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Selection of initial therapy for symptomatic or advanced chronic lymphocytic leukemia

Selection of initial therapy for symptomatic or advanced 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: Dec 2022. | This topic last updated: Dec 19, 2022.

INTRODUCTION — Chronic lymphocytic leukemia (CLL) is a chronic lymphoproliferative disorder (lymphoid neoplasm). It is characterized by a progressive accumulation of functionally incompetent B 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), a non-Hodgkin lymphoma. 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".)

Patients with asymptomatic, stable, early stage CLL are followed closely without treatment. The selection of initial therapy for advanced stage or symptomatic disease will be reviewed here. General issues regarding management, including the treatment of relapsed/refractory disease, the use of hematopoietic cell transplantation, 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 "Overview of the treatment of chronic lymphocytic leukemia".)

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

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

(See "Hematopoietic cell transplantation in 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".)

PRETREATMENT EVALUATION — The pretreatment evaluation documents the extent and characteristics of disease and identifies comorbidities that may impact treatment options. Our approach is consistent with that recommended by the International Workshop on Chronic Lymphocytic Leukemia (iwCLL) [1]. Details on the Rai and Binet staging systems used in CLL are presented separately (table 1A-B). (See "Staging and prognosis of chronic lymphocytic leukemia".)

The history and physical examination should document the following findings of particular interest:

Performance status (table 2A-B)

Fatigue, night sweats, weight loss, and/or fever

Subjective changes in the size of lymph nodes, liver, and/or spleen; and/or pain in these areas

Bidirectional diameters of the largest palpable lymph nodes in the cervical, axillary, and inguinal regions, assessed by physical examination

Measurements of the spleen and liver as palpated with respect to the costal margins

Laboratory and imaging evaluation includes the following:

Complete blood count with differential and reticulocyte count, chemistries with liver and renal function and electrolytes, alkaline phosphatase, lactate dehydrogenase (LDH), beta-2 microglobulin, direct antiglobulin test (DAT), haptoglobin, and serum immunoglobulin levels.

All patients should undergo testing for human immunodeficiency virus (HIV), hepatitis B (HBV), and hepatitis C. Antiviral therapy can be initiated in patients with chronic active HBV prior to the administration of immunosuppressive therapy to decrease the risk for hepatitis B reactivation. Serology for cytomegalovirus (IgM and IgG) should be performed in patients being treated with agents associated with reactivation (eg, idelalisib, alemtuzumab). (See "Hepatitis B virus reactivation associated with immunosuppressive therapy".)

Not all patients need a bone marrow evaluation. Unilateral bone marrow aspirate and biopsy is recommended for patients who have cytopenias of unknown cause. This sample should be sent for pathologic review, including morphology (hematoxylin and eosin stain) and immunophenotype.

Evaluation of tumor cells (usually from peripheral blood) with fluorescence in situ hybridization (FISH) for del17p, del11q, trisomy 12, and del13q. FISH for t(11;14) is performed, to rule out mantle cell lymphoma. TP53 mutation and immunoglobulin heavy chain variable (IGHV) mutation status are tested by Sanger sequencing. Testing for del17p, TP53 mutation, and IGHV mutation status is critical for the selection of appropriate treatment. While testing for CD38 expression and ZAP-70 expression are performed by many clinicians, we do not perform these routinely since treatment decisions are not made on the basis of these results.

A chest radiograph should be obtained to evaluate for hilar and mediastinal adenopathy. Computed tomography (CT) of the chest, abdomen, and pelvis is not required for the pretreatment evaluation and is usually reserved for patients enrolled in clinical trials [1,2]. However, a CT should be performed in any patient in whom enlarged abdominal or pelvic nodes are suspected based upon evidence of complications such as obstructive jaundice, or obstruction of the inferior vena cava or ureters.

Men and women with child-bearing potential should receive counseling about the potential effect of treatment on their fertility and options for fertility-preserving measures. Contraception is needed while on therapy. (See "Fertility and reproductive hormone preservation: Overview of care prior to gonadotoxic therapy or surgery".)

GOALS OF THERAPY — Patients with advanced CLL are not cured with conventional therapy. Treatment alleviates symptoms and reverses cytopenias, and is given with the overall goals of improving quality of life and, importantly, prolonging 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.

