Citations

Intro: Venous thromboembolism (VTE) is a common cause of death among cancer patients, second only to cancer progression. Identifying factors predicting worse outcomes among cancer patients with VTE would be useful clinically. For cancer patients with pulmonary emboli (PE), it remains unclear whether concomitant leg deep vein thrombosis (DVT) as a source for further embolization adversely impacts this risk. The aim of this project was to determine the impact of residual DVT on adverse outcomes among cancer patients suffering acute PE. Methods: Consecutive patients with confirmed acute PE (March 1, 2013 - June 30, 2021) underwent ultrasound (US) imaging and were divided into two groups depending on the presence or absence of leg DVT. PE severity was classified based on AHA criteria. Patients were followed prospectively for VTE recurrence, major and clinically relevant non-major bleeding (CRNMB) and all-cause mortality. Results: Over the study interval, 1,035 cancer patients with PE were enrolled (Table 1). Of these, 375 (36.2%) had leg DVT confirmed by US. Patients with leg DVT were older (64.2 vs 61.4 years, p = 0.01), heavier (90.2 vs 85.1 kg, p <0.001), with lower metastatic disease prevalence (49.1% vs 57.1%, p = 0.01) compared to those without leg DVT. Cancer type distribution also differed between groups. PE patients with DVT more often had prostate, genitourinary, and hematologic cancers while those without DVT more often had pancreatic and breast cancers. Patients with DVT more often had symptomatic PE (48.2% vs. 35.9%, p < 0.001), massive (2.9% vs 0.5%, p < 0.001), and submassive (22.0% vs 7.6%, p < 0.001). Patients with DVT more often received unfractionated heparin (39.5% vs 18.7%, p < 0.001) whereas those without DVT were more frequently treated with low molecular weight heparin (57.5% vs. 44.3%, p <0.001), and apixaban (16.4% vs. 11.7%, p < 0.05). Anticoagulant duration, VTE recurrence, major bleeding and CRNMB were similar between groups (Table 2). Conclusion: Among a large cohort of cancer patients with pulmonary emboli, significant clinical and cancer specific differences exist comparing those with and without leg DVT.While theoretically increasing the risk of recurrent embolization, the presence of residual DVT does not appear to adversely impact important outcomes among cancer patients adequately treated with anticoagulation.

Background: Most older patients (pts) with relapsed or refractory (R/R) AML cannot tolerate intensive treatment and are not eligible for curative allogeneic hematopoietic cell transplant (alloHCT). 131I-apamistamab, an anti-CD45 radioimmunoconjugate, delivers high dose targeted radiation to hematopoietic cells, allowing for myeloablation and eradication of leukemic cells. 131I-apamistamab led induction and conditioning can provide these pts with access to alloHCT. Methods: SIERRA (NCT02665065) was a multi-center, randomized, controlled phase 3 study comparing the efficacy of 131I-apamistamab led induction and conditioning versus physician's choice of conventional care (CC) in pts ≥55 years of age with active, R/R AML. Pts were randomized (1:1, n=153) to CC or 131I-apamistamab with fludarabine and total body irradiation (2 Gy) followed by alloHCT. Primary endpoint was durable complete remission (dCR), defined as CR ≥6 mos with or without platelet recovery (CRp). Pts not achieving CR in CC could crossover (CO) to receive 131I-apamistamab. Treatment with 131I-apamistamab was prescribed as an individualized dose for each pt following a dosimetric infusion and biodistribution analysis, with the prescribed activity of 131I set to deliver a maximum estimated radiation dose to the liver as the dose limiting organ of 24 Gy (determined as the maximum tolerable dose (MTD)) in earlier studies), thereby providing the highest dose to the diseased bone marrow and circulating leukemic cells without exceeding individual organ radiation dose tolerances. Here, we performed an analysis to determine whether a radiation dose-response relationship could be established based on either 1) administered radiation dose to liver and the rate of achieving the primary endpoint of dCR (with 95% binomial confidence intervals) or 2) dCR rate and the ratio of bone marrow/liver absorbed radiation dose as an indicator of favorable biodistribution between target/risk organ. Results: All pts receiving the therapeutic dose of 131I-apamistamab (n=66) were able to receive an alloHCT, and the primary endpoint (dCR) was achieved in 13 pts receiving 131I-apamistamab vs 0 pts in CC (p<0.0001). The median absorbed liver dose was 21.6 Gy (IQR: 21.0 - 22.8 Gy), median absorbed dose to bone marrow was 16.0 Gy (IQR: 11.5 - 22.3 Gy), and median ratio between marrow/liver dose was 0.79 (IQR: 0.52 - 1.02). Table 1 shows the distribution and rate of dCR for pts who received above or below 22 Gy administered dose to liver (24 Gy to liver was the established MTD from earlier studies, in which doses were escalated in 2 Gy increment and thus, 22 Gy represented MTD-1), and for pts stratified by marrow/liver dose ratio (higher ratio representing more favorable biodistribution). Pts with ≤22 Gy liver dose had a dCR rate of 13.5% vs. 27.6% for pts with >22 Gy liver dose, and pts with <median dose to bone marrow had a dCR rate of 12.1% vs. 27.3% for pts with ≥median estimated marrow dose. Importantly, pts with increasingly favorable biodistribution had nominally higher dCR rates of 10.0%, 20.0% and 26.9% for a marrow/liver ratio <0.6, 0.6-0.9 and >0.9, respectively, as illustrated in Figure 1. Taken together this demonstrates a radiation dose-response for the primary endpoint in this study. Overall, safety was similar across doses to the liver. Conclusion: 131I-apamistamab led induction and conditioning followed by alloHCT resulted in statistically significant improvement in dCR at 6 mos vs conventional care. A dose-response was demonstrated for pts receiving 131I-apamistamab with those receiving a liver dose closer to the MTD of 24 Gy having about twice the dCR rate compared to pts 22 Gy (MTD-1) or less. We also found pts with higher marrow/liver ratio experienced considerably higher rates of dCR which highlights the importance of maximizing the dose to target tissues, within the limits of established risk organ dose tolerances.

