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Abstract Background: Undetectable minimal residual disease (uMRD) at the end of first-line (1L) treatment (tx) with 12-cycles (C) of venetoclax (ven) + obinutuzumab (obin) is associated with prolonged survival for patients (pts) with chronic lymphocytic leukemia (CLL, Al Sawaf et al. Blood 2024). We hypothesized that MRD may be used to guide ven tx duration for CLL pts treated with 1L ven + obin. Methods In this ongoing phase II, multicenter investigator-initiated study, pts receive ven + obin for 1L tx of CLL/small lymphocytic lymphoma (NCT04447768). Eligible pts have a CIRS score of ≤ 6 and require 1L tx per iwCLL 2018 criteria. Pts receive 6 x 28-day C of obin and initiate ven on C1D22. Ven duration is dependent on peripheral blood (PB) MRD status measured by ClonoSeq next generation sequencing. At C7, pts undergo MRD testing. Pts uMRD6 (<10-6 sensitivity) at both C7 and C9 dc ven after 9C and enter treatment free observation (TFO). Pts with detectable MRD6 (dMRD6) at C7 undergo repeat testing at C12; if uMRD5 (<10-5) pts dc ven after 12C. Pts dMRD5 at C12 continue ven for an additional 12C (24C total) prior to TFO. The primary study endpoint is 36-month PFS; the unpromising rate is set at 82% and will be tested by a nonparametric survival estimate (Kaplan-Meier) along with Greenwood's formula. RNA sequencing (RNAseq) was performed pre-tx on patient bone marrow (or PB if inaspirable) samples. Unsupervised clustering using machine learning (ML) based on consensus nonnegative matrix factorization was applied to the most variable genes to identify patient clusters. Clusters were then biologically characterized by gene signature scoring using xCell algorithm and assessed for association with uMRD6 at C7 using a Fisher exact test. Results Baseline characteristics of the 100 pts who initiated tx include: median age 58 (range 34-81); 71% male, 90% White, 3% Black and 2% Asian, 5% unknown; 49% IGHV unmutated, 16% TP53 mutation, 8% del17p (previously reported, Roeker et al. ASH 2024). 3 pts stopped tx prior to C7. 51 pts were uMRD6 at C7 and C9 and completed 9C ven. 46 pts were dMRD6 at C7; 6 pts stopped tx outside of meeting protocol requirements and are included in intention-to-treat (IIT) analyses. 32 pts were uMRD5 at C12 and dc ven after 12C. 8 pts were dMRD5 at C12: 5 continued ven per protocol (3 completed 24C ven, 2 ongoing tx as of 15 May 2025 data cut-off), 2 stopped ven outside of protocol requirements (included in ITT analyses), and 1 pt withdrew consent. At a median follow-up of 35 months, the 36-month PFS rate is 90% (95% CI: 84%, 97%). 36-month OS is 94% (95% CI: 89%, 99%). Landmark PFS analyses from EOT were performed for pts who dc ven after 9C due to uMRD6 (24-month PFS 92%, 95% CI: 85, 100%, n=51) and pts who dc ven after 12C due to uMRD5 (24-month PFS 96%, 95% CI: 89%, 100%, n=32). For pts dc ven after 9C due to uMRD6 (n=51), PB MRD at 12C after EOT was: 59% uMRD6, 12% uMRD5, 4% uMRD4, 8% dMRD4 and 18% unknown. For pts dc ven after 12C due to uMRD5 status (n=32), PB MRD at 12C following EOT was: 9% uMRD6, 31% uMRD5, 9% uMRD4, 25% dMRD4 and 25% unknown. Of the 5 pts with PD, 3 pts have had Richter Transformation to diffuse large B-cell lymphoma (all uMRD6 at C7 / 9). Two pts with PD have not met iwCLL tx criteria and remain in TFO. Five pts have died (suicide, West Nile encephalitis, COVID-19, complications of glioblastoma and RT DLBCL). Five C12 dMRD5 pts who continued ven have reached C18, with only 1 of 5 converting to uMRD5 in PB. However, all 5 maintained uMRD4 (<10-4). Of 3 pts that completed 24C ven (2 ongoing tx), 1 pt had deepening of response to uMRD5 at C24, and 2 pts had rising MRD on ven (dMRD4 at C24). To investigate patient heterogeneity at baseline and its relationship to uMRD, we clustered patient RNAseq samples into two clusters using artificial intelligence/ML based unsupervised clustering. The clusters associated with uMRD6 at C7 (Fisher exact test p=0.038), and patients in the cluster with significantly higher immunosuppressive cells such as T-regulatory cells and M2 macrophages were less likely to be uMRD6 at C7. Conclusions At a median follow-up of 35 months, the estimated 36-month PFS rate is 90%. RNAseq transcriptomic analyses identified that patients with enriched immunosuppressive cells were less likely to be uMRD6 at C7. Additional follow-up is required to confirm the durability of this MRD-guided ven + obin tx strategy.

