Abstract: Background: Patients with follicular lymphoma (FL) have a heterogenous prognosis. Recently a simple score, the PRIMA-PI, was developed based on the PRIMA clinical trial (Bachy et al Blood. 2018). With only two factors (beta-2-microglobulin level & gt; 3 mg/L and bone marrow involvement), this index was at least as discriminatory as FLIPI on the training and validation cohorts. The validity of the PRIMA-PI was confirmed on Czech and German FL cohorts and a patient group from the Nordic Lymphoma Group. However, further validation is needed to confirm the use of PRIMA-PI in place of FLIPI for prognostic assessment. Indeed, in the era of new chemo-free treatments, it seems important to challenge the potency of traditional prognostic factors and scores. Recently, rituximab combined with lenalidomide (R2) was compared to conventional immunochemotherapy (R-chemo) in the phase III RELEVANCE trial. The aim of our study was to validate PRIMA-PI in the RELEVANCE trial cohort and compare its performance with FLIPI (Solal-Celigny et al. Blood. 2004) and FLIPI2 (Federico et al. JCO. 2009). A secondary objective was to evaluate potential differences in terms of prognostic bio-clinical parameters between the R2 and R-chemo arms. Methods: All patients with available data for FLIPI, FLIPI2, and PRIMA-PI from the intention to treat population of the RELEVANCE study were included in the analysis. PFS according to each prognostic score were assessed in the total population and by treatment arms. Data were not mature enough to compare OS distributions. Performance metrics (log-rank p value and Net Reclassification Improvement [NRI]) were calculated for each group to assess concordance and discriminating ability of each score. Results: Median follow-up time for the study was 38 months. Overall, 846 RELEVANCE patients were included in the analysis. Data were available for 845 patients for FLIPI score assessment, 832 for FLIPI2 and 807 for PRIMA-PI. Group repartition according to the FLIPI and the FLIPI2 were largely imbalanced compared with PRIMA-PI. FLIPI classified very few patients in the low risk group (15% LR) while 49% of the patients were at high risk (HR), and 36% were at intermediate risk (IR). Similarly, FLIPI2 risk categories were as follow: 8% LR, 50% IR, and 42% HR. On the contrary, PRIMA-PI divided the study population into three equal groups (33%, 33% and 34%). In the total population, FLIPI and PRIMA-PI were predictive of PFS (p=0.029 and p=0.004, respectively); FLIPI2 showed poor performance (p=0.094). PFS curves based on each score are shown in Figure 1. NRI index indicated that the PRIMA-PI yielded analogous segregation for PFS with FLIPI (NRI 0.16; 95% CI: -0.008, 0.318; Table 1). In the R-chemo arm, both FLIPI and PRIMA-PI could isolate different prognostic groups for PFS, whereas FLIPI2 could not. Conversely, none of the indices were able to significantly discriminate outcomes for patients treated with R2. Interestingly, analysis showed that some usual prognostic factors, especially those likely to reflect tumor burden such as beta-2 microglobulin and LDH, were not predictive for PFS in the R2 arm. In contrast, low albumin ( & lt;40 g/L) and low hemoglobin ( & lt;120 g/L) levels were significantly associated with worse PFS in the R2 arm (p=0.001, and p=0.023), but not in the R-chemo arm. Conclusion: For patients with FL treated upfront with immunochemotherapy, the PRIMA-PI is a valid scoring system that allows to segregate patients as efficiently as the FLIPI while using only two factors. These results confirm that the PRIMA-PI could substitute for the FLIPI for patients treated with upfront R-chemo. Athough our data have to be interpreted in light of the short median follow-up time, they also suggest that other clinical/biological parameters might be considered and new prognostic indexes established for patients treated with R2. Considering possible mechanisms of action of lenalidomide, prognostic factors related to the underlying patient's immunological status might be more predictive. Disclosures Fowler: Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy; ABBVIE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: 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. Bachy:Roche: Consultancy; Janssen Cilag: Honoraria; Gilead Science: Honoraria; Amgen: Honoraria; Roche: Honoraria; Janssen Cilag: Other: Travel, accomodation, Expense. Feugier:abbvie: Honoraria, Research Funding, Speakers Bureau; roche: Honoraria, Research Funding, Speakers Bureau; janssen: Honoraria, Research Funding, Speakers Bureau; gilead: Honoraria, Research Funding, Speakers Bureau. Tilly:roche: Membership on an entity's Board of Directors or advisory committees; servier: Honoraria; merck: Honoraria; Gilead: Honoraria; Janssen: Honoraria; BMS: Honoraria; Karyopharm: Consultancy; Astra-Zeneca: Consultancy; Roche: Consultancy; Celgene: Consultancy, Research Funding. Palomba:Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Noble Insights: Consultancy; Evelo: Other: Immediate family