Citations

7067 Background: High intensity induction with regimens such asDA-EPOCH-R, CODOX-M/IVAC-R and HyperCVAD are often used for young patients with DHL/THL despite no overall survival (OS) benefit compared to R-CHOP. Reports on the application of CODOX-M/IVAC-R are subject to selection bias as only young fit patients can tolerate it. We aimed to investigate outcomes difference between CODOX-M/IVAC-R and DA-EPOCH-R in patients ≤ 60 years with DHL/THL diagnosed via FISH. Methods: Retrospective review of DHL/THL patients from the Mayo Clinic diagnosed between July15th 2010-October19th 2023 treated with CODOX-M/IVAC-R or DA-EPOCH-R at age of up to 60 years. Event free survival (EFS) was defined as time from diagnosis to progression, relapse, next line of treatment or death from any cause. Results: 113 patients were included; CODOX-M/IVAC-R (N=49) and DA-EPOCH-R (N=64). Patient and disease characteristics are in table. 80% (N=39) achieved CR on end of treatment (EOT) PET CT with CODOX-M/IVAC-R compared to only 58% (N=37) with DA-EPOCH-R. CODOX-M/IVAC-R was associated with superior EFS on univariate (HR=0.54, 95%CI=0.31-0.97) and multivariable analysis adjusted for age, BCL2 vs BCL6 translocation and receipt of consolidation ASCT (aHR=0.53, 95%CI=0.29-0.95), however, there was no significant influence on OS (aHR=0.97, 95%CI=0.50-1.91). At a median follow-up of 5.3 years and 3.3 years for the CODOX-M-IVAC and DA-R-EPOCH group respectively; EFS was superior in the CODOX-M/IVAC-R group having 1, 2 and 5 years EFS of 68.3%, 64.1 and 61.5% respectively compared to 52.4%, 48.9% and 39.5% respectively in the DA-EPOCH-R group (p=0.035). 33%(16/49) of the CODOX-M/IVAC-R patients had R/R disease (No CR on EOT PET CT or relapsed) with a median OS of 10.3 months compared to 33.7 months in the R/R DA EPOCH-R group (54%, 35/64). Number of patients who were able to receive salvage ASCT, CAR T and Allo-SCT were 5, 17 and 4 respectively in the DA EPOCH-R group compared to 1, 6 and 3 patients respectively in the CODOX-M/IVAC-R group. None died of regimen toxicity in both groups. 19% underwent ASCT consolidation after CR with initial induction (11 patients in each group); no OS was noticed however consolidation with ASCT was associated with increased EFS regardless of the induction regimen with best outcomes being in the CODOX-M/IVAC-R group (P=0.0072). Conclusions: Our study showed that young patients with DHL/THL who received CODOX-M/IVAC-R had superior EFS compared to DA-EPOCH-R with no OS benefit. CODOX-M/IVAC-R can spare patients receiving more subsequent therapies. Patients who have R/R disease following CODOX-M/IVAC-R have poor outcomes. [Table: see text]

7050 Background: The management of Richter transformation (RT) of CLL represents an unmet clinical need. We previously reported modest efficacy of pembrolizumab monotherapy in an initial cohort of patients with RT (Ding, et al, Blood 2017). Here we report updated results of this trial, including an expansion cohort and a combination therapy cohort. Methods: Patients with biopsy proven RT to diffuse large B-cell lymphoma were enrolled and treated with single agent pembrolizumab (200 mg IV Q3W). Patients with progressive disease (PD) or stable disease (SD) after 3 months of pembrolizumab monotherapy were allowed to add a B-cell receptor (BCR) kinase inhibitor. The primary end point was overall response rate (ORR). Results: A total of 26 patients with RT were enrolled (9 in initial cohort and 17 in expansion cohort). The median age was 68.5 years. Ten (38%) patients had del(17p) or TP53 mutation. The median number of prior lines of therapy was 3 (range 1-10). Fifteen (58%) patients had received ibrutinib previously (14 of whom had PD on ibrutinib). With pembrolizumab monotherapy (n=26), the ORR was 23.1%, with 2 (7.7%) complete response (CR), 4 (15.4%) partial response (PR), and 7 (26.9%) SD. Of the 6 patients with confirmed CR or PR, responses occurred after a median of 2 cycles of monotherapy. The median duration of response (DOR) was 3.2 months (95% CI 2.8-NA). The median progression-free survival (PFS) was 2.6 months (95% CI 1.6-3.6). Sixteen patients went on to receive a BCR kinase inhibitor (ibrutinib [n=15], idelalisib [n=1]) in combination with pembrolizumab, after SD or PD on pembrolizumab monotherapy. The ORR to combination therapy was 62.5%, with 4 (25.0%) CR and 6 (37.5%) PR. Of the 10 patients with confirmed CR or PR to combination therapy, responses occurred after a median of 4 cycles of therapy. The median DOR was 4.5 months (95% CI 1.6-NA). The median PFS was 7.6 months (95% CI 2.3-13.3). After a median follow-up of 50.4 (95% CI 34.0-56.0) months, the median overall survival (OS) for all 26 patients with RT was 11.6 months (95% CI 7.5-20.1), and the 2-year OS rate was 27%. Treatment-related adverse events (TRAEs) of any grade occurred in 24 (92%) patients, including anemia (54%), thrombocytopenia (58%), neutropenia (54%), leukopenia (35%), lymphopenia (23%), dyspnea (23%), diarrhea (19%), and nausea (23%). Treatment-related grade 3 or above AEs occurred in 21 (81%) patients, including neutropenia (38%), leukopenia (31%), thrombocytopenia (27%), anemia (15%), febrile neutropenia (12%), and lung infection (12%). Conclusions: This expanded analysis confirmed that pembrolizumab has modest single agent activity in RT. Combination therapy with pembrolizumab and a BCR kinase inhibitor is associated with increased efficacy (ORR >60%), similar to other reports. These results support further investigation of immune checkpoint inhibitor-based combination therapy in RT. Clinical trial information: NCT02332980 .

