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Background: Although BTK inhibitors provide long-term disease-control in patients with chronic lymphocytic leukaemia, they need to be combined with BCL2 inhibitors or antibodies to achieve deep responses with undetectable minimal residual disease (uMRD), which allows for time-limited treatment. This trial aims to evaluate the triple combination of obinutuzumab, acalabrutinib, and venetoclax after an optional debulking with bendamustine., Methods: This multicentre, open-label, investigator-initiated, phase 2 study evaluates a sequential treatment consisting of a debulking with two cycles of bendamustine for patients with a higher tumour load (70 mg/m 2 intravenously on days 1 and 2, repeated after 28 days), followed by an induction and a 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), acalabrutinib (100 mg orally twice daily continuously from induction cycle 2 day 1 onwards) and venetoclax (starting in induction cycle 3 with 20 mg per day with a weekly dose ramp-up over 5 weeks to the target dose of 400 mg per day). Eligible patients were aged 18 years or older with an ECOG performance score 0-2 and had relapsed or refractory chronic lymphocytic leukaemia requiring treatment according to the 2018 International Workshop on Chronic Lymphocytic Leukemia criteria. The primary endpoint was uMRD (<10 -4 ) in peripheral blood at the end of induction treatment assessed centrally at the final restaging, 12 weeks after the start of the last induction cycle. As per protocol, all patients with more than two induction cycles were included in the analyses. This study is registered with ClinicalTrials.gov, number NCT03787264, and is ongoing., Findings: Between Jan 14, 2019, and June 25, 2020, 45 evaluable patients with relapsed or refractory chronic lymphocytic leukaemia were enrolled; 13 (29%) were female, 32 (71%) were male, 21 (47%) had already received a targeted agent, and 14 (32%) had del(17)(p13.1) or TP53 mutation. Ethnicity-race data was not collected. At data cutoff (Feb 25, 2021), all patients had completed the induction treatment. 34 patients (76%; 95% CI 61-87, p=0·26) had uMRD in peripheral blood after 6 months of triple therapy. Until data cutoff, 32 (71%) patients started maintenance and nine (28%) were able to stop with uMRD. After a median observation time of 13·8 months (IQR 10·4-18·4), there were two (4%) Richter transformations, but no progressions and no deaths observed. The most common adverse events of grade 3 and 4 during the entire treatment were thrombocytopenia and neutropenia (12 [27%] of 45 patients each), tumour lysis syndrome and infections (five [11%] of 45 patients each, grade 3 adverse events only), infusion-associated reactions (four [9%] of 45 patients) and anaemia (four [9%] of 45 patients)., Interpretation: With 76% of patients achieving uMRD in peripheral blood, this trial did not reach the prespecified activity threshold. Triple therapy with obinutuzumab, acalabrutinib, and venetoclax after an optional debulking with bendamustine regimen requires further evaluation in larger trials to define its value compared with double treatment with a BTK or BCL2 inhibitor combined with obinutuzumab or a combination of the two oral targeted drugs. Until these trials show a clear benefit, the use of the triple combination in routine practice cannot be recommended., Funding: Acerta, AstraZeneca, F Hoffmann-La Roche, and AbbVie., Competing Interests: Declaration of interests PC reports research funding from Acerta, AstraZeneca, Beigene, F Hoffmann-LaRoche, Gilead, Janssen-Cilag and Novartis, honoraria for scientific talks from AbbVie, AstraZeneca, F Hoffmann-LaRoche and Janssen-Cilag, advisory boards at AbbVie, AstraZeneca, and BeiGene, travel grants from AbbVie, AstraZeneca, F Hoffmann LaRoche, and Janssen-Cilag. SR reports honoraria from AstraZeneca. A-MF reports research funding from AstraZeneca and Celgene (Bristol Myers Squibb) and travel grants from AbbVie. KF reports honoraria, consulting, and advisory board from AbbVie and F Hoffmann-LaRoche, and travel grants from F Hoffmann-LaRoche. PL reports research funding, travel grants, and honoraria from AbbVie, F Hoffmann-LaRoche, and Janssen-Cilag. OA-S reports consultant or advisory board member, honoraria, and personal fees from