Steroid-refractory acute graft-versus-host disease graded III-IV in pediatric patients. A mono-institutional experience with a long-term follow-up
Pediatric transplantation. 2020;:e13806
aGvHD remains a major obstacle to successful HSCT. We report our experience on steroid-refractory aGvHD III and IV from 1989 to 2017. Ninety patients with aGvHD III or IV were stratified according to the HSCT year: 1989-1998, 1999-2007, and 2008-2017 and to aGvHD extension (GvHD III vs IV) and finally the probability of OS, RI, and TRM was calculated accordingly. aGvHD III patients had a substantial improvement over time: day 100 OS raised from 64% (95% CI 39-89) in the first cohort to 100% in the latest (P = .022), and it was mainly due to a reduction of TRM (it was 28% [95% CI 12-65] in the first cohort to 0% in the latest (P = .01). The aGvHD IV patients did not present a significant improvement. Day 100 OS was 42% (95% CI 16-68) in the first group and 54% (95% CI 25-83) in the year 2008-2017 (P = NS), and the day-100 TRM was very similar (it was 57% [95% CI 36-90] in the first cohort and 45% [95% CI 23-89] in the latest (P = NS). We report significant improvements in OS and TRM in patients diagnosed with grade III aGvHD. Patients with the most severe aGvHD appear to have no or fewer benefits on long-term outcomes.
Study 275: Updated Expanded Access Program for Remestemcel-L in Steroid-Refractory Acute Graft-Versus-Host Disease (SR-aGVHD) in Children
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2020
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.
A Phase 3, Single-arm, Prospective Study of Remestemcel-L, Ex-vivo Culture-Expanded Adult Human Mesenchymal Stromal Cells, for the Treatment of Pediatric Patients who Failed to Respond to Steroid Treatment for Acute GVHD
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2020
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.
Children with primary steroid refractory aGVHD, naive to other immunosuppressant therapies (n=54)
Mesenchymal stromal cell 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%). 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) and through day 180 (78.9% vs. 43.8%) Remestemcel-L was well-tolerated with no identified infusion-related toxicities or other safety concerns.
Dose-escalated interleukin-2 therapy for refractory chronic graft-versus-host disease in adults and children
Blood advances. 2019;3(17):2550-2561
Low-dose interleukin-2 (IL-2) therapy for chronic graft-versus-host disease (cGVHD) generates a rapid rise in plasma IL-2 levels and CD4(+)CD25(+)CD127(-)Foxp3(+) regulatory T-cell (CD4Treg) proliferation, but both decrease over time despite continued daily administration. To test whether IL-2 dose escalation at the time of anticipated falls in plasma levels could circumvent tachyphylaxis and enhance CD4Treg expansion, we conducted a phase 1 trial in 10 adult and 11 pediatric patients with steroid-refractory cGVHD (www.clinicaltrials.gov: NCT02318082). Daily IL-2 was initiated in children and adults (0.33 x 10(6) and 0.67 x 10(6) IU/m(2) per day, respectively). Dose escalations were scheduled at weeks 2 and 4 to a maximum dose of 1 x 10(6) IU/m(2) per day in children and 2 x 10(6) IU/m(2) per day in adults. Patients continued at their maximum tolerated dose (MTD) until week 8. Children tolerated IL-2 dose escalation with partial responses (PRs) in 9 of 11 patients (82%) at multiple cGVHD sites, including lung. Patient-reported outcome scores for skin and lung improved significantly in pediatric patients. In contrast, 5 of 10 adults required dose reduction, and only 2 of 7 evaluable patients (29%) had PRs at week 8. CD4Tregs and natural killer cells expanded in both cohorts without significant changes in conventional CD4(+) T cells (Tcons) or CD8(+) T cells. Children achieved a higher median CD4Treg/Tcon ratio at week 8 (0.4 vs 0.18, P = .02) despite lower IL-2 doses. We show for the first time that low-dose IL-2 is safe and effective in children with advanced cGVHD. In adults, escalation above the previously defined MTD did not improve CD4Treg expansion or clinical response.
