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Patients with follicular lymphoma (FL) frequently require multiple treatments during their disease course; however, survival based on lines of treatment remains poorly described in the post-rituximab era. Also, the Follicular Lymphoma International Prognostic Index (FLIPI) score was developed to predict survival at diagnosis, yet it remains unknown whether increase in FLIPI score following an initial observation period is associated with less-favorable outcomes. To address these knowledge gaps, we retrospectively studied 1088 patients with FL grade 1–3A managed between 1998 and 2009 at our institution. Median overall survival (OS) and progression-free survival (PFS) after first-line treatment were not reached and 4.73 years, respectively. Following successive lines of treatment, years of median OS and PFS were, respectively: after second-line, 11.7 and 1.5; third-line, 8.8 and 1.1; fourth-line, 5.3 and 0.9; fifth-line, 3.1 and 0.6; sixth-line, 1.9 and 0.5. In initially observed, subsequently treated patients, FLIPI score increase after observation was associated with inferior survival following first-line treatment. The reduced survival we observed after second-line and later therapy supports the development of new treatments for relapsed patients and benchmarks historical targets for clinical endpoints. This study also highlights the utility of changes in FLIPI score at diagnosis and after observation in identifying patients likely to have worse outcomes.

Although methotrexate (MTX) is the most widely used therapy for central nervous system (CNS) prophylaxis in patients with diffuse large B-cell lymphoma (DLBCL), the optimal regimen remains unclear. We examined the efficacy of different prophylactic regimens in 585 patients with newly diagnosed DLBCL and high-risk for CNS relapse, treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or R-CHOP-like regimens from 2001 to 2017, of whom 295 (50%) received prophylaxis. Intrathecal (IT) MTX was given to 253 (86%) and high-dose MTX (HD-MTX) to 42 (14%). After a median follow-up of 6.8 years, 36 of 585 patients relapsed in the CNS, of whom 14 had received prophylaxis. The CNS relapse risk at 1 year was lower for patients who received prophylaxis than patients who did not: 2% vs. 7.1%. However, the difference became less significant over time (5-year risk 5.6% vs. 7.5%), indicating prophylaxis tended to delay CNS relapse rather than prevent it. Furthermore, the CNS relapse risk was similar in patients who received IT and HD-MTX (5-year risk 5.6% vs. 5.2%). Collectively, our data indicate the benefit of MTX for CNS prophylaxis is transient, highlighting the need for more effective prophylactic regimens. In addition, our results failed to demonstrate a clinical advantage for the HD-MTX regimen.

Extranodal (EN) diffuse large B-cell lymphoma (DLBCL) has been historically associated with inferior survival outcomes compared to nodal DLBCL. However, outcomes of patients with EN DLBCL following chimeric antigen receptor T-cell (CAR-T) therapy are not well established. In this multi-center retrospective cohort study, we evaluated the outcomes of patients with EN DLBCL who underwent CAR-T in the relapsed/refractory (R/R) setting. The primary objective was overall survival (OS), while secondary objectives included progression-free survival (PFS), response rates, and toxicity rates. A total of 218 patients were included in the analysis. The most common sites of EN involvement were skin/soft tissue (25%), bone (22%), and lung (17%). Overall response rate (ORR) and complete response rate (CRR) at first post-treatment evaluation were 62% ( n  = 127) and 40% ( n  = 82), respectively. Median follow-up was 3.5 years. Median PFS and OS were 4.0 months (95% CI = 3.1–7.2) and 25.7 months (95% CI = 16.1–51.6), respectively. Cytokine release syndrome (CRS) of any grade occurred in 73% ( n  = 159) of patients, and 6% ( n  = 12) had grade ≥ 3 CRS. Immune effector cell-associated neurotoxicity syndrome (ICANS) of any grade occurred in 37% ( n  = 81) of patients, and 19% ( n  = 41) developed grade ≥ 3 ICANS. In the multivariable analysis, factors that were independently prognostic of inferior OS were 3 or more lines of therapy prior to CAR-T, bulky disease at the time of CAR-T, hepatobiliary, and pancreas involvement, while refractory disease to the most recent therapy prior to CAR-T was associated with inferior PFS. Future studies should further evaluate outcomes of CAR-T in patients with specific EN sites of involvement that appear to be associated with inferior survival such as the liver and pancreas.