AbbVie, Adaptive, AstraZeneca, BeiGene, Janssen, Gilead, and Roche, and research support from AbbVie, BeiGene, Janssen, and Roche. ET reports consultant or advisory board member, honoraria, and research support from AbbVie, Janssen-Cilag, and Roche. JS reports lecture fees and advisory board member honoraria from AbbVie, AstraZeneca, BeiGene, Janssen, Roche, and Gilead. PD reports a consultancy for AbbVie, AstraZeneca, Gilead, Janssen, Novartis, Riemser, and Roche, speakers bureau for AbbVie, Gilead, Novartis, Riemser, and Roche, and research support from Neovii and Riemser. SB reports honoraria from AbbVie, AstraZeneca, F Hoffmann-LaRoche, Janssen-Cilag, and Sanofi, and research support by Janssen-Cilag Neuss (to Institution). K-AK reports consultant or advisory board member, honoraria, paid expert testimony, speakers bureau, and research support from AbbVie, Amgen, Celgene, F Hoffmann-LaRoche, Gilead, Janssen-Cilag and Mundipharma. MR reports consultancy payments from AbbVie, Chugai, F Hoffmann-LaRoche, MSD, research funding from AbbVie, F Hoffmann-LaRoche and, travel grants from AbbVie, Celgene, F Hoffmann-LaRoche, and MSD. MB was a consultant or advisory board member at, or reports research support, or travel support from Affimed, Amgen, Incyte, Janssen, Regeneron. SS was a consultant or advisory board member at, or reports research support, and travel support from AbbVie, Amgen, Boehringer-Ingelheim, Celgene, F Hoffmann-LaRoche, Genentech, Genzyme, Gilead, GlaxoSmithKline, Janssen-Cilag, Mundipharma, Novartis, Pharmacyclics, and Sunesis. BE was a consultant or advisory board member at, or reports research support, or travel support from AbbVie, AstraZeneca, and F Hoffmann-LaRoche. MH was a consultant or advisory board member at, or reports honoraria and research support from AbbVie, Amgen, Celgene, F Hoffmann-LaRoche, Gilead, Janssen-Cilag and Mundipharma. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: The combined use of genetic markers and detectable minimal residual disease identifies patients with chronic lymphocytic leukaemia with poor outcome after first-line chemoimmunotherapy. We aimed to assess lenalidomide maintenance therapy in these high-risk patients., Methods: In this randomised, double-blind, phase 3 study (CLLM1; CLL Maintenance 1 of the German CLL Study Group), patients older than 18 years and diagnosed with immunophenotypically confirmed chronic lymphocytic leukaemia with active disease, who responded to chemoimmunotherapy 2-5 months after completion of first-line therapy and who were assessed as having a high risk for an early progression with at least a partial response after four or more cycles of first-line chemoimmunotherapy, were eligible if they had high minimal residual disease levels or intermediate levels combined with an unmutated IGHV gene status or TP53 alterations. Patients were randomly assigned (2:1) to receive either lenalidomide (5 mg) or placebo. Randomisation was done with a fixed block size of three, and was stratified according to the minimal residual disease level achieved after first-line therapy. Maintenance was started with 5 mg daily, and was escalated to the target dose of 15 mg. If tolerated, medication was administered until disease progression. The primary endpoint was progression-free survival according to an independent review. The pre-planned interim analysis done by intention to treat was done after 20% of the calculated progression-free survival events. This study is registered with ClinicalTrials.gov, number NCT01556776; treatment in the lenalidomide group is still ongoing., Findings: Between July 5, 2012, and March 15, 2016, 468 previously untreated patients with chronic lymphocytic leukaemia were screened for the study; 379 (81%) were not eligible. Recruitment was closed prematurely due to poor accrual after 89 of 200 planned patients were randomly assigned: 60 (67%) enrolled patients were assigned to the lenalidomide group and 29 (33%) to the placebo group, of whom 56 (63%) received lenalidomide and 29 (33%) placebo, with a median of 11·0 (IQR 4·5-20·5) treatment cycles at data cutoff. After a median observation time of 17·9 months (IQR 9·1-28·1), the hazard ratio for progression-free survival assessed by an independent review was 0·168 (95% CI 0·074-0·379). Median progression-free survival was 13·3 months (95% CI 