Citations

Abstract Abstract Introduction: Leukemia, a heterogeneous group of hematologic malignancies, has established associations with modifiable risk factors such as tobacco use. Despite the widespread implementation of tobacco control measures over the past three decades, disparities persist in tobacco-attributable leukemia mortality across sex and socio- demographic strata. This study aimed to quantify and compare long-term global and regional trends in mortality due to tobacco-associated leukemia between 1990 and 2021, with a focus on sex-based and income-level disparities. Methods: We obtained age-standardized mortality rates (ASMRs) for leukemia attributable to tobacco use from the Global Burden of Disease (GBD) 2021 dataset for 204 countries and territories. ASMRs were analyzed for the years 1990 and 2021 and stratified by sex (male, female, both) and socio-demographic index (SDI) regions (high, high-middle, middle, low- middle, low). Temporal trends were assessed using Average Annual Percent Change (AAPC) with corresponding 95% confidence intervals (CI). Additionally, univariate linear regressions by location were conducted to quantify associations between time and mortality. Results: Globally, tobacco-related leukemia mortality decreased substantially between 1990 and 2021. The overall ASMR declined from 0.64 to 0.40 per 100,000 population (AAPC: –1.51%; 95% CI: –1.59 to –1.43). Sex-disaggregated data revealed a more favorable reduction in females (from 0.23 to 0.12; AAPC: –2.25%; 95% CI: –2.41 to –2.09) compared to males (from 1.20 to 0.77; AAPC: –1.45%; 95% CI: –1.51 to –1.39), suggesting persistent gender disparities in tobacco exposure and/or access to care. These trends were statistically significant (p < 0.001), and global univariate regression confirmed a significant negative slope (–0.0088; p = 0.021). Marked regional differences emerged by SDI status. High-SDI countries experienced the steepest declines in mortality. In these regions, ASMRs dropped from 1.16 to 0.69 among both sexes combined (AAPC: –1.70%; 95% CI: –1.80 to –1.61), with females improving from 0.56 to 0.31 (AAPC: –1.90%; 95% CI: –2.03 to –1.76) and males from 2.07 to 1.17 (AAPC: –1.88%; 95% CI: –1.96 to –1.80). The associated regression slope (–0.0183) was statistically significant (p = 0.0014), with an R² of 0.10, indicating a strong temporal association. High-middle SDI regions showed moderate progress: ASMRs declined from 0.62 to 0.45 among both sexes (AAPC: –0.99%; 95% CI: –1.10 to –0.88). Reductions were steeper in females (0.12 to 0.07; AAPC: –1.32%; 95% CI: –1.55 to –1.09) than in males (1.40 to 0.96; AAPC –1.19%; 95% CI: –1.29 to –1.09). However, regression slopes were not statistically significant (p = 0.18), suggesting heterogeneous trends within this group. Low-SDI regions, in stark contrast, exhibited minimal improvements. Between 1990 and 2021, ASMRs decreased marginally from 0.098 to 0.074 (AAPC: –1.01%; 95% CI: –1.10 to –0.91), with male mortality decreasing from 0.17 to 0.12 (AAPC: –1.22%; 95% CI: –1.32 to –1.13) and female rates from 0.037 to 0.027 (AAPC: –0.88%; 95% CI: –1.04 to –0.72). However, the regression slope (–0.00084) was not statistically significant (p = 0.17), and the effect size (R² = 0.02) suggested only a weak temporal association. Middle and low-middle SDI countries also demonstrated underwhelming progress. In low- middle SDI settings, the combined-sex ASMR dropped from 0.21 to 0.16 per 100,000, with a weak negative slope (–0.0012; p = 0.43), and an AAPC of –0.83% (95% CI: –0.95 to –0.71). These results highlight stagnation and growing inequities in health burden mitigation. Conclusion: From 1990 to 2021, global mortality due to tobacco-attributable leukemia significantly declined, with the greatest improvements seen in high-SDI countries and among females. However, regions with lower income levels lagged, showing minimal or no significant decline in mortality despite decades of global tobacco control efforts. The pronounced disparities by sex and socioeconomic status underscore the need for context- specific, equity-focused tobacco cessation initiatives and leukemia screening programs, especially in underserved populations. Without urgent intervention, the global burden of leukemia attributable to tobacco may continue to disproportionately affect those with the fewest resources and weakest health infrastructure.