While some treatments have demonstrated improved overall survival, this is a rapidly evolving field and the follow-up of some newer treatments is too short to assess survival. In such settings, we consider improvement in progression-free survival at a follow-up of at least five years to be a reasonable finding of clinical benefit. Clinical trials are evaluating the role of measurable residual disease (MRD, also called "minimal residual disease") as a surrogate endpoint. MRD testing is reserved for patients enrolled in clinical trials and has no role in the routine care of patients with CLL.

CHOICE OF THERAPY — Our choice of initial therapy for patients with symptomatic or advanced CLL is made based on patient and tumor characteristics, patient preference, and goals of therapy (algorithm 1). While we offer this guidance, there is no single agreed-upon standard treatment for CLL.

These different approaches incorporate the following agents, usually administered as combinations:

Bruton tyrosine kinase (BTK) inhibitors (eg, ibrutinib, acalabrutinib, zanubrutinib)

The BCL2 inhibitor venetoclax

Monoclonal antibodies (eg, rituximab, ofatumumab, obinutuzumab)

Purine analogs (eg, fludarabine, pentostatin)

Alkylating agents (eg, chlorambucil, cyclophosphamide, bendamustine)

The optimal therapy for young adults, older adults, and patients with high-risk features is the subject of multiple ongoing studies. Trials are evaluating new combinations of these agents and incorporation of other agents. We always encourage patients to enroll in a well-conducted clinical trial. (See "Treatment of relapsed or refractory chronic lymphocytic leukemia", section on 'Investigational therapies'.)

Treatment regimens differ significantly in their rates of complete remission (CR) and measurable residual disease (MRD), time to progression, and associated toxicities. The burden of administration is also different (eg, oral versus intravenous medications, continuous versus fixed duration therapy). Given these differences, patient preferences weigh substantially in the final treatment decision.

Risk stratification and assessment of fitness — Our preferred initial therapy depends upon a genetic risk stratification of the tumor and an assessment of patient fitness (algorithm 1).

Our genetic risk stratification is as follows:

Very high-risk disease: 17p deletion and/or TP53 mutations – Patients with these findings are at high risk of either not responding to initial treatment with chemoimmunotherapy, or relapsing soon after achieving remission. Outside of clinical trials, treatments that use targeted agents (eg, ibrutinib, acalabrutinib, zanubrutinib, venetoclax) are preferred. While targeted agents are superior to chemoimmunotherapy in this population, 17p deletion and TP53 mutation retain their prognostic impact; patients with 17p deletion and/or TP53 mutation treated with targeted agents have inferior outcomes when compared with other patients treated with these same agents. (See 'Del(17p) and/or TP53 mutations (very high risk)' below.)

High-risk disease: IGHV unmutated (without 17p deletion and without TP53 mutation) – While these patients usually respond to initial treatment with chemoimmunotherapy, targeted agents are preferred due to a clear improvement in progression-free survival (PFS), with a demonstrated overall survival (OS) benefit in some trials. (See 'IGHV unmutated (high risk)' below.)

Standard-risk disease: IGHV mutated (without 17p deletion and without TP53 mutation) – For these patients, OS appears to be similar regardless of whether chemoimmunotherapy or targeted therapy is used. Long-term follow-up of prospective trials have demonstrated that a subset of patients with IGHV-mutated CLL treated with chemoimmunotherapy obtain prolonged durable remissions, possibly suggesting cure. (See 'IGHV mutated (standard risk)' below.)

While an assessment of clinical fitness is incorporated into the evaluation of all patients with CLL, it is particularly important for patients with IGHV-mutated CLL contemplating treatment with chemoimmunotherapy. Experts vary in the tools they use to assess fitness to determine eligibility for various treatment regimens. This evaluation usually includes an assessment of comorbidities and their impact on general function, kidney function, and liver function. Tools that may be helpful for this assessment include the cumulative illness rating scale (CIRS (table 3) [3]), Eastern Cooperative Oncology Group performance status (ECOG PS) (table 2B), more specific geriatric assessment tools, and renal function estimated by creatinine clearance. Special considerations for the use of chemotherapy in older adults are discussed separately. (See "Comprehensive geriatric assessment for patients with cancer" and "Systemic chemotherapy for cancer in older adults".)

