Reduced Intensity Conditioning with Combined Haploidentical and Cord Blood Transplantation Results in Rapid Engraftment and Durable Remissions in Hematological Malignancies

Abstract 830

Haplo-cord transplant, the co-infusion of CD34+ stem cells from a haploidentical (haplo) family member with a cord blood (UCB) unit has been proposed as a method to reduce duration of pancytopenia after UCB SCT. We prospectively investigated reduced intensity conditioning (RIC) of fludarabine, melphalan and rATG followed by haplo-cord SCT in 45 patients with high-risk hematological malignancies. Thirteen patients (29%) belonged to ethnic or racial minorities, and almost half had AML. Median age was 50; weight 80 kg and twenty six (58%) had active disease at the time of transplant. The median CD34+ cell content post-selection of the haplo graft was 3.5 ×10⁶/kg (25%–75% inter quartile range (IQR) 1.36–4.63). Minimal required UCB cell dose was 1×10⁷ nucleated cells/kg. Median infused UCB total nucleated cell was 1.55×10⁷ (range 1.24 to 2.09). 36 pts (80%) had at least a 5/6 matched UCB. The cumulative incidence of neutrophil recovery at day +50 was 95% (95% CI, 87–100%) with a median time to engraftment of 11 days (IQR 9 –15 days). The cumulative incidence of platelet recovery at day +100 was 83% (95% CI, 69–97%) with median time to platelet engraftment of 19 days (IQR 15–33 days). Patients received a median number of 12 platelet transfusions (IQR 6–22) and 7 red blood cell units (IQR 4–12) after the transplant. The median number of day of hospitalization during the first 100 days after transplant was 26 days (IQR 15–43 days). In the majority of patients, early haploidentical engraftment was replaced by durable engraftment of UCB cells by 100 days. The median percentage of haploidentical cells in unfractionated peripheral blood was 86% on day 30, but declined to 22% by day 100, and to 2% by day 180. Conversely, the median percentage of cells of UCB origin increased from 10% by day 30, to 78% by day 100, and to 95% by day 180. There was also some re-emergence of host hematopoiesis over time. The percentage of day 100 haplo donor chimerism correlated closely with the CD34+ cell content of the haplo-identical graft (10⁶/kg) (r=0.6225; P=0.0003). TNC, CD34+ cells, or CD3+ cells of the UCB did not correlate with cord donor chimerism. The cumulative incidence of acute GVHD (Grade II -IV) was 25% (95% CI 11–39). There were only two patients with chronic GVHD for a cumulative incidence of 6% at 1 year. Cumulative incidence of treatment related mortality was 9% (95% CI 1–17) at day 100 and 28% (95% CI 13–43) at one year. Cumulative incidence of disease recurrence was 11% (95% CI 3–19) at day 100 and 30% (95% CI 14–44) at one year. With a median follow up for survivors of 330 days (range 64–1259), estimated one year survival was 55% (95% CI 39–71) and progression free survival was 42% (95% CI 25–79). Active disease at the time of haplo-cord SCT tended to impair PFS, but this difference did not reach statistical significance (P=0.06). The cumulative incidence of CMV viremia was 42% (95% CI 26–58), but there were only four cases of CMV disease. The cumulative incidence of EBV viremia was 42% (95% CI 26–58%), but most cases were self limited or transient. Five patients developed biopsy or radiological proven PTLD, for a cumulative incidence of 11% (95% CI 0–22). RIC and haplo-cord transplant results in fast engraftment of neutrophils and platelets, low incidences of acute and chronic GVHD, low frequency of delayed opportunistic infections, reduced transfusion requirements, shortened length of hospital stay and promising long term outcomes. UCB cell dose has no impact on time to hematopoietic recovery and UCB selection can prioritize matching, and better matched donors can be identified rapidly for most patients.