Abstract Background: Older adults with newly diagnosed ALL treated with conventional chemotherapy have poor survival due to high rates of toxic death and disease relapse. The Alliance A041703 trial (NCT0373981) tested chemotherapy-free treatment with the anti-CD22 antibody-drug conjugate inotuzumab ozogamicin (InO) followed by the anti-CD19-CD3 bifunctional T-cell engager blinatumomab (blina) without maintenance in older adults to reduce toxicity and increase efficacy of therapy for this patient (pt) population. We previously reported with 22-month (mo) median follow-up that the study met its primary endpoint with a 1-year (yr) event-free survival (EFS) of 75% (90% confidence interval [CI] 63-89% lower bound exceeding null rate of 10%; JCO 2023 41, 7006). Here we report secondary outcomes with 45-mo median follow-up: 3-yr EFS, 3-yr overall survival (OS), response, and relapse characteristics. Methods: Eligible pts were ≥60 yrs old with newly diagnosed, Ph-negative, CD22-positive (≥20% of blasts) B-cell ALL without planned allogeneic HCT (alloHCT), liver disease, or CNS involvement at enrollment. Induction IA was InO 0.8 mg/m2 day (d) 1, 0.5 mg/m2 d8, d15 IV on a 21d cycle. Pts with adequate cytoreduction (marrow blasts reduced ≥50% or marrow cellularity ≤20%) after IA went to IB if in CR/CRi (InO 0.5 mg/m2 d1, d8, d15 IV; 28d cycle) or IC if no CR/CRi (InO 0.8 mg/m2 on d1 and 0.5 mg/m2 on d8 and d15 IV; 28d cycle). Those without cytoreduction to IA started course II blina. Pts without events in IA/B/C received course II blina continuous IV (9 mcg/d x 7d then 28 mcg/d x 21d; 14d break; 28 mcg/d x28d). Pts with CR/CRi to InO received 2 more 28d cycles of blina; others received 3 more. CNS prophylaxis was methotrexate 15 mg intrathecal x 8 doses. EFS was time from therapy start to failure to achieve CR/CRh/CRi by the end of course II, progression, relapse, or death, whichever occurred first, censored at last follow up. OS was time from registration to death from any cause censored at the last known alive date. Results: The median age of the 33 treated pts was 71 yrs (range 60-84). Eight pts had prior therapy for alternate malignancy in CR for >2 yrs prior to enrollment (6 multiple myeloma, 1 non-Hodgkin lymphoma, 1 breast cancer). Median CD22 expression was 92% (range 21-100%) and 49% had NCCN poor-risk genetics. Five pts underwent alloHCT in first CR/CRi and 2 pts received POMP maintenance after early discontinuation of blina (1 toxicity, 1 physician choice). The CR/CRi rate after InO was 85% (1 early death/refractory, 2 refractory, 2 undetermined due to low marrow cellularity on remission assessment marrow) with CR/CRi rate of 97% by completion of course II blina. With 45 mo median follow-up, the estimated 3-yr EFS was 48% (95% CI 33-70%) with a median EFS of 31 mo (95% CI 17.4-not reached [NR]) and no events after 31 mo. Sixteen events occurred: 12 relapses, 1early death, and 3 deaths in remission (1 encephalopathy, 1 relapse of multiple myeloma, 1 pulmonary complications after alloHCT). No isolated CNS relapse has been reported. Among relapses, 10 had immunophenotyping. Four (40%) were CD19-negative, one of which was also CD22-negative. Among CD19-negative relapses, genetics were hypodiploid (2), Pax5alt (1), and ZNF384-like (1, also CD22-negative). TP53 mutation or loss was observed in 5/12 (42%) relapses. Thirteen pts died. The estimated 3-yr OS was 59% (95% CI 44-79%) with median OS NR (95% CI 32-NR) with no deaths after 36 mo. In univariate analysis, EFS and OS were not impacted by age, gender, genetic risk (NCCN), prior therapy for alternate malignancy, or alloHCT in first remission. EFS was better with higher CD22 expression at diagnosis (≥90% vs <90%, 3-yr EFS 60% vs 25%, P=0.044). EFS and OS were worse for detectable minimal residual disease (MRD) at any timepoint by ASO-PCR. Undetectable MRD after course IA (1 cycle InO induction) was associated with EFS with a 3-yr EFS of 52% vs 0% for detectable MRD (median NR vs 8 mo, hazard ratio [HR] 0.07, P=0.004) and a 3-yr OS of 100% vs 0% for detectable MRD (median NR vs 20 mo, HR 0.00, P=0.0014). Conclusions: Longer follow-up of chemotherapy-free treatment with InO and blina for older pts with newly diagnosed, Ph-negative, CD22-positive, B-cell ALL reveals durable remissions and survival. The A041703 regimen is a compelling option for first-line treatment of this pt population. Support: U10CA180821, U10CA18088; https://acknowledgments.alliancefound.org.

