Unrelated Donor Transplant Recipients Research Articles

Incidence of cutaneous graft-versus-host disease in a Singapore academic medical centre - A retrospective cohort study.

Cutaneous graft-versus-host disease (GVHD) is common in allogeneic haematopoietic stem cell transplantation. HLA mismatch is the most significant determinant of GVHD. Our study aimed to compare the incidence of cutaneous GVHD haploidentical (Haplo) and matched donors in an Asian population. Retrospective cohort study of the 2015-2019 bone marrow transplant registry was conducted in a transplant centre. We compared the incidence of cutaneous GVHD in Haplo with allogeneic matched unrelated donor (MUD) and matched-sibling donor (MSD) transplant recipients. Secondary objectives include acute and chronic GVHD incidence, dermatology referrals, and histological findings. One hundred and seventy-nine out of 203 cases were reviewed; 17 (9.5%) Haplo, 80 (44.7%) MUDs and 82 (45.8%) MSDs. The median follow-up for Haplo, MUD and MSD was 15.2, 34.2 and 35.7months, respectively. Haplo had a higher cumulative incidence of cutaneous GVHD than MUD and MSD (p=0.053). Chronic GVHD was only reported in MSD. The most common histology was vacuolar interface changes (13 [44.8%]) with a wide range of onset post-transplant (19-456 days). Haplo donors may have a higher GVHD incidence than MUD and MSD in our predominantly Asian cohort. This information may be helpful when counselling patients pre-transplant. Further prospective studies are required.

Natural History of Epstein-Barr Virus Replication and Viral Load Dynamics after Alemtuzumab-Based Allogeneic Stem Cell Transplantation

Epstein-Barr virus (EBV) load monitoring after allogeneic hematopoietic stem cell transplantation (HSCT) enables earlier detection of EBV replication and often serves as a trigger for preemptive therapies aimed at reducing EBV-related diseases. Our institutional strategy is to treat patients with clinical signs of EBV-related disease accompanied by a rising viral load, rather than to intervene based solely on viral load. This affords an opportunity to study the natural history of EBV replication and to assess whether our strategy reduces overtreatment without compromising outcomes. The objectives of the present study were to assess the natural history of untreated EBV replication in patients who underwent an alemtuzumab-based allogeneic HSCT and to examine whether our clinical strategy reduced overtreatment without compromising patient outcomes. In this retrospective single-center observational study of 515 consecutive patients (age ≥18 years) undergoing T cell-depleted allogeneic HSCT incorporating alemtuzumab, patients underwent surveillance monitoring for EBV by quantitative PCR in the peripheral blood at least weekly up to 100 days post-transplantation and longer if they remained on immunosuppressive therapy. The cumulative incidence of EBV detection and EBV-related disease were assessed. Among the 515 patients, 192 had EBV DNA detectable on ≥1 occasion, with a cumulative incidence of 35.8% (31.8% to 40.4%), although this remained below the limit of quantification in 93 patients. The median time to first detection was 89.5 days (range, 0 to 2254 days). The incidence was higher in recipients of sibling donor transplants (45.4% versus 30%; P=.00021) compared with recipients of unrelated donor transplants. Twenty patients developed EBV-related disease (cumulative incidence, 3.9%). Two patients had immunosuppression reduction alone, 18 received rituximab, and 5 required additional therapies. Five patients died from post-transplantation lymphoproliferative disorder, all of whom had received rituximab. The positive predictive value of EBV load for disease was higher in the unrelated donor cohort but remained <75% regardless of EBV threshold (57.1% to 72.7%). The cumulative incidence of EBV-related disease in our study (3.9%) is comparable to that reported in other studies incorporating alemtuzumab, and our clinical strategy reduced overtreatment in this patient population. PCR-based surveillance strategies have limitations, as reflected in the relatively low sensitivity of the assay coupled with the low positive predictive value, which may influence the potential choice of a threshold for preemptive intervention. We conclude that it remains unclear whether treatment based on a rising EBV viral load alone provides superior overall results to treatment based on the development of clinical signs of EBV-related disease in the context of a rising viral load.

An Overview of the Long-term Follow-up of the Adult Post-kidney Transplant Recipients in Sudan: A Single-Center Experience.

Kidney transplant remains the definitive treatment for patients with end-stage renal disease. A retrospective cohort was conducted in Dr. Selma Center for Kidney Diseases (DSCKD) to determine the pattern of follow-up and outcomes of adult kidney transplant recipients (KTRs) on long-term follow-up. Patients presented for follow-up during the period from January to June 2018 were studied regarding their demographic features, kidney transplant surgery, immunosuppressive therapy, graft function, and post-transplant complications. Data analysis was done using the Statistical Package for the Social Sciences version 16.0. During the study period, a total of 941 adult and pediatric KTR presented to DSCKD for follow-up. Only 792 KTRs were included in the study; those were adults, with their first kidney transplant, completed one year post-transplant, and agreed for enrollment. The mean age of the studied population was 47 ± 4.3 years. The majority were males, 74.2%. The median duration of follow-up was 7.4 years (interquartile range 3-11). Most transplants were through living-related donations, 78.8%. The combination of prednisolone, tacrolimus, and azathioprine remains the most common immunosuppressive regimen prescribed; delivered to 47.5% of recipients. Post-transplant complications were predominantly recurrent infections, diabetes mellitus, and hyperlipidemia seen in 54.5%, 42.4%, and 24.7% of recipients, respectively. On cross-comparisons living unrelated donor transplant recipients were found to have increased post-transplant complications, with a reduced kidney graft function at the end of the 1st year and throughout follow-up, when compared to living related donor transplant recipients. A prospective multi-center study with long-term follow-up remains essential for further evaluation of the long-term outcomes of the KTR in Sudan.

