Peripheral Blood Grafts Research Articles

Donor types and outcomes of transplantation in myelofibrosis: a CIBMTR study

AbstractWe evaluate the impact of donor types on outcomes of hematopoietic cell transplantation (HCT) in myelofibrosis, using the Center for International Blood and Marrow Transplant Research registry data for HCTs done between 2013 and 2019. In all 1597 patients, the use of haploidentical donors increased from 3% in 2013 to 19% in 2019. In study-eligible 1032 patients who received peripheral blood grafts for chronic-phase myelofibrosis, 38% of recipients of haploidentical HCT were non-White/Caucasian. Matched sibling donor (MSD)–HCTs were associated with superior overall survival (OS) in the first 3 months (haploidentical hazard ratio [HR], 5.80 [95% confidence interval (CI), 2.52-13.35]; matched unrelated (MUD) HR, 4.50 [95% CI, 2.24-9.03]; mismatched unrelated HR, 5.13 [95% CI, 1.44-18.31]; P < .001). This difference in OS aligns with lower graft failure with MSD (haploidentical HR, 6.11 [95% CI, 2.98-12.54]; matched unrelated HR, 2.33 [95% CI, 1.20-4.51]; mismatched unrelated HR, 1.82 [95% CI, 0.58-5.72]). There was no significant difference in OS among haploidentical, MUD, and mismatched unrelated donor HCTs in the first 3 months. Donor type was not associated with differences in OS beyond 3 months after HCT, relapse, disease-free survival, or OS among patients who underwent HCT within 24 months of diagnosis. Patients who experienced graft failure had more advanced disease and commonly used nonmyeloablative conditioning. Although MSD-HCTs were superior, there is no significant difference in HCT outcomes from haploidentical and MUDs. These results establish haploidentical HCT with posttransplantation cyclophosphamide as a viable option in myelofibrosis, especially for ethnic minorities underrepresented in the donor registries.

Peripheral blood stem cell versus bone marrow graft for patients ≥60 years undergoing reduced intensity conditioning haploidentical transplantation for acute myeloid leukemia in complete remission: An analysis of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation.

In the context of T-cell replete haploidentical stem cell transplantation (Haplo-SCT) using post-transplantation cyclophosphamide (PT-Cy), it is still unknown whether peripheral blood (PB) or bone marrow (BM) is the best graft source. While PB is associated with a higher incidence of graft-versus-host disease (GVHD), it may induce a stronger graft-versus-leukemia effect compared to BM, notably in acute myeloid leukemia (AML). From the EBMT registry database, we compared T-cell replete PB (n = 595) versus BM (n = 209) grafts in a large cohort of 804 patients over the age of 60 years who underwent Haplo-SCT with PT-Cy for an AML in first or second complete remission. The risk of acute GVHD was significantly higher in the PB group (Grade II-IV: HR = 1.67, 95% CI [1.10-2.54], p = 0.01; Grade III-IV: HR = 2.29, 95% CI [1.16-4.54], p = 0.02). No significant difference was observed in chronic GVHD or non-relapse mortality. In the PB group, the risk of relapse was significantly lower in the PB group (HR = 0.65, 95% CI [0.45-0.94], p = 0.02) and leukemia-free survival was significantly better (HR = 0.76, 95% CI [0.59-0.99], p = 0.04), with a trend toward better overall survival (HR = 0.78, 95% CI [0.60-1.01], p = 0.06). We conclude that in the specific context of Haplo-SCT with PT-Cy, PB grafts represent a valid option to decrease the risk of relapse and improve outcome of older AML patients who usually do not benefit from conditioning intensification.

Graft CD8 T-cell-based risk system predicts survival in antithymocyte globulin-based myeloablative haploidentical peripheral blood stem cell transplantation.

This study investigated the cellular composition of peripheral blood grafts for anti-thymocyte globulin (ATG)-based myeloablative haploidentical haematopoietic stem cell transplantation (haplo-HSCT). Clinical characteristics were retrospectively evaluated in a training cohort with ATG-based myeloablative haplo-HSCT between January 2016 and February 2020 and confirmed in a validation cohort between March 2020 and June 2021. A higher dose of graft CD8+ T cells (≥ 0.85 × 108 kg-1) was significantly improved overall survival (OS;hazard ratio [HR], 1.750; P = 0.002) and disease-free survival (DFS; HR, 1.751; P < 0.001) in the training cohort, according to multivariate Cox regression analysis. Higher doses of mononuclear cells (MNCs) demonstrated better OS (HR, 1.517; P = 0.038) and DFS (HR, 1.532; P = 0.027). Older patient age (> 46 years), older donor age (≥ 50 years) and a higher refined disease risk index (rDRI) were also related to OS. A graft CD8+ T-cell risk system based on graft CD8+ T-cell dose, donor age and rDRI was constructed using a nomogram model after LASSO Cox regression analysis. It showed acceptable discrimination, with a C-index of 0.62 and 0.63, respectively. Graft CD8+ T-cell dose was negatively correlated with donor age (P < 0.001) and positively correlated with a higher lymphocyte percentage in the peripheral blood before mobilisation (P < 0.001). A higher CD8+ T-cell dose in peripheral blood-derived grafts improves patients' survival with ATG-based myeloablative haplo-HSCT. Younger donors with higher lymphocyte percentages improved patients' survival with an intermediate rDRI risk.

Trends in Allogeneic Stem Cell Transplantation for Good Risk Acute Myelogenous Leukemia in First Complete Remission: A Longitudinal Study of > 15 Years from the ALWP/EBMT

Background: Favorable acute myelogenous leukemia (AML) includes AML with t (8:21), inv (16), and those with NPM1 without FLT3- ITD without adverse cytogenetics (ELN 2022). The incidence of relapse (RI) in favorable-risk AML with chemotherapy is 35%-40%. Although RI is ~20% lower with allogeneic transplantation (HSCT), transplantation is usually not indicated in favorable risk AML at first complete remission (CR1) due to transplant-related mortality. However, in recent years, HSCTs have been associated with significantly lower non relapse mortality (NRM) and better outcomes. Methods:Our aim was to assess outcomes of HSCT in favorable risk AML (t (8:21), inv (16), and NPM1 mutFLT3 WT) in CR1, comparing 3 time periods: 2005-2009, 2010-2014, and 2015-2021. Statistical tests included a multivariate analysis (MVA) adjusting for potential confounding factors performed using a Cox proportional-hazards regression model for main outcomes. Results: 1850 patients (pts) were included, 526 with t (8:21), 625 with inv (16), and 699 with NPM1 mutFLT3 WT (normal karyotype). 222 pts were transplanted in 2005-2009, 392 in 2010-2014, and 1236 in 2015-2021. As the follow-up period differed, being 103.1 (IQR, 92.1-114.0), 78.3 (IQR, 69.4-86.3), and 32.0 (IQR, 29.5-34.5) months, respectively (p&amp;lt;0.0001), all survival events were censored at 3 y. Pts undergoing HSCT in 2015-2021 were older, with a median age of 50.9 (range 18.2-76.4) vs40.4 (range 18.3-67.7) and 42.4 (range 18.4-71) y, in those transplanted in 2005-2009 and 2010-2014, respectively (p&amp;lt;0.0001). More pts &amp;gt;50 y of age were transplanted in the latest period with 52.7% vs the 2 earlier periods 27.9% and 32.1% (p&amp;lt;0.0001) and figures for &amp;gt;60 y were 25.4% vs 8.1% and 11% (p&amp;lt;0.0001), respectively. In 2005-2009 the most frequent diagnosis was t (8:21) at 44.6%, while in 2015-2021, it was NPM1 mutFLT3 WT at 45.6% (p&amp;lt;0001). In 2005-2009, the most frequent donors were matched siblings (MSD) (63.1%), while in 2015-2021 they were unrelated (UD) (50.7%). Haploidentical (haplo) transplants increased from 5.9% to 14.5% (p&amp;lt;0.0001). Bone marrow grafts decreased from 24.8% to 13.2%, while peripheral blood (PB) grafts increased from 75.2% to 86.8% (p&amp;lt;0.0001). Conditioning was myeloablative in 69.8%, 64.8%, and 60.2% and was reduced intensity in 30.2%, 35.2%, and 39.8% in pts transplanted in 2005-2009, 2010-2014, and 2015-2021 (p=0.014). Graft-versus-host disease (GVHD) prophylaxis with in vivo T cell depletion or post-transplant cyclophosphamide (PTCy) was more frequent in 2015-2021 compared to the other two periods (p&amp;lt;0.0001). Day 60 engraftment (ANC &amp;gt;0.5 x 10 9/L) was 98.2 % vs 98.4% vs 98.5% (p=0.17). Day 180 incidence of acute (a) GVHD grade II-IV was 18.2%, 21.1%, and 21.6%; grade III-IV was 5.1% 5.7%, and 7.3% while the incidence of 3-y chronic (c) GVHD was 49.3%, 50.4% and 39.2%. On MVA the incidence of total cGVHD was reduced in HSCTs performed &amp;gt;2015 compared to those performed in 2005-2009, hazard ratio (HR) =0.74 (95% CI 0.56-0.99, p=0.046) and GVHD-free, relapse-free survival (GRFS) improved for pts transplanted from 2010-2014 vs those transplanted in 2005-2009, HR=0.74 (95% CI 0.56-0.98, p=0.037) (Figure 1). All other HSCT outcome parameters including NRM, RI, leukemia-free survival (LFS), and overall survival (OS) did not differ (Figure 1) with no improvement &amp;gt;2015 compared to 2010-2014 (Figure-1 A). LFS, OS, and GRFS were superior in pts with t (8:21) with HR=1.32 (95% CI 1.03-1.68, p=0.026), HR=1.38 (95% CI 1.04-1.83, p=0.027) and HR=01.25 (95% CI 1.02-1.53, p=0.035), respectively. Other poor prognostic factors were older pt age (by 10 y) for NRM and OS; 10/10 and 9/10 UD vs MSD for aGVHD II-IV (9/10 also for III-IV aGVHD) and haplo vs MSD for NRM, OS, aGVHD II-IV, and total cGVHD. The combination of female donor to male pt was a poor prognostic factor for NRM, OS, GRFS, and cGVHD. In vivo T cell depletion was a positive prognostic factor for GRFS and reduced incidence of aGVHD and cGVHD. PTCy was associated with a lower incidence of cGVHD and PB grafts with an increased risk of total cGVHD. Conclusions: In this retrospective analysis of HSCT in pts with favorable risk AML in CR1, transplanted over 16 years, we observed an increased number of transplants in pts &amp;gt;60y, from UD and haplo with PB grafts and in vivo T cell depletion or PTCy as GVHD prophylaxis. Most importantly, 3-y GRFS improved &amp;gt;2010 and total cGVHD reduced &amp;gt;2015, while other HSCT outcome parameters have not changed.

