Double Umbilical Cord Blood Transplantation after Novel Myeloablative Conditioning Using FluBu4/TLI

Introduction:  Double-unit umbilical cord blood transplantation (dCBT) is a validated strategy to broaden access to hematopoietic stem cell transplantation (HSCT), but is limited by delayed engraftment and immune reconstitution. ATG is a part of conventional myeloablative (MA) conditioning for CBT, and although it may facilitate engraftment, it can also contribute to delayed immune reconstitution through T-cell depletion. We conducted a Phase II trial to assess the safety and efficacy of dCBT following a preparative regimen combining total lymphoid irradiation (TLI, 400 cGy) in lieu of ATG, with Fludarabine/Busulfan 3.2mg/kg IV x4 (FluBu4). Tacrolimus and mycophenolate mofetil were used as GVHD prophylaxis.

Methods and Results:  Twenty consecutive patients with hematological malignant or non-malignant disorders were enrolled between 2008 and 2012 at the University of Michigan Blood and Marrow Transplantation Program. Transplants consisted of two umbilical cord blood (UCB) units that were at least a 4/6 HLA match to the pt, and 3/6 match to each other.  Median age was 49 yrs (range, 13-64 yrs).  Most patients had AML in CR1 or CR2 (40%), followed by NHL in PR or better (25%), MDS (20%), ALL in early relapse (5%), MM in VGPR (5%), and aplastic anemia (5%).  Median HCT-CI pre-transplant was 3 (0-7).  Median total cells infused were 5.3x10^7 (4-15.6x10^7) of recipient body wt. Neutrophil engraftment occurred in 85% of pts (95% CI, 60-95%), at a median of 16 days (12-31), and 14/17 patients engrafted within 26 days.  Platelet engraftment occurred in 65% of pts (95% CI, 40-82%) at a median of 43 days (26-86).  Cumulative incidences of grade II-IV and grade III/IV acute GVHD was 35% and 10%, respectively, and cumulative incidence of chronic GVHD at 1 year was 25%.  Relapse was the primary cause of death and occurred in 6 pts (30%), all within 1 yr.  At days 100 and 365, cumulative incidence of TRM was 25% (95% CI, 9-45%) and 35% (95% CI, 16-55%) respectively. Transplant-related mortality trended to pts >50 yrs (p=0.058).  The cause of TRM was GVHD in 5 patients and graft failure in 2 patients.  Two GVHD deaths resulted from HSV-2 or HHV6 viremia while receiving high dose steroids.  OS at 1 year was 40% (95% CI, 19-60%), and 7 (35%) are in CR after median follow up of 2.35 years post-transplant. 

Conclusion:  In summary, dCBT after MA conditioning with FluBu4/TLI provides high engraftment rates with early neutrophil recovery.  Although conclusions regarding survival are limited due to sample size, this seemed to be in line with previous reports, and was clearly better for younger patients (<50 years old).