Kumar, Anita J.

Introduction: Treatments for R/R MCL have evolved with NTs, including BTK inhibitors (BTKis). Little is known about RW treatment patterns and clinical outcomes of pts with R/R MCL for chemoimmunotherapy (CIT) vs NTs among pts of different race/ethnicity. Data on RW testing and clinical outcomes of pts with R/R MCL harboring a TP53 mutation are limited. Methods: This retrospective cohort study included adult pts with R/R MCL who initiated second-line (2L) or third-line (3L) treatment on 1/1/2018 or later and were followed up until loss to follow-up, death, or data cut-off using US Flatiron Health electronic health record-derived de-identified databases. Median RW time to next treatment (mrwTTNT) and median RW overall survival (mrwOS) were estimated based on Kaplan-Meier analyses and adjusted for age and sex. CIT included any MCL treatment with chemotherapy + anti-CD20 antibody. NTs included BTKis, BCL2 inhibitors, lenalidomide, bortezomib, and CAR-T, or combinations. Results:This study included 1,377 pts with R/R MCL who received 2L+ therapy. Of these, 1,028 (75%) were non-Latinx (NL)-White, 53 (4%) were NL-Black, 86 (6%) were Latinx, 108 (8%) were NL-Asian or other race, and 102 (7%) were of unknown/undocumented race. The overall 2L+ population had a median age of 71 y (range 63-78), were mostly male (74%), had a diagnosis of MCL not otherwise specified (NOS; 85%), and had stage IV disease (62%). Sixty-three percent had disease progression within 24 mo from first-line (1L) treatment (POD24) before starting 2L therapy. Relative to all pts, NL-Black and NL-Asian/other race pts had more variants of MCL (blastic, leukemic, pleomorphic) and higher Ki67% and lactose dehydrogenase (LDH) levels at 2L/3L index date. In contrast, Latinx pts had more MCL NOS (92%) and lower Ki67% and LDH levels at 2L index date. More NL-Black and unknown race pts had POD24 than did other races (70% and 76%, respectively). Overall, the most common NTs used were BTKis. 1L treatments were bendamustine-rituximab (BR; 54%), R-CHOP (18%), and cytarabine-containing CIT (9.7%). The most common 2L treatments were BR (32%), acalabrutinib (31%), ibrutinib (21%), zanubrutinib (11%), and RCHOP (11%). The most common 3L therapies were BR (34%), acalabrutinib (21%), zanubrutinib (12%), ibrutinib (10%), R-CHOP (9.2%), and brexucabtagene autoleucel (7.4%). Transplantation rates before 2L and CAR-T use in 3L was highest among White pts. When assessing mrwTTNT and mrwOS by therapy in 2L, 766 pts (70%) received NTs and 333 (30%) received CIT. Among all pts, mrwTTNT (mo [95% CI]) was longer with 2L NT (11.9 [10.6, 14.5]) vs CIT (9.9 [8.1, 12.9]). NL-White, NL-Black, and NL-Asian/other race pts had longer mrwTTNT with NT (11.9 [10.5, 14.6], 12.9 [7.6, NR], and 14.6 [8.5, 21.4], respectively) vs CIT (9.9 [7.6, 12.9], 9.7 [3.0, NR], and 6.0 [3.2, 21.2]). Latinx pts had longer mrwTTNT with CIT (14.9 [11.8, NR]) vs NT (9.0 [3.8, 24.2]). Among all pts, mrwOS (mo [95% CI]) was longer with 2L CIT (43.0 [34.1, 56.5]) vs NT (35.6 [29.9, 41.2]). White and Latinx pts had longer mrwOS with CIT (47.3 [33.9, NR] and NR [33.3, NR], respectively) vs NT (35.0 [28.8, 48.4] and 42.3 [31.0, NR]). Black and Asian/other race pts had longer mrwOS with NT (41.2 [32.8, NR] and 38.8 [23.5, NR], respectively) vs CIT (34.8 [9.7, NR] and 13.5 [8.3, NR]). Among all 3L pts (n=364 on NTs, n=119 on CIT), mrwTTNT (mo [95% CI]) improved when using NTs (7.9 [6.8, 10.3]) vs CIT (4.4 [3.5, 6.9]). NTs demonstrated better mrwTTNT vs CIT in all race/ethnic groups except Latinx pts. For all race/ethnic groups, mrwOS was improved with NTs (32.5 [24.7, 42.6]) vs CIT (19.5 [13.7, 47.3]). Overall RW testing for TP53 aberrations was limited, with 72 pts (5%) found to be positive for a TP53 mutation. For pts with TP53 mutations, mrwTTNT and mrwOS were longer for 2L NTs (3.3 [2.2, 6.4] and 18.3 [9.0, NR], respectively; n=42) vs CIT (3.0 [1.9, 7.6] and 15.0 [7.2, NR]; n=16). Conclusions: High-risk features, treatment patterns, and clinical outcomes for NTs vs CIT in R/R MCL differed by race/ethnicity. Use of 2L+ NTs was associated with a trend towards improved mrwTTNT and mrwOS among NL-Black and NL-Asian/other race pts. NT use in 3L numerically improved mrwTTNT and mrwOS for most pts vs CIT. RW pts with TP53 mutations had a poor prognosis and numerically improved outcomes with the use of 2L NT, although testing remains limited. Future research evaluating reasons for these differences and increased RW TP53 testing is warranted.