Machine Learning Validates Risk Biomarkers of Chronic Graft-Versus-Host Disease in 936 Patients from BMT CTN 0201 & 1202 Cohorts

Introduction Our previous work identified susceptibility/risk biomarkers for developing chronic GVHD (cGVHD) in individuals without clinically apparent disease (Logan et al. 2023, JCI), which is a major contributor to morbidity and mortality following allogeneic hematopoietic cell transplant (HCT). In this study, we used machine learning (ML) algorithms to build biomarker-based prediction models for development of cGVHD and non-relapse mortality (NRM). Methods Data were obtained on 9 pre-transplant factors and 7 plasma proteins at Day 90 post HCT in 936 HCT recipients from the BMT CTN 0201 and 1202 studies. The study population was split into separate training (80%) and validation (20%) datasets. Associations of each protein marker with the hazards of cGVHD and NRM were evaluated using Cox proportional hazards (PH) models. To evaluate the predictive ability of the proteins, ML models were constructed from them and the time varying Area Under the ROC curve (AUCt) was estimated at Days 180, 270, 360, and 540 post HCT. We considered ML approaches within the PH model framework, including Boosting (XGBoost), Group SCAD, and Adaptive Group Lasso, as well as methods avoiding the PH assumption, including Random Survival Forests and Bayesian Additive Regression Trees (BART). DeepSurv and DeepHit models were also used in the first application of deep learning to GVHD biomarker risk evaluation to our knowledge. A p-value cutoff of 0.05 determined statistical significance. Results Of the 7 proteins tested, 5 (CXCL9, CXCL10, MMP3, DKK3, and CD163) were associated with cGVHD risk, while 4 (MMP3, DKK3, ST2, CD163) were correlated with NRM (p&amp;lt;0.05 for all). Moreover, effects of some markers varied depending on the graft type, with higher MMP3 found to have a larger, deleterious effect on cGVHD risk in patients with bone marrow (BM) compared to peripheral blood (PB) graft (p=0.03). CD163 had a similar interaction with graft type such that its effects on cGVHD and NRM risk are significant with BM graft but not with PB graft (p&amp;lt;0.05 for both). The abilities of the ML methods to risk stratify cGVHD and NRM were assessed and contrasted to a Group SCAD model having clinical factors only. Because graft type was found to impact both the risks of cGVHD and NRM as well as the biomarkers' effects, the ML models considered markers, graft type, and their interactions. In modeling cGVHD risk, the Group SCAD model with only clinical factors selected 4 variables: age, graft type, donor-recipient sex-mismatch, and GVHD prophylaxis; while Adaptive Group Lasso and Group SCAD with biomarkers selected 5 proteins: CXCL9, CXCL10, MMP3, ST2, and CD163. In the validation dataset, all ML methods with biomarkers provided similar or higher AUCt for cGVHD after Day 270 compared to clinical factors only, suggesting that plasma proteins measured as early as Day 90 can inform underlying cGVHD biology that has not manifested clinically ( Fig). BART and Boosting yielded the highest AUCt and were better than the model with only clinical factors, attaining AUCt &amp;gt; 0.60 from Day 270-540. To assess the variables' importance in ML, we examined BART's posterior probabilities of selection, which describe how frequently each variable is used in the BART tree ensemble. For cGVHD, variables with selection probabilities &amp;gt; 0.10 were graft type, CXCL9, and MMP3. Notably, the protein markers that were significant in separate models also had the largest selection probabilities of all markers. The AUCt for NRM was stable across time points in the 0.65-0.72 range and superior to clinical factors after Day 180 ( Fig). For NRM, variables with selection probabilities &amp;gt; 0.10 were graft type, ST2, MMP3, CD163, and DKK3. Conclusions ML methods using non-invasive plasma proteins can successfully identify and validate risk biomarkers of cGVHD. ML algorithms using objective and early measurements of soluble markers including CXCL9, CXCL10, MMP3, DKK3, and ST2 perform better in predicting cGVHD than ML with known clinical factors only. ML with MMP3, DKK3, ST2, and CD163 improved NRM prediction. Deep learning models did not outperform more classical ML methods, possibly due to a limited sample size that could not reveal intricate relationships between proteins and cGVHD/NRM risk. Several proteins represent potential therapeutic targets. These data support future research to further validate these biomarkers and to develop ML algorithms to identify patients at risk for developing cGVHD and NRM.

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 (&amp;lt;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&amp;lt;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&amp;lt;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&amp;lt;0.05) and MUD (HR=0.57, 95% CI: 0.33-0.99, p&amp;lt;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&amp;lt;0.01) and higher NRM (HR=1.58, 95% CI 1.1-2.27; p&amp;lt;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&amp;lt;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.