Abstract Background: The addition of the CD19/CD3 bispecific T-cell engager, blinatumomab, to standard consolidation chemotherapy in adults with ALL who achieved a measurable residual disease negative (MRDneg) remission (CR), demonstrated an improvement in 3-year overall survival (OS, 85% vs 68%, HR 0.41, P=0.002) and 3-year relapse-free survival (RFS, 80% vs 64%, HR 0.53) compared to conventional chemotherapy in the ECOG-ACRIN E1910 study (Litzow et al, NEJM 2024). Given the complex therapy in this study, treatment delays and modifications are expected. We herein explored the impact of such delays on patient outcomes. Methods: In the phase 3 ECOG-ACRIN E1910 trial (NCT02003222), adults aged 30-70 years with newly diagnosedALL who had achieved MRDneg CR following induction and intensification were randomized to consolidation chemotherapy with blinatumomab (blina arm) or chemotherapy alone (chemo arm). We examined the association between the timing of the initiation of maintenance therapy and OS and RFS. The expected duration of consolidation was 252 days vs 126 days for patients on the blina and chemo arms, respectively. For this analysis, participants were classified into two groups (no/short delay or long delay) depending on whether they started on time/before or after the median time between the beginning of consolidation and start of maintenance therapy for their treatment group (medians: 335 days, range, 181-457 days vs 176 days, range, 139-265 days for blina and chemo arms, respectively). Multivariate analyses of OS and RFS were performed to examine the effect of no/short delay vs. long delay in starting maintenance. Patients were stratified according to their assigned consolidation treatment arm, and the models were further adjusted for age, sex, white blood cell count, platelets, hemoglobin, peripheral blood blasts, bone marrow blasts, performance status and genetic-genomic risk at diagnosis. Results: Of the 488 patients enrolled, 224 MRDneg patients were randomized to consolidation chemotherapy with or without blinatumomab and 135 of the 224 went on to maintenance therapy on study (N= 66 on blina arm and 69 on chemo arm, respectively). The median follow-up from the time of maintenance registration was 43.4 months. There were no significant differences in baseline characteristics between patients in either arm who experienced no/short delay or long delay. In the blina group, 60 of 66 patients (90.9%) received all 8 cycles of consolidation therapy of which 31 (45.6%) had long delays. Sixty-eight of 69 patients on the chemo arm (98.5%) received all cycles of consolidation therapy, of which 34 (50%) had a long delay. Strikingly, patients who had a long delay before initiation of maintenance had a significant improvement in OS in multivariate analysis compared to patients who had no/short delay (HR 0.31, 95% CI: 0.11-0.91; P =0.03). However, within each treatment group, OS benefit did not reach statistical significance (blina arm: HR 0.04, 95% CI: 0.001-1.64; P =0.09; chemo arm: HR 0.32, 95% CI: 0.08-1.38; P =0.13). Similar results were observed for RFS in multivariate analysis (HR 0.40, 95% CI: 0.16-1.01; P =0.05), though this impact on improved RFS was noted in the chemo arm but not in blinatumomab treated patients (blina arm: HR 0.56, 95% CI: 0.10-3.24; P =0.52; chemo arm: HR 0.19, 95% CI: 0.04-0.83; P=0.03). Additionally, patients who had no/short delay before starting maintenance experienced a longer median duration of maintenance treatment (blina arm, 548 days; chemo arm, 708 days) compared to patients who had a long delay (blina arm 488 days; chemo arm 598 days) before initiation of maintenance (P=0.0008). Conclusion: In the phase 3 randomized ECOG-ACRIN E1910 clinical trial, long delays between initiation of consolidation therapy and start of maintenance therapy were associated with improved OS compared to no/short delays. However, within each treatment group (blina or chemo), no significant difference of OS was observed. We postulate that these longer delays allowed more patients to receive all of the recommended protocol-assigned therapy thereby resulting in improved survival. Furthermore, patients who had no/short delays had a significantly longer duration of maintenance therapy. These data indicate that treatment delays during consolidation do not worsen survival. Further studies are being done to better understand why patients with long delays had better overall survival.

