Abstract: The CD‐20 antibody rituximab is a standard component of treatment of non‐Hodgkin B‐cell lymphomas, including diffuse large B‐cell lymphoma (DLBCL). Primary DLBCL of the central nervous system, also called primary central nervous system lymphoma (PCNSL), is a DLBCL confined to the central nervous system. There has been debate whether intravenous rituximab accumulates sufficiently in the central nervous system to exert an effect. In this systematic review, we assess the benefits and harms of rituximab in the treatment of immunocompetent patients with PCNSL. By searching MEDLINE, CENTRAL, and ClincialTrials.gov up to March 2019, we identified randomized controlled trials (RCTs) investigating the effect of rituximab in patients with PCNSL. We extracted study characteristics and results, assessed risk of bias, performed trial‐level random‐effects meta‐analyses, and graded the certainty of evidence. The protocol was registered with PROSPERO (CRD42019121965). Main outcomes were overall survival (time to death), progression‐free survival (time to progression or death), quality of life, grades 3 and 4 toxicity, and treatment‐related mortality. We included two RCTs with a total of 343 participants. Overall survival was not statistically significantly improved (HR 0.76; 95% CI, 0.52‐1.12; low certainty), with 187 fewer to 39 more deaths after 2 years in 1000 treated patients. Low certainty of evidence indicated that rituximab improved progression‐free survival (HR 0.65; 95% CI, 0.45‐0.95), which translated into 137 fewer progressions or deaths after 2 years in 1000 treated patients (231 to 18 fewer). None of the RCTs provided data on quality of life. We found no evidence that rituximab increased grades 3 and 4 toxicity or treatment‐related mortality (RR 0.53; 95% CI, 0.20‐1.37; low certainty). Overall, the available evidence suggests with low certainty that rituximab in combination with methotrexate‐based chemotherapy may improve progression‐free survival in immunocompetent patients with newly diagnosed PCNSL, the pooled effect estimates did not show evidence for improvement of overall survival.

Abstract: Invasive aspergillosis (IA) by a triazole-resistant Aspergillus fumigatus is associated with high mortality. Real-time resistance detection will result in earlier initiation of appropriate therapy. Methods In a prospective study, we evaluated the clinical value of the AsperGenius polymerase chain reaction (PCR) assay in hematology patients from 12 centers. This PCR assay detects the most frequent cyp51A mutations in A. fumigatus conferring azole resistance. Patients were included when a computed tomography scan showed a pulmonary infiltrate and bronchoalveolar fluid (BALf) sampling was performed. The primary end point was antifungal treatment failure in patients with azole-resistant IA. Results Of 323 patients enrolled, complete mycological and radiological information was available for 276 (94%), and probable IA was diagnosed in 99/276 (36%). Sufficient BALf for PCR testing was available for 293/323 (91%). Aspergillus DNA was detected in 116/293 (40%) and A. fumigatus DNA in 89/293 (30%). The resistance PCR was conclusive in 58/89 (65%) and resistance detected in 8/58 (14%). Two had a mixed azole-susceptible/azole-resistant infection. In the 6 remaining patients, treatment failure was observed in 1. Galactomannan positivity was associated with mortality (P = .004) while an isolated positive Aspergillus PCR was not (P = .83). Conclusions Real-time PCR-based resistance testing may help to limit the clinical impact of triazole resistance. In contrast, the clinical impact of an isolated positive Aspergillus PCR on BALf seems limited. The interpretation of the EORTC/MSGERC PCR criterion for BALf may need further specification (eg, minimum cycle threshold value and/or PCR positive on & gt;1 BALf sample).

Abstract: Immunochemotherapy with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) has become standard of care for patients with diffuse large B-cell lymphoma (DLBCL). This randomized trial assessed whether rituximab intensification during the first 4 cycles of R-CHOP could improve the outcome of these patients compared with standard R-CHOP. PATIENTS AND METHODS A total of 574 patients with DLBCL age 18 to 80 years were randomly assigned to induction therapy with 6 or 8 cycles of R-CHOP-14 with (RR-CHOP-14) or without (R-CHOP-14) intensification of rituximab in the first 4 cycles. The primary end point was complete remission (CR) on induction. Analyses were performed by intention to treat. RESULTS CR was achieved in 254 (89%) of 286 patients in the R-CHOP-14 arm and 249 (86%) of 288 patients in the RR-CHOP-14 arm (hazard ratio [HR], 0.82; 95% CI, 0.50 to 1.36; P = .44). After a median follow-up of 92 months (range, 1-131 months), 3-year failure-free survival was 74% (95% CI, 68% to 78%) in the R-CHOP-14 arm versus 69% (95% CI, 63% to 74%) in the RR-CHOP-14 arm (HR, 1.26; 95% CI, 0.98 to 1.61; P = .07). Progression-free survival at 3 years was 74% (95% CI, 69% to 79%) in the R-CHOP-14 arm versus 71% (95% CI, 66% to 76%) in the RR-CHOP-14 arm (HR, 1.20; 95% CI, 0.94 to 1.55; P = .15). Overall survival at 3 years was 81% (95% CI, 76% to 85%) in the R-CHOP-14 arm versus 76% (95% CI, 70% to 80%) in the RR-CHOP-14 arm (HR, 1.27; 95% CI, 0.97 to 1.67; P = .09). Patients between ages 66 and 80 years experienced significantly more toxicity during the first 4 cycles in the RR-CHOP-14 arm, especially neutropenia and infections. CONCLUSION Early rituximab intensification during R-CHOP-14 does not improve outcome in patients with untreated DLBCL.

