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Abstract Introduction: Lisocabtagene maraleucel (liso-cel) was approved in the United States for the treatment of CLL in 3/2024 for patients who have received two prior lines of therapy including a covalent BTK inhibitor and a BCL-2 inhibitor. Data regarding outcomes of liso-cel is limited to reports from the registrational TRANSCEND-CLL 004 clinical trial which had strict inclusion and exclusion criteria. This work investigates the real-world efficacy and safety of liso-cel for patients with CLL and its efficacy in specific sub-populations. Methods: This is a multi-institutional retrospective study (Collaborative Assessment of Real-World Evidence of Lisocabtagene Maraleucel in Patients with Relapsed/Refractory CLL/SLL [CARE CAR-T CLL]) of patients with CLL who received commercial liso-cel in the United States. Patients with Richter transformation were excluded. Response was defined by iwCLL criteria. Patients who did not undergo a marrow biopsy but met other criteria for a complete response (CR) were categorized as unconfirmed CR (CRu). CRS and ICANS were graded per ASTCT criteria. Results: A total of 30 patients were identified with a median age of 67 years (range 44 – 80). Twenty of thirty patients (67%) had either del17p and/or mutated TP53, and 8/30 (27%) had complex karyotype (≥ 3 abnormalities) at time of liso-cel infusion. Patients received a median of 6 prior lines of therapy (range 1 - 12), and 24 (80%) were previously treated with chemotherapy. All patients had previous exposure to a covalent BTK inhibitor and a BCL-2 inhibitor. Twenty-seven (90%) of patients had prior exposure to pirtobrutinib. Twenty-nine patients (96.7%) received bridging treatment that was stopped after leukapheresis with 1 patient in CR and 25 patients in PR at time of liso-cel. Eighteen patients (60%) were treated with pirtobrutinib as the last line of treatment prior to liso-cel. Median length of time on pirtobrutinib prior to liso-cel infusion was 4 months (interquartile range [IQR], 2 – 8 months). Twelve (66.7%) patients stopped pirtobrutinib between leukapheresis and lymphodepletion, and 6 continued after liso-cel. Best CR/CRu rate was 60.0% (CR, n = 17/30; CRu, n = 1/30), and best overall response rate (ORR) was 83.3% (25/30) with median time to best response of 30 days (IQR, 28 – 30 days). Of the 18 patients who received pirtobrutinib as their last line of therapy, 13 (72%) achieved a CR/CRu. Meanwhile, of the 12 patients who did not receive pirtobrutinib as their last line of therapy, only 5 (28%) achieved a CR. Measurable residual disease testing (MRD) by flow cytometry was done in 14/30 patients, and 9 patients (64%) had achieved undetectable MRD (uMRD). MRD by next generation sequencing (NGS) was done in 17 patients, and 7 (41%) patients had uMRD. Twenty-seven of 30 patients (90%) were alive at time of data collection. Median follow-up was 3.3 months (IQR, 1.2 – 8.9 months). Twenty-six patients (87%) experienced any grade cytokine release syndrome (CRS), and 3 patients experienced grade 3 CRS (10%). Twelve patients (40%) experienced any grade immune effector cell-associated neurotoxicity syndrome (ICANS), and 4 patients (13%) experienced grade 3 ICANS. There were no grade 4 or 5 CRS or ICANS. One patient experienced grade 3 immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS). At day 30, patients had a median absolute neutrophil count of 1.7K/μL (IQR, 0.8 – 3.6K/μL), hemoglobin of 11.7 g/dL (IQR, 8.6 – 13.1 g/dL), and platelet count of 72K/μL (IQR, 29 – 119K/μL). Conclusion: Real-world analysis of liso-cel for patients with relapsed/refractory CLL showed CR and ORR of 60.0% and 83.3%, respectively. Despite having a heavily pre-treated and chemotherapy-exposed population and with over half the patients having high-risk features, these response rates are higher than what was described in the TRANSCEND-CLL 004 clinical trial. These results are limited by the short follow-up period and the variability in response assessment typical of a retrospective study. As we increase our sample size, we will also be interested if the use of the non-covalent BTK inhibitor pirtobrutinib prior to liso-cel is associated with a higher CR rate, mimicking the findings of the sub-cohort analysis of TRANSCEND-CLL 004 where the concurrent use of ibrutinib led to higher CR rates. Further updates and patients from additional collaborators will be presented at the meeting.

