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B-cell non-Hodgkin lymphoma (B-NHL) encompasses multiple clinically and phenotypically distinct subtypes of malignancy with unique molecular etiologies. Common subtypes of B-NHL, such as diffuse large B-cell lymphoma, have been comprehensively interrogated at the genomic level, but rarer subtypes, such as mantle cell lymphoma, remain less extensively characterized. Furthermore, multiple B-NHL subtypes have thus far not been comprehensively compared using the same methodology to identify conserved or subtype-specific patterns of genomic alterations. Here, we employed a large targeted hybrid-capture sequencing approach encompassing 380 genes to interrogate the genomic landscapes of 685 B-NHL tumors at high depth, including diffuse large B-cell lymphoma, mantle cell lymphoma, follicular lymphoma, and Burkitt lymphoma. We identified conserved hallmarks of B-NHL that were deregulated in the majority of tumors from each subtype, including frequent genetic deregulation of the ubiquitin proteasome system. In addition, we identified subtype-specific patterns of genetic alterations, including clusters of co-occurring mutations and DNA copy number alterations. The cumulative burden of mutations within a single cluster were more discriminatory of B-NHL subtypes than individual mutations, implicating likely patterns of genetic cooperation that contribute to disease etiology. We therefore provide the first cross-sectional analysis of mutations and DNA copy number alterations across major B-NHL subtypes and a framework of co-occurring genetic alterations that deregulate genetic hallmarks and likely cooperate in lymphomagenesis.

PD-1 blockade enhances the function of antitumor T cells and antibody-dependent, cell-mediated cytotoxicity (ADCC) of NK cells. In a single-center, open-label, phase 2 trial, we tested the combination of pembrolizumab, an anti-PD-1 monoclonal antibody, and rituximab, an anti-CD20 monoclonal antibody that induces ADCC, in 30 patients with follicular lymphoma (FL) with rituximab-sensitive disease who had relapsed after ≥1 prior therapy. Pembrolizumab was administered at 200 mg IV every 3 weeks for up to 16 cycles, and rituximab was given at 375 mg/m2 IV weekly for 4 weeks in cycle 1 only. The most common grade 3/4 adverse events (AEs) were liver enzyme abnormalities (3%), diarrhea (3%), nausea (3%), aseptic meningitis (3%), and pancreatitis (3%). Low-grade immune-related AEs were reported in 80% of patients, including diarrhea (43%), liver enzyme abnormalities (33%), thyroid dysfunction (27%), and rash (23%). Grade 3 or 4 immune-related AEs occurred in 13% of the patients. Treatment-related AEs led to discontinuation in 6 (20%) patients. The overall response rate (primary end point) was 67%, and the complete response (CR) rate was 50%. Median progression-free survival (PFS) was 12.6 months (95% confidence interval, 8.2-27.6), the 3-year overall survival rate was 97%, and 23% of patients were in remission at a median follow-up of 35 months. The presence of a high CD8+ T-effector score at baseline in the tumor was associated with induction of a CR and improved PFS. In this single-arm, phase 2 study, the combination of pembrolizumab and rituximab demonstrates favorable efficacy and safety profile in relapsed FL. This trial is registered at www.clinicaltrials.gov as #NCT02446457., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Purpose: Tafasitamab, an Fc-modified, humanized, anti-CD19 monoclonal antibody, in combination with lenalidomide, demonstrated efficacy in transplant-ineligible patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL), in the single-arm, phase II L-MIND study (NCT02399085). RE-MIND, a retrospective observational study, generated a historic control for L-MIND to delineate the contribution of tafasitamab to the efficacy of the combination., Patients and Methods: Data were retrospectively collected from patients with R/R DLBCL treated with lenalidomide monotherapy for comparison with tafasitamab + lenalidomide-treated patients (L-MIND). Key eligibility criteria were aligned with L-MIND. Estimated propensity score-based Nearest Neighbor 1:1 Matching methodology balanced the cohorts for nine prespecified prognostic baseline covariates. The primary endpoint was investigator-assessed best overall response rate (ORR). Secondary endpoints included complete response (CR) rate, progression-free survival (PFS), and overall survival (OS)., Results: Data from 490 patients going through lenalidomide monotherapy were collected; 140 qualified for matching with the L-MIND cohort. The primary analysis included 76 patients from each cohort who received a lenalidomide starting dose of 25 mg/day. Cohort baseline covariates were comparable. A significantly better ORR of 67.1% (95% confidence interval, 55.4-77.5) was observed for the combination therapy versus 34.2% (23.7-46.0) for lenalidomide monotherapy [odds ratio, 3.89 (1.90-8.14); P < 0.0001]. Higher CR rates were achieved with combination therapy compared with lenalidomide monotherapy [39.5% (28.4-51.4) vs. 13.2% (6.5-22.9)]. Survival endpoints favored combination therapy. Lenalidomide monotherapy outcomes were similar to previously published data., Conclusions: RE-MIND enabled the estimation of the additional treatment effect achieved by combining tafasitamab with lenalidomide in patients with R/R DLBCL., (©2021 The Authors; Published by the American Association for Cancer Research.)