Basiliximab as treatment of steroid-refractory acute graft-versus-host disease in pediatric patients after haploidentical hematopoietic stem cell transplantation
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2019
Basiliximab has been used successfully as a second-line treatment for steroid-refractory (SR) acute graft-versus-host disease (aGVHD) in adult patients after haploidentical hematopoietic stem cell transplantation (haplo-HSCT) but has not been studied separately in the pediatric setting. We retrospectively reviewed 100 pediatric patients after haplo-HSCT receiving basiliximab for grades II (57%), III (27%), and IV (16%) SR-aGVHD between January 2015 and December 2017. The median number of basiliximab doses was 4 (range, 2-9). The day 28 overall response rate (ORR) was 85%, with complete response (CR) in 74% of patients, partial response (PR) in 11% of patients, and no response in 15% of patients. The day 28 ORR was 94.6% in skin SR-aGVHD, 81.6% in gut SR-aGVHD, and 66.7% in liver SR-aGVHD. Infectious complications included bacterial infection (11%), presumed or documented fungal infections (7%), CMV viremia (53%), EBV viremia (11%), HHV-6 viremia (7%), and HSV viremia (1%). The 3-year overall survival (OS), disease-free survival (DFS), nonrelapse mortality (NRM), and relapse rates between responders and nonresponders were 81.3% vs. 46.7% (P<0.001), 79.0% vs. 46.7% (P=0.001), 6.1% vs. 33.3% (P<0.001), and 14.9% vs. 20.0% (P=0.46), respectively. We conclude that basiliximab is an effective second-line agent for pediatric patients with SR-aGVHD after haplo-HSCT, particularly for skin SR-aGVHD.
Children and Adults with Refractory Acute Graft-versus-Host Disease Respond to Treatment with the Mesenchymal Stromal Cell Preparation "MSC-FFM"-Outcome Report of 92 Patients
(1) Background: Refractory acute graft-versus-host disease (R-aGvHD) remains a leading cause of death after allogeneic stem cell transplantation. Survival rates of 15% after four years are currently achieved; deaths are only in part due to aGvHD itself, but mostly due to adverse effects of R-aGvHD treatment with immunosuppressive agents as these predispose patients to opportunistic infections and loss of graft-versus-leukemia surveillance resulting in relapse. Mesenchymal stromal cells (MSC) from different tissues and those generated by various protocols have been proposed as a remedy for R-aGvHD but the enthusiasm raised by initial reports has not been ubiquitously reproduced. (2) Methods: We previously reported on a unique MSC product, which was generated from pooled bone marrow mononuclear cells of multiple third-party donors. The products showed dose-to-dose equipotency and greater immunosuppressive capacity than individually expanded MSCs from the same donors. This product, MSC-FFM, has entered clinical routine in Germany where it is licensed with a national hospital exemption authorization. We previously reported satisfying initial clinical outcomes, which we are now updating. The data were collected in our post-approval pharmacovigilance program, i.e., this is not a clinical study and the data is high-level and non-monitored. (3) Results: Follow-up for 92 recipients of MSC-FFM was reported, 88 with GvHD ≥ degrees III, one-third only steroid-refractory and two-thirds therapy resistant (refractory to steroids plus ≥2 additional lines of treatment). A median of three doses of MSC-FFM was administered without apparent toxicity. Overall response rates were 82% and 81% at the first and last evaluation, respectively. At six months, the estimated overall survival was 64%, while the cumulative incidence of death from underlying disease was 3%. (4) Conclusions: MSC-FFM promises to be a safe and efficient treatment for severe R-aGvHD.
Prophylaxis and treatment with mycophenolate mofetil in children with graft-versus-host disease undergoing allogeneic hematopoietic stem cell transplantation: a nationwide survey in Japan
International journal of hematology. 2019
We investigated the safety and efficacy of mycophenolate mofetil (MMF) in the prevention and treatment of graft-versus-host disease (GVHD) using a nationwide retrospective survey in Japanese children undergoing hematopoietic stem cell transplantation (HSCT). Overall, 141 children undergoing allogeneic HSCT for hematological malignancy (n = 84), non-malignancy (n = 52), and solid tumors (n = 5) were administered MMF orally (median 8 years; range 0-15 years; 89 males and 52 females) during 1995-2011. Donors were primarily unrelated and mismatched related. In the GVHD prophylaxis group, 29% and 8.6% of patients developed grade II-IV and III-IV GVHD, respectively. Of the 32 evaluable patients, 16% developed chronic [limited (n = 4) and extensive (n = 1)] GVHD. In the acute GVHD treatment group, 61% had decreased grade. In the chronic GVHD treatment group, 36% had improved symptoms. Combined immunosuppressant was reduced or discontinued in 61% patients. Major adverse events (AEs) were neutropenia (4.3%), infection (3.5%), thrombocytopenia (2.1%), myelosuppression (2.1%), and diarrhea (1.4%). MMF dosage was reduced in two children due to grade ≥ 3 AEs; two children died from infection. MMF thus may be well tolerated in children, and may be an effective option for prophylaxis and treatment of acute and chronic GVHD.