Peripheral Blood Grafts Vs Bone Marrow Grafts in Young Acute Myeloid Leukemia Patients with HLA-Matched Sibling Donors Undergoing Myeloablative Conditioning

In allogeneic hematopoietic cell transplantation (allo-HSCT), graft source has been changed from bone marrow grafts (Bone marrow stem cell, BMSC) to peripheral blood grafts (Peripheral blood stem cell, PBSC) mobilized by granulocyte colony-stimulating factor. PBSC transplantation is known to have numerous advantages over BMSC, including faster engraftment, improved survival outcomes, and for the donor, the elimination of invasive marrow harvesting procedure under general anesthesia. However, previous studies regarding graft source included various hematologic malignancies and lacked consistency in conditioning intensity and disease status at allo-HSCT. Still, there are limited data on the comparison of graft sources specifically in patients with acute myeloid leukemia (AML) undergoing myeloablative conditioning. In this background, we conducted an analysis to investigate the impact of graft source on transplant outcomes in AML patients who underwent HLA A, B, C, DR-matched sibling donor (MSD) HSCT with myeloablative conditioning. This study was a retrospective, single-center study for patients with AML who received first allo-HSCT from 2002 to 2022. We included the patients aged &amp;lt; 60 at the time of allo-HSCT, in a state of complete remission (CR) or CR with incomplete hematologic recovery, from a MSD, and underwent myeloablative conditioning. We classified the patients into three groups: the BMSC graft group (BMSC group), the PBSC graft group without antithymocyte globulin (ATG) (PBSC/ATG- group), and the PBSC graft group with ATG (PBSC/ATG+ group). Patients who received both PBSC and BMSC grafts were excluded from the analysis. We examined the differences in overall survival (OS), relapse-free survival (RFS) among these three groups. A total of 480 patients were included in this analysis, with 234 patients in the BMSC group, 66 patients in the PBSC/ATG+ group, and 180 patients in the PBSC/ATG- group. BMSC transplantation was mostly performed before 2010, whereas PBSC transplantation started in 2007, and allo-HSCT with ATG administration were conducted after 2014. In the PBSC/ATG+ group, the median ATG dose was 2.5 mg/kg (Interquartile range, IQR: 1.6-2.5). The BMSC group tended to be younger at the time of HSCT (median 38 years [31-46]) compared to the other groups (median age of PBSC/ATG+ group: 44 years [37-51], PBSC/ATG- group: 46 years [39-51], p&amp;lt;0.01). Of total patients in the three groups, there was only 1 case of neutrophil engraftment failure (in the PBSC/ATG- group) and 5 cases of platelet engraftment failure (3 in the BMSC group and the other 2 in the PBSC/ATG- group). BMSC patients demonstrated superior OS compared to PBSC patients, with the most pronounced difference was observed over PBSC/ATG- group (Figure A). Similar trends were presented in relapse-free survival (RFS) as well. After adjusting for other covariates through multivariate Cox modeling, the difference caused by the graft source remained significant, particularly in terms of RFS (Figure B). The hazard ratios for RFS of PBSC comparing to BMSC were as follows; PBSC/ATG+: 1.64 [1.04-2.58], PBSC/ATG-: 1.95 [1.45-2.63]. In conclusion, Despite the clear differences in allo-HSCT era between groups, even BMSC patients underwent allo-HSCT at an earlier time, patients receiving BMSC grafts showed superior survival compared to those receiving PBSC grafts in young AML patients undergoing MSD myeloablative allo-HSCT. Parallel evaluation of the transplant outcomes between BMSC and PBSC would be crucial for assessing the advantages and disadvantages of PBSC and BMSC grafts in this setting.

Final Results from Phase 1 Study of Briquilimab, an Anti-CD117 Monoclonal Antibody, in Combination with Low Dose Irradiation and Fludarabine Conditioning, Shows Durable Remissions in Older Adults with Acute Myeloid Leukemia in Complete Remission and Myelodysplastic Syndrome Undergoing Allogeneic Hematopoietic Cell Transplantation

Background: Allogeneic hematopoietic cell transplantation (HCT) with non-myeloablative conditioning (NMA) is a potential cure for AML and MDS in older/frail patients. NMA is associated with better tolerability but higher relapse rates compared to more intensive regimens. In a phase 1 study (NCT#04429191), briquilimab (JSP191), a first-in-class monoclonal antibody (mAb) that inhibits stem cell factor binding to CD117 (c-Kit) to deplete hematopoietic stem and progenitor cells (HSPC), in combination with standard NMA conditioning of low dose total body radiation (TBI) and fludarabine (Flu) for HCT, was evaluated in older adults with AML and MDS. Pre-clinical experiments suggest briquilimab synergizes with low dose TBI to deplete normal and malignant HSPC to facilitate donor cell engraftment. Final 1-year efficacy endpoints for all subjects enrolled in this study are presented. Methods: 32 subjects, median age 70 yrs (range 62-79), with AML in morphologic CR (CR1 or CR2+) (n=13), MDS (n=16), or AML not in CR (n =3), and HLA-matched related or unrelated donors were enrolled. Following infusion of briquilimab 0.6 mg/kg, serum levels were assessed to determine start of Flu at 30 mg/m 2/day on Transplant Day (TD)-4, -3, -2, and TBI 2-3 Gy on TD0. Peripheral blood grafts were infused on TD0 (10-14 days after JSP191). GVHD prophylaxis was tacrolimus, sirolimus, and mycophenolate mofetil. Primary endpoints were safety, tolerability, and briquilimab pharmacokinetics. Secondary endpoints included engraftment, chimerism, measurable residual disease (MRD) clearance, acute GVHD (aGVHD), chronic GVHD (cGVHD), NRM, RFS, and OS at 1 year. Results: Summary of main efficacy outcomes is presented in Fig 1. 10 of 13 AML in CR and 14 of 16 MDS subjects had MRD at pre-HCT screening assessed by cytogenetics, flow cytometry, and/or next generation sequencing. There were no infusion toxicities and no briquilimab-related SAEs. Consistent with our previous reports, briquilimab exhibited predictable clearance prior to donor cell infusion, and all subjects engrafted, with neutrophil recovery between TD+19 and TD+26. Compared to baseline marrow, briquilimab alone depleted HSPC with a mean decrease of 62.4±22.7% prior to Flu/TBI (Fig 2). The 28 evaluable subjects at TD+90 achieved median donor myeloid chimerism of 99% (range 96-100%) and median total chimerism of 95% (range 81-100%). There was one secondary graft failure without relapse, who received a 2 nd HCT. Among 13 AML in CR subjects, by 1 year, there were 3 relapses, 1 NRM (GVHD), 9 subjects were alive, and 8 were MRD negative. The 1 subject who was MRD positive at 1 year had only a detectable DNMT3A mutation at low level. 1 of 13 AML in CR subjects had TP53+ disease at screening and this subject was alive and MRD negative at 1 year post-AHCT. Among 16 MDS subjects, by 1 year, there were 5 disease progression/relapses, 1 subject withdrew consent due to persistent disease 3 months post-HCT, 1 NRM (sepsis), 8 subjects were alive, and 6 were MRD negative. 5 of 16 MDS subjects had TP53+ disease, 3 of whom had persistent disease/progressed/relapsed prior to 1 year post-HCT, and the other 2 of whom had MRD positive disease/molecular relapse at 1 year post-HCT. Median time to MRD negativity in all subjects who converted from MRD-positive disease to MRD-negative disease was TD+28. All 3 subjects with AML not in CR had disease progression before 4 months post-AHCT. There was no apparent correlation between level of HSPC depletion at the assessed timepoint (Fig 2) and relapse or survival. Of the 32 enrolled subjects, 4 had MAGIC Grade 2 aGVHD, 1 had MAGIC grade 3-4 aGVHD, 13 had mild/moderate cGVHD, and none had severe cGVHD. Conclusions: These results demonstrate that targeting CD117 with briquilimab together with TBI/Flu as a novel conditioning regimen is safe, well-tolerated, facilitates full donor myeloid chimerism, and sustained clearance of MRD in older adults with AML in CR and MDS without TP53 undergoing NMA AHCT.

