Iqbal, Madiha

Abstract Allogeneic stem cell transplant (ASCT) remains the only curative option in chronic myelomonocytic leukemia (CMML). We retrospectively analyzed 138 CMML patients who underwent ASCT at the Mayo Clinic. Patients who transitioned to ASCT while in chronic phase (Group A) displayed superior post-transplant survival (PTS), compared to those in whom ASCT was performed after blast transformation (BT; Group B) (median 95 vs. 16 months; p=0.01). In Group A, PTS was superior in patients with <5% bone marrow (BM) blasts at time of ASCT (median 164 vs. 13.5 months; p=0.01). Other predictors of superior PTS included day-100 BM blast <5% or normal cytogenetics (median 164 vs 18 months; p=0.01) or presence of chronic graft-versus-host-disease (GVHD; median 164 vs. 26 months; p=0.01). Pre-ASCT hypomethylating agent exposure (HR=2.03; p=0.03), and receiving more than one line of pre-ASCT chemotherapy (p=0.01) predicted inferior PTS. In multivariable analysis, predictors of superior GVHD-free and relapse-free survival (GRFS) included the use myeloablative conditioning and the absence of morphologically or cytogenetically apparent disease at day-100. The use of post-transplant cyclophosphamide (PTCy) was associated with higher cumulative incidence of relapse (p=0.02) and numerically inferior PTS (p=0.1). Group B patients also appeared to benefit from achieving BM blast <5% at time of ASCT (p=0.4) as well as at day-100 (p=0.01), in terms of PTS, while full chimerism and normal cytogenetics at day-100 were associated with superior GRFS. These observations support the value of ASCT in CMML, especially if performed prior to BT and in the presence of <5% BM blasts at time of ASCT. Additionally, the observed detrimental impact of PTCy requires additional studies to confirm and investigate the underlying mechanisms.

9029 Background: Addressing guideline concordant FP and TPP with cancer is challenging, especially for OT. SIM, a well-known education tool, has not been traditionally used to teach these topics. As part of the hematology/oncology fellowship curriculum, we designed a SIM applying LSP to bridge this educational gap. Methods: Applying LSP of contrasting cases, elaboration, feedback, generation and just-in-time telling, chief OTs and faculty designed a SIM with 3 clinical scenarios (CS) and 3 standardized pts (SP): FP for a female pt hospitalized for acute lymphoblastic leukemia tx, FP for a male pt in clinic for germ cell tumor tx, and breast cancer tx for a pregnant pt in 2 nd trimester. OT received written educational materials (WEM) and attended a lecture 1 week and 1 day pre SIM, respectively. OT were split into 2 groups; 1 started in the FP CS and 1 in the TPP CS, and then they switched. To reduce cognitive overload, each OT participated in 1 of 2 FP CS: half in the female FP CS and half in the male. Faculty and chiefs led debriefing sessions after all CS. The FP debrief ended with a special “learner as a teacher” part, where OT who attended the female CS taught those from the male CS about their topic and vice versa. The SIM concluded with "take-home" points. Pre (after having WEM) and post SIM anonymous surveys and verbal feedback assessed OT comfort, perceptions, and knowledge. Results: A 3 hour SIM with 14 OT and 5 faculty was completed successfully. SIM ended with all OT verbally sharing a learning point and positive feedback. All OT filled pre and post SIM surveys. Pre SIM, 17% reported having prior FP education, and 42% had prior TPP education. However, only 8% and 25% felt adequately prepared for FP and TPP discussions, respectively. Post SIM survey showed major improvement in comfort and knowledge about FP and TPP (see table 1). 75% of OT favored a combination of SIM and learning by teaching over other SIM formats. 83% supported having a TPP lecture before SIM. 100% reported satisfaction with FP and TPP SIM’s quality and wanted similar activities in the future. 92% were satisfied with the learner as a teacher tool. 100% felt education about FP and TPP with cancer should be part of fellowship training. Moral/cultural concerns were discussed as possible challenges in FP education. Conclusions: The application of LSP through SIM significantly increased OTs’ comfort discussing FP and TPP with cancer, and objectively enhanced their knowledge on these topics compared to after reading WEM. The SIM was largely perceived as a successful activity to educate about challenging topics and should become part of fellowship curriculum. Pre SIM % Post SIM % Comfortable addressing FP 17 92 Comfortable addressing TPP 8 100 Correct answers about female FP 63 83 Correct answers about male FP 67 94 Correct answers about TPP with cancer 68 98