Chimeric antigen receptor (CAR) T-cell therapy targeting CD19 may be associated with long-term adverse effects such as cytopenia and immune deficiency. In order to characterize these late events, we analyzed 31 patients with relapsed or refractory large B-cell lymphoma treated with axicabtagene ciloleucel at our institution on two clinical trials, ZUMA-1 (clinicaltrials gov. Identifier: NCT02348216) and ZUMA-9 (clinicaltrials gov. Identifier: NCT03153462). Complete blood counts, lymphocyte subsets, and immunoglobulin levels were measured serially until month 24 or progression. Fifteen (48%) patients had grade 3-4 cytopenia, including anemia (five, 16%), neutropenia (nine, 29%), or thrombocytopenia (13, 42%) at day 30. Cytopenia at day 30 was not significantly associated with later diagnosis of myelodysplasia. Among patients with ongoing remission, grade 3-4 cytopenia was observed in one of nine (11%) at 2 years. While peripheral CD8+ T cells recovered early, CD4+ T-cell recovery was delayed with a count of <200/mL in three of nine (33%) patients at 1 year and two of seven (29%) at 2 years. Immunoglobulin G levels normalized in five of nine (56%) patients at 2 years. Thirteen (42%) patients developed grade 3-4 infectious complications, including herpes zoster and Pneumocystis jiroveci pneumonia. These results suggest the need for prolonged monitoring and prophylaxis against opportunistic infections in these patients, to improve the longterm safety of axicabtagene ciloleucel therapy.

