Alternative Donor Research Articles

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

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

Alternative Donor Transplantation for Severe Aplastic Anemia: A Comparative Study of the Saawp EBMT

Alternative donor transplantation for severe aplastic anemia: a comparative study of the SAAWP EBMT INTRODUCTION Allogeneic stem cell transplantation (allo-SCT) from an HLA-matched sibling donor (MSD) is considered the standard of care for younger patients with severe aplastic anemia (SAA). For patients lacking a suitable MSD, matched unrelated donors (MUD) have increasingly been used for SAA patients who do not respond to immunosuppressive therapy. However, a significant number of SAA patients who require allo-SCT are unable to access a fully HLA-matched unrelated donor or experience delays in finding one. In such cases, other alternative options, such as mismatched unrelated donors (MMUD), and haploidentical family donors (Haplo), have been explored. Limited research exists on MUD, MMUD, and Haplo allo-SCT efficacy and safety in SAA. Drawing definitive conclusions for the optimal alternative donor transplant approach remains challenging. This study compares the outcomes of allo-SCT from MUD, MMUD, and Haplo donors in patients with SAA from the SAAWP EBMT. PATIENTS AND METHODS Inclusion criteria All patients diagnosed with SAA who underwent their first allo-SCT between January 2012 and December 2021 from either a MUD, MMUD or Haplo, were included. Only transplants from Haplo donors who received post-transplant cyclophosphamide (PTCy) as prophylaxis for graft-versus-host disease (GVHD) were considered. Statistical Analysis The study utilized statistical methods such as Kaplan-Meier estimation, Log-Rank test, competing risks analysis, and Cox proportional hazards regression. The analyses included OS, EFS, GRFS, NRM, aGVHD, cGVHD, and graft failure. The statistical software R and relevant packages were used. RESULTS Patient and Transplantation Characteristics Table 1 summarizes patient and transplant characteristics for the 1652 participants. Engraftment Neutrophil recovery at 28 days was 85% (95% CI; 83-87) for MUD, 84% (95% CI; 80-88) for MMUD, and 75% (95% CI; 69-81) for Haplo (p = 0.033). Platelet engraftment at 100 days was 88% (95% CI; 86-91) for MUD, 82% (95% CI; 78-87) for MMUD and 72% (95% CI; 65-78) for Haplo (p < 0.001). Graft failure The 1-year cumulative incidence of primary graft failure (PGF) for the MUD, MMUD, and Haplo cohorts was 4% (95% CI; 3-6%), 5% (95% CI; 3-8%) and 16% (95% CI; 11-21%), respectively (p < 0.001). In multivariable analysis, compared with MUD, Haplo (HR, 3.72; 95% CI, 1.97-7.03; p<0.001) was associated with a higher PGF. Other predictors for a higher PGF are shown in Table 2. GVHD The cumulative incidence of aGVHD grades II-IV at 100 days for the MUD, MMUD, and Haplo cohorts was 13% (95% CI; 11-15), 22% (95% CI; 17-26), and 18% (95% CI; 13-24), respectively (p < 0.001). In multivariable analysis, MMUD was associated with an increased risk of aGVHD grades II-IV, when compared with MUD (HR 1.97; 95% CI, 1.4-2.77; p < 0.001). Other predictors associated with a higher risk of aGVHD grades II-IV are shown in Table 2. The 3-year cumulative incidence of cGVHD for the MUD, MMUD, and Haplo cohorts was 18% (95% CI; 15-20), 19% (95% CI; 14-24), and 18% (95% CI; 11-24), respectively (p = 0.9). NRM The 3-year cumulative incidence of NRM was 12% (95% CI; 10-14) for MUD, 17% (95% CI; 13-22) for MMUD, and 22% (95% CI; 15-28) for Haplo (p < 0.001). Survival The 3-year EFS for the MUD, MMUD, and Haplo cohorts was 73% (95% CI; 71-76), 64% (95% CI; 59-70), and 53% (95% CI; 46-61), respectively (p < 0.001), whereas OS was 81% (95% CI; 79-84), 74% (95% CI; 69-79), and 63% (95% CI; 54-71), respectively (p < 0.001). In multivariable analysis, compared to MUD, MMUD (HR, 1.54; 95% CI, 1.12-2.11; p = 0.007) and Haplo (HR, 1.97; 95% CI, 1.35-2.86; p<0.001) were associated with worse survival. Other predictors for a worse OS are shown in Table 2. The 3-year GRFS for the MUD, MMUD, and Haplo cohorts was 71% (95% CI; 68-74), 66% (95% CI; 60-72), and 53% (95% CI; 44-61), respectively (p < 0.001). In multivariable analysis, compared with MUD, MMUD (HR, 1.42; 95% CI, 1.1-1.82; p = 0.006) and Haplo (HR, 1.71; 95% CI, 1.27-2.31; p<0.001) were associated with worse GRFS. Other factors associated with a worse GRFS are shown in Table 2. CONCLUSION In conclusion, our study supports MUD transplantation as the preferred option for SAA patients without a MSD. While MMUD and Haplo transplants are feasible, MMUD appears more favorable than Haplo, even in the era of PTCy.

Improved detection of aberrant splicing with FRASER 2.0 and the intron Jaccard index

Detection of aberrantly spliced genes is an important step in RNA-seq-based rare-disease diagnostics. We recently developed FRASER, a denoising autoencoder-based method that outperformed alternative methods of detecting aberrant splicing. However, because FRASER's three splice metrics are partially redundant and tend to be sensitive to sequencing depth, we introduce here a more robust intron-excision metric, the intron Jaccard index, that combines the alternative donor, alternative acceptor, and intron-retention signal into a single value. Moreover, we optimized model parameters and filter cutoffs by using candidate rare-splice-disrupting variants as independent evidence. On 16,213 GTEx samples, our improved algorithm, FRASER 2.0, called typically 10 times fewer splicing outliers while increasing the proportion of candidate rare-splice-disrupting variants by 10-fold and substantially decreasing the effect of sequencing depth on the number of reported outliers. To lower the multiple-testing correction burden, we introduce an option to select the genes to be tested for each sample instead of a transcriptome-wide approach. This option can be particularly useful when prior information, such as candidate variants or genes, is available. Application on 303 rare-disease samples confirmed the relative reduction in the number of outlier calls for a slight loss of sensitivity; FRASER 2.0 recovered 22 out of 26 previously identified pathogenic splicing cases with default cutoffs and 24 when multiple-testing correction was limited to OMIM genes containing rare variants. Altogether, these methodological improvements contribute to more effective RNA-seq-based rare diagnostics by drastically reducing the amount of splicing outlier calls per sample at minimal loss of sensitivity.

Pediatric Bone Marrow Failure: A Broad Landscape in Need of Personalized Management.

Irreversible severe bone marrow failure (BMF) is a life-threatening condition in pediatric patients. Most important causes are inherited bone marrow failure syndromes (IBMFSs) and (pre)malignant diseases, such as myelodysplastic syndrome (MDS) and (idiopathic) aplastic anemia (AA). Timely treatment is essential to prevent infections and bleeding complications and increase overall survival (OS). Allogeneic hematopoietic stem cell transplantation (HSCT) provides a cure for most types of BMF but cannot restore non-hematological defects. When using a matched sibling donor (MSD) or a matched unrelated donor (MUD), the OS after HSCT ranges between 60 and 90%. Due to the introduction of post-transplantation cyclophosphamide (PT-Cy) to prevent graft versus host disease (GVHD), alternative donor HSCT can reach similar survival rates. Although HSCT can restore ineffective hematopoiesis, it is not always used as a first-line therapy due to the severe risks associated with HSCT. Therefore, depending on the underlying cause, other treatment options might be preferred. Finally, for IBMFSs with an identified genetic etiology, gene therapy might provide a novel treatment strategy as it could bypass certain limitations of HSCT. However, gene therapy for most IBMFSs is still in its infancy. This review summarizes current clinical practices for pediatric BMF, including HSCT as well as other disease-specific treatment options.