Combined Effect of Unrelated Donor Age and HLA Peptide-Binding Motifs (PBM) Match Status on HCT Outcomes

Background: HLA-mismatched unrelated donors (MMUDs) can be either matched or mismatched at protein binding motifs (PBM), while all HLA-matched donors are PBM-matched. A MMUD who is class I PBM-matched in the graft-vs-host (GVH) direction is preferred over a PBM-mismatched donor [ JCO.2023;41(13):2416]. As donor age is also an important prognostic factor, we hypothesized that using a younger donor could compensate for the inferior overall survival (OS) associated with PBM-mismatches. Specifically, we tested if OS after transplantation with HLA-mismatched/PBM-matched/younger donors is similar to that with HLA-matched/older donors, and if OS is similar with HLA-mismatched/PBM-mismatched/younger donors as with HLA-mismatched/PBM-matched/older donors. Methods: We analyzed the outcomes of patients with acute leukemia or myelodysplastic neoplasms who underwent HLA-matched or single class I MMUD HCT with a calcineurin inhibitor (CNI) for GVHD prophylaxis using a publicly available Center for International Blood and Marrow Transplant Research dataset. HLA class I MMUDs were categorized as “PBM-mismatched” if there was any GVH mismatch for the PBM, or “PBM-matched” if there was PBM-matching or only host-versus-graft mismatching. Donor age was dichotomized as “older” (&amp;gt; 35 years) or “younger” (&amp;lt; 35 years). Six groups were compared: HLA-matched/younger donor (n=10,531), HLA-matched/older donor (n=3572), PBM-matched/younger donor (n=357), PBM-matched/older donor (n=257), PBM-mismatched/younger donor (n=616), and PBM-mismatched/older donor (n=339). The primary outcome of interest was OS. Results: Median patient age was 50.3-56.2 years. Acute myeloid leukemia was the most common diagnosis in all groups (53-60%), most had early/intermediate disease (64-70%), most received myeloablative conditioning (60-69%) and peripheral blood (PB) graft (76-81%). A minority (18-23%) had T-cell epitope -DPB1 non-permissive GVH mismatched. All patients received CNI-based prophylaxis, without post-transplant cyclophosphamide (PTCy). Median follow-up among survivors was 48-61 months. In multivariate analysis, transplantation from HLA-matched/younger donors was associated with superior OS relative to any other group [ Figure]. The notable findings of pairwise comparisons were three-fold. First, donor age significantly impacts OS in both HLA-matched and HLA-mismatched groups, but the negative impact of older donors relative to younger donors increases with increased mismatching for the PBM (18%, 25% and 35% increased mortality in older compared to younger donors within HLA-matched, PBM-matched and PBM-mismatched groups, respectively) [ Table, pairwise comparison group 1]. Secondly, younger donors appear to negate the detrimental effect of PBM-mismatching [comparison group 2]. Specifically, the PBM-matched/younger donor group had similar OS as the HLA-matched/older donor group and the PBM-mismatched/younger donor group had similar OS as the PBM-matched/older donor group. Thirdly, HLA/PBM-matching is important within the younger and the older donor groups [comparison group 3]; however, the impact of PBM-mismatching was higher with older donors (25% and 62% increased risk of mortality with PBM-matched and PBM-mismatched, respectively than HLA-matched) than with younger donors (18% and 42% increased risk of mortality with PBM-matched and PBM-mismatched than HLA-matched). Conclusion: Older unrelated donor age and PBM-mismatching confer similarly adverse effects on OS after transplantation with CNI prophylaxis and the impacts are additive. The preferred donor is HLA-matched, followed by HLA-mismatched/PBM-matched, and HLA-mismatched/PBM-mismatched. Transplantation from younger donors with inferior matching led to comparable outcomes as the older donors with better matching - a finding which may widen the “acceptable” donor pool. The best OS is observed with HLA-matched/younger donors and the worst with PBM-mismatched/older donors. Whether the use of PTCy modifies the impact of donor age and/or HLA/PBM-mismatching needs investigation.

Post Transplant Cyclophosphamide (PTCY) in Peripheral Blood Stem Cell Transplant Results in Successful Engraftment and Substantially Low Frequency of Chronic Graft Versus Host Disease (GvHD), without Impaired Cellular Immune Reconstitution

The Post-Transplant Cyclophosphamide (PTCY) approach was first studied in the haploidentical transplant setting, and it resulted in high percentages of engraftment and reduced frequency of acute and mainly chronic GvHD as well as non-relapsed mortality. PTCY is now increasingly being used in HLA-partially and fully matched unrelated, as well as matched related donors. The aim of this study was to investigate the impact of PTCY on the incidence of chronic GvHD, disease relapse and infections because of possible cellular immune impairment. Fifty-one consecutive patients who underwent allogeneic hematopoietic stem cell transplant from an unrelated donor were studied. PTCΥ was administered on days +3 and +4 post-transplant at a dose of 50 mg/kg/day. Additional GvHD prophylaxis included tacrolimus and mycophenolate mofetil starting on day +5. In patients with no evidence of GvHD, immunosuppression was gradually tapered, and eventually stopped by day +90. We evaluated the safety and efficacy of PTCY, focusing on toxicity, engraftment, aGvHD and cGvHD frequency, relapse, non-relapse mortality, survival and immune reconstitution. We performed 51 unrelated donor transplants with PTCY from January 2021 to May 2023 in patients with a median age of 52 (18-69) years. The indication for transplant was AML/MDS (n=36), NHL/CLL, (n=2), pMF (n=2), CML (n=2) και ALL (n=9). Disease risk index (DRI) was intermediate for most patients (34/51), 7 had low and 10 had high DRI. Thirty-seven patients received myeloablative conditioning and 14 reduced-intensity. Overall, three patients were transplanted from a matched sibling, 36 from an 8/8 matched unrelated donor and 12 from an 7/8 HLA-matched unrelated donor. All patients received a peripheral blood graft with a median CD34+ cell dose of 6.97×10e6/kg (3.27-15.82). The most common toxicities observed were mucositis (n=34), diarrhea (n=40), vomit (n=12), liver toxicity (n=3) and acute kidney injury (n=4) - which in all cases were grade Ι-ΙΙ. Engraftment, defined as neutrophils &amp;gt;500/μl, was achieved in 46 cases in a median of 16 (13-27) days. Three patients died before day +28 due to NRM and two additional patients with myelofibrosis and MDS respectively had primary graft failure. The cumulative incidence of aGvHD, grade ΙΙ-IV at 100 days was 46.7% (95%CI: 34.1-63.8). However, aGvHD, grade ΙΙΙ-IV was only 3.9% (95%CI: 1.0-15.5). The cumulative incidence of cGvHD at 18 months was 13,4% (95%CI: 5.8-31.0), with only one case of extensive cGvHD. In a median follow-up of 14.5 (1-28) months, disease free (DFS) was 76,8% (95%CI: 65.5-90.0) at 18 months and overall survival (OS) was 76.3% (95%CI: 64.9-89.8) and 71.6% (95%CI: 58.6-88.3) respectively. There was no statistically significant difference in survival rates for patients who received an HLA mismatched and those who received an HLA-matched unrelated-donor transplant. cGvHD-Relapse-Free Survival was 63.5% (95%CI: 50.3-80.1). Two patients died of their disease and non-relapse mortality was 19.1%. Specifically, 6 patients died of Infections, 1 due to primary graft failure, 1 due to heart failure, and 1 due to Idiopathic Pulmonary Syndrome. Immune reconstitution at month 6 was 420 cells/ul (20-2225) and 179 (13-594) for CD8 and CD4 respectively. At month 12 CD8 and CD4 were 552 (55-3002) and 364 (60-787). 31 viral infections were documented in 28 patients (Respiratory viruses n=13, BKV n=11, CMV n=7). In regard with opportunistic infections, 2 patients had fungal infections and 1 patient atypical mycobacterium. We used PTCY for GvHD prophylaxis in mismatched, full-matched unrelated and matched sibling donor transplants with peripheral blood stem cell graft. This approach was well tolerated. Engraftment was documented in most patients, with a low incidence of grade III-IV aGvHD. Importantly cGvHD, which is the most important barrier in unrelated donor transplant, was substantially low with this method. Cellular immune reconstitution was adequate for CD8 but somewhat impaired for CD4. However, the incidence of viral and opportunistic infections was not increased. Overall, there are implications that PTCY may revert the negative impact of HLA mismatch on the outcomes of unrelated donor transplantation, while it is also a viable option for MUD and MSD transplant.