Abstract Introduction: Elranatamab (Elra) is a bispecific antibody (BsAb) targeting BCMA that is approved for patients with triple class exposed relapsed refractory myeloma (RRMM) on the basis of the MagnetisMM-3 phase 2 trial. For BCMA naïve patients, an overall response rate (ORR) of 61.0% and median progression free survival (PFS) of 17.2m was observed with a median overall survival (OS) of 24.6m. However, efficacy and safety information in the real world is lacking. Methods: This was an international retrospective study of patients with RRMM treated with Elra monotherapy outside of clinical trials. Data was collected through the International Myeloma Foundation Immunotherapy Database from 7 countries (UK, USA, Canada, Greece, Spain, Czech Republic and Singapore). High-risk cytogenetic abnormalities (HRCA) were defined as 1q+, t(4;14), t(14;16), t(14;20), and/or del(17p). Response was assessed using IMWG consensus criteria. Patient characteristics were summarized by frequency (percentage) or median (range). PFS, OS were evaluated using the Kaplan-Meier method and reported with 95% confidence intervals. Results: 79 patients were included. Median age was 67 years (range: 41-95y) with 20% ≥75 years. Racial distribution was: 75% White, 16% Black/African American, 8% Asian/Pacific. 55% were ECOG performance status (PS) 1-2. Patients received a median of 5 prior lines (range 1-11), and 35% were BCMA exposed (9% CAR-T, 5% ADC, 7% BsAb, 8% BsAb plus CAR-T, 4% ADC plus BsAb). Of those with available data, 45% had HRCA,13% had extramedullary disease (EMD) and 32% had penta-drug refractory RRMM. Overall, 48% would not have been eligible for the MagnetisMM-3 trial. Median follow-up was 6.3m (range 0.5-35.0). ORR was 53% (PR 11%, VGPR 33%, CR 8%, sCR 1%) and 67% for BCMA naïve patients. Responses were significantly lower for BCMA exposed patients (ORR 31%) but did not differ by age (51% <75yrs vs 60% ≥75yrs). On univariate analysis, prior BCMA exposure, platelets <50, presence of HRCA and penta-refractoriness were significantly associated with a lower response rate. PFS for the whole cohort at 6 and 12m was 64% (95%CI, 54-77%) and 52% (40-67%); for BCMA naïve patients, it was 77% (65-90%) and 67% (54-84%), respectively. Within the whole cohort, PFS was shorter for: BCMA exposed (median 4.0m vs not reached (NR)), platelets <50 (2.0 vs 21.7m), HRCA (7.2m vs NR), penta-refractory (4.3m vs NR). PFS did not differ significantly by EMD, PS, age, or creatinine clearance. OS for the whole cohort at 6 and12m was 74% (64-85%) and 58% (45-74%); for BCMA-naïve patients, it was 80% (43-85%) and 70% (57-87%), respectively. Within the whole cohort, OS was shorter for: BCMA exposed (median 10.3m vs NR), platelets <50 (4.3m vs NR), HRCA (10.7m vs NR) and penta-refractory (10.3m vs NR). Univariate regression analysis demonstrated that prior BCMA exposure, platelets <50 and penta-refractoriness were significantly associated with a worse PFS and OS, and HRCA predicted poorer survival CRS was observed in 41% of patients (grade(G)1: 35%, G2: 5%, ≥G3: 0%) with most occurring with the first step up dose (SUD): SUD1: 29%, SUD2: 15%, full dose: 4%. Tocilizumab was used in 20% and steroids in 3%. ICANS was observed in 4 cases (5%): G1: 2, G2: 1, G4: 1. Treatment was with steroids (n=3) and tocilizumab (n=2). G3-4 thrombocytopenia was observed in 19% and 14% required platelet transfusions. G3-4 neutropenia occurred in 25% with overall 31% requiring GCSF. Infections were reported in 33 (42%) patients with median time to infection of 41 days. A total of 94 infection episodes were observed over 581 personal months. There were 2 infection-related deaths reported (1 had IVIG, 1 did not). 64% had hypogammaglobulinemia (IgG < 400mg/dl) and IVIG was given in 65% of patients. Conclusions: In this first international real world analysis, Elranatamab achieved a response rate of 67% and a 12m PFS of 67% in BCMA naïve patients, similar to the MagnetisMM-3 trial despite almost half not meeting trial eligibility. However, prior BCMA exposure, platelets <50, high risk cytogenetics and penta refractory status were predictors of poorer outcomes. Acknowledgements: The International Myeloma Foundation, International Myeloma Working Group (IMWG)

Abstract Background: The phase II and III GRIFFIN and PERSEUS studies evaluated DVRd vs. VRd in NDMM pts that were transplant eligible (TE). These studies included consolidation (cons) and dual agent maintenance (maint) with dara and len (DR). Little is known about the efficacy of DVRd in RW practice including frequency of bor use, use of cons, use of DR maint, and subsequent treatment after progression (PD) on DVRd. We aim to evaluate the RW efficacy of NDMM pts treated with DVRd across the tri-site Mayo Clinic Comprehensive Cancer (MCCC). Methods: We retrospectively analyzed the medical records of pts treated with DVRd between June 2018 and June 2024 at the MCCC. Outcomes were estimated using the Kaplan-Meier method. Results: 464 pts were included; 278 pts were male, and the median (m) age of MM diagnosis was 64 years (yr). 114 pts had ISS III, 205 pts had R-ISS III, 266 pts had high risk (HR) FISH, 80 pts had extramedullary disease, 165 pts had ultra HR disease (dz) (as per 2025 IMS/IMWG consensus), and 47 pts had renal insufficiency (RI) with creatinine >2 mg/dL. Starting len dose was 25mg in 356 pts, 15 mg in 40 pts and ≤10mg in 65 pts. 399 pts received bor 1x per week and 63 2x per week, 91 pts received 1-2 cycles of a different regimen prior to DVRd due to hospitalization (n=23), RI (n=38), poor performance status (n=6), other (n=34). 