Khurana, Arushi

PURPOSE:High-dose methotrexate (HDMTX; > 500 mg/m2) is an important component of lymphoma therapy. Serum MTX monitoring at 48 hours is the standard approach to identify those at increased risk of developing MTX toxicity. Our aim was to characterize the incidence of complications and their association with MTX levels.METHODS:A retrospective review of our institutional electronic medical record was conducted to identify patients with lymphoma who received HDMTX between January 1, 2002, and December 31, 2018. We characterized the incidence of acute kidney injury (AKI), intensive care unit (ICU) admission, length of hospital stay (LOS), and 30-day mortality across 48-hour MTX levels. To establish an association between 48-hour MTX levels and the complications listed, we performed chi-square analysis for dichotomous variables and Kruskal-Wallis for nonparametric data. Receiver operator characteristic curve analysis was performed to identify the MTX level where AKI grade ≥ 2 was more likely. Multivariate logistic regression analysis was performed to identify risk factors for this MTX level.RESULTS:We identified 642 patients with 2,804 cycles of HDMTX. The incidence of AKI was 19.1% with AKI grade ≥ 2 making up 21% of cases. Rates of AKI, ICU admission, and 30-day mortality are associated with elevated 48-hour MTX levels. There was a significant increase in median LOS with elevated MTX levels ( P < .001). Receiver operator characteristic curve analysis for AKI grade ≥ 2 demonstrated a 48-hour MTX level threshold of 1.28 μmol/L. Multivariate logistic regression analysis revealed age, male sex, elevated body surface area, higher MTX dose, monotherapy, and first cycle as independent factors.CONCLUSION:Elevated MTX levels are associated with a significant increased rate of AKI, ICU admission, prolonged LOS, and 30-day mortality. Elevated 48-hour MTX levels, particularly > 1.28 μmol/L, should alert clinicians for complications and to initiate measures to reduce MTX levels.

Abstract Low-grade B-cell lymphomas other than follicular and small lymphocytic lymphoma (LGBCL) account for 10% of all B-cell non-Hodgkin lymphomas. Despite improvements in survival outcomes for these patients, little is known about cause of death (COD) in the rituximab era. For a better understanding, we studied 822 newly diagnosed patients with marginal zone, lymphoplasmacytic, and unclassifiable low-grade B-cell lymphoma prospectively enrolled in the University of Iowa/Mayo Clinic Specialized Program of Research Excellence Molecular Epidemiology Resource from 2002 to 2015. COD was assigned based on medical record review using a standard protocol. At a median follow-up of 107 months, 219 (27%) patients had died. The incidence of lymphoma-related deaths when pooling across subtypes was lower than non–lymphoma-related deaths (10-year incidence, 8.0%; 95% confidence interval [CI]: 6.2-10.4 vs 13.6%; 95% CI: 11.2-16.6). The incidence of lymphoma-related deaths varied by subtype, ranging from 3.7% at 10 years in extranodal marginal zone lymphoma to 19.3% in lymphoplasmacytic lymphoma/Waldenström macroglobulinemia. Patients with early progression or retreatment events, defined using event-free survival at 24 months from diagnosis, had significantly higher likelihood of lymphoma-related death compared with patients without early events (10-year estimate: 19.1% vs 5.1%, respectively; P &lt; .001), whereas the rates for non–lymphoma-related death were comparable in patients with or without early events (10-year estimates: 11.0% vs 15.3%, respectively). In conclusion, the most common COD in LGBCLs in the first decade after diagnosis was for causes other than lymphoma. Progression or retreatment within the first 2 years of diagnosis was a strong predictor for risk of lymphoma-related death.

