Donor Hematopoietic Cell Transplantation Research Articles

Optimizing Access to Unrelated Donors in Canada: Re-Examining the Importance of Donor Factors on Outcomes Following Hematopoietic Cell Transplantation

HLA-matched allogeneic hematopoietic cell transplantation (HCT) is a curative therapy for many patients. Unrelated HLA-matched donors are the most frequently used donor for HCT. When more than one donor transplant option is available, transplant centers can select donors based on non-HLA factors. With improved ability to prevent and treat immune complications, such as graft-versus-host disease and infections, it may be possible to proceed more often using HLA-mismatched donors, allowing greater consideration of non-HLA factors, such as donor age, CMV serostatus, and ABO blood group matching, which have demonstrated important impacts on transplant outcomes. Additional factors to consider are donor availability rates and the usage of domestic donors to optimize outcomes. A review of non-HLA factors and considerations on the selection of optimal unrelated donors for HCT are provided within this updated current context.

Good engraftment after reduced intensity targeted busulfan-based conditioning and matched related donor hematopoietic cell transplantation in hemoglobinopathies.

Hematopoietic cell transplantation (HCT) is an established curative therapy for transfusion-dependent thalassemia (TDT) and sickle cell disease (SCD). The latest American Society of Hematology guidelines recommend myeloablative preparative regimen in patients under 18years of age. The objective was to demonstrate safety and efficacy of a reduced intensity conditioning (RIC) regimen including high-dose fludarabine, anti-thymocyte globulin, and targeted busulfan as a single alkylator to sub-myeloablative exposures. Between 2012 and 2021, 11 patients with SCD and five patients with TDT and matched related donor (MRD) HCT were included. The median age at transplantation was 8.3years (range: 3.7-18.8years). The median administered busulfan AUC was 67.4mg/L×h (range: 60.7-80mg/L×h). Overall survival was 93.8% and event-free survival 87.5% with one engrafted SCD patient with pre-existing moyamoya disease succumbing after drainage of a subdural hematoma. One SCD patient developed a secondary graft failure and was treated with a second HCT. Myeloid chimerism was full in all other patients with a median follow-up time of 4.1years (range: 2.0-11.1years), whereas T-cell donor chimerism was frequently mixed. This RIC conditioning followed by MRD HCT is sufficiently myeloablative to cure pediatric patients with hemoglobinopathies without the need for additional total body irradiation or thiotepa.

Donor whole blood DNA methylation is not a strong predictor of acute graft versus host disease in unrelated donor allogeneic haematopoietic cell transplantation.

Allogeneic hematopoietic cell transplantation (HCT) is used to treat many blood-based disorders and malignancies, however it can also result in serious adverse events, such as the development of acute graft-versus-host disease (aGVHD). This study aimed to develop a donor-specific epigenetic classifier to reduce incidence of aGVHD by improving donor selection. Genome-wide DNA methylation was assessed in a discovery cohort of 288 HCT donors selected based on recipient aGVHD outcome; this cohort consisted of 144 cases with aGVHD grades III-IV and 144 controls with no aGVHD. We applied a machine learning algorithm to identify CpG sites predictive of aGVHD. Receiver operating characteristic (ROC) curve analysis of these sites resulted in a classifier with an encouraging area under the ROC curve (AUC) of 0.91. To test this classifier, we used an independent validation cohort (n = 288) selected using the same criteria as the discovery cohort. Attempts to validate the classifier failed with the AUC falling to 0.51. These results indicate that donor DNA methylation may not be a suitable predictor of aGVHD in an HCT setting involving unrelated donors, despite the initial promising results in the discovery cohort. Our work highlights the importance of independent validation of machine learning classifiers, particularly when developing classifiers intended for clinical use.

Umbilical Cord Blood Transplantation for Fanconi Anemia With a Special Focus on Late Complications: a Study on Behalf of Eurocord and SAAWP-EBMT

Hematopoietic cell transplantation (HCT) remains the sole available curative treatment for Fanconi anemia (FA), with particularly favorable outcomes reported after matched sibling donor (MSD) HCT. This study aimed to describe outcomes, with a special focus on late complications, of FA patients who underwent umbilical cord blood transplantation (UCBT). In this retrospective analysis of allogeneic UCBT for FA performed between 1988 and 2021 in European Society for Blood and Marrow Transplantation (EBMT)-affiliated centers, a total of 205 FA patients underwent UCBT (55 related and 150 unrelated) across 77 transplant centers. Indications for UCBT were bone marrow failure in 190 patients and acute leukemia/myelodysplasia in 15 patients. The median age at transplantation was 9 years (range, 1.2 to 43 years), with only 20 patients aged >18 years. Among the donor-recipient pairs, 56% (n = 116) had a 0 to 1/6 HLA mismatch. Limited-field radiotherapy was administered to 28% (n = 58) and 78% (n = 160) received a fludarabine (Flu)-based conditioning regimen. Serotherapy consisted of antithymocyte globulin (n = 159; 78%) or alemtuzumab (n = 12; 6%). The median follow-up was 10 years for related UCBT and 7 years for unrelated UCBT. Excellent outcomes were observed in the setting of related UCBT, including a 60-day cumulative incidence (CuI) of neutrophil recovery of 98.1% (95% confidence interval [CI], 93.9% to 100%), a 100-day CuI of grade II-IV acute graft-versus-host disease (GVHD) of 17.3% (95% CI, 9.5% to 31.6%), and a 5-year CuI of chronic GVHD (cGVHD) of 22.7% (95% CI, 13.3% to 38.7%; 13% extensive). Five-year overall survival (OS) was 88%. In multivariate analysis, none of the factors included in the model predicted a better OS. In unrelated UCBT, the 60-day CuI of neutrophil recovery was 78.7% (95% CI, 71.9% to 86.3%), the 100-day CuI of grade II-IV aGVHD was 31.4% (95% CI, 24.6% to 40.2%), and the 5-year CuI of cGVHD was 24.3% (95% CI, 17.8% to 32.2%; 12% extensive). Five-year OS was 44%. In multivariate analysis, negative recipient cytomegalovirus serology, Flu-based conditioning, age <9 years at UCBT, and 0 to 1/6 HLA mismatch were associated with improved OS. A total of 106 patients, including 5 with acute leukemia/myelodysplasia, survived for >2 years after UCBT. Nine of these patients developed subsequent neoplasms (SNs), including 1 donor-derived acute myelogenous leukemia and 8 solid tumors, at a median of 9.7 years (range, 2.3 to 21.8 years) post-UCBT (1 related and 8 unrelated UCBT). In a subset of 49 patients with available data, late nonmalignant complications affecting various organ systems were observed at a median of 8.7 years (range, 2.7 to 28.8 years) post-UCBT. UCB is a valid source of stem cells for transplantation in patients with FA, with the best results observed after related UCBT. After unrelated UCBT, improved survival was observed in patients who underwent transplantation at a younger age, with Flu-based conditioning, and with better HLA parity. The incidence of organ-specific complications and SNs was relatively low. The incidence of SNs, mostly squamous cell carcinoma, increases with time. Rigorous follow-up and lifelong screening are crucial in survivors of UCBT for FA.