Functional B Cell Reconstitution Following Allogeneic Stem Cell Transplantation

Immune reconstitution is critical to long term survivability in recipients of allogeneic hematopoietic cell transplantation (HCT), mitigating both relapse as well as infection risk. However, both graft versus host disease (GVHD) and post HCT immunosuppression used to prevent it impair immune recovery, particularly functional B cell reconstitution which may not happen for several months post-transplant. This is relevant for post-transplant vaccination which in some centers is delayed till immune cell recovery. In this retrospective, Virginia Commonwealth University institutional review board (IRB) approved study, T helper and B cell recovery for up to two years following HCT was evaluated in 212 patients transplanted between 2015 and 2019. There were 69 HLA matched related &amp; 143 unrelated donor transplant recipients. Median age of the patients was 56 years (range 19-74); conditioning regimens utilized were reduced intensity (RIC) in ~62% of the patients and rabbit anti-thymocyte globulin was used in ~72% of the patients. Blood stem cells were given in 183 patients and bone marrow in 29. Only patients with hematological malignancies were included in this study. Landmark analysis was carried out, with patients who did not survive the first 6 months post-transplant excluded. Of these patients, 85% are surviving. Median CD3+/4+ (Th) cell counts were 153 at 6 months, 228 at 1-year, 296 at 2 years, and corresponding B cell counts were 70, 175, &amp; 273. Plotting Th and B cell counts over time in each individual donor-recipient pair demonstrated close correspondence between Th and B cell recovery, with synchronous recovery observed in most patients, median R 0.76 (range: 0.01-0.99). The slope of the B/Th cell curves for each patient then were compared in a subset of patients, and demonstrated a significant difference between those patients who either did not develop GVHD or only had acute GVHD as opposed to those who developed both acute and chronic GVHD (1.3±1.4 B cells/Th cells and 1.1±1.2 vs. 0.5±1, P=0.02 and 0.06 respectively), suggesting poor B cell recovery in those with chronic GVHD. Different immune recovery kinetics were observed amongst patients (Figure 1); A) rapid B cell recovery, highest absolute B cell count between 30 and 180 days post-HCT, B) intermediate B cell recovery, days 180 and 455, C) delayed B cell recovery, days 455 and 725 days, and D) minimal to no B cell recovery. A higher relative risk for developing acute + chronic GVHD was seen in the intermediate B cell recovery group when compared to those with delayed recovery, RR = 2.38 (95% CI 1.08-5.25). Functional B cell studies were performed in a subset, by measuring IgG levels and anti-pneumococcal antibody titers. Correlation was observed between Th cell count and IgG levels over time in individual patients (median R = 0.57). Pneumococcal titers were also measured at approximately 6 months, 1- and 2-years post-transplant as patients were given a series of PCV13 &amp; PSV23 vaccinations 6 months after HCT. When the antibody titers against unique pneumococcal serotypes were analyzed in individual patients, these varied within each individual, following a declining trend in levels for antibodies against different serotypes; this decline occurred on a logarithmic scale suggesting differential immunogenicity of the pneumococcal antigens, and also mathematically ordered, rather than random Th and B cell responses (Figure 2A). When the serotypes with the highest titers in most patients were correlated with Th and B cell counts measured simultaneously, no association was observed. Further, when fold increase in pneumococcal titers beyond 1-year post transplant were compared across different groups of patients based on their GVHD status, no significant difference was observed in their antibody responses (Figure 2B). In conclusion, our data suggest synchronous Th and B cell reconstitution post allogeneic HCT, both in numeric and functional terms, and thus strategies to help promote T cell recovery, such as IL-7 administration post-transplant, are necessary to encourage optimal immune reconstitution. Vaccine responses beyond 6 months, as in the institutional practice reported here, are independent of GVHD status and numeric immune cellular recovery. These findings are consistent with the notion that immune recovery is a dynamical, rather than a stochastic process. Disclosures No relevant conflicts of interest to declare.

Unrelated Donor Transplant Recipients Given Thymoglobuline Have Superior GRFS When Compared to Matched Related Donor Recipients Undergoing Transplantation without ATG.

Recipients of allogeneic hematopoietic stem cell transplantation (HSCT) from unrelated donors (URDs) and mismatched related donors (MMRDs) typically have a higher incidence of acute and chronic graft-versus-host disease (GVHD) compared with matched related donors (MRDs). Anti-T-cell globulins (ATGs) are often used to reduce GVHD in these recipients. We report the outcomes of 211 adult peripheral blood stem cell transplant recipients with myeloid malignancies who received a standardized transplant protocol, in which ATG (Thymoglobuline 4.5 mg/kg) was administered to recipients of URD and MMRD (n=147) but not MRD (n=64) transplant. For all patients, incidence of acute GVHD grades 2 to 4 was 21.4%, and chronic GVHD was 35.0%. Two-year overall survival was 63.2% (95% confidence interval, 55.8% to 71.5%), relapse-free survival was 55.3% (47.4% to 64.6%), and GVHD-free, relapse-free survival (GRFS) was 30.7% (23.2% to 40.8%). There were no differences between recipients of MRDs and other donors in relapse, nonrelapse mortality, and overall and relapse-free survival. However, compared with MRD, recipients from URDs and MMRDs had reduced moderate to severe chronic GVHD (10.4% versus 30.1%, P= .002), less chronic GVHD requiring systemic therapy (19.4% versus 38.9%, P=.006), and superior 2-year GRFS (35.5% versus 20.0%, P=.003). In this retrospective review of nonrandomized transplant groups, outcomes of HSCT performed using an URD with ATG during conditioning were superior to transplant from an MRD without ATG. The addition of Thymoglobuline to conditioning in HSCT from MRD should be further examined in prospective trials.

