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Extracorporeal photopheresis versus alternative treatment for chronic graft-versus-host disease after haematopoietic stem cell transplantation in children and adolescents
Buder, K., Zirngibl, M., Bapistella, S., Meerpohl, J. J., Strahm, B., Bassler, D., Weitz, M.
The Cochrane database of systematic reviews. 2022;6(6):Cd009898
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Editor's Choice
Abstract
BACKGROUND Chronic graft-versus-host disease (cGvHD) is a major cause of morbidity and mortality after haematopoietic stem cell transplantation, occurring in 6% to 65% of the paediatric recipients. Currently, the therapeutic mainstay for cGvHD is treatment with corticosteroids, frequently combined with other immunosuppressive agents in people with steroid-refractory manifestations. There is no established standard treatment for steroid-refractory cGvHD. The therapeutic options for these patients include extracorporeal photopheresis (ECP), an immunomodulatory treatment that involves ex vivo collection of mononuclear cells from peripheral blood, exposure to the photoactive agent 8-methoxypsoralen, ultraviolet radiation and re-infusion of the processed cell product. The mechanisms of action of ECP are not completely understood. This is the second update of a Cochrane Review first published in 2014 and first updated in 2015. OBJECTIVES To evaluate the effectiveness and safety of ECP for the management of cGvHD in children and adolescents after haematopoietic stem cell transplantation. SEARCH METHODS We searched the Cochrane Register of Controlled Trials (CENTRAL) (2021), MEDLINE (PubMed) and Embase databases from their inception to 25 January 2021. We searched the reference lists of potentially relevant studies without any language restrictions. We searched five conference proceedings and nine clinical trial registries on 9 November 2020 and 12 November 2020, respectively. SELECTION CRITERIA We aimed to include randomised controlled trials (RCTs) comparing ECP with or without alternative treatment versus alternative treatment alone in children and adolescents with cGvHD after haematopoietic stem cell transplantation. DATA COLLECTION AND ANALYSIS Two review authors independently performed the study selection. We resolved disagreements in the selection of trials by consultation with a third review author. MAIN RESULTS We found no studies meeting the criteria for inclusion in this 2021 review update. AUTHORS' CONCLUSIONS We could not evaluate the efficacy of ECP in the treatment of cGvHD in children and adolescents after haematopoietic stem cell transplantation since the second review update again found no RCTs. Current recommendations are based on retrospective or observational studies only. Thus, ideally, ECP should be applied in the context of controlled trials only. However, performing RCTs in this population will be challenging due to the limited number of eligible participants, variable disease presentation and the lack of well-defined response criteria. International collaboration, multicentre trials and appropriate funding for such trials will be needed. If treatment decisions based on clinical data are made in favour of ECP, recipients should be carefully monitored for beneficial and harmful effects. In addition, efforts should be made to share this information with other clinicians, for example by setting up registries for children and adolescents treated with ECP.
PICO Summary
Population
Children and adolescents with chronic graft-versus-host disease (GvHD) taking part in randomised controlled trials
Intervention
Extracorporeal photopheresis (ECP) with or without alternative treatment
Comparison
Alternative treatment alone
Outcome
The authors found no studies meeting the criteria for inclusion in this systematic review.
2.
Ibrutinib treatment of pediatric chronic graft-versus-host disease: primary results from the phase 1/2 iMAGINE study
Carpenter, P. A., Kang, H. J., Yoo, K. H., Zecca, M., Cho, B., Lucchini, G., Nemecek, E. R., Schultz, K. R., Stepensky, P., Chaudhury, S., et al
Transplantation and cellular therapy. 2022
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Editor's Choice
Abstract
BACKGROUND Chronic graft-vs-host disease (cGVHD) is a potentially life-threatening complication of allogeneic hematopoietic stem cell transplantation. Clinical data surrounding cGVHD therapies in younger children is limited and critically needed. OBJECTIVES Primary endpoints were to determine the recommended pediatric equivalent dose (RPED) and assess PK and safety. Secondary endpoints included overall response rate (ORR; complete response and partial response) per 2014 NIH criteria at 24 weeks, overall survival, and duration of response (DOR). STUDY DESIGN We present the primary results from the open-label, multicenter, international phase 1/2 iMAGINE study (PCYC-1146-IM), which evaluated pharmacokinetics (PK), safety, and efficacy of ibrutinib in patients aged ≥1 to <22 years with treatment-naive (TN) or relapsed/refractory (R/R) moderate/severe chronic graft-versus-host disease (cGVHD). Patients aged <12 years received once-daily ibrutinib starting at 120 mg/m(2) and escalating to 240 mg/m(2) (full adult dose equivalent) after 14 days if free from ibrutinib-related grade ≥3 toxicity; patients aged ≥12 years received once-daily ibrutinib 420 mg. RESULTS Fifty-nine patients (12 TN and 47 with R/R cGVHD; median age 13 years [range 1-19]) were enrolled. Plasma concentration-time profiles for ibrutinib 240 mg/m(2) (RPED) were comparable to those observed in adults with cGVHD at a dose of 420 mg/day. Safety was consistent with the known profile of ibrutinib in cGVHD. ORR by 24 weeks was 64% (38/59): 83% (10/12) for the TN subgroup and 60% (28/47) for R/R. Among 46 responders (median follow-up, 20 months [range 2-32]), 12-month DOR (95% confidence interval) for each subgroup was 60% (25-83%) in TN and 58% (35-75%) in R/R. CONCLUSIONS Responses were durable, with the rates numerically higher than previously observed with ibrutinib in adults, demonstrating that ibrutinib provides clinically meaningful activity with acceptable safety in children with moderate/severe cGVHD.
PICO Summary
Population
Children aged ≥1 to <22 years with treatment-naive (TN) or relapsed/refractory (R/R) moderate/severe chronic graft-versus-host disease (cGVHD) enrolled in the iMAGINE study (n=59)
Intervention
Children aged <12 years: once-daily ibrutinib starting at 120 mg/m(2) and escalating to 240 mg/m(2) (full adult dose equivalent) after 14 days if free from ibrutinib-related grade ≥3 toxicity; Children aged ≥12 years: once-daily ibrutinib 420 mg.
Comparison
None
Outcome
Plasma concentration-time profiles for ibrutinib 240 mg/m(2) (RPED) were comparable to those observed in adults with cGVHD at a dose of 420 mg/day. Safety was consistent with the known profile of ibrutinib in cGVHD. ORR by 24 weeks was 64% (38/59): 83% (10/12) for the TN subgroup and 60% (28/47) for R/R. Among 46 responders (median follow-up, 20 months [range 2-32]), 12-month DOR (95% confidence interval) for each subgroup was 60% (25-83%) in TN and 58% (35-75%) in R/R.
3.
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
Kurtzberg, J., Abdel-Azim, H., Carpenter, P., Chaudhury, S., Horn, B., Mahadeo, K., Nemecek, E., Neudorf, S., Prasad, V., Prockop, S., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2020
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Editor's Choice
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.
PICO Summary
Population
Children with primary steroid refractory aGVHD, naive to other immunosuppressant therapies (n=54)
Intervention
Mesenchymal stromal cell product (remestemcel-L) dosed at 2x10(6) cells/kg twice weekly for four weeks.
Comparison
None
Outcome
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.