Incidence Of Grade II-IV aGVHD Research Articles

Outcomes of Human Leukocyte Antigen-Matched Related Donor and Haploidentical Allogeneic Hematopoietic Cell Transplantation Recipients by Immune Profiles of Recipients and Donors

Haploidentical (Haplo) allogeneic HCTs (alloHCT) have been used more frequently over the last decade as survival is similar to HLA-matched related donor (MRD) alloHCTs. We aimed to identify donor and recipient immune signatures before alloHCT that are associated with clinically meaningful outcomes in MRD vs Haplo alloHCT recipients. This retrospective cohort study of 165 MRD (n = 132) and Haplo (n = 33) alloHCT recipients and their related donors between 2007-2019 with paired peripheral blood samples immunophenotyped for T-cell, B-cell, NK cell and dendritic cell (DC) subsets. Immune cells were quantified before alloHCT in donors and recipients; calculations of immune cell ratios were classified as high, intermediate, and low and analyzed with alloHCT outcomes. Haplo donors were younger than MRD donors (median: 35 vs 51 years), whereas Haplo recipients were older than MRD recipients (median: 68 vs 54 years), were more likely to have a Karnofsky Performance Score ≤ 70 (76% vs 57%), 3+ comorbidities (54% vs 47%), and were in complete remission prior to alloHCT (58% vs 42%). In MRD alloHCT, a lower ratio of CD4+ to CD8+ effector memory cells in the donor was associated with lower 4-yr overall survival (OS; 25% vs 61%; P = .009), lower 4-yr progression free survival (PFS; 25% vs 58%; P = .014) and higher incidence of 1-yr transplant-related mortality (TRM; 39% vs 7%; P = .009) in recipients. A higher ratio of CD8+ effector memory to total NK cells measured in MRD recipients was associated with a higher incidence of grade II-IV aGvHD (63% vs 37%; P = .004) but was not statistically significant for III-IV aGvHD (23% vs 12%). In Haplo alloHCT, a lower ratio of total T-regulatory to CD4+ central memory cells in the donor was associated with lower 4-yr PFS (22% vs 60%; P = .0091). A higher ratio of CD4+ effector memory to CD8+ effector memory cells measured in Haplo recipients pre-alloHCT was associated with lower 4-yr OS (25% vs 88%; P = .0039). In both MRD and Haplo recipients, a higher ratio of CD4+ naïve to CD4+ central memory cells was associated with a higher incidence of grade II-IV aGvHD (64% vs 38%; P = .04). Evaluation of pre-alloHCT immune signatures of the donor and recipient may influence clinically meaningful patient outcomes in both MRD and Haplo transplants.

Reduced human leukocyte antigen mismatching is associated with more favourable outcomes after unrelated donor haematopoietic stem cell transplantation.

The patient-donor human leukocyte antigen (HLA) match remains the most important prognostic factor for successful unrelated donor haematopoietic stem cell transplantation (UD-HSCT). This single-centre study comprised 125 adult patients with malignant haematological diseases undergoing their first UD-HSCT. The primary goal of this study was to validate the impact of HLA matching on HSCT outcomes, specifically at the HLA-DPB1 and HLA-DRB3/4/5 loci. A multivariable Cox regression analysis with a backward selection algorithm was employed to assess the associations of selected prognostic factors with outcomes after UD-HSCT. Any HLA locus mismatch was found to be associated with an increased incidence of grade II-IV acute graft versus host disease (aGvHD) at 100 days (p=.031; hazard ratio [HR] 1.935) and 6 months (p=.004; HR 2.284) after HSCT. The results of the following analyses also confirmed the strong impact of HLA-DPB1-only mismatch on the incidence of grade II-IV aGvHD at 100-day (p=.006; HR 2.642) as well as at 6-month (p=.007; HR 2.401) time periods. The HLA-DPB1-only mismatch was also shown to be statistically significantly associated with lower relapse incidence (p=.034; HR 0.333). The impact of the HLA-DRB3/4/5 mismatch on outcomes was inconclusive, though the two and more HLA-DPB1+DRB3/4/5-only mismatches showed a trend towards worse outcomes than a single mismatch. Based on our findings and those of more comprehensive studies, the extended HLA loci typing of patients and donors is suggested to avoid unexpected HLA mismatches during the UD selection.

A dynamic time-to-event model for prediction of acute graft-versus-host disease in patients after allogeneic hematopoietic stem cell transplantation.

Acute graft-versus-host disease (aGvHD) is a major cause of death for patients following allogeneic hematopoietic stem cell transplantation (HSCT). Effective management of moderate to severe aGvHD remains challenging despite recent advances in HSCT, emphasizing the importance of prophylaxis and risk factor identification. In this study, we analyzed data from 1479 adults who underwent HSCT between 2005 and 2017 to investigate the effects of aGvHD prophylaxis and time-dependent risk factors on the development of grades II-IV aGvHD within 100 days post-HSCT. Using a dynamic longitudinal time-to-event model, we observed a non-monotonic baseline hazard overtime with a low hazard during the first few days and a maximum hazard at day 17, described by Bateman function with a mean transit time of approximately 11 days. Multivariable analysis revealed significant time-dependent effects of white blood cell counts and cyclosporine A exposure as well as static effects of female donors for male recipients, patients with matched related donors, conditioning regimen consisting of fludarabine plus total body irradiation, and patient age in recipients of grafts from related donors on the risk to develop grades II-IV aGvHD. Additionally, we found that higher cumulative hazard on day 7 after allo-HSCT are associated with an increased incidence of grades II-IV aGvHD within 100 days indicating that an individual assessment of the cumulative hazard on day 7 could potentially serve as valuable predictor for later grades II-IV aGvHD development. Using the final model, stochastic simulations were performed to explore covariate effects on the cumulative incidence over time and to estimate risk ratios. Overall, the presented model showed good descriptive and predictive performance and provides valuable insights into the interplay of multiple static and time-dependent risk factors for the prediction of aGvHD.

Alemtuzumab, Dual Graft-versus-Host Disease Prophylaxis, and Lower CD3+ T Cell Doses Equalize Rates of Acute and Chronic Graft-versus-Host Disease in Pediatric Patients Receiving Allogeneic Hematopoietic Stem Cell Transplantation with Matched Unrelated Donor Peripheral Blood Stem Cells or Bone Marrow Grafts

Data comparing hematopoietic stem cell transplantation (HSCT) using bone marrow (BM) or peripheral blood stem cell (PBSC) grafts in children after alemtuzumab-based conditioning are lacking. We investigated whether in vivo T cell depletion using alemtuzumab could reduce the risk of severe acute graft-versus-host disease (aGVHD) and chronic GVHD (cGVHD) after HSCT with matched unrelated donor (MUD) BM or PBSCs. This retrospective multicenter study included 397 children (BM group, n = 202; PBSC group, n = 195) who underwent first MUD HSCT at 9 pediatric centers in the United Kingdom between 2015 and 2019. The median age at transplantation was 7.0 years (range, .1 to 19.3 years), and the median duration of follow-up was 3.1 years (range, .3 to 7.5 years). The 3-year overall survival was 81% for the entire cohort (BM group, 80%; PBSC group, 81%). The incidence of grade II-IV aGVHD was significantly higher in the PBSC group (31%) compared to the BM group (31% versus 19%; P = .003), with no difference in the incidence of grade III-IV aGVHD (BM, 7%; PBSC, 12%; P = .17). CD3+ T cell dose >5 × 108/kg and the use of PBSCs were independent predictors of grade II-IV aGVHD. When considering CD3+ T cell dose and GVHD prophylaxis, PBSC transplantation with a calcineurin inhibitor (CNI) and mycophenolate mofetil (MMF) and a CD3+ T cell dose ≤5 × 108/kg had a comparable grade II-IV aGVHD to BM transplantation plus a CNI (20% versus 18%; P = .52). PBSC transplantation was associated with a lower incidence of cGVHD compared to BM transplantation (6% versus 11%; P = .03). Within the limits of this study, we identified a potential strategy to reduce the risk of severe GVHD in pediatric PBSC recipients that includes a combination of in vivo T cell depletion using alemtuzumab and dual GVHD prophylaxis (with a CNI and MMF) and limiting the CD3+ T cell dose to ≤5 × 108/kg.

