Abstract

Acute graft-versus-host disease (aGVHD) is a potentially fatal complication of allogeneic hematopoietic cell transplantation that fails to improve with intense immunosuppression in some patients. We hypothesized that urinary-derived human chorionic gonadotropin (uhCG) could help facilitate resolution of life-threatening aGVHD when added as supportive care via 2 potential mechanisms: immunomodulation (akin to its role in pregnancy) and supplementation of epidermal growth factor (EGF; to aid in epithelial repair). In a phase 1 study, 26 participants received subcutaneous injections of uhCG in addition to standard immunosuppression (13 receiving initial therapy for high-risk aGVHD [according to the Minnesota criteria] and 13 receiving second-line therapy). Participants underwent serial blood testing for biomarkers of hormone response, immune modulation, and aGVHD activity on study. uhCG was well tolerated, with no dose-limiting toxicities. Sixty-two percent of patients in the high-risk cohort and 54% of patients in the second-line cohort had a complete response at study day 28. Plasma EGF was elevated sixfold (from 4 to 24 pg/mL; P = .02) at 6 hours postdose in the high-risk cohort, in contrast to no peak in plasma EGF in the more severe second-line cohort. After 1 week of uhCG, patients reported a twofold increase in the regulatory T cell to conventional T-cell ratio, suggesting immune modulation despite high-dose steroids. Responding patients reported significantly lower plasma amphiregulin and higher plasma butyrate levels at study completion, suggesting improvement in mucosal damage over time. uhCG is a novel, safe, supportive therapy, proceeding to phase 2 testing at 2000 units/m2 in high-risk aGVHD. This study was registered at www.clinicaltrials.gov as #NCT02525029.

Abstract

Graft failure (GF) is a life-threatening complication after allogeneic stem cell transplantation. Although salvage cord blood transplantation (CBT) is a curative therapy for GF, the optimal immunosuppression after salvage CBT remains unknown. Using nationwide registration data, we compared the transplant outcomes of patients who developed GF and underwent salvage CBT using immunosuppressants, including calcineurin (CNI) alone (n?=?177); CNI plus methotrexate (CNI+MTX, n?=?150); and CNI plus mycophenolate mofetil (CNI+MMF, n?=?161). The CNI+MMF group, in comparison with the CNI+MTX and CNI alone groups, demonstrated better neutrophil recovery at 30 days (62.7 vs. 42.7 vs. 53.1%, P?

Abstract

Patients who develop steroid-refractory acute graft-versus-host disease (aGVHD) following 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 ≥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 endpoint was overall response rate (ORR) at Day 28; the key secondary endpoint was duration of response (DOR) at 6 months. As of July 2, 2018, 71 patients received ≥1 dose of ruxolitinib. Forty-eight patients (67.6%) had grade III/IV aGVHD at enrollment. At Day 28, 39 patients (54.9% [95% CI, 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, 24/43 patients (55.8%) receiving ruxolitinib and corticosteroids had a ≥50% 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.

Abstract

We have treated 69 patients with steroid refractory acute graft versus host disease (SR-aGvHD), with an anti-CD26 monoclonal antibody (Begelomab): 28 patients in two prospective studies (EudraCT No. 2007-005809-21; EudraCT No. 2012-001353-19), and 41 patients on a compassionate use study. The median age of patients was 42 and 44 years; the severity of GvHD was as follows: grade II in 8 patients, grade III in 33, and grade IV in 28 patients. There were no adverse events directly attributable to the antibody. Day 28 response was 75% in the prospective studies and 61% in the compassionate use patients, with complete response rates of 11 and 12%. Response for grade III GvHD was 83 and 73% in the two groups; response in grade IV GvHD was 66 and 56% in the two groups. Non relapse mortality (NRM) at 6 months was 28 and 38%. Overall there were 64, 56, 68% responses for skin, liver, and gut stage 3-4 GvHD. The overall survival at 1 year was 50% for the prospective studies and 33% for the compassionate use patients. In conclusion, Begelomab induces over 60% responses in SR-aGvHD, including patients with severe gut and liver GvHD, having failed one or more lines of treatment.

Abstract

Clinical outcomes in children with steroid-refractory acute graft-versus-host disease (SR-aGVHD) are generally poor with a high mortality rate and limited therapeutic options. We report here our updated investigational experience with mesenchymal stromal cell therapy (remestemcel-L) used in a multicenter expanded access protocol (NCT00759018) in 241 children with aGVHD who failed to respond to steroids with or without other secondary and tertiary immunosuppressive therapies (IST). A total of 241 children with Grade B-D steroid refractory (SR) aGVHD were enrolled in 50 sites in eight countries and received eight biweekly intravenous infusions of human mesenchymal stromal cells (hMSCs) 2x10(6) per kg for four weeks, with an option for an additional four weekly infusions after day 28 for subjects who achieved either a partial or mixed response. Mean age of subjects was 9.6 years; 39% were female, and 60% were white. Most of the subjects had grade C (30%) or grade D (50%) disease and in most cases, the subjects had failed to respond to other immunosuppressive agents after failing steroids. The primary endpoint was overall response rate (ORR, the sum of complete and partial response) at day 28. Across all subjects, the 28 day ORR, was observed in n=157 (65.1%) with 34 (14.1%) and 123 (51.3%) achieving complete and partial responses, respectively. Stratified by aGVHD grade at baseline, the rate of overall response at day 28 was 72.9% for aGVHD grade B, 67.1% for grade C, and 60.8% for grade D subjects. Survival through day 100, a secondary endpoint of the study was 66.9% (n=160/239). Importantly, survival through day 100 was significantly greater in subjects that achieved a day 28 OR (82.1%) compared with non-responders (38.6%), log rank p<0.001. Remestemcel-L safety was generally well tolerated with no infusional toxicity and no identified safety concerns. In summary, this update to the remestemcel-L EAP confirms the reported clinical and survival benefits of remestemcel-L therapy in children with aGVHD who have exhausted all conventional therapeutic options.

