Patients with chronic lymphocytic leukemia (CLL) may be more susceptible to Coronavirus disease 2019 (COVID-19) due to age, disease, and treatment-related immunosuppression. We aimed to assess risk factors of outcome and elucidate the impact of CLL-directed treatments on the course of COVID-19. We conducted a retrospective, international study, collectively including 941 patients with CLL and confirmed COVID-19. Data from the beginning of the pandemic until March 16, 2021, were collected from 91 centers. The risk factors of case fatality rate (CFR), disease severity, and overall survival (OS) were investigated. OS analysis was restricted to patients with severe COVID-19 (definition: hospitalization with need of oxygen or admission into an intensive care unit). CFR in patients with severe COVID-19 was 38.4%. OS was inferior for patients in all treatment categories compared to untreated (p < 0.001). Untreated patients had a lower risk of death (HR = 0.54, 95% CI:0.41–0.72). The risk of death was higher for older patients and those suffering from cardiac failure (HR = 1.03, 95% CI:1.02–1.04; HR = 1.79, 95% CI:1.04–3.07, respectively). Age, CLL-directed treatment, and cardiac failure were significant risk factors of OS. Untreated patients had a better chance of survival than those on treatment or recently treated.

Background: For fit CLL patients (pts), continuous BTK inhibitor treatment is replacing CIT as standard of care in frontline setting, particularly in pts with unfavorable prognostic factors. The time limited combinations venetoclax plus obinutuzumab (GVe) and venetoclax plus rituximab (RVe) have produced high rates of undetectable minimal residual disease (uMRD), which strongly associates with long progression-free survival (PFS) both in frontline and relapsed setting. For frontline therapy GVe is approved in this setting based on data from the CLL14 trial in an unfit population. However, data from a fit cohort are not yet available. The GAIA (CLL13) trial evaluated the efficacy and safety of three Ven+CD20 antibody-based regimens in comparison to CIT as a frontline treatment for fit pts with CLL and without TP53 mutation/deletion. Methods: Treatment-naïve fit (CIRS ≤6, normal creatinine clearance with ≥ 70ml/min) CLL pts requiring therapy were eligible. Based on known poor response to CIT, pts with TP53 aberrations were excluded. Pts were randomized in a 1:1:1:1 ratio to receive six courses of CIT (FCR for pt ≤65 years: fludarabine 25 mg/m² d1-3, cyclophosphamide 250 mg/m² d1-3, rituximab 375 mg/m² d1 cycle 1 and 500 mg/m² d1 cycle 2-6; BR for pt &gt;65 years: bendamustine 90mg/m² d1-2, rituximab) or one of three venetoclax (V) combinations (standard ramp-up from cycle 1 d22, 400 mg/d cycle 2-12): V and rituximab (375/500mg/m² d1 cycle 1-6) [RVe], V and obinutuzumab (1000 mg d1, 8, 15 cycle 1 and d1 cycle 2-6) [GVe], or V, obinutuzumab and ibrutinib (420 mg/d cycle 1-12, if MRD-detectable continued until cycle 36) [GIVe] . Pts were stratified according to country, Binet stage and age (≤ 65/&gt; 65 years). The co-primary endpoints of the trial are (1) the rate of uMRD (&lt;10-4) by flow in peripheral blood (PB) at month 15 (MO15, GVe vs CIT) and (2) PFS (GIVe vs CIT), each with a significance level of 2.5%. The co-primary endpoint PFS will be analyzed within a pre-planned interim analysis as soon as 138 (65%) PFS events will have been reported in the GIVe and CIT arm. The co-primary endpoint analysis of uMRD per protocol was performed after the last MO15 MRD sample had been collected. In addition, comparisons regarding uMRD for all study arms were performed using a pre-specified hierarchical test sequence. Bone marrow (BM) was evaluated 3 months after end of treatment (MO9 for CIT, MO15 for all others arms) in pts with clinical CR. Key secondary endpoints as investigator-assessed responses according to iwCLL 2008 guidelines and safety were analyzed. Trial is registered at ClinicalTrials.gov (NCT02950051). Results: A total of 926 pts (CIT: 229 (150 FCR, 79 BR), RVe: 237, GVe: 229, GIVe: 231) with a median age of 61 years (range 27-84) were accrued between 12/2016 and 09/2019. The majority of pts were in advanced Binet stage (B: 37.8%, C: 35.6%) and unmutated IGHV status was present in 56%. Fourteen pts did not receive study treatment (13 FCR, 1 GVe) and were not included in the safety population. The data cut for the first co-primary endpoint analysis was February 28, 2021. The median observation time was 27.9 months. The co-primary endpoint uMRD in PB at MO15 was met as the rate of uMRD in ITT population was significantly higher in GVe compared to CIT: 86.5% (97.5% CI 80.6-91.1) vs 52.0% (CI 44.4-59.5; p&lt;0.0001), respectively. GIVe also showed a superior uMRD rate of 92.2% (CI 87.3-95.7) compared to CIT (p&lt;0.0001), while RVe (57.0%, CI 49.5-64.2) did not (p=0.317) (Figure 