Abstract Allogeneic hematopoietic stem cell transplant (alloHCT) is considered for all patients with myeloid neoplasms (MNs) harboring TP53 mutations (TP53mut). The aim of this international study across 7 transplant centers in the United States and Australia was to identify factors associated with improved post-alloHCT survival. Of 134 TP53mut MN cases who underwent alloHCT, 80% harbored complex karyotype; 94% of TP53 variants were localized to the DNA-binding domain (DBD). Most common comutations were ASXL1 (7%), TET2 (7%), and DNMT3A (6%). Median post-HCT survival was 1.03 years, and overall survival (OS) at 1 year, 2 years, and 3 years was 51.4%, 35.1%, and 25.1%, respectively. A total of 103 cases (76.9%) met the International Consensus Classification (ICC) criteria for MN with mutated TP53 (referred to as ICC-defined TP53mut MN hereafter). The 3-year OS of ICC-defined TP53mut was significantly shorter compared with that of other TP53mut MNs (3-year OS, 16.9% vs 54.9%; P = .002). ICC-defined TP53mut MNs was independently associated with inferior OS (hazard ratio [HR], 2.62; P = .019). The presence of non-DBD TP53mut only (HR, 3.40; P = .005), DNMT3A comutation (HR, 2.64; P = .016), and pre-alloHCT bone marrow blasts ≥5% (HR, 2.76; P = .006) was independently associated with inferior relapse-free survival (RFS), whereas melphalan-based conditioning was associated with superior RFS (HR, 0.52; P = .005). Combining these variables, we constructed a hierarchical model that stratified patients into low-, intermediate-, and high-risk categories with 1-year RFS of 81.3%, 31.3%, and 6.7%, respectively (P &lt; .001). In conclusion, a subset of MN harboring TP53mut who have low blasts pre-alloHCT and received melphalan-based conditioning derived long-term benefit from alloHCT.

Introduction Chimeric antigen receptor T-cell therapy (CART) has revolutionized the treatment algorithm of relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (NHL). However, approximately only 40% of cases achieve long-term durable remissions. Prognostication remains important as it would allow more precise prediction of outcomes and develop a personalized treatment approach. Currently, it is unclear whether prognostic factors that have been predictive of outcomes in the pre-CART era, remain important in the current era. We conducted a single center observational study to assess the prognostic significance of extra nodal involvement (ENI) on long-term outcomes following CART in B-cell NHL. Methods The primary aim was to evaluate the prognostic significance of ENI on long-term outcomes in patients with B-cell NHL treated with CART. The second aim was to specifically evaluate the impact of gastrointestinal (GI) involvement. Continuous variables were summarized as median (range) and categorical variables were reported as frequency (percentage). Kaplan-Meier method was used to estimate freedom from events at different time points and draw corresponding survival curves. Log-rank test was used to compare freedom from events between histology groups. Results 74 patients were included in this analysis, with a median age of 62 (18-85) years. Fifty-three (72%) had evidence of ENI. Twenty-four (47%) had GI involvement as the sole site of ENI or with other sites of ENI. Forty-three (58%) patients were male and diffuse large B-cell lymphoma (DLBCL) was the most common histology (n=50 [54%]) followed by transformed follicular lymphoma (n=20 [27%]). Most patients had advanced stage disease at time of CART (n=71 [96%]) and 3 (4%) had CNS involvement at any time prior to CART. Median number of prior lines of systemic treatment were 2 (1-7) and 64 (87%) had progressive disease at time of CART. Axicabtagene ciloleucel was the most used CART product (n=68 [92%]); Grade 3-4 cytokine release syndrome was reported in 6 (8%) patients and grade 3-4 immune effector cell associated neurotoxicity syndrome was reported in 13 (18%) patients. ICU level of care was needed in 22 (30%) patients and 2 patients (3%) developed hemophagocytic lymphohistiocytosis-like syndrome. Sixty patients (87%) achieved an objective response and 34(49%) achieved a complete response. The 1-year OS was 66% (53-81) in patients who had ENI vs. 72% (54-97) in those without ENI (p=0.82); 1-year relapse rates were at 39% (20-54) vs. 36% (10-54) (p=0.95) for patients with ENI vs. those without ENI. No difference was noted between the two groups regarding progression-free survival and non-relapse mortality (NRM). No difference in outcomes was observed when patients who had GI involvement as the only site of ENI or in combination with other sites of ENI were compared to those who did not have GI involvement as one of the sites of ENI. Elevated LDH at the time of CART (HR 2.27 [95% CI 1.05-4.94], p=0.03), development of any grade ICANS (HR 2.77 [95% CI 1.27-6.04], p=0.01) and requirement for ICU level of care (HR 3.25 [95% CI 1.54-6.86], p=0.002) adversely affected OS; the impact of elevated LDH on OS remained significant in multivariate models (HR 2.34 [95% CI 1.05-5.27], p=0.04). Development of any grade CRS was associated with a decreased risk of relapse (HR 0.25 [95% CI 0.11-0.56], p=&lt;0.001) and the requirement of ICU stay adversely affected NRM (HR 2.27 [95% CI 1.05-4.94], p=0.032). Conclusion These results suggest that ENI does not appear to be predictive of long-term outcomes in the setting of CART therapy. Patients who had ENI appeared to derive equal benefit from CART therapy. GI involvement as a site of ENI has been known to be associated with worse survival when compared to other sites of ENI but we did not observe any difference in this subgroup also. Evolving predictive models and/or biomarkers that take in account the dynamics of the interaction between the malignant and CART cells might help better inform prognostication in the current era.