Abstract Background: A randomized multicenter trial (BMT CTN 1703) demonstrated that after reduced intensity conditioning HCT, PT-Cy-based GVHD prophylaxis led to significant reductions in acute and chronic GVHD, but was associated with significantly more Grade 2 (moderate) infections and similar overall survival vs Tac/MTX. A linked mechanistic study (BMT CTN 1801) found that PT-Cy led to pan-T cell depletion and reduced T cell receptor (TCR) repertoire diversity vs Tac/MTX. To discover the molecular mechanisms driving the association of PT-Cy with increased infections, we examined pathogen-specific T cell reconstitution in BMT CTN 1801 patients (n=165 PT-Cy, n=159 Tac/MTX). Methods: We performed deep TCR sequencing on 2,369 blood samples collected pre-HCT (recipient baseline) and on Days +7, 14, 28, 63, 100, 180, 270, 365, 730, and from the graft infusion product. We then applied a novel set of TCR classifiers (Adaptive Biotechnologies) capable of identifying pathogen-specific clones associated with CMV, EBV, SARS-CoV-2, HSV-1, HSV-2, parvovirus, RSV, influenza A, rhinovirus, adenovirus, HHV-6B, norovirus and Toxoplasma. Single-cell (sc) TCR/RNA-sequencing on a sample subset (n=26) was performed to determine the phenotype of pathogen-specific T cells. Results. By linking scRNA-seq with pathogen-specific TCR barcoding, we identified CD4 and CD8 memory T cells as their predominant T cell reservoir. We found that the total number of pathogen-specific singleton TCRs was significantly lower with PT-Cy, starting early post-HCT and persisting through 2 years. For example, at Day +14, PT-Cy patients had 7.8-fold fewer pathogen-specific singleton TCRs vs Tac/MTX (mean of 6.9 vs 54.1, p<0.001). Consistent differences between PT-Cy and Tac/MTX were observed for TCRs specific for each pathogen individually. Patients who developed Grade 3 (severe) viral infections had significantly fewer pathogen-specific singleton TCRs at Day +14 compared to those who had no viral infections (mean of 4.0 vs 32.5, p=0.03). Leveraging intrinsic TCR barcoding of the HCT infusion (“graft”) and of the patient's baseline samples (“recipient”), we could assign the graft/recipient origin of the pathogen-specific cells with high fidelity. This analysis revealed pronounced differences in the origin of pathogen-specific T cells with PT-Cy vs Tac/MTX, especially prior to Day +100. The absolute number of pathogen-specific TCRs originating from the graft was significantly higher with Tac/MTX vs PT-Cy. This difference was observed from day +7 through 6 months post-HCT, with up to 7.1-fold more graft-derived pathogen-specific TCRs in Tac/MTX vs PT-Cy (p<0.001 at each timepoint before day +100). Within patients who received Tac/MTX, the balance of graft vs recipient pathogen-specific clones significantly favored graft clones (for example, a mean of 14.9 graft vs 8.6 recipient pathogen-specific TCRs at Day+14, p=0.02). By contrast, with PT-Cy, in addition to having substantially fewer pathogen-specific TCRs overall, the proportion of these TCRs was not significantly different between graft and recipient clones (mean of 2.1 graft vs 3.3 recipient pathogen-specific TCRs at Day+14, p=0.42). These data uncover that, in addition to the reduction in pathogen-specific T cells with PT-Cy, there was a relative skewing of the anti-microbial T cell reservoir towards recipient cells that persisted after conditioning. Conclusions: PT-Cy led to in vivo T cell depletion across all T cell subsets, which prominently included clones tracked from the allograft itself into the HCT recipient, with a relative sparing of recipient T cell clones that survived transplant conditioning. While the mechanism for relative sparing of recipient cells has not yet been determined, these conditioning-exposed cells may be less proliferative than newly infused graft T cells. The depletion of graft T cells included CD4 and CD8 memory cells specific for infections, which may have contributed to relative deficits in protective immunity against infection in patients receiving PT-Cy. Importantly, these data suggest that with PT-Cy, persisting recipient TCRs may play a key role in preserving anti-infectious immunity. Taken together, these results provide a mechanistic basis for key post-transplant clinical outcomes of the landmark BMT CTN 1703 study. They also underscore the importance of recipient immune status with PT-Cy, creating the opportunity for targeted infection risk assessment in these patients.

Abstract Introduction Obecabtagene autoleucel (obe-cel) and brexucabtagene autoleucel (brexu-cel) are CD19 targeted chimeric antigen receptor T cell (CAR-T) therapies, approved for the treatment of adults with relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (ALL). Mechanistic differences between obe-cel and brexu-cel including differing costimulatory domains (4-1BB vs. CD28), CD19 binding domains (intermediate vs. high affinity) and split dose (Days 1 and 10) vs. single infusion may impact in-vivo cellular kinetics that translate into variant clinical outcomes. In pivotal trials, obe-cel resulted in lower rates of severe cytokine release syndrome (CRS) and immune effector cell associated neurotoxicity syndrome (ICANS) compared to brexu-cel with comparable efficacy (Roddie et al., NEJM 2025; Shah et al., Lancet 2021). Real-world utilization and outcomes with obe-cel are unknown given the relatively recent approval. Methods The ROCCA database, comprising real world data from patients (pts) with r/r ALL treated at 40 North American institutions was utilized in this analysis. Pts with r/r ALL were eligible if they were apheresed for obe-cel since its approval (11/8/2024) or brexu-cel over a comparable period (since 8/1/24) and had at least 30 days of follow up. Data cut off was 7/15/2025. CRS/ICANS were graded per ASTCT criteria. Measurable residual disease (MRD) was assessed by flow cytometry and/or next generation sequencing per institutional standards. Results 38 pts have undergone apheresis for obe-cel (36 infused, all received both infusions) and 54 (53 infused) for brexu-cel over the study period. Pts in the obe-cel and brexu-cel cohorts had the following baseline characteristics: median age, 47 vs. 39 years; ECOG 2+, 15% vs. 26%; Ph+ disease, 24% vs 13%; KMT2Ar, 0 vs. 4%; TP53m, 11% vs 11%, and hypodiploid karyotype, 5% vs 6%. The following prior treatment patterns were observed: median lines of therapy before CAR-T 3 vs. 3; prior SCT 24% vs. 30%, prior blinatumomab 68% vs. 46%, prior inotuzumab 45% vs. 30%. At apheresis, active disease (>5% bone marrow blasts) was present in 47% vs. 55% of