LBA7005 Background: Despite recent advances, there remains a need for novel therapies for pts with R/R DLBCL. BV, an anti-CD30 antibody-drug conjugate, has shown efficacy and safety when combined with lenalidomide (len) and with rituximab (R) in heavily pretreated populations (Bartlett 2022; Ward 2022). The double-blind, global phase 3 ECHELON-3 study (NCT04404283) compared BV with R+len (R2) vs R2 in pts with R/R DLBCL who are ineligible for HSCT or CAR T-cell therapy. Here, we present results from the interim analysis (IA) for overall survival (OS). Methods: Pts with R/R DLBCL received BV+R2 or placebo+R2 (randomized 1:1). Pts received BV (1.2 mg/kg) or placebo q3w, R (375 mg/m2) q3w, and len (20 mg) qd. The primary endpoint was OS in the intent-to-treat population. Secondary endpoints were investigator-assessed progression-free survival (PFS), objective response rate (ORR), and complete response (CR) rate. The preplanned IA was performed at 134 OS events with a prespecified efficacy boundary of 2-sided P=0.0232. Results: 230 pts were randomized: 112 to BV+R2 and 118 to R2; all but 2 pts (both in R2 arm) received ≥1 dose of study drug. Median age was 71 yrs (range, 21-89), 56.5% were male, and 10.9% had an ECOG of 2. Median prior lines of therapy was 3 (range, 2-8); 29% had prior CAR T-cell therapy and 68% were CD30- (<1% CD30 tumor expression). At median follow-up of 16.4 months (mos) (range, 0.1-31.5) (cut-off: January 22, 2024), median OS was 13.8 mos (95% CI: 10.3-18.8) with BV+R2 vs 8.5 mos (95% CI: 5.4-11.7) with R2 (HR 0.629; 95% CI: 0.445-0.891; P=0.0085); OS benefit was consistent across key subgroups. Median PFS was 4.2 mos (95% CI: 2.9-7.1) with BV+R2 vs 2.6 mos (95% CI: 1.4-3.1) with R2 (HR 0.527; 95% CI: 0.380-0.729; P<0.0001). ORR was 64.3% (95% CI: 54.7-73.1) with BV+R2 vs 41.5% with R2 (95% CI: 32.5-51.0; P=0.0006); CR rate was 40.2% vs 18.6%, respectively. In CD30+ vs CD30- subgroups, ORR/CR was 72.2%/38.9% vs 60.5%/40.8% with BV+R2, respectively, and 50.0%/26.3% vs 37.5%/15.0% with R2, respectively. Efficacy analysis including cell of origin will be presented. The safety profile of BV+R2 was tolerable vs R2: Grade (Gr) ≥3 treatment-emergent adverse events (TEAEs) were 88% vs 77%, serious TEAEs were 60% vs 50%, and Gr 5 TEAEs were 12% vs 8%, respectively. Most common TEAEs were neutropenia (46% vs 32%), anemia (29% vs 27%), and diarrhea (31% vs 23%). Rates of peripheral neuropathy for BV+R2 vs R2 were 31% vs 24% (all Gr) and 6% vs 2% (Gr 3). Median treatment duration was 3.6 mos with BV+R2 vs 2.0 mos with R2. Conclusions: Treatment with BV+R2 triplet, compared to R2, demonstrated statistically significant and clinically meaningful improvements in all key efficacy outcomes including OS in high-risk subgroups, with manageable safety. This triplet regimen represents a novel treatment option for pts with heavily pretreated R/R DLBCL. Clinical trial information: NCT04404283 .

