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Concurrent administration pembrolizumab with chemotherapy in untreated classical Hodgkin lymphoma (CHL) has not previously been studied. To investigate this combination, we conducted a single arm study of concurrent pembrolizumab with AVD (APVD) for untreated CHL. We enrolled 30 patients (6 early favorable, 6 early unfavorable, and 18 advanced stage, median age 33 years (range 18-69 years)) and met the primary safety endpoint with no observed significant treatment delays in the first two cycles. Twelve patients experienced grade 3-4 non-hematologic adverse events (AEs) most commonly febrile neutropenia (5, 17%) and infection/sepsis (3, 10%). Grade 3-4 immune-related AEs were seen in 3 patients, including ALT elevation (3, 10%) and AST elevation (1, 3%). One patient experienced an episode of grade 2 colitis and arthritis. Six (20%) patients missed at least one dose of pembrolizumab due to adverse events, primarily grade 2 or higher transaminitis (5, 17%). Among 29 response-evaluable patients, the best overall response rate was 100% and CR rate of 90%. With median follow up of 2.1 years, 2-year progression-free survival (PFS) and overall survival were 97% and 100%, respectively. To date, no patient who withheld or discontinued pembrolizumab due to toxicity has progressed. Clearance of ctDNA was associated with superior PFS when measured after cycle 2 (p=0.025) and at end of treatment (EOT, p=0.0016). None of the 4 patients with persistent disease by FDG-PET at EOT yet negative ctDNA have relapsed to date. Concurrent APVD shows promising safety and efficacy, but may yield spurious PET findings in some patients. Trial Registration Number: NCT03331341

The POLARIX trial demonstrated the superiority of polatuzumab vedotin (Pola) over vincristine in the R-CHOP regimen for large B-cell lymphomas, but it is unknown if Pola can be safely incorporated into intensified regimens (eg. DA-EPOCH-R) typically utilized for the highest risk histologies. This was a single-center, open label, prospective clinical trial of 6 cycles of Pola-DA-EPCH-R in aggressive large B-cell lymphomas. The primary endpoint was to estimate the safety of Pola-DA-EPCH-R as measured by the rate of dose-limiting toxicities (DLTs) in the first 2 cycles with pre-specified suspension rules. Secondary and exploratory endpoints included efficacy and correlation with ctDNA levels. We enrolled 18 patients on study, and with only three DLTs observed, the study met its primary endpoint for safety. There were five serious adverse events including grade 3 febrile neutropenia (3, 17%), grade 3 colonic perforation in the setting of diverticulitis (1, 6%), and grade 5 sepsis/typhlitis (1, 6%). Among 17 evaluable patients, the best overall response rate was 100% and complete response rate of 76%. With median follow up of 12.9 months, 12-month EFS was 72% (95% CI 54-96%) and 12-month OS was 94% (95% CI 84-100%). No patient with undetectable ctDNA at the end of treatment has relapsed to date. Using Pola to replace vincristine in the DA-EPOCH-R regimen met its primary safety endpoint. These data support the further evaluation and use of this approach in histologies where the potential benefit of both an intensified regimen and Pola may be desired.

Summary Background Relapsed or refractory classical Hodgkin lymphoma could be treated with multiagent salvage chemotherapy followed by autologous haematopoietic stem-cell transplantation. The aim of this study is to establish the safety and activity of dose-dense brentuximab vedotin combined with ifosfamide, carboplatin, and etoposide (BV-ICE) chemotherapy in second-line treatment of classical Hodgkin lymphoma. Methods We conducted a single-arm, open-label, phase 1/2 study of dose-dense BV-ICE at the Seattle Cancer Care Alliance, University of Washington (Seattle, WA, USA). Eligibility criteria were age 18 years or older; diagnosis of first relapse, primary refractory classical Hodgkin lymphoma after one previous line of therapy; measurable disease of at least 1 cm in the longest axis, CT of chest, abdomen, and pelvis with PET within the past 28 days; Eastern Cooperative Oncology Group performance status of 0–1; and adequate organ function. A 3 + 3 dose escalation study was done for the phase 1 part of the trial to establish the maximum tolerated dose to be used for the phase 2 study. Brentuximab vedotin was delivered on days 1 and 8 at either 1·2 mg/kg (dose level 1) or 1·5 mg/kg (dose level 2) intravenously (capped at 150 mg) with standard dosing of ICE on days 1–3 (ifosfamide 5 g/m2 plus mesna 5 g/m2 intravenously over 24 h on day 2, carboplatin area under the curve 5 on day 2 in one intravenous injection, and etoposide 100 mg/m2 on days 1–3 in one intravenous injection per day) for two 21-day cycles. The primary endpoint was to establish the recommended phase 2 dose (phase 1 part) and complete response rate after two cycles, with a prespecified target of 78% (phase 2 part). Safety analysis was done in all enrolled participants and the primary activity analysis was done in all patients with evaluable response data. This study is registered with ClinicalTrials.gov (NCT02227199); enrolment and study treatment are complete. Findings Between Oct 16, 2014, and Feb 10, 2020, we enrolled 45 patients with a median age of 31 years (IQR 28–45). The recommended phase 2 dose of brentuximab vedotin was established to be 1·5 mg/kg. After a median follow-up of 3·1 years (IQR 1·7–4·1), 32 (74%; 95% CI 58·8–86·5) of 43 evaluable patients had complete responses after two cycles of treatment. Grade 3–4 haematological toxic effects were common, including neutropenia (33 [73%]), anaemia (six [13%]), and thrombocytopenia (36 [80%]). The most common grade 3–4 non-haematological toxic effects were febrile neutropenia (four [9%]), sepsis (six [13%]), increased alanine aminotransferase (five [11%]), hyperglycaemia (three [7%]), pulmonary embolism (two [4%]), and increased aspartate aminotransferase (two [4%]). There was one (2%) on-treatment death due to multisystem organ failure that was considered treatment related. Serious adverse events occurred in 13 (29%) patients. Interpretation Our data suggest that dose-dense BV-ICE is a rapidly administered and active salvage regimen for patients with relapsed or refractory classical Hodgkin lymphoma despite a complete response in this trial lower than the prespecified phase 2 target. Although cross-trial comparisons should be made with caution, activity results seem to be similar to previously presented brentuximab vedotin chemotherapy salvage combinations delivered over much longer durations and can be considered in young ( Funding Seagen, Lymphoma Research Foundation, National Institutes of Health/National Cancer Institute, and generous philanthropic donations to the University of Washington from numerous individuals and families in support of lymphoma research.

Patients with core-binding factor (CBF) acute myeloid leukemia (AML), caused by either t(8;21)(q22;q22) or inv(16)(p13q22)/t(16;16)(p13;q22), have higher complete remission rates and longer survival than patients with other subtypes of AML. However, ∼40% of patients relapse, and the literature suggests that patients with inv(16) fare differently from those with t(8;21). We retrospectively analyzed 537 patients with CBF-AML, focusing on additional cytogenetic aberrations to examine their impact on clinical outcomes. Trisomies of chromosomes 8, 21, or 22 were significantly more common in patients with inv(16)/t(16;16): 16% vs 7%, 6% vs 0%, and 17% vs 0%, respectively. In contrast, del(9q) and loss of a sex chromosome were more frequent in patients with t(8;21): 15% vs 0.4% for del(9q), 37% vs 0% for loss of X in females, and 44% vs 5% for loss of Y in males. Hyperdiploidy was more frequent in patients with inv(16) (25% vs 9%, whereas hypodiploidy was more frequent in patients with t(8;21) (37% vs 3%. In multivariable analyses (adjusted for age, white blood counts at diagnosis, and KIT mutation status), trisomy 8 was associated with improved overall survival (OS) in inv(16), whereas the presence of other chromosomal abnormalities (not trisomy 8) was associated with decreased OS. In patients with t(8;21), hypodiploidy was associated with improved disease-free survival; hyperdiploidy and del(9q) were associated with improved OS. KIT mutation (either positive or not tested, compared with negative) conferred poor prognoses in univariate analysis only in patients with t(8;21).

Background Histologic transformation to diffuse large B-cell lymphoma (tDLBCL) occurs in a significant proportion of indolent lymphomas. However, few studies of novel agents inform its management, particularly when relapsed after or refractory (R/R) to prior treatment. Patients and Methods We prospectively evaluated ibrutinib monotherapy in pathologically documented patients with R/R tDLBCL in a single-arm study. The primary endpoint was overall response rate. Results Twenty patients who had received a median of 4 (range, 2-9) prior lines of therapy overall (median, 2.5; range, 1-9 for tDLBCL) were treated. The overall response rate was 35%, including complete responses in 15%. The median progression-free survival and overall survival were 4.1 months (95% confidence interval, 2.4-6.2 months) and 22.4 months (95% confidence interval, 7.5 months to not reached), respectively. Disease control > 2 months was seen in 75% and > 1 year in 15%. Response was associated with either low tumor bulk or low metabolic tumor volume (P = .05) but not with antecedent lymphoma histology (P = 1.0). Treatment-related adverse events were consistent with prior studies of ibrutinib. Conclusions Ibrutinib showed low toxicity and meaningful efficacy in R/R tDLBCL, including short-term disease control in most cases. Results demonstrate the potential utility of ibrutinib in this challenging clinical setting, including as a potential bridge to more definitive treatments.

Purpose: This clinical trial combined pembrolizumab and vorinostat in recurrent/metastatic squamous cell carcinomas of the head and neck (HN), and salivary gland cancer (SGC). Patients and Methods: Patients with progressing incurable HN and SGC, Eastern Cooperative Oncology Group (ECOG) ≤1, no prior immunotherapy, RECIST1.1 measurable disease, and normal organ function were eligible. Pembrolizumab 200 mg was given intravenous every 21 days, and vorinostat 400 mg given orally 5 days on and 2 days off during each 21-day cycle. Primary endpoints were safety and objective response rates. Results: From November 2015 to August 2017, 25 patients with HN and 25 SGC were enrolled. Median age was 61 (range, 33–86) years, 39 (78%) were male, 21 (62%) were never smokers, and 27 (54%) had ECOG 0. In HN, 13 (52%) were p16+ oropharynx. Most common SGC histologies were adenoid cystic 12 (48%), acinic cell 3 (12%), and mucoepidermoid 3 (12%). Adverse events (AEs) in all patients were: 27 (54%) with grade ≥ 1 and 18 (36%) with grade ≥ 3. The most common AEs in all patients were renal insufficiency in seven, (14%), fatigue in six, (12%), and nausea in three (6%). There were three (12%) deaths on study. Responses in HN were complete response (CR) 0, partial response (PR) eight (32%), and stable disease (SD) five (20%). Efficacy in SGCs was CR 0, PR four (16%) in one lymphoepithelioma-like carcinoma, two acinic cell, one adenoid cystic, and SD 14 (56%). In the HN group, median follow-up (mFUP) was 12.6 months, median overall survival (mOS) was 12.6 months, and median progression-free survival (mPFS) was 4.5 months. In SGC, mFUP was 13.1 months, mOS was 14.0 months, and mPFS was 6.9 months. Conclusions: This combination demonstrated activity in HN, with fewer responses in SGC. Toxicities were higher than reported with pembrolizumab alone.

