Matched Unrelated Donor Group Research Articles

Comparison of Older Related versus Younger Unrelated Donors for Older Recipients of Allogeneic Hematopoietic Cell Transplantation with Acute Myeloid Leukemia or Myelodysplastic Syndrome: A Large Single-Center Analysis

For patients undergoing allogeneic hematopoietic cell transplantation (alloHCT), HLA-matched related donors (MRDs) have traditionally been the preferred donor source. However, as the age of recipients increases, their sibling donors are aging as well. In this study, we investigated whether younger matched unrelated donors (MUDs) might be a better donor source than similarly aged sibling donors for patients age >60 years with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). A total of 499 patients age 60 to 70 years with AML or MDS who underwent alloHCT from an older MRD (donor age ≥50 years) or a younger MUD (donor age ≤35 years) between 2010 and 2022 were evaluated. Of these, 360 patients (72%) received an MUD graft and 139 (28%) received an MRD graft. The median recipient age was 64 years in the MRD group and 66 years in the MUD group. With a median follow-up among survivors of 53 months (range, 9 to 147 months ), the 4-year progression-free survival was 40% in the MRD group and 41% in the MUD group (P = .79) and the 4-year overall survival was 50% and 44%, respectively (P = .15), with no between-group differences in nonrelapse mortality, relapse, and acute or chronic graft-versus-host disease. In the MUD group, we also compared the effect of donor age 18 to 24 years and donor age 25 to 35 years and found no differences in outcomes between the groups. We conclude that outcomes are comparable between the use of older MRDs and use of younger MUDs for elderly patients with AML or MDS, that there is no donor age effect among younger MUDs, and that the use of either donor type is reasonable.

Allogeneic hematopoietic stem cell transplantation: A single-center experience, 2017 to 2021

IntroductionHematopoietic stem cell transplantation (HSCT) remains a critical treatment for advanced or high-risk hematological malignancies, posing challenges such as finding suitable donors and managing of graft-versus-host disease (GvHD). This study estimates 3-year overall survival in patients who underwent HSCT at our referral service in the state of Minas Gerais, Brazil. Material and methodsThis retrospective observational cohort study involved 41 patients who received HSCT between 2017 and 2021 at the Felício Rocho Hospital. Recipients received HSCT from either haploidentical donor (Haplo), matched unrelated donor (MUD), or HLA-matched sibling donor (MSD). The study evaluated parameters that included 3-year overall survival (OS), treatment-related mortality (TRM), GvHD incidence, post-transplant relapse rate, and engraftment. ANOVA, Kruskal-Wallis, and chi-square tests were used for statistical analysis. Survival curves were calculated using the Kaplan-Meier method and the Log-rank test compared the curves. ResultsOur study found that the engraftment time differed among groups: Haplo recipients engrafted earlier within a median of 16 days (ranging between 10 and 20 days) than MSD recipients with 18 days (ranging between 11 and 28 days), and MUD recipients with 19 days (ranging between 11 and 24 days; p = 0.019). Mild acute GvHD (grade I-II) was observed in 13 patients, progressing to chronic GvHD in 5 patients. Three-year OS rates were as follows: MSD group - 67.7%, Haplo group - 42.2%, and MUD group - 44.4% (MSD vs Haplo, p = 0.039). Three-year cumulative treatment-related mortality (TRM) rates were 17.8% for MSD group, 22.9% for Haplo group, and 22.1% for MUD group (pairwise comparisons p > 0.05). Infection-related mortality was reported in eight patients, while relapse rates at 3 years were similar across MSD, Haplo, and MUD groups (p = 0.891). Donor age influenced OS rates, showing better outcomes with donors under 45 years old, and significant differences were found in pairwise comparisons (p = 0.015). ConclusionDonor type and donor age significantly impacted HSCT outcomes in our analysis, thus emphasizing the importance of rigorous donor selection in risk stratification and suggesting potential benefits for younger donors.

Different Sources of Hematopoietic Stem Cell Transplantation in Patients with Thalassemia Major: Relationship between Immune Reconstitution, Graft-Versus-Host Disease, and Viral Infections

Objective: To compare the relationship among immune reconstitution, graft-versus-host disease (GVHD), and viral infections in three kinds of hematopoietic stem cell transplantation(HSCT) using different host sources for thalassemia major(TM) patients: matched unrelated donor (MUD) HSCT, haploidentical (Haplo) HSCT with post-transplant cyclophosphamide (PTCy)-based prophylactic therapy, and TCRαβ-T cell-depleted HSCT (TDH). Methods: A total of 191 TM patients in our center between October 2018 and June 2022 were included in this study, comprising three transplant groups: MUD group (n=56), PTCy group (n=45), and TDH group (n=90). Four-color flow cytometry was used to detect the proportions and absolute counts of lymphocyte subsets at the 12th month after transplantation for the three different donor types. The immune reconstitution was analyzed and compared with the occurrence of GVHD and virus infections. Results: 1. Immune Reconstitution: (1) The ratio of helper cells (CD3 +CD4 +)/cytotoxic T cells (CD3 +CD8 +) at the 12 months after transplantation was compared among the three groups. There were statistically significant differences between the TDH and PTCy groups, as well as between the TDH and MUD groups(P=022 and 0.011, respectively). No statistical difference was found between the PTCy and MUD groups (P=0.932). The CD4 +/CD8 + ratio in the TDH group recovered the fastest and had already returned to the normal reference range (0.7-2.7). (2) The comparison of B cells (CD3 -CD19 +) at the 12 months after transplantation showed statistically significant differences between the TDH and PTCy groups, as well as between the MUD and PTCy groups (P=0.049 and 0.034, respectively). No statistical difference was found between the TDH and MUD groups (P=0.447). The recovery of B cells was faster in the TDH and MUD groups, while it was slowest in the PTCy group. (3) The comparison of natural killer cells (NK cells) (CD3 -CD56 +) at the 12 months after transplantation showed statistically significant differences between the TDH and PTCy groups, as well as between the TDH and MUD groups (P=0.048 and 0.000, respectively). No statistical difference was found between the PTCy and MUD groups (P=0.366). The TDH group exhibited the fastest recovery of NK cells. 2. Chronic GVHD (cGVHD): (1) 7/90 cases (7.78%) of cGVHD appeared in the TDH group, 19/45 cases (42.22%) in the PTCy group, and 2/56 cases (3.57%) n the MUD group. (2) No statistical difference showed in the incidence of cGVHD between the TDH and MUD groups (P=0.500). There was a statistical difference in the incidence of cGVHD between the TDH and PTCy groups (P=0.000), as well as between the MUD and PTCy groups (P=0.000). 3. Viral Infection: (1) 22/90 cases (24.44%) of viral infection occurred in the TDH group, 7/45 cases (15.56%) in the PTCy group, and 6/56 cases (10.71%) in the MUD group. (2) Among the 90 cases of TDH group, the CD4/CD8 ratio at the 6 months after transplantation was 0.41±0.24 in the 22 cases with viral infection and 0.69±0.40 in the 68 cases without that. There was a statistical difference in the mean CD4/CD8 ratio between the two divisions in the TDH group (P=0.013). Conclusion:The TDH group exhibited faster immune reconstitution compared to the other two groups, especially in terms of CD4/CD8 ratio, B cells, and NK cells. This may be related to two special factors for patients underwent TDH in our center: a rather high average infusion of CD34 cells (30×10 6/kg) , and the preservation of γδ cells, B cells, and NK cells with the removing of TCRαβ-T cells in the TDH treatment protocol. The TDH and MUD groups showed a lower incidence of cGVHD, while the PTCy group had a higher incidence. The occurrence of viral infection in the TDH group was 24.44%. Also, the lower a CD4/CD8 ratio at the 6 months after transplantation, the higher the incidence of viral infection. Table 1. The Absolute Counts of Lymphocyte Subsets at the 12th Month after Transplantation