Improving Outcomes of Peripheral Blood Stem Cell (PBSC) HLA-Mismatched Unrelated Donor (MMUD) Hematopoietic Cell Transplantation (HCT): Effect of Graft Versus Host Disease (GVHD) Prophylaxis

Human leukocyte antigen (HLA) well matched donor (related or unrelated) has remained the preferred donor source for patients undergoing HCT for hematological disease, but the probability of finding a suitable related or unrelated donor has varied based on ethnic groups. HLA-mismatch unrelated donor (MMUD) transplantation has improved access to HCT in underrepresented minority groups and patients of mixed race. Historically, MMUD HCT has been associated with inferior survival outcomes compared to matched unrelated donor HCT when using conventional platforms of GVHD prophylaxis. (PMID: 31449184, 20538804). Efforts to improve outcomes have investigated the addition of a third agent such as anti-thymocyte globulin (ATG), mini-methotrexate (MTX) or mycophenolate mofetil (MMF). More recently, a study by the National Marrow Donor Program (NMDP) demonstrated the feasibility of post-transplant cyclophosphamide (PTCy) based GVHD prophylaxis in MMUD HCT using bone marrow (BM) grafts (PMID: 33905264). Additionally, our group demonstrated promising overall survival (OS) and GVHD-free/relapse-free-survival (GRFS) rates in peripheral blood stem cell (PBSC) MMUD HCT using PTCy based GVHD prophylaxis (PMID: 34156440). Here, we compare outcomes of PBSC MMUD HCT among patients receiving GVHD prophylaxis with either: (1) tacrolimus plus sirolimus (T/S), (2) T/S plus mini-methotrexate (T/S/MTX), or (3) PTCy, MMF, and tacrolimus or sirolimus (PTCy). Patients with various hematologic malignancies that underwent PBSC MMUD HCT (≥5/8 HLA-matched donors) at City of Hope between January 2005 and December 2021 were included in this retrospective review. Of 390 subjects included, GVHD prophylaxis included T/S (n=114), T/S/MTX (n=160), and PTCy (n=116). The median age was 51 (range:15-79), 53.3% of patients belonged to a racial/ethnic minority, and 34.8% (n=136) patients had disease risk index high or very high. Degree of HLA mismatch was 7/8 (91.3%), 6/8 (8.5%), and 5/8 (0.3%). Hematologic diseases included AML (40.3%), ALL (20.3%), MDS/MPN (15.9%), Lymphoma (16.9%), and CML/CMMol (6.7%). Most common conditioning regimens were fTBI-based (34.4%) and melphalan-based (57.2%). HCT comorbidity index was ≥ 3 in 30.8% (n=120), which was most common in PTCy compared to T/S and T/S/MTX: 48.3% vs. 23.7% vs. 23.1%, P&amp;lt;.001. The rate of neutrophil engraftment (15 days vs. 15 days vs 16 days, P=0.002) and platelet engraftment (15 days vs. 16 days vs 27 days, P=0.004) were shorter in T/S compared to T/S/MTX and PTCy, respectively. With median follow-up of 5.4 years (range: 1.0-16.7) the 5-year OS was superior in PTCy (P=0.045) compared to T/S and T/S/MTX: 58.0% (95% CI: 46.6-67.8) vs. 41.1% (95% CI: 31.9-50.1) and 39.6% (95% CI: 32-47.2). The 5-year disease-free survival (DFS) was superior in PTCy (P=0.042) compared to T/S and T/S/MTX: 54.2% (95% CI: 43.3-63.9) vs. 37.1% (95% CI: 28.2-46.0) vs. 37.2% (95% CI: 29.7-44.6), respectively. There was no significant difference in 5-year cumulative incidence of relapse (CIR) in T/S vs. T/S/MTX vs. T/S vs. PTCy: 29.1% (95% CI: 21.0-37.6) vs. 29.5% (95% CI: 22.6-36.7) vs. 22.1% (95% CI: 14.3-31.0), respectively. Additionally, there was no significant difference in 2-year NRM between the cohorts (P=0.459): 24.6% (95% CI: 17.1-32.9) vs. 23.1% (95% CI: 16.9-29.9) vs. 20.4% (95% CI: 13.5-28.4), respectively. The rate of 100-day Grade III-IV acute GVHD were similar between in the cohorts (P=0.321): 19.3% (95% CI: 12.6-27.0) vs. 18.1% (95% CI: 12.6 -24.5) vs. 12.9% (95% CI: 7.6-19.7). When comparing T/S vs. T/S/MTX and PTCy, the incidence of chronic GVHD was less in the PTCy cohort at both 1-year and 2-years (P&amp;lt;.001) with 1-year incidence of 55.0% (95% CI: 45.1-63.7) vs. 61.9% (95% CI: 53.8-68.9) vs. 38.9% (95% CI: 30-47.8), respectively, and 2-year incidence of 58.9% (95% CI: 49.0-67.6) vs. 66.2% (95% CI: 58.3-73.1) vs. 42.7% (95% CI: 33.4-51.6), respectively. To our knowledge, this is the largest reported single center outcome of PBSC MMUD HCT. In this study, we demonstrate the superiority of PTCy based GVHD prophylaxis compared to T/S and T/S/MTX in outcomes of 5-year OS (P=0.045), 5-year DFS (P=0.042), and incidence of chronic GVHD (P&amp;lt;.001). Our experience further supports the superiority of PTCy as the preferred GVHD prophylaxis in the PBSC MMUD HCT setting achieved by lowering chronic GVHD and associated complications.

