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Progressive disease (PD) occurred in 67 cases in the Ven-Obi arm with 39 second-line treatments, and in 141 cases in the Clb-Obi arm (with 103 second-line treatments). B Background: b One-year fixed-duration venetoclax-obinutuzumab (Ven-Obi) is a standard-of-care for patients (pts) with previously untreated chronic lymphocytic leukemia (CLL). Overall, 48 deaths were reported in the Ven-Obi arm (9 PD related) and 70 in the Clb-Obi arm (26 PD related); 6-year-OS rate was 78.7% in the Ven-Obi and 69.2% in the Clb-Obi arm (HR 0.69 [0.48-1.01], I p i = 0.052). [Extracted from the article]

B Conclusions: b Early ibrutinib-treatment of patients with asymptomatic Binet stage A CLL at high risk of progression failed to demonstrate an overall survival benefit when compared to placebo. B Introduction: b We present the final analysis of the phase 3, double-blind, placebo-controlled CLL12 trial evaluating ibrutinib in patients with early stage CLL at increased risk of progression defined by a comprehensive score (NCT02863718). [Extracted from the article]

Using digitized, genomically annotated peripheral blood smears (PBS) of patients with CLL, we evaluated whether deep learning can predict presence of I TP53 i aberrations (del[17p] and/or I TP53 mutation i ) and unmutated IGHV status solely based on cytomorphology. B Introduction: b Patient stratification based on genomic biomarkers is critical to optimize treatment of chronic lymphocytic leukemia (CLL). [Extracted from the article]

Competing Interests: OA-S received research funding from AbbVie, Janssen, Roche, and BeiGene; received consulting fees from Janssen, Ascentage, AbbVie, Gilead, Genmab, AstraZeneca, BeiGene, Roche, and Lilly; received honoraria from Janssen, Ascentage, AbbVie, Gilead, Genmab, AstraZeneca, BeiGene, Roche, Lilly, and Adaptive; and participated on data monitoring boards for Ascentage and AstraZeneca. BE received research funding from Janssen, Gilead, Roche, AbbVie, BeiGene, and AstraZeneca; received consulting fees from Janssen, AbbVie, Gilead, AstraZeneca, MSD, BeiGene, and Lilly; and received honoraria from Roche, AbbVie, BeiGene, AstraZeneca, and MSD.

Purpose: Surrogate endpoints are commonly used to estimate treatment efficacy in clinical studies of chronic lymphocytic leukemia (CLL). This patient- and trial-level analysis describes the correlation between progression-free survival (PFS) and minimal residual disease (MRD) with overall survival (OS) in first-line trials for CLL., Patients and Methods: First, patient-level correlation was confirmed using source data from 12 front-line GCLLSG-trials. Additionally, a joint-frailty copula model was fitted to validate correlation in the setting of targeted therapies.Second, a meta-analysis of first-line phase III trials in CLL from 2008-2024 was performed. Treatment effect correlation was quantified from seven GCLLSG and nine published trials, using hazard ratios for time-to-event and odds ratios for binary endpoints., Results: The GCLLSG analysis set comprised 4237 patients. Patient-level correlation for PFS/OS was strong with Spearman's Rho >0.9. The joint-frailty copula indicated a weak correlation for C/CIT with a tau of 0.52, (95% CI: 0.49 - 0.55) while the correlation was strong for TT (tau = 0.91, 95% CI: 0.89 - 0.93).The meta-analysis set contained a total of 8065 patients including 5198 (64%) patients treated with C/CIT and 2867 (36%) treated with TT. Treatment effect correlation of the hazard ratios (HR) for PFS and OS was R = 0.75 (95% CI: 0.74 - 0.76, R 2 = 0.56), while correlation of end-of-treatment MRD with PFS and OS was R = 0.88 (95%CI: -0.87 - 0.89; R 2 = 0.78) and 0.71 (95%CI: 0.69 - 0.73; R 2 = 0.5), respectively., Conclusion: Patient-level correlation was confirmed in the setting of targeted therapies while treatment-effect correlation between PFS and OS remains uncertain. MRD response status showed a high treatment-effect correlation with PFS but not OS, with the caveat of a limited number of randomized trials with available MRD data.