Abstract Introduction: T-PLL is a rare, aggressive leukemia with poor prognosis and limited therapies. Previous studies on T-PLL patients receiving an allogeneic stem cell transplant (alloSCT) are limited by small numbers with limited data on disease and transplant characteristics. Further, recent data from our large national cohort of patients demonstrated significant survival difference between TCL1A+ and TCL1A- T-PLL, and CD8+ T-PLL vs CD8- T-PLL. In this large multi-center series, utilizing comprehensive disease subtype and alloSCT clinical data, we evaluated prognostic and survival therapeutic outcomes in T-PLL patients that had an alloSCT with a particular focus on T-PLL disease subtypes. Methods: We retrospectively evaluated 572 diagnosed with T-PLL at 21 academic cancer centers throughout the USA between 2000-2023, of which we performed a further evaluation on the169 that proceeded with alloSCT. Overall survival (OS) and progression-free survival (PFS) were assessed using Kaplan-Meier methods and Cox proportional hazard models. Results: Among n=169 alloSCT recipients with T-PLL, the median follow-up time was 20.9 months post-alloSCT (range: 0.2-182.9), the median age at transplant was 59 years (range: 35-77) and 52% were male. In evaluated patients (n=109), TCL1A was positive by cytogenetics or FISH in 69%. As our recent analysis demonstrated significant differences in survival among specific subtypes of T-PLL, we evaluated outcomes in patients with CD4+CD8- T-PLL (n=90, 53%), CD4-CD8+ (n=17, 10%) T-PLL, and CD4+CD8+ T-PLL (n=52, 31%). 53% (87/164) had known nodal involvement at diagnosis identified by PET or CT scan and 45% (43/96) of known patients had minimal residual disease (MRD) at the time of transplant [defined as <5% T-PLL in marrow by flow, or +cytogenetics (e.g. TCL1A)] prior to alloSCT. At the time of alloSCT, 136 (80%) patients were in CR and 23 (14%) patients were in PR. Forty-nine (30%) had a myeloablative (MAC)conditioning regimen and 114 (70%) had a reduced intensity chemotherapy (RIC) conditioning regimen. Eighty (49%) patients had TBI as part of their regimen. The most common regimens were fludarabine (flu)/melphalan based regimens (n=44; 26.0%), flu/cyclophosphamide (cy) based regimens (n=33; 19.5%), flu/busulfan based regimens (n=22; 13.0%), flu/total body irradiation (TBI) (n=8; 4.7%), and cy/TBI (n=4; 2.4%). Across the whole cohort, the median OS and PFS post-alloSCT was 32.6 months (95% CI: 21.0-41.9) and 20.8 months (95% CI: 14.4-30.5) months while the 1-year cumulative incidences (CI) of NRM and relapse were 17% and 20%, respectively. The incidences of grade II-IV acute GVHD and cGVHD were 19% and 23%. There was no difference between patients with myeloablative conditioning (MAC) (n=49, 29%) when compared to patients that received reduced intensity conditioning (RIC) (n=114, 67%) in OS (33.1 vs 29.2; p=0.68) and PFS (20.2 vs 20.8; p=0.97). Patients that were MRD+ (n=31) had worse OS (22.2 vs 48.6; p=0.1) and PFS (14.1 vs 32.5; p=0.04) and higher rates of relapse (1-year relapse 20% vs 8%; p=0.08) than patients that were MRD- (n=50). PFS was improved in those who received alloSCT though only trended towards significance due to low numbers (HR 0.76, p=0.09). In subtype analysis, TCL1A+ T-PLL had significantly worse outcomes compared to TCL1A negative T-PLL. TCL1A+ disease had significantly worse OS (21.6 vs 63.1; p=0.01) and PFS (12.4 vs 50.7; p=0.01) compared to TCL1A-. Additionally, in TCL1A+ disease CI of NRM (24% vs 3%; p=0.02) and relapse (25% vs 12%; p=0.86) was higher vs TCL1A- PLL. CD4+CD8-, CD4-CD8+, and CD4+CD8+ disease had no difference in survival via either OS (28.0 vs 34.4 vs 21.0; p=0.17) or PFS (29.4 vs 23.5 vs 13.6; p=0.09) as well as no difference 1-year CI of NRM ( 11.6 vs 23.5 vs 26.2; p=0.35) and relapse (18.5 vs 23.5 vs 20.0; p=0.67).Conclusions: AlloSCT significantly improved outcomes for patients with T-PLL compared to those who did not proceed to alloSCT and remains he only curative therapy for those with T-PLL. OS, PFS, and CI relapse were significantly worse for patients with TCL1A+ subtype of T-PLL, or those with MRD positivity or PR prior to alloSCT. Novel strategies to decrease relapse such as post-alloSCT maintenance therapy to improve outcomes are urgently needed in these patients.