7556 Background: The majority of R/R NHL progressions after CART involve pre-existing sites, suggesting a promising role for bridging radiotherapy (bRT). We assessed the local control rate of disease sites bridged with radiotherapy prior to CART and identified predictors of in-field recurrence. Methods: We retrospectively reviewed 35 patients with aggressive B-cell NHL who received bRT between leukapheresis and CART infusion between 2018 and 2021 at a multi-site single institution. bRT local control rate (LC), calculated based on the total number of irradiated sites, was defined from bRT end date. Progression-free survival (PFS) and overall-survival (OS) were defined from the date of CART infusion. In-field recurrence was defined as disease relapse occurring within the radiation planning target volume. Kaplan-Meier plots and cox regression modeling were used to estimate the desired output. Results: Median age of the cohort at time of CART infusion was 59 (range 19-73). The median equivalent 2 Gy dose (EQD2) administered was 23.3 Gy (range 4-41 Gy). The median time from end of bRT to CART infusion was 14 days (range 6-42). Five (14%) patients also received bridging chemotherapy with bRT. Among the 34 evaluable patients, 30 (88%) achieved an objective response (59% complete response and 29% partial response). At a median follow-up of 12 months, 1-year PFS was 48% and 1-year OS was 72%. No progression occurred beyond 240 days. On review of treatment plans and pre-treatment PET/CT scans, 59 sites were identified that received bRT prior to CART infusion. The median size and SUVmax of the irradiated sites were 8.7cm (range 1.5-22) and 13 (range 4-46), respectively. Of the 59 irradiated sites, 8 sites (13.6%) in 7 patients had in-field local recurrence, translating to 1-year LC of 84%. No in-field recurrence occurred beyond 180 days. Moreover, no local recurrence occurred in patients who received radiation to all known sites of active disease to EQD2> 30 Gy (n = 4 patients); these patients remained in remission except for 1 who experienced progression outside the bRT field. On univariate analysis, triple hit lymphoma (THL) (OR 22.8, 95% CI: 3.8-138.3; p < 0.001), tumor size (OR 1.25, 95% CI: 1.1-1.4; p < 0.001), specifically ≥ 9cm (OR 9.4, CI: 1.2-77.3; p = 0.036) and SUVmax (OR 1.1, CI: 1.02-1.15; p = 0.008), specifically ≥ 20 (OR 5.6, CI: 1.3-23.7; p = 0.018), were significantly associated with increased risk of in-field recurrence. On multivariate analysis, THL (OR 32.9, CI: 3.2-336.0; p = 0.03) and tumor size (OR 1.3, CI: 1.1-1.6; p = 0.01) retained significant association with in-field recurrence. Conclusions: Bridging radiotherapy prior to CART provides excellent and durable in-field local control for R/R B-cell NHL. Patients with triple hit histology and bulky disease are likely at higher risk of in-field recurrence and may benefit from higher doses of bRT.

Abstract Polatuzumab vedotin (PV) is an antibody–drug conjugate targeting CD79b that is approved for patients with relapsed/refractory large B-cell lymphoma (LBCL). Patients who relapse after chimeric antigen receptor (CAR) T-cell therapy were not included in the registration study, and reports of PV use after CAR T cells are limited. This multicenter retrospective analysis included patients with LBCL who relapsed or progressed after CAR T-cell therapy and subsequently received PV with or without rituximab and bendamustine between July 2019 and May 2021. Response to treatment and progression were assessed based on the 2014 Lugano criteria. Fifty-seven patients were included in the study: 18 (32%) patients were primary refractory to CAR T-cell therapy, and 34 (60%) patients received PV-based therapy immediately after CAR T-cell therapy. PV was combined with rituximab in 54 (95%) patients and administered with bendamustine in 35 (61%) patients. A response was achieved in 25 (44%) patients, including complete remission in 8 (14%). No significant association between baseline characteristics and response was observed. After a median follow-up of 47 weeks (95% confidence interval [CI], 40-54), 46 (81%) patients had disease progression or died, and the median progression-free survival was 10 weeks (95% CI, 5-15). On a multivariate analysis, bone marrow involvement (hazard ratio, 5.2; 95% CI, 1.8-15; P = .003) and elevated lactate dehydrogenase levels (hazard ratio, 5.0; 95% CI, 1.4-16; P = .01) were associated with shorter progression-free survival. Studies aimed at better characterizing the intrinsic mechanism of resistance and identifying optimal consolidation strategies for these patients are warranted.

