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Abstract Introduction: Richter transformation (RT) refers to transformation of chronic lymphocytic leukemia (CLL) to an aggressive lymphoma, most commonly diffuse large B-cell lymphoma (DLBCL). Most studies on the management of RT were either small retrospective series or early phase non-randomized trials before the era of novel agents. The natural history, prognostication and optimal treatment of patients with RT remain undefined. Here we report the clinical characteristics and outcomes of a large series of RT from a single center. Methods: Biopsy-confirmed RT (limited to non-Hodgkin lymphoma) diagnosed from 4/1993 to 4/2018 were identified from the Mayo Clinic CLL database. Clinical characteristics, treatment information and follow-up data were abstracted by chart review. Overall survival (OS) was defined as time from RT diagnosis to death from any cause and analyzed using the Kaplan-Meier method. Statistical analysis was done in SAS 9.4. Results: A total of 204 patients with CLL who developed RT were identified. The median age at CLL diagnosis was 62 years (range 22-85), and 148 (73%) were male. The median time to transformation was 4.7 years (range 0-34.5). Prior to RT, 68 (33.3%) patients received no treatment for CLL, 109 (53.4%) received chemoimmunotherapy (CIT) only, and 27 (13.2%) received at least one novel agent (idelalisib, ibrutinib, or venetoclax) for CLL. The median lines of CLL therapy prior to RT was 2 (range 0-13). The median age at RT diagnosis was 69 years (range 30-88). Pathology of RT was DLBCL and high grade B-cell lymphoma in 193 (94.6%) and 11 (5.4%) patients, respectively. The median LDH was 306 IU/L (range 99-9000). 62/125 (49.6%) patients had bulky disease (≥ 5 cm), and the median PET SUVmax was 13.9 (range 2.9-30.0). 45/131 (34.4%) patients had del(17p) or TP53 mutation, 12 (9.2%) had del(11q), 21 (16.0%) had trisomy 12, 27 (20.6%) had del(13q), and 25 (19.1%) had normal FISH. The CLL and RT were clonally related in 12/21 (57.1%) patients. For the transformed lymphoma, cell of origin by Han's algorithm was germinal center B cell-like (GCB) and non-GCB in 31/100 (31.0%) and 69/100 (69.0%) patients, respectively. EBV was positive in 14/52 (26.9%) patients. The median Ki-67 was 80% (range 10-100). Myc and Bcl-2 were positive by IHC in 31/43 (72.1%) and 83/103 (80.6%) patients, respectively; 27/56 (48.2%) were double-expressors. MYC, BCL2, and BCL6 rearrangement was positive by FISH in 18/68 (26.5%), 10/34 (29.4%), and 4/31 (12.9%) patients, respectively; 8/66 (12.1%) were double/triple-hit. The most common first-line treatment (Table 1 notes) of RT was R-CHOP-like regimen (n=114, 65.5%). Other treatments included R-EPOCH-like (n=6, 3.4%), high-intensity chemotherapy (n=15, 8.6%), novel agents (eg, ibrutinib, venetoclax, pembrolizumab; n=19, 10.9%), other chemotherapy (n=12, 6.9%), and palliative therapy (n=8, 4.6%). Response to first-line treatment was CR in 57 (38.0%), PR in 33 (22.0%), SD in 18 (12.0%), and PD in 42 (28.0%) patients. The median OS of the entire cohort after RT diagnosis was 12.0 months. The median OS for patients who received no prior CLL treatment, CIT only or at least one novel agent for CLL were 65.5, 7.3, and 12.0 months, respectively (P<0.0001; Figure 1). Of note, in patients who received CIT only for CLL, ~10% and 60% received high-intensity and R-CHOP/R-EPOCH-like chemotherapy, respectively, as first-line RT therapy. In contrast, in patients who had prior novel agents for CLL, 56% and 26% were treated with novel agents and R-CHOP/R-EPOCH-like chemotherapy, respectively, as first-line RT therapy. Patients with or without del(17p)/TP53 mutation had a median OS of 8.3 and 12.8 months, respectively (P=0.046). Patients who were treated with high intensity chemotherapy, R-CHOP/R-EPOCH-like regimens, novel agents, and other therapies for RT had a median OS of 35.1, 14.4, 10.9 and 6.1 months, respectively (P=0.02; Figure 2). OS comparisons by CLL/RT clonal relationship, double expressor or double/triple-hit status are shown in Table 1, with no significant differences noted. Conclusions: Over two thirds of RT were the non-GCB subtype, and about half were Myc/Bcl-2 double expressors. Patients who developed RT without prior CLL therapies had a significantly better OS. In contrast, patients who had received prior CLL therapies had poor outcomes. Myc/Bcl-2 double expressor and MYC/BCL2/BCL6 double/triple hit status had no impact on OS. Disclosures Kenderian: Humanigen: Research Funding; Novartis: Patents & Royalties; Tolero Pharmaceuticals: Research Funding. Kay:Infinity Pharm: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Agios Pharm: Membership on an entity's Board of Directors or advisory committees; Morpho-sys: Membership on an entity's Board of Directors or advisory committees; Tolero Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Acerta: Research Funding; Cytomx Therapeutics: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees. Parikh:Janssen: Research Funding; Abbvie: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; MorphoSys: Research Funding; Gilead: Honoraria; Pharmacyclics: Honoraria, Research Funding. Ding:Merck: Research Funding.