Introduction: In October 2021, the FDA approved brexu-cel for the treatment of adults ≥ 18 years old with R/R B-ALL. Following this approval, a consortium of cancer centers was formed across the US to investigate outcomes following commercial brexu-cel use for adults with R/R B-ALL. One area of interest is the toxicity profile of brexu-cel when given in the real-world context, including the respective incidences and severity of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity (ICANS). Methods: Eligible pts included adults ≥ 18 years old who received commercial brexu-cel starting in October 2021 onward at a participating center in the US (N = 25). Retrospective patient data were collected across participating institutions, with the most recent data lock occurring on June 30, 2023. Criteria from the ASTCT were used to grade CRS and ICANS severity. Statistical methods included the use of medians and simple ratios for descriptive outcomes; univariate logistic regression models were used to assess the association of various factors with the probability of CRS and ICANS, and Cox regression was used to examine the association of each with the hazards of mortality and failure for event-free survival (EFS; earliest of progression, relapse, or death). Results: Key demographics and toxicities are described in Tables 1 and 2 (respectively). Of the 152 pts infused with brexu-cel, 82% (N = 125) developed CRS and 56% (N = 85) developed ICANS. CRS and ICANS did NOT develop in 12% (N = 19). Twenty percent of all pts (N = 31) required ICU-level care for management of CAR-related toxicities, with a median LOS in ICU of 4 days (range 1-79). In univariate models, grade 3+ ICANS was most likely to occur in pts with active disease (≥ 5% marrow blasts and/or EMD) at the time of apheresis (OR 2.63, 1.28-5.38, p = 0.008); a numerical increase for grade 3+ CRS (OR 2.35, 0.69-8, p = 0.17) was seen in pts with active disease at apheresis. Therapies received for these CAR-related toxicities included steroids, tocilizumab (toci), and anakinra (Table 2). Among pts who received steroids (N = 94), 37% (N = 34) achieved a sufficient response to the first steroid trial and did not require subsequent therapies; otherwise, toxicities improved with the first steroid course but later worsened in 16% (N = 15); the first trial of steroids was not effective but improved when further steroids were given in 31% (N = 29); there were no responses to any doses of steroids in 10% (N = 9). In pts receiving toci (N = 103), 31% (N = 32) achieved a sufficient response to the first dose and did not require any further therapy; toxicities improved with the first dose but later worsened in 31% (N = 32); the first dose was ineffective but improvement was seen with subsequent doses in 21% (N = 22); 9% (N = 9) did not respond at all to toci. The rate of death within day +28 was 6% (N = 9), and the respective causes were typically multifactorial: CRS was implicated in 3 cases, ICANS in 3, infection in 5, disease relapse/progression in 2, and HLH in 1 case. In total, uncontrolled ICANS was implicated in the death of 6 pts (between day +9 to day +106). HLH was reported in 6 pts: in most cases, this was a biochemical diagnosis, and it either overlapped with concurrent CRS or infection or occurred following CRS/ICANS. The most common infections between day 0 and day +28 included bacteremia in 8% of pts (N = 12), fungal infections in 4% (N = 6), pneumonia in 3% (N = 5), and CMV infections in 3% (N = 4). The fungal infections included 4 instances of invasive sinopulmonary infections (2 due to aspergillus; 2 due to mucormycosis) and 2 cases of candidemia. With both CRS and ICANS treated as a time-varying covariate, the development of grade 3+ CRS was associated with a higher hazard of death (HR 2.38, 1.00-5.66, p = 0.05); grade 3+ ICANS was not associated with a demonstrably higher risk of death (HR 1.11, 0.60-2.05, p = 0.74). The HR of EFS failure for Grade 3+ CRS was 1.81 (0.87-3.79, p = 0.12) and for grade 3+ ICANS HR = 0.93 (0.56-1.53, p = 0.77). Conclusions: In this real-world study of toxicities from brexu-cel use for adults with R/R B-ALL, we observed CRS and ICANS in the majority of pts, and no new safety signals were observed. Rates of severe CRS and ICANS were more common with active disease. Interestingly, though CRS-related mortality was rare, grade 3+ CRS was associated with a higher risk of death. Efforts to identify mechanisms and mitigable risk factors for these toxicities are warranted.