Introduction: CAR-T (chimeric antigen receptor T-cell) therapy is known to be associated with immune-mediated toxicities including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). [18F]-Flurodeoxyglucose-positron emission tomography (FDG-PET) is frequently utilized for cancer staging before and after CAR-T therapy. Case series have demonstrated cerebral glucose hypometabolism (CGHM) on FDG-PET imaging in patients who developed CRS and ICANS. In this study, we aim to further characterize CART-CGHM. Methods: Patients who received CAR-T therapy at our institution from October 2019 to December 2023 were included. Clinical data was collected from retrospective review of the electronic medical record including patient age, sex, diagnosis, cancer stage, development of CRS or ICANS, and survival outcome. Standard of care whole body FDG-PET scans obtained before and approximately 30 days post CAR-T therapy were utilized. FDG-PET images of the brain were sub-selected and processed with dedicated imaging software (GE AW server 3.2 with Cortex ID, MIM Neuro, version 7.2.7). To identify CART-CGHM, visual and statistical comparison was made between the pre-CAR-T FDG-PET and the post-CAR-T FDG-PET using the age and gender matched normal cohort in the database as controls. Z-score changes &gt; 1.5 were considered significant. Baseline variables were reported as frequency (%) and compared between patients with and without CGHM using Chi-squared test. Kaplan-Meier method was used to estimate the overall survival rate (OS) at different time points and log rank test was used to compare survival rates between the groups with and without CGHM. Multivariable Cox regression model was performed to evaluate the association between CGHM and OS with adjustment for ICANS. All tests were two-sided with p&lt;0.05 considered statistically significant. Results: In total, 84 patients (41 women, 49%) were included. The median age at time of CAR-T therapy was 66 (33-85) years old. The most common diagnosis was multiple myeloma (n=39, 46%) followed by diffuse large B-cell lymphoma (n=33, 39%), follicular lymphoma (n=7, 8%), mantle cell lymphoma (n=3, 4%), and B-cell acute lymphoblastic leukemia (n=2, 2%). CART-CGHM was identified in 27 patients (32%). The pattern of CGHM was either global (n=15, 56%) or focal (n=12, 44%) with the prefrontal cortex predominantly affected. Of these 27 patients with CART-CGHM, 17 patients (63%) experienced ICANS and 23 patients (85%) experienced CRS. The diagnosis of lymphoma and development of ICANS were significantly associated with CGHM (p- 0.038 and &lt;0.001 respectively). On univariate analysis, CGHM and ICANS were associated with negative impact on OS. The post-CAR-T 12-month OS for patients with CGHM was 76% versus 84% without CGHM (p-0.016), and 12-month OS for patients with ICANS was 64% versus 91% without ICANS (p-0.001). The post-CAR-T median OS for patients with CGHM, patients with ICANS, and patients with both CGHM and ICANS were 17.1 months, 13.5 months, and 12.6 months, respectively. On multivariate analysis, after adjusting for ICANS, CGHM alone did not have an impact on OS [HR 1.76 (0.71, 4.37); p-0.2250] but ICANS continued to have a negative impact on OS [HR 3.03 (1.21, 7.57); p-0.0178]. Conclusions: Our study represents the largest study to date on CART-CGHM. CART-CGHM was seen in 32% of CAR-T patients and had a strong association with ICANS and lymphoma patients. ICANS was found in 63% of CART-CGHM patients. ICANS alone or CGHM with ICANS were associated with a negative impact on OS. Although the underlying biological mechanism of CART-CGHM is not clear, it likely represents a significant immune-mediated reduction in cerebral glucose uptake. We suggest that CGHM represents a novel metabolic complication of CAR-T therapy and significantly contributes to CAR-T therapy associated neuro-cognitive toxicity. Although CART-CGHM can resolve completely, our study also showed patients with persistent CGHM on post-CART follow up FDG-PET scans. As such, CART-CGHM can potentially result in chronic neuro-cognitive complications. The current therapeutic interventions for CRS and ICANS do not appear to be adequately effective for CART-CGHM. Further research, involving multiple institutions, is urgently needed for better understanding of CART-CGHM and to develop specific therapeutic interventions.