Patients with chronic lymphocytic leukemia (CLL) exhibit diverse clinical outcomes. An expanding array of genetic tests is now employed to facilitate the identification of patients with high-risk disease and inform treatment decisions. These tests encompass molecular cytogenetic analysis, focusing on recurrent chromosomal alterations, particularly del(17p). Additionally, sequencing is utilized to identify TP53 mutations and to determine the somatic hypermutation status of the immunoglobulin heavy variable gene. Concurrently, a swift advancement of targeted treatment has led to the implementation of novel strategies for patients with CLL, including kinase and BCL2 inhibitors. This review explores both current and emerging diagnostic tests aimed at identifying high-risk patients who should benefit from targeted therapies. We outline existing treatment paradigms, emphasizing the importance of matching the right treatment to the right patient beyond genetic stratification, considering the crucial balance between safety and efficacy. We also take into consideration the practical and logistical issues when choosing a management strategy for each individual patient. Furthermore, we delve into the mechanisms underlying therapy resistance and stress the relevance of monitoring measurable residual disease to guide treatment decisions. Finally, we underscore the necessity of aggregating real-world data, adopting a global perspective, and ensuring patient engagement. Taken together, we argue that precision medicine is not the mere application of precision diagnostics and accessibility of precision therapies in CLL but encompasses various aspects of the patient journey (e.g., lifestyle exposures and comorbidities) and their preferences toward achieving true personalized medicine for patients with CLL., Competing Interests: Kostas Stamatopoulos has received honoraria from AbbVie, AstraZeneca, Janssen, Lilly and BMS and research support from AbbVie, AstraZeneca, Janssen. Othman Al‐Sawaf has received honoraria from AbbVie, Adaptive, AstraZeneca, Ascentage, BeiGene, Gilead, Eli Lilly, Janssen, Roche, and research funding from AbbVie, BeiGene, Janssen and Roche. Gianluca Gaidano has received honoraria from Abbvie, AstraZeneca, BeiGene, Hikma, Incyte, Janssen, and Lilly. Florence Cymbalista has performed advisory board activities for AstraZeneca, Lilly, AbbVie, and BeiGene. Arnon P. Kater reports research grants from AbbVie, Astra Zeneca, BMS, Janssen, and Roche Genentech and has performed advisory board activities for AbbVie, Astra Zeneca, BMS, Janssen, LAVA, and Roche Genentech. Lydia Scarfò has received honoraria from AbbVie, AstraZeneca, BeiGene, Janssen, and Lilly was part of the speakers bureau of Octapharma. Paolo Ghia has received honoraria from AbbVie, AstraZeneca, BeiGene, BMS, Galapagos, Janssen, LoxoOncology@Lilly, MSD, Roche; research support from AbbVie, AstraZeneca, BMS, Janssen, and is an Editor of HemaSphere. Thomas Chatzikonstantinou has received honoraria from AbbVie. Richard Rosenquist has received honoraria from AbbVie, AstraZeneca, Janssen, Illumina, and Roche. The remaining authors declare no conflict of interest., (© 2024 The Author(s). HemaSphere published by John Wiley & Sons Ltd on behalf of European Hematology Association.)

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.)

