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Long-term data of chronic lymphocytic leukemia (CLL) patients with favorable risk who were treated with fludarabine, cyclophosphamide, and rituximab (FCR) within clinical trials show good efficacy. We here report long-term data collected within the GCLLSG registry. Altogether, 417 CLL patients who received first-line treatment with FCR were analyzed, of which 293 (70.3%) were treated outside of clinical trials. The median observation time from first-line was 95.8 (interquartile range 58.7-126.8) months. Focusing on data of 194 (46.5%) patients who received FCR first-line treatment after 2013 (start of data collection within GCLLSG registry), responses were documented in 85% of the patients, non-responses in 15%, and for 3.6% the assessment was missing. Median event-free survival (EFS, time until disease progression, subsequent treatment, or death) was 60.2 months with a 5-year EFS-rate of 50.6%. Patients with higher-risk disease, characterized by unmutated IGHV (N = 78), had a median EFS of 45.4 months with a 5-year EFS rate of 36.3%, while the median EFS was 77.5 months with a 5-year EFS rate of 60.3% in patients with mutated IGHV (N = 40). Median overall survival was not reached with a 5-year survival rate of 92.7%. In summary, first-line FCR was associated with long EFS, especially in patients exhibiting a mutated IGHV status., (© 2024 The Authors. European Journal of Haematology published by John Wiley & Sons Ltd.)

Abstract: The phase 2 CLL2-BAAG trial tested the measurable residual disease (MRD)-guided triple combination of acalabrutinib, venetoclax, and obinutuzumab after optional bendamustine debulking in 45 patients with relapsed/refractory chronic lymphocytic leukemia (CLL). MRD was measured by flow cytometry (FCM; undetectable MRD <10-4) in peripheral blood (PB) and circulating tumor DNA (ctDNA) using digital droplet polymerase chain reaction of variable-diversity-joining (VDJ) rearrangements and CLL-related mutations in plasma. The median number of previous treatments was 1 (range, 1-4); 18 patients (40%) had received a Bruton tyrosine kinase inhibitor (BTKi) and/or venetoclax before inclusion, 14 of 44 (31.8%) had TP53 aberrations, and 34 (75.6%) had unmutated immunoglobulin heavy-chain variable region genes. With a median observation time of 36.3 months and all patients off-treatment for a median of 21.9 months, uMRD <10-4 in PB was achieved in 42 of the 45 patients (93.3%) at any time point, including 17 of 18 (94.4%) previously exposed to venetoclax/BTKi and 13 of 14 (92.9%) with TP53 aberrations. The estimated 3-year progression-free and overall survival rates were 85.0% and 93.8%, respectively. Overall, 585 paired FCM/ctDNA samples were analyzed and 18 MRD recurrences (5 with and 13 without clinical progression) occurred after the end of treatment. Twelve samples were first detected by ctDNA, 3 by FCM, and 3 synchronously. In conclusion, time-limited MRD-guided acalabrutinib, venetoclax, and obinutuzumab achieved deep remissions in almost all patients with relapsed/refractory CLL. The addition of ctDNA-based analyses to FCM MRD assessment seems to improve early detection of relapses. This trial was registered at www.clinicaltrials.gov as #NCT03787264., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Background: In the primary analysis report of the GAIA/CLL13 trial, we found that venetoclax-obinutuzumab and venetoclax-obinutuzumab-ibrutinib improved undetectable measurable residual disease (MRD) rates and progression-free survival compared with chemoimmunotherapy in patients with previously untreated chronic lymphocytic leukaemia. However, to our knowledge, no data on direct comparisons of different venetoclax-based combinations are available., Methods: GAIA/CLL13 is an open-label, randomised, phase 3 study conducted at 159 sites in ten countries in Europe and the Middle East. Eligible patients were aged 18 years or older, with a life expectancy of at least 6 months, an Eastern Cooperative Oncology group performance status of 0-2, a cumulative illness rating scale score of 6 or lower or a single score of 4 or lower, and no TP53 aberrations. Patients were randomly assigned (1:1:1:1), with a computer-generated list stratified by age, Binet stage, and regional study group, to either chemoimmunotherapy, venetoclax-rituximab, venetoclax-obinutuzumab, or venetoclax-obinutuzumab-ibrutinib. All treatments were administered in 28-day cycles. Patients in the chemoimmunotherapy group received six cycles of treatment, with patients older than 65 years receiving intravenous bendamustine (90 mg/m 2 , days 1-2), whereas patients aged 65 years or younger received intravenous fludarabine (25 mg/m 2 , days 1-3) and intravenous cyclophosphamide (250 mg/m 2 , days 1-3). Intravenous rituximab (375 mg/m 2 , day 1 of cycle 1; 500 mg/m 2 , day 1 of cycles 2-6) was added to chemotherapy. In the experimental groups, patients received daily venetoclax (400 mg orally) for ten cycles after a 5-week ramp-up phase starting on day 22 of cycle 1. In the venetoclax-rituximab group, intravenous rituximab (375 mg/m 2 , day 1 of cycle 1; 500 mg/m 2 , day 1 of cycles 2-6) was added. In the obinutuzumab-containing groups, obinutuzumab was added (cycle 1: 100 mg on day 1, 900 mg on day 2, and 1000 mg on days 8 and 15; cycles 2-6: 1000 mg on day 1). In the venetoclax-obinutuzumab-ibrutinib group, daily ibrutinib (420 mg orally, from day 1 of cycle 1) was added until undetectable MRD was reached in two consecutive measurements (3 months apart) or until cycle 36. The planned treatment duration was six cycles in the chemoimmunotherapy group, 12 cycles in the venetoclax-rituximab and the venetoclax-obinutuzumab group and between 12 and 36 cycles in the venetoclax-obinutuzumab-ibrutinib group. Coprimary endpoints were the undetectable MRD rate in peripheral blood at month 15 for the comparison of venetoclax-obinutuzumab versus standard chemoimmunotherapy and investigator-assessed progression-free survival for the comparison of venetoclax-obinutuzumab-ibrutinib versus standard chemoimmunotherapy, both analysed in the intention-to-treat population (ie, all patients randomly assigned to treatment) with a split α of 0·025 for each coprimary endpoint. Both coprimary endpoints have been reported elsewhere. Here we report a post-hoc exploratory analysis of updated progression-free survival results after a 4-year follow-up of our study population. Safety analyses included all patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT02950051, recruitment is complete, and all patients are off study treatment., Findings: Between Dec 13, 2016, and Oct 13, 2019, 1080 patients were screened and 926 were randomly assigned to treatment (chemoimmunotherapy group n=229; venetoclax-rituximab group n=237; venetoclax-obinutuzumab group n=229; and venetoclax-obinutuzumab-ibrutinib group n=231); mean age 60·8 years (SD 10·2), 259 (28%) of 926 patients were female, and 667 (72%) were male (data on race and ethnicity are not reported). At data cutoff for this exploratory follow-up analysis (Jan 31, 2023; median follow-up 50·7 months [IQR 44·6-57·9]), patients in the venetoclax-obinutuzumab group had significantly longer progression-free survival than those in the chemoimmunotherapy group (hazard ratio [HR] 0·47 [97·5% CI 0·32-0·69], p<0·0001) and the venetoclax-rituximab group (0·57 [0·38-0·84], p=0·0011). The venetoclax-obinutuzumab-ibrutinib group also had a significantly longer progression-free survival than the chemoimmunotherapy group (0·30 [0·19-0·47]; p<0·0001) and the venetoclax-rituximab group (0·38 [0·24-0·59]; p<0·0001). There was no difference in progression-free survival between the venetoclax-obinutuzumab-ibrutinib and venetoclax-obinutuzumab groups (0·63 [0·39-1·02]; p=0·031), and the proportional hazards assumption was not met for the comparison between the venetoclax-rituximab group versus the chemoimmunotherapy group (log-rank p=0·10). The estimated 4-year progression-free survival rate was 85·5% (97·5% CI 79·9-91·1; 37 [16%] events) in the venetoclax-obinutuzumab-ibrutinib group, 81·8% (75·8-87·8; 55 [24%] events) in the venetoclax-obinutuzumab group, 70·1% (63·0-77·3; 84 [35%] events) in the venetoclax-rituximab group, and 62·0% (54·4-69·7; 90 [39%] events) in the chemoimmunotherapy group. The most common grade 3 or worse treatment-related adverse event was neutropenia (114 [53%] of 216 patients in the chemoimmunotherapy group, 109 [46%] of 237 in the venetoclax-rituximab group, 127 [56%] of 228 in the venetoclax-obinutuzumab group, and 112 [48%] of 231 in the venetoclax-obinutuzumab-ibrutinib group). Deaths determined to be associated with study treatment by the investigator occurred in three (1%) patients in the chemoimmunotherapy group (n=1 due to each of sepsis, metastatic squamous cell carcinoma, and Richter's syndrome), none in the venetoclax-rituximab and venetoclax-obinutuzumab groups, and four (2%) in the venetoclax-obinutuzumab-ibrutinib group (n=1 due to each of acute myeloid leukaemia, fungal encephalitis, small-cell lung cancer, and toxic leukoencephalopathy)., Interpretation: With more than 4 years of follow-up, venetoclax-obinutuzumab and venetoclax-obinutuzumab-ibrutinib significantly extended progression-free survival compared with both chemoimmunotherapy and venetoclax-rituximab in previously untreated, fit patients with chronic lymphocytic leukaemia, thereby supporting their use and further evaluation in this patient group, while still considering the higher toxicities observed with the triple combination., Funding: AbbVie, Janssen, and F Hoffmann-La Roche., Competing Interests: Declaration of interests MF reports research funding from AbbVie, AstraZeneca, BeiGene, Janssen, and Roche, and honoraria from AbbVie. JvT reports honoraria from AbbVie, BeiGene, Amgen, AstraZeneca, Janssen, Lilly, and Roche; travel grants from AbbVie, AstraZeneca, BeiGene, Roche, Lilly, and Janssen; and has received consulting fees from and participated on advisory boards for AbbVe, BeiGene, Amgen, and AstraZeneca. MG has received honoraria for participation in symposia and advisory boards from AbbVie, Amgen, AstraZeneca, BeiGene, Bristol Myers Squibb (BMS)/Celgene, GSK, Novartis, Incyte, Janssen-Cilag, Jazz, Roche, Pfizer, Sanofi, and Servier; travel support from AbbVie, BeiGene, Pfizer, and Roche; all fees went to their institution. GJ has received honoraria from Astellas and AbbVie and participated on advisory boards for AbbVie and Servier. M-DL reports travel grants from AbbVie and Janssen. CdC-B reports consulting fees from Janssen, honoraria for lectures from Octapharma, support for attending meetings from AbbVie and Octapharma, and participation on advisory boards for Janssen, BeiGene, and AstraZeneca. CSchn reports speakers fees from AstraZeneca and AbbVie, travel support from AbbVie, and participation on an advisory board for Janssen. RB reports travel support from BeiGene, Janssen, and AbbVie, and honoraria for participation on an advisory board from AbbVie. TN reports honoraria for lectures or presentations and has participated at advisory boards from AbbVie, Roche, AstraZeneca, Gilead, BeiGene, and Janssen. CBP is the chairman of the Danish CLL group. HF reports research funding from Sanofi, Novartis, and Alexion and honoraria for lectures from Sanofi. NK reports research funding from AstraZeneca; honoraria from AbbVie, AstraZeneca, Kite/Gilead, BMS, and Lilly; and travel support from AbbVie, AstraZeneca, BeiGene, Lilly, and Janssen; and participation on advisory boards for AstraZeneca and Janssen. JD reports consulting fees, honoraria, and travel support from AbbVie and Janssen. SB reports honoraria from and participation on speakers bureaus for Roche, Janssen, AbbVie, AstraZeneca, and Sanofi; travel support from Janssen, BeiGene, and Roche; and research funding from Janssen and Miltenyi. FS reports speakers fees from AstraZeneca, travel support from Lilly, and research funding from AstraZeneca. A-MF reports research funding and honoraria from AstraZeneca and travel support from AbbVie. KF reports research grants from AbbVie and Roche, honoraria for advisory boards from AstraZeneca, and travel support from Roche. K-AK reports consulting fees, participation on speakers bureaus, and research funding from Roche, AbbVie, and Janssen. MR reports honoraria from Janssen, Roche, and AstraZeneca; consulting fees from Roche, Janssen, AstraZeneca, and AbbVie; research funding from AbbVie and Roche, and travel support from AstraZeneca. MBr reports research funding and consulting fees from Amgen; honoraria for speakers bureaus from Amgen, Becton Dickinson, Janssen, and Pfizer; travel support from Janssen; and participation on advisory boards for Incyte and Amgen. ET reports participation on advisory boards and honoraria from AbbVie, Janssen-Cilag, and BeiGene, AstraZeneca, and Roche; and travel support from AstraZeneca, AbbVie, BeiGene, Janssen. SS reports honoraria from AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, and Sunesis; research funding from AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, and Sunesis; travel support from AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, Sunesis; and speaker fees from AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, and Sunesis. MH reports consulting fees from Roche, Gilead, Janssen, BMS, AbbVie, and AstraZeneca and honoraria from Roche, Gilead, Janssen, BMS, AbbVie, and AstraZeneca. APK reports honoraria from AbbVie, AstraZeneca, BMS, Janssen, LAVA, and Roche/Genentech; travel grants from AbbVie and Janssen; research funding from AstraZeneca, Janssen, Roche/Genentech, AbbVie, and BMS. CUN reports research funding from Octapharma and AstraZeneca; consultancy and speaker fees from AbbVie, AstraZeneca, Janssen, Genmab, BeiGene, Octapharma, CSL Behring, Takeda, Lilly, and MSD; and participation on advisory boards for AstraZeneca, MSD, Genmab, and Janssen. BE reports consulting fees fromJanssen, AbbVie, Gilead, AstraZeneca, MSD, BeiGene, and Lilly; participation on speakers bureau for Roche, AbbVie, BeiGene, AstraZeneca, and MSD; honoraria from Roche, AbbVie, AstraZeneca, BeiGene, and MSD; research funding from Janssen, Gilead, Roche, AbbVie, BeiGene, and AstraZeneca; and travel support from BeiGene. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

The therapy of relapsed or refractory (r/r) mantle cell lymphoma (MCL) patients remains a major clinical challenge to date. We conducted a randomized, open-label, parallel-group phase-III trial hypothesizing superior efficacy of rituximab, high-dose cytarabine and dexamethasone with bortezomib (R-HAD + B) versus without (R-HAD) in r/r MCL ineligible for or relapsed after autologous stem cell transplant (ASCT). Primary endpoint was time to treatment failure (TTF), secondary endpoints included response rates, progression free survival, overall survival, and safety. In total, 128 of 175 planned patients were randomized to R-HAD + B (n = 64) or R-HAD (n = 64). Median TTF was 12 vs. 2.6 months (p = 0.045, MIPI-adjusted HR 0.69; 95%CI 0.47-1.02). Overall and complete response rates were 63 vs. 45% (p = 0.049) and 42 vs. 19% (p = 0.0062). A significant treatment effect was seen in the subgroup of patients >65 years (aHR 0.48, 0.29-0.79) and without previous ASCT (aHR 0.52, 0.28-0.96). Toxicity was mostly hematological and attributable to the chemotherapeutic backbone. Grade ≥3 leukocytopenia and lymphocytopenia were more common in R-HAD + B without differences in severe infections between both arms. Bortezomib in combination with chemotherapy can be effective in r/r MCL and should be evaluated further as a therapeutic option, especially if therapy with BTK inhibitors is not an option. Trial registration: NCT01449344., (© 2024. The Author(s).)