Peripheral Blood Haploidentical Allogeneic Stem Cell Transplantation in Older Adults with Acute Myeloid Leukemia and Myelodysplastic Syndromes Demonstrates Long Term Survival, Results from Australia and New Zealand Transplant and Cellular Therapies

There is a limited body of evidence for haploidentical hematopoietic stem cell transplantation (haplo-HSCT) in older patients. Previous studies have used a high proportion of bone marrow–derived grafts and a variety of conditioning regimens. In Australia and New Zealand, haplo-HCST is predominantly performed using peripheral blood (PB) with universal use of post-transplantation cyclophosphamide (PTCy). To characterize the outcomes of older recipients undergoing haplo-HSCT for acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). Data were collected through the Australasian Bone Marrow Transplant Recipient Registry (ABMTRR) for patients aged 65 or older receiving a PB haplo-HSCT for AML/MDS between January 2010 and July 2020. A total of 44 patients were included in the analysis. The median follow-up time was 377 days. The median age was 68 (range 65-74) with a median Karnofsky performance status of 90. Thirty patients (68.2%) had AML, whereas 14 (31.8%) had MDS. The median donor age was 40. The most common conditioning regimen was nonmyeloablative fludarabine, cyclophosphamide, and total body irradiation (75%); the remainder of the patients received either melphalan- or busulfan-based regimens, and the majority were reduced intensity, with only 2 patients undergoing myeloablative conditioning. All patients received post-transplantation cyclophosphamide and mycophenolate mofetil, with the majority also receiving tacrolimus (90.5%) and the remainder receiving cyclosporine (9.5%). No patients received anti-thymocyte globulin. Neutrophil engraftment was achieved in 97.6% of patients at a median of 18 days, whereas platelet engraftment was achieved in 92.7% of patients at a median of 28 days. The cumulative incidences of cytomegalovirus (CMV) reactivation and CMV disease were 52.5% and 5.1% at 1 year. The incidence of grade 2-4 acute Graft Versus Host Disease (GVHD) was 18.2%. The incidence of chronic GVHD at 2 years was 40.7%, with extensive chronic GVHD occurring in 17.7% of patients. The incidences of relapse and non-relapse mortality (NRM) at 2 years were 8.8% and 20.7% respectively. The leading causes of death were infection (64.7%) followed by relapse (14.2%). The 2-year overall survival was 74%. Relapse free survival and GVHD free, relapse free survival at 2 years was 70% and 48%. Haplo-HSCT using a peripheral blood graft and PTCy GVHD prophylaxis demonstrates long-term disease control with acceptable rates of NRM for older patients with AML/MDS.

Impact of Donor Age in Haploidentical-Post-Transplantation Cyclophosphamide versus Matched Unrelated Donor Post-Transplantation Cyclophosphamide Hematopoietic Stem Cell Transplantation in Patients with Acute Myeloid Leukemia

Haploidentical hematopoietic cell transplantation (HCT) with post-transplantation cyclophosphamide (PTCy) graft-versus-host-disease (GVHD) prophylaxis is associated with inferior overall survival (OS) compared to HLA-matched unrelated donor (MUD) HCT with PTCy prophylaxis in patients receiving reduced-intensity conditioning (RIC). Given prognostic implications of donor age, we investigated the differences in outcomes of patients with acute myeloid leukemia (AML; n=775) undergoing RIC-HCT with a younger MUD (age <35 years; n=84) versus a younger haploidentical donor (age <35 years; n=302) versus an older haploidentical donor (age ≥35 years; n=389). The older MUD group was excluded from the analysis because of small numbers. The younger haploidentical donor group (median age, 59.5 years) was somewhat younger than the younger MUD group (median age, 66.8 years) and the older haploidentical donor group (median age, 64.7 years). More patients in the MUD group received peripheral blood grafts (82%) compared to the haploidentical donor groups (55% to 56%). In multivariate analysis, compared to the younger MUD group, the younger haploidentical donor group (hazard ratio [HR], 1.95; 95% confidence interval [CI], 1.22 to 3.12; P=.005) and the older haploidentical donor group (HR, 2.36; 95% CI, 1.50 to 3.71; P < .001) had a significantly inferior OS, and the younger haploidentical donor group (HR, 3.72; 95% CI, 1.39 to 9.93; P=.009) and older haploidentical donor group (HR, 6.91; 95% CI, 2.75 to 17.39; P < .001) had a significantly higher risk of nonrelapse mortality. The older haploidentical group had a significantly higher risk of grade II-IV acute GVHD (HR, 2.29; 95% CI, 1.38 to 3.80; P=.001) and grade III-IV acute GVHD (HR, 2.70; 95% CI, 1.09 to 6.71; P=.03). There were no significant differences across the groups in the incidence of chronic GVHD or relapse. Among adult AML patients in CR undergoing RIC-HCT with PTCy prophylaxis, a young MUD may be preferred over a young haploidentical donor.

Abstract B121: HLA-mismatched unrelated donor hematopoietic cell transplantation with post-transplant cyclophosphamide improves clinical outcomes for racial and ethnic minority patients with hematologic malignancies

Abstract Introduction: Racial and ethnic disparities exist in three areas related to hematopoietic cell transplantation (HCT): donor availability, access, and post-HCT outcomes. A significant barrier to access to HCT for patients (pts) of racial or ethnic minorities (REM) is the limited availability of fully matched donors (i.e., grafts matched at HLA-A, -B, -C, and -DRB1 loci) in volunteer registries. While mismatched unrelated donor (MMUD) grafts (i.e., &amp;lt;7/8 match) can be offered to pts without matched donors, MMUD HCT results in poor survival when traditional graft-versus-host disease (GVHD) prophylaxis (PPx) is used. GVHD PPx with post-transplantation cyclophosphamide (PTCy) is associated with favorable survival after haploidentical HCT, and promising outcomes have been reported in a prospective multicenter study utilizing PTCy in MMUD HCT. Herein, we analyzed the outcomes of an ethnically diverse cohort of pts who underwent MMUD HCT with PTCy at two large urban transplant centers. Objectives and Methods: Subjects receiving HCT from an MMUD from 2010-to 2020 at the University of Miami and Memorial Sloan-KetteringCancer Center were included. Pts were stratified by age, HCT indication, race/ethnicity, graft type, conditioning intensity, disease status, and degree of HLA mismatch. The primary study endpoint was one-year overall survival (OS). Secondary endpoints were event-free survival (EFS), non-relapse mortality (NRM), and cumulative incidence of acute and chronic GVHD. Results: A total of 82 pts were evaluated. The median age at HCT was 60 years (21-75), the most common indication for HCT was acute leukemia (51%), 41% of pts received an ablative conditioning regimen, and 50% received peripheral blood (PB) grafts. Forty-four percent identified as non-Hispanic white (NHW), and 56% identified as REM (Non-Hispanic Black: 30%; Hispanic: 64%; Asian/Pacific: 4.3%). The two groups (NHW vs. REM) were well-matched for leading HCT indication, disease-risk index, degree of mismatch, and disease status at HCT. REM pts were younger (median age at HCT 65 vs 56 years for NHW, p=0.001) and more likely to receive a PB graft (63% vs 40%, P = 0.04). One-year OS was 75%, EFS was 69%, and NRM was 16% for the entire cohort. Grade 3-4 acute GVHD at day 180 post-HCT was 15%, and one-year severe chronic GVHD was 9%. OS was comparable between 7/8-matched and highly-mismatched (&amp;lt;6/8) HCT recipients (75% vs. 76%, respectively; P &amp;gt;0.9). There were no differences in one-year OS (77% vs 74%, p = 0.9) and EFS (63% vs 72%, p = &amp;gt;0.9) between NHW and REM pts. Similarly, rates of acute (17% vs 13%, p = 0.5) and chronic GVHD (5.7% vs 11%, p = 0.5) were comparable between NHW and REM pts. Conclusion: PTCy resulted in encouraging clinical outcomes following MMUD HCT. Post-HCT OS, RFS, and GVHD rates were comparable between NHW and REM pts and those receiving 7/8 or highly mismatched grafts. Favorable post-HCT outcomes following MMUD with PTCy may increase HCT utilization and access for REM pts. Citation Format: Antonio M. Jimenez Jimenez, Sunil Iyer, Krishna Komanduri, Samantha Brown, Trent Wang, Stephanie Chinapen, Denise Pereira, Sean Devlin, Mark Goodman, Amer Beitinjaneh, Craig Sauter, Lazaros Lekakis, Miguel Angel Perales, Doris Ponce, Brian Shaffer. HLA-mismatched unrelated donor hematopoietic cell transplantation with post-transplant cyclophosphamide improves clinical outcomes for racial and ethnic minority patients with hematologic malignancies [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr B121.