1A). Corresponding BM uMRD rates in ITT population were 37.1% (CIT), 43.0% (RVe), 72.5% (GVe) and 77.9% (GIVe), respectively. MO15 overall response rates and complete response rates (CRR) are shown in Figure 1B. The most common grade 3-5 treatment-emergent AE were neutropenia (50.5% of all pts), thrombocytopenia (12.2%), tumor lysis syndrome (7.5%), infusion-related reaction (7.2%), febrile neutropenia (6.5%) and pneumonia (5.3%)). Atrial fibrillation and bleeding events occurred more frequently in GIVe while infusion-related reactions were most common in the GVe arm (Table 1). The absolute numbers of second malignancies were 33, 19, 22 and 21 for CIT, RVe, GVe and GIVe. Fatal AEs occurred in 5, 7, 6 and 9 of the patients. Conclusions: The time-limited therapies of GVe and GIVe provided superior uMRD rates in PB at MO 15 compared to CIT. In addition, uMRD rates in BM and CRR were higher in GVe and GIVe in particular than in CIT. All arms showed a good safety profile in this fit pt population. Figure 1 Figure 1. Disclosures Eichhorst: AbbVie: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Research Funding, Speakers Bureau; BeiGene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Speakers Bureau; Adaptive Biotechnologies: Speakers Bureau; Hexal: Speakers Bureau; ArQule: Membership on an entity's Board of Directors or advisory committees; Oxford Biomedica (UK): Membership on an entity's Board of Directors or advisory committees; MSD: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Research Funding, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Research Funding, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Research Funding, Speakers Bureau; Consultant Department I for Internal Medicine: Consultancy; University Hospital of Cologne: Current Employment. Kater: Genmab, LAVA: Other: Ad Board, Steering Committee; Janssen, AstraZeneca: Other: Ad Board, steering committee, Research Funding; Abbvie: Honoraria, Other: Ad Board, Research Funding; BMS, Roche/Genentech: Other: Ad Board, , Research Funding. Von Tresckow: Celgene: Other: travel grant; AstraZeneca: Honoraria, Other; Roche: Honoraria, Other: Reasearch support, travel grant; Janssen: Honoraria, Other: Reasearch support, travel grant; AbbVie: Honoraria, Other: advisory board, travel grant. Staber: Roche: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Astra Zeneca: Consultancy, Honoraria; Takeda: Consultancy, Research Funding; MSD: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Incyte: Consultancy, Honoraria, Research Funding; Beigene: Consultancy, Honoraria. Tadmor: Janssen: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding. Poulsen: Janssen: Consultancy; Abbvie: Consultancy. Janssens: Sanofi: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Beigene, AstraZeneca: Consultancy, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Trael Grant, Speakers Bureau; Abbvie, Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Noesslinger: Roche: Speakers Bureau; Abbvie,: Speakers Bureau; Janssen: Speakers Bureau; AstraZeneca: Honoraria; Gilead: Honoraria; Celgene: Honoraria. Jaeger: Norvartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Frederiksen: Abbvie: Research Funding; Gilead: Research Funding; Alexion: Research Funding; Novartis: Research Funding; Janssen Pharmaceuticals: Research Funding. Hebart: Roche: Honoraria; BMS: Honoraria; AstraZeneca: Honoraria; AbbVie: Honoraria; Janssen: Honoraria. Simon: Gilead: Other: Travel support. Fink: AbbVie: Other: travel grant; Janssen: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Research Funding; Celgene: Research Funding. Fischer: Abbvie: Honoraria; Roche: Honoraria, Other: Travel Grants. Kreuzer: Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Abbvie: Consultancy, Honoraria, Research Funding, Speakers Bureau; Mundipharma: Consultancy, Honoraria, Research Funding, Speakers Bureau. Ritgen: Abbvie: Consultancy, Other: Travel support, Research Funding; Chugai: Consultancy; MSD: Consultancy, Other: Travel support; Roche: Consultancy, Other: Travel support, Research Funding; Celgene: Other: Travel support. Brüggemann: Amgen: Other: Advisory Board, Travel support, Research Funding, Speakers Bureau; Incyte: Other: Advisory Board; Janssen: Speakers Bureau. Levin: Roche, Janssen, Abbvie: Other: Travel Expenses, Ad-Board. Stilgenbauer: AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, Sunesis: Other: Research Support; AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, Sunesis: Consultancy; AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, Sunesis: Honoraria; AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, Sunesis: Research Funding. Hallek: Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau; Abbvie: Consultancy, Research Funding, Speakers Bureau. OffLabel Disclosure: Ibrutinib in combaintion with Venetoclax + Obinutuzumab is not approved.