Abstract: Studies on the efficacy of rituximab in primary CNS lymphoma (PCNSL) reported conflicting results. Our international randomized phase 3 study showed that the addition of rituximab to high-dose methotrexate, BCNU, teniposide, and prednisolone (MBVP) in PCNSL was not efficacious in the short term. Here we present long-term results after a median follow-up of 82.3 months. Methods One hundred and ninety-nine eligible newly diagnosed, nonimmunocompromised patients with PCNSL aged 18–70 years with WHO performance status 0–3 was randomized between treatment with MBVP chemotherapy with or without rituximab, followed by high-dose cytarabine consolidation in responding patients, and reduced-dose WBRT in patients aged ≤ 60 years. Event-free survival was the primary endpoint. Overall survival rate, neurocognitive functioning (NCF), and health-related quality of life (HRQoL) were additionally assessed, with the IPCG test battery, EORTC QLQ-C30 and QLQ-BN20 questionnaires, respectively. Results For event-free survival, the hazard ratio was 0.85, 95% CI 0.61–1.18, P = .33. Overall survival rate at 5 years for MBVP and R-MBVP was 49% (39–59) and 53% (43–63) respectively. In total, 64 patients died in the MBVP arm and 55 in the R-MBVP arm, of which 69% were due to PCNSL. At the group level, all domains of NCF and HRQoL improved to a clinically relevant extent after treatment initiation, and remained stable thereafter up to 60 months of follow-up, except for motor speed which deteriorated between 24 and 60 months. Although fatigue improved initially, high levels persisted in the long term. Conclusions Long-term follow-up confirms the lack of added value of rituximab in addition to MBVP and HD-cytarabine for PCNSL.

Abstract: Background: Mantle cell lymphoma (MCL), an aggressive B-cell non-Hodgkin lymphoma, remains incurable with standard therapies. The highly selective, potent Bruton tyrosine kinase (BTK) inhibitor acalabrutinib was approved by the US Food and Drug Administration for the treatment of relapsed/refractory MCL based on clinical data showing a high rate of durable responses and a favorable safety profile (Lancet 2017;391:659-667). Here, we present long-term follow-up in these patients. Methods: Eligible patients were aged ≥18 years, had confirmed MCL, Eastern Cooperative Oncology Group performance status ≤2, and had relapsed and/or were refractory to 1-5 prior therapies. Exclusion criteria included prior BTK or BCL-2 inhibitor exposure and concomitant warfarin or equivalent vitamin K antagonists. Oral acalabrutinib 100 mg twice daily was administered until progressive disease or unacceptable toxicity. Response was assessed by investigators based on the Lugano classification (J Clin Oncol 2014;32:3059-3068).Analysis of minimal residual disease using next-generation sequencing (10-6) is ongoing for a subset of patients with available samples and will be presented upon completion. Results: A total of 124 patients were treated; 80% were men, and median age was 68 years (range, 42-90 years) with 65% aged ≥65 years. At baseline, 93% of patients had Eastern Cooperative Oncology Group performance status ≤1, 8% had bulky lymph nodes ≥10 cm, 72% had extranodal involvement, and 44%/17% had intermediate-/high-risk simplified MCL International Prognostic Index scores. The median number of prior therapies was 2 (range, 1-5); 24% were refractory to the most recent prior treatment. As of February 12, 2018, median time on study was 26.3 months (range, 0.3-35.1 months), and 40% of patients remain on treatment. Median relative dose intensity (ratio of actual to planned cumulative dose during drug exposure period) was 99% (range, 27%-100%). Investigator-assessed overall response rate was 81% (95% CI: 73%, 87%), with 43% (95% CI: 34%, 52%) achieving complete response (Table). Overall response rates were consistent across prespecified subgroups of tumor bulk, presence of refractory disease and number/type of prior treatment. Median duration of response was 25.7 months (95% CI: 17.5 months, not reached). Median progression-free survival (PFS) was 19.5 months (95% CI: 16.5 months, 27.7; Figure). Median overall survival (OS) was not reached; the estimated 24-month OS rate was 72% (95% CI: 64%, 80%). The most frequent adverse events (AEs; ≥20%) were primarily Grade 1/2 and included headache (38%), diarrhea (36%), fatigue (28%), cough (22%) and myalgia (21%). Grade 3/4 AEs (≥5%) included anemia (10%), neutropenia (10%) and pneumonia (6%). There were 13 patients (10%) with 16 cardiac events, including 4 Grade 3/4 events (3%) in 1 patient each (acute coronary syndrome, acute myocardial infarction, cardiorespiratory arrest, coronary