Abstract Somatic mutations in hematopoietic stem and progenitor cells (clonal hematopoiesis) are known to alter the immune milieu and can result in autoimmune disorders including VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) syndrome. There are currently no curative strategies for CH-linked autoimmune disorders besides allogenic hematopoietic stem cell transplantation. Recent work has shown a high prevalence of autoimmune syndromes among patients with IDH1/2 mutant myeloid neoplasms (MN). We thus hypothesized that IDH1/2-mutant CH might drive a subset of autoimmune disorders. To further characterize a possible association between IDH-mutant CH and autoimmune disease, we used data from two observational cohort studies, the UK Biobank (N=454,218) and All of Us (N=414,830). We observed 264 individuals with IDH1/2-mutant CH. IDH1/2 CH was associated with autoimmune disease (OR=1.8, p=4e-3), and, when compared to other CH genes with at least 100 carriers, showed the strongest effect size. When comparing autoimmune subtypes, we observed significant associations with polymyalgia rheumatica (OR=4.0, p=1e-3) and giant cell arteritis (OR=8.1, p=1e-6). IDH1/2 CH carriers had elevated CRP levels compared to other CH-carriers (p=1e-2) and non-carriers (p=8e-3). IDH1/2 CH was associated with lower neutrophil counts and higher monocyte counts. While most (68%) had blood counts outside the normal range, only a minority (11%) had severe cytopenias that met criteria for CCUS. Since IDH1/2 CH is associated with both autoimmune disease and blood count abnormalities, we sought to define the frequency, clinical presentation, and outcomes of IDH1/2-associated autoimmune disease among individuals with bone marrow biopsy confirmed CCUS. We used data from three CCUS cohorts: first, a multi-institutional cohort of CCUS patients with systemic autoinflammatory disease (SAID) who were UBA1-negative, second, a hospital-based cohort at Mayo Clinic, and third, a cohort of IDH1 carriers enrolled on a phase II clinical trial of ivosidenib (NCT05030441). Within 193 SAID patients who were free of myeloid neoplasm at the time of recruitment, IDH1/2 pathogenic variants were the most observed CH driver, occurring in 2% of individuals. These individuals (N=4) all had recurrent fevers and dermatologic manifestations, requiring chronic glucocorticoid treatment with 75% having inflammatory arthritis requiring multiple Disease-Modifying Antirheumatic Drugs (range 1-7, median=5). Within the Mayo Clinic cohort, 275 patients with CCUS were serially ascertained. Among those 8 (2.9%) were IDH1-mutant of whom 50% had autoimmune disease (three with seronegative rheumatoid arthritis and one with Sweet syndrome). At last follow up (median 16 months), 2 (25%) of 8 patients had progressed to MN. Within our open-label decentralized trial of ivosidenib (IDH1 inhibitor) in CCUS, we enrolled 20 patients, of whom 5 (25%) had a diverse array of pre-existing autoimmune disorders, including two cases of seronegative rheumatoid arthritis and one case each of Sweet syndrome, polymyalgia rheumatica, and Sjögren's syndrome. Underlying the clinical presentation of all five cases was episodic joint pain, with half also experiencing episodic dermatologic manifestations. The majority (58%, 11/19) of the IDH1mt-CCUS patients had an elevated hsCRP (>=5; range 6.91–46.2) including all four with co-occurring autoimmune disorders (range 7.97–46.2). Out of the 20 enrolled patients, 17 received at least 8 weeks of therapy, of which 9 had elevated hsCRP at baseline. Most of these (7/9) had normalization of hsCRP (falling below 5 mg/L) while on treatment (median time to hsCRP normalization of 58 days). Among the four patients with autoimmune disease, all had subjective improvement in their autoimmune symptoms following treatment with ivosidenib. In conclusion, we show that IDH1/2 CH is associated with autoimmune disorders and is particularly enriched among IDH1/2 CH carriers with co-occurring cytopenias. IDH1/2-associated autoimmune disease can range from classic rheumatic conditions such as rheumatoid arthritis to more severe VEXAS like presentations. IDH inhibition demonstrates efficacy for improving inflammatory manifestations within an ongoing clinical trial. Together these results nominate IDH mutant CH as a driver of autoimmune diseases with therapeutic implications.

