Rutherford, Sarah C.

8038 Background: Bone marrow biopsies (BMB) are performed pre/post therapy to confirm complete response (CR) in patients (pts) with lymphoma on clinical trials. We evaluated 2 prior data sets and concluded that BMB impact response assessment in a minority of pts with follicular lymphoma (FL) (Rutherford BJH 2017; Rutherford ASH abstract 1605, 2018). We sought to establish if BMB add value in assessing response or identify distinct progression free (PFS) or overall survival (OS) outcomes in a large, multicenter, multi-trial cohort. Methods: Data were pooled from 7 trials of 580 pts with untreated FL conducted through the Alliance for Clinical Trials in Oncology and SWOG from 2002-2016. The proportion of pts with positive (+) baseline BMB, CR on imaging after treatment, and (+) repeat BMB was calculated using total pts enrolled as the denominator. We tested against the null hypothesis that the proportion was = 10%, the threshold below which BMB would be considered irrelevant for response assessment, versus (vs) the alternative hypothesis that this proportion was < 10%, using 1-sided exact binomial test. Response criteria were CT-based. Imaging was not used to assess BM involvement. Because confirmatory BMB were not completed in all indicated pts, landmark survival analyses compared PFS/OS of pts with CR on imaging and negative (-) BMB vs pts with CR on imaging without repeat BMB. Pts with CR on imaging were categorized as having (-) repeat BMB or no repeat BMB within 60 days of first CR on imaging. PFS and OS were calculated from time of first CR and estimated using Kaplan-Meier and Cox models adjusting for age, sex, stage, Follicular Lymphoma International Prognostic Index (FLIPI) score, and treatment type (targeted vs chemotherapy plus targeted therapy), and stratified by treatment arm. Results: Median age was 55 with 51% male, 96% stage III-IV, and 88% grade I-II. FLIPI scores were 113 low, 265 intermediate, and 199 high risk. 67% received chemotherapy-based regimens. Baseline BMB was (+) in 321 (55%). Only 5/580 (0.8%) had (+) baseline BMB, CR on imaging, and subsequent (+) BMB (p < 0.0001). Of pts with CR on imaging, PFS and OS were not different among pts with (-) BMB vs pts without repeat BMB (PFS: HR = 1.08, 95%CI 0.61-1.93, p = 0.783; OS: HR = 0.52, 95%CI 0.20-1.40, p = 0.199). Conclusions: BMB requirements may discourage pt participation in trials and add pain, expense and time without providing necessary information. We recommend eliminating BMB for response assessment from FL clinical trials. Clinical trial information: NCT00553501, NCT01145495, NCT01190449, NCT01286272, NCT01829568, NCT00822120, and NCT00770224 .

8017 Background: LAM-002 is a selective inhibitor of PIKfyve that disrupts lysosomal homeostasis, inducing cytotoxicity in B-cell lymphoma models as monotherapy or with anti-CD20 or anti-PDL1 antibodies (Gayle et al., Blood 2017;129(13):1768). Methods: In this study, patients received LAM-002 orally 2-3 times per day (BID or TID) in a 3+3 escalation. Additional patients received LAM-002 125 mg BID as monotherapy; with rituximab 375 mg/m2 intravenously (IV) and or subcutaneously weekly (Q1W) x 4 → Q8W x 4; or atezolizumab 1200 mg IV Q3W until disease progression or unacceptable toxicity. Pharmacokinetics (PK) were assessed for 8 hours postdose on Days 1 and 8. Efficacy was evaluated Q6-12W. Results: The study enrolled 62 patients (M:F n = 32/30); median [range] age = 69 [46-89] years; with diagnoses (n) of diffuse large B-cell lymphoma (25), follicular lymphoma (19), marginal zone lymphoma (8), mantle cell lymphoma (5), or chronic lymphocytic leukemia (5) to receive LAM-002 alone (n) at 50 mg BID (3), 100 mg BID (8), 150 mg BID (8), 75 mg TID (4), or 125 mg BID (20); LAM-002/rituximab (12); or LAM-002/atezolizumab (7). During LAM-002 dose-ranging (50 mg BID → 100 mg BID → 150 mg BID → 75 mg TID → 125 mg BID) transient, reversible nausea and/or diarrhea occurred at 150 mg BID and 75 mg TID, resulting in a LAM-002 recommended Phase 2 dosing regimen (RP2DR) of 125 mg BID. Among 39 patients receiving LAM-002, 125 mg BID, alone or in combination for up to 22 cycles (1.9 years), adverse events were typically low-grade. LAM-002 PK showed rapid absorption, dose proportionality, minimal accumulation, and no substantive changes with rituximab or atezolizumab coadministration. In patients with follicular lymphoma and median [range] prior therapies = 3 [1-9] treated with the RP2DR, objective response rates were 2/7 (29%; 1 complete response [CR], 1 partial response [PR]) with LAM-002, 5/8 (63%; 1 CR, 4 PRs) with LAM-002/rituximab, and 2/2 (100%; 2 PRs) with LAM-002/atezolizumab. Conclusions: LAM-002, the first clinical PIKfyve inhibitor, is safe alone or with full-dose anti-CD20 or anti-PD-L1 inhibition. LAM-002 does not cause the myelosuppressive or immune adverse events associated with lenalidomide or PI3K inhibitors. Promising efficacy supports registration-directed Phase 2/3 testing of LAM-002 monotherapy and combination therapy for patients with previously treated follicular lymphoma. Clinical trial information: NCT02594384 .

