Impact of Refined Disease Risk Index after Single and Double Umbilical Cord Blood Transplantation in Adults with Hematological Malignancies
Authors: Paviglianiti Annalisa , Ruggeri Annalisa , Sanz Guillermo , Milpied Noel , Blaise Didier , Esquirol Albert , Arcese William , Ferra Christelle , Ifrah Norbert , Bouris Jean Henri , Raj Kavita , Veelken Joan Hendrik , Sica Simona , Contentin Nathalie , Bloor Adrian , Volt Fernanda , Kenzey Chantal , Rocha Vanderson , Gluckman Eliane 
Published: October 2019

Abstract
Identifying pre-transplant risk factor before allogeneic transplantation (HSCT) is important, regardless of the graft source. Nonetheless, it has been demonstrated that disease type and status at the time of HSCT significantly affect outcome. Disease risk index (DRI) has been recently defined for stratifying large and heterogeneous cohorts of patients (pts) undergoing HSCT. The original DRI included all hematological malignancies (except very rare diseases) and was able to define 4 distinct groups with different outcomes, dividing patients by disease type and status and considering cytogenetics that turned to be determinant for acute myeloid leukemia and myelodysplastic syndromes (MDS). Recently, DRI was refined by including rare diseases and improving MDS stratification by blast percentage, cytogenetics and response to prior therapy. DRI has been demonstrated to be applicable to pts undergoing HSCT regardless of age, conditioning regimen and graft source, and it has also been validated in pts undergoing T-cell depleted HSCT. Currently, there are no available reports on large cohort of pts undergoing umbilical cord blood transplantation (UCBT). Our aim was to determine the impact of DRI after UCBT. We retrospectively analyzed 2337 adults who underwent UCBT between 2004 and 2014, were reported to Eurocord and had available data for DRI scoring. Diagnosis was acute leukemia (AL) in 66% of the cases; 56% of AL were transplanted in first complete remission (CR), 39% in CR2 and 6% in >CR2. The median age at UCBT was 43 (range 18-76) years. Cytomegalovirus (CMV) serology was positive in 62% of pts; 45% of pts were female. Performance status at UCBT was <90% in 56% of pts and >90% in 44%. Fifty-two percent of pts received double and 48% single UCBT. Conditioning regimen was reduced intensity (RIC) for 52% of pts, and the most common regimen was cyclophosphamide+fludarabine+low dose total body irradiation (2Gy) for 72% of pts. Cyclosporine A (CsA) and mycophenolate mofetil (MMF) were used for graft-versus-host-disease (GVHD) prophylaxis in 61% of the pts. Anti-thymocyte globulin (ATG) was given in 41% of pts. Median TNC at cryopreservation was 4.2 x 107/Kg (range 0.4-13) and 56% of pts received a graft with 2or more HLA mismatches.The median follow-up was 30 (range 1-120) months. Overall survival (OS) and progression free survival (PFS) were 44% and 38% at 2 years, respectively. Refined DRI stratified pts in 4 subgroup (low risk, n=352, intermediate, n=1303, high, n=544, and very high-risk, n=138). OS was 56±3% for pts with low-risk DRI, 48±2% for intermediate-risk DRI, 31±2% for pts with high-risk DRI and 26±4% for pts with very high-risk DRI (p <0.0001). PFS was 46±3%, 42±2%, 25±2%, 22±4% for low, intermediate, high and very-high risk, respectively (p <0.0001).
According toconditioning intensity regimen and DRI, OS was 49% (for low risk), 47% (for intermediate), 29% (for high risk) and 20% (for very high risk) (p< 0.0001) for myeloablative (MAC) regimen and 60% (for low risk), 49% (for intermediate), 33% (for high risk) and 32% (for very high risk) for RIC (p < 0.0001). DRI was also statistically associated with different PFS stratifying for type of conditioning regimen (MAC and RIC)(p <0.0001).
In multivariate analysis adjusted for ATG use, CMV serology, DRI, median age at UCBT, median TNC at cryopreservation and type of UCBT (single or double), ATG use (HR=1.52, CI 95%=1.3-1.7, p< 0.0001), age at UCBT (median) (HR=1.4, CI 95%=1.2-1.6, p <0.001), very-high DRI (HR=2.7, CI 95%=2-3.7, p< 0.001), positive CMV serology (HR=1.2, CI 95%=1.07-1.4, p 0.03) were associated with a decreased OS. Furthermore, ATG use (HR=1.4, CI 95%=1.2-1.5, p< 0.0001), age at UCBT (median) (HR=1.3, CI 95%=1.2-1.5, p <0.0001), very-high DRI (HR=2.2, CI 95%=1.6-3, p< 0.0001), positive CMV serology (HR=1.2, CI 95%=1.04-1.4, p 0.008) were associated with decreased PFS.
Refined DRI is a valid system for risk-stratifying pts with different diseases undergoing UCBT in retrospective large cohort studies. This index represents a simple and robust means of stratifying large cohort of pts in the UCBT setting, complementary to other existing pre-transplant index. Our results confirm the prognostic value of refined DRI in UCBT and support the use of this simple tool for prospective trials in the future.

Disclosures
Bloor: Janssen: Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GSK: Consultancy, Speakers Bureau; Gilead: Honoraria; Abbvie: Membership on an entity's Board of Directors or advisory committees.