Abstract Background: Glofit, a CD20/CD3 bispecific antibody, has shown efficacy in prospective trials, including the Phase III STARGLO study evaluating glofit plus gemcitabine/oxaliplatin (GemOx) in transplant-ineligible patients (pts) with R/R large B-cell lymphoma (BCL). However, concerns raised by the FDA's Oncology Drug Advisory Committee regarding the generalizability of the STARGLO data to U.S. pts underscore the need for real-world evidence. We report real-world outcomes of Glofit-GemOx in U.S. pts with R/R aggressive BCL. Methods: We conducted a multicenter retrospective review across 8 U.S. academic centers, identifying 31 pts with R/R aggressive BCL treated with Glofit-GemOx outside clinical trials. Baseline characteristics, treatment history, and outcomes were abstracted from medical records. Results: At Glofit-GemOx initiation: median age was 72 years (range, 34–88); 90% had stage III/IV disease. Histologic subtypes included DLBCL in 58% (n=18), high-grade BCL in 29% (n=9), PTLD/DLBCL in 6.5% (n=2), follicular lymphoma (FL) grade 3B in 3.2% (n=1), and Burkitt lymphoma (BL) in 3.2% (n=1). Germinal center B-cell phenotype was seen in 80% of evaluable cases. Double- (n=8) or triple-hit (n=1) cytogenetics were observed in 31% (n=9). Elevated LDH was present in 74%, and 16% had B symptoms. Median ECOG performance status was 1 (range, 0–3), and 23% (n=7) had received prior CAR T-cell therapy. Pre-treatment biopsy was performed in 77% (n=24) with CD20 expression tested in 74% (n=23). CD20 expression was negative in 3 pts by flow cytometry and/or immunohistochemistry. Pts received a median 1 prior line of therapy (range, 0-6); Glofit-GemOx was administered as 1L in 7% (n=2), and 2L in 58% (n=18). Median 4 cycles (range, 1-11); both 1L pts had prior FL (1 and 3 prior lines for FL). Twelve pts remain on therapy, 2 on Glofit monotherapy. Four pts were unevaluable (2 death pre-assessment; 2 pending evaluation). Among 27 evaluable pts, ORR was 78% (21/27) and CR rate was 41% (11/27). Among CD20- negative cases on pre- Glofit-GemOx biopsy (n=3), ORR was 33% (1/3), with 1 CR lasting 3.5 months. Of 11 pts who progressed on Glofit-GemOx, 6 were rebiopsied; 1 showed CD20 loss, 1 was previously CD20-negative. Among the 24 pts who received Glofit-GemOx as destination therapy, ORR of 75% (15/20 evaluable). Among pts with prior CAR T (n=7), the ORR and CR rate were both 43% (3/7). None received Glofit-GemOx within 30 days of CAR T-cell infusion; 4 received within 6 mo; 2 of whom achieved CR. Seven pts (24%) received Glofit-GemOx as bridging to CAR T. ORR pre-CAR T was 86% (6/7); 4 pt successfully proceeded to CAR T, 2 are pending infusion, and 1 progressed after 2 cycles and transitioned to alternate therapy. Three pts were evaluable post-CAR T with an ORR of 100% (3/3) and CR rate of 67% (2/3). At data cutoff, 23/31 pts were alive. Full PFS and OS data will be presented at ASH. Notable individual responses included a patient with relapsed BL post–DA-EPOCH-R who received Glofit-GemOx as 2L therapy and achieved a 6 mo CR without consolidation before progression. Another patient treated with Glofit-GemOx in the 7L setting after prior allogeneic transplant achieved a 3 mo CR prior to progression. CRS occurred in 58% (18/31), with grade ≥3 in 13% (4/31), including 2 possible treatment-related deaths. One occurred in a frail patient after the 1st dose, though neutropenic fever was present prior to Glofit administration. The second followed influenza A infection, respiratory failure, and possible grade 4 ICANS after the 2nd dose; attribution to CRS vs. infection was unclear. ICANS occurred in 10% (3/31), with one possible grade ≥3 case. Conclusions: This is the first U.S.-based real-world analysis of Glofit-GemOx, including more U.S. pts than the STARGLO trial, appear to demonstrate comparable response rates, potentially supporting its use as both bridging and destination therapy. Notable toxicities, including CRS, were observed, with 2 possible treatment-related deaths, with plausible alternate non-treatment related causes. Favorable responses were seen in bridging therapy and high-risk subgroups (transformed, HGBCL) which were excluded in the STARGLO trial. These findings support the real-world utility of Glofit-GemOx in the management of R/R aggressive BCL but underscore the need for caution due to associated toxicities. Further real-world and prospective evaluation are warranted, particularly in rare subgroups and as bridging therapy.

Abstract BACKGROUND Ivosidenib is an oral inhibitor of mutant isocitrate dehydrogenase type I (IDH1) currently approved for the treatment of IDH1 mutated acute myeloid leukemia and myelodysplastic syndrome (MDS). Hematopoietic stem and progenitor cells carrying preleukemic mutations, referred to as clonal hematopoiesis (CH), are the origin of myeloid neoplasms (MN). Individuals who have cytopenias and CH, but do not meet diagnostic criteria for a hematologic malignancy, are classified as having Clonal Cytopenias of Undetermined Significance (CCUS), a condition associated with a high risk of progression to MN. While CCUS patients (pts) can have multiple mutations, they show lower mutational burden on average compared to MN. Thus, we hypothesized that treatment with ivosidenib would improve cytopenias in IDH1-mutant CCUS. METHODS; We performed a decentralized phase II single-arm study to characterize the safety and efficacy of ivosidenib in IDH1-mutant CCUS (NCT0503044). Drug was shipped to pts with local oncologists performing standard-of-care clinical exams supplemented by study team lead interviews for adverse event monitoring. Research labs were drawn by local providers or through Quest. QT corrected interval (QTc) was monitored through a mobile