of steroid-refractory or steroid-dependent GvHD after donor FMT was associated with improved survival at 24 weeks after donor FMT. This study highlights the potential of donor FMT as a treatment for steroid-refractory or steroid-dependent GvHD, but larger clinical trials are needed to confirm the safety and efficacy of this procedure.

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