Venetoclax-obinutuzumab (Ven-Obi) is a standard-of-care for patients with previously untreated chronic lymphocytic leukemia (CLL). In the CLL14 study, patients with previously untreated CLL and coexisting conditions were randomized to 12 cycles of Ven-Obi (n=216) or chlorambucil-obinutuzumab (Clb-Obi, n=216). Progression-free survival (PFS) was the primary endpoint. Key secondary endpoints included time-to-next-treatment (TTNT), rates of undetectable minimal residual disease (uMRD), overall survival (OS) and rates of adverse events. Patient reported outcomes (PROs) of time until definitive deterioration (TUDD) in quality of life (QoL) were analyzed. At a median observation time of 76.4 months, PFS remained superior for Ven-Obi compared to Clb-Obi (median 76.2 vs 36.4 months; HR 0.40[95%CI 0.31-0.52], p<0.0001). Likewise, TTNT was longer after Ven-Obi (6-year-TTNT 65.2% vs 37.1%; HR 0.44, 95%CI 0.33-0.58, p<0.0001). In the Ven-Obi arm, presence of del(17p), unmutated-IGHV and lymph node size ≥5 cm were independent prognostic factors for shorter PFS. Five years after treatment, 17 patients (7.9% of intention-to-treat-population) in the Ven-Obi arm had uMRD (<10-4 in peripheral blood) compared to 4 (1.9%) in the Clb-Obi arm. 6-year-OS rate was 78.7% in the Ven-Obi and 69.2% in the Clb-Obi arm (HR 0.69[95%CI 0.48-1.01], p=0.052). A significantly longer TUDD in global health status/QoL was observed in the Ven-Obi compared to the Clb-Obi arm (median 82.1 vs 65.1 months; HR 0.70[95%CI 0.51-0.97]). Follow-up adjusted SPM incidence rates were 2.3 and 1.4/1000 patient-months in the Ven-Obi and Clb-Obi arm, respectively. The sustained long-term survival, uMRD and QoL benefits support the use of one-year fixed-duration Ven-Obi in CLL. NCT02242942, EudraCT 2014-001810-24., (Copyright © 2024 American Society of Hematology.)

Chromosomal aberrations are a common feature of cancer and can fuel cancer progression and treatment resistance. In chronic lymphocytic leukemia (CLL), the presence of multiple chromosomal aberrations is commonly referred to as "genomic complexity" or "complex karyotype"- (CKT). In the context of chemo- and chemoimmunotherapy, genomic complexity is associated with poor response to treatment and short survival, while some targeted therapies are able to mitigate its adverse prognostic impact. This article reviews currently available data and literature on the role of genomic complexity in CLL. The currently established tools to measure genomic complexity in patients with CLL are summarized and their strengths and weaknesses for routine diagnostics are evaluated. Moreover, possible definitions of CKT as an indicator for genomic complexity are discussed. Finally, data on the impact of CKT on clinical outcomes of patients with CLL are reviewed and the implications for patient stratification are presented.

Abstract: We evaluated the chronic lymphocytic leukemia International Prognostic Index (CLL-IPI) in patients with CLL treated first line with targeted drugs (n = 991) or chemoimmunotherapy (n = 1256). With a median observation time of 40.5 months, the 3-year progression-free survival (PFS) rates for targeted drug-treated patients varied by CLL-IPI risk group: 96.5% (low), 87.6% (intermediate), 82.4% (high), and 78.7% (very high). Differences between consecutive CLL-IPI risk groups were observed for intermediate vs low and high vs intermediate, but not very high vs high. CLL-IPI factors β2-microglobulin, immunoglobulin heavy variable (IGHV) status, and TP53 status each retained prognostic value for PFS. The 3-year overall survival (OS) rates by CLL-IPI risk groups were 100%, 96%, 93.9%, and 89.4%, respectively, with no differences between consecutive risk groups. Age, Binet stage, β2-microglobulin, and TP53 status each retained prognostic value for OS. In chemoimmunotherapy patients (median observation time, 66.9 months), 3-year PFS rates for CLL-IPI risk groups were 78.1%, 51.4%, 40.1%, and 16.5%, respectively; corresponding 3-year OS rates were 97.4%, 93.1%, 81.8%, and 57.3%. In a matched-pair analysis, PFS differences in targeted therapies (n = 812) vs chemoimmunotherapy (n = 812) across all risk groups and OS differences in all but patients at low risk were demonstrated. The CLL-IPI maintains its prognostic value in predicting PFS outcomes with targeted drugs, but its impact in predicting survival appears diminished. Targeted therapies showed enhanced outcomes over chemoimmunotherapy, highlighting their effectiveness across various risk groups. Our findings support ongoing assessment of prognostic tools in CLL treatment evolution. These trials were registered at www.ClinicalTrials.gov as #NCT02345863, #NCT02401503, #NCT02689141, #NCT02445131, #NCT02758665, #NCT02950051, #NCT02242942, #NCT00262782, #NCT00281918, and #NCT01010061., (© 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.)