Copanlisib, an intravenous pan-class I PI3K inhibitor, showed efficacy and safety as monotherapy in patients with relapsed or refractory indolent non-Hodgkin lymphoma who had received at least two therapies. The CHRONOS-3 study aimed to assess the efficacy and safety of copanlisib plus rituximab in patients with relapsed indolent non-Hodgkin lymphoma. CHRONOS-3 was a multicentre, double-blind, randomised, placebo-controlled, phase 3 study in 186 academic medical centres across Asia, Australia, Europe, New Zealand, North America, Russia, South Africa, and South America. Patients aged 18 years and older with an Eastern Cooperative Oncology Group performance status of no more than 2 and histologically confirmed CD20-positive indolent B-cell lymphoma relapsed after the last anti-CD20 monoclonal antibody-containing therapy and progression-free and treatment-free for at least 12 months, or at least 6 months for patients unwilling or unfit to receive chemotherapy, were randomly assigned (2:1) with an interactive voice-web response system via block randomisation (block size of six) to copanlisib (60 mg given as a 1-h intravenous infusion on an intermittent schedule on days 1, 8, and 15 [28-day cycle]) plus rituximab (375 mg/m2 given intravenously weekly on days 1, 8, 15, and 22 during cycle 1 and day 1 of cycles 3, 5, 7, and 9) or placebo plus rituximab, stratified on the basis of histology, progression-free and treatment-free interval, presence of bulky disease, and previous treatment with PI3K inhibitors. The primary outcome was progression-free survival in the full analysis set (all randomised patients) by masked central review. Safety was assessed in all patients who received at least one dose of any study drug. This study is registered with ClinicalTrials.gov, NCT02367040 and is ongoing. Between Aug 3, 2015, and Dec 17, 2019, 652 patients were screened for eligibility. 307 of 458 patients were randomly assigned to copanlisib plus rituximab and 151 patients were randomly assigned to placebo plus rituximab. With a median follow-up of 19·2 months (IQR 7·4–28·8) and 205 total events, copanlisib plus rituximab showed a statistically and clinically significant improvement in progression-free survival versus placebo plus rituximab; median progression-free survival 21·5 months (95% CI 17·8–33·0) versus 13·8 months (10·2–17·5; hazard ratio 0·52 [95% CI 0·39–0·69]; p<0·0001). The most common grade 3–4 adverse events were hyperglycaemia (173 [56%] of 307 patients in the copanlisib plus rituximab group vs 12 [8%] of 146 in the placebo plus rituximab group) and hypertension (122 [40%] vs 13 [9%]). Serious treatment-emergent adverse events were reported in 145 (47%) of 307 patients receiving copanlisib plus rituximab and 27 (18%) of 146 patients receiving placebo plus rituximab. One (<1%) drug-related death (pneumonitis) occurred in the copanlisib plus rituximab group and none occurred in the placebo plus rituximab group. Copanlisib plus rituximab improved progression-free survival in patients with relapsed indolent non-Hodgkin lymphoma compared with placebo plus rituximab. To our knowledge, copanlisib is the first PI3K inhibitor to be safely combined with rituximab and the first to show broad and superior efficacy in combination with rituximab in patients with relapsed indolent non-Hodgkin lymphoma. Bayer.

