Significance of Degree of HLA Disparity When Using Haploidentical Donors with T-Replete PBSC and Post-Transplantation Cyclophosphamide (PTCy) in Acute Myeloid Leukemia (AML) in First Complete Hematologic Remission (CR1)

Background: Haploidentical allogeneic hematopoietic cell transplantation (haplo) has expanded applicability of the procedure to patients for whom a suitable HLA compatible donor was not available in the past. A small multicenter retrospective study of 185 patients with hematologic malignancies who received a nonmyeloablative preparative regimen followed by infusion of bone marrow (BM) hematopoietic cells from haploidentical donors showed no significant association between the number of HLA mismatches (HLA-A, -B, -C, and -DRB1 combined) and risk of acute grade 2-4 graft-versus-host disease (GVHD) (hazard ratio [HR]=0.89; P=0.68 for 3-4 mismatches vs fewer antigen mismatches). This haploidentical transplant platform has certainly evolved. Nowadays, G-CSF mobilized peripheral blood stem cells (PBSC) are commonly used owing to its increased convenience vis-à-vis performing a BM harvest. Study population: Here, we evaluate post transplant outcomes when using haploidentical donors with T-replete PBSC and PTCy in AML in CR1. A total of 494 patients (4/8 HLA mismatch (group 1)=360, 2-3/8 HLA mismatch (group 2)=134) underwent the procedure at an EBMT participating center. The primary endpoints were cumulative incidences of grade 2-4 acute GVHD and chronic (all grades) GVHD. Secondary endpoints included cumulative incidence of relapse (RI), non-relapse mortality (NRM), leukemia-free (LFS) and overall survival (OS) and GVHD-free relapse-free survival (GRFS). Results: Group 1 and group 2 were not statistically different in regards to median age at allografting (54.1 vs. 56.1 years, p=0.51), median year of haplo transplantation (2018 vs. 2018, p=0.36), incidence of de novo AML (86.4% vs. 88.1%, p=0.63), Karnofsky equal or more than 90 (77.5% vs. 79.1%, p=0.70), and use of myeloablative conditioning (MAC) (44.7% vs. 48.5%, p=0.45). Patients in group 1 had a longer time from diagnosis to haplo-transplantation (5.3 vs. 4.9 months, p=0.03). In multivariate analysis, group 1 and group 2 did not differ in cumulative incidence of grade 2-4 acute GVHD (Hazard ratio (HR)=0.89 (95%CI=0.62-1.26), p=0.51) but group 1 had a significantly higher incidence of chronic (all grades) GVHD (HR=1.49 (95%CI=1.02-2.16), p=0.04). There was no difference in RI (HR=0.73 (95%CI=0.47-1.14), p=0.17), NRM (HR=1.25 (95%CI=0.78-2.02), p=0.36), LFS (HR=0.95 (95%CI=0.69-1.31), p=0.76), OS (HR=1.09 (95%CI=0.76-1.55), p=0.64) and GRFS (HR=1.07 (95%CI=0.81-1.42), p=0.64) between the groups. Presence of adverse cytogenetics was independently associated with higher RI (HR=1.90 (95%CI=1.20-2.99), p=0.006), inferior LFS (HR=1.59 (95%CI=1.15-2.19), p=0.005), inferior OS (HR=1.48 (95%CI=1.05-2.08), p=0.03), and worse GRFS (HR=1.54 (95%CI=1.17-2.04), p=0.002). Conclusion: Results show that patients undergoing haplo-transplantation with 4/8 (vs. 2-3/8) HLA mismatches have a higher incidence of chronic GVHD (all grades) without adversely affecting acute grade 2-4 GVHD, RI, LFS, OS and GRFS. Disclosures Labopin: Jazz Pharmaceuticals: Honoraria. Bazarbachi: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Hikma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees. Blaise: Jazz Pharmaceuticals: Honoraria. McDonald: BioCryst Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees. Forcade: Novartis: Other: travel grant. Ciceri: IRCCS Ospedale San Raffaele: Current Employment. Mohty: Takeda: Honoraria; Astellas: Honoraria; Adaptive Biotechnologies: Honoraria; Novartis: Honoraria; Celgene: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria; Sanofi: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Gilead: Honoraria; Jazz: Honoraria, Research Funding; Pfizer: Honoraria; Amgen: Honoraria.