Purpose: The outgrowth of antigen-negative variants is a significant challenge for adoptive therapy with T cells that target a single specificity. Chimeric antigen receptors (CAR) are typically designed with one or two scFvs that impart antigen specificity fused to activation and costimulation domains of T-cell signaling molecules. We designed and evaluated the function of CARs with up to three specificities for overcoming tumor escape using Designed Ankyrin Repeat Proteins (DARPins) rather than scFvs for tumor recognition. Experimental Design: A monospecific CAR was designed with a DARPin binder (E01) specific for EGFR and compared with a CAR designed using an anti-EGFR scFv. CAR constructs in which DARPins specific for EGFR, EpCAM, and HER2 were linked together in a single CAR were then designed and optimized to achieve multispecific tumor recognition. The efficacy of CAR-T cells bearing a multispecific DARPin CAR for treating tumors with heterogeneous antigen expression was evaluated in vivo. Results: The monospecific anti-EGFR E01 DARPin conferred potent tumor regression against EGFR+ targets that was comparable with an anti-EGFR scFv CAR. Linking three separate DARPins in tandem was feasible and in an optimized format generated a single tumor recognition domain that targeted a mixture of heterogeneous tumor cells, each expressing a single antigen, and displayed synergistic activity when tumor cells expressed more than one target antigen. Conclusions: DARPins can serve as high-affinity recognition motifs for CAR design, and their robust architecture enables linking of multiple binders against different antigens to achieve functional synergy and reduce antigen escape.

296 Background: Immune checkpoint inhibitors (ICI) are approved for recurrent and/or metastatic squamous head and neck cancers (R/M HNSCC). Landmark trials have shown stable or improved patient (pt) reported quality of life outcomes. It is unclear how these translate into gastrostomy (G) and tracheostomy (T) dependence, opioid use, or ER/unplanned hospitalizations (UH) in an unselected population. We sought to explore these in our large single institution cohort. Methods: We reviewed R/M HNSCC pts receiving ICI at a tertiary referral NCI designated cancer center. Outcomes were assessed between the first dose of ICI and 100 days after the last dose of ICI. Overall survival (OS) was estimated via Kaplan-Meier estimation. Differences between groups were assessed via log-rank testing procedure and adjusted for age, tumor characteristics, and smoking status. Results: Between 1/2012 and 12/2019, we treated 152 pts with ICI, mostly male (n = 142, 82%), partnered/married (n = 103, 68%), with median age 64 years (range 23 – 90). The most common primary sites were oropharynx (n = 55, 36%) and oral cavity (n = 33, 22%). 50 (35%) had ≥2 lines of prior systemic therapy and 29 (19%) had an ECOG ≥2. The most common pt races were white (n = 114, 75%), Asian (n = 14, 9%), and Hispanic, any race (n = 6, 4%). 83 (55%) and 23 (15%) had history of smoking and heavy alcohol use respectively. Median duration of ICI therapy was 95 days (range 1-1720). Prior to ICI, 49 (32%) had G, 17 (11%) had T, and 15 (10%) had both. While on ICI, 6 (4%) had G placed, and 1 (1%) had a G removed; 1 (1%) had T placed, and 2 (1%) had T removed. 69 (45%) had ER visits and 57 (38%) had UH; 11 (7%) were directly related to ICI adverse effects. Prior to ICI, 104 (68%) were on opiates; requirements increased in 58 (41%) pts and decreased in 17 (12%) pts. Pre-existing G prior to ICI had worse OS on log-rank testing, but significance was lost when adjusted for variables. Pre-existing T prior to ICI (p = 0.001, HR 3.08, 95% Cl [1.56,6.08]), and pts with increasing opiate requirements on ICI (p value = 0.0007, HR 2.13, 95% Cl [1.38,3.28]) had worse OS. Conclusions: In our cohort, ICI did not change G or T usage. Pre-existing T and increasing opiate use were also associated with worse survival. Our data supports augmentation of palliative care and advanced care planning in the R/M HNSCC population.

153 Background: Immune checkpoint inhibitors (ICI) are now a therapeutic standard for recurrent/metastatic head and neck squamous cell cancer (R/M HNSCC). There is limited data on the impact of demographics and socioeconomic (SES) factors on outcomes in this population, and we sought to evaluate these in our single institution cohort. Methods: R/M HNSCC patients (pts) receiving ICI were retrospectively reviewed from an institutional database. SES factors included income, distance to center (dist), marital status, race, and insurance. Median household income by residence zip code was obtained from the US Census Bureau. Time to ICI initiation (TTI) was time from initial visit recommending ICI and first ICI dose. Opiate use was calculated using morphine equivalents prior to ICI initiation and either at best response or end of ICI if no response. Associations between SES factors with overall survival (OS) and TTI were assessed using Cox proportional hazards regression. Binary outcomes were assessed using logistic regression and included ER visits/unplanned hospitalizations (UH) and increase in opioid use. Analyses were adjusted for disease characteristics, smoking status, ECOG, and demographics. Results: Between 1/2012-12/2019, 152 pts received ICI; 124 (82%) were male, with median age of 64 years (range 23-90), and 103 (68%) were partnered/married. The most common races were 114 white (75%), 14 Asian (9%) and 6 Hispanic, any race (4%). Out of 149 (98%) insured pts, 27 (18%) were Medicaid and 69 (46%) Medicare. Median dist was 39 miles (Q1 21, Q3 100), and median income was $80,586 (Q1 $61,202, Q3 $103,059). The most common primary sites were oropharynx (36%), oral cavity (22%), and nasopharynx (7%); 29 (19%) had an ECOG ≥2. While on or within 100 days of ICI, 69 (45%) had ER visits, and 57 (38%) had UH. Increased dist was associated with improved OS (4th vs 1st quartile, p = 0.0002; HR 0.33; 95% CI [0.18,0.59]); we observed no other SES association with OS. Increased opioid use was associated with Medicaid/no insurance (p = 0.05; OR 2.89; 95% CI [1.02,8.77]). No SES association with TTI was found, although there was a nonsignificant trend of higher TTI with increasing dist. We saw no correlation with ER/UH and any SES variables. Conclusions: Among R/M HNSCC pts receiving ICI, insurance had an impact on opiate usage, suggesting more advance disease/higher burden of symptoms and indicating need for augmentation of supportive care in this group. Higher dist was associated with improved OS, even accounting for performance status, which may reflect increased resources in this group. Further studies should examine pt factors that may contribute to disparities in the setting of novel therapies for R/M HNSCC pts.

Background: Classical Hodgkin lymphoma (CHL) patients (pts) requiring second line therapy may still be cured with multiagent salvage chemotherapy followed by autologous stem cell transplant (ASCT). The likelihood of long-term remission following ASCT for relapsed/refractory (R/R) CHL is predicted by response to pre-ASCT salvage therapy (Moskowitz et al. Blood 2012). The anti-CD30 antibody-drug conjugate brentuximab vedotin (BV) is effective as a single agent in R/R CHL. We hypothesized that concurrent therapy with dose-dense BV and 2 cycles of ICE would be safe, efficient, and produce high CR rates necessary for superior outcomes after ASCT. (#NCT02227199) Methods: Patients (pts) ≥ 18 years old with first relapse or primary refractory CD30+ cHL were eligible for this IRB-approved prospective clinical trial. Treatment included BV on Days 1 and 8 at either 1.2 or 1.5 mg/kg (based on 3+3 dose-escalation schema; capped at 150 mg), ifosfamide and mesna 5 g/m2 each on Day 2, carboplatin AUC 5 (capped at 800 mg) on Day 2, and etoposide 100 mg/m2 daily on Days 1-3. Two 21-day cycles were given with G-CSF support. BV 1.5 mg/kg was selected as the phase II dose based on reported dose escalation data (ASH 2016, #1834). PET was performed after Cycle 2, with response assigned per Cheson 2007. Stem cells were collected after Cycle 2 at discretion of treating investigator. Peripheral blood (PB) pre- and post-treatment, stem cell (PBSC) product, and (when available) archived formalin-fixed paraffin-embedded tissue (FFPET) from presentation and relapse were collected for correlative studies. Pre-treatment PB cytokine levels were measured by Luminex. Immunohistochemistry (IHC) on FFPET identified components of inflammatory microenvironment. The primary endpoint was to determine the MTD and CR rate after 2 cycles. Secondary endpoints included PFS, OS, stem cell collection, and molecular correlates. Results: All 45 pts have enrolled and completed study treatment, including 42 pts who were assigned treatment at the MTD of 1.5 mg/kg on day 1 and 8 of each cycle. Median age was 31 (range, 21-61). 16/45 (36%) were male, 28/45 (62%) had primary refractory disease, and 11/45 (24%) had extranodal involvement at relapse. 41 pts completed both cycles of therapy. One pt experienced grade 5 multi-system organ-failure during cycle 1, one pt was removed from protocol due to non-compliance, and two pts omitted cycle 2 due to toxicity (grade 4 sepsis, grade 3 Sweet syndrome attributable to G-CSF). 2 pts received all ICE dosing, but omitted at least one dose of BV due to toxicity. In addition, 13/41 (32%) pts delayed initiation of cycle 2 by a median of 7 days (range 6-17) due to toxicity, primarily elevated transaminases (10/13, 77%). 16/45 (36%) pts experienced neuropathy, but grade ≥2 neuropathy was rare (3/45, 7%). Other grade 3-4 non-hematologic toxicity included febrile neutropenia/sepsis (11%), elevated ALT (11%), hyperglycemia (7%), pulmonary embolism (4%), and elevated AST (4%). 36 pts underwent PBSC collection at our institution and had all data available for analysis. 30/36 pts were able to collect at least 5x106 CD34+ cells/kg. 5/6 of the remaining pts were still able to proceed with ASCT with the amount collected, and the other pt was not deemed an ASCT candidate due to social reasons. 37/43 pts (86%) who were evaluable for response proceeded to ASCT (2 subjects declined ASCT, 2 were ineligible due to social issues, one was lost to follow up, one remained chemorefractory despite additional salvage chemotherapy). Only 4/37 pts who received an ASCT subsequently relapsed. 43 pts were evaluable for efficacy. Overall response rate (ORR) and CR for all enrolled patients were 91% and 74%, respectively. Among primary refractory pts, ORR and CR were 86% and 68%, respectively. With a median follow-up of 26.5 months (range 0.7-62) months, 2-year PFS and OS were 82% and 98%. Updated results will be presented at the meeting. Conclusions: BV-ICE is a rapid, active and tolerable salvage regimen for R/R CHL patients, including those with primary refractory disease. Efficacy results are comparable to previously presented BV-chemo salvage combinations often delivered over longer durations. BV-ICE should be considered in R/R CHL prior to ASCT. Figure Disclosures Lynch: Juno Therpeutics: Research Funding; TG Therapeutics: Research Funding; Takeda: Research Funding; Incyte: Research Funding; Rhizen Pharmaceuticals: Research Funding; Bayer: Research Funding; Cyteir: Research Funding; MorphoSys: Consultancy; Genentech: Research Funding. Cassaday:Merck: Research Funding; Amgen: Consultancy, Research Funding; Pfizer: Honoraria, Research Funding; Vanda Pharmaceuticals: Research Funding; Seattle Genetics: Current Employment, Current equity holder in publicly-traded company; Kite/Gilead: Consultancy, Research Funding. Smith:AstraZeneca: Research Funding; Acerta Pharma BV: Research Funding; Beigene: Consultancy; Millenium/Takeda: Consultancy; AstraZeneca: Consultancy; Seattle Genetics: Research Funding; Portola: Research Funding; Pharmacyclics: Research Funding; Merck: Research Funding; Incyte: Research Funding; Ignyta: Research Funding; Genentech: Research Funding; De Novo Biopharma: Research Funding; Bristol Meyers Squibb: Research Funding; Bayer: Research Funding; Ayala: Research Funding; Karyopharm: Consultancy. Fromm:Merck: Research Funding. Cowan:Abbvie: Research Funding; Bristol Myers Squibb: Research Funding; Cellectar: Consultancy; Sanofi: Consultancy; Janssen: Consultancy, Research Funding. Shadman:Mustang Bio, Celgene, Pharmacyclics, Gilead, Genentech, Abbvie, TG therapeutics, Beigene, Astra Zeneca, Sunesis, Beigene: Research Funding; Abbvie, Genentech, Astra Zeneca, Sound Biologics , Pharmacyclics, Verastem, ADC therapeutics, Beigene, Cellectar, BMS, Morphosys and Atara Biotherapeutics: Consultancy. Shustov:Seattle Genetics: Research Funding. Till:Mustang: Patents & Royalties, Research Funding. Ujjani:MorphoSys: Consultancy; Genentech: Consultancy, Honoraria; Atara: Consultancy, Honoraria; Gilead/Kite: Consultancy, Research Funding; Verastem Oncology: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding. Gopal:IgM bio, BMS, merck: Research Funding; imab bio, takeda,astrazeneca,gilead: Research Funding; Seattle Genetics; Janssen; Takeda; IgM Bio; IMab Bio; BMS; Astra Zeneca; Merck; Gilead: Research Funding; Seattle Genetics; Janssen; IMab Bio; TG Therapeutics; Astra Zeneca; Merck; Gilead; ADC Therapeutics; Nurix; TG therapeutics, Cellectar; Actinium: Consultancy.

