Macon, William R.

Background: Observation or "wait and watch" (W/W) strategy remains a viable option in the rituximab era for asymptomatic, stage II-IV, low-tumor burden patients with FL grade 1-2, 3A. Studies to date both in pre and post rituximab era have not shown an overall survival benefit from immediate treatment in such low-risk patients.To improve our understanding and to better counsel FL patients on W/W strategy, we sought to estimate the incidence of treatment initiation at landmark time points in our prospectively observed cohort from the Molecular Epidemiology Resource (MER) of the University of Iowa/Mayo Clinic Lymphoma Specialized Program of Research Excellence (SPORE). We further evaluate the association between the presence of GELF criteria (MER treatment criteria) at diagnosis and initiation of treatment patterns, transformation rates and cause of death in FL patients managed by W/W. Methods: FL patients on W/W strategy were identified from MER of the University of Iowa/Mayo Clinic Lymphoma SPORE. From 2002-2015, consecutive patients with newly diagnosed FL were offered enrollment. Patients were managed per treating physician and followed prospectively. Baseline clinical and pathological data were abstracted using a standard protocol. Cumulative incidence estimates of treatment initiation for follicular lymphoma were calculated using transformation to large cell lymphoma (as the first event) and death due to any cause as competing risks. Transformation was defined based on biopsy-proven disease. Patients were retrospectively considered to meet treatment criteria at diagnosis if they had the presence of any GELF criteria components per available abstracted data in the MER database. Not all GELF criteria were prospectively assessed and captured for all patients, and thus the MER treatment criteria utilized here will be conservative for formal GELF assessment. Results: A total of 401 FL patients were identified in MER on W/W strategy. Baseline characteristics for W/W patients showed a favorable profile such as normal LDH (89%), low and intermediate FLIPI score in 48% and 35% respectively, no B symptoms (97%), low tumor burden (<4 nodal groups) in 72%, and GELF positive vs. negative in 36% and 64% respectively. At a median follow up of 8 years (IQR 5.9-12), 64% initiated treatment for FL only. Cumulative incidence estimates of treatment initiation at sequential time points were calculated from the initiation of observation (Table1&2). At diagnosis, the likelihood of treatment initiation was 15%, 26%, and 42% in the next 1, 2, and 5 years. The incidence of treatment initiation decreased over time as patients remained treatment-free after diagnosis (Figure 1A [blue curve]). Patients that met MER treatment criteria had increased rates of therapy initiation (33.2% vs. 21.9%) in the next two years and untreated transformation to large cell lymphoma [red curve] (8.7% vs. 4.5%) during the next 5 years (Figure 1B). Despite this, the rate of lymphoma related death at 10 years was similar between groups (met treatment criteria = 6.2% vs. 7.1%) (Figure 1C, [green curve]). Discussion: The longer duration of W/W strategy suggests a decreasing need for treatment over time. We provide time point estimates, which would be helpful for counseling patients. Of note, long-term continuous oncologic assessment and follow-up is necessary since approximately 66% of patients in this mature cohort initiated treatment by 8 years median follow up. MER treatment criteria at diagnosis identified patients with higher rates of transformation and therapy initiation in the first two years but did not identify those with worse lymphoma specific survival. Identification of biological differences in patients with early vs. late or no progression is a critical next step in understanding outcomes in W/W patients. Disclosures Ansell: Bristol Myers Squibb: Research Funding; Seattle Genetics: Research Funding; Takeda: Research Funding; AI Therapeutics: Research Funding; Regeneron: Research Funding; Affimed: Research Funding; ADC Therapeutics: Research Funding; Trillium: Research Funding. Cerhan:BMS/Celgene: Research Funding; NanoString: Research Funding. Wang:Incyte: Research Funding; Innocare: Research Funding; Novartis: Research Funding. Witzig:MorphSys: Consultancy; AbbVie: Consultancy; Incyte: Consultancy; Acerta: Research Funding; Karyopharm Therapeutics: Research Funding; Immune Design: Research Funding; Spectrum: Consultancy; Celgene: Consultancy, Research Funding. Maurer:Morphosys: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Nanostring: Research Funding; Kite: Membership on an entity's Board of Directors or advisory committees; Celgene / BMS: Research Funding. Nowakowski:NanoString: Research Funding; Kite: Consultancy; Seattle Genetics: Consultancy; Kymera: Consultancy; Celgene/BMS: Consultancy, Research Funding; MorphoSys: Consultancy, Research Funding; Curis: Consultancy; Ryvu: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Introduction: Transformation of low grade follicular lymphoma (FL) to diffuse large B cell lymphoma (DLBCL) carries a poor prognosis. In retrospective studies, 5-year survival of transformed DLBCL treated with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) without autologous stem cell transplant is 40-60%, underscoring need to improve frontline treatment of transformed DLBCL beyond R-CHOP. The overall response rate (ORR) to lenalidomide used as a single agent for relapsed transformed non Hodgkin lymphoma was 45% with 21% complete response (CR) rate and a median duration of response of 12 months (Witzig et al, Ann Onc 2011). These data provided the rationale to include patients with transformed DLBCL (with historical and concurrent FL) in MC078E, a phase II clinical trial testing lenalidomide plus R-CHOP (R2CHOP) for patients with new and untreated de novo and transformed DLBCL (NCT00670358). Here we present analysis of the subset of transformed DLBCL patients. Methods: Adult patients with transformed DLBCL and either historical or concurrent FL, stage >=2, measurable disease by Positron Emission Tomography/computed tomography (PET/CT) and adequate organ function were included. Patients with Central Nervous System (CNS) involvement, significant comorbidities, active non-lymphomatous malignancy, life-threatening thromboembolism (TE) and contraindication to aspirin prophylaxis were excluded. Study participants received up to 6 cycles of rituximab (375 mg/m2), cyclophosphamide (750 mg/m2), doxorubicin (50 mg/m2), and vincristine (1.4 mg /m2) on day 1, prednisone (100 mg) on day 1-5, pegfilgrastim on day 2, and Lenalidomide 25 mg day 1-10 of 21 day cycle. Tumor lysis prophylaxis was per local practice; patients also received TE prophylaxis with aspirin. Primary outcome was event free survival (EFS) at 12 months, where an event was defined as death, progression or subsequent anti-lymphoma therapy. Secondary outcomes included ORR, CR, progression free survival (PFS), and overall survival (OS). Response was evaluated by PET/CT after cycle 2 and cycle 6 with revised response criteria (Cheson et al, 2007). Adverse events were recorded according to CTCAE version 3.0. The Kaplan-Meier method was used to estimate time to event endpoints. Results: Thirty-nine patients were accrued from August 5, 2013 to July 28, 2020 and 33 were eligible by central pathology review. Median age was 64 (range 24-80) years and 18 (54%) were >60 years old. Eighteen (54%) were male, and 32 (97%) had ECOG performance status <2. Twenty-three (70%) had historical FL and 10 (30%) had concurrent FL. Twenty-six (79%) had advanced stage (III-IV). Median number of extra nodal sites were 1 (0-4). Thirteen (39%) had high international prognostic index (IPI) (4-5). Thirty-two (97%) completed at least 2 cycles (30 completed all 6 cycles) and were evaluable for response. ORR was 97% (32/33), 29 (88%) had CR and 3 had PR. EFS at 12 months was 87.9% (95% CI: 71.8, 96.6). Two-year PFS and OS were 84.5% (95% CI: 72.8%-98%) and 96.9% (95% CI: 91-100%) (Figure 1). Twenty nine completed study protocol, 4 discontinued protocol early for disease progression (1), adverse event (AE) (1), refusal (1) and noncompliance (1). Thirty (91%) had hematologic AE of grade 3 or above, 27 (82%) had neutropenia, 16 (48%) had thrombocytopenia, and 7 (21%) had anemia. Sixteen (48%) had grade 3 or above non-hematologic AE. Eight (24%) had febrile neutropenia. There were 3 deaths on this study, 1 due to progressive DLBCL, 1 due to AML and 1 due to malignant melanoma. Conclusion: R2CHOP appears effective in transformed DLBCL with high response rates, event free, progression free and overall survival seen in current study. This study supports the inclusion of anthracycline naive patients with transformed DLBCL in future randomized studies of lenalidomide or other novel immunomodulatory (IMiD) analogues. Disclosures Wang: Novartis: Research Funding; Innocare: Research Funding; Incyte: Research Funding. Ansell:Bristol Myers Squibb: Research Funding; Takeda: Research Funding; AI Therapeutics: Research Funding; Regeneron: Research Funding; Trillium: Research Funding; Affimed: Research Funding; Seattle Genetics: Research Funding; ADC Therapeutics: Research Funding. Witzig:Spectrum: Consultancy; Immune Design: Research Funding; Karyopharm Therapeutics: Research Funding; Acerta: Research Funding; Incyte: Consultancy; AbbVie: Consultancy; MorphSys: Consultancy; Celgene: Consultancy, Research Funding. Nowakowski:Celgene/BMS: Consultancy, Research Funding; MorphoSys: Consultancy, Research Funding; Ryvu: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite: Consultancy; Kymera: Consultancy; Curis: Consultancy; Seattle Genetics: Consultancy; NanoString: Research Funding.