Alloreactive Immune Response Associated to Human Mesenchymal Stromal Cells Treatment: A Systematic Review

The well-known immunomodulatory and regenerative properties of mesenchymal stromal cells (MSCs) are the reason why they are being used for the treatment of many diseases. Because they are considered hypoimmunogenic, MSCs treatments are performed without considering histocompatibility barriers and without anticipating possible immune rejections. However, recent preclinical studies describe the generation of alloantibodies and the immune rejection of MSCs. This has led to an increasing number of clinical trials evaluating the immunological profile of patients after treatment with MSCs. The objective of this systematic review was to evaluate the generation of donor specific antibodies (DSA) after allogeneic MSC (allo-MSC) therapy and the impact on safety or tolerability. Data from 555 patients were included in the systematic review, 356 were treated with allo-MSC and the rest were treated with placebo or control drugs. A mean of 11.51% of allo-MSC-treated patients developed DSA. Specifically, 14.95% of these patients developed DSA and 6.33% of them developed cPRA. Neither the production of DSA after treatment nor the presence of DSA at baseline (presensitization) were correlated with safety and/or tolerability of the treatment. The number of doses administrated and human leucocyte antigen (HLA) mismatches between donor and recipient did not affect the production of DSA. The safety of allo-MSC therapy has been proved in all the studies and the generation of alloantibodies might not have clinical relevance. However, there are very few studies in the area. More studies with adequate designs are needed to confirm these results.

P–418 Different immunoregulatory components at the decidua basalis of oocyte donation pregnancies

Study question Is the number of regulatory T-cells (Tregs) and immunoregulatory cytokines in the decidua basalis of oocyte donation (OD) pregnancies different compared to naturally conceived pregnancies? Summary answer This study suggests that the immunoregulation at the fetal-maternal interface in OD pregnancies with a higher amount of fetal-maternal HLA mismatches appears to be altered. What is known already Tregs and related immunoregulatory cytokines, such as interleukins, transforming growth factor-β, and galectin–1, play a key role in maintaining tolerance at the decidua basalis in human pregnancy. Previous studies observed decreased numbers of decidual Tregs in miscarriage and preeclamptic pregnancies. These complications occur in higher frequencies in OD pregnancies, which are characterized by more fetal-maternal human leukocyte antigen (HLA) mismatches compared with naturally conceived (NC) and non-donor in vitro fertilization (IVF) pregnancies, since the fetus obtains paternal and donor-derived HLA genes. Consequently, the maternal immune system has to cope with greater immunogenetic dissimilarity. Involved immunoregulatory mechanisms however remain poorly understood. Study design, size, duration: This case-control study included 27 OD, 11 IVF, and 16 NC placentas of uncomplicated pregnancies, which were collected after delivery at 37–42 weeks of gestation between 2005 and 2013. Clinical data, maternal peripheral blood and umbilical cord blood were collected. Participants/materials, setting, methods Decidua basalis was dissected from the placentas, and processed to formalin-fixed, paraffin-embedded slices (4 µm). Immunohistochemical staining for FOXP3, interleukin 10, interleukin 6, galectin–1, transforming growth factor-β, and Flt–1 was performed. Semi-quantitative (FOXP3+ Tregs) and computerized analysis (cytokines), using Image-J software, were executed. Maternal peripheral blood and fetal umbilical cord blood were typed for HLA class I and II, using the Sequence Specific Oligonucleotides PCR technique, to calculate the number of fetal-maternal HLA mismatches. Main results and the role of chance All the deciduae basalis of OD, IVF and NC pregnancies showed FOXP3+ Tregs. No significant differences were found when comparing the three groups for the mean number of FOXP3+ Tregs. However, when the amount of fetal-maternal HLA mismatches was related to the percentage of FOXP3+ Tregs, the Tregs were significantly higher in pregnancies with 4–6 HLA class I mismatches (n = 16), than in those with 0–3 HLA class I mismatches (n = 38; p = 0.029). Furthermore, OD pregnancies express less interleukin 10, interleukin 6, galectin–1 and Flt–1 in the decidua basalis compared to NC pregnancies. Moreover, the amount of interleukin 10 was significantly lower with 3–4 fetal-maternal HLA class II mismatches (p = 0.032). Limitations, reasons for caution This study is limited by a small sample size. Moreover, only term placentas were collected. It would be worthwhile investigating immunological alterations in the decidua throughout the whole gestation, since maternal adaptation of the fetal allograft could be more prominent early in pregnancy. Wider implications of the findings: Unravelling the mechanisms of immunomodulation during OD pregnancy, reflected by a high level of fetal-maternal dissimilarity, could help to reach the ultimate goal in transplantation; the induction of donor-specific tolerance. In addition, it might help to understand the development of complications in OD pregnancy. Trial registration number Not applicable