Thiotepa, Busulfan and Fludarabine Conditioning Regimen in Adult Patients Undergoing Allogeneic Stem Cell Transplantation for Lymphoid Malignancies. a Study on Behalf of Geth-TC

Background: The optimal conditioning regimen in allogeneic hematopoietic stem cell transplant (alloHCT) for lymphoid malignancies remains unclear. Reduced intensity regimens (RIC) allow older and more comorbid patients to receive alloHCT since lower non-relapse mortality (NRM) is observed, but disease control may still be a concern. The use of reduced toxicity conditioning regimens allows better disease control with a cost of higher toxicity. To date, no data are available regarding the use of thiotepa, busulfan and fludarabine (TBF) in adult patients allografted for lymphoma. Our aim is to describe survival outcomes and treatment-related toxicities of patients with lymphoid malignancies conditioned with TBF. Methods: Between December 2011 and July 2022, 116 patients diagnosed with lymphoid malignancies received a first alloHCT conditioned with a TBF-based regimen in 9 Spanish institutions. All consecutive patients were included in the study and data were collected retrospectively. Low-dose TBF was defined as the use of 5 mg/kg of thiotepa (T5) while a high-dose TBF was considered as the administration of 10 mg/Kg of thiotepa (T10). Main outcome variables were overall survival (OS), progression-free survival (PFS), NRM, relapse incidence (RI), cumulative incidence of acute (aGVHD) and chronic GVHD (cGVHD), and hematological recovery. Probabilities of OS and PFS were calculated using the Kaplan-Meier estimator method, and NRM, RI, GVHD and hematological recovery as cumulative incidences. Results: Baseline characteristics are summarized in Table 1. The median age was 52 (range 23-70) years and 62.1% of the patients were males. Aggressive B-cell lymphoma was the most common diagnosis (43.1%). Seventy-seven (66.4%) patients received T10, and 39 (33.6) T5. Median follow-up among survivors was 46.9 (range 16.9-136.5) months. At 3 years, OS, PFS, NRM and RI were 54.7% (95% confidence interval [CI], 45.5-63.9%) ( Figure 1), 44.9% (95% CI, 35.7-54.1%), 34.9% (95% CI, 27.1-44.9%) and 20.2% (95% CI, 14-29.2%), respectively. Of the 53 patients who died during follow up, causes of death were: 12 relapses and 41 transplant toxicities (16=infections, 8=GVHD, 5=endothelial complications, 1=traumatism, 11=missing). Fifty-one percent of toxicity-related deaths were observed during the first 3 months from transplant. All but 2 patients engrafted. The cumulative incidence of neutrophil engraftment at day +30 was 91.4% (95% CI, 86.3-96.8%). The cumulative incidence of grade II-IV aGVHD at day +100 was 25.4% (95% IC, 18.5-34.9%), with 8 patients presenting grade III-IV aGVHD. The 3-years cumulative incidence of all grade cGVHD was 29.8% (95% CI, 22.5-39.6%), with 15 patients presenting with moderate-severe cGVHD. Seventeen patients developed venooclusive disease (14.7%) with a median time from alloHCT infusion of 14 (range 7-93) days. On univariate analysis, no prognostic factors were found in terms of NRM, OS and PFS. However, higher doses of thiotepa were associated to a lower relapse incidence (13.2% vs 35%, p=0.0075) without differences in terms of NRM. The use of myeloablative conditioning (vs RIC) showed a trend towards a lower relapse incidence although it was not statistically significant (9.4% vs 24.5%, p=0.059) with no impact in NRM rates. On multivariate analysis these results could not be confirmed. Conclusions: In our series, TBF conditioning regimen allows efficient disease control at the expense of increased incidence of severe early toxicities. Despite higher NRM, TBF conditioning regimen showed similar OS rated compared to other regimens used for lymphoid malignancies. This regimen could be considered for fit patients with high-risk lymphoid diseases.

A Multi-Center Retrospective Analysis of Outcomes Post Allogeneic Stem Cell Transplantation in AML Patients with TET2 Mutations: A Study on Behalf of the Global Committee and the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation

Background Mutations in TET2 present in about 15% of adult AML are reported in some limited series as an adverse prognostic factor for overall survival. However the impact of allogeneic hematopoietic cell transplantation (allo-HCT) for the treatment of these patients remains unclear. We addressed this issue in a EBMT global multi-center registry-based study. Patients and Methods 644 adult AML patients with TET2 mutations receiving first non ex-vivo depleted allo-HCT from 2013-2022 in 127 centers were analyzed. All patients achieved first complete remission (CR1) before allo-HCT. Results The median age of the 644 AML patients was 59.4 (range, 18.1-86.3) years. 556 patients (86.3%) had de novo, and 88 (13.7%) had secondary AML, respectively. 367 (57.2%) patients were male. The median interval from diagnosis to allo-HCT was 4.9 (IQR, 3.8-6.2) months. Patients were categorized into favorable -(N=23, 3.9%), intermediate-(N=475, 79.8%) and adverse (N=97, 16.3%) risk categories according to cytogenetic characteristics. Conditioning regimen was myeloablative (MAC) in 46.7% of patients. 149 patients (23.1%) received a matched-sibling donor, 176 (27.3%) a haploidentical donor (Haplo), 268 (41.6%) a 10/10 unrelated donor (UD) and 51 (7.9%) a 9/10 UD allo-HCT, respectively. For the entire cohort, with a median follow-up of 1.9 years, the 30-day cumulative incidence of engraftment was 97.6%. The 100-day cumulative incidence of grade II-IV aGVHD was 22.9% and the 2-year cumulative incidence of extensive cGVHD was 13.7%. In addition, the 2-year relapse incidence and NRM were 23.2% and 12.8%, respectively. Finally, the 2-year OS, LFS and GRFS were 69.8%, 63.9% and 49.8%, respectively. In multivariable analyses, a donor type 9/10 UD was associated with a higher RI (HR=2.33, 95% CI 1.21-4.48; p=0.01), a lower LFS (HR=2.20, 95% CI 1.31-3.70; p<0.01) and OS (HR=2.29, 95% CI 1.33-3.96; p<0.01) as compared to MSD as reference. Compared to MSD, 10/10 UD and Haplo had similar outcomes. The adverse-cytogenetic group was associated with higher RI (HR=1.85, 95% CI 1.19-2.86; p<0.01), and higher incidence of grade II-IV acute GVHD (HR=1.74, 95% CI 1.14-2.64; p=0.01) as compared to other groups combined as reference. Compared to de novo AML (reference), secondary AML was associated with lower LFS (HR=1.49, 95% CI 1.03-2.15; p<0.05) and OS (HR=1.68, 95% CI 1.15-2.45; p<0.01). When age increased, patients faced higher RI (HR for 10y increment=1.24, 95% CI 1.01-1.53; p<0.05) and extensive chronic GVHD (HR=1.34, 95% CI 1.02-1.77; p<0.05), which translated into higher NRM (HR=1.66, 95% CI 1.23-2.24; p<0.01), lower LFS (HR=1.36, 95% CI 1.14-1.62; p<0.01) and OS (HR=1.60, 95% CI 1.31-1.96; p<0.01). Later year of transplantation was associated with lower incidence of II-IV acute GVHD (HR for 2y increment=0.76, 95% CI 0.63-0.92; p<0.01), chronic GVHD (HR=0.67, 95% CI 0.54-0.83; p<0.01) and extensive chronic GVHD (HR=0.72, 95% CI 0.52-0.99; p<0.05). Female to male, patient CMV status and interval between diagnosis and HCT did not affect significantly the transplant outcomes in multivariable analysis. Conclusion No significant difference was observed in outcomes of AML patients with TET2 mutations following MSD, HAPLO and 10/10 UD allo-HCTs, while 9/10 UD was associated with higher relapse incidence and lower survival outcomes. Higher patient age, secondary AML and adverse cytogenetics predicted worse transplant outcomes. GVHD prevention improved with time for these patients.

