Abstract: Of the estimated 21,000 patients who will receive a new diagnosis of chronic lymphocytic leukemia (CLL) this year in the United States, approximately 80% will have early-stage disease. Patients with early-stage disease do not meet the criteria in the 2018 International Workshop on CLL guidelines for the initiation of therapy, and therefore they are not routinely offered treatment. The current management of these patients follows a “watch-and-wait” paradigm, which entails a regular follow-up every 3 to 6 months that includes a physical examination and relevant laboratory testing to evaluate for disease progression. These recommendations are based on decades of careful observations showing that treatment in early-stage CLL does not improve overall survival. With the advent of better prognostic tools to identify patients at high risk, in addition to the recent approval of several novel oral agents with impressive efficacy, the time is ripe to re-examine this question. This review (1) summarizes the results of studies of early intervention in CLL that led to the current consensus for “watch and wait” in early-stage CLL, (2) discusses the role of contemporary risk stratification in early-stage CLL, (3) describes the adverse clinical complications of untreated CLL, and (4) presents the results of ongoing clinical trials of novel agents used in patients with early-stage CLL.
Chronic lymphocytic leukemia (CLL) is a low-grade B-cell lymphoproliferative neoplasm. It is estimated that 21,000 new cases will be diagnosed in the United States in 2021,1 and in the majority of patients, the diagnosis will be discovered incidentally on the basis of lymphocytosis noted in a complete blood cell count. CLL is considered incurable, and most patients ultimately experience significant disease-related morbidity and die of the disease or its complications.2,3 In the past 4 decades, as the result of significant advances that have been made, the armamentarium of treatments for CLL has expanded tremendously. The treatment of CLL has evolved from single-agent alkylator therapy with an agent such as chlorambucil (Leukeran, Aspen Global), to combination therapy with a purine nucleoside analogue and an alkylating agent (eg, fludarabine and cyclophosphamide), and then to combination chemoimmunotherapy (eg, fludarabine, cyclophosphamide, and rituximab [FCR], or bendamustine and rituximab [BR]). Recombinant genetically based approaches to enhance the cytotoxicity of anti-CD20 monoclonal antibodies led to the approval of ofatumumab (Arzerra, Novartis) and obinutuzumab (Gazyva, Genentech), which have contributed to impressive strides in the management of CLL. In the past decade, several novel oral agents have been approved for the treatment of CLL. These include the Bruton tyrosine kinase (BTK) inhibitors ibrutinib (Imbruvica, Pharmacyclics/Janssen) and acalabrutinib (Calquence, AstraZeneca); the phosphoinositide 3-kinase (PI3K) inhibitors idelalisib (Zydelig, Gilead) and duvelisib (Copiktra, Verastem); and the B-cell lymphoma 2 (BCL2) inhibitor venetoclax (Venclexta, AbbVie). Collectively, these therapies represent a paradigm shift in our approach to the management of patients with CLL.
The 2018 International Workshop on Chronic Lymphocytic Leukemia (iwCLL) guidelines are consensus recommendations that provide widely accepted indications for the initiation of anti-CLL therapy (Table 1).4 Approximately 80% of patients with CLL have early-stage asymptomatic disease at the time of diagnosis and do not meet any of the 2018 iwCLL criteria for the initiation of therapy. A “watch-and-wait” approach is typically favored for these patients if they are not enrolled in a clinical trial. However, in the era of novel agents with greater effectiveness and more favorable side effect profiles (such as less marrow toxicity), and with the development of robust prognostic models, discussed below, we believe that an evaluation of the benefits of early treatment intervention in patients with asymptomatic CLL is timely. In this review, we highlight past efforts to conduct treatment in early-stage CLL, describe how prognostic models permit the detection of high-risk early-stage CLL, and summarize the emerging data from recent clinical trials, based on novel agents, that assessed the efficacy and safety of early intervention in CLL.
Historical Overview of Early Intervention in CLL
Early intervention refers to the administration of anti-CLL therapy to patients who otherwise would be under observation alone owing to a lack of symptoms related to CLL. This situation typically applies to patients with a new diagnosis who do not meet the 2018 iwCLL criteria for the initiation of therapy. A number of studies have been conducted in the past 4 decades to determine if early intervention in patients with asymptomatic CLL can improve outcomes. In a small phase 3 study of interferon alfa (n=21) vs observation (n=23), the use of interferon alfa did not improve progression-free survival (PFS) and overall survival (OS) in patients with Binet stage A CLL.5 In 2 randomized phase 3 studies that enrolled a total of 1535 patients, the French Cooperative Group on Chronic Lymphocytic Leukemia reported that continuous chlorambucil therapy (administered orally as a single agent at a daily dose of 0.1 mg/kg) or intermittent chlorambucil therapy (administered with prednisone: chlorambucil dosed at 0.3 mg/kg daily for 5 days each month, and prednisone dosed at 40 mg/m2 daily for 5 days each month) for a total of 3 years improved disease control compared with no treatment.6 Similar results were published by Shustik and colleagues in a Cancer and Leukemia Group B (CALGB) study comparing treatment with chlorambucil (administered at a dose of 0.5 mg/kg orally on day 1 of each month, with subsequent monthly dose increases of 0.1 mg/kg until clinical improvement or toxicity) in 48 patients who had early-stage CLL vs no treatment.7 Neither study showed an OS benefit when chlorambucil was compared with no treatment. A meta-analysis of chlorambucil-based treatments by the CLL Trialists’ Collaborative Group also demonstrated no improvement in OS for immediate vs deferred chlorambucil-based treatments.8 Given the lack of an OS benefit with these approaches, chlorambucil-based treatments for early-stage asymptomatic CLL have not been incorporated into routine practice.
