Outcomes and Immune Phenotype Recovery after Double Cord Blood Transplantation in Patients with High Risk Hematological Diseases
Authors: Ruggeri Annalisa , de Latour Regis Peffault , Carmagnat Maryvonnick , Robin Marie , Madureira Adrienne , Larghero Jerome , Traineau Richard , Ribaud Patricia , Ferry Cristele , Devergie Agnes , Rabian Claire , Toubert Antoine , Gluckman Eliane , Socié Gerard , Rocha Vanderson 
Published: April 2020

Abstract
Umbilical cord blood transplantation (UCBT) is a valid option to treat haematological disease when an HLA-matched donor is lacking. Advantages of UCB include the absence of risk for the donors, and its prompt availability when an unrelated donor needs urgently. The naivety of the UCB, allows UCBT recipients to a decreased risk of graft versus host disease (GvHD). Due to the low cell dose contained in a UCB unit, double UCBT (dUCBT) is used for adult patients. UCBT may be associated with an increased risk of graft failure with delayed immune recovery and infections. We report a phase II study on 35 dUCBT from 2004 to 2007. Twenty one patients had high risk malignant disorders (ALL=6, AML=6, MDS=4, CML=3, Hodgkin disease= 2) and 14 high risk of rejection (Fanconi Anemia=8, SAA=4, PNH=1 and congenital dyskeratosis= 1). Among all patients, 9 had undergone previous non-engrafted transplants (previous source: UCB and BM in 5 and 4 cases respectively). Median age was 19 years (6–55). CMV serology was negative for 14 patients. Median follow-up was 21 months (4–42 months). Half of patients received myeloablative conditioning, reduced intensity regimen was performed mostly for second transplant. ATG was used in 22 patients. Most of patients received at least 1 or 2-HLA antigen and/or allelic mismatched unit. aGVHD prophylaxis consisted in cyclosporine+steroids in 21 patients and associated with mycophenolate in 14. Median infused cell doses were 4×10/7 NC/Kg (1.8–9.7) and 3×10/5 CD34+cells/Kg (0.5–7.46). Twenty four patients (69%) engrafted with a median time of 25 days (11–42), 11 subjects had primary graft failure. Among the patients who did not engrafted, 5 patients died early due to rejection, 2 had autologous reconstitution and 1 patient relapsed. The remaining 3 patients underwent a second dUCBT. Median time to platelet recovery &gt;20 ×10/9 cells/L was 103 days (36–180). Before day 100 chimerism data were evaluable in 29 patients. A single UCB unit predominated in 18 patients with full donor chimerism. In 6 patients a combination of both UCB units was detected and 5 patients had persistent host hematopoiesis. In eight out of 15 patients, the predominant UCB unit was the first infused. After day 100, 16 out of 19 evaluable patients had a complete donor chimerism with only one unit contributing to hematopoiesis and 3 showed both CB units engraftment. No patients had secondary graft failure. aGVHD developed in 18 patients (grade III–IV, n=6) and cGVHD in 15 out of 26 patients at risk. During the first 100 days 19 CMV reactivations were observed, 4 disseminated HSV, 1 HHV6-related meningoencephalitis, 4 EBV infections, 4 VRS infections, 3 adenovirus diseases, 5 bacterial infections, 2 probable toxoplasmosis. Twelve patients had a probable or proved IFI. After day 100 we observed 9 CMV reactivations, 3 HSV, 1 EBV-PTLD and 2 fungal infections. Lymphocyte subset phenotype analyses were performed in the patients with donor cells engraftment at 3, 6, 9, 12 months after dUCBT. Median numbers of lymphocytes were 400 mm3 at 3 months (n=19); 430 at 6 months (n=18), 710 at 9 months (n=11), 630 at 12 months (n=12), 860 at 15 months (n=7). Median numbers of CD3/CD4 at 3, 6, 9, 12 and 15 months were: 46, 55, 130, 80, 180 mm3, respectively; of NK cells 220, 230, 250, 190, 190 mm3 and of B cells were 1, 10, 70, 80, 240 mm3, respectively. Naive cells (CD45RA+CCR7+), early or central memory cells (CD45RA+CCR7+), effector memory cells (CD45RA+CCR7+), and late effector memory cells (CD45RA+CCR7+) were analysed. Over a period of 9 months after transplant a high proportion of central and effector memory T cells and a paucity of naïve cells were detected. Naïve cells increased consistently during the follow up period, reaching a trend towards normalization at 15 months, compared with the normal value. At 1 year overall survival was 57±8%. Relapse occurred in 5/35 patients and was cause of death in 3. TRM at 100 days was 29±7%. Seventeen patients died. Infection was a major cause of death in 6 subjects. Five of 9 patients have been rescued of previous non-engraftment and are alive and well (10–41 months). In conclusion, dUCBT is an option to treat patients with high risk diseases lacking a suitable HLA matched donor. In this high risk population immune recovery and consequently infections are major complications after dUCBT. Modifications in the conditioning regimen and GVHD prophylaxis, better surveillance and treatment of infections after dUCBT may improve outcomes.