Phase II Study of Myeloablative 8/8- or 7/8-Matched Allotransplantation with Post-Transplant Cyclophosphamide, Tacrolimus, and Mycophenolate Mofetil: Marked Reduction in Gvhd Risk without Increased Relapse Risk Compared to Historical Cyclosporine/Methotrexate

Introduction Allogeneic hematopoietic cell transplantation (HCT) is the only potentially curative treatment for many high-risk hematologic malignancies. Myeloablative conditioning (MAC) is currently the standard of care for young and fit patients; however, graft-versus host disease (GVHD) continues to be a major limitation to the success of HCT, increasing post-transplant morbidity and mortality. An ideal HCT is one that combines strategies to reduce the incidence and severity of GVHD, without compromising graft versus-tumor effect. We hypothesized that the GVHD prophylaxis regimen consisting of post-transplant cyclophosphamide (PTCy), tacrolimus (Tac) and mycophenolate mofetil (MMF) would reduce the incidence of chronic GVHD in patients receiving a standard MAC HCT without an increase in risk of malignant relapse. Methods This is an analysis of a phase II study at the University of Minnesota using a MAC regimen of either: 1. total body irradiation (TBI, total dose 1320 cGy administered twice a day from days -4 to -1) or 2. Busulfan 3.2mg/kg daily (cumulative AUC 19,000 - 21,000 μmol/min/L) plus fludarabine 160mg/m2 days -5 to -2 for patients unable to receive further radiation, followed by a GVHD prophylaxis regimen of PTCy (50mg/kg days +3 and +4), Tac and MMF (beginning day +5). The primary endpoint is cumulative incidence of chronic GVHD requiring systemic immunosuppressive treatment at 1 year post-transplant. Eligibility included: age ≤ 60 years, malignant or non-malignant diagnosis, matched related (MRD) or unrelated (MUD) donor with either a bone marrow (BM) or filgrastim-mobilized peripheral blood (PB) graft. We compared those results to our previous MAC protocol which utilized a regimen of either cyclophosphamide (60mg/kg days -6 and -5)/TBI (1320 cGy administered twice a day from days -4 to -1) or busulfan (0.8 mg/kg/dose IV in 4 daily doses days -9 to -6 [total 12.8 mg/kg])/ cyclophosphamide (50 mg/kg days -5 to -2) and GVHD prophylaxis consisted of cyclosporine and methotrexate. Results Through June 2022, we treated 125 patients with a median follow up of 472 days post-transplant. Of those, 48% were female and 22 (17.6%) were ≤ 18 years old with median age at HCT of 38 years (range, 1-59 yrs; Interquartile range [IQR], 22-50 yrs). Donor source was 8/8 MRD in 69 patients (55.2%), 8/8 MUD in 44 (35.2%), and 7/8 MUD in 12 (9.6%). Graft source was bone marrow in 43 patients (34.4%) and PB in 82 (65.6%). Preparative regimen was TBI in 89.6% of patients. 124 of 125 patients achieved primary neutrophil engraftment by 42 days, median 16 days (range, 13-30). 119 of 125 achieved platelet engraftment by 6 months, median 25.5 days (range, 14-98). 91 patients (72.8%) required total parenteral nutrition (TPN) for oral mucositis and regimen-related toxicities during their initial transplant admission. Cumulative incidence of Grade II-IV acute GVHD by day +100 was 16% (95% confidence interval (CI): 9-23%); Grade III-IV acute GVHD was 4% (CI: 0-8%). No patients experienced grade IV GVHD and there were no deaths due to GVHD. At 1 year, only 3 of 105 patients developed chronic GVHD requiring immune suppression, for a cumulative incidence of 4% (CI: 0-8%). Two-year cumulative incidence of relapse was 25% (CI: 15-36%). Two-year overall survival was 80% (CI: 69-87%) and two-year GVHD-free relapse free survival (GRFS) was 57% (CI: 45-67%). Kaplan-Meier curves comparing overall survival and GRFS between this cohort and our previous MAC protocol without PTCy are shown in Figure 1. Figure 2 shows the comparison between these two consecutive cohorts in incidence of acute and chronic GVHD, transplant-related mortality (TRM) and relapse. Discussion Myeloablative HCT with a TBI or Busulfan/Fludarabine-based preparative regimen, followed by a GVHD prophylaxis regimen of PTCy, Tac, and MMF results in extremely low incidence of chronic GVHD, the primary objective of this clinical trial. Importantly, this regimen is feasible and effective for pediatric and adult patients. Further improvement in outcomes could potentially be achieved by incorporating post-transplant relapse mitigating strategies as well as supportive care measures to decrease regimen-related toxicities. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Artificial Intelligence Methods to Estimate Overall Mortality and Non-Relapse Mortality Following Allogeneic Hematopoietic Cell Transplantation in the Modern Era: An EBMT Transplant Complications Working Party Study

Introduction Allogeneic hematopoietic cell transplantation (alloHCT) is a life-saving procedures for many hematological diseases. However, its toxicity counterbalances its curative potential. Several prognostic scores have been created in the last two decades. Most scores derive from small sized and monocentric cohorts of patients. Also, contemporary patients and alternative donors are usually excluded from these scores. Methods We selected patients from the EBMT registry with the following characteristics: age > 18 years old; allogeneic hematopoietic cell transplantation (alloHCT) performed between 2010 and 2019; hematological disease diagnosis (AML/ALL; MDS/MPN; NHL/HL; plasma cell dyscrasias); any disease status at transplant; use of HLA-matched (familiar or unrelated) or haploidentical donor; myeloablative or RIC/NMA conditioning regimen; peripheral blood or bone marrow graft source. The primary objective was to create a prognostic score able to predict overall mortality (OM) at +2 years. The secondary objective was to predict non-relapse mortality (NRM) at 2 years. To create a newer prognostic score, we explored the following statistic and machine-learning techniques: step-wise logistic regression, support vector machine with linear and radial kernels, random forest, gradient boosting, elasticnet. We also tested simple fully connected neural network. The score included all the pre-transplant variables with a well-known prognostic role in terms of NRM related to disease (disease type) patient (age, gender, Karnofsky score, body mass index, presence of significant comorbidities, CMV status) transplant (time from diagnosis to transplant, donor type, GVHD prophylaxis, conditioning intensity, graft type) and transplant center characteristics (JACIE accreditation, > 20 alloHCT/year). OM model development was made on 70% of the data set, optimized on 15% and validated on the 15% of remaining data. Models with the best accuracy were selected to build the prognostic score. Results A total of 48984 patients were included into the analysis (Table 1). Median follow-up time for survivors was 38.4 months. Overall mortality and NRM at +2 years were 39.5% (95% CI=39.0-40.0%) and 19.0% (95% CI=18.5-19.5%), respectively. The 5 models predicted 2-year OM and NRM with similar AUC values. Best models were, for OM, gradient boosting (XGBoost) with AUC=0.64 (95% CI 0.630-0.655) and for NRM, elasticnet with AUC=0.58 (0.566-0.594). Neural networks had slightly higher performance for NRM but has limitations regarding the explicability of results. Same results were observed also when performing the analysis with the haploidentical cohort (n=5.934, AUC 0.66 for OM and 0.57 for NRM). In the final prognostic score including all the variables, gradient boosting was used to predict OM and elasticnet to predict NRM. The score was able to furnish a personalized prediction for each patient with continuous values. Patients with the lowest score had a 2-year OM and NRM of 22.2% and 8.7%, respectively. Patients with the highest score had a 2-year OM and NRM of 81.2% and 87.1%, respectively. A visual representation of the score prediction distribution was made on the validation cohort grouping the potential results into 4 groups (figure 1). Conclusion Our score showed to be useful in improving risk stratification of OM and NRM in the current era, including haploidentical transplants and post-transplant cyclophosphamide GVHD prophylaxis which were not included in previous scores. However, a generally poor accuracy despite the robust methodology confirms previous observations highlighting that the results of a prognostic score itself should not be used to exclude patients from a life-saving procedure. In such high-risk cases, more comprehensive evaluations (e.g. geriatric scores), biological scores (e.g. EASIX scores) and the overall patient's clinical phenotype should be evaluated to establish the actual transplantation risk and help in this difficult therapeutic choice Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Allogeneic Hematopoietic Cell Transplant Yields Long Term Disease Free Survival in a Significant Number of Patients with Classic Hodgkin Lymphoma