Diastereoselective Self-Assembly of Low-Symmetry Pdn L2n Nanocages through Coordination-Sphere Engineering.

Metal-organic cages (MOCs) are popular host architectures assembled from ligands and metal ions/nodes. Assembling structurally complex, low-symmetry MOCs with anisotropic cavities can be limited by the formation of statistical isomer libraries. We set out to investigate the use of primary coordination-sphere engineering (CSE) to bias isomer selectivity within homo- and heteroleptic Pdn L2n cages. Unexpected differences in selectivities between alternative donor groups led us to recognise the significant impact of the second coordination sphere on isomer stabilities. From this, molecular-level insight into the origins of selectivity between cis and trans diastereoisomers was gained, highlighting the importance of both host-guest and host-solvent interactions, in addition to ligand design. This detailed understanding allows precision engineering of low-symmetry MOC assemblies without wholesale redesign of the ligand framework, and fundamentally provides a theoretical scaffold for the development of stimuli-responsive, shape-shifting MOCs.

Comparison of Stem Cell Transplantation Using Unrelated, Haploidentical, and Sibling Donors for Patients with Acquired Severe Aplastic Anemia: A Single-Center Retrospective Cohort Study

The preferred donor (haploidentical vs. matched unrelated donor) choice in patients with acquired severe aplastic anemia (SAA) who lack a human leukocyte antigen (HLA)-matched sibling donors (MSDs) and fail upfront immunosuppressive treatment (IST) therapy is unknown. We retrospectively investigated SAA patients (n=58) who underwent allogeneic stem cell transplantation (allo-SCT) between January 2012 and October 2022. The 5-year overall survival (OS) (87.5% ± 11.7% vs. 98.0% ± 6.5% vs. 83.3% ± 7.6%, respectively, p= 0.926) and 5-year failure-free survival (FFS) (60.0% ± 18.2% vs. 87.0% ± 7.0% vs. 78.3% ± 8.6%, respectively, p= 0.222) were comparable among the unrelated donors (URD; n=8), haploidentical donors (HID; n=25), and MSD cohorts (n=25). Multivariate analysis revealed that primary engraftment failure independently predicted OS, and secondary graft failure predicted FFS among SAA patients who underwent allo-SCT, although donor type and age did not predict the outcomes. An urgent second SCT for patients with engraftment failure may be an effective salvage treatment. Summarily, our findings showed that an alternative donor SCT is indicated for eligible SAA patients without MSDs even if these patients are aged ⩾ 40 years.

Diastereoselective Self‐Assembly of Low‐Symmetry PdnL2n Nanocages through Coordination‐Sphere Engineering**

AbstractMetal‐organic cages (MOCs) are popular host architectures assembled from ligands and metal ions/nodes. Assembling structurally complex, low‐symmetry MOCs with anisotropic cavities can be limited by the formation of statistical isomer libraries. We set out to investigate the use of primary coordination‐sphere engineering (CSE) to bias isomer selectivity within homo‐ and heteroleptic PdnL2n cages. Unexpected differences in selectivities between alternative donor groups led us to recognise the significant impact of the second coordination sphere on isomer stabilities. From this, molecular‐level insight into the origins of selectivity between cis and trans diastereoisomers was gained, highlighting the importance of both host–guest and host‐solvent interactions, in addition to ligand design. This detailed understanding allows precision engineering of low‐symmetry MOC assemblies without wholesale redesign of the ligand framework, and fundamentally provides a theoretical scaffold for the development of stimuli‐responsive, shape‐shifting MOCs.

Combining Low-Dose Post-Transplant Cyclophosphamide(PTCY) with Anti-Thymocyte Globulin(ATG) for Prophylaxis of Graft-Versus-Host Disease in Alternative-Donor Hematopoietic Stem Cell Transplantation for β-Thalassemia Major

Background ： The 5-year overall survival rate (OS) for children with thalassemia major who undergo allogeneic stem cell transplantation is 90% and the event-free survival (EFS) rate is 86%. Due to the limited availability of matched sibling donors, the proportion of transplantations from alternative donors is increasing, particularly from haplo-identical donors. Post-transplant infections and graft-versus-host disease (GVHD) remain the major causes of mortality, especially in those who receive transplantation from alternative donors. Post-transplant cyclophosphamide (PTCY) has shown outstanding results of GVHD prophylaxis in haploidentical matched related donors transplantation with hematological malignancies. However, there is insufficient clinical evidence for its application in pediatric patients who received transplantation from haplo-identical donors with non-malignant hematological disease. Here, we retrospectively analyzed the results of 40 cases that underwent allogeneic stem cell transplantation from haploidentical matched related donors (Haplo-RD) and unrelated donors (UD) to evaluate the safety and efficacy of the novel regimen in GVHD prophylaxis. Method A total of 40 patients with β-thalassemia major received stem cell transplantation, 10 haploid donors (Group Haplo-RD), and 30 unrelated donors (Group UD). Among Group UD, 15 donors were 1 or 2 HLA locus mismatched, remaining 15 were identically matched. The median age of the patients was 5.5 years, ranging from 2 to 12. The Conditioning regimen mainly consisted of fludarabine, busulfan, cyclophosphamide, and thiotepa. GVHD prophylaxis included ATG 1.5mg/kg×3d, cyclophosphamide (CTX) 25mg/kg×2d, cyclosporin A (CsA), and mycophenolate mofetil (MMF). We analyzed the engraftment rate, GVHD incidence, survival rate, and virus reactivation rate for each group. Results Engraftment rate was 100%, with a median time of 11 (10-15) days for neutrophil implantation and 12 (6-31) days for platelet implantation. All patients achieved complete chimerism on day 30 after transplantation. Three cases (7.5%) suffered from Ⅲ-Ⅳ aGVHD, with one being in the Group Haplo-RD group and two in the Group UD. Four cases (10.0%) of cGVHD were recorded. The overall survival (OS) rate and thalassemia-free survival rate were both 92.5%. In Group Haplo-RD, both the OS and thalassemia-free survival rates were 100%. Eight cases reported cytomegaloviremia but no one developed to CMV disease. The total activation rate for CMV was 20%. Nine cases suffered from BK virus urinary tract infection, resulting in a total activation rate of 22.5%. Detailed results are shown in Table 1 and Figure 1. Discussion Due to the high risk of GVHD and infection, stem cell transplantation from haploidentical and unrelated donors cannot be routine therapy for children with thalassemia major. Standard-dose PTCY regimen significantly increases the risk of CMV and BK infection after transplantation and is not suitable for non-malignant disease. The results have been reported that low-dose PTCY/ ATG can reduce the risk of GVHD as compared with standard-dose ATG in haploidentical donor stem cell transplantation. In our study, the novel GVHD prophylaxis regimen, semi-dose PTCY (25mg/kg×2d) combined with low-dose ATG (1.5mg/kg×3d), was used for stem cell transplantation from haploidentical and unrelated mismatched donors. The incidence of III-IV aGVHD was 7.5% and cGVHD was 10.0%, and there was no rejection of the transplant. The activation rate of CMV and BKV was significantly lower than reported in the literature, and the non-relapse mortality (NRM) after transplantation was significantly reduced. There was no statistical difference in the rate of OS, EFS, aGVHD, and cGVHD between Group Haplo-RD and Group UD. The results provide an effective approach for preventing GVHD and infectious diseases in thalassemia patients who underwent allo-HSCT with high-risk GVHD.