artery disease). Four patients had hypertension events (3%); 1 event was Grade 3. The most common bleeding events were contusion (13%) and petechiae (9%); all bleeding events were Grade 1/2 except for 3 Grade 3 events (gastrointestinal hemorrhage, hematuria, hematoma). Grade 3/4 infections occurred in 15% of patients and none were Grade 5; there was one case of cytomegalovirus viremia and one case of pneumocystis jiroveci pneumonia (both Grade 2). Treatment discontinuation was primarily due to progressive disease (n=54; 44%) and AEs (n=10; 8%).Twelve AEs led to discontinuation in 10 patients; all of these AEs occurred in only 1 patient each.There were 43 deaths (35%), most commonly from progressive disease (n=29; 23%) or AEs (n=6; 5%). Deaths due to AEs included bilateral pulmonary embolism, critical aortic stenosis, myelodysplastic syndrome, pneumonia, suicide, and non-small cell lung cancer; none were considered to be related to acalabrutinib. Conclusion: Response to acalabrutinib remained consistent during long-term ( 〉 24-month) follow-up, including high response rates, median PFS of 19.5 months, and a median OS that has not yet been reached, confirming efficacy in patients with relapsed/refractory MCL. The AE profile was largely similar to earlier reporting, with limited additional safety events observed with an additional year of follow-up. Disclosures Wang: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Dava Oncology: Honoraria; AstraZeneca: Consultancy, Research Funding; Pharmacyclics: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Juno: Research Funding; MoreHealth: Consultancy; Acerta Pharma: Honoraria, Research Funding; Kite Pharma: Research Funding; Novartis: Research Funding. Rule:Celltrion: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences, Inc.: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Roche: Honoraria; Kite: Membership on an entity's Board of Directors or advisory committees. Zinzani:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: 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, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Speakers Bureau; SERVIER: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; MSD: Honoraria, Speakers Bureau. Casasnovas:MSD: Honoraria; Merck: Honoraria; Takeda: Honoraria; Roche: Honoraria; Gilead Sciences: Research Funding; Roche: Research Funding; Janssen: Consultancy; Gilead Sciences: Consultancy; MSD: Consultancy; merck: Consultancy; takeda: Consultancy; Roche: Consultancy; Gilead Sciences: Honoraria; Janssen: Honoraria; Celgene: Honoraria. Smith:Genentech: Research Funding; Portola: Research Funding; Pharmacyclics: Research Funding; Merck Sharpe Dohme and Corp: Consultancy, Research Funding; Seattle Genetics: Research Funding; Acerta Pharma BV: Research Funding. Morschhauser:BMS: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Other: Scientific Lectures; Epizyme: Consultancy; Roche: Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees. Panizo:Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees; Acerta Pharma: Research Funding; Roche: Consultancy, Speakers Bureau. Davies:Janssen: Consultancy, Honoraria; Karyopharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria, Research Funding; Acerta Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; F. Hoffman-La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite: Consultancy; ADC Therapeutics: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Research Funding. Jacobsen:Seattle Genetics: Consultancy; AstraZeneca: Consultancy; Merck: Consultancy. Kater:Janssen: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Acerta/AZ: Research Funding; Genentech: Honoraria, Research Funding. Robak:Gilead: Consultancy; Janssen: Consultancy, Honoraria; AbbVie, Inc: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria. Dua:Acerta Pharma: Employment. Frigault:AstraZeneca: Employment, Equity Ownership. Izumi:Acerta Pharma: Employment, Equity Ownership, Patents & Royalties: Acerta Pharma, various patents for ACP-196. Nguyen:Acerta Pharma: Employment. Patel:Acerta Pharma: Employment, Equity Ownership. Yin:Acerta Pharma: Employment. Jurczak:European Medicines Agency: Consultancy; Astra Zeneca/Acerta: Consultancy, Research Funding; Sandoz-Novartis: Consultancy; Janssen: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Afimed: Research Funding; Bayer: Research Funding; Beigene: Research Funding; Celgene: Research Funding; Epizyme: Research Funding; Nordic Nanovector: Research Funding; Merck: Research Funding; Morphosys: Research Funding; Pharmacyclics: Research Funding; Servier: Research Funding; Roche: Research Funding; TG Therapeutics: Research Funding.