315 (67.9%) pts underwent autologous transplant (ASCT). The m number of induction cycles was 5; 4 for pts who underwent ASCT and 6 for pts who did not. The best ORR to induction for pts who underwent ASCT was 98% with 247 (79%) achieving ≥VGPR, and 82 (26%) achieving minimal residual disease negativity (MRD-) to at least 10-5. The best ORR for pts who did not undergo ASCT was 87%. For those who underwent ASCT, (96% with melphalan 200mg/m2), the ORR at day 100 was 97% with 56% achieving MRD-. At 1-yr post ASCT, 30% (93/312) were MRD-. 42 pts (13%) received post ASCT cons with DVRd for a m of 2 cycles. 281 pts received post ASCT maint including 107 (38%) len, 53 (19%) bor-len, 91 (32%) dara-len, 14 (5%) dara, 16 (6%) other. 61(13%) pts had change in treatment, due to change to second line therapy (35; 55%), discontinuation (d/c) of len (11; 17%), d/c of dara (3; 5%), d/c of bor (15; 23%), d/c of dex (0; 0%). The m follow-up time for all pts was 26 months (mo) (17-39). The m PFS of pts who underwent ASCT was not reached (NR), and was 57 mo (52-NA) for pts who did not undergo ASCT. For pts who underwent ASCT, the PFS at 24mo for pts who did not have HR FISH was 93% (88-99%) compared to 80% (73-88%) for pts with HR FISH (p=0.12) and 77% (68-87%) for pts with ultra-HR dz (p=0.013).The PFS at 24mo of pts with RI who underwent ASCT was 81% (66-98%) compared to 86% (82-92%) for those without RI, p=0.57. The PFS at 24mo of pts with RI who did not undergo ASCT was 53% (28-100%) compared to 64% (55-75%) for those without RI, p=0.42. The ORR and MRD- rate for pts who received once-weekly bor was 94% and 24%, compared to 94% and 27% for pts who received 2x weekly bor (p=0.85, p=0.93). For pts who underwent ASCT, the PFS at 24mo for pts who received len maint was 91% vs. 83% for pts who receive dual agent maint (DR or VR) (p=0.25), although pts who got dual agent maint were more likely to have HR FISH than pts who received len maint (p<0.001). The PFS at 24mo for pts that received post-ASCT cons was 91% compared to 85% for those that did not (p=0.53); pts who got post-ASCT cons were more likely to have HR FISH (p=0.07). For pts that underwent ASCT, the 3 yr PFS rate is 85% and the 3 yrs OS rate is 96%. For pts that did not undergo ASCT the 3 yrs PFS rate is 60% and the 3 yr OS rate is 85%. 55 pts had functional HR (FHR) MM (relapse within 18 mo) and m PFS for FHR pts who underwent ASCT was 15 mo (11-NA), while m PFS was NR for pts without FHR MM (p<0.001). 79 pts relapsed after 1st line DVRd. The most common 2nd line therapies (tx) were dara-carfilzomib (K)-D, dara-pomalidomide(P)-D, KPD, and other. The m follow-up time from 2nd line tx was 10 mo, the best ORR to 2nd line tx was 76%, and the m PFS with 2nd line tx was 18 mo (7-NA). Conclusion: In this RW analysis, the efficacy and survival outcomes of NDMM pts treated with DVRd was comparable to that reported in the PERSEUS and GRIFFIN trials, although MRD- rates appear lower. DR maint and post-ASCT cons use was not common and was used more frequently in pts with HR FISH. Pts can be effectively salvaged following PD on front-line DVRd with available tx.

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 Hispanic and non-Hispanic Black (NHB) patients have worse HCT survival compared to non-Hispanic White (NHW) patients and were less likely to utilize an unrelated HCT donor (Khera et al. Blood Adv. 2024; Hahn et al. JAMA Netw Open. 2024), but this difference has not been evaluated in the PTCy era. PTCy reduces graft-versus-host disease (GvHD) and allows for increased availability of allogeneic donors in minority patients. It is important to know the best donor source for each ethnicity. In this study, we investigated the association of race/ethnicity and donor type on overall survival (OS). Methods We performed a secondary analysis of adult patients (>19 yrs) who were selected if they had a peripheral blood allogeneic HCT from 2013-2018 and received PTCy for GVHD prophylaxis using a publicly available dataset from the Center for International Blood and Marrow Transplantation Research Program. Kaplan-Meier curves estimated 2-year OS, and differences were compared using log-rank tests. X2 tests helped identify potential confounders. Analyses were stratified by donor type and self-reported race/ethnicity. The Cox Proportional Hazards model evaluated 2-year OS using a backwards elimination method to build the final prediction model. P<0.05 was considered statistically significant. Results Of 4,031 patients included, 70% were NHW, 16% were NHB, and 13% were Hispanic. The most common donor was Haploidentical (Haplo; 64%), followed by matched unrelated donor (MUD; 19%), matched related donor (MRD; 10%), and mismatched unrelated donor 7%). Hispanic patients were younger than NHW and NHB (P<0.0001) and more were transplanted in CR (P<0.0001). Additionally, most Hispanic and NHB patients received a Haplo HCT (77 and 83%, respectively). NHW patients also received Haplo HCTs (57%) as well as MUD HCTs (24%). Most patients had acute myeloid leukemia (40%) followed by myelodysplastic syndrome (22%) and received reduced intensity conditioning (58%). MUD patients who received PTCy had