9·9-19·7) in the placebo group and not reached (95% CI 32·3-not evaluable) in the lenalidomide group. The most frequent adverse events were skin disorders (35 patients [63%] in the lenalidomide group vs eight patients [28%] in the placebo group), gastrointestinal disorders (34 [61%] vs eight [28%]), infections (30 [54%] vs 19 [66%]), haematological toxicity (28 [50%] vs five [17%]), and general disorders (28 [50%] vs nine [31%]). One fatal adverse event was reported in each of the treatment groups (one [2%] patient with fatal acute lymphocytic leukaemia in the lenalidomide group and one patient (3%) with fatal multifocal leukoencephalopathy in the placebo group)., Interpretation: Lenalidomide is an efficacious maintenance therapy reducing the relative risk of progression in first-line patients with chronic lymphocytic leukaemia who do not achieve minimal residual disease negative disease state following chemoimmunotherapy approaches. The toxicity seems to be acceptable considering the poor prognosis of the eligible patients. The trial independently confirms the clinical significance of a novel, minimal residual disease-based algorithm to predict short progression-free survival, which might be incorporated in future clinical trials to identify candidates for additional maintenance treatment., Funding: Celgene Corporation., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Objective: Despite high rates of long-lasting remissions in patients with chronic lymphocytic leukaemia (CLL) treated with chemoimmunotherapy, none of the current therapeutic approaches is curative with the exception of allogeneic transplantation. One strategy to extend progression-free survival and long-term survival might be the establishment of consolidation therapies., Methods: In this trial, patients with complete or partial second remission after fludarabine-based treatment received consolidation therapy with alemtuzumab. The aim of this phase I/II trial was to determine the maximal tolerable dose (MTD) of alemtuzumab consolidation and to evaluate safety and efficacy in patients who responded to second-line fludarabine-based treatment. Thirteen patients in complete (CR) or partial remission (PR) received alemtuzumab dose escalation starting with 10 mg intravenously (iv) once weekly for 8 wk and increasing in 10-mg intervals per dose level., Results: The main dose-limiting toxicities (DLTs) were infectious complications, and the MTD was determined at 10 mg. After alemtuzumab consolidation, seven of 13 patients (53%) were in CR, and four of these patients (30.7%) achieved minimal residual disease (MRD) negativity (<1 × 10E-4). At a median follow-up of 71.5 months, four patients were progression-free, with a median progression-free survival (PFS) of 28.5 months after the end of second-line treatment., Conclusion: The results provide a safe and efficient schedule with weekly intravenous application of 10 mg of alemtuzumab as a consolidation regime in patients with CLL., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Deletion of chromosome 17p (del[17p]) in patients with chronic lymphocytic leukaemia confers very poor prognosis when treated with standard chemo-immunotherapy. Venetoclax is an oral small-molecule BCL2 inhibitor that induces chronic lymphocytic leukaemia cell apoptosis. In a previous first-in-human study of venetoclax, 77% of patients with relapsed or refractory chronic lymphocytic leukaemia achieved an overall response. Here we aimed to assess the activity and safety of venetoclax monotherapy in patients with relapsed or refractory del(17p) chronic lymphocytic leukaemia., Methods: In this phase 2, single-arm, multicentre study, we recruited patients aged 18 years and older with del(17p) relapsed or refractory chronic lymphocytic leukaemia (as defined by 2008 Modified International Workshop on Chronic Lymphocytic Leukemia guidelines) from 31 centres in the USA, Canada, UK, Germany, Poland, and Australia. Patients started once daily venetoclax with a weekly dose ramp-up schedule (20, 50, 100, 200, 400 mg) over 4-5 weeks. Patients were then given daily 400 mg continuous dosing until disease progression or discontinuation for another reason. The primary endpoint was the proportion of patients achieving an overall response, assessed by an independent review committee. Activity and