Eligibility for targeted agents differs according to the most common and serious toxicities with each agent and the predicted tolerability given the patient's general fitness and comorbidities. Eligibility is more restrictive for chemoimmunotherapy. Patients with one or more of the following findings are usually considered unfit for chemoimmunotherapy with intense regimens such as fludarabine, cyclophosphamide, and rituximab (FCR): CIRS >6 (table 3), creatinine clearance (CrCl) <70 mL/min, significant hepatic impairment (Child-Pugh class B or C (table 4)), and ECOG PS of 2 or greater (table 2B).

Treatment regimens and outcomes may differ between younger and older adults. Although there is no clear dividing line when considering age in CLL, in most studies, the term "older adults" has been defined as over age 65 or 70 years. Such age cutoffs are by their nature arbitrary, and clinicians should not rely solely on such definitions. In actual practice there might be patients who are chronologically age 60 and "act" or seem "older" (sometimes referred to as "clinically unfit") [4]. Such patients should be treated as older adults. On the other extreme, there might be patients who are chronologically age 70 who act and behave like a younger person (sometimes referred to as "clinically fit").

Del(17p) and/or TP53 mutations (very high risk) — Patients with 17p deletion or TP53 mutations are at high risk of either not responding to initial treatment with chemoimmunotherapy, or relapsing soon after achieving remission. Outside of clinical trials, targeted agents (eg, BTK inhibitor-based therapy or venetoclax-based therapy) are preferred. While targeted agents are superior to chemoimmunotherapy in this population, 17p deletion and TP53 mutation retain their prognostic impact; patients with 17p deletion and/or TP53 mutation treated with targeted agents have inferior outcomes when compared with other patients treated with these same agents [5]. Allogeneic hematopoietic cell transplantation (HCT) is reserved as an option for younger/fit patients with relapsed disease [6].

Initial treatment options include (algorithm 1):

Single-agent BTK inhibitor (eg, ibrutinib, acalabrutinib, zanubrutinib) until progression (all ages)

BTK inhibitor (ie, ibrutinib or acalabrutinib) plus obinutuzumab until progression (younger patients)

Fixed duration venetoclax plus obinutuzumab for one year (all ages)

Single-agent venetoclax until progression (all ages)

The largest trials of these agents had a limited number of patients with 17p deletion or TP53 mutation. Studies of targeted agents in very high-risk CLL/small lymphocytic lymphoma (SLL) are limited by a small sample size, often enrolling highly selected patients. Cross trial comparisons are likely to be inaccurate. A choice is dependent upon comorbidities and patient preferences.

BTK-inhibitor-based therapy – Continuous BTK inhibitor-based therapy may be preferred based on high response rates, oral administration, and good tolerability. While we have the most experience and longest follow-up with ibrutinib, extrapolation of data from other populations suggests that acalabrutinib and zanubrutinib are at least as effective and better tolerated than ibrutinib. As such, for most patients, we suggest acalabrutinib or zanubrutinib rather than ibrutinib. (See 'Choice of BTK inhibitor' below.)

Ibrutinib – Of the BTK inhibitors, we have the most direct experience and longest follow-up with ibrutinib. The addition of rituximab does not improve outcomes in older adults [7], although it deepens responses in younger adults [8,9]. The addition of obinutuzumab may improve PFS but also adds toxicity.

Acalabrutinib – Acalabrutinib is another option in this population, although there are less data regarding its use, and no long-term experience. Trials of this combination were performed in an older population most of whom did not have 17p deletion or TP53 mutation. In the relapsed setting, acalabrutinib has similar efficacy to ibrutinib, but fewer class-associated adverse effects including less cardiac toxicity, atrial fibrillation, hypertension, arthralgia, and bleeding [10]. The addition of obinutuzumab increases toxicity; a potential increase in efficacy seen in CLL/SLL with other populations has not been demonstrated in CLL/SLL with 17p deletion or TP53 mutation. (See 'Acalabrutinib-based therapy' below.)

Zanubrutinib – Zanubrutinib is another option for select patients, although, there are the least data regarding its use, and no long-term experience. Zanubrutinib is approved in Europe for the treatment of CLL/SLL, and is undergoing regulatory review in the United States. Trials of this combination were performed in an older population most of whom did not have 17p deletion or TP53 mutation. When compared with ibrutinib in the relapsed setting, zanubrutinib delays progression and has less cardiac toxicity, in particular less atrial fibrillation, but similar rates of other toxicities [11]. (See 'Zanubrutinib' below.)