Less Chronic Graft-Versus-Host Disease, Immunosuppressive Therapy and Better Survival after Anti-Thymocyte Globulin in Unrelated Donor Stem Cell Transplant Recipients: Longer Follow-up of a Multicentre Cell Therapy Transplant Canada Randomized Trial

Less Chronic Graft-Versus-Host Disease, Immunosuppressive Therapy and Better Survival after Anti-Thymocyte Globulin in Unrelated Donor Stem Cell Transplant Recipients: Longer Follow-up of a Multicentre Cell Therapy Transplant Canada Randomized Trial

Risk Factors for Transplant Outcomes in Children and Adolescents with Non-Malignant Diseases Following Allogeneic Hematopoietic Stem Cell Transplantation.

BackgroundThe objective of this study was the analysis of transplant outcomes and survival in children treated with allogeneic hematopoietic cell transplantation (alloHCT) for non-malignant disorders, with a focus on risk factor analysis of transplant-related mortality (TRM).Material/MethodsThe treatment outcome was analyzed retrospectively in 10 consecutive years in 4 pediatric transplant centers in Poland. To compare the outcomes, patient data were analyzed according to the diagnosis, age at transplant, donor type, stem cell source, conditioning regimens, transplanted CD34+ cells dose, and pediatric TRM score.ResultsFrom 183 analyzed patients, 27 (14.8%) died, all of them due to transplant-related complications. TRM occurred more frequently in matched unrelated donor (MUD) transplant recipients vs. matched sibling donor (MSD) transplant recipients (p=0.02); in peripheral blood (PB) recipients vs. bone marrow (BM) recipients (p=0.004); and in patients receiving >5×106/kg CD34+ cells (p<0.0001). OS differed significantly according to underlying disease comparing to other diagnoses. Lower survival was found in patients transplanted from MUD (p=0.02). OS was higher in patients receiving BM (p=0.001) and in those receiving ≤5×106/kg CD34+ cells (p<0.001). Multivariate analysis showed lower probability of TRM in BM recipients (p=0.04). The probability of TRM was higher in SCID patients (p=0.02) and in patients receiving >5×106/kg CD34+ cells (p=0.0001).ConclusionsUnderlying disease, stem cell source, and CD34+ dose higher than 5×106/kg were the most important risk factors for TRM, and they all affected OS.

Effect of antithymocyte globulin source on outcomes of bone marrow transplantation for severe aplastic anemia.

For treatment of severe aplastic anemia, immunosuppressive therapy with horse antithymocyte globulin results in superior response and survival compared with rabbit antithymocyte globulin. This relative benefit may be different in the setting of transplantation as rabbit antithymocyte globulin results in more profound immunosuppression. We analyzed 833 severe aplastic anemia transplants between 2008 and 2013 using human leukocyte antigen (HLA)-matched siblings (n=546) or unrelated donors (n=287) who received antithymocyte globulin as part of their conditioning regimen and bone marrow graft. There were no differences in hematopoietic recovery by type of antithymocyte globulin. Among recipients of HLA-matched sibling transplants, day 100 incidence of acute (17% versus 6%, P<0.001) and chronic (20% versus 9%, P<0.001) graft-versus-host disease were higher with horse compared to rabbit antithymocyte globulin. There were no differences in 3-year overall survival, 87% and 92%, P=0.76, respectively. Among recipients of unrelated donor transplants, acute graft-versus-host disease was also higher with horse compared to rabbit antithymocyte globulin (42% versus 23%, P<0.001) but not chronic graft-versus-host disease (38% versus 32%, P=0.35). Survival was lower with horse antithymocyte globulin after unrelated donor transplantation, 75% versus 83%, P=0.02. These data support the use of rabbit antithymocyte globulin for bone marrow transplant conditioning for severe aplastic anemia.

Impact of Donor-Recipient Histocompatibility and CMV-Mismatch on Outcome of Allogeneic Stem Cell Transplantation for AML and MDS: A Retrospective Registry Study of the German Stem Cell Transplant Registry (DRST) of the German Working Group for Blood and Marrow Transplantation (DAG-KBT)

