1.
Management of Chronic Graft-vs.-Host Disease in Children and Adolescents With ALL: Present Status and Model for a Personalised Management Plan
Sobkowiak-Sobierajska, A., Lindemans, C., Sykora, T., Wachowiak, J., Dalle, J. H., Bonig, H., Gennery, A., Lawitschka, A.
Frontiers in pediatrics. 2022;10:808103
Abstract
Herein we review current practice regarding the management of chronic graft-vs.-host disease (cGvHD) in paediatric patients after allogeneic haematopoietic stem cell transplantation (HSCT) for acute lymphoblastic leukaemia (ALL). Topics covered include: (i) the epidemiology of cGvHD; (ii) an overview of advances in our understanding cGvHD pathogenesis; (iii) current knowledge regarding risk factors for cGvHD and prevention strategies complemented by biomarkers; (iii) the paediatric aspects of the 2014 National Institutes for Health-defined diagnosis and grading of cGvHD; and (iv) current options for cGvHD treatment. We cover topical therapy and newly approved tyrosine kinase inhibitors, emphasising the use of immunomodulatory approaches in the context of the delicate counterbalance between immunosuppression and immune reconstitution as well as risks of relapse and infectious complications. We examine real-world approaches of response assessment and tapering schedules of treatment. Furthermore, we report on the optimal timepoints for therapeutic interventions and changes in relation to immune reconstitution and risk of relapse/infection. Additionally, we review the different options for anti-infectious prophylaxis. Finally, we put forth a theory of a holistic view of paediatric cGvHD and its associated manifestations and propose a checklist for individualised risk evaluation with aggregated considerations including site-specific cGvHD evaluation with attention to each individual's GvHD history, previous medical history, comorbidities, and personal tolerance and psychosocial circumstances. To complement this checklist, we present a treatment algorithm using representative patients to inform the personalised management plans for patients with cGvHD after HSCT for ALL who are at high risk of relapse.
2.
A Prospective, Multicenter Study of Closed System Extracorporeal Photopheresis for Children With Steroid-Refractory Acute Graft-Versus-Host Disease
Kitko, C. L., Abdel-Azim, H., Carpenter, P. A., Dalle, J. H., Diaz-de-Heredia, C., Gaspari, S., Gennery, A. R., Handgretinger, R., Lawitschka, A.
Transplantation and cellular therapy. 2022
Abstract
BACKGROUND Steroid-refractory (SR) acute graft-versus-host disease (aGvHD) therapy involves intensive immunosuppression, which is associated with significant infectious risk. Extracorporeal photopheresis (ECP) is used to treat SR-aGvHD and is considered to be more immunomodulatory than immunosuppressive. However, pediatric data are mostly retrospective and often involve multi-step ECP that includes apheresis followed by separate photosensitizing/reinfusion on another device. OBJECTIVE To prospectively evaluate the efficacy and safety of a single-device ECP system in children with SR-aGvHD. STUDY DESIGN Open-label, multicenter, phase 3 study of the THERAKOS® CELLEX® Photopheresis System in children/young adults aged 1 to 21 years with SR-aGvHD. Patients were treated 3 times per week for 4 weeks, then twice weekly through week 12 while maintaining standard aGvHD prophylaxis. The primary efficacy endpoint was the proportion of patients achieving overall response (OR) at day 28 without the addition of next-line systemic treatment. Secondary endpoints included the proportion of patients achieving OR at weeks 8 and 12; the mean weekly steroid dose at weeks 4, 8, and 12; and treatment-emergent adverse events (TEAEs). RESULTS Twenty-nine children (median age, 8 years) were enrolled. OR was 55% by day 28, 74% by week 8, and 79% by week 12. Progressive improvements were observed in the skin and the gastrointestinal tract. Mean steroid dose decreased from 1.54 mg/kg/day at baseline to 0.90 mg/kg/day at week 4; 35% of patients achieved >50% steroid dose reduction at week 4 and 75% achieved >50% steroid dose reduction at week 12. Of 168 TEAEs reported among 25 patients (86%), 28 (17%) events were infections and 14 (8%) events were considered to be probably treatment related (all nonserious). Of 627 ECP treatments administered in children/young adults, 68% required blood priming. Treatment-related AEs, including hypotension, hypocalcemia, central line infection, and catheter-site bruising, were rare (1 event each). Three deaths occurred and were deemed unrelated to ECP by the investigators. CONCLUSION Use of the THERAKOS® CELLEX® Photopheresis System was effective in children with SR-aGvHD, with more than half experiencing improvement by day 28 and further responses observed over 12 weeks. Very few TEAEs were attributable to ECP, and no new safety signals were observed.
3.
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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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.