Blood and Marrow Transplant Clinical Trials Network (BMT CTN) Reduced Intensity Conditioning for Children and Adults With Hemophagocytic Syndromes or Selected Primary Immune Deficiencies (1204)
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November 2013 - December 2016
June 11, 2021
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Commercial Use Data Restrictions No
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To test the safety and efficacy of intermediate timing (day −14) of alemtuzumab as part of a reduced-intensity conditioning protocol in subjects with hemophagocytic lymphohistiocytosis and other primary immunodeficiencies.
Hematopoietic cell transplant (HCT) is required for long-term survival in many patients with primary defects of the immune system. The major obstacles to long-term survival in these patients, many of whom have significant morbidities at the time of transplant, are treatment-related mortality and durable immune reconstitution. Several studies have shown that reduced-intensity conditioning (RIC) significantly improved outcomes in patients with immune deficiencies such as hemophagocytic lymphohistiocytosis (HLH). However, the decrease in treatment-related morbidity and mortality comes with increased risk of inadequate durable engraftment. In an institutional case series of patients with HLH and related disorders, “intermediate” (Day -14) timing of alemtuzumab administration maintained excellent survival rates with improved stable engraftment.
Although a RIC approach for HLH appears to be effective, the optimal dose and timing of alemtuzumab and other therapeutic agents used in conditioning to achieve maximum survival with improved engraftment remained to be defined. Therefore, this study was initiated to test the efficacy of intermediate-timed alemtuzumab as part of a RIC protocol in patients with HLH and other primary immunodeficiencies.
Eligible patients were > 3 months and ≤ 45 years of age with Lansky/Karnofsky performance status ≥ 50% who have hemophagocytic lymphohistiocytosis (HLH) or related disorders, or selected immune deficiencies [chronic active Epstein-Barr virus disease (CAEBV), chronic granulomatous disease (CGD), hyperimmunoglobulin M (HIGM1) syndrome, X-linked (IPEX) syndrome, or leukocyte adhesion deficiency (LAD)], with an indication for HCT. Patients had adequate cardiac, renal, hepatic, and pulmonary organ function. Exclusion criteria included prior HCT within 6 months of enrollment and administration of alemtuzumab within 2 weeks of enrollment.
46 patients were enrolled and underwent HCT, 34 patients with HLH and 12 patients with other primary immune deficiency diseases.
BMT CTN 1204 was a multicenter prospective phase 2 trial designed to test a RIC regimen consisting of alemtuzumab, fludarabine, and melphalan in children and younger adults with HLH and other primary immunodeficiencies.
The transplant-conditioning regimen included alemtuzumab on days −14 through −10 (1 mg/kg subcutaneous with a maximum cumulative dose of 90 mg), fludarabine on days −8 through −4 (150 mg/m² or 5 mg/kg in patients weighing <10 kg), and melphalan on day −3 (140 mg/m² or 4.7 mg/kg in patients weighing <10 kg). Bone marrow was the specified graft and was infused on day 0 per local institutional guidelines. GVHD prophylaxis consisted of cyclosporine (day −3 through day +100) tapered through day +180 and methylprednisolone 2 mg/kg/day (day −2 and −1), 1 mg/kg/day through day+28, and then tapered over a month. Oral prednisone (1.2 mg/kg/day) may have been substituted after HCT. Supportive care recommendations included prophylaxis and surveillance for infections. Granulocyte colony-stimulating factor was not required but could be given at provider discretion. Chimerism studies (overall and T cell) were required monthly after engraftment, day +100, day +180, day +365.
Donors were unaffected siblings matched at HLA-A and HLA-B (intermediate or higher resolution) and HLA-DRB1 (high-resolution DNA-based typing), or an unaffected relative or adult unrelated donor matched or mismatched at 1 HLA locus at HLA-A, HLA-B, HLA-C (intermediate or higher resolution), and HLA-DRB1 (high-resolution DNA-based typing).
Patients were followed on protocol for 1-year post-HCT. The primary end point was 1-year overall survival.
Although the RIC provided successful engraftment in the majority of patients, the regimen cannot be considered safe for widespread adoption without modification due to regimen-related toxicity and the high rate of chronic graft-versus-host disease (GVHD), which was the predominant cause of mortality.
Allen CE, Marsh R, Dawson P, et al. Reduced-intensity conditioning for hematopoietic cell transplant for HLH and primary immune deficiencies. Blood. 2018;132(13):1438-1451. doi:10.1182/blood-2018-01-828277
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