Double Umbilical Cord Blood Transplantation Offers Stable Donor Engraftment and The Prospect Of Cure In Adult Patients With High-Risk Hematologic Malignancies
Authors: Baltathakis Ioannis , Panitsas Fotios , Komitopoulou Anna , Tzannou Ifigeneia , Gigantes Stavros , Vasileiou Spyridoula , Poulopoulou Zoi , Garofalaki Maria , Tziotziou Eirini , Karatza Maria-Eleni , Grispou Eirini , Apostolidis John , Harhalakis Nikolaos , Karakassis Dimitrios 
Published: October 2019

Abstract
Allogeneic stem cell transplantation (allo-SCT) remains the main therapeutic option for patients with high-risk hematologic malignancies, albeit with the requirement of a properly matched and timely available donor. Dual-unit umbilical cord blood transplantation (dUCBT) has become an alternative modality, which offers immediate access to allo-SCT for most adult patients who lack an appropriate volunteer donor.
We retrospectively analyzed the outcomes of consecutive dUCBT procedures that were undertaken by our center over a seven-year period, with focus on factors affecting engraftment and survival.
Between 2006 and 2013, 40 patients underwent dUCBT at a median age of 37 years (range, 16-60) for various hematologic malignancies (acute myeloid leukemia: 22, myelodysplastic syndrome: 5, chronic myelogenous leukemia: 2, acute lymphoblastic leukemia: 6, mixed-phenotype acute leukemia: 2, plasmacytoid dendritic cell neoplasm: 1, hepatosplenic T cell lymphoma: 1, chronic lymphocytic leukemia: 1). The majority of patients (73.7%) had advanced or intermediate-phase disease at the time of transplantation, with a median time from diagnosis to transplant of 17.7 months (range:3.1-92.3). Recipient body weight ranged from 48 to 110 kg (median, 73). The conditioning regimen was myeloablative in 33 (82.5%) patients (busulfan-based in 22, and total body irradiation-based in 11 cases). Antithymocyte globulin was not administered during conditioning, with the exception of one case.
Most units (55/80, 68.75%) were 4/6 antigen matched to recipient at HLA-A, -B, and -DRB1 loci, and the remaining were 5/6 matched. By retrospective high-resolution typing for class I HLA alleles, histocompatibility was demoted in 62.3% of units. By additional allele-level typing at HLA-C and -DQB1 loci, the degree of compatibility varied from 8/10 to 3/10, with 80.5% of the units being ≤6/10 matched to the patient. The median dose of cryopreserved total nucleated cells (TNC) per unit was 2.53 x 107/kg (range, 1.09-5.66). At infusion, patients received in total a median of 4.55 x 107 TNC/kg (range, 2.65-9.3) and 1.7 x 105 CD34+ cells/kg (range, 0.54-5.14) from both units.
The cumulative incidence (CI) of neutrophil engraftment was 92.5% (37/40 patients), with achievement of an absolute neutrophil count (ANC) greater than 500/uL at a median of 20 days (range, 12-52) (Figure 1). Platelet recovery (>50x109/L) occurred at a CI of 63.2%, and a median time of 84 days (range, 32-363). No influence of cell dose (TNC or CD34+) or of the degree of HLA match on the incidence and kinetics of engraftment could be detected. Acute graft-versus-host disease (aGVHD) of grades II-IV and III-IV developed in 85% and 12.65% of patients, respectively. The CI of chronic GVHD was 31% (extensive in 54.5% of cases). There was a statistical trend for increased incidence of cGVHD with <6/10 HLA match at the allele level (p=0.068; HR, 3.35; 95% confidence interval [ci], 0.92-12.24). Non-relapse mortality (NRM) reached 43.1% (95% ci, 27.0-58.2) at 10.3 months, but no case of NRM was noted thereafter (Figure 2). Major causes of NRM were infection/sepsis (n=11), GVHD (n=3), and engraftment failure (n=3). The CI of relapse was 22.7% (95% ci, 10.7-37.5). Relapse was the cause of death of 6 patients. With a median follow-up of 30 months (range, 2-84), overall (OS) and disease-free survival (DFS) rates at 2 years were 36.5% (95% ci, 21-52) and 34.2% (95% ci, 19.3-49.6), respectively (Figure 3). Sixteen of 40 patients are alive and disease-free for a median time of 30 months from transplant. Age ≤37 years, recipient CMV seronegativity, and early disease phase at transplant were associated with improved OS in univariate analysis. Age remained as the only independent risk factor for OS in multivariate analysis of OS (p=0.022). Age ≤37 years was also found to be associated with reduced NRM (p=0.055), and favorable DFS (p=0.04).Figure 1Cumulative Incidence curve of neutrophil (ANC>500/uL) engraftment.Figure 1. Cumulative Incidence curve of neutrophil (ANC>500/uL) engraftment.Figure 2Cumulative Incidence curve of non-relapse mortality.Figure 2. Cumulative Incidence curve of non-relapse mortality.Figure 3Overall Survival (Kaplan-Meier curve).Figure 3. Overall Survival (Kaplan-Meier curve).
In conclusion, dUCBT can lead to stable donor engraftment even across multiple HLA disparities and can overcome the barrier of cell dose. Despite considerable early mortality, dUCBT offers the possibility of long-term survival in about one third of adult patients with poor-prognosis hematologic malignancies, for whom allo-SCT would not be otherwise feasible.

Disclosures:
No relevant conflicts of interest to declare.