Donor Age Matters in Haploidentical Donor Transplantation Rather Than in Matched Unrelated Donor Transplantation in Older Adults with Acute Myeloid Leukemia

Allogeneic hematopoietic cell transplantation (HSCT) has curative potential for Acute myeloid leukemia (AML). Given that the median age of acute myeloid leukemia (AML) patient is 68 years, the majority of HSCT candidates in AML are inevitably elderly patients. Advances in alternative donor HSCT and reduced intensity conditioning have expanded the opportunities for elderly patients to undergo HSCT. Previously, we reported HSCT outcomes of older adults with AML according to donor type, showing comparable outcomes among haploidentical donor (HID), matched unrelated donor (MUD) and matched sibling donor group, with especially superior survival in the MUD group ( Transplantation and Cellular Therapy 2021; 27: 774.e1-774.e12.). Since donor age has been shown to be a significant factor in HSCT outcomes, we investigated the HSCT outcomes of older AML HSCT recipients from HID according to donor age, and compared to those of MUD HSCT recipients. We retrospectively evaluated older adults with AML aged 60 and above, who underwent first HSCT at Catholic Hematology Hospital between 2007 and 2022, in complete remission (CR) or CR with incomplete hematologic recovery. We analyzed the HSCT outcomes (Overall Survival [OS], Relapse-Free Survival [RFS], and Graft-versus-Host Disease [GVHD], Relapse-Free Survival [GRFS]) in patients who underwent either HID or MUD HSCT. A total of 204 patients were included, with 117 (57.4%) in the HID group and 87 (42.6%) in the MUD group. For MUD HSCT, conditioning regimens consisted of cyclophosphamide 120 mg/kg combined with 1320 cGy of fractionated total body irradiation (TBI) or busulfex [12.8 mg/kg], or busulfex [6.4 mg/kg] and fludarabine [150 mg/m2] with 400 cGy of fractionated TBI. Conditioning for HID HSCT comprised of busulfex [6.4 mg/kg] and fludarabine [150 mg/m2] with 400-800 cGy of fractionated TBI. Rabbit antithymocyte globulin was administered at a dose of 1.25 mg/kg/day on days -3 to -2 for MUD HSCT and days -4 to -1 for HID HSCT. There was no significant difference in the clinical characteristics between the MUD and the HID groups, except donor age (MUD vs. HID: median 28 years vs. 37 years, p <0.01). In the survival analysis, 196 patients whose donor age was identified were included. The difference in survival based on donor age was striking. Patients who received transplantation from donors aged below 35 showed superior outcomes compared to those with donors aged 35 and above (Figure A). The impact of donor age on survival differences was also pronounced in RFS (Figure B). However, the differences based on donor age were mitigated in terms of GRFS (Figure C), suggesting that donor age may play a role in the occurrence of GVHD and relapse. In the cumulative incidence analysis, there was a significant difference in relapse and non-relapse mortality between patients who received HID HSCT from younger donors aged below 35, patients who received HID HSCT from older donors aged 35 and above, and patients who received MUD HSCT. The patients who underwent MUD HSCT showed a significantly higher relapse rate than those who underwent HID HSCT regardless of donor age. HID HSCT patients with older donors (aged 35 and above) showed significantly higher non-relapse mortality than the other two groups. In the analysis of cumulative incidence of GVHD, with death as a competing risk, patients who underwent MUD HSCT showed lower incidence of acute GVHD than those who underwent HID HSCT (Figure D). Our data showed equally promising outcomes of HID HSCT from a younger donor (age <35) compared to MUD-HSCT, suggesting the necessity for more sophisticated strategies to improve survival outcomes in HID HSCT from older donors. Further studies comparing donor age are warranted in various transplantation settings.

Letermovir Prophylaxis for Cytomegalovirus Reactivation in β Thalassemia Major Children after Hematopoietic Cell Transplantation

Background: Cytomegalovirus(CMV) is one of the most important infections following allogeneic haematopoietic stem cell transplantation (HSCT). Although Letermovir is licensed for prophylaxis of CMV infection in allogeneic hematopoietic cell transplant adult CMV seropositive patients. There are limited data for letermovir as primary CMV prophylaxis in pediatric patients . The objective of the study was to analyze the the use of letermovir for prophylaxis from CMV infection in β thalassemia major children undergoing allo-HSCT in a single center. M ethods : This study was an retrospective, single-center evaluation of β thalassemia major pediatric recipients treated by allo-HSCT in the First Affiliated Hospital of Guangxi Medical University. 34 patients included in the study were CMV-seropositive, underwent allo-HSCT, and were started on letermovir for primary CMV prophylaxis between June 2022 and July 2023. CMV monitoring was performed 2 times a week until day +100 after HSCT. The primary end point was CMV reactivation on days +100. Results: 34 patients were analyzed. 20 patients were transplanted from haploidentical donor, 9 patients were transplanted from matched-related donor, 5 patients were transplanted from matched-unrelated donor. The median followed-up was 129 days (range, 50-405 days).The median age was 9 years (range, 2-16 years). The GVHD prophylaxis for matched-related donor group was cyclosporine-based , and the GVHD prophylaxisfor haploidentical and matched-unrelated donor groups were tacrolimus-based. Letermovir start at median 21 days (range 10-35 days) after HSCT. The median weight at the initiation of letermovir was 18.8 kg (range, 12-25 kg). The dose of letermovir was 240mg and 120mg orally once daily in tacrolimus co-administration and cyclosporine co-administration, respectively. During the follow-up period , CMV reactivation was observed in 8 patients totally (23.5%). Among them, 6 patients(17.6%) were in haploidentical donor group. 1 patient (2.9%) in matched-related group and 1 patient (2.9%) in matched-unrelated donor group was CMV reactivated, respectively. Throughout letermovir prophylaxis, the median CMV DNAemia level was 1945 copies (range,526-3800 copies), and the CMV DNAemia lasting time were 17.5 days (range,15-59 days). No patients developed clinically significant CMV infection. 1 patient died because of pulmonary infection of mucor. No serious hepatotoxicity, nephrotoxicity or letermovir intolerance was described. Conclusion: Our data support letermovir prophylaxis efficacy and safety in β thalassemia major children after allo-HSCT.

Post-Transplant Cyclophosphamide-Based Graft-Versus-Host Disease Prophylaxis in HLA-Matched and Haploidentical Donor Transplants for Patients with Hodgkin disease: A Comparative Study of the LWP EBMT