With the availability of the purine nucleoside fludarabine for the management of CLL in the 2000s, the German CLL Study Group (GCLLSG) conducted the CLL1 trial, which compared fludarabine (25 mg/m2 intravenously daily for 5 days, repeated every 28 days for a maximum of 6 cycles) with observation in patients who had early-stage CLL. To be eligible for trial participation, all patients were required to have 2 of the following 4 adverse characteristics: diffuse bone marrow infiltration, rapid lymphocyte doubling time (LDT), serum ß2-microglobulin level above 4.35 mg/dL, and serum thymidine kinase level above 10 IU/L (the latter being a marker for the proliferation rate in CLL, with a higher value predicting a more aggressive course). Among the 189 patients enrolled in the study, fludarabine therapy led to a significant improvement in PFS (30 vs 13 months; P<.01) and in treatment-free survival (74 vs 41 months; P=.04). Nonetheless, improvement in OS did not occur (127 months vs not reached; P=.75).9 The subsequent CLL7 study intensified the treatment regimen to 6 cycles of standard FCR vs observation in 201 patients with asymptomatic CLL. Patients in this study had at least 2 of the following 4 adverse characteristics: rapid LDT, serum thymidine kinase level above 10 IU/L, unmutated immunoglobulin heavy chain variable (IGHV) genes, and high-risk fluorescence in situ hybridization (FISH) results, including del(11q), del(17p), and trisomy 12. After approximately 5 years of follow-up, the median event-free survival (EFS) was significantly better with FCR than with observation (median not reached vs 18.5 months; P<.001); however, the 5-year OS rate did not differ between the 2 arms (82.9% vs 79.9%, respectively; P=.86).10 Given the excessive toxicities associated with FCR (mainly hematologic toxicities and infections) and the lack of a difference in OS, fludarabine-based therapies are not recommended in patients with early-stage asymptomatic CLL.
Several studies have tested the use of anti-CD20 monoclonal antibody treatments such as rituximab, which provide a far less toxic treatment platform than cytotoxic chemotherapy for early-intervention trials. These approaches used rituximab either as a single agent or in combination with other monoclonal antibodies, such as alemtuzumab (Campath, Genzyme).11-13 The studies demonstrated response rates of 80% to 95%, a response duration of approximately 18 months, and an improvement in time to the initiation of cytotoxic therapy in comparisons with historical controls who had high-risk disease. However, these approaches have not been adopted into routine practice, given the small numbers of patients and lack of long-term outcome data.
Contemporary Risk Models for CLL Progression Among Patients With Newly Diagnosed Disease
The risk for progression to symptomatic disease in CLL is variable. Some patients live for decades without therapy, whereas others die within a few years after diagnosis owing to disease progression despite treatment.14 Therefore, one of the essential components for successful early treatment in asymptomatic patients is rigorous patient selection. The importance of patient selection was well demonstrated in a recent phase 3 clinical study of patients with smoldering multiple myeloma, another example of a relatively indolent hematologic malignancy. Smoldering multiple myeloma, like CLL, is observed until specific criteria for therapy are met. In this study, treatment with lenalidomide (Revlimid, Celgene) was compared with observation and was found to be superior in reducing the risk for progression to symptomatic disease, with a favorable risk-to-benefit ratio seen mainly in patients at high risk for disease progression.15 Therefore, given that patients at higher risk for progression to symptomatic disease are more likely to benefit from early intervention than are those at lower risk for disease progression, appropriate patient selection is an essential component of efforts to assess the benefits of early treatment in CLL.
Prognostic models for risk stratification in CLL have evolved from the early Rai and Binet staging systems16,17 to contemporary models integrating clinical, biological, and genomic characteristics. These novel models improve prognostic accuracy and thus serve as a better guide for clinicians and patients alike.18 Such prognostic models were developed primarily to predict OS, the most robust endpoint in cancer. However, in the context of appropriate patient selection for early intervention, the optimal risk model is one that accurately predicts time to first therapy (TTFT). Four such models exist and are listed in Table 2. The best validated and most widely accepted model is the CLL International Prognostic Index (CLL-IPI),19 which is based on 5 readily available factors and categorizes patients with CLL into 4 risk groups. It was originally developed to predict OS among treatment-naive patients with CLL enrolled in several phase 3 studies. However, by applying this model to patients with untreated CLL, investigators were able to predict TTFT in 2 cohorts of untreated patients, one from the Mayo Clinic and the other a Scandinavian population-based cohort.
The CLL1 study researchers recently published their own independent prediction model for TTFT among 539 patients with CLL who were enrolled into the observation arm of the study.20 Their CLL prognostic model, CLL1-PM, is a 6-factor model and has considerable overlap with the CLL-IPI score. However, the former model includes a del(11q) abnormality on FISH and an LDT of less than 12 months, neither of which is part of the CLL-IPI model, whereas Rai stage I to IV is included in the CLL-IPI model but not in the CLL1-PM model.