Venetoclax is a standard treatment for patients with chronic lymphocytic leukemia (CLL) following covalent Bruton tyrosine kinase inhibitor (cBTKi) therapy, despite relatively limited prospective data in this setting. Pirtobrutinib is a highly selective, non-covalent (reversible) BTKi that was designed to overcome the pharmacologic limitations of cBTKi and re-establish BTK inhibition. An unanchored matching-adjusted indirect comparison (MAIC) was conducted to estimate the treatment effect of pirtobrutinib versus venetoclax monotherapy in patients with cBTKi-pretreated CLL. Data from patients with CLL who were venetoclax-naïve and pretreated with cBTKi received pirtobrutinib (N=146) in the phase I/II BRUIN study were compared with the only identified trial of patients with CLL receiving venetoclax after a cBTKi (N=91), as administered as monotherapy until progression. Outcomes included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and treatment-emergent adverse events. Both unweighted and weighted analyses were conducted. PFS and OS of pirtobrutinib and venetoclax were comparable in both unweighted and weighted analyses (weighted hazard ratios for PFS: 1.01, 95% confidence interval [CI]: 0.58-1.73, P=0.98 and OS: 0.64, 95% CI: 0.25-1.67, P=0.34). ORR was significantly higher for pirtobrutinib (80.2% vs. 64.8%, P=0.01). Grade ≥3 treatment-emergent adverse events were lower in weighted analyses for pirtobrutinib versus venetoclax (all P<0.01), except for pneumonia, which was similar. These results suggest that pirtobrutinib may also be considered as an effective and well-tolerated treatment for patients with relapsed CLL following cBTKi.

Acquired mutations in BTK, PLCG2, and BCL2 are associated with resistance to continuous targeted agent therapy in chronic lymphocytic leukemia (CLL). Here, we discuss new evidence that limiting the duration of CLL therapy may prevent the evolution of such resistance mutations, potentially facilitating effective retreatment strategies. See related article by Jain et al., p. 498., (©2023 American Association for Cancer Research.)

Purpose of Review: In this review, we provide an overview of different time-limited combination therapies of chronic lymphocytic leukemia (CLL) and summarize the data of pivotal clinical studies. Furthermore, we discuss the relevance of MRD in clinical trials and summarize the challenges that arise in routine clinical care. Finally, we provide an outlook on studies and datasets needed to optimize the use of time-limited treatment strategies and MRD assessments in modern CLL management., Recent Findings: In recent years, first-line treatment of CLL has undergone a considerable transformation, with targeted substances having largely replaced chemoimmunotherapy (CIT) as a time-limited strategy in the frontline setting. BTK inhibitors were the first class of targeted agents introduced in CLL, which achieved longer progression-free survival (PFS) and in some cases also overall survival (OS) than CIT. However, this required an indefinite drug intake until disease progression, while CIT is generally administered over the course of few months. In contrast to BTK inhibitors, BCL2 inhibitors, another class of targeted agents, can achieve high rates of undetectable minimal residual disease (uMRD) levels and induce deep molecular remissions with the potential to stop treatment while maintaining remissions. Combinations of BCL2 inhibitors with CD20 antibodies or with BTK inhibitors have been explored to establish time-limited treatment strategies with targeted agents. In this context, one of the strongest predictors of long-term outcomes is MRD status at the end of treatment, which has been shown to correlate closely with PFS and OS in most cases., (© 2024. The Author(s).)

Background: The level of minimal residual disease (MRD), often binarized into detectable or undetectable MRD according to certain thresholds, is strongly associated with long-term outcomes after chemo- and chemoimmunotherapy., Summary: Driven by our improved understanding of the biology of chronic lymphocytic leukemia (CLL), the recent decade has shown a shift from chemotherapy-based regimens to regimens based on targeted agents that exploit distinct biological vulnerabilities of CLL. These targeted agents can be broadly classified into inhibitors of Bruton tyrosine kinase (BTK) and BCL2 as well as CD20-directed antibodies. Depending on which agent and which combination of agents is used, the levels or status of MRD can have varying clinical relevance. This has implications on the prognosis after therapy as well as on possible strategies to guide treatment duration and intensity., Key Messages: This review summarizes the main discoveries related to MRD in the context of targeted therapies. Furthermore, it provides an overview on current hurdles and caveats related to the implementation of MRD in regular clinical care and summarize open research questions that need to be addressed with future clinical studies., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

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).)