Haploidentical Hematopoietic Stem Cell Transplantation with Post-Transplant Cyclophosphamide in the Chilean National Health System. a Single Center Study

Haploidentical peripheral blood stem cell transplantation with post-transplant cyclophosphamide (Haplo-PTCy) is the most common transplantation modality in low-and-middle-income countries (LMIC). Registry data has shown comparable outcomes when using haploidentical donors versus Matched Unrelated Donors (MUD) in patients with acute leukemias. In the Chilean Public Health System Haplo-PTCy was incorporated in 2016 for adults up to 60 years old. We analyzed all adult patients who received an Haplo-PTCy at Hospital del Salvador, in a prospective registry study between 2016 and 2021. The primary outcome was overall survival (OS). Secondary outcomes were event-free survival (EFS), cumulative incidence of relapse, and incidence of grade II-IV acute graft-versus-host disease (aGVHD) at day +100. Overall survival and EFS were estimated using the Kaplan-Meier method. The cumulative incidence of relapse was calculated using relapse as the primary event and death without relapse as a competing event. Acute GVHD is shown as absolute incidence at day +100. All statistical analyses were performed with R. This study was done in compliance with the Helsinki Declaration and was approved by the Institutional Review Board. Eighty-five Haplo-PTCy were performed in 82 patients (Table 1). Three-second Haplo-PTCy were excluded from this analysis. The median age was 25 years (range, 15-51), and 65% were male. Ninety-four percent of patients had a neoplastic disease (77/82), and the most common diagnosis was acute lymphoblastic leukemia (57%). Forty-seven percent proceeded to transplant in the first complete response. Most of the patients (76%) presented a low hematopoietic cell transplantation (HCT)-specific comorbidity index. Conditioning was mostly myeloablative (96%). The median dose of CD34+ cells infused was 8.1 x 106/kg (range, 2.4-10.0). No patient needed a desensitization regimen. Cytokine release syndrome (CRS) was common (86%) but no grade 3 CRS was observed. Primary graft failure was observed in one patient (1.2%). Poor graft function was observed in 11 patients (13%). Five patients (6.1%) died before engraftment. The incidence of grade II-IV aGVHD at day +100 was 29% (grade IV was not observed). With a median follow-up of 33 months (range 0-84), the estimated 3-year OS and EFS were 68.3% (95% CI 59-79%) and 64.6% (95% CI 55-76%), respectively (Figure 1). In patients with neoplastic disease (n=77), the 3-year cumulative incidence of relapse was 23% (95% CI 15-33%). Haplo-PTCy is feasible in LMIC. This cohort of cases, mostly young patients with neoplastic disease, shows encouraging survival with an acceptable aGVHD and relapse incidence.

Easix Score Correlates With Endothelial Dysfunction Biomarkers and Predicts Risk of Acute Graft-Versus-Host Disease After Allogeneic Transplantation

Plasma biomarkers of endothelial dysfunction have been postulated for the diagnosis and prognosis of acute graft-versus-host disease (aGVHD). However, their use is not validated in clinical practice yet. The endothelial activation and stress index (EASIX), a simple score based on routine laboratory parameters, is considered to be an indirect marker of endothelial damage. High value of EASIX was correlated with worse non-relapse mortality (NRM) and overall survival (OS) and a high risk of sinusoidal obstructive syndrome and transplant-associated thrombotic microangiopathy (TA-TMA). This study investigates the predictive value of plasma biomarkers and the EASIX score for the prediction of aGVHD. We assessed vascular cell adhesion molecule-1 (VCAM-1), tumor necrosis factor receptor 1 (TNFR1), and VWF:Ag plasma levels and the EASIX score before allogeneic hematopoietic stem cell transplantation (allo-HSCT) and on days 0, 3, 7, 14, and 21 in an experimental cohort (n = 33). EASIX was transformed to a base-2 logarithm to perform the analysis. For the most relevant biomarkers, we estimate the optimal cutoff values and the discriminatory ability to differentiate patients with high-risk of aGVHD. The conclusions obtained in the experimental cohort were validated in a large cohort of 321 patients at the same institution. Plasma biomarkers and EASIX showed similar post-transplantation dynamics consisting of a progressive increase. Multivariate analysis showed an association between high TNFR1 levels and Log-2 EASIX score on day 7 after transplantation with an increased likelihood of developing aGVHD (hazard ratio [HR] = 1, P = .002; HR = 2.31, P = .013, respectively). Patients with TNFR1 ≥1300 ng/mL (HR = 7.19, P = .006) and Log2-EASIX ≥3 (HR = 14.7, P <.001) at day 7 after transplantation were more likely to develop aGVHD with high predictive accuracy (C-index of 74% and 81%, respectively). In the validation cohort, patients with Log2-EASIX ≥3 on day 7 after transplantation presented a significantly higher incidence of grade II-IV aGVHD (HR = 1.94, P = .004) independent of GVHD prophylaxis (HR = 0.38, P = .004), conditioning regimen (HR = 0.59, P =.02) and type of donor (HR = 2.38, P = .014). Differential degree of endothelial damage can be measured using both EASIX score and plasma biomarkers in the early post-transplantation period. Patients at risk of developing aGVHD could be easily identified by a high EASIX score. Both indicators of endothelial activation represent a promising approach to predict aGVHD.