A head-to-head comparison of these 2 models conducted by the CLL1 investigators from the GCLLSG revealed similar performances, although the C-statistic score (a measure of model prediction accuracy in which a score of 1.0 indicates a perfect predictor) marginally favored the CLL1-PM over the CLL-IPI (0.74 vs 0.71, respectively).20 However, the observation arm in the CLL1 study had a higher proportion of favorable-risk patients (62% very low-risk patients compared with 46% low-risk patients in the Mayo validation cohort of the CLL-IPI). This finding suggests selection bias, which likely affected model performance. The 2 other notable prognostic models for TTFT are the MD Anderson Cancer Center (MDACC) nomogram21 and the GCLLSG model.22 The MDACC nomogram, the first model to predict TTFT, utilizes 5 readily available parameters. The nomogram is based on a complex formula, however, and its application in the clinic is challenging. The GCLLSG model is limited by the incorporation of the thymidine kinase level, a measurement that is not widely available in the United States. In our clinical practice, we use the CLL-IPI model to predict the TTFT, given its ease of clinical applicability and its multicenter design and validation across several studies.23-25
With the emergence of models to predict TTFT, the next question that comes up is, which risk group(s) would be considered suitable for assessing the effect of early intervention vs the traditional “watch-and-wait” approach in asymptomatic patients? The OS and TTFT among patients with newly diagnosed CLL seen at Mayo Clinic from January 1995 through December 2019 are shown in the Figure. Among 1448 patients, the median TTFT values in the very high-risk and high-risk groups were 0.5 and 1.9 years, respectively, compared with 3.8 and 14.6 years in the intermediate-risk and low-risk groups, respectively. To maximize proof of efficacy for early intervention, the risk for disease progression in selected patients should be higher than the rate of treatment failure owing to toxicity or resistance. If we assume that (1) the response rate in patients with asymptomatic CLL is similar to the rate in those with symptomatic CLL and (2) the rate of treatment failure at 3 years with the use of contemporary therapies in patients with symptomatic CLL is 10% to 25%,26-29 then patients in the CLL-IPI high-risk and very high-risk groups (who have 3-year TTFT rates of 50% and 75%, respectively) are likely the ones most suitable to provide evidence for the efficacy of early intervention.
Adverse Clinical Consequences of Untreated CLL
Data about the adverse clinical consequences of a “watch-and-wait” management strategy are slowly emerging. In a study of 1475 patients with newly diagnosed CLL seen at Mayo Clinic in Rochester, Minnesota, approximately 25% of the patients had hypogammaglobulinemia at the time of diagnosis, and among the patients with a normal serum level of immunoglobulin G at the time of diagnosis, hypogammaglobulinemia developed in approximately 25% over time (even in the absence of treatment), suggesting that immune dysfunction may occur as a consequence of expansion of the malignant B-cell clone.30 In a recent study of 2905 patients from the Danish National CLL Registry with newly diagnosed CLL, the cumulative incidence of infection (the proportion of individuals who had blood cultures drawn was used as a proxy for infection, regardless of whether infection was identified) was 12% in the first year among untreated patients with CLL.31 Older age, male sex, advanced Binet stage, unmutated IGHV genes, serum ß2-microglobulin level above 4 mg/dL, and hypogammaglobulinemia were predictors of an increased risk for infection in these patients. Using a competing-risk model, the authors demonstrated that the cumulative risk for needing therapy at 1 year after diagnosis was 11% and the risk for death at 1 year was 1%, suggesting that infectious complications are an important source of morbidity in patients with untreated CLL. The authors extended these findings in a larger cohort of patients and with the use of machine learning developed the CLL Treatment Infection Model (CLL-TIM), which identified patients at risk for infection or CLL treatment within 2 years of diagnosis.32
In addition to infections, patients with CLL are at increased risk for the development of nonhematologic malignancies in comparison with age- and sex-matched healthy controls.33-38 The risk for nonhematologic malignancies, particularly nonmelanoma skin cancers, was significantly increased in patients who had a high-risk or very high-risk CLL-IPI score compared with patients who had a low-risk or intermediate-risk CLL-IPI score (4-year risk: 30% vs 10%, respectively).39 Finally, the occurrence of clonal evolution in patients with untreated CLL during the watch-and-wait phase of disease management is being increasingly recognized. Studies have demonstrated the acquisition of novel genetic aberrations before the administration of therapy that are distinct from the original clonal genetic features, even among individuals with favorable-risk markers such as mutated IGHV genes and del(13q) by FISH. This finding suggests that the accumulation of novel somatic mutations is not restricted to the post-therapy setting.40,41 It is important to note that despite these observations, no evidence available to date indicates that early intervention to treat CLL will reverse many of these immune deficits or genomic aberrations and lead to improved outcomes. Carefully conducted clinical trials specifically examining such biological outcomes of interest, as well as clinical benefits, are critical if we are to acquire a full understanding of the long-term implications of early therapy.