Abstract Introduction: The addition of Rituximab to chemotherapy has significantly improved the outcome of patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL). Patients treated with immunochemotherapy for DLBCL who achieve EFS24 (event-free for 2 years after diagnosis) have an overall survival equivalent to that of the age- and sex-matched general population. Relapses after achieving EFS24 have been considered to be unusual but have been understudied. We sought to define the rate, clinical characteristics, treatment pattern, and outcomes of such relapses. Methods: 1448 patients with newly diagnosed DLBCL from March 2002 to June 2015 were included. Patients were enrolled in the Molecular Epidemiology Resource (MER) of the University of Iowa/Mayo Clinic Lymphoma SPORE, treated per physician choice (predominantly R-CHOP immunochemotherapy) and followed prospectively. An event was defined as progression or relapse, unplanned re-treatment after initial therapy, or death from any cause. Cumulative incidence of relapse and non-relapse mortality after achieving EFS24 were analyzed as competing events using Gray's test in the EZR software. Post-relapse survival was defined as time from relapse to death from any cause and analyzed using Kaplan-Meier method in SPSS (V22). Results: Among the 1448 patients, 1260 (87%) had DLBCL alone at diagnosis, and 188 (13%) had concurrent indolent lymphoma (follicular lymphoma 115, marginal zone lymphoma 18, chronic lymphocytic leukemia 14, lymphoplasmacytic lymphoma 4, unspecified 37) at diagnosis. After a median follow-up of 83.9 months, 896 patients achieved EFS24. For all 896 patients who achieved EFS24, the cumulative incidence of relapse (CIR) was 5.7%, 9.3% and 13.2%, respectively, at 2, 5 and 10 years after achieving EFS24. Patients with concurrent indolent lymphoma at diagnosis had a higher CIR compared to those with DLBCL alone at diagnosis (10.2 vs 4.8% at 2 years, 15.7 vs 8.0% at 5 years, 28.8 vs 9.7% at 10 years, P<0.001; Figure 1). There were a total of 84 patients who relapsed after achieving EFS24. The median age at initial diagnosis was 66 years (range 35-92), and 48 (57%) were male. At diagnosis, 11 (13%) had ECOG PS >1, 37 (50%) had LDH elevation, 62 (74%) were stage III-IV, 14 (17%) had more than 1 extranodal site, and 26 (31%) were poor risk by R-IPI score. There were 58 patients with DLBCL alone at diagnosis who relapsed after achieving EFS24, and 38 (75%) relapsed with DLBCL, 13 (25%) relapsed with indolent lymphoma (predominantly follicular lymphoma), and pathology was unknown in 7 patients. In contrast, there were 26 patients with concurrent indolent lymphoma at diagnosis who relapsed after achieving EFS24, and 9 (41%) relapsed with DLBCL, 13 (59%) relapsed with indolent lymphoma, and pathology was unknown in 4 patients. In the 47 patients who relapsed with DLBCL after achieving EFS24, 45% received intensive salvage chemotherapy, 19% received regular intensity chemotherapy, 9% received CNS directed chemotherapy, and 36% went on to receive autologous stem cell transplant (ASCT). In the 26 patients who relapsed with indolent lymphoma after achieving EFS24, 27% were initially observed, 54% received regular intensity chemotherapy, 4% received intensive salvage chemotherapy, and 19% received ASCT after subsequent progression. The median post-relapse survival (PRS) for all patients with a relapse after achieving EFS24 was 38.0 months (95% CI 27.5-48.5). The median PRS for patients who relapsed with DLBCL and indolent lymphoma after achieving EFS24 were 29.9 (19.9-39.9) and 89.9 (NR-NR) months, respectively (P=0.002; Figure 2). Conclusions: Relapses after achieving EFS24 in patients with DLBCL were uncommon in the rituximab era. Patient with DLBCL alone at diagnosis can relapse with either DLBCL or indolent lymphoma (3:1 ratio). Patients with concurrent DLBCL and indolent lymphoma at diagnosis had a significantly higher CIR, and relapses with DLBCL and indolent lymphoma were similar (2:3 ratio). Even with high intensity salvage chemotherapy and consolidative ASCT, patients who relapsed with DLBCL had a significantly worse survival compared to those who relapsed with indolent lymphoma. Late