Venetoclax-based therapy – The combination of venetoclax plus obinutuzumab is an equally acceptable option, largely based on the extrapolation of data in older adults and the relapsed setting. It may be preferred in patients with comorbidities (eg, history of atrial fibrillation, moderate hepatic impairment, history of severe bleeding) or concomitant medications (eg, anticoagulants) that make them poor candidates for ibrutinib, and in those who place a high value on having a treatment-free interval and are willing to receive infusions and be monitored for tumor lysis syndrome. Trials of this combination had a limited number of patients with 17p deletion or TP53 mutation. (See 'Venetoclax plus obinutuzumab' below.)

BTK inhibitor plus venetoclax – While initial reports suggest deep responses when a BTK inhibitor is given in combination with venetoclax [12], further study is needed before this combination should be used in routine practice. (See 'BTK inhibitor plus venetoclax (investigational)' below.)

Idelalisib – Although approved in Europe for this population, we avoid idelalisib-based regimens in previously untreated CLL due to reports of excessive toxicity.

Data regarding the efficacy of ibrutinib and venetoclax as the initial treatment for patients with del(17p) or TP53 mutation come from small single-arm trials [13-20], subgroup analyses of randomized trials (eg, venetoclax plus obinutuzumab in CLL14 [5,21] and ibrutinib in ILLUMINATE [22] and RESONATE-2 [23]), and extrapolation of data from larger studies in the relapsed/refractory setting, which have demonstrated high response rates. Efficacy in relapsed/refractory disease is presented separately. (See "Treatment of relapsed or refractory chronic lymphocytic leukemia", section on 'BCL2 inhibitors: Venetoclax' and "Treatment of relapsed or refractory chronic lymphocytic leukemia", section on 'Ibrutinib'.)

In a small, single-center phase II trial of ibrutinib in highly selected patients with del(17p) or TP53 mutation, analysis of the 34 previously untreated patients followed for a median of 6.5 years revealed a best response of complete remission (CR) in 10 (30 percent) and partial response (PR) in 21 (64 percent) [13-15]. One additional patient demonstrated PR with lymphocytosis and one had progressive disease. This cohort had an estimated five-year PFS of 70 percent (95% CI 56-88 percent) and OS of 85 percent (95% CI 74-98 percent), rates that were superior to those seen in the relapsed/refractory cohort. Median time to disease progression was 53 months. Progression was more common among those with unmutated IGHV than among those with mutated IGHV. At the time of progression, 83 percent had mutations in BTK or phospholipase C gamma 2 (83 percent) and there were several cases of histologic transformation (4 of 12 patients).

A randomized phase II trial that evaluated the addition of rituximab to ibrutinib included 77 patients with high-risk CLL [16]. Responses were seen in all but one of the 27 treatment-naïve patients with high-risk disease (9 CR/CRi, 15 PR, and 2 PR with lymphocytosis). The estimated three-year PFS among all high-risk patients was similar in the two treatment arms (78 percent with ibrutinib and 73 percent with ibrutinib plus rituximab). After a median follow-up of 70 months, 9 of the 27 treatment-naïve patients remained on study with estimated six-year PFS and OS of 60 and 79 percent, respectively [20].

In an international, single-arm phase II trial of venetoclax for CLL with 17p deletion, the five patients with previously untreated disease had an overall response rate of 80 percent (2 CR/CRi, 2 PR/nodular PR, 1 stable disease) [17,18]. When analyzed with the 153 patients with relapsed disease, the estimated median duration of response was 33 months, and estimated PFS and OS at two years were 54 and 73 percent, respectively.

These results compare favorably with those seen after FCR. Among patients treated in the randomized CLL8 trial evaluating FCR versus FC in previously untreated CLL, median PFS rates following FCR for those with del(17p), TP53 mutations, del(11q), or normal cytogenetics were approximately 12, 15, 50, and 50 months, respectively [24]. There are less data regarding the efficacy of idelalisib-based regimens in the initial treatment of high-risk CLL. Several phase II trials of idelalisib-based regimens in previously untreated CLL have been stopped early despite high response rates when safety analyses identified increased rates of serious adverse events and fatalities [25-30].

Alemtuzumab has also demonstrated activity patients with CLL and chromosome 17p deletion but is rarely used to treat CLL anymore [31-37].