INTRODUCTION Post-transplant cyclophosphamide (PTCy) has proven to be a highly effective strategy in preventing graft-versus-host disease (GVHD) in haploidentical (haplo) hematopoietic stem cell transplantation (HSCT), but it is being increasingly used in HLA-matched transplants. The outcomes of haplo HSCT with PTCY in various hematologic malignancies, particularly in relapsed/refractory Hodgkin disease (HD), have shown promising results, challenging those obtained in transplant patients from HLA-matched donors without PTCy. However, there is limited information on the impact of donor types on the outcomes of patients with HD undergoing allogenic HSCT when using homogeneous GVHD prophylaxis with PTCy. To address this knowledge gap, we have conducted an extensive study using the Lymphoma Working Party of the European Society for Blood and Marrow Transplantation (LWP-EBMT) registry. The aim of this study was to compare the outcomes of patients with HD undergoing HSCT from both HLA-matched donors, which include matched sibling donors (MSD) and matched unrelated donors (MUD), and haplo donors, using PTCy as GVHD prophylaxis approach in all cohorts. PATIENTS AND METHODS Inclusion criteria All adults (≥ 18 years) patients diagnosed with HD who underwent their first HSCT between January 2010 and December 2020 from either a MSD, MUD or haplo, and whose data were reported to the EBMT registry were included. For the purposes of this study, only transplants who received PTCy-based as GVHD prophylaxis were considered. Statistical Analysis The study utilized statistical methods such as Kaplan-Meier estimation, Log-Rank test, competing risks analysis, and Cox proportional hazards regression. The analyses included OS, PFS, NRM, aGVHD, cGVHD, and graft failure. The statistical software R and packages were used. RESULTS Patient and Transplantation Characteristics Patient, disease and transplant-related characteristics of the 860 patients are summarized in Table 1. Engraftment The cumulative incidence (Cum Inc) of neutrophil recovery at day 30 was 95% (95% CI, 93-96) in the HLA-matched group and 96% (95% CI, 91-98) in the haplo cohort (p=0.18). The 60-day Cum Inc of platelet recovery in similar order was 94% (95% CI, 88-97) and 86% (95% CI, 83-88) (p<0.001). GVHD The Cum Inc of acute GVHD grade II-IV at 100 days in the HLA-matched and the haplo cohorts was 24% (95% CI, 17-31) and 34% (95% CI, 30-37), respectively (p=0.01), whereas for grade III-IV it was 8% (95% CI, 4-13) and 10% (95% CI, 8-13), (p=0.44). In multivariable analysis (table 2), haplo was associated with an increased risk of acute GVHD grades II-IV, when compared with HLA-matched (HR 0.65; 95% CI, 0.46-0.93; p=0.01). Other variables are shown in table 2. The 2-year Cum Inc of chronic GVHD in the HLA-matched and haplo cohorts was 26% (95% CI, 19-33) and 27% (95% CI, 24-31), respectively (p=0.75). Other variables are shown in table 2. NRM and relapse The Cum Inc of NRM at 2 years was 10% (95% CI; 6-16) for HLA-matched and 18% (95% CI; 15-21) for haplo (p=0.02). In multivariable analysis (table 2), haplo was associated with an increased risk of NRM, when compared to HLA-matched (HR 0.5; 95% CI, 0.28-0.89; p=0.01). Other variables are shown in table 2. The Cum Inc of relapse at 2 years was 22% (95% CI; 15-29) for HLA-matched and 24% (95% CI; 20-27) for haplo (p=0.81). Other variables are shown in table 2. Survival The 2-year OS for the HLA-matched and haplo cohorts was 82% (95% CI; 75-88) and 70% (95% CI; 67-74), respectively (p=0.002). In multivariable analysis (table 2), compared to HLA-matched, haplo (HR, 0.51; 95% CI, 0.34-0.77; p=0.001) was associated with worse survival. Other variables are shown in table 2. The 2-year PFS was similar between HLA-matched and haplo (66%; 95% CI, 58-74; and 58%; 95% CI, 54-62, respectively; p=0.17). Other variables are shown in table 2. Comparison of outcomes for MSD and MUD With regards to the donor type, most posttransplant outcomes did not exhibit significant differences, except for a higher incidence of grades II-IV acute GVHD in the MUD group (33%; 95% CI, 32-44) compared to the MSD group (17%; 95% CI, 10-25) (p=0.01). CONCLUSION Our study shows that in patients with HD undergoing HSCT with PTCy for GVHD prophylaxis, no significant differences in 2-year PFS were observed between HLA-matched and haplo. A higher risk of acute GVHD and NRM is associated with haplo, leading to lower OS compared to HLA-matched transplantation.

Comparative Study for Haplo, MSD and MUD Allo-Hcts for Core-Binding Factor AML Patients in CR2: A Study from the Global Committee and the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation

Background Although core-binding factor acute myeloid leukemia (CBF-AML) generally has a favorable prognosis, relapse occurs in ~40% of cases. Allogeneic hematopoietic cell transplantation (allo-HCT) is recommended when patients achieve second complete remission (CR2). However, transplant outcomes and donor preference for these patients remain unclear. We compared in an EBMT global multi-center registry-based analysis the outcomes following allo-HCT using either haploidentical donors (HAPLO), matched siblings donors (MSD), or 10/10 matched unrelated donors (MUD). Methods Data from 865 de novo adult CBF AML patients in CR2 receiving allo-HCT in 227 EBMT centers from 2010-2022 were analyzed. Transplants from mismatched UD (<10/10), umbilical cord blood or grafts with ex-vivo manipulation were excluded. Univariate analyses and Cox regression models were used. Results Results from 329 MSD, 374 MUD, and 162 HAPLO HCTs were analyzed. For the entire cohort, median age was 43y (range: 18-76). Inv(16)/CBFBMYH11 was detected in 503 patients (58%) and t(8;21)/RUNX1-RUNX1T1 was detected in 362 patients (42%). Peripheral blood was the major graft source (86.1%), and myeloablative conditioning was used for the majority (60.1%) of all allo-HCTs. Female-to-male transplants were more common in the MSD group (25.5%) than in the HAPLO (19.8%) or MUD (14.2%) group, respectively (p<0.01). 83% of patients in the HAPLO group received post transplant cyclophosphamide (PTCy) as graft-versus-host disease (GVHD) prophylaxis. Engraftment rates were higher in the MSD (98.8%) and MUD (98.9%) than in the HAPLO (94.9%) group (p<0.01). Original disease was the major cause of death for the MSD and MUD cohorts, while in the HAPLO group, it was infection. On univariate analysis, HAPLO HCT was associated with a higher 2-year non-relapse mortality (NRM) (MSD 17.1%, MUD 15.3%, HAPLO 25.7%). The 180-day cumulative incidence of grade II-IV acute GVHD was higher in HAPLOs (14.8%) than in MSD (6.8%) or MUD (7.9%) recipients, respectively . No significant difference was observed among the three cohorts for 2-year leukemia-free survival (LFS), overall survival (OS) and GVHD-free/relapse free survival (GRFS). CBF-AML with inv(16) was associated with lower relapse incidence RI (18.1%) than with t(8;21) (28.3%), which contributed to better OS (75.7% vs 59.8% at 2 years), LFS (65.8% vs 51.2%) and GRFS (50.8% vs 38.5%) . Older patient age i.e., above the median age, was associated with a higher NRM (22.4% vs 13.3%) and a lower OS (63.8% vs 74.8%) than younger age i.e., below the median age. Peripheral blood grafts were associated with higher incidences of chronic GVHD (41.5% vs 25.8%) and extensive cGVHD (21.6% vs 9.7%) than bone marrow grafts. On multivariate analysis, no significant difference was observed among HAPLO, MSD and MUD allo-HCTs on NRM. HAPLO HCT was associated with lower RI compared to MSD (hazard ratio [HR]=0.56, 95% CI 0.32-0.97; p<0.05) and MUD (HR=0.57, 95% CI: 0.33-0.99, p<0.05) while there was no significant differences between the 3 types of donors on LFS, OS and GRFS. CBF-AML with t(8;21) was associated with both higher RI (HR=1.79, 95% CI 1.3-2.47; p<0.01) and higher NRM (HR=1.58, 95% CI 1.1-2.27; p<0.01) than CBF-AML with inv(16), which led to worse LFS, OS and GRFS. Higher age (per 10 year) was associated with higher risk of NRM (HR=1.29, 95% CI 1.11-1.5; p<0.01) and worse OS (HR=1.13, 95% CI 1.01-1.27; p=0.03). Conclusions For CBF-AML patients in CR2, haploidentical HCTs were associated with a lower RI compared to MSD and MUD allo-HCTs. HAPLO achieved similar LFS, OS and GRFS to MSD or MUD, respectively. In addition, CBF AML with inv(16) had better outcomes than with t(8;21) after allo-HCT.

