Habermann, Thomas M.

Abstract Introduction Recent advances in the understanding of the WM pathobiology led to the expansion of our therapeutic options in this disease. A number of targeted drugs are either available or under investigation and are poised to change the chemo-immunotherapy paradigm in the treatment of WM. Now more than ever, an individualized treatment approach for patients with WM is possible, where patient characteristics and preferences can be matched by different treatment goals and side effect profiles. While deep responses have been associated with longer disease-free survival in other hematologic malignancies, data on patients with WM are sparse. We report the impact of depth of response in disease-free and overall survival (OS) in WM. Methods WM patients consecutively seen at Mayo Clinic between 01/1998 and 12/2016 were reviewed for response to therapy and disease burden. The best response achieved after the treatment of interest (TOI) was classified using the IWWM-7 Response Criteria. The included TOI were: BR, DRC, BDR and high-dose chemotherapy followed by ASCT. All time-to-event analyses were performed from the TOI initiation date using the Kaplan-Meier method and the log-rank test. A landmark analysis from the date-of-best response was also performed for OS to prevent immortal-time bias. Univariate and multivariate analyses of progression-free survival (PFS) and time-to-next therapy (TTNT) were performed using the Cox regression method. Results A total of 181 patients had disease response assessed after the TOI. Baseline characteristics at time of diagnosis are summarized in table 1. The median follow up from TOI was 3.8 years (95% CI: 3-4), the majority of patients received TOI as salvage therapy [n=112 (63%); median 2nd line (rage 1-11)]. Best response rates with the corresponding 5-year PFS and TTNT are summarized in table 2. The median OS from TOI was longer in patients who achieved at least a PR [median 7.2 years (95% CI: 5-NR) vs 3.7 years (95% CI: 1.6-NR), p=0.01]. A trend towards a longer OS was also seen with deeper responses (PR or better) achieved with frontline therapy [median 5.8 years (95% CI: 5.8-NR) vs 3.4 years (95% CI: 1.6-NR), p=0.24]. Figure 1 shows the correlation between deeper responses with PFS and TTNT. Among patients achieving a PR or VGPR, those with a normal FLC ratio post TOI demonstrated a longer PFS and TTNT [PFS: median NR (95% CI: 3.4-NR) vs 4.9 years (95% CI: 2.8-8.7), p=0.01; TTNT: median NR (95% CI: 3.5-NR) vs 5.2 years (95% CI: 4.2-9.4), p=0.04], figure 2. In a multivariate analysis including normal FLC ratio, normal IgM level and minimal BM involvement (<5%) post TOI, normal FLC ratio remained an independent prognostic factor for longer PFS and TTNT. Similar trends were seen when considering treatment naïve and relapsed/refractory patients independently (data not shown). Discussion Our results not only suggest an association between depth of response with PFS and TTNT, but also with OS in patients with WM. A normal FLC ratio (not part of the IWWM-7 response criteria) seems to predict a longer disease-free interval in patients achieving a PR or VGPR. Disclosures Gertz: Ionis: Honoraria; Apellis: Consultancy; annexon: Consultancy; Prothena: Honoraria; janssen: Consultancy; Physicians Education Resource: Consultancy; Alnylam: Honoraria; Teva: Consultancy; spectrum: Consultancy, Honoraria; Medscape: Consultancy; celgene: Consultancy; Research to Practice: Consultancy; Amgen: Consultancy; Abbvie: Consultancy. Kapoor:Takeda: Research Funding; Celgene: Research Funding. Ailawadhi:Amgen: Consultancy; Janssen: Consultancy; Takeda: Consultancy; Pharmacyclics: Research Funding; Celgene: Consultancy. Reeder:Affimed: Research Funding. Witzig:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Dispenzieri:Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding. Lacy:Celgene: Research Funding. Kumar:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Ansell:Seattle Genetics: Research Funding; Celldex: Research Funding; Bristol-Myers Squibb: Research Funding; LAM Therapeutics: Research Funding; Trillium: Research Funding; Pfizer: Research Funding; Takeda: Research Funding; Merck & Co: Research Funding; Affimed: Research Funding; Regeneron: Research Funding.