Introduction: Daratumumab, lenalidomide, and dexamethasone (DRd) and bortezomib, lenalidomide, and dexamethasone (VRd) are the only two regimens that are considered as preferred per the National Comprehensive Care Network for transplant ineligible (TIE) patients with newly diagnosed multiple myeloma (NDMM). While there are no head-to-head studies comparing clinical outcomes of DRd and VRd in this population, an indirect comparison (PEGASUS study [Durie et al., 2020]) has shown that DRd was associated with significantly lower risk of disease progression or death compared with VRd and Rd. This study aims at supplementing this information by comparing real-world time-to-next-treatment (TTNT) or death between NDMM TIE patients treated with front-line (FL) DRd or VRd. Methods: A retrospective cohort study was conducted for patients with NDMM who initiated FL DRd or VRd in Acentrus (1/1/2018 - 5/31/2023), an electronic medical record (EMR) database from academic and non-teaching hospitals in the United States. Patients were included if they had ≥2 records with an ICD-10-CM diagnosis code for MM, ≥6 months of data availability prior to first record with MM diagnosis (without use of antineoplastic agent), initiated FL treatment (initiation of DRd or VRd; index date) within 12 months of first record of MM diagnosis, and ≥90 days of data availability post-index. Patients with pre-index diagnosis of amyloidosis or other cancers and those who participated in a clinical trial before or during FL treatment were excluded. To limit the analysis to the TIE population, patients who had a record of a stem-cell transplant (SCT) before or during FL treatment and those who were <65 years old (used as proxy to SCT eligibility) were excluded. Patient characteristics were evaluated up to 12-months pre-index (baseline period). Patients were followed from the index date until earliest of date of initiation of a next line of treatment, death, or end of data availability. Medications received within 60 days from the date of the first MM antineoplastic agent were considered as FL therapy regimen. Next line of treatment was identified as initiation of a new antineoplastic agent (excluding corticosteroids) outside of FL therapy or re-treatment of FL after >90-day gap. Inverse probability of treatment weighting (IPTW) was used to balance baseline characteristics between study cohorts, with variables with standardized differences <10% considered balanced. Weighted Kaplan-Meier (KM) curves and a doubly-robust Cox proportional hazards model adjusting for baseline variables remaining imbalanced after IPTW were used compare TTNT or death between study cohorts. Results: Overall, 149 and 494 patients were identified in the DRd and VRd cohorts, respectively. After weighting (N DRd weighted = 302, N VRd weighted = 341), most baseline characteristics in both cohorts were similar, including mean age (DRd: 75.3, VRd: 74.5), female sex (DRd: 48.9%, VRd: 45.8%), white race (DRd: 55.8%, VRd: 58.7%), black race (DRd: 8.8%, VRd: 11.3%), Medicare insurance coverage (DRd: 62.7%, VRd: 65.9%), and mean Quan-Charlson comorbidity index (DRd: 3.8, VRd: 3.6; Table 1). Some imbalances remained for mean age, race, ethnicity, and index year, thus they were additionally adjusted for in doubly-robust Cox model. The median duration of follow-up was 20.2 months and 21.5 months among DRd and VRd patients, respectively. A total of 98 (32.4%) DRd patients and 175 (51.2%) VRd patients received a subsequent line of therapy or died, with the median TTNT or death being 37.8 and 18.7 months in the DRd and VRd cohorts, respectively (hazard ratio: 0.58, 95% CI: 0.35, 0.81; p<0.001; Figure 1). KM estimates for patients remaining on FL therapy were significantly higher for DRd than VRd at 6 months (93.0% vs. 80.1%), 12 months (80.0% vs. 61.0%), 18 months (64.9% vs. 51.3%), and 24 months (60.2% vs. 42.9%). Conclusion: In this retrospective cohort study using EMR data, TIE NDMM patients who initiated DRd had a significantly longer time to next treatment or death than patients who initiated VRd. Results from this real-world study fills an unmet data gap by providing information on the comparative effectiveness evidence for DRd versus VRd among TIE NDMM patients. These findings support the use of DRd as an effective treatment option in the TIE NDMM patient population.