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Observation is the current standard of care for patients with early stage asymptomatic chronic lymphocytic leukemia (CLL), as chemotherapy-based interventions have failed to prolong survival. We hypothesized that early intervention with ibrutinib would be well tolerated and lead to superior disease control in a subgroup of early stage patients with CLL. The phase 3, double-blind, placebo-controlled CLL12 trial randomly assigned asymptomatic, treatment-naïve Binet stage A CLL patients at increased risk of progression in a 1:1 ratio to receive ibrutinib (N=182) or placebo (N=181) at a dose of 420 mg daily. At a median follow up of 31 months the study met its primary endpoint by significantly improving event-free survival in the ibrutinib group (median, not reached vs. 47.8 months; hazard ratio=0.25; 95% confidence interval=0.14-0.43, P&lt;0.0001). Compared to placebo, ibrutinib did not increase overall toxicity, yielding similar incidence and severity of adverse events. The most common serious adverse events were atrial fibrillation, pneumonia and rash in the ibrutinib group, and basal cell carcinoma, pneumonia and myocardial infarction in the placebo group. Ibrutinib-associated risk for bleeding (33.5%) was decreased by prohibiting use of oral anticoagulants through an amendment of the study protocol and by avoiding CYP3A4 drug-drug interactions. Taken together, ibrutinib confirms efficacy in CLL patients at early stage with increased risk of progression. However, the results do not justify to change the current standard of 'watch and wait'. The trial is registered at clinicaltrials.gov as NCT02863718.

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The introduction of chemoimmunotherapy and more recently the implementation of novel agents into first-line and relapse treatment have substantially improved treatment outcomes in patients with chronic lymphocytic leukaemia (CLL). With longer progression-free survival and more frequently observed deep remissions there is an emerging need for sensitive methods quantitating residual disease after therapy. Over the last decade, assessment of minimal residual disease (MRD) has increasingly been implemented in CLL trials. The predictive value of MRD status on survival outcomes has repeatedly been proven in the context of chemoimmunotherapy and cellular therapies. Recent data suggests a similar correlation for Bcl-2 inhibitor-based therapy. While the relevance of MRD assessment as a surrogate endpoint in clinical trials is largely undisputed, its role in routine clinical practice has not yet been well defined. This review outlines current methods of MRD detection in CLL and summarizes MRD data from relevant trials. The significance of MRD testing in clinical studies and in routine patient care is assessed and new MRD-guided treatment strategies are discussed.

NCT01132248; ATMR2010020001429343.

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