IntroductionAllogeneic stem cell transplantation (allo-SCT) is a curative treatment for several hematological diseases. Donor-recipient histo-incompatibility is associated with poorer outcome. Transplant outcome of CMV positive patients is reported to be poorer, if the unrelated donor is CMV negative (CMV-mismatch). Recent developments in transplant strategies including high resolution HLA-typing, toxicity-reduced conditioning regimens, CMV-monitoring, and improved supportive care have made transplants from HLA- as well as CMV- mismatched unrelated donors more feasible. We present a retrospective registry analysis from a large, and recent cohort of patients transplanted under these conditions.Patients and methods:We report data from adult recipients of allo-SCT treated between 2005 and 2013 in 10 transplant centers across Germany. Inclusion criteria were: 1.) consecutive patients from each center with AML or MDS as reported to the German Stem Cell Transplant Registry (DRST), 2) age >/= 18 years, 3) availability of high-resolution typing for HLA-A, -B, C, DRB1 and DQB1 in case of unrelated donor. Patients with ex-vivo T cell depletion were excluded.3215 patients with AML (n = 2648) or MDS (n = 567) were included in the study. Donors were matched related (MRD, n =872), matched unrelated (MUD, n = 1553) or mismatched unrelated (9/10 MMUD, n= 620; 8/10 MMUD n = 137; <8/10 MMUD n = 33). Remission status at transplant was CR (49%), not in CR (40%) or untreated (11%). The vast majority of patients (96%) received peripheral blood stem cell grafts. Conditioning was reduced intensity (51%) or myeloablative (49%) according to EBMT criteria. ATG (56%) or alemtuzumab (8%) were used for in vivo T cell depletion. Median patient age was 56 (18-79) years. Median donor age was 38 (12-80) years. Median follow-up was 54 months (34-81 months). Primary endpoint was overall survival (OS) at 3 years.Results:Kaplan-Meier estimates for OS at 3 years was similar after transplants from MRD = 55% (95%CI 51-59%) compared to MUD = 53% (95%CI 51-59%), p = 0.26. OS at 3 years was worse for 9/10 MMUD with 45% (95% CI 41-49%, p<0.001), for 8/10 MMUD with 35% (95% CI: 27%-43%, p < 0.001) and for <8/10 MMUD with 29% (95% CI 13%-45%, p = 0.005) (figure 1).In recipients of unrelated donor transplants, multivariate cox regression analysis revealed significant negative impact of increasing patient age, increasing donor age, sex-mismatch (male patient/female donor), CMV-mismatch (patient pos/ donor neg), diagnosis of AML or sAML compared to MDS, lack of complete remission at transplant, abnormal cytogenetics and HLA-mismatching (table 1a).In a subgroup analysis restricted to patients transplanted from unrelated donors after myeloablative conditioning and T cell depletion, 3 years OS was better after 10/10 MUD: 60% (55-65%) compared to 9/10 MMUD: 49% (41-57%), p = 0.02. This was also true after reduced intensity conditioning and T cell depletion with ATG, with 3 year OS after 10/10 MUD: 49% (45-53) compared to 9/10 MMUD: 37% (31-43%), p = 0.001. Excluding HLA-DQB1-mismatches and HLA-C0303/0304-mismatches from the 9/10 MMUD group did not significantly alter results.Acknowledging the negative impact of both HLA and CMV-mismatching, we sought to determine which of these two parameters is of higher relevance for donor selection. For this purpose subgroup analyses were performed including only CMV-positive patients who received transplants from an unrelated donor (10/10 MUD or 9/10 MMUD). HLA-DQB1-mismatches and HLA-C0303/0304-mismatches were excluded. For this subgroup of n = 1167 patients multivariate cox regression analysis revealed better outcome after 10/10 MUD from CMV neg. donors compared to 9/10 MMUD from a CMV pos. donors (RR: 1.31, p = 0.04, table 1b and figure 2). Restricting the analysis only to patients who received T cell depletion with ATG did not significantly alter these findings.Conclusions:In this large multicenter cohort of recently transplanted patients, we find similar survival outcomes for matched related and fully matched unrelated donor transplants. We confirm the negative impact of HLA-mismatching on survival outcome, irrespective of conditioning intensity. Our results show that though CMV-mismatching is associated with poorer outcome, its relevance is secondary to HLA-mismatching.Acknowledgments:This work was supported by a research grant of the DKMS-Stiftung to FA and WB. [Display omitted] [Display omitted] [Display omitted] DisclosuresStelljes:Pfizer: Consultancy. Kobbe:Jansen: Honoraria, Other: travel support; Celgene: Honoraria, Other: travel support, Research Funding. Kröger:Sanofi: Honoraria, Research Funding; Neovii: Honoraria, Research Funding; Riemser: Honoraria, Research Funding; Novartis: Honoraria, Research Funding.

Impact of Donor and Recipient Cytomegalovirus Serostatus on Outcomes of Antithymocyte Globulin–Conditioned Hematopoietic Cell Transplantation

Although previous studies involving allogeneic hematopoietic cell transplantation (HCT) without in vivo T cell depletion by rabbit antithymocyte globulin (ATG) have reported a substantial survival difference between D−R− and D+R− patients, but little to no survival difference between D−R+ and D+R+ patients (D, donor; R, recipient; +, cytomegalovirus [CMV] seropositive; −, CMV seronegative), whether this applies to HCT using ATG is unknown. We studied 928 patients who underwent myeloablative HCT for hematologic malignancies in Alberta between 1999 and 2014 who received graft-versus-host disease (GVHD) prophylaxis using ATG (Thymoglobulin, 4.5 mg/kg) in addition to methotrexate and cyclosporine. D−R− and D+R− patients had similar survival (no significant difference). D−R+ patients had a substantially lower survival than D+R+ patients (41% versus 59% at 5 years; P = .001). This difference was attributed to higher nonrelapse mortality, apparently due to higher GVHD-associated mortality. Survival rates were also lower for D−R+ HLA-matched sibling transplant recipients compared with D+R+ HLA-matched unrelated donor transplant recipients (44% versus 66% at 5 years; P = .009). In conclusion, when using ATG, choosing a seronegative donor for a seronegative patient is relatively unimportant, whereas choosing a seropositive donor for a seropositive patient is important, even if this requires the use of a seropositive matched unrelated donor graft.

Increased Disease Progression in HLA-a, -B, -C, -DRB1 and -DBP1 Matched Recipients of Unrelated Donor Transplants with Peripheral Blood Is Independent of Risk Groups By Disease Risk Index

