Ibrutinib treatment of pediatric chronic graft-versus-host disease: Primary results from the phase 1/2 iMAGINE study Journal Article
| Authors: | 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.; Oshrine, B.; Khaw, S. L.; Harris, A. C.; Verna, M.; Zubarovskaya, L.; Lee, Y.; Wahlstrom, J.; Styles, L.; Shaw, P. J.; Dalle, J. H. |
| Article Title: | Ibrutinib treatment of pediatric chronic graft-versus-host disease: Primary results from the phase 1/2 iMAGINE study |
| Abstract: | Chronic graft-versus-host disease (cGVHD) is a potentially life-threatening complication of allogeneic hematopoietic stem cell transplantation. Clinical data surrounding cGVHD therapies in younger children are limited and critically needed. Primary endpoints were to determine the recommended pediatric equivalent dose (RPED) and assess pharmacokinetics (PK) and safety. Secondary endpoints included overall response rate (ORR; comprising complete response and partial response) according to the 2014 National Institutes of Health criteria at 24 weeks, overall survival, and duration of response (DOR). Here we present the primary results from the open-label, multicenter, international phase 1/2 iMAGINE study (PCYC-1146-IM), which evaluated the PK, safety, and efficacy of ibrutinib in patients age ≥1 to <22 years with treatment-naive (TN) or relapsed/refractory (R/R) moderate/severe cGVHD. Patients age <12 years received once-daily ibrutinib starting at 120 mg/m2 and escalating to 240 mg/m2 (full adult dose equivalent) after 14 days if free from ibrutinib-related grade ≥3 toxicity; patients age ≥12 years received once-daily ibrutinib 420 mg. Fifty-nine patients (12 TN and 47 with R/R cGVHD; median age, 13 years; range, 1 to 19 years) were enrolled. Plasma concentration-time profiles for ibrutinib 240 mg/m2 (the 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 of 59), including 83% (10 of 12) for the TN subgroup and 60% (28 of 47) for R/R. Among 46 responders (median follow-up, 20 months; range, 2 to 32 months), 12-month DOR for each subgroup was 60% (95% confidence interval [CI], 25% to 83%) in TN patients and 58% (95% CI, 35% to 75%) in R/R patients. Responses were durable, with numerically higher rates than those previously observed with ibrutinib in adults, demonstrating that ibrutinib provides clinically meaningful activity with acceptable safety in children with moderate/severe cGVHD. © 2022 The American Society for Transplantation and Cellular Therapy |
| Keywords: | adolescent; adult; child; controlled study; preschool child; school child; treatment response; young adult; major clinical study; overall survival; clinical trial; neutropenia; diarrhea; drug dose reduction; drug efficacy; drug safety; drug withdrawal; hypertension; systemic therapy; treatment duration; united states; comparative study; methotrexate; rituximab; follow up; imatinib; interleukin 2; bortezomib; phase 2 clinical trial; anemia; bleeding; nausea; stomatitis; vomiting; clinical assessment; relapse; pyrimidines; pediatric; abdominal pain; arthralgia; coughing; drug dose escalation; fever; alanine aminotransferase; hypokalemia; chronic graft versus host disease; hla matching; death; pneumothorax; pyrazole derivative; multicenter study; pyrazoles; graft versus host reaction; mesenchymal stem cell; open study; azathioprine; piperidines; headache; phase 1 clinical trial; kaplan meier method; corticosteroid; pyrimidine derivative; tacrolimus; graft vs host disease; pneumococcal infection; epistaxis; disease exacerbation; bone necrosis; cytomegalovirus infection; sirolimus; cyclosporine; national health organization; pentostatin; plasma concentration-time curve; opportunistic infection; heart tamponade; adult respiratory distress syndrome; unrelated donor; petechia; piperidine derivative; childhood disease; septic shock; patient-reported outcome; infliximab; overall response rate; chronic graft-versus-host disease; hematothorax; gingiva bleeding; contusion; basiliximab; tocilizumab; mycophenolate mofetil; ruxolitinib; ibrutinib; humans; human; male; female; article; bruton's tyrosine kinase inhibitor; staphylococcal toxic shock syndrome; tension pneumothorax |
| Journal Title: | Transplantation and Cellular Therapy |
| Volume: | 28 |
| Issue: | 11 |
| ISSN: | 2666-6375 |
| Publisher: | Elsevier Inc. |
| Date Published: | 2022-11-01 |
| Start Page: | 771.e1 |
| End Page: | 771.e10 |
| Language: | English |
| DOI: | 10.1016/j.jtct.2022.08.021 |
| PUBMED: | 36044977 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 December 2022 -- Source: Scopus |
