A BMT CTN phase II trial of unrelated donor marrow transplantation for children with severe sickle cell disease

Shalini Shenoy, Mary Eapen, Julie A. Panepinto, Brent R. Logan, Juan Wu, Allistair Abraham, Joel Brochstein, Sonali Chaudhury, Kamar Godder, Ann E. Haight, Kimberly A. Kasow, Kathryn Leung, Martin Andreansky, Monica Bhatia, Jignesh Dalal, Hilary Haines, Jennifer Jaroscak, Hillard M. Lazarus, John E. Levine, Lakshmanan Krishnamurti, David Margolis, Gail C. Megason, Lolie C. Yu, Michael A. Pulsipher, Iris Gersten, Nancy DiFronzo, Mary M. Horowitz, Mark C. Walters and Naynesh Kamani

Key points

  • Children with SCD engrafted unrelated donor marrow after reduced intensity conditioning.

  • A high incidence of GVHD and associated mortality compromised safety of the trial.


Children with sickle cell disease (SCD) experience organ damage, impaired quality of life, and premature mortality. Allogeneic bone marrow transplantation from an HLA-matched sibling can halt disease progression but is limited by donor availability. A multicenter phase II trial conducted from 2008-2014 enrolled 30 children aged 4-19 years; 29 were eligible for evaluation. The primary objective was 1-year event-free survival (EFS) after HLA allele-matched (at HLA-A, -B, -C and –DRB1 loci) unrelated donor transplantation. Conditioning regimen included alemtuzumab, fludarabine, and melphalan. Graft-versus-host disease (GVHD) prophylaxis included calcineurin inhibitor, short course methotrexate and methylprednisolone. Transplant indications included stroke (N=12), trans-cranial Doppler velocity >200 cm/second (N=2), ≥3 vaso-occlusive pain crises/year (N=12) or ≥2 acute chest syndrome episodes (N=4) in the 2 years preceding enrollment. Median follow up was 26 months (range 12–62); graft rejection was 10%. One and 2-year EFS were 76% (95% CI 56–88) and 69% (95% CI, 48–82), respectively. The corresponding rates for overall survival (OS) were 86% (95% CI 67–95) and 79% (95% CI 59-90). The day-100 incidence of grade II-IV acute GVHD was 28% (95% CI 13-45); 1-year incidence of chronic GVHD was 62% (95% CI 41-77); 38% classified as extensive. There were 7 GVHD-related deaths. A 34% incidence of posterior reversible encephalopathy syndrome was noted in the first 6 months. Although the 1-year EFS met the pre-specified target of ≥75%, this regimen cannot be considered sufficiently safe for widespread adoption without modifications to achieve more effective GVHD prophylaxis. The trial is registered to as NCT00745420.

  • Submitted May 24, 2016.
  • Accepted September 6, 2016.