Purpose: Phosphatidylinositol-3-kinase (PI3K) inhibitors have shown activity in relapsed or refractory (R/R) indolent non-Hodgkin lymphoma (iNHL). PI3K inhibitors have been hampered by poor long-term tolerability and toxicity, which interfere with continuous use. Umbralisib, a dual inhibitor of PI3Kδ/casein kinase-1ε, exhibits improved selectivity for PI3Kδ compared with other PI3K inhibitors. This phase IIb trial was designed to evaluate the efficacy and safety of umbralisib in patients with R/R iNHL., Patients and Methods: In this multicohort, open-label, phase IIb study, 208 patients with R/R marginal zone, follicular, or small lymphocytic lymphoma (MZL, FL, or SLL) unresponsive to prior treatments (≥ 1 MZL; ≥ 2 FL/SLL), including ≥ 1 anti-CD20-based therapy, were administered umbralisib 800 mg orally once daily until disease progression, unacceptable toxicity, or study withdrawal. Primary end point is overall response rate; secondary end points include time to response, duration of response, progression-free survival, and safety., Results: The median follow-up is 27.7 months (efficacy) and 21.4 months (safety). The overall response rate was 47.1%, and tumor reduction occurred in 86.4% of patients. The median time to response was 2.7-4.6 months. The median duration of response was not reached for MZL, 11.1 months for FL, and 18.3 months for SLL. Median progression-free survival was not reached for MZL, 10.6 months for FL, and 20.9 months for SLL. At least one grade ≥ 3 treatment-emergent adverse event (TEAE) was reported in 53.4% of patients. TEAEs led to umbralisib discontinuation in 32 patients (15.4%). A total of 31 patients (14.9%) discontinued because of a treatment-related adverse event. Grade ≥ 3 TEAEs reported in ≥ 10% of patients: neutropenia (11.5%) and diarrhea (10.1%). Increased ALT/AST (grade ≥ 3) occurred in 6.7%/7.2% of patients., Conclusion: Umbralisib achieved meaningful clinical activity in heavily pretreated patients with iNHL. The safety profile was manageable, with a relatively low incidence of immune-mediated toxicities and adverse event-related discontinuations., Competing Interests: Nathan H. FowlerEmployment: BostongeneConsulting or Advisory Role: Roche/Genentech, TG Therapeutics, Verastem, Bayer, Celgene, NovartisResearch Funding: Roche, Celgene, Gilead Sciences, TG Therapeutics, Novartis, AbbVie, BeiGene Felipe SamaniegoConsulting or Advisory Role: Astex Pharmaceuticals, ADC Therapeutics, Imbrium Therapeutics Wojciech JurczakResearch Funding: TG Therapeutics Nilanjan GhoshConsulting or Advisory Role: Seattle Genetics, TG Therapeutics, AstraZeneca, Verastem, Pharmacyclics/Janssen, Karyopharm Therapeutics, Genmab, Bristol-Myers Squibb, Gilead Sciences, Adaptive Biotechnologies, Beigene, AbbVie, IncyteSpeakers' Bureau: AbbVie, Janssen Oncology, Kite/Gilead Sciences, Seattle Genetics, AstraZeneca, Bristol-Myers Squibb, Celgene, Pharmacyclics/Janssen, EpizymeResearch Funding: Pharmacyclics, TG Therapeutics, Genentech/Roche, Seattle Genetics, Bristol-Myers Squibb/Celgene, Gilead Sciences Enrico DerenziniConsulting or Advisory Role: AstraZenecaResearch Funding: TG-Therapeutics, ADC Therapeutics James A. ReevesResearch Funding: Sarah Cannon Research Institute, Eli Lilly, Tesaro, TG Therapeutics, Genentech, Celgene, Merck, Bristol-Myers Squibb, Boston Biomedical Inc, AstraZeneca, NovoCure, Calithera Biosciences, Novartis, Guardant Health, Acerta Pharma, Rhizen Pharmaceuticals, Takeda, Onconova Therapeutics, Sanofi, CTI Biopharma, Eisai, Janssen Chan Y. CheahHonoraria: Roche/Genentech, Janssen-Cilag, TG Therapeutics, Loxo/Lilly, AstraZeneca, Bristol-Myers Squibb, Gilead Sciences, Ascentage Pharma, MDSConsulting or Advisory Role: Janssen-Cilag, Roche/Genentech, TG Therapeutics, Loxo/Lilly, Gilead Sciences, AstraZeneca, Bristol-Myers Squibb, Ascentage Pharma, MDSSpeakers' Bureau: Janssen-CilagResearch Funding: Roche, Celgene, AbbVieTravel, Accommodations, Expenses: Roche Tycel PhillipsHonoraria: Seattle Genetics, Incyte, Pharmacyclics, Bayer, Gilead Sciences, GenentechConsulting or Advisory Role: Seattle Genetics, Pharmacyclics, Incyte, Genentech, Bayer, Gilead Sciences, Curis, Kite/Gilead, Celgene, GenmabResearch Funding: AbbVie, Pharmacyclics/Janssen, Bayer Ewa Lech-MarandaConsulting or Advisory Role: Roche, Amgen, AbbVie, Astellas Pharma, Novartis, Janssen-Cilag, Sanofi/Aventis, Takeda, Gilead Sciences Bruce D. ChesonConsulting or Advisory Role: TG Therapeutics, AbbVie, Pharmacyclics/Janssen, Morphosys, Celgene, Karyopharm Therapeutics, Epizyme, Gilead Sciences, SymBio Pharmaceuticals, Parexel, Merck, Glaxo Smith Kline, Beigene, Kite, Reddy Biosimilar, Bayer, CelgeneResearch Funding: TG Therapeutics, Trillium Therapeutics, Seattle Genetics, Bristol-Myers Squibb, Gilead Sciences, Pharmacyclics, AbbVie, AstraZenecaTravel, Accommodations, Expenses: SymBio Pharmaceuticals Paolo F. CaimiConsulting or Advisory Role: Genentech, Seattle Genetics, TG Therapeutics, Kite Pharma, ADC Therapeutics, Bayer, Amgen, Verastem, EpizymeSpeakers' Bureau: CelgeneResearch Funding: Genentech, ADC Therapeutics Lori A. LeslieConsulting or Advisory Role: Kite/Gilead, TG Therapeutics, Celgene/BMS, Seattle Genetics, AbbVie, PCYC/Janssen, ADC Therapeutics, BeiGene, AstraZenecaSpeakers' Bureau: Kite Pharma, Celgene/BMS, Seattle Genetics, AbbVie, PCYC/Janssen, ADC Therapeutics, BeiGene, AstraZeneca, Epizyme, Karyopharm Julio C. ChavezConsulting or Advisory Role: Kite/Gilead, Novartis, Karyopharm Therapeutics, MorphoSys, TeneoBio, AbbVie, JanssenSpeakers' Bureau: AstraZeneca, BeiGene, MorphoSys, EpizymeResearch Funding: Merck Gustavo FonsecaHonoraria: Amgen, CelgeneConsulting or Advisory Role: Amgen, Celgene, Bayer, Abvie/Pharmacyclics, Dava Oncology, KaryopharmSpeakers' Bureau: Amgen, CelgeneResearch Funding: Celgene, Amgen, TG Therapeutics, Verastem OncologyTravel, Accommodations, Expenses: Amgen, Celgene Sunil BabuStock and Other Ownership Interests: Fort Wayne Medical Oncology & Hematology, Lutheran HospitalHonoraria: Bristol-Myers Squibb, Alexion Pharmaceuticals, Lilly, Bayer, AstraZenecaConsulting or Advisory Role: Bristol-Myers Squibb, Alexion Pharmaceuticals, AstraZeneca, argenx, Boehringer Ingelheim, Bayer, Kite Pharma, Janssen OncologySpeakers' Bureau: Alexion PharmaceuticalsResearch Funding: Bristol-Myers Squibb, Novartis, Genentech/Roche, AstraZeneca/MedImmune, Janssen Oncology, Amgen, TG Therapeutics, AbbVie, Lilly, Alexion Pharmaceuticals, Merck, Novartis, Syndax, Nektar, Sanofi, argenxTravel, Accommodations, Expenses: Bristol-Myers Squibb, Alexion Pharmaceuticals, Lilly, Janssen Oncology, Genentech/Roche Daniel J. HodsonResearch Funding: Gilead Sciences John M. BurkeConsulting or Advisory Role: Genentech/Roche, AbbVie, Seattle Genetics, Bayer, AstraZeneca, Adaptive Biotechnologies, Verastem, MorphoSys, Kura Oncology, Epizyme, BeiGene, Kymera, NovartisSpeakers' Bureau: Seattle Genetics, Beigene Jeff P. SharmanLeadership: US OncologyConsulting or Advisory Role: Pharmacyclics, Celgene, TG Therapeutics, Genentech, AbbVie, Acerta Pharma/AstraZeneca, Beigene, PfizerResearch Funding: Pharmacyclics, Genentech, Celgene, Acerta Pharma, Gilead Sciences, Seattle Genetics, TG Therapeutics, Merck, Takeda John M. PagelConsulting or Advisory Role: Gilead Sciences, AstraZeneca, Actinium Pharmaceuticals, BeiGene, Loxo Hari P. MiskinEmployment: TG TherapeuticsLeadership: TG TherapeuticsStock and Other Ownership Interests: TG TherapeuticsTravel, Accommodations, Expenses: TG Therapeutics Peter SportelliEmployment: TG TherapeuticsLeadership: TG TherapeuticsStock and Other Ownership Interests: TG TherapeuticsTravel, Accommodations, Expenses: TG Therapeutics Owen A. O'ConnorEmployment: TG TherapeuticsLeadership: TG TherapeuticsBoard Appointments, Stock, and Other Ownership Interests: TG Therapeutics, Kymera, Myeloid Therapeutics, NomoCan PharmaceuticalsHonoraria: MundipharmaConsulting or Advisory Role: Mundipharma Research, Astex PharmaceuticalsResearch Funding: Merck, Celgene/Bristol-Myers Squibb, Seagen, Mundipharma, Astex Pharmaceuticals, ADC Therapeutics Michael S. WeissEmployment: TG TherapeuticsLeadership: TG TherapeuticsStock and Other Ownership Interests: TG TherapeuticsTravel, Accommodations, Expenses: TG Therapeutics Pier Luigi ZinzaniConsulting or Advisory Role: Sanofi, Verastem, Celltrion, Gilead Sciences, Janssen-Cilag, Bristol-Myers Squibb, SERVIER, Sandoz, MSD, Immune Design, Celgene, Portola Pharmaceuticals, Roche, EUSA Pharma, Kyowa Hakko Kirin, TG Therapeutics, TakedaSpeakers' Bureau: Verastem, Celltrion, Gilead Sciences, Janssen-Cilag, Bristol-Myers Squibb, SERVIER, Sandoz, MSD, Immune Design, Celgene, Portola Pharmaceuticals, Roche, EUSA Pharma, Kyowa Hakko KirinNo other potential conflicts of interest were reported.