relapses with DLBCL remain clinically challenging, with a median survival of 2.5 years after relapse. Figure 1. Figure 1. Disclosures Maurer: Celgene: Research Funding; Nanostring: Research Funding; Morphosys: Research Funding. Witzig:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Ansell:Takeda: Research Funding; Pfizer: Research Funding; Affimed: Research Funding; Regeneron: Research Funding; Seattle Genetics: Research Funding; Celldex: Research Funding; LAM Therapeutics: Research Funding; Trillium: Research Funding; Merck & Co: Research Funding; Bristol-Myers Squibb: Research Funding. Cerhan:Celgene: Research Funding; Jannsen: Other: Scientific Advisory Board; Nanostring: Research Funding.

Abstract Background: Bortezomib is a proteasome inhibitor that can lead to cell-cycle arrest and apoptosis. Bortezomib-based regimens are widely used as induction therapy of multiple myeloma (MM). Unlike lenalidomide (an immunomodulatory drug), the role of bortezomib in the consolidation and maintenance therapy of multiple myeloma is less clear. This study aims to examine the efficacy and safety of bortezomib-based regimens as consolidation/maintenance therapy in MM patients following induction therapy with or without autologous stem cell transplantation (ASCT). Methods: PubMed, ASH, and ASCO databases were searched for randomized controlled trials (RTC) of bortezomib-based regimens (either single-agent or combination) as consolidation/maintenance therapy for MM patients through July 2018. Study endpoints included overall survival (OS), progression-free survival (PFS), and adverse events (AE). Pooled hazard ratios (HR) for survival outcomes and relative risks (RR) for dichotomous data with 95% confidence interval (CI) were calculated with a random effect model using MedCalc (MedCalc Software, Ostend, Belgium). For studies that did not report HRs for survival outcomes but provided graphical survival curves, the log HRs and variances were estimated based on the method by Parmar et al (Stat Med 1998; 17: 2815-2834). Heterogeneity was assessed using the I2 statistic of inconsistency, with statistically significant heterogeneity defined as I2 > 50% or p-value < 0.1. Results: Eight randomized controlled trials (7 phase III, 1 phase II; 2 were published in a single article) were identified. Bortezomib-based regimens were administered as consolidation treatment in 5 RTCs and maintenance therapy in 3 RTCs, following induction therapy +/- ASCT. A total of 2439 patients were included: 1154 patients received bortezomib-based regimens, and 1285 patients received non-bortezomib-based regimens or observation. Two RCTs (1 for consolidation, 1 for maintenance) did not provide HRs, which were estimated as described as above. Pooled data from the 8 RCTs showed that bortezomib-based consolidation/maintenance therapy improved progression-free survival (HR 0.71, 95% CI 0.64-0.79, P < 0.001; I2 = 6.61%) and overall survival (HR 0.80, 95% CI 0.68-0.94, P = 0.005; I2 = 0%) compared to observation or regimens without bortezomib. When the 2 RCTs that did not report HRs were excluded from the meta-analysis, it did not alter the favorable outcome of bortezomib-based consolidation/maintenance therapy: PFS (HR 0.70, 95% CI 0.60-0.82, P < 0.001; I2 = 40.54%) and OS (HR 0.76, 95% CI 0.64-0.91, P = 0.002; I2 = 0%). The PFS benefit was maintained in a subgroup analysis by the setting of treatment (consolidation, HR 0.73, 95% CI 0.63-0.85, P < 0.001; I2 = 0%, maintenance, HR 0.70, 95% CI 0.56-0.0.86, P = 0.001; I2 = 55.63%). Bortezomib-based therapy prolonged OS in the maintenance setting (HR 0.71, 95% CI 0.58-0.86, P < 0.001; I2 = 0%) but not in the consolidation setting (HR 1.01, 95% CI 0.77-1.33, P = 0.935; I2 = 0%). Regarding safety, bortezomib-based consolidation/maintenance therapy significantly increased the risk of grade 3 or 4 peripheral sensory neuropathy and neuralgia (RR 2.09, 95% CI 1.11-3.95, p = 0.022; I2 = 52.64%) compared to observation or regimens without bortezomib. There was a trend toward increased rates of grade 3 or 4 thrombocytopenia (RR 1.54, 95% CI 0.95-2.52, p = 0.08; I2 = 21.67%), GI symptoms (RR 2.54, 95% CI 0.63-10.25, p = 0.19; I2 = 76.72%), vascular