Long Term Follow-up after Treatment with Allogeneic Off-the-Shelf CAR T Cell Therapy for Relapsed or Refractory B-Cell Malignancies

CAR T cells provide benefit in patients with relapsed/refractory (R/R) hematologic malignancies. However, limitations of autologous products include cost, production complexity, quality of T cells, and life-threatening toxicity. To overcome these limitations, we developed allogeneic, “off-the-shelf” CD19-specific CAR T cells by transducing our institutional second-generation CD28-containing CAR (19-28z) into Epstein-Barr Virus (EBV)-specific cytotoxic lymphocytes (19-28z CAR EBV-CTLs). Patients with R/R B-cell malignancies were stratified into 3 treatment cohorts: cohort 1 (disease recurrence after allogeneic or autologous hematopoietic cell transplant (HCT)), cohort 2 (19-28z CAR EBV-CTLs as consolidative therapy after autologous HCT), or cohort 3 (19-28z CAR EBV-CTLs as consolidative therapy after allogeneic HCT). The objectives were determining dose limiting toxicity (DLT; primary endpoint) and optimal dose for multiple infusions. Sixteen patients were treated with 19-28z CAR EBV-CTLs with 8 in cohort 1 (B-ALL n=6; Burkitt lymphoma n=1; CLL n=1), 6 in cohort 2 (PMBCL n=2; DLBCL n=3; marginal zone lymphoma n=1), and 2 in cohort 3 (DLBCL n=2). Median age at treatment was 30 years (range 1-71 years). All patients were heavily pretreated, receiving a median of 5 lines of therapy (including any HCT received; range 3-11 lines of therapy) prior to 19-28z CAR EBV-CTLs. Dosing on this protocol was based off T cells/kg: median dose infused was 3x10 6 T cells/kg (range 1-10x10 6 T cells/kg). Twelve patients received multiple doses (overall median 2.5; range 1-3) with 3x10 6 T cells/kg determined to be the optimal dose enabling multiple treatments per manufactured cell line. Products had variable transduction efficiencies with a median of 28.7% (range 7.4-41%), and median 19-28z CAR EBV-CTL dose was 0.7x10 6/kg (range 0.05-2.7x10 6/kg). 19-28z CAR EBV-CTL sources were primary HCT donors (n=4) and third-party donors (n=12). HLA matching between patients and donors was 10/10 (n=3), 6/10 (n=2), 5/10 (n=1), 4/10 (n=3), and 2/10 (n=7). Ten of the patients were EBV-seropositive, four were seronegative, and two were serostatus unknown. Severe cytokine release syndrome (CRS) or neurotoxicity did not occur post-infusion, and no DLT was noted in the trial. Six patients developed diffuse skin rash with 3 patients' rashes deemed to be graft-versus-host disease (n=1 HLA-matched HCT donor; n=2 third-party donor), which resolved with topical steroids (n = 3). Median follow-up was 53.3 months (range 4.2-135 months) with 4 deaths due to disease progression. Overall survival of all patients was 81% at 12 months and 74% at 24 months ( Figure 1). In summation, we successfully treated 16 patients with an allogeneic, “off-the-shelf” 19-28z CAR EBV-CTL product without significant toxicity. The manufacturing platform effectively overcomes many of the limitations of autologous CAR T cell products including cost, need for patient-specific manufacturing, and life-threatening toxicity. CAR EBV-CTLs also broaden the applicability of CAR T cell therapy for patients with insufficient circulating T cells to generate autologous products. This trial determined an optimal manufacturing dose of allogeneic CAR T cells to enable repeated dosing. In the cohort of heavily pre-treated patients, long-term outcomes following multiple infusions of 19-28z CAR EBV-CTLs were excellent. Allogeneic, “off-the-shelf” CAR EBV-CTLs provide a readily available therapy for patients with limited therapeutic options, and this trial demonstrates the safety of CAR T cell infusions as consolidation after HCT. This trial was registered at www.clinicaltrials.gov as NCT01430390. Figure 1: Overall survival following 19-28z CAR EBV-CTLs of all patients by disease (A) and donor source (B).

Early Prognostic Biomarkers of Non-Relapse Mortality in Allogeneic Mismatched Unrelated Hematopoietic Cell Transplantation

Introduction A major challenge in allogeneic hematopoietic cell transplantation (HCT) has been advancing outcomes for individuals lacking a fully matched donor who require a mismatched unrelated donor (MMUD) HCT. Recently, the 15-MMUD study demonstrated encouraging results for post-transplant cyclophosphamide (PT-Cy)-based prophylaxis in MMUD recipients (Shaw, Jimenez, JCO 2021). Our retrospective analysis confirmed improvement in MMUD survival with PT-Cy compared to historical anti-thymocyte globulin (ATG)/calcineurin-based regimens (Jimenez, Blood Adv 2022). Elevations of plasma biomarkers such as Stimulation-2 (ST2) have demonstrated increased risk of non-relapse mortality (NRM) and GVHD, however these have not been validated in the MMUD setting. Here, we carried out a pilot study to determine if biomarker analysis of ST2, Chemokine ligand-9 (CXCL-9), and Regenerating islet-derived 3-α (REG3α) at Day 14 (D14) and 30 (D30) can identify patients at higher risk for NRM after MMUD HCT. Methods Patients with banked samples and underwent MMUD HCT with either ATG or PT-Cy as GVHD prophylaxis at the University of Miami between 2016 - 2020 were included. Enzyme-linked immunosorbent assays for ST2, CXCL-9, and REG3α were performed in batches on cryopreserved plasma. Descriptive statistics of demographic variables were compared using chi-squared, Fisher's exact, or Wilcoxon rank sum tests. ST2 values were treated as continuous variables, and CXCL-9 was dichotomized due to frequent values below the lower limit of detection. Cumulative incidences of NRM were analyzed with relapse as a competing risk. Time-dependent receiver operating curves (ROC) were constructed and Area Under the ROC Curve (AUC) calculated. Youden's index was used to select optimum thresholds for each biomarker. Results We included 47 patients (ATG: 23; PT-Cy: 24). The PT-Cy group had more bone marrow graft representation (50% vs 22%, p = 0.04) and more donors mismatched at &amp;gt;1 HLA-locus (29% vs 0%, p&amp;lt;0.01). Median follow up was 746 days (range 44-1968). Point estimate of overall survival at 2 years was 35% (95% CI 20-61) for ATG and 71% (95% CI 55-92) for PT-Cy (p=0.02). Median overall survival was estimated at 413 days among ATG patients and could not be estimated for PT-Cy patients. The cumulative incidence of NRM at 2-years was 30% (95% CI 13-51%) for ATG and 17% (95% CI 5-35%) for PT-Cy (p=0.03). Among all patients, ST2 was prognostic for NRM using time-varying covariates including combined D14 and D30 (D14+30) with a HR of 2.14 (95% CI 1.04-4.39, p = 0.04). The D14+30 ROC to predict NRM at 1-year using ST2 showed an AUC of 0.83 (95% CI 0.66-1). D+14 thresholded ST2 value maximizing Youden's index of ≥79.89 ng/mL was discriminative for 1-year NRM (p=0.002) (Fig. 1). Additionally, combination of CXCL-9 to ST2 could optimize the prognostic value when compared to ST2 alone: HR at D14+D30: 3.82 (95% CI 1.01-14.47, p=0.048) with an improved AUC of 0.9 (95% CI 0.79-1) (Fig. 2). REG3α did not significantly add to the AUC. Although limited by sample size, we explored the association by GVHD prophylaxis (ATG or PT-Cy). First, in the ATG group, the D14 ST2 value that maximized thresholded Youden's index of 61.39 ng/mL was predictive of 1-year NRM (p=0.04). Similarly, the D+30 ST2 values of 148.06 ng/mL was predictive of NRM (p&amp;lt;0.001). The AUC for prediction of 1-year NRM for Second, in the PT-Cy group, elevations of D30 ST2 were prognostic of 1-year NRM with HR 15.05 (95% CI 1.77-27.83, p=0.01). Consequently, the AUC for prediction of 1-year NRM for D30 ST2 was 0.92 (95% CI 0.77-1) and for ST2 + CXCL-9 was 0.96 (95% CI 0.86-1). Conclusions This pilot study suggests that after MMUD HCT, D14 and D30 biomarkers are prognostic for NRM across GVHD prophylaxis platforms. Importantly, we find that ST2 maintains its prognostic capacity in the increasingly popular PT-Cy group. This supplements what we previously reported in the haploidentical and matched unrelated donor PT-Cy setting (Kanakry, Haematologica 2017). Biomarker combination ST2 + CXCL-9 showed improved AUC over ST2 alone, and the composite D14+30 timepoint may have additive utility over a single timepoint. While the optimal time for biomarker collection is unknown, our data suggests D14 had value for ATG-treated patients, whereas D30 may be more important in the PT-Cy-treated group. A validation cohort is being assembled for PT-Cy based MMUD HCT.