the highest 2-year OS compared to other donors (65 vs 58-61%; P=0.03). Higher OS was observed in younger patients (20-39 yrs: 69% vs 60+ yrs: 53%; P<0.001) and patients with non-malignant diseases (80%) or Hodgkin lymphoma (79%) compared to patients with plasma cell (52%) and myelodysplastic disorders (55%; P<0.0001). For NHW patients, patients transplanted with a MUD had higher OS than other donor types (67 vs 58-60%; p=0.0006). In contrast, NHB transplanted with MRD, Haplo, or MMUD had the highest OS compared to MUD, although this was not statistically significant (61-66% vs 42%; p=0.4). Hispanic patients transplanted with a related donor (MRD and Haplo) had higher OS compared to patients who had an unrelated donor (MUD and MMUD; 66-67 vs 48-58%; P=0.1). Within each donor source, we tested for a racial disparity in OS. There was no difference in OS by race/ethnicity in MRD or MMUD HCTs. In Haplo HCTs, Hispanic patients had the highest OS followed by NHB and then NHW (66, 61, vs 58%; P=0.005). In MUD HCTs, NHW patients had higher OS than Hispanic or NHB patients (67, 48, vs 42%; P=0.02). Significant factors associated with OS in multivariable analyses included donor type, age, disease, year of transplant, conditioning intensity, Karnofsky Performance Score, donor/recipient CMV serostatus, and disease risk index. Results were stratified by race/ethnicity. For NHW patients, mortality risk was higher for HCT patients receiving a MRD, Haplo, or MMUD compared to a MUD (HR=1.25-1.39; P=0.001). In contrast, NHB patients receiving a MUD had a higher risk of mortality compared to a Haplo, MRD, or MMUD (HR=1.67; P=0.06). In Hispanic patients, MUDs and MMUDs had a higher mortality risk than MRD or Haplo HCT (HR=1.48; P=0.07). Conclusion OS differed by race/ethnicity and donor type. Our findings should be validated by expanding the analysis to include patients treated with PTCy after the publication of BMT CTN 1703 results (Bolaños-Mead et al. NEJM. 2023). When selecting donors for HCT patients, consideration should be given to patient race/ethnicity.

Abstract Introduction The European Leukemia Net (ELN) 2022 stratified acute myeloid leukemia (AML) patients (pts) treated with intensive chemotherapy (IC) into three groups based on genetic features. ELN 2024 (Döhner et al, Blood) and Beat AML 2024 (Hoff et al, Blood Advances) proposed revised systems to better capture the impact of genetic features in pts receiving less-intensive therapy (LIT). Real-world validation across treatment settings, including allogeneic hematopoietic stem cell transplantation (allo-HCT), is warranted. Methods We evaluated the performance of ELN 2022, ELN 2024, and Beat AML 2024 among AML pts treated at Mayo Clinic from 2016 to 2025. Only treated pts with available molecular data included. Response was assessed according to the ELN 2022 criteria. Overall survival (OS) was calculated from diagnosis. Multivariable Cox proportional hazard (CPH) models were used to adjust for covariates. Model performances were assessed using Harrell's c-index. Results 426 AML pts (median age 68 years; 60% male) were included; 195 (46%) received IC and 231 (54%) received LIT, while Allo-HCT was performed in 133 (31%) pts. Complex karyotype was present in 126 (30%) and normal cytogenetics in 143 (34%) pts. Molecular mutations included TP53 (20%), TET2 (18%), DNMT3A (16%), SRSF2 (16%), RUNX1 (16%), ASXL1 (16%), and NPM1 (15%). Among evaluable pts (83%), complete remission (CR) after first-line therapy was achieved in 47%. Risk group assignments varied: ELN 2022 vs. ELN 2024 classified pts as favorable (20% vs. 55%), intermediate (20% vs. 24%), and adverse (60% vs. 20%); Beat AML 2024 categorized pts as favorable (41%), intermediate (21%), and adverse (38%). ELN 2024 reclassified 229 (54%) pts of whom 5% upstaged and 49% downstaged, primarily affecting ELN 2022 adverse (67%) and intermediate (46%) groups. Among LIT-treated, CR rates did not differ across groups in any classification. Per ELN 2024, CR was achieved in 43% (favorable), 67% (intermediate), and 29% (adverse) of the LIT-treated pts. However, among IC-treated pts, CR was higher in favorable/intermediate vs. adverse groups across all models (p<0.0001). Allo-HCT was most common in ELN 2024 intermediate (41%) and favorable (32%) vs. adverse (16%) groups. Median OS (months; 95% CI) for the entire cohort was 15.7 (12.5–20.9) with median follow-up time of 49.8 (40.9-55). By ELN 2022, OS of the entire cohort was 49.4 (30.7–NA) for favorable, 50.0 (29.2–NA) for intermediate, and 8.8 (7.7–11.2) for adverse (p<0.0001). Per ELN 2024, OS of the entire cohort was 25.4 (18.5–37.3), 20.3 (13.4–39.8), and 5.7 (3.4–8.2), respectively (p<0.0001). Beat AML 2024 stratified OS of the entire cohort as 42.5 (30.7–NA), 11.4 (9.3–16.7), and 5.6 (3.5–8.0) for favorable, intermediate, and adverse groups (p<0.0001). ELN 2024 stratified the OS of the pts treated with LIT as 15.7 (10.1-24.9), 8.0 (4.9-13.9), and 6.8 (3.4-10.2) for favorable, intermediate and adverse risk groups, (p <0.0001). Among ELN 2022 adverse-risk pts, those reclassified as favorable per ELN 2024 had superior OS (15.0, 9.8–22.7) compared to intermediate (7.8, 5.0–9.3) or adverse (5.4, 3.3–8.0) risk groups, p<0.0001. C-index (95% CI) for OS in the entire cohort was highest for Beat AML 2024 (0.658, 0.629–0.688), followed by ELN 2022 (0.627, 0.599–0.655), and ELN 2024 (0.600, 