Comparative Study for Haplo, MSD and MUD Allo-Hcts for AML Patients with KMT2A Rearrangement: A Study from the Global Committee and the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation

Background Acute myeloid leukemia (AML) patients with KMT2A rearrangement (KMT2Ar, except for t(9;11)(p21.3;q23.3)/MLLT3::KMT2A) are classified as adverse risk in the 2022 European LeukemiaNet (ELN) classification. There is uncertainty on their outcome following allogeneic cell transplantation (allo-HCT). We compared, in an European Society for Blood and Marrow Transplantation (EBMT) global multi-center registry-based analysis, outcomes following an allogeneic stem cell transplantation (allo-HCT) with either a matched sibling donor (MSD), matched unrelated donor (MUD) or haploidentical donor (HAPLO). Methods Data from 586 AML patients with KMT2Ar receiving a first allo-HCT in 183 EBMT centers from 2010-2022 were analyzed. All patients achieved first complete remission (CR1) before transplantation. Patients with t(9;11), without details on translocation, receiving mismatched UD (<10/10), umbilical cord blood, or grafts with ex-vivo manipulation were excluded. Univariant analysis and Cox regression models were used. Results KMT2A rearranged AML patients received allo-HCT from 201 MSD, 256 10/10 MUD, and 129 HAPLOs. For KMT2Ar type, t(6;11), t(11;19), t(10;11) or other translocations account for 27.8%, 37.5%, 23.9% and 10.8%, respectively. Peripheral blood was the major graft source (83.2%), and myeloablative conditioning accounted for the majority (60.2%) of all allo-HCTs. Engraftment rates were comparable in the three cohorts (MSD 99.5%, MUD 98.4% and HAPLO 96.9% p=0.17). AML relapse was the major cause of death in each donor cohort. On univariate analysis, HAPLO was associated with a lower 2-year relapse incidence (RI) (MSD 41.1%, MUD 37.2%, HAPLO 20%) but a higher 2-year non-relapse mortality (NRM) (MSD 6.1%, MUD 19.3%, HAPLO 21.3%) compared with MSD and MUD. The 180-day cumulative incidence of grade II-IV acute GVHD (aGVHD) was lower in MSD (18.8%) than in MUD (31.3%) or HAPLO groups (26.5%), respectively. The 2-year leukemia-free survival (LFS), overall survival (OS) and GVHD-free/relapse free survival (GRFS) were comparable among the three cohorts. Lower RI was observed in patients with t(11;19) compared with t(6;11) or t(10;11). Complex karyotype (CK) (at least 3 abnormalities) or monosomal karyotype (MK) were both associated with higher RI compared with those without. In addition, in-vivo T cell depletion was related to lower intensive chronic GVHD (cGVHD) incidence. On multivariate analysis, HAPLO HCT was associated with lower RI (hazard ratio [HR=0.46], 95% CI 0.28-0.77; p<0.01) but higher incidence of NRM (HR=2.36, 95% CI 1.17-4.78; p<0.01) compared with MSD, while HAPLO had no significant impact on LFS, OS and GRFS. MUD HCT was associated with higher incidence of grade II-IV aGVHD (HR=1.82, 95% CI 1.19-2,78; p<0.01), NRM (HR=2.73, 95% CI 1.51-4.94; p<0.01), and lower LFS (HR=1.37, 95% CI 1.03-1.83; p<0.05) compared with MSD (reference). Concerning translocation type, t(11;19) was associated with a lower RI (HR=0.64, 95% CI 0.43-0.94; p=0.022), a better LFS (HR=0.66, 95% CI 0.48-0.91; p=0.012), OS (HR=0.63, 95% CI 0.45-0.89; p=0.008) and GRFS (HR=0.75, 95% CI 0.57-1; p=0.049) compared with t(6;11)(reference). Translocations other than t(6;11), t(11;19) or t(10;11) were related to a lower RI (HR=0.45, 95% CI 0.24-0.87) and better OS (HR=0.57, 95% CI 0.34-0.95) compared to t(6;11). MK was associated with higher RI (HR=1.59, 95% CI 1.04-2.45; p<0.05) and lower LFS (HR=1.47, 95% CI 1.01-2.14; p<0.05). Conclusions For AML patients with KMT2Ar, HAPLO HCT was associated with a lower RI but higher NRM, leading to similar LFS, OS and GRFS compared with MUD and MSD HCTs. In the setting of allo-HCT, t(11;19) seems to be associated with favorable outcomes compared with other KMT2Ar.

Younger haploidentical donor versus older matched unrelated donor for patients with AML/MDS.

Optimal donor selection is fundamental to successful allogeneic hematopoietic cell transplantation (HCT), and donor age influences survival after both matched unrelated donor (MUD) and haploidentical donor HCT. Though recent studies have shown similar outcomes between MUD and haploidentical HCT, it is unknown if outcomes differ following HCT with younger haploidentical donors compared to HCT with older MUDs. Therefore, we performed a retrospective analysis comparing outcomes of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) patients who underwent HCT with younger (≤35 years) haploidentical donors (n=494) or older (>35 years) MUDs (n=1005). Patients in the haploidentical and MUD groups received post-transplant cyclophosphamide (PTCy) and conventional graft-versus-host-disease (GVHD) prophylaxis, respectively. In multivariate analysis, use of younger haploidentical donors was associated with improved overall survival (hazard ratio [HR] 0.81, 95% confidence interval [CI] 0.69-0.95, p=.01) and lower rates of grade II-IV acute GVHD (HR 0.64, 95% CI 0.53-0.77, p < .001), grade III-IV acute GVHD (HR 0.37, 95% CI 0.25-0.53, p < .001), and chronic GVHD (HR 0.49, 95% CI 0.40-0.60, p < .001). Relapse rates were similar among those who received myeloablative conditioning but were higher in patients of the younger haploidentical group who received reduced intensity conditioning (HR 1.49, 95%CI 1.18-1.88, p=.001). The younger haploidentical group had significantly lower non-relapse mortality ≥3months post-HCT (HR 0.59, 95% CI 0.38-0.90, p=.02). Our data support the use of younger haploidentical donors with PTCy over older MUDs with conventional prophylaxis in patients with MDS or AML. Further studies on the importance of donor age in haploidentical and MUD HCT with PTCy prophylaxis are warranted.

Post-Transplantation Cyclophosphamide-Based Haploidentical versus Matched Unrelated Donor Peripheral Blood Hematopoietic Stem Cell Transplantation Using Myeloablative Targeted Busulfan-Based Conditioning for Pediatric Acute Leukemia

The use of haploidentical related donors (HRDs) is a common alternative donor strategy used when matched sibling or unrelated donors are not available for hematopoietic stem cell transplantation (HSCT). However, there have been no studies comparing HRD HSCT with post-transplantation cyclophosphamide (PTCy) and matched unrelated donor (MUD) HSCT with antithymocyte globulin using similar busulfan-based myeloablative conditioning regimens in pediatric acute leukemia. Here we compared the outcomes in children and adolescents with high-risk acute leukemia who underwent HRD HSCT with PTCy (n=35) or MUD HSCT (n=45) after targeted busulfan-based myeloablative conditioning using intensive pharmacokinetic monitoring. The median duration of follow-up was 3.7 years in the HRD group and 4.6 years in the MUD group. No engraftment failure was observed in either group. There were no significant between-group differences in the cumulative incidence of grade II-IV acute graft-versus-host disease (GVHD) (34.3% versus 48.9%; P=.142), grade III-IV acute GVHD (2.9% versus 8.9%; P=.272), moderate to severe chronic GVHD (11.4% versus 18.3%; P=.417), relapse (25.6% versus 28.0%; P=.832), and nonrelapse mortality (0% versus 2.2%; P=.420). The 3-year severe chronic GVHD-free/relapse-free survival (GRFS), leukemia-free survival (LFS), and overall survival (OS) rates in the HRD and MUD groups were 62.9% (95% confidence interval [CI], 45.8% to 80.0%) versus 49.8% (95% CI, 34.9% to 64.7%; P=.318), 74.4% (95% CI, 58.7% to 90.1%) versus 67.5% (95% CI, 53.4% to 81.6%; P=.585), and 88.6% (95% CI, 78.0% to 99.2%) versus 83.7% (95% CI, 72.5% to 94.9%; P=.968), respectively. In a subgroup analysis of patients with acute lymphoblastic leukemia (HRD, n=17; MUD, n=26), the 3-year GRFS, LFS, and OS rates in the HRD and MUD groups were 49.4% (95% CI, 24.3% to 74.5%) versus 39.5% (95% CI, 19.7% to 59.3%; P=.601), 61.8% (95% CI, 37.5% to 86.1%) versus 63.6% (95% CI, 44.4% to 82.8%; P=.872), and 82.4% (95% CI, 64.4%, 100%) versus 84.2% (95% CI, 70.1% to 98.3%; P=.445), respectively. In patients with acute myelogenous leukemia (AML) (HRD, n=16; MUD, n=16), the 3-year GRFS, LFS, and OS rates in the HRD and MUD groups were 80.8% (95% CI, 61.2% to 100%) versus 61.9% (95% CI, 37.8% to 86.0%; P=.326), 87.1% (95% CI, 70.2% to 100%) versus 73.9% (95% CI, 51.8% to 96.0%; P=.478), and 93.8% (95% CI, 81.8% to 100%) versus 85.6% (95% CI, 67.0% to 100%; P=.628), respectively. Although the difference was not statistically significant and the number of patients was small, the promising outcomes of HRD HSCT in AML patients were encouraging. Our results demonstrate that HRD HSCT with PTCy using a targeted busulfan-based myeloablative conditioning regimen has outcomes similar to those of MUD HSCT with antithymocyte globulin. HRD HSCT with PTCy could be a feasible option for pediatric high-risk acute leukemia patients who lack an HLA-matched related or unrelated donor.