The final analysis of the open-label, multicenter phase 2 CLL2-GIVe trial shows response and tolerability of the triple combination of obinutuzumab, ibrutinib, and venetoclax (GIVe regimen) in 41 previously untreated patients with high-risk chronic lymphocytic leukemia (CLL) with del(17p) and/or TP53 mutation. Induction consisted of 6 cycles of GIVe; venetoclax and ibrutinib were continued up to cycle 12 as consolidation. Ibrutinib was given until cycle 15 or up to cycle 36 in patients not achieving a complete response and with detectable minimal residual disease. The primary end point was the complete remission rate at cycle 15, which was achieved at 58.5% (95% CI, 42.1-73.7; P < .001). The last patient reached the end of the study in January 2022. After a median observation time of 38.4 months (range, 3.7-44.9), the 36-month progression-free survival was 79.9%, and the 36-month overall survival was 92.6%. Only 6 patients continued ibrutinib maintenance. Adverse events of concern were neutropenia (48.8%, grade ≥3) and infections (19.5%, grade ≥3). Cardiovascular toxicity grade 3 occurred as atrial fibrillation at a rate of 2.4% between cycles 1 and 12, as well as hypertension (4.9%) between cycles 1 and 6. The incidence of adverse events of any grade and grade ≥3 was highest during induction and decreased over time. Progressive disease was observed in 7 patients between cycles 27 and 42. In conclusion, the CLL2-GIVe regimen is a promising fixed-duration, first-line treatment for patients with high-risk CLL with a manageable safety profile., (© 2023 by The American Society of Hematology.)

Data on long-term outcomes and biological drivers associated with depth of remission after BCL2 inhibition by venetoclax in the treatment of chronic lymphocytic leukemia (CLL) are limited. In this open-label parallel-group phase-3 study, 432 patients with previously untreated CLL were randomized (1:1) to receive either 1-year venetoclax-obinutuzumab (Ven-Obi, 216 patients) or chlorambucil-Obi (Clb-Obi, 216 patients) therapy (NCT02242942). The primary endpoint was investigator-assessed progression-free survival (PFS); secondary endpoints included minimal residual disease (MRD) and overall survival. RNA sequencing of CD19-enriched blood was conducted for exploratory post-hoc analyses. After a median follow-up of 65.4 months, PFS is significantly superior for Ven-Obi compared to Clb-Obi (Hazard ratio [HR] 0.35 [95% CI 0.26-0.46], p < 0.0001). At 5 years after randomization, the estimated PFS rate is 62.6% after Ven-Obi and 27.0% after Clb-Obi. In both arms, MRD status at the end of therapy is associated with longer PFS. MRD + ( ≥ 10 -4 ) status is associated with increased expression of multi-drug resistance gene ABCB1 (MDR1), whereas MRD6 (< 10 -6 ) is associated with BCL2L11 (BIM) expression. Inflammatory response pathways are enriched in MRD+ patient solely in the Ven-Obi arm. These data indicate sustained long-term efficacy of fixed-duration Ven-Obi in patients with previously untreated CLL. The distinct transcriptomic profile of MRD+ status suggests possible biological vulnerabilities., (© 2023. The Author(s).)