0.568–0.631). In LIT-treated pts, ELN 2024 (0.597, 0.558–0.637) and Beat AML 2024 (0.586, 0.545–0.627) outperformed ELN 2022 (0.559, 0.521–0.596). Among allo-HCT pts, regardless of treatment type, ELN 2022 (0.610, 0.539–0.681) performed better than ELN 2024 (0.568, 0.487–0.648). In multivariable CPH models adjusted for age, bone marrow blasts, treatment intensity, and complex karyotype, ELN 2022 and ELN 2024 adverse-risk groups had higher hazard of death (HR 2.4, 1.6–3.5 and HR 1.7, 1.1–2.5, respectively, vs. favorable). No significant difference was observed between intermediate and favorable risk for ELN 2022 (HR 1.4, 0.9–2.2) or ELN 2024 (HR 1.4, 0.9–1.9). Allo-HCT was associated with a lower hazard of death (HR 0.4, 0.3–0.5). Conclusions In this real-world AML cohort, ELN 2024 and Beat AML 2024 improved OS prediction in LIT-treated pts compared to ELN 2022. This advantage was not observed in allo-HCT pts. Multivariable analysis confirmed the adverse-risk group as having the worst prognosis across all models. These findings highlight the importance of aligning molecular risk stratification with treatment modalities to enhance prognostication in AML.

Abstract Introduction While outcomes in patients with R/R FL have improved with T-cell–redirecting treatments (e.g. CAR T-cell therapy, bispecific antibodies), there remains an unmet need for safe, efficacious, and more convenient chemotherapy-free treatment options (Caridà et al, Eur J Haematol. 2025). GOLCA is a potential, first-in-class, oral CELMoD agent designed for the treatment of lymphoma, with preferential distribution to lymphoid organs and enhanced activity in lymphoma cell lines. GOLCA drives the closed, active conformation of cereblon to induce rapid and deep degradation of Ikaros and Aiolos, leading to direct cell killing (agnostic of cell of origin) and immunomodulatory activity. In the two-part, multicenter, first-in-human Phase 1/2 study (CC-99282-NHL-001; NCT03930953), GOLCA was well tolerated and effective in patients with R/R FL (Cordoba et al, ICML 2025, #441). Here, we provide longer follow-up in patients with R/R FL from Part B of the study. Methods Patients with R/R FL with ≥ 2 prior lines of therapy (≥ 1 in Part B if prior anti-CD20 therapy) were included in the study. Patients received GOLCA monotherapy orally, once daily at different dosing schedules in Part A. In Part B, GOLCA was dosed at 0.2 or 0.4 mg (14 days on/14 days off) ± R. Total GOLCA treatment duration was up to 2 years or until progressive disease (PD)/unacceptable toxicity. Primary objectives included safety and recommended Phase 2 dose determination. Results As of April 3, 2025, a total of 72 patients with R/R FL were enrolled: 12 in Part A (GOLCA monotherapy) and 60 in Part B Cohort D (22 received GOLCA 0.2 mg + R; 38 received GOLCA 0.4 mg + R). Patients were heavily pre-treated. Median number of prior treatments was 4.5 (range, 2–6) in Part A and 3 (range, 1–12) in Part B Cohort D. Approximately one-third of the treated patients were exposed to prior T-cell–redirecting therapy, approximately one-third had prior lenalidomide (len) exposure, and approximately one-third were refractory to the last regimen received. At the time of data cutoff, in Part A, 4 patients completed 2 years of GOLCA, remaining in remission at last follow-up; 8 discontinued due to PD. In Part B Cohort D, 41% of patients treated with 0.2 mg and 63% with 0.4 mg were ongoing. PD was the most common reason for discontinuation. In the safety evaluable population (n = 60; GOLCA 0.2 or 0.4 mg + R), neutropenia, an on-target side effect of GOLCA, was the most common grade 3/4 treatment-emergent adverse event (TEAE) and occurred in 65% of patients, followed by anemia (13%) and febrile neutropenia (8%). Serious AEs related to GOLCA occurred in 22% of patients, most commonly infections (17%) and febrile neutropenia (7%); pulmonary embolism occurred in 1 patient with 0.2 mg. The most common causes of GOLCA interruption in the overall safety population were infections (32%) and neutropenia (18%). Dose reductions were mostly due to neutropenia (10%) and febrile neutropenia (5%). No discontinuations or deaths occurred from GOLCA-related TEAEs. Non-hematologic TEAEs were infrequent and mostly low grade, with the most common being gastrointestinal disorders (7%). In the efficacy evaluable patients (n = 56; GOLCA 0.2 or 0.4 mg + R) at a median follow-up of 10.8 months, the overall response rate (ORR) was 89% (complete response rate [CRR], 61%). With 0.2 mg, ORR was 81% (CRR, 43%) and with 0.4 mg, ORR was 94% (CRR, 71%). In the 0.4-mg group, responses were consistent in high-risk subsets, including patients with prior len (ORR, 100%; CRR, 73%) and/or T-cell–redirecting therapy (ORR, 91%; CRR, 64%). With GOLCA 0.4 mg, 10 patients had response lasting > 12 months, including 5 with prior T-cell–redirecting therapy and 6 with prior len. Conclusions With additional follow-up, GOLCA + R continued to show promising efficacy with durable responses and no new safety signals. A higher ORR/CRR and similar tolerability were observed with GOLCA 0.4 mg + R vs GOLCA 0.2 mg + R, including in patients with prior len-based and/or T-cell–redirecting treatment. These data support continued development of GOLCA 0.4 mg + R as a fixed-duration, chemotherapy-free, outpatient option in the ongoing Phase 3 GOLSEEK-4 study in 2L+ FL (NCT06911502).