obe-cel and brexu-cel pts, respectively; the remainder were in CR (with 18% vs. 22% in MRD- CR, respectively). Among obe-cel (n= 35 [92% of cohort]) and brexu-cel (21 [38% of cohort] pts with disease re-assessment prior to lymphodepletion (LD), 31% vs. 43% had active BM disease, respectively; few pts (24% vs. 17%) had >20% marrow disease burden prior to LD. CAR-mediated toxicity differed significantly between the cohorts. CRS occurred in 56% of obe-cel pts compared to 94% of brexu-cel pts (p < 0.0001). There were no Gr3+ CRS events among the obe-cel pts; 3 (6%) brexu-cel pts had Gr3+ CRS (p = 0.27). ICANS occurred in 17% of obe-cel pts vs. 51% of brexu-cel pts (p = 0.001). Gr3+ ICANS occurred in 6% of obe-cel vs. 32% of brexu-cel pts (p = 0.0027). Among the obe-cel pts, CRS occurred in 31% after the first infusion and 46% after the second; ICANS occurred in 3% after the first infusion and 15% after the second. Prolonged Gr4 neutropenia (ANC < 500 cells/uL beyond day 30 from infusion) occurred in 24% of obe-cel vs. 28% of brexu-cel pts (p = 0.73). Deaths within the first 28 days of infusion occurred in 0 obe-cel pts and 4 brexu-cel pts (2 of infection, 1 of infection/brain bleed, and 1 of liver failure in the setting of Gr4 CRS and HLH). Response rates were high and did not significantly differ between cohorts (p = 0.85). Among the 31 obe-cel pts with available response data, 25 (81%) achieved an MRD- CR/CRi, 3 (10%) had an MRD+ CR/CRi, 2 (6%) had a CR/CRi with unknown MRD, and 1 (3%) did not respond. Among 41 brexu-cel pts with available response data, 33 (80%) had an MRD- CR/CRi, 4 (10%) an MRD+ CR/CRi, and 4 (10%) CR/CRi with unknown MRD. Conclusion Pts selected for obe-cel apheresis were similar to those for brexu-cel over the study period (noting that not all centers had access to obe-cel during this time). Similar to clinical trial results, obe-cel was associated with lower rates of CRS/ICANS. Rates of MRD-negative CR were high and did not differ between cohorts. A larger sample and longer follow up are required for further analyses; we anticipate a cohort of ~75 obe-cel treated pts by the annual meeting and will provide updated data.

Abstract Introduction: Brexucabtagene autoleucel (Brexu-cel) is a CD19-targeted chimeric antigen receptor (CAR-)T cell therapy approved for treatment of relapsed/refractory (r/r) B-ALL. Brexu-cel's approval was founded on data from the ZUMA-3 trial, in which 78 patients (pts) were treated at the pivotal dose of 1x10e6 CAR-T cells/kg, resulting in a complete remission (CR) rate of 73%. Three-year follow-up from ZUMA-3 demonstrated median relapse-free and overall survival (RFS/OS) of 11.6 and 25.6 months (mos) for all treated pts. Amongst responders, the median OS was 60.4 mos for those who did not receive a subsequent allogeneic hematopoietic cell transplant (HCT) (n=43), but only 36.3 months for those who did (n=14). This has led some to conclude that HCT may not be beneficial following brexu-cel therapy for r/r B-ALL; however, it must be noted that 29 (37%) of the pts treated on ZUMA-3 received brexu-cel for post-HCT relapse. T cells collected from individuals who relapse in the post-HCT setting are largely of donor origin, making the CAR-T product comparable to a genetically modified donor lymphocyte infusion (DLI). The immunology at play in this scenario may be different from that in which CAR-T cells are of truly autologous origin. Methods: The Real-World Outcomes Collaborative for CAR-T in ALL (ROCCA) consortium database includes pt characteristics and outcomes of brexu-cel therapy given as standard-of-care across 41 US institutions. We identified pts who achieved an MRD negative (neg) CR by either flow cytometry (minimum sensitivity 10e-4) or NGS following brexu-cel for r/r Ph neg B-ALL and categorized them into three groups with regard to use of HCT: Never HCT, Pre-CAR HCT, or Post-CAR HCT. Pts who received second HCT following brexu-cel for post-HCT relapse (n=9) were excluded. Pt/disease characteristics, RFS, and OS were assessed for each group, landmarked at 73 days after brexu-cel infusion (the median time to consolidative allogeneic HCT). Results: In the ROCCA database we identified 165 pts who achieved MRD neg CR following brexu-cel, amongst whom 69 never underwent HCT, 49 were transplanted pre-CAR (ie, brexu-cel served as a genetically modified DLI), and 47 underwent post-CAR consolidative HCT while in CR. The median follow-up is 373 days. The median age was higher in the Never HCT group (49, range 19-83) in comparison with the Pre-CAR HCT (40, 24-72) and Post-CAR HCT (34, 18-70) groups. Thirty-five percent were >60yo in the Never HCT group vs 20% in the Pre-CAR HCT and 9% in the Post-CAR HCT groups. Ph-like disease was present in 38%, 29%, and 43% of the Never HCT, Pre-CAR HCT, and Post-CAR HCT groups, respectively (p=0.35). No significant differences were observed in pre-apheresis bone marrow blasts, presence of CNS disease at apheresis, prior blinatumomab or inotuzumab treatment, or use of bridging therapy across the groups, though there was a higher prevalence of non-CNS extramedullary disease in the Pre- and Post-CAR HCT groups (32, 39%) vs the Never HCT group (13%) (p=0.004). A minority of pts in all groups were deemed to be in MRD neg CR prior to apheresis (6-20%). Median RFS was 260 days in the Never HCT group and not reached in the Pre- and Post-CAR HCT groups (p=0.002), with respective 1-yr RFS of 38%, 64%, and 67%. Median OS was not reached in any group and was similar for all at 1-yr at 68-79% (p=0.13). Characteristics of those in the Never HCT group who were least likely to relapse included age >60 (OR 0.22, CI 0.07-0.73 vs age 18-39, p=0.024) and those with non-Ph-like B-ALL (OR 0.33, CI 0.12-0.94, vs Ph-like, p=0.037) in univariate analyses. Conclusions: Real-world data regarding outcomes following brexu-cel therapy allow evaluation of the role for consolidative allogeneic HCT, which remains one of the most important unresolved questions in the use of CAR-T therapy for r/r B-ALL. This analysis demonstrates that a first consolidative HCT after achieving MRD neg CR with brexu-cel is associated with a significant decrease in relapse. Additionally, use of brexu-cel for post-HCT relapse is also associated with a significantly lower risk of relapse compared with those who never received an allogeneic HCT. With the current duration of followup, OS is not significantly different across the three groups. These data suggest there is a benefit for relapse-free survival in pts receiving an allogeneic HCT at some point in the course of treatment for r/r Ph neg B-ALL.