Background: Few studies have estimated the real-world economic burden such as all-cause and follicular lymphoma (FL)-related costs and health care resource utilization (HCRU) in patients with FL., Objectives: This study evaluated outcomes in patients who were newly initiated with FL indicated regimens by line of therapy with real-world data., Methods: A retrospective study was conducted among patients with FL from MarketScan ® databases between January 1, 2010 and December 31, 2013. Patients were selected if they were ≥18 years old when initiated on a FL indicated therapy, had at least 1 FL-related diagnosis, ≥1 FL commonly prescribed systemic anti-cancer therapy after diagnosis, and did not use any FL indicated regimen in the 24 months prior to the first agent. These patients were followed up at least 48 months and the outcomes, including the distribution of regimens by line of therapy, the treatment duration by line of therapy, all-cause and FL-related costs, and HCRU by line of therapy were evaluated., Results: This study identified 598 patients who initiated FL indicated treatment. The average follow-up time was approximately 5.7 years. Of these patients, 50.2% (n=300) were female, with a mean age of 60.7 years (SD=13.1 years) when initiating their treatment with FL indicated regimens. Overall, 598 (100%) patients received first-line therapy, 180 (43.6%) received second-line therapy, 51 received third-line therapy, 21 received fourth-line therapy, and 10 received fifth-line therapy. Duration of treatment by each line of therapy was 370 days, 392 days, 162 days, 148 days, and 88 days, respectively. The most common first-line regimens received by patients were rituximab (n=201, 33.6%), R-CHOP (combination of rituximab, cyclophosphamide, doxorubicin hydrochloride [hydroxydaunomycin]; n=143, 24.0%), BR (combination of bendamustine and rituximab; n=143, 24.0%), and R-CVP (combination of rituximab, cyclophosphamide, vincristine, and prednisone; n=71, 11.9%). The most common second-line treatment regimens were (N=180): rituximab (n=78, 43.3%) and BR (n=41, 22.8%). Annualized all-cause health care costs per patient ranged from US$97 141 (SD: US$144 730) for first-line to US$424 758 (SD: US$715 028) for fifth-line therapy., Conclusions: The primary regimens used across treatment lines conform to those recommended by the National Comprehensive Cancer Network clinical practice guidelines. The economic burden for patients with FL is high and grows with subsequent lines of therapy.

Neurotoxicity or immune effector cell-associated neurotoxicity syndrome (ICANS) is the second most common acute toxicity after chimeric antigen receptor (CAR) T-cell therapy. However, there are limited data on the clinical and radiologic correlates of ICANS. We conducted a cohort analysis of 100 consecutive patients with relapsed or refractory large B-cell lymphoma (LBCL) treated with standard of care axicabtagene ciloleucel (axi-cel). ICANS was graded according to an objective grading system. Neuroimaging studies and electroencephalograms (EEGs) were reviewed by an expert neuroradiologist and neurologist. Of 100 patients included in the study, 68 (68%) developed ICANS of any grade and 41 (41%) had grade ≥3. Median time to ICANS onset was 5 days, and median duration was 6 days. ICANS grade ≥3 was associated with high peak ferritin (P = .03) and C-reactive protein (P = .001) levels and a low peak monocyte count (P = .001) within the 30 days after axi-cel infusion. Magnetic resonance imaging was performed in 38 patients with ICANS and revealed 4 imaging patterns with features of encephalitis (n = 7), stroke (n = 3), leptomeningeal disease (n = 2), and posterior reversible encephalopathy syndrome (n = 2). Abnormalities noted on EEG included diffuse slowing (n = 49), epileptiform discharges (n = 6), and nonconvulsive status epilepticus (n = 8). Although reversible, grade ≥3 ICANS was associated with significantly shorter progression-free (P = .02) and overall survival (progression being the most common cause of death; P = .001). Our results suggest that imaging and EEG abnormalities are common in patients with ICANS, and high-grade ICANS is associated with worse outcome after CAR T-cell therapy in LBCL patients., (© 2020 by The American Society of Hematology.)