Post-Transplant Cyclophosphamide, Abatacept, and Vedolizumab to Prevent Graft-Versus-Host Disease after Hematopoietic Stem Cells Transplantation from Haploidentical Donors in Children with Acute Leukemia: Results of a Prospective Trial

Introduction Graft-versus-host disease (GvHD) remains a crucial complication associated with significant morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). High-dose post-transplantation cyclophosphamide (PTCy) targets alloreactive donor T cells proliferating early after HSCT, promotes regulatory T cells, and prevents severe GVHD. The effectiveness of PTCy-based regimens varies depending on the graft source and intensity of the preparative regimen. Improvement of GVHD control with novel targeted agents, added to the backbone of PTCy, could further increase the safety of HSCT and reduce the morbidity and complications of standard regimens of pharmacological immune suppression. In this pilot trial, we evaluated the safety and efficacy of abatacept and vedolizumab in unmanipulated haploidentical transplantation among children with leukemia. Materials and methods A total of 54 pts with acute leukemia (AML- 18, ALL-36, 26 female, 28 male, the median age at HSCT - 7,4 years (0,4-16,8), underwent unmanipulated allogeneic bone marrow (BM) (n=53) or peripheral blood stem cell (PBSC)(n=1) transplantation between March 2022 and May 2023. All donors were haploidentical relatives, represented Disease status at transplant was CR1 in 25 pts, CR³2 in 29 pts. For all patients, it was the 1-st transplantation. All patients received myeloablative conditioning, either TBI-based (n=30) or 24 treosulfan-based (n=24), with either cyclophosphamide (n=47) or etoposide (n=7) as a second agent. Prophylaxis of graft-versus-host-disease (GVHD) consisted of CsA from day-1 to day 180, 50 mg/kg of Cph on days +3 and +4, abatacept at 10 mg/kg on days +5, +14, +28, +45, +60 and vedolizumab at 10 mg/kg (capped at 300 mg) on days -1, +14, +28. The median dose of CD34+ cells was 4,7 x10 6/kg (range 1,2-17), and the CD3 dose was 42 x10 6/kg. Results Primary engraftment was achieved in 53 (98%) pts; the median time to neutrophil and platelet recovery was 20 and 23 days, respectively. All engrafted pts had verified morphologic remission and achieved complete donor chimerism by day +30. One patient failed to engraft, relapsed, and required rescue with a second HSCT from an alternative donor. The regimen was generally well tolerated. Acute toxicity consisted of grade III-IV mucositis (n=5); grade II-III hemorrhagic cystitis (n=4); grade III-V veno-occlusive disease (n=2) (all cases of VOD developed after pre-HSCT use of inotozumab); bloodstream infections (n=8). Four patients were admitted to the intensive care unit due to septic events or VOD. The median follow-up time for survivors was seven months (range: 1 -15). Transplant-related mortality was 2% (95% CI:0,3-14): one patient with ALL previously treated with inotozumab died in CR due to consequences of severe VOD on day + 60. The cumulative incidence of aGVHD grade II-IV was 36% (95% CI, 25 - 52), and grade 3-4 was 9% (95% CI, 4 - 22). In 13 cases, aGVHD was limited to skin: grade 2 (n=12), grade 4 (n=1), in two cases to the gut: grade 3(n=1), grade 4(n=1), three patients had skin and gut GVHD: grade 2 (n=2), grade 3(n=1) and one had skin and liver GVHD grade 3. The cumulative incidence of gut aGVHD grade II-IV was 9% (95% CI, 4 - 22). Eleven patients with GVHD responded to first-line immunosuppressive treatment, while 8 received additional therapy. The cumulative incidence of relapse was 11% (95%CI:5-26) in the entire cohort. EFS and OS were 89% (95%CI: 79-97) and 98% (95%CI: 94-100). The GVHD- and relapse-free survival was 78% (95%CI:67-88). Conclusion Our data suggest that adding vedolizumab and abatacept to the PTCy-based GVHD prophylaxis backbone is well tolerated and may reduce the incidence of gut GVHD among children with acute leukemia grafted from haploidentical donors. This approach can be further developed to reduce exposure to calcineurin inhibitors and deploy additional anti-leukemia effectors after HSCT.

Gender Disparities in Allograft Access Due to HLA-Sensitization in Multiparous Women: Implications for Evaluation of Female Patients for Alternative Donor Transplantation

Introduction: The relationship between allograft patient (pt) demographics & HLA-antibody (HLA-Ab) burden, & the degree to which HLA-Ab burden impacts donor type received in the current era of “donors for all”, is not established. Methods: We examined associations between pt sex/ parity, ancestry, & HLA-Ab burden in consecutive adult allograft recipients (excluding HLA-identical siblings) with acute leukemia, MDS, or MPN, transplanted 1/2018-12/2022. We also assessed the impact of HLA-Ab burden on donor type received. We classified HLA-Ab burden by the number & intensity of class I (HLA-A, B, -C) & II (HLA-DR, -DQ, -DP) HLA-Abs. A mean fluorescence intensity (MFI) > 1,000 defined a positive HLA-Ab. Pts were classified as broadly sensitized (more than the median number of class I/ II HLA-Abs among Ab positive pts) &/or highly sensitized (MFI > 10,000 for ≥ 1 HLA-Ab). For pts with > 1 screen, the one closest to transplant was used. We hypothesized that multiparous females have the greatest HLA-Ab burden, limiting provision of haploidentical (haplo) grafts in these pts due to the rejection risk. Results: Of 672 pts [median age 60 yrs (range 29-79), 419/672 (62%) with acute leukemia, 472/672 (70%) with European ancestry], 278/672 (41%) were female of whom 54/278 (19%) were nulliparous, 52/278 (19%) uniparous & 172/278 (62%) multiparous. Overall, 367/672 (55%) received 8/8 unrelated donor (URD) & 305/672 (45%) HLA-disparate grafts [137 cord blood (CB), 88 haplo, & 80 5-7/8 URD (mmURD)]. As expected, non-European pts received 2x the proportion of HLA-disparate grafts [165/472 (35%) vs 141/200 (70%), p < .001]. Pt ancestry was not associated with HLA-Ab burden. Pt sex/ parity & HLA-Ab burden associations are shown in Table 1A & Fig. 1. Over one third [254/672 (38%)] of pts had a positive screen for class I/ II HLA-abs (median of 8 HLA-Abs of positive pts, range 1-113). In the 254 positive pts, 3,563 Abs were detected with the MFI distribution being 1,001-4,000 in 1,340/3,563 (38%), 4,001-10,000 in 874/3,563 (25%) & > 10,000 in 1,349/3,563 (38%). Of the total pt cohort, 140/672 (21%) pts were broadly &/or highly sensitized with 90/672 (13%) being both broadly & highly sensitized. Compared with males & nulliparous females, uni- & multi-parous female pts had over 2x the proportion of positive screens [117/448 (26%) vs 137/224 (61%), p < .001]. They also had more than 8x the proportion broadly & highly sensitized [17/448 (4%) vs 73/224 (33%), p < .001]. HLA-Ab burden by donor type is shown in Table 1B. Among HLA-disparate graft recipients, compared with recipients of CB & mmURDs, fewer haplo recipients had positive screens [96/217 (44%)CB/ mmURD vs 27/88 (31%) haplo, p = .029]. Less than half the proportion were broadly & highly sensitized [37/217 (17%) CB/ mmURD vs 7/88 (8%) haplo, p = .041]. Also, haplo recipients included the fewest multiparous females [16/88 (18%)] compared with making up over one quarter of 8/8 URD [98/367 (27%)], CB [36/137 (26%)], or mmURD [22/80 (28%)] transplants. Conclusion: Over 10% of transplanted pts were broadly & highly sensitized to HLA. The HLA-Ab burden was predominantly in parous females (33% of our pt cohort), most of whom had HLA-Abs with one-third of this group being both broadly & highly sensitized. Moreover, pts with a high HLA-Ab burden were the least likely to receive haplos, & thus these transplants were less common in multiparous females. These data have immediate implications for alternative donor transplant evaluations of female patients: given that HLA-Abs should be expected among parous females, in the absence of a matched adult donor, mmURD or CB may need to be considered over haplo grafts. This could compound allograft access for multiparous female pts of non-European heritage, given many will lack a fully matched adult donor & non-European pts have greatly decreased URD availability (Fingrut et al., ASH 2023). These challenges are under-appreciated in the transplant field. At initial allograft evaluation, transplant centers should obtain ancestry & parity histories & screen for HLA-Abs. In the absence of a suitable HLA-identical sibling donor, this information, together with the URD search prognosis (ie Davis et al., TCT 2023), should then guide triage to alternative donor allografts. Finally, prospective analysis of the impact of donor-specific HLA-Abs on donor selection & transplant outcomes as well as development of effective HLA de-sensitization strategies are urgently needed.