Abstract Introduction: Autologous CD19 CART therapies have been utilized across a wide range of B cell driven autoimmune diseases (AD), including systemic lupus erythematous (SLE), idiopathic inflammatory myopathies (IIM), systemic sclerosis (SSc), & myasthenia gravis (MG). To date, a number of autologous CD19-CART therapies have delivered durable drug free responses in AD patients. However, the safety profile of autologous CD19-CART therapies across different AD has yet to be fully explored. This is especially true for CRS & ICANS. Here, we provide novel insight into the mechanism underlying the safety profile of resecabtagene autoleucel (rese-cel) an autologous CD19 41BBz CART therapy across four separate Phase I/II clinical trials in SLE, IIM, SSc, & MG. Objectives: The primary objective of each trial is safety & tolerability of rese-cel at Day 29. Key secondary objectives include changes in clinical scores & use of immunomodulatory agents. Key translational assessments include CART cell pharmacokinetics (PK), impact on peripheral B cell populations (pharmacodynamics), & serum cytokine levels. Methods: 19 Patients (data cutoff: 6/2/2025 SLE; 5/6/2025 IIM, SSc, and MG), with active disease refractory to standard of care have been treated across 4 Phase I/II clinical trials in SLE (8 patients; NCT06121297), IIM (8 patients; NCT06154252), SSc (2 patients; NCT06328777), & MG (1 patient; NCT06359041). All patients were treated with a single weight-based infusion of rese-cel at a dose of 1 x 106 cells/kg following lymphodepletion (flu 25 mg/m2/d on Days -5, -4, & -3, & cy 1,000 mg/m2/d on Day -3). All non-glucocorticoid immunomodulatory agents were stopped prior to lymphodepletion. Glucocorticoids were tapered post-infusion. Patients were not given prophylactic tocilizumab pre-infusion. Translational assessments were determined as follows: CART PK was evaluated by flow cytometry & dPCR; B-cell enumeration & phenotyping were evaluated by flow cytometry; & serum cytokines were evaluated via immunoassay. Results: Across all indications (19 patients), 7 episodes of CRS were observed (7/19). 6 of 7 patients experienced a Grade 1 CRS, & 1 patient had a Grade 2 CRS. 2 patients developed ICANS; 1 patient had a Grade 4 (previously presented at ACR Convergence 2024), & the other patient had a Grade 3. Both ICANS events were rapidly resolved without sequelae using standard therapy. These CRS and ICANS events differed across indications. In IIM, 4 of 8 patients experienced Grade 1 CRS and no patients experienced ICANs. In SLE, 2 patients experienced Grade 1 CRS and one developed Grade 4 ICANs. In SSC, 1 of 2 patients experienced Grade 2 CRS & the other experienced Grade 3 ICANS. In MG, no CRS or ICANS was observed. Rese-cel infusion products were ~ 66% transduced, with a mean CD4:CD8 ratio of 6. Post-infusion, peak CART expansion was observed on day 12 & the mean peak expansion was 89 cells/µL (SD +/- 214). B cells were rapidly depleted from peripheral blood post-infusion, with nadir occurring at 13 days & repopulation beginning at 62 days post-infusion on average. Re-emergent B cells were largely of the CD24+CD38+ transitional naïve phenotype. Commensurate with B cell depletion, serum BAFF induction was observed, with a mean fold induction of 16 & mean peak level of 56,404 pg/µL (SD: +/- 45,547). Serum cytokines associated with CRS & ICANS; IFNg, IL6, & IL8 reached peak elevation on days 10, 9, & 10 respectively post-infusion. The mean peak elevation for IFNg, IL6, & IL8 were 232 pg/ µL (SD: +/- 320), 44 pg/ µL (SD: +/- 60), & 80 pg/ µL (SD +/- 73), respectively. Conclusion: Rese-cel appears to be well tolerated in autoimmune patients with rates of CRS & ICANS of 37% & 11% across all autoimmune indications, respectively (SLE patients had a 25% CRS rate & 12.5% ICANS rate, IIM patients had a 50% CRS rate & 0% ICANS rate, SSC patients had a 50% CRS & 50% ICANS rate, & MG patients had a 0% CRS & ICANS rate). Notably, the frequency & severity of CRS appears to be low, with no CRS in 63% of patients (12/19) & most CRS events (6/7) being Grade 1. The lower frequency & severity of both CRS & ICANS events are likely correlated with the relatively modest induction of serum IFNg, IL6, & IL8 found in autoimmune patients post rese-cel weight-adjusted dose infusion. High BAFF levels reflect deep systemic B cell depletion. Together, these data support further support late-stage clinical development of rese-cel in autoimmune disease.