Abstract Introduction. About 60% of patients with large B-cell lymphoma (LBCL) relapse after standard of care (SOC) anti-CD19 autologous chimeric antigen receptor (CAR) T-cell therapy, CD19 downregulation representing a major mechanism of resistance. Therefore, agents able to target B-cell antigens other than CD19 could be clinically effective for these patients. Polatuzumab vedotin (PV) is an antibody-drug conjugate targeting CD79b, and approved by the FDA in combination with bendamustine and rituximab for patients with relapsed or refractory (r/r) LBCL. Patients who relapsed after CAR T-cell therapy were not included in the registration study, and reports of PV use after CAR T-cells in real world practice are very limited. Methods. This is a multi-center retrospective analysis of patients with LBCL who relapsed after SOC CAR T-cell therapy and subsequently received SOC PV with or without rituximab and bendamustine between 07/2019 and 04/2021. PV was given at the standard dose of 1.8 mg/kg IV every 3 weeks in all patients (except for one patient, who received 1.4 mg/Kg). Response to treatment and progression were defined according to 2014 Lugano criteria. Survival curves were calculated using Kaplan-Meier estimates, and were compared between subgroups using the log-rank test. Cox regression was used for multivariate analysis (MVA). Results. Fifty-four patients were included in the study: median age was 59 (range, 22-79 years), 38 (70%) were male, and 30 (56%) had an internal prognostic index score &gt; 3. Median number of systemic therapies before CAR T-cell therapy was 2 (range, 2-6), 16 (30%) patients previously had autologous stem cell transplant (SCT), and 2 (4%) had allogeneic SCT. Sixteen (30%) patients were primary refractory to CAR T-cell therapy, and median time from CAR T-cell therapy to PV was 5 months (range, 1-40 months). CD19 status at time of relapse after CAR T-cell therapy was assessed by immunohistochemistry and/or flow cytometry in 41 patients, and positive in 34 (83%); CD79b status was assessed in 14 patients, and positive in all cases (100%). Thirty-two (59%) patients received PV-based therapy immediately after CAR T cell therapy, while 22 (41%) had intervening treatments (median 1, range 1-5). At time of PV initiation, median absolute neutrophil count was 2.9 (range 0.5-19 X10 9/L), median platelet count was 87 X10 9/L (range 15-437 X10 9/L), median serum creatinine was 0.9 mg/dL (range 0.4-22 mg/dL), and 44 (81%) patients had elevated serum lactate dehydrogenase (LDH). The median number of PV cycles was 2 (range, 1-16): PV was combined with rituximab in 51 (94%) patients, and administered with bendamustine in 33 (61%). A response was achieved in 24 (45%) patients, including complete remission (CR) in 8 (14%) patients and partial remission in 16 (30%)(Figure A), with a median duration of response of 11 weeks (95%CI, 5-17 weeks). No significant association between baseline characteristics and response was observed. To date, 49 (91%) patients stopped PV: 38 (70%) due to progression, 7 (13%) because of CR/patient decision, 3 (6%) to proceed to allogeneic SCT, and 1 (2%) to proceed to an immunotherapy clinical trial (despite absence of progression). No patients stopped therapy because of toxicity. After a median follow up of 45 weeks (95% CI, 20-70 weeks), 44 (81%) patients progressed/died, and median PFS was 9 weeks (95% CI, 4-14 weeks). To date, 34 (63%) died, and median OS was 16 weeks (95% CI, 13-19 weeks)(Figure B). Causes of death included progression in 31 patients and transplant-related complications in 3. On univariate analysis, a shorter median progression-free survival (PFS) was observed for patients with bone marrow (BM) involvement (3 vs 10 weeks, p=0.002), prior central nervous system involvement (4 vs 10 weeks, p=0.02), and elevated LDH (6 months vs not reached, p=0.004). On MVA, the association was maintained only for BM involvement (hazard ratio [HR] 4.8; 95% confidence interval [CI] 1.6-12.5, p=0.004) and elevated LDH (HR 5; 1.4-16.7, p=0.01)(Figure C). Discussion. PV is safe and effective, but has short duration of response in r/r LBCL after anti-CD19 CAR T-cell therapy, except for patients with normal LDH. Studies aimed at better characterizing intrinsic mechanism of resistance, including upregulation of BCL2 family proteins, to