Introduction: Outcomes from multidisciplinary lymphoma tumor boards in the molecular era are limited, and the effects of transitioning to virtual formats during the COVID-19 pandemic are not well-documented. This study evaluates how the transition of the Mayo Clinic Lymphoma Tumor Board to a virtual format has impacted its effectiveness and operations. The board, part of the International Mayo Clinic Care Network (MCCN), involves case presentations, subspecialist reviews, and collaborative recommendations. Methods: The Mayo Clinic Lymphoma Tumor Board, an integral part of the Mayo Clinic Care Network (MCCN), conducted a comprehensive review of lymphoma cases from 2014 to 2024. The board's review process involves a structured approach including the presentation of clinical case details, radiology and hematopathology findings, proposed treatment options, relevant literature review, and discussions. From 2014 to 2024, the Mayo Clinic Lymphoma Tumor Board reviewed a total of 722 patients. The review process involves a multidisciplinary team, including physicians, pharmacists, clinical research associates, and trainees. Recommendations and changes related to radiology interpretation, pathologic diagnosis, and treatment approaches were documented and tracked prospectively. In March 2020, the board transitioned to a virtual format due to the COVID-19 pandemic. This shift allowed for remote participation and continued collaborative review while maintaining the board's structured approach and documentation practices. Results: In a total of 722 patients, changes in care were identified in 423 patients, including 287 with newly diagnosed lymphoma and 136 with relapse or refractory disease. Among those who experienced changes, 94 had diffuse large B-cell lymphoma, 49 had follicular lymphoma, 39 had marginal zone lymphoma, 36 had classical Hodgkin lymphoma, and 29 had mantle cell lymphoma. Prior to the COVID-19 pandemic, 431 patients were analyzed, with 217 (50.3%) experiencing changes. A total of 268 changes were documented among these patients. Changes in radiologic interpretation occurred in 9 patients (2.1% of 431 total patients). Pathologic diagnosis changes were noted in 42 patients (9.7%). Additional testing was recommended for 73 patients (16.9%), and clinical management was altered for 144 patients (33.4%). After transitioning to a virtual format, 291 patients were reviewed post-COVID, with 206 (70.8%) having recommended changes. The total number of change recommendations was 322, reflecting increases across all components compared to previous data, with adjustments for varying numbers of patients reviewed. Specifically, radiologic interpretation changes occurred in 21 patients (7.2%), pathologic diagnosis changes in 57 patients (19.6%), additional testing recommendations for 85 patients (29.2%), and clinical management alterations in 159 patients (54.7%). Conclusion: Transitioning to a virtual format in the Mayo Clinic Lymphoma Tumor Board's continued to demonstrate the effectiveness, with increased changes in diagnostic interpretations and clinical management. These results illustrate the potential of virtual tumor boards to improve collaborative decision-making and adapt to evolving clinical needs.