Impact of HLA Mismatching on Early Subclinical Inflammation in Low-Immunological-Risk Kidney Transplant Recipients

The impact of human leukocyte antigen (HLA)-mismatching on the early appearance of subclinical inflammation (SCI) in low-immunological-risk kidney transplant (KT) recipients is undetermined. We aimed to assess whether HLA-mismatching (A-B-C-DR-DQ) is a risk factor for early SCI. As part of a clinical trial (Clinicaltrials.gov, number NCT02284464), a total of 105 low-immunological-risk KT patients underwent a protocol biopsy on the third month post-KT. As a result, 54 presented SCI, showing a greater number of total HLA-mismatches (p = 0.008) and worse allograft function compared with the no inflammation group (48.5 ± 13.6 vs. 60 ± 23.4 mL/min; p = 0.003). Multiple logistic regression showed that the only risk factor associated with SCI was the total HLA-mismatch score (OR 1.32, 95%CI 1.06–1.64, p = 0.013) or class II HLA mismatching (OR 1.51; 95%CI 1.04–2.19, p = 0.032) after adjusting for confounder variables (recipient age, delayed graft function, transfusion prior KT, and tacrolimus levels). The ROC curve illustrated that the HLA mismatching of six antigens was the optimal value in terms of sensitivity and specificity for predicting the SCI. Finally, a significantly higher proportion of SCI was seen in patients with >6 vs. ≤6 HLA-mismatches (62.3 vs. 37.7%; p = 0.008). HLA compatibility is an independent risk factor associated with early SCI. Thus, transplant physicians should perhaps be more aware of HLA mismatching to reduce these early harmful lesions.

Can PIRCHE-II Matching Outmatch Traditional HLA Matching?

We analyzed in a cohort of 68,606 first deceased donor kidney transplantations reported to the Collaborative Transplant Study whether an epitope-based matching of donor-recipient pairs using the Predicted Indirectly ReCognizable HLA Epitopes algorithm (PIRCHE-II) is superior to currently applied HLA antigen matching. PIRCHE-II scores were calculated based on split antigen HLA-A, -B, -DRB1 typing and adjusted to the 0–6 range of HLA mismatches. PIRCHE-II scores correlated strongly with the number of HLA mismatches (Spearman ρ = 0.65, P < 0.001). In multivariable analyses both parameters were found to be significant predictors of 5-year death-censored graft loss with high prognostic power [hazard ratio (HR) per adjusted PIRCHE-II score = 1.102, per HLA mismatch = 1.095; z-value PIRCHE-II: 9.8, HLA: 11.2; P < 0.001 for both]. When PIRCHE-II scores and HLA mismatches were analyzed simultaneously, their predictive power decreased but remained significant (PIRCHE-II: P = 0.002; HLA: P < 0.001). Influence of PIRCHE-II was especially strong in presensitized and influence of HLA mismatches in non-sensitized recipients. If the level of HLA-incompatibility was low (0–3 mismatches), PIRCHE-II scores showed a low impact on graft survival (HR = 1.031) and PIRCHE-II matching did not have additional significant benefit (P = 0.10). However, if the level of HLA-incompatibility was high (4–6 mismatches), PIRCHE-II improved the positive impact of matching compared to applying the traditional HLA matching alone (HR = 1.097, P = 0.005). Our results suggest that the PIRCHE-II score is useful and can be included into kidney allocation algorithms in addition to HLA matching; however, at the resolution level of HLA typing that is currently used for allocation it cannot fully replace traditional HLA matching.