Abstract Diffuse large B-cell lymphoma (DLBCL) is characterized by clinical and molecular heterogeneity; however, this heterogeneity is rarely taken into account by standard-of-care treatment approaches. While the disease was traditionally classified based on transcriptome signatures purporting the tumor cell of origin, recent classification systems have further differentiated these subtypes into clusters based on molecular and genetic features. Alongside a better understanding of the biology of the disease and the signaling pathways involved, emerging therapeutic agents may be better aimed at attacking distinct disease subsets. It is hoped that molecular subtyping at diagnosis will allow patients to be allocated to the appropriate treatment that targets their specific disease subtype, thus advancing the promise of precision medicine in lymphoma, an approach that is most needed. For high-risk disease subsets, this is particularly important, and much research is still needed to develop agents effective in this population. Here, we review recent advances in DLBCL biology and how they can be translated into clinical care. This article reviews recent advances in the biology of diffuse large B cell lymphoma and how to translate into better management of the heterogenous disease.

As the survival of patients with mantle cell lymphoma (MCL) continues to improve, patients are increasingly being treated with multiple regimens. However, outcome after each line remains poorly characterized in the modern era. To address this knowledge gap, we retrospectively studied 404 consecutive MCL patients who were managed between 2000 and 2014 at Memorial Sloan Kettering Cancer Center. Histologic diagnosis was centrally confirmed, and patients were followed longitudinally from diagnosis throughout their disease course. Progression-free survival (PFS) and overall survival (OS) were determined by Kaplan–Meier method. The median OS and PFS after first-line treatment were 9.7 and 4.0 years, respectively. After second-line therapy, the median OS and PFS were 41.1 and 14.0 months, third line were 25.2 and 6.5 months, and fourth line were 14.4 and 5.0 months. In patients less than 65 years, stem cell transplant (SCT)-based frontline regimens were associated with improved PFS compared with non-SCT regimens (median PFS: 86.2 versus 40.0 months; P < 0.01), with a trend toward longer OS (median OS: 165.0 versus 120.0 months; P = 0.06). Early treatment failure after first-line regimens was associated with worse OS (5.9 versus 2.5 years; P < 0.01). Our study should facilitate establishing proper endpoints for future clinical trials using novel treatment approaches.

Recent prospective clinical trial data suggest that patients with Hodgkin’s lymphoma who continue treatment with ABVD, despite failing to attain a complete metabolic response on interim PET (PET2+), may fare better than previously published. We describe the outcomes of PET2+ patients who continued ABVD and compare the performance of a quantitative measure based on the lesion-to-liver SUV ratio (LLS qPET2+) to that of the subjective Deauville criteria (dvPET2+). We analyzed all patients with newly diagnosed advanced-stage Hodgkin lymphoma treated with frontline ABVD at the Memorial Sloan Kettering Cancer Center between 2008 and 2017. Eligibility was set to correspond with the RATHL inclusion criteria. Images were reviewed by two nuclear medicine physicians and discordant cases were resolved with a third expert in consensus. qPET2+ was defined as LLS ≥ 1.3. We identified 227 patients of whom 25% (57) were qPET2+, but only 14% (31) were dvPET2+. Forty-eight patients (84%) continued ABVD with a 3-year PFS of 70% for qPET2+ and 64% for dvPET2+. In conclusion, interim PET interpretation in clinical practice may be associated with a higher rate of scans deemed positive. Irrespective of the criteria for PET2 positivity, a subset of patients may continue ABVD without a dismal outcome.

Anaphylaxis is a potentially life-threatening allergic reaction characterized by a syndrome of dermatologic and systemic signs and symptoms, at times including cardiovascular collapse from distributive shock. Although it is recognized that the incidence of anaphylaxis is increasing, the extent of its prevalence, both from individual causes and in toto, remains unclear. Common causes include pharmacologic agents, such as antibiotics and radiocontrast media, as well as foods, insect stings, and latex exposure. The available literature suffers from methodologic shortcomings, limiting the accuracy of estimated prevalence. However, current data suggest that there are approximately 1500 annual deaths from anaphylaxis, and between 2.8 million and 42.7 million Americans are at risk of experiencing an episode of anaphylaxis during their lives.