events (RR 1.90, 95% CI 0.80-4.53, p = 0.15; I2 = 0.00%), and fatigue (RR 2.10, 95% CI 0.83-5.30, p = 0.12; I2 = 0.00%) with bortezomib-based consolidation/maintenance, but these did not reach statistical significance. Conclusions: Bortezomib-based consolidation/maintenance significantly improves PFS and OS in MM patients following induction therapy +/- ASCT. The OS benefit appears to be limited to the maintenance setting based on a subgroup analysis. Bortezomib-based regimen increases the risk of grade 3 or 4 peripheral sensory neuropathy and neuralgia. Disclosures Bachanova: Gamida Cell: Research Funding; GT Biopharma: Research Funding; Kite Pharma: Membership on an entity's Board of Directors or advisory committees.

Abstract In this month's CME article, an analysis of over 1300 patients with diffuse large B-cell lymphoma (DLBCL), Wang et al demonstrate that the approximately 13% of patients with concurrent indolent lymphoma at diagnosis had the same prognosis as those patients with isolated DLBCL.

PURPOSE In patients with diffuse large B-cell lymphoma (DLBCL), most relapses occur within the first 2 years of diagnosis. We sought to define the rate and outcome of late relapses that occurred after achieving event-free survival at 24 months (EFS24). METHODS We prospectively followed 1,324 patients with newly diagnosed DLBCL from 2002 to 2015 and treated with immunochemotherapy. Cumulative incidences of late DLBCL and indolent lymphoma relapses were analyzed as competing events. Postrelapse survival was defined as time from first relapse to death from any cause. RESULTS In 847 patients who achieved EFS24, the cumulative incidence of late relapse was 6.9% at 3 years, 9.3% at 5 years, and 10.3% at 8 years after EFS24. The incidence of DLBCL relapse was similar in patients with DLBCL alone at diagnosis (6.3% at 5 years), compared with patients with concurrent indolent lymphoma at diagnosis (5.2%; P = .46). However, the rate of indolent lymphoma relapse was higher in patients with concurrent indolent lymphoma (7.4% v 2.1% at 5 years; P < .01). In patients with DLBCL alone, the rate of DLBCL relapse was similar in the germinal center B-cell–like (GCB) (4.1% at 5 years) and non-GCB (4.0%; P = .71) subtypes, whereas the rate of indolent lymphoma relapse was higher in patients with the GCB subtype (3.9% v 0.0% at 5 years; P = .02). Postrelapse survival was inferior for patients who relapsed with DLBCL than for those who relapsed with indolent lymphoma (median 29.9 months v unreached; P < .01). CONCLUSION Patients with DLBCL with a concurrent indolent lymphoma and those with the GCB subtype had a higher rate of late relapse, owing to increased relapses with indolent lymphoma. Patients who relapsed with DLBCL had a worse prognosis than those who relapsed with indolent lymphoma.

SummaryThe diabetes mellitus (DM) drug metformin targets mechanistic/mammalian target of rapamycin and inhibits lymphoma growth in vitro. We investigated whether metformin affected outcomes of newly diagnosed diffuse large B‐cell (DLBCL, n = 869) and follicular lymphoma (FL, n = 895) patients enrolled in the Mayo component of the Molecular Epidemiology Resource cohort study between 2002 and 2015. Hazard ratios (HR) and 95% confidence intervals (CIs) adjusted for age, sex, body mass index, prognostic index and treatment were used to estimate the association of metformin exposure (No DM/No metformin; DM/No metformin; DM/Metformin) with event‐free (EFS), lymphoma‐specific (LSS) and overall (OS) survival. Compared to No DM/No metformin DLBCL patients, there was no association of DM/Metformin (n = 48; HR = 1·05, 95% CI 0·59–1·89) or DM/No metformin(n = 54; HR = 1·41, 95% CI 0·88–2·26) with EFS; results were similar for LSS and OS. Compared to No DM/No metformin FL patients, there was no association of DM/Metformin (n = 37; HR = 1·16, 95% CI 0·71–1·89) or DM/No metformin (n = 19; HR = 1·16, 95% CI 0·66–2·04) with EFS; results were similar for LSS. However, DM/Metformin was associated with inferior OS (HR = 2·17; 95% CI 1·19–3·95) compared to No DM/No metformin. In conclusion, we found no evidence that metformin use was associated with improved outcomes in newly diagnosed DLBCL and FL.