Post-Transplant Cyclophosphamide Equalizes Clinical Outcomes of Allogeneic Hematopoietic Cell Transplantation across Racial and Ethnic Populations

Background Despite being the only curative option for many hematologic malignancies, allogeneic hematopoietic cell transplant (HCT) has been plagued by health disparities due to differences in access, donor availability, and outcomes across racial and ethnic minority populations (REM) (Gragert, NEJM, 2014). Even when a matched donor is available, HCT outcomes for REM patients are historically worse compared to non-Hispanic white (NHW) patients. (Landry, Stem Cell Investigation, 2021). The development of post-transplant cyclophosphamide (PTCy) for graft-versus-host disease (GVHD) prophylaxis has led to increased use of HLA haploidentical (haplo) or mismatched unrelated donors (MMUD) with comparable outcomes to HLA matched HCT (McCurdy, Advances in Hematology, 2015). While PTCy allows for almost every transplant-eligible REM patient to have a suitable donor, there is limited data evaluating whether this transplant platform results in similar outcomes for REM patients compared to NHW patients. The aim of this study was to investigate if disparities in transplant outcomes still exist between REM patients and NHW patients who received an HLA mismatched transplant with PTCy. Methods We retrospectively analyzed 302 consecutive adult patients who underwent haplo or MMUD HCT with PTCy at Moffitt Cancer Center between 2014 and 2022. All endpoints were compared between four groups: NHW, Hispanic-White, Black, and Other (Asian, biracial, or multiracial.) Results In this cohort, 59% (n=178) of patients identified as NHW, 14% (n=41) as Hispanic-White, 16% (n=48) as Black, 7% (n=21) as biracial or multiracial, and 4% (n=11) identified as Asian. Most patients were male (57%). The median age of all patents was 58. The most common indication for transplant was acute myeloid leukemia (48%), myeloablative conditioning (MAC) was utilized in 42%, and 89% received peripheral blood stem cells grafts. REM patients were more likely to be &amp;lt;65 years of age (60% vs 66-90%, p&amp;lt;0.001), female (36% vs 50-54%, p=0.04), and receive MAC conditioning (33% vs 40-71%, p&amp;lt;0.001). Median follow-up was 21 months. In all clinical outcomes, no significant differences were observed between NHW and REM patients. At day 100, the cumulative incidence of Grade II-IV aGVHD was 37% [95% CI 30-44%] for NHW patients, 32% [95% CI, 18-46%] for Hispanic-White patients, 27% [95% CI, 15-40%] for Black patients, and 26% [95% CI, 13-41%] for patients of Other races (p= 0.38). The cumulative incidence of moderate to severe cGVHD at 2 years was 21% [95% CI 15-28%] for NHW patients, 25% [95% CI, 13-39%] for Hispanic-White, 17% [95% CI, 7.8-29%] for Black, and 27% [95% CI, 13-42%] for patients of Other races (p = 0.80). At 2 years, the probability of relapse was 25% [95% CI 19-32%] for NHW patients, 24% [95% CI, 12-39%] for Hispanic-White patients, 27% [95% CI, 15-40%] for Black patients, and 18% [95% CI, 7.1-33%] for patients of Other races (p = 0.97). During the same time interval, non-relapse mortality (NRM) for NHW patients, Hispanic-White patients, Black patients, and patients of Other races were 19% [95% CI, 13-25%], 15% [95% CI, 5.9-27%], 19% [95% CI, 9.4-32%], and 24% [95% CI, 11-40%] (p = 0.73), respectively. At 2 years, relapse free survival (RFS) was 56% [95% CI 49-64%] for NHW patients, 61% [95% CI, 47-79%] for Hispanic-White patients, 54% [95% CI, 41-71%] for Black patients, and 58% [95% CI, 43-78%] for patients of Other races (p = 0.77). Comparably, OS at 2 years for NHW, Hispanic-White patients, Black patients, and patients of Other races was 64% [95% CI, 57-72%], 72% [95% CI, 60-88%], 53% [95% CI, 40-71%], and 63% [95% CI, 49-83%] respectively after two years (p = 0.92). In multivariate analysis, race/ethnicity had no significant impact on incidence of Grade II-IV aGVHD (p= 0.40), moderate/severe cGVHD (p = 0.80), rates of relapse (p = 0.86), NRM (p= 0.77), RFS (p = 0.69), or OS (p = 0.64) (Table). Conclusions These results show that the use of HLA mismatched donor HCT with PTCy achieves comparable clinical outcomes between REM and NHW patients. Our study suggests that PTCy effectively contributes to equitable healthcare in the setting of allogeneic HCT for REM patients.

Comparison of Therapeutic Effects between Young Haploidentical Donors and Elderly HLA-Matched Relative Donors for AML Patients Who Undergoing Allogeneic Hematopoietic Stem Cell Transplantation with Conditioning Regime Including ATG

Objective: Donor selection is one of the issues faced in allogeneic hematopoietic stem cell transplantation (allo-HSCT). This study aims to compare the impact of young haploidentical donors and elderly matched relative donors on the outcomes of AML patients undergoing allo-HSCT with conditioning regime including ATG, providing reference for donor selection. Methods: A retrospective analysis was conducted on 708 AML patients who underwent allo-HSCT at our hospital from 2014 to 2021. Among them, 354 patients were included in this study, with 289 patients receiving haploidentical transplantation from donors under the age of 50 (haplo group) and 65 patients receiving fully matched sibling transplantation from donors over the age of 50 (MSD group). Clinical characteristics and transplantation outcomes of both groups of patients and donors were compared. Results: Among the 354 AML-MRC patients, there were 178 males and 176 females, with a median age of 41 (18~56) years. The median follow-up time was 35 (95% CI 30~49) months, and the median overall survival (OS) was 78 (95% CI 23~) months. The 3-year OS rate was 63.1% (95% CI 45.6%~81.4%), the 3-year event-free survival (EFS) rate was 59.0% (95% CI 40.8%~66.1%), the cumulative incidence of relapse (CIR) was 26.8% (95% CI 16.6%~30.0%), and the transplantation-related mortality (TRM) was 22.7% (95% CI 13.2%~33.8%). There were no statistically significant baseline differences between the haplo group and MSD group. The 3-year OS rates for haplo group vs. MSD group were 0.660 (95% CI 0.597-0.731) vs. 0.670 (95% CI 0.558-0.806) (p=0.7), the 3-year EFS rates were 0.620 (95% CI 0.543-0.720) vs. 0.570 (95% CI 0.458-0.656) (p=0.6), and the TRM rates were 0.165 (95% CI 0.121-0.282) vs. 0.134 (95% CI 0.062-0.234) (p=0.6). The CIR rates were 0.199 (95% CI 0.147-0.250) vs. 0.275 (95% CI 0.165-0.397) (p=0.196), and the cumulative incidence of grade II-IV aGVHD was 0.288 (0.237-0.342) vs. 0.309 (95% 0.200-0.424) (P=0.891). The incidence of cGVHD was 0.140 (0.099-0.188) vs. 0.250 (95% 0.147-0.367) (p=0.032). Conclusion: For AML patients undergoing allo-HSCT with conditioning regime including ATG, compared to elderly fully matched donors, young haploidentical donors may reduce the occurrence of post-transplant cGHVD.

Effectiveness of In Vivo T-Cell Depleted Regimen Containing Porcine Antilymphocyte Globulin and Rabbit Antithymocyte Globulin in Preventing Acute Gvhd after Haploid Hematopoietic Stem Cell Transplantation