Background: Classic Hodgkin's lymphoma (cHL) is a highly curable disease. A minority of patients, however, will have relapse/refractory (RR) disease and these patients are challenging to manage especially those who relapse after autologous hematopoietic cell transplant (auto-HCT). Even though a number of salvage options are available for these patients none of them is considered curative except allogeneic hematopoietic cell transplant (allo-HCT). Design and Methods: Retrospective analysis of 33 patients who had allo-HCT using matched family donors for cHL between January 2007 and December 2021. Continuous variables were summarized using medians and ranges. Categorical variables were summarized using frequencies and percentages. Probabilities of overall survival (OS) and disease free survival (DFS) were calculated using Kaplan-Meier estimate. Statistical analysis was conducted sing R studio (version 1.3.959 © 2009-2020 RStudio, PBC). Results: The median patient age at allo-HCT was 27 years. Seventeen patients were males and 16 were females. Five patients had early stage disease (Ann Arbor stage I, II) and 28 had advanced stage disease (Ann Arbor III, IV). Regarding the histologic type of cHL, eighteen had nodular sclerosis (NS), eight had mixed cellularity (MC), one had lymphocyte rich (LR), one had lymphocyte depleted (LD) and five cases were labeled as classic HL without further classification. Seventeen patients received brentuximab vedotin and fourteen patients received check point inhibitors prior to allo-HCT. The median number of chemotherapy lines prior to allo-HCT was 4 (range: 2-8). Twenty seven patients had chemosensitive disease (complete or partial remission) while 6 patients had chemoresistant disease (stable or progressive) prior to allo-HCT. Twenty seven patients had undergone auto-HCT prior to allo-HCT. Eighteen patients had elevated (>50) erythrocyte sedimentation rate (ESR) while 15 had normal ESR prior to allo-HCT. The majority of patients were conditioned with a reduced intensity regimen (29 patients versus 4 patients conditioned with myeloablative regimen). Twenty five patients received non-TBI (total body irradiation) based conditioning while 8 patients had TBI based regimen. The most frequently used conditioning regimen was fludarabine + melphalan. Nine patients received ATG (anti thymoglobulin) as a part of the conditioning while 24 patients did not. Thirty one patients received peripheral blood graft while 2 patients received bone marrow graft. The five years DFS was 37.5%. Twenty seven % of patients had acute GVHD (graft versus host disease) and 48% had chronic GVHD. The effect of a number of variables (number of chemotherapy lines, pre-allo-HCT ESR, conditioning intensity, ATG vs no ATG, receipt of pre-allo-HCT brentuximab or check point inhibitors, prior auto-HCT, chemosensitivity pre-allo-HCT and histologic subtype) was tested on the DFS. The only two variable that were statistically associated with a better DFS were pre-allo-HCT chemosensitivity (P=0.006) and non-NS histologic subtype (P=0.027). (Figure 1 and 2). Conclusions: Allogeneic stem cell transplantation can result in long-term progression-free survival in heavily pre-treated patients with Hodgkin's lymphoma. Patients with no response to salvage chemotherapy pre-allo-HCT and patients with NS subtype had detrimental outcomes. Better selection of patients before allo-HCT can result in a higher cure rates. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Outcomes of Patients with TP53-Mutated Myeloid Neoplasms (TP53-MN) and the Role of Allogenic Blood or Marrow Transplantation (alloBMT)

Background: TP53 mutations are present in up to 20% of patients with myeloid malignancies and are frequently associated with a complex karyotype (CK) and poor responses to therapy. Even though overall response rates have improved significantly with less intensive induction modalities such as hypomethylating (HMA) agents alone or in combination with venetoclax, most patients succumb to their disease. AlloBMT remains the only curative option and even though the outcomes after alloBMT are disappointing, some patients achieve long-term survival. In the current study, we aimed to determine the clinical outcome of patients with TP53-MN and the impact of therapies including alloHCT on outcomes. Methods: We performed a single-center retrospective review of adult patients with TP53-MN evaluated at Johns Hopkins between November 2015 and February 2020. The analysis of somatic mutations was performed using a 59-gene targeted next-generation sequencing (NGS) assay. Cytogenetic analysis was performed on bone marrow or peripheral blood using standard methods including G-banding by trypsin with Giemsa staining. Results: We identified a total of 93 patients with TP53-MN. Disease subtypes included de novo AML (n = 22), AML arising from MDS/MPN (n = 15), MDS (n = 23), therapy-related myeloid neoplasm (n = 29), MDS/MPN overlap syndrome (n = 2) and MPN (n = 2). The median (Q1, Q3) age was 67 years (59 - 73 years). Cytogenetics was available for 89/93 (95.7%) patients. Of those, 73 (82.0%) patients had complex karyotype (CK). The median maximum TP53 variant allele frequency (VAF) per patient was 42.5%. Sixty-two (66.6%) patients had TP53 null phenotype: 14 (15.1%) patients had multiple TP53 mutations, 37 (41.6%) had deletion 17p and 11 (12.0%) had copy-neutral loss-of-heterozygosity (CnLOH). Overall, 79/93 (85%) patients received therapy: 20 (25.3%) were treated with HMA alone, 30 (38.0%) with HMA+venetoclax, 10 (12.7%) with HMA+others, 15 (19.0%) with intensive chemotherapy, 2 (2.5%) with an immunomodulatory drug, 1 (1.3%) with ivosidenib and 1 (1.3%) with a JAK2 inhibitor. Of those, 29 (36.7%) patients received non-myeloablative alloBMT with post-transplant cyclophosphamide (10 (34.5%) bone marrow and 19 (65.5%) mobilized peripheral blood grafts (PBSCT)). Median overall survival (OS) in patients receiving alloBMT, any therapy, or supportive care was 18.9, 4.1, and 2.5 months respectively (p < 0.001, Figure 1). Among patients in the alloBMT group, there was a significant OS difference between TP53-MN CK vs. non-CK (median OS 13.7 months vs not reached, p = 0.01, Figure 2). Also, patients with TP53-MN CK demonstrated better OS when treated with alloBMT compared to any therapy or supportive care. However, most TP53-MN CK patients ultimately succumbed to their disease regardless of the therapeutic modality. Therapeutic modalities prior to alloBMT did not appear to affect post-alloBMT outcomes but among patients who received PBSCT, OS was significantly better in patients receiving 400cGy vs 200 cGy total body irradiation (median OS 8.9 vs. 21 months, p=0.01). Conclusions: TP53-MN appears to be a heterogeneous disease with a variable prognosis. While OS of patients with TP53 mutations and non-CK who underwent alloBMT resembled that of intermediate-risk AML, patients with TP53 null phenotype associated with CK had a worse outcome. Even though OS appears to be significantly improved with alloBMT, particularly patients receiving PBSCT+400cGy TBI, most patients eventually relapse. Novel therapeutic strategies are urgently needed to improve the outcomes of TP53 CK patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Abatacept/Tacrolimus or Abatacept/Tacrolimus/Post-Transplant Cyclophosphamide Are Safe and Highly Effective in Preventing Graft-Versus-Host Disease in Matched or Mismatched Donor Peripheral Blood Stem Cell Transplantation