member, Equity Ownership; MSK (IP for Juno and Seres): Other: Immediate Family Member, Patents & Royalties - describe: intellectual property rights ; Hemedicus: Other: Immediate Family Member, Speakers Bureau ; Merck & Co Inc.: Other: Immediate Family Member, Consultancy (includes expert testimony); Seres Therapeutics: Other: Immediate Family Member, Equity Ownership and Membership on an entity's Board of Directors or advisory committees; STRAXIMM: Other: Immediate Family Member, Membership on an entity's Board of Directors or advisory committees; Kite Pharmaceuticals: Other: Immediate Family Member, Membership on an entity's Board of Directors or advisory committees. Libby:Akcea: Consultancy; Alnylam: Consultancy; Abbvie: Consultancy; Pharmacyclics and Janssen: Consultancy. Casasnovas:Merck Sharp and Dohme: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses. Flinn:TG Therapeutics, Trillum Therapeutics, Abbvie, ArQule, BeiGene, Curis, FORMA Therapeutics, Forty Seven, Merck, Pfizer, Takeda, Teva, Verastem, Gilead Sciences, Astra Zeneca (AZ), Juno Therapeutics, UnumTherapeutics, MorphoSys, AG: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; TG Therapeutics, Trillum Therapeutics, Abbvie, ArQule, BeiGene, Curis, FORMA Therapeutics, Forty Seven, Merck, Pfizer, Takeda, Teva, Verastem, Gilead Sciences, Astra Zeneca (AZ), Juno Therapeutics, UnumTherapeutics, MorphoSys, AG: Research Funding; AbbVie, Seattle Genetics, TG Therapeutics, Verastem: Consultancy; Acerta Pharma, Agios, Calithera Biosciences, Celgene, Constellation Pharmaceuticals, Genentech, Gilead Sciences, Incyte, Infinity Pharmaceuticals, Janssen, Karyopharm Therapeutics, Kite Pharma, Novartis, Pharmacyclics, Portola Pharmaceuticals: Research Funding. Haioun:Novartis: Honoraria; Janssen: Honoraria; F. Hoffmann-La Roche Ltd: Honoraria; Servier: Honoraria; Takeda: Honoraria; Miltenyi: Honoraria; Gilead: Honoraria; Celgene: Honoraria; Amgen: Honoraria. Bartlett:Pharmacyclics: Research Funding; Pfizer: Research Funding; Affimed: Research Funding; Celgene: Research Funding; Millenium: Research Funding; Merck: Research Funding; Seattle Genetics: Research Funding; Forty Seven: Research Funding; Bristol-Myers Squibb: Research Funding; ADC Therapeutics: Consultancy, Research Funding; Genenetech: Research Funding; Gilead: Research Funding; Immune Design: Research Funding; Janssen: Research Funding. Bouabdallah:Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Brice:BMS: Honoraria; Millennium Takeda: Research Funding; Takeda France: Consultancy, Honoraria. Ribrag:Nanostring: Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy, Research Funding; ArgenX: Research Funding; Roche: Other: Travel, accommodations, and expenses ; BMS: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, and expenses ; MSD: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Infinity: Membership on an entity's Board of Directors or advisory committees; AZ: Membership on an entity's Board of Directors or advisory committees. Le Gouill:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Roche-Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support. Martín:Teva: Research Funding; Gilead: Consultancy, Honoraria; Kiowa Kirin: Consultancy; Roche: Consultancy, Honoraria, Other: Travel Expenses; iQone: Consultancy; Servier: Honoraria, Other: Travel Expenses; Janssen: Honoraria, Other: Travel Expenses, Research Funding; Celgene: Consultancy, Honoraria, Other: Travel Expenses, Research Funding. Lopez-Guillermo:Roche: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Janssen: Research Funding. Larouche:Bayer; Gilead Sciences; Merck; Roche: Research Funding. Ando:Eisai: Research Funding. Maria:Janssen Cilag: Consultancy, Other: Travel support; Gilead Sciences: Other: Travel support, Research Funding; Abbvie: Consultancy, Other: Travel support; Celgene: Consultancy; Roche: Consultancy, Other: Travel support. André:Takeda: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers-Squibb: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Other: Travel grants; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Roche: Other: Travel grants, Research Funding; Amgen: Other: Travel grants, Research Funding; Johnson & Johnson: Research Funding; Takeda Millenium: Research Funding; Chugai: Research Funding; Celgene: Other: Travel grants, Research Funding. Sehn:Merck: Consultancy, Honoraria; Acerta: Consultancy, Honoraria; TEVA Pharmaceuticals Industries: Consultancy, Honoraria; F. Hoffmann-La Roche/Genentech: Consultancy, Honoraria, Research Funding; TEVA Pharmaceuticals Industries: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Astra Zeneca: Consultancy, Honoraria; Lundbeck: Consultancy, Honoraria; Kite Pharma: Consultancy, Honoraria; Kite Pharma: Consultancy, Honoraria; Astra Zeneca: Consultancy, Honoraria; Acerta: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; Janssen-Ortho: Honoraria; Janssen-Ortho: Honoraria; F. Hoffmann-La Roche/Genentech: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; Lundbeck: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria. Tobinai:Daiichi