TPS8073 Background: Response rates to salvage immunochemotherapy in patients with DLBCL relapsing after or refractory (R/R DLBCL) to front line therapy remain unsatisfactory. Lenalidomide (Len) has significant single agent activity in relapsed/refractory DLBCL. The addition of lenalidomide (Len) days 1-7 to rituximab plus ifosfamide-carboplatin-etoposide (RICE) was shown to be feasible with promising efficacy in phase 1b study (Feldman T, et al. BJH, 2014). We developed phase I/II study to evaluate the safety and efficacy of the addition of Len (extended to 14 day schedule) to RICE (R2-ICE) for R/R-DLBCL patients who are candidates for stem cell transplant. Methods: The phase I portion was designed to determine the maximally tolerated dose Len in combination with RICE using the standard cohort 3+3 design. The escalation dose levels were 15 mg and 20 mg daily x 14 days. Prophylactic aspirin and growth factor support is mandatory. After 2 cycles of therapy response is evaluated with a PET/CT scan; the responding patients are eligible for 1-2 additional cycles of R2ICE as a bridging before HDC/SCT. The estimated overall response rate for two cycles of R-ICE in R/R DLBCL to RCHOP was estimated to be approximate 45%. We hypothesize that the addition of lenalidomide in the relapse setting could increase the overall response rate by approximately 20%. The one-stage design with an interim analysis being utilized in phase 2 requires 45 evaluable patients (one sided alpha = 0.09, power 90%). For Phase I, all types of B-cell lymphomas were eligible. For phase II portion only DLBCL patients are eligible per central pathology review. Other eligibility criteria include: received one line of previous anti-lymphoma therapy, ≥ 2 weeks from completion of prior anti-lymphoma therapy, candidate for HDC and SCT, adequate organ (creatinine clearance ≥ 60ml/min by Cockcroft-, total bilirubin ≤ 2 × ULN) and bone marrow function (ANC) ≥1500/mm3; platelet count ≥75,000/mm3). The use of steroids and/or rituximab up to 1 week prior to registration for management of symptoms is allowed. 9 patients cleared phase 1 without DLT and dose of 20 mg days 1 -14 was recommend for phase 2 part (RP2D) of the study. The phase 2 study passed interim futility analysis and accrual continues. Correlatives include cell of origin by Nanostring, Myc/bcl2 expression and by FISH and minimal residual disease. PET scans are centrally reviewed including metabolic tumor volume. Clinical trial information: NCT02628405 .

