Prospective Phase II Study of Biologic Assignment One Vs Two Unit Umbilical Cord Blood Transplant (UCBT) in the Reduced-Intensity Conditioning Setting.

Retrospective analyses of UCBT using early historic controls show more robust graft vs leukemia effect in recipients given two-units vs one-unit. We present herein analyses from this single institution, prospective phase II clinical trial conducted 9/2003 to 5/2008 comparing 1 vs 2 unit UCBT in patients (pts) with high-risk, recurrent hematologic malignancies treated with reduced-intensity conditioning. The number of units infused in each pt was determined by biologic assignment based on the number of cells contained in the primary unit. Pts received 1 UCB unit if the cell dose was ≥ 2.5 x 10⁷ nucleated cells/kg recipient weight and 2 UCB units for a minimum total combined cell dose of 1.5 x 10⁷ cells/kg recipient weight if only smaller units were available. The UCB grafts were matched at ≥ 4/6 HLA loci (antigen level matching at class I A and B loci, and allele level matching class II DRB1 loci) except for 1 pt (3/6). If 2 UCB units were used they needed to be at least a 4/6 match to each other. The conditioning regimen included: Fludarabine 35 mg/m²/d x 5 days, cyclophosphamide 1 g/m²/day x 2 days, ATG 30 mg/kg/day x 2 days and single fraction TBI 200 cGy. Thirty-seven pts, 14 females, 23 males, median age 49 (range 20–71) years were enrolled. Most pts had advanced stage or high-risk hematologic malignancies; 28 pts (76%) had MDS/AML and 9 (24%) had other hematologic malignancies. Two pts underwent 2 transplants on this study after relapsing following the first UCBT. Twenty-seven pts received 1 unit and 10 pts received 2 units. The median follow up for survivors is 17.9 (range 1.2–55.9) months (mos) and median follow up for all pts is 10.1 mos. Median time to an ANC > 500/μL on 3 consecutive evaluations was 24.5 (range 12–55) days and 25 (range 13–43) days for 1 and 2 units, respectively (p=0.361). Median time to platelets > 20,000/μL without transfusion support on 3 consecutive evaluations was 38.5 (range 24–84) days and 63.5 (range 38–117) days for 1 and 2 UCB units, respectively (p=0.009). Median event-free survival (EFS) and median overall survival (OS) did not differ comparing 1 vs 2 units: 127 (range 16–1785+) days and 216 (range 16–1785+) days for 1 unit UCBT vs 92.5 (range 27– 1545+) days and 112 (range 27–1545+) days for 2 unit UCBT. The Kaplan-Meier (K-M) OS for 1 unit UCBT was 35.6% at 4 years compared to 33.3% for 2 unit UCBT (p=0.403). No statistically significant difference in K-M 4 year EFS was seen (p=0.894). At day +100, 7 pts (26%) had progressive disease or died in the 1 unit UCBT arm compared to 5 pts (50%) in the 2 unit UCBT arm. To date 51.8% of pts in the 1 unit arm have relapsed compared to 30% in the 2 unit arm (p=0.288). A total of 15/27 pts (56%) in the 1 unit UCBT arm died and 6/10 (60%) in the 2 unit UCBT arm died. Treatment-related mortality occurred in 3/10 pts in the 2 unit UCBT arm vs 2/27 in the 1 unit UCBT arm. Chimerism analyses were performed by VNTR analyses of blood mononuclear cells to confirm donor engraftment. Ten pts failed to achieve > 60% donor chimerism by day T+42, 8/26 in the 1 unit arm and 2/9 in the 2 unit arm (p=0.625). One pt died in each arm prior to T+42. Primary engraftment failure was defined by failure to restore donor or pt hematopoiesis requiring UCBT with the back up graft. Notably, 4 pts had primary and 1 pt had secondary engraftment failure in the 1 unit UCBT arm while no engraftment failures were observed in the 2 unit UCBT arm. No pts had grade 4 acute GVHD and no differences for overall incidence acute GVHD were noted comparing 1 vs 2 unit UCBT. Grade 3 acute GVHD was seen in 5/26 (19%) pts in the 1 unit UCBT arm and 3/10 (30%) in the 2 unit UCBT arm (p=0.658). Chronic GVHD was seen in 3 of 23 (3 limited) evaluable 1 unit UCBT pts and 2 of 7 (1 limited, 1 extensive) 2 unit UCBT pts. Pts who received a 2 unit UCBT had increased number of CD3+ cells (p=0.011) and total nucleated cells (TNC) (p<0.0001) per actual body weight infused compared to pts receiving only 1 unit of UCB. Those pts who relapsed had a trend toward lower numbers of CD3+ cells (p=0.054) and TNC (p=0.05) infused per actual body weight compared to pts without relapse. Total numbers of CD34+ cells, CD3+ cells and TNC infused were not predictive of EFS or OS by Cox univariate analysis. Equivalent clinical outcomes were seen in this prospective comparison of 1 vs 2 unit UCBT in the reduced-intensity conditioning setting. A trend towards better engraftment and improved donor chimerism at T+42 were seen in the 2 unit UCBT arm.