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Overview of the treatment of chronic lymphocytic leukemia

Overview of the treatment of chronic lymphocytic leukemia
Authors:
Kanti R Rai, MD
Stephan Stilgenbauer, MD
Section Editor:
Richard A Larson, MD
Deputy Editor:
Rebecca F Connor, MD
Literature review current through: Oct 2022. | This topic last updated: Feb 01, 2022.

INTRODUCTION — Chronic lymphocytic leukemia (CLL) is one of the chronic lymphoproliferative disorders (lymphoid neoplasms). It is characterized by a progressive accumulation of functionally incompetent lymphocytes, which are usually monoclonal in origin.

CLL is considered to be identical (ie, one disease with different manifestations) to the mature (peripheral) B cell neoplasm small lymphocytic lymphoma (SLL), one of the indolent non-Hodgkin lymphomas. The term CLL is used when the disease manifests primarily in the blood, whereas the term SLL is used when involvement is primarily nodal. (See "Clinical features and diagnosis of chronic lymphocytic leukemia/small lymphocytic lymphoma".)

General issues regarding the treatment of CLL will be reviewed here. The selection of initial therapy for advanced stage or symptomatic disease, the treatment of relapsed or refractory disease, and the management of complications of CLL and its treatment are discussed separately. The pathophysiology, clinical manifestations, diagnosis, staging, and prognosis of CLL are also discussed separately.

(See "Selection of initial therapy for symptomatic or advanced chronic lymphocytic leukemia".)

(See "Treatment of relapsed or refractory chronic lymphocytic leukemia".)

(See "Overview of the complications of chronic lymphocytic leukemia".)

(See "Clinical features and diagnosis of chronic lymphocytic leukemia/small lymphocytic lymphoma".)

(See "Staging and prognosis of chronic lymphocytic leukemia".)

(See "Pathobiology of chronic lymphocytic leukemia".)

INITIAL MANAGEMENT

Indications for treatment ("active disease") — Not all patients with CLL require treatment at the time of diagnosis. This is principally because:

CLL is an extremely heterogeneous disease with certain subsets of patients having survival rates without treatment that are similar to the normal population [1-4].

With the possible exception of allogeneic hematopoietic cell transplantation (HCT), CLL cannot be cured by current treatment options.

Randomized trials evaluating immediate versus delayed treatment strategies have found no improvement in long-term survival with early treatment [4]. (See 'Early stage asymptomatic CLL' below.)

Spontaneous regression of variable duration is a rare occurrence [5,6].

Treatment is indicated for patients with the following disease-related complications, termed "active disease" by the International Workshop on Chronic Lymphocytic Leukemia (iwCLL) (table 1) [7]:

Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia and/or thrombocytopenia. Cytopenias unrelated to CLL should be excluded. Hemoglobin <10 g/dL or platelet count <100,000/microL are generally regarded as indications for treatment (Rai stages III or IV; Binet stage C (table 2A-B)). However, platelet counts <100,000/microL may remain stable over a long period of time in some patients, and this situation does not automatically require treatment. Autoimmune mediated anemia or thrombocytopenia is treated with therapy directed at the autoimmune process; treatment directed at the CLL is indicated if there is an inadequate response. (See "Overview of the complications of chronic lymphocytic leukemia", section on 'Autoimmune hemolytic anemia'.)

Massive (ie, ≥6 cm below the left costal margin) or progressive or symptomatic splenomegaly.

Massive (ie, ≥10 cm in longest diameter) or progressive or symptomatic lymphadenopathy.

Progressive lymphocytosis with an increase of >50 percent over a two-month period or lymphocyte doubling time (LDT) of <6 months. LDT can be calculated by linear regression extrapolation of absolute lymphocyte counts obtained at intervals of two weeks over an observation period of two to three months. Patients with initial blood lymphocyte counts of <30,000/microL may require a longer observation period to determine the LDT, and the LDT may be less likely to impact treatment decisions. For example, a doubling of the white cell count from 10,000 to 20,000 in less than 12 months in an early stage patient who is free of symptoms does not have the same weight in deciding to initiate therapy as a rapid doubling of the white cell count from 75,000 to 150,000. In addition, factors contributing to lymphocytosis or lymphadenopathy other than CLL (eg, infection) should be excluded.

Symptomatic or functional extranodal involvement (eg, skin, kidney, lung, spine).