Abstract Introduction. The peripheral blood absolute lymphocyte (ALC)/monocyte (AMC) ratio (ALC/AMC), as a surrogate of host immunity (i.e. ALC) and tumor microenvironment (i.e. AMC), is a predictive biomarker for clinical outcomes in diffuse large B-cell (DLBCL) patients. An ALC/AMC ratio ≥ 1.1 has been shown to be predictive of better survival both at baseline and during each therapy cycle in patients treated with R-CHOP [Porrata et al, 2014]. Lenalidomide is an immunomodulatory drug, effective in DLBCL patients, with various mechanisms of actions on the tumor microenvironment and the host immune response. In this study we analyze the prognostic value of ALC/AMC ratio in a cohort of newly diagnosed DLBCL patients treated with Lenalidomide plus R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone, R2-CHOP) in a phase II trial (MC078E trial, [Nowakowski et al, 2015]). Methods. All patients with de-novo DLBCL enrolled in the phase II trial MC078E and treated at diagnosis with R2-CHOP regimen were included in the analysis. We investigated the ALC/AMC ratio at baseline and each R2-CHOP cycle as predictor of progression-free survival (PFS) and overall survival (OS). The ALC/AMC ratio was obtained by dividing the ALC by the AMC from the automated white blood cell differential obtained from the complete blood cell count on day 0 of each treatment cycle (range from day -3 to day 0 of each course). Patients were then divided in 4 groups on the basis of pattern of ALC/AMC ratio during treatment: group A: patients with ALC/AMC ratio ≥ 1.1 throughout all cycles; group B: patients with ALC/AMC ratio ≥ 1.1 at baseline, but then obtained an ALC/AMC < 1.1 during treatment; group C: patients with ALC/AMC ratio < 1.1 at baseline, but then gained an ALC/AMC ≥ 1.1 during treatment; group D: patients with ALC/AMC ratio < 1.1 throughout all cycles. PFS and OS were analyzed in the different groups. We separately conducted the same analysis in a matched control cohort of 94 DLBCL patients from the Mayo Clinic Lymphoma Database treated with standard R-CHOP. Results. A total of 63 patients with de-novo DLBCL treated with R2CHOP regimen at diagnosis were included in the analysis. Clinical characteristics were: median age 67 years (22-87), male sex 61.9%, III-IV advance stage 87.3%, elevated LDH serum levels 66.7%, intermediate-high/high International Prognostic index (IPI) score in 54% cases. No differences in 3y-PFS and 3y-OS in patients with ALC/AMC ratio ≥ 1.1 vs ALC/AMC < 1.1 at baseline and at each R2-CHOP course have been observed. In a landmark analysis from day 0 of the last cycle, 3y-PFS in group A vs B vs C vs D was: 71.4% vs 67.1% vs 66.7% vs 85.7%, respectively (p 0.80); 3y-OS in group A vs B vs C vs D was: 85.7% vs 86.5% vs 66.7% vs 100%, respectively (p 0.74). No differences in both 3y-PFS and 3y-OS were observed comparing group A vs B, in group C vs D, and in group A vs D. Unlike what was observed in the R-CHOP treated DLBCL patients, in a univariate analysis ALC/AMC < 1.1 during all cycles of R2CHOP was not a predictor for inferior outcomes (Figure 1.a). In the matched cohort of patients treated with standard R-CHOP, ALC/AMC < 1.1 at baseline and at each course demonstrated to be predictive of worse outcome (p <0.01),survival was significantly different in the 4 groups identified according to ALC/AMC ratio during treatment and ALC/AMC < 1.1 maintained during all cycles of R2CHOP was predictive of worse PFS and OS (Figure 1.b). Conclusions. Lenalidomide in combination with standard R-CHOP (R2-CHOP), in previously untreated DLBCL patients, appears to overcome the negative prognostic value of ALC/AMC ratio observed in patients treated with R-CHOP alone. This could reflect the additional effect of lenalidomide to standard therapy on tumor microenvironment and on host immunity response. Figure 1: Landmark Analysis for Progression Free Survival and Overall Survival by ALC/AMC groups within R2CHOP (1.A) and R-CHOP (1.B). Group A: ALC/AMC >=1.1 for all cycles; Group B: ALC/AMC >=1.1 at baseline and obtained <1.1 during treatment; Group C: ALC/AMC <1.1 at baseline and obtained >=1.1 during treatment; Group D: ALC/AMC <1.1 for all cycles. Disclosures Witzig: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, 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 An association has been identified between the diagnosis-to-treatment interval (DTI) and prognostic clinical factors and outcomes in patients with previously untreated diffuse large B-cell lymphoma (DLBCL) (Maurer et al, JCO 2018). This association can result in inadvertent selection bias in clinical trials to exclude patients with aggressive disease due to the inability to delay treatment long enough to fulfill enrollment criteria, compromising the validity of clinical trial study results to the general population. A similar concern exists in the relapsed/refractory (r/r) DLBCL setting regarding patient selection bias against patients with aggressive disease requiring immediate treatment following relapse or progression. Here we examine the time from progression after immunochemotherapy (IC) to the initiation of first salvage chemotherapy and its association with outcome. Patients and Methods: Newly diagnosed patients were prospectively enrolled within 9 months of diagnosis in the University of Iowa/Mayo Clinic Lymphoma SPORE Molecular Epidemiology Resource (MER), now a subcohort of the Lymphoma Epidemiology of Outcomes (LEO) Cohort Study, and followed for progression/relapse, retreatment, and death. This analysis includes patients with their first r/r DLBCL following frontline IC who initiated aggressive salvage chemotherapy as identified and included in a previous publication (Farooq et al, BJH 2017). The progression-to-treatment interval (PTI) was defined as the time in days from date