Objective To compare the clinical efficacy of porcine antilymphocyte globulin (p-ALG) and rabbit antithymocyte globulin (r-ATG) in the treatment of hematologic malignancies using haploid hematopoietic stem cell transplantation (haplo- HSCT), this study was conducted. Methods This was a single center retrospective analysis of 178 subjects who received haplo-HSCT with p-ALG or r-ATG from January 2020 to December 2022. The patients were divided into three groups according to the doses of p-ALG or r-ATG used in the conditioning regimens. The study evaluated and compared the occurrence of early fever, graft versus host disease (GVHD), infection, and survival among the three groups of patients. Results A total of 178 patients were enrolled in the study with a median age of 30 (14-61) years, including 95 men and 83 women. The median follow-up time post-transplantation was 20.1 (1.7-36.9) months. The study included 57 patients in the p-ALG 75mg/kg group, 49 patients in the p-ALG 90mg/kg group, and 72 patients in the r-ATG 7.5mg/kg group, respectively. The incidences of neutrophil and platelet engraftment, respectively, were 100%,93.5%, and 91.3% (p=0.133); 100%, 93.6%, 90.3% (p=0.033) in P-ALG 75mg/kg, P-ALG 90mg/kg and r-ATG 7.5mg/kg. The median time to neutrophil engraftment was 11 days for the P-ALG 75mg/kg group, 12 days for the P-ALG 90mg/kg group, and 12 days for the r-ATG 7.5mg/kg group (p=0.133). The median time to platelet engraftment was 12 days for the P-ALG 75mg/kg group, 14 days for the P-ALG 90mg/kg group, and 13 days for the r-ATG 7.5mg/kg group (p=0.033). In the p-ALG 75mg/kg, p-ALG 90mg/kg, and r-ATG 7.5mg/kg groups, 16 patients (28.1%), 24 patients (49.0%) and 35 patients (48.6%) developed fever within 14 days after transplantation, respectively. Cytokine release syndrome was found to be the most common cause of fever. The incidence of grades Ⅱ-Ⅳ acute GVHD (aGVHD) and grades Ⅲ-Ⅳ aGVHD, respectively, were 15.8%, 12.2%, and 12.5% (p=0.853); 5.3%, 2.0%, and 5.6% (p=0.523) in P-ALG 75mg/kg, P-ALG 90mg/kg and r-ATG 7.5mg/kg. The cumulative incidence of chronic GVHD at 1 year was 14.0%, 10.2%, and 15.3% (p=0.731) in the three groups. 43.9%, 71.4%, and 61.1% of patients in the p-ALG 75mg/kg, p-ALG 90mg/kg and r-ATG 7.5mg/kg groups, respectively, experienced at least one infection within 1 year after haplo-HSCT (p=0.0.13). Notably, the CMV infection rate in the p-ALG 75mg/kg group was significantly lower than in the p-ALG 90mg/kg and r-ATG 7.5mg/kg groups. The 2-year overall survival (OS) rates of p-ALG 75mg/kg, p-ALG 90mg/kg and r-ATG 7.5mg/kg groups were 78.2%, 70.6%, and 72.3% (p=0.491). The cumulative incidence of 2-year relapse were 33.0%, 29.8%, and 30.0% (p=0.834). ConclusionsCompared with r-ATG group, the p-ALG 75mg/kg group showed a lower incidence of infection. However, there were no significant differences between the two groups in terms of the incidence of grades Ⅱ-Ⅳ aGVHD, 2-year overall survival (OS), and 2-year cumulative incidence of relapse. p-ALG (75mg/kg) has a comparable effect on the prevention of GVHD after haplo-HSCT with a lower incidence of infection. Keywords: Porcine antilymphocyte globulin; Rabbit antithymocyte Globulin; Haploidentical hematopoietic cell transplantation; Graft versus host disease; Infection

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 (&amp;lt;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&amp;lt;0.01) but higher incidence of NRM (HR=2.36, 95% CI 1.17-4.78; p&amp;lt;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&amp;lt;0.01), NRM (HR=2.73, 95% CI 1.51-4.94; p&amp;lt;0.01), and lower LFS (HR=1.37, 95% CI 1.03-1.83; p&amp;lt;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&amp;lt;0.05) and lower LFS (HR=1.47, 95% CI 1.01-2.14; p&amp;lt;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.

The association of intestinal microbiota diversity and outcomes of allogeneic hematopoietic cell transplantation: a systematic review and meta-analysis.

Growing evidence suggests that highly intestinal microbiota diversity modulates host inflammation and promotes immune tolerance. Several studies have reported that patients undergoing allo-HSCT have experienced microbiota disruption that is characterized by expansion of potentially pathogenic bacteria and loss of microbiota diversity. Thus, the primary aim of this meta-analysis was to determine the association of intestinal microbiota diversity and outcomes after allo-HSCT, and the secondary aim was to analyze the associations of some specific microbiota abundances with the outcomes of allo-HSCT. Electronic databases of Pubmed, Embase, Web of Science, and Cochrane Library were searched from inception to August 2023, and 17 studies were found eligible. The pooled estimate suggested that higher intestinal microbiota diversity was significantly associated with overall survival (OS) benefit (HR = 0.66, 95% CI: 0.55-0.78), as well as decreased risk of transplant-related mortality (HR = 0.56, 95% CI: 0.41-0.76), and lower incidence of grade II-IV aGVHD (HR = 0.41, 95% CI: 0.27-0.63). Furthermore, higher abundance of Clostridiales was associated with a superior OS (HR = 0.40, 95% CI: 0.18-0.87), while higher abundance of Enterococcus (HR = 2.03, 95% CI: 1.55-2.65), γ-proteobacteria (HR = 2.82, 95% CI: 1.53-5.20), and Candida (HR = 3.80, 95% CI: 1.32-10.94) was an adverse prognostic factor for OS. Overall, this meta-analysis highlights the protective role of higher intestinal microbiota diversity on outcomes after allo-HSCT during both pre-transplant and post-transplant periods. Some specific microbiota can be useful in the identification of patients at risk of mortality, offering new tools for individualized pre-emptive or therapeutic strategies to improve allo-HSCT outcomes.

Discrepancy between recipient and donor rs4364254 heparanase single nucleotide polymorphism impacts graft-versus-host disease after allogeneic stem cell transplant.

The heparanase (HPSE) gene is highly polymorphic, but only a minority of its single nucleotide polymorphisms (SNPs) have been studied. Among these, rs4693608 and rs4364254 SNPs are closely associated with mRNA expression and HPSE protein levels in healthy subjects. Given the association between HPSE and inflammatory response, we aimed to evaluate whether HPSE rs4693608 and rs4364254 SNPs could have an impact on graft-versus-host disease after allogeneic stem cell transplants (HSCT). A total of 228 consecutive patients who underwent HSCT at our center between 2005 and 2018 were included. The rs4693608 SNP was identified by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis, while the rs4364254 was detected by allele-specific amplification. The recipient-donor discrepancy for rs4364254 HPSE SNP was significantly associated with grade II-IV aGvHD (HR 1.75, p = 0.03). Patients were stratified into risk groups as follows: low-risk group (LDR) including TT-TT, TT-CT, CT-TT, CC-CC; high-risk group (HDR) including CC-CT, CC-TT, CT-CC, CT-CT, TT-CC. Day 100 cumulative incidence of grade II-IV aGvHD was 23.4% in the LDR group and 41.4% in the HDR group (p = 0.01). One-year cumulative incidence of moderate/severe cGvHD was 42.6% in the LDR group and 58.6% in the HDR group (p = 0.04). Independent variables for moderate/severe cGvHD in patients who received myeloablative conditioning included donor rs4693608 SNP (GA/AA vs. GG: HR 6.86, p = 0.008), rs4693608-rs4364254 SNP combination in recipient (HR/MR vs. LR: HR 3.67, p = 0.01), and previous grade II-IV aGvHD (HR 3.28, p = 0.0005). Finally, donors with rs4364254 SNP CC conferred increased transplant-related mortality (TRM) (39.1% vs. 25%, p = 0.03) and decreased graft-relapse free survival (GRFS) (23.5% vs. 34.4%, p = 0.04) compared with CT or TT genotypes. The differences in incidence of GvHD according to recipient-donor genotype combinations suggests a possible role for rs4364254 HPSE SNP in predicting GvHD. A high level of HPSE, particularly linked to CC genotype of rs4364254 SNP may promote alloreactive T lymphocytes activation and migration toward target organs.