electrocardiogram device (AliveCor). Eligible patients were aged ≥ 18 years and had confirmed IDH1-mutant CCUS with at least 6 months of unexplained cytopenias (hemoglobin<10 g/dL, platelets<100 x109/L or absolute neutrophil count <1.8 x109/L). The primary endpoint was hematologic response of at least 8 weeks in duration based on the IWG 2006 criteria for MDS. RESULTS 20 pts with IDH1-mutant CCUS have been enrolled. Most were male (70%) with a median age of 66 (range 41-79). Overall, 74% had a self-reported race of non-Hispanic white, 11% of Hispanic white, 5% of Asian and 11% of black or African American. Most pts presented with neutropenia (95%) including some with co-occurring thrombocytopenia (21%). One pt presented with anemia and thrombocytopenia without neutropenia. Prior to treatment, the average number of co-mutations beyond IDH1 was 2 (range 0-3), with most pts (74%) harboring a co-occurring spliceosome gene mutation. The IDH1 variant allele fraction (VAF) was lower in the blood (mean=19%, range 3-35%) than in the bone marrow (mean=31%, range 18-43%) in most (93%) patients. Out of the 20 enrolled pts, 17 received at least 8 weeks of therapy at the time of our data cutoff (7/29/2025) and were included in the efficacy analysis. Grade ≥3 adverse events (AEs) occurred in five patients (26%) including two with grade ≥3 treatment-related adverse events (pancytopenia and sepsis in the first pt, rash in the second pt). The most common all-grade treatment-related adverse events were nausea (n=5, 26%), prolonged QTc (n=3, 16%), anemia (n=3, 16%), and diarrhea (n=3, 16%). There were no instances of reported differentiation syndrome. Overall, 82% of pts achieved a hematologic response (14/17) including improvement in neutropenia (88%) and thrombocytopenia (75%). With a median follow-up of 16 months (range 0.6-24 months), the median duration of hematologic response was not reached. Among responders, 86% had a continued response at one year. Two pts progressed to MDS after 4 and 17 months of treatment characterized by recurrence of cytopenias and the emergence of new clones. A surveillance bone marrow biopsy was performed at 18 cycles for the 8 pts who remained on treatment with none showing disease progression. Most pts (90%, N=9/10) treated for at least 12 months had a decrease in IDH1-mutant CH VAF over time and 40% (N=4/10) showed IDH1 mutation clearance (VAF <2%) with a median time to clearance of 9 months. Among those with decreasing IDH1 clonal burden, all had a corresponding decrease in other co-occurring mutations present at baseline with one responder showing emergence of a newly detectable CHEK2 mutation without disease progression. CONCLUSIONS Decentralized trials represent a feasible solution for the conduct of clinical trials in rare hematologic neoplasms and precursor conditions. Ivosidenib was well-tolerated and induced durable hematologic remissions in IDH1-mutant CCUS. Most pts showed a reduction in clonal burden with mutation clearance commonly seen with long-term treatment demonstrating that ivosidenib modifies the natural history of IDH1-mutant CCUS.

Abstract Background: For LS-DLBCL, clinical trials (FLYER, LYSA/GOELAMS 02-03, LYSA LNH09-1B, S1001) have shown that 4 cycles of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (RCHOP4) without radiation (RT) leads to durable remissions in >90% of cases. However, only patients (pts) with non-bulky disease and/or international prognostic index (IPI) of 0 and complete metabolic response (CMR) on interim positron emission tomography (PET) scan, if performed, were eligible for RCHOP4 alone in these studies. Outcomes in trial-ineligible LS-DLBCL and the appropriate real-world candidates for RCHOP4 are still undefined. Methods: We conducted a multicenter retrospective study of adult pts with stage I/II DLBCL of any tumor bulk, IPI and with or without B-symptoms diagnosed after 2011 and treated with RCHOP4 +/- 2 cycles R from 21 U.S. centers. Pts with PMBCL, PTLD or receiving non-standard dose RCHOP for cycle (C) 1 or planned consolidative RT were excluded. The primary endpoint was PFS from C1 by Kaplan-Meier method, not counting indolent lymphoma relapse. Event free survival (EFS) was time to next therapy without progression (including unplanned RT for non-CR), progression or death. A competing risks analysis of non-relapse mortality (NRM) vs. DLBCL progression was performed. Results: The characteristics of the 428 pts were: median age 60 (18-88), 60% male, 11% Hispanic and 4% non-Hispanic Black, 62% stage I, 15% elevated LDH, 3% ECOG PS>1, 5% tumor bulk >7cm, 9% had B-symptoms and median Charlson Comorbidity Index (CCI) was 4 (2-12). IPI was 0, 1 and 2-3 in 42%, 46% and 12% and stage-modified IPI (smIPI) was 0, 1, 2 and 3-4 in 25%, 48%, 21% and 6% of pts. 66% had nodal (59% head/neck, 11% pelvic, 9% multiple above diaphragm, 7% abdominal) and 46% extranodal sites (37% head/neck, 20% gastric/intestinal, 9% spleen, 8% skin/soft tissue); 6% had transformed/concurrent FL/MZL or grade 3B FL, 33% (138/408) were non-GCB cell of origin (COO), 