2087 Background: PCNSL is a rare and aggressive form of NHL in the central nervous system or vitreoretinal space. Despite high initial rates of responses to HD-MTX-based induction chemotherapies, most patients relapse in two years. R/R PCNSL is associated with poor prognosis, representing a clear unmet medical need, as there are no currently approved treatments for this disease. IRAK4 kinase activity is required for TLR and IL-1R signaling in a variety of myeloid and lymphoid cell types, including PCNSL. Recruitment of IRAK4 to these receptors and subsequent activation is facilitated by the MyD88 adaptor protein, which is mutated in ~70% of PCNSL. This leads to constitutive activation of the NF-κB signaling pathway, increased inflammation, and tumor growth. Emavusertib is a novel and potent oral inhibitor of IRAK4 and FLT3, which has demonstrated the ability to cross the blood-brain barrier in PCNSL xenografts. In preclinical studies, the combination of emavusertib with ibrutinib overcomes resistance to BTK inhibitors. This combination has an acceptable safety profile across a broad population of R/R NHL patients, including PCNSL. Here we present updated safety and efficacy data for emavusertib in combination with ibrutinib in patients with R/R PCNSL. Methods: The safety, clinical activity, and potential biomarkers of emavusertib in R/R PCNSL are being investigated in the ongoing open-label, Phase 1/2 TakeAim Lymphoma trial (NCT03328078). The eligible patients with R/R PCNSL received emavusertib (100-300 mg BID) in combination with ibrutinib (560 mg QD) in a 21-day cycle until tumor progression or unacceptable toxicity. Results: Here, we present updated data from R/R PCNSL patients with prior ibrutinib exposure who were treated with emavusertib in combination with ibrutinib. The median number of prior lines of anti-cancer therapies was 3 (range: 2-5), all patients were R/R to both frontline therapy and subsequent ibrutinib regimens. Prior responses to ibrutinib based regimens included only 1 CR. Here, we report a higher CR rate when these patients are subsequently treated with emavusertib in combination with ibrutinib.Results revealed no dose-limiting toxicities. Conclusions: Emavusertib in combination with ibrutinib was well tolerated with an acceptable safety profile and promising efficacy in R/R PCNSL patients with previous exposure to ibrutinib (BTKi). Enrollment in this trial is ongoing (NCT03328078). Clinical trial information: NCT03328078 .

Abstract Patients with large B-cell lymphoma (LBCL) that fail to achieve a complete response (CR) or who relapse early after anthracycline-containing immunochemotherapy (IC) have a poor prognosis and are commonly considered to have “primary refractory disease.” However, different definitions of primary refractory disease are used in the literature and clinical practice. In this study, we examined variation in the time to relapse used to define refractory status and association with survival outcomes in patients with primary refractory LBCL in a single-center prospective cohort with validation in an independent multicenter cohort. Patients with newly diagnosed LBCL were enrolled in the Molecular Epidemiological Resource cohort (MER; N = 949) or the Lymphoma Epidemiology of Outcomes cohort (LEO; N = 2755) from September 2002 to May 2021. Primary refractory LBCL was defined as no response (stable disease [SD]) or progressive disease (PD) during, or by the end of, frontline (1L) IC (primary PD; PPD); partial response at end of treatment (EOT PR); or relapse within 3 to 12 months after achieving CR at EOT to 1L IC (early relapse). In the MER cohort, patients with PPD had inferior overall survival (OS; 2-year OS rate: 15% MER, 31% LEO) when compared with other subgroups considered in defining primary refractory disease, EOT PR (2-year OS rate: 38% MER, 50% LEO) and early relapse (2-year OS rate: 44% MER, 58% LEO). Among patients receiving 1L IC with curative intent, we identified that patients with PPD are the key subgroup with poor outcomes. We propose a definition of primary refractory LBCL as SD or PD during, or by the end of, 1L treatment.