B-cell maturation antigen (BCMA) is a validated target for chimeric antigen receptor (CAR) T-cell therapy in multiple myeloma (MM). Despite promising objective response rates, most patients relapse, and low levels of BCMA on a subset of tumor cells has been suggested as a probable escape mechanism. BCMA is actively cleaved from the tumor cell surface by the ubiquitous multisubunit γ-secretase (GS) complex, which reduces ligand density on tumor cells for CAR T-cell recognition and releases a soluble BCMA (sBCMA) fragment capable of inhibiting CAR T-cell function. Sufficient sBCMA can accumulate in the bone marrow of MM patients to inhibit CAR T-cell recognition of tumor cells, and potentially limit efficacy of BCMA-directed adoptive T-cell therapy. We investigated whether blocking BCMA cleavage by small-molecule GS inhibitors (GSIs) could augment BCMA-targeted CAR T-cell therapy. We found that exposure of myeloma cell lines and patient tumor samples to GSIs markedly increased surface BCMA levels in a dose-dependent fashion, concurrently decreased sBCMA concentrations, and improved tumor recognition by CAR T cells in vitro. GSI treatment of MM tumor-bearing NOD/SCID/γc(−/−) mice increased BCMA expression on tumor cells, decreased sBCMA in peripheral blood, and improved antitumor efficacy of BCMA-targeted CAR T-cell therapy. Importantly, short-term GSI administration to MM patients markedly increases the percentage of BCMA(+) tumor cells, and the levels of BCMA surface expression in vivo. Based on these data, a US Food and Drug Administration (FDA)-approved clinical trial has been initiated, combining GSI with concurrent BCMA CAR T-cell therapy. This trial was registered at www.clinicaltrials.gov as #NCT03502577.

Autologous T cells engineered to express a CD19-specific chimeric antigen receptor (CAR) have produced impressive minimal residual disease–negative (MRD-negative) complete remission (CR) rates in patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL). However, the factors associated with durable remissions after CAR T-cell therapy have not been fully elucidated. We studied patients with relapsed/refractory B-ALL enrolled in a phase 1/2 clinical trial evaluating lymphodepletion chemotherapy followed by CD19 CAR T-cell therapy at our institution. Forty-five (85%) of 53 patients who received CD19 CAR T-cell therapy and were evaluable for response achieved MRD-negative CR by high-resolution flow cytometry. With a median follow-up of 30.9 months, event-free survival (EFS) and overall survival (OS) were significantly better in the patients who achieved MRD-negative CR compared with those who did not (median EFS, 7.6 vs 0.8 months; P < .0001; median OS, 20.0 vs 5.0 months; P = .014). In patients who achieved MRD-negative CR by flow cytometry, absence of the index malignant clone by IGH deep sequencing was associated with better EFS (P = .034). Stepwise multivariable modeling in patients achieving MRD-negative CR showed that lower prelymphodepletion lactate dehydrogenase concentration (hazard ratio [HR], 1.38 per 100 U/L increment increase), higher prelymphodepletion platelet count (HR, 0.74 per 50 000/μL increment increase), incorporation of fludarabine into the lymphodepletion regimen (HR, 0.25), and allogeneic hematopoietic cell transplantation (HCT) after CAR T-cell therapy (HR, 0.39) were associated with better EFS. These data allow identification of patients at higher risk of relapse after CAR T-cell immunotherapy who might benefit from consolidation strategies such as allogeneic HCT. This trial was registered at www.clinicaltrials.gov as #NCT01865617.

e13640 Background: Evidence-based, national guidelines for the diagnosis of recurrent metastatic breast cancer (MBC) recommend confirmation of recurrence with biopsy and reassessment of biomarker status. Real world practice patterns may demonstrate disparities in adherence to guidelines with implications for patients and health systems. Methods: We utilized the Hutchinson Institute for Cancer Outcomes Research (HICOR) data repository that links Washington State cancer registry data to enrollment and claims from the major insurance payers in the state. We identified women > 18 years old diagnosed with recurrent MBC between 2008 and 2017 with evidence of enrollment in a commercial plan (Premera or Regence), Medicare, or Medicaid. Recurrence in Stage I-III patients was detected through identification of ICD 9/10 codes for metastatic disease or resumption of breast cancer systemic therapy (after minimum of 4 months from completion of early breast cancer therapy). Using claims, we identified receipt of and factors associated with biopsy, biomarker re-assessment, and treatment administered at recurrence. Results: We identified 715 patients with recurrent MBC (any ER or HER2 status) with median age of 62 (range 52-73). The majority of the cohort were Caucasian (89%) with the rest comprising of Asian, Black, American Indian, and Hispanic patients. Based on the Rural Urban Commuting Area (RUCA) classification, patients predominantly lived in metropolitan neighborhoods (97%). Approximately 13% of patients lived in areas of high deprivation (area of deprivation index, ADI, 8-10). Patients had either Commercial (53.1%), Medicaid (4.2%), Medicare (29.7%) or multiple (13.0%) insurance. Patients were primarily treated at high volume centers (70.9%), though 23% of patients were seen at low volume centers (2) were more likely to undergo biopsy confirmation (20.3% vs 13.0%, p = 0.02). Biopsy was more often performed in patients receiving care at a high-volume center compared to low-volume center (74.3% vs 18.6%, p = 0.03). First line treatment selection was directly associated with receipt of biopsy and biomarker testing. Hormone therapy only was more common in patients who did not undergo biopsy (62.3% vs 37.7%, p

7546 Background: The phase 3 POLARIX trial demonstrated the superiority of polatuzumab vedotin (Pola) over vincristine in the R-CHOP regimen for large B-cell lymphomas. However, it is unknown if Pola can be safely incorporated into intensified regimens typically utilized for the highest risk histologies. To address this question, we conducted a prospective trial (NCT04231877) evaluating Pola with dose adjusted etoposide, cyclophosphamide, doxorubicin, and rituximab (Pola-DA-EPCH-R). Methods: This is a single center, open label, investigator-initiated clinical trial of 6 cycles of Pola-DA-EPCH-R in aggressive large B-cell lymphomas where DA-EPOCH-R is considered standard (eg. HGBCL, PMBCL, and select DLBCL-NOS). Pola is given at 1.8 mg/kg on day 1 without intra-patient dose escalation. All other components of the regimen including escalation of chemotherapy dosing based on neutrophil and platelet nadirs from the previous cycle are given according to Dunleavy et al NEJM 2013. The primary objective is to estimate the safety of Pola-DA-EPCH-R as measured by the rate of dose-limiting toxicities (DLTs) in the first 2 cycles with pre-specified suspension rules if the lower limit of an 80% confidence interval cannot exclude a DLT rate of > 20%. Efficacy, survival, and correlative analyses will also be performed. Results: 18 patients enrolled on study and as of Feb 15, 2022, 3 patients remain on study treatment. Median age was 64 years (range 41-74). With only 3 DLTs, the study met its primary endpoint for safety. Five SAEs were observed, including one grade 5 sepsis/typhlitis (during cycle 1), 3 episodes of febrile neutropenia, and a grade 3 perforation of a colonic diverticula which required a treatment delay of 12 days before completing all expected study therapy. Other grade 3+ non-heme AEs in more than one pt. include hyperglycemia (17%), oral mucositis (17%), incidental asymptomatic pulmonary embolism (17%), abdominal pain (11%), and hypokalemia (11%). Grade 1 peripheral sensory neuropathy was uncommon (22%), no grade 2+ neuropathy was observed. One patient required a decrease in Pola dosing due to a platelet nadir at dose level 1. Among those with at least 2 cycles of treatment, 94% were able to increase chemotherapy to at least dose level 2 (Table). Post cycle 2 interim overall response rate (ORR) and complete response (CR) rate was 88% and 24%, respectively. EOT ORR and CR was 93% and 71%, respectively, with one PD. Updated data will be presented at the meeting. Conclusions: Using Pola at 1.8 mg/kg to replace vincristine in the DA-EPOCH-R regimen appears feasible and met its primary safety endpoint. These data support the further evaluation and use of this approach in histologies where the potential benefit of both an intensified regimen and Pola may be desired. Clinical trial information: NCT04231877. [Table: see text]

PURPOSE: Young adult (YA) cancer survivors have high rates of adverse health and psychosocial outcomes. This risk-stratified, multicenter, randomized controlled trial (RCT) compared a self-management survivorship intervention to usual care in YA survivors with symptoms of cancer-related distress, insomnia, fatigue, pain, and/or depression. METHODS: Eligibility included age 18–39 at diagnosis with an invasive malignancy in the previous 1–5 years. Baseline assessment determined “high need” participants, with 2–5 elevated targeted symptoms. We randomized high need participants to intervention or usual care and offered intervention participants a survivorship clinic visit, which included mutually decided action plans for symptoms. Follow-up calls at 1 and 3 months after the clinic visit reviewed action plan progress. Outcomes compared rates of improved symptoms for intervention vs usual care at 6 months and 12 months. RESULTS: N = 344 completed baseline assessment, with n = 147 (43%) categorized as high need and randomized. Of n = 73 randomized to the intervention, n = 42 (58%) did not attend their survivorship clinic visit. In intent-to-treat analyses, aggregate symptom scores did not differ between arms, though distress improved for 46% in the intervention arm at 6 months compared to 18% in usual care (p = 0.03) among those with elevated distress at baseline. CONCLUSIONS: Distress improved for YAs who received self-management survivorship care. However, the study demonstrates a need for alternative strategies for providing YA survivorship care. TRIAL REGISTRATION: NCT02192333 IMPLICATIONS FOR CANCER SURVIVORS: While YA survivors demonstrate some improved distress when provided survivorship care, to make care accessible and effective, they require options such as remote delivery of care.