Constitutional symptoms, defined as any one or more of the following:

Significant fatigue (ie, Eastern Cooperative Oncology Group performance status [ECOG PS] ≥2, inability to perform usual activities)

Night sweats for ≥1 month without evidence of infection

Unintentional weight loss ≥10 percent within the previous six months

Fevers for ≥2 weeks without other evidence of infection

Treatment is not indicated solely on the basis of hypogammaglobulinemia or the presence of a monoclonal or oligoclonal paraproteinemia. Likewise, lymphocytosis itself, even if extreme, is not a strict indication for treatment if patients have no symptoms and adequate bone marrow function; some patients can have stable non-progressive disease even with high leukocyte counts. However, in our experience, extreme lymphocytosis (leukocyte counts >200,000/microL) is associated with an increased risk of hyperviscosity syndrome and related complications (eg, transient ischemic attack). In addition, a transient rise in the lymphocyte count can be seen with treatment, especially when targeted therapies are used. Therefore, the empiric threshold of leukocyte counts >200,000/microL may serve as an indication for therapy in otherwise asymptomatic patients with early stage CLL.

It is premature to use newer, adverse prognostic features (eg, ZAP-70, CD38, unmutated IGHV, genomic aberrations, gene mutations) as the basis for deciding when to initiate treatment, except in the context of prospective clinical trials. At this time, we consider the patient's clinical presentation and course to be of greater weight and importance than the results of specific prognostic markers. (See "Staging and prognosis of chronic lymphocytic leukemia", section on 'Clinical staging'.)

Patients without "active disease"

Early stage asymptomatic CLL

Initial observation as standard care — For all patients with early stage asymptomatic CLL (eg, Rai stage <3, Binet stage A or B), regardless of risk factors (eg, 17p deletion, unmutated IGHV genes), the standard of care is observation ("watch and wait") rather than immediate treatment (algorithm 1).

During the observation period, we perform blood counts at three-month intervals along with a clinical examination. At the end of 12 months, a clear decision as to whether the patient has aggressive disease can be made based on these evaluations. The interval of examination may be lengthened for those with clinically stable disease. Treatment is indicated for those who develop "active disease" at any time (table 1). (See 'Indications for treatment ("active disease")' above.)

Support for this approach comes from several randomized trials and a meta-analysis that found increased toxicity and no clinical benefit with immediate chemotherapy in patients with early stage asymptomatic CLL [4,8,9]. Ongoing clinical trials are evaluating the use of more modern targeted therapies in patients with early stage disease and prognostic markers associated with worse clinical outcomes (eg, 17p deletion, unmutated IGHV genes). While we acknowledge that such patients can have increased psychological stress and a desire to start treatment right away, it is not yet known whether earlier treatment provides clinical benefit to justify the expected toxicity. Until studies demonstrate a clear clinical benefit, early treatment of asymptomatic persons should be reserved for patients enrolled on these clinical trials irrespective of risk factors (eg, IGHV mutation status, 17p deletion).

Targeted therapy was evaluated in the phase 3, double-blind, placebo-controlled CLL12 trial, in which 363 patients with asymptomatic, treatment naïve Binet stage A CLL with prognostic markers associated with worse clinical outcomes were randomly assigned to receive ibrutinib or placebo [10]. Treatment with ibrutinib postponed the development of active disease and the need for additional CLL-directed therapy, as reflected in improved event-free survival (EFS, 87 versus 60 percent at three years), progression-free survival (PFS, 81 versus 29 percent at three years), and time to next CLL treatment (TTNT, 91 versus 68 percent without next treatment at three years). Longer follow-up is needed to assess overall survival (OS). Those assigned to ibrutinib experienced more drug discontinuations due to adverse events (29 versus 14 percent), dose reductions (17 versus 3 percent), atrial fibrillation (12 versus 1 percent), hypertension (10 versus 5 percent), and bleeding (34 versus 15 percent). It is not clear whether improvement in these short-term measures (EFS, PFS, and TTNT) will translate into clinically meaningful benefit for patients, including improved overall survival. An OS benefit has not been demonstrated and analysis of the numerical events does not suggest that a difference will materialize with longer follow-up.  

Predicting time to first treatment — Some patients with early stage CLL require therapy within the first few years, while others remain asymptomatic without treatment for decades.