Myocardial Fibrosis Improves in Young Patients with Sickle Cell Disease after Hematopoietic Cell Transplantation

Introduction: Cardiovascular complications are a leading cause of early mortality in patients with sickle cell disease (SCD). Chronic anemia, iron overload and repeated microvascular ischemic insults with reperfusion injury often result in progressive myocardial injury and maladaptive remodeling in SCD patients. Patients with SCD develop diffuse myocardial fibrosis, which can be detected by quantifying the myocardial extracellular volume (ECV) using cardiovascular magnetic resonance (CMR) imaging. Our group and others have previously shown that diffuse myocardial fibrosis is highly prevalent in both children and young adults with SCD, including those who have normal ventricular size and function by echocardiography. Additionally, we have shown that the disease modifying therapies (DMT) such as hydroxyurea or chronic transfusions do not appear to be protective against development of diffuse myocardial fibrosis. In a retrospective study, we found no difference in the myocardial ECV in patients who began DMT early (less than 6 years of age) versus later in life (at least 6 years or after) (Morin CE and Sharma A et al. Blood 2023.). Hematopoietic cell transplantation (HCT) can cure SCD, but myocardial effects of the therapy are unknown. Our goal was to evaluate cardiovascular parameters of function and injury, especially the progression of diffuse myocardial fibrosis, by comparing serial CMR studies performed before and after HCT in patients with SCD. Methods: We performed prospective CMR evaluation of children and young adults with SCD who received a matched sibling donor (MSD) or haploidentical donor (HAPLO) HCT following a reduced toxicity conditioning on a clinical trial (NCT04362293). CMR was performed pre-HCT, and at 1 month, and 12 months post-HCT. CMR-derived ventricular and atrial volumes were calculated. ECV was measured from T1 maps with a modified Look-Locker inversion recovery (MOLLI) sequence in short-axis. T2 and T2* maps were obtained. Regions of interest in the mid-ventricular septum were identified for analysis. We report descriptive statistics for CMR measures along with paired t-tests comparing patient ECV levels at 1-month and 12-months post-HCT to their respective baseline ECV. Results: Our study cohort consisted of 14 patients with SCD who underwent HCT and had serial CMR evaluations available. Thirteen patients had HbSS genotype and one had HbSC genotype. All patients were receiving DMT, either with hydroxyurea or chronic transfusions prior to HCT. Participants were majority male (57%) with median age of 15.2 years (range 6.8-21.3) at the pre-HCT CMR. Six received an MSD HCT and 8 received a HAPLO HCT. Ten patients each had follow up CMR evaluations performed at 1 month, and 12 months post-HCT. At 1 and 12 months post-HCT ejection fraction was preserved while biventricular volume and cardiac index decreased (Table 1). Compared to pre-HCT, ECV decreased from median 29% [range 27-38] to 28% (range 21-35, P= 0.061) at 1 month and 27% (range 24-31, P= 0.043) at 12 months post-HCT. There was no difference in the cardiac chamber sizes or the ECV measurements of those who received a MSD versus HAPLO HCT. Conclusions: We observed an improvement in cardiac chamber sizes with preservation of cardiac function as early as one month after HCT in patients with SCD. We further noted a reduction in ECV indicating a decrease in diffuse myocardial fibrosis in these young patients with SCD. To our knowledge, this is the first study to show that diffuse myocardial fibrosis can improve in patients with SCD after HCT. In addition to further corroborating the organ function protective effects of HCT in patients with SCD, these data further demonstrate the use of CMR as an essential non-invasive tool to assess the effects of therapeutic interventions on SCD-cardiac injury.

Post-Transplant Cyclophosphamide Eliminates Disparity in GvHD-Free, Relapse-Free Survival and Overall Survival between 8/8 Matched and 7/8 Mismatched Unrelated Donor Hematopoietic Cell Transplantation in Adults with Hematologic Malignancies