Cancer-associated cachexia (CAC) is a major contributor to morbidity and mortality in individuals with non-small cell lung cancer. Key features of CAC include alterations in body composition and body weight. Here, we explore the association between body composition and body weight with survival and delineate potential biological processes and mediators that contribute to the development of CAC. Computed tomography-based body composition analysis of 651 individuals in the TRACERx (TRAcking non-small cell lung Cancer Evolution through therapy (Rx)) study suggested that individuals in the bottom 20th percentile of the distribution of skeletal muscle or adipose tissue area at the time of lung cancer diagnosis, had significantly shorter lung cancer-specific survival and overall survival. This finding was validated in 420 individuals in the independent Boston Lung Cancer Study. Individuals classified as having developed CAC according to one or more features at relapse encompassing loss of adipose or muscle tissue, or body mass index-adjusted weight loss were found to have distinct tumor genomic and transcriptomic profiles compared with individuals who did not develop such features. Primary non-small cell lung cancers from individuals who developed CAC were characterized by enrichment of inflammatory signaling and epithelial-mesenchymal transitional pathways, and differentially expressed genes upregulated in these tumors included cancer-testis antigen MAGEA6 and matrix metalloproteinases, such as ADAMTS3. In an exploratory proteomic analysis of circulating putative mediators of cachexia performed in a subset of 110 individuals from TRACERx, a significant association between circulating GDF15 and loss of body weight, skeletal muscle and adipose tissue was identified at relapse, supporting the potential therapeutic relevance of targeting GDF15 in the management of CAC., (© 2023. The Author(s) under exclusive license to Springer Nature America, Inc.)

Inhibitors targeting B-cell receptor (BCR) signaling pathway proteins and B-cell lymphoma-2 (BCL2) in chronic lymphocytic leukemia (CLL) are recommended in the first-line and relapsed/refractory disease settings. Measurable residual disease (MRD) is an important prognostic tool in patients treated with the BCL2-targeted agent, venetoclax. We explored the relationship between MRD status and progression-free (PFS)/overall survival (OS) in patients with CLL, following treatment with novel BCR- and BCL2-targeted agents. Compared with chemoimmunotherapy, higher rates of undetectable (u)MRD were achieved with BCL2-targeted therapies; achieving uMRD status was associated with longer PFS and OS than MRD-positivity. Continuous treatment with BCR-targeted agents did not achieve uMRD status in many patients, and outcomes were not correlated with uMRD status. Future clinical trials of targeted treatment combinations could be designed to demonstrate uMRD as a treatment objective, and allow a response-driven, personalized strategy to optimize treatment and improve OS outcomes.

Patients aged 80 years and older make up a fifth of patients with CLL but are underrepresented in clinical trials. We analyzed the outcomes of these patients treated with targeted agents in the front-line setting in six trials of the German CLL Study Group. Targeted agents included venetoclax, ibrutinib, and idelalisib, mainly used in combination with anti-CD20 antibodies. Among 716 patients, 33 matched the selection criteria (5%). Of those, the majority had relevant comorbidity, organ dysfunctions, and/or high-/very high-risk disease. The overall response rate was 73%. The median progression-free survival was 49.2 months compared with those not reached in younger patients. There were 11 documented deaths of which two were deemed related to therapy. Additional results including 40 patients treated with BTK-inhibitors from the GCLLSG registry suggest that treatment with targeted agents is feasible and effective. Dedicated studies are warranted for this particular subgroup of patients.

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.)

Introduction: This study aims to investigate pharmacokinetics (PK) and exposure-response parameters of the 400 mg once-daily venetoclax dose regimen in combination with obinutuzumab, which was approved for the first-line (1L) treatment of chronic lymphocytic leukemia (CLL) based on data from the phase 3 CLL14 study and the phase 1b dose-finding GP28331 study., Methods: Parameter estimates and uncertainty, which were estimated by a previously developed population PK (popPK) model, were used as informative priors for this analysis. They were re-estimated, and then used to evaluate additional covariate effects, describe venetoclax PK when administered with obinutuzumab, and provide empirical Bayes estimates of PK parameters and exposure. Exposure-progression-free survival (PFS) and exposure-safety relationships were assessed using data from CLL14, with steady-state nominal venetoclax exposure (C meanSS,nominal ) as the predictor variable. Exposure-safety analyses were conducted using logistic regression for selected treatment-emergent grade ≥ 3 adverse events (AEs) and serious AEs (SAEs). Dose intensities were summarized by tertiles of C meanSS,nominal ., Results: PK data from 274 patients (CLL14, n = 194; GP28331, n = 80) were included. The final model provided good fit of the observed data. Obinutuzumab co-administration, history of prior treatments, and disease severity at baseline had no appreciable influence on venetoclax steady-state exposure. No significant correlations were observed between venetoclax exposure and PFS, or between venetoclax exposure and the probability of treatment-emergent grade ≥ 3 neutropenia, grade ≥ 3 thrombocytopenia, grade ≥ 3 infections, and SAEs. Median dose intensities for venetoclax and obinutuzumab remained similar across venetoclax exposure tertiles., Conclusion: PopPK and exposure-efficacy, exposure-safety, and exposure-tolerability analyses support the 400 mg once-daily venetoclax dose plus obinutuzumab for 1L treatment in patients with CLL., Clinical Trial Registration: ClinicalTrials.gov Identifiers NCT02242942 and NCT02339181., (© 2022. The Author(s).)