favor the development of more effective PV-based combination strategies for these patients, are warranted. Figure 1 Figure 1. Disclosures Crombie: Roche: Research Funding; Merck: Research Funding; Abbvie: Research Funding; Bayer: Research Funding; Karyopharm: Consultancy; Incyte: Consultancy. Kamdar: Celgene (BMS): Consultancy; Adaptive Biotechnologies: Consultancy; Genentech: Research Funding; Kite: Consultancy; AstraZeneca: Consultancy; ADC Therapeutics: Consultancy; Genetech: Other; TG Therapeutics: Research Funding; SeaGen: Speakers Bureau; Celgene: Other; KaryoPharm: Consultancy; AbbVie: Consultancy. Hess: ADC Therapeutics: Consultancy; BMS: Speakers Bureau. Neelapu: Takeda Pharmaceuticals and related to cell therapy: Patents & Royalties; Kite, a Gilead Company, Bristol Myers Squibb, Merck, Poseida, Cellectis, Celgene, Karus Therapeutics, Unum Therapeutics (Cogent Biosciences), Allogene, Precision BioSciences, Acerta and Adicet Bio: Research Funding; Kite, a Gilead Company, Merck, Bristol Myers Squibb, Novartis, Celgene, Pfizer, Allogene Therapeutics, Cell Medica/Kuur, Incyte, Precision Biosciences, Legend Biotech, Adicet Bio, Calibr, Unum Therapeutics and Bluebird Bio: Honoraria; Kite, a Gilead Company, Merck, Bristol Myers Squibb, Novartis, Celgene, Pfizer, Allogene, Kuur, Incyte, Precision BioSciences, Legend, Adicet Bio, Calibr, and Unum Therapeutics: Other: personal fees. Lin: Novartis: Consultancy; Bluebird Bio: Consultancy, Research Funding; Juno: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Gamida Cell: Consultancy; Sorrento: Consultancy; Legend: Consultancy; Takeda: Research Funding; Merck: Research Funding; Vineti: Consultancy. Strati: Astrazeneca-Acerta: Research Funding; Roche-Genentech: Consultancy.

Abstract Introduction: Chimeric antigen receptor T-cell (CAR-T) therapy is an effective treatment that has transformed hematologic malignancy management. However, its significant short-term toxicities, mainly cytokine release syndrome (CRS) and neurotoxicity, require frequent monitoring almost universally achieved via prolonged inpatient admissions. We have reported our institution's specialized, multi-disciplinary hospital-based outpatient (HBO) CAR-T service and experience (Bansal et.al, ASCO 2021). To enhance the HBO practice, we implemented a remote patient monitoring (RPM) program, comprised of in-home, electronic health record-integrated technology to monitor vital signs and neurologic symptoms for 30 days post CAR-T infusion. The RPM program's triaging algorithm generates alerts based on predetermined parameters to guide escalation of care if needed. In this report, we describe the characteristics of RPM program patients (pts), focusing on the alerts received within 48 hours (h) of first hospitalization in the post-CAR-T setting. Methods: Pts undergoing commercial CAR-T cell therapy at Mayo Clinic Rochester were enrolled in the RPM program as part of our standard of care from 06/2020 to 05/2021. Pts with detailed RPM data available were included in this analysis. Patient characteristics, health care utilization, inpatient interventions, and RPM alert data were reviewed. Wilcoxon test was used for continuous variables, chi-squared test was used for categorical variables. Results: Baseline characteristics are summarized in Table 1. Of 20 pts in this analysis, 13 had RPM alerts in the 48h preceding the first hospitalization post CAR-T. For the remaining 7 pts without RPM alerts, 3 were hospitalized within 24h of CAR-T infusion without significant RPM data, 1 patient hospitalized with acute pancreatitis (day +8 post CAR-T infusion), 1 for doubling of CRP (day +10), 1 for acute pain crisis (day +5), and 1 with neutropenic fever (day +5) with not reporting RPM data. The median RPM program duration was 18 days (range 3-32) which accounts for interruptions in the RPM monitoring while pts are hospitalized. The median number of data points per patient was 231 (range 22-532), with a median of 20 alerts per patient (range 2-81). The median missing data points per patient were 20 (10%) (range 0-95). Of the 13 pts with RPM alerts within 48h of first hospitalization, alerts met our definition of urgent criteria in 6 pts [temperature (temp) &gt; 100F (n=3), temp &gt; 100F + tachycardia (n=1), temp &gt; 100F + hypoxia (n=1), and hypoxia (n=1)]. In the