The use of unrelated donors matched in all alleles of HLA-A, -B, -C, and -DRB1 loci has been associated with superior outcomes compared with those having 1 or more mismatches. Recent studies showed increased transplant-related mortality (TRM) with the use of HLA-DPB1 mismatched donors supporting the notion that the ideal volunteer unrelated donor should fully match at HLA-A, -B, -C, and -DRB1 and lack -DPB1 mismatches. The issue of the effect of HLA-DPB1 mismatch on the disease progression rate is still controversial and we aimed to investigate the impact of HLA-DPB1 mismatch in the graft versus host direction on transplant outcomes in patients categorized according to the recently defined disease risk index (DRI) for disease risk classification.Our study cohort included 1,211 transplant patients with hematological malignancies whohave received an hematopoietic stem cell transplant (HSCT) from an unrelated HLA-A, -B, -C,-DRB1 matched donor by high resolution typing (8/8 matched) after 2005 through 2014. The study cohort had a median age of 55 (range, 19-77); the hematopoietic stem cell source was peripheral blood (PB) in 698 and bone marrow (BM) in 513 patients. Disease risk index (DRI) at HSCT was high or very high in 382 (33%), intermediate in 598 (51%), low in 185 (16%) patients.Of the pairs, 1,154 (95%) were matched atHLA-DQB1 and 1,116 (92%) at HLA- DRB3/4/5 by high resolution testing. However, 633 (52%) had mismatch at one of the DPB1 alleles and 208 (17%) had two mismatches. There was association between matching for DPB1and matching for DRB3/4/5 (p=0.002) but not with DQB1.In PB recipients, there was a highly significant decreaseof disease progression in DPB1 mismatched pairs (one and two allele; HR=0.7, p=0.01 and HR=0.6, p=0.01 respectively) as compared tothose pairs with DPB1 matched. The impact of mismatches at one or two alleles were not different on disease progression (HR=1.2, p=0.4). However, the impact of DPB1 mismatch on disease progression was not uniform in different disease risk groups by DRI. Mismatch at DPB1 significantly decreased disease progression only in the intermediate risk group (HR=0.5, p=0.002) but not in low risk and high/very high disease groups by DRI (HR=0.9, p=0.8 and HR=0.7, p=0.1 respectively) (Figure 1a-c).In BM recipients, increasing number of DPB1 incompatibilities decreased disease progression (HR=0.9, p=0.4 and HR=0.6, p=0.1 for 1 and 2 allele mismatches respectively) but did not reach significance. Mismatches at HLA-DQB1 and -DRB3/4/5 had no impact on disease progression in both PB and BM recipients.Pairs with one or two allele-level DPB1 mismatches increased TRM compared with DPB1 matched pairs in PB (HR=1.5, p=0.04 and HR=1.9, p=0.006 respectively) and BM recipients (HR=1.8, p=0.03 and HR=1.9, p=0.05). There was no difference between two and one allele DPB1 mismatched for TRM in PB and BM recipients. Multivariate analyses revealed that the negative impact of DPB1 mismatch on TRM was not uniform in younger or (?) older patients. Interestingly, DPB1 mismatches increased TRM only in younger (aged<55) patients (HR=2.3, p=0.02) if they were PB recipients but only in older patients (HR=2.03, p=0.046) if they were BM recipients.We next analyzed the impact of DPB1 matching on progression free survival (PFS) and did not observe any impact of DPB1 mismatches on PFS in PB (HR=0.9, p=0.9) and BM (HR=1.12, p=0.6) recipients. Subgroup analyses by DRI to identify a specific risk group that the use of HLA-A, -B, -C and -DRB1 matched but DPB1 mismatched unrelated donor might lead to improved PFS did not reveal any particular risk group in both PB and BM recipients.Thus, in recipients of HLA-A, -B-C and DRB1 allele-level matched unrelated donors a mismatch for DPB1 is associated with a significantlydecreased risk of disease progression with no impact on PFS in intermediate risk group by DRI. Further analysis permissive vs. non-permissive DPB1 mismatches would be warranted. [Display omitted] [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Cytomegalovirus (CMV) Serostatus: High Importance of Choosing Seropositive Donors for Seropositive Patients When Using Rabbit Antithymocyte Globulin (ATG)

Introduction: In published studies that included mostly hematopoietic cell transplants (HCTs) not using in vivo T cell depletion by ATG, there is a substantial survival difference between D-R- and D+R- patients, and a very small or no survival difference between D-R+ and D+R+ patients. We set out to determine the impact of donor CMV serostatus on survival after HCTs using ATG.Methods: A total of 919 patients underwent myeloablative HCT for hematologic malignancies in Alberta between 1999 and 2014, with a uniform graft versus host disease (GVHD) prophylaxis using ATG (4.5 mg/kg given between day -2 and 0) in addition to methotrexate and cyclosporine. Monitoring for CMV reactivation was performed until at least day 100 after transplant using pp65 antigenemia (before 2008) or CMV DNAemia by quantitative polymerase chain reaction (since 2008). Preemptive therapy typically with ganciclovir was started whenever pp65 antigenemia exceeded 10 to 20 positive cells/200,000 granulocytes or CMV DNAemia exceeded 25,000 IU/mL plasma. Significance of survival difference between patient groups was tested using Cox proportional hazards analysis. Significance of difference in nonrelapse mortality (NRM) or cumulative incidence of relapse (CIR) was tested using Fine-Gray analysis (nonrelapse death was a competing risk of relapse and vice versa, in addition to graft failure and second malignancy). In all analyses, covariates included patient age (>45 vs ≤45), disease stage (acute leukemia in first remission, chronic myeloid leukemia in first chronic phase and myelodysplasia with <5% marrow blasts were considered good risk, all others poor risk), graft type (marrow vs PBSCs) and donor type (human leucocyte antigen [HLA] matched sibling vs other [typically matched unrelated]).Results: D-R- and D+R- patients had similar survival (no significant difference) (blue vs orange curve, figure 1). D-R+ patients had a substantially lower survival than D+R+ patients with an estimated 5 year survival of 41% versus 60% respectively (Hazard Ratio [HR], 1.6; P = 0.001; 95% confidence interval[CI], 1.22-2.09) (red vs green curve, figure 1). This was due to higher NRM (sub hazard ratio [SHR], 1.76; P = 0.003; 95% CI, 1.212-2.58), not CIR. This appeared to be due to higher GVHD-associated mortality. We then compared D-R+ HLA matched sibling transplants with D+R+ HLA matched unrelated donor transplants to assess whether for a CMV seropositive patient with a CMV seronegative HLA matched sibling, search for a CMV seropositive HLA matched unrelated donor could be justified. D-R+ HLA matched sibling transplant recipients had a substantially lower survival than D+R+ 8/8 HLA allele matched unrelated donor transplant recipients with an estimated 5 year survival of 45% versus 66% respectively (HR, 1.7, P = 0.01, 95% CI, 1.10-2.89) (green vs orange curve, figure 2). This suggests that in the scenario of a seropositive patient with a seronegative matched sibling, unrelated donor search is justified.Conclusion: Contrary to recommendations for HCTs not using ATG, choosing a seronegative donor for a seronegative patient is unimportant, whereas choosing a seropositive donor for a seropositive patient is very important (~20% absolute 5 year survival gain). Even if a seronegative HLA matched sibling donor is available for a seropositive patient, it is better to select a seropositive HLA matched unrelated donor. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Haploidentical transplant with posttransplant cyclophosphamide vs matched unrelated donor transplant for acute myeloid leukemia

