Optimization of the criteria for cord blood unit selection for transplantation in recipients of the different age groups: current view and prospects in Ukraine

Umbilical cord blood has been widely used to treat both malignant and non-malignant hematological diseases for over 30 years. During this time, more than 40,000 successful hematopoietic stem cell (HSC) transplantations of umbilical cord blood have been performed. However, today in Ukraine there is no public umbilical cord blood bank established for unrelated HSC transplantation to patients with oncohematological disorders (both children and adults). In this regard, the HSC units must be purchased abroad or the patients are sent to foreign clinics for high-cost treatment. The organization of a public umbilical cord blood bank in Ukraine would help in a short time to meet the needs of patients with oncohematological disorders for donor HSCs for unrelated transplantation and save significant funds for the treatment of patients abroad. According to the experience of the world's leading oncohematological centers, when it is impossible to find either a related or haploidentical donor or in all available registries – a unrelated transplant, the search continues in the registers of public cord blood banks and an umbilical cord blood unit that matches the criteria is usually found. The optimal choice of umbilical cord blood unit is crucial to maximize the likelihood of successful transplant engraftment and recipient survival after the transplantation, so the criteria for cord blood unit selection for unrelated transplantation are a bit broader than those used when matching donor-recipient pairs. The review presents the main criteria for cord blood unit selection according to the assessment of its quality, cell dose, HLA matching for unrelated transplantation to recipients of different age groups in accordance with international guidelines developed by the National Marrow Donor Program (NMDP), USA Center for International Blood and Brain Transplantation Research (CIBMTR), in collaboration with the NMDP Council Advisory Group, as well as in accordance with the American Society for Transplantation and Cellular Therapy (ASTCT) and the Seventh Edition of the NetCord-FACT International Standards for Cord Blood Collection, Banking, and Release for Administration.

Mesenchymal Stromal Cells (MSCs) Experience in France to Prevent Graft Failure after Hematopoietic Stem Cell Transplantation: A Retrospective Study from the MSCs/CTL Group of the Francophone Society SFGM-TC

Graft failure occurs in 3-5% of hematopoietic stem cell transplantations (HSCT) and raises up to 10% for mismatched HSCT. It is a severe complication leading to lethal infections or bleedings. Several studies reported that engraftment could be improved by mesenchymal stromal cells (MSCs) infusion. Those cells are multipotent cells capable of differentiation in at least 3 lineages (adipocytes, chondrocytes and osteocytes) and of supportive effects on hematopoiesis. This treatment is considered as an Advanced Therapy Medicinal Product in France and there is currently no authorization for its use outside of clinical trials. We retrospectively analyzed the demands from HSCT French centers to the expert committee of the SFGMTC and the French regulatory agency (ANSM), since 2014, in order to ask for MSCs exceptional recourse for patients with graft failure. Nine requests for MSCs were made. One patient did not receive any MSCs because MSCs bag was contaminated, another one had an haploidentical transplantation without MSCs instead. Finally, 7 patients received 1 or 2 infusions of MSCs (Table). Median age was of 6 years (4-23), sex ratio was of 2,5. Two patients (29%) had an acute lymphoblastic leukemia (ALL) and 5 patients (71%) had an aplastic anemia (idiopathic n=4, congenital n=1). Five patients had received one transplantation, and 2 patients had received two transplantations, followed by a primary graft failure (n=6) and a secondary graft failure (n=1). Only 2 patients had received a myeloablative conditioning regimen (MAC) for the first procedure, one chemo- and one TBI- based. The other 5 patients had received a reduced-intensity conditioning (RIC) regimen, 4 of them with 2 grays TBI. Two patients had received a cord blood unit and 5 bone marrows from 1 sibling, 3 haploidentical and 1 mismatched donors. Only 2 patients had received antithymoglobulins in their previous regimen. Engraftments failed despite a median richness of 5,14.106 CD34 cells/kg/bone marrow graft (1,84-9,5) and of 1,25.105CD34 cells/kg/cord blood unit (1,2-1,3). Median delay between first HSCT with graft failure and MSCs infusion was of 2 months (1-32). To prepare last HSCT,six patients received a reduced intensity conditioning regimen with 2 grays TBI (Baltimore), and one patient received a myeloablative, chemo-based, regimen, with antithymoglobulins. Three patients received a graft from the same previous donor. Six patients received a haploidentical graft (5 bone marrows, 1 peripheral blood stem cells), and 1 received bone marrow from a mismatched donor. Median number of CD34+ cells was of 9,02.106/kg (1,61-12,43). All MSCs were from 8 pooled donors (OBNITIX®) except for one patient who received MSCs from a relative donor (which was different from the HSCT donor). All infusions were well tolerated and made on the same day as HSCT, apart from one patient who received MSCs for a secondary graft failure on day 228 post-transplantation, followed by an infusion of CD34+ cells on day 231, and a second infusion of MSCs on day 259. Mean dose of MSCs was of 1,72.106/kg (1,25-3,1). Median time for neutrophil recovery (neutrophils over 0.5 G/L) and platelet recovery (platelets over 50 G/L) on 3 consecutive days was respectively of 23 days (10-34) and 35 days (26-238). At day 30, 5 patients (71%) had a full donor chimerism. Only one patient presented a graft failure leading to a third HSCT. No secondary graft failure occurred after a median follow-up of 13 months (4-104). At last follow-up, none of the patients who achieved platelet and neutrophil recovery required neither blood or platelets transfusion nor thrombopoietin receptor analogs. Infusion of MSCs at the time of HSCT to prevent graft failure was safe and effective for 6/7 patients. Larger prospective trials are necessary to confirm MSCs impact on engraftment and graft function. Table Disclosures Dalle: AbbVie Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Orchard: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Medac: Consultancy, Honoraria; Bellicum: Consultancy, Honoraria; Sanofi-Genzyme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; bluebird bio: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees. Rubio:Medac: Consultancy; Gilead: Honoraria; MSD: Honoraria; Novartis: Honoraria; Neovii: Research Funding.