Introduction: CD20xCD3 bispecific antibodies (BsAbs) represent a major advance in the treatment of relapsed or refractory (r/r) large B-cell lymphoma (LBCL). In their pivotal trials, epcoritamab (Epcor) and glofitamab (Glofi) showed an overall response rate (ORR) and complete response rate (CRR) of 52-63% and 39%, respectively, in patients (pts) with r/r LBCL after 2 or more prior lines of therapy (LOT). Data on the efficacy and safety of BsAbs in standard of care (SOC) setting is limited. Here, we report our multicenter retrospective study on SOC BsAbs for the approved indication in r/r LBCL. Methods: All pts who received SOC BsAbs for r/r LBCL at four cancer centers in Florida were included. Pts who died before the first response evaluation were considered to have disease progression. Median follow up time was calculated using reverse Kaplan Meier (KM) method. Univariate analysis (UVA) and multivariate analysis (MVA) of response rates were done using logistic regression. UVA and MVA of PFS and OS were done using Cox proportional hazard model. Median PFS (mPFS) and median OS (mOS) were estimated using KM method. Results: As of June 1, 2024, a total of 69 pts received SOC BsAbs for r/r LBCL (43 epcor and 26 glofi). Forty pts (58.0%) were male; median age was 66 years (range 32-89); ECOG &gt;= 3 in 14 (20.3%) pts; transformed indolent lymphoma in 20 (29.0%); Richter transformation in 3 (4.4%); HGBL with MYC/BCL2 rearrangements (double-hit lymphoma [DHL]) in 12 (17.4%); bulky disease&gt;10cm in 33 (47.8%); IPI score &gt;= 4 in 15 (21.7%). Pts received a median of 3 prior LOT (range 2-12); 46 (66.7%) had primary refractory disease; 40 (58.0%) received prior CD19 CAR-T therapy; 35 pts (50.7%) would not have met the inclusion criteria of the pivotal trials due to: ECOG&gt;=3 (n=14), thrombocytopenia (n=11), neutropenia (n=2), CNS involvement (n=6), recent infection (n=6), prior CAR-T within 30 days (n=1), and CrCL&lt;45 (n=2). Among the 69 pts, 65 were evaluable for response. At a median follow up of 7 months, the ORR and CRR were 52.3% and 26.2%, respectively. Median PFS was 4.2 months (m) (95%CI: 2.8-6.9). Median OS was 6.2m (95%CI: 5.9-not reached [NR]). The ORRs in pts without prior CAR-T (CART-naive), progressed after achieving CR/PR to prior CAR-T (CART-R), and not achieving CR/PR to prior CAR-T (CART-NR) were 13/25 (52.0%), 18/24 (75%), and 3/16 (18.8%), respectively, p&lt;0.01. In the UVA of ORR, the following factors were associated with lower response: CART-NR (18.8% vs 63.3%, p&lt;0.01) and ECOG &gt;=3 (21.4% vs 60.8%, p=0.01). Bulky disease, IPI &gt;=4, DHL, &gt;=4 prior lines of therapy, DLBCL subtype or BsAb type was not associated with response. In MVA, only CART-NR was a significant predictor of lack of response to BsAb (odds ratio 5.6, 95%CI: 1.3-24). In the UVA of PFS, CART-NR and ECOG &gt;=3 were associated with shorter mPFS (1.9m [95%CI: 0.6-3] vs 5.4m [95%CI: 4.0-NR] in CAR-T non-responders vs responders; 1.1m [95%CI: 0.4-3.2] vs 5.4m [95%CI: 3.2-NR] in ECOG&gt;=3 vs &lt;3). In the MVA, CART-NR and ECOG&gt;=3 were associate with shorter PFS (HR 2.7, p&lt;0.01 and 2.5, p&lt;0.02, respectively). One of the 3 pts with Richter transformation had continuous PR at 5 months. Cytokine release syndrome (CRS) occurred in 21 pts (36.2%), including 4 (5.8%) grade (Gr) &gt;= 3. Immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 12 pts (17.4%) with 6 (8.7%) Gr &gt;= 3. Gr3-4 neutropenia was observed in 18 pts (26.1%); Gr3-4 thrombocytopenia in 10 (14.5%). Infection all grades and Gr &gt;= 3 occurred in 26 pts (37.7%) and 19 pts (27.5%), respectively. Among them, bacterial infection was identified in 13, COVID in 5, fungal in 2, and CMV in 1 patient. Conclusion: BsAbs had comparable efficacy in SOC setting as in the pivotal trials. CRS and ICANS were mostly low-grade; however, a high incidence of serious infection was observed. Pts with no response to prior CAR-T also had poor BsAbs response. This could reflect a common mechanism of resistance to immunotherapy, either due to tumor characteristics or host T-cell exhaustion. Longer follow-up is needed to evaluate the durability of response.