Posttransplant Cyclophosphamide-Based Haploidentical Vs Matched Unrelated Donor Peripheral Blood Hematopoietic Stem Cell Transplantation Using Myeloablative Targeted Busulfan-Based Conditioning for Pediatric Acute Leukemia

Haploidentical related donor (HRD) is a common alternative donor strategy used when matched sibling or unrelated donors are not available for hematopoietic stem cell transplantation (HSCT). Post-transplant cyclophosphamide-based graft-versus-host disease prophylaxis is an attractive option when performing a HRD HSCT because of its promising outcomes and easy application. However, there have been no studies comparing HRD HSCT with PTCy and MUD HSCT with antithymocyte globulin, using similar busulfan-based myeloablative conditioning regimen in pediatric acute leukemia. Herein, we compared the outcomes in children and adolescents with acute leukemia after HRD HSCT with PTCy (n=35) and matched unrelated donor (MUD) HSCT (n=45) after targeted busulfan-based myeloablative conditioning using intensive pharmacokinetic monitoring. The median follow-up times of the HRD and MUD groups were 3.7 and 4.6 years. No engraftment failure was observed. The cumulative incidence of GVHD grades II-IV (34.3% versus 48.9%, p=0.142), grades III-IV (2.9% vs. 8.9%, p=0.272), extensive chronic GVHD (11.4% vs. 18.3%, p=0.417), relapse (25.6% vs. 28.0%, p=0.832), and non-relapse mortality (0% vs. 2.2%, p=0.420) were not significantly different. The 3-year severe chronic GVHD-free/relapse-free, leukemia-free and overall survival rates in the HRD and MUD groups were 62.9±8.7% versus 49.8±7.6% (p=0.318), 74.4±8.0% versus 67.5±7.2% (p=0.585), and 88.6±5.4% versus 83.7±5.7% (p=0.968), respectively. In subgroup analyses of patients with acute lymphoblastic leukemia and acute myeloid leukemia, there were no significant differences in outcomes between the groups. Our results demonstrated that HRD HSCT with PTCy using a targeted busulfan-based myeloablative conditioning shows outcomes similar to those of MUD HSCT. HRD HSCT with PTCy could be considered for pediatric acute leukemia patients who lack an HLA-matched donor. DisclosuresKang: Cartexell: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis Korea: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen Korea: Membership on an entity's Board of Directors or advisory committees, Research Funding.

High-Dose Cyclophosphamide and Tacrolimus as Graft-versus-Host Disease Prophylaxis for Matched and Mismatched Unrelated Donor Transplantation

The optimal prophylaxis regimen for graft-versus-host disease (GVHD) in the setting of single-locus mismatched unrelated donor (MMUD) allogeneic hematopoietic stem cell transplantation (alloHSCT) is unclear. The use of high-dose post-transplant cyclophosphamide (PTCy) after haploidentical transplantation is effective at overcoming the negative impact of HLA disparity on survival. Limited information is available regarding the efficacy of this strategy in alloHSCT from MMUDs. Most of the published studies have used the triple immunosuppressant model of haploidentical transplant combining PTCy with calcineurin inhibitors and mycophenolate mofetil or methotrexate. In our study, we propose the use of a simpler GVHD prophylaxis protocol comprising PTCy in combination with tacrolimus for MMUD and matched unrelated donor (MUD) alloHSCT. We performed a retrospective analysis of 109 consecutive recipients of alloHSCT from unrelated donors (MMUD, n=55; MUD, n=54) in a single center. Graft source was primarily peripheral blood (98%). No differences were observed between the MMUD and MUD groups with respect to 100-day cumulative incidence of grade II to IV acute GVHD (aGVHD; 31% versus 32%, respectively, P=.9), grade III to IV aGVHD (9% versus 7%, P=.7), and moderate/severe chronic GVHD (cGVHD) at 2 years (18% versus 14%, P=.6). Both groups showed similar cumulative incidence of 1 year nonrelapse mortality (13% versus 9%; P=.5) and 3-year relapse rates (24% versus 25%, P=.7). Progression-free survival and overall survival at 3 years for MMUD and MUD were 56% and 57% (P=.9) and 64% and 65% (P=.6), respectively. The 3-year probability of survival free of moderate/severe cGVHD and relapse was 56% and 55%, respectively. GVHD prophylaxis with PTCy and tacrolimus achieves low rates of severe aGVHD and cGVHD, as well as good survival outcomes, in recipients of both MMUD and MUD peripheral blood alloHSCT. This strategy overcomes the negative impact of single-locus HLA disparity.

Superior Graft-versus-Host Disease-Free Relapse-Free Survival in Matched Unrelated Donor Hematopoietic Stem Cell Transplantation with Anti-Thymocyte Globulin (ATG) Compared to Matched Related Donor without ATG

The use of anti-T cell globulin (ATG) in allogeneic stem cell transplantation with matched unrelated donors (MUDs) is considered standard of care in many transplant centers, as these patients are at higher risk of developing acute and chronic graft-versus-host disease (GVHD). Several publications have reported reduced incidence of chronic GVHD compared to matched related donors (MRDs). This may support the idea of introducing ATG in prospective clinical trials, also in MRDs, in an effort to reduce the long-term complications with moderate and severe GVHD. We retrospectively analyzed 169 patients, in whom ATG was given to patients who underwent transplantation with MUDs (n=124) and not MRDs (n=45). The incidence acute GVHD II to IV and III to IV was significantly lower in the MUD group compared to the MRD group (28.2% versus 51.3% and 8.1% versus 24.7%). Extensive chronic GVHD incidence was 5% versus 40%. Our results further support the rationale for examining the efficacy of ATG in MRDs in prospective randomized trials.

Impact of Donor Search Strategy for Allogeneic Hematopoietic Stem Cell Transplantation from Haploidentical or Matched Unrelated Donor for Patients Older Than 55 Years with Hematological Malignancies: Randomized Prospective Phase III Study

Impact of Donor Search Strategy for Allogeneic Hematopoietic Stem Cell Transplantation from Haploidentical or Matched Unrelated Donor for Patients Older Than 55 Years with Hematological Malignancies: Randomized Prospective Phase III Study

Matched Family versus Alternative Donor Hematopoietic Stem Cell Transplantation for Patients with Thalassemia Major: Experience from a Tertiary Referral Center in South India.