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 < 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.

ImportanceAnthracycline-containing regimens are highly effective for diffuse large B-cell lymphoma (DLBCL); however, patients with preexisting heart failure (HF) may be less likely to receive anthracyclines and may be at higher risk of lymphoma mortality.ObjectiveTo assess the prevalence of preexisting HF in older patients with DLBCL and its association with treatment patterns and outcomes.Design, Setting, and ParticipantsThis longitudinal cohort study used data from the Surveillance, Epidemiology, and End Results (SEER)–Medicare registry from 1999 to 2016. The SEER registry is a system of population-based cancer registries, capturing more than 25% of the US population. Linkage to Medicare offers additional information from billing claims. This study included individuals 65 years and older with newly diagnosed DLBCL from 2000 to 2015 with Medicare Part A or B continuously in the year prior to lymphoma diagnosis. Data were analyzed from September 2020 to December 2022.ExposuresPreexisting HF in the year prior to DLBCL diagnosis ascertained from billing codes required one of the following: (1) 1 primary inpatient discharge diagnosis, (2) 2 outpatient diagnoses, (3) 3 secondary inpatient discharge diagnoses, (4) 3 emergency department diagnoses, or (5) 2 secondary inpatient discharge diagnoses plus 1 outpatient diagnosis.Main Outcomes and MeasuresThe primary outcome was anthracycline-based treatment. The secondary outcomes were (1) cardioprotective medications and (2) cause-specific mortality. The associations between preexisting HF and cancer treatment were estimated using multivariable logistic regression. The associations between preexisting HF and cause-specific mortality were evaluated using cause-specific Cox proportional hazards models with adjustment for comorbidities and cancer treatment.ResultsOf 30 728 included patients with DLBCL, 15 474 (50.4%) were female, and the mean (SD) age was 77.8 (7.2) years. Preexisting HF at lymphoma diagnosis was present in 4266 patients (13.9%). Patients with preexisting HF were less likely to be treated with an anthracycline (odds ratio, 0.55; 95% CI, 0.49-0.61). Among patients with preexisting HF who received an anthracycline, dexrazoxane or liposomal doxorubicin were used in 78 of 1119 patients (7.0%). One-year lymphoma mortality was 41.8% (95% CI, 40.5-43.2) with preexisting HF and 29.6% (95% CI, 29.0%-30.1%) without preexisting HF. Preexisting HF was associated with higher lymphoma mortality in models adjusting for baseline and time-varying treatment factors (hazard ratio, 1.24; 95% CI, 1.18-1.31).Conclusions and RelevanceIn this study, preexisting HF in patients with newly diagnosed DLBCL was common and was associated with lower use of anthracyclines and lower use of any chemotherapy. Trials are needed for this high-risk population.

Abstract Acute lymphoblastic leukemia (ALL) has a high relapse rate in adults. While the biology of the patient may be responsible for the marked difference in survival seen in comparison to children, variable adherence to complex chemotherapy regimens may also play a role. However, there is very little understanding about the risk factors for delays in therapy and the impact of delays on survival. To study delays in newly diagnosed adult ALL patients, we conducted an observational study using data from ECOG 2993/ MRC_UKALLXII (Rowe, Blood 2005). We analyzed Ph- patients who started intensification after documented complete remission (CR). A long delay (LD) was defined as > 98 days from start of induction to start of intensification (IS), which was >2 weeks delay beyond the 84 days recommended per protocol. A Very Long Delay (VLD) was defined as a >4 weeks delay. Of 2109 patients enrolled, 1247 patients met inclusion criteria for analysis. Of note, 435 Ph- patients who achieved CR after induction but did not proceed to intensification were excluded. In univariate analysis, female sex (p<0.001), Black race (p=0.01), and older age (p<0.001) were associated with increased odds of LD. During induction presence of infection (p=0.01), dose reductions (p=0.001), duration of neutropenia (p=0.007), thrombocytopenia (p<0.001), and hospitalization duration (p<0.001) were associated with LD. In multivariate regression, age, female sex, dose reduction, Black race, and hospitalization duration were significantly associated with LD and VLD (Table I). At 2 years after diagnosis, 801/1247 (64.2%) patients were alive. Of the surviving patients, 181 (22.5%) had VLD, and 620 (77.4%), had delay <4 weeks, p=0.073. Of the alloHCT patients, 333 were alive: 57/333 (17%) had VLD, and 276/333 (83%) had been delayed <4 weeks (p=0.036). As of July 2014, 687/1247 (55%) patients have died, with a median time to death from start of intensification of 13.3 months (range 0.8-231). Survival analysis was stratified by post-remission therapy, with living patients censored at date last seen. Patients who received myeloablative allogeneic HCT (allo HCT) had poorer overall survival from start of intensification (OS-IS) and event free survival (EFS-IS) after LD or VLD. While OS-IS and EFS-IS were significantly worse for alloHCT patients after VLD (p=0.02 and p=0.03) respectively, survival was not worse for non-transplant patients after VLD (p=0.24 and p=0.10) (Figure I). In a multivariate Cox regression, adjusting for other high-risk disease features (age, cell lineage, and white cell count at diagnosis), patients who underwent allo HCT had significantly worse OS-IS (HR 1.4, p=0.02) and EFS-IS (HR 1.4, p=0.02) after experiencing VLD compared to alloHCT patients who experienced <4 weeks delay. When evaluating OS and EFS from diagnosis, VLD was still associated with poorer OS (HR 1.34, p=0.04) and EFS (HR 1.34, p=0.03). There was no difference in OS or EFS in patients who received non-transplant post-remission therapy based on delay. In a comprehensive analysis of the largest adult ALL study ever reported, we identified significant risk factors predictive of LD and VLD (>2 and >4 weeks beyond mandatory rest period). Our findings highlighted that patients were delayed because of chemotherapy toxicity and also identified healthcare disparities. VLD was associated with poorer OS and EFS in patients undergoing alloHCT, but not in patients undergoing non-transplant post remission therapy. Further studies are planned to prospectively identify patient barriers to on-schedule treatment with a goal of earlier intervention. The ability to better predict and intervene on risk factors for delay can improve adherence to protocol and optimize long-term survival. Table I: Multivariate Regression for LD and VLD Risk Factors Variable Odds Ratio 95% Confidence Interval p-value Days in the hospital Phase I Induction 1.01 1.00-1.02 0.04 Duration of Thrombocytopenia, Phase I 1.02 1.01-1.03 0.001 Age by Decade 1.2 1.08-1.31 <0.001 Reduced Dose in Induction 1.54 1.08-2.22 0.019 Sex, Female 1.56 1.22-2.0 <0.001 Race, Black 3.4 1.41-7.96 0.006 Figure 1 Figure 1. p=0.023 Disclosures No relevant conflicts of interest to declare.

Key Points Compared with parous female sibling donors, male URDs confer more aGVHD in all patients and more cGVHD in females. There was no difference in survival, relapse, or transplant mortality between recipients of parous female sibling or male URD grafts.

Adults with acute lymphoblastic leukemia (ALL) have a poorer prognosis than children due to a high risk of relapse. One explanation may be variable adherence to dose‐intense chemotherapy. However, little is known about risk factors for delays in therapy and their impact on survival. We conducted an analysis of ECOG 2993/UKALLXII trial to study delays in postremission chemotherapy in adults with newly diagnosed ALL. Logistic regression was used to identify risk factors for a very long delay (VLD, >4 weeks) in start of intensification therapy. Cox regression was used to evaluate the impact of delays on overall survival (OS) and event‐free survival (EFS). We evaluated 1076 Philadelphia chromosome negative (Ph−) patients who completed induction chemotherapy, achieved complete remission, and started intensification. Factors independently associated with VLD included duration of hospitalization (odds ratio [OR] = 1.2, P < 0.001) during Phase I; thrombocytopenia during Phase I (OR = 1.16, P = 0.004) or Phase II (OR 1.13, P = 0.001); chemotherapy dose reductions during Induction Phase I (OR = 1.72, P < 0.014); female sex (OR = 1.53, P = 0.010); Black (OR = 3.24, P = 0.003) and Asian (OR = 2.26, P = 0.021) race; and increasing age (OR = 1.31, P < 0.001). In multivariate Cox regression, patients who underwent allogeneic stem cell transplant (alloHCT) had significantly worse OS (HR 1.4, P = 0.03) and EFS (HR 1.4, P = 0.02) after experiencing a VLD compared to alloHCT patients who experienced ≤4 weeks delay. Specific populations (female, older, Black, and Asian patients) were more likely to experience delays in chemotherapy, as were those with significant toxicity during induction. VLDs in therapy negatively affected outcomes in patients undergoing allografting. Am. J. Hematol. 91:1107–1112, 2016. © 2016 Wiley Periodicals, Inc.