Abstract Allogeneic hematopoietic cell transplantation (HCT) using an HLA mismatched unrelated donor (MMUD) with calcineurin inhibitor-based graft versus host disease (GVHD) prophylaxis results in increased incidence of non-relapse mortality (NRM) and lower survival compared to matched donor HCT. The NMDP sponsored 15-MMUD study demonstrated that post-transplant cyclophosphamide (PTCy)-based prophylaxis following bone marrow derived MMUD HCT resulted in reduced incidence of GVHD and favorable survival. Because marrow grafts can be difficult to procure and vary in quality, we conducted a phase II, prospective, multicenter study to evaluate PTCy-based GVHD prophylaxis in adult recipients of MMUD using peripheral blood stem cell (PBSC) allografts. The primary study aim was to estimate the probability of one-year overall survival (OS) post HCT. Secondary aims were to assess other key clinical endpoints and determine the rate of severe infections. Initial results of the first 70 recipients who received reduced intensity conditioning (RIC) were previously reported by Al Malki et al (JCO 2025) demonstrating a 1-year OS of 78.6% (95% CI, 67% to 86.5%). Here, we report results from a planned expansion of the study that included 123 additional RIC recipients, with updated results from the initial cohort of 70 patients (total N = 193 subjects) treated at 33 centers. Study participants received cyclophosphamide 50 mg/kg (ideal body weight) administered on days 3 and 4 post HCT with tacrolimus and mycophenolate mofetil as previously described (Al Malki, JCO, 2025). The median study participant age was 65.0 (range: 22.9-78.9); 92 (47.7%) of participants were male, and 84 (43.5%) identified as having other than non-Hispanic white ancestry. The HCT comorbidity index was high-risk (>3) in 65 (33.7%). Underlying histologic diagnosis was AML in 96 (49.7%) participants, MDS in 43 (22.3%), ALL in 20 (10.4%), lymphoma or CLL in 24 (12.4%), and CML/other leukemias in 10 (5.2%). Conditioning regimens used were fludarabine and melphalan (100 or 140 mg/m2) (N=120; 62.2%), 2-day busulfan and fludarabine (N=38; 19.7%), and fludarabine, cyclophosphamide and total body irradiation (200 cGy) (N=32; 16.6%). Donor HLA matching (considering HLA-A, -B, -C, and -DRB1) was 7/8 in 131 (67.9%) of participants, 6/8-matched in 51 (26.4%), and 4-5/8-matched in 11 (5.7%) participants. Median donor age was 25.5 years (range: 18.7-35.7). The one-year overall OS estimate was 79.6% (95% confidence interval [CI]: 73.2-84.7). Survival was similar among HLA 7/8-matched donor recipients (77.8%, 69.7-84%) and <7/8 matched donor recipients (83.7%, 71.8-90.9%). The one-year GVHD-free, relapse-free survival (GRFS) was 49.9% (42.6-56.9%) and the one-year progression-free survival was 70.2% (63.2-76.2%). The one-year cumulative incidence (CI) rates of NRM and relapse were 12.5% (8.3-17.6%) and 17.3%(12.3-23%), respectively. The 6-month CI of grade II-IV and grade III-IV acute GVHD were 40.0% (33.0-46.8%) and 7.8% (4.6-12.1%), respectively. The one-year incidence of all chronic GVHD and severe chronic GVHD were 15.6% (10.7-21.2%) and 3.7% (1.6-7%), respectively, by NIH consensus criteria. The CI of grade 1-4 cytokine release syndrome (CRS) by day 7 post HCT was 28.0% (21.8-34.9%), and grade 3-4 CRS was 0.5% (0-2.9%). Primary engraftment failure occurred in 9 (4.7%) participants. Among 145 evaluated participants, 85.5% were >95% donor in blood chimerism at day 100 post HCT. Within the first 100 days after HCT, CTCAE grade 2-5 infections occurred in 113 (58.5%) of participants and grade 3-5 infections occurred in 59 (30.6%) of participants. The most common etiologies of grade 2-5 infections were bacterial (N=78), followed by viral (N=48). The most common grade 3-5 non-infectious toxicities were cardiac disorders, which occurred in 4 (2.1%) of participants. In conclusion, the results including this expansion cohort demonstrate encouraging 1-year OS, NRM and relapse rates in RIC recipients of PTCy-based GVHD prophylaxis and PBSC allografts from MMUDs. This larger cohort of 193 recipients re-affirm the results from the initial cohort with greater robustness.Measures to mitigate infection risk are likely to further improve outcomes. Reducing the dose of PTCy is a candidate approach currently being tested in the ongoing OPTIMIZE trial (NCT 06001385).These results support the extension of PBSC MMUD using PTCy to individuals who lack an HLA-matched donor and require RIC HCT.