The impact of pre-treatment maximum standardized uptake value (SUV max ) on the outcome of follicular lymphoma (FL) following specific frontline regimens has not been explored. We performed a retrospective analysis of 346 patients with advanced stage follicular lymphoma (FL) without histological evidence of transformation, and analyzed the impact of SUV max on outcome after frontline therapy. Fifty-two (15%) patients had a SUV max >18, and a large lymph node ≥6 cm was the only factor associating with SUV max >18 on multivariate analysis (odds ratio 2.7, 95% confidence interval [CI]: 1.3-5.3, P =0.006). The complete response rate was significantly lower among patients treated with non-anthracycline-based regimens if SUV max was >18 (45% vs 92%, P <0.001), but not among patients treated with R-CHOP ( P =1). SUV max >18 was associated with significantly shorter progression-free survival among patients treated with non-anthracycline-based regimens (77 months vs. not reached, P =0.02), but not among patients treated with R-CHOP ( P =0.73). SUV max >18 associated with shorter overall survival (OS) both in patients treated with R-CHOP (8-year OS 70% vs. 90%, P =0.02) and non-anthracycline-based frontline regimens (8-year OS 50% vs 85%, P =0.001). In conclusion, pre-treatment PET scan has prognostic and predictive value in patients with advanced stage FL receiving frontline treatment., (Copyright© 2020 Ferrata Storti Foundation.)

In 2 randomized phase 3 trials BR resulted in longer progression-free survival (PFS) than frontline R-CHOP in patients with indolent and mantle cell lymphoma. However, in subset analyses of follicular lymphoma (FL), the results were incongruent. We conducted a retrospective matched-pair analysis to compare the outcome of patients with advanced stage FL, receiving frontline BR ( N  = 73) or R-CHOP ( N  = 73), matched by age, gender, stage, and FL International Prognostic Index score. On multivariable analysis, baseline maximum standardized uptake value (SUV max ) >13 was associated with use of R-CHOP ( p  = .001). After a median follow-up of 69 months for the BR arm and 126 months for the R-CHOP arm, 5-year PFS was 80% and 70%, respectively ( p  = .07). After adjusting for SUV max >13, the trend for better PFS in BR was not maintained. Prospective studies are needed to validate the role of pretreatment SUV max as a stratification factor in future randomized therapeutic trials in FL.

Lack of consensus for first-line marginal zone lymphoma (MZL) treatment and toxicities associated with currently available systemic therapies have inspired evaluation of immunotherapeutic agents yielding robust outcomes with improved tolerability. We previously reported durable efficacy with first-line lenalidomide and rituximab (R 2 ) in follicular lymphoma, MZL and small lymphocytic lymphoma with a subsequent long-term follow-up shown here in MZL patients. This phase 2 investigator-initiated study included previously untreated, stage III/IV MZL patients treated with lenalidomide 20 mg/day on days 1-21 and rituximab 375 mg/m 2 on day 1 of each 28-day cycle, continuing in responders for ≥6-12 cycles. The primary endpoint was overall response rate (ORR); secondary endpoints were complete and partial response (CR, PR), safety, and progression-free survival (PFS). The ORR was 93% with 70% attaining CR/CR unconfirmed. At median follow-up of 75·1 months, median PFS was 59·8 months and 5-year OS was 96%. Most non-haematological adverse events (AE) were grade 1/2. Grade 3 haematological AEs were neutropenia (33%) and leucopenia (7%), and grade 4 were leucopenia (3%) and thrombocytopenia (3%). Two patients died of secondary malignancies; no treatment-related fatalities occurred. With extended follow-up, outcomes for MZL patients receiving R 2 were robust with no unexpected late or delayed toxicities., (© 2019 British Society for Haematology and John Wiley & Sons Ltd.)

Purpose: Patients with indolent non-Hodgkin lymphoma typically respond well to first-line immunochemotherapy. At relapse, single-agent rituximab is commonly administered. Data suggest the immunomodulatory agent lenalidomide could increase the activity of rituximab., Methods: A phase III, multicenter, randomized trial of lenalidomide plus rituximab versus placebo plus rituximab was conducted in patients with relapsed and/or refractory follicular or marginal zone lymphoma. Patients received lenalidomide or placebo for 12 cycles plus rituximab once per week for 4 weeks in cycle 1 and day 1 of cycles 2 through 5. The primary end point was progression-free survival per independent radiology review., Results: A total of 358 patients were randomly assigned to lenalidomide plus rituximab (n = 178) or placebo plus rituximab (n = 180). Infections (63% v 49%), neutropenia (58% v 23%), and cutaneous reactions (32% v 12%) were more common with lenalidomide plus rituximab. Grade 3 or 4 neutropenia (50% v 13%) and leukopenia (7% v 2%) were higher with lenalidomide plus rituximab; no other grade 3 or 4 adverse event differed by 5% or more between groups. Progression-free survival was significantly improved for lenalidomide plus rituximab versus placebo plus rituximab, with a hazard ratio of 0.46 (95% CI, 0.34 to 0.62; P < .001) and median duration of 39.4 months (95% CI, 22.9 months to not reached) versus 14.1 months (95% CI, 11.4 to 16.7 months), respectively., Conclusion: Lenalidomide improved efficacy of rituximab in patients with recurrent indolent lymphoma, with an acceptable safety profile.