of progression from IC to initiation of salvage therapy. The date of progression was defined as either a) the date biopsy was obtained for patients who had a biopsy to confirm progressive disease or b) the date of the scan or clinical examination indicating progression in patients who did not have a biopsy performed. Event-free survival (EFS) was defined as time from initiation of first salvage therapy to progression or relapse, initiation of new anti-lymphoma therapy, or death due to any cause; overall survival (OS) was defined as time from initiation of salvage therapy until death due to any cause. Results: 162 patients with r/r DLBCL enrolled in the MER from 2002-2012 who initiated aggressive salvage chemotherapy with intent to transplant and had confirmed dates for both progression after IC and start of salvage therapy were evaluated. Median age at first progression for these patients was 64 years (range 36-76) and 104 (64%) were male. Median time from diagnosis to first progression on IC was 6.7 months (IQR: 4.6-12.7). Initial salvage therapy was R-ICE (80%), R-DHAP (8%), rituximab, oxaliplatin, cytosine arabinoside, and dexamethasone (ROAD) (6%), and other (7%). At a median follow-up of 49 months from initiation of salvage therapy (IQR: 33-74), 116 patients had died (72%). Median PTI was 6 days (IQR: 2-13). 110 patients (68%) had biopsy confirmation of disease prior to initiating salvage therapy; median PTI was 2 days (IQR: 1-7) for patients who had biopsy confirmation vs. 7 days (IQR: 3-16) in patients without biopsy confirmation, Wilcoxon p=<0.0001. There was no difference in OS from initial salvage therapy between patients who did not have biopsy confirmation (HR=1.09, 95% CI: 0.74-1.60, p=0.68) compared to patients with biopsy confirmation. Patients with short PTI (0-6 days) had significantly worse overall survival from initiation of salvage therapy (median OS = 7.6 months, HR=2.10 (95% CI: 1.43-3.08) compared to patients who initiated therapy 7 or more days from progression (median OS = 29.7 months), logrank p<0.0001. This association remained consistent (HR=2.20, 95% CI: 1.48-3.26, p<0.0001) after adjusting for age and biopsy confirmation of progression. Short PTI was also associated with inferior response rate to initial salvage therapy (51% vs. 65%, p=0.058), lower rate of proceeding to transplant after initial salvage therapy (33% vs. 55%, p=0.0063), lower rate of being event-free 24 months from initial salvage therapy (16% vs 33%, p=0.011) and lower rate of ever proceeding to transplant (44% vs. 59%, p=0.057). Conclusions: A short progression-to-treatment interval is strongly associated with inability to proceed to transplant and inferior overall survival in r/r DLBCL. These results have implications for the design and interpretation of clinical trials in the relapsed/refractory setting. Figure. Figure. Disclosures Maurer: Celgene: Research Funding; Nanostring: Research Funding; Morphosys: Research Funding. Ansell:Trillium: Research Funding; Merck & Co: Research Funding; Affimed: Research Funding; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; LAM Therapeutics: Research Funding; Pfizer: Research Funding; Celldex: Research Funding; Takeda: Research Funding. Witzig:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Cerhan:Nanostring: Research Funding; Celgene: Research Funding; Jannsen: Other: Scientific Advisory Board.

Abstract Background We have previously reported and validated that the E-IPI, provided better discrimination of overall survival (OS) than the IPI for DLBCL patients > 60 years of age treated with R-CHOP (Advani et al., BJH 2010 and 12-ICML 2013 Abstract 222). Recent reports suggest that males > 60 years treated with R-CHOP have worse outcomes likely related to differences in rituximab clearance (Muller et al., Blood 2012). In this study, we explored if the addition of male sex to the E-IPI further improved risk stratification. Methods DLBCL patients > 60 years treated with R-CHOP on the E4494, RICOVER-60 and GELA 98-5 trials were included. A multivariate analysis was performed to assess whether male sex is an independent prognostic factor for OS in addition to the five E-IPI risk factors, E-IPI score, and E-IPI risk group. Male sex (S) was added as an additional risk factor to the E-IPI (S-EIPI, 0-6) and patients regrouped according to the number of risk factors: low (L)=0-1, low intermediate (LI)=2, high intermediate (HI)=3 and high (H)=4-6 based on the observed OS using Kaplan-Meier curves. C-statistic was used to compare the discrimination ability. The 5 year OS was estimated using the Kaplan-Meier method. Results 1079 patients (E4494, n=267; RICOVER-60, n=610; GELA 98-5, n=202) with a median follow-up of 8.9 years were included. In multivariate analyses, male sex was a significant independent predictor for OS adjusting for all five E-IPI factors, (HR 1.5, p < 0.0001), E-IPI score (HR 1.42, p < 0.001), and E-IPI risk group (HR 1.42, p < 0.001) (Table 1). C-statistic was 0.66 for S-EIPI and 0.64 for EIPI. Incorporation of sex into the E-IPI shifted 35% patients to higher risk groups, including 110 patients into the highest risk group (Table 2). The estimated 5 year OS for the S-EIPI L, LI, HI, and H risk groups was 87%, 70%, 58%, and 40%, respectively (Table 3). Compared to E-IPI, the 95% C.I. did not overlap among S-EIPI risk groups. Conclusion For DLBCL patients >60 years treated with R-CHOP, our results suggest the addition of male sex to the E-IPI may improve categorization of patients into well-defined clinically relevant risk groups. Patients with low risk S-EIPI have an excellent outcome (5 year OS 87%). Patients with high risk S-EIPI have a 5 year OS of only 40% and therapies beyond standard R-CHOP need to be explored. Disclosures: Horning: Genentech: Employment; Roche: Equity Ownership.