Selection of Endpoints for Early-Intervention Studies in CLL
The choice of endpoint(s) for early intervention in studies of patients with asymptomatic CLL is an important design question. The possible clinical endpoints, and details of the pros and cons of each, are listed in Table 3. OS is the gold standard as a primary endpoint but requires a long follow-up, which makes it a problematic choice. Moreover, OS benefit may be “diluted” by the ongoing emergence of therapeutic options that gradually improve OS in this disease.42-45 Indeed, the US Food and Drug Administration (FDA) accelerated approvals of drugs to treat hematologic cancers were based mostly on surrogate endpoints, such as response rate and PFS.46,47 Therefore, PFS is the current leading endpoint for drug approval, including in studies of early intervention in other hematologic malignancies, as discussed earlier.15 Studies relying on PFS as the primary endpoint are still expected to require a long follow-up, although the sample size is generally smaller than with an OS endpoint. Critics of PFS as an endpoint in early-intervention studies note that the results of comparing a drug that is approved for a particular indication with placebo are a foregone conclusion, and therefore such studies generally do not truly inform practice. In addition, “progression” in CLL typically manifests as worsening lymphocytosis or asymptomatic lymph node enlargement. Neither of these meets the 2018 iwCLL criteria for the initiation of therapy, so that PFS is a particularly challenging endpoint to include in trials of early-stage CLL. In contrast, EFS, which is defined as the interval before the occurrence of symptomatic progression, the initiation of CLL therapy, or death for any reason, is a better endpoint for trials of early-stage CLL.
The response rate served as a surrogate marker for disease control in the chemotherapy era. However, the attainment of a response in the era of novel agents is frequent (>90%) and is expected to be similar in the population of patients with asymptomatic early-stage CLL. For this reason, it is challenging to use the response rate as a primary measure of effectiveness when comparing an FDA-approved medication with placebo, just as it is to use a PFS endpoint. Moreover, the traditional response criteria are challenged in the current treatment era by the typical rapid reduction of lymphadenopathy with BTK inhibitors but paradoxical rise in peripheral blood lymphocytosis, a phenomenon also known as partial response with lymphocytosis.48
The surrogate endpoint of minimal residual disease (MRD) is attractive in many hematologic cancers.49 MRD assessment has the advantage of early measurement of outcome, shortening the duration of a clinical trial. Various methods are available for MRD measurement, including multiparameter flow cytometry, allele-specific polymerase chain reaction, and next-generation sequencing.4 The presence of less than 1 CLL cell per 10,000 leukocytes is the accepted definition for undetectable MRD (uMRD), and the European Research Initiative on CLL (ERIC) has recently made attempts to harmonize MRD assessment across multiple centers.50,51 MRD has been established as a prognostic marker for survival in patients who have CLL treated with chemoimmunotherapy (CIT).52-56 CIT is no longer the standard of care, however, and the role of MRD in response evaluation and its prognostic role in CLL should undergo reassessment in the era of novel agents. The prognostic significance of uMRD may depend on the specific novel agent used; with venetoclax, a significant proportion of patients with CLL achieve uMRD in both bone marrow and blood, in both the frontline27 and relapsed settings.57,58 Although uMRD has not been fully validated as a surrogate endpoint in CLL in the United States, the European Medicines Agency has determined that it may be used as an intermediate endpoint in randomized trials, with subsequent confirmation of efficacy on longer-term follow-up.59
Quality-of-life (QoL) measurements are an increasingly important endpoint in cancer therapy. Although results are not consistent across trials, patients with CLL report functional impairment in physical well-being, emotional strength, energy, sleep quality, and other QoL domains.28,60-63 These impairments in QoL measures appear during early-stage disease, when patients are observed without active treatment, and generally increase with disease stage. Patients treated with ibrutinib had better social functioning, less fatigue, and less loss of appetite than did patients on CIT,63 illustrating the more favorable toxicity profiles of novel agents. This is an important finding because it increases the chances of successful early intervention in the novel-agent era compared with the previous unsuccessful CIT approaches.
Unique endpoints measuring other complications related to CLL, such as nonhematologic cancers and infections, may also be of interest in patients with untreated CLL because these can lead to significant morbidity during the “wait-and-watch” phase of disease management. The challenges of incorporating novel agents such as BTK inhibitors and BCL2 inhibitors in such situations are that these treatments may themselves increased the risk for infections27,64 and nonhematologic malignancies.65,66 Early-intervention studies with a randomized design platform can provide the best evidence regarding whether the risk for nonhematologic cancers and serious infections is related to underlying CLL vs CLL therapy.
Studies of Early Intervention in Patients With Asymptomatic CLL in the Novel-Agent Era
The key studies of early intervention in CLL that use novel oral agents are summarized in Table 4. The largest and first study of novel agents in patients with asymptomatic CLL was CLL12. In this placebo-controlled, double-blind, randomized phase 3 study, patients who had Binet stage A CLL without an indication for therapy were risk stratified according to the GCLLSG model.22 Patients with low-risk disease were observed, whereas patients with intermediate-, high-, or very high-risk disease were randomly assigned to ibrutinib at 420 mg daily or placebo. Treatment was continued until symptomatic disease progression (but no later than 60 months after randomization). The study recruited 515 patients. A total of 363 patients were randomized to receive ibrutinib (n=182) or placebo (n=181). Patients with low-risk disease by the model (n=152) were not included in the primary efficacy endpoint.67 After a median follow-up of 31 months, the median EFS was not reached in the ibrutinib arm and was 47.8 months in the placebo arm (hazard ratio, 0.25; 95% CI, 0.14-0.43; P<.0001). Twelve deaths occurred in the study, and the data are still immature for OS analysis. Any-grade adverse events (AEs) occurred at similar rates in the ibrutinib arm (82.2%) and the placebo arm (84.8%). The most commonly reported AEs leading to interruption in the ibrutinib arm vs the placebo arm included arrhythmias (18 vs 0 patients), bleeding (8 vs 1 patient), diarrhea (4 vs 3 patients), and neoplasia (4 vs 3 patients). Treatment was discontinued by 34.1% of the ibrutinib-treated patients vs 45.9% of the patients who received placebo. AEs (n=53) were the primary cause of discontinuation in the ibrutinib arm, whereas disease progression (n=45) was more common in the placebo arm.