safety analyses included all patients who received at least one dose of study drug (per protocol). This study is registered with ClinicalTrials.gov, number NCT01889186. Follow-up is ongoing, and patients are still receiving treatment., Findings: Between May 27, 2013, and June 27, 2014, 107 patients were enrolled into the study. At a median follow-up of 12·1 months (IQR 10·1-14·2), an overall response by independent review was achieved in 85 (79·4%; 95% CI 70·5-86·6) of 107 patients. The most common grade 3-4 adverse events were neutropenia (43 [40%]), infection (21 [20%]), anaemia (19 [18%]), and thrombocytopenia (16 [15%]). Serious adverse events occurred in 59 (55%) patients, irrespective of their relationship to treatment, with the most common (≥5% of patients) being pyrexia and autoimmune haemolytic anaemia (seven [7%] each), pneumonia (six [6%]), and febrile neutropenia (five [5%]). 11 patients died in the study within 30 days of the last dose of venetoclax; seven due to disease progression and four from an adverse event (none assessed as treatment related)., Interpretation: Results of this trial show that venetoclax monotherapy is active and well tolerated in patients with relapsed or refractory del(17p) chronic lymphocytic leukaemia, providing a new therapeutic option for this very poor prognosis population. Additionally, in view of the distinct mechanism-of-action of venetoclax, combinations or sequencing with other novel targeted agents should be investigated to further advance treatment of del(17p) chronic lymphocytic leukaemia., Funding: AbbVie and Genentech., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Simple Summary: Up to 50% of patients with chronic lymphocytic leukemia relapse within four years after anti-CD20-directed treatment with a need for a subsequent treatment, which can potentially include anti-CD20 agents again. To retrospectively study the influence of CD20 expression in CLL patients receiving anti-CD20 directed therapy on therapy response, we designed and evaluated a bead-based normalization approach for the analysis of CD20 expression levels to reduce variation of flow cytometric measurements due to technical issues. Normalization significantly reduced the variability of median fluorescence intensities of fluorochrome-conjugated beads without artificially rendering the instruments' performances, and longitudinal biological variations of marker expression based on MFI values could be robustly assessed. In a cross-trial comparison, strong MRD response correlated with the CD20 expression level before therapy started in patients receiving Ofatumumab, but not in patients receiving Obinutuzumab. Background: CD20 expression is a controversial issue regarding response prediction to anti-CD20 therapy in chronic lymphocytic leukemia (CLL). Methods: Median fluorescence intensities (MFIs) of standard fluorescence beads from the daily calibration of flow cytometers according to EuroFlow protocols were used to establish a normalization approach to study CD20 expression on CLL cells. CD20 MFI was retrospectively assessed prior to and during treatment from flow cytometric measurements of peripheral blood in patients with different depths of molecular response in the four phase-II CLL2-BXX trials (BIG; BAG; BIO; BCG; N = 194) administering either Obinutuzumab or Ofatumumab in combination with targeted agents. Results: No significant difference was observed between the normalized and measured MFIs of CD19 and CD20 on CLL cells. During treatment, CD20 expression levels on CLL cells did not significantly differ between the four investigated different treatment schemes, but a strong molecular response to Ofatumumab seemed to correlate with higher CD20 expression prior to therapy. Conclusions: Standardized staining and instrument monitoring enable a robust assessment of longitudinal biological variations of marker expression based on MFI values. Obinutuzumab showed a higher proportion of patients with a strong MRD response independent from initial CD20 expression, whereas high pre-therapeutic CD20 expression levels seem to correlate with a profound response to Ofatumumab. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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/m2 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. [ABSTRACT FROM AUTHOR]