AbstractWe studied adults with acute myeloid leukemia (AML) after haploidentical (n = 192) and 8/8 HLA-matched unrelated donor (n = 1982) transplantation. Haploidentical recipients received calcineurin inhibitor (CNI), mycophenolate, and posttransplant cyclophosphamide for graft-versus-host disease (GVHD) prophylaxis; 104 patients received myeloablative and 88 received reduced intensity conditioning regimens. Matched unrelated donor transplant recipients received CNI with mycophenolate or methotrexate for GVHD prophylaxis; 1245 patients received myeloablative and 737 received reduced intensity conditioning regimens. In the myeloablative setting, day 30 neutrophil recovery was lower after haploidentical compared with matched unrelated donor transplants (90% vs 97%, P = .02). Corresponding rates after reduced intensity conditioning transplants were 93% and 96% (P = .25). In the myeloablative setting, 3-month acute grade 2-4 (16% vs 33%, P < .0001) and 3-year chronic GVHD (30% vs 53%, P < .0001) were lower after haploidentical compared with matched unrelated donor transplants. Similar differences were observed after reduced intensity conditioning transplants, 19% vs 28% (P = .05) and 34% vs 52% (P = .002). Among patients receiving myeloablative regimens, 3-year probabilities of overall survival were 45% (95% CI, 36-54) and 50% (95% CI, 47-53) after haploidentical and matched unrelated donor transplants (P = .38). Corresponding rates after reduced intensity conditioning transplants were 46% (95% CI, 35-56) and 44% (95% CI, 0.40-47) (P = .71). Although statistical power is limited, these data suggests that survival for patients with AML after haploidentical transplantation with posttransplant cyclophosphamide is comparable with matched unrelated donor transplantation.

Clinical Outcomes Among Unrelated Donor Transplant Recipients for Acute Myelogenous Leukemia As a Function of Socioeconomic Status and Related Transcriptome Differences

Clinical Outcomes Among Unrelated Donor Transplant Recipients for Acute Myelogenous Leukemia As a Function of Socioeconomic Status and Related Transcriptome Differences

Low-dose antithymocyte globulin enhanced the efficacy of tacrolimus and mycophenolate for GVHD prophylaxis in recipients of unrelated SCT

We performed a retrospective analysis of the outcome of 197 consecutive unrelated donor transplant recipients who received GVHD prophylaxis either TM regimen (tacrolimus and mycophenolate) (121 patients) or TM/ATG-G regimen (TM with low-dose antithymocyte globulin (ATG) of 4.5 mg/kg, ATG-G, Genzyme) (76 patients). Cumulative incidences of grade II-IV acute GVHD for the TM and TM/ATG-G cohorts were 49% and 61% (P=0.11) and grade III-IV acute GVHD for the TM and TM/ATG-G cohorts were 27% and 14% (P=0.02), respectively. There was no difference in the incidence of relapse or disease progression between TM and TM/ATG-G-16% and 23% (P=0.64). TM/ATG-G cohort had lower incidence of non-relapse mortality (NRM; 37% vs 20%, P=0.01), chronic GVHD (56% vs 43%, P<0.001) and more favorable global chronic GVHD severity (P<0.001). Univariate analyses showed improved OS and PFS of patients who received TM/ATG-G. Multivariate analysis confirmed TM/ATG-G had a favorable influence on OS (P=0.05) but not on PFS (P=0.07). We concluded that low-dose ATG of 4.5 mg/kg given in conjunction with TM improved GVHD prophylaxis without increased risk of relapse. Lower NRM, lower incidence and severity of chronic GVHD could potentially improve survival.

IL‐10 promoter polymorphisms influence susceptibility to aGvHD and are associated with proportions of CD4+FoxP3+ lymphocytes in blood after hematopoietic stem cell transplantation