Minimal residual disease (MRD) has evolved as a sensitive and highly prognostic surrogate parameter of response to therapy in chronic lymphocytic leukemia (CLL). Multiple methods have been established to measure and quantify MRD during and after therapy. The improved sensitivity of MRD measurements has made it possible to develop limited-duration therapies, first with chemotherapy and chemoimmunotherapy and now also with combined targeted therapy. Moreover, concepts to integrate MRD information beyond prognostication--to guide duration of treatment and determine sensitivity--are at present being explored in prospective trials. In this review, we summarize currently available methods of MRD detection, provide recent MRD data and outcomes from clinical trials in CLL, and discuss open questions and future approaches for MRD within and outside clinical trials.

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 < .0001). Compared with placebo, ibrutinib did not increase overall toxicity, yielding similar incidence and severity of adverse events (AEs). The most common serious AEs 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 the use of oral anticoagulants through an amendment of the study protocol and by avoiding CYP3A4 drug-drug interactions. Ibrutinib confirms efficacy in CLL patients at an early stage with an increased risk of progression. However, the results do not justify changing the current standard of "watch and wait." This trial was registered at www.clinicaltrials.gov as #NCT02863718., (© 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.

Competing Interests: KF reports honoraria from and consulting or advisory roles for AbbVie and Roche; and travel, accommodations, and expenses from Roche. OA-S reports honoraria from Janssen-Cilag, Roche, Gilead Sciences, AbbVie, AstraZeneca, Adaptive Biotechnologies, and BeiGene; consulting or advisory roles for Roche, Janssen-Cilag, Gilead Sciences, and AbbVie; research funding to his institute from BeiGene, Roche, AbbVie, and Janssen/Pharmacyclics; and travel, accommodations, expenses from Roche, AbbVie, Gilead Sciences, and Janssen-Cilag.

Disease Overview: Chronic lymphocytic leukemia (CLL) is one of the most frequent types of leukemia. It typically occurs in elderly patients and has a highly variable clinical course. Leukemic transformation is initiated by specific genomic alterations that interfere with the regulation of proliferation and of apoptosis in clonal B-cells., Diagnosis: The diagnosis is established by blood counts, blood smears, and immunophenotyping of circulating B-lymphocytes, which identify a clonal B-cell population carrying the CD5 antigen as well as typical B-cell markers., Prognosis and Staging: The clinical staging systems provide prognostic information by using the results of physical examination and blood counts. Various biological and genetic markers provide additional prognostic information. Deletions of the short arm of chromosome 17 (del[17p]) and/or mutations of the TP53 gene predict resistance to chemoimmunotherapy and a shorter time to progression with most targeted therapies. The CLL international prognostic index integrates genetic, biological, and clinical variables to identify distinct risk groups of patients with CLL., Therapy: Only patients with active or symptomatic disease or with advanced Binet or Rai stages require therapy. When treatment is indicated, several therapeutic options exist: a combination of the B-cell lymphoma 2 (BCL2) inhibitor venetoclax with obinutuzumab, monotherapy with inhibitors of Bruton tyrosine kinase (BTK) such as ibrutinib and acalabrutinib, or chemoimmunotherapy. At relapse, the initial treatment may be repeated, if the treatment-free interval exceeds 3 years. If the disease relapses earlier, therapy should be changed using an alternative regimen. Patients with a del(17p) or TP53 mutation are usually resistant to chemotherapy and should, therefore, be treated with targeted agents., Future Challenges: Combinations of targeted agents are now being investigated to create efficient, potentially curative therapies of CLL with fixed duration. One of the most relevant questions currently addressed in clinical trials is the comparison of monotherapies with BTK inhibitors with fixed duration combination therapies. Moreover, the optimal sequencing of targeted therapies remains to be determined. Alternative therapies are needed for patients with BTK and BCL2 inhibitor double-refractory disease., (© 2021 The Authors. American Journal of Hematology published by Wiley Periodicals LLC.)