The International Prognostic Score for Early-stage CLL (IPS-E) uses three variables (unmutated IGHV, lymphocytes >15,000/microL, palpable lymph nodes) to stratify patients with early stage CLL at diagnosis into three risk groups with differing likelihood of requiring treatment at one and five years [11]:

Low risk (no risk factors) – <1 percent treated at 1 year; 8 percent treated at 5 years

Intermediate risk (one risk factor) – 3 percent treated at 1 year; 28 percent treated at 5 years

High risk (two or three risk factors) – 14 percent treated at 1 year; 61 percent treated at 5 years  

The IPS-E was developed and validated using individual patient data from 11 international cohorts of approximately 5000 patients with early stage CLL (Rai stage 0, I, or II or Binet stage A) initially managed with active surveillance. Unmutated IGHV, lymphocytes >15,000/microL, and palpable lymph nodes consistently and independently correlated with time to first treatment with similar magnitude allowing for equal weighting in the IPS-E score. In contrast, del(17p) and TP53 mutation were not prognostic for time to first treatment even though these are important predictors of treatment response and help guide the choice of therapy once indicated.

Other prognostic markers and prognostic scores are discussed in more detail separately. (See "Staging and prognosis of chronic lymphocytic leukemia".)

Localized SLL — Rarely, patients present with what appears to be a small lymphocytic lymphoma (SLL) involving a single nodal site. As with other patients with asymptomatic CLL, we suggest observing these patients until there are clear signs or symptoms of "active disease" rather than offering systemic therapy or radiation therapy (RT) (table 1). Other experts offer RT delivered with curative intent as is used for early stages of the more common indolent non-Hodgkin lymphoma, follicular lymphoma (FL). Patients contemplating RT for what appears to be stage I SLL require an extensive pretreatment staging evaluation (ie, imaging and bone marrow biopsy) to rule out more extensive involvement.

Data regarding the use of RT in localized SLL are limited to small retrospective series. As an example, a retrospective series of 54 patients with SLL included 14 patients with stage I or II disease [12]. Among patients with stage I or stage II SLL treated with RT alone (40 to 44 Gy given as involved or extended-field), 10-year freedom from relapse rates were 80 and 62 percent, respectively. However, it is not known how these rates compare to outcomes without RT.

Similar rates of long-term control have been described following RT for early stage FL. These studies are described in detail separately. (See "Initial treatment of stage I follicular lymphoma", section on 'Our approach'.)

Patients with "active disease" — While highly variable, patients with asymptomatic early stage (Rai stage <3, Binet stage A or B) CLL have a median survival greater than 10 years without treatment. In contrast, patients with more advanced stage CLL or those who demonstrate symptoms or progressive disease have a median survival without treatment between 18 months and three years [7,13-16]. Treatment of the underlying CLL is indicated for patients who develop disease-related signs or symptoms or evidence of progressive disease, termed "active disease." Therapy is offered with the goals of ameliorating symptoms and improving progression-free and overall survival. It is difficult to estimate survival with modern therapies that incorporate novel agents given the short follow-up of trials evaluating these combinations. With novel treatments, expected overall survival can range from a few years to decades and depends on disease features, patient characteristics, and treatment choice. (See "Selection of initial therapy for symptomatic or advanced chronic lymphocytic leukemia", section on 'Goals of therapy'.)

There is no agreed-upon single standard front-line treatment regimen for all patients with symptomatic or advanced CLL. There are several initial treatment options. While overall survival rates with the different regimens may be similar, they differ in their rates of complete remission, time to progression, and associated toxicities. A choice from among these therapies is made based on patient and tumor characteristics and goals of therapy (algorithm 1). (See "Selection of initial therapy for symptomatic or advanced chronic lymphocytic leukemia".)

Managing complications of CLL and its therapy — Patients with CLL commonly develop complications associated with an intrinsic immune dysfunction resulting in immunodeficiency and autoimmune disorders. The most common disease-related complications are infection, anemia, and thrombocytopenia. Less common but potentially life-threatening complications include tumor lysis syndrome and second cancers. These issues are discussed in more detail separately:

Immune defects and spectrum of infections – (See "Risk of infections in patients with chronic lymphocytic leukemia".)

Prevention of infection with vaccines and other modalities – (See "Prevention of infections in patients with chronic lymphocytic leukemia".)

Evaluation of suspected infection – (See "Overview of the complications of chronic lymphocytic leukemia", section on 'Evaluation of suspected infection'.)

Anemia and thrombocytopenia – (See "Overview of the complications of chronic lymphocytic leukemia", section on 'Anemia' and "Overview of the complications of chronic lymphocytic leukemia", section on 'Thrombocytopenia'.)

Second cancers – (See "Overview of the complications of chronic lymphocytic leukemia", section on 'Second cancers'.)

Tumor lysis syndrome – (See "Tumor lysis syndrome: Pathogenesis, clinical manifestations, definition, etiology and risk factors" and "Tumor lysis syndrome: Prevention and treatment".)