Pilot Study of Donor-Engrafted Clonal Hematopoiesis Evolution and Clinical Outcomes in Allogeneic Hematopoietic Cell Transplantation Recipients Using a National Registry

Improved treatment options, such as reduced-intensity conditioning (RIC), enable older patients to receive potentially curative allogeneic hematopoietic cell transplantation (HCT). This progress has led to increased use of older HLA-matched sibling donors. An unintended potential risk associated with older donors is transplantation of donor cells with clonal hematopoiesis (CH) into patients. We aimed to determine the prevalence of CH in older HLA-matched sibling donors pretransplantation and to assess the clinical impact of donor-engrafted CH on HCT outcomes. This was an observational study using donor peripheral blood samples from the Center for International Blood and Marrow Transplant Research repository, linked with corresponding recipient outcomes. To explore engraftment efficiency and evolution of CH mutations following HCT, recipient follow-up samples available through the Bone Marrow Transplant Clinical Trials Network (Protocol 1202) were included. Older donors and patients (both ≥55 years) receiving first RIC HCT for myeloid malignancies were eligible. DNA from archived donor blood samples was used for targeted deep sequencing to identify CH. The associations between donor CH status and recipient outcomes, including acute graft-versus-host disease (aGVHD), chronic GVHD (cGVHD), overall survival, relapse, nonrelapse mortality, disease-free survival, composite GVHD-free and relapse-free survival, and cGVHD-free and relapse-free survival, were analyzed. A total of 299 donors were successfully sequenced to detect CH. At a variant allele frequency (VAF) ≥2%, there were 44 CH mutations in 13.7% (41 of 299) of HLA-matched sibling donors. CH mostly involved DNMT3A (n=27; 61.4%) and TET2 (n= 9; 20.5%). Post-HCT samples from 13 recipients were also sequenced, of whom 7 had CH+ donors. All of the donor CH mutations (n=7/7; 100%) were detected in recipients at day 56 or day 90 post-HCT. Overall, mutation VAFs remained relatively constant up to day 90 post-HCT (median change, .005; range, -.008 to .024). Doubling time analysis of recipient day 56 and day 90 data showed that donor-engrafted CH mutations initially expand then decrease to a stable VAF; germline mutations had longer doubling times than CH mutations. The cumulative incidence of grade II-IV aGVHD at day 100 was higher in HCT recipients with CH+ donors (37.5% versus 25.1%); however, the risk for aGVHD by donor CH status did not reach statistical significance (hazard ratio, 1.35; 95% confidence interval, .61 to 3.01; P=.47). There were no statistically significant differences in the cumulative incidence of cGVHD or any secondary outcomes by donor CH status. In subset analysis, the incidence of cGVHD was lower in recipients of grafts from DNMT3A CH+ donors versus donors without DNMT3A CH (34.4% versus 57%; P=.035). Donor cell leukemia was not reported in any donor-recipient pairs. CH in older HLA-matched sibling donors is relatively common and successfully engrafts and persists in recipients. In a homogenous population (myeloid malignancies, older donors and recipients, RICr, non-cyclophosphamide-containing GVHD prophylaxis), we did not detect a difference in cGVHD risk or other secondary outcomes by donor CH status. Subgroup analyses suggest potential differential effects by clinical characteristics and CH mutations. Larger prospective studies are needed to robustly determine which subsets of patients and CH mutations elicit meaningful impacts on clinical outcomes.

Unique Reduced-Intensity Conditioning Haploidentical Peripheral Blood Stem Cell Transplantation Protocol for Patients with Hematologic Malignancy

Reduced-intensity conditioning (RIC) haploidentical (haplo-) hematopoietic stem cell transplantation (HSCT) requires more hematopoietic progenitor and stem cells (HPSCs) to promote engraftment and immune reconstitution and needs a stronger graft-versus-leukemia effect. Peripheral blood stem cells (PBSCs) offer advantages over bone marrow; however, the use of higher-dose non-T cell-depleted (non-TCD) in vitro PBSCs may increase the occurrence of severe graft-versus-host disease (GVHD). This prospective, single-arm clinical study was performed to investigate using high-dose non-TCD in vitro PBSCs as the graft source, using fludarabine/Ara-C/busulfan (FAB) as the conditioning regimen, using rabbit antithymocyte globulin to remove T cells in vivo, and enhancing GVHD prophylaxis with an IL-2 receptor antagonist in RIC-haplo-HSCT in patients with hematologic malignancies age 50 to 70 years or <50 years with comorbidities (Hematopoietic Cell Transplantation Comorbidity Index score ≥2) classified as intermediate to high risk. The primary endpoint was day 100 acute GVHD (aGVHD). A total of 47 patients were enrolled; the median age was 52 years (range, 30 to 68 years), the median duration of follow-up was 34 months (range, 2 to 99 months), and the medium-infused doses of mononuclear cells, CD34+ cells, and CD3+ cells were 15.93×108/kg, 8.68×106/kg, and 5.57×108/kg, respectively. The cumulative incidence of grade II-IV aGVHD at day 100 was 30.3% (95% confidence interval [CI], 15.9% to 44.8%), and that of grade III-IV aGVHD was 10.2% (95% CI, .6% to 19.8%). The 2-year cumulative incidence of chronic GVHD (cGVHD) was 34.9% (95% CI, 19.0% to 50.8%). The 2-year cumulative incidences of localized and extensive cGVHD were 26.1% (95% CI, 11.80% to 40.40%) and 8.7% (95% CI, 3.26% to 20.65%), respectively. The 2-year cumulative incidence of relapse was 17.3% (95% CI, 5.1% to 29.5%), the 2-year overall survival rate was 71.2% (95% CI, 57.9% to 84.5%), and the 2-year disease-free survival rate was 66.2% (95% CI, 52.1% to 80.3%). The incidence of aGVHD was not high, and the overall efficacy was good. This study demonstrates that this unique RIC-haplo-PBSC transplantation protocol was effective in treating hematologic malignancies. Nonetheless, larger prospective multicenter clinical trials and experimental studies should be performed to further confirm our findings.

Improved Grfs Observed in a Multicenter Prospective Study of Tcrαβ- and CD45RA-Depleted Haploidentical Transplant in Children with Acute Leukemia