Hematopoietic stem cell transplantation (HSCT) is the only curative option available for patients with thalassemia major in India with increasing access to alternate donor transplantation for patients with no matched family donor. We aimed to analyze the impact of family and alternate donor HSCT on morbidity and mortality post-HSCT. We conducted a retrospective study in the department between July 2007 and December 2018 where all children who underwent HSCT for thalassemia major were included. A total of 264 children were included with a median age of 6 years (male/female, 1.4:1). The graft source was matched related donor (MRD) (76%; parent 15%, sibling 85%) and matched unrelated donor (MUD) (22%). All children received a myeloablative conditioning regimen with treosulfan/thiotepa/fludarabine in 93% and busulfan/cyclophosphamide in 7%. The source of stem cells was peripheral blood in 61%, bone marrow in 38%, and umbilical cord blood in 3%. The incidence of bacteremia was 14% versus 25% in MRD versus MUD groups. There was a higher incidence of posterior reversible encephalopathy syndrome (PRES) in the MUD group (10% versus 3%). Engraftment occurred in 97% with a higher trend toward mixed chimerism in the MRD group (12% versus 2%). When indicated, whole-blood donor lymphocyte infusion was used to ensure complete chimerism in children in the MRD group. A statistically significant difference was found in the incidence of graft versus host disease (GVHD), both acute and chronic between the MUD versus MRD groups, 60% versus 20% and 41% versus 17%, respectively (P=.001). Similarly, immune cytopenia and cytomegalovirus reactivation were also significantly higher in the MUD group, 27% versus 1.4% and 25% versus 2%, respectively (P=.001). Thalassemia-free survival in our cohort was 96%, 94%, and 84% with a median follow-up of 65 months in the matched sibling donor, matched family donor, and MUD groups, respectively. Overall survival of 95% and 90% with a median follow-up of 65 months was noted in those who underwent transplantation less than and greater than 7 years of age, respectively. MUD transplantation for patients with thalassemia major involves specific challenges such as PRES and unusual manifestations of GVHD such as immune cytopenia. Early interventions to optimize supportive care and measures to reduce GVHD are required to ensure survival rates of over 90%.

Mismatched related vs matched unrelated donors in TCRαβ/CD19-depleted HSCT for primary immunodeficiencies

AbstractTCRαβ+/CD19+ graft depletion effectively prevents graft-versus-host disease (GVHD). In the current study, we compared the outcomes of hematopoietic stem cell transplantation (HSCT) with TCRαβ+/CD19+ depletion from matched unrelated donors (MUDs) and mismatched related donors (MMRDs) in patients with primary immunodeficiency (PID). A total of 98 pediatric patients with various PIDs underwent HSCT with TCRαβ+/CD19+ graft depletion from MUDs (n = 75) and MMRDs (n = 23). All patients received a fludarabine-/treosulfan-based conditioning regimen, with 73 also receiving a second alkylating agent. For GVHD prophylaxis, all but 2 received serotherapy (antithymocyte globulin) before HSCT and a short course of posttransplant immunosuppression. Neutrophil and platelet engraftment in both the MUD and MMRD groups occurred on days 14 and 13, respectively. The incidence of secondary graft failure was 0.16 and 0.17 (P = .85), respectively. The cumulative incidence of acute GVHD grade 2 to 4 was 0.17 in the MUD group and 0.22 in the MMRD group (P = .7). The incidence of cytomegalovirus (CMV) viremia was 0.5 in the MUD group and 0.6 in the MMRD group (P = .35). The frequency of CMV disease was high (17%), and the most common manifestation was retinitis. The kinetics of immune recovery was similar in both groups. The overall survival was 0.86 in the MUD group and 0.87 in the MMRD group (P = .95). In our experience, there was no difference in the outcomes of HSCT performed from MUD and MMRD. Hence, given the immediate availability of donors, in the absence of HLA-identical siblings, HSCT with TCRαβ+/CD19+ graft depletion from MMRDs can be considered as the first choice in patients with PID.

Comparison of Outcomes between HSCT Donor Sources for Pediatric Patients with Hematologic Malignancies

Background: Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative therapy for pediatric patients with hematologic malignancies. Historically, matched sibling donors (MSD) have been the preferred donor source given ease of availability and lower rates of graft-versus-host-disease (GVHD). However, only 30% of patients have a MSD and relapse rates are high after MSD HSCT, raising the question of best donor choice. As conditioning regimens evolve, GVHD management improves and supportive care advances, it is important to evaluate the role of donor source on short and long-term clinical outcomes to inform donor selection. We performed a single-center retrospective analysis comparing post-HSCT outcomes in a cohort of pediatric patients undergoing MSD, matched unrelated donor (MUD), and umbilical cord blood (CB) transplants from 2006 to 2018. Methods: A retrospective analysis was performed on an IRB-approved protocol through Fred Hutchinson Cancer Research Center. 232 patients were included who received MSD (n=56), MUD (n=89) or CB (n=87) transplants. Of note, 24 CB patients received expanded CB cells in addition to unmanipulated unit(s). GVHD prophylaxis in all patients consisted of a calcineurin inhibitor and MMF or methotrexate. The vast majority received a high-intensity conditioning regimen (86%, 96%, and 82% respectively for MSD, MUD and CB). Overall survival (OS) and disease-free survival (DFS) were evaluated using the Kaplan-Meier method. Probabilities of non-relapse mortality (NRM), relapse, and acute GVHD were evaluated using cumulative incidence (CI) estimates with appropriate competing risks. The Cox regression model was used for adjusted analysis for age, year of transplant, sex, CMV status, MRD status, disease risk, and conditioning regimen. Results: Patient/treatment/donor demographics are shown in Table 1. Median follow-up was 2.6, 3.7 and 3.1 years for MSD, MUD and CB respectively. Patient diagnosis, disease risk, gender, age, and CMV serology were balanced between groups. CI of engraftment was similar as well, with only one graft failure in the MUD group (Fig 1). Median time to platelet recovery was significantly faster in MUD and MSD groups as compared to the CB group (p&lt;0.0001; p&lt;0.0001). There was no difference in unadjusted 5 year OS (Fig 2) and NRM (Fig 3) between groups. Five-year DFS was significantly higher in CB v. MSD (71% v. 54%, p=0.03) but not between CB v. MUD (71% v. 61%, p=0.18) or between MSD and MUD (p=0.38) (Fig 4). The CI of relapse at 5 years was 20% for CB patients, significantly lower than that of MSD recipients (49%, p=0.003) and not different from MUD (32%, p=0.11) (Fig 5). After adjusted analysis, the risk of DFS failures was higher among recipients of MSD than CB [HR: 1.88 (CI 95%: 1.01-3.47), p=0.04]. When CB versus MUD groups were compared, there was a trend of higher risk of DFS failures in the MUD group [HR: 1.28 (CI 95%: 0.96-1.66), p=0.09]. No difference was observed in risk of DFS failures between MSD versus MUD groups [HR:0.77 (CI 95%: 0.44-1.4), p=0.43]. Incidence of grade II-IV acute GVHD was 90% (95%CI: 82-95%), 75% (95%CI: 61-84%) and 88% (95%CI: 80-94%), for CB, MSD and MUD, respectively (p=0.25). Incidence of grade III-IV acute GVHD was 33% (95%CI: 23-43%) for CB, 9% (95%CI: 3-18%) for MSD, and 11% (95%CI: 5-18%) for MUD. Incidence of grade III-IV was significantly higher for the CB group compared to the other groups (p=0.001); however, nearly 60% of CB recipients with grade III-IV acute GVHD were diagnosed before engraftment had occurred and in retrospect met criteria for pre-engraftment syndrome. Among surviving patients, 23 CB recipients developed chronic GVHD (26% - 15 mild, 4 moderate, 4 severe) as compared to 14 MSD patients (25% - 13 mild, 1 moderate) and 40 MUD patients (45% - 27 mild, 11 moderate, 2 severe). Conclusions: Our data demonstrate no difference in unadjusted OS between MSD, MUD and CB recipients. Importantly, despite this equivalence, 5-year DFS was significantly better in the CB v. MSD group, reflecting the lower relapse rate observed in CB patients and seen previously by us and others. CB continues to be viewed as an "alternative" donor for HSCT due to the low stem cell dose in a CB graft resulting in delayed neutrophil recovery, primary graft failure and increased NRM. However, this was not observed herein, supporting the use of CB for pediatric HSCT perhaps especially in patients at high risk of post-transplant relapse. Disclosures Milano: ExCellThera: Research Funding; Amgen: Research Funding. Delaney:Nohla Therapeutics: Employment, Equity Ownership; Biolife Solutions: Membership on an entity's Board of Directors or advisory committees. Bleakley:HighPass Biotherapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents &amp; Royalties, Research Funding.