CD19-targeted chimeric antigen receptor (CAR) T-cell therapy has demonstrated remarkable efficacy in patients with relapsed/refractory B-cell malignancies; however, it is associated with toxicities including cytokine release syndrome (CRS), neurotoxicity, and impaired hematopoietic recovery. The latter is associated with high-grade cytopenias requiring extended growth factor or transfusional support, potentially leading to additional complications such as infection or hemorrhage. To date, the factors independently associated with hematologic toxicity have not been well characterized. To address this deficit, we retrospectively analyzed 173 patients who received defined-composition CD19 CAR T-cell therapy in a phase 1/2 clinical trial (https://clinicaltrials.gov; NCT01865617), with primary end points of absolute neutrophil count and platelet count at day-28 after CAR T-cell infusion. We observed cumulative incidences of neutrophil and platelet recovery of 81% and 75%, respectively, at 28 days after infusion. Hematologic toxicity was noted in a significant subset of patients, with persistent neutropenia in 9% and thrombocytopenia in 14% at last follow-up. Using debiased least absolute shrinkage selector and operator regression analysis for high-dimensional modeling and considering patient-, disease-, and treatment-related variables, we identified increased CRS severity as an independent predictor for decreased platelet count and lower prelymphodepletion platelet count as an independent predictor of both decreased neutrophil and platelet counts after CD19 CAR T-cell infusion. Furthermore, multivariable models including CRS-related cytokines identified associations between higher peak serum concentrations of interleukin-6 and lower day-28 cell counts; in contrast, higher serum concentrations of transforming growth factor-β1 were associated with higher counts. Our findings suggest that patient selection and improved CRS management may improve hematopoietic recovery after CD19 CAR T-cell therapy.

A growing number of loci within the human leukocyte antigen (HLA) region have been implicated in non-Hodgkin lymphoma (NHL) etiology. Here, we test a complementary hypothesis of “heterozygote advantage” regarding the role of HLA and NHL, whereby HLA diversity is beneficial and homozygous HLA loci are associated with increased disease risk. HLA alleles at class I and II loci were imputed from genome-wide association studies (GWAS) using SNP2HLA for 3,617 diffuse large B-cell lymphomas (DLBCL), 2,686 follicular lymphomas (FL), 2,878 chronic lymphocytic leukemia/small lymphocytic lymphomas (CLL/SLL), 741 marginal zone lymphomas (MZL), and 8,753 controls of European descent. Both DLBCL and MZL risk were elevated with homozygosity at class I HLA-B and -C loci (OR DLBCL = 1.31, 95% CI = 1.06–1.60; OR MZL = 1.45, 95% CI = 1.12–1.89) and class II HLA-DRB1 locus (OR DLBCL = 2.10, 95% CI = 1.24–3.55; OR MZL = 2.10, 95% CI = 0.99–4.45). Increased FL risk was observed with the overall increase in number of homozygous HLA class II loci (P trend < 0.0001, FDR = 0.0005). These results support a role for HLA zygosity in NHL etiology and suggests that distinct immune pathways may underly the etiology of the different NHL subtypes. Significance: HLA gene diversity reduces risk for non-Hodgkin lymphoma. Cancer Res; 78(14); 4086–96. ©2018 AACR.

Introduction ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) represents standard frontline therapy for classical Hodgkin lymphoma (CHL) in North America. Substituting brentuximab vedotin for bleomycin in this regimen demonstrated improved efficacy in advanced stage patients (pts) but also increased toxicity (Connors et al NEJM 2017). PD-1 inhibitors are highly active in relapsed/refractory CHL, and the first-line setting may represent the ideal time for incorporating PD1 inhibition given the relatively intact host immunity and juxtaposition of malignant cells with T cells in the tumor microenvironment. Methods This was a single arm pilot study combining pembrolizumab with AVD in untreated CHL of any stage. Eligibility requiredECOG 0-1, adequate organ function, and measurable disease. The trial intended to enroll 30 pts. AVD was given at standard doses on days 1 and 15 of a 28-day cycle. Pembrolizumab (200 mg IV) was given starting cycle 1 day 1 and every 21 days thereafter (cycle 1 day 22, cycle 2 day 15 etc.). The primary objective was to estimate the safety of delivering 2 cycles of APVD. The secondary objective was to estimate the FDG-PET2 negative (Deauville score 1-3) rate after 2 cycles of APVD. Exploratory objectives included overall and progression free survival, predictive capacity of PET2 after APVD, analysis of ctDNA as well as assessments of metabolic tumor volume. After PET2 response assessment, subjects could continue APVD for up to 6 total cycles as deemed appropriate for their stage/risk factors (including alternate systemic therapy or radiotherapy). Results All 30 subjects have enrolled and received at least 2 cycles of therapy. Median age was 32 years (range 18-69). Most pts had advanced stage (stage I n =1 (3%), stage II n=11 (37%), stage III n=7 (23%), stage IV n=11, (37%)). Thirteen (43%) pts had B symptoms at diagnosis and 5 (17%) had bulky disease. Among the 30 pts enrolled, 28 are evaluable for response (one pt declined interim-PET and further treatment and final patient will have PET2 shortly after abstract deadline.Nineteen (68%) pts were PET2 neg (5PS 1-3). No PET2+ pts have progressed to date. End of therapy (EOT) PET negativity (after 2-6 cycles) was 78% (18/23). Among the 5 pts with residual FDG uptake at EOT, only 1 (20%) has developed recurrent lymphoma. With median follow-up of 10.3 months, 1-year PFS and OS were 96% and 100%, respectively. Six (20%) pts required interruption of pembrolizumab due to toxicity, primarily grade ≥ 2 transaminitis (83%). Those with grade 2 transaminitis (2/6) completed chemotherapy prior to resolving to grade 1 and did not receive additional pembrolizumab. Those with grade ≥ 3 transaminitis (3/6) were required to permanently discontinue pembrolizumab. All transaminitis was transient and resolved with steroids and/or withholding pembrolizumab. No pneumonitis and no other grade ≥ 3 immune-related AEs were observed. Toxicities were otherwise similar to those expected with ABVD chemotherapy. No pt had a treatment delay of > 21 days during the first 2 cycles, and no pt who interrupted pembrolizumab due to toxicity has relapsed. Updated efficacy and more detailed safety data will be presented at the meeting. Conclusion Pembrolizumab + AVD without a PD-1 lead-in is safe and effective therapy for frontline HL. In this study, PET2+ following APVD does not appear to be associated with high risk of disease relapse. Additional analyses of MTV and ctDNA are ongoing to better understand these results. Concurrent APVD, without an anti-PD-1 run-in, represents a well-tolerated, and efficacious backbone that can be further evaluated in all stages of CHL. Figure 1 Figure 1. Disclosures Lynch: Incyte: Research Funding; TG Therapeutics: Research Funding; Cyteir: Research Funding; Genentech: Research Funding; SeaGen: Research Funding; Bayer: Research Funding; Juno Therapetics: Research Funding; Morphosys: Consultancy. Ujjani: ACDT: Honoraria; Kite, a Gilead Company: Honoraria; Gilead: Honoraria; TG Therapeutics: Honoraria; Janssen: Consultancy; Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Atara Bio: Consultancy; Loxo: Research Funding; Adaptive Biotechnologies: Research Funding; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding. Poh: Acrotech: Honoraria; Incyte: Research Funding; Morphosys: Consultancy. Smith: Incyte Corporation: Research Funding; Merck Sharp & Dohme Corp: Research Funding; Ignyta (spouse): Research Funding; Acerta Pharma BV: Research Funding; Portola Pharmaceuticals: Research Funding; ADC Therapeutics: Consultancy; Karyopharm: Consultancy; Ayala (spouse): Research Funding; De Novo Biopharma: Research Funding; KITE pharm: Consultancy; Genentech: Research Funding; AstraZeneca: Consultancy, Research Funding; Bristol Myers Squibb (spouse): Research Funding; Incyte: Consultancy; Bayer: Research Funding; Beigene: Consultancy, Research Funding; Millenium/Takeda: Consultancy. Shadman: Mustang Bio, Celgene, Bristol Myers Squibb, Pharmacyclics, Gilead, Genentech, Abbvie, TG Therapeutics, Beigene, AstraZeneca, Sunesis, Atara Biotherapeutics, GenMab: Research Funding; Abbvie, Genentech, AstraZeneca, Sound Biologics, Pharmacyclics, Beigene, Bristol Myers Squibb, Morphosys, TG Therapeutics, Innate Pharma, Kite Pharma, Adaptive Biotechnologies, Epizyme, Eli Lilly, Adaptimmune , Mustang Bio and Atara Biotherapeutics: Consultancy. Shustov: Seagen Inc.: Research Funding. Till: Mustang Bio: Consultancy, Patents & Royalties, Research Funding. Alizadeh: Gilead: Consultancy; Janssen Oncology: Honoraria; Roche: Consultancy, Honoraria; Celgene: Consultancy, Research Funding; Foresight Diagnostics: Consultancy, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; Bristol Myers Squibb: Research Funding; Forty Seven: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; CAPP Medical: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; Cibermed: Consultancy, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Gopal: Epizyme: Consultancy, Honoraria; MorphoSys: Honoraria; Gilead: Consultancy, Honoraria, Research Funding; I-Mab bio: Consultancy, Honoraria, Research Funding; Genetech: Consultancy, Honoraria, Research Funding; Teva: Research Funding; Beigene: Consultancy, Honoraria; SeaGen: Consultancy, Honoraria, Research Funding; Incyte: Honoraria; Acrotech: Consultancy, Honoraria; Cellectar: Consultancy, Honoraria; Nurix Inc: Consultancy, Honoraria; ADC Therapeutics: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Merck: Consultancy, Honoraria, Research Funding; Takeda: Research Funding; Astra-Zeneca: Research Funding; Agios: Research Funding; Bristol Meyers Squibb: Research Funding; Karyopharm: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; IGM Biosciences: Research Funding; Kite: Consultancy, Honoraria.