Abstract Background Age has long been recognized as a poor prognostic factor in diffuse large B-cell lymphoma (DLBCL) and more recently, a lower baseline quality of life (QOL) in patients with aggressive lymphomas has been associated with an inferior overall survival (OS) (Thompson et al, 2018). Older patients with DLBCL are a heterogeneous population and commonly have comorbid conditions. A concerted effort to identify prognostic factors specific to this population is needed, including QOL. Event free survival at 24 months (EFS24) is a well validated endpoint in DLBCL (Maurer et al, 2014) and is clinically relevant in older patients. We hypothesized that baseline clinical factors and QOL would be associated with EFS24 this patient group. Methods Newly diagnosed lymphoma patients were prospectively enrolled within 9 months of diagnosis into the University of Iowa/Mayo Clinic Lymphoma SPORE Molecular Epidemiology Resource (MER). Patients ≥70 years of age with DLBCL were utilized in this study. All pathology was reviewed by a lymphoma hematopathologist. Clinical variables were abstracted from the medical record. QOL was assessed at enrollment using a single item Linear Analogue Self-Assessment (LASA) and the 27-item Functional Assessment of Cancer Treatment-General questionnaire (FACT-G), which includes physical, social, emotional, and functional well-being domains. QOL scores were converted to a 0-100 scale to facilitate modeling. QOL was analyzed in patients who completed 80% of the FACT-G questions. Characteristics of the study population were compared using the Wilcoxon rank sum test. Odds ratios (ORs) and 95% confidence intervals (CI) were used to estimate the associations of clinical and continuous QOL variables with failure to achieve EFS24 using logistic regression models, with a stepwise approach to identify parsimonious multivariate models. Results A total of 389 patients ≥70 years were identified with DLBCL in the MER from 2002-2015; patient characteristics are described in the Table. In the entire study population, univariate predictors of EFS24 failure included age (OR per 10 years=1.85, 95% CI: 1.26-2.71), ECOG PS ≥2 (OR=4.78, 95% CI: 2.92-7.83), elevated LDH (OR=3.59, 95% CI: 2.27-5.65), stage III-IV (OR=1.94, 1.25-3.02), bulky disease (OR=2.86, 95% CI: 1.43-5.72), international prognostic index (OR=8.71 for IPI 5 vs IPI 0, 95% CI: 3.04-24.9), and receipt of an anthracycline (OR=0.25, 95% CI: 0.12-0.51), while none of the other variables in the Table, including the QOL variables, were statistically significant. In a stepwise multivariate analysis, only ECOG PS ≥2 (OR= 3.56, 95% CI: 2.09-6.06) and elevated LDH (OR=2.86, 95% CI: 1.78-4.60) remained significant predictors of EFS24 failure. QOL data were available on 220 patients, with 120 completing QOL questionnaires prior to receipt of chemotherapy. Compared to participants who completed their FACT-G before the initiation of chemotherapy, the median FACT-G physical (85.7 v. 71.4, p=0.005) and functional (71.4 vs 57.1, p=0.008) scores were lower in participants completing FACT-G after initiation of therapy, were higher on FACT-G emotional (79.2 vs 83.3, p=0.03), and showed no differences on FACT-G social (89.3 vs 91.7, p=0.60) or FACT-G total score (78.2 vs 74.1, p=0.17). Given these differences, we restricted the QOL analysis to those with pre-treatment data. In univariate analysis, the LASA score (OR= 0.98, 95% CI: 0.84-1.14), the FACT-G total (OR=0.99, 95% CI: 0.96-1.01), physical (OR=0.98, 95% CI: 0.97-1.00), social (OR=1.00, 95% CI: 0.98-1.03), emotional (OR= 1.00, 95% CI: 0.98-1.02), and functional (OR=0.99, 95% CI: 0.98-1.01) scores were not associated with EFS24 failure. In a stepwise multivariate analysis of clinical variables in patients with pretreatment QOL scores, only ECOG PS ≥2 (OR=3.56, 95% CI: 1.30-9.72) and female sex (OR=0.37, 95% CI: 0.16-0.85) were associated with failure to achieve EFS24. Conclusions In patients aged 70 years and older, ECOG PS and LDH were the strongest independent predictors of failure to achieve EFS24. As expected, physical and functional scores were lower in patients who completed their QOL after initiation of treatment. Restricting the analysis to patients with pre-treatment data, QOL was not associated with failure to achieve EFS24. Additional studies are needed to identify the most robust clinical predictors of EFS24, while QOL does not appear to be an important predictor of EFS24. Disclosures Reagan: Seattle Genetics: Research Funding. Maurer:Morphosys: Research Funding; Celgene: Research Funding; Nanostring: Research Funding. Cerhan:Celgene: Research Funding; Nanostring: Research Funding; Jannsen: Other: Scientific Advisory Board.