Background: Immunochemotherapy is the current standard-of-care frontline therapy for diffuse large B-cell lymphoma (DLBCL). Our group previously reported that addition of the mTOR inhibitor everolimus to R-CHOP resulted in excellent efficacy in the Alliance N1085 trial (Witzig TE et al, Blood Cancer J, 2017, 7(6):e576), with 23 of 24 patients achieving event-free survival at 24 months (EFS24), supporting further investigation of PI3K/mTOR targeting in DLBCL. New insights into molecular classification of DLBCL suggest that multiple genetic subtypes of DLBCL (eg, MCD, BN2, ST2, and EZB per LymphGen classification) may be susceptible to PI3K/mTOR targeting. Therefore, we conducted a phase 1/1b trial to investigate the safety and efficacy of combination therapy with a novel PI3K inhibitor parsaclisib and standard immunochemotherapy. Methods: Adult patients with newly diagnosed DLBCL were eligible if any of the following was present: 1) non-GCB subtype per the Hans algorithm; 2) protein expression of either MYC (≥40%) or BCL2 (≥50%) by immunohistochemistry; or 3) MYC rearrangement by FISH. Patients with high grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements were also eligible. Phase 1 followed a 3+3 design to determine the maximum tolerated dose (MTD) of parsaclisib (plus R-CHOP) to be used in Phase 1b (dose expansion). The primary efficacy endpoint in phase 1/1b was complete response (CR) rate by PET. A polatuzumab vedotin (Pola) safety lead-in cohort was added later to explore the safety and efficacy of parsaclisib (at MTD) plus Pola-R-CHP. Results: From July 2020 to May 2023, 50 patients were enrolled; 1 patient withdrew consent before study treatment and was excluded from this analysis. Nine patients were treated in Phase 1, 33 in Phase 1b, and 7 in the Pola cohort. The median age at diagnosis was 66 years (range 20-86), and 20 (41%) were female. Two (4%) patients had ECOG PS ≥2, 26 (53%) had elevated LDH, 19 (39%) had &gt;1 extranodal site, 37 (76%) had stage III/IV, and 25 (51%) had high-intermediate or high-risk International Prognostic Index (3-5). 23 (47%) had non-GCB subtype, 23 (46.9%) had MYC or BCL2 single expression, 21 (42.9%) had MYC/BCL2 double expression, and 6 (12%) had MYC rearrangement (2 with BCL2 and/or BCL6 rearrangements). In Phase 1, 3 patients were treated at dose level 1 (parsaclisib 20 mg QD, d1-10) and 6 at dose level 2 (parsaclisib 20 mg QD, d1-14). No dose limiting toxicity was observed. Therefore, dose level 2 for parsaclisib was the MTD and was used in Phase 1b. In the Pola cohort (n=7), only 1 of 6 evaluable patients experienced significant toxicity (grade 3 diarrhea). Among all 49 patients, the most common treatment-related adverse event (TRAE) of any grade included neutropenia (83.7%), thrombocytopenia (79.6%), leukopenia (77.6%), lymphopenia (71.4%), anemia (71.4%), nausea (63.3%), fatigue (40.8%), peripheral sensory neuropathy (36.7%), constipation (24.5%), and diarrhea (22.4%), and the most common grade ≥3 TRAE included neutropenia (71.4%), leukopenia (69.4%), lymphopenia (49.0%), thrombocytopenia (20.4%), anemia (16.3%), febrile neutropenia (6.1%), and diarrhea (6.1%). In Phase 1/1b (n=42), the overall response rate (ORR) to parsaclisib plus R-CHOP was 97.6%, and the CR rate was 90.5%. After a median follow-up of 28.5 months (95% CI 27.7-32.7), the estimated 2-year progression-free survival (PFS) rate was 84.6% (95% CI 73.9-96.8), and the estimated 2-year overall survival (OS) rate was 95.1% (95% CI 88.7-100.0). In the Pola cohort, the ORR to parsaclisib plus Pola-R-CHP was 100% and the CR rate was 100%. After a median follow-up of 15.6 months (95% CI 13.5-NE), 1 patient had disease relapse at 11.95 months, and all patients were alive. Conclusions: Addition of the PI3K inhibitor parsaclisib to R-CHOP or Pola-R-CHP immunochemotherapy is considered safe in patients with newly diagnosed DLBCL. Combination of parsaclisib and standard immunochemotherapy resulted in high ORR and CR rate and encouraging preliminary PFS and OS outcomes patients with high-risk DLBCL. These data support further investigation of PI3K/mTOR targeting in newly diagnosed DLBCL in future trials.