Four hundred and ninety-five patients (390 and 105 grafted from unrelated and sibling (SIB) donors, respectively) and their donors were analyzed for the impact of interleukin-10 (IL-10) promoter genotype [rs18000896 (-1082 G/A), rs18000871 (-819 C/T) and rs18000872 (-592 C/A)] on the outcome of hematopoietic stem cell transplantation (HSCT). Patients having ACC haplotype were at a lower risk of acute graft versus host disease (aGvHD, grade > I) if transplanted from human leukocyte antigen (HLA) well-matched (10/10) unrelated donors (20/135 vs 39/117, P < 0.001, Pcorr = 0.002), which was not seen if patients were transplanted from either sibling (SIB) or poorly matched (<10/10) unrelated donors (MUD). In addition, GCC haplotype positive recipients of unrelated donor transplants tended to be more susceptible to aGvHD (68/199 vs 39/169, P = 0.019, Pcorr = 0.057). Multivariate logistic regression analysis in the MUD transplanted group showed that donor-recipient human leukocyte antigen (HLA) mismatch [odds ratio (OR) = 3.937, P = 0.001] and a lack of ACC haplotype in recipients (OR = 0.417, P = 0.013) played a significant role as independent risk factors of aGvHD grade > I. ACC carriers had higher proportions of FoxP3+ lymphocytes gated in CD4+ lymphocytes as compared with patients with other IL-10 haplotypes. It was seen at the time of hematological recovery (mean ± SEM: 3.80 ± 0.91% vs 2.06 ± 0.98%, P = 0.012) and 2 weeks later (5.32 ± 0.87% vs 2.50 ± 0.83%, P = 0.013); -592 C/A polymorphism was separately analyzed and it was found that AA homozygotes tended to have a higher incidence of aGvHD (8/15 vs 116/456, P = 0.034) and low proportions of FoxP3 CD4+ lymphocytes in blood (0.43 ± 0.22% vs 4.32 ± 0.71%, P = 0.051) measured 2 weeks after hematological recovery. Functional IL-10 polymorphism associated features influenced the risk of aGvHD with a positive effect of ACC on the pool of Treg in blood.

Prolonged Transportation Time Of Haemopoietic Progenitor Cells Does Not Impact Upon Engraftment Or Overall Survival Following Allogeneic Voluntary Unrelated Donor Transplantation

▪ IntroductionThe transportation of haemopoietic progenitor cells (HPC) from collection centre to transplant centre is a critical, but often overlooked process during allogeneic transplantation using voluntary unrelated donors (VUD). The policies of international donor registries support the rapid retrieval and infusion of HPC. However transplant centres are often challenged by transit times in excess of 24h when retrieving HPC from intercontinental collection centres. This single institutional retrospective study aimed to investigate if a prolonged transit time between collection and transplant centre impacted upon the rate of engraftment and overall survival of recipients of HPC collected from VUDs. MethodologyA retrospective analysis of outcomes following an initial allogeneic transplant performed at our institution between 1987 and 2013 was conducted using institutional databases. The time to neutrophil and platelet engraftment and overall survival was compared between recipients of VUD transplants with HPC retrieved from collection centres located overseas (transit time of > 24h) (n = 241; BM n = 50, PBPC n = 191), recipients of unrelated donor transplants with HPC retrieved from collection centres within Australia (transit time of <8h) (n = 334; BM n = 112, PBPC n = 222) and recipients of related HPC collected at the transplant centre (n = 807; BM n = 320, PBSC n = 487). All HPC retrieved from local and intercontinental VUD collection centres were transported in rigid coolers containing refrigerated gel packs prior to 2003 or isothermal cooling inserts post 2003. The temperature was monitored and maintained by the courier at between 2 and 8oC. ResultsThere was no significant difference in the days to neutrophil and platelet recovery (Table 1) between recipients of a VUD allogeneic transplant with HPC retrieved from a local collection centre compared with those recipients whose HPC was retrieved from an international collection centre. Retrieval and infusion of HPC from local collection centres is generally completed within 8h from collection whereas the interval from collection to infusion may vary between 24 to 90h when HPC are retrieved from intercontinental collection centres. Furthermore there was no significant difference in overall survival (Figure 1) of recipients of related donor allogeneic transplants performed without transportation of HPC and recipients of VUD allogeneic transplants whose HPC were retrieved from either a local collection centre or an intercontinental collection centre (Figure 1).Table 1Neutrophil and platelet engraftment post VUD allogeneic transplantationDays to Neutrophil Count of 0.5 x 109/L(median)Days to Platelet Count of 20 x 109/L(median)Unrelated BM (transit < 8h)1727Unrelated BM (transit > 24h)1726Unrelated PBPC (transit < 8h)1619Unrelated PBPC (transit > 24h)1619 [Display omitted] ConclusionOur study demonstrated no adverse effect on neutrophil and platelet recovery, or overall survival resulting from retrieval of HPC (BM and PBPC) from collection centres with transit times in excess of 24h and with some international retrievals requiring up to 90h transit times. A previous study had reported higher mortality rates and delayed platelet engraftment following HLA matched unrelated donor BM transplants facilitated by the National Marrow Donor Program with an interval of greater than 24h between collection and infusion (Lazarus et. al, Biol Blood Marrow Transplant 15: 589-596, 2009). At our centre HPC (BM and PBPC) are retrieved by trained couriers that monitor and maintain the temperature between 2 and 8oC. This is in contrast to NMDP recommendations that BM is transported at ambient temperature. Our data suggest that all HPC should be refrigerated to between 2 and 8oC and the temperature monitored during transportation. In addition, the courier should be trained to re-establish the optimal temperature for transportation if the temperature deviates from the recommended range. Disclosures:No relevant conflicts of interest to declare.

Outcomes of Hematopoietic Stem Cell Transplantation in Primary Immunodeficiency: A Report from the Australian and New Zealand Children’s Haematology Oncology Group and the Australasian Bone Marrow Transplant Recipient Registry

We performed a retrospective analysis on the outcomes of 135 hematopoietic stem cell transplantations (HSCTs) for primary immunodeficiency disorders in Australian and New Zealand Children’s Haematology Oncology Group transplantation centers between 1992 and 2008. The most common indications for HSCT were severe combined immunodeficiency, Wiskott-Aldrich syndrome, and chronic granulomatous disease. Five-year overall survival (OS) was 72% for the entire cohort. Disease-specific 5-year OS was 70% for severe combined immunodeficiency, 81% for Wiskott-Aldrich syndrome, and 69% for chronic granulomatous disease. Transplantation-related mortality (TRM) was 10% at day +100. TRM and OS were equivalent in recipients of related and unrelated donor transplants. Source of stem cells had no impact on TRM or OS with outcomes following unrelated umbilical cord blood similar to unrelated bone marrow. The presence of interstitial pneumonitis, active cytomegalovirus infection, or veno-occlusive disease were all independent variables that significantly decreased OS. This large series supports the use of HSCT as curative therapy for a range of primary immunodeficiency disorders, demonstrating excellent survival after both related and unrelated donor transplantation.