25% (90/357) double expressor (DEL) and 0.5% (2/379) double-hit. 13% had completely resected disease, 97% staging PET and 47% bone marrow biopsy. Median diagnosis to treatment interval was 30 days (IQR 20-43), 6% had dose reductions after C1, 77% had an interim PET (iPET) after C2 (33%) or C3 (67%), 15% received 2 additional cycles R and 4% CNS prophylaxis. CMR rates by iPET were 83% after C2 and 94% after C3, and 95% by end-of-treatment PET. iPET PMR was more likely if smIPI>2 or bulky disease. Median follow-up time was 2.7 years. There were 32 progression events: 14 occurred at the primary site and 17 at distant sites (1 unknown), and 12 occurred after 2 years. Another 11 pts received unplanned RT after RCHOP4 for non-CR. There were 24 deaths, 12 without prior progression. Cause of death was DLBCL in 7 and non-DLBCL in 17 cases (6 infection, 2 ILD, 2 heart failure, 2 second cancer, 1 seizure, 4 unknown). EFS, PFS and OS rates were 88%, 90% and 96% at 3 years. By univariable Cox regression, Black race, elevated LDH, smIPI>2, DEL, increasing CCI, multiple subdiaphragmatic nodal sites and iPET PMR were associated with worse PFS. Non-significant variables of note included COO, extranodal sites, complete resection, missing bone marrow biopsy, missing iPET and additional cycles R. By multivariable analysis (including age>60, stage, ECOG PS>1, elevated LDH, bulky disease, CCI, B-symptoms and DEL), ECOG PS>1 (HR 3.95 p=0.050), CCI (HR 1.29 p=0.003) and DEL (HR 2.02 p=0.069) were associated with worse PFS. Cumulative incidence of DLBCL progression and NRM were 8% and 2% at 3 years. Competing risk analysis by univariable models found that age>60, ECOG PS>1, smIPI>2, elevated LDH, CCI and bulky disease were associated with NRM, while DEL and B-symptoms were associated with DLBCL progression.Conclusion: Presented is the largest retrospective cohort of LS-DLBCL treated uniformly with RCHOP4 to date. Despite modest follow-up time and lack of an “intention-to-treat“ population, this study shows that abbreviated RCHOP4 leads to excellent outcomes in the real-world, albeit with continuous risk of late relapse. smIPI risk factors were associated with worse PFS, though this may in part be driven by risk of non-lymphoma death. As pts with advanced age, poor performance status or comorbidities may benefit from reduced treatment exposure, RCHOP4 should still be considered for these and other “trial-ineligible” pts, particularly if other high-risk features (iPET PMR, DEL or B-symptoms) are absent.

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.

Abstract Introduction: Brexu-cel is a highly effective treatment for R/R B-ALL, with complete responses achieved in 71% of patients (pts) treated in the pivotal ZUMA-3 trial. Patients with B-ALL with high-risk (HR) genetics are known to have inferior outcomes with chemotherapy, but little is known about the influence of HR ALL genetics on responses to chimeric antigen receptor (CAR)-T in adults. In this study, we assessed the impact of HR ALL genetics on outcomes in a large cohort of adult patients treated with brexu-cel for R/R Philadelphia chromosome (Ph)-negative B-ALL. Methods: Patient characteristics and outcomes were obtained from the Real-World Outcomes Collaborative of CAR-T in Adult ALL (ROCCA) database which includes data from 40 U.S. centers. NCCN guidelines (NCCN Guidelines in Oncology, ALL v2.2025) were used to define HR B-ALL genetics; lack of HR genetics was defined as standard-risk (SR). The primary outcome was event-free survival (EFS), defined as lack of response, disease progression, or death from any cause. Secondary outcomes were overall survival (OS), relapse free survival (RFS) and response rates including complete response (CR), CR incomplete count recovery (CRi), measurable residual disease negative CR (MRD-) by flow or NGS and progressive disease (PD). Multivariable models were adjusted for age, pre-infusion blast percentage, prior allo-HCT, and post CAR-T allo-HCT (modeled as a time-varying covariate). Results: The cohort included 286 pts: 169 with HR and 117 with SR B-ALL. The HR cohort included TP53m (n=24, 14%), KMT2Ar (n=16, 9%), CRLF2r (n=65, 39%) and other HR genetics such as JAK2 and other Ph-like, IKZF1, complex cytogenetics (n=64, 38%). Relative to SR pts, HR pts were more commonly Hispanic (50% vs 28%). HR and SR pts had similar disease burden pre-apheresis (>5% blasts: 58% vs 53%), prior blinatumomab (60% vs 58%), prior inotuzumab (42% vs 46%), and prior allo HCT (27% vs 37%). The presence of CNS disease (11% HR vs 12% SR) and extramedullary disease (EMD, 22% HR vs 29% SR) at apheresis was also similar. CR/CRi was achieved in 90.5% of evaluable HR pts (n=147) and 90.2% of evaluable SR pts (n=102); MRD- rates were also similar between HR and SR pts at 78.9% and 78.2% respectively. In unadjusted analyses, EFS did not significantly differ between HR pts (median 9.6 mos; 1-yr: 46%, 95% CI 38%-54%) and SR pts (median 11.6 mos; 1-yr: 48%, 95% CI 38%- 58%). Median RFS (HR: 12.2 mos, SR: 13.3 mos) and median OS (HR: 22.4 mos, SR: 21.0 