No del(17p) and no TP53 mutation

IGHV unmutated (high risk) — For most patients with IGHV-unmutated CLL without del(17p) or TP53 mutations, we suggest treatment with targeted agents (eg, BTK inhibitor-based therapy or venetoclax-based therapy) rather than chemoimmunotherapy (algorithm 1). Options include:

Single-agent BTK inhibitor (eg, ibrutinib, acalabrutinib, zanubrutinib) until progression (all ages)

BTK inhibitor (ie, ibrutinib or acalabrutinib) plus obinutuzumab until progression (younger patients)

Fixed duration venetoclax plus obinutuzumab (all ages, use in younger patients extrapolated from trials in older adults)

The choice among these is strongly dependent upon patient comorbidities and preferences. We have longer-term data regarding the efficacy and toxicity of the BTK inhibitor ibrutinib. BTK inhibitors are oral therapies that are given continuously until progression. While response rates are high, few patients achieve CR or undetectable MRD. In contrast, undetectable MRD can be achieved by the majority of patients treated with a fixed duration of venetoclax plus obinutuzumab. However, we have less trial experience and shorter follow-up with venetoclax plus obinutuzumab. Trials evaluating these regimens are discussed briefly below and in more detail separately. (See 'Targeted agents' below.)

Trials in older adultsIbrutinib improves PFS when compared with bendamustine plus rituximab (BR) or obinutuzumab plus chlorambucil in older adults [7,22]. Adding rituximab or obinutuzumab dampens the lymphocytosis seen with ibrutinib but has not yet demonstrated deeper and more durable responses, although follow-up of trials examining this is short. (See 'Ibrutinib-based therapy' below.)

Fixed duration venetoclax plus obinutuzumab deepens responses and improves PFS when compared with chlorambucil plus obinutuzumab [21]. It has not been compared with BR, FCR, or ibrutinib. Venetoclax plus obinutuzumab is particularly useful for patients with comorbidities (eg, atrial fibrillation, history of severe bleeding) or concomitant medications (eg, anticoagulants) that make them poor candidates for ibrutinib. Venetoclax plus obinutuzumab may also be preferred by patients who place a high value on having a treatment-free interval and are willing to receive infusions and to be monitored for tumor lysis syndrome. (See 'Venetoclax plus obinutuzumab' below.)

Acalabrutinib with or without obinutuzumab improves PFS when compared with chlorambucil plus obinutuzumab [38]. It has not been compared with BR, FCR, or venetoclax-based therapy. Extrapolation of data from the relapsed setting suggests that acalabrutinib has a similar efficacy to ibrutinib, but a different toxicity profile with less cardiotoxicity [10]. The addition of obinutuzumab to these agents likely increases both efficacy and toxicity. (See 'Acalabrutinib-based therapy' below.)

Zanubrutinib improves PFS when compared with BR [39]. It has not been compared with venetoclax-based therapy or FCR. Extrapolation of data from the relapsed setting suggests that zanubrutinib improves PFS over that seen with ibrutinib and has less cardiac toxicity, in particular less atrial fibrillation, but similar rates of other toxicities [11]. (See 'Zanubrutinib' below.)

Trials in younger adultsIbrutinib plus rituximab improves PFS over that seen with FCR in young, fit patients [8,40,41]. Whether this translates into improved OS is not clear, as an OS benefit was seen in one trial (E1912) but not another (FLAIR). Although these trials administered ibrutinib plus rituximab, the addition of rituximab does not appear to improve PFS or OS [7,16]. As such, most experts offer single-agent ibrutinib. Ibrutinib may also be given in combination with obinutuzumab, which improves PFS but also adds toxicity. (See 'Efficacy in younger patients' below.)

The use of fixed-duration venetoclax plus obinutuzumab in younger adults is largely extrapolated from its use in older adults and the use of venetoclax plus rituximab in the relapsed setting. (See 'Venetoclax plus obinutuzumab' below and "Treatment of relapsed or refractory chronic lymphocytic leukemia", section on 'BCL2 inhibitors: Venetoclax'.)

The use of acalabrutinib in younger adults is extrapolated from its use in older adults and in the relapsed setting. (See 'Acalabrutinib-based therapy' below and "Treatment of relapsed or refractory chronic lymphocytic leukemia", section on 'Acalabrutinib'.)