Background: CD19-directed chimeric antigen receptor T-cell (CAR-T) therapy is an established treatment with high efficacy in treating relapsed or refractory (R/R) mantle cell lymphoma (MCL). However, with CAR-T therapy, refractory disease occurs and a continuous pattern of relapse over time has been observed. Limited data exist about post-CAR-T progression of disease (POD) management and outcomes in MCL. Such data would meaningfully inform practice and set a critical benchmark for future studies in the post-CAR-T setting. We characterized treatment patterns and outcomes for pts with POD after CD19 CAR-T therapy for R/R MCL. Methods: We queried institutional databases to identify pts with R/R MCL who received CD19-directed CAR-T therapy. Treatment may have occurred as standard-of-care or in a clinical trial. We performed chart review to extract variables and categorized therapies by mechanism(s) of action. We used descriptive statistics to characterize patient/disease characteristics and treatment patterns, the reverse Kaplan-Meier method to calculate follow-up, the Kaplan-Meier method to calculate survival, and Cox proportional hazards to associate clinical and disease features with survival outcomes. Results: Across 9 sites, we identified 306 pts who received CD19 CAR-T for R/R MCL, of which 104 (34%) experienced POD and were investigated in detail: pts with POD were mostly men (73%), had a median age of 67 yrs (range 36-86) at infusion, and had received a median of 3 lines of therapy pre-leukapheresis, including a BTK inhibitor (BTKi) in 97% of patients; 36% of BTKi-exposed patients had BTKi-unresponsive disease. High-risk tumor features were common pre-CAR-T: 47/68 (69%) with a TP53 mutation, 66/93 (71%) with Ki67 ≥50%, and 47/102 (46%) with blastoid/pleomorphic MCL. Most pts (75%) received bridging therapy. Pts received brexucabtagene autoleucel (88%) or lisocabtagene maraleucel (12%). Regarding best CAR-T response for pts with POD, 71% had a complete response (CR), 13% partial response (PR), and 15% had no response. The median time from CAR-T infusion to POD was 6 months (IQR 3-12). At time of POD, high-risk MCL features were again common: 55% blastoid/pleomorphic, 42/56 (75%) Ki67 ≥50%, 51/83 (61%) MIPIb high-risk, and 21/35 (60%) TP53-mutated MCL. Among 69 pts with CD19 assessed on a post-POD biopsy, 8 (12%) had CD19-negative disease. 30% of pts had an ECOG performance status of ≥2 at time of POD. After POD occurred, 15 pts received no anti-lymphoma therapy (Tx), 11 pts underwent excision or radiation, and 78 pts received systemic therapy. The most commonly used first-line systemic Tx post-CAR-T progression included: pirtobrutinib in 13 pts [overall response rate (ORR) 31%], chemoimmunotherapy in 12 pts (ORR 25%), venetoclax in 10 patients (ORR 20%), bispecific antibodies (BsAb) in 10 pts (ORR 60%), and small molecule combinations (at least 2 of BTK inhibitor, BCL2 inhibitor, and lenalidomide) in 8 patients with ORR 50%. The ORR to all first systemic Tx post-POD was 42%. The median follow-up from POD is 15.2 months among survivors. The median progression-free and overall survival (OS) from time of POD were 2.3 (95% CI 1.9-3.4) and 5.4 months (95% CI 4.5-9.4), respectively, and 1-year OS rate was 33%. TP53 mutations predicted inferior OS (HR 2.83, 95% CI 1.08-7.43, P = 0.026) as did age ≥65 years at time of POD (HR 1.83, 95% CI 1.07-3.15, P = 0.023), MIPIb high-risk (HR 3.56, 95% CI 1.08-11.7, P = 0.042), and non-response to CAR-T (HR 3.55, 95% CI 1.93-6.53, P &lt; 0.001). Discussion: Our data, the largest reported cohort of pts with POD post-CAR-T with R/R MCL, confirm the poor prognosis in this patient population, with a median OS of 5.4 months. BsAbs showed promise with an overall response rate of 60%. The presence of a TP53 mutation significantly predicted inferior OS, corroborating the prognostic importance of this finding in the post-CAR-T context. Data from pts treated at additional sites and updated analyses will be presented at the meeting.