Background: Post-transplant cyclophosphamide (PTCy) has become a standard of care for graft-versus-host disease (GvHD) prophylaxis in recipients of human leukocyte antigen (HLA)-matched and mismatched unrelated donor (MMUD) allografts, generating new opportunities for successful hematopoietic cell transplantation (HCT) regardless of patient ancestry. The National Marrow Donor Program (NMDP)-sponsored 15-MMUD study, which used PTCy-based GvHD prophylaxis (PMID 3390526), demonstrated encouraging overall survival (OS) in adult patients receiving MMUD bone marrow grafts matched at ≤7/8 HLA alleles. Currently, the follow-up ACCESS study (NCT04904588) will determine if similar outcomes can be achieved using MMUD peripheral blood stem cell allografts. As part of its 5-year strategic plan, the NMDP aims to determine the extent of differences in GvHD-free, relapse-free survival (GRFS) between 8/8 and 7/8 URD allografts using PTCy and seeks to develop approaches over time to close the presumed gap in URD outcomes. Methods: The primary objective was to compare GRFS between 8/8 and 7/8 URD HCT using the Center for International Blood &amp; Marrow Transplant Research (CIBMTR) database. After analyzing primary results, secondary objectives were added to compare GRFS, OS, and other clinical outcomes among 8/8 URD, 7/8 URD, and haploidentical-related donor (Haplo) HCT. The study included adult patients (age≥18y) with hematologic malignancies (ALL, AML, MDS) undergoing first URD or Haplo HCT between 2017-2020 using PTCy-based GvHD prophylaxis. Kaplan-Meier curves were used to estimate probability of GRFS and OS. Cox regression examined the independent effect of HLA match controlling for other clinical factors on outcomes referenced to 8/8 URD HCT. A priori clinically selected factors considered as possible confounders in the regression model included disease risk index, comorbidity risk, pre-HCT Karnofsky score, conditioning regimen intensity, graft source, donor/recipient CMV serostatus, year of HCT, donor/recipient age and race/ethnicity. Final models were stratified by factors violating the proportional hazards assumption. Factors were eliminated in a backwards fashion if p-values were &amp;gt;0.10 unless inclusion affected the hazard ratio (HR) of HLA match by more than 10%. Interactions were tested against a p-value of &amp;lt;0.01. Results: Table 1 shows demographics for the three patient cohorts: Haplo (n=2772), 8/8 URD (N=1517), and 7/8 MMUD (N=540). Notable differences among the cohorts included: 8/8 URD recipients had younger, predominantly Caucasian donors and were more likely to receive myeloablative conditioning. Haplo recipients had more donor/recipient CMV seropositivity and received more reduced intensity conditioning. Otherwise patient characteristics were similar. Contrary to our expectations, multivariable regression analysis (MVA) showed no significant differences in either GRFS or OS between recipients of 8/8 and 7/8 URD HCT at 1, 2 and 3-years post-HCT ( Figure 1). Outcomes, including relapse and NRM, between 8/8 and 7/8 URD HCT were similar irrespective of conditioning intensity. However, 8/8 URD HCT associated with lower two-year moderate/severe chronic GvHD than 7/8 URD [1.30 (1.00-1.68), p=0.049]. We next compared GRFS and OS among 8/8 and 7/8 URD and Haplo at 3y after HCT. On MVA, GRFS [HR 1.15 (1.04-1.26), p=0.005] and OS [HR 1.15 (1.03-1.29), p=0.013] were significantly better in 8/8 URD compared to Haplo HCT. Differences between 8/8 URD and Haplo appeared to be driven by significantly higher NRM [HR 1.46 (1.22-1.74), p&amp;lt;0.001)] and two-year moderate/severe chronic GvHD [HR 1.28 (1.07-1.54), p=0.007] in Haplo. No significant differences were seen in GRFS or OS at 3 years when comparing 7/8 URD to Haplo. Causes of death among donor types were similar with primary disease relapse/progression, infection and organ failure being the most frequent. Conclusions: Use of PTCy-based GvHD prophylaxis seems to have resolved previously observed differences in GRFS and OS between 8/8 and 7/8 URD HCT. HCT using an 8/8 URD HCT, if available, continues to be the best option for patients lacking a matched sibling donor. Further studies comparing Haplo to 7/8 URD HCT are warranted, but will require larger numbers of 7/8 URD HCT. Both mismatched donor sources substantially increase access to HCT for patients regardless of their ancestry.

Initial Results of a Phase 1 Trial of TSC-100 and TSC-101, Engineered T Cell Therapies That Target Minor Histocompatibility Antigens to Prevent Relapse after Allogeneic Hematopoietic Cell Transplantation

Introduction: To date, engineered T cell therapies have not proven effective for non-B cell hematologic malignancies due to a lack of antigens that spare healthy myeloid cells. Allogeneic hematopoietic cell transplantation (HCT) remains the best curative option for these malignancies, yet ~40% of patients relapse post-HCT with high mortality after relapse. A potential solution to prevent relapse is to target hematopoietic lineage-specific minor histocompatibility antigens (MiHAs) that are genetically mismatched between HCT patients and donors. These mismatches enable engineered T cells to selectively eliminate residual patient hematopoietic cells, normal or malignant, and spare donor cells. TSC-100 and TSC-101 are allogeneic, donor derived T-cell receptor-engineered T (TCR-T) cells that target MiHAs HA-1 and HA-2 respectively, both presented on HLA-A*02:01. By choosing HCT patients who are HLA-A*02:01 positive and donors who are either HLA-A*02:01 or MiHA negative, TSC-100 or TSC-101 are designed to eliminate residual patient hematopoietic cells post-HCT and thus prevent relapse (figure). Methods: Study TSCAN-001 (NCT05473910) is a multi-center, multi-arm non-randomized, controlled Phase 1 study evaluating the feasibility, safety and preliminary efficacy of TSC-100 and TSC-101. Adults with AML, MDS or ALL eligible for reduced intensity conditioning (RIC)-based haploidentical donor transplantation from HLA or MiHA mismatched donors are enrolled. HLA-A*02:01 and HA-1 or HA-2-positive patients receive either TSC-100 or TSC-101 after HCT. HLA-A*02:01-negative control arm patients receive HCT alone. Upon count recovery after HCT, patients in treatment arms receive a single dose of TSC-100 or TSC-101 at Dose Level 1 or repeat doses at Dose Levels 2 and 3. Dose escalation follows interval 3+3 rules. Primary endpoints include adverse event profiles and dose-limiting toxicities (DLTs). Secondary endpoints are relapse rates, disease-free and overall survival. Exploratory endpoints include biomarkers of efficacy such as minimal residual disease (MRD) by deep next-generation sequencing (NGS), and donor chimerism using novel high-sensitivity and standard assays. Results: At submission time, 8 patients were enrolled, 5 in treatment arms (3 TSC-101, 2 TSC-100) and 3 in the control arm, with a median of 111 days post-HCT follow-up (range 33-266 days). No DLTs occurred, and patients were enrolled at Dose Level 2 in both TSC-100 and TSC-101 arms. Safety analysis found expected post-HCT adverse events similar in treatment and control arms. Incidence of graft-versus-host disease (GvHD) was similar in control (3 events) and treatment arms (4 events). Serious adverse events of grade 3 GvHD and infections were observed in TSC-101 and control arms (1 event each). No cytokine release syndrome or neurotoxicity occurred after TSC-100/101 and minimal changes in CRP/ ferritin occurred, consistent with general safety of TCR-Ts with low target cell burden. No clinical relapses occurred to date. Translational analysis found peak TSC-100/101 expansion and activation 7-14 days post dosing, with ongoing persistence at longest follow-up of 138 days. In repeat dose cohorts, substantial increases of early expansion were noted after dose 2 of TSC-101/100, supporting the benefit of repeat dosing. Chimerism analysis (table) using a novel high-sensitivity NGS-based AlloHeme assay (limit of detection (LOD) 0.13%) in whole blood, CD33+ or CD3+ subsets found mixed chimerism in 2 out of 2 control patients but complete donor chimerism in 4 out of 4 TSC-100/101 patients after Day 42. Both control patients had declining donor chimerism after Day 100 by AlloHeme and standard STR-based chimerism assays (LOD 1-2%) prompting early withdrawal of immunosuppression in one patient. Marrow MRD analysis by NGS (LOD &amp;lt;0.05%) found 1 control patient was MRD positive pre-HCT and remained MRD positive post-HCT. In contrast, 2 TSC-100/101 patients who were MRD positive pre-HCT turned MRD negative after HCT and TSC-100/101 therapy including a TP53 mutated MDS patient confirmed MRD negative by droplet digital PCR (LOD 0.01%). Conclusions: Targeting MiHAs HA-1 or HA-2 with TSC-100/ 101 following HCT shows early safety and biomarker evidence of efficacy by completing elimination of all detectable patient hematopoietic cells, normal or malignant, thereby reducing relapse risk. Updated results will be presented at the meeting.

Donor Hemoglobin Genotype Does Not Impact Outcomes Following Matched Related Donor Hematopoietic Cell Transplantation for Sickle Cell Disease: A STAR Study

Sickle cell disease (SCD) is an inherited hemoglobin (Hb) disorder which leads to significant morbidity and early mortality. Hematopoietic cell transplantation (HCT) is the only curative treatment with long-term outcome data, demonstrating excellent symptom-free survival particularly when a matched related donor (MRD) is available. Most MRD have sickle cell trait (Hb AS), but trait donor HCT is considered acceptable by the FDA and without negative impact. Further, initial gene addition and editing approaches for SCD have resulted in a trait-like status with benefit. Sickle trait, however, is associated with complications such as papillary necrosis, bacteriuria, splenic infarction, and exercise-induced death. The primary aim of this study was to compare long-term outcomes following MRD HCT for SCD based on donor Hb genotype, to objectively describe any impact on outcomes. Retrospective data was available for this analysis on 182 SCD patients ≥1 year post MRD HCT at 10 participating Sickle Transplant Advocacy and Research (STAR) Alliance centers. Summary statistics were presented as mean (standard deviation) for continuous variables and count (%) for categorical variables. Comparisons were made between Hb AA and Hb AS donor groups using both parametric and non-parametric tests for continuous variables and Chi-square test/exact test for categorical variables, with p-value &amp;lt;0.05 set as significant. Amongst 182 patients undergoing MRD HCT, 67% (n=122) had a Hb AS donor ( Table). In the overall cohort, median age at HCT was 8.7 (4.8) years and most patients had HbSS (n=174; 96%) with a severe clinical phenotype (n=97; 54%). HCT was performed using bone marrow (n=166; 92%) with myeloablative conditioning (n=156; 86%) in the majority. Patients with a severe disease phenotype and Hb AS donor were significantly more likely to have recurrent vaso-occlusive pain crises as an indication for HCT (p=0.033), otherwise there were no differences in baseline patient or HCT characteristics between cohorts. With mean post-HCT follow up of 4.5 (3.9) and 5.1 (4.1) years in Hb AA and Hb AS donor cohorts (p=0.145), no significant differences were seen in recipient outcomes including time to neutrophil and platelet engraftment, number of or time to last platelet transfusion, myeloid or unsorted % donor chimerism, number with acute (day 100) or chronic GVHD (1 year), or time to discontinue immunosuppression (data not shown). Disease recurrence and need for 2 nd HCT were rare in both cohorts (AA: 2 [3%] and 2 [3%]; AS: 3 [3%] and 4 [3%]; p=0.665 and 1.0, respectively). Two (3%) and 5 (4%) patients died in the AA and AS cohorts, respectively (p=1.0). Aside from a statistically (but not clinically) significant difference in Hb at day 30 (p=0.044), no difference was seen in longitudinal Hb or markers of hemolysis (LDH and ARC; Figure). No significant difference was seen in median number of RBC units transfused (AA: 4.0 [2.0-6.0]; AS: 3.0 [2.0-6.0]; p=0.454) or days to last transfusion (AA: 23.0 [14.0-77.0]; AS: 22.0 [13.0-75.0]; p=0.86). SCD complications were rare post-HCT, with no difference seen between cohorts in number (%) with VOC (AA: 1 [2%; had 2 separate VOC events]; AS: 3 [3%]; p=1.0), ACS (none reported), chronic pain (AA: 0 [0%]; AS: 1 [&amp;lt;1%]; p=1.0), or other SCD-related complications (AA: 2 [3%]; AS: 9 [7%; had 11 separate other events]; p=0.456). Stroke occurred in a significantly higher proportion with an AA versus AS donor (5 [8%] and 2 [2%], respectively; p=0.04). No significant differences were seen in longitudinal (1 and 2 years and at last follow up) post-HCT cardiac (EF, SF, TRJ velocity), pulmonary (FEV1, FVC, DLCO), or renal (GFR) function between cohorts (data not shown). Our results indicate that in MRD HCT for SCD, AS and AA donors yield comparable long-term outcomes. In this retrospective and registry-based study design, detailed analyses did not show differences between the two cohorts at baseline or at any timepoint post-HCT. While there were some outcome differences between the cohorts, they were either not clinically significant or did not have a scientific rationale, and thus were likely due to chance alone (denoted by bolding in Table). Given the young age of our cohort at HCT and thus a smaller proportion with SCD-related organ dysfunction, our results may not be applicable to an older cohort with significant organ dysfunction which will require a separate analysis.

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.

Clinical Characteristics, Management, and Allogeneic Hematopoietic Cell Transplantation of Patients with Toll-like Receptor 8 Gain-of-Function Mutations

Toll-like receptor 8 gain-of-function (TLR8 GOF) is a recently described inborn error of immunity due to germline or somatic mutations in the TLR8 gene and characterized by severe neutropenia, infections, lymphoproliferation, humoral immune defects, and in some cases, bone marrow failure. Treatment of TLR8 GOF has been challenging to date, and guidance for optimal therapy is lacking. We describe the clinical characteristics and management of 10 patients with TLR8 GOF variants, including the first female patient and further clinical outcome on the 6 patients initially reported with this disease with a focus on the role of allogeneic hematopoietic cell transplantation (HCT). All but one patient were male ranging from 0.5 months to 28 years at age of symptom onset. Eight patients had somatic mutations with variant allele frequencies of 7-26%; two patients had germline mutations. The 9 male patients all had severe neutropenia and varying degrees of anemia and/or thrombocytopenia. Oral ulcers, recurrent infections, hepatosplenomegaly, and hypogammaglobulinemia were common. Immune phenotype was variable, ranging from severe lymphopenia to marked T cell lymphoproliferation. Several patients had an inverted CD4:CD8 T cell ratio and skewing of T cell subsets to the terminal effector memory phenotype. Increased double-negative T cells were also observed. All patients had low class switched memory B cells. Bone marrows were hypo- to hypercellular with marked myeloid hypoplasia, and in most cases, with increased T cells, large granular lymphocytes, and/or lymphoid aggregates. Neutropenia was initially responsive to granulocyte colony stimulating factor (GCSF) +/- steroids in several patients but ultimately become refractory to therapy. Immunomodulatory agents and chemotherapy were unsuccessful. Six patients underwent allogeneic HCT; two patients died at 8 and 18 years without definitive therapy; and one patient was lost to follow-up. The female patient had germline disease and presented with pure red blood cell aplasia at 2 weeks of life and is scheduled to undergo HCT. Transplant data were available for 5 of 6 patients who underwent HCT. Age at transplant was 3 to 21 years. One patient who received a graft from a 7/8 HLA-matched unrelated donor developed severe veno-occlusive disease and secondary graft failure. The patient underwent a second transplant and ultimately died. Another patient received a matched sibling donor HCT while critically ill from Candida lusitaniae and mucormycosis infection with associated multisystem organ failure. The patient engrafted with 100% donor chimerism but died on day +15 post-HCT. The remaining 3 patients are alive and well 8 months to 2 years post-HCT. Two patients received grafts from HLA-matched donors (1 sibling and 1 unrelated) with reduced intensity conditioning and cyclophosphamide, mycophenolate mofetil and vorinostat for graft-versus-host disease (GVHD) prophylaxis. The third patient underwent a haploidentical HCT with myeloablative conditioning and post-transplant cyclophosphamide. Post-HCT complications included acute skin and/or gastrointestinal GVHD that was responsive to therapy in all patients, and severe lung GVHD in one patient. There were no major infectious complications. All three patients had full donor chimerism in myeloid and T cells with complete resolution of disease phenotype at last follow-up. The patient for whom detailed transplant data is not available received a haploidentical HCT. He developed mixed myeloid chimerism for which he received multiple donor lymphocyte infusions and was alive at last contact &amp;gt;3 years post-HCT. TLR8 GOF should be considered in male and female patients with severe, unexplained neutropenia refractory to GCSF, and particular care should be taken when investigating for mutations given the disease-causing variant allele frequencies as low as 7%. Neutropenia and immune dysregulation were refractory to all therapies in our cohort, and TLR8 GOF was fatal in two patients who did not receive definitive therapy. Allogeneic HCT is curative and should be considered without delay for medically suitable patients.

Post-transplantation cyclophosphamide is associated with increased bacterial infections.

Post-transplant cyclophosphamide (PTCy) is increasingly used to reduce graft-versus-host disease after hematopoietic cell transplantation (HCT); however, it might be associated with more infections. All patients who were ≥2 years old, receiving haploidentical or matched sibling donor (Sib) HCT for acute leukemias or myelodysplastic syndrome, and either calcineurin inhibitor (CNI)- or PTCy-based GVHD prophylaxis [Haploidentical HCT with PTCy (HaploCy), 757; Sibling with PTCy (SibCy), 403; Sibling with CNI-based (SibCNI), 1605] were included. Most bacterial infections occurred within the first 100 days; 953 patients (34.5%) had at least 1 infection and 352 patients (13%) had ≥2 infections. Patients receiving PTCy had a greater incidence of bacterial infections by day 180 [HaploCy 46%; SibCy 48%; SibCNI 35%; p < 0.001]. Compared with the SibCNI without infection cohort, 1.99-fold, 3.33-fold, 2.78-fold, and 2.53-fold increased TRM was seen for the HaploCy cohort without infection and HaploCy, SibCy, and SibCNI cohorts with infection, respectively. Bacterial infections increased mortality [HaploCy (HR1.84, 99% CI: 1.45-2.33, p < 0.0001), SibCy cohort (HR,1.68, 99% CI: 1.30-2.19, p < 0.0001), and SibCNI cohort (HR,1.76, 99% CI: 1.43-2.16, p < 0.0001). PTCy was associated with increased bacterial infections regardless of donor, and bacterial infections were associated with increased mortality irrespective of GVHD prophylaxis. Patients receiving PTCy should be monitored carefully for bacterial infections following PTCy.

HLA haplotype frequencies and diversity in patients with hemoglobinopathies.

The genetic diversity of the human leukocyte antigen (HLA) system was shaped by evolutionary constraints exerted by environmental factors. Analyzing HLA diversity may allow understanding of the underlying pathways and offer useful tools in transplant setting. The aim of this study was to investigate the HLA haplotype diversity in patients with sickle cell disease (SCD, N=282) or β-thalassemia (β-Thal, N=60), who received hematopoietic cell transplantation (HCT) reported to Eurocord and the Société Francophone de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC). We identified 405 different HLA-A-B-DRB1 haplotypes in SCD and 108 in β-Thal patients. Using data from African and European populations of the "1000 Genomes Project" for comparison with SCD and β-Thal, respectively, we found that the haplotypes HLA-A*30-B*14-DRB1*15 (OR 7.87, 95% CI: 1.66-37.3, p b=0.035), HLA-A*23-B*08 (OR 6.59, 95% CI: 1.8-24.13, p b=0.023), and HLA-B*14-DRB1*15 (OR 10.74, 95% CI: 3.66-31.57, p b=0.000) were associated with SCD, and the partial haplotypes HLA-A*30-B*13 and HLA-A*68-B*53 were associated with β-Thal (OR 4.810, 95% CI: 1.55-14.91, p b=0.033, and OR 17.52, 95% CI: 2.81-184.95, p b=0.011). Our results confirm the extreme HLA genetic diversity in SCD patients likely due to their African ancestry. This diversity seems less accentuated in patients with β-Thal. Our findings emphasize the need to expand inclusion of donors of African descent in HCT donor registries and cord blood banks.

Biologic indicators of donor socioeconomic disadvantage and recipient mortality following allogeneic hematopoietic cell transplantation.

6500 Background: Allogeneic hematopoietic cell transplantation (HCT) carries significant risks, with low socioeconomic status (SES) being predictive of increased mortality. Our team recently discovered that socioeconomic disadvantage among unrelated HCT donors results in decreased recipient overall survival (OS) and increased treatment-related mortality (TRM) within a cohort from the Center for International Blood and Marrow Transplant Research (CIBMTR). We also demonstrated that upregulation of the stress- and SES-related gene expression profile termed the ‘conserved transcriptional response to adversity’ (CTRA) is associated with low SES and worse outcomes among HCT recipients. Here, we hypothesize that donor immunologic characteristics associated with neighborhood socioeconomic disadvantage (CTRA) will confer prognostic risk to HCT recipients as indicated by inferior long-term recipient outcomes. Methods: Among a subset of the above cohort for which donor whole blood samples were available from the CIBMTR repository, we evaluated whether donor cell CTRA gene regulation was associated with inferior HCT outcomes at 3 years in recipients being treated for hematologic malignancy. Multivariable models adjusted for donor and recipient characteristics evaluated associations between donor CTRA and recipient OS, TRM, disease free survival (DFS), relapse, and acute and chronic graft versus host disease. Results were considered significant if P&lt;0.05. Results: We identified 263 donor-recipient pairs for study inclusion. Median recipient age at hematologic malignancy diagnosis was 53 years (range 19-77), 46% were female, and 54% had acute myeloid leukemia. Donors were 35% female and median age at donation was 31 years (range 18-60). In RNA sequencing data from HCT donors, greater CTRA expression was associated with reduced OS (covariate-adjusted HR=1.94/CTRA SD, 95% CI [1.01, 3.71], p=.046) which was driven predominately by increased TRM (adjusted HR=5.04, [2.20, 11.50], p=.0001). These clinical outcomes are consistent with those observed to be associated with donor SES in our prior work. Donor cell effects on transplant outcomes derived predominately from the pro-inflammatory component of the CTRA (OS: adjusted HR=1.67, [1.20, 2.33], p = .0026; TRM: adjusted HR=2.21, [1.21, 4.06], p=.010) and emerged above and beyond the effects of the recipients’ own SES, as well as multiple other recipient disease, treatment, and demographic factors. Donor CTRA was not associated with relapse, DFS, or other transplant outcomes. Conclusions: For the first time, we show that transcriptome patterning among HCT donors, consistent with neighborhood SES disadvantage, results in adverse recipient HCT outcomes. These findings suggest that SES has a biologic impact at either the stem or immune cell level that persists even when transplanted into a new host.

Conditional survival and standardized mortality ratios of patients with severe aplastic anemia surviving at least one year after hematopoietic cell transplantation or immunosuppressive therapy.

Immunosuppressive treatment (IST) and hematopoietic cell transplant (HCT) are standard therapies for severe aplastic anemia (SAA). We report on conditional survival and standardized mortality ratios (SMR), which compare the mortality risk with the general population adjusted for age, gender, and race/ethnicity, in patients with SAA alive for at least 12 months after treatment with IST or HCT between 2000 and 2018. Given changes to treatment regimens and differences in length of follow-up, two treatment periods were defined a priori: 2000-2010 and 2011-2018. The SMR of patients treated during the period 2000-2010 and who survived one year were 3.50 (95% confidence interval [CI]: 2.62-4.58), 4.12 (95% CI: 3.20-5.21), and 8.62 (95% CI: 6.88-10.67) after IST, matched related donor HCT, and alternative donor HCT, respectively. For the period 2011-2018, the corresponding SMR were 2.89 (95% CI: 1.54-4.94), 3.12 (95% CI: 1.90-4.82), and 4.75 (95% CI: 3.45-6.38), respectively. For IST patients, their mortality risk decreased over time, and became comparable to the general population by five years. For patients who underwent HCT during 2000-2010 and 2011-2018, their mortality risk became comparable to the general population after ten years and after five years, respectively. Thus, 1-year survivors after IST or HCT can expect their longevity beyond five years to be comparable to that of the general US population.

Posttransplant cyclophosphamide beyond haploidentical transplantation.

Posttransplant cyclophosphamide (PTCy) has practically revolutionized haploidentical (Haplo) hematopoietic cell transplantation (HCT). Comparisons between Haplo with PTCy and unrelated donor (URD) with conventional graft-versus-host disease (GVHD) prophylaxis have shown comparable overall survival with lower incidences of GVHD with Haplo/PTCy and led to the following question: is it PTCy so good that can be successfully incorporated into matched related donor (MRD) and URD HCT? In this review, we discuss other ways of doing PTCy, PTCy in peripheral blood haploidentical transplants, PTCy in the context of matched related and matched unrelated donors, PTCy with mismatched unrelated donors, and PTCy following checkpoint inhibitor treatment. PTCy is emerging as a new standard GVHD prophylaxis in haploidentical, HLA-matched, and -mismatched HCT.

Abatacept GVHD prophylaxis in unrelated hematopoietic cell transplantation for pediatric bone marrow failure.

Hematopoietic cell transplantation (HCT) is the only readily available cure for many life-threatening pediatric nonmalignant diseases (NMD), but most patients lack a matched related donor and are at higher risk for graft-versus-host disease (GVHD). Use of abatacept (Aba) to target donor T-cell activation has been safe and effective in preventing GVHD after unrelated donor (URD) HCT for malignant diseases (Aba2 trial). Our primary objective wasto evaluate the tolerability of Aba added to standard GVHD prophylaxis (cyclosporine and mycophenolate mofetil) in pediatric patients with NMD undergoing URD HCT. In this single-arm, single-center phase 1 trial, 10 patients receiving reduced intensity or nonmyeloablative conditioning underwent URD HCT. Immune reconstitution was assessed longitudinally via flow cytometry and compared to pediatric patients on Aba2. Nine patients successfully engrafted, with 1 primary graft rejection in the setting of inadequate cell dose; secondary graft rejection occurred in 1 patient with concurrent cytomegalovirus viremia. Two deaths occurred, both unrelated to Aba. One patient developed probable posttransplant lymphoproliferative disease, responsive to rituximab and immune suppression withdrawal. No patients developed severe acute or chronic GVHD, and 8 patients were off systemic immunosuppression at 1 year. Immune reconstitution did not appear to be impacted by Aba, and preservation of naïve relative to effector memory CD4+ T cells was seen akin to Aba2. Thus, 4 doses of Aba were deemed tolerable in pediatric patients with NMD following URD HCT, with encouraging preliminary efficacy and supportive immune correlatives in this NMD cohort.

Haploidentical vs matched unrelated donors for patients with ALL: donor age matters more than donor type.

Haploidentical hematopoietic cell transplantation (HCT) with posttransplant cyclophosphamide (PTCy) graft-versus-host-disease (GVHD) prophylaxis yields a similar overall survival (OS) to HLA-matched unrelated donor (MUD) HCT with conventional prophylaxis. Given the prognostic implications of donor age, we investigated the impact of donor age (younger [<35 years, n= 868] vs older [≥35 years, n= 418]) and donor type (haploidentical [n= 373] vs MUD [n= 913]) on OS in adult patients with acute lymphoblastic leukemia (ALL). Older donor age was independently associated with significantly poor OS, whereas donor type was not. Next, we directly compared the outcomes of a younger haploidentical donor (n= 187) vs an older MUD (n= 232). In this cohort, more patients in the haploidentical group had B-cell immunophenotype (89% vs 77%, respectively, P< .001), poor cytogenetics (61% vs 51%, respectively, P= .44), Philadelphia chromosome-negative (53% vs 48%, respectively, P= .38), received bone marrow graft (42% vs 16%, respectively, P< .001), and reduced-intensity conditioning (45% vs 23%, respectively, P< .001). In the multivariate analysis, the older MUD group was associated with a significantly higher risk of chronic GVHD, higher nonrelapse mortality (NRM), lower relapse, and poorer OS. Despite a higher risk of relapse, younger donor haploidentical HCT with PTCy prophylaxis may be preferred over older MUD HCT with conventional prophylaxis in patients with ALL due to lower NRM and better OS. Further analysis comparing the effect of donor age in haploidentical PTCy vs MUD PTCy is warranted.