Optimizing selection of double cord blood units for transplantation of adult patients with malignant diseases

Double-unit unrelated cord blood transplantation (DUCBT) is an option in patients for whom a single unit is not sufficient to provide an adequate number of cells. As current guidelines on UCB unit selection are mainly based on single-unit UCB data, we performed a retrospective analysis of 1375 adult recipients of DUCBT for hematologic malignancies to determine optimal criteria for graft selection. Cryopreserved total nucleated cells (TNCs; ≤3.5 vs >3.5 × 107/kg: hazard ratio [HR], 1.53; 30% vs 45%; P = .01), number of HLA mismatches (≥2 vs 0-1: HR, 1.28; 42% vs 48%; P = .01), and ABO compatibility (minor/major ABO incompatibility vs compatibility: HR, 1.28; P = .04) were independent risk factors for OS. Cryopreserved CD34+ cell dose ≥0.7 × 105/kg in the winning UCB was associated with improved OS (HR, 1.34; P = .03). Low TNC (≤3.5 × 107/kg) and CD34+ (≤1.4 × 105/kg) cell doses were related to decreased neutrophil recovery (HR, 0.65 [P = .01] and HR, 0.81 [P = .01], respectively). DUCBT recipients with ≥2 HLA mismatches had a higher incidence of grade II-IV and III-IV acute graft-versus-host disease (HR, 1.26 [P = .03] and 1.59 [P = .02], respectively). Low TNC dose (HR, 1.57; P = .02) and receiving UCB with ≥2 HLA mismatches (HR, 1.35; P = .03) were associated with increased transplant-related mortality. Our data support selecting adequately HLA-matched UCB units with a double-unit cryopreserved TNC dose >3.5 × 107/kg and CD34+ cell dose of ≥0.7 × 105/kg per unit in DUCBT candidates.

Impact of tacrolimus versus cyclosporine on one-year renal transplant outcomes: A single-centre retrospective cohort study

Background: Calcineurin inhibitors are the cornerstone of maintenance immunosuppression after kidney transplant. While studies on predominantly Caucasian populations recommend tacrolimus over cyclosporine, the effects on Singapore’s local population remain unclear. Objectives: This study aimed to compare the impact of tacrolimus against cyclosporine on post-transplant outcomes in our local kidney transplant population. Methods: A single-centre retrospective chart review was conducted on ABO- and human leucocyte antigen (HLA)-compatible kidney transplantations between 1 January 2011 and 15 August 2018. Patients who received basiliximab induction, prednisolone, mycophenolate and either tacrolimus or cyclosporine were included and followed up for at least one year. Recipients of transplantations at other institutions or other immunosuppressive regimens were excluded. Patient and graft outcomes and adverse effects were collected. Results: Overall, 120 patients on tacrolimus and 49 on cyclosporine were included. Patients on tacrolimus were older. This group had more deceased donor transplants, a higher proportion with donor-specific antibodies (DSAs) present and more HLA mismatches. There were no differences in patient and graft survival, graft function and acute rejections at one year, despite adjusting for age, transplant type, presence of DSAs and total HLA mismatches. The tacrolimus group had more infectious admissions (odds ratio=0.27, 95% confidence interval 0.098–0.73, p=0.01) after adjusting for age, transplant type, HLA mismatches, presence of DSAs and acute rejections, with increased severity and more opportunistic infections. More patients on cyclosporine required a change to alternative immunosuppressants (p=0.003). Conclusion: Our study demonstrated comparable short-term post-transplant outcomes between cyclosporine and tacrolimus. Tacrolimus appears more tolerable but may be associated with infection risks.