Objective: To test the hypothesis that TCRαβ- and CD45RA-depleted haploidentical hematopoietic stem cell transplantation (HSCT) with a reduced-intensity conditioning regimen and short-course graft-versus-host disease (GVHD) prophylaxis in children with refractory/relapse/high-risk acute leukemia (AL) could reduce the incidence of acute/chronic GVHD without compromising the graft versus leukemia effect, resulting in improved GVHD-free/relapse-free survival (GRFS). METHODS: The outcome of TCRαβ- and CD45RA-depleted haploidentical HSCT (TCD group) was compared with that of concurrent traditional haploidentical HSCT (control group) during the same time period. The proportion of cases in TCD group and control group was 1:2. The incidence of grade II-IV aGVHD, cGVHD, transplant-related mortality (TRM), CMV and EBV reactivation rate, leukemia relapse, overall survival (OS), event-free survival (EFS) were analyzed. GRFS was defined as patients survived without relapse, grade II-IV aGVHD, or moderate to severe cGVHD. RESULTS: From November 2020 to May 2022, 28 patients were enrolled in the TCD group and 56 patients in the control group from three centers in China with median follow-up time of 8 months（range, 2.5-20）and 7.5 months（range, 0.5-20）, respectively. There were no statistically significant differences in age, gender, type of leukemia, pretransplant disease status, degree of HLA mismatch, and number of infused CD34+ cells between the two groups. The TCD group received a reduced-intensity conditioning with TBI 3Gy, -8D; cyclophosphamide 60mg/kg/D, -7D; fludarabine 40mg/m2/D, -7 to -4D; busulfan 3.2-4.8mg/kg/D, -5 to -4D; and melphalan 70mg/m2/D, -3 to -2D. GVHD prophylaxis lasted only 1 month with mycophenolate mofetil from -1D to +30D. The control group received a conventional T-cell replete haploidentical HSCT with myeloablative conditioning and GVHD prophylaxis. The median time of neutrophil and platelet engraftment was 10 days (range, 9-13) and 12 days (range, 9-56) respectively in the TCD group, which were both faster than the control group with 13 days (range, 8-20) and 18 days (range, 8-74) respectively (P < 0.05). The incidence of graft failure was higher in TCD group (5/28, 1 primary failure and 4 secondary failures) than in control group (2/56, all primary failures, P = 0.013). The incidence of grade II-IV aGVHD (22% vs 42.6%, P = 0.071) and cGVHD (10.0% vs 42.0%，P=0.010) were lower in the TCD group than the control group. None of the patients in the TCD group developed moderate or severe cGVHD or TRM. TCD group also have lower incidence of CMV or EBV reactivation and hemorrhagic cystitis compared to the control group (21.4% vs 49.1%, 18.5% vs 46.3%, and 10.7% vs 39.3%, all P<0.05). The relapse rates was comparable between the two groups (4/28 versus 6/56; P = 0.725). One patient died in the TCD group (who received a salvage haploidentical transplantation after graft failure, relapsed again half a year later, and then died of severe hemorrhagic cystitis after third HSCT). Seven (7/56) patients died of TRM in the control group. The 1-year OS (100% vs 85.8%±5.2%) and EFS (72.4%±9.0% vs 68.0%±8.3%) were similar between the two groups (P > 0.050), but the GRFS of TCD group was significantly better than the control group (63.3%±10.1% vs 35.3%±8.5%，P=0.036). CONCLUSIONS: TCRαβ- and CD45RA-depleted HSCT engrafted faster with very low incidences of a/cGVHD，virus reactivation , and TRM. There was no apparent increased risk of relapse, resulting in an improved GRFS. Graft failure remains a problem but all patients could be successfully regrafted without additional TRM, in part because their general status remained relatively well after their initial reduced-intensity conditioning. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

HLA B-Leader Mismatch Is Associated with Poor Outcomes in NIMA/NIPA Mismatched Haploidentical Sibling Donor HCT

Background: Sibling haplo donors can be broadly categorized as non-inherited maternal (NIMA) or paternal (NIPA) antigen mismatched based on the non-shared haplotype with the recipient. Older studies with non-PTCy prophylaxis suggested a benefit of NIMA-mismatched over NIPA-mismatched donors, but the same has not been studied with PTCy prophylaxis, especially in the context of increasing recognition of the impact of specific loci HLA-mismatches in haplo HCT, such as the B-leader, which is a leader peptide that is preferentially bound by HLA-E, the ligand for natural killer (NK) receptor NKG2. Objective: To compare the outcomes of NIMA-vs NIPA-mismatched haplo sibling donors and specific loci HLA-mismatches in the setting of T-cell replete HCT with PTCy prophylaxis. Results: We included 57 patients: 29 were NIMA-mismatched and 28 were NIPA-mismatched. Median age at HCT (31 yrs vs 37 yrs, p=0.1) and donor age (32 yrs vs 41 yrs, p=0.1) were similar in both groups. Most received RIC (72% vs 68%, p=0.5), BM graft (79% vs 82%, p=0.8), had HCT-CI >3 (55% vs 54%, p=0.9) and low/intermediate DRI (62% vs 54%, p=0.4) and were ABO matched (65% vs 71%, p=0.8) with the donor. There was a significantly higher proportion of female-donor to male-recipients in the NIMA- than NIPA-mismatched group (55% vs 21%, p=0.005). Specific HLA-mismatches were similar in both groups: B-leader (52% vs 32%, p=0.1), DRB1 (96% each), DQB1 (90% vs 86%, p=0.5), DPB1 (76% vs 79%, p=0.9). The median follow-up was 38 vs 13 months. There were no graft failures, and the median time to engraftment was similar (18 vs 19 days, p=0.3). The cumulative incidence of grade II-IV aGVHD was 31% vs 58%, p=0.04; with no differences in grade III-IV aGVHD (10% vs 11%, p=0.9), cGVHD (11% vs 13%, p=0.9); NRM (28% vs 33%, p=0.9), relapse (21% vs 11%, p=0.4), or OS (54% vs 55%, p=0.8) in NIMA-vs NIPA-mismatched, respectively. In multivariate analysis, NIMA-mismatch (HR 0.1, 95% CI 0.02-0.6, p=0.01 in females) and HLA-A mismatch (HR 0.2, 95% CI 0.1-0.6, p=0.005) were associated with significantly lower risk of grade II-IV aGVHD, while age at HCT >50 yr was high risk for grade II-IV aGVHD (HR 2.7, 95% CI 1.1-6.9, p=0.04). No factor predicted grade III-IV aGVHD, cGVHD or relapse, likely related to a small number of events. B-leader mismatch was associated with high NRM (HR 3.8, 95% CI 1.04-13, p=0.04), poor PFS (HR 2.7, 95% CI 1.1-6.7, p=0.03), and a trend for lower OS (HR 2.4, 95% CI 0.9-6.3, p=0.06). High/very-high DRI was associated with high NRM (HR 4.4, 95% CI 1.5-13, p=0.008) and poor OS (HR 2.6, 95% CI 1-6.6, p=0.05). HCT-CI >3 (HR 2.9, 95% CI 0.9-8.8, p=0.05) was associated with poor OS. Neither NIMA-mismatch nor any other independent HLA-locus mismatches (except B-leader) had an impact on NRM, relapse, PFS, or OS. Conclusion: Among sibling haplo donors, a B-leader matched donor should be prioritized whenever possible. When multiple B-leader matched donors are available, considering the sample size limitations, our data suggest that a donor mismatched at A-locus (lower aGVHD) and/or a NIMA-mismatched donor (lower aGVHD in females) could be selected. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Mother Vs Father Haploidentical Donor for T Cell-Replete HCT with Ptcy Prophylaxis