Abstract Allogeneic hematopoietic cell transplantation (HCT) remains inaccessible to many patients, particularly those of non-European ancestry, due to the limited availability of matched unrelated donors (URD). While single-HLA mismatched donors (7/8) often yield acceptable outcomes, URD HCT mismatched at ≥ 2 HLA alleles (<7/8) has historically been associated with poor survival and prohibitive toxicity. Post-transplant cyclophosphamide (PTCy) has improved outcomes following mismatched unrelated donor (MMUD) HCT, potentially enabling less stringent donor matching. Whether the degree of donor-recipient HLA disparity remains prognostic after MMUD HCT when PTCy is used is unknown. The ACCESS trial (NCT04904588) was conducted by the Center for International Blood and Marrow Transplant Research Clinical Research Organization and prospectively evaluated PTCy-based graft versus host disease (GVHD) prophylaxis in adult recipients of 4–7/8 (HLA-A, -B, -C and -DRB1) MMUD peripheral blood stem cells (PBSC) from donors age ≤35 years old following either myeloablative (MAC) or reduced intensity/non-myeloablative (RIC/NMA) conditioning. This analysis focused on all adult recipients of <7/8 grafts enrolled on the study across both conditioning strata, with descriptive comparison to patients who received 7/8 MMUD PBSC grafts. The primary endpoint was 1-year overall survival (OS). Secondary endpoints included primary graft failure (PGF), non-relapse mortality (NRM), relapse, acute and chronic GVHD, and GVHD-free relapse-free survival (GRFS). A total of 268 adults received MMUD PBSC grafts: 85 with <7/8 matches (MAC: n=23; RIC/NMA: n=62) and 183 with 7/8 matches (MAC: n=52; RIC/NMA: n=131). Among <7/8 recipients, median age was 57 years old (range, 24–78), 49% were male, with diagnoses of acute myeloid leukemia (AML) (55%), myelodysplastic syndromes (MDS) (15%), and lymphoma (14%). HLA mismatch distribution in the <7/8 group was 6/8 in 82%, 5/8 in 14%, and 4/8 in 4%. Most received fludarabine/melphalan (44%) or myeloablative busulfan/fludarabine (21%). Median CD34+ cell dose was 5.5 ×10^6/recipient kg (range: 3.2-8.0) and 75% of grafts were cryopreserved prior to infusion. Median donor age was 25.8 (range: 18.7-35.7) in the 7/8 group and 25.0 (range: 18.3-34.8) in the <7/8 group. The <7/8 cohort was racially and ethnically diverse, with 61% identifying as other than non-Hispanic white. The 7/8 cohort had a median age of 63 years old (range, 20–79), with 52% male. Disease distribution, conditioning intensity, and infused cell doses were similar to the <7/8 group. A smaller proportion of grafts were cryopreserved (61%), and 47% of patients identified as other than non-Hispanic White. One-year OS for <7/8 recipients was 86% (95% CI: 76–92%), compared to 79% (95% CI: 72–84%) in 7/8 recipients. One-year incidence of relapse was 23% (95% CI: 14–33%) in the <7/8 group and 17% (95% CI: 12–23%) in 7/8 recipients; NRM was 8% (95% CI: 4–16%) and 14% (95% CI: 9–19%), respectively. GRFS was 55% (95% CI: 43–65%) for <7/8 and 51% (95% CI: 44–58%) for 7/8 recipients. PGF occurred in 8% (95% CI: 3–18%) of <7/8 RIC recipients and 3% (95% CI: 1–8%) of 7/8 RIC recipients; no MAC recipients had PGF. At 6 months post-HCT, grade II–IV acute GVHD occurred in 34% (95% CI: 24–44%) of <7/8 patients and 39% (95% CI: 32–46%) of 7/8; grade III–IV acute GVHD was observed in 7% (95% CI: 3–14%) and 8% (95% CI: 5–13%), respectively. Moderate to severe chronic GVHD (NIH consensus criteria) at one year occurred in 8% (95% CI: 3–15%) of <7/8 recipients and 11% (95% CI: 7–16%) of 7/8 recipients. When grouped by conditioning intensity, 1-year outcomes within the <7/8 cohort were: OS 91% after MAC and 84% after RIC/NMA; relapse in 32% after MAC and 20% after RIC/NMA, respectively; GRFS was 53% for MAC and 55% for RIC/NMA; and NRM remained low at 9% after MAC and 8% after RIC/NMA. In this cohort of adult recipients of <7/8 MMUD PBSC grafts with PTCy-based GVHD prophylaxis enrolled on the ACCESS study, 1-year OS exceeded 80% and was comparable to 7/8 recipients. Relapse, NRM, and GVHD rates were similarly favorable and consistent with outcomes reported in 7/8 donor recipients. These findings support extending suitable MMUD match considerations to include 4-6/8 in the context of PTCy, potentially enabling near-universal donor access, while allowing for optimization of other non-HLA donor factors.