Several phase 2 studies that are exploring novel agents for early-stage CLL are looking at BTK inhibitors alone or in combination. A phase 2 study from The Ohio State University randomly assigned 44 patients with high-risk genomics (unmutated IGHV genes, high-risk results by FISH, or complex karyotype) to receive ibrutinib concurrently with or sequentially after vaccine administration.68 Therapy with ibrutinib was reported to be safe, with no grade 4 toxicities and no grade 3/4 hematologic AEs. Grade 3 atrial fibrillation developed in 2 patients. Early treatment was associated with improvement in QoL measures of cancer-related stress: anxiety and loss of sleep. Three phase 2 studies of patients with high-risk asymptomatic early-stage CLL assessing the efficacy and safety of ibrutinib, acalabrutinib with or without obinutuzumab, and ibrutinib in combination with pembrolizumab (Keytruda, Merck) are ongoing, with no outcome results reported to date.
EVOLVE is a phase 3 North American Intergroup Study that is expected to open enrollment this year to patients with previously untreated early-stage CLL who are at high or very high risk for disease progression according to the CLL-IPI. Patients will be randomly assigned to therapy with venetoclax and obinutuzumab at diagnosis or to delayed therapy with venetoclax and obinutuzumab when disease progression occurs and they meet 2018 iwCLL criteria for the initiation of therapy. The primary endpoint of this study is OS in the immediate-therapy vs the delayed-therapy arm (NCT04269902). Another study, PreVent-ACaLL (NCT03868722), will randomly assign 212 patients at high risk for infection and/or needing therapy, according to the CLL-TIM algorithm,32 in a 1:1 ratio to combination therapy with acalabrutinib and venetoclax vs placebo for a fixed duration of 12 weeks. The primary endpoint of this study is survival free of grade 3 or higher infection in the treatment arm vs the observation arm after 24 weeks (12 weeks after the end of treatment).69
The current paradigm of “watch and wait” in early-stage CLL can quickly morph into “wait and worry” for many patients who do not need therapy at the time of diagnosis. Previous clinical trials of treatments for patients with early-stage CLL did not extend into routine clinical practice owing to the excessive toxicity and/or ineffectiveness of the treatments and a lack of robust prognostic models for appropriate patient selection. We have now reached an exciting era in which a plethora of effective anti-CLL therapies are available that have fewer toxic effects on bone marrow reserve and immune status than did past therapies. The parallel improvement in prognostic tools for disease progression has created a new opportunity to reassess the role of early treatment in patients with asymptomatic (or minimally symptomatic) disease who are at high risk for disease progression. Several ongoing clinical trials will ultimately pave the way for the adoption of an early-treatment approach in patients with high-risk asymptomatic CLL, and we strongly support enrolling appropriate patients with early-stage CLL in rationally designed trials. However, until the mature results of such trials become available, we continue to follow the 2018 iwCLL guidelines for starting therapy in patients with newly diagnosed, early-stage CLL.
Dr Muchtar has no disclosures. Dr Kay has received institutional research funding from Acerta Pharma, Bristol-Myers Squibb, Pharmacyclics, Tolero Pharmaceuticals, MEI Pharma, AbbVie, and Sunesis Pharmaceuticals; has served on data safety monitoring committees for Agios Pharmaceuticals, AstraZeneca, CytomX Therapeutics, and Rigel Pharmaceuticals; and has served on advisory boards for CytomX Therapeutics, Pharmacyclics, Juno Therapeutics, AstraZeneca, and ONCOtracker. Dr Parikh has received institutional research funding from Pharmacyclics, Janssen, AstraZeneca, TG Therapeutics, Merck, AbbVie, and Ascentage Pharma for clinical studies in which he is a principal investigator. He also has participated in advisory board meetings of Pharmacyclics, AstraZeneca, Genentech, Gilead, GlaxoSmithKline, Verastem Oncology, and AbbVie but was not personally compensated for his participation.
Dr Parikh acknowledges support from the Mayo Clinic K2R Career Development Program. The authors would like to acknowledge the contribution of Kari G. Rabe, who provided the Figure.
1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin. 2020;70(1):7-30.
2. Dighiero G, Binet JL. When and how to treat chronic lymphocytic leukemia. N Engl J Med. 2000;343(24):1799-1801.
3. Strati P, Parikh SA, Chaffee KG, et al. Relationship between co-morbidities at diagnosis, survival and ultimate cause of death in patients with chronic lymphocytic leukaemia (CLL): a prospective cohort study. Br J Haematol. 2017;178(3):394-402.