Sankyo: Consultancy, Honoraria; Eisai: Honoraria, Research Funding; Verastem: Honoraria; Mundi Pharma: Consultancy, Honoraria, Research Funding; Zenyaku Kogyo: Consultancy, Honoraria; Yakult: Honoraria; Janssen Pharmaceutical: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; HUYA Bioscience: Consultancy, Honoraria; Ono Pharmaceutical: Consultancy, Honoraria, Research Funding; Chugai Pharmaceutical: Honoraria, Research Funding; AbbVie: Research Funding; Solasia: Honoraria; Meiji Seika: Honoraria; Kyowa Kirin: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria; Takeda Pharmaceutical: Consultancy, Honoraria, Research Funding. Cartron:Roche, Celgene: Consultancy; Sanofi, Gilead, Janssen, Roche, Celgene: Honoraria. Delarue:Celgene Corporation: Employment, Equity Ownership. Czuczman:Celgene Corporation: Employment, Equity Ownership. Salles:BMS: Honoraria; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Autolus: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis, Servier, AbbVie, Karyopharm, Kite, MorphoSys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Amgen: Honoraria, Other: Educational events; Epizyme: Consultancy, Honoraria; Roche, Janssen, Gilead, Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Morschhauser:Bayer: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Epizyme: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; BMS: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Abstract: Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. In 2004, the European Mantle Cell Lymphoma (MCL) Network initiated the randomized open-label, phase III MCL Younger trial for first-line treatment of patients with advanced-stage MCL, age 〈 66 years, comparing an alternating rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone/rituximab plus dexamethasone, high-dose cytarabine, and cisplatin (R-CHOP/R-DHAP) induction followed by high-dose cytarabine-containing myeloablative radiochemotherapy conditioning and autologous peripheral blood stem-cell transplantation (R-DHAP arm) to R-CHOP with standard myeloablative radiochemotherapy and autologous stem-cell transplantation (R-CHOP arm). After a median follow-up of 10.6 years, the time to treatment failure was still significantly improved in the R-DHAP versus R-CHOP arms (medians 8.4 v 3.9 years, 5-/10-year rates 64%/46% v 41%/25%, P = .038, hazard ratio, 0.59). Median overall survival (OS) was not reached in the R-DHAP arm versus 11.3 years in R-CHOP arm (5-/10-year rates, 76%/60% v 69%/55%, P = .12). The unadjusted OS hazard ratios (0.80 [95% CI, 0.61 to 1.06], P = .12) reached significance when adjusted for Mantle Cell Lymphoma International Prognostic Index (MIPI) and MIPI + Ki-67 (MIPI-c) (0.74; 95% CI, 0.56 to 0.98; P = .038 and .60; 95% CI, 0.41 to 0.87; P = .0066). The incidence of secondary hematologic malignancies tended to be higher in the R-DHAP arm (4.5% v 1.4% at 10 years). With mature long-term data, we confirm the previously observed substantially prolonged time to treatment failure and, for the first time to our knowledge, show an improvement of OS. Some patients with MCL may be cured.

Abstract: Patients with relapsed or refractory primary mediastinal large B-cell lymphoma (rrPMBCL) have a poor prognosis, and their treatment represents an urgent and unmet need. Because PMBCL is associated with genetic aberrations at 9p24 and overexpression of programmed cell death-1 (PD-1) ligands (PD-L1), it is hypothesized to be susceptible to PD-1 blockade. METHODS In the phase IB KEYNOTE-013 (ClinicalTrials.gov identifier: NCT01953692 ) and phase II KEYNOTE-170 (ClinicalTrials.gov identifier: NCT02576990 ) studies, adults with rrPMBCL received pembrolizumab for up to 2 years or until disease progression or unacceptable toxicity. The primary end points were safety and objective response rate in KEYNOTE-013 and objective response rate in KEYNOTE-170. Secondary end points included duration of response, progression-free survival, overall survival, and safety. Exploratory end points included association between biomarkers and pembrolizumab activity. RESULTS The objective response rate was 48% (7 complete responses; 33%) among 21 patients in KEYNOTE-013 and 45% (7 complete responses; 13%) among 53 patients in KEYNOTE-170. After a median follow-up time of 29.1 months in KEYNOTE-013 and 12.5 months in KEYNOTE-170, the median duration of response was not reached in either study. No patient with complete response experienced progression, including 2 patients with complete response for at least 1 year off therapy. Treatment-related adverse events occurred in 24% of patients in KEYNOTE-013 and 23% of patients in KEYNOTE-170. There were no treatment-related deaths. Among 42 evaluable patients, the magnitude of the 9p24 gene abnormality was associated with PD-L1 expression, which was itself significantly associated with progression-free survival. CONCLUSION Pembrolizumab is associated with high response rate, durable activity, and a manageable safety profile in patients with rrPMBCL.