Use of the HLA-B leader to optimize cord-blood transplantation

Cord-blood transplantation (CBT) can cure life-threatening blood disorders. The HLA-B leader affects the success of unrelated donor transplantation but its role in CBT is unknown. We tested the hypothesis that the HLA-B leader influences CBT outcomes in unrelated single-unit cord-blood transplants performed by Eurocord/European Blood and Marrow Transplant (EBMT) centers between 1990 and 2018 with data reported to Eurocord. Among 4822 transplants, 2178 had one HLA-B mismatch of which 1013 were HLA-A and HLA-DRB1-matched. The leader (M or T) was determined for each HLA-B allele in patients and units to define the genotype. Among single HLA-B-mismatched transplants, the patient/unit mismatched alleles were defined as leader-matched if they encoded the same leader, or leader-mismatched if they encoded different leaders; the leader encoded by the matched (shared) allele was determined. The risks of GVHD, relapse, non-relapse mortality and overall mortality were estimated for various leaderdefined groups using multivariable regression models. Among the 1013 HLA-A, -DRB1- matched transplants with one HLA-B mismatch, increasing numbers of cord-blood unit M-leader alleles was associated with increased risk of relapse (hazard ratio [HR] for each increase in one M-leader allele 1.30, 95% confidence interval [CI] 1.05 to 1.60, P 0.02). Furthermore, leader mismatching together with an M-leader of the shared HLA-B allele lowered non-relapse mortality (HR 0.44, 95% CI 0.23 to 0.81; P 0.009) relative to leader-matching and a shared T-leader allele. The HLA-B leader may inform relapse and non-relapse mortality risk after CBT. Future patients might benefit from the appropriate selection of units that consider the leader.

Antipneumococcal Seroprotection Years After Vaccination in Allogeneic Hematopoietic Cell Transplant Recipients

Background International guidelines recommend vaccinating allogeneic hematopoietic cell transplant (HCT) recipients at 3 months after transplant, giving 3 doses of pneumococcal conjugate vaccine (PCV) followed by either a dose of 23-valent pneumococcal polysaccharide vaccine (PSV23) or a fourth PCV dose in the case of graft-versus-host disease (GvHD). However, the long-term immunity after this regimen is unknown, and there is no recommendation from 24 months after transplant regarding boosts. Our objective was to assess the antipneumococcal antibody titers and seroprotection rates of allogeneic HCT recipients years after different schedules of vaccination. Methods We assessed 100 adult HCT recipients a median of 9.3 years (range: 1.7–40) after transplant. All patients had received at least one dose of PCV and were assessed for antipneumococcal immunoglobulin G (IgG) antibody titers against the 7 serotypes shared by PCV7, PCV13, and PSV23. Sixty-six percent of the patients had been vaccinated according to the current guidelines. Results Considering an IgG titer ≥ 0.35 µg/mL as protective for each serotype, the seroprotection rate was 50% for 7/7 serotypes and 70% for 5/7 serotypes, with no differences between the different vaccination schedules. The lack of seroprotection was associated with a transplant performed not in complete remission or from a cord-blood unit, a relapse after transplant, or chronic GvHD at assessment. Conclusion Because only half of the vaccinated patients had long-term protection, pending prospective studies defining the best boost program after the initial one, we recommend the assessment of specific IgG titers starting from 24 months to decide for further doses.