Abstract Introduction: Chimeric antigen receptor T-cell (CAR-T) therapy is an established treatment modality for the management of refractory and/or relapsed non-Hodgkin lymphoma (NHL). Despite restrictions on granulocyte colony-stimulating factor (G-CSF) use in registration clinical trials due to potential worsening of cytokine release syndrome (CRS), G-CSF is often prescribed for neutrophil recovery post-CAR-T in clinical practice. We conducted a retrospective study to assess the association between G-CSF use and the safety and efficacy of CAR-T. Methods: Following Institutional Review Board approval, we retrospectively analyzed NHL patients receiving commercial CD19-targeted CAR-T across Mayo Clinic sites (Arizona, Florida, and Minnesota) between October 2017 and May 2023. Demographics, labs, and post CAR-T events were collected. Electronic medical records were reviewed for G-CSF exposure within Day 1 - 100 post-CAR T. Differences by G-CSF status were examined using a Chi-square test and Kruskal Wallis tests. Hazard ratios (HR) and 95% confidence intervals (CI) for overall survival (OS) were calculated using Cox model. Results: Among 270 CAR-T patients; 106 received G-CSF within 30 days and 164 did not. Median age was 56.9 with G-CSF and 58.3 without G-CSF. Most were male (75.2% G-CSF, 62.6% no G-CSF). Diffuse large B cell lymphoma was the predominant NHL subtype (67.0% G-CSF, 65.2% no G-CSF). G-CSF within 30 days was not associated with reduced incidence of neutropenic fever (11.7% G-CSF vs 9.9% no G-CSF, p = 0.6593) or documented infection (22.1% vs 18.3%, p = 0.4439). G-CSF correlated with decreased profound neutropenia duration (ANC &lt; 100 μL, 0 vs 2 days, p &lt; 0.0001) and incidence within 30 days ( 31.7% vs 60.4%, p &lt; 0.0001) as well as incidence of protracted profound neutropenia (&gt; 7 days, 3.8% vs 22.8%, p &lt; 0.0001). G-CSF was associated with a higher incidence of cytopenias between days 30 -100: severe neutropenia (ANC &lt; 500/uL, 28.8% vs 15.2%, p = 0.0075), severe anemia (Hb &lt; 8 g/dL, 21% vs 9.7%, p = 0.0114), and severe thrombocytopenia (Plt &lt; 50 g/L, 35.2% vs 20.9%, p = 0.0099). Logistic regression analysis showed that none of the examined covariates, including prior autologous stem cell transplant, ECOG PS score, and receipt of bridging therapy, were associated with severe neutropenia likelihood. G-CSF was associated with a higher CRS incidence (89.6% vs 79.9%, p = 0.0343), but grade 3 CRS or higher (4.7% vs 3.7%, p = 0.6675) was no different. No difference in complete response rates (66% vs 61.1%, p = 0.4707) or 2-year OS (p = 0.523) was observed between the 2 groups. Conclusion: G-CSF within 30 days was associated with reduced duration and incidence of profound neutropenia without a significant impact on incidence of neutropenic fever or documented infections. There was a signal of association between G-CSF and increased incidence of low-grade CRS and delayed cytopenias (day 30-100) that warrants confirmation in larger studies. Citation Format: Lay She Ng, Claire I. Yee, Radhika Bansal, Mohamed A. Kharfan-Dabaja, Grzegorz S. Nowakowski, Allison C. Rosenthal, Javier Munoz, Januario Castro, Wern Lynn Ng, Hemant S. Murthy, Yi Lin, Matthew R. Buras, Madiha Iqbal, Yucai Wang, Talal Hilal. Impact of G-CSF on safety and efficacy of CAR T-cell therapy in non-Hodgkin lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6327.

The 2023 Precision Oncology Summit was organized by Binaytara foundation in San Francisco on October 7 th and 8 th . The conference’s theme was the advances in precision oncology and future directions to move away from a one-size-fits-all model to improve outcomes. This manuscript outlines the proceedings of the hematology-focused session during the conference.