The use of zanubrutinib in younger adults is extrapolated from its use in older adults and in the relapsed setting. (See 'Zanubrutinib' below and "Treatment of relapsed or refractory chronic lymphocytic leukemia", section on 'Zanubrutinib'.)

IGHV mutated (standard risk)

Fit patients — Clinically fit patients with IGHV-mutated CLL and without 17p deletion or TP53 mutation may reasonably choose treatment with targeted therapy or chemoimmunotherapy depending upon their values and preferences (algorithm 1).

Options include:

Fludarabine, cyclophosphamide, rituximab (FCR, (table 5)) for six cycles (younger patients).

BR for six cycles (older patients). (See 'Bendamustine plus rituximab' below.)

Ibrutinib as a single agent (all ages) or in combination with obinutuzumab (younger patients). (See 'Ibrutinib-based therapy' below.)

Fixed duration venetoclax plus obinutuzumab (all ages, use in younger patients extrapolated from trials in older adults). (See 'Venetoclax plus obinutuzumab' below.)

Acalabrutinib as a single agent (all ages). (See 'Acalabrutinib-based therapy' below.)

Acalabrutinib plus obinutuzumab until progression (younger patients).

Chemoimmunotherapy (FCR or BR) may be preferred by those willing to undergo a more intensive therapy with the potential for a long treatment-free interval. Long-term follow-up of prospective trials have demonstrated that a subset of patients with IGHV-mutated CLL treated with FCR obtain prolonged durable remissions, possibly suggesting cure in a minority [42-44]. In addition, in subset analyses of the randomized trials comparing ibrutinib versus FCR (in younger patients) or versus BR (in older patients or those with comorbidities), the improvement in PFS seen in the general population was of lesser magnitude and did not always reach statistical significance in patients with IGHV-mutated CLL [7,8,40]. If chemoimmunotherapy is chosen, the preferred regimen depends on age and comorbidities; FCR is not well tolerated by patients over age 65 years and by those with comorbidities, due to high rates of prolonged myelosuppression and infection. (See 'Fludarabine, cyclophosphamide, and rituximab' below and 'Bendamustine plus rituximab' below.)

While cross-trial comparisons are limited by differences in patient populations and other confounders, BTK inhibitors and fixed-duration combination therapy with venetoclax plus obinutuzumab appear to have similar efficacy with different toxicities and treatment burdens.

A BTK inhibitor may be preferred by patients who desire low intensity long-term therapy with an oral medication. Ibrutinib and acalabrutinib are both given as continuous therapy until progression. Follow-up of prospective trials with ibrutinib is slightly shorter than for FCR or BR, while trials of acalabrutinib are significantly shorter. Extrapolation of data from the relapsed setting suggests that acalabrutinib has a similar efficacy to ibrutinib, but a different toxicity profile with less cardiotoxicity [10]. The addition of obinutuzumab to these agents likely increases both efficacy and toxicity. (See 'Ibrutinib-based therapy' below and 'Acalabrutinib-based therapy' below.)

Fixed duration combination therapy with venetoclax plus obinutuzumab may be preferred in patients with comorbidities (eg, history of atrial fibrillation, moderate hepatic impairment, history of severe bleeding) or concomitant medications (eg, anticoagulants) that make them poor candidates for a BTK inhibitor and those who place a high value on a treatment-free period. Use in younger patients is extrapolated from trials as initial therapy in older adults and use in the relapsed setting. (See 'Venetoclax plus obinutuzumab' below.)

Unfit patients — As with clinically fit patients, the management of patients with limited functional status is informed by the genetic features of the tumor (17p deletion, TP53 mutation, and IGHV mutation status) (algorithm 1). Many patients with comorbidities will be eligible for treatment with single-agent ibrutinib, single-agent acalabrutinib, fixed duration venetoclax plus obinutuzumab, and/or the combination of BR.

Chlorambucil plus obinutuzumab is an additional option for IGHV-mutated CLL in older adults and those with comorbidities. (See 'Chlorambucil-based therapy' below.)

INITIAL TREATMENT OPTIONS — This section describes the evidence supporting our risk-stratified approach to the initial treatment of CLL (algorithm 1).