4. Hallek M, Cheson BD, Catovsky D, et al. iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL. Blood. 2018;131(25):2745-2760.
5. Langenmayer I, Nerl C, Knauf W, et al. Interferon-alpha 2b (IFN alpha) for early-phase chronic lymphocytic leukaemia with high risk for disease progression: results of a randomized multicentre study. Br J Haematol. 1996;94(2):362-369.
6. Dighiero G, Maloum K, Desablens B, et al; French Cooperative Group on Chronic Lymphocytic Leukemia. Chlorambucil in indolent chronic lymphocytic leukemia. N Engl J Med. 1998;338(21):1506-1514.
7. Shustik C, Mick R, Silver R, Sawitsky A, Rai K, Shapiro L. Treatment of early chronic lymphocytic leukemia: intermittent chlorambucil versus observation. Hematol Oncol. 1988;6(1):7-12.
8. Chemotherapeutic options in chronic lymphocytic leukemia: a meta-analysis of the randomized trials. CLL Trialists’ Collaborative Group. J Natl Cancer Inst. 1999;91(10):861-868.
9. Bergmann MA, Busch R, Eichhorst B, et al. Overall survival in early stage chronic lymphocytic leukemia patients with treatment indication due to disease progression: follow-up data of the CLL1 trial of the German CLL Study Group (GCLLSG) [ASH abstract 4127]. Blood. 2013;122(21)(suppl).
10. Herling CD, Cymbalista F, Groß-Ophoff-Müller C, et al. Early treatment with FCR versus watch and wait in patients with stage Binet A high-risk chronic lymphocytic leukemia (CLL): a randomized phase 3 trial. Leukemia. 2020;34(8):2038-2050.
11. Ferrajoli A, Keating MJ, O’Brien S, Cortes J, Thomas DA. Experience with rituximab immunotherapy as an early intervention in patients with Rai stage 0 to II chronic lymphocytic leukemia. Cancer. 2011;117(14):3182-3186.
12. Zent CS, Call TG, Bowen DA, et al. Early treatment of high risk chronic lymphocytic leukemia with alemtuzumab, rituximab and poly-(1-6)-beta-glucotriosyl-(1-3)- beta-glucopyranose beta-glucan is well tolerated and achieves high complete remission rates. Leuk Lymphoma. 2015;56(8):2373-2378.
13. Zent CS, Call TG, Shanafelt TD, et al. Early treatment of high-risk chronic lymphocytic leukemia with alemtuzumab and rituximab. Cancer. 2008;113(8):2110-2118.
14. Shanafelt TD. Predicting clinical outcome in CLL: how and why. Hematology Am Soc Hematol Educ Program. 2009:421-429.
15. Lonial S, Jacobus S, Fonseca R, et al. Randomized trial of lenalidomide versus observation in smoldering multiple myeloma. J Clin Oncol. 2020;38(11):1126-1137.
16. Binet JL, Auquier A, Dighiero G, et al. A new prognostic classification of chronic lymphocytic leukemia derived from a multivariate survival analysis. Cancer. 1981;48(1):198-206.
17. Rai KR, Sawitsky A, Cronkite EP, Chanana AD, Levy RN, Pasternack BS. Clinical staging of chronic lymphocytic leukemia. Blood. 1975;46(2):219-234.
18. Parikh SA, Shanafelt TD. Prognostic factors and risk stratification in chronic lymphocytic leukemia. Semin Oncol. 2016;43(2):233-240.
19. International CLL-IPI working group. An international prognostic index for patients with chronic lymphocytic leukaemia (CLL-IPI): a meta-analysis of individual patient data. Lancet Oncol. 2016;17(6):779-790.
20. Hoechstetter MA, Busch R, Eichhorst B, et al. Prognostic model for newly diagnosed CLL patients in Binet stage A: results of the multicenter, prospective CLL1 trial of the German CLL study group. Leukemia. 2020;34(4):1038-1051.
21. Wierda WG, O’Brien S, Wang X, et al. Multivariable model for time to first treatment in patients with chronic lymphocytic leukemia. J Clin Oncol. 2011;29(31):4088-4095.
22. Pflug N, Bahlo J, Shanafelt TD, et al. Development of a comprehensive prognostic index for patients with chronic lymphocytic leukemia. Blood. 2014;124(1):49-62.
23. Gentile M, Shanafelt TD, Rossi D, et al. Validation of the CLL-IPI and comparison with the MDACC prognostic index in newly diagnosed patients. Blood. 2016;128(16):2093-2095.
24. Molica S, Shanafelt TD, Giannarelli D, et al. The chronic lymphocytic leukemia international prognostic index predicts time to first treatment in early CLL: independent validation in a prospective cohort of early stage patients. Am J Hematol. 2016;91(11):1090-1095.
25. Muñoz-Novas C, Poza-Santaella M, González-Gascón Y Marín I, et al. The International Prognostic Index for Patients with Chronic Lymphocytic Leukemia has the higher value in predicting overall outcome compared with the Barcelona-Brno Biomarkers Only Prognostic Model and the MD Anderson Cancer Center Prognostic Index. Biomed Res Int. 2018;2018:9506979.