Background: Adding ibrutinib to standard immunochemotherapy might improve outcomes and challenge autologous stem-cell transplantation (ASCT) in younger (aged 65 years or younger) mantle cell lymphoma patients. This trial aimed to investigate whether the addition of ibrutinib results in a superior clinical outcome compared with the pre-trial immunochemotherapy standard with ASCT or an ibrutinib-containing treatment without ASCT. We also investigated whether standard treatment with ASCT is superior to a treatment adding ibrutinib but without ASCT., Methods: The open-label, randomised, three-arm, parallel-group, superiority TRIANGLE trial was performed in 165 secondary or tertiary clinical centres in 13 European countries and Israel. Patients with previously untreated, stage II-IV mantle cell lymphoma, aged 18-65 years and suitable for ASCT were randomly assigned 1:1:1 to control group A or experimental groups A+I or I, stratified by study group and mantle cell lymphoma international prognostic index risk groups. Treatment in group A consisted of six alternating cycles of R-CHOP (intravenous rituximab 375 mg/m 2 on day 0 or 1, intravenous cyclophosphamide 750 mg/m 2 on day 1, intravenous doxorubicin 50 mg/m 2 on day 1, intravenous vincristine 1·4 mg/m 2 on day 1, and oral prednisone 100 mg on days 1-5) and R-DHAP (or R-DHAOx, intravenous rituximab 375 mg/m 2 on day 0 or 1, intravenous or oral dexamethasone 40 mg on days 1-4, intravenous cytarabine 2 × 2 g/m 2 for 3 h every 12 h on day 2, and intravenous cisplatin 100 mg/m 2 over 24 h on day 1 or alternatively intravenous oxaliplatin 130 mg/m 2 on day 1) followed by ASCT. In group A+I, ibrutinib (560 mg orally each day) was added on days 1-19 of R-CHOP cycles and as fixed-duration maintenance (560 mg orally each day for 2 years) after ASCT. In group I, ibrutinib was given the same way as in group A+I, but ASCT was omitted. Three pairwise one-sided log-rank tests for the primary outcome of failure-free survival were statistically monitored. The primary analysis was done by intention-to-treat. Adverse events were evaluated by treatment period among patients who started the respective treatment. This ongoing trial is registered with ClinicalTrials.gov, NCT02858258., Findings: Between July 29, 2016 and Dec 28, 2020, 870 patients (662 men, 208 women) were randomly assigned to group A (n=288), group A+I (n=292), and group I (n=290). After 31 months median follow-up, group A+I was superior to group A with 3-year failure-free survival of 88% (95% CI 84-92) versus 72% (67-79; hazard ratio 0·52 [one-sided 98·3% CI 0-0·86]; one-sided p=0·0008). Superiority of group A over group I was not shown with 3-year failure-free survival 72% (67-79) versus 86% (82-91; hazard ratio 1·77 [one-sided 98·3% CI 0-3·76]; one-sided p=0·9979). The comparison of group A+I versus group I is ongoing. There were no relevant differences in grade 3-5 adverse events during induction or ASCT between patients treated with R-CHOP/R-DHAP or ibrutinib combined with R-CHOP/R-DHAP. During maintenance or follow-up, substantially more grade 3-5 haematological adverse events and infections were reported after ASCT plus ibrutinib (group A+I; haematological: 114 [50%] of 231 patients; infections: 58 [25%] of 231; fatal infections: two [1%] of 231) compared with ibrutinib only (group I; haematological: 74 [28%] of 269; infections: 52 [19%] of 269; fatal infections: two [1%] of 269) or after ASCT (group A; haematological: 51 [21%] of 238; infections: 32 [13%] of 238; fatal infections: three [1%] of 238)., Interpretation: Adding ibrutinib to first-line treatment resulted in superior efficacy in younger mantle cell lymphoma patients with increased toxicity when given after ASCT. Adding ibrutinib during induction and as maintenance should be part of first-line treatment of younger mantle cell lymphoma patients. Whether ASCT adds to an ibrutinib-containing regimen is not yet determined., Funding: Janssen and Leukemia & Lymphoma Society., Competing Interests: Declaration of interests MD reports research grants for clinical studies from AbbVie, Bayer, Bristol-Myers Squibb/Celgene, Gilead/Kite, Janssen, and Roche; speakers' honoraria from AstraZeneca, BeiGene, Gilead/Kite, Janssen, Lilly, Novartis, and Roche; travel support from Janssen and Roche; and participation on a Data Safety Monitoring Board or Advisory Board for AbbVie, AstraZeneca, BeiGene, Bristol-Myers Squibb/Celgene, Gilead/Kite, Janssen, Lilly/Loxo Oncology, Novartis, and Roche. JDo reports payment for expert testimony (once Advisory Board) from Lilly. EG reports grants from Janssen; honoraria (educational lecture) from Genmab, Gilead, Janssen, and Lilly; support for attending meetings or travel from Janssen and Roche; and participation on a Data Safety Monitoring Board or Advisory Board for Gilead/Kite and Miltenyi Biotec. MJ reports payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from AbbVie, Gilead/Kite, and Roche; participation on a Data Safety Monitoring Board or Advisory Board for AbbVie, Gilead/Kite, Janssen, and Pierre Fabre. JW reports grants to his institution from GlaxoSmithKline/Novartis and Roche; honoraria for lectures from AbbVie, Amgen, Gilead, Novartis, Roche, Servier, and Takeda; participation on an Advisory Board from AbbVie, Gilead, Novartis, Roche, and Takeda. MHu reports payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from AbbVie, AstraZeneca, Celgene, Genmab, Janssen, Merck, Roche, and Takeda; participation on a Data Safety Monitoring Board or Advisory Board for AbbVie, AstraZeneca, Celgene, Genmab, Janssen, Merck, Roche, and Takeda. UM reports travel support from Amgen, Bristol-Myers Squibb/Celgene, Gilead, Janssen-Cilag, and Roche; Advisory Board role for Amgen, AstraZeneca, BeiGene, Bristol-Myers Squibb/Celgene, Gilead, Incyte, Janssen-Cilag, Novartis, Pfizer, Roche, Sanofi, and Takeda; participation in national Guideline committee for the German-Swiss-Austrian Guideline for Mantle Cell Lymphoma. JR reports participation on an Advisory Board for AstraZeneca. VV reports consulting fees from AbbVie, BeiGene, Gilead, Lilly, and Roche; payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Janssen; payment for expert testimony from Gilead and Roche; support for attending meetings or travel from AbbVie and Gilead. MGdS reports a research grant from AstraZeneca; payment for Advisory Boards from AbbVie, Gilead, Janssen-Cilag, Roche, and Takeda; payment or honoraria for educational events from Gilead and Janssen-Cilag; support for attending meetings or travel from AbbVie, Janssen-Cilag, Roche, and Takeda; participation on a Data Safety Monitoring Board or Advisory Board for Roche; leadership in a scientific society (Sociedade Portuguesa de Hematologia); administration board on a patient advocacy group (Associação Portuguesa Contra a Leucemia). SL reports grants or contracts to her institution from Bristol-Myers Squibb/Celgene, Genmab, HUTCHMED, Novartis, and Roche; consulting fees from AbbVie, Genmab, Gilead, Novartis, ORION Pharma, Roche, and Swedish Orphan Biovitrum (sobi); payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Gilead, Incyte, and Novartis; participation on a Data Safety Monitoring Board or Advisory Board for Incyte. StS reports grants or contracts from any entity from AbbVie, Acerta Pharma, Amgen, AstraZeneca, BeiGene, Bristol-Myers Squibb/Celgene, Roche, Gilead, GlaxoSmithKline, Infinity Pharmaceuticals, Janssen, Novartis, Sunesis Pharmaceuticals, and Verastem; consulting fees from AbbVie, Acerta Pharma, Amgen, AstraZeneca, BeiGene, Bristol-Myers Squibb/Celgene, Roche, Gilead, GlaxoSmithKline, Infinity Pharmaceuticals, Janssen, Novartis, Sunesis Pharmaceuticals, and Verastem; payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from AbbVie, Acerta Pharma, Amgen, AstraZeneca, BeiGene, Bristol-Myers Squibb/Celgene, Roche, Gilead, GlaxoSmithKline, Infinity Pharmaceuticals, Janssen, Novartis, Sunesis Pharmaceuticals, and Verastem; support for attending meetings or travel from AbbVie, Acerta Pharma, Amgen, AstraZeneca, BeiGene, Bristol-Myers Squibb/Celgene, Roche, Gilead, GlaxoSmithKline, Infinity Pharmaceuticals, Janssen, Novartis, Sunesis Pharmaceuticals, and Verastem; participation on a Data Safety Monitoring Board or Advisory Board for AbbVie, Acerta Pharma, Amgen, AstraZeneca, BeiGene, Bristol-Myers Squibb/Celgene, Roche, Gilead, GlaxoSmithKline, Infinity Pharmaceuticals, Janssen, Novartis, Sunesis Pharmaceuticals, and Verastem; receipt of equipment, materials, drugs, medical writing, gifts, or other services from AbbVie, Acerta Pharma, Amgen, AstraZeneca, BeiGene, Bristol-Myers Squibb/Celgene, Roche, Gilead, GlaxoSmithKline, Infinity Pharmaceuticals, Janssen, Novartis, Sunesis Pharmaceuticals, and Verastem. AK reports payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from AbbVie, Bristol-Myers Squibb/Celgene, Novartis, Roche, Swedish Orphan Biovitrum (sobi), and Takeda; support for attending meetings or travel from AbbVie, BeiGene, EUSA Pharma, Swedish Orphan Biovitrum (sobi), and Takeda. RJ reports travel support for meeting attendance from BeiGene; meeting fee from Janssen. GH reports grants or contracts for clinical research from AbbVie, Gilead/Kite, Incyte, Janssen, MorphoSys, Pfizer, and Roche; consulting fees from AbbVie, ADC Therapeutics, AstraZeneca, Bristol-Myers Squibb, Genmab, Gilead/Kite, Incyte, Janssen, Lilly, Miltenyi Biotec, Novartis, and Roche; payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from AbbVie, AstraZeneca, BeiGene, Bristol-Myers Squibb, Genmab, Gilead, Incyte, Janssen, Lilly, and Roche; support for attending meetings or travel from Gilead/Kite and Janssen; participation on a Data Safety Monitoring Board or Advisory Board for Miltenyi Biotec. CV reports payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from AbbVie, AstraZeneca, BeiGene, Bristol-Myers Squibb, Gilead/Kite, Incyte, Istituto Gentili, Janssen, Lilly, Novartis, Pfizer, Roche, and Servier; participation on a Data Safety Monitoring Board or Advisory Board for AbbVie, Bristol-Myers Squibb, Incyte, Janssen, Lilly, Pfizer, and Roche. TvM reports payment or honoraria for educational lectures from Bristol-Myers Squibb/Celgene, Gilead/Kite, Janssen, and Lilly; participation on a Data Safety Monitoring Board or Advisory Board for GE HealthCare and Gilead/Kite. SW reports payment to his institution from AbbVie, Stemline Therapeutics, and Takeda; payment for expert testimony from Stemline Therapeutics; support for attending meetings or travel from AbbVie and BeiGene; participation on a Data Safety Monitoring Board or Advisory Board for AbbVie, Astra Zeneca, Roche, and Stemline Therapeutics. PLZ reports payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from AstraZeneca, BeiGene, Bristol-Myers Squibb, Gilead, Incyte, Janssen, Kyowa Kirin, Merck Sharp and Dohme, Novartis, Roche, Swedish Orphan Biovitrum (sobi), and Takeda; participation on a Data Safety Monitoring Board or Advisory Board for AstraZeneca, BeiGene, Bristol-Myers Squibb, Gilead, Incyte, Janssen, Kyowa Kirin, Merck Sharp and Dohme, Novartis, Roche, Swedish Orphan Biovitrum (sobi), and Takeda. UN reports consulting fees to his institution from AstraZeneca, BeiGene, Bristol-Myers Squibb/Celgene, Gilead, Incyte, Janssen-Cilag, Kyowa Kirin, Novartis, Pierre Fabre, Roche, and Takeda; payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events to his institution from Bristol-Myers Squibb/Celgene, Gilead, Novartis, and Takeda; support for attending meetings or travel from Janssen, Gilead, Roche, and Takeda; participation on a Data Safety Monitoring Board or Advisory Board for AstraZeneca, BeiGene, Bristol-Myers Squibb/Celgene, Gilead, Incyte, Janssen-Cilag, Kyowa Kirin, Novartis, Pierre Fabre, Roche, and Takeda. CH reports payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Bristol-Myers Squibb, Janssen, and Pfizer; support for attending meetings or travel from AbbVie and Janssen. MHa reports payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Falk Foundation, Gilead, Novartis, and Swedish Orphan Biovitrum (sobi); payment for expert testimony from Amgen, Bristol-Myers Squibb/Celgene, Gilead, Incyte, Janssen, Novartis, Pizer, Roche, Sanofi-Aventis, and Swedish Orphan Biovitrum (sobi). WK reports research grants provided to his institution from Amgen, Janssen, Roche, and Takeda. DG reports support for attending meetings and travel from Janssen. CS reports consulting fees from Bristol-Myers Squibb and Janssen; payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from AstraZeneca and Bristol-Myers Squibb; support for attending meetings or travel from Gilead/Kite. MU reports institutional funding of the TRIANGLE trial from Janssen. ML reports consulting fees from AstraZeneca, BeiGene, Janssen, and Lilly; honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from AstraZeneca, BeiGene, Janssen, and Lilly; participation on a Data Safety Monitoring Board with Acerta. All other authors (MT, OS, LJ, MC, LA, PH, FB, KS, JDi, CP, and EH) declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

