Summary Lenalidomide maintenance therapy prolonged progression‐free survival (PFS) versus placebo in elderly patients with diffuse large B‐cell lymphoma (DLBCL) responding to induction chemotherapy in the phase 3 REMARC study. This subpopulation analysis assessed the impact of lenalidomide maintenance and treatment‐emergent adverse events (TEAEs) on health‐related quality of life (HRQOL). Global health status (GHS), and physical functioning and fatigue subscales were evaluated in patients who completed the European Organisation for Research and Treatment of Cancer quality‐of‐life questionnaire‐C30 v3.0. The impact of TEAEs classified post hoc as subjective (patients can feel) or observable (only measurable by physicians) on dose reductions and discontinuations was assessed. Among 457 patients (lenalidomide, n = 229; placebo, n = 228), mean (standard deviation) GHS was similar between treatment arms [68·2 (20·7) Versus 72·0 (17·8)] at randomisation and remained similar during maintenance. Patients receiving lenalidomide experienced no meaningful changes in GHS, physical functioning, or fatigue. Observable TEAEs were more common (81·1% Versus 66·3%) and more likely to lead to dose reductions, than subjective TEAEs in both arms. PFS was superior in the lenalidomide arm regardless of dose reduction. Lenalidomide maintenance prolonged PFS and did not negatively impact HRQOL in patients with DLBCL despite TEAEs being more common, when compared with placebo.

No abstract

Introduction: Indolent non-Hodgkin lymphomas (iNHL), including follicular lymphoma (FL) and marginal zone lymphoma (MZL), are slow-growing lymphoid malignancies with high response rates to first-line treatment, but most patients (pts) will eventually relapse after initial response to treatment. For those with refractory disease (relapse ≤ 6 months after ending treatment), outcomes are worse. A number of treatment options based on chemo- and/or immunotherapy exist for pts with relapsed/refractory (R/R) iNHL, but currently there is no single standard treatment approach. There is a need to better understand the reported efficacy of available systemic treatments for R/R FL and MZL to guide treatment of iNHL. Methods: A SLR was carried out in accordance with PRISMA guidelines on September 1, 2017. Publications from MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), and clinicaltrials.gov databases, as well as proceedings from the European Hematology Association and American Society of Clinical Oncology conferences held from 2015 to 2017, the International Conference on Malignant Lymphomas from 2013, 2015, and 2017, and from the American Society of Hematology, and European Society for Medical Oncology conferences from 2014 to 2016, were included. Studies were limited to articles published in English, sample sizes ≥ 40, and studies evaluating systemic therapy for adults with any-stage R/R FL, MZL, or mixed histologies with ≥ 70% R/R FL/MZL pts. Controlled or uncontrolled clinical trials and observational studies were included. Studies varied with respect to prior treatment received and pt response to prior treatment at enrollment. Pts were classified as relapsed, refractory, refractory to rituximab (R-refractory including double-refractory pts), R/R but sensitive or naïve to rituximab, or as general R/R if the type of relapse and/or refractoriness was not specified. Efficacy measures included overall response rate, complete response rate, progression-free survival (PFS), and duration of response (DoR). Relevant interventions included bendamustine (B) (alone or with rituximab [BR] or obinutuzumab [O+B]), idelalisib (ID), ibrutinib (IB), copanlisib (C), lenalidomide (L) (alone or with rituximab [R2]), R + cyclophosphamide + doxorubicin + vincristine + prednisone (R-CHOP), R + cyclophosphamide + vincristine + prednisone (R-CVP), and R + chlorambucil (R-Chl). Results: Of 58 publications identified representing 36 studies involving 3,759 pts: 1 study reported on R2, 2 on L, 5 on B, 6 on BR, 3 on ID, 3 on IB, 2 on C, 1 on O+B, 1 on R-CHOP, and 12 on R alone. After excluding studies that did not meet criteria for similarity, 19 studies reporting outcomes in iNHL pts were included. Six studies each reported on general R/R pts or R-refractory pts, 4 studies reported on pts with relapsed disease, and 2 studies each reported on pts with refractory disease or R-naïve/sensitive refractory disease. PFS in the general R/R population (n = 1,668) ranged from 4.4 months (mo) in pts treated with L to 17.9 mo in pts treated with BR. Only 1 study reported DoR for pts in the general R/R population. In relapsed pts, PFS was only reported or reached in 1 study (22.9 mo) and DoR ranged from 21.0 to 41.9 mo for BR. In R-refractory pts, PFS ranged from 9.3 mo in B-treated pts to 29.2 mo in O+B-treated pts. DoR ranged from 9.2 to 22.6 mo. BR was investigated in the widest variety of disease subsets (4) with PFS ranging from 17.9 mo in the general R/R population to 34.2 mo in the R-naïve/sensitive R/R population (Table). Outcomes are likely to have been influenced by pt and disease characteristics (e.g., relapsed vs refractory, rituximab sensitive vs refractory, FL International Prognostic Index risk) and response criteria used (Cheson 1999, Cheson 2007, Laboratory of Experimental Oncology and Radiobiology [LEXOR], or unknown). Conclusions: In pts with R/R iNHL (FL and MZL), there is significant variation in reported response and survival outcomes following systemic therapy. Currently, there is no clear standard of care for R/R iNHL, as demonstrated by the use of 9 different therapies across 19 studies identified in this SLR. Limited information is available on treatment outcomes for pts with different disease status and further studies are needed to determine the most appropriate treatment approach for specific subgroups of pts with R/R iNHL. Disclosures Bachy: Roche: Honoraria; Beigene: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Takeda: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees. Fox:Celgene: Consultancy, Other: travel support, Speakers Bureau; Roche: Consultancy, Other: travel support, Research Funding, Speakers Bureau; Gilead: Consultancy, Other: travel support, Research Funding, Speakers Bureau; Janssen: Consultancy, Other: travel support, Speakers Bureau; Abbvie: Consultancy, Other: travel support, Research Funding, Speakers Bureau; Sunesis: Consultancy. Howlett:Celgene: Employment, Equity Ownership. Snedecor:Celgene: Research Funding. Franek:Celgene Corp.: Consultancy. Zaidi:Celgene Corp.: Consultancy. Tabah:Celgene Corporation: Employment.