26. Burger JA, Tedeschi A, Barr PM, et al; RESONATE-2 Investigators. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med. 2015;373(25):2425-2437.
27. Fischer K, Al-Sawaf O, Bahlo J, et al. Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. N Engl J Med. 2019;380(23):2225-2236.
28. Shanafelt TD, Wang XV, Kay NE, et al. Ibrutinib-rituximab or chemoimmunotherapy for chronic lymphocytic leukemia. N Engl J Med. 2019;381(5):432-443.
29. Woyach JA, Ruppert AS, Heerema NA, et al. Ibrutinib regimens versus chemoimmunotherapy in older patients with untreated CLL. N Engl J Med. 2018;379(26):2517-2528.
30. Parikh SA, Leis JF, Chaffee KG, et al. Hypogammaglobulinemia in newly diagnosed chronic lymphocytic leukemia: natural history, clinical correlates, and outcomes. Cancer. 2015;121(17):2883-2891.
31. Andersen MA, Eriksen CT, Brieghel C, et al. and predictors of infection among patients prior to treatment of chronic lymphocytic leukemia: a Danish nationwide cohort study. Haematologica. 2018;103(7):e300-e303.
32. Agius R, Brieghel C, Andersen MA, et al. Machine learning can identify newly diagnosed patients with CLL at high risk of infection. Nat Commun. 2020;11(1):363.
33. Hisada M, Biggar RJ, Greene MH, Fraumeni JF Jr, Travis LB. Solid tumors after chronic lymphocytic leukemia. Blood. 2001;98(6):1979-1981.
34. Maddocks-Christianson K, Slager SL, Zent CS, et al. Risk factors for development of a second lymphoid malignancy in patients with chronic lymphocytic leukaemia. Br J Haematol. 2007;139(3):398-404.
35. Morton LM, Curtis RE, Linet MS, et al. Second malignancy risks after non-Hodgkin’s lymphoma and chronic lymphocytic leukemia: differences by lymphoma subtype. J Clin Oncol. 2010;28(33):4935-4944.
36. Schöllkopf C, Rosendahl D, Rostgaard K, Pipper C, Hjalgrim H. Risk of second cancer after chronic lymphocytic leukemia. Int J Cancer. 2007;121(1):151-156.
37. Solomon BM, Chaffee KG, Moreira J, et al. Risk of non-hematologic cancer in individuals with high-count monoclonal B-cell lymphocytosis. Leukemia. 2016;30(2):331-336.
38. Tsimberidou AM, Wen S, McLaughlin P, et al. Other malignancies in chronic lymphocytic leukemia/small lymphocytic lymphoma. J Clin Oncol. 2009;27(6):904-910.
39. Kleinstern G, Rishi A, Achenbach SJ, et al. Delineation of clinical and biological factors associated with cutaneous squamous cell carcinoma among patients with chronic lymphocytic leukemia. J Am Acad Dermatol. 2020;83(6):1581-1589.
40. Hernández-Sánchez M, Kotaskova J, Rodríguez AE, et al. CLL cells cumulate genetic aberrations prior to the first therapy even in outwardly inactive disease phase. Leukemia. 2019;33(2):518-558.
41. Leeksma AC, Taylor J, Wu B, et al. Clonal diversity predicts adverse outcome in chronic lymphocytic leukemia. Leukemia. 2019;33(2):390-402.
42. Kristinsson SY, Dickman PW, Wilson WH, Caporaso N, Björkholm M, Landgren O. Improved survival in chronic lymphocytic leukemia in the past decade: a population-based study including 11,179 patients diagnosed between 1973-2003 in Sweden. Haematologica. 2009;94(9):1259-1265.
43. Lenartova A, Johannesen TB, Tjønnfjord GE. National trends in incidence and survival of chronic lymphocytic leukemia in Norway for 1953-2012: a systematic analysis of population-based data. Cancer Med. 2016;5(12):3588-3595.
44. Pulte D, Castro FA, Jansen L, et al; GEKID Cancer Survival Working Group. Trends in survival of chronic lymphocytic leukemia patients in Germany and the USA in the first decade of the twenty-first century. J Hematol Oncol. 2016;9:28.
45. Weide R, Feiten S, Chakupurakal G, et al. Survival improvement of patients with chronic lymphocytic leukemia (CLL) in routine care 1995-2017. Leuk Lymphoma. 2020;61(3):557-566.
46. Beaver JA, Howie LJ, Pelosof L, et al. A 25-Year experience of US Food and Drug Administration accelerated approval of malignant hematology and oncology drugs and biologics: a review. JAMA Oncol. 2018;4(6):849-856.
47. Smith BD, DeZern AE, Bastian AW, Durie BGM. Meaningful endpoints for therapies approved for hematologic malignancies. Cancer. 2017;123(10):1689-1694.
48. Cheson BD, Byrd JC, Rai KR, et al. Novel targeted agents and the need to refine clinical end points in chronic lymphocytic leukemia. J Clin Oncol. 2012;30(23):2820-2822.
49. Ben Lassoued A, Nivaggioni V, Gabert J. Minimal residual disease testing in hematologic malignancies and solid cancer. Expert Rev Mol Diagn. 2014;14(6):699-712.