Fifty-one of 189 evaluable patients from 3 prospective phase 2 trials evaluating a sequential targeted treatment had high-risk chronic lymphocytic leukemia (CLL) with a 17p deletion, TP53 mutation, or both. Twenty-seven patients started treatment with bendamustine debulking before induction and maintenance treatment, which was ibrutinib/ofatumumab (IO) in 21 patients, ibrutinib/obinutuzumab (IG) in 13, and venetoclax/obinutuzumab (AG) in 17. The primary end point was overall response rate after 8 months of induction treatment, which was 81%, 100%, and 94% for IO, IG, and AG, respectively. Minimal residual disease (MRD) was undetectable (uMRD) in peripheral blood (<10-4 by flow cytometry) in 0%, 23%, and 82% of patients, respectively. Median progression-free survival (PFS) was 45 months. Seventeen patients discontinued maintenance treatment due to uMRD: 9 progressed, 2 died without progression (median PFS, 28 months after discontinuation of treatment), and 6 remained in remission after a median observation time of 46 months (range, 6-47 months) after treatment discontinuation. Thus, MRD-guided fixed-duration therapies combining obinutuzumab with venetoclax or ibrutinib can induce deep and durable remissions in CLL patients with high-risk genetic lesions, which can persist after treatment discontinuation (due to a predefined fixed-duration or MRD-guided early termination). The median PFS was 45 months. These trials were registered at www.clinicaltrials.gov as #NCT02345863, #NCT02401503, and #NCT02689141., (© 2021 by The American Society of Hematology.)

Chronic lymphocytic leukemia (CLL)-related symptoms impair the well-being of patients, making improvement of health-related quality of life (QoL) a goal of treatment. The CLL14 trial demonstrated higher efficacy of fixed-duration venetoclax-obinutuzumab (Ven-Obi) compared to chlorambucil-obinutuzumab (Clb-Obi) in patients with previously untreated CLL. To assess patients' QoL, the following patient-reported outcomes (PRO) measures were assessed: the M.D. Anderson Symptom Inventory (MDASI) core instrument and CLL module and the EORTC Quality of Life Questionnaire Core 30 (EORTC QLQ-C30). At treatment start, physical functioning (mean 75.9 [standard deviation (SD) ± 20.1] in the Clb-Obi arm and 76.9 [±19.4] in the Ven-Obi arm), role functioning (73.6 [±27.86] and 72.6 [±26.9]) and GHS/QoL (63.6 [±21.0] and 60.3 [±20.5]) were comparable between treatment arms per EORTC QLQ-C30 scale scores. Baseline levels of physical and role functioning were maintained throughout treatment and follow-up, with no relevant improvement or deterioration. On average, patients treated with Ven-Obi showed a meaningful improvement of GHS/QoL during treatment and follow-up by at least eight points at cycle three, whereas improvement was delayed until cycle eight with Clb-Obi. According to MDASI scores, CLL symptoms (1.5 [±1.2] and 1.6 [±1.3]), core cancer symptoms (1.5 [±1.4] and 1.8 [±1.7]) and symptom interference (2.1 [±2.3] and 2.3 [±2.3]) were generally low and comparable between treatment arms at baseline and were maintained throughout treatment and follow-up. This analysis demonstrates that the higher efficacy of Ven-Obi is not associated with QoL impairment and that Ven-Obi achieves early relief of CLL-related symptoms in elderly unfit patients., (© 2021 The Authors. American Journal of Hematology published by Wiley Periodicals LLC.)