Background: DLBCL without an event (disease progression, retreatment or death) within 24 months post diagnosis have a subsequent overall survival equivalent to that of the age- and sex-matched general population. In contrast, patients with an event with 24 months post diagnosis have poor survival. Patients experiencing early events are a heterogeneous group, consisting of patients with primary refectory disease and responding patients who later developed relapse. While the outcome of patients with primary refractory disease have been recently studied, little is known about or patients who have a response following immunochemotherapy (IC) and proceed to surveillance. These patients are the subject of recently completed and ongoing post-IC maintenance trials. To provide perspective, we analyzed outcomes of patients from a prospective observational study entering post IC. Methods: Newly diagnosed patients with DLBCL and treated with anthracycline-based immunochemotherapy were enrolled in the University of Iowa/Mayo Clinic SPORE Molecular Epidemiology Resource (MER) from 2002-2009. End of immunochemotherapy (EOIC) was defined as the date the patient entered surveillance after completion of anthracycline-based IC as per our previous study of surveillance imaging. Response status at EOIC was abstracted as reported from the clinical and radiographic (CT and/or PET) reports. EFS24 was defined being event-free at 24 months from diagnosis, where events consisted of progression, re-treatment, or death (any cause) after initial immunochemotherapy. Survival from EOIC was compared to the general United States population using standardized mortality ratios (SMR) and expected survival. Logistic regression with EFS24 as the endpoint was used to identify pretreatment variables that inform prognosis at the time of EOIC, using Odds ratios (ORs) and 95% confidence intervals (CI) as the measure of association. A subset analysis was performed in the patients aged 60-80 with aaIPI 1-3. Results: 680 patients with DLBCL were enrolled in the MER and initiated R-CHOP or comparable IC from 2002-2009. 552 pts (81%) completed therapy and proceeded to surveillance. Median age of the 552 patients was 61 years (range 18-92) and 51% were male. At a median FU of 89 months from EOIC (range 5-156), 146 pts (26%) had died, and 467 (86%) achieved EFS24. From EOIC, the 5 year overall survival was 82% compared to 91% expected based on age and sex matched general population; SMR was 1.88 (95% CI: 1.60-2.22). In the patients age 60-80 with aaIP1 1-3, (N=203), 79% achieved EFS24 and the 5-year OS from EOIC was 75% compared to 89% expected; SMR was 2.08 (95% 1.65-2.61). When examining all 552 patients proceeding to surveillance at end of EOIC, several high-risk disease characteristics at diagnosis were associated with higher risk of failing EFS24 after completion of therapy: ECOG PS 2-4 (OR = 2.72, 95% CI: 1.55-4.78) , LDH> ULN (OR = 3.54, 95% CI: 1.99-6.31), Stage III/IV (OR=2.43, 95% CI: 1.41-4.16), and aaIPI (per-point OR = 2.02, 95% CI: 1.54-2.64). Patients reported to be in CR at EOIC were more likely to achieve EFS24 (90%) compared to patients not in CR (72%, p<0.001). Conclusion: Patients entering surveillance after IC have shortened overall survival when compared with the general US population, with significant proportion of patients having an event within 24 months of diagnosis. Increased aaIPI and response less than CR are risk factors for inferior EFS24 in this group. Assessment of the prognostic value of EOIC response (PR vs. CR based on central review) is ongoing. Disclosures Nowakowski: Celgene: Research Funding; Morphosys: Research Funding; Bayer: Consultancy, Research Funding. Maurer:Celgene: Research Funding; Kite Pharma: Research Funding. Howlett:Celgene: Employment, Equity Ownership. Ansell:BMS, Seattle Genetics, Merck, Celldex and Affimed: Research Funding.