In patients with chronic lymphocytic leukemia, Richter transformation (RT) reflects the development of an aggressive lymphoma that is associated with poor response to chemotherapy and short survival. We initiated an international, investigator-initiated, prospective, open-label phase 2 study in which patients with RT received a combination of the PD-1 inhibitor tislelizumab plus the BTK inhibitor zanubrutinib for 12 cycles. Patients responding to treatment underwent maintenance treatment with both agents. The primary end point was overall response rate after six cycles. Of 59 enrolled patients, 48 patients received at least two cycles of treatment and comprised the analysis population according to the study protocol. The median observation time was 13.9 months, the median age was 67 (range 45-82) years. Ten patients (20.8%) had received previous RT-directed therapy. In total, 28 out of 48 patients responded to induction therapy with an overall response rate of 58.3% (95% confidence interval (CI) 43.2-72.4), including 9 (18.8%) complete reponse and 19 (39.6%) partial response, meeting the study's primary end point by rejecting the predefined null hypothesis of 40% (P = 0.008). Secondary end points included duration of response, progression-free survival and overall survival. The median duration of response was not reached, the median progression-free survival was 10.0 months (95% CI 3.8-16.3). Median overall survival was not reached with a 12-month overall survival rate of 74.7% (95% CI 58.4-91.0). The most common adverse events were infections (18.0%), gastrointestinal disorders (13.0%) and hematological toxicities (11.4%). These data suggest that combined checkpoint and BTK inhibition by tislelizumab plus zanubrutinib is an effective and well-tolerated treatment strategy for patients with RT. ClinicalTrials.gov Identifier: NCT04271956 ., (© 2023. The Author(s).)

Background: Randomized trials of venetoclax plus anti-CD20 antibodies as first-line treatment in fit patients (i.e., those with a low burden of coexisting conditions) with advanced chronic lymphocytic leukemia (CLL) have been lacking., Methods: In a phase 3, open-label trial, we randomly assigned, in a 1:1:1:1 ratio, fit patients with CLL who did not have TP53 aberrations to receive six cycles of chemoimmunotherapy (fludarabine-cyclophosphamide-rituximab or bendamustine-rituximab) or 12 cycles of venetoclax-rituximab, venetoclax-obinutuzumab, or venetoclax-obinutuzumab-ibrutinib. Ibrutinib was discontinued after two consecutive measurements of undetectable minimal residual disease or could be extended. The primary end points were undetectable minimal residual disease (sensitivity, <10 -4 [i.e., <1 CLL cell in 10,000 leukocytes]) as assessed by flow cytometry in peripheral blood at month 15 and progression-free survival., Results: A total of 926 patients were assigned to one of the four treatment regimens (229 to chemoimmunotherapy, 237 to venetoclax-rituximab, 229 to venetoclax-obinutuzumab, and 231 to venetoclax-obinutuzumab-ibrutinib). At month 15, the percentage of patients with undetectable minimal residual disease was significantly higher in the venetoclax-obinutuzumab group (86.5%; 97.5% confidence interval [CI], 80.6 to 91.1) and the venetoclax-obinutuzumab-ibrutinib group (92.2%; 97.5% CI, 87.3 to 95.7) than in the chemoimmunotherapy group (52.0%; 97.5% CI, 44.4 to 59.5; P<0.001 for both comparisons), but it was not significantly higher in the venetoclax-rituximab group (57.0%; 97.5% CI, 49.5 to 64.2; P = 0.32). Three-year progression-free survival was 90.5% in the venetoclax-obinutuzumab-ibrutinib group and 75.5% in the chemoimmunotherapy group (hazard ratio for disease progression or death, 0.32; 97.5% CI, 0.19 to 0.54; P<0.001). Progression-free survival at 3 years was also higher with venetoclax-obinutuzumab (87.7%; hazard ratio for disease progression or death, 0.42; 97.5% CI, 0.26 to 0.68; P<0.001), but not with venetoclax-rituximab (80.8%; hazard ratio, 0.79; 97.5% CI, 0.53 to 1.18; P = 0.18). Grade 3 and grade 4 infections were more common with chemoimmunotherapy (18.5%) and venetoclax-obinutuzumab-ibrutinib (21.2%) than with venetoclax-rituximab (10.5%) or venetoclax-obinutuzumab (13.2%)., Conclusions: Venetoclax-obinutuzumab with or without ibrutinib was superior to chemoimmunotherapy as first-line treatment in fit patients with CLL. (Funded by AbbVie and others; GAIA-CLL13 ClinicalTrials.gov number, NCT02950051; EudraCT number, 2015-004936-36.)., (Copyright © 2023 Massachusetts Medical Society.)

Despite considerable treatment advances with targeted therapies for patients with chronic lymphocytic leukemia (CLL) deemed high-risk [del(17p) and/or TP53 mutation], the outcome is still inferior compared with other CLL patients. Combining multiple agents with distinct mechanisms of action may further improve outcomes. CLL2-GIVe is an open-label, multicenter trial which enrolled patients with previously untreated CLL with del(17p) and/or TP53 mutation. Patients received induction therapy with obinutuzumab (GA-101), ibrutinib, and venetoclax (GIVe) for cycles 1 through 6 and consolidation therapy with venetoclax and ibrutinib for cycles 7 through 12. Ibrutinib monotherapy was continued for cycles 13 through 36 in patients not reaching a complete response (CR) with serial undetectable minimal residual disease (uMRD) after consolidation. The primary endpoint was CR rate at cycle 15 (final restaging). Secondary endpoints included MRD, survival, and safety. All 41 patients enrolled between September 2016 and August 2018 received study treatment and were included in efficacy and safety populations. With a CR rate of 58.5% at cycle 15, the primary endpoint was met (95% CI: 42.1-73.7; P < .001). At final restaging, 78.0% of patients had uMRD in peripheral blood (PB); 65.9% of patients had uMRD in bone marrow (BM). Estimated progression-free survival (PFS) and overall survival (OS) rates at 24 months were both 95.1%. Adverse events were reported in all patients; most were low grade (grade ≥3: 23.9%). Two deaths were reported (cardiac failure and ovarian carcinoma), neither related to study treatment. The CLL2-GIVe treatment regimen has a manageable safety profile and is a first-line treatment of good efficacy for patients with high-risk CLL., (© 2022 by The American Society of Hematology.)

Purpose: The CLL14 study has established one-year fixed-duration treatment of venetoclax and obinutuzumab (Ven-Obi) for patients with previously untreated chronic lymphocytic leukemia. With all patients off treatment for at least three years, we report a detailed analysis of minimal residual disease (MRD) kinetics and long-term outcome of patients treated in the CLL14 study., Patients and Methods: Patients were randomly assigned to receive six cycles of obinutuzumab with 12 cycles of venetoclax or 12 cycles of chlorambucil (Clb-Obi). Progression-free survival (PFS) was the primary end point. Key secondary end points included rates of undetectable MRD and overall survival. To analyze MRD kinetics, a population-based growth model with nonlinear mixed effects approach was developed., Results: Of 432 patients, 216 were assigned to Ven-Obi and 216 to Clb-Obi. Three months after treatment completion, 40% of patients in the Ven-Obi arm (7% in the Clb-Obi arm) had undetectable MRD levels < 10 -6 by next-generation sequencing in peripheral blood. Median MRD doubling time was longer after Ven-Obi than Clb-Obi therapy (median 80 v 69 days). At a median follow-up of 52.4 months, a sustained significant PFS improvement was observed in the Ven-Obi arm compared with Clb-Obi (median not reached v 36.4 months; hazard ratio 0.33; 95% CI, 0.25 to 0.45; P < .0001). The estimated 4-year PFS rate was 74.0% in the Ven-Obi and 35.4% in the Clb-Obi arm. No difference in overall survival was observed (hazard ratio 0.85; 95% CI, 0.54 to 1.35; P = .49). No new safety signals occurred., Conclusion: Appearance of MRD after Ven-Obi is significantly slower than that after Clb-Obi with more effective MRD reduction. These findings translate into a superior long-term efficacy with the majority of Ven-Obi-treated patients remaining in remission., Competing Interests: Othman Al-SawafHonoraria: Janssen-Cilag, Roche, Gilead Sciences, AbbVie, AstraZeneca, Adaptive Biotechnologies, BeiGeneConsulting or Advisory Role: Roche, Janssen-Cilag, Gilead Sciences, AbbVieResearch Funding: BeiGene (Inst), Roche (Inst), AbbVie (Inst), Janssen/Pharmacyclics (Inst)Travel, Accommodations, Expenses: Roche, AbbVie, Gilead Sciences, Janssen-Cilag Tong LuEmployment: Genentech/RocheStock and Other Ownership Interests: RochePatents, Royalties, Other Intellectual Property: P36418-US Title: Methods and systems for placebo response modeling Michael Z. LiaoEmployment: Genentech/RocheStock and Other Ownership Interests: Roche, Amgen Anesh PanchalEmployment: Genentech/Roche Travers ChingEmployment: Adaptive BiotechnologiesStock and Other Ownership Interests: Adaptive Biotechnologies Maneesh TandonEmployment: Roche (I)Stock and Other Ownership Interests: Roche Pharma AG Anna-Maria FinkResearch Funding: Celgene/Bristol Myers Squibb (Inst), AstraZeneca (Inst)Travel, Accommodations, Expenses: AbbVie Eugen TauschConsulting or Advisory Role: Roche, AbbVieSpeakers' Bureau: Roche, AbbVie, Janssen-CilagTravel, Accommodations, Expenses: AbbVie Matthias RitgenHonoraria: Roche, Janssen Oncology, AstraZeneca, AbbVie, MSDConsulting or Advisory Role: AbbVie, Roche, AstraZenecaResearch Funding: Roche (Inst), AbbVie (Inst)Patents, Royalties, Other Intellectual Property: Partial patent holder, only intellectual propertyTravel, Accommodations, Expenses: AstraZeneca, Takeda Sebastian BöttcherHonoraria: Roche, AbbVie, AstraZeneca, Janssen, SanofiConsulting or Advisory Role: AstraZeneca, JanssenResearch Funding: Janssen (Inst) Karl-Anton KreuzerHonoraria: Roche, AbbVieConsulting or Advisory Role: Roche, AbbVieSpeakers' Bureau: Roche, AbbVieResearch Funding: Roche (Inst), AbbVie (Inst)Expert Testimony: Roche, AbbVieTravel, Accommodations, Expenses: Roche, AbbVie Brenda ChylaEmployment: AbbVieStock and Other Ownership Interests: AbbVie Dale MilesEmployment: GenentechStock and Other Ownership Interests: GenentechTravel, Accommodations, Expenses: Genentech Clemens-Martin WendtnerHonoraria: Roche, Janssen-Cilag, AbbVie/Genentech, AstraZeneca, Gilead SciencesConsulting or Advisory Role: Roche, Janssen-Cilag, AbbVie/Genentech, AstraZeneca, Gilead SciencesResearch Funding: Roche, Janssen-Cilag, AbbVie/Genentech, AstraZeneca, Gilead SciencesTravel, Accommodations, Expenses: Roche, Janssen-Cilag, AbbVie/Genentech, AstraZeneca, Gilead Sciences Barbara EichhorstHonoraria: Roche, AbbVie, Gilead Sciences, Janssen, Novartis, Hexal, AstraZeneca, Adaptive Biotechnologies, Oxford Biomedica, Miltenyi BiotecConsulting or Advisory Role: Gilead Sciences, Janssen-Cilag, Roche, AbbVie, Novartis, Celgene, AstraZeneca, ArQuleSpeakers' Bureau: Roche/Genentech, Janssen-Cilag, Gilead Sciences, Celgene, AbbVie, NovartisResearch Funding: Roche, AbbVie, Gilead Sciences, Janssen, Beijing Genomics InstituteTravel, Accommodations, Expenses: Roche, AbbVie, Gilead Sciences, Janssen Stephan StilgenbauerHonoraria: AbbVie, AstraZeneca, Celgene, Gilead Sciences, GlaxoSmithKline, Roche, JanssenConsulting or Advisory Role: AbbVie, AstraZeneca, Celgene, Gilead Sciences, GlaxoSmithKline, Roche, JanssenSpeakers' Bureau: AbbVie, AstraZeneca, Celgene, Gilead Sciences, GlaxoSmithKline, Roche, JanssenResearch Funding: AbbVie, AstraZeneca, Celgene, Gilead Sciences, GlaxoSmithKline, Roche, JanssenTravel, Accommodations, Expenses: AbbVie, AstraZeneca, Celgene, Gilead Sciences, GlaxoSmithKline, Roche, Janssen Yanwen JiangEmployment: GenentechStock and Other Ownership Interests: Genentech Michael HallekHonoraria: Roche, Janssen, AbbVie, Gilead Sciences, AstraZenecaConsulting or Advisory Role: Janssen, AbbVie, Gilead Sciences, Genentech/Roche, AstraZenecaSpeakers' Bureau: Janssen, AbbVie, Gilead Sciences, Roche/Genentech, AstraZenecaResearch Funding: Roche (Inst), AbbVie (Inst), Janssen (Inst), Gilead Sciences (Inst), AstraZeneca (Inst), Travel, Accommodations, Expenses: Roche, Janssen Kirsten FischerHonoraria: AbbVie, RocheConsulting or Advisory Role: AbbVie, RocheTravel, Accommodations, Expenses: RocheNo other potential conflicts of interest were reported.

Purpose: Among Bruton's tyrosine kinase inhibitors, acalabrutinib has greater selectivity than ibrutinib, which we hypothesized would improve continuous therapy tolerability. We conducted an open-label, randomized, noninferiority, phase III trial comparing acalabrutinib and ibrutinib in patients with chronic lymphocytic leukemia (CLL)., Methods: Patients with previously treated CLL with centrally confirmed del(17)(p13.1) or del(11)(q22.3) were randomly assigned to oral acalabrutinib 100 mg twice daily or ibrutinib 420 mg once daily until progression or unacceptable toxicity. The primary end point was independent review committee-assessed noninferiority of progression-free survival (PFS)., Results: Overall, 533 patients (acalabrutinib, n = 268; ibrutinib, n = 265) were randomly assigned. At the data cutoff, 124 (46.3%) acalabrutinib patients and 109 (41.1%) ibrutinib patients remained on treatment. After a median follow-up of 40.9 months, acalabrutinib was determined to be noninferior to ibrutinib with a median PFS of 38.4 months in both arms (95% CI acalabrutinib, 33.0 to 38.6 and ibrutinib, 33.0 to 41.6; hazard ratio: 1.00; 95% CI, 0.79 to 1.27). All-grade atrial fibrillation/atrial flutter incidence was significantly lower with acalabrutinib versus ibrutinib (9.4% v 16.0%; P = .02); among other selected secondary end points, grade 3 or higher infections (30.8% v 30.0%) and Richter transformations (3.8% v 4.9%) were comparable between groups and median overall survival was not reached in either arm (hazard ratio, 0.82; 95% CI, 0.59 to 1.15), with 63 (23.5%) deaths with acalabrutinib and 73 (27.5%) with ibrutinib. Treatment discontinuations because of adverse events occurred in 14.7% of acalabrutinib-treated patients and 21.3% of ibrutinib-treated patients., Conclusion: In this first direct comparison of less versus more selective Bruton's tyrosine kinase inhibitors in CLL, acalabrutinib demonstrated noninferior PFS with fewer cardiovascular adverse events., Competing Interests: John C. ByrdStock and Other Ownership Interests: Vincerx PharmaHonoraria: Pharmacyclics, AstraZeneca, Novartis, Syndax, Trillium TherapeuticsConsulting or Advisory Role: Acerta Pharma, Janssen, Kura Oncology, Novartis, Syndax, AstraZenecaResearch Funding: Acerta Pharma, Pharmacyclics, ZencorPatents, Royalties, Other Intellectual Property: OSU PatentsTravel, Accommodations, Expenses: Gilead Sciences, Janssen, Novartis, Pharmacyclics, TG Therapeutics Peter HillmenHonoraria: Janssen, AbbVie, RocheResearch Funding: Janssen, Pharmacyclics, Roche, Gilead Sciences, AbbVieTravel, Accommodations, Expenses: Janssen, AbbVie Paolo GhiaHonoraria: AbbVie, BeiGene, Janssen Oncology, Gilead Sciences, Juno Therapeutics, Sunesis Pharmaceuticals, ArQule, Adaptive Biotechnologies, Dynamo Therapeutics, MEI Pharma, Acerta Pharma/AstraZeneca, Juno/Celgene/Bristol Myers Squibb, MSD, Lilly, RocheConsulting or Advisory Role: AbbVie, BeiGene, Janssen, Gilead Sciences, Sunesis Pharmaceuticals, Juno Therapeutics, ArQule, Adaptive Biotechnologies, Dynamo Therapeutics, MEI Pharma, Acerta Pharma/AstraZeneca, MSD, Lilly, RocheResearch Funding: AbbVie, Janssen Oncology, Gilead Sciences, Sunesis Pharmaceuticals, Novartis, AstraZeneca Arnon P. KaterConsulting or Advisory Role: Janssen Oncology, AbbVie/Genentech, AstraZeneca, Bristol Myers Squibb/Celgene, Lava TherapeuticsResearch Funding: Janssen Oncology, Roche/Genentech, Bristol Myers Squibb/Celgene, AbbVie, AstraZenecaTravel, Accommodations, Expenses: Acerta Pharma/AstraZeneca, Roche/Genentech Asher Chanan-KhanStock and Other Ownership Interests: Matthew & Asher Inc, NanoDev Therapeutics, STARTON TherapeuticsHonoraria: BeiGene, Ascentage PharmaResearch Funding: Ascentage PharmaPatents, Royalties, Other Intellectual Property: Patent on PSMB9 biomarker Richard R. FurmanHonoraria: Janssen, AstraZenecaConsulting or Advisory Role: Pharmacyclics, Janssen Biotech, Genentech/Roche, Loxo, TG Therapeutics, Verastem, Acerta Pharma, AstraZeneca, Beigene, Incyte, OncoTracker, AbbVie, MorphoSys, SanofiResearch Funding: Acerta Pharma, TG TherapeuticsExpert Testimony: AbbVie, Janssen OncologyTravel, Accommodations, Expenses: TG Therapeutics, Janssen OncologyOther Relationship: Incyte, Janssen Biotech Susan O'BrienEmployment: University of California, IrvineHonoraria: Celgene, Janssen, Pharmacyclics, Gilead Sciences, Pfizer, Amgen, Astellas Pharma, GlaxoSmithKline, Aptose Biosciences, Vaniam Group, AbbVie, Sunesis Pharmaceuticals, Alexion Pharmaceuticals, Eisai, TG Therapeutics, Nova Research CompanyConsulting or Advisory Role: Amgen, Celgene, GlaxoSmithKline, Janssen Oncology, Aptose Biosciences, Vaniam Group, AbbVie/Genentech, Sunesis Pharmaceuticals, Alexion Pharmaceuticals, Astellas Pharma, Gilead Sciences, Pharmacyclics, TG Therapeutics, Pfizer, Sunesis PharmaceuticalsResearch Funding: Acerta Pharma, Regeneron, Gilead Sciences, Pfizer, TG Therapeutics, Pharmacyclics, Kite, a Gilead company, Sunesis PharmaceuticalsTravel, Accommodations, Expenses: Celgene, Janssen, Gilead Sciences, Regeneron, Janssen Oncology Mustafa Nuri YenerelConsulting or Advisory Role: Pfizer, Alexion PharmaceuticalsSpeakers' Bureau: Janssen OncologyTravel, Accommodations, Expenses: Pfizer Arpad IllésConsulting or Advisory Role: Janssen, Takeda, Novartis, Pfizer, Roche, CelgeneResearch Funding: Takeda, Seattle GeneticsTravel, Accommodations, Expenses: Novartis, Janssen, Pfizer, Roche Neil KayConsulting or Advisory Role: MorphoSys, Celgene, Agios, CytomX Therapeutics, AstraZeneca, Pharmacyclics, DAVA Pharmaceuticals, Juno Therapeutics, Rigel, Oncotracker, Bristol Myers Squibb, AbbVie, Targeted Oncology, Acerta Pharma/AstraZeneca, MEI Pharma, Sunesis Pharmaceuticals, TG Therapeutics, Tolero Pharmaceuticals, Janssen Biotech, Genentech/AbbVieResearch Funding: Pharmacyclics/Janssen, Tolero Pharmaceuticals, Acerta Pharma, MEI Pharma, Celgene, Genentech, Sunesis Pharmaceuticals, AbbVie, TG Therapeutics, Bristol Myers Squibb Jose A. Garcia-MarcoConsulting or Advisory Role: AbbVie, Janssen, AstraZeneca SpainSpeakers' Bureau: AbbVie, Janssen, AstraZeneca SpainResearch Funding: AbbVie, JanssenTravel, Accommodations, Expenses: AbbVie, Janssen Anthony MatoConsulting or Advisory Role: TG Therapeutics, AbbVie/Genentech, Celgene, Pharmacyclics, Adaptive Biotechnologies, Verastem, Johnson & Johnson, Acerta Pharma/AstraZeneca, DTRM, Loxo/Lilly, Curio/Vaniam Group, Merck, Bristol Myers Squibb/PfizerResearch Funding: Regeneron, TG Therapeutics, Sunesis Pharmaceuticals, LOXO, AbbVie/Genentech, Pharmacyclics, Adaptive Biotechnologies, Johnson & Johnson, Acerta Pharma/AstraZeneca, DTRM, Genmab, Nurix Javier Pinilla-IbarzHonoraria: Novartis, Pharmacyclics, Janssen, AbbVie, Takeda, AstraZenecaConsulting or Advisory Role: Novartis, Pharmacyclics, Janssen, AbbVieSpeakers' Bureau: Pharmacyclics/Janssen, AbbVie, Takeda, AstraZenecaPatents, Royalties, Other Intellectual Property: From a WT vaccine patent by Memorial Sloan Kettering Cancer Center John F. SeymourHonoraria: AbbVie, Acerta Pharma, Janssen, Roche, Sunesis Pharmaceuticals, TakedaConsulting or Advisory Role: AbbVie, Acerta Pharma, Janssen, Roche, Sunesis Pharmaceuticals, Takeda, AstraZeneca, BMS, Gilead Sciences, MEI Pharma, MorphoSysSpeakers' Bureau: AbbVie, RocheResearch Funding: AbbVie, Celgene, Janssen, RocheExpert Testimony: RocheTravel, Accommodations, Expenses: AbbVie, Roche Stephan StilgenbauerHonoraria: AbbVie, AstraZeneca, Celgene, Gilead Sciences, GlaxoSmithKline, Roche, JanssenConsulting or Advisory Role: AbbVie, AstraZeneca, Celgene, Gilead Sciences, GlaxoSmithKline, Roche, JanssenSpeakers' Bureau: AbbVie, AstraZeneca, Celgene, Gilead Sciences, GlaxoSmithKline, Roche, JanssenResearch Funding: AbbVie, AstraZeneca, Celgene, Gilead Sciences, GlaxoSmithKline, Roche, JanssenTravel, Accommodations, Expenses: AbbVie, AstraZeneca, Celgene, Gilead Sciences, GlaxoSmithKline, Roche, Janssen Tadeusz RobakHonoraria: AbbVieConsulting or Advisory Role: AbbVieResearch Funding: AbbVie/Genentech Wayne RothbaumLeadership: Iovance BiotherapeuticsStock and Other Ownership Interests: Acerta Pharma/AstraZeneca, Telios, Kartos TherapeuticsPatents, Royalties, Other Intellectual Property: Telios Pharma and Kartos TherapeuticsTravel, Accommodations, Expenses: Iovance Biotherapeutics, Kartos TherapeuticsUncompensated Relationships: Kartos Therapeutics, Telios Raquel IzumiEmployment: Acerta Pharma, Vincerx PharmaStock and Other Ownership Interests: Acerta Pharma, Vincerx PharmaPatents, Royalties, Other Intellectual Property: Patents pending for Acerta PharmaExpert Testimony: Diablo Valley Oncology Ahmed HamdyEmployment: Acerta Pharma/AstraZenecaStock and Other Ownership Interests: Acerta PharmaPatents, Royalties, Other Intellectual Property: Acalabrutinib multiple patents Priti PatelEmployment: AstraZeneca, Neoleukin TherapeuticsLeadership: Neoleukin TherapeuticsStock and Other Ownership Interests: AstraZeneca, Neoleukin Therapeutics Kara HigginsEmployment: AstraZeneca, PROMETRIKA LLC Sophia SohoniEmployment: AstraZeneca, Portola PharmaceuticalsStock and Other Ownership Interests: Theravance Wojciech JurczakConsulting or Advisory Role: Janssen-Cilag, Roche, AstraZeneca, Debiopharm Group, EpizymeResearch Funding: Acerta Pharma, TG Therapeutics, Incyte, Bayer, Sandoz-Novartis, Roche, Takeda, Epizyme, Janssen-Cilag, BeiGene, Debiopharm Group, MorphoSys, MEI PharmaNo other potential conflicts of interest were reported.

Low-density lipoprotein (LDL) receptor-related protein-associated protein 1 (LRPAP1) had been identified by B-cell receptor (BCR) expression cloning and subsequent protein array screening as a frequent and proliferation-inducing autoantigen of mantle cell lymphoma (MCL). Of interest, high-titered and light chain-restricted LRPAP1 autoantibodies were detected in 8 of 28 patients with MCL. In the present study, LRPAP1 autoantibodies in sera of patients treated within the Younger and Elderly trials of the European MCL Network were analyzed regarding frequency, association with disease characteristics, and prognostic impact. LRPAP1 autoantibodies were detected in 41 (13%) of 312 evaluable patients with MCL. These LRPAP1 autoantibodies belonged predominantly to the immunoglobulin G (IgG) class and were clonally light chain restricted (27 with κ light chains, 14 patients with λ light chains). Titers ranged between 1:400 and 1:3200. The presence of LRPAP1 autoantibodies was not significantly associated with any baseline clinical characteristic, however, it was associated with a superior 5-year probability for failure-free survival (FFS) of 70% (95% confidence interval [CI], 57% to 87%) vs 51% (95% CI, 44% to 58%), P = .0052; and for overall survival (OS) of 93% (95% CI, 85% to 100%) vs 68% (95% CI, 62% to 74%), P = .0142. LRPAP1-seropositive patients had a Mantle Cell Lymphoma International Prognostic Index-adjusted hazard ratio for FFS of 0.48 (95% CI 0.27-0.83, P = .0083) and for OS of 0.47 (95% CI 0.24-0.94, P = .032). LRPAP1 autoantibodies were frequently detected in a large cohort of MCL patients treated within prospective multicenter clinical trials. Our results suggest better outcomes for LRPAP1-autoantibody seropositive patients., (© 2021 by The American Society of Hematology.)

We report a randomized prospective phase 3 study (CLL7), designed to evaluate the efficacy of fludarabine, cyclophosphamide, and rituximab (FCR) in patients with an early-stage high-risk chronic lymphocytic leukemia (CLL). Eight hundred patients with untreated-stage Binet A disease were enrolled as intent-to-treat population and assessed for four prognostic markers: lymphocyte doubling time <12 months, serum thymidine kinase >10 U/L, unmutated IGHV genes, and unfavorable cytogenetics (del(11q)/del(17p)/trisomy 12). Two hundred and one patients with ≥2 risk features were classified as high-risk CLL and 1:1 randomized to receive either immediate therapy with 6xFCR (Hi-FCR, 100 patients), or to be observed according to standard of care (Hi-W&W, 101 patients). The overall response rate after early FCR was 92.7%. Common adverse events were hematological toxicities and infections (61.0%/41.5% of patients, respectively). After median observation time of 55.6 (0-99.2) months, event-free survival was significantly prolonged in Hi-FCR compared with Hi-W&W patients (median not reached vs. 18.5 months, p < 0.001). There was no significant overall survival benefit for high-risk patients receiving early FCR therapy (5-year OS 82.9% in Hi-FCR vs. 79.9% in Hi-W&W, p = 0.864). In conclusion, although FCR is efficient to induce remissions in the Binet A high-risk CLL, our data do not provide evidence that alters the current standard of care "watch and wait" for these patients.

Genetic parameters are established prognostic factors in chronic lymphocytic leukemia (CLL) treated with chemoimmunotherapy, but are less well studied with novel compounds. We assessed immunoglobulin heavy variable chain (IGHV) mutation status, common genomic aberrations, and gene mutations in 421 untreated patients within the CLL14 trial (NCT02242942), comparing obinutuzumab+chlorambucil (GClb) vs obinutuzumab+venetoclax (VenG). The incidences of genomic aberrations considering the hierarchical model were del(17p) 7%, del(11q) 18%, +12 18%, and del(13q) 35%, whereas IGHV was unmutated in 60% of patients. NOTCH1 mutations were most common (23%), followed by SF3B1 (16%), ATM (13%), and TP53 (10%). Although the overall response rate (ORR) for GClb was lower in patients with del(17p), del(11q), mutated TP53, ATM, and BIRC3, none of these parameters reduced complete remission (CR) rate and ORR with VenG. At a median follow-up of 28 months, del(17p) and mutated TP53 were the only abnormalities with an effect on progression-free survival (PFS) for both treatment groups: GClb (hazard ratio [HR], 4.6 [P < .01]; HR, 2.7 [P < .01], respectively) and VenG (HR, 4.4 [P < .01]; HR, 3.1 [P < .01], respectively). No other factors affected outcome with VenG, whereas for GClb del(11q), BIRC3, NOTCH1, and unmutated IGHV were associated with shorter PFS. Multivariable analysis identified del(17p), del(11q), unmutated IGHV, and mutated TP53, BIRC3, and SF3B1 as independent prognostic factors for PFS with GClb, whereas for VenG, only del(17p) was significant. VenG was superior to GClb across most genetic subgroups. Patients with adverse genetic markers had the strongest benefit from VenG, particularly subjects with unmutated IGHV, which was identified as a predictive factor in a multivariable treatment-interaction analysis., (© 2020 by The American Society of Hematology.)

Purpose: In the phase III DUO trial, duvelisib, an oral dual PI3K-δ,γ inhibitor, demonstrated significantly improved efficacy versus ofatumumab [median (m) progression-free survival (PFS), 13.3 vs. 9.9 months (HR, 0.52; P < 0.0001); overall response rate [ORR], 74% vs. 45% ( P < 0.0001)], with a manageable safety profile in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). We report results from patients with progressive disease (PD) after ofatumumab who crossed over to duvelisib in the DUO trial., Patients and Methods: Patients with radiographically confirmed PD after ofatumumab received duvelisib 25 mg twice daily in 28-day cycles until PD, intolerance, death, or study withdrawal. The primary endpoint was ORR per investigator. Secondary endpoints included duration of response (DOR), PFS, and safety., Results: As of December 14, 2018, 90 ofatumumab-treated patients in the DUO trial prior to crossover had an ORR of 29%, mDOR of 10.4 months, and mPFS of 9.4 months. After crossover, 77% of patients (69/90) achieved a response, with an mDOR of 14.9 months and mPFS of 15.7 months. Patients with del(17p) and/or TP53 mutations had similar outcomes [ORR, 77% (20/26); mPFS, 14.7 months]. Notably, 73% of patients (47/64) with disease previously refractory to ofatumumab achieved a response. The most frequent any-grade/grade 3/4 treatment-emergent adverse events were diarrhea (47%/23%), neutropenia (26%/23%), pyrexia (24%/4%), cutaneous reactions (23%/4%), and thrombocytopenia (10%/6%)., Conclusions: Duvelisib demonstrated high response rates with good durability and a manageable safety profile in patients with R/R CLL/SLL who progressed on ofatumumab, including patients with high-risk disease and disease previously refractory to ofatumumab., (©2020 American Association for Cancer Research.)

GREEN (NCT01905943) is a nonrandomized, open-label, single-arm, phase 3b study investigating the safety and efficacy of obinutuzumab alone or in combination with chemotherapy in chronic lymphocytic leukemia (CLL). We report the preplanned subgroup analysis of 140 previously untreated, fit CLL patients who received obinutuzumab plus fludarabine and cyclophosphamide (G-FC). The primary endpoint was safety and tolerability. Efficacy was the secondary endpoint. Obinutuzumab 1000 mg was administered intravenously on Day (D)1 (dose split D1‒2), D8 and D15 of Cycle (C)1, and D1 of C2-6 (28-day cycles). Standard intravenous/oral doses of fludarabine and cyclophosphamide were administered on D1-3 of C1-6. Overall, 87.1% of patients experienced grade ≥ 3 adverse events (AEs), including neutropenia (67.1%) and thrombocytopenia (17.1%). Serious AEs were experienced by 42.1% of patients. Rates of grade ≥ 3 infusion-related reactions and infections were 19.3% and 15.7%, respectively. Overall response rate was observed in 90.0%, with 46.4% of patients achieving complete response (CR; including CR with incomplete marrow recovery). Minimal residual disease negativity rates were 64.3% in peripheral blood and 35.7% in bone marrow (intent-to-treat analysis). After a median observation time of 25.6 months, 2 year progression-free survival was 91%. Frontline G-FC represents a promising treatment option for fit patients with CLL.

Purpose: In an update of the randomized, open-label, phase III European Mantle Cell Lymphoma (MCL) Elderly trial (ClinicalTrials.gov identifier: NCT00209209), published in 2012, we aimed to confirm results on long-term outcome focusing on efficacy and safety of long-term use of rituximab maintenance., Patients and Methods: Five hundred sixty patients with newly diagnosed MCL underwent a first random assignment between rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and rituximab, fludarabine, and cyclophosphamide (R-FC) induction, followed by a second random assignment in 316 responders between rituximab and interferon alfa maintenance, to be continued until progression. We compared progression-free survival from the second randomization and overall survival (OS) from the first or second randomizations., Results: After a median follow-up time of 7.6 years, the previously described difference in OS between the induction arms persisted (median, 6.4 years after R-CHOP [n = 280] v 3.9 years after R-FC [n = 280]; P = .0054). Patients responding to R-CHOP had median progression-free survival and OS times of 5.4 and 9.8 years, respectively, when randomly assigned to rituximab (n = 87), compared with 1.9 years ( P < .001) and 7.1 years ( P = .0026), respectively, when randomly assigned to interferon alfa (n = 97). In 58% and 32% of patients treated with R-CHOP, rituximab maintenance was still ongoing 2 and 5 years from start of maintenance, respectively. After R-FC, rituximab maintenance was associated with an unexpectedly high cumulative incidence of death in remission (22% at 5 years). Toxicity of rituximab maintenance was low after R-CHOP (grade 3-4 leukopenia or infection < 5%) but more prominent in patients on rituximab maintenance after R-FC, in whom grade 3-4 leukopenia (up to 40%) and infections were frequent (up to 15%)., Conclusion: The excellent results of R-CHOP followed by rituximab maintenance until progression for older patients with MCL persisted in a mature follow-up. Prolongation of rituximab maintenance beyond 2 years is effective and safe.

Background: Six cycles of R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) are the standard treatment for aggressive B-cell non-Hodgkin lymphoma. In the FLYER trial, we assessed whether four cycles of CHOP plus six applications of rituximab are non-inferior to six cycles of R-CHOP in a population of patients with B-cell non-Hodgkin lymphoma with favourable prognosis., Methods: This two-arm, open-label, international, multicentre, prospective, randomised phase 3 non-inferiority trial was done at 138 clinical sites in Denmark, Israel, Italy, Norway, and Germany. We enrolled patients aged 18-60 years, with stage I-II disease, normal serum lactate dehydrogenase concentration, ECOG performance status 0-1, and without bulky disease (maximal tumour diameter <7·5 cm). Randomisation was computer-based and done centrally in a 1:1 ratio using the Pocock minimisation algorithm after stratification for centres, stage (I vs II), and extralymphatic sites (no vs yes). Patients were assigned to receive either six cycles of R-CHOP or four cycles of R-CHOP plus two doses of rituximab. CHOP comprised cyclophosphamide (750 mg/m 2 ), doxorubicin (50 mg/m 2 ), and vincristine (1·4 mg/m 2 , with a maximum total dose of 2 mg), all administered intravenously on day 1, plus oral prednisone or prednisolone at the discretion of the investigator (100 mg) administered on days 1-5. Rituximab was given at a dose of 375 mg/m 2 of body surface area. Cycles were repeated every 21 days. No radiotherapy was planned except for testicular lymphoma treatment. The primary endpoint was progression-free survival after 3 years. The primary analysis was done in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of assigned treatment. A non-inferiority margin of -5·5% was chosen. The trial, which is completed, was prospectively registered at ClinicalTrials.gov, NCT00278421., Findings: Between Dec 2, 2005, and Oct 7, 2016, 592 patients were enrolled, of whom 295 patients were randomly assigned to receive six cycles of R-CHOP and 297 were assigned to receive four cycles of R-CHOP plus two doses of rituximab. Four patients in the four-cycles group withdrew informed consent before the start of treatment, so 588 patients were included in the intention-to-treat analysis. After a median follow-up of 66 months (IQR 42-100), 3-year progression-free survival of patients who had four cycles of R-CHOP plus two doses of rituximab was 96% (95% CI 94-99), which was 3% better (lower limit of the one-sided 95% CI for the difference was 0%) than six cycles of R-CHOP, demonstrating the non-inferiority of the four-cycles regimen. 294 haematological and 1036 non-haematological adverse events were documented in the four-cycles group compared with 426 haematological and 1280 non-haematological adverse events in the six-cycles group. Two patients, both in the six-cycles group, died during study therapy., Interpretation: In young patients with aggressive B-cell non-Hodgkin lymphoma and favourable prognosis, four cycles of R-CHOP is non-inferior to six cycles of R-CHOP, with relevant reduction of toxic effects. Thus, chemotherapy can be reduced without compromising outcomes in this population., Funding: Deutsche Krebshilfe., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Fludarabine, cyclophosphamide, and rituximab (FCR) has become a gold-standard chemoimmunotherapy regimen for patients with chronic lymphocytic leukaemia. However, the question remains of how to treat treatment-naive patients with IGHV-unmutated chronic lymphocytic leukaemia. We therefore aimed to develop and validate a gene expression signature to identify which of these patients are likely to achieve durable remissions with FCR chemoimmunotherapy., Methods: We did a retrospective cohort study in two cohorts of treatment-naive patients (aged ≥18 years) with chronic lymphocytic leukaemia. The discovery and training cohort consisted of peripheral blood samples collected from patients treated at the University of Texas MD Anderson Cancer Center (Houston, TX, USA), who fulfilled the diagnostic criteria of the International Workshop on Chronic Lymphocytic Leukemia, had received at least three cycles of FCR chemoimmunotherapy, and had been treated between Oct 10, 2000, and Oct 26, 2006 (ie, the MDACC cohort). We did transcriptional profiling on samples obtained from the MDACC cohort to identify genes associated with time to progression. We did univariate Cox proportional hazards analyses and used significant genes to cluster IGHV-unmutated samples into two groups (intermediate prognosis and unfavourable prognosis). After using cross-validation to assess robustness, we applied the Lasso method to standardise the gene expression values to find a minimum gene signature. We validated this signature in an external cohort of treatment-naive patients with IGHV-unmutated chronic lymphocytic leukaemia enrolled on the CLL8 trial of the German Chronic Lymphocytic Leukaemia Study Group who were treated between July 21, 2003, and April 4, 2006 (ie, the CLL8 cohort)., Findings: The MDACC cohort consisted of 101 patients and the CLL8 cohort consisted of 109 patients. Using the MDACC cohort, we identified and developed a 17-gene expression signature that distinguished IGHV-unmutated patients who were likely to achieve a long-term remission following front-line FCR chemoimmunotherapy from those who might benefit from alternative front-line regimens (hazard ratio 3·83, 95% CI 1·94-7·59; p<0·0001). We validated this gene signature in the CLL8 cohort; patients with an unfavourable prognosis versus those with an intermediate prognosis had a cause-specific hazard ratio of 1·90 (95% CI 1·18-3·06; p=0·008). Median time to progression was 39 months (IQR 22-69) for those with an unfavourable prognosis compared with 59 months (28-84) for those with an intermediate prognosis., Interpretation: We have developed a robust, reproducible 17-gene signature that identifies a subset of treatment-naive patients with IGHV-unmutated chronic lymphocytic leukaemia who might substantially benefit from treatment with FCR chemoimmunotherapy. We recommend testing the value of this gene signature in a prospective study that compares FCR treatment with newer alternative therapies as part of a randomised clinical trial., Funding: Chronic Lymphocytic Leukaemia Global Research Foundation and the National Institutes of Health/National Cancer Institute., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: The BCL2 inhibitor venetoclax has shown activity in patients with chronic lymphocytic leukemia (CLL), but its efficacy in combination with other agents in patients with CLL and coexisting conditions is not known., Methods: In this open-label, phase 3 trial, we investigated fixed-duration treatment with venetoclax and obinutuzumab in patients with previously untreated CLL and coexisting conditions. Patients with a score of greater than 6 on the Cumulative Illness Rating Scale (scores range from 0 to 56, with higher scores indicating more impaired function of organ systems) or a calculated creatinine clearance of less than 70 ml per minute were randomly assigned to receive venetoclax-obinutuzumab or chlorambucil-obinutuzumab. The primary end point was investigator-assessed progression-free survival. The safety of each regimen was also evaluated., Results: In total, 432 patients (median age, 72 years; median Cumulative Illness Rating Scale score, 8; median creatinine clearance, 66.4 ml per minute) underwent randomization, with 216 assigned to each group. After a median follow-up of 28.1 months, 30 primary end-point events (disease progression or death) had occurred in the venetoclax-obinutuzumab group and 77 had occurred in the chlorambucil-obinutuzumab group (hazard ratio, 0.35; 95% confidence interval [CI], 0.23 to 0.53; P<0.001). The Kaplan-Meier estimate of the percentage of patients with progression-free survival at 24 months was significantly higher in the venetoclax-obinutuzumab group than in the chlorambucil-obinutuzumab group: 88.2% (95% CI, 83.7 to 92.6) as compared with 64.1% (95% CI, 57.4 to 70.8). This benefit was also observed in patients with TP53 deletion, mutation, or both and in patients with unmutated immunoglobulin heavy-chain genes. Grade 3 or 4 neutropenia occurred in 52.8% of patients in the venetoclax-obinutuzumab group and in 48.1% of patients in the chlorambucil-obinutuzumab group, and grade 3 or 4 infections occurred in 17.5% and 15.0%, respectively. All-cause mortality was 9.3% in the venetoclax-obinutuzumab group and 7.9% in the chlorambucil-obinutuzumab group. These differences were not significant., Conclusions: Among patients with untreated CLL and coexisting conditions, venetoclax-obinutuzumab was associated with longer progression-free survival than chlorambucil-obinutuzumab. (Funded by F. Hoffmann-La Roche and AbbVie; ClinicalTrials.gov number, NCT02242942.)., (Copyright © 2019 Massachusetts Medical Society.)

Purpose: A randomized, double-blind, phase III study of idelalisib (IDELA) plus rituximab versus placebo plus rituximab in patients with relapsed chronic lymphocytic leukemia (CLL) was terminated early because of superior efficacy of the IDELA-plus-rituximab (IDELA/R) arm. Patients in either arm could then enroll in an extension study to receive IDELA monotherapy. Here, we report the long-term efficacy and safety data for IDELA-treated patients across the primary and extension studies., Patients and Methods: Patients were randomly assigned to receive rituximab in combination with either IDELA 150 mg twice daily (IDELA/R; n = 110) or placebo (placebo/R; n = 110). Key end points were progression-free survival (PFS), overall response rate (ORR), overall survival (OS), and safety., Results: The long-term efficacy and safety of treatment with IDELA was assessed in 110 patients who received at least one dose of IDELA in the primary study, 75 of whom enrolled in the extension study. The IDELA/R-to-IDELA group had a median PFS of 20.3 months (95% CI, 17.3 to 26.3 months) after a median follow-up time of 18 months (range, 0.3 to 67.6 months). The ORR was 85.5% (94 of 110 patients; n = 1 complete response). The median OS was 40.6 months (95% CI, 28.5 to 57.3 months) and 34.6 months (95% CI, 16.0 months to not reached) for patients randomly assigned to the IDELA/R and placebo/R groups, respectively. Prolonged exposure to IDELA increased the incidence of all-grade, grade 2, and grade 3 or greater diarrhea (46.4%, 17.3%, and 16.4%, respectively), all-grade and grade 3 or greater colitis (10.9% and 8.2%, respectively) and all-grade and grade 3 or greater pneumonitis (10.0% and 6.4%, respectively) but did not increase the incidence of elevated hepatic aminotransferases., Conclusion: IDELA improved PFS and OS compared with rituximab alone in patients with relapsed CLL. Long-term IDELA was effective and had an expected safety profile. No new IDELA-related adverse events were identified with longer exposure.

Obinutuzumab (GA101) and ibrutinib show excellent efficacy for treatment of chronic lymphocytic leukemia (CLL). Preclinical investigations and a complementary safety profile were in support of testing their combined use. The exploratory CLL2-BIG-trial evaluated a sequential combination therapy following a recently proposed strategy. Two courses of bendamustine were used for debulking in patients with a high tumor load, followed by six courses of induction therapy with ibrutinib and GA101, followed by an MRD-triggered maintenance phase. The results of a pre-planned analysis at the end of the induction phase are presented. 61 patients were included, 30 previously untreated and 31 with relapsed/refractory CLL. 44 patients received bendamustine. During induction, neutropenia (14.8%) and thrombocytopenia (13.1%) were the most common CTC grade 3 and 4 events. One fatality (duodenitis) occurred. The overall response rate was 100%. 54.1% of patients achieved a partial remission, 41% a clinical complete remission (cCR) without confirmation by CT scan or bone marrow (BM) biopsy according to protocol and 4.9% a cCR with incomplete recovery of the BM. 29 patients (47.5%) had no detectable (<10 -4 ) minimal residual disease assessed by flow cytometry in peripheral blood. In conclusion, the BIG regimen is a safe and highly effective therapy for CLL.

Clinical trials in T-cell prolymphocytic leukemia (T-PLL) are scarce. Based on a precursor study testing fludarabine, mitoxantrone, and cyclophosphamide followed by alemtuzumab (FMC-A), we aimed to improve this regimen by upfront combining subcutaneous (s.c.) alemtuzumab with FMC for four cycles followed by an alemtuzumab-maintenance (FMCA + A). This prospective multicenter phase-II trial assessed response, survival, and toxicity of that regimen administered to pretreated (n = 4) and treatment-naïve (n = 12) T-PLL patients. The best overall response rate after FMCA was 68.8% (n = 11) including five CRs (31.3%) and six PRs (37.5%). Six patients entered the alemtuzumab-maintenance. Median overall and progression-free survival was 16.7 and 11.2 months, respectively. Hematologic toxicities were the most frequent grade 3/4 side effects. A reduced incidence of CMV-reactivations was attributed to the prophylactic administration of valganciclovir. Overall, FMCA + A did not improve the efficacy of the FMC-A-regimen or of single i.v. alemtuzumab. It suggests that a chemotherapy backbone prevents efficient alemtuzumab dosing and confirms that intravenous alemtuzumab is to be preferred over its s.c. route in T-PLL. ClinicalTrials.gov identifier: NCT01186640.

Clinical management of chronic lymphocytic leukaemia (CLL) in patients aged ≥80 years is based on limited evidence due to the lack of published information. Therefore, we analysed CLL patients aged ≥80 years using data from seven phase III clinical trials of the German CLL Study Group. Among 3552 participants, 152 were ≥80 years old at initiation of first-line study treatment. Median age was 82 years (range 80-90). Concomitant diseases were present in 99% of the patients, with a median cumulative illness rating scale score of 8 (0-18). Chemoimmunotherapy with chlorambucil-obinutuzumab (CLB-OB) or chlorambucil-rituximab (CLB-R) was administered to 61 (40%) and 56 (37%) patients. The remaining patients received CLB (n = 19) or fludarabine (F, n = 10), F/cyclophosphamide (FC, n = 1), FC/rituximab (FCR, n = 2) or bendamustine/rituximab (BR, n = 3). Rates of grade 3 or 4 neutropenia and infections were 35% and 13%. Overall response rate was 77% with 13% complete remissions. Median progression-free survival and treatment-free survival were 17·2 and 32·3 months, respectively. Median overall survival was 48·3 months; adverse events (22%) and progressive CLL (16·4%) were the most frequent causes of death. These findings suggest that anti-leukaemic treatment including chemoimmunotherapy is feasible and efficacious in ≥80-year-old CLL patients. However, this group of patients lives for a shorter time than age-matched controls of the general population., (© 2018 British Society for Haematology and John Wiley & Sons Ltd.)

The safety of obinutuzumab, alone or with chemotherapy, was studied in a non-randomized, open-label, non-comparative, phase IIIb study (GREEN) in previously untreated or relapsed/refractory chronic lymphocytic leukemia. Patients received obinutuzumab 1000 mg alone or with chemotherapy (investigator's choice of fludarabine-cyclophosphamide for fit patients, chlorambucil for unfit patients, or bendamustine for any patient) on days 1, 8 and 15 of cycle 1, and day 1 of cycles 2-6 (28-day cycles), with the cycle 1/day 1 dose administered over two days. The primary end point was safety/tolerability. Between October 2013 and March 2016, 972 patients were enrolled and 971 treated (126 with obinutuzumab monotherapy, 193 with obinutuzumab-fludarabine-cyclophosphamide, 114 with obinutuzumab-chlorambucil, and 538 with obinutuzumab-bendamustine). Grade ≥3 adverse events occurred in 80.3% of patients, and included neutropenia (49.9%), thrombocytopenia (16.4%), anemia (9.6%), and pneumonia (9.0%); rates were similar in first-line and relapsed/refractory patients, and in first-line fit and unfit patients. Using expanded definitions, infusion-related reactions were observed in 65.4% of patients (grade ≥3, 19.9%; mainly seen during the first obinutuzumab infusion), tumor lysis syndrome in 6.4% [clinical and laboratory; highest incidence with obinutuzumab-bendamustine (9.3%)], and infections in 53.7% (grade ≥3, 20.1%). Serious and fatal adverse events were seen in 53.1% and 7.3% of patients, respectively. In first-line patients, overall response rates at three months post treatment exceeded 80% for all obinutuzumab-chemotherapy combinations. In the largest trial of obinutuzumab to date, toxicities were generally manageable in this broad patient population. Safety data were consistent with previous reports, and response rates were high. ( clinicaltrials.gov identifier: 01905943 )., (Copyright© 2018 Ferrata Storti Foundation.)

Background: Targeted agents such as the type II anti-CD20 antibody obinutuzumab and the B-cell lymphoma-2 antagonist venetoclax have shown impressive therapeutic activity in chronic lymphocytic leukaemia. The CLL2-BAG trial was initiated to investigate the combination of these two agents in patients with chronic lymphocytic leukaemia., Methods: In this ongoing multicentre, open-label, investigator-initiated phase 2 trial, patients (aged ≥18 years) with chronic lymphocytic leukaemia requiring treatment according to the 2008 International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria and an Eastern Cooperative Oncology Group performance status of 0-2 were enrolled at 16 sites in Germany. Patients with a relevant tumour load (absolute lymphocyte count ≥25 000 cells per μL or lymph nodes with a diameter of ≥5 cm) received sequential treatment of debulking with two cycles of bendamustine (70 mg/m 2 intravenously on days 1 and 2 of each of the two 28-day cycles), followed by induction and maintenance with obinutuzumab (1000 mg intravenously on days 1-2, 8, and 15 of the first induction cycle, every 4 weeks in induction cycles 2-6, and every 12 weeks in the maintenance phase) and oral venetoclax (starting in induction cycle 2 with 20 mg/day, with a weekly dose escalation over 5 weeks to the target dose of 400 mg/day). The primary endpoint was the proportion of patients achieving an overall response by investigator assessment at the end of induction treatment. All patients who received at least two induction cycles were included in the efficacy analyses and all patients who received at least one dose of study drug were included in the safety analyses. This study is registered with ClinicalTrials.gov, number NCT02401503., Findings: Between May 6, 2015, and Jan 4, 2016, 66 patients were enrolled (35 treatment naive and 31 with relapsed or refractory disease), three of whom were excluded from the efficacy analysis because they received fewer than two induction cycles. Of the remaining 63 patients in the efficacy-evaluable population, 34 patients (54%) were treatment naive and 29 (46%) had relapsed or refractory disease. At data cutoff (Feb 28, 2017), all patients had completed induction treatment. At the end of the induction, 60 (95%) of 63 patients (95% CI 87-99) had responded, including all 34 patients in the treatment-naive cohort and 26 [90%] of 29 relapsed or refractory patients. The most common grade 3-4 adverse events during debulking were neutropenia and anaemia (five [11%] of 47 patients each), and thrombocytopenia and infection (three [6%] each). The most common grade 3-4 adverse events during induction were neutropenia (29 [44%] of 66 patients), infection (nine [14%]), thrombocytopenia (eight [12%]), infusion-related reactions (five [8%]), and secondary primary malignancy (four [6%]). 89 serious adverse events, including 69 related to study treatment, were reported. These serious adverse events were also mainly infections (four cases in four patients during debulking and 18 cases in 11 patients during induction) and cytopenia (four cases in four patients during debulking and ten cases in seven patients in induction). Five relapsed or refractory patients died: three cases of sepsis were deemed related to study treatment, whereas two deaths from Richter's transformation were not., Interpretation: The sequential application of bendamustine and obinutuzumab combined with venetoclax caused no unexpected or cumulative toxicities. The high proportion of patients who achieved overall responses, both treatment-naive and relapsed or refractory patients irrespective of physical fitness and genetic risk factors, compare favourably to established chronic lymphocytic leukaemia therapies. Further follow-up will help to define whether the remissions with eradication of minimal residual disease achieved with this combination are durable after treatment discontinuation., Funding: F Hoffmann-La Roche and AbbVie., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

GREEN (NCT01905943) is a non-randomized, open-label phase IIIb study investigating obinutuzumab alone or plus chemotherapy in chronic lymphocytic leukemia (CLL). We report a preplanned subgroup analysis of 158 previously untreated CLL patients receiving obinutuzumab-bendamustine (G-B). Patients received six 28-day cycles (C) of G-B: obinutuzumab day (D)1/D2 of C1 (25 mg D1/975 mg D2), 1000 mg D8 and D15 of C1, and D1 of C2-6; and bendamustine 70/90 mg/m 2 D1 and D2 of C1-6. The primary endpoint was safety/tolerability. Grade ≥3 adverse events (AEs) occurred in 82.3% of patients, including neutropenia (49.4%), thrombocytopenia (12.0%) and febrile neutropenia (10.8%). Serious AEs included neutropenia (12.7%), febrile neutropenia (9.5%) and pneumonia (7.6%). Rates of grade ≥3 infections and infusion-related reactions were 20.3% and 17.1%, respectively. Due to tumor lysis syndrome (TLS; 8.2%), including two associated fatalities (one in another study cohort), additional risk-minimization measures were implemented. Overall response rate was 81.0%. After 32.8 months' median observation time, 2-year progression-free survival was 81.8%. Minimal residual disease was undetectable in 59.5% (94/158) and 27.8% (44/158) of patients for blood and bone marrow, respectively. Frontline G-B appears to have manageable toxicity with clinical activity in CLL. Careful TLS risk assessment, pretreatment and monitoring is required.

Aim: Four Phase II trials (clinical trials numbers: NCT02345863, NCT02401503, NCT02445131 and NCT02689141) evaluate a different combination of targeted agents in an all-comer population of approximately 60 patients with chronic lymphocytic leukemia irrespective of prior treatment, physical fitness and genetic risk factors. Patients with a higher tumor load start with a debulking treatment with bendamustine. The subsequent induction and maintenance treatment with an anti-CD20 antibody (obinutuzumab or ofatumumab) and a targeted oral agent (ibrutinib, idelalisib or venetoclax) are continued until achievement of a complete response and minimal residual disease negativity., Conclusion: This strategy represents a new era of chronic lymphocytic leukemia therapy where chemotherapy is increasingly replaced by targeted agents and treatment duration is tailored to the patient's individual tumor load and response.

Background: Bendamustine plus rituximab is a standard of care for the management of patients with relapsed or refractory chronic lymphocytic leukaemia. New therapies are needed to improve clinically relevant outcomes in these patients. We assessed the efficacy and safety of adding idelalisib, a first-in-class targeted phosphoinositide-3-kinase δ inhibitor, to bendamustine plus rituximab in this population., Methods: For this international, multicentre, double-blind, placebo-controlled trial, adult patients (≥18 years) with relapsed or refractory chronic lymphocytic leukaemia requiring treatment who had measurable lymphadenopathy by CT or MRI and disease progression within 36 months since their last previous therapy were enrolled. Patients were randomly assigned (1:1) by a central interactive web response system to receive bendamustine plus rituximab for a maximum of six cycles (bendamustine: 70 mg/m 2 intravenously on days 1 and 2 for six 28-day cycles; rituximab: 375 mg/m 2 on day 1 of cycle 1, and 500 mg/m 2 on day 1 of cycles 2-6) in addition to either twice-daily oral idelalisib (150 mg) or placebo until disease progression or intolerable study drug-related toxicity. Randomisation was stratified by high-risk features (IGHV, del[17p], or TP53 mutation) and refractory versus relapsed disease. The primary endpoint was progression-free survival assessed by an independent review committee in the intention-to-treat population. This trial is ongoing and is registered with ClinicalTrials.gov, number NCT01569295., Findings: Between June 26, 2012, and Aug 21, 2014, 416 patients were enrolled and randomly assigned to the idelalisib (n=207) and placebo (n=209) groups. At a median follow-up of 14 months (IQR 7-18), median progression-free survival was 20·8 months (95% CI 16·6-26·4) in the idelalisib group and 11·1 months (8·9-11·1) in the placebo group (hazard ratio [HR] 0·33, 95% CI 0·25-0·44; p<0·0001). The most frequent grade 3 or worse adverse events in the idelalisib group were neutropenia (124 [60%] of 207 patients) and febrile neutropenia (48 [23%]), whereas in the placebo group they were neutropenia (99 [47%] of 209) and thrombocytopenia (27 [13%]). An increased risk of infection was reported in the idelalisib group compared with the placebo group (grade ≥3 infections and infestations: 80 [39%] of 207 vs 52 [25%] of 209). Serious adverse events, including febrile neutropenia, pneumonia, and pyrexia, were more common in the idelalisib group (140 [68%] of 207 patients) than in the placebo group (92 [44%] of 209). Treatment-emergent adverse events leading to death occurred in 23 (11%) patients in the idelalisib group and 15 (7%) in the placebo group, including six deaths from infections in the idelalisib group and three from infections in the placebo group., Interpretation: Idelalisib in combination with bendamustine plus rituximab improved progression-free survival compared with bendamustine plus rituximab alone in patients with relapsed or refractory chronic lymphocytic leukaemia. However, careful attention needs to be paid to management of serious adverse events and infections associated with this regimen during treatment selection., Funding: Gilead Sciences Inc., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Purpose To determine the value of minimal residual disease (MRD) assessments, together with the evaluation of clinical response in chronic lymphocytic leukemia according to the 2008 International Workshop on Chronic Lymphocytic Leukemia criteria. Patients and Methods Progression-free survival (PFS) and overall survival of 554 patients from two randomized trials of the German CLL Study Group (CLL8: fludarabine and cyclophosphamide [FC] v FC plus rituximab; CLL10: FC plus rituximab v bendamustine plus rituximab) were analyzed according to MRD assessed in peripheral blood at a threshold of 10 -4 and clinical response. The prognostic value of different parameters defining a partial response (PR) was further investigated. Results Patients with MRD-negative complete remission (CR), MRD-negative PR, MRD-positive CR, and MRD-positive PR experienced a median PFS from a landmark at end of treatment of 61 months, 54 months, 35 months, and 21 months, respectively. PFS did not differ significantly between MRD-negative CR and MRD-negative PR; however, PFS was longer for MRD-negative PR than for MRD-positive CR ( P = .048) and for MRD-positive CR compared with MRD-positive PR ( P = .002). Compared with MRD-negative CR, only patients with MRD-positive PR had a significantly shorter overall survival (not reached v 72 months; P = .001), whereas there was no detectable difference for patients with MRD-negative PR or MRD-positive CR ( P = 0.612 and P = 0.853, respectively). Patients with MRD-negative PR who presented with residual splenomegaly had only a similar PFS (63 months) compared with patients with MRD-negative CR (61 months; P = .354), whereas patients with MRD-negative PR with lymphadenopathy showed a shorter PFS (31 months; P < .001). Conclusion MRD quantification allows for improved PFS prediction in both patients who achive PR and CR, which thus supports its application in all responders. In contrast to residual lymphadenopathy, persisting splenomegaly does not impact outcome in patients with MRD-negative PR.

Purpose: A phase I/II trial to assess safety and efficacy of the combination bendamustine, rituximab, and lenalidomide (BRL) in patients with chronic lymphocytic leukemia (CLL)., Patients and Methods: Seventeen relapsed or refractory (R/R) and five previously untreated (FL) CLL patients were enrolled in the trial. In the R/R cohort, four different dose levels of lenalidomide (maximum 15 mg/d) were used. In the FL cohort, lenalidomide was dose escalated from 5 mg/d to 15 mg/d. Bendamustine was used at doses of 50 or 90 mg/m(2) for R/R or FL treatment, respectively. 375 mg/m(2) Rituximab were used for the first and 500 mg/m(2) for subsequent treatment courses. Treatment consisted of up to six courses of 28 d., Results: The maximal tolerable dose of lenalidomide was 5 mg/d. The response rate was 47.1% in R/R and 60% in FL patients. Median progression-free survival was 8.0 months. Median overall survival was 22.9 and 12.3 months, respectively, in R/R and FL patients. Grade 3/4 hematological toxicity was observed in 71.4%, and severe infections in 47.6% of patients. Due to high toxicity and low response rate of BRL, the trial was closed prematurely., Conclusion: BRL was associated with a high toxicity rate, a high number of treatment interruptions, and a low remission rate. Therefore, BRL cannot be considered an appropriate treatment option for patients with CLL., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Mantle cell lymphoma is characterised by a poor long-term prognosis. The European Mantle Cell Lymphoma Network aimed to investigate whether the introduction of high-dose cytarabine to immunochemotherapy before autologous stem-cell transplantation (ASCT) improves outcome., Methods: This randomised, open-label, parallel-group, phase 3 trial was done in 128 haemato-oncological hospital departments or private practices in Germany, France, Belgium, and Poland. Patients aged 65 years or younger with untreated stage II-IV mantle cell lymphoma were centrally randomised (1:1), with computer-assisted random block selection, to receive either six courses of R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) followed by myeloablative radiochemotherapy and ASCT (control group), or six courses of alternating R-CHOP or R-DHAP (rituximab plus dexamethasone, high-dose cytarabine, and cisplatin) followed by a high-dose cytarabine-containing conditioning regimen and ASCT (cytarabine group). Patients were stratified by study group and international prognostic index. The primary outcome was time to treatment failure from randomisation to stable disease after at least four induction cycles, progression, or death from any cause. Patients with stage II-IV mantle cell lymphoma were included in the primary analysis if treatment was started according to randomisation. For safety analyses, patients were assessed according to the treatment actually started. This study is registered with ClinicalTrials.gov, number NCT00209222., Findings: Of 497 patients (median age 55 years [IQR 49-60]) randomised from July 20, 2004, to March 18, 2010, 234 of 249 in the control group and 232 of 248 in the cytarabine group were included in the primary analysis. After a median follow-up of 6.1 years (95% CI 5.4-6.4), time to treatment failure was significantly longer in the cytarabine group (median 9.1 years [95% CI 6.3-not reached], 5 year rate 65% [95% CI 57-71]) than in the control group (3.9 years [3.2-4.4], 40% [33-46]; hazard ratio 0.56; p=0.038). During induction immunochemotherapy, patients who received high-dose cytarabine had increased grade 3 or 4 haematological toxicity (haemoglobin 71 [29%] of 241m vs 19 [8%] of 227 controls; platelets 176 [73%] of 240 vs 21 [9%] of 225), grade 3 or 4 febrile neutropenia (39 [17%] of 230 vs 19 [8%] of 224), and grade 1 or 2 renal toxicity (creatinine 102 [43%] of 236 vs 22 [10%] of 224). The number of ASCT-related deaths was similar (eight [3.4%]) in both groups., Interpretation: Immunochemotherapy containing high-dose cytarabine followed by ASCT should be considered standard of care in patients aged 65 years or younger with mantle cell lymphoma., Funding: European Commission, Lymphoma Research Foundation, and Roche., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: High-dose methotrexate-based chemotherapy is standard for primary CNS lymphoma, but most patients relapse. High-dose chemotherapy with autologous stem cell transplantation (HCT-ASCT) is supposed to overcome the blood-brain barrier and eliminate residual disease in the CNS. We aimed to investigate the safety and efficacy of HCT-ASCT in patients with newly diagnosed primary CNS lymphoma., Methods: In this prospective, single-arm, phase 2 trial, we recruited patients aged 18-65 years with newly diagnosed primary CNS lymphoma and immunocompetence, with no limitation on clinical performance status, from 15 hospitals in Germany. Patients received five courses of intravenous rituximab 375 mg/m(2) (7 days before first high-dose methotrexate course and then every 10 days) and four courses of intravenous high-dose methotrexate 8000 mg/m(2) (every 10 days) and then two courses of intravenous rituximab 375 mg/m(2) (day 1), cytarabine 3 g/m(2) (days 2 and 3), and thiotepa 40 mg/m(2) (day 3). 3 weeks after the last course, patients commenced intravenous HCT-ASCT (rituximab 375 mg/m(2) [day 1], carmustine 400 mg/m(2) [day 2], thiotepa 2 × 5 mg/kg [days 3 and 4], and infusion of stem cells [day 7]), irrespective of response status after induction. We restricted radiotherapy to patients without complete response after HCT-ASCT. The primary endpoint was complete response at day 30 after HCT-ASCT in all registered eligible patients who received at least 1 day of study treatment. This trial is registered at ClinicalTrials.gov, number NCT00647049., Findings: Between Jan 18, 2007, and May 23, 2011, we recruited 81 patients, of whom two (2%) were excluded, therefore we included 79 (98%) patients in the analysis. All patients started induction treatment; 73 (92%) commenced HCT-ASCT. 61 (77·2% [95% CI 66·1-86·6]) patients achieved a complete response. During induction treatment, the most common grade 3 toxicity was anaemia (37 [47%]) and the most common grade 4 toxicity was thrombocytopenia (50 [63%]). During HCT-ASCT, the most common grade 3 toxicity was fever (50 [68%] of 73) and the most common grade 4 toxicity was leucopenia (68 [93%] of 73). We recorded four (5%) treatment-related deaths (three [4%] during induction and one [1%] 4 weeks after HCT-ASCT)., Interpretation: HCT-ASCT with thiotepa and carmustine is an effective treatment option in young patients with newly diagnosed primary CNS lymphoma, but further comparative studies are needed., Funding: University Hospital Freiburg and Amgen., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab is the standard therapy for physically fit patients with advanced chronic lymphocytic leukaemia. This international phase 3 study compared the efficacy and tolerance of the standard therapy with a potentially less toxic combination consisting of bendamustine and rituximab., Methods: Treatment-naive fit patients with chronic lymphocytic leukaemia (aged 33-81 years) without del(17p) were enrolled after undergoing a central screening process. Patients were randomly assigned (1:1) with a computer-generated randomisation list using randomly permuted blocks with a block size of eight and were stratified according to participating country and Binet stage. Patients were allocated to receive six cycles of intravenous fludarabine (25 mg/m(2) per day) and cyclophosphamide (250 mg/m(2) per day) for the first 3 days or to intravenous bendamustine (90 mg/m(2) per day) for the first 2 days of each cycle. Rituximab 375 mg/m(2) was given intravenously in both groups on day 0 of cycle 1 and subsequently was given at 500 mg/m(2) during the next five cycles on day 1. The primary endpoint was progression-free survival with the objective to assess non-inferiority of bendamustine and rituximab to the standard therapy. We aimed to show that the 2-year progression-free survival with bendamustine and rituximab was not 67·5% or less with a corresponding non-inferiority margin of 1·388 for the hazard ratio (HR) based on the 90·4% CI. The final analysis was done by intention to treat. The study is registered with ClinicalTrials.gov, number NCT%2000769522., Findings: 688 patients were recruited between Oct 2, 2008, and July 11, 2011, of which 564 patients who met inclusion criteria were randomly assigned. 561 patients were included in the intention-to-treat population: 282 patients in the fludarabine, cyclophosphamide, and rituximab group and 279 in the bendamustine and rituximab group. After a median observation time of 37·1 months (IQR 31·0-45·5) median progression-free survival was 41·7 months (95% CI 34·9-45·3) with bendamustine and rituximab and 55·2 months (95% CI not evaluable) with fludarabine, cyclophosphamide, and rituximab (HR 1·643, 90·4% CI 1·308-2·064). As the upper limit of the 90·4% CI was greater than 1·388 the null hypothesis for the corresponding non-inferiority hypothesis was not rejected. Severe neutropenia and infections were more frequently observed with fludarabine, cyclophosphamide, and rituximab (235 [84%] of 279 vs 164 [59%] of 278, and 109 [39%] vs 69 [25%], respectively) during the study. The increased frequency of infectious complications with fludarabine, cyclophosphamide, and rituximab was more pronounced in patients older than 65 years., Interpretation: The combination of fludarabine, cyclophosphamide, and rituximab remains the standard front-line therapy in fit patients with chronic lymphocytic leukaemia, but bendamustine and rituximab is associated with less toxic effects., Funding: Roche Pharma AG, Mundipharma, German Federal Ministry of Education and Research., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Standard treatment for patients with primary CNS lymphoma remains to be defined. Active therapies are often associated with increased risk of haematological or neurological toxicity. In this trial, we addressed the tolerability and efficacy of adding rituximab with or without thiotepa to methotrexate-cytarabine combination therapy (the MATRix regimen), followed by a second randomisation comparing consolidation with whole-brain radiotherapy or autologous stem cell transplantation in patients with primary CNS lymphoma. We report the results of the first randomisation in this Article., Methods: For the international randomised phase 2 International Extranodal Lymphoma Study Group-32 (IELSG32) trial, HIV-negative patients (aged 18-70 years) with newly diagnosed primary CNS lymphoma and measurable disease were enrolled from 53 cancer centres in five European countries (Denmark, Germany, Italy, Switzerland, and the UK) and randomly assigned (1:1:1) to receive four courses of methotrexate 3·5 g/m(2) on day 1 plus cytarabine 2 g/m(2) twice daily on days 2 and 3 (group A); or the same combination plus two doses of rituximab 375 mg/m(2) on days -5 and 0 (group B); or the same methotrexate-cytarabine-rituximab combination plus thiotepa 30 mg/m(2) on day 4 (group C), with the three groups repeating treatment every 3 weeks. Patients with responsive or stable disease after the first stage were then randomly allocated between whole-brain radiotherapy and autologous stem cell transplantation. A permuted blocks randomised design (block size four) was used for both randomisations, and a computer-generated randomisation list was used within each stratum to preserve allocation concealment. Randomisation was stratified by IELSG risk score (low vs intermediate vs high). No masking after assignment to intervention was used. The primary endpoint of the first randomisation was the complete remission rate, analysed by modified intention to treat. This study is registered with ClinicalTrials.gov, number NCT01011920., Findings: Between Feb 19, 2010, and Aug 27, 2014, 227 eligible patients were recruited. 219 of these 227 enrolled patients were assessable. At median follow-up of 30 months (IQR 22-38), patients treated with rituximab and thiotepa had a complete remission rate of 49% (95% CI 38-60), compared with 23% (14-31) of those treated with methotrexate-cytarabine alone (hazard ratio 0·46, 95% CI 0·28-0·74) and 30% (21-42) of those treated with methotrexate-cytarabine plus rituximab (0·61, 0·40-0·94). Grade 4 haematological toxicity was more frequent in patients treated with methotrexate-cytarabine plus rituximab and thiotepa, but infective complications were similar in the three groups. The most common grade 3-4 adverse events in all three groups were neutropenia, thrombocytopenia, anaemia, and febrile neutropenia or infections. 13 (6%) patients died of toxicity., Interpretation: With the limitations of a randomised phase 2 study design, the IELSG32 trial provides a high level of evidence supporting the use of MATRix combination as the new standard chemoimmunotherapy for patients aged up to 70 years with newly diagnosed primary CNS lymphoma and as the control group for future randomised trials., Funding: Associazione Italiana del Farmaco, Cancer Research UK, Oncosuisse, and Swiss National Foundation., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Despite promising results with targeted drugs, chemoimmunotherapy with fludarabine, cyclophosphamide (FC), and rituximab (R) remains the standard therapy for fit patients with untreated chronic lymphocytic leukemia (CLL). Herein, we present the long-term follow-up of the randomized CLL8 trial reporting safety and efficacy of FC and FCR treatment of 817 treatment-naïve patients with CLL. The primary end point was progression-free survival (PFS). With a median follow-up of 5.9 years, median PFS were 56.8 and 32.9 months for the FCR and FC group (hazard ratio [HR], 0.59; 95% confidence interval [CI], 0.50-0.69, P < .001). Median overall survival (OS) was not reached for the FCR group and was 86.0 months for the FC group (HR, 0.68; 95% CI, 0.54-0.89, P = .001). In patients with mutated IGHV (IGHV MUT), FCR improved PFS and OS compared with FC (PFS: HR, 0.47; 95% CI, 0.33-0.68, P < .001; OS: HR, 0.62; 95% CI, 0.34-1.11, P = .1). This improvement remained applicable for all cytogenetic subgroups other than del(17p). Long-term safety analyses showed that FCR had a higher rate of prolonged neutropenia during the first year after treatment (16.6% vs 8.8%; P = .007). Secondary malignancies including Richter's transformation occurred in 13.1% in the FCR group and in 17.4% in the FC group (P = .1). First-line chemoimmunotherapy with FCR induces long-term remissions and highly relevant improvement in OS in specific genetic subgroups of fit patients with CLL, in particular those with IGHV MUT. This trial was registered at www.clinicaltrials.gov as #NCT00281918., (© 2016 by The American Society of Hematology.)

Multidimensional geriatric assessment (GA) has been demonstrated to predict outcomes in older patients with cancer. This study evaluated GA in a cohort of older patients with chronic lymphocytic leukemia (CLL). Seventy-five of 97 subjects with CLL who were enrolled in a clinical trial of the German CLL Study Group underwent GA prior to the start of study treatment (low-dose chemotherapy with fludarabine). GA included cumulative illness rating scale (CIRS), timed-up-and-go (TUG) test, dementia detection (DEMTECT) test and instrumental activities of daily living (IADL) index. There was little correlation between CIRS, TUG, DEMTECT or IADL results and treatment toxicity, feasibility or efficacy in this study. CIRS and IADL had no statistically significant impact on overall prognosis. However, under-performance in TUG or DEMTECT test was strongly associated with poor survival. The latter findings provide a rationale to further investigate geriatric assessment in CLL and in the context with other CLL treatments.

To evaluate the effect of first-line and subsequent therapies, the outcome of 1,558 patients with chronic lymphocytic leukemia from five prospective phase II/III trials conducted between 1999 and 2010 was analyzed. The 3-year overall survival rate was higher after first-line treatment with chemoimmunotherapies such as fludarabine/cyclophosphamide/rituximab (87.9%) or bendamustine/rituximab (90.7%) compared to chemotherapies without an antibody (fludarabine/cyclophosphamide: 84.6%; fludarabine: 77.5%; chlorambucil: 77.4%). Furthermore, the median overall survival was longer in patients receiving at least one antibody-containing regimen in any treatment line (94.4 months) compared to the survival in patients who never received an antibody (84.3 months, P<0.0001). Univariate Cox regression analysis demonstrated that patients who did receive antibody treatment had a 1.42-fold higher risk of death (hazard ratio, 1.42; 95% confidence interval: 1.185-1.694). Therapies administered at relapse were very heterogeneous. Only 55 of 368 patients (14.9%) who started second-line treatment >24 months after first-line therapy repeated the first-line regimen. Among 315 patients requiring treatment ≤24 months after first-line therapy, cyclophosphamide/doxorubicin/vincristine/prednisone with or without rituximab as well as alemtuzumab were the most commonly used therapies. In these early relapsing patients, the median overall survival was shorter following therapies containing an anthracycline and/or three or more cytotoxic agents (e.g. cyclophosphamide/doxorubicin/vincristine/prednisone or fludarabine/cyclophosphamide/mitoxantrone, 30.0 months) compared to single agent chemotherapy (e.g. fludarabine; 39.6 months) and standard chemoimmunotherapy (e.g. fludarabine/cyclophosphamide/rituximab: 61.6 months). In conclusion, the analysis confirms the superior efficacy of chemoimmunotherapies in patients with chronic lymphocytic leukemia. Moreover, the use of aggressive chemo(immuno)therapy combinations in patients with an early relapse does not offer any benefit when compared to less intensive therapies. Trial identifier: NCT00281918, ISRCTN75653261, ISRCTN36294212, NCT00274989 and NCT00147901., (Copyright© Ferrata Storti Foundation.)

This phase II trial evaluated efficacy and tolerability of R-CHOP for up to 8 courses in Richter transformation (RT) and up to 6 courses in CLL plus autoimmune cytopenia (AIC) or high-risk (HR) features. HR was defined as fludarabine-refractoriness or early relapse (<36 months) after fludarabine-based treatment; 26 patients were included as HR, 19 patients had AIC, and 15 patients had RT. In the HR cohort, overall response rate was 54%, progression-free and overall survival were 9 and 21 months. In AIC patients overall response rate was 74%, progression-free and overall-survival were 10 and 41 months, respectively, and median increase in hemoglobin was 3.4 g/L. RT patients responded in 67%, progression-free was 10 and overall survival 21 months. The most common adverse events were hematologic toxicities in 92%. Severe infections occurred in 28%. Treatment was discontinued early in 45% of all patients mainly as a result of toxicity. This trial shows that R-CHOP has no role in treating complicated CLL. R-CHOP is associated with significant toxicities and fairly low efficacy compared with almost every other CLL-regimen. In RT, it might still be used as an induction therapy before allogeneic stem cell transplantation., (© 2014 Wiley Periodicals, Inc.)

Purpose: Mantle-cell lymphoma (MCL) is a distinct B-cell lymphoma associated with poor outcome. In 2008, the MCL International Prognostic Index (MIPI) was developed as the first prognostic stratification tool specifically directed to patients with MCL. External validation was planned to be performed on the cohort of the two recently completed randomized trials of the European MCL Network., Patients and Methods: Data of 958 patients with MCL (median age, 65 years; range, 32 to 87 years) treated upfront in the trials MCL Younger or MCL Elderly were pooled to assess the prognostic value of MIPI with respect to overall survival (OS) and time to treatment failure (TTF)., Results: Five-year OS rates in MIPI low, intermediate, and high-risk groups were 83%, 63%, and 34%, respectively. The hazard ratios for OS of intermediate versus low and high versus intermediate risk patients were 2.1 (95% CI, 1.5 to 2.9) and 2.6 (2.0 to 3.3), respectively. MIPI was similarly prognostic for TTF. All four clinical baseline characteristics constituting the MIPI, age, performance status, lactate dehydrogenase level, and WBC count, were confirmed as independent prognostic factors for OS and TTF. The validity of MIPI was independent of trial cohort and treatment strategy., Conclusion: MIPI was prospectively validated in a large MCL patient cohort homogenously treated according to recognized standards. As reflected in current guidelines, MIPI represents a generally applicable prognostic tool to be used in research as well as in clinical routine, and it can help to develop risk-adapted treatment strategies to further improve clinical outcome in MCL.

Background: The monoclonal anti-CD20 antibody rituximab, combined with chemotherapeutic agents, has been shown to prolong overall survival in physically fit patients with previously untreated chronic lymphocytic leukemia (CLL) but not in those with coexisting conditions. We investigated the benefit of the type 2, glycoengineered antibody obinutuzumab (also known as GA101) as compared with that of rituximab, each combined with chlorambucil, in patients with previously untreated CLL and coexisting conditions., Methods: We randomly assigned 781 patients with previously untreated CLL and a score higher than 6 on the Cumulative Illness Rating Scale (CIRS) (range, 0 to 56, with higher scores indicating worse health status) or an estimated creatinine clearance of 30 to 69 ml per minute to receive chlorambucil, obinutuzumab plus chlorambucil, or rituximab plus chlorambucil. The primary end point was investigator-assessed progression-free survival., Results: The patients had a median age of 73 years, creatinine clearance of 62 ml per minute, and CIRS score of 8 at baseline. Treatment with obinutuzumab-chlorambucil or rituximab-chlorambucil, as compared with chlorambucil monotherapy, increased response rates and prolonged progression-free survival (median progression-free survival, 26.7 months with obinutuzumab-chlorambucil vs. 11.1 months with chlorambucil alone; hazard ratio for progression or death, 0.18; 95% confidence interval [CI], 0.13 to 0.24; P<0.001; and 16.3 months with rituximab-chlorambucil vs. 11.1 months with chlorambucil alone; hazard ratio, 0.44; 95% CI, 0.34 to 0.57; P<0.001). Treatment with obinutuzumab-chlorambucil, as compared with chlorambucil alone, prolonged overall survival (hazard ratio for death, 0.41; 95% CI, 0.23 to 0.74; P=0.002). Treatment with obinutuzumab-chlorambucil, as compared with rituximab-chlorambucil, resulted in prolongation of progression-free survival (hazard ratio, 0.39; 95% CI, 0.31 to 0.49; P<0.001) and higher rates of complete response (20.7% vs. 7.0%) and molecular response. Infusion-related reactions and neutropenia were more common with obinutuzumab-chlorambucil than with rituximab-chlorambucil, but the risk of infection was not increased., Conclusions: Combining an anti-CD20 antibody with chemotherapy improved outcomes in patients with CLL and coexisting conditions. In this patient population, obinutuzumab was superior to rituximab when each was combined with chlorambucil. (Funded by F. Hoffmann-La Roche; ClinicalTrials.gov number, NCT01010061.).

Background: Patients with relapsed chronic lymphocytic leukemia (CLL) who have clinically significant coexisting medical conditions are less able to undergo standard chemotherapy. Effective therapies with acceptable side-effect profiles are needed for this patient population., Methods: In this multicenter, randomized, double-blind, placebo-controlled, phase 3 study, we assessed the efficacy and safety of idelalisib, an oral inhibitor of the delta isoform of phosphatidylinositol 3-kinase, in combination with rituximab versus rituximab plus placebo. We randomly assigned 220 patients with decreased renal function, previous therapy-induced myelosuppression, or major coexisting illnesses to receive rituximab and either idelalisib (at a dose of 150 mg) or placebo twice daily. The primary end point was progression-free survival. At the first prespecified interim analysis, the study was stopped early on the recommendation of the data and safety monitoring board owing to overwhelming efficacy., Results: The median progression-free survival was 5.5 months in the placebo group and was not reached in the idelalisib group (hazard ratio for progression or death in the idelalisib group, 0.15; P<0.001). Patients receiving idelalisib versus those receiving placebo had improved rates of overall response (81% vs. 13%; odds ratio, 29.92; P<0.001) and overall survival at 12 months (92% vs. 80%; hazard ratio for death, 0.28; P=0.02). Serious adverse events occurred in 40% of the patients receiving idelalisib and rituximab and in 35% of those receiving placebo and rituximab., Conclusions: The combination of idelalisib and rituximab, as compared with placebo and rituximab, significantly improved progression-free survival, response rate, and overall survival among patients with relapsed CLL who were less able to undergo chemotherapy. (Funded by Gilead; ClinicalTrials.gov number, NCT01539512.).