Targeted agents

Bruton tyrosine kinase (BTK) inhibitors

Choice of BTK inhibitor — The selection of a BTK inhibitor (ibrutinib, acalabrutinib, zanubrutinib) is individualized based on available agents, comorbidities, and goals of therapy. Ibrutinib and acalabrutinib are approved for the treatment of CLL/SLL in the United States; zanubrutinib is undergoing regulatory evaluation. All three BTK inhibitors are approved in Europe.

For most patients, we suggest acalabrutinib or zanubrutinib rather than ibrutinib. While we have the most experience and longest follow-up with ibrutinib, extrapolation of data from the relapsed setting suggests that acalabrutinib and zanubrutinib are at least as effective and better tolerated than ibrutinib. If both are available, the choice depends on individual treatment goals and a desire to balance efficacy and tolerability. If the goal is best efficacy with acceptable tolerability, we offer zanubrutinib. In contrast, if the goal is best tolerability with acceptable efficacy, we offer acalabrutinib.  

When compared with ibrutinib in the relapsed setting, single agent acalabrutinib has similar efficacy and an overall better tolerability profile (eg, fewer class-associated adverse effects including cardiac toxicity, atrial fibrillation, hypertension, arthralgia, and bleeding) [10]. Efficacy can be improved with the addition of obinutuzumab, although at a cost of increased toxicity [38,45]. (See "Treatment of relapsed or refractory chronic lymphocytic leukemia", section on 'Acalabrutinib' and 'Acalabrutinib-based therapy' below.)

The improvement in tolerability is more narrow for zanubrutinib (ie, less cardiac toxicity, in particular less atrial fibrillation, but similar rates of other toxicities) [11]; however, zanubrutinib appears to be more effective than ibrutinib in the relapsed setting with deeper responses and improved progression-free survival (PFS). (See "Treatment of relapsed or refractory chronic lymphocytic leukemia", section on 'Zanubrutinib' and 'Zanubrutinib' below.)

Experience with acalabrutinib and zanubrutinib is relatively short and ibrutinib remains a reasonable alternative for select patients despite an increased risk for atrial fibrillation, hypertension, bleeding, and arthralgias. (See 'Ibrutinib-based therapy' below.)

Ibrutinib-based therapy

Efficacy in older patients — Single-agent ibrutinib is a highly effective treatment for older adults with CLL (algorithm 1). Ibrutinib improves both PFS and overall survival (OS) when compared with single-agent chlorambucil in older patients. Ibrutinib also improves PFS when compared with bendamustine plus rituximab (BR). Adding rituximab dampens the lymphocytosis seen with ibrutinib but has not yet demonstrated more durable responses, although follow-up of trials examining this is short. Ibrutinib plus obinutuzumab improves PFS when compared with chlorambucil plus obinutuzumab, although single-agent ibrutinib has not been directly compared with the combination of chlorambucil plus obinutuzumab. Until a benefit is demonstrated, we prefer single-agent ibrutinib in this population, based on the cost, inconvenience, toxicity, and uncertain benefit of adding an anti-CD20 monoclonal antibody.

The trials described below demonstrate the efficacy of ibrutinib in older adults with CLL, especially those with unmutated IGHV. Efficacy in patients with 17p deletion or TP53 mutation is discussed separately. (See 'Del(17p) and/or TP53 mutations (very high risk)' above.)

In a three-arm, multicenter phase III trial (Alliance A041202), 547 older adults (median age 71 years) with previously untreated CLL were randomly assigned to initial therapy with single-agent ibrutinib (420 mg once daily until progression), ibrutinib plus rituximab, or six cycles of BR [7]. Crossover was allowed and 30 patients assigned to BR received ibrutinib at the time of progression. At a median follow-up of 38 months, the following results were reported:

Single-agent ibrutinib resulted in a higher overall response rate (ORR; 93 versus 81 percent), lower complete response (CR) rate (7 versus 26 percent), and lower rate of undetectable minimal residual disease (MRD) (1 versus 8 percent) when compared with BR.

Single-agent ibrutinib improved PFS over that seen with BR (estimated PFS at two years of 87 versus 74 percent; HR 0.39, 95% CI 0.26-0.58). On subset analysis, this benefit was seen across all Rai staging groups and in those with or without del17p and/or del11q; however, the benefit lost statistical significance among those with methylated ZAP-70 (a marker that is strongly associated with the presence of mutated IGHV). OS data are immature, but there is no hint for a difference in the full population as yet.

The addition of rituximab to ibrutinib increased CR rates (12 versus 26 percent), but not PFS (HR 1.00, 95% CI 0.62-1.62).

Toxicity profiles were different with greater hematologic adverse effects with BR and greater nonhematologic adverse effects with ibrutinib-containing regimens. In both groups, toxicity was greatest during the first six cycles of treatment [46]. After six cycles, patients receiving ibrutinib experienced cumulative toxicity, although at a lower rate, reaching a cumulative incidence of grade 3 or higher atrial fibrillation, hypertension, and infection of 8, 15, and 21 percent at 36 months. Patients receiving BR experienced minimal toxicity after completing the six-cycle course of therapy.

These results demonstrated the efficacy of ibrutinib in older adults, especially among those with unmutated IGHV. A benefit for CLL with mutated IGHV is less clear. Although a survival benefit has not been demonstrated, follow-up is short and this analysis is limited by the availability of ibrutinib and venetoclax for the treatment of relapsed disease. There does not appear to be a benefit from the addition of rituximab, although longer follow-up is needed to confirm this finding.

In another phase III trial (RESONATE-2), 269 older adults (median age 73 years) with previously untreated CLL were randomly assigned to initial therapy with ibrutinib or up to 12 cycles of chlorambucil [23,47-49]. Crossover was allowed and 55 patients assigned to chlorambucil received ibrutinib at the time of progression. Ibrutinib resulted in the following:

Higher ORR (86 versus 35 percent) and CR (4 versus 2 percent) rates at 18 months, with higher rates of sustained improvements in hemoglobin (84 versus 45 percent) and platelet count (77 versus 43 percent). Responses to ibrutinib improved further with longer follow-up such that 34 percent achieved CR or CR with incomplete blood count recovery.

Superior PFS (89 versus 34 percent at 2 years; 70 versus 12 percent at 5 years; 59 versus 9 percent at 7 years; HR 0.15; 95% CI 0.10-0.22). On subset analysis, this benefit was seen across all subgroups, including those with and without del17p and/or del(11q) and in those with mutated IGHV and unmutated IGHV.

Superior OS (95 versus 84 percent at 2 years; 83 versus 68 percent at 5 years; HR 0.45; 95% CI 0.28-0.74).

Longer time on therapy with >80 percent of patients receiving continuous ibrutinib for >2 years, and 42 percent remaining on ibrutinib for ≥8 years.

Fewer discontinuations due to adverse events (9 versus 23 percent) at 18 months; patients assigned to ibrutinib had a higher rate of diarrhea (42 versus 17 percent), peripheral edema (19 versus 9 percent), dry eye (17 versus 5 percent), and arthralgia (16 versus 7 percent) and a lower rate of neutropenia, nausea, and vomiting. The higher rate of toxicity may be at least partially due to the longer time on ibrutinib therapy. The prevalence of many adverse events decreased over time. Longer follow-up of those taking ibrutinib revealed cases of upper respiratory tract infection (26 percent), hypertension (26 percent), atrial fibrillation (16 percent), and major hemorrhage (11 percent).

In a third trial (iLLUMINATE), 229 mostly older adults with previously untreated CLL were randomly assigned to receive ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab [22]. Median durations of exposure to ibrutinib and chlorambucil were 29 and 5 months, respectively, in the two treatment arms. After a median follow-up of 31 months, the ibrutinib combination prolonged PFS (median not reached versus 19 months, PFS at 30 months 79 versus 31 percent; HR 0.23, 95% CI 0.15-0.37). Crossover was allowed and 46 patients assigned to chlorambucil plus obinutuzumab received ibrutinib at the time of progression. Estimated OS rates at 30 months were similar between the arms (86 versus 85 percent). These results provide further support for ibrutinib in this population. The study design does not allow for a direct assessment of the impact of obinutuzumab in the combination. Among those treated with ibrutinib plus obinutuzumab, the rate of CR (19 percent) and undetectable MRD (35 percent) compare favorably to those seen with single-agent ibrutinib in other trials.

Efficacy in younger patients — Ibrutinib is a highly effective treatment for younger adults with CLL (algorithm 1). Most experts do not add rituximab; while it may shorten time to response, benefits in PFS or OS have not been demonstrated [7,16]. In contrast, the addition of obinutuzumab may improve PFS but with added toxicity. Efficacy in patients with 17p deletion or TP53 mutation is discussed separately. (See