e20068 Background: FL grade 3B (FL3B) is an aggressive subtype of FL with a distinct morphologic, cytogenetic and immunohistochemical profile that is associated with higher mortality compared to other subtypes of FL. FL3B is a rare disease, and data regarding its prognostication beyond grading is lacking. Recent data suggests that spleen and extranodal (EN) involvement on PET/CT predict early clinical failure in FL grades 1-3A[1]. We aimed to determine the incidence of spleen and EN involvement on PET/CT in FL3B, and whether these can predict EFS. Methods: Patients with untreated FL3B diagnosed between 2003-2016, with available pre-treatment PET/CT, were identified using the Mayo Clinic Lymphoma Database and the University of Iowa/Mayo Clinic Lymphoma SPORE database. 27 patients were included in this analysis. All but two patients received treatment with immunochemotherapy. Associations with outcomes were assessed using EFS, defined as disease progression, relapse, transformation, or death. Results: 11/27 (40.7%) of patients had EN involvement on PET/CT. The most common EN site was bone, in 8/27 (29.5%) of patients. Soft tissue involvement was present in 4/27 (14.8%) of patients. Liver, brain, and endometrial involvement were each noted once. 11/27 (40.7%) of patients had spleen involvement on PET/CT. Presence of bone involvement as detected on PET/CT was associated with lower EFS (p = 0.02). EN involvement was associated with a trend toward a lower EFS but statistical significance was not reached likely secondary to low numbers in this cohort. Results in the table are compared to results obtained from our analysis in patients with FL grade 1-3A[1]. Conclusions: Bone involvement on pre-treatment PET/CT in FL3B was associated with early clinical failure in this small cohort of 27 patients. EN involvement at diagnosis may also be associated with poorer outcomes. These findings are similar to our analysis of a large (n = 613) cohort of patients with FL grade 1-3A. These findings may aid in the prognostication of patients with newly diagnosed FL3B, to guide therapy in select higher risk patients. [Table: see text]

AbstractBackgroundStandard bone marrow biopsy (BMB) and bone involvement with follicular lymphoma (FL) on positron emission tomography (PET)/computed tomography (CT) both predict early clinical failure in FL. The key clinical question is whether PET/CT findings can obviate the need for BMB. The goal of this study was to determine the value of PET/CT in determining bone involvement in FL, using posterior iliac crest BMB as the gold standard.Materials and MethodsA total of 548 patients with newly diagnosed grade 1–3A FL were included. The presence, pattern, and location of bone involvement, spleen involvement, and standardized uptake values (SUVs) in the L3 vertebral body were recorded for all patients and compared with the BMB report.ResultsExcluding patients with focal bone lesions on PET/CT, the sensitivity and specificity of PET/CT in detecting bone or marrow involvement, compared with BMB, were 53% and 88%, respectively. The sensitivity and specificity of spleen involvement on PET/CT in predicting a positive BMB were 55% and 86%, respectively. An L3 SUVmax of less than 2.0 resulted in a negative predictive value (NPV) of 96% for marrow involvement on BMB; an L3 SUVmean below 1.4 resulted in an NPV of 100%.ConclusionIn newly diagnosed FL, PET/CT-detected bone and splenic involvement is highly specific for a positive BMB, and very low SUV values (<2.0 SUVmax and < 1.4 SUVmean) in the lumbar spine have a high NPV for a negative BMB. Routine BMB may be obviated in these patients. BMB remains necessary to definitively exclude bone marrow involvement in a large majority of patients with a negative PET.Implications for PracticePredicting early clinical failure in follicular lymphoma (FL) is important but difficult. Bone marrow involvement by FL is associated with early clinical failure, and determining this involvement is a key component of the initial staging. This study highlights that in certain patients, positron emission tomography/computed tomography is sufficient in determining bone or marrow involvement, without the need for a confirmatory bone marrow biopsy (BMB). An algorithm is provided based on these findings to help clinicians determine which patients would benefit from BMB and when it can be avoided.