e20639 Background: Multiple randomized controlled trials (RCTs) have shown a robust benefit of immunotherapy with immune checkpoint inhibitors (ICI) in non-small cell lung cancer (NSCLC). We did a meta-analysis to examine the benefit of ICI in various subgroups. Methods: PubMed was searched up to Jan 15, 2019 for RCTs comparing overall survival (OS) between ICI and control (without ICI) arms. Pooled hazard ratio (HR) and 95% confidence interval (CI) was calculated for each subgroup. Interaction tests were done to compare relative benefit between opposed subgroups of interest (eg. men vs women; reported as Pheterogeneity). All analyses were performed with a random effects model in Comprehensive Meta Analysis (v2). Results: Twelve phase 2/3 RCTs involving 7244 patients were included. A significant OS benefit of ICI was found in both squamous and non-squamous histology. Current/former smokers, EGFR wild-type, and KRAS mutant patients had a significant OS benefit from ICI, but never smokers, EGFR mutant, and KRAS wild-type patients did not. An OS benefit of ICI was found in patients with or without baseline brain metastasis, PD-L1 < 1% or ≥1%, men or women, age < 65 or ≥65, and ECOG PS 0 or ≥1. No significant difference of relative benefit from ICI over control was found in patients with different PD-L1 expression, sex, age, or ECOG PS (Table). Conclusions: OS benefit of ICI in NSCLC was associated with a smoking history, wild-type EGFR or KRAS mutation. However, the OS benefit of ICI was seen regardless of histology, PD-L1 expression, sex, age, and ECOG PS. [Table: see text]

e20600 Background: Immune checkpoint inhibitors (ICIs) have changed the treatment paradigm of advanced NSCLC and SCLC. The populations in clinical trials generally were composed of patients (pts) with excellent performance status (PS), a minimal number of prior lines of therapy, and no history of (h/o) autoimmune disease (AD). The aim of this retrospective study was to investigate the predictors of survival in less fit and more heavily pretreated lung cancer pts at our institution. Methods: Medical records of lung cancer pts who started single-agent ICI from 2015 to 2018 were reviewed for data collection. Progression-free survival (PFS) and overall survival (OS) were compared by age, PS, smoking, PD-L1 expression, brain metastasis, prior lines of systemic therapy, h/o AD, and immune-related adverse events (irAE). Results: We included 150 pts who received at least 1 dose of nivolumab, pembrolizumab, or atezolizumab (median age 66, range 36-92, 56% female, 89% NSCLC, 97% stage 4, 13% never smoker, 34% ECOG ≥ 2, 37% ≥ 2 prior lines of therapy, 29% developed irAE). The overall response rate was 30% and clinical benefit rate 51% (3% CR, 27% PR, 21% SD). The median PFS was 3.7 months (m) overall and 12.3 m for those with ≥ 4 cycles of therapy. The median OS was 12.4 m overall and 26.0 m for those with ≥ 4 cycles. The median PFS and OS were not significantly different by age, PS, smoking, PD-L1, brain metastasis, prior lines of therapy, or h/o AD. The median OS was longer for pts with ECOG 0-1 than those ≥ 2 (14.6 vs 7.5 m, p < .001). The median PFS and OS for pts with irAE were longer compared to those without irAE (12.3 vs 2.6 m, p < .001 for PFS and 28.9 vs 9.1 m, p = .001 for OS). Multiple Cox regression analysis identified ECOG 0-1 (HR 0.54, p = .007) and irAE (HR 0.48, p = .003) to be independently associated with improved OS. 27 pts (18%) required steroids for irAE. There were no treatment-related deaths. Of 11 pts with h/o AD, only 1 experienced disease flare. Conclusions: The clinical benefit of ICIs persists in older or heavily pretreated pts. ECOG 0-1 and incident irAE predicted for improved survival. Survival for pts with ECOG ≥ 2 is very limited, suggesting ICIs should be used judiciously in this group. Therapy was well tolerated, with a low risk for flare of previous autoimmune disease.