mos) were also similar. Multivariable models demonstrated no significant associations between HR B-ALL and EFS (HR 1.09, 95% CI 0.73-1.63), RFS (HR 1.13, 95% CI 0.71-1.80), or OS (HR 0.96, 95% CI 0.62- 1.48) relative to SR ALL. 28% of HR patients and 21% of SR patients underwent consolidative allo-HCT. Among the HR subgroup, CR/CRi rate was lowest in KMT2Ar (71%) relative to TP53m (95%), CRLF2r (95%), and other HR genetics (89%). The median EFS was lowest in KMT2Ar (4.1 mos), followed by TP53m (6.9 mos), CRLF2r (11.6 mos), and other HR (11.1 mos). Median OS was also lowest in KMT2Ar (6.8 mos) vs 22.4 mos in TP53m and not reached in CRLF2r or other HR. PD was highest in KMT2Ar pts (29%), as compared to 11% HR other, 10% SR, and 5% TP53 and CRLF2r. The rate of relapse among those that achieved CR across the groups was similar and ranged between 28% -40%. Rates of CD19 negative relapse were similar between all subgroups (13%-15%), however 21% of KMT2A pts underwent myeloid transformation as compared 0% for TP53 and CRLF2 pts, and 2% among other HR and SR pts. 25% of KMT2Ar patients underwent consolidative allo-HCT as compared to 32% CRLF2 pts, 29% TP53 pts, 25% other HR pts and 21% SR pts. Multivariable models evaluating the different genomic subgroups demonstrated that relative to SR B-ALL, only KMT2Ar was associated with inferior OS (HR 3.17, 95% CI 1.53-6.58, p=0020). No associations were seen between HR subgroups and EFS. Conclusion: To our knowledge, this analysis represents the largest examination of adult B-ALL recipients of CAR-T assessed by genomic risk group. We found that response rates and survival outcomes following brexu-cel were similar among HR and SR B-ALL pts, including pts with TP53m and CRLF2r. However, pts with KMT2Ar had lower response rates and dismal EFS and OS, with higher rates of PD and myeloid transformation at relapse, suggesting that alternative strategies are necessary to improve outcomes for patients with R/R KMT2Ar B-ALL.

Abstract Pancreatic ductal adenocarcinoma (PDAC) remains among the most aggressive cancers, due to its limited therapeutic options and poor prognosis. Even with the adoption of total neoadjuvant therapy (TNT) and potentially curative surgical resection, PDAC relapse rates remain unacceptably high. Current systems for evaluating tumor response are valuable but limited, as they fail to capture the ecological complexity and broader architecture of the tumor microenvironment (TME). This results in uncertainty regarding the prognosis and recurrence risk of patients. To address this and to capture the complexity of the PDAC TME, we developed the Tumor Landscape Analysis (TLA). Using digitized H&E slides from 203 PDAC patients who received TNT and surgical resection at our institution, we applied a machine-learning pipeline to segment tumor and stromal compartments. We then quantified the TME architecture using ecological frameworks to assess the disease in multiple scales: individual patches, whole-slide landscapes, and aggregated patient-level summaries. Our analysis revealed that higher-order spatial features are independently prognostic of disease-free survival (DFS). Two statistical models showed different but complementary spatial characteristics that predict disease risk. In the first model, patients with more irregular cancer patch shapes and lower variability in stromal shape had significantly better DFS, with high-risk patients relapsing in a median of 7.2 months compared to 11.6 months in the low-risk group (HR=1.82, p=0.0003). In the second model, smaller stromal patch areas combined with greater tumor-stroma edge density identified patients at elevated risk, with high-risk individuals showing a median DFS of 8.0 months versus 15.7 months in low-risk patients (HR=1.73, p=0.0007). Importantly, these associations persisted even after adjustment for the T and N stage, showing that spatial features provide unique information beyond traditional pathology measures. These models help visualize PDAC as a comprehensive ecosystem that carries clinical significance. By quantifying tumor conformation and configuration, our models reveal prognostic information not available through CAP grading, percent tumor burden, or routine cell counts. This study suggests that tumor-stroma interactions and their spatial organizations are potentially biologically important for recurrence. We present a new, ecologically inspired approach to digital pathology for PDAC that not only improves our ability to predict recurrence and survival in PDAC but also sheds light on cancer as a complex, evolving ecosystem. Citation Format: Merih D. Toruner, Luis H. Cisneros, Miranda Lin, Andrea Maraone, Carlo Maley, Paul Dizona, Qian Shi, Martin E. Fernandez-Zapico, Ryan M. Carr. Ecological landscape analysis of the tumor microenvironment predicts recurrence risk in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Cancer Evolution: The Dynamics of Progression and Persistence; 2025 Dec 4-6; Albuquerque, NM. Philadelphia (PA): AACR; Cancer Res 2025;85(23_Suppl):Abstract nr B027.