Abstract Background : Ibrutinib, a Bruton's tyrosine kinase (BTK) inhibitor was approved for the treatment of Waldenstrom Macroglobulinemia (WM) in January, 2015 based on the results of a clinical trial of 63 previously-treated patients with WM. Data on outcomes with ibrutinib outside of clinical trials are limited. Methods : Medical records of patients with WM seen consecutively between 02/01/2015 and 06/01/2018 at Mayo Clinic, MN, FL and AZ were reviewed and those treated with ibrutinib at any point during their disease were included. Refractoriness to prior therapy was defined as disease progression on therapy or within 2 months of stopping treatment. The response rates were assessed by WM VI International Workshop Criteria. Adverse events were graded using National Cancer Institute Common Toxicity Criteria for Adverse Events (AEs) v4.03. All time-to-event analyses were performed from the time of initiation of ibrutinib. Results : Eighty patients [previously treated, n=67 (84%), treatment-naïve, n=13 (16%)] received ibrutinib for active WM. Median follow-up was 18 months (95% CI: 12-19) and the median overall survival (OS) was not reached (NR) (95% CI: 27-NR) for the entire cohort at the date of last follow-up. The median age was 67 years (range: 50-88) and the median ECOG performance score was 1 (range: 0-3) at the time of ibrutinib initiation. Median lines of therapies prior to ibrutinib for the previously-treated patients was 2 (range: 1-9) and 35 patients (44%) had received ≥3 prior lines of therapy. Of the 80 patients, 52 patients (43 previously treated, 9 treatment-naïve) had data for response assessment. The baseline characteristics and laboratory parameters at initiation of ibrutinib are outlined in Table 1a and prior therapies are mentioned in Table 1b. Overall response rate (ORR) was 90% (100% in patients with ibrutinib as primary therapy and 88% in salvage therapy setting); major-response rate (MRR) was 77%. Median time to first and best response was 2.1 months (95% CI: 1.5-3.5) and 5.4 months (95% CI: 3.5-13), respectively. Other clinically relevant endpoints and AEs related to ibrutinib therapy are outlined in Table 2 and 3, respectively. The median time-to-next therapy was 33 months (95% CI: 28-NR). At last follow-up, 25 (32%) patients had discontinued ibrutinib therapy. The reasons for discontinuation was progression (n=8), elevated liver enzymes (n=4), cognitive changes (n=1), inability to achieve better than MR (n=1), atrial fibrillation (n=3), consolidation with autologous stem cell transplantation after PR with ibrutinib (n=1), transition to hospice care due to progressive head and neck cancer (n=1), infection in lower extremity (n=1), transformation to DLBCL (n=1), blistering rash which resolved after ibrutinib discontinuation (n=1), obscure GI bleed that resolved after ibrutinib discontinuation (n=1), fatigue (n=1) and for unclear reasons recorded as treatment intolerance (n=1). Following discontinuation of ibrutinib, 21 patients received salvage therapy. Of these, data regarding the response to salvage therapy was available in 9 (43%) patients (VGPR=2, PR=3, SD=3 and progressive disease=1); median PFS from the salvage therapy following ibrutinib discontinuation was 18 months (95% CI: 2-25). Of the 4 patients who were not treated following ibrutinib discontinuation; 1 elected hospice care due to concurrent head and neck cancer progression, and the other 3 patients elected to be monitored off therapy (one had achieved SD and two had PR from ibrutinib). Fourteen patients were evaluable for IgM rebound following ibrutinib discontinuation. Of those, 5 (36%) had sudden increase in IgM level [median: 158% from the IgM level after ibrutinib discontinuation (range: 22%-1368%)] within a median of 2 months (range: 1-3 months) and 1 patient required plasmapheresis for symptomatic hyperviscosity. Four of 5 patients received salvage therapy between 0-15 months. At last follow-up, 11 patients (14%) had died of whom 3 were on ibrutinib at the time of death [CNS involvement, (n=1), causes unrelated to WM, (n=2)]. Conclusions : Ibrutinib is an effective agent in WM patients with MYD88L265Pmutation. Our data regarding outcomes in non-trial setting appear comparable to the results observed in the pivotal clinical trial. Hematologists should be aware of unique ibrutinib associated toxicities and clinically relevant IgM rebound phenomenon following abrupt discontinuation of ibrutinib. Disclosures Ailawadhi: Celgene: Consultancy; Janssen: Consultancy; Takeda: Consultancy; Pharmacyclics: Research Funding; Amgen: Consultancy. Gertz:janssen: Consultancy; Prothena: Honoraria; Medscape: Consultancy; Teva: Consultancy; celgene: Consultancy; annexon: Consultancy; Alnylam: Honoraria; Physicians Education Resource: Consultancy; spectrum: Consultancy, Honoraria; Apellis: Consultancy; Amgen: Consultancy; Abbvie: Consultancy; Ionis: Honoraria; Research to Practice: Consultancy. Kumar:Novartis: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Research Funding; AbbVie: 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, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: 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, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding. Lacy:Celgene: Research Funding. Dispenzieri:Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding. Witzig:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Dingli:Millennium Takeda: Research Funding; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Millennium Takeda: Research Funding. Kapoor:Celgene: Research Funding; Takeda: Research Funding.