Introduction: Most induction regimens for multiple myeloma (MM) contain bortezomib. In most clinical trials, bortezomib has been prescribed either intravenously or subcutaneously twice per week in 21-day or 28-day cycles. However, several retrospective single-center studies have shown that once-weekly bortezomib has comparable efficacy and less peripheral neuropathy compared to twice-weekly bortezomib ( Sidana et al, PLoS One 2017; Cook et al, AJH 2021). These findings have also been confirmed by a secondary analysis of data from three prospective Phase 3 randomized studies ( Mateos et al, Haematologica 2014). As such, many clinicians have adopted once-weekly bortezomib regimens in routine care in the past decade. However, the real-world (RW) prevalence and efficacy of once-weekly vs twice-weekly bortezomib regimens in a larger population have not yet been characterized. Methods: This study used US nationwide longitudinal Flatiron Health electronic health record-derived de-identified data. We included patients aged 18-70 years with newly diagnosed MM between 2017-2022 with ≥ 6 months of follow-up and ≥ 2 clinical visits who were treated with a first-line (1L) bortezomib-containing regimen. Patients aged >70 were excluded a priori given the likelihood of altered practice patterns and more frequent comorbidities. Twice-weekly bortezomib was defined as patients for whom the most frequent interval between two doses of 1L bortezomib within a cycle was 3.0-4.9 days, while once-weekly bortezomib was defined as a corresponding interval of 5.0-9.9 days. We used multivariable logistic regression to assess demographic and clinical factors associated with once-weekly vs twice-weekly (reference) bortezomib. RW progression free survival (rwPFS) and RW overall survival (rwOS) from 1L treatment initiation were estimated using the Kaplan-Meier method. Outcomes were compared using Cox proportional hazards model including transplant as a time-varying covariate and adjustment for other demographic and clinical factors. Results: Of 2,522 patients included, 927 (36.8%) received twice-weekly while 1,522 (63.2%) received once-weekly bortezomib. Approximately half of patients (50.3%) were non-Latinx White, 21.7% non-Latinx Black, and 8.0% Latinx. Most patients were treated in the community setting (78.8%). Rates of once-weekly bortezomib administration were 66.2% and 62.1% among patients treated at academic and community practices, respectively. The frequency of weekly bortezomib use increased over time, from 58.0% between 2017-2019 to 68.8% between 2020-2022. In multivariate analysis, ECOG PS ≥ 2 (odds ratio [OR] 1.50; [95% CI 1.14 to 1.99] vs ECOG PS 0), and more recent year of diagnosis (OR 1.14; [95% CI 1.08 to 1.20] per year) were associated with higher odds of receiving once-weekly bortezomib. Conversely, Latinx patients vs non-Latinx White (OR 0.60 [95% CI 0.44 to 0.82]) and patients with ≥ 2 high-risk cytogenetic abnormalities (HRCA) vs 0 HRCA (OR 0.66 [95% CI 0.48 to 0.91]) had lower odds of receiving once-weekly bortezomib administration. No significant associations were found between gender, ISS stage, practice setting, insurance category, or baseline creatinine. There was no statistically significant difference in rwPFS among patients receiving once-weekly (median 37.3 months, 95% CI 33.8 to 42.5) vs twice-weekly bortezomib (median 39.2 months, 95% CI 32.9 to 42.8) (HR 0.87 [95% CI 0.77 to 1.00]) (Figure 1A). Similarly, there was no statistically significant difference in rwOS with median 25.5 months follow-up (Figure 1B). Median rwOS was not reached in either group (hazard ratio 0.89 [95% CI 0.75 to 1.07]). Discussion: We evaluated US bortezomib prescribing patterns for the first time in the modern era using a large nationwide RW-study. Whereas prescribing patterns have shifted towards once-weekly bortezomib over time, over 30% of patients diagnosed in the last three years received twice-weekly bortezomib. Importantly, once-weekly and twice-weekly bortezomib performed comparably with regard to rwPFS and rwOS. While our study did not analyze neuropathy or patient quality of life, once-weekly bortezomib is known to be associated with less neuropathy and less time in clinic. These data further support the conclusion that once-weekly bortezomib should be considered the standard of care for newly diagnosed patients with MM.