Abstract Introduction: Standardized reporting of clinical trials results for MDS is essential to improve clinical interpretation and cross-study comparison. However, reporting of patient characteristics, response criteria, and endpoints in publications is often inconsistent; there is no systemic analysis of MDS trial reporting available. We conducted a systematic review of published MDS trial manuscripts on behalf of the international consortium for MDS (icMDS) to assess variability in reporting practices. Methods We searched ClinicalTrials.gov to identify all clinical trials registered for adults (≥18 years) with MDS that reported results between 2015-2024. Clinical trials that included acute myeloid leukemia (AML) or MDS/myeloproliferative neoplasms (MPN) were included if they enrolled ≥5 MDS patients. We excluded trials without an MDS cohort; non-therapeutic trials; trials focused on transplant interventions; or those which enrolled solid malignancies or other hematologic malignancies (chronic myeloid leukemia or lymphoid diseases). Finally, trials were required to have a manuscript available on Larvol, PubMed, or Google Scholar. Trials were categorized by disease risk (lower-risk [LR] vs. higher-risk [HR]) and trial phase (early phase [EP] vs. late phase [LP]). Results We identified 502 MDS trials on ClinicalTrials.gov, of which 351 did not meet inclusion criteria and 79 lacked a manuscript. A total of 72 trials (32 EP, 40 LP) with 80 publications (34 EP, 46 LP) were analyzed. Frequently reported baseline characteristics included age (100% EP, 100% LP), disease risk (74% EP, 74% LP), Eastern Cooperative Oncology Group performance status (85% EP, 72% LP), prior treatments (71% EP, 67% LP), and RBC transfusion dependency (32% EP, 70% LP). Less frequently reported characteristics included blood counts (hemoglobin [Hb; 38% EP, 54% LP], platelet count [38% EP, 54% LP], neutrophil count [24% EP and LP]) and bone marrow blasts (29% EP, 43% LP). Although disease risk was widely reported, definitions varied: IPSS and IPSS-R were each reported in 54% of manuscripts, while IPSS-M appeared in only 3%. Cytogenetic risk was separately reported in 39% of manuscripts (38% EP, 39% LP), and mutational data in 45% (47% EP, 43% LP). Responses per IWG 2006 criteria were reported in 84% of manuscripts. The primary endpoint involved safety/tolerability in 85% of EP manuscripts, though definitions were variable; recommended phase 2 dose was the most common (26% of EP manuscripts). In LP trials, primary endpoints were risk-specific: transfusion independence (TI) in 77% of LR, overall response rate (ORR) in 28% of HR, and complete remission (CR) or overall survival (OS) in 22% of HR. In HR manuscripts, CR was reported in 100%, ORR in 73%, hematologic improvement (HI) in 48%, RBC-TI in 23%, and OS in 80%. However, seven different definitions were used for ORR: CR + marrow CR + partial remission + HI per IWG 2006 was most common (35%). Event-free survival was reported in 25%; progression-free survival and relapse-free survival in 13%; and leukemia-free survival in 5%. Early mortality rate was reported in 35% (18% EP, 56% LP) and transplant rate in 58% (50% EP, 67% LP). Only 47% of HR and 90% of LR manuscripts identified HI-eligible patients. In LR-MDS, RBC-TI was reported in 72% of manuscripts but used six definitions. The most common were RBC-TI ≥8 weeks at any time during treatment (24%), ≥8 weeks within 28 weeks of treatment (13%), ≥8 weeks with Hb increase ≥1.0 (4%), ≥12 weeks with Hb increase ≥1.5 (4%), and ≥16 weeks within 24 weeks of treatment (12%). The remainder did not report RBC-TI, did not define it, or used a custom definition not used in another trial. HI was reported in 80% of LR papers with most of those reporting HI using IWG 2006 criteria (90%). Conclusion Reporting of baseline characteristics, response criteria, and outcomes is inconsistent in MDS clinical trials, with wide variability in response definitions, including ORR and TI. This heterogeneity limits interpretability, hampers historical comparisons and may obscure efficacy signals. Our findings highlight the need for standardized reporting guidelines to ensure clarity and consistency in MDS trial publications. As a next phase of this effort, we will conduct a formal Delphi process among icMDS experts to establish consensus recommendations for minimal and optimal MDS clinical trial reporting in manuscripts by disease risk (LR/HR) and trial phase (EP/LP).