Abstract BACKGROUND: DNA methyltransferase inhibition offers palliative benefit but does not alter disease biology. in chronic myelomonocytic leukemia (CMML, Merlevede J et al. Nat Comm 2016). This was conclusively demonstrated in the phase 3 DACOTA study, where decitabine did not improve event-free survival in comparison to hydroxyurea (median 12.1 versus 10.3 months, P=0.27) in advanced myeloproliferative CMML (MP-CMML). Hence, there is in urgent need to develop disease modifying therapies for this dismal condition. We and others have demonstrated a role for RAS mutations in MP-CMML through the activation of the KMT2A-PLK1 axis. Targeting of this axis using onvansertib, an inhibitor of PLK1, has demonstrated its pre-clinical efficacy in MP-CMML patient-derived organoid and xenograft models. (Carr RM et al. Nat Comm 2021). METHODS: We conducted a single center phase 1 study to assess the safety and efficacy of onvansertib in relapsed/refractory MP-CMML (NCT05549661). We used a Bayesian Optimal Interval (BOIN) study design to determine the maximum tolerated dose (MTD). The three dose cohorts included 6, 9 and 12 mg/m2 given orally from days 1 to 21 of each 28-day cycle. Key inclusion criteria included a WHO-defined diagnosis of MP-CMML with a white blood cell (WBC) count > 13,000/mm3 and adequate organ function (estimated GFR > 50 mL/min/m2). Response was evaluated per the MDS/MPN International Working Group Criteria (Savona et al. Blood 2015). Targeting efficacy was assessed by measuring phosphorylation of TCTP (a PLK1 substrate), specifically pTCTP/TCTP ratios by immunoblotting in peripheral blood mononuclear cell (PBMC) samples pre and post cycle 1 (Days 1, 7, 21) and end of cycle 3. Pharmacokinetic studies and translational correlative studies were conducted per protocol. RESULTS: Between April 2023 and July 2025, a total of 9 patients were enrolled. The median age at enrollment was 68 years (range: 60-83); all caucasian with 4 (44%) males. All patients had a diagnosis of CMML-1 with a median bone marrow (BM) blast percentage of 4 (0-9), median hemoglobin 10 (7.1-13.2) g/dL, median WBC count of 11.1 (3.1-72.7) x 109/L (4 patients had a WBC count < 13 x 109/L at enrollment due to hydroxyurea use but were confirmed to be MP-CMML at diagnosis), absolute monocyte count 2.1 (1.9-19.6) x 109/L, and platelet count of 36 (20-494) x 109/L. TET2 (89%), SRSF2 (78%), ASXL1 (56%), NRAS, KRAS and CBL (22% each) were the most frequent molecular abnormalities. Previous therapies included hydroxyurea (n=8) and decitabine (n=1). Four patients were enrolled at the 6mg/m2dose level, 2 at the 9 mg/m2 dose level and we currently have one patient at the 12 mg/m2 dose level. While there were 2 planned patients at the 6 mg/m2 dose level, due to a case of pericardial effusion that was possibly drug related, an additional two patients were enrolled at the same dose level, without any dose limiting toxicity (DLT). Targeting efficacy was confirmed by pTCTP immunoblotting in PBMC samples from 4 patients (6 and 9 mg/m2 dose levels) showing suppressed pTCTP/TCTP ratios. No confirmed DLT has been identified thus far, and no grade 3 or 4 toxicities attributable to the study drug have been reported. Possible or unrelated grade 3 adverse effects included infections (sepsis/cellulitis, n=2, 22%), acute kidney injury (n=1, 11%), pericardial effusion (n=1, 11%), and atrial fibrillation with rapid ventricular response (n=1, 11%). Median duration on therapy was 124 (range: 15-654) days with most common cause of study discontinuation being disease progression (33%). Response was assessed as per the MDS/MPN IWG criteria in patients who received at least 1 cycle (n=8) with 3 (38%) patients meeting criteria for either hematological or optimal marrow response. Specifically, there was one (14%) patient with >100% platelet response, one (14%) with normalization of WBC count (baseline WBC count >50 x 109/L), one (14%) optimal marrow response with BM blast% reduction from 8 to 2, facilitating candidacy for an allogeneic hematopoietic stem cell transplantation, and three patients (38%) remained as stable disease. CONCLUSION: In MP-CMML, PLK1 inhibition with onvansertib is relatively well tolerated and shows preliminary efficacy in approximately 40% of patients, with one patient having an optimal marrow response at the 9 mg/m2 dose. Future directions include a dose expansion phase and studying upfront combination with DNA methyltransferase inhibitors.