Introduction: Chimeric antigen receptor T-cell therapy (CAR-T) has revolutionized the treatment of non-Hodgkin lymphoma (NHL). Despite having an increased risk of NHL, patients with pre-existing autoimmune disease (AID) were excluded from pivotal CAR-T trials due to concerns that CAR-T may exacerbate AID. As a result, there are limited data on the safety and efficacy of CAR-T for NHL in patients with AID. Interestingly, there is also growing evidence that CAR-T can be therapeutically effective for AID, such as in the treatment of systemic lupus erythematosus (SLE). As CAR-T utilization for NHL increases, it is essential to characterize the safety and efficacy of this potentially curative therapy in patients with AID. This study aimed to evaluate the impact of AID on outcomes in patients treated with commercial CD19-targeted CAR-T for NHL. Methods: Following Institutional Review Board approval, we conducted a retrospective analysis of all patients who were treated with commercial CD19-targeted CAR-T for NHL and had a pre-existing AID across the Mayo Clinic Enterprise (Arizona, Florida, and Minnesota) between January 2018 and May 2023. Variables collected included age, gender, NHL type, AID type, and CAR-T product. Efficacy outcomes, including response rates at 6 and 12 months after CAR-T, were collected. Toxicities, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), were collected and analyzed. Our chart review for AID included SLE, sarcoidosis, ulcerative colitis, celiac disease, pernicious anemia, Crohn's disease, psoriasis, Sjogren's syndrome, hypothyroidism (Hashimoto's disease), hyperthyroidism (Graves' disease), rheumatoid arthritis (RA), vasculitis, scleroderma, and mixed connective tissue disease (MCTD). Results: A total of 235 patients who received commercial CD19-targeted CAR-T for NHL across the Mayo Clinic Enterprise were identified (Table 1). Of these 235 patients, 27 had a pre-existing AID and 208 did not. The median age was 66 years (range 39-81) for patients with AID and 59 years (range 18-88) for patients without AID. Over half of the patients were male (59% of patients with AID and 51% of patients without AID). The most common NHL type was diffuse large B cell lymphoma (41% of patients with AID and 56% of patients without AID). Most patients received axicabtagene ciloleucel (85% of patients with AID and 84% of patients without AID). The most common AID was hypothyroidism (81%, n=22), although other conditions were also identified, including RA (11%, n=3), SLE (4%, n=1), pulmonary sarcoidosis (4%, n=1), psoriasis (4%, n=1), and MCTD (4%, n=1). Two patients had more than one AID. Median follow-up was 18 months (range 1-36) for patients with AID and 14 months (range 2-49) for patients without AID. Six months after CAR-T, the complete response (CR) rate was 77.2% and 45.1% in patients with AID and without AID, respectively (p=0.0042). Twelve months after CAR-T, the CR rate was 50% and 31.4% in patients with AID and without AID, respectively (p=0.0801). CRS of any grade occurred in 78% and 88% of patients with and without AID, respectively. ICANS of any grade occurred in 41% and 54% of patients with and without AID, respectively. Conclusion: AID did not appear to adversely impact the safety or efficacy of CAR-T for NHL. Limitations of our study include the small number of patients with AID and the fact that the most common AID was hypothyroidism. Larger studies are warranted to confirm these findings. Additional data are needed to characterize the impact of CAR-T for NHL on AID outcomes and to describe the effect of disease-modifying antirheumatic drugs on NHL outcomes after CAR-T.

Background: Primary central nervous system lymphoma (PCNSL) is a rare and aggressive form of NHL isolated to the central nervous system or vitreoretinal space. Despite high initial rates of responses to available therapies, most PCNLS relapse in two years, presenting a very poor prognosis. Combination with novel therapies may overcome resistance (Guidetti 2023a). Upregulation of the B-cell receptor (BCR/NF-κB) and toll-like receptor (TLR)/NF-κB) signaling axis have been identified as key pathways in the pathogenesis of PCNSL. MYD88 L265P, a widely expressed somatic mutation in more than 70% of PCNSL patients, activates NF-κB signaling through stimulation of BTK and IRAK4. Emavusertib (CA-4948) is a novel, potent oral inhibitor of interleukin 1 receptor-associated kinase 4 (IRAK4), with additional inhibitory activity against FMS-like tyrosine kinase 3 (FLT3) and CDC-like kinases (CLK1/2/4). Targeted inhibition of IRAK4 with emavusertib in PCNSL xenografts indicated sufficient blood brain barrier penetration of emavusertib, target inhibition, and antitumor activity (von Roemeling 2022). Further preclinical studies have demonstrated that emavusertib synergizes with ibrutinib and can re-sensitize and overcome resistance to BTK inhibitors (Guidetti 2023a and 2023b). Initial clinical data have reported responses in BTK-resistant PCNSL and good tolerance of the combination (Iqbal 2022; Grommes 2023). Study Design: This is an ongoing multi-center, open-label trial (NCT03328078) in adult patients with hematologic malignancies to evaluate the safety, PK, and anti-cancer activity of oral administration of emavusertib alone or in combination with ibrutinib. Part Bis an open trial expansion cohort with BTKi relapsed or refractory PCNSL. About 20 evaluable PCNSL patients will be enrolled globally. Patients will receive oral CA-4948 at 100 or 200 mg BID in combination with ibrutinib at 560 mg QD in 28-day cycles until disease progression or intolerable toxicity. The primary endpoint is expanded safety/tolerability; secondary endpoints include ORR, DOR, PFS, OS, and pharmacokinetics. Key inclusion criteria for this expansion cohort: pathologically confirmed diagnosis of PCNSL with evidence of disease progression, measurable disease, relapsed or refractory with no more than 3 lines of prior anti-PCNSL therapy (including BTKi), and absence of residual Grade ≥2 toxicity from prior therapy. Key exclusion criteria: intraocular PCNSL without brain lesion or CSF involvement or significant co-morbidity. Key clinical assessments include brain imaging, CSF- and ocular examinations.