Background: Rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone (RCHOP) remains standard therapy for previously untreated diffuse large B-cell lymphoma (DLBCL). We previously reported that adding pembrolizumab to RCHOP (PR-CHOP), shows no significant additive toxicity and a promising 2-year progression free survival of 83% (Smith B J Haem 2019), with no progression events among 19 pts with known PDL-1+ tumors. In that analysis, we noted 83% of patients had tumor PDL-1 expression by IHC using a centralized standard assay, including 18/23 (78%) and 13/23 (56%) demonstrating positivity in ≥5% and ≥30% of lymphoma cells respectively. Herein we report long-term clinical follow up, as well as results of high-resolution molecular karyotyping using chromosome genomic array testing (CGAT), to assess whether 9p24.1 abnormalities explained the extent of PDL1 tumor expression. Methods: Pts age 18 years or older with previously untreated DLBCL, transformed lymphoma and grade 3 B follicular lymphoma eligible for 6-cycle, curative-intent RCHOP were eligible. Steroids within 7 days of treatment, active autoimmune disease, or history of pneumonitis were excluded. This phase I study combined pembrolizumab (200 mg IV q 3 weeks x 6) to RCHOP x 6, with supportive care per standard practice. There was no maintenance or consolidation therapy. Baseline PDL1 expression was analyzed centrally (Merck/Qualtek). CGAT was performed from DNA extracted from formalin-fixed, paraffin-embedded tissue sections using the OncoScan platform (ThermoFisher). H&E slides of adjacent sections of the tissue used for CGAT were evaluated by a pathologist to ensure a minimum of 30% tumor content. Patients were followed for relapse and survival. Results: Among 30 treated pts with a median follow up of 32 months, there have been no additional DLBCL relapses or deaths since the published report. There has been one relapse of follicular lymphoma in a patient with initial composite lymphoma , who is now in remission 1 year after autologous stem cell transplantation. 3-year estimated PFS is 83% and OS is 86%. On univariate analysis, only tumor bulk 7.5 cm or greater (p=.02) and absence tumor PDL-1 expression by IHC (p=.001) predicted inferior PFS. Tumor bulk, (p=.03), IPI 3 or higher (p=.01), and absence of tumor PDL-1 expression (p=.001) predicted worse overall survival. PFS and OS were unaffected by cell of origin by IHC, double expresser status, or diagnosis to treatment interval greater than median (29 days). Regarding safety, there were late cases of paraneoplastic pemphigus and rheumatoid arthritis 5 and 8 months from last dose of pembrolizumab, respectively. Both of these were managed successfully with immunosuppression. Chromosome genomic array testing CGAT) was performed to assess copy number aberrations (CNAs) and copy neutral loss of heterozygosity (cnLOH), particularly for the presence of gains or amplifications involving locus 9p24.1, containing the CD274 (PDL1) gene. Of 15 tested pretreatment baseline diagnostic tissue specimens, 14 provided informative result with 12 abnormal and 2 normal. Notably, no gain or amplification in 9p24.1 were seen; there was one case of deletion and 1 with cnLOH. The percent genome altered among abnormal cases ranged from 2% to 37% (median 12%). Complex karyotype, defined as genomic aberrations involving at least 3 chromosome arms (or % genome altered greater than 5% by CGAT), was seen in 10/14 pts (71%). This 14-sample data set included 6/14 pts with >30% PDL1 tumor expression (and 10 with 5% or greater PDL1-tumor expression). Conclusions: No additional safety signals have been observed, and PFS/OS remain favorable for the combination of pembrolizumab + RCHOP in this single arm trial with the best results in PDL-1+ disease. Despite frequent tumor PDL1-expression at baseline, no gains or implications of 9p24.1 were observed suggesting alternative mechanisms for overexpression of PDL-1. Further study this regimen and others testing combinations of immune checkpoint inhibition with first-line DLBCL therapy are warranted, to better ascertain the potential superiority of this strategy in this setting. Disclosures Smith: Portola: Research Funding; Incyte: Research Funding; Ignyta: Research Funding; Genentech: Research Funding; AstraZeneca: Research Funding; Acerta Pharma BV: Research Funding; Karyopharm: Consultancy; Beigene: Consultancy; Seattle Genetics: Research Funding; AstraZeneca: Consultancy; Millenium/Takeda: Consultancy; Pharmacyclics: Research Funding; Merck: Research Funding; De Novo Biopharma: Research Funding; Bayer: Research Funding; Ayala: Research Funding; Bristol Meyers Squibb: Research Funding. Fromm:Merck: Research Funding. Till:Mustang: Patents & Royalties, Research Funding. Shadman:Mustang Bio, Celgene, Pharmacyclics, Gilead, Genentech, Abbvie, TG therapeutics, Beigene, Astra Zeneca, Sunesis, Beigene: Research Funding; Abbvie, Genentech, Astra Zeneca, Sound Biologics , Pharmacyclics, Verastem, ADC therapeutics, Beigene, Cellectar, BMS, Morphosys and Atara Biotherapeutics: Consultancy. Lynch:Bayer: Research Funding; Rhizen Pharmaceuticals: Research Funding; Incyte: Research Funding; TG Therapeutics: Research Funding; Takeda: Research Funding; Juno Therpeutics: Research Funding; MorphoSys: Consultancy; Genentech: Research Funding; Cyteir: Research Funding. Cowan:Janssen: Consultancy, Research Funding; Bristol Myers Squibb: Research Funding; Sanofi: Consultancy; Cellectar: Consultancy; Abbvie: Research Funding. Ujjani:Gilead/Kite: Consultancy, Research Funding; Atara: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; MorphoSys: Consultancy; Verastem Oncology: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding. Shustov:Seattle Genetics: Research Funding. Cassaday:Vanda Pharmaceuticals: Research Funding; Seattle Genetics: Current Employment, Current equity holder in publicly-traded company; Merck: Research Funding; Pfizer: Honoraria, Research Funding; Amgen: Consultancy, Research Funding; Kite/Gilead: Consultancy, Research Funding. Gopal:Seattle Genetics; Janssen; Takeda; IgM Bio; IMab Bio; BMS; Astra Zeneca; Merck; Gilead: Research Funding; Seattle Genetics; Janssen; IMab Bio; TG Therapeutics; Astra Zeneca; Merck; Gilead; ADC Therapeutics; Nurix; TG therapeutics, Cellectar; Actinium: Consultancy; IgM bio, BMS, merck: Research Funding; imab bio, takeda,astrazeneca,gilead: Research Funding.

Chimeric antigen receptor (CAR)-T cell therapy is a novel treatment with promising results for patients with hematological malignancies. Currently three FDA approved products are available for treatment of relapsed/refractory lymphoid malignancies, and several products are in different stages of clinical investigations for treatment of multiple myeloma and other hematological malignancies. CAR-T cell therapy has known early toxicities of cytokine release syndrome (CRS) and neurotoxicity, but little is known about long-term neuropsychiatric adverse effects. We previously reported neuropsychiatric patient-reported outcomes (PROs) of long-term survivors after CAR-T cell therapy (Ruark at al. BBMT 2020; 26: 34-43), but without baseline PROs before treatment for comparison. In this study we have utilized PROs, including PROMIS® measures, to assess symptoms and quality of life (QOL) of patients with relapse/refractory non-Hodgkin lymphoma (NHL), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), and multiple myeloma (MM) at time of arrival to our cellular immunotherapy clinic for CAR-T cell therapy. Between February 2019 and March 2020, patients received a PRO questionnaire at time of their arrival to our immunotherapy clinic. The questionnaire included the PROMIS Scale v1.2-Global Health, PROMIS-29 Profile v2.1, PROMIS Cognitive Function Short-Form v2.0, as well as 30 additional questions, including questions pertaining to cognitive function. As of March 30, 2020, 58 questionnaires were returned (59% response rate for online questionnaire versus 80% for paper questionnaire) and included in the analysis. Patients' characteristics are summarized in Table 1. PROMISmeasures are standardized to a T-score metric, with a score of 50 representing the general US population mean. Clinically meaningful differences were defined as a 5-point difference in scores (1/2 standard deviation). Cognitive function was assessed for all patients by asking if patients had experienced difficulties with concentration, finding words, memory, or solving problems; answering "yes" to each of the questions received "1" point to determine the total cognitive difficulty score (0-4). The PROMIS Cognitive Function Short-Form was added later to the PRO questionnaire and data are available for 28 patients. The cohort's self-reported cognitive difficulties and PROMIS mean T scores are shown in Table 2. Mean T score of PROMIS Global Physical Health was clinically meaningfully different from the mean in the general US population (43.7), while the mean T scores of all the other domains, including Global Mental Health, Social Function, Anxiety, Depression, Fatigue, Pain Interference, Sleep Disturbance and Cognitive Function were not clinically meaningfully different from the mean in the general US population. 23 of the 56 participants for whom complete data were available (41%) reported at least one cognitive difficulty and/or clinically meaningful depression and/or anxiety (Figure 1). On univariate risk factor analysis, older age was found to be associated with worse Global Physical Health (p=0.04) but with a trend for less depression (p=0.07). Diagnosis of ALL was found to be a risk factor for depression (p Our study demonstrates overall worse physical function in our cohort of 58 patients with hematological malignancies at time of CAR-T cell therapy, compared to the general population, but no clinically meaningful difference was found in neuropsychiatric status. 41% of the participants reported depression, anxiety or cognitive difficulties at time of CAR-T cell therapy, compared to 47.5% of participants 1-5 years after CAR-T cell therapy in our prior published work (Ruark at al. BBMT 2020; 26: 34-43). Ten participants (17.2%) reported 1-4 cognitive difficulties at time of CAR-T cell therapy compared to 37.5% of participants 1-5 years after CAR-T cell therapy. However, conclusions cannot be drawn from these two independent cohorts, and longitudinal data are needed to compare patients' neuropsychiatric status before and after CAR-T cell therapy in order to determine the treatment effect. Such study is currently ongoing in our institution. Disclosures Maloney: Celgene: Consultancy, Honoraria, Research Funding; Gilead Sciences: Consultancy, Honoraria; Juno Therapeutics: Consultancy, Honoraria, Patents & Royalties: Patents are pending, but not issued, licensed, no royalties, no licensees., Research Funding; Amgen: Consultancy, Honoraria; A2 Biotherapeutics: Consultancy, Current equity holder in publicly-traded company, Honoraria; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria; MorphoSys: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria; Bioline Rx: Consultancy, Honoraria.