Pediatric acute GVHD: clinical phenotype and response to upfront steroids
Bone marrow transplantation. 2019
To better understand the clinical phenotype of acute graft-versus-host disease (GVHD) in children, we examined the GVHD clinical stage, grade, and response to prednisone 60 mg/m(2)/day PO in a diverse group of 370 pediatric patients with acute GVHD treated from 1990 to 2016 at a single institution. Overall response [complete response (CR) + partial response (PR)] at day 28 occurred in 65%, (CR 52%; PR 13%). Initial GVHD grade did not predict day 28 response. However, the Minnesota GVHD Risk Score predicted response with 68% standard risk (SR)-GVHD patients achieving CR/PR at day 28 versus 48% high risk (HR)-GVHD patients (p < 0.01). Multivariable analysis confirmed that response rates were lower in patients with HR-GVHD [odds ratio (OR), 0.4, p < 0.01] and in recipients of HLA mismatched URD (OR 0.4, p = 0.03). Transplant-related mortality (TRM) at 2 years was greater in HR-GVHD patients, recipients of HLA-partially matched or mismatched unrelated donor (URD) grafts, but not umbilical cord blood (UCB). These data highlight the importance of including children in novel acute GVHD treatment trials. Compared with initial GVHD grade, the Minnesota GVHD Risk Score better demarcates risk of steroid failure and TRM in children and could be used for risk stratification in pediatric acute GVHD studies.
Etanercept as treatment of steroid-refractory acute graft versus host disease in pediatric patients
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2018
INTRODUCTION Corticosteroids are the standard of care for first line treatment of patients who develop grades II-IV of acute Graft-versus-Host Disease (a-GvHD), but the optimal second-line treatment has not been determined yet. We prospectively evaluated the use of anti-TNFalpha monoclonal antibody Etanercept (ET) as second line treatment in children with steroid-refractory a-GvHD. MATERIALS AND METHODS Twenty-five children with either malignant or non malignant diseases experiencing grade II-IV steroid-refractory (SR)-a-GvHD received ET as second line treatment. ET was administered after a median of 14 days (5-135 days) from onset of a-GvHD. RESULTS Seventeen out of 25 patients (68%) developed complete or partial response (CR or PR) to ET. Overall response rate (ORR) (CR or PR) was 78% of patients with cutaneous SR-a-GvHD, 78% with gastro-intestinal a-GvHD, and 57% with hepatic a-GvHD. On day +100 after the start of ET, 52% of children were in CR, 16% in PR, while the remaining 32% failed to respond. Overall Survival (OS) in responders was 76.5% and 16.7% in non- responders (p=0.004). Transplant-related mortality (TRM) at 5 years was 34.1% (95% CI; 18.6%- 57.1%). CONCLUSION In our experience, ET proved to be effective as second line treatment in children with SR-a-GvHD.
Thymopoiesis following HSCT; a retrospective review comparing interventions for aGVHD in a pediatric cohort
Clinical immunology (Orlando, Fla.). 2018
Acute graft-versus-host disease (aGVHD) complicates allogeneic hematopoietic stem cell transplantation (HSCT), and is treated with topical and/or systemic corticosteroids. Systemic corticosteroids and aGVHD damage thymic tissue. We compared thymopoietic effect of topical steroid therapy, corticosteroids and extracorporeal photopheresis (ECP) in 102 pediatric allogeneic HSCT patients. We categorized patients into 4 groups: - no aGVHD, aGVHD treated with topical or systemic steroid, or ECP. Naive CD4(+)CD45RA(+)CD27(+) T-lymphocyte values at 3, 6, 9, 12months post-HSCT were recorded: for ECP patients, values were recorded at 3, 6, 9, 12months during ECP. Differences were compared using the Kruskal-Wallis test. 41 patients had no aGVHD, 23 had aGVHD treated topically or systemically (25), 13 received ECP. Rate of thymopoiesis was significantly different between all groups at all time-points post-transplant (p=0.002, p<0.001, p<0.001, p=0.001 respectively). Even mild aGVHD impairs thymopoiesis. Worst recovery was in ECP patients. Earlier institution of ECP may speed thymic recovery.