Results of a Multicentre, Randomized, Controlled Open-Label Study on the Use of Anti-T-Lymphocyte Globulin (ATLG) and Rituximab for Immunomodulation of Graft-Versus-Host Disease (GvHD) and Graft Failure (GF) in Patients with Non-Malignant Disorders

BACKGROUND: Allogeneic hematopoietic stem-cell transplantation (allo-HSCT) is increasingly used to treat a wide range of non-malignant disorders. However, the optimal strategy to be employed for GvHD prevention remains a matter of debate. In particular, the use of ATLG for the prevention of immune-mediated complications in patients transplanted from a matched-related donor (MRD) is still controversial. In the matched unrelated donor (MUD) setting, there is retrospective evidence that Rituximab used as prophylaxis of EBV viremia may protect from acute GvHD (aGvHD) development, but the clinical benefit of pre-transplant Rituximab has never been assessed in prospective randomized studies. METHODS: We conducted a multicentre, randomized, open-label, trial (NCT01810926) in 5 Italian centres enrolling patients with non-malignant haematological and inherited metabolic disorders transplanted from either a MRD or a MUD, selected using high-resolution typing for HLA-class I/II loci and stringent criteria of HLA-compatibility (&gt;9/10). All patients received the same myeloablative regimen consisting of Treosulfan, Thiotepa and Fludarabine. Enrolled patients were randomized (1:1) to receive either standard or intensified GvHD prophylaxis. Cyclosporine-A plus short-term methotrexate was the standard GvHD prophylaxis in MRD HSCT recipients. In the experimental arm, patients were additionally given ATLG (Grafalon®, Neovii, 5 mg/kg/day on day -4,-3, and -2). In patients transplanted from a MUD, standard GvHD prophylaxis consisted of Cyclosporine-A plus short-term methotrexate and ATLG (10 mg/kg on day -4,-3 and-2). In the experimental arm, patients were additionally given Rituximab 200 mg/sq on day -1 (Mabthera®, Roche). In MRD group randomization was stratified by disease (hemoglobinopathies vs. other conditions) and in the MUD group by center. For patients given MRD HSCT, the primary end-point was the probability of survival (SUR) free from: a) primary and secondary GF, b) grade II-IV aGvHD, c) chronic GvHD (cGvHD), d) death, whichever occurred first. For patients transplanted from a MUD, the primary end-point was the SUR probability free from: a) grade II-IV aGvHD, b) EBV viremia (&gt;1,000 copies of viral DNA/ml whole blood), whichever occurred first. Secondary endpoint was overall SUR (OS). Statistical analyses were conducted according to intention-to-treat. FINDINGS: Between August 2011 and February 2018, 126 patients were enrolled. Patient and disease characteristics by randomized treatment are shown in Table 1. Median age at HSCT was 6.1 years in the MRD group (range 0.8-38) and 4.9 years in the MUD group (range 0.9-20.7). Median follow-up was 3.6 years. Among the 51 MRD-HSCT recipients, 25 were randomly assigned to the ATLG group and 26 to the NO-ATLG group. No death and no cases of grade II-IV aGvHD were observed in either of the two randomization arms. Two GF occurred in each of the two arms, while 1 and 2 cases of cGvHD occurred in the ATLG and NO-ATLG groups, respectively. Consequently, no statistically significant difference in the probability of SUR without events was observed (p=0.75) and the 3-years estimates (±SE) were 86.9%±7.1% vs. 83.8%±7.5%, respectively. In the MUD setting, 38 patients were allocated in the Rituximab group and 37 in the NO-Rituximab group. Although no statistically significant difference in OS (p=0.21) was observed between the two arms (3-years estimates: 94.1%±4.1% for Rituximab, 85.7%±5.9% for No-Rituximab), patients receiving Rituximab had a better probability of SUR without events (73.0%±7.3% vs 26.5%±7.3%, respectively; p=0.0002), entirely due to a lower incidence of EBV viremia. One case of fatal post-transplant lymphoproliferative disorder was observed in the No-Rituximab arm. Eight patients developed grade II-IV aGvHD in each of the two arms. No patient has persistent dependence on ivIG replacement therapy. CONCLUSIONS Our data indicate that, in patients with non-malignant disorders given a MRD HSCT, the addition of ATLG does not confer any advantage in the prevention of both acute and chronic GvHD, as well as of GF. In MUD-HSCT recipients, the administration of a fixed dose of pre-transplant Rituximab as part of the conditioning regimen does not affect the risk of aGvHD and transplant-related mortality, while it significantly reduces the incidence of episodes of EBV-viremia, without impairing B-cell recovery. Disclosures Algeri: Bluebird bio: Consultancy, Honoraria; Miltenyi: Honoraria; Atara Biotherapeutics: Consultancy, Honoraria. Merli:Novartis: Honoraria; Sobi: Consultancy; Amgen: Honoraria; Bellicum: Consultancy. Locatelli:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; bluebird bio: Consultancy; Miltenyi: Honoraria; Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Fludarabine Melphalan Versus Fludarabine Treosulfan As Reduced Intensity Conditioning Regimens in Allogeneic Hematopoietic Stem Cell Transplant - a Retrospective Analysis