RESPONSE ASSESSMENT — Response to treatment is assessed using guidelines originally developed by the National Cancer Institute Working Group on CLL and revised by the International Workshop on CLL (iwCLL) (table 3). This response evaluation and criteria are presented separately. (See "Evaluating response to treatment of chronic lymphocytic leukemia".)

RELAPSED DISEASE — Patients with CLL are not cured with conventional therapy. While most patients will have an initial complete or partial response to treatment, most will relapse eventually. Asymptomatic relapse does not necessarily require immediate treatment but is followed closely for the development of active disease (table 1).

Our choice of subsequent therapy for patients with progressive disease or intolerance to initial treatment is individualized and takes into account prior therapy, response, and reason for discontinuation; patient and tumor characteristics; patient preference; and goals of therapy (algorithm 2 and table 4). Patients with CLL experience serial relapses and many will be treated with all available agents at some point during their disease course (table 5). A preferred order for their use has not been established. (See "Treatment of relapsed or refractory chronic lymphocytic leukemia".)

SPECIAL CONSIDERATIONS DURING THE COVID-19 PANDEMIC — The coronavirus disease 2019 (COVID-19) pandemic has increased the complexity of cancer care. Important issues include balancing the risk from treatment delay versus harm from COVID-19, ways to minimize negative impacts of social distancing during care delivery, and appropriately and fairly allocating limited health care resources. These issues and recommendations for cancer care during the COVID-19 pandemic are discussed separately. (See "COVID-19: Considerations in patients with cancer".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Chronic lymphocytic leukemia/small lymphocytic lymphoma".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient education" and the keyword(s) of interest.)

Basics topics (see "Patient education: Chronic lymphocytic leukemia (CLL) (The Basics)" and "Patient education: Leukemia in adults (The Basics)")

Beyond the Basics topics (see "Patient education: Chronic lymphocytic leukemia (CLL) in adults (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

CLL versus SLL – Chronic lymphocytic leukemia (CLL) is one of the B cell chronic lymphoproliferative disorders and is characterized by a progressive accumulation of functionally incompetent lymphocytes, which are usually monoclonal in origin. CLL is considered to be identical (ie, one disease with different manifestations) to the mature (peripheral) B cell neoplasm small lymphocytic lymphoma (SLL).

Indications for treatment ("active disease") – CLL/SLL is an extremely heterogeneous disease and most patients have early stage disease at the time of diagnosis. Therapy is indicated for patients with "active disease" as manifested by advanced stage, high tumor burden, anemia, thrombocytopenia, or severe disease-related "B" symptoms (table 1). (See 'Indications for treatment ("active disease")' above.)

Observation for early stage asymptomatic CLL/SLL – For patients with early stage asymptomatic CLL, we recommend observation rather than immediate treatment (Grade 1B). For patients with asymptomatic SLL involving a single nodal site, we suggest observation rather than radiation therapy (RT) (Grade 2C). Patients contemplating RT for what appears to be stage I SLL require an extensive pretreatment staging evaluation (ie, imaging and bone marrow biopsy) to rule out more extensive involvement. (See 'Patients without "active disease"' above and 'Localized SLL' above.)

Risk stratified treatment for active disease – There is no single agreed-upon standard front-line treatment regimen for patients with symptomatic or advanced CLL/SLL. There are several initial treatment options and most have not been directly compared. While overall survival rates with the different available regimens are similar, they differ in their rates of complete remission, time to progression, and associated toxicities. A choice between these therapies is made based upon patient and disease characteristics as well as the goals of care (algorithm 1). (See "Selection of initial therapy for symptomatic or advanced chronic lymphocytic leukemia".)

Response assessment – Response to treatment is assessed using guidelines from the International Workshop on CLL (iwCLL) (table 3). (See "Evaluating response to treatment of chronic lymphocytic leukemia".)

Management of relapse – Patients with CLL/SLL are not cured with conventional therapy and most will relapse eventually. Asymptomatic relapse does not require immediate treatment but is followed closely for the development of "active disease." Our choice of subsequent therapy for patients with progressive disease or intolerance to initial treatment is individualized and takes into account prior therapy, response, and reason for discontinuation; patient and tumor characteristics; patient preference; and goals of therapy (algorithm 2 and table 4). Patients with CLL experience serial relapses and many will be treated with all available agents at some point during their disease course (table 5). A preferred order for their use has not been established. (See "Treatment of relapsed or refractory chronic lymphocytic leukemia".)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Michael J Keating, MD, who contributed to earlier versions of this topic review.

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