Background: CD19-targeted chimeric antigen receptor-engineered T cell(CAR-T) therapy with axicabtagene ciloleucel (axi-cel) is approved for patients (pts) with large cell lymphoma (LCL) [diffuse large cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL) and transformed follicular lymphoma (tFL)] after ≥ 2 lines of treatment. In addition to cytokine-release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), prolonged cytopenias may occur after axi-cel and can limit eligibility for subsequent treatments, especially clinical trials. In this study, we sought to determine the rate of clinically significant cytopenias and identify pre- and post- treatment factors associated with cytopenias after axi-cel. Methods: Pts with DLBCL, PMBCL, or tFL who received axi-cel between Feb 2018 and Feb 2020 were included. We collected details about patients' demographics, disease characteristics, pre-CAR-T treatments, and post CAR-T specific toxicities (Table 1 footnote). We included details on blood counts, and transfusion/growth factor support needs from 30 days before leukapheresis (LA) until 30 days after treatment with axi-cel. We defined severe cytopenia if at least one of the following were present: (1) grade ≥ 3 thrombocytopenia (< 50x109/L), (2) neutropenia (< 1.0 x109/L), or (3) anemia (Hb < 8.0 g/dl) at day 30 after axi-cel, or (4) need for ≥ 2 doses of G-CSF, (5) ≥ 2 red blood cell (RBC) transfusions, or (6) ≥ 2 platelet (plt) transfusions between days 20-30 after axi-cel. Univariate and multivariable logistic regression was used to evaluate the association between each risk factor and the primary endpoint of severe cytopenia (Yes vs. No). For multivariable analysis, a novel high dimensional inference (HDI) approach was applied, which provides the de-biased estimates of the regression coefficients. HDI allows computation of adjusted odds ratios, confidence intervals and p values from high-dimensional datasets. This approach solves variable selection issues in CAR-T cell studies with small sample sizes and large number of predictors. Results: 53 pts (41 DLBCL, 1 PMBCL, 11 tFL) received axi-cel during the study period. Median age was 63 (25-79) and 17 (32%) were female. Nineteen pts (36%) had bulky disease (> 5 cm) and 23 (43%) had elevated LDH (>210 U/L). Median number of therapies before CAR-T including stem cell transplant (SCT) and bridging therapy was 3 (2-9). Seventeen pts (32%) had a prior stem cell transplant (SCT) (16 autologous, 1 allogeneic) before CAR-T. Median time from last treatment to CAR-T was 4 weeks (0.3-130). Twenty six pts (49%) received bridging therapy between LA and lymphodepletion (LD). Following CAR-T, 37 (74%) patients achieved complete or partial remission (CR/PR) while 13 patients (26%) had progressive or stable disease (PD/SD). 45 (85%) pts developed CRS (grade 3-4: 5; 11% of all pts) and 31 (59%) developed ICANS (grade 3-4: 9; 15% of all pts). Forty two (79%) patients had severe cytopenia as defined by one or more of the categories (Cat) listed in the methods; 24 (45%) by Cat 1 (thrombocytopenia), 19 (36%) by Cat 2 (neutropenia), 1 (2%) by Cat 3 (anemia), 10 (19%) by Cat 4 (GCS-F need), 11 (21%) by Cat 5 (RBC transfusion), or 15 (28%) by Cat 6 (plt transfusion). Severe cytopenia was more common in non-responders (SD/PD) vs. responders (PR/CR) (100% vs. 70%; P=.01). In the univariate analysis, lower pre-LA hematocrit (hct) (P=.005), pre-LD hct (P Conclusion: Severe cytopenia is common after axi-cel, -especially in non-responders in need of subsequent therapies. Our detailed analysis of pre- and post- CAR-T variables identified pre-CAR-T cytopenia and transfusion needs as well as post-CAR-T steroid use as potential predictors of day 30 severe cytopenia in pts with LCL receiving axi-cel. Disclosures Gauthier: JMP, Eusapharma, Multerra Bio: Honoraria. Cassaday:Amgen: Consultancy, Research Funding; Vanda Pharmaceuticals: Research Funding; Pfizer: Honoraria, Research Funding; Seattle Genetics: Current Employment, Current equity holder in publicly-traded company; Kite/Gilead: Consultancy, Research Funding; Merck: Research Funding. Kiem:Magenta Therapeutics, CSL,Homology Medicines, Vor Biopharma , Enochian, Umoja, Rocket Pharma: Consultancy. Lynch:TG Therapeutics: Research Funding; Takeda: Research Funding; MorphoSys: Consultancy; Genentech: Research Funding; Cyteir: Research Funding; Bayer: Research Funding; Rhizen Pharmaceuticals: Research Funding; Incyte: Research Funding; Juno Therpeutics: Research Funding. Ujjani:Atara: Consultancy, Honoraria; Gilead/Kite: Consultancy, Research Funding; Verastem Oncology: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria; MorphoSys: Consultancy. Smith:AstraZeneca: Research Funding; Acerta Pharma BV: Research Funding; Beigene: Consultancy; Millenium/Takeda: Consultancy; AstraZeneca: Consultancy; Portola: Research Funding; Seattle Genetics: Research Funding; Pharmacyclics: Research Funding; Merck: Research Funding; Incyte: Research Funding; Ignyta: Research Funding; Genentech: Research Funding; De Novo Biopharma: Research Funding; Ayala: Research Funding; Bristol Meyers Squibb: Research Funding; Bayer: Research Funding; Karyopharm: Consultancy. Gopal:Seattle Genetics; Janssen; Takeda; IgM Bio; IMab Bio; BMS; Astra Zeneca; Merck; Gilead: Research Funding; Seattle Genetics; Janssen; IMab Bio; TG Therapeutics; Astra Zeneca; Merck; Gilead; ADC Therapeutics; Nurix; TG therapeutics, Cellectar; Actinium: Consultancy; imab bio, takeda,astrazeneca,gilead: Research Funding; IgM bio, BMS, merck: Research Funding. Till:Mustang: Patents & Royalties, Research Funding. Turtle:Kite/Gilead: Consultancy; Humanigen: Consultancy; Physician Education Resource: Consultancy; Century Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Research Funding; PACT Pharma: Consultancy; Allogene: Consultancy; T-CURX: Membership on an entity's Board of Directors or advisory committees; Myeloid Therapeutics: Current equity holder in private company, Honoraria, Membership on an entity's Board of Directors or advisory committees; Arsenal Bio: Current equity holder in private company, Honoraria, Membership on an entity's Board of Directors or advisory committees; Caribou Biosciences: Current equity holder in private company, Honoraria, Membership on an entity's Board of Directors or advisory committees; Eureka Therapeutics: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Precision Biosciences: Current equity holder in publicly-traded company, Honoraria, Membership on an entity's Board of Directors or advisory committees; Nektar Therapeutics: Consultancy, Research Funding; Juno/BMS: Patents & Royalties, Research Funding; Novartis: Consultancy. Maloney:Genentech: Consultancy, Honoraria; A2 Biotherapeutics: Consultancy, Current equity holder in publicly-traded company, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Bioline Rx: Consultancy, Honoraria; Juno Therapeutics: Consultancy, Honoraria, Patents & Royalties: Patents are pending, but not issued, licensed, no royalties, no licensees., Research Funding; MorphoSys: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria. Shadman:Mustang Bio, Celgene, Pharmacyclics, Gilead, Genentech, Abbvie, TG therapeutics, Beigene, Astra Zeneca, Sunesis, Beigene: Research Funding; Abbvie, Genentech, Astra Zeneca, Sound Biologics , Pharmacyclics, Verastem, ADC therapeutics, Beigene, Cellectar, BMS, Morphosys and Atara Biotherapeutics: Consultancy.

Aim: Acute myeloid leukemia (AML) is an aggressive hematopoietic clonal disorder characterized by the increased blasts and poor survival outcome, which is mainly driven by cytogenetic and molecular abnormalities. Here, we investigated the prognostic impact of other demographic parameters on the survival outcomes in AML patients. Method: We reviewed the Surveillance, Epidemiology, and End Result (SEER) database to collect demographic information, including age, diagnosis, gender, race, and geographic region in patients with non-acute promyelocytic leukemia AML, between 2004–2008. The primary end-point of our study was 3-year overall survival (OS), which was estimated by the Kaplan–Meier method and Cox regression model. Results: A total of 13,282 patients were included in our analyses. Increasing age (HR 1.2, p

Background: Postmenopausal hormone therapy (HT) increases the risk of stroke. Here we evaluate whether leisure time physical activity (LTPA) can change stroke risk in women using HT, leveraging data from the California Teachers Study. Methods: Female California educators without a prior history of stroke (n = 118,294) were followed from 1995 through 2015 for stroke end points. Based on statewide hospitalization data, 4,437 women had ischemic (n = 3,162; International Classification of Diseases [ICD]-9 433, 434, 436) or hemorrhagic (n = 1,275; ICD-9 430–432, excluding 432.1) stroke. LTPA and HT use were evaluated at 2 time points (baseline [1995–1996] and 10-year follow-up [2005–2006]). LTPA was assessed using American Heart Association (AHA) recommendations (>150 min/week moderate or >75 min/week strenuous physical activity). Using multivariable Cox proportional hazards models, we estimated the hazard ratios (HRs) and 95% CIs for the associations between HT use and concurrent LTPA with incident stroke. Results: Compared to women who never used HT, stroke risk was highest among women who were current HT users and did not meet AHA recommendations for LTPA at the time of their HT use: HRbaseline 1.28 (95% CI 1.13–1.44); HR10-year follow-up 1.17 (95% CI 0.91–1.50). Based on the baseline questionnaire, current HT users who met AHA recommendations for LTPA in 1995–1996 still had elevated stroke risk in the 20-year follow-up (HR 1.22, 95% CI 1.08–1.37). However, among current HT users who met AHA recommendations for LTPA at the 2005–2006 follow-up questionnaire, stroke risk was not elevated (HR 1.01, 95% CI 0.80–1.29). Evaluation of the 2 time points in concert further demonstrated that meeting AHA recommendations for LTPA at the most recent follow-up time point was required to reduce HT-related stroke risk. Conclusion: Concurrent physical activity may attenuate the short-term increase in risk of stroke risk associated with HT use.

Patients with follicular lymphoma (FL) with early relapse after initial chemoimmunotherapy, refractory disease, or histologic transformation (tFL) have limited progression-free and overall survival. We report efficacy and long-term follow-up of 21 patients with relapsed/refractory (R/R) FL (n = 8) and tFL (n = 13) treated on a phase 1/2 clinical trial with cyclophosphamide and fludarabine lymphodepletion followed by infusion of 2 × 106 CD19-directed chimeric antigen receptor–modified T (CAR-T) cells per kilogram. The complete remission (CR) rates by the Lugano criteria were 88% and 46% for patients with FL and tFL, respectively. All patients with FL who achieved CR remained in remission at a median follow-up of 24 months. The median duration of response for patients with tFL was 10.2 months at a median follow-up of 38 months. Cytokine release syndrome occurred in 50% and 39%, and neurotoxicity in 50% and 23% of patients with FL and tFL, respectively, with no severe adverse events (grade ≥3). No significant differences in CAR-T cell in vivo expansion/persistence were observed between FL and tFL patients. CD19 CAR-T cell immunotherapy is highly effective in adults with clinically aggressive R/R FL with or without transformation, with durable remission in a high proportion of FL patients. This trial was registered at clinicaltrials.gov as #NCT01865617.

CD19-targeted chimeric antigen receptor-modified T cell (CAR-T cell) therapy has shown excellent antitumor activity in patients with relapsed/refractory B cell malignancies, with very encouraging response rates and outcomes. However, the late effects following this therapy remain unknown. Here we report late adverse events-defined as starting or persisting beyond 90 days after CAR-T cell infusion-in patients who survived at least 1 year after therapy. The median duration of follow-up was 28.1 months (range, 12.5 to 62.6 months). At last follow-up, 73% of patients were still alive and 24% were in ongoing complete remission (CR). The most common late adverse event was hypogammaglobulinemia (IgG400 mg/dL or i.v immunoglobulinm (IVIG) replacement, observed in 67% of the patients with available data. Infection density was .55 infection/100 days at risk (2.08 per patient-year). The majority (80%) of the infections were treated in the outpatient setting, and 5% necessitated admission to the intensive care unit (ICU). Subsequent malignancies occurred in 15% of patients, including 5% with myelodysplastic syndrome (MDS). Among patients with ongoing CR and with no MDS, 16% experienced prolonged cytopenia requiring transfusions or growth factor support. Graft-versus-host disease occurred in 3 of 15 patients (20%) who had undergone previous allogeneic hematopoietic cell transplantation. Most of the late events observed in this cohort were not severe, and many could be related to previous or subsequent therapies, suggesting a safe long-term profile of CD19-targeted CAR-T cell immunotherapy.

Allogeneic hematopoietic cell transplantation (allo-HCT) is offered to selected patients after chimeric antigen receptor-modified T-cell (CAR-T) therapy. Lymphodepleting chemotherapy and CAR-T therapy have immunosuppressive and immunomodulatory effects that could alter the safety profile of subsequent allo-HCT. We reviewed our experience with 32 adults (acute lymphoblastic leukemia [ALL], n = 19; B-cell non-Hodgkin lymphoma [NHL]/chronic lymphocytic leukemia [CLL], n = 13) who received an allo-HCT after CAR-T therapy, with a focus on posttransplant toxicities. Myeloablative conditioning (MAC) was used in 74% of ALL patients and 39% of NHL/CLL patients. The median time from CAR-T therapy to allo-HCT was 72 days in ALL patients and 122 days in NHL/CLL patients. Cumulative incidences of grade 3-4 acute graft-versus-host disease (GVHD) and chronic GVHD were 25% and 10%, respectively. All patients had neutrophil recovery (median, 18.5 days) and all but 3 had platelet recovery (median, 12 days). Twenty-two percent had viral or systemic fungal infection within 100 days after allo-HCT. The 100-day and 1-year cumulative incidences of NRM were 16% and 21%, respectively, for ALL patients and 15% and 33%, respectively, for NHL/CLL patients. In ALL patients, later utilization of allo-HCT after CAR-T therapy was associated with higher mortality. In NHL/CLL patients, MAC was associated with higher mortality. Toxicities did not exceed the expected incidences in this high-risk population.