remaining 7 pts, the RPM alerts met our routine criteria definition [temp 99-100 (n=2), tachycardia + hypertension + weight loss (n=2), hypertension (n=2), new incontinence (n=1)]. CRS was reported in 12 pts [grade 1-2 (n=11), grade 3-4 (n=1)] and neurotoxicity in 8 pts [grade 1-2 (n=7), grade 3-4 (n=1)]. The median post CAR-T first hospitalization day was day +4 (range day +2-10), Figure 1. The median time from the last RPM alert to hospitalization was 5.8h for pts meeting urgent criteria vs 10.8h for those meeting routine criteria (p=0.13). Tocilizumab was used in 5 pts during the first hospitalization [3 (50%) in the urgent criteria group and 2 (28%) in the routine criteria group], with a median time from admission to tocilizumab of 12h in the urgent criteria group vs 43h in the routine criteria group (p=0.05). Early hospitalization (≤ 3 days) post CAR-T infusion was associated with later need for tocilizumab [median 51h (range 30-57) vs. 11.5h (range 6-33) from admission, p=0.03] than late hospitalization (&gt; 4 days post CAR-T). Upon admission, oxygen supplementation was started on both pts with hypoxia noted in the RPM alerts. Only 1 patient (routine criteria group) required use of vasopressors while hospitalized, initiated more than 48h after admission. Conclusion: A CAR-T RPM program can identify adverse symptoms and vital sign changes in CAR-T pts managed in the outpatient setting. In this pilot implementation, the CAR-T RPM triaging algorithm identified pts requiring expedited hospitalization and facilitated early initiation of tocilizumab. The intermittent monitoring and proportion of missing data are the main limitations of the RPM in the acute care setting post-CAR-T infusion. Incorporation of wearable devices for continuous remote monitoring is being explored as a mitigating strategy to these limitations. Figure 1 Figure 1. Disclosures Paludo: Karyopharm: Research Funding. Dingli: Apellis: Consultancy; Janssen: Consultancy; GSK: Consultancy; Novartis: Research Funding; Sanofi: Consultancy; Alexion: Consultancy. Kapoor: Glaxo SmithKline: Research Funding; Sanofi: Consultancy; Amgen: Research Funding; AbbVie: Research Funding; Sanofi: Research Funding; Karyopharm: Research Funding; Ichnos Sciences: Research Funding; Pharmacyclics: Consultancy; Takeda: Research Funding; Regeneron Pharmaceuticals: Research Funding; Karyopharm: Consultancy; Cellectar: Consultancy; BeiGene: Consultancy. Gertz: Aurora Biopharma: Other: Stock option; Ionis Pharmaceuticals: Other: Advisory Board; Akcea Therapeutics, Alnylam Pharmaceuticals Inc, Prothena: Consultancy; AbbVie Inc, Celgene Corporation: Other: Data Safetly & Monitoring; Akcea Therapeutics, Ambry Genetics, Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Karyopharm Therapeutics, Pfizer Inc (to Institution), Sanofi Genzyme: Honoraria. Wang: InnoCare: Research Funding; LOXO Oncology: Membership on an entity's Board of Directors or advisory committees, Research Funding; MorphoSys: Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; Genentech: Research Funding; Eli Lilly: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kenderian: Humanigen, Inc.: Consultancy, Honoraria, Research Funding. Kumar: Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Research Funding; Oncopeptides: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche-Genentech: Consultancy, Research Funding; Carsgen: Research Funding; Antengene: Consultancy, Honoraria; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Bluebird Bio: Consultancy; Beigene: Consultancy; Tenebio: Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding. Bennani: Purdue Pharma: Other: Advisory Board; Daichii Sankyo Inc: Other: Advisory Board; Kyowa Kirin: Other: Advisory Board; Vividion: Other: Advisory Board; Kymera: Other: Advisory Board; Verastem: Other: Advisory Board. Ansell: Bristol Myers Squibb, ADC Therapeutics, Seattle Genetics, Regeneron, Affimed, AI Therapeutics, Pfizer, Trillium and Takeda: Research Funding. Lin: Merck: Research Funding; Vineti: Consultancy; Gamida Cell: Consultancy; Juno: Consultancy; Bluebird Bio: Consultancy, Research Funding; Legend: Consultancy; Celgene: Consultancy, Research Funding; Sorrento: Consultancy; Takeda: Research Funding; Janssen: Consultancy, Research Funding; Novartis: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding.