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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.) more...

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.) more...

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.) more...

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. more...

Based on centroblast frequency, follicular lymphoma (FL) is subdivided into grades 1-2, 3A, and 3B. Grade FL3A frequently coexists with FL1-2 (FL1-2-3A). Based on clinical trials, FL1-2 is treated with rituximab (R) or obinutuzumab plus bendamustine (B) or CHOP, while FL3B is treated with R-CHOP. In contrast, there are little data guiding therapy in FL3A. We present a retrospective, multicenter analysis of 95 FL3A or FL1-2-3A and 203 FL1-2 patients treated with R-CHOP or R-B first-line. R-CHOP facilitated a higher response rate (95% versus 76%) and longer overall survival (OS) (3-year OS 89% versus 73%, P = 0.008) in FL3A or FL1-2-3A, whereas the difference in progression-free survival (PFS) did not reach statistical significance. While transformation rates into aggressive lymphoma were similar between both groups, there were more additional malignancies after R-B compared with R-CHOP (6 versus 2 cases). In FL1-2, R-B achieved a higher 3-year PFS (79% versus 47%, P < 0.01), while there was no significant difference regarding OS or transformation. With the limitations of a retrospective analysis, these results suggest a benefit for R-CHOP over R-B in FL3A or FL1-2-3A. Confirmatory data from prospective clinical trials are needed. more...

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. more...

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. more...

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. more...

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.) more...

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. more...

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. more...

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. more...

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.) more...

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.) more...

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.) more...

Updated results of the CLL8 trial confirm that the addition of rituximab to chemotherapy with fludarabine and cyclophosphamide (FC) leads to a prolongation of progression-free (PFS) and overall survival (OS) in first-line treatment of physically fit patients. After a median observation time of 47 months, median PFS was 57.9 months for patients treated with FC and rituximab (FCR) and 32.9 months for patients treated with FC alone (hazard ratio 0.56, 95% confidence interval 0.465-0.673; p < 0.001). A total of 232 patients were treated for relapse, among them 91 of 408 (22%) initially treated with FCR and 141 of 409 (35%) initially treated with FC. The drugs most frequently used either alone or in combination were rituximab (52% of all second-line therapies), fludarabine (21%), bendamustine (21%) and alemtuzumab (12%). The regimens chosen for second-line treatment after FC or FCR were heterogeneous, which underlines a need for further trials in order to define treatment recommendations for patients with relapsed chronic lymphocytic leukemia. more...

Purpose: We investigated the safety and efficacy of bendamustine and rituximab (BR) in previously untreated patients with chronic lymphocytic leukemia (CLL)., Patients and Methods: In all, 117 patients, age 34 to 78 years, 46.2% of patients at Binet stage C, and 25.6% of patients age 70 years or older received BR chemoimmunotherapy for first-line treatment of CLL. Bendamustine was administered at a dose of 90 mg/m(2) on days 1 and 2 combined with 375 mg/m(2) rituximab on day 0 of the first course and 500 mg/m(2) on day 1 during subsequent courses for up to six courses., Results: Overall response rate was 88.0% (95% CI, 80.7% to 100.0%) with a complete response rate of 23.1% and a partial response rate of 64.9%. Ninety percent of patients with del(11q), 94.7% with trisomy 12, 37.5% with del(17p), and 89.4% with unmutated IGHV status responded to treatment. After a median observation time of 27.0 months, median event-free survival was 33.9 months, and 90.5% of patients were alive. Grade 3 or 4 severe infections occurred in 7.7% of patients. Grade 3 or 4 adverse events for neutropenia, thrombocytopenia, and anemia were documented in 19.7%, 22.2%, and 19.7% of patients, respectively., Conclusion: Chemoimmunotherapy with BR is effective and safe in patients with previously untreated CLL. more...

Purpose: To determine the clinical significance of flow cytometric minimal residual disease (MRD) quantification in chronic lymphocytic leukemia (CLL) in addition to pretherapeutic risk factors and to compare the prognostic impact of MRD between the arms of the German CLL Study Group CLL8 trial., Patients and Methods: MRD levels were prospectively quantified in 1,775 blood and bone marrow samples from 493 patients randomly assigned to receive fludarabine and cyclophosphamide (FC) or FC plus rituximab (FCR). Patients were categorized by MRD into low- (< 10(-4)), intermediate- (≥ 10(-4) to <10(-2)), and high-level (≥ 10(-2)) groups., Results: Low MRD levels during and after therapy were associated with longer progression-free survival (PFS) and overall survival (OS; P < .0001). Median PFS is estimated at 68.7, 40.5, and 15.4 months for low, intermediate, and high MRD levels, respectively, when assessed 2 months after therapy. Compared with patients with low MRD, greater risks of disease progression were associated with intermediate and high MRD levels (hazard ratios, 2.49 and 14.7, respectively; both P < .0001). Median OS was 48.4 months in patients with high MRD and was not reached for lower MRD levels. MRD remained predictive for OS and PFS in multivariate analyses that included the most important pretherapeutic risk markers in CLL. PFS and OS did not differ between treatment arms within each MRD category. However, FCR induced low MRD levels more frequently than FC., Conclusion: MRD levels independently predict OS and PFS in CLL. Therefore, MRD quantification might serve as a surrogate marker to assess treatment efficacy in randomized trials before clinical end points can be evaluated. more...

