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Reduced intensity conditioning for hematopoietic cell transplant for HLH and primary immune deficiencies: BMT CTN 1204

Carl Allen, Rebecca Marsh, Peter Dawson, Catherine M. Bollard, Shalini Shenoy, Philip Roehrs, Rabi Hanna, Lauri Burroughs, Leslie Kean, Julie-An Talano, Kirk R. Schultz, Sung-Yun Pai, K. Scott Baker, Jeffrey R. Andolina, Elizabeth O. Stenger, James Connelly, Alyssa Ramirez, Christopher Bryant, Mary Eapen and Michael A. Pulsipher

Key points

  • A prospective reduced intensity HCT trial for HLH/PID resulted in low early mortality and one year overall survival of 80%.

  • Conditioning with fludarabine, melphalan and alemtuzumab was associated with high rates of mixed chimerism and graft failure.

Abstract

Allogeneic hematopoietic cell transplantation (HCT) with myeloablative conditioning for disorders associated with excessive inflammation such as hemophagocytic lymphohistiocytosis (HLH) is associated with early mortality. A multicenter prospective phase 2 trial of reduced intensity conditioning with melphalan, fludarabine and intermediate-timing alemtuzumab was conducted for HLA matched or single HLA-locus mismatched related or unrelated donor HCT in a largely pediatric cohort. Graft-versus-host disease (GVHD) prophylaxis was cyclosporine with methylprednisolone. The primary endpoint was 1-year overall survival (OS). Thirty-four patients with HLH and 12 with other primary immune deficiencies were transplanted. With a median follow up of 20 months, the one-year OS for transplanted patients was 80.4% (90% CI: 68.6 – 88.2). Five additional deaths by 16 months yielded an 18-month OS probability of 66.7% (90% CI: 52.9 – 77.3). Two patients experienced primary graft failure and 18 patients either experienced a secondary graft failure or required a second intervention (mostly donor lymphocyte infusion (DLI)). At one year the proportion of patients alive with sustained engraftment without DLI or second HCT was 39.1% (95% CI: 25.2 – 54.6) and that of being alive and engrafted (with or without DLI) was 60.9% (95% CI: 45.4 – 74.9). The day-100 incidence of grade II-IV acute GVHD was 17.4% (95% CI: 8.1 – 29.7) and one-year incidence of chronic GVHD was 26.7% (95% CI: 14.6 – 40.4). Although the trial demonstrated low early mortality, the majority of surviving patients required DLI or second HCT. These results demonstrate a need for future approaches that maintain low early mortality with improved sustained engraftment. The trial was registered at Clinical Trials.gov (NCT 01998633).

  • Submitted January 18, 2018.
  • Accepted July 1, 2018.