Background: Tumor programmed death-ligand 1 (PD-L1) expression in diffuse large B-cell lymphoma (DLBCL) is associated with inferior outcomes. We hypothesized that the first-line immunologically-replete setting may be an opportune time for introducing PD-1 inhibition. We thus evaluated pembrolizumab in combination with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) in untreated patients with DLBCL. Methods: Eligible patients were age 18 or older, had adequate organ function, and had DLBCL or grade 3B FL requiring full-course therapy. Patients received pembrolizumab 200 mg/cycle with R-CHOP for 6 cycles, every 21 days, measuring toxicity as the primary endpoint. Response assessment utilized standard criteria, and PD-L1 staining was performed at a validated central laboratory. Findings: Among 30 treated patients, toxicity was comparable to standard R-CHOP but with two grade ≥3 immune related adverse events (rash, pneumonitis). The overall and complete response rate was 90% and 77%. Only 1 of 4 partial responders has progressed. With 25·5 months of median follow-up, 2-year progression-free survival (PFS) is 83%. PD-L1 tumor expression was associated with non-GCB subtype, and improved PFS and survival.InterpretationPembrolizumab can safely be added to R-CHOP, and is associated with a high CR rate and 2-year PFS. Improved PFS with PR-CHOP in PD-L1 expressing tumors contradicts historical data in R-CHOP treated patients, and supports further trials evaluating PD-L1 as a biomarker to identify DLBCL patients who may benefit from this first-line strategy. Trial Registration: NCT02541565. Funding Statement: In addition to primary funding from Merck Sharpe and Dohme Corp, the authors recognize additional support from grant K24CA184039, NIH/NCI Cancer Center Support Grant P30 CA015704, and donations from Frank and Betty Vandermeer and Sonya and Tom Campion. Declaration of Interests: S.D.S. reports grants and nonfinancial research support from Acerta Pharma BV, Astrazeneca, De Novo Biopharma, Genentech, Jannsen Pharmaceuticals, Incyte Corporation, Merck Sharp and Dohme Corp., Pharmacyclics, Portola Pharmaceuticals, and Seattle Genetics; S.D.S.’ spouse receives research support from Ayala, Bristol Myers Squibb, Merck Sharp Dohme Corp, and Ignyta. S.D.S reports personal fees from Merck Sharp and Dohme Corp and Astrazeneca. A.K.G. reports grants and nonfinancial research support from Teva, Bristol-Myers Squibb, Merck, Takeda, Seattle Genetics, Pfizer, Janssen, Takeda, and Effector; Personal fees and nonfinancial support from Seattle Genetics, Pfizer, Janssen, Gilead, Sanofi, Spectrum, Amgen, Aptevo, BRIM bio, Acerta, I-Mab-pharma, Compliment, Asana Bio, and Incyte. H.R., K.B., J.V., Q.W. report no relevant financial disclosures. M.S. reports grands and nonfinancial research support from Mustang Bio, Celgene, Pharmacyclics, Gilead, Genentech, Abbvie, TG therapeutics, Beigene, Acerta Pharma, Merck Sharp and Dohme Corp; personal fees and nonfinancial support from Abbvie, Genentech, Astra Zeneca, Sound Biologics, Verastem, ADC therapeutics and Atara Biotherapeutics. B.G.T. reports grants and nonfinancial research support from Mustang Bio and RocheGenentech, and patents/royalties from Mustang Bio. R.C.L. reports grants and nonfinancial research support from Incyte Corporation, TG Therapeutics, Takeda, Juno Therapeutics, Rhizen Pharmaceuticals. A.J.C. reports grants and nonfinancial research support from Janssen, AbbVie, Juno Therapeutics, and Celgene; personal fees and nonfinancial support from Celgene. C.U. reports grants and nonfinancial research support from Pharmacyclics, Abbvie, and Celgene; personal fees and nonfinancial support from Amgen, bayer, Pfizer, Gilead, Astrazeneca, Genentech, Pharmacyclics, Abbvie, and Atara. A.R.S. reports grants and nonfinancial research support from Seattle Genetics, Spectrum Pharmaceuticals, and personal fees and nonfinancial support from Kyowa Hakko Kirin. R.D.C reports grants and nonfinancial research support from Merck Sharp and Dohme Corp., Incyte, Seattle Genetics, Vanda Pharmaceuticals, Amgen, Pfizer, Kite/Gilead; and personal fees and nonfinancial support from Amgen, Pfizer, Jazz, and Adaptive Biotechnologies. Ethics Approval Statement: This study was approved by the Fred Hutchinson Cancer Center- University of Washington Consortium IRB and all patients provided written informed consent to participate in the trial.

e13038 Background: Evidence-based, national guidelines for the management of metastatic breast cancer (MBC) recommend numerous treatment options that do not capture the nuances of real-world practice. Disparities may exist across Washington State with financial implications for patients and health systems. The objective of this study was to assess practice patterns around treatment of ER+/HER2- MBC in actual clinical practice. Methods: We collaborated with Hutchinson Institute for Cancer Outcomes Research (HICOR) to link enrollment and insurance claims records with Washington State cancer registries from 2008-2017. Our cohort comprised of women >18 years old with de novo ER+/HER2- MBC who met enrollment criteria in one of four payors (Premera, Regence, Medicare, or Medicaid). We identified receipt of first line treatment, categorized as CDK4/6 inhibitors plus endocrine therapy (CDKi+ET), chemotherapy (CT), or endocrine therapy alone (ET). We examined factors influencing treatment selection using Fisher's and Kruskal-Wallis tests. Total costs (defined as costs from inpatient and outpatient claims one year after diagnosis) was estimated for patients and payors. Results: We identified 140 patients with de novo ER+/HER2- MBC with median age of 64 (range 28-95). The majority of the cohort were Caucasian (90%) with the rest comprising of Asian, Black, American Indian, and Hispanic patients. Based on the Rural Urban Commuting Area (RUCA) classification, patients predominantly lived in metropolitan neighborhoods (96%). Over 20% of patients lived in areas of high deprivation (area of deprivation index, ADI, 8-10). Patients had either Commercial (40.7%), Medicaid/Medicare (43.6%) or multiple (15.7%) insurance. Our data show that 17 patients (12%) received first line therapy with CDKi + ET, 64 patients (46%) with CT, and 59 patients (42%) with ET alone. Factors influencing treatment selection include age, co-morbidity score, and payor type. Older patients (>65 years old) were more likely to receive ET alone compared to younger patients (56% vs 44%, p value

e18052 Background: Timely administration of postoperative radiation therapy (PORT) impacts oncologic outcomes in resected squamous cell carcinomas of the head and neck. Salivary gland cancers (SGCs) are uncommon, and timing of PORT has not been extensively explored. We aimed to determine if the interval between surgery and PORT impacts outcomes in SGCs. Methods: We retrospectively identified patients with SGCs who underwent curative intent surgical resection followed by adjuvant PORT at our tertiary referral center. Demographic, tumor, and treatment data were collected. Patients with non-oncologic resections and/or delay of > 6 months to radiation start were excluded. Locoregional control (LRC), relapse free survival (RFS), and overall survival (OS) were estimated using the Kaplan Meier method. A multivariate analysis explored the association between demographics, tumor characteristics, and PORT timing with oncologic outcomes using a stepwise Cox proportional hazards model. Results: Between 1/1/1997 and 12/31/2017 180 eligible patients were identified. Patient characteristics are described in Table. The median time to PORT start was 61 (range 8-121) days, 169 (93.9%) of patients received neutron beam PORT. With a median follow up of 8.2 years in surviving patients, the 5-year OS and LRC estimates were 73% and 67%, respectively. In a multivariate analysis, only nodal involvement, histologic grade, and age at diagnosis were associated with OS, while nodal involvement, tumor size, and age at time of diagnosis were associated with LCR and RFS. Time to PORT start or completion was not statistically associated with survival outcomes on multivariate analysis. Conclusions: SGC patients who underwent surgery in our tertiary institution received PORT within a median of 61 days after surgery. With long term follow up, PORT timing in this retrospective series was not associated with worse oncologic outcomes, and support timely administration of PORT with 3 months of surgical resection. Further work is necessary to assess generalizability of these results.[Table: see text]

e18004 Background: Anti-PD1 checkpoint inhibitors (ICI) represent an established standard of care for patients with recurrent/metastatic head & neck squamous cell carcinoma (RMHNSCC). Landmark studies excluded patients with ECOG performance status (PS) ≥ 2; the benefit of ICI in this population is therefore unknown. Methods: We retrospectively reviewed RMHNSCC patients who received at least 1 dose of ICI at our institution. Demographic data and clinical outcomes were obtained; the latter included objective response to ICI (ORR), physician-documented CTCAE grade 2+ toxicity (irAE), and any unplanned hospitalization within 100-days of last ICI dose (UH). Associations between demographic data and clinical outcomes were explored using both uni- and multivariate analysis. Overall survival (OS) was estimated using a Cox proportional hazards model; ORR, irAE, and UH were evaluated with logistic regression. This project was approved by our institutional IRB. Results: We identified 152 RMHNSCC patients who were treated with ICI between 1/2013 and 1/2019. ECOG PS was 0 in 42 (27%), 1 in 75 (50%), 2 in 27 (18%), 3 in 2 (1%), and unknown in 6 (4%) patients. The median age was 61 (range: 25 - 90). 124 (82%) were male, 124 (82%) were white, and 69 (45%) were never-smokers. The most common primary sites were the oropharynx (n = 59, 40%), oral cavity (n = 39, 26%), nasopharynx (n = 11, 7%), and larynx (n = 10, 6%). 54 (36%) were p16+ oropharynx cancers. CPS score was available in 10 (6.6%). Single agent ICI was received by 118 (77%) patients. 66 (44%) had a documented irAE and 54 (36%) had an UH. A multivariate model for OS containing PS, smoking status and HPV status showed a strong association between inferior OS and ECOG 2/3 compared to 0/1 (p < 0.001; HR = 3.30, CI = 2.01-5.41), as well as former (vs. never) smoking status (p < 0.001; HR = 2.17, CI = 1.41-3.35). Current smoking (p = 0.25) did not reach statistical significance. On univariate analysis, poor PS was associated with inferior ORR (p = 0.03; OR = 0.25, CI = 0.06-0.77) and increased UH (p = 0.04; OR = 2.43, CI = 1.05—5.71). There was no significant association between irAE and any patient characteristic. Conclusions: We observed inferior overall survival among ICI-treated RMHNSCC patients with ECOG 2/3 in our single-institution, retrospective series. Our findings help frame discussion of therapeutic options in this poor-risk population. Further study must be done to determine which interventions are of greatest benefit for RMHNSCC patients with declining performance status.