Intent to Treat Allogeneic Stem Cell Transplantation Outcomes in Relapsed/Refractory T-Cell Lymphomas

Introduction T-cell lymphomas (TCL) are a heterogeneous group of lymphoproliferative malignancies with an overall poor prognosis. Despite aggressive first-line therapy, most patients experience disease relapse or progression. Allogeneic stem cell transplant (AlloSCT) is a standard of care for relapsed/refractory (R/R) TCL. However, many patients do not receive this potentially curative therapy. There is a paucity of data regarding the frequency of and barriers to undergoing AlloSCT in R/R TCL. To address this knowledge gap, we conducted a retrospective analysis of R/R TCL patients intending to undergo AlloSCT and hypothesized the primary barrier to AlloSCT to be lack of effective disease control. Methods We identified patients with a primary diagnosis of R/R TCL seen at the University of Washington/Fred Hutchinson Cancer Center (UW/FHCC) between 1/2008 and 6/2023 and linked these patients with the UW/FHCC bone marrow transplant (BMT) database to identify those who were intended for transplant. Intention to transplant (ITT) was defined as undergoing human leukocyte antigen (HLA) typing for purposes of AlloSCT. Patients with T-cell lymphoblastic leukemia/lymphoma were excluded. The primary endpoint was the rate of patients who underwent AlloSCT. Secondary endpoints included progression-free (PFS) and overall survival (OS) in patients who underwent AlloSCT and specific barriers to AlloSCT. Results Overall, 163 patients met ITT criteria. Males comprised 66% of patients. Median age was 65 (range 34-81) years and the median number of treatment regimens prior to HLA typing was 3 (range 1-10). The majority of patients (60%) were non-Hispanic whites (NHW), with Asians/Pacific Islanders (API), Hispanics/Latinos (HL), African Americans (AA) and Alaskan Natives/American Indians (ANAI) contributing 17%, 12%, 7% and 4%, respectively. Sixty-four patients (39%) had peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), 23 (14%) had angioimmunoblastic TCL (AITL), 17 (10%) had anaplastic large cell lymphoma (ALCL; 6 with ALK+), 16 (10%) had NK/TCL, 11 (7%) had hepatosplenic TCL, 12 (7%) had T-cell prolymphocytic leukemia, 5 (3%) had adult T-cell leukemia/lymphoma and 12 (7%) had primary cutaneous TCL. Twenty-two (13%) patients had secondary CNS involvement and 27 (17%) had previous autologous stem cell transplant. Of all patients who received HLA typing, 154 (94%) had a transplant consult, 54 (33%) initiated pre-AlloSCT workup and 51 (31%) underwent AlloSCT. Barriers to AlloSCT included progressive disease, patient preference, inability to identify a donor, indolent disease, poor functional status/multiple comorbidities and lack of a caregiver in 55%, 9%, 8%, 5%, 3% and 1%, respectively (Figure 1A). Six (5%) patients are currently receiving salvage therapy with plans for subsequent AlloSCT. AlloSCT occurred in NHW, API, HL, AA and ANAI patients at rates of 35%, 11%, 26%, 36% and 50%, respectively. All patients who were unable to undergo transplant due to lack of a donor were from groups other than NHW. AlloSCT rates were 30%, 39% and 17% in PTCL-NOS, AITL and ALCL, respectively. At a median follow-up time of 24.2 months, 101 (63%) patients are deceased with 83 (82%) due to disease. Twenty (39%), 17 (33%), 11 (22%) and 3 (6%) patients received an AlloSCT with a matched unrelated, matched related, mismatched unrelated and haploidentical donor, respectively. Fifteen (29%) patients underwent a myeloablative while 36 (71%) underwent a reduced intensity conditioning regimen. None of the 51 patients who underwent AlloSCT had pre-transplant measurable disease. Of transplanted patients, median PFS was 55.7 months and OS was 62.4 months (Figure 1B). Sixteen (31%) patients had eventual disease relapse. Eighty percent of relapses occurred within 3 months after AlloSCT. Seven (13%) and 6 (12%) of the transplanted patients were deceased within 12 months after AlloSCT due to disease relapse and complications of AlloSCT, respectively. Conclusions Although AlloSCT may be highly effective for R/R TCL achieving a CR, only a small minority of patients are able to undergo AlloSCT and the outcomes for the ITT population is dismal. Common barriers to undergoing AlloSCT include progressive disease and inability to identify suitable donors, particularly in minority populations. More effective pre-transplant salvage therapies and alternative AlloSCT donors are greatly needed.