Background: Therapeutic approaches for B-cell malignancies continue to evolve, especially with regard to combination approaches. We assessed the safety and efficacy of the triplet ublituximab, umbralisib, and ibrutinib in patients with advanced B-cell malignancies., Methods: We did an open-label, phase 1 study with dose-escalation and dose-expansion phases, at five centres in the USA. Eligible patients were aged 18 years or older with histologically confirmed lymphocytic leukaemia or relapsed or refractory B-cell non-Hodgkin lymphoma, had measurable disease, adequate organ function, and an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less. Patients with known CNS lymphoma, active hepatitis B or C infection, or HIV were excluded. In the dose-escalation cohort, patients were treated in cycles of 28 days with escalating doses of oral umbralisib (400, 600, or 800 mg) and fixed doses of intravenous ublituximab (900 mg) and oral ibrutinib (420 mg for patients with chronic lymphocytic leukaemia; 560 mg for patients with B-cell non-Hodgkin lymphoma) in a standard 3 × 3 design until disease progression or intolerance. In the dose-expansion phase, patients were given the recommended dose of the drug combination as determined from the dose-escalation phase. The primary endpoints were safety, dose-limiting toxicities, and the maximum tolerated dose of umbralisib, when given in combination with ublituximab and ibrutinib. Safety was assessed in patients who received at least one dose of study drug; activity was assessed in all patients who had at least one post-treatment efficacy measurement. The study is ongoing but no longer recruiting patients. This trial is registered with ClinicalTrials.gov, number NCT02006485., Findings: Between Sept 2, 2014, and Nov 6, 2017, we enrolled 46 patients: 24 in the dose-escalation cohort (n=14 chronic lymphocytic leukaemia or small lymphocytic lymphoma; n=10 B-cell non-Hodgkin lymphoma) and 22 in the dose-expansion cohort (n=9 chronic lymphocytic leukaemia or small lymphocytic lymphoma; n=13 B-cell non-Hodgkin lymphoma). 46 patients received at least one dose of study drug. The maximum tolerated dose of umbralisib was not reached. The recommended dose for the dose-expansion phase was umbralisib 800 mg orally once daily plus ibrutinib orally once daily and intravenous ublituximab 900 mg administered on days 1, 8, and 15 of cycle 1, day 1 of cycles 2-6, and on day 1 of cycles 9 and 12. 37 (84%) of 44 patients achieved an overall response (complete or partial response). The most common any-grade adverse events were diarrhoea (n=27 [59%]), fatigue (n=23 [50%]), infusion-related reaction (n=20 [43%]), dizziness (n=17 [37%]), nausea (n=17 [37%]), and cough (n=16 [35%]). Grade 3-4 adverse events were manageable with the most common being neutropenia (n=10 [22%]) and cellulitis (n=6 [13%]). Serious adverse events occurred in 11 (24%) of 46 patients and included rash (n=2 [4%]), pneumonia (n=2 [4%]), atrial fibrillation (n=2 [4%]), sepsis (n=2 [4%]), abdominal pain (n=1 [2%]), syncope (n=1 [2%]), cellulitis (n=1 [2%]), pneumonitis (n=1 [2%]), headache (n=1 [2%]), lung infection (n=1 [2%]), skin infection (n=1 [2%]), pleural effusion (n=1 [2%]), pericardial infusion (n=1 [2%]), upper gastrointestinal bleeding (n=1 [2%]), diarrhoea (n=1 [2%]), and weakness (n=1 [2%]). No deaths related to adverse events occurred., Interpretation: The combination of ublituximab, umbralisib, and ibrutinib seems to be tolerable and is associated with encouraging activity in advanced chronic lymphocytic leukaemia and B-cell non-Hodgkin lymphoma. This triplet combination will require further investigation in future studies to improve understanding of this novel, chemotherapy-free triplet combination in the management of these cancers., Funding: TG Therapeutics., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Rituximab plus chemotherapy has been shown to be effective in patients with advanced-stage, previously untreated follicular lymphoma; nevertheless, most patients will have a relapse. Combination immunotherapy with lenalidomide and rituximab is an immunomodulatory regimen that has shown promising activity in patients with indolent B-cell non-Hodgkin's lymphoma., Methods: We conducted this multicenter, international, phase 3 superiority trial to evaluate rituximab plus lenalidomide, as compared with rituximab plus chemotherapy, in patients with previously untreated follicular lymphoma. Patients were randomly assigned to receive one of the two regimens, followed by maintenance monotherapy with rituximab. Treatment with rituximab plus lenalidomide consisted of 18 cycles of the two drugs, followed by rituximab maintenance therapy every 8 weeks for 12 cycles (six additional doses). Treatment with rituximab plus chemotherapy consisted of the investigator's choice of one of three rituximab-based regimens, followed by maintenance monotherapy with rituximab every 8 weeks for 12 cycles. The primary end points were complete response (confirmed or unconfirmed) at 120 weeks and progression-free survival., Results: A total of 1030 patients were randomly assigned to receive rituximab plus lenalidomide (513 patients) or rituximab plus chemotherapy (517 patients). The rate of confirmed or unconfirmed complete response at 120 weeks was similar in the two groups: 48% (95% confidence interval [CI], 44 to 53) in the rituximab-lenalidomide group and 53% (95% CI, 49 to 57) in the rituximab-chemotherapy group (P=0.13). The interim 3-year rate of progression-free survival was 77% (95% CI, 72 to 80) and 78% (95% CI, 74 to 82), respectively. A higher percentage of patients in the rituximab-chemotherapy group had grade 3 or 4 neutropenia (32% vs. 50%) and febrile neutropenia of any grade (2% vs. 7%), and a higher percentage of patients in the rituximab-lenalidomide group had grade 3 or 4 cutaneous reactions (7% vs. 1%)., Conclusions: Among patients with previously untreated follicular lymphoma, efficacy results were similar with rituximab plus lenalidomide and rituximab plus chemotherapy (with both regimens followed by rituximab maintenance therapy). The safety profile differed in the two groups. (Funded by Celgene; RELEVANCE ClinicalTrials.gov numbers, NCT01476787 and NCT01650701 , and EudraCT number, 2011-002792-42 .).