e18516 Background: Demographic and EOLHCU trends are undefined in the growing population of IO-treated RMHNSCC; we sought to study these in a single institution retrospective study. Methods: We identified 228 RMHNSCC pts who received ≥1 IO dose between 01/2013 and 12/2018; of these, 74 were deceased with accessible EOLHCU data such as advanced care plan documentation (ACPD) or evidence of systemic therapy or ER/hospital/ICU admission within 30 days of death (DOD). Demographic, tumor and treatment data were obtained. Overall survival (OS) was estimated using the Kaplan Meier method; multivariable analysis was performed using a Cox proportional hazards model. In an exploratory analysis, EOLHCU was compared to a cohort of 379 deceased thoracic malignancy (TM) pts using a chi-square test. This project was approved by our institutional IRB. Results: Median pt age was 62 (25 – 90). Most were male (56, 75%), white (60, 81%), current/former smokers (46, 62%); 34 (46%) smoked ≥10 pack years. Common primary sites included the oral cavity (28, 37.8%) and oropharynx (24, 32.4%). ECOG PS at IO initiation was 0 in 15 pts (20%,) 1 in 37 (50%), 2 in 20 (27%), 3 in 1 (1%), and unknown in 1 (1%). Of the 42 (57%) treated off-trial, 18 (42%) had an ECOG ≥ 2. 71 (95%) had prior curative intent therapy. 42 (57%) had distant metastases. Compared to TM, IO-treated RMHNSCC pts were more likely to have ACPD (66% vs. 45% p < 0.01), an ED visit (42.3% vs 19.5%, p < 0.01) and/or a hospital admission (42.3% vs 17%, p < 0.01) within 30 DOD. There was no difference in ICU admissions within 30 DOD (9.9% vs. 8.2%, p = 0.81), ICU deaths (7% vs. 4%, p = 0.4), or systemic therapy within 7 (4.2% vs. 2.4%, p = 0.63), 14 (8.5% vs. 6.6%, p = 0.76) or 30 (25% vs 19%, p = 0.31) DOD. Among IO-treated RMHNSCC pts, multivariable analysis revealed inferior OS with worse PS (ECOG 2-3 vs. 0: HR = 7.76, p = 0.00002, 95% CI = 3.07 - 19.64; ECOG 1 vs. 0: HR = 2.97, p = 0.008, CI = 1.33 - 6.62). OS also decreased with smoking status (current/former vs. never: HR 2.18, p = 0.007, CI = 1.24-3.84). No association was observed between ECOG PS, age or smoking status at IO initiation and any EOLHCU metric. Conclusions: At our center, a significant proportion of deceased, IO-treated RMHNSCC pts had an ECOG PS ≥ 2 and an inferior OS compared to ECOG 0/1. Exploratory comparison with a non-RMHNSCC TM cohort suggests high rates of EOLHCU within 30 DOD despite ACPD, representing an opportunity for supportive care augmentation. Whether EOLHCU differs among IO vs non-IO treated RMHNSCC is unknown and merits further study.

Factors associated with durable remission after CD19 chimeric antigen receptor (CAR)-modified T-cell immunotherapy for aggressive B-cell non-Hodgkin lymphoma (NHL) have not been identified. We report multivariable analyses of factors affecting response and progression-free survival (PFS) in patients with aggressive NHL treated with cyclophosphamide and fludarabine lymphodepletion followed by 2 × 106 CD19-directed CAR T cells/kg. The best overall response rate was 51%, with 40% of patients achieving complete remission. The median PFS of patients with aggressive NHL who achieved complete remission was 20.0 months (median follow-up, 26.9 months). Multivariable analysis of clinical and treatment characteristics, serum biomarkers, and CAR T-cell manufacturing and pharmacokinetic data showed that a lower pre-lymphodepletion serum lactate dehydrogenase (LDH) level and a favorable cytokine profile, defined as serum day 0 monocyte chemoattractant protein-1 (MCP-1) and peak interleukin-7 (IL-7) concentrations above the median, were associated with better PFS. MCP-1 and IL-7 concentrations increased after lymphodepletion, and higher intensity of cyclophosphamide and fludarabine lymphodepletion was associated with higher probability of a favorable cytokine profile. PFS was superior in patients who received high-intensity lymphodepletion and achieved a favorable cytokine profile compared with those who received the same intensity of lymphodepletion without achieving a favorable cytokine profile. Even in high-risk patients with pre-lymphodepletion serum LDH levels above normal, a favorable cytokine profile after lymphodepletion was associated with a low risk of a PFS event. Strategies to augment the cytokine response to lymphodepletion could be tested in future studies of CD19 CAR T-cell immunotherapy for aggressive B-cell NHL. This trial was registered at www.clinicaltrials.gov as #NCT01865617.

The transcriptional regulator far upstream element binding protein 1 (FUBP1) acts as an oncoprotein in solid tumor entities and plays a role in the maintenance of hematopoietic stem cells. However, its potential function in leukemia is unknown. In murine models of chronic (CML) and acute myeloid leukemia (AML) induced by BCR-ABL1 and MLL-AF9, respectively, knockdown of Fubp1 resulted in prolonged survival, decreased numbers of CML progenitor cells, decreased cell cycle activity and increased apoptosis. Knockdown of FUBP1 in CML and AML cell lines recapitulated these findings and revealed enhanced DNA damage compared to leukemia cells expressing wild type FUBP1 levels. FUBP1 was more highly expressed in human CML compared to normal bone marrow cells and its expression correlated with disease progression. In AML, higher FUBP1 expression in patient leukemia cells was observed with a trend toward correlation with shorter overall survival. Treatment of mice with AML with irinotecan, known to inhibit topoisomerase I and FUBP1, significantly prolonged survival alone or in combination with cytarabine. In summary, our data suggest that FUBP1 acts as cell cycle regulator and apoptosis inhibitor in leukemia. We demonstrated that FUBP1 might play a role in DNA repair, and its inhibition may improve outcome in leukemia patients.

Understanding the socioeconomic impact of chronic graft-versus-host disease (GVHD) on affected patients is essential to help improve their overall well-being. Using data from the Chronic GVHD Consortium, we describe the insurance, employment, and financial challenges faced by these patients and the factors associated with the ability to work/attend school and associated financial burdens. A 15-item cross-sectional questionnaire designed to measure financial concerns, income, employment, and insurance was completed by 190 patients (response rate, 68%; 10 centers) enrolled on a multicenter Chronic GVHD Consortium Response Measures Validation Study. Multivariable logistic regression models examined the factors associated with financial burden and ability to work/attend school. The median age of respondents was 56years, and 87% of the patients were white. A higher proportion of nonrespondents had lower income before hematopoietic cell transplantation and less than a college degree. All but 1 patient had insurance, 34% had faced delayed/denied insurance coverage for chronic GVHD treatments, and 66% reported a financial burden. Patients with a financial burden had greater depression/anxiety and difficulty sleeping. Nonwhite race, lower mental functioning, and lower activity score were associated with a greater likelihood of financial burden. Younger age, early risk disease, and higher mental functioning were associated with a greater likelihood of being able to work/attend school. In this multicenter cohort of patients with chronic GVHD, significant negative effects on finances were observed even with health insurance coverage. Future research should investigate potential interventions to provide optimal and affordable care to at-risk patients and prevent long-term adverse financial outcomes in this vulnerable group.

Introduction CD19 chimeric antigen receptor (CAR)-T cell therapy has shown efficacy in Non-Hodgkin lymphoma (NHL), but the factors associated with durable remission have not been identified. Objectives We report multivariate analyses of factors impacting progression-free survival (PFS) in NHL patients (pts) treated with cyclophosphamide and fludarabine (Cy/Flu) lymphodepletion (LD) and CD19 CAR-T cells. Methods We conducted a phase 1/2 open-label clinical trial (NCT01865617) with the primary objective of evaluating the feasibility and safety of a defined composition of CD19 CAR-T cells after LD in pts with R/R CD19+ B-cell malignancies. PFS was defined as the time from CAR-T cell infusion until disease progression or death. Multivariate models using elastic net were performed for analysis of response and PFS. Results Characteristics of the 57 pts in the study are shown in Tbl 1. Thirty-six (63%) received high-intensity (HI) Cy/Flu and 21 (37%) received low-intensity (LI) Cy/Flu LD (Tbl 1). All pts received 2 × 106 CD19 CAR-T cells/kg. The best overall response (OR) rate was 57%, with 48% complete remission (CR). Pts who achieved CR had a median PFS not reached (median follow-up [fu] 20.2 months; mo), with only 1 relapse beyond 12 mo after CAR-T cell infusion (Fig. 1). Eight of 9 pts with indolent NHL achieved CR (89%) and none relapsed (median fu 14.5 mo). For the 47 pts with aggressive NHL, the best OR rate was 51%, with 40% CR. The median PFS of aggressive NHL pts achieving CR was 20.0 mo (median fu 26.9 mo), and 24-mo probabilities of PFS and OS were 46% and 72%, respectively. In aggressive NHL, multivariate analysis showed that the probability of CR was associated with lower pre-LD serum LDH and greater increase in serum MCP-1 concentration from LD to the day of CAR-T cell infusion. HI LD was associated with more CAR-T cells in blood, but there was no difference in response in pts who received HI (CR 14/31, 45%) compared to LI LD (CR 5/16, 31%; P = .53). Multivariate analysis in aggressive NHL showed that lower pre-LD serum LDH and higher day 0 MCP-1 and peak IL-7 after CAR-T cell infusion were associated with better PFS. The IL-7 peak after CAR-T cell infusion (median day 4) correlated with day 0 IL-7, consistent with an effect of LD. MCP-1 and IL-7 increased after LD, independent of prior bridging therapy, and their concentrations correlated with Cy/Flu LD intensity. However, LD intensity was not independently associated with CR or PFS. Independent of LD intensity, a subset of pts had a robust increase in day 0 MCP-1 and peak IL-7 after LD and achieved better responses (CR 10/16, 63%) compared to those with limited cytokine increase (CR 9/30, 30%; P = .06). Conclusion Multivariate analyses show that cytokines associated with effective LD are, unlike the intensity of Cy/Flu LD, independently associated with CR and PFS. Strategies to augment biological LD efficacy could be tested in studies of CD19 CAR-T cells for aggressive NHL.

Background and Purpose— Whether changes in leisure-time physical activity (LTPA) over time are associated with lower risk of stroke is not well established. We examined the association between changes in self-reported LTPA 10 years apart, with risk of incident stroke in the CTS (California Teachers Study). We hypothesized that the risk of stroke would be lowest among those who remained active. Methods— Sixty-one thousand two hundred and fifty-six CTS participants reported LTPA at 2 intensity levels (moderate and strenuous activity) at 2 time points (baseline 1995–96; 10-year follow-up 2005–2006). LTPA at each intensity level was categorized based on American Heart Association (AHA) recommendations (moderate, >150 minutes/week; strenuous, >75 minutes/week). Changes in LTPA were summarized as follows: (1) not meeting recommendations at both time points; (2) meeting recommendations only at follow-up; (3) meeting recommendations only at baseline; and (4) meeting recommendations at both time points. Incident strokes were identified through California state hospitalization records. Using multivariable Cox models, we examined the associations between changes in LTPA with incident stroke. Results— Nine hundred and eighty-seven women were diagnosed with stroke who completed both questionnaires. Meeting AHA recommendations at both the time points was associated with a lower risk of all stroke (adjusted hazard ratio, 0.84; 95% confidence interval, 0.72–0.98). The protective effects for stroke were driven by meeting AHA recommendations for moderate activity and largely observed for ischemic strokes (adjusted hazard ratio, 0.70; 95% confidence interval, 0.55–0.88). Conclusions— Meeting AHA recommendations for moderate activity had a protective effect for reducing ischemic stroke risk. Participants who met AHA recommendations at baseline but not at follow-up, however, were not afforded reduced stroke risk.