A Novel Protocol Improves Engraftment in Tαβ + Cell Depleted Haplo-HSCT for Patients with Thalassemia Major

Background: Hematopoietic stem cell transplantation (HSCT) remains a proven curative approach for patients with thalassemia major (TM) over long-term practice. However, achieving successful engraftment and managing graft-versus-host disease (GVHD) continue to pose significant challenges. While low incidence of GVHD has been observed in Tαβ + cell-depleted HSCT (TDH) from haploidentical donors, graft failure (GF) remains a considerable concern, particularly in patients with TM. To enhance the engraftment in TM-TDH, we conducted this prospective/retrospective single-center clinical study. Method: A total of 137 patients diagnosed with TM received TDH at the BMT-center, Taixin Hospital, between March 2021 and April 2023. The median age of the patients was 7 years (ranging from 2 to 19 years), with 89 males and 48 females. The median follow-up time was 408 days (ranging from 99 to 857 days). The conditioning regimen consisted of Thymoglobulin on -day 21, followed by 3-Gy total body irradiation on -day 11. On -day 10, the patients received an infusion of donor lymphocytes (2*10 8/kg), followed by cyclophosphamide (Cy) at a dose of 50mg/kg on days -8, -7, and -2, and 25mg/kg on day -1. Additionally, blood-concentration adjusted busulfan was administered on days -6 to -4, fludarabine at a dose of 40mg/kg on days -6 to -2, and thiotepa at 10mg/kg on day -3. For GVHD prophylaxis, short-term (< 6 months) low-dose tacrolimus or sirolimus with or without mycophenolate mofetil was used. The mean infused CD34+ cells were 31.09 (ranging from 14.25 to 61.12) *10 6/kg, TCRγδ+ cells were 39.49 (ranging from 5.18 to 140.39) *10 6/kg, and NK cells were 109.18 (ranging from 27.52 to 309.41) *10 6/kg, respectively. The targeted infusion of TCRαβ+ cells was aimed at 1.5-2.0*10 5/kg. Results: Out of the 137 patients, 133 achieved successful engraftment (97.1%) with median engraftment times of 16 days (ranging from 9 to 48 days) for ANC to reach 0.5x10 9/L, 11 days (ranging from 1 to 23 days) for HB to reach 80g/L, and 10 days (ranging from 5 to 22 days) for platelets to reach 20x10 9/L, respectively. GF was observed in four patients. Among them, two patients with GF underwent salvage alternative donor second HSCT on +day 19 and +day 32, respectively, and are currently thalassemia-free. One patient received infusion of cryopreserved auto-peripheral blood stem cell and continues to live with TM. Unfortunately, four patients passed away, with one GF patient dying from suspected virus myocarditis on +day 11, one potentially due to virus hepatitis or hepatic GVHD on day +188, and the remaining two from virus bronchiolitis obliterans on +day 211 and +day 254, respectively. The overall survival (OS) and thalassemia-free survival (TFS) rates were 96.5% and 94.3%, respectively. The incidence of GF and transplant-related mortality (TRM) were 2.9% and 3.5%, respectively (Fig.). Acute GVHD of grade I-II and grade III-IV was observed in 10.53% and 9.02% of patients, respectively, while mild and moderate chronic GVHD occurred in 7(5.1%) and 1(0.7%) patient(s), respectively. The incidence of veno-occlusive disease was mild and limited. C onc lusion: The current study demonstrates the efficacy of a novel protocol in enhancing engraftment in TDH for patients with TM and with low incidence of both acute GvHD and chronic GvHD. This approach represents a significant advancement in the field of TM-TDH. Fig.1 Curve of OS, TFS, TRM and Rejection in TM-TDH

Comparison of Non-Relapse Mortality after Haploidentical Hematopoietic Stem Cell Transplantation with Post-Transplant Cyclophosphamide Versus Single Umbilical Cord Blood Transplantation for Hematologic Disease

Introduction: Unrelated cord blood transplantation (UCBT) and haploidentical stem cell transplantation with post-transplant cyclophosphamide as graft-versus-host disease (GVHD) prophylaxis (PTCy-haplo) are alternative options for patients with hematologic disease lacking a human leukocyte antigen (HLA)-matched donor. Non-relapse mortality (NRM) after UCBT may vary depending on the cord blood CD34+ cell count, but no study has accounted for CD34+ cell count when comparing the outcomes after UCBT and PTCy-haplo. Therefore, we analyzed transplant outcomes after UCBT and PTCy-haplo in patients with hematologic disease from data of a nationwide registry that included cord blood CD34+ cell count. Methods: Patients with hematologic disease receiving first UCBT or PTCy-haplo between 2014 and 2020 were identified from the nationwide registration data of the Japanese Data for Hematopoietic Cell Transplantation. Acute GVHD-related mortality was defined as death caused primarily by GVHD or occurred secondary to GVHD, and infection-related mortality as death due to graft failure or infection but not acute GVHD. Patients treated by UCBT were stratified by the median CD34+ cell count for comparison (0.84 × 10 5/kg). Results: A total of 7,499 patients were enrolled and classified into 3 groups: PTCy-haplo (n = 1,142), UCBT with high CD34+ cell count (UCB-H; ≥ 0.84 × 10 5/kg, n = 3,185), and UCBT with low CD34+ cell count (UCB-L; < 0.84 × 10 5/kg, n = 3,172). Patients in the PTCy-haplo group were slightly younger than UCB-H and UCB-L patients (median age: 54 vs. 56 and 55 years). The PTCy-haplo group also included a greater proportion of males than the UCB-H group (62.4% vs. 50.0%) but not the UCB-L group (64.2%). A greater proportion of PTCy-haplo patients had a PS score of 0 (53.2% vs. 46.2% and 45.6%), a hematopoietic cell transplantation-specific comorbidity index of 0 (57.6% vs. 52.7% and 54.4%) and donor-specific anti-HLA antibody (2.7% vs. 1.0% and 1.6%), received reduced-intensity conditioning (58.0% vs. 40.5% and 41.6%), calcineurin inhibitor with mycophenolate mofetil (88.5% vs. 38.6% and 38.4%), and underwent transplantation in the later period (82.0% vs. 54.6% and 50.7%). There were no significant differences in disease-risk index between groups. At 2 years post-transplantation, NRM and overall survival (OS) were significantly better in the PTCy-haplo group than the UCB-H and UCB-L groups (NRM: 18.8% vs. 21.6% and 25.3%, P < 0.001; OS: 56.2% vs. 53.3% vs. 49.6%, P < 0.001). Neutrophil engraftment rate at 42 days was also significantly higher in the PTCy-haplo group than the UCB-H and UCB-L groups (93.7% vs. 87.5% and 82.9%, P < 0.001). The PTCy-haplo group less frequently developed grade II-IV (26.4% vs. 37.3% and 34.4%, P < 0.001) and III-IV acute GVHD (7.0% vs. 12.2% and 10.5%, P < 0.001). While neither the differences in NRM nor that in OS remained significant between PTCy-haplo and UCB-H groups in multivariable analysis (NRM: hazard ratio [HR], 1.18, 95% confidence interval [CI], 0.99-1.41, P = 0.073; OS: HR, 1.05, 95% CI, 0.94-1.17, P = 0.42), significant differences were maintained between PTCy-haplo and UCB-L groups (NRM: HR, 1.35, 95% CI, 1.13-1.61, P = 0.001; OS: HR, 1.12, 95% CI, 1.00-1.26, P = 0.042). Regarding the cause-specific mortality, infection-related mortality was also significantly lower in the PTCy-haplo group compared to UCB-H and UCB-L groups (8.1% vs. 11.1% and 13.6%, P < 0.001) while GVHD-related mortality did not differ among groups (5.0% vs. 5.2% and 4.9%, P = 0.69). Conclusion: UCBT-H resulted in similar NRM and OS as patients receiving PTCy-haplo, whereas outcomes were worse in UCBT-L. These findings indicate that high CD34+ cell count in cord blood is a critical criterion for alternative donor selection.