Abstract PURPOSE Urgency to initiate therapy has to be weighed against the time required for screening and consenting to enroll a patient onto a clinical trial. Exclusion of patients with rapidly progressive or symptomatic disease may lead to selection of patients with less aggressive disease. We recently identified that a short diagnosis to treatment interval (DTI) is associated with adverse clinical factors and inferior outcome in patients with diffuse large B-cell lymphoma (DLBCL) (Maurer et al, JCO 2018); shorter time to treatment was also found to be associated with outcome in other aggressive lymphomas, including mantle cell lymphoma (MCL), in the National Cancer Database (Olszewski et al, BJH 2018). Here we assess the association of DTI with clinical variables and outcome in MCL from an observational cohort with validation in patients enrolled on an NCTN clinical trial. PATIENTS AND METHODS Newly diagnosed patients with MCL were prospectively enrolled in the University of Iowa/Mayo Clinic Lymphoma SPORE Molecular Epidemiology Resource (MER), now a subcohort of the Lymphoma Epidemiology of Outcomes (LEO) Cohort Study. Patients initially managed with observation were excluded. DTI was defined as the time in days from date of first lymphoma-containing biopsy to the initiation of therapy. Associations of DTI with clinical factors and outcome were examined using a 14 day split based on the previous MER study of DTI in DLBCL. Odds ratios (OR) and Cox model hazard ratios (HR) are reported. Outcome was assessed using event-free survival (EFS) where events were defined as progression/relapse, initiation of new anti-lymphoma therapy, or death due to any cause. A validation cohort was assembled from patients enrolled in CALGB (Alliance) clinical trial 50403. Protocol therapy was high dose chemotherapy with autologous hematopoietic stem cell transplantation (ASCT) consolidation and post-ASCT rituximab followed by bortezomib as either consolidation or maintenance. DTI was defined as time from diagnosis to study registration and outcome was assessed using progression-free survival (PFS) as defined on the clinical trial. RESULTS 271 patients with MCL enrolled in the MER from 2002-2015 and initiated treatment within 100 days of diagnosis. Median age at diagnosis was 64 years (range 36-76), 211 (78%) were male, and 92% were stage III-IV; MIPI was Low (41%), Intermediate (36%) and High (23%). Induction therapy was R-CHOP based (50%), B-R based (16%), HyperCVAD based (8%), 2-CDA based (11%), and other (15%). Median EFS of the cohort was 41 months (95% CI: 34-46). Median DTI was 26 days (IQR: 14-38) and 28% enrolled within 14 days of diagnosis, exhibiting a longer DTI than DLBCL patients enrolled in the MER during the same time period. Short DTI (0-14 days) was associated with adverse clinical factors including ECOG PS 2-4 (OR=5.74, 95% CI: 2.51-13.1, p<0.0001), elevated LDH (OR=2.30 95% CI: 1.25-4.22, p=0.0072), and higher MIPI score (OR=1.48, 95% CI: 1.04-2.07, p=0.025) but was not significantly associated with age, sex, B-symptoms, or stage (all p>0.30). Short DTI was also associated with inferior EFS (HR=1.78, 95% CI: 1.27-2.49, p=0.0008) which remained significant after adjusting for MIPI score (HR=1.72, 95% CI: 1.23-2.41, p=0.0016). In the validation cohort, 144 patients enrolled on 50403 within 100 days of diagnosis from 2006-2010. Median age at diagnosis was 59 years (range 29-69), 77% were male, and 97% were stage III-IV; MIPI was Low (51%), Intermediate (31%) and High (17%). Median PFS of the cohort was 84 months (95% CI: 50-109). Median DTI was 35 days (IQR: 22-46) and 11% enrolled within 14 days of diagnosis. Short DTI (0-14 days) was associated with PS (OR=9.00, 95% CI: 1.18-69.0, p=0.034) and) higher MIPI score (OR=2.09, 95% CI: 1.08-4.04, p=0.029) but not elevated LDH (OR=1.27, 95% CI: 0.43-3.74, p=0.66). Short DTI was associated with inferior PFS (HR=2.21, 95% CI:1.19-4.09, p=0.011) which remained clinically significant after adjusting for MIPI score (HR=1.85, 95% CI: 0.98-3.47, p=0.056). CONCLUSION A short diagnosis-to-treatment interval is strongly associated with adverse clinical factors and poor outcome in newly diagnosed MCL in the MER. Clinical trials are encouraged to facilitate enrollment of patients with short DTI to avoid potential selection bias. Support: U01 CA195568, P50 CA097274, U10CA180821, U10CA180882; ClinicalTrials.gov Identifier: NCT00310037 (CALGB 50403) Figure. Figure. Disclosures Maurer: Celgene: Research Funding; Nanostring: Research Funding; Morphosys: Research Funding. Kaplan:Bayer Pharmaceuticals: Consultancy. Cohen:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Infinity Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BioInvent: Consultancy; Takeda: Research Funding. Martin:Gilead: Consultancy; Kite: Consultancy; Seattle Genetics: Consultancy; AstraZeneca: Consultancy; Janssen: Consultancy; Bayer: Consultancy. Kahl:Abbvie: Consultancy; AstraZeneca: Consultancy; Gilead: Consultancy; Acerta: Consultancy; Juno: Consultancy; Celgene: Consultancy; Genentech: Consultancy; Seattle Genetics: Consultancy; CTI: Consultancy; ADC Therapeutics: Consultancy. Bartlett:ImaginAB: Research Funding; Bristol-Meyers Squibb: Research Funding; Novartis: Research Funding; Immune Design: Research Funding; Janssen: Research Funding; Merck & Co: Research Funding; Forty Seven: Research Funding; Novartis: Research Funding; Pharmacyclics: Research Funding; Affimed: Research Funding; Astra Zeneca: Research Funding; Pharmacyclics: Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Millennium: Research Funding; Genentech: Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Cerhan:Celgene: Research Funding; Jannsen: Other: Scientific Advisory Board; Nanostring: Research Funding. Leonard:Karyopharm: Consultancy; Biotest: Consultancy; Bayer: Consultancy; Pfizer: Consultancy; ADC Therapeutics: Consultancy; Novartis: Consultancy; AstraZeneca: Consultancy; Juno: Consultancy; BMS: Consultancy; Sutro: Consultancy; MEI Pharma: Consultancy; Genentech/Roche: Consultancy; Celgene: Consultancy; Gilead: Consultancy; United Therapeutics: Consultancy.