50. Ghia P, Rawstron A. Minimal residual disease analysis in chronic lymphocytic leukemia: a way for achieving more personalized treatments. Leukemia. 2018;32(6):1307-1316.
51. Rawstron AC, Fazi C, Agathangelidis A, et al. A complementary role of multiparameter flow cytometry and high-throughput sequencing for minimal residual disease detection in chronic lymphocytic leukemia: an European Research Initiative on CLL study. Leukemia. 2016;30(4):929-936.
52. Böttcher S, Ritgen M, Fischer K, et al. Minimal residual disease quantification is an independent predictor of progression-free and overall survival in chronic lymphocytic leukemia: a multivariate analysis from the randomized GCLLSG CLL8 trial. J Clin Oncol. 2012;30(9):980-988.
53. Kovacs G, Robrecht S, Fink AM, et al. Minimal residual disease assessment improves prediction of outcome in patients with chronic lymphocytic leukemia (CLL) who achieve partial response: comprehensive analysis of two phase III studies of the German CLL Study Group. J Clin Oncol. 2016;34(31):3758-3765.
54. Letestu R, Dahmani A, Boubaya M, et al; French Innovative Leukemia Organization (FILO). Prognostic value of high-sensitivity measurable residual disease assessment after front-line chemoimmunotherapy in chronic lymphocytic leukemia. Leukemia. 2020.
55. Thompson PA, Tam CS, O’Brien SM, et al. Fludarabine, cyclophosphamide, and rituximab treatment achieves long-term disease-free survival in IGHV-mutated chronic lymphocytic leukemia. Blood. 2016;127(3):303-309.
56. Dimier N, Delmar P, Ward C, et al. A model for predicting effect of treatment on progression-free survival using MRD as a surrogate end point in CLL. Blood. 2018;131(9):955-962.
57. Ahn IE, Farooqui MZH, Tian X, et al. Depth and durability of response to ibrutinib in CLL: 5-year follow-up of a phase 2 study. Blood. 2018;131(21):2357-2366.
58. Kater AP, Wu JQ, Kipps T, et al. Venetoclax plus rituximab in relapsed chronic lymphocytic leukemia: 4-year results and evaluation of impact of genomic complexity and gene mutations from the MURANO phase III study. J Clin Oncol. 2020;38(34):4042-4054.
59. European Medicines Agency. Appendix 4 to the guideline on the evaluation of anticancer medicinal products in man – condition specific guidance. EMA/CHMP/703715/2012 Rev. 2. https://www.ema.europa.eu/en/appendix-4-guideline-evaluation-anticancer-medicinal-products-man-condition-specific-guidance. Accessed October 19, 2020.
60. Holtzer-Goor KM, Schaafsma MR, Joosten P, et al. Quality of life of patients with chronic lymphocytic leukaemia in the Netherlands: results of a longitudinal multicentre study. Qual Life Res. 2015;24(12):2895-2906.
61. Holzner B, Kemmler G, Kopp M, Nguyen-Van-Tam D, Sperner-Unterweger B, Greil R. Quality of life of patients with chronic lymphocytic leukemia: results of a longitudinal investigation over 1 yr. Eur J Haematol. 2004;72(6):381-389.
62. van den Broek EC, Oerlemans S, Nijziel MR, Posthuma EF, Coebergh JW, van de Poll-Franse LV. Impact of active surveillance, chlorambucil, and other therapy on health-related quality of life in patients with CLL/SLL in the Netherlands. Ann Hematol. 2015;94(1):45-56.
63. Youron P, Singh C, Jindal N, et al. Quality of life in patients of chronic lymphocytic leukemia using the EORTC QLQ-C30 and QLQ-CLL17 questionnaire. Eur J Haematol. 2020;105(6):755-762.
64. Rogers KA, Mousa L, Zhao Q, et al. Incidence of opportunistic infections during ibrutinib treatment for B-cell malignancies. Leukemia. 2019;33(10):2527-2530.
65. Bond DA, Huang Y, Fisher JL, et al. Second cancer incidence in CLL patients receiving BTK inhibitors. Leukemia. 2020;34(12):3197-3205.
66. Sharman JP, Egyed M, Jurczak W, et al. Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzmab for treatment-naive chronic lymphocytic leukaemia (ELEVATE TN): a randomised, controlled, phase 3 trial. Lancet. 2020;395(10232):1278-1291.
67. Langerbeins P, Bahlo J, Rhein C, et al. Ibrutinib versus placebo in patients with asymptomatic, treatment‐naïve early stage CLL: primary endpoint results of the phase 3 double‐blind randomized CLL12 trial [EHA abstract 007]. Hematol Oncol. 2019;37:38-40.
68. Awan FT, Thangavadivel S, Weiss D, et al. A phase 2 trial of early intervention with ibrutinib in patients with asymptomatic, high-risk CLL [ASH abstract 1748]. Blood. 2017;130(1)(suppl).
69. Da Cunha-Bang C, Agius R, Kater AP, et al. PreVent-ACaLL short-term combined acalabrutinib and venetoclax treatment of newly diagnosed patients with CLL at high risk of infection and/or early treatment, who do not fulfil IWCLL treatment criteria for treatment. A randomized study with extensive immune phenotyping [ASH abstract 4304]. Blood. 2019;134(1)(suppl).