Follicular lymphoma is one of the most common non-Hodgkin's lymphomas. Although current frontline regimens are associated with high response rates, most patients still relapse. When progression is discovered, re-establishing the diagnosis and ruling out transformation in paramount. The outcomes following relapse have been improving due to the activity and increasing availability of novel agents with various mechanisms of action. Despite these advances, single agent activity is limited and the disease remains incurable in the majority of cases. Examples of drug classes with promising activity in relapsed disease include anti-CD20 monoclonal antibodies, immunomodulatory drugs (IMiDs), small molecule tyrosine kinase inhibitors, bcl2 inhibitors, epigenetic modifiers, conjugated antibodies, and checkpoint inhibitors. Many drugs in each class are associated with unique, variable and often surprising toxicity profiles. Combination studies are currently underway with novel-novel combinations and with traditional chemotherapy regimens. This overview will discuss the results of several recent studies exploring activity of novel drugs in relapsed follicular lymphoma., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Purpose: The aim of this study was to determine rates of positive findings on positron emission tomography (PET) and bone marrow biopsy performed during staging workup for ocular adnexal lymphoma (OAL)., Methods: A retrospective review of OAL patients was conducted. Demographics, primary versus secondary OAL, histologic subtype, and findings on PET and bone marrow biopsy performed as part of the initial staging workup for OAL were recorded., Results: The study included 119 patients with OAL. There were 85 primary and 34 secondary OALs. The main histologic subtypes of lymphoma were mucosa-associated lymphoid tissue (n = 61), follicular (n = 26), diffuse large B-cell (n = 17), and mantle cell (n = 10). Positive PET findings were seen in 42 of 68 patients (62%) with primary OAL and 19 of 24 (79%) with secondary OAL. Positive PET findings were seen in 24 of 47 patients (51%) with mucosa-associated lymphoid tissue, 13 of 17 (76%) with follicular, 14 of 15 (93%) with diffuse large B-cell, and 9 of 10 (90%) with mantle cell lymphoma. Positive findings on bone marrow biopsy were seen in 7 of 59 patients (12%) with mucosa-associated lymphoid tissue, 4 of 23 (17%) with follicular, 1 of 17 (6%) with diffuse large B-cell, and 2 of 9 (22%) with mantle cell lymphoma., Conclusions: Our findings suggest that a significant proportion of patients with primary and secondary OAL have positive findings on PET and bone marrow biopsy at initial diagnosis, suggesting a reasonable yield for these tests as part of the initial staging workup in patients with a new diagnosis of OAL.

Inhibition of the phosphatidylinositol-3-kinase (PI3K) pathway as an anticancer therapeutic strategy was realized with the approval of the orally bioavailable small molecule PI3Kδ inhibitor idelalisib. In this focused review, we highlight the rationale for targeting the pathway in lymphomas, provide a brief summary of the preclinical data, and describe the clinical experience with this agent in patients with lymphoma. We describe some of the idiosyncratic toxicities of this agent, some of the mechanisms of resistance, and some of the ongoing combination strategies., (© 2016 by The American Society of Hematology.)

The tumor microenvironment is the cellular and molecular environment in which the tumor exists and with which it continuously interacts. In B-cell lymphomas, this microenvironment is intriguing in that it plays critical roles in the regulation of tumor cell survival and proliferation, fostering immune escape as well as the development of treatment resistance. The purpose of this review is to summarize the proceedings of the Second Annual Summit on the Immune Microenvironment in Hematologic Malignancies that took place on September 11-12, 2014 in Dublin, Ireland. We provide a timely overview of the composition and biological relevance of the cellular and molecular microenvironment interface and discuss the role of interactions between the microenvironment and neoplastic cells in a variety of B-cell lymphomas. In addition, we focus on various novel therapeutic strategies that target the tumor microenvironment, including agents that modulate B-cell receptor pathways and immune-checkpoints, chimeric antigen receptor T cells and immunomodulatory agents., (Copyright© Ferrata Storti Foundation.)

Background: Primary intraocular lymphoma is a rare variant of primary CNS lymphoma for which the optimum treatment strategy remains unknown., Methods: We performed a retrospective single-center study including patients who underwent uniform management from October 2007 in which patients were offered sequential rituximab, methotrexate, procarbazine, and vincristine (R-MPV) followed by binocular radiotherapy and consolidative high-dose cytarabine., Results: Eleven patients with median age 66 years (range, 48-72) were included. All patients received binocular radiotherapy to a median dose of 36 Gy (range, 30.6-39.6) in 20 fractions. Grade 3+ anemia, thrombocytopenia, and neutropenia occurred in 1 (9%), 2 (18%), and 3 (27%) patients, respectively; raised creatinine and peripheral sensory neuropathy occurred in 4 (36%) and 3 (27%) patients, respectively. Grade 3+ ocular toxicities included cataract formation and keratitis in 6 (54%) and 3 (27%) patients, respectively. Ten patients (91%) achieved complete response and 1 (9%) partial response. After median follow-up of 4.2 years (range, 1.8-7.6), the median progression-free survival was 3.8 years and the estimated 4-year overall survival was 75.8% (95% CI: 30.5%-93.7%). The initial site of disease progression was the CNS in 4 of 7 patients (57%) and within the eye in 3 of 7 (43%). Five patients achieved responses to salvage therapies., Conclusions: Combined modality treatment with R-MPV, binocular radiation, and high-dose cytarabine is effective with moderate toxicity. Both local and CNS relapses occur; however, the achievement of second and subsequent remissions is possible., (© The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Standard treatments for indolent non-Hodgkin lymphomas are often toxic, and most patients ultimately relapse. Lenalidomide, an immunomodulatory agent, is effective as monotherapy for relapsed indolent non-Hodgkin lymphoma. We assessed the efficacy and safety of lenalidomide plus rituximab in patients with untreated, advanced stage indolent non-Hodgkin lymphoma., Methods: In this phase 2 trial, undertaken at one instution, patients with follicular lymphoma and marginal zone lymphoma were given lenalidomide, orally, at 20 mg/day on days 1-21 of each 28-day cycle. For patients with small lymphocytic lymphoma, dosing began at 10 mg/day to avoid tumour flare, with an escalation of 5 mg/month to 20 mg/day. Rituximab was given at 375 mg/m(2) as an intravenous infusion on day 1 of each cycle. Patients responding after six cycles could continue therapy for up to 12 cycles. The primary endpoint was overall response, defined as the proportion of patients who achieved a partial or complete response; patients were assessed for response if they had any post-baseline tumour assessment. This trial is registered with ClinicalTrials.gov, number NCT00695786., Findings: 110 patients with follicular lymphoma (n=50), marginal zone lymphoma (n=30), and small lymphocytic lymphoma (n=30) were enrolled from June 30, 2008, until Aug 12, 2011. 93 of 103 evaluable patients had an overall response (90%, 95% CI 83-95). Complete responses occurred in 65 (63%, 95% CI 53-72) and partial responses in 28 patients (27%, 19-37). Of 46 evaluable patients with follicular lymphoma, 40 (87%) patients had a complete response and five (11%) had a partial response. Of 27 evaluable patients with marginal zone lymphoma, 18 (67%) had a complete response and six (22%) had a partial response. Of 30 evaluable patients with small lymphocytic lymphoma, seven (23%) had a complete response and 17 (57%) had a partial response. The most common grade 3 or 4 adverse events were neutropenia (38 [35%] of 110 patients), muscle pain (ten [9%]), rash (eight [7%]), cough, dyspnoea, or other pulmonary symptoms (five [5%]), fatigue (five [5%]), thrombosis (five [5%]), and thrombocytopenia (four [4%])., Interpretation: Lenalidomide plus rituximab is well tolerated and highly active as initial treatment for indolent non-Hodgkin lymphoma. An international phase 3 study (NCT01476787) to compare this regimen with chemotherapy in patients with untreated follicular lymphoma is in progress., Funding: Celgene Corporation and Richard Spencer Lewis Memorial Foundation and Cancer Center Support Grant., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Mantle cell lymphoma is an uncommon lymphoma subtype that is currently considered incurable and lacks a single standard of care. Choice of treatment is complicated by the disease’s clinical heterogeneity. The course of the disease may be indolent, moderately aggressive, or aggressive. A translocation between chromosomes 11 and 14 is observed in the majority of mantle cell lymphoma patients, and the diseased cells may develop a variety of other genetic aberrations. Although the disease tends to respond well to treatment, patients almost invariably relapse, with many becoming chemotherapy refractory over time. The development of new treatment strategies has improved the prognosis for these patients. Novel approaches include intensive chemotherapy, often in combination with stem cell transplantation; maintenance therapy with extended duration; and new targeted treatments such as ibrutinib, bendamustine, bortezomib, lenalidomide, and idelalisib. Many of these new agents have shown promising activity, both as single agents and in combination regimens.

Mantle cell lymphoma is one of the most challenging hematologic malignancies, owing to an aggressive disease course, a high rate of relapse, and lack of standard of care. In the United States, mantle cell lymphoma accounts for approximately 6% of all newly diagnosed cases of non-Hodgkin lymphoma. Because most patients are initially diagnosed with advanced-stage disease, they are often symptomatic at presentation. Common features include widespread lymphadenopathy and splenomegaly, as well as bone marrow infiltration. Leukemic involvement is found in 20% to 30% of patients. The disease course can be highly variable. Some patients may have very aggressive disease, whereas others may have a much more indolent course. The optimal frontline therapy remains undefined. Strategies include chemotherapy, immunotherapy, radioimmunotherapy, stem cell transplantation, and novel biologic agents. Although mantle cell lymphoma often responds well to frontline chemotherapy, the responses are not durable and often of relatively short duration. Effective treatment options in the frontline setting have included the addition of rituximab to bendamustine. Once mantle cell lymphoma has entered the relapsed/refractory stage, it becomes more difficult to treat. Bortezomib and lenalidomide are approved for treatment of relapsed/refractory mantle cell lymphoma. The novel Bruton’s tyrosine kinase inhibitor ibrutinib appears to be highly active in relapsed/refractory mantle cell lymphoma. Other agents in clinical trials include cladribine, idelalisib, and IPI-145.

Although follicular lymphoma remains incurable, recent advances in first-line therapy have resulted in improved response rates and response duration. Maintenance therapy with rituximab (Rituxan) after induction treatment with rituximab alone or chemotherapy in combination with or without rituximab has resulted in further improvement in progression-free survival in both treatment-naive and previously treated patients. Efficacy results from the large phase 3, randomized Primary Rituximab and Maintenance (PRIMA) trial in the first-line setting have dem onstrated significant improvements in progression-free survival, in the rate of patients achieving complete remission, and in the proportion of patients remaining in complete remission using maintenance rituximab.The use of maintenance therapy is also under study in additional hematological malignancies, including diffuse large B-cell lymphoma and chronic lymphocytic leukemia. Clinical investigation is ongoing to address the optimal duration of maintenance therapy and the question of whether re-treatment upon disease progression is as beneficial as maintenance for follicular lymphoma.