Introduction Allogeneic hematopoietic stem cell transplantation (AHSCT) has evolved as a curative therapy for various hematological malignancies. Regimen-related toxicity and transplant-related mortality (TRM) preclude the use of myeloablative conditioning (MAC) regimens in older and unfit patients. Reduced intensity conditioning (RIC) regimens have enabled AHSCT in such patients. There is a recent rise in use of RIC regimens even in younger patients in view of decreased toxicity and equal efficacy as reported in some studies. Fludarabine + Melphalan (FM) and Fludarabine + Treosulfan (FT) are 2 such regimens. There are no prospective randomised comparisons between these regimens. We retrospectively analysed these 2 regimens for toxicities and outcomes. Methods This is a retrospective single centre analysis of all consecutive patients with haematological cancers who received either FM or FT from April 2008 to December 2018. The entire cohort was divided into two groups - Matched Sibling Donor (MSD)/Matched Unrelated Donor (MUD) and Haploidentical (Haplo) transplants for analysis. We compared patient characteristics, toxicities and outcomes in both the groups based on conditioning regimen. The FT regimen consisted of fludarabine (30 mg/m2 on days − 6 to − 2) combined with treosulfan (12-14 gm/m2 on days − 6 to − 4) with or without 2 Gy TBI on day-1. The FM regimen consisted of fludarabine (30 mg/m2 on days − 7 to − 3) combined with melphalan (140 mg/m2 on day -1).Prophylaxis for GVHD consisted of calcineurin inhibitor (CNI) plus methotrexate (MTX)or mycophenolate mofetil (MMF) in MSD/MUD. Rabbit ATG (2.5-5 mg/kg) was used for MUD. Haplo transplant patients received post-transplant cyclophosphamide with CNI and MMF. Comorbidities were scored according to the HCT-CI. Disease Risk Index(DRI) and EBMT score were recorded for all patients. Neutrophil (NE) and platelet engraftment (PE) were defined as per standard criteria. Early toxicity after AHCT was graded according to CTCAE version 4. Total parenteral nutrition (TPN) was used in patients as per the physician's discretion. Acute GVHD and chronic GVHD were recorded according to standard criteria. All patients underwent chimerism studies at day 15, 30 and then monthly for 1 year. Mixed chimerism was defined as &gt; 5% to &lt; 95% donor chimerism. The toxicities in various arms were compared by Chi-square test or Fisher exact test, while OS was calculated by Kaplan Meier method and the survival probabilities were compared using log-rank test. Competing risk analysis was used to calculate cumulative incidence of relapse and TRM. Results The study included 138 patients, 98 males and 40 females. The diagnoses were AML- 53, ALL- 30, MDS/MPN- 49 and lymphoma -6. Patient characteristics are outlined in Table 1. MSD/MUD transplants were 105 (FM- 94; FT-11); 33 were Haplo (FM-17; FT-16) transplants. PBSC was the stem cell graft in 136 (99%) patients. In both MSD/MUD and Haplo groups, there were no significant differences in median age, gender, pre transplant CMV status, HCT-CI and EBMT score between the two conditioning regimens. In MSD/MUD group, significantly more patients had high/very high DRI in FT arm (45% vs 17%; P=0.056) Comparison of engraftment and toxicity variables of both FM and FT arms are outlined in Table 2. In MSD/MUD group, 44 (47%) patients in FM arm had grade 3/4 oral mucositis compared to 1 (9%) in FT arm (P=0.02). Corresponding numbers were 7 (41%) and 1 (6%) in Haplo group (P=0.039). Grade 3/4 diarrhoea was higher in the FM vs FT arm of Haplo group (41% vs 6%; P=0.039) but not in the MSD/MUD cohort. More patients received TPN in the FM arms of both MSD/MUD and Haplo groups (Table 2). Incidence of grade III-IV acute GVHD was higher in FT vs FM in MSD/MUD group (27% vs 17%; P=0.04). The median follow up of entire cohort was 4.8 years. The OS (figure 1) at 5 years was 62% in FM arm of MSD/MUD group vs 53% in FT arm (P=NS). Similarly OS (figure 2) at 5 years was 41% and 28 %( P=NS) in FM and FT arms respectively of Haplo group. The cumulative incidence of TRM and relapse at 2 years were not different in FM and FT arms of both MSD/MUD and Haplo groups (Table 2). Conclusion Grade 3 and 4 oral mucositis and diarrhoea were significantly less with FT than FM in both MSD/MUD and Haplo groups. FT provided comparable outcomes to FM in the MSD / MUD group in spite of having higher proportions of patients with high / very high DRI. Prospective randomised studies are required to compare various RIC regimens. Disclosures No relevant conflicts of interest to declare.

Post-Transplant Cyclophosphamide (PT-Cy) Based Haploidentical Cell Transplantation (Haplo) Versus Rabbit Anti-Thymocyte Globulin (r-ATG) Based HLA Matched Unrelated Donor (MUD) Transplantation in Patients (pts) with Relapsed/Refractory Lymphoma

Background PT-Cy has emerged as an effective strategy for graft-versus-host disease (GVHD) prophylaxis in Haplo. The reported risk of GVHD with non-PT-Cy in pts receiving MUDs varies between centers. In this report, we compared the engraftment rates, survival, risk of GVHD and comorbidities between PT-Cy Haplo and r-ATG-based MUDs approach in pts with relapse/refractory lymphoma receiving an allogeneic transplantation. Method We retrospectively evaluated 160 adult pts with lymphoma who received Haplo (n=35) or r-ATG-MUDs (n=125) at our center between 2012 and 2018. Pts received GVHD prophylaxis of r-ATG (2-4 mg/kg total on days -3 to -1), tacrolimus and methotrexate if MUD, and tacrolimus and mycophenolate mofetil in addition to PT-Cy (50 mg/kg on days+3, +4) if Haplo. Tacrolimus taper was initiated at 6 months after transplantation in pts with no active GVHD. The study was IRB-approved. Results Haplo pts were more likely to be younger (median age 47 vs 55 yrs; P=0.032), have a lower HCT-Comorbidity Index (median 2 vs 3; P=0.048), and to include more diffuse large b-cell lymphoma (31% vs 22%, and Hodgkins disease (29% vs 16%) (P=0.015). Significant differences were also observed in the conditioning intensity and cell source of transplants between the 2 groups. The majority of Haplo pts (80%) received a reduced intensity-conditioning (RIC) of melphalan/fludarabine +/- 2Gy TBI; the remaining received a myeloablative (MA) busulfan-based regimen (9%) or nonmyeloablative (NMA) (11%) conditioning. In comparison, the percentage of MUDs pts receiving RIC, MA and NMA [bendamustine, fludarabine, rituximab or fludarabine, cyclophophamide, rituximab were 31%, 22% and 46%, respectively (P&lt;0.001). The percentage of pts receiving bone marrow as a source of cells in the Haplo and MUDs groups were 74% vs 14%, respectively (P&lt;0.001). There was no difference in the # of prior therapies received (median = 3, in both), the # of pts who failed a prior autologous (37% vs 26%; P=0.21), disease status (CR vs PR vs refractory; P=0.3), IPI &gt;2 (25% vs 19%, P=0.73) or PET-positive status (55% vs 44%, P=0.33) at study entry between the 2 groups. PT-Cy Halplo group had a significantly higher incidence of symptomatic BK- induced hemorrhagic cystitis compared to r-ATG MUD group (49% vs 10%, P&lt; 0.001). Delayed engraftment was noted in PT-Cy Haplo group compared to r-ATG MUD group with median time to achieve ANC &gt; 500 (18 days vs 10 days; P&lt;0.001), and platelets &gt; 20k were 25.5 days vs 10 days (P&lt;0.001), respectively. The median follow-up time for pts treated with PT-Cy Haplo and r-ATG MUD pts was 12.1 and 20.8 months, respectively. Similar survival and non-relapse mortality (NRM) rates were observed between the 2 groups. The 1-year OS rates were 64% vs 67% (P=0.76) and the 1-year PFS rates were 52% vs 58% (P=0.67). The cumulative incidence (CI) of 1-year NRM was 30% vs 26%, respectively (P=0.66). Chemo-sensitivity (Figure 1), NMA conditioning (Figure 2), and HCT-Comorbidity Index of &lt; 4 were associated with a better OS and PFS in univariate and multivariable analyses. Among histologies, pts with follicular lymphomas had the best OS and PFS. T-cell lymphoma had the worse outcomes. In addition, cystitis was associated with a lower survival rate by univariate analysis (P=0.036). The CI of acute 2-4 GVHD (26% vs 33%, P=0.43), acute 3-4 GVHD (14% vs 12%, P=0.66), and 1-year CI of chronic GVHD (6% vs 15%, P=0.19) were not statistically different between PT-Cy Haplo and r-ATG MUD. By univariate analysis, bone marrow source of graft was the only factor that was found to be significantly associated with a lower risk of chronic GVHD (HR 0.34; P=0.041) (Figure 3). Conclusion Our data show similar survival rates and risk of acute and chronic GVHD in pts with lymphoma who received PT-Cy Haplo and r-ATG MUD. The use of bone marrow graft was the only predictor of a lower incidence of chronic GVHD. Considering the statistically significant delayed time to engraftment and the higher risk of hemorrhagic cystitis, a MUD remains the donor of choice in lymphoma pts who have this option. Disclosures Jabbour: Takeda: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Cyclacel LTD: Research Funding; AbbVie: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; BMS: Consultancy, Research Funding. Bashir:Imbrium: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; StemLine: Research Funding; Acrotech: Research Funding; Celgene: Research Funding. Oran:Astex pharmaceuticals: Research Funding; AROG pharmaceuticals: Research Funding. Kebriaei:Kite: Honoraria; Amgen: Research Funding; Jazz: Consultancy; Pfizer: Honoraria. Popat:Bayer: Research Funding; Incyte: Research Funding; Jazz: Consultancy. Champlin:Johnson and Johnson: Consultancy; Sanofi-Genzyme: Research Funding; Actinium: Consultancy.