A Matched Controlled Analysis of Post-Transplant Cyclophosphamide (CY) Versus Tacrolimus and Mini-Dose Methotrexate in Matched Sibling and Unrelated Donor Transplant Recipients Receiving Reduced-Intensity Conditioning: Post-Transplant CY Is Associated with Higher Rates of Acute Gvhd

AbstractAbstract 4200Graft-vs.-Host Disease (GVHD) remains a common complication following matched sibling and unrelated donor hematopoietic cell transplantation (HCT). Standard GVHD prophylaxis calls for prolonged immune suppression, typically with a calcineurin-inhibitor. Recently, post-transplant cyclophosphamide (CY) has been studied as sole prophylaxis in matched related and unrelated bone marrow (BM) transplant recipients following an ablative conditioning regimen with busulfan (Bu) and CY and demonstrated comparable rates of acute GVHD and lower rates of chronic GVHD as traditional GVHD prophylaxis regimens. We recently conducted a phase II study of post-transplant CY following a reduced-intensity conditioning (RIC) regimen of Busulfan (Bu) and Fludaribine (Flu) in matched related and unrelated donor transplants and performed a matched-control analysis comparing their results with patients who received traditional GVHD prophylaxis with tacrolimus and mini-dose methotrexate (MTX) during the same time period.Forty-nine (49) patients were enrolled onto this study. They received Flu at a dose of 40mg/m2 over 1hour followed by intravenous Bu over 3 hours targeting a daily AUC of 4,000 microMol-min on days –6 to –3. Recipients of unrelated transplants received ATG on days –3 to –1 (total dose 4 mg/kg). CY was given as sole GVHD prophylaxis at a dose of 50 mg/kg on days +3 and +4. During the same period of time, 133 patients received a RIC regimen with intravenous Bu/Flu or Flu and melphalan (Mel) and received GVHD prophylaxis with tacrolimus plus mini-dose MTX (10mg/m2 on day +1, 5mg/m2on days +3, +6, +11). Unrelated donor transplants also received ATG. A computer generated algorithm was used to identify a comparable control group from our departmental database matching, in order of priority, on age, diagnosis, disease status, donor (matched-related versus unrelated) and graft source (PB versus BM). Matched controls (control group) were successfully identified for 37 study patients (Post-Cy group). Results:The median age for the Post- CY group and control group was 61 (range, 39–72) and 62 years (range, 37–72). Eight-one (81) % of patients in both groups had AML or MDS, 3% had ALL and 16% had NHL or CLL. Fifty-nine (59) % of patients in both groups had unrelated donors and received ATG in the conditioning. Disease status for the Post-CY and control groups respectively were CR1: 14 and 14%, CR2: 8 and 11%, >CR2: 38 and 32% and Primary Induction Failure / Untreated: 40 and 32%. Seventy (70) % of the post-CY group received BM versus 48% of the control group, whereas sex mismatching (Male donor for Female patient) occurred in 22% of the post-Cy and 8% of the control group. The cumulative incidence of grade II-IV acute GVHD and chronic GVHD in the post-CY and control groups were: 46% versus 19% (Hazard Ratio (HR): 2.8, 95% CI, 1.1–6.7; p=0.02) and 14% versus 21% (HR: 0.8, 95% CI, 0.2–2.6, p=0.7). Grades III/IV acute GVHD occurred in 14% (95% CI, 6–32) of the patients in the post-CY group whereas there were no cases of grade III/IV in the control group (p=0.02). Overall, progression-free and non-relapse mortality at 2-years are shown in the table below. Conclusion:Post-transplant CY following RIC is associated with higher rates of acute GVHD, with resultant trends for higher non-relapse mortality and lower overall survival when compared to tacrolimus and mini-dose MTX. The use of post-transplant CY as a sole GVHD prophylaxis regimen should be avoided following RIC transplant in matched-related and unrelated donors.Post-Transplant CYTacrolimus and MethotrexateHazard Ratio (95% CI, p- value)Acute GVHD Grade II-IV46% (32–66)19% (10–37)2.8 (1.1–6.7, 0.02)Chronic GVHD @ 1-year14% (6–32)21% (11–43)0.8 (0.2–2.6, 0.7)Non-Relapse Mortality @ 2-years36% (23–55)16% (7–35)2.4 (0.8–6.7, 0.1)Progression-Free Survival @ 2-years22% (10–37)33% (16–51)1.3 (0.7–2.3, 0.4)Overall Survival @ 2 years26% (13–42)46% (26–64)1.8 (0.9–3.3, 0.08) Disclosures:Off Label Use: azacitidine: off-label use as maintenance therapy following allogeneic stem cell transplant for MDS/AML.

Graft-versus-Host Disease: State of the Science

Despite concerted research efforts, prevention and treatment of graft-versus-host disease (GVHD) have not changed significantly over the past 3 decades. The goal of this session is to provide an outline of the current state of the science with respect to the prevention, treatment, and evaluation of acute and chronic GVHD. In addition, we detail those strategies most likely to be at the forefront of clinical research in the upcoming years.