Abstract

Steroid-refractory acute graft-versus-host disease (SR-aGVHD) following hematopoietic cell transplantation (HSCT) is associated with poor clinical outcomes. Currently, there are no safe and effective therapies approved for use in the pediatric population under the age of 12 years. Accordingly, there is an urgent need for new treatments that are safe, well-tolerated and effective in managing this debilitating and potentially fatal complication of HSCT. In early phase clinical trials, Mesenchymal stromal cells (MSCs) have demonstrated efficacy in the treatment of acute GVHD (aGVHD) in pediatric patients. We now report the results of a phase 3, prospective, single arm, multicenter study (NCT02336230) in 54 children with primary SR-aGVHD who were naive to other immunosuppressant therapies (IST) for aGVHD treated with MSC product (remestemcel-L) dosed at 2x10(6) cells/kg twice weekly for four weeks. Remestemcel-L therapy significantly improved day 28 overall response rate (OR) compared to the pre-specified control OR value of 45% (70.4% versus 45%, P =0.0003). The statistically significant OR (70.4%) was sustained through day 100 including an increase in complete response (CR) from 29.6% at day 28 to 44.4% at day 100. Overall survival was 74.1% at day 100 and 68.5% at day 180. Overall response in all participants at day 28 was highly predictive of improved survival through 180 days and survival was significantly greater in day 28 responders compared with non-responders through day 100 (86.8% vs. 47.1% for responders and non-responders, respectively, P=0.0001) and through day 180 (78.9% vs. 43.8%, p=0.003). Remestemcel-L was well-tolerated with no identified infusion-related toxicities or other safety concerns. This study provides robust, prospective evidence of the safety, tolerability and efficacy of remestemcel-L as first-line therapy after initial steroid failure in pediatric SR-aGVHD.

Abstract

The a4ß7 integrin is upregulated on naive and memory T cell subsets in patients who subsequently develop gastrointestinal (GI) acute GVHD. Natalizumab (Tysabri(®), Biogen Inc.) acts against the a4 subunit that mediates homing of lymphocytes to the GI tract. We initiated a phase II study of natalizumab with corticosteroids for initial treatment of acute GI GVHD. In total, 300?mg IV of natalizumab was given, with steroids initiated up to 3 days prior. Twenty-one subjects were treated, median age was 63 years (range 38-74), and 15 (71%) were male. Eighteen (86%) underwent RIC, 15 (71%) received MUD, and all received PBSCs. Overall GVHD at enrollment was grade II in 4 and grade III in 17. The primary endpoint, day 56 GVHD-free survival rate, was attained in 33.3%. The overall response rate at day 28 and 56 was 57% and 52%, respectively. Six of eight CRs were durable for 1 year. Five experienced toxicity possibly related to natalizumab and ten had infections before day 100. 2-year OS was 43% (95% CI 22-62%) and 2-year NRM was 52% (95% CI 29-71%). Natalizumab with corticosteroids as initial treatment of acute GI GVHD is safe, effective, and durable.

Abstract

Vulvovaginal Graft-versus-host disease (VV-GVHD) is an underdiagnosed complication of hematopoietic stem cell transplantation (HSCT). The severity of the disease varies greatly, ranging from minor discomfort to severe, irreversible anatomic changes. This study sought to assess the long-term course of VV-GVHD. A retrospective analysis was conducted of 64 women who underwent HSCT and were followed over 9 years in a designated vulvovaginal clinic. VV-GVHD was detected in 56% of transplanted women. Adherence with follow-up correlated with diagnosis of VV-GVHD (p < 0.001) and with sexual activity (p = 0.023). Most of the women with VV-GVHD were symptomatic; however, 22% were asymptomatic upon diagnosis. Women were treated with topical steroids, topical estrogen, vaginal dilators, and vaginal silicone rings. Vaginal silicone rings were associated with higher patient adherence and better results. VV-GVHD is a common complication of HSCT and can adversely impact patients' sexuality and quality of life. The disease pattern is chronic, necessitating long term follow-up and adherence with treatment. Vulvar anatomical changes occurred despite treatment; however, vaginal patency can be maintained by early diagnosis, constant surveillance, and early treatment, consequently allowing preservation of normal sexual function. Awareness of VV-GVHD must be raised in order to better serve female patients and facilitate early diagnosis and treatment.

Abstract

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.