Abstract Introduction Pronounced disparities in pediatric B-lymphoblastic leukemia (B-ALL) outcomes by race and ethnicity persist in the contemporary era. Gaps in overall survival (OS) from initial diagnosis are wider than event-free survival, suggesting that post-relapse mechanisms may contribute. However, data on treatment and outcomes after relapse are lacking. In a large, multicenter, real-world cohort of children and young adults with high-risk 1st relapse of B-ALL, we sought to (1) define survival outcomes by race/ethnicity and (2) explore if differences in therapy utilization drive outcomes. Methods We conducted an analysis within the Retrospective Study of Contemporary Approaches to 1st Relapse in B-ALL (ReCALL-1) cohort, which includes patients <30 years who initiated 1st relapse therapy between 2018-2022. This analysis was restricted to patients treated at US centers for “high-risk” 1st relapse, defined as relapse for which hematopoietic cell transplant (HCT) is generally standard-of-care: Early relapse (medullary <36m; isolated extramedullary <18m), late relapse with persistent end of reinduction disease, Ph+ B-ALL or age ≥18 years. Patients with Trisomy 21, those who received cell therapy before relapse and those who died during reinduction were excluded. The primary exposure was race/ethnicity categorized as Hispanic, non-Hispanic Black (NHB), non-Hispanic White (NHW), and other/unknown. The primary outcome was OS from relapse. Multivariable Cox regression models were constructed to include other social drivers of health (SDOH; health insurance, preferred language) and disease characteristics. Results Of 479 patients in ReCALL-1, 311 from 31 centers met inclusion for this analysis (41% Hispanic, 7% NHB, 46% NHW, 5% NH-other/unknown). With a median follow-up of 47m, OS differed by race/ethnicity (log-rank p=0.017): Hispanic, 4y OS 59%; NHB, 37%; NHW, 68%. Compared to NHW patients, NHB patients had an increased hazard of death (HR 2.3, 95% CI 1.3-4.3, p=0.006), while Hispanic patients were more similar to NHW patients (HR 1.3, 95% CI 0.9-2.0, p=0.16). Adjustment for SDOH only marginally attenuated the risk for NHB patients (aHR 2.0, 95% CI, 1.1-3.7, p=0.031) and led to equivalent outcomes for Hispanic patients (aHR 0.9, 95% CI, 0.5-1.5, p=0.66). Adjusting for disease characteristics that differed by race/ethnicity at p<0.2 (time to relapse, Ph+, Ph-like, KMT2Ar, age ≥18, or relapsed infant ALL) did not diminish the risk for NHB patients (aHR 2.0, 95% CI, 1.1-3.7, p=0.032) while outcomes remained equivalent for Hispanic patients (aHR 1.2, 95% CI, 0.8-1.8, p=0.40). Point estimates of cumulative incidence of non-relapse mortality (NRM) were highest in NHB patients (Hispanic, 4y NRM 13%, NHB 22%, NHW 11%), but this trend was not statistically significant (Gray’s p=0.52). Only 17% of patients initiated therapy for relapse on a clinical trial with no differences observed by race/ethnicity. Most patients received definitive treatment for relapse with either CAR T cell therapy (CART) or HCT: 79% overall, 74% Hispanic, 91% NHB, and 83% NHW. CART and HCT were utilized equally (39% and 40%, respectively) and the proportion that received each therapy did not vary by race/ethnicity. Time to CART/HCT, external referral for treatment, receipt of investigational v commercial CART, and use of post-CART consolidative HCT revealed no differences by race/ethnicity. Of the 66 patients (21%) who did not receive cell therapy, 26 had planned for CART or HCT, but did not receive due to disease progression or NRM (n=24; 12 Hispanic, 10 NHW), or insurance barriers (n=2, both Hispanic). After HCT, OS was worse for NHB patients (log-rank p=0.03) with 4y OS of 42% v 85% for NHW and 75% for Hispanic. Post-CART, 4y OS was 40% for NHB v 59% for NHW and 51% for Hispanic, but this difference was not statistically significant. Conclusion In a large real-world cohort of children with high-risk 1st relapse of B-ALL, we found a two-fold increased hazard of death for NHB patients compared to NHW patients, even after adjustment for other SDOH factors and high-risk disease features. In contrast to previous studies of adult patients, children appeared to have equal access to cell therapies across races/ethnicities. We found that Hispanic patients, who comprised >40% of the cohort, had similar survival to NHW children, suggesting that availability of cellular and immunotherapies may be mitigating historically observed disparities for children with relapsed B-ALL.

Abstract Introduction: The landscape of classical hematology has undergone substantial evolution over the last decade, marked by new diagnostic tools, nuanced therapeutic strategies, and an expanding understanding of underlying pathophysiology. This increasing complexity often presents unique diagnostic and therapeutic challenges. These challenges are further compounded by workforce shortages in classical hematology marked by educational gaps, geographic limitations, and difficulty accessing prompt specialty care. Unlike the well-established “Tumor Boards” in oncology, a comparable dedicated, widely accessible forum for classical hematology has largely been absent. This gap contributes to potential practice heterogeneity and isolation, especially across dissimilar care settings and geographic regions, impacting the consistent application of evidence-based practices and access to specialized expertise. To address this critical need, the “Blood Board” initiative was created to serve as an informal, virtual resource for discussing classical hematology topics and cases, fostering diverse perspectives, and collaborative problem-solving. Methods: The Blood Board was formally launched in April 2025, operating as a bi-monthly, hour-long virtual meeting conducted via non-recorded videoconferencing. The forum was designed with broad inclusivity in mind, welcoming all healthcare professionals involved in the care of adult patients with classical hematologic disorders, including trainees such as hematology/oncology fellows, academic and community-based hematologists, and any other interested providers. To date, dissemination of this initiative has been by word of mouth and e-mails containing a calendar invitation have been sent to anyone interested in participating (https://forms.gle/doyHNSx1SVFBJZmy8). To facilitate participation from various practice models and geographical locations, the virtual format was prioritized, eliminating barriers of travel and time commitment often associated with traditional in-person conferences. Participation is voluntary, encouraging an open and informal environment for de-identified case presentations, didactic discussions, and expert opinion sharing. Self-reported data on participant demographics (e.g., role, practice setting) and geographical representation have been collected to assess the initiative's reach and impact. Results: To date, sessions have consistently garnered engagement with a median of five participants in attendance at each session. There have been over 20 unique participants representing a broad spectrum of roles including both trainees and practicing hematologists/hematologist-oncologists and drawing from private practice, community-based hospitals, and academic medical centers. Over half of all participants were either in fellowship or within five years of completion of training. The virtual format has successfully overcome geographical limitations, attracting attendees from numerous states including Alabama, Florida, Georgia, Maryland, Minnesota, Missouri, Pennsylvania, South Dakota, and Wisconsin highlighting its broad appeal and potential for knowledge dissemination across a wide professional network. Conclusions: The Blood Board has demonstrated utility and met a previously unaddressed need. Sustained intellectual interest in Blood Board, coupled with a wide geographical and professional reach underscores a critical role for accessible, free, and multidisciplinary collaborative platforms in the evolving field of classical hematology. Similar to Tumor Boards, Blood Board promotes knowledge exchange and evidence-based care, garners expert support for challenging cases, and harmonizes clinical approaches, which we hope may ultimately improve patient care outcomes across diverse settings. Furthermore, this platform facilitates a national classical hematology community to support workforce development. Future goals include expanding dissemination efforts, measuring specific educational benefits, analyzing impacts on patient care, and increasing participant diversity, including recruitment of advanced practice providers and pharmacists.