Abstract Introduction: Lenalidomide (Len) in association with standard Rituximab-CHOP (R2CHOP21) has been shown to be safe and effective in newly diagnosed Diffuse Large B-cell Lymphomas (DLBCL) [Nowakowski et al. JCO 2014, Vitolo et al. Lancet Oncol 2014]. The addition of lenalidomide appears to benefit primarily patients with non-Germinal Center B-cell (non-GCB) phenotype as determined by immunohistochemistry (IHC). These early results led to currently ongoing randomized trial in ABC subtype of DLBCL, however efficacy of R2CHOP in ABC DLBCL as defined by Gene Expression Prophyling (GEP) has not been reported. In the present combined analysis of two independent phase 2 studies, we report the long-term follow-up (FU) outcome in DLBCL patients treated with R2CHOP, comparing GCB and ABC according to Nanostring Platform. Methods: We included all newly diagnosed histologically-confirmed de-novo DLBCL patients enrolled in two R2CHOP21 phase 2 trials, conducted by Mayo Clinic (MC) and Italian Lymphoma Foundation (FIL). Inclusion criteria in the two trials were similar, main differences included: all age and all International Prognostic Index (IPI) vs age between 60 and 80 years old and IPI >1, in MC vs FIL study, respectively. All pts received R-CHOP21 plus Len at 25 mg/day for 10 days/cycle and 15 mg/day for 14 days/cycle in MC and FIL trial, respectively. Cell of origin (COO) was determined by IHC, according to Hans algorithm, and retrospectively, in patients with available pathological material, by Nanostring, performed according to Scott algorithm and Masque-Soler signature in MC and FIL study, respectively. We analyzed the long-term FU outcome in terms of progression-free survival (PFS), time to progression (TTP), overall survival (OS), comparing between GCB and ABC phenotypes according to GEP. Results: A total of 112 DLBCL pts (63 MC, 49 FIL) were included. Main characteristics were: median age 69 years (y) (range 22-87), male 65 (58%) pts, advanced stage III-IV in 94 (84%), B symptoms in 38 (34%), International Prognostic Index (IPI) intermediate-high/high in 71 (63%). At a median follow-up of 5.1 years (y), 5y-PFS was 63.5%, 5y-TTP 70.1% and 5y-OS 75.4%. A total of 32 relapses were observed, with only 2 cases of Central Nervous System (CNS) relapse. Late relapse occurring beyond 3 years was observed in 4 cases (3 cases with GCB phenotype and one case with missing COO data). In a subgroup analysis by IPI 0-2 vs 3-5 were: 5y-PFS, 5y-TTP and 5y-OS were: 69.0% vs 59.0% (p=0.100), 73.2% vs 67.4% (p=0.285) and 82.3% vs 70.2% (p=0.059), respectively. Regarding for COO defined by IHC, GCB phenotype vs non-GCB were 45 (40%) vs 41 (37%) patients respectively; 26 (23%) patients were not evaluable. 5y-PFS, 5y-TTP and 5y-OS were: 52.8% vs 64.5% (p=0.198), 61.6% vs 69.6% (p=0.444) and 68.6% vs 74.1% (p=0.238) in GCB vs non-GCB, defined by IHC, respectively. Regarding Nanostring analysis, GCB vs ABC vs Unclassified (Uncl) were 31 (46%) vs 22 (32%) vs 15 (22%) respectively; 44 pts were not evaluable. 5y-PFS, 5y-TTP and 5y-OS were: 62.3% vs 70.8% vs 64.2% (p=0.645), 68.1% vs 79.8% vs 64.2% (p=0.662) and 76.0% vs 74.8% vs 79.0% (p=0.658) in GCB vs ABC vs Uncl, defined by Nanostring, respectively (Table1, Fig1). Conclusions: The association of Len with R-CHOP21 appears to overcome the negative prognostic impact of ABC phenotype determined by GEP, with high PFS, TTP and OS rate, maintained at a long-term FU analysis. Figure 1. Figure 1. Disclosures Chiappella: Teva: Other: lecture fees; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: lecture fees; Nanostring: Other: lecture fees; Roche: Other: lecture fees; Amgen: Other: lecture fees; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: lecture fees. Gaidano:Roche: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Morphosys: Honoraria. Witzig:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Vitolo:Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sandoz: Speakers Bureau; Gilead: Speakers Bureau.