Introduction Secondary central nervous system (CNS) involvement develops in 2-10% of large B-cell lymphoma (LBCL) cases. Current treatment approaches for relapsed or refractory CNS disease generally do not provide durable responses. Limited data suggest efficacy and feasibility of CAR-T therapy in SCNSL. We report here the largest multicenter retrospective analysis of the safety and efficacy of CD19-directed CAR-T therapy in SCNSL patients. Methods This study included SCNSL patients who received commercial CD19-directed CAR-T therapy at 9 academic institutions in the United States between 2016 and 2022. SCNSL was defined as history of parenchymal and/or leptomeningeal/cerebrospinal fluid (CSF) involvement by lymphoma at any time prior to receiving CAR-T therapy. Systemic response was assessed using the Lugano criteria while CNS response was assessed as per International PCNSL Collaborative Group criteria. Kaplan-Meier curves were generated for progression-free survival (PFS) and overall survival (OS) for entire cohort, as well as subsets of patients with and without active CNS disease at the time of CAR-T infusion. Results Ninety patients were included in the analysis, with baseline characteristics shown in Table 1. CAR-T products utilized include axicabtagene ciloleucel (n= 38, 42%), tisagenlecleucel (n=37, 41%) and lisocabtagene maraleucel (n= 15, 14%). Fludarabine/cyclophosphamide was used as lymphodepletion in 84 patients (93%). 28 patients received CNS directed radiation therapy (RT) prior to CAR-T infusion (31%) within a median time of 28.5 days (range 5 - 906) from last day of RT. Amongst all patients at the time of CAR-T infusion 82 (91.1%) had active CNS and/or systemic involvement while 8 (8.9%) had no evidence of disease; 68 (75.5%) had active CNS involvement while 22 (24.5%) had a prior history of CNS involvement but no active at the time of CAR-T infusion. ( Table 1) Median follow up all patients was 0.5 year (range 0.01 - 4.7). 71 patients (79%) developed cytokine release syndrome (CRS; median time to onset 3 days) with 3.3% patients developing Grade 3-4. Immune effector cell-associated neurotoxicity syndrome (ICANS; median time to onset 5 days) was reported in 55 patients (61%), with 28.8% developing Grade 3-4. No patients died due to CRS or ICANS. At 1-month post CAR-T, 80 patients were evaluable for CNS response and 71 patients in the entire cohort were evaluable for systemic response. Similarly, at 3-months these numbers were 66 and 60, respectively. Objective response rates (ORR) were 75% and 80% at 1-month for CNS and systemic disease respectively, while corresponding ORRs at 3-months were 68% and 76.7%. At 1- and 3-months timepoint 36 (45%) and 33 (50%) patients, respectively achieved CNS complete remission (CR), while 44 (62%) and 42 (70%) patients respectively achieved systemic CR. 1- and 2-year PFS for entire cohort were 25% (95%Cl 15% - 34%) and 16% (95%Cl 8.5% - 28%) respectively, while 1- and 2-year OS were 46% (95%Cl 36% - 59%) and 31% (95%Cl 22% - 46%). Non-relapse mortality (NRM) were 4.6% (95%CI, 1.8% -12%) and 7.2% (95%CI 2.9% - 18%) at 1- and 2-year. Cumulative incidence of relapse at 1- and 2-year were 73% (95%Cl 63% - 83%) and 77% (95%Cl 68% - 88%), respectively. ORRs for CNS response in patients with active CNS disease at 1-month and 3-month interval were 71% (n=45) and 60% (n=31). Similarly, ORR for systemic response with active CNS disease at 1-month and 3-month interval were 85% (n=43) and 74.3% (n=32).The 2-year PFS for patients with and without active CNS disease at CAR-T infusion were 12% (95%Cl 5.4% - 27%) and 28% (95%Cl 12% - 65%) respectively, with a corresponding OS of 25% (95%Cl 15% - 41%) and 58% (95%Cl 37% - 91%). ( Figure 1) The 2-year NRM rates for patients with and without active CNS disease at CAR-T infusion were 4.6% (95%Cl 1.5% - 14%) and 14% (95%Cl 3.6% - 53%) respectively, while the cumulative incidence of relapse in similar order were 83% (95%Cl 73% - 95%) and 58% (95%Cl 39% - 88%). Conclusion In this largest known case series to date, CAR-T therapy appeared safe and feasible in patients with SCNSL, but is associated with high rates of treatment failure, particularly in patients with active CNS disease at CAR-T infusion. This warrants further study of optimal CNS-directed treatment strategies prior to CAR-T, development of novel cellular therapy platforms or consideration of post CAR-T maintenance therapy in these high-risk patients.

