Unrelated Cord Blood Transplantation after Reduced Intensity Conditioning (RIC) in Adults with Hematological Malignancy. An EBMT-Eurocord-Netcord, Société Française de Greffe de Moelle et de Thérapie Cellulaire and University of Minnesota Collaborative Study.

Single center studies have demonstrated promising results in recipients of unrelated umbilical cord blood transplantation (UCBT) treated with a reduced intensity conditioning (RIC). However, little is known about risk factors for outcomes with this strategy. We retrospectively evaluated outcomes after RIC-UCBT in 176 patients with hematological malignancies: 116 had acute leukemia (21 ALL, 77 AML, 18 secAML), 36 lymphoid/plasma-cell diseases (6 Hodgkin, 24 NHL, 4 CLL and 2 Myeloma) and 24 myelodysplastic/myeloproliferative diseases (14 MDS and 10 CML). Median follow-up was 12 months (3–80) and median age 45 years (16–76). At transplant, 51% of patients were in advanced phase of disease and 30% had a previous autologous transplants. The conditioning regimen varied according to disease and centre; however, 95% received Fludarabine (FLU)-containing regimen, 55% being FLU-CY-TBI(2Gy), and ATG/ALG was added in 23%. GVHD prophylaxis consisted most commonly (72%) of CsA+MMF. All received a single UCB unit graft that was HLA identical (6/6) (HLA A and B low resolution and DRB1 allelic typing) in 6%, 5/6 in 27%, 4/6 55% and 3/6 in 11%. The median total nucleated cell dose infused was 2.7 × 10⁷/kg. Median time to neutrophil recovery was 20 days (5–56) and probability of neutrophil recovery was 78±3% at day-60. Chimerism analysis at 3 months was complete in 64%, mixed in 16% and absent (autologous reconstitution) in 19%. In multivariate analysis, cell dose (< vs >2.7 × 10⁷/kg, HR=1.6, p=0.02), HLA compatibility (5–6/6 vs 3–4/6, HR=1.5, p=0.04) and use of FLU+CY+TBI versus other regimens (HR=1.7, p=0.01), were independently associated with neutrophil recovery. At day-100, probability of acute GVHD II–IV was 30% (18% grade II; 6% grade III, 6% grade IV), and no risk factor was associated with its incidence. At 1 year, probability of chronic GVHD was 30%. TRM was 38% at 1 year, being 19% for patients given low dose TBI (<6Gy), vs 61% for those without TBI and 40% for those given a low cell dose (<2.7 × 10⁷/kg), vs 21% for the remainder. In multivariate analysis, both factors were associated with TRM. Probability of relapse at 1 year was 41% and it was associated with disease status and aGVHD (26% in those with and 47% in those without aGVHD, p=0.02). DFS at 1 year was 41% for patients with acute leukaemia, 31% for MDS/CML and 42% for lymphoid/plasma diseases. For those treated with FLU-CY-TBI, DFS was 51% as compared to 28% for those treated with other RICs (p=0.0002). In a multivariate analysis, advanced disease status (HR=1.6, p=0.03) and conditioning regimens other than FLU-CY-TBI (HR=1.9, p=0.004) were associated with decreased DFS. In conclusion, cell dose plays a critical role on engraftment and risk of TRM after UCBT in the RIC setting. Specific RIC regimen, namely FLU-CY-TBI, provides better engraftment, reduced TRM and better DFS. These results support the use of FLU-CY-TBI and UCBT as a strategy for broadening the application of transplant to patients previously excluded on the basis of age, co-morbidities and/or absence of a HLA-matched unrelated donor.