Background: When several haplo donors of similar ages are available, which factors should be prioritized remains a matter of debate. This is a frequent clinical question for recipients who are undergoing haplo hematopoietic cell transplantation (HCT) from a parent donor. Although conventionally a female donor is avoided for a male recipient due to the high risk of graft-versus-host disease (GVHD), gender-mismatch (female-to-male) has not been identified as an independent predictor of worse outcomes in the setting of T cell-replete haploidentical HCT with post-transplant cyclophosphamide (PTCy) prophylaxis. On the other hand, certain (mis)matches at specific HLA loci with haplo HCT are now being recognized as predictors of survival. Thus, it has become even more ambiguous whether HLA or non-HLA factors should be prioritized for a haploidentical donor selection. Whether HLA factors trump non-HLA factors (e.g female-to-male, donor age, relationship) remains an area of active investigation. As patient and donor ages and relationships are important predictors of outcomes and are very tightly correlated to each other, we studied the effects of HLA and non-HLA factors stratified by donor relationship (mother vs father). Objective: We sought to compare the outcomes of T-cell replete haplo HCT using a mother vs father donor with PTCy prophylaxis, after accounting for (mis)matching at individual HLA loci and patient/donor age. Results: We included 57 patients with a mother (n=29) vs father (n=28) donor. Median age at HCT (23 yrs vs 27 yrs, p=0.1) and donor age (50 yrs vs 52 yrs, p=0.9) were similar in both groups. Most received RIC (79% vs 86%, p=0.5), BM graft (83% vs 75%, p=0.5), had HCT-CI >3 (46% vs 64%, p=0.2), and low/intermediate DRI (45% vs 54%, p=0.8), were CMV seropositive (86% vs 79%, p=0.04), and B-leader matched (51% vs 48%, p=0.9) and ABO matched with the donor (76% vs 64%, p=0.4). The recipient was male in 59% (mother donor) vs 61% (father donor). The median follow-up was 54 vs 28 months. Graft failure occurred in 0% vs 4%, p=0.3; the median time to neutrophil engraftment was 18 days in both groups. The cumulative incidence of grade II-IV aGVHD (65% vs 56%, p=0.3) and grade III-IV aGVHD at day 180 (31% vs 15%, p=0.2), 3-yr cGVHD (31% vs 15%, p=0.2); NRM (35% vs 26%, p=0.5), relapse (21% vs 32%, p=0.4), PFS (39% vs 36%, p=0.9) and OS was (53% vs 41%, p=0.3) in mother vs father donor, respectively. In multivariate analysis, no statistically significant differences were noted in any outcome between mother vs father donors, likely due to small number of events. However, B-leader mismatch was associated with a significantly higher risk of NRM (HR 2.7, 95% CI 1.03-7.02, p=0.04), and HLA-A mismatch was associated with a lower risk of NRM (HR 0.3, 95% CI 0.1-0.8, p=0.02), better PFS (HR 0.2, 95% CI 0.1-0.4, p<0.001) and OS (HR 0.1, 95% CI 0.05-0.4, p<0.001). HCT-CI >3 was associated with inferior PFS (HR 3.5, 95% CI 1.5-7.6, p=0.002) and OS (HR 4.1, 95% CI 1.7-9.8, p=0.002). Conclusion: HLA factors, such as B-leader mismatch (high NRM) and HLA-A mismatch (low NRM and high PFS and OS) may have a stronger prognostic impact on mortality than donor-relationship. Recognizing the limitations of the small sample size, our data suggest that among parent haplo donors, in cases where both father and mother are B-leader matched and/or HLA-A mismatched with the recipient, father should be preferred due to a 2-fold higher risk of grade III-IV aGVHD and cGVHD (although statistically non-significant) with maternal donors. However, it remains unclear whether a B-leader mismatched (and/or HLA-A matched) father be selected over a B-leader matched (and/or HLA-A mismatched) mother. Further large-scale studies are needed to comprehend these complex immunobiological relationships. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Son Vs Daughter Haploidentical Donor for T Cell-Replete HCT with Ptcy Prophylaxis

Background: A younger haplo donor is usually preferred over an older donor. However, when several donors of similar ages are available, which factors should be prioritized remains a matter of debate. This is a frequent clinical question for older recipients who are undergoing haplo hematopoietic cell transplantation (HCT) from a child donor. Although conventionally a female donor is avoided for a male recipient due to the high risk of graft-versus-host disease (GVHD), this has not been consistently seen in the setting of T cell-replete haploidentical HCT with post-transplant cyclophosphamide (PTCy) prophylaxis. Additionally, there is increasing recognition of the impact of (mis)matches at specific HLA loci with haplo HCT. Whether HLA factors trump non-HLA factors (e.g female-to-male, donor age, relationship), or vice-a-versa, is unclear. As patient and donor ages and relationships are important predictors of outcomes and are very tightly correlated to each other, we studied the effects of HLA and non-HLA factors stratified by donor relationship (son vs daughter). Objective: We sought to compare the outcomes of T-cell replete haplo HCT using a son vs daughter donor with PTCy prophylaxis, after accounting for (mis)matching at individual HLA loci and patient/donor age. Results: We included 298 consecutive patients with a daughter (n=96) vs son (n=202) donor. Median age at HCT (56 yrs vs 58 yrs, p=0.05) and donor age (27 yrs vs 29 yrs, p=0.1) were similar in both groups. Most received RIC (78% vs 76%, p=0.5) and had HCT-CI >3 (52% vs 54%, p=0.6). Fewer patients with a daughter donor received BM graft (56% vs 74%, p=0.002) and had high/very high DRI (20% vs 41%, p<0.001). Most patients were CMV seropositive (83% vs 81%, p=0.09) and ABO matched with donor (60% vs 61%, p=0.9). Significantly more patients with a daughter donor had HLA-C mismatch (97% vs 88%, p=0.01); other mismatches were similar in both groups: A (91% vs 96%, p=0.2), B-leader (43% vs 37%, p=0.6), DRB1 (92% vs 94%, p=0.5), DQB1 (86% vs 90%, p=0.3), DPB1 (76% vs 80%, p=0.4). The median follow-up was 24 vs 27 months. Graft failure occurred in 2% vs 4%, p=0.5; the median time to neutrophil engraftment was similar (20 vs 19 days). The cumulative incidence of grade II-IV aGVHD (39% vs 34%, p=0.5) and grade III-IV aGVHD at day 180 (12% vs 6%, p=0.1), 2-yr cGVHD (18% vs 12%, p=0.4); NRM (28% vs 33%, p=0.5), relapse (24% vs 29%, p=0.4), PFS (47% vs 38%, p=0.2) and OS (50% vs 46%, p=0.4) were similar in daughter vs son, respectively. In multivariate analysis, daughter donors were associated with similar risk of grade II-IV aGVHD (HR 1.2, 95% CI 0.8-1.9, p=0.3), cGVHD (HR 1.03, 95% CI 0.5-2.3, p=0.9), and NRM (HR 0.9, 95% CI 0.6-1.4, p=0.7) as sons. For survival, significant interactions were noted between donor gender and DRI. In patients with low DRI, there was no impact of donor gender, but in patients with high/v high DRI, daughter donors were associated with improved PFS (HR 0.5, 95% CI 0.2-0.9, p=0.03) and OS (HR 0.5, 95% CI 0.3-0.9 p=0.04) as compared to sons. Relapse rate was highest with son-to-mother (HR 1.7, 95% CI 1.02-2.7, p=0.04). PB graft was associated with a significantly higher risk of cGVHD (HR 3.1, 95% CI 1.5-6.4, p=0.003). High/very high DRI was associated with a high risk of relapse (HR 2.4, 95% CI 1.5-3.9, p<0.001). Patient age >50 yrs had high NRM (HR 2.03, 95% CI 1.1-3.7, p=0.02), poor PFS (HR 1.5, 95% CI 1.02-2.3, p=0.04) and OS (HR 1.6, 95% CI 1-2.5, p=0.05). There was no significant impact of specific HLA mismatches on any of the outcomes. Having 3 class II HLA (vs <3) mismatches was associated with a high risk of cGVHD (HR 3.3, 95% CI 1.3-8.7, p=0.01), with no impact on survival. Conclusion: Among child haplo donors, our data suggest that female donors do not result in any inferior outcomes as compared to male donors. A daughter may even be a preferred donor for patients with high/very-high DRI as it conferred survival benefit as compared to a son donor. This may partly be related to a higher risk of relapse seen in son donor to mother recipient. Also, certain HLA mismatches (e.g. B-leader), which have prognostic implications in haplo HCT in general, did not appear to be of significance when accounted for donor relationship and age in patients with a child donor. Further large-scale studies are needed to comprehend these complex immunobiological relationships. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal