Since the introduction of allogeneic bone marrow transplantation (BMT) as a treatment for aplastic anemia (AA), major advances have occurred, such as refinements in conditioning regimens, graft-versus-host disease (GVHD) prophylaxis, high-resolution HLA typing, pretransplant transfusion practices, and general supportive care. We present a comprehensive retrospective single-center cohort study of 607 children and adults who underwent allogeneic transplantation for AA over 6 decades at a single BMT center. We highlight key temporal changes in conditioning strategies for related donor transplantation, GVHD prophylaxis, and HLA matching that correspond with improved nonrelapse mortality, reduced GVHD rates, and better overall survival among HLA-matched related and unrelated donor transplants. This work provides a historical perspective on the evolution of BMT for AA among HLA-matched related and unrelated donor recipients and identifies persistent barriers to curative therapy, including patient age and donor availability. Further studies are needed to clarify the role of antithymocyte globulin in conditioning regimens, improve GVHD prevention and management, and expand the use of alternative donors.

BACKGROUND Allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative for many malignant and non-malignant diseases. However, pre-existing autoimmune disease (AD) raises concern for excess toxicities and immune dysregulation that may delay immune reconstitution, and increase the risk of infections and GVHD, thereby contributing to higher non-relapse mortality and reduced relapse-free and overall survival. In this retrospective study, we compared allo-HCT recipients with active AD at the time of transplant vs. inactive/remote AD, assessing hazards of all-grade and high-grade aGVHD and cGVHD, relapse, and overall survival. METHODS Between January 2014 and January 2024, 70 patients with AD underwent allo-HCT, comprising 84 total autoimmune diagnoses; 23 were classified as active and 47 as inactive/remote. Active AD was defined as systemic immunosuppression within 6 months before conditioning (≥ 10 mg/day prednisone-equivalent for ≥ 14 days or any pulse-dose steroids; topical therapy 60 days; conventional DMARDs; biologic/B-cell-depleting agents), a clinician-documented AD flare 3 months, or organ-threatening AD involvement 12 months; all others, including physiologic steroids ≤ 5 mg/day, thyroid replacement, insulin, or “history only”, were inactive/remote. Patients were censored at last follow-up.Cox regression was used to estimate hazard ratio (HR) for the association between AD activity at transplant and all-cause mortality, relapse, and hazards of all-/high-grade aGVHD and cGVHD. Relapse and high-grade aGVHD were adjusted for age; mortality and high-grade cGVHD, for age and conditioning regimen; all-grade aGVHD and cGVHD for age, conditioning regimen, and transplant type. Low event counts precluded adjustment for disease risk and GVHD prophylaxis (PTCY vs non-PTCY, 2 vs 3 drugs). RESULTS Multivariable analysis showed that, compared to the active group, the inactive group had a lower hazard of mortality (HR 0.71, 95% CI 0.32-1.54) and lower hazard of high-grade aGVHD (HR 0.61, 95% CI 0.21-1.77), but also had a higher hazard of relapse (HR 2.12, 95% CI 0.43-10.46), all-grade cGVHD (HR 1.67, 95% CI 0.80-3.51), and high-grade cGVHD (HR 2.75, 95% CI 0.77-9.76). The hazard of all-grade aGVHD was similar between groups (HR 1.32, 95% CI 0.69-2.54). Collectively, confidence intervals were wide, and estimates do not suggest worse outcomes in patients with active AD at transplant. CONCLUSION In this single-center cohort, AD activity at transplant was not observed to be independently associated with overall survival, relapse, or GVHD after adjustment, acknowledging the small sample size.These findings suggest that active AD alone may not confer worse post-transplant outcomes, supporting ongoing evaluation of this population in larger multicenter studies.

Donor-derived cytogenetic abnormalities are a rare finding following allogeneic hematopoietic cell transplantation. Deletion of the long arm of chromosome 20 [del(20q)] is one of the more frequently observed structural abnormalities, but its significance in the post-transplant setting remains unclear. We describe a unique case of donor-derived del(20q) with 26 years of post-transplant follow-up, the longest reported to date. The recipient remains well with normal blood counts despite persistent del(20q) in both myeloid and lymphoid lineages and the presence of coexisting somatic mutations in DNMT3A and TP53. Retrospective analysis of the donor’s marrow confirmed del(20q) and low-level DNMT3A and TP53 mutations at the time of transplant; the donor later developed therapy-related MDS after radiation therapy for thyroid cancer. To contextualize this case, we reviewed 20 published reports of donor-derived del(20q) post-transplant. The median time to detection was 16 months post-transplant, and 35% of cases progressed to donor-derived malignancy. Among those who progressed, the median time to malignancy diagnosis was 22 months post-transplant. Clinical outcomes across cases ranged from asymptomatic persistence and cytopenias to donor-derived myeloid malignancies, highlighting the need for long-term follow-up and potential use of molecular profiling to better define the neoplastic potential of donor-derived del(20q) after transplantation.

Introduction In hematopoietic cell transplantation (HCT), donor hematopoietic cells (HC) must engraft and maintain hematopoiesis for a recipient's lifetime. Epigenetic regulation, in particular DNA methylation, plays a critical role in HC self-renewal. Prior comparison of donor-recipient pairs after HCT show epigenetic age acceleration in recipients a few years post-HCT using Horvath's ‘epigenetic clock’ based on 353 CpG sites. Objective Here we investigated genome-wide DNA methylation to characterize differential patterns in very long-term surviving donor-recipient pairs post-HCT, using an agnostic approach that, to our knowledge that has not previously been reported. Methods We analyzed blood sampled from 12 pairs of recipients and related donors at a median of 36 years post-HCT (Table 1). Genomic DNA was isolated from blood mononuclear cells and processed using high-throughput multi-omics PIXUL–Methylated DNA immunoprecipitation sequencing platform. Using R, DiffBind, and edgeR software, we performed differential binding analysis of genome-wide DNA methylation data comparing donors and recipients. Sites with false discovery rate (FDR) <0.5 were analyzed using linear regression to examine associations between DNA methylation differences (recipient minus donor normalized peak scores) and donor/recipient age at HCT, time since HCT, and hematopoietic age (donor age at HCT + time since HCT). Results We detected 181311 shared donor-recipient CpG binding regions, representing 84% and 80% of total CpG binding regions in donors (n=214650) and recipients (n=227378). Of the 37 sites with FDR < 0.5, differential methylation density by normalized score was observed in donors vs. recipients (Fig. 1), with 28 (76%) sites showing higher methylation in recipients. The top 10 differentially methylated regions included 7 genes (Table 2) including KLF14, a known epigenetic marker of aging. Time since HCT and hematopoietic age were positively associated with greater recipient-donor DNA methylation differences at 18 (49%) and 21 (57%) sites, respectively. Conclusions Epigenetics analysis of blood cells from donors and recipients >3 decades post-HCT show high concordance of methylated sites, and most sites show higher methylation in recipients. Time since HCT and hematopoietic age were associated with higher methylation in recipients compared to donors in about half of binding sites. Hypermethylation of sites associated with gene regulation and transcription were predominant in recipients, whereas none of the genes hypermethylated in donors were transcription factors. In addition to expanding the cohort, future studies will decipher how progressive epigenetic remodeling of long-term engrafted HCs shapes the transcriptome, proteome, and metabolome, thereby elucidating the functional consequences of these enduring epigenetic changes in long-term HCT survivors.

Methodological advancements now allow older adults with AML to receive allografts although conflicting data exist regarding relative outcomes across age groups and benefits of different conditioning intensities. We retrospectively analyzed 495 adults aged 60–64 (n = 184), 65–69 (n = 189), or ≥70 (n = 122) allografted for AML in remission at our institution from 2006 to 2023. There were no significant differences in relapse or relapse-free survival (RFS) among the 3 age cohorts after multivariable adjustment. Patients aged ≥70 years had higher non-relapse mortality (NRM) than those aged ≥60–64 (P = 0.022) but their overall survival (OS) was only statistically non-significantly shorter (P = 0.11). There was an important interplay between age, conditioning intensity, and outcomes. Relative to age 60–64, age ≥70 years was associated with a higher risk of relapse (hazard ratio [HR] = 3.47; P = 0.012) and NRM (HR = 3.88; P = 0.001) with reduced intensity conditioning (RIC), leading to shorter RFS (HR = 3.79; P < 0.001) and OS (HR = 3.46; P < 0.001), while no such associations were found with nonmyeloablative (NMA) conditioning. Underlying, patients aged 60–64 and 65–69, but not those aged ≥70, had a significantly lower relapse risk with RIC relative to NMA conditioning, whereas NRM risks increased across all age cohorts. Our findings support allografting for adults ≥70 with AML in remission, especially with NMA conditioning.

Introduction: Severe aplastic anemia (SAA) is a life-threatening bone marrow failure disorder curable with allogeneic hematopoietic cell transplantation (HCT). Early efforts with conditioning using cyclophosphamide alone (Cy; 50 mg/kg/day x 4 days) demonstrated a rejection rate of approximately 36% among transfused patients who received unmodified blood products pre-HCT. The addition of horse anti-thymocyte globulin (ATG) then reduced rejection rates down to about 7%. Extensive preclinical studies from our group demonstrated that buffy coat (BC) depleted blood products—removal of the buffy coat layer via centrifugation—lowered the rejection risk in that model from 100% to 35%, and in vitro irradiation of unmodified products with 2,000 cGy reduced the risk from 100% to 10%. These interventions later became routine in blood banks. When combined, they theoretically reduce the rejection risk to approximately 3.5%—even without ATG. Given these advances, the continued need for ATG inclusion in SAA conditioning should be re-evaluated, especially since ATG is thought to not only reduce the risk of graft rejection but also the risk of graft-versus-host disease (GVHD). This analysis specifically addresses whether omitting ATG from conditioning regimens might increase the risk of GVHD. Methods: We retrospectively identified 392 patients with SAA who received HLA-matched related bone marrow grafts at Fred Hutchinson Cancer Center between 1970 and 2024. GVHD severity was graded by two primary investigators using Seattle criteria for acute GVHD; NIH consensus criteria were used for chronic GVHD. We assessed the association between ATG use and GVHD outcomes using multivariable regression models (logistic for acute GVHD, Cox for chronic GVHD). Covariates in adjusted models included use of BC infusions in addition to marrow, age at transplant, GVHD prophylaxis strategy (monotherapy vs. combination cyclosporine [CSP] and methotrexate [MTX]), acute GVHD grader, and year of HCT. Additional analyses were performed in the subgroup receiving combination GVHD prophylaxis due to strong collinearity between ATG and prophylaxis regimen. Two patients were excluded from acute GVHD analyses due to missing acute GVHD data. Results: Among 392 patients, 124 (32%) received ATG. The distribution of GVHD prophylaxis was as follows: 53% (208/392) received monotherapy without ATG, 31% (123/392) received ATG with dual-agent prophylaxis (CSP+MTX), 15% (60/392) received dual-agent prophylaxis without ATG, and one patient received ATG with monotherapy. After adjustment for the factors listed above, the odds of grades II-IV acute GVHD after ATG use was 1.48-times that among those who did not receive ATG (odds ratio (OR)=1.48 95% CI [0.50 -4.38]; p=0.483), and the adjusted OR for grades III-IV acute GVHD was 2.67 (95% CI [0.61-11.62]; p=0.190). The adjusted cause-specific hazard ratio for chronic GVHD was 0.89 (95% CI [0.41-1.94]; p=0.764). Among patients in the subgroup who received multi-agent acute GVHD prophylaxis, the above results were qualitatively similar. In particular, the adjusted OR for grades II-IV acute GVHD was 1.87 (95% CI [0.55-6.33]; p=0.312). Due to the limited number of cases of grades III-IV acute GVHD, the corresponding model was adjusted only for age and acute GVHD grader. The adjusted OR for grades III-IV acute GVHD was 2.83 (95% CI [0.64-12.49]; p=0.169). The adjusted cause-specific HR for chronic GVHD in the subgroup was 0.77 (95% CI [0.34-1.77]; p=0.54). The adjusted HR for mortality comparing ATG vs non-ATG regimens was 0.88 (95% CI [0.44-1.75]; p=0.712). Conclusion: In this single-center cohort of HLA-matched related allo-HCT recipients with SAA, ATG use was associated with a numerically higher incidence of acute GVHD after adjusting for potential confounders. Although ATG was linked to a numerically lower incidence of chronic GVHD, the magnitude of this reduction was modest and may be attributable to chance. Given current practices of BC-poor and in vitro irradiated transfusion products, these findings suggest that the routine inclusion of ATG in the conditioning regimen may not be needed for preventing both graft rejection and GVHD, challenging long-held assumptions about its dual benefit in conditioning regimens. These data support reconsideration of conditioning regimens for HLA-matched related allogeneic marrow grafts in SAA that do not include horse ATG.

Graft-versus-host disease (GVHD) is a risk of hematopoietic cell transplantation (HCT) in the clinical setting. The acute form of the disease is well managed, but the chronic form is more problematic. The canine HCT model, instrumental in establishing successful clinical HCT protocols, reproducibly recapitulates the clinical manifestations of GVHD. Thus, therapies for the prevention and treatment of GVHD in the canine model may be applicable to the clinic. Here, we present the methods necessary to establish both acute and chronic GVHD models in dogs.

After allogeneic hematopoietic cell transplantation (HCT), a very small number of donor stem cells reconstitute the recipient hematopoietic system, whereas the donor is left with a near-normal pool of stem cells. We hypothesized that the increased replicative stress on transplanted donor cells in the recipient could lead to the disproportionate proliferation of clonal hematopoiesis (CH) variants. We obtained blood samples from 16 related donor-recipient pairs at a median of 33.8 years (range: 6.6 to 45.7) after HCT, including the longest surviving HCT recipients in the world. For 11 of 16 pairs, a donor sample from the time of HCT was available for comparison. We performed ultrasensitive duplex sequencing of genes recurrently mutated in myeloid malignancies and CH, as well as a set of functionally neutral genomic regions representative of human genomic content at large. CH variants were observed in all donors, even those as young as 12 years old. Where donor pre-HCT sample was available, the average mutation rate in donors compared to recipients post-HCT was similar (2.0% versus 2.6% per year, respectively) within genes recurrently mutated in myeloid malignancies. Twenty-two (5.6%) of the 393 variants shared between paired donors and recipients post-HCT showed ≥10-fold higher variant allele frequency (VAF) in the recipient. A longer time since HCT was positively associated with the expansion of shared variant VAFs in the recipient. In conclusion, even decades after HCT, there does not appear to be widespread accelerated clonal expansion in the transplanted cells, highlighting the immense regenerative capacity of the human hematopoietic system.

Background: Advances in transplant platforms and supportive care have enabled allografting in adults with acute myeloid leukemia (AML) older than age 60 (up to their late seventies) but conflicting data exist on their relative outcomes. Methods: We retrospectively studied all 493 adults aged ≥60 years with AML or myelodysplastic neoplasm (MDS)/AML who underwent a first allogeneic HCT between 2006 and 2023 at our institution. The analysis aimed to assess the post-HCT outcomes with a specific focus on categorizing the patients by age groups (60-64, 65-69, and ≥70 years). Results: Among 493 patients, 184 (37%) were aged 60-64, 189 (38%) 65-69, and 120 (24%) ≥70 years. There were no significant differences in gender, disease type, cytogenetic risk, remission status, positivity for measurable residual disease (MRD) by multiparameter flow cytometry, cytogenetic abnormalities, blood count recovery, stem cell source, or HCT-CI among the age groups. However, younger patients more frequently received myeloablative conditioning (MAC) (P<0.001). Regression models were used to assess the relationship between age and post-HCT outcomes. After multivariable adjustment, patients aged ≥70 years had a statistically significantly higher risk of non-relapse mortality (NRM) than those age ≥60-64 (hazard ratio [HR]=1.75 [95% confidence interval: 1.10-2.79]; P=0.019), and their risk of death was statistically non-significantly higher (HR=1.32 [0.96-1.82]; P=0.085), whereas risks of relapse and relapse/death were similar. There were no statistically significant differences regarding relapse, relapse-free survival (RFS), overall survival (OS), or NRM between patients aged 60-64 years and those aged 65-69 years after adjustment. Across all age cohorts, there was a statistically significant association between HCT-CI score ≥4 and increased NRM (HR=2.12 [1.36-3.31]; P<0.001), RFS (HR=1.39 [1.05-1.84]; P=0.023), and OS (HR=1.52 [1.14-2.04]; P=0.005) but not relapse (P=0.67) after adjustment. Findings in the subset patients with AML (n=416) and those who received an allograft from a 10/10 HLA-matched related or unrelated donor (n=369) were similar to the entire study group. Among patients receiving nonmyeloablative (NMA) conditioning (n=240), there was no significant association between age group and relapse, RFS, OS, or NRM. In contrast, among patients allografted after reduced-intensity conditioning (RIC; n=144), age ≥70 years was associated with higher risk of relapse (HR=4.19 [1.31-8.10]; P=0.011, shorter RFS (HR=3.42 [1.88-6.23]; P<0.001) and OS (HR=3.16 [1.66-5.99]; P<0.001), and higher risk of NRM (HR=4.19 [1.88-9.36]; P=0.001). Patients aged 60-64 and 65-69 but not those aged ≥70 had a significantly lower risk of relapse when receiving RIC compared to those receiving NMA. The risk of NRM was similar for those getting NMA conditioning or RIC in the 60-64 age group. Patients ≥70 years had substantially higher NRM with RIC compared to NMA conditioning (HR=3.43 [1.68-7.00]; P<0.001). This resulted in a statistically significantly better RFS (HR=0.55 [0.33-0.94]; P=0.027) with RIC among patients aged 60-64, whereas RIC was associated with worse RFS (HR=2.03 [1.22-3.37]; P=0.006) and OS (HR=2.01 [1.17-3.47]; P=0.012) in patients aged ≥70 relative to those receiving NMA conditioning. Conclusion: For patients 60-64 years, reduced relapse risk and no increase in NRM led to improved RFS and OS with RIC compared to NMA conditioning. Uncertainty regarding optimal conditioning intensity remains for patients aged 65-69, where RIC showed reduced relapse risk but increased NRM, resulting in comparable RFS and OS to NMA conditioning. However, in patients aged ≥70, RIC was associated with higher NRM and worse RFS and OS compared to NMA conditioning but similar relapse risk. Since Patients aged ≥70 faced more toxicities with RIC and did not benefit from reduced relapse risks, our data suggest such older individuals should receive HCT after NMA conditioning.

Reduced intensity conditioning (RIC) and nonmyeloablative (NMA) conditioning regimens have expanded use of allogeneic hematopoietic cell transplantation (HCT) in AML to include older and medically less-fit patients, but relative efficacies and toxicities remain poorly defined. Here, we analyzed outcomes from 343 adults transplanted in remission after RIC (n = 137) or NMA (n = 206) conditioning between 2006 and 2021. The characteristics of RIC and NMA HCT patients were similar except that RIC patients were younger and their time between most recent remission achievement and allografting was shorter. There were no significant differences in relapse risk, relapse-free survival (RFS), overall survival (OS), and non-relapse mortality (NRM) between RIC and NMA HCT patients, both overall (relapse: hazard ratio [HR] = 0.80, P = 0.27; RFS: HR = 0.93, P = 0.61; OS: HR = 0.93, P = 0.66; NRM: HR = 1.13, P = 0.59) and when patients were stratified by pre-HCT measurable residual disease (MRD) status. After multivariable adjustment, there was no statistically significant association between conditioning intensity and relapse (HR = 0.69, P = 0.088), RFS (HR = 0.86, P = 0.37), OS (HR = 0.89, P = 0.49), or NRM (HR = 1.37, P = 0.19). In this non-randomized cohort of adults undergoing allografting for AML in first or second remission at our center, we could not detect statistically significant differences in outcomes between those assigned to RIC and those assigned to NMA conditioning.

Some retrospective studies have suggested that long-term donor statin use may protect against graft-versus-host disease (GVHD) in patients receiving cyclosporine (CSP)-based immunosuppression after allogeneic hematopoietic cell transplantation (HCT), but prospective studies of short-term treatment of donors with statin have shown conflicting results. We conducted 2 consecutive prospective clinical trials to assess whether donor statin treatment was associated with protection against severe acute GVHD (aGVHD). In a single-arm phase II trial (study 1), we evaluated whether short-term statin treatment of HLA-matched related donors for 14 days before HCT prevented grade III-IV aGVHD. In a prospective observational cohort study (study 2), we evaluated whether longer-term (>14 days) donor statin use was required for GVHD-protective effects. Study 1 was terminated after 6 of the 35 recipients (17%) developed grade III-IV GVHD. For study 2, we identified 135 patients whose unrelated donors had received long-term treatment with statins up to the time of HCT and 4942 patients whose donors had not received long-term statin treatment. The adjusted odds ratio for grade III-IV aGVHD (statin versus no statin) was .83 (95% confidence interval [CI], .46 to 1.50; P = .54). Multivariable analysis showed no statistically significant differences between the 2 groups in the risk of grade II-IV aGVHD, chronic GVHD, nonrelapse mortality, recurrent malignancy, or overall mortality. Among patients receiving CSP-based immunosuppression, including 35 with donors receiving long-term statin treatment and 973 with donors who did not receive statins, the adjusted odds ratio of grade III-IV aGVHD was .30 (95% CI, .07 to 1.35; P = .12). In study 1, short-term statin treatment of donors was ineffective in preventing grade III-IV GVHD. In study 2, in the prespecified subgroup of recipients given CSP-based immunosuppression, nondefinitive evidence suggested that donor statin use was associated with a reduced risk of severe aGVHD.(c) 2023 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.

BACKGROUND: Unprecedented reductions in multiple myeloma (MM) tumor burden after treatment with B cell maturation antigen (BCMA) directed bispecific T-cell engagers, or chimeric antigen receptor modified T-cells, have translated into improved progression free and overall survival; however, virtually all patients are predicted to ultimately relapse. The mechanisms of resistance to BCMA targeting agents are currently being explored, but presumably reflect persistence of MM cell subpopulations that either lack target antigen or otherwise evade immune-mediated tumor cell killing. Antigen targeted delivery of radiation to tumor cells leverages a unique effector mechanism that capitalizes on the exquisite sensitivity of malignant plasma cells to radiation. The α-emitter astatine-211 ( 211At) has particular promise as it deposits a very large amount of energy (~100 keV/μm) within a few cell diameters (50-90 μm) resulting in irreparable double-stranded DNA breaks. The high energy cell killing mediated by 211At is agnostic to MM cell heterogeneity, facilitates bystander delivery of radiation to target antigen negative clones, and limits radiation exposure to normal cells. We hypothesized that 211At targeting BCMA may be uniquely suited to eliminate residual MM cells. METHODS: We conjugated a human IgG1 anti-BCMA mAb and an isotype matched nonbinding control mAb (ofatumumab), with the amine-reactive labeling agent B10-NCS to enable 211At radiolabeling. In biodistribution studies of 211At-BCMA-B10 and 211At-ofatumumab-B10 using NOD.Cg-Rag1 tm1MomIl2rg tm1Wjl/SzJ (NRG) mice bearing flank MM tumor cell xenografts (MM1R or NCI-H929; n=5 mice/group), we demonstrated tumor-specific uptake of BCMA-B10 relative to control mAb and identified the optimal dose of 211At-mAb-B10 (210μg) for assessing therapeutic efficacy. In subsequent therapy studies, NRG mice (n=7-10/group) received 0.3-0.4e6 NCI-H929 luc tumor cells by tail vein injection 6-7 days prior to administration of 210 µg of 211At-BCMA-B10 or 211At-ofatumumab-B10 or no therapy (non-treatment control). Animal body weight was monitored serially, and disease was tracked using in vivo bioluminescence imaging (IVIS Spectrum) performed at 8 or more timepoints over 150 days. RESULTS: Disease elimination was defined as survival with no measurable disease by IVIS at 150 days following treatment. All mice receiving 6 or 8 µCi of 211At-BCMA-B10 (n=36) were cured (100%) after a single infusion of 211At-BCMA-B10. Mice in the untreated control groups uniformly experienced exponential tumor growth. At the lowest 211At dose (6 µCi), all BCMA targeted mice survived for more than 150 days while no untreated control mice survived beyond day 60 (median duration of survival 49 days [range 42-60 days]). Mice receiving 211At-ofatumumab had expected attenuation in tumor growth relative to untreated controls (presumably a consequence of non-specific radiation exposure); with a median duration of survival of 85 days; no mice survived beyond 108 days (range 65-108 days) [Figure 1, Figure 2]. No significant toxicity was observed in the 211At-BCMA-B10 treated groups. Among mice receiving 8 μCi of 211At-BCMA-B10 median animal body weight on day 14 post-treatment was 106% of baseline (range 97%-109%). Among mice receiving 6 μCi of 211At-BCMA-B10 the median body weight on day 14 was 107% of baseline (range 100% to 111%) and on day 150 the median weight was 123% of baseline (range 116% to 126%). CONCLUSIONS: Tumor responses are encouraging with 100% of mice cured of MM after receiving low doses of BCMA targeted 211At. While we have previously demonstrated that 211At-CD38 could eliminate MM in a similar model system, in that setting fewer than 50% of mice bearing the same NCI-H929 Luc tumors, and treated with 8 μCi of 211At, survived to day 150 [O'Steen S. Blood, 2019]. In contrast, here we show that 100% of mice are cured after receiving 6 μCi of 211At-BCMA-B10. These findings support further evaluation of BCMA targeted 211At in other tumor model systems and in clinical trials aimed at eliminating minimal residual disease.

After more than 60 years of intense research in allogeneic hematopoietic cell transplantation (HCT), this therapy has progressed from one that was fraught with seemingly insurmountable complications to a standard treatment of patients with aplastic anemia. During the 1970s and 1980s, HCT donors were almost exclusively HLA-identical siblings. Subsequent advances in the understanding of the complexity of the HLA region along with the development of molecular HLA typing and the establishment of unrelated volunteer donor registries have resulted in an ever-increasing use of such donors. Most recent breakthroughs have enabled HLA-haploidentical HCT and, thereby, finding donors for nearly every patient. The outstanding outcomes reported with any of the donor options have made allogeneic HCT the preferred treatment over immunosuppressive therapy.

Abstract Autologous peripheral blood haematopoietic stem cell transplantation (HCT) cures 33%–40% of dogs with high‐grade B‐cell lymphoma. We hypothesized, based on human allogeneic bone marrow transplantation literature, that transplanting dogs using canine donor leukocyte‐matched CD34+ cells would lead to fewer relapses and increased cure rates. We retrospectively reviewed medical records of dogs diagnosed with high‐grade B‐cell lymphoma who received an identical allogeneic HCT. A total of 15 dogs transplanted at four facilities were identified. Five of fifteen dogs relapsed before transplant. The mean number of donor CD34+ cells/kg harvested and infused into recipient dogs was 8.0 × 106/kg (range: 2.08 × 106/kg–2.9 × 107/kg). The median disease‐free interval and overall survival of all dogs was 1095 days (range: 9–2920 days) and 1115 days (range: 9–2920 days), respectively. Two of five dogs, not in remission at transplant, died in the hospital. The median disease‐free interval and overall survival of the remaining three dogs was 25 days (range: 15–250 days) and 1100 days (range: 66–1902 days), respectively. The median disease‐free interval and overall survival of the 10 dogs who had not relapsed was 1235 days (range: 19–2920 days) and 1235 days (range: 19–2920 days), respectively. One dog died soon after discharge of presumed gastric‐dilatation‐volvulus. Eight of nine remaining dogs lived >4 yrs post‐alloHCT, leading to a cure rate of 89%. Acute graft versus host disease was seen in three dogs. These results suggest that allogeneic HCT can cure ~50% more dogs than those treated with autologous HCT.

There is long-standing interest in estimating non-relapse mortality (NRM) after allogeneic hematopoietic cell transplantation (HCT) for AML, but existing tools have limited discriminative capacity. Using single-institution data from 861 adults with AML, we retrospectively examined the Treatment-Related Mortality (TRM) score, originally developed to predict early mortality following induction chemotherapy, as a predictor of post-HCT outcome. NRM risks increased stepwise across the four TRM score quartiles (at 3 years: 9% [95% confidence interval: 5–13%] in Q1 vs. 28% [22–34%] in Q4). The 3-year risk of relapse was lower in patients with lower TRM score (26% [20–32%] in Q1 vs. 37% [30–43%] in Q4). Consequently, relapse-free survival (RFS) and overall survival (OS) estimates progressively decreased (RFS at 3 years: 66% [59–72%] in Q1 vs. 36% [29–42%] in Q4; OS at 3 years: 72% [66–78%] in Q1 vs. 39% [33–46%] in Q4). With a C-statistic of 0.661 (continuous variable) or 0.642 (categorized by quartile), the TRM score predicted NRM better than the Pretransplantation Assessment of Mortality (PAM) score (0.603) or the HCT-CI/age composite score (0.576). While post-HCT outcome prediction remains challenging, these findings suggest that the TRM score may be useful for risk stratification for adults with AML undergoing allogeneic HCT.