Abstract Backgrounds B cell receptor (BCR) signals and microenvironment protection have been recognized to have key influences on CLL survival and activation. Akt activation is down-stream of the BCR signaling cascade and is critical in the mediation of the bi-directional interactions between CLL B-cells and bone marrow stroma. MK2206 is an allosteric Akt inhibitor previously tested for safety in solid tumor patients. Our preclinical data has demonstrated the synergy of MK2206 with bendamustine (B) to induce CLL apoptosis in vitro. MK2206 also abolished the signal activation and cytokine production induced by BCR ligation in CLL leukemic cells (Ding, ASH 2012). Therefore, we conducted a phase 1 trial testing the safety and efficacy of MK2206 in combination with bendamustine and rituximab (BR) for patients with relapsed/refractory CLL. Methods A phase 1 dose-escalation study was designed to define the maximum tolerated dose (MTD) as well as the safety and efficacy of 3 dose levels (90 mg or 135 mg or 200 mg weekly) of the oral Akt inhibitor MK2206 in combination with bendamustine (70 mg/m2 daily for 2 days in each cycle) and rituximab (cycle 1: 375 mg/m2, cycle 2-6: 500 mg/m2) therapy in relapse/refractory CLL patients. To test the targeting efficacy of MK2206 on Akt and downstream signals, we designed a one-week “run-in” of single agent MK2206 before the initiation of BR during cycle 1. MK2206 was then given along with BR on day 1 of cycles 2-6. Tumor response was evaluated 2 months after the 6th/last cycle of therapy based on IWCLL 2008 criteria. Correlative laboratory studies included assessment of Akt signaling and the plasma cytokine levels (multiplex beads assay (Invitrogen)) at baseline and after one week of first dose of single agent MK2206. Results Nine patients (median age 68) were enrolled in the phase I portion of this trial. All 9 patients had unmutated immunoglobulin heavy chain variable region genes (IGHV) and 4 had del(11q). Six had received prior chemoimmunotherapy (CIT: FCR or PCR or PCO) and 5 had high risk disease defined as early progression within 26 months of the last CIT. Three had received alemtuzumab containing regimen. We have observed potent lymphocyte mobilization in all evaluated patients (n=7) after one-dose of MK2206 during week 1 (mean increase ALC: 35%) as well as reductions of plasma CCL3, CCL4 and CCL2 in the majority of the patients. A single dose-limiting toxicity (DLT) (febrile neutropenia and hemolytic anemia) was observed at dose level 1 (90 mg weekly) among 6 patients treated at this dose. Two patients with dose-limiting toxicities at dose level 2 (135 mg weekly) were observed where one patient had a rash and one patient had dehydration and febrile neutropenia among three patients treated at this dose. Accordingly, the 90 mg once weekly dose was determined to be the MTD for phase 2 trial testing. The most frequent grade 3 or 4 adverse events observed to date were neutropenia (44%) including febrile neutropenia (22%), rash (22%), diarrhea (22%), nausea and vomiting (11%), dehydration (11%), hemolytic anemia (11%) and thrombocytopenia (11%). The frequency of cytopenias was similar to the published German experience with BR (50% grade 3 or 4 hematological toxicities compared to 44% in N1087) in relapsed CLL patients (Fischer, JCO 2011). The median number of cycles received was 6 (range 1-6). Using an intent to treat analysis, two patients achieved complete response (CR, n= 2, 22%), one patient achieved nodular partial response (nPR, n=1, 11%) and five patients achieved a partial response (PR, n=5, 56%). The overall response rate (ORR) is 89%. Conclusion The Akt inhibitor MK2206 in combination with BR is well tolerated in patients with relapsed/refractory CLL. Single dose of MK2206 inhibits Akt phosphorylation, mobilizes leukemic cells and decreases plasma cytokines involved in BCR signals. The preliminary efficacy of this combination demonstrated promising results with a 89% ORR and 22% CR albeit in the small phase 1 cohort. These results compare favorably to BR alone (9% CR and 59% ORR) in relapsed/refractory CLL patients. Phase 2 testing of this combination is now underway. Acknowledgment This work was supported by the funding from NCI grant K23CA160345 (WD), NCI grant CA95241 (NEK) and Alliance for Clinical Trials in Oncology (CA025224 and CA33601). Disclosures: Off Label Use: MK2206, used in a phase 1 trial of relapsed CLL disease. Shanafelt:Genentech: Research Funding; Glaxo-Smith-Kline: Research Funding; Cephalon: Research Funding; Hospira: Research Funding; Celgene: Research Funding; Polyphenon E International: Research Funding. Zent:Novartis: Research Funding; GlaxSmithKline: Research Funding; Biothera: Research Funding; Genzyme: Research Funding; Genentech : Research Funding. Reeder:Celgene: Research Funding; Novartis: Research Funding; Millenium: Research Funding.