Abstract Background: Non-Hodgkin lymphoma (NHL) is a malignancy of lymphocytes, and may develop in the setting of inflammation and immune dysfunction. Small scale evaluations have suggested that common genetic variation in candidate genes related to immune function may predispose to the development of NHL. Here we report a comprehensive analysis of variants within genes associated with immunity and inflammation and risk of NHL. Methods: We used ParAllele’s Immune and Inflammation panel of 9,412 single nucleotide polymorphisms (SNPs) from 1,450 immune/inflammation genes as a discovery tool in a clinic-based study of 458 NHL cases and 484 frequency matched controls seen at the Mayo Clinic from 2002–2005. The panel included 537 coding non-synonymous SNPs (nsSNPs), with the remainder of the SNPs selected as tags from HapMap (tagSNPs) to provide coverage of the candidate genes (r2 = 0.8 and minor allele frequency >0.05). To assess the association of individual SNPs with risk of NHL, we calculated Odds Ratios (ORs) and 95% confidence intervals, adjusted for age and gender. The most prevalent homozygous genotype was used as the reference group, and each polymorphism was modeled individually as having a log-additive effect in the regression model. Associations between haplotypes from each gene and the risk of NHL were calculated using a score test implemented in HAPLO.SCORE. We also modeled the main effects for all independent (r2 <0.25) SNPs from a gene in a multivariate logistic regression model. Results: The mean age at diagnosis was 60 years for cases and 58% were male; in controls the mean age at enrollment was 61.6 years and 55% were male. In the gene analyses, the strongest findings (p≤0.001 from multiple SNP logistic regression or haplotype analysis) were for cAMP responsive element binding protein 1 (CREB1; p=0.0004), fibrinogen alpha chain (FGA; p=0.0006), TNF receptor-associated factor 1 (TRAF1; p=0.001), dual specificity phosphatase 2 (DUSP2; p=0.001), and fibrinogen gamma chain (FGG; p=0.001). In the nsSNP analyses, the strongest findings (p≤0.01) were for integrin β3 (ITGB3) L59P (OR=0.64, 0.50–0.83), Beta-1,3-N-acetylglucosaminyltransferase 3 (B3GNT3) H328R (OR=0.72, 0.57–0.91), transporter 2, ATP-binding cassette (TAP2) T665A (OR=1.32, 1.07–1.63), HLA-B associated transcript 2 (BAT2) V1895L (OR=0.60, 0.42–0.85), and complement component 7 (C7) T587P (OR=1.39, 1.07–1.80). Conclusions. Our results suggest that genetic variability in genes associated with antigen processing (CREB1 and TAP2), lymphocyte trafficking (B3GNT3), immune activation (TRAF1, BAT2), complement and coagulation pathways (FGA, FGG, ITGB3, C7), and MAPK signaling (DUSP2) may be important in the etiology of NHL, and should be pursued in replication studies.

Abstract Background: Recent literature suggests that statins may have anticancer potential. This effect is thought to be mediated through 2 primary mechanisms - impairment of protein prenylation and interference with the formation of cholesterol-rich lipid microdomains, or “lipid rafts” within the cell membrane. Both of these processes are critical for signaling activity of numerous proteins important for lymphomagenesis and tumor survival. Recent data, however, suggest that statin use may directly inhibit rituximab binding to CD20 and therefore rituximab efficacy. These findings raised significant concerns about statin use during rituximab treatment. Here we report on statin use and clinical outcome in a cohort of FL and DLBCL treated patients, most of whom were treated with rituximab containing regimens. Methods: 293 newly diagnosed FL patients and 228 newly diagnosed DLBCL patients were prospectively enrolled in our Lymphoma SPORE registry from 9/2002 through 6/2007. Pathology was centrally reviewed. All patients were followed for retreatment, progression-free and overall survival. Statin use at the time of diagnosis and time of initial treatment was abstracted from the medical record. An event was defined by disease progression, retreatment, or death due to any cause. Results: 19% of FL patients and 22% of DLBCL patients were on statins at diagnosis; 16% and 19% were on statins during treatment, respectively. Initial therapy for the FL patients was observation (40%), R-CHOP (19%), R-CVP (12%), rituximab alone (8%), CVP (7%), RT (6%), and other (8%). All DLBCL patients received rituximab with CHOP or a CHOP-like regimen. At a median follow-up of 36 months (range 3–73), 109 (37%) and 65 (29%) of FL and DLBCL patients had an event; 19 (6%) and 46 (20%) of FL and DLBCL patients died, respectively. After adjusting for FLIPI, grade, and initial therapy type, statin use at diagnosis was associated with better event-free survival (HR = 0.57, 95% CI: 0.34–0.95, p=0.03) in FL patients. Statin use during treatment in FL patients was also associated with better event-free survival, though not statistically significant (HR = 0.67, 95% CI: 0.39–1.16, p=0.15). The improvement in EFS for FL patients was consistent across initial therapies, including observation. Statin use was not associated with IPI-adjusted overall survival or event-free survival in DLBCL (all p > 0.50). Conclusions: Statin therapy does not appear to be associated with inferior clinical outcome in DLBCL treated with rituximab and CHOP or CHOP-like therapy. Therefore direct inhibition of rituximab binding to CD20 may have limited clinical significance or/and may be overcome by inhibitory impact of statins on cell signaling. The latter possibility is supported by our observation that statin use is associated with improved event-free survival in follicular lymphoma. Figure Figure Figure Figure