Purpose: The objective of this trial was to evaluate safety and efficacy of bendamustine combined with rituximab (BR) in patients with relapsed and/or refractory chronic lymphocytic leukemia (CLL)., Patients and Methods: Seventy-eight patients, including 22 patients with fludarabine-refractory disease (28.2%) and 14 patients (17.9%) with deletion of 17p, received BR chemoimmunotherapy. Bendamustine was administered at a dose of 70 mg/m(2) on days 1 and 2 combined with rituximab 375 mg/m(2) on day 0 of the first course and 500 mg/m(2) on day 1 during subsequent courses for up to six courses., Results: On the basis of intent-to-treat analysis, the overall response rate was 59.0% (95% CI, 47.3% to 70.0%). Complete response, partial response, and nodular partial response were achieved in 9.0%, 47.4%, and 2.6% of patients, respectively. Overall response rate was 45.5% in fludarabine-refractory patients and 60.5% in fludarabine-sensitive patients. Among genetic subgroups, 92.3% of patients with del(11q), 100% with trisomy 12, 7.1% with del(17p), and 58.7% with unmutated IGHV status responded to treatment. After a median follow-up time of 24 months, the median event-free survival was 14.7 months. Severe infections occurred in 12.8% of patients. Grade 3 or 4 neutropenia, thrombocytopenia, and anemia were documented in 23.1%, 28.2%, and 16.6% of patients, respectively., Conclusion: Chemoimmunotherapy with BR is effective and safe in patients with relapsed CLL and has notable activity in fludarabine-refractory disease. Major but tolerable toxicities were myelosuppression and infections. These promising results encouraged us to initiate a further phase II trial evaluating the BR regimen in patients with previously untreated CLL. more...

Background: On the basis of promising results that were reported in several phase 2 trials, we investigated whether the addition of the monoclonal antibody rituximab to first-line chemotherapy with fludarabine and cyclophosphamide would improve the outcome of patients with chronic lymphocytic leukaemia., Methods: Treatment-naive, physically fit patients (aged 30-81 years) with CD20-positive chronic lymphocytic leukaemia were randomly assigned in a one-to-one ratio to receive six courses of intravenous fludarabine (25 mg/m(2) per day) and cyclophosphamide (250 mg/m(2) per day) for the first 3 days of each 28-day treatment course with or without rituximab (375 mg/m(2) on day 0 of first course, and 500 mg/m(2) on day 1 of second to sixth courses) in 190 centres in 11 countries. Investigators and patients were not masked to the computer-generated treatment assignment. The primary endpoint was progression-free survival (PFS). Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00281918., Findings: 408 patients were assigned to fludarabine, cyclophosphamide, and rituximab (chemoimmunotherapy group) and 409 to fludarabine and cyclophosphamide (chemotherapy group); all patients were analysed. At 3 years after randomisation, 65% of patients in the chemoimmunotherapy group were free of progression compared with 45% in the chemotherapy group (hazard ratio 0·56 [95% CI 0·46-0·69], p<0·0001); 87% were alive versus 83%, respectively (0·67 [0·48-0·92]; p=0·01). Chemoimmunotherapy was more frequently associated with grade 3 and 4 neutropenia (136 [34%] of 404 vs 83 [21%] of 396; p<0·0001) and leucocytopenia (97 [24%] vs 48 [12%]; p<0·0001). Other side-effects, including severe infections, were not increased. There were eight (2%) treatment-related deaths in the chemoimmunotherapy group compared with ten (3%) in the chemotherapy group., Interpretation: Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab improves progression-free survival and overall survival in patients with chronic lymphocytic leukaemia. Moreover, the results suggest that the choice of a specific first-line treatment changes the natural course of chronic lymphocytic leukaemia., Funding: F Hoffmann-La Roche., (Copyright © 2010 Elsevier Ltd. All rights reserved.) more...

The prognostic impact of minimal residual disease (MRD) was analyzed in 259 patients with mantle cell lymphoma (MCL) treated within 2 randomized trials of the European MCL Network (MCL Younger and MCL Elderly trial). After rituximab-based induction treatment, 106 of 190 evaluable patients (56%) achieved a molecular remission (MR) based on blood and/or bone marrow (BM) analysis. MR resulted in a significantly improved response duration (RD; 87% vs 61% patients in remission at 2 years, P = .004) and emerged to be an independent prognostic factor for RD (hazard ratio = 0.4, 95% confidence interval, 0.1-0.9, P = .028). MR was highly predictive for prolonged RD independent of clinical response (complete response [CR], complete response unconfirmed [CRu], partial response [PR]; RD at 2 years: 94% in BM MRD-negative CR/CRu and 100% in BM MRD-negative PR, compared with 71% in BM MRD-positive CR/CRu and 51% in BM MRD-positive PR, P = .002). Sustained MR during the postinduction period was predictive for outcome in MCL Younger after autologous stem cell transplantation (ASCT; RD at 2 years 100% vs 65%, P = .001) and during maintenance in MCL Elderly (RD at 2 years: 76% vs 36%, P = .015). ASCT increased the proportion of patients in MR from 55% before high-dose therapy to 72% thereafter. Sequential MRD monitoring is a powerful predictor for treatment outcome in MCL. These trials are registered at www.clinicaltrials.gov as #NCT00209222 and #NCT00209209. more...