Background: QOL can be affected by disease burden, side effects of treatment, and psychosocial effects of living with cancer. Although MZL is considered incurable, we previously found that patients diagnosed from 2002-2015 had a good QOL both at baseline (BL) and the first decade after diagnosis, regardless of treatment choice (Bommier et al., submitted). Here, we evaluate whether these findings can be extended to the 2015-2020 treatment era and a more diverse US cohort. Methods: Adults with newly diagnosed MZL from 8 academic centers were prospectively enrolled within 6 months of diagnosis from 2015-2020 in the LEO cohort (NCT02736357). Participants were actively followed for disease progression/relapse, retreatment and death. QOL was measured at BL, and at 1, 2, 3 and 5 years after diagnosis using the Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) scale (range 0-164), which consists of the FACT-General (FACT-G, range 0-104) plus a lymphoma-specific scale (range 0-60). Total FACT-G measures 4 QOL domains (range): physical (0-28), social/family (0-28), emotional (0-24), and functional (0-28) well-being (WB). We also used the Trial Outcome Index (TOI; range 0-112), which consists of FACT-G physical and functional WB plus the lymphoma-specific scale and is commonly used as an endpoint in treatment trials. All MZL patients with both BL and at least one follow-up QOL questionnaire were eligible for analysis. Patients were grouped by initial management: active surveillance (observation), local/antibiotic therapy (radiation, surgery, or anti- H. pylori therapy), or systemic therapy (chemotherapy, targeted agents, or antibody therapy). Change in QOL scores over time was analyzed using mixed models for repeated measurements, and initial treatment groups were compared. Results: Of 384 patients, 60% were female, 91% were White, 6.6% were Black/African American, and 13% were Hispanic (all races). The median age was 64 years (range 19-94). For initial management, 28% (N=106) were observed, 31% (N=118) received local/antibiotic therapy, and 42% (N=160) received systemic therapy. Across treatment groups, there were no significant differences by age, gender, race, or performance status, while there were differences by Hispanic ethnicity (p=0.006), Ann Arbor stage (p<0.001) and MALT-IPI score (p<0.001) (Table). At BL, patients receiving systemic therapy had lower physical WB (p=0.008), emotional WB (p=0.04), functional WB (p=0.03), FACT-G total score (p=0.008), lymphoma subscale (p<0.001), FACT-Lym (p=0.001) and TOI (p<0.001) compared to observation and local/antibiotic therapy (Table). While FACT-G total scores were largely stable through 5 years after diagnosis, social/family WB declined from BL for patients initially receiving either local/antibiotic therapy (mean at 1-year -1.4, p<0.05; 2-year -2.1, p<0.05; 3-year -1.6, p<0.05; 5-year-2.9, p<0.05) or systemic therapy (mean at 2-year -1.2 , p<0.05; 3-year -1.4, p<0.05; and 5-year -1.2, p<0.05), while this was stable for observed patients. In patients receiving initial systemic therapy, there was a transient improvement in the lymphoma-specific scale (mean +1.7, p<0.05) and TOI (mean +3.7, p<0.05). Otherwise, QOL remained stable over time and global QoL (FACT-G, FACT-Lym), TOI, Lymphoma-specific scale (Figure), and the other FACT-G subscales (physical, emotional, or functional WB) did not differ by initial treatment strategy. Conclusions: In the diverse LEO cohort from the recent treatment era, we confirm our prior findings for newly diagnosed MZL patients that QOL is globally stable over the first 5 years after diagnosis; emotional WB is not associated with initial treatment type, providing evidence that being initially observed does not negatively impact emotional health; and there is a decline in social/family WB (support from friends and family, family acceptance of illness, family communication, close to partner), which supports the need to consider interventions for patients to address these unmet needs. In addition, this study extends these findings to the lymphoma-specific scale, FACT-Lym, and TOI, which all showing largely stable trends in the 5 years after diagnosis and suggest that recent MZL treatment strategies, including systemic therapies, neither impair nor improve QOL.

Introduction: MDS are primarily diseases of the elderly, with median age at diagnosis of 72 years. Focused data on clinical and molecular characteristics, as well as outcomes, in younger pts under age 60 years are limited. We conducted this multicenter retrospective study to describe pt characteristics, cytogenetic and molecular profiles, treatment modalities, and outcomes in younger pts with MDS, including adolescent and young adults (AYA). Methods: The study included pts diagnosed with MDS between 2002-2023 at 7 academic centers. We compared baseline characteristics, treatment, and outcomes of AYA (18-39 years) and younger adult (YA) pts (40-59 years). Responses were assessed using the modified IWG 2006 response criteria which included complete remission (CR), marrow CR (mCR), and hematologic improvement (HI). Wilcoxon rank sum test and Fisher's exact (and Chi-square) test were used to compare pt and disease characteristics for continuous and categorical variables, respectively. Overall survival (OS) was estimated using the Kaplan-Meier method and compared using log-rank test. Results: A total of 173 pts were identified (AYA, N=50; YA, N=123). Median age at diagnosis was 50 years (range, 18-59), with 51% females. Baseline characteristics are shown in Table 1. Therapy-related MDS (t-MDS) was observed in 40 pts (23%) with the remaining classified as de novo MDS (N=133; 77%). Inherited bone marrow failure syndromes were documented in 15 pts (9%), with Shwachman-Diamond Syndrome (N=4) and Fanconi anemia (N=4) being the most frequent. Using the WHO 2016 classification, the most common subtypes of MDS in both the AYA and YA cohorts were MDS with multilineage dysplasia (38% vs 19%), MDS with excess blasts-2 (MDS-EB) (24% vs 29%), and MDS-EB-1 (16% vs 20%). Similarly, using the WHO 2022 classification, the most common subtypes were MDS with low blasts (50% vs 21%), MDS with increased blasts-2 (MDS-IB-2) (24% vs 24%), and MDS-IB-1 (16% vs 18%). Stratifying pts using the IPSS-R cytogenetic (CG) risk group, the most common CG risk category identified was good CG (34% vs 52%, p=0.012). Poor/very poor CG were present in 34% and 37% of the AYA and YA groups, respectively. STAG2 and NRAS mutations occurred more frequently in the AYA pts compared to the YA group, while the YA cohort was enriched for the following mutations: TP53, DNMT3A, SF3B1, SRSF2, and TET2 (Figure 1). In the AYA population, 18 pts (38%) had very low/low, 10 (21%) intermediate, and 20 pts (42%) had high/very high risk MDS using IPSS-R. In the YA population, 32 pts (26%) had very low/low, 32 (26%) intermediate, and 57 pts (47%) had high/very high risk MDS using IPSS-R. Twenty-seven percent of pts with very low to intermediate-risk MDS using IPSS-R were upstaged to moderate high to very high-risk MDS using IPSS-M. The majority of pts (AYA: 75%; YA: 63%, p=0.5) were transfusion independent at baseline. Single-agent hypomethylating agents were the most frequently used frontline therapy, used in 17 AYA pts (34%) and 58 YA pts (48%), with more AYA pts receiving upfront allogeneic stem cell transplantation (Allo-SCT) compared to YA pts (28% vs 5%). After frontline therapy (Table 1), an additional 14 AYA (28%) and 52 YA (42%) pts received Allo-SCT. In pts with IPSS-R intermediate to very high-risk, response rates (HI+CR+mCR+mCR with HI) to frontline therapies were 46% and 54.5% in the AYA and YA groups, respectively. After median follow-up of 24 months [range, 1-218], median OS was numerically longer in the AYA versus YA group (155 vs 53 months, p=0.2). AML transformation occurred in 24% and 20% of the pts in the AYA and YA groups, respectively. Median OS was significantly longer in de novo compared to t-MDS pts (56 vs 27 months, p=0.03). Median OS among Allo-SCT compared to non-SCT pts were not reached vs 155 months ( p=0.9) in the AYA group and 53 vs 54 months ( p=0.4) in the YA group. IPSS-R (very low+low vs intermediate vs high+very high) was able to distinguish differences in OS in the YA (133 vs 53 vs 17 months, p=0.0002) and AYA (155 vs not reached vs 18 months, p=0.006) pts, with the exception of the intermediate-risk group in the AYA cohort. Conclusions: In this study, d e novoMDS was seen in the majority of younger pts with MDS (both AYA and YA). Mutations in STAG2 and NRAS were more common in the AYA pts, while YA pts had MDS more enriched for TP53, DNMT3A, TET2 and splicing mutations. This study is still ongoing with a plan to compare the abovementioned groups to older pts (≥60 years) with MDS.