Outcomes after Bone Marrow Versus Peripheral Blood Stem Cell Matched Unrelated Donor Hematopoietic Stem Cell Transplantation

Background: Matched unrelated donors (MUD) have become an acceptable alternative donor for patients requiring potentially curative hematopoietic stem cell transplantation (HSCT) and lacking a matched sibling donor. Patients may undergo a bone marrow (BM) or peripheral blood stem cell (PBSC) graft, with previous studies showing similar survival outcomes. However, BM grafts have shown a lower incidence of chronic graft-versus-host disease (GVHD) but a higher relapse rate and slower engraftment. We aimed to compare the outcomes of BM versus PBSC in patients undergoing MUD HSCT. Methods: For this retrospective single-center study, we included all (n=276) adult MUD HSCT recipients at the University of Kansas Medical Center who had at least one year of follow-up (August 2016 to July 2021). We conducted a bivariate analysis using chi-squared and ANOVA tests. The Kaplan-Meier and regression analyses were also performed. Data analyses were conducted using SPSS version 28. Statistical significance was considered at p<0.05. Results: Our study included 276 MUD patients including 110 PBSC (40%) and 166 BM (60%) grafts. The median age was 55 (range 21-77) years, and 158 patients (57%) were males. Eighteen patients (6%) were ethnic minorities, and 89 (32%) patients had a Karnofsky performance status of ≥90%. 118 (43%) patients had a hematopoietic cell transplantation-specific comorbidity index of 3 or higher. Hematologic diseases included acute myeloid leukemia (n=119, 43%), myeloid disorders (n=77, 28%), acute lymphoblastic leukemia (ALL) (n=35, 13%), Lymphoma (n=15, 5%), and others (n=30, 11%). Sixty-two percent of patients were in complete remission at the time of transplantation, and patients not in remission included myelodysplastic syndrome, myelofibrosis, and lymphoma patients. Reduced-intensity conditioning (RIC, n=162, 58%) and myeloablative conditioning (MAC) (n=114, 41%) were used. The median follow-up was 55 (21-73) months. Overall survival (OS) was not reached in either BM or PBSC MUD HSCT group, while a median disease-free survival of 45 and 49 months was noted in PBSC and BM groups respectively (p=0.915). We observed similar rates of relapse (25% vs 27%, p=0.413), one-year overall survival (75% vs 72%, p=0.679), one-year disease-free survival (63% vs 62%, p=1.00), and one-year non-relapsed morality (NRM, 23% vs 21%, p=0.779) after PBSC or BM graft. Bone marrow graft recipients had delayed engraftment of neutrophils (20 days vs 16 days, p<0.001) and platelets (>20 K/uL: 24 days vs 16 days, p<0.001; >50 K/uL: 28 days vs 18 days, p=0.006) compared to PBSC recipients. Bone marrow graft recipients had similar rates of grade II-IV acute GVHD (50% vs 52%, p=0.714) and grade III-IV GVHD (12% vs 11%, p=0.847), but lower rates of 1-year chronic GVHD (39 % vs 55%, p=0.014) compared to PBSC recipients. In the subgroup analysis stratified by conditioning intensity, faster engraftment of neutrophils (median 16 vs 21 days, p<0.001) and platelets (>20 K/uL: 18 days vs 27 days, p<0.001; >50 K/uL: 18 days vs 33 days, p<0.001) was observed with PBSC as compared to BM graft in myeloablative transplant recipients, while there was no statistically significant association with the rates of acute or chronic GVHD, NRM, Relapse, DFS, and OS after a PBSC or BM graft. Among the RIC transplant recipients, faster neutrophil engraftment (mean 17 vs 20 days, p<0.001) and higher 1-year extensive chronic GVHD (52% vs 32%, p=0.015) were observed with PBSC compared to BM graft whereas no statistically significant difference was noted in platelet engraftment, acute GVHD, NRM, Relapse, DFS, and OS after a BM or PBSC graft. Conclusions: Allogeneic matched unrelated donor hematopoietic stem cell transplant recipients had similar rates of overall and disease-free survival, relapse, non-relapse mortality, and acute GVHD after a bone marrow or peripheral blood stem cell graft; however, delayed neutrophil and platelet engraftment with a lower incidence of chronic GVHD was noted after a bone marrow graft compared to peripheral blood stem cell graft.

The Frailty Syndrome As Predictor of Allogeneic Hematopoietic Cell Transplantation Outcomes. Prospective Study on Behalf of the Grupo Español De Trasplante Hematopoyético y Terapia Celular

INTRODUCTION Including frailty in the evaluation of patients before HCT is recommended, but more needs to be done to reach a consensus on how to evaluate and manage this syndrome in clinical practice. Since 2021, sixteen institutions members of the Grupo Español de Trasplante Hematopoyético y Terapia Celular (GETH-TC) have participated in a multicenter and prospective study with the purpose of investigating the state of frailty of adult patient candidates to HCT and evaluate the effect of frailty in transplant outcomes. METHODS All Spanish institutions members of the Group were invited to participate in the study and finally 16 of them were actively involved in it. All patient candidates for HCT were eligible to be included in the study after providing informed consent. Frailty was evaluated at first consultation, at admission, and after the stem cell infusion, using the HCT Frailty Scale (Salas et al. BMT 2023) as described in Table 1. According to their respective total frailty score, patients were classified into three levels of frailty: fit, pre-frail, and frail. The frailty assessment was made by the hematologists and nurse team as part of the clinical practice, utilizing existing human resources and without requiring additional medical appointments for patients. The median time to complete the evaluation ranged from 8 to 10 minutes. The evaluation of physical frailty was complemented with the Mini-Cog test. The results obtained from the frailty assessment were not used to determine HCT eligibility and/or to design the HCT process. This study did not have external funding. RESULTS Between February 2021 and May 2023, 916 consecutive adult candidates for HCT in any of the participating institutions were included in the project. Of all of them, the results reported here correspond only to the 341 adult candidates for allogeneic (allo)-HCT. Median patients' age was 56 (range, 18-76); 65.3% were males; the most prevalent baseline diagnosis was myeloid malignancies (57.5%). Prior to HCT, 36.8% adults had an KPS<90% and 11.5% an HCT-CI>3, 53.1% patients received reduced intensity conditioning regimens, 25.5% alternative donor grafts, and 61.6% received PTCY-based prophylaxis. At the first consultation, 94 (27.6%) adults were classified as fit, 203 (59.5%) as pre-frail, and 44 (12.9%) as frail. Frail patients were more likely to have a KPS<90% (OR 2.80, p<0.01) and an abnormal result of the Mini-Cog test (<3) (OR 8.21, P<0.001). The probability of being frail was independent of age (continuous) (p=0.654), sex (p=0.323), and comorbidities (HCT-CI>3) (p=0.196) (multivariate binary regression analysis). As shown in Table 1, the state of frailty changed throughout the study period, confirming the dynamic nature of the frailty syndrome. A total of 59 (17.3%) patients went through a pre-transplant rehabilitation (pre-hab) program. With this information, the dynamics of frailty of these patients was compared with that of patients who did not join a pre-hab program. At HCT admission, the distribution of patients across the frailty categories was different between the two groups (p=0.028). The proportion of fit patients was higher in the pre-hab group (55.1% vs. 26.7%) because part of the pre-frail patients changed to the fit category. The power of the HCT Frailty Scale to predict OS was evaluated in the subsample of 216 patients that had a minimum follow-up of 120 days among survivors. Table 1 shows that the probability of OS at 1-year increases with the level of fitness of the patients at first consultation, as follows: 35.6% (frail), 70.5% (pre-frail) and 72% (fit), (p<0.001). Secondly, the effect of the level of fitness in the probability of 1-year OS was higher with frailty measured at the time of HCT admission; respectively, 20%, 66.8% and 78.9%. (p<0.001) ( Figure 1). The difference is explained by the improvement in fitness of the patients that participated in a pre-hab program between first consultation and admission. CONCLUSIONS This study validates the applicability of the HCT Frailty Scale at HCT institutions that are part of a health care system different from that where it was first implemented. The HCT Frailty Scale classifies adult patients to allo-HCT in three categories of frailty, frail that have predictive power over transplant outcomes. Frailty syndrome is independent of age and comorbidities and can be improved through pre-hab programs with the positive result of improving the OS of transplanted patients.

Preparation and Physicochemical Properties of Organic Semiconducting Materials from the Reaction of Imidazo[1,2‐a]pyridines with Tetracyanoethylene

AbstractOrganic donor‐acceptor (DA) complexes have emerged in recent years as materials of choice for organic binary electronics. The reactivity descriptors derived from the conceptual DFT reveal imidazo[1,2‐a]pyridines as potential donors. Thus, four imidazo[1,2‐a]pyridines were reacted with tetracyanoethylene (TCNE) in 1 : 2 molar ratio to afford four new DA complexes. The spectral studies, namely IR, 1H, 13C, DEPT 135, 2D HMQC NMR, and HRMS were used to establish structures of the products. The UV‐vis. spectroscopy reveals intramolecular charge transfer. All the four compounds fluoresce giving excitation emission fluorescence spectra with a red shift ranging from 64 to 151 nm and quantum yields from 0.004 to 16.35. Unexpectedly, nitro group in one of the products does not act as quencher; instead, it enhances the quantum yield to make it highest in this series. The products exhibit electrical conductivity which increases with temperature. The FESEM and HRTEM images reveal distinct and homogenous surface morphology with holes which facilitate flow of electrons as manifested by electrical conductivity. The powder XRD and SAED results establish the polycrystalline nature of the products. The theoretical studies indicate an alternate donor acceptor stacking pattern.

Analysis of 3,843 Unrelated Donors (URD) for 455 Allograft Candidates Reveals Low URD Availability with Marked Racial/ Ethnic Disparities: Major Implications for Transplant Center & Registry Operations

Introduction: Although hematologic malignancies patients (pts) often require urgent transplants, the degree to which unrelated donor (URD) availability is a barrier to prompt allografting is not established. Methods: We evaluated availability of requested URDs 1/2020-12/2022, overall & by pt ancestry, in 455 consecutive adults with acute leukemia, MDS or MPN who had a formal URD search & for whom ≥ 1 URDs were pursued for confirmatory typing (CT). We also examined donor location & Donor Readiness Score (DRS; the prediction of a donor's likelihood of availability for CT) by pt ancestry. We hypothesized that URD availability is a major barrier to transplant for underserved racial/ ethnic groups & this has not improved in the post-pandemic era. Results: Of 455 pts [median age 63 yrs, range 21-81; 250/455 (55%) with acute leukemia], 74% (335/455) had European (EURO) & 26% (120/455) non-European (non-EURO) ancestry. For these 455 pts, 3,843 URDs (median age 27 yrs, range 17-61; 1,951/3,843 [51%] male) were requested for CT or simultaneous CT-workup; 71% (2,730/3,843) of URDs were for EURO & 29% (1,113/3,843) for non-EURO pts; & 56% (2,140/3,843) were from domestic & 44% (1,703/3,843) international registries. Of 2,775 URDs with an assigned DRS, the median score was 63% (range 16-94%). URDs requested for non-EURO pts were more likely to be domestic [EUROs: 1,411/2,730 (52%) vs non-EUROs: 729/1,113 (65%), p < .001]. Also, URDs for non-EUROs had markedly lower median DRS (EUROs: 71% vs non-EUROs: 52%) with over 15x the proportion with DRS ≤ 30% [EUROs: 30/2,073 (1.5%) vs non-EUROs: 160/702 (23%), p < .001]. Table 1A-C outlines URD availability at CT & workup, overall & by pt ancestry. In summary: At CT, per pt: More non-EURO pts had greater than 10 URDs requested (p = .045), less than 5 URDs that agreed to CT (p < .001), & at least 5 URDs unavailable (p < .001), compared with EUROs.At workup, per pt: For over one-quarter (134/455, 29%), 3-5 URDs were requested. More non-EURO pts had less than 2 URDs that agreed to workup (p = .007) & at least 2 URDs unavailable (p = .017), compared with EUROs.At CT: Only half (2,036/3,843, 53%) of requested URDs were available for CT or CT-workup. URDs were less likely to agree to CT if requested for non-EURO pts ( vs EUROs), if domestic ( vs international), or if lower DRS (p < .001 for each).At workup: Of URDs requested for workup after CT, while 461/598 (77%) agreed, URDs requested for non-EURO pts were less likely to agree (p < .001).Overall: Availability of the 3,843 URDs requested for the 455 pts was low, with less than half available (Fig. 1A). Notably, URDs requested for non-EURO pts had lower availability (p < .001).By ancestry sub-type: African & non-Black Hispanic pts had the lowest URD availability.Over time: When examining 2020-2022, the worse URD availability for non-EURO pts is not improving in the post-pandemic era (Fig. 1B).URD provision: Of pts with ≥ 1 URD who agreed to workup, 12% did not have an URD available within 14 days of the 1st proposed collection date, & of 263 5-8/8 URD recipients for whom a primary URD was selected, over one third (103/263, 39%) were not transplanted with that donor. Of transplanted pts, as expected, non-EURO pts were less likely to receive 8/8 URDs (p < .001) &, for those who did, their URDs were older (p = .018), & 5-7/8 URDs requested for non-EUROs were more HLA-mismatched (p < .001). Conclusions: We demonstrate significant ongoing disparities in URD access that have major implications for transplant center & registry operations. Incorporating careful assessment of pt ancestry, transplant centers should pursue, & registries should permit, simultaneous pursuit of multiple URDs, especially for non-EURO pts, deciding at the outset what degree of HLA-mismatch will be accepted if an URD is desired but an 8/8 URD is unlikely (Davis et al, TCT 2023). Moreover, centers are ethically obliged to inform pts if timely URD procurement is unlikely, especially as these pts are commonly from underserved racial/ ethnic groups. Registries need to address high URD attrition, & prospective investigation of efforts to speed donor identification are needed. Finally, utilization of all alternative donors (5-7/8 URD, haploidentical & cord blood) is needed to facilitate donors for all in the time required for optimized transplantation.

CR1 Favors PTCy-haplo over UCB in Allogeneic Stem Cell Transplantation for Adult Patients with AL

[Introduction] HLA-haploidentical stem cell transplantation using post-transplant cyclophosphamide (PTCy-haplo) and umbilical cord blood transplantation (UCB) are alternative to HLA-matched hematopoietic stem cell transplantation (HSCT). However, advantage of PTCy-haplo versus UCB has not been determined in patients with acute lymphoblastic leukemia (ALL). Thus, we compared post-HSCT outcomes of PTCy-haplo and UCB in adult patients with ALL to determine patient subgroups who benefit from PTCy-haplo. [Methods] We analyzed data on adult patients (≥16 years) with ALL who underwent HSCT with PTCy-haplo or single-unit UCB between January 2013 and December 2021, using the Japanese nationwide registry database. Endpoints of the analysis included overall survival (OS), disease-free survival (DFS), cumulative incidence of relapse, non-relapse mortality (NRM), engraftments, acute and chronic graft-versus-host disease (GVHD), and infections. In addition to multivariate analysis, propensity score matching was performed as a sensitivity analysis. [Results] We analyzed 1999 patients (PTCy-haplo, 330; UCB, 1669). Median age at HSCT was 44.5 years (range, 16-73) in PTCy-haplo and 45 years (range, 16-74) in UCB group. The proportion of patients who underwent HSCT in the first complete remission (CR1) (PTCy-haplo, 50.3%; UCB, 48.8%) and median time from diagnosis to HSCT (PTCy-haplo, 7.8 months; UCB, 7.7 months) were comparable between the groups. Regarding conditioning, the proportion of those who received myeloablative conditioning (PTCy-haplo, 50.6%; UCB, 54.8%), or conditioning with total body irradiation (PTCy-haplo, 82.4%; UCB, 79.3%) were comparable between the groups. Multivariate analyses showed that PTCy-haplo recipients had comparable 3-year OS (54.1% vs. 52.3%; adjusted hazard ratio [aHR], 0.93; p = 0.51) and DFS (49.7% vs. 47.1%; aHR, 1.06; p = 0.60) with UCB recipients. PTCy-haplo recipients had a significantly higher 3-year relapse rate (32.2% vs. 26.4%; aHR, 1.47; p = 0.01), but had a significantly lower 3 -year NRM (18.1% vs. 26.5%; aHR, 0.70; p = 0.03) as compared to UCB along with significantly faster neutrophil (median, 16 days vs. 20 days) and platelet (median, 30 days vs. 42 days) engraftments, and lower incidence of viral, fungal and bacterial infections. There was no significant difference in cumulative incidence of acute GVHD (30.9% vs. 36.4%, grade II-IV at 100 days; p = 0.15), or chronic GVHD (22.5% vs. 20.9% at 3 years; p = 0.85) between the two groups. These comparable OS and DFS between the two groups were confirmed after minimizing differences in patient characteristics with propensity score matching analysis (Figure 1A). Then, to identify patient subgroups who benefit from PTCy-haplo rather than UCB transplant, we performed subgroup analyses of OS. Significantly favorable effects of PTCy-haplo over UCB were observed in patients with CR1 at HSCT (HR, 0.66; p = 0.03). Indeed, propensity score matching analysis showed that PTCy-haplo recipients had a significantly higher 3-year OS (76.4% vs. 67.6%; HR, 0.57; p = 0.01) and DFS (70.5% vs. 60.6%; HR, 0.66; p = 0.03) than UCB recipients, along with a significantly lower NRM (12.9% vs. 26.3%; HR, 0.39; p < 0.01), and a comparable relapse rate (16.6% vs. 13.1%; HR, 1.41; p = 0.25) with UCB. These results suggest that the low NRM in PTCy-haplo transplant outweighs potential concerns of relapse among patients transplanted in CR1 (Figure 1B). By contrast, in patients with ≥ 2 nd CR or non-CR at HSCT, survival benefits of PTCy-haplo were not observed. [Conclusions] Our results suggest that while both PTCy-haplo and UCB are suitable alternative donor sources for adult ALL patients without HLA-matched donors, in patients with CR1, selection of PTCy-haplo rather than UCB improves post-transplant prognosis.

Successful Use of Haploid Hematopoietic Stem Cell Transplantation for Severe Glanzmann's Thrombasthenia

Objective: Glanzmann's thrombasthenia (GT) is a rare autosomal recessive disorder, which characterized by the clinical manifestations from purpura to severe bleeding. It was caused by mutations of the ITGA2B or ITGB3 gene on chromosome 17, which lead to deficits or reduced expression of the platelet membrane glycoprotein GPIIb/IIIa. We report 5 pediatric patients with severe Glanzmann's thrombasthenia who underwent allogeneic hematopoietic stem cell transplant, to observe the outcomes of allo-HSCT in children with severe Glanzmann's thrombasthenia. Methods: We retrospectively summarized the clinical and genetic profiles of five patients with Glanzmann's thrombasthenia who underwent allo-HSCT from June 2021 to July 2023. All patients were reduced intensity conditioning (Bufulsan 3.2-6.4mg/kg, CTX 120mg/kg, FLU 180mg/m 2, ATG 10mg/kg). After conditioning chemotherapy, all the patients received stem cells collected via bone marrow harvest and/or peripheral blood apheresis (PBSC) with CD34 dose of 2.89-7.2×10 6/kg and received graft vs. host disease (GvHD) prophylaxis with cyclosporine (CSA) and methotrexate (MTX). Results: There were five children were involved in this observation, one patient suffered from recurrent epistaxis bleeding which was life-threatening; the second suffered from gastrointestinal bleeding and could only accept liquid diet to 10-years-old; other patients also suffered from epistaxis bleeding, gum bleeding or gastrointestinal bleeding. For all the patients, regular red cell transfusions were required, platelet transfusions and recombinant factor VIIa were also used in severe and life-threatening bleeding events. Two of the five developed antiplatelet antibodies before HSCT. All the patients were successfully treated with allo-HSCT. One case received non-relative matched donor of 10/10 HLA, one case with sibling matched donor, and 3 cases with haploid transplantation of HLA 5-6/10 matched. The mean time to neutrophil engraftment was 11 days (11-12 days), and the mean time to platelet engraftment was 16 days (15-18 days). One case had CMV reactivation, one case had HHV-6b infection, one case had grade II acute GVHD of the skin which was controlled rapidly. There was no evidence of chronic GVHD for all the patients. The platelet disorder was corrected to a normal level after allo-HSCT, with no significant complication related to the transplantation. Comparing with HLA matched donor, either from sibling or non-related, the patients receiving haploid transplantation with 5-6/10 HLA matched got similar outcome. Conclusions: We proposed haploid transplantation treated with the reduced intensity conditioning regimens produced similar outcomes as HLA matched did which could be recommended as an alternative donor for severe Glanzmann's thrombasthenia.

Asymmetric A‐DA′D‐A′′ Molecular Configuration Type‐I Photosensitizer with Two Complementary Reactive Oxygen Species for Efficient Imaging and Photodynamic Therapy

AbstractType‐I photosensitizers (PSs) can efficiently generate reactive oxygen species (ROS) in the hypoxia condition of tumors, which show less oxygen dependence and are considered better candidates for photodynamic therapy (PDT). However, relatively few efficient type‐I organic PSs simultaneously generating two or more type‐I ROS under irradiation are reported. Herein, new alternate donor (D)‐acceptor (A) type molecules containing ladder‐type core (DA′D) fused with an electron‐deficient benzothiadiazole core are reported, which show symmetrical A‐DA′D‐A (QY1) and asymmetrical A‐DA′D‐A′′ (QY2) configurations, respectively. As these ROSs possess complementary properties of strong oxidizing ability (•OH) and long radical lifetime (O2•−), in vitro and in vivo experiments demonstrate that QY1 and QY2 show excellent PDT effects for tumor cells under normoxia or hypoxia, and can achieve remarkable tumor growth inhibition (TGI) rate of 90% for the QY2. More importantly, the generation of •OH in these PSs is revealed by experiments both in aqueous and in vitro, including the well‐known transformation of O2•− and direct electron transition from water to excited triplet PS. It thus provides a comprehensive understanding of the O2 dependence property of •OH radical and deep insights into the mechanism of type‐I PS.