Introduction. The VES-13 is a simple, self-reported, function based tool originally developed to screen community-dwelling populations to identify persons age 65 years and older at risk of death and functional decline, including death in the next 12 months. The VES-13 items include patient's age, self-rated overall health status, functional limitations in physical activity, and functional disabilities in more complex activities of daily living. As part of the Lymphoma Epidemiology of Outcomes (LEO) cohort study, we collected self-reported VES-13 data at study enrollment on all participants regardless of age, and here we report on the prevalence of vulnerable status defined by the VES-13 and its association with 1-year mortality, overall, stratified at age 65 years, and in the subset of diffuse large B-cell lymphoma (DLBCL) treated with immunochemotherapy. Methods. From 7/2015 to 6/2017, 3253 participants with NHL were enrolled within 6 months of their diagnosis into the LEO cohort. 2004 were evaluable on VES-13, and 1183 (59%) completed it before the initiation of therapy. VES-13 scores range from a minimum of 0 (low risk for decline) to a maximum of 10 (greatest risk for decline), and a score ≥3 was classified as vulnerable. Clinical, pathology and treatment data were abstracted using a standard protocol, and participants were contacted every 6 months for the first three years and then annually thereafter to identify outcomes. Medical records were reviewed by LEO clinicians to classify cause of death according to a standard protocol. Therapy was determined by the treating physician, and this was independent of knowledge of the VES-13 score. The association of VES-13 with 1-year mortality from date of diagnosis was estimated using odds ratios (OR) and 95% confidence intervals (CI) from logistic regression models, which also provided model c-statistics. Results. The median age of the 2004 participants in this analysis was 62 years (range 18-94); 57% were male; 54% were ≥65 years; and 28% had a normal body mass index (BMI), 1% were underweight, 35% were overweight, and 36% were obese. Clinically, 59% of participants had an aggressive subtype, 65% were stage III-IV, 24% had B-symptoms, and 11% had a performance status (PS) of ≥2. Overall, 28% of participants were classified as vulnerable (95% CI 26%-30%), with a higher prevalence among those completing the survey after initiation of therapy (38%, 95% 34%-41%) versus before initiation of therapy (22%, 95% CI 20%-24%), and a higher prevalence for those ≥65 years (32%, 95% CI 29%-34%) versus &lt;65 (25%, 95% CI 22%-28%). During the first year of follow-up, there were 147 deaths, with 61% due to lymphoma, 14% therapy-related, 12% due to another malignancy, 3% other causes, and 10% unknown. Significant univariate predictors of 1-year mortality included vulnerable status, older age, PS 2+, stage III-IV, aggressive subtype, lower quality of life score, lower BMI, and 1 or more comorbidities, and were included the backward stepwise modeling. Vulnerable status (OR=3.26, 95% CI 2.15-4.96) was retained in the final model that also included age, PS, stage, and NHL subtype (Table), with a model c-statistic of 0.81. As shown in the Table, these associations were similar whether VES-13 was assessed before (c-statistic 0.77) or after (c-statistic 0.81) initiation of therapy. After adjustment for age, PS, stage and NHL subtype, vulnerable status predicted 1-year mortality in participants ≥65 years (OR=1.96, 95% CI 1.15-3.36; model c-statistic 0.80) as well as &lt;65 years (OR=6.38, 95% CI 3.07-13.3; model c-statistic 0.83). Finally, in the DLBCL patients treated with immunochemotherapy (N=521), vulnerable status (38% of patients) also predicted 1-year mortality (OR=2.11, 95% CI 1.05-4.26) after adjusting for age, PS and stage (model c-statistic 0.78). Conclusion. Based on a self-administered VES-13, 28% of newly diagnosed NHL patients in the LEO cohort were classified as vulnerable, including 25% of those &lt;65 years, and vulnerable status was a strong predictor of 1-year-mortality, even in the subset of DLBCL patients treated with presumed curative intent. These results highlight the potential value of screening for vulnerable status overall and across a wider age spectrum in order to optimize patient management and reduce early mortality. Disclosures Martin: Karyopharm: Consultancy; Sandoz: Consultancy; I-MAB: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Teneobio: Consultancy. Casulo:Gilead: Honoraria, Other: Travel, accommodation, expenses; Celgene: Research Funding; Roche: Other: Travel, accommodation, expenses. Cohen:Takeda Pharmaceuticals North America, Inc.: Research Funding; Bristol-Meyers Squibb Company: Research Funding; Hutchison: Research Funding; Astra Zeneca: Research Funding; Lymphoma Research Foundation: Research Funding; ASH: Research Funding; LAM Therapeutics: Research Funding; UNUM: Research Funding; Gilead/Kite: Consultancy; Janssen Pharmaceuticals: Consultancy; Seattle Genetics, Inc.: Consultancy, Research Funding; Genentech, Inc.: Consultancy, Research Funding. Farooq:Kite Pharma: Research Funding; Celgene: Honoraria. Friedberg:Acerta: Other: Data & Safety Monitoring Committee; Bayer: Honoraria, Other: Data & Safety Monitoring Committee. Kahl:Seattle Genetics: Consultancy; ADC Therapeutics: Consultancy, Research Funding; BeiGene: Consultancy; TG Therapeutics: Consultancy. Lossos:Janssen Scientific: Membership on an entity's Board of Directors or advisory committees; NIH: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees. Maurer:Nanostring: Research Funding; Celgene: Research Funding; Morphosys: Membership on an entity's Board of Directors or advisory committees. Nastoupil:Spectrum: Honoraria; Genentech, Inc.: Honoraria, Research Funding; Gilead: Honoraria; Janssen: Honoraria, Research Funding; Novartis: Honoraria; TG Therapeutics: Honoraria, Research Funding; Bayer: Honoraria; Celgene: Honoraria, Research Funding. Rutherford:Heron: Consultancy, Honoraria; Janssen Scientific Affairs: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Juno Therapeutics Inc: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Verastem: Consultancy, Honoraria; Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees. Flowers:National Cancer Institute: Research Funding; BeiGene: Consultancy, Research Funding; Eastern Cooperative Oncology Group: Research Funding; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Pharmacyclics/Janssen: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Bayer: Consultancy; Spectrum: Consultancy; Karyopharm: Consultancy; Acerta: Research Funding; TG Therapeutics: Research Funding; Millenium/Takeda: Research Funding; AstraZeneca: Consultancy; Optimum Rx: Consultancy; V Foundation: Research Funding; Celgene: Consultancy, Research Funding; Burroughs Wellcome Fund: Research Funding; Denovo Biopharma: Consultancy; Gilead: Consultancy, Research Funding. Cerhan:NanoString: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding.

INTRODUCTION Complete staging via bone marrow assessment is standard of practice for most newly diagnosed non-Hodgkin lymphoma (NHL) patients, though the methods and patterns of bone marrow assessment vary in clinical practice. The 2014 Lugano Classification recommends that in diffuse large B cell lymphoma (DLBCL), positron emission tomography-computed tomography (PET/CT) alone can designated advanced-stage disease in many, but not all cases. For most other NHL subtypes, obtaining bone marrow biopsy (BMB) remains recommended. We aimed to assess clinical practice patterns of marrow assessment and the performance of PET/CT in the clinical setting. METHODS The Lymphoma Epidemiology of Outcomes (LEO) cohort is a prospective cohort from 8 academic medical centers. All patients were enrolled in the cohort within 6 months of diagnosis, and prospectively followed. Patients with lymphoma enrolled in the cohort between July 2015 and June 2017 were included for study. Baseline clinical characteristics at diagnosis, whether BMB and/or PET/CT were performed, and the result of these assessments were extracted from the database. Bone marrow involvement on PET/CT was abstracted via review of radiology reports. No central review of images was utilized. RESULTS In total, 3,251 patients were included, consisting of the following subtypes: DLBCL (n=1,098), follicular lymphoma (FL n=730), mantle cell lymphoma (MCL n=302), T-cell lymphoma (TCL n=278), marginal zone lymphoma (MZL n=269), other NHL (n=505) and composite lymphoma (n=69). Other clinical characteristics are shown in table 1. Staging BMB was obtained in 78% of patients, PET/CT was obtained in 56%, both BMB and PET/CT were obtained in 46% while neither were obtained in 9% (table 1). There were significant differences in lymphoma subtype between patients having any bone marrow assessment vs no bone marrow assessment (p<0.0001). MCL (96%) and DLBCL (94%) most frequently had any bone marrow assessment, while MZL was least frequently assessed (84%). Patients undergoing any bone