Background: Abatacept blocks CD28-CD80/86 axis and prevents T-cell co-stimulation. In early studies, abatacept has shown promising results when added to methotrexate and tacrolimus in matched and mismatched donor SCT. Further promising results have been demonstrated with a combination of post-transplant cyclophosphamide (PTCy), abatacept, and a short course of tacrolimus to improve the results of GvHD prevention in the setting of haploidentical SCT. Based on this data we initiated a phase Ib-II clinical trial of the efficacy and toxicity of the Abatacept/Tacrolimus/PTCy combination for patients who received HLA-mismatched grafts and Abatacept/Tacrolimus combination for patients who received HLA-matched grafts. Aim: assess the frequency of acute and chronic GVHD grade II-IV. Patients received G-CSF mobilized peripheral blood grafts from related and unrelated donors. GvHD prevention consisted of PTCy 50mg/kg IV on day +3 and +4, abatacept 10mg/kg IV on day -1, +5, +14 and +28 and tacrolimus. Tacrolimus was started on day -1 at 0.02 mg/kg/day by continuous IV and adjusted thereafter to maintain a trough level of 5-12 ng/mL. Tacrolimus taper was planned to begin on day +90 and complete by day +120 in the absence of GvHD. All patients received standard supportive care including acyclovir and co-trimoxazole until CD4-count >200 cells/muL, posaconazole/voriconazole until day +60, and if CMV positive by serology, ganciclovir 5 mg/kg per day until day +100. G-CSF was administered routinely until neutrophil engraftment. From Oct 2020 to Jul 2022, 51 patients were enrolled. The median age was 44 years (23-64) M/F 49%/51%. Diagnosis: AML 23,5% (12/51), B-NHL 17,6% (9/51), HD 17,6% (9/51), ALL 15,6% (8/51), MDS 9,8% (5/51), MF 5,9% (3/51), CLL 4% (2/51), MM 4% (2/51), AA 2% (1/51). Disease status before conditioning: 30/51 had CR, 15/51 - PR, 6/51- active disease. Conditioning regimens: Treo/Flu for AML, ALL, MDS and MF (28/51, 55%), Benda/Flu for B-NHL, HD, CLL and MM (22/51, 43%), Flu/Cy/ATG for AA (1/51, 2%). RIC/MAC: 65%/35%. 29,4% (15/51) of patients received cryopreserved products. Median times to ANC and platelet engraftment were 15 (8-60) and 18 days. 2 patients had primary graft failure (absence of engraftment > 28 days, non-response MDS before SCT and B-NHL, both 5/10, both older than 60). In both cases, a second HSCT was performed from the same donors. In the first case (non-response MDS), repeated HSCT without any effect and the patient died, in the second case, there was graft engraftment with the restoration of blood parameters. 1 patient (ETP ALL, mismatched related donor 5/10) had poor graft function. Transfusion of purified CD34+ cells (Miltenyi Biotec) from the same donor was accompanied by restoration of hematopoiesis. With a median follow-up was 154 days (25-641) with 34 patients having >120 days, 23 >180 days, and 7 >365 days of follow-up, 13,7% (7/51) patients developed acute GvHD grade II-IV (mostly skin, gut, liver). 9,8% (5/51) of patients developed chronic GvHD grade II-IV (skin, lungs, mucous eyes, liver, joints). 47% (24/51) completed tacrolimus taper by day +120. 3 patients switched from tacrolimus to sirolimus and one to prednisone due to intolerance or toxicity. 3 patients with MF received ruxolitinib from day +30 as a treatment for MF (no signs of GVHD of any grade). All patients with GvHD grade II-IV received systemic steroids. 7 patients received ruxolitinib, 3 - MMF, 4 - rituximab, 1 - daratumumab, 2 - ibrutinib, 1 - acalabrutinib and 2 - imatinib. CMV activation rate was 35,3%. There were 1 case of BK virus and 1 case of JC virus (patient with HD after aGVHD and cGVHD). 2 patients developed thrombotic microangiopathy (one received tacrolimus, one did not). During the observation period, 25,5% (13/51) patients died: 3 due to COVID-19, 4 due to relapse/progression, 3 from infectious complications (2 sepsis and 1 PML due to JCPyV), 1 from non-engraftment, and 1 due to uncontrolled AIHA. Summary: our preliminary results suggest that Abatacept/Tacrolimus +- PTCy is feasible and seems to offer very promising outcomes with low rates of acute and chronic GvHD grade II-VI. Based on this and previous trials we need a phase III clinical trial to evaluate abatacept. In our practice, abatacept-based immunosuppressive therapy has become routine. Additional reducing mortality is possible due to the widespread use of anti-covid antibodies and the exclusion of patients with a lack of response to disease therapy.

Predictive Factors and Outcomes after Allogeneic Stem Cell Transplantation for Adults with Acute Lymphoblastic Leukemia in Brazil

Allogeneic stem cell transplantation (HSCT) remains a potentially curative approach for acute lymphoblastic leukemia (ALL), especially for high-risk patients and those with relapsed/refractory disease, although its efficacy is offset by a not-negligible toxicity. Adult patients with ALL fare worse in developing countries, with little data about the HSCT in this setting. In this study, we aimed to describe outcomes and examine risk factors for overall survival (OS), leukemia-free survival (LFS), cumulative incidence of relapse (CIR), nonrelapse mortality (NRM), and graft-versus-host disease (GVHD) after HSCT for ALL in Brazilian centers. This retrospective registry study included patients with ALL or ambiguous lineage leukemia age >16 years who underwent a first HSCT at 5 Brazilian centers between January 2007 and December 2017. A total of 275 patients were included, with a median age of 31 years (range, 16 to 65 years). Thirty-five percent were Philadelphia chromosome-positive. A matched sibling donor was used in 53%, a matched unrelated donor (MUD) in 19%, a mismatched unrelated donor in 9%, a haploidentical donor in 19%, and umbilical cord blood in 5%. The engraftment failure rate was 1.5%. The 5-year cumulative incidence of acute grade II-IV was 54.2%, and that of chronic GVHD was 26.2%. Five-year CIR and NRM were 28.1% and 34.1%, respectively. Central nervous system involvement at diagnosis (hazard ratio [HR], 2.2) and disease status (HR, 1.8 for second or later complete response and 7.9 for refractory) were associated with increased relapse incidence, whereas the use of peripheral blood graft (HR, .51) and a haploidentical donor (HR, .4) significantly decreased relapse incidence. Five-year OS and LFS were 40.7% (95% confidence interval [CI], 35.1-47.1) and 37.8% (95% CI, 32.3-44.1), respectively. Patient age, donor age, and disease status were independently associated with OS and LFS. Pre-HSCT positivity of minimal residual disease (>.01%) was associated with worse LFS (HR, 1.47) in available cases. This is the largest series of adults with ALL undergoing HSCT from Brazil reported to date. Although OS and LFS were similar to data reported in the literature, NRM was higher. Patient age and donor age outweighed donor type or graft source in our analysis. Interestingly, haploidentical HSCT was associated with lower CIR, whereas the use of MUDs was associated with higher NRM and GVHD rates. These results impact donor selection strategy in Brazil with the aim of offering timely HSCT for high-risk ALL patients in our setting.

Post-Transplantation Cyclophosphamide Versus Tacrolimus and Methotrexate Graft-Versus-Host Disease Prophylaxis for HLA-Matched Donor Transplantation

The use of post-transplantation cyclophosphamide (PTCy) for graft-versus-host disease (GVHD) prophylaxis is increasing in patients undergoing HLA-matched sibling (MSD) or unrelated (MUD) donor hematopoietic cell transplantation (HCT), but data about its comparative efficacy against the traditional GVHD prophylaxis are scarce. Two broad questions assessed in this study were (a) comparison of PTCy-based GVHD prophylaxis versus Tac/MTX (without ATG) in the MSD and (b) comparison of PTCy-based GVHD prophylaxis versus Tac/MTX (with ATG) in the MUD group. This retrospective single-center study analyzed the outcomes of 964 patients who received Tac/MTX (n=578) versus PTCy-based (n=386) GVHD prophylaxis. All MUD recipients in the Tac/MTX group also received ATG; thus separate analyses were conducted for MSD (n=412) and MUD (n=552) cohorts. In the MUD cohort, 306 patients received Tac/MTX/ATG and 246 received PTCy-based GVHD prophylaxis. In the MSD cohort, 272 received Tac/MTX and 140 received PTCy-based prophylaxis. Both PTCy groups included somewhat older patients than the Tac/MTX groups and more patients had myeloid malignancy (85%-90% versus 59%-64%, respectively). A majority of patients in all groups received myeloablative conditioning and peripheral blood graft. Both PTCy groups had a significantly delayed neutrophil engraftment, higher risk of hemorrhagic cystitis, and higher risk of bacterial infections than the Tac/MTX groups. The risks of viral infections and related deaths were significantly higher in Tac/MTX group in the MUD cohort. In multivariate analysis, the risk of grade III-IV acute GVHD was similar in PTCy and Tac/MTX groups in both MSD and MUD cohorts, but the risk of chronic GVHD was significantly lower with PTCy in the MSD cohort. PTCy was associated with a significantly lower risk of non-relapse mortality and better progression-free survival in the MUD. PTCy was associated with improved GVHD-free relapse-free survival in both MSD and MUD groups. Our data suggest a benefit of using PTCy-based GVHD prophylaxis in both MSD (versus Tac/MTX) and MUD (versus Tac/MTX/ATG) HCT.