Abstract Introduction: CD19-directed CAR T-cell (CAR-T) therapy has substantially improved clinical outcomes for adults with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL). However, notable toxicities are associated with CAR-T, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Variable practice patterns have emerged regarding the use of CRS/ICANS prophylaxis (ppx) via corticosteroids and/or other pharmacologic agents, but the utility of these approaches on reducing CRS or ICANS following CAR-T in B-ALL remains unknown. Thus, we utilized the Real-World Outcomes Collaborative for CAR T in ALL (ROCCA) database to evaluate associations between ppx and the development and severity of CRS or ICANS following brexucabtagene autoleucel (brexu-cel) for B-ALL. Methods: Adult patients (pts) who received standard-of-care brexu-cel for relapsed/refractory B-ALL across 40+ US centers were included. Primary endpoints were the incidence of CRS and ICANS within 28 days of CAR-T infusion. Secondary endpoints included timing of CRS and ICANS onset, progression-free survival (PFS) and overall survival (OS). Univariable and multivariable logistic regression evaluated associations between ppx and incidence of CRS/ICANS; KM and log-rank methods were used for survival analyses. Results: A total of 378 pts were included: 53 pts (14.0%) received CRS/ICANS ppx and 325 (86.0%) received no ppx. Ppx agents included steroids only (26.4%), steroid and anakinra (52.8%), anakinra only (15.1%), and steroid and tocilizumab (5.7%). Pts in the ppx group had a higher proportion of Hispanic pts (64% vs 34%), Ph-like (36% vs 19%) and a lower proportion had 0-5% bone marrow blasts at apheresis (38% vs 53%). The ppx and no ppx groups were similar in age, prior therapies, CAR-T indication, and marrow blasts >50%. Cumulative incidence of any grade (gr) CRS was 94% with ppx and 86% with no ppx (p=0.025), of any gr ICANS was 53% with ppx and 51% with no ppx (0= 0.85). Cumulative incidence of gr 3-4 CRS was 9% in the ppx group and 10% in the no ppx group (p=1.00), of gr 3-4 ICANS was 26% in the ppx group and 29% in the no ppx group (p=0.71). Median time to onset for any gr CRS or any gr ICANS was identical in the ppx and no ppx cohorts (CRS: 5 days, range ppx 1-9 days, no ppx 0-14 days; ICANS: 7 days, ppx 1-20 days, no ppx 0-16 days). Univariate logistic regression analyses showed no significant association between ppx and the incidence of gr 2-4 CRS (OR 1.34, 95% CI: 0.75-2.40, p=0.326) or gr 3-4 ICANS (OR 0.88, 95% CI: 0.46-1.70, p=0.708). Multivariate analysis adjusting for ethnicity, leukemia genetic sub-type, and pre-apheresis disease burden similarly found no significant associations between ppx and gr 2-4 CRS (adjusted OR 1.06, 95% CI: 0.55-2.01, p=0.870) or gr 3-4 ICANS (OR 1.23, 95% CI: 0.59-2.55, p=0.584). When comparing steroid-only ppx (N=14) to steroid combinations or other drug ppx (N=39), there was no significant differences in gr 2-4 CRS (57% vs 44%, p=0.345) or gr 3-4 ICANS (43% vs 21%, p=0.115). Comparing cumulative incidence of dexamethasone (dex) exposure, pts in the ppx group had numerically greater dex exposure than pts in the no ppx group, with median (range) dosing of 182 mg (10-1386mg) and 100mg (1-4000mg), respectively. Finally, we found no significant differences in PFS or OS based on ppx. Median PFS was 9.6 months in the ppx group vs 13.3 months in the no ppx group (p=0.646) and median OS was 17.2 months in the ppx group vs 34.4 months in the no ppx group (p=0.170). Conclusions: In this large cohort of adult patients with R/R ALL receiving brexu-cel CAR-T therapy, prophylaxis intended to prevent CRS/ICANS was ineffective at reducing CRS/ICANS incidence, time to onset, or overall steroid exposure. Furthermore, PFS and OS were comparable between patients who received prophylaxis and those who did not. In the absence of prospective trials in B-ALL, these data suggest that current strategies of CRS/ICANS prophylaxis has limited benefit.