marrow assessment had higher median lactate dehydrogenase (247 U/L vs 206 U/L, p=0.0002). Among the 8 enrolling medical centers, the frequency of bone marrow biopsy at diagnosis ranged from 53% to 86%, and the frequency of PET/CT at diagnosis ranged from 34% to 94% (p<0.0001, table 1). Among patients with DLBCL who had positive bone marrow by either PET/CT or BMB (N=107), 41% (44/107) were positive by BMB only, 19% (20/107) were positive by PET/CT only, and 40% (43/107) were positive by both. Figure 1 shows results of similar analyses for FL, MCL, MZL, and TCL. Using BMB as a gold standard for marrow involvement, the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of PET/CT for marrow assessment in DLBCL is 49%, 90%, 68% and 91%, respectively. Data for other subtypes are shown in table 2. Patients undergoing both PET/CT and BMB had lower median LDH (231 U/L vs 254 U/L, p=0.0032) than those undergoing one or neither assessments. CONCLUSION Overall, 91% of all patients with newly diagnosed NHL had bone marrow assessments via either PET/CT, BMB or both. The significant variation in the frequency of BMB and PET/CT use among the 8 centers reflects a lack of clear consensus on staging practices regarding bone marrow assessment. The sensitivity of PET/CT for detection of marrow involvement was less than 50% across all subtypes. It is possible the sensitivity of PET/CT could be improved via a centralized review process of the images, as is performed in some clinical trials, however practical approaches for implementing such reviews in clinical practice have not been developed. Between 92-100% of all positive bone marrows were detected by BMB, except in cases with DLBCL in which 19% of positive bone marrows were missed by BMB but detected by PET/CT. Thus, in our analysis, BMB more reliably captured marrow involvement that PET/CT in all subtypes in which both assessments were performed. However, neither PET/CT nor BMB alone were able to identify all cases of bone marrow involvement and use of both modalities may be necessary in cases where marrow involvement would have clinically important implications. Disclosures Rutherford: Juno Therapeutics Inc: Consultancy, Honoraria; Janssen Scientific Affairs: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Verastem: Consultancy, Honoraria; Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Heron: Consultancy, Honoraria. Kahl:ADC Therapeutics: Consultancy, Research Funding; Seattle Genetics: Consultancy; TG Therapeutics: Consultancy; BeiGene: Consultancy. Lossos:Janssen Scientific: Membership on an entity's Board of Directors or advisory committees; NIH: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees. Friedberg:Acerta: Other: Data & Safety Monitoring Committee; Bayer: Honoraria, Other: Data & Safety Monitoring Committee. Casulo:Celgene: Research Funding; Roche: Other: Travel, accommodation, expenses; Gilead: Honoraria, Other: Travel, accommodation, expenses. Cohen:Astra Zeneca: Research Funding; Takeda Pharmaceuticals North America, Inc.: Research Funding; Hutchison: Research Funding; Gilead/Kite: Consultancy; Bristol-Meyers Squibb Company: Research Funding; LAM Therapeutics: Research Funding; UNUM: Research Funding; Lymphoma Research Foundation: Research Funding; ASH: Research Funding; Seattle Genetics, Inc.: Consultancy, Research Funding; Janssen Pharmaceuticals: Consultancy; Genentech, Inc.: Consultancy, Research Funding. Nastoupil:TG Therapeutics: Honoraria, Research Funding; Novartis: Honoraria; Spectrum: Honoraria; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Genentech, Inc.: Honoraria, Research Funding; Gilead: Honoraria; Bayer: Honoraria. Flowers:Denovo Biopharma: Consultancy; Spectrum: Consultancy; National Cancer Institute: Research Funding; Optimum Rx: Consultancy; Burroughs Wellcome Fund: Research Funding; Acerta: Research Funding; Bayer: Consultancy; BeiGene: Consultancy, Research Funding; Eastern Cooperative Oncology Group: Research Funding; TG Therapeutics: Research Funding; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Karyopharm: Consultancy; AstraZeneca: Consultancy; Pharmacyclics/Janssen: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; V Foundation: Research Funding; Millenium/Takeda: Research Funding; Celgene: Consultancy, Research Funding. Cerhan:Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; NanoString: Research Funding. Martin:Sandoz: Consultancy; Karyopharm: Consultancy; Celgene: Consultancy; Teneobio: Consultancy; I-MAB: Consultancy; Janssen: Consultancy.