PURPOSE Limited evidence exists regarding methotrexate (MTX) resumption after patients with lymphoma receive glucarpidase for toxic MTX levels and acute kidney injury (AKI). METHODS This retrospective review included adults with lymphoma treated with glucarpidase after MTX at Mayo Clinic between January 31, 2020, and October 10, 2022. Descriptive statistics summarize patient characteristics and clinical outcomes. RESULTS Of 11 patients treated with glucarpidase after MTX, seven (64%) were rechallenged with MTX. Indications for MTX rechallenge included confirmed CNS disease (n = 6, 86%) and intravascular lymphoma (n = 1, 14%). Compared with the nonrechallenged subgroup, before receiving MTX that required glucarpidase rescue, the rechallenged patients had lower median pretreatment serum creatinine (Scr; 0.7 v 1.2 mg/dL), and none had AKI with previous MTX doses, n = 0 (0%) versus n = 2 (50%). During the MTX dose requiring glucarpidase rescue, the rechallenged group had lower median peak Scr (1.26 v 3.32 mg/dL) and lower incidence of AKI stage III (n = 1 [14%] v n = 3 [75%]), and none of the rechallenged patients required renal replacement therapy (RRT; n = 0 [0%] v n = 1 [25%]). At the first rechallenge after glucarpidase administration, the median MTX dose reduction was 56% (range, 46%-75%), and the lowest used dose when prescribed according to each treatment protocol schedule was 1.5 g/m2. Two (29%) patients experienced AKI (n = 1 stage I, n = 1 stage II) after MTX rechallenge. Zero patients required RRT, and zero required another glucarpidase administration. Six (86%) patients completed all recommended MTX doses. CONCLUSION In selected adults with lymphoma who required glucarpidase for toxic MTX levels after administration of high-dose MTX, resumption of MTX therapy at lower doses is safe. Patients selected for MTX resumption had experienced less severe AKI during the previous cycle compared with those not selected for MTX resumption.

Abstract Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is considered the standard-of-care for patients with advanced-stage diffuse large B-cell lymphoma (DLBCL), despite findings that patients with nongerminal center B-cell like (non-GCB) have significantly worse outcome with this regimen. We evaluated the prognostic significance of baseline risk factors, including cell of origin (COO) classified by the Hans algorithm, within an alternative chemoimmunotherapy program. At Memorial Sloan Kettering Cancer Center (MSK), 151 patients with DLBCL received sequential R-CHOP induction and (R)-ICE (rituximab, ifosfamide, carboplatin, and etoposide) consolidation. Outcome analysis based on COO was validated with a propensity score–matched cohort treated with R-CHOP from the Mayo Clinic component of the Molecular Epidemiology Resource (MER). Among the patients with GCB (n = 69) and non-GCB (n = 69) at MSK, event-free survival (EFS) of non-GCB was superior to that of GCB (hazard ratio [HR], 0.53; 95% confidence interval [CI], 0.29-0.98). Overall survival (OS) demonstrated an association in the same direction but was not statistically significant (HR, 0.68; 95% CI, 0.33-1.42). Propensity score–matched patients from MSK (n = 108) demonstrated a small attenuation in the HRs for EFS (HR, 0.57; 95% CI, 0.27-1.18) and OS (HR, 0.76; 95% CI, 0.33-1.79) and were no longer statistically significant. In contrast, the matched MER cohort (n = 108) demonstrated an EFS association (HR, 1.17; 95% CI, 0.70-1.95) and OS association (HR, 1.13; 95% CI, 0.64-2.00) in the opposite direction, but were also not statistically significant. R-CHOP induction and (R)-ICE consolidation may overcome the negative prognostic impact of the non-GCB phenotype, per the Hans algorithm, and can be preferentially selected for this population. This trial was registered at www.ClinicalTrials.gov as #NCT00039195 and #NCT00712582.

Background Patients with peripheral artery disease are at increased risk for major adverse cardiac events, major adverse limb events, and all‐cause death. Developing tools capable of identifying those patients with peripheral artery disease at greatest risk for major adverse events is the first step for outcome prevention. This study aimed to determine whether computer‐assisted analysis of a resting Doppler waveform using deep neural networks can accurately identify patients with peripheral artery disease at greatest risk for adverse outcome events. Methods and Results Consecutive patients (April 1, 2015, to December 31, 2020) undergoing ankle–brachial index testing were included. Patients were randomly allocated to training, validation, and testing subsets (60%/20%/20%). Deep neural networks were trained on resting posterior tibial arterial Doppler waveforms to predict major adverse cardiac events, major adverse limb events, and all‐cause death at 5 years. Patients were then analyzed in groups based on the quartiles of each prediction score in the training set. Among 11 384 total patients, 10 437 patients met study inclusion criteria (mean age, 65.8±14.8 years; 40.6% women). The test subset included 2084 patients. During 5 years of follow‐up, there were 447 deaths, 585 major adverse cardiac events, and 161 MALE events. After adjusting for age, sex, and Charlson comorbidity index, deep neural network analysis of the posterior tibial artery waveform provided independent prediction of death (hazard ratio [HR], 2.44 [95% CI, 1.78–3.34]), major adverse cardiac events (HR, 1.97 [95% CI, 1.49–2.61]), and major adverse limb events (HR, 11.03 [95% CI, 5.43–22.39]) at 5 years. Conclusions An artificial intelligence–enabled analysis of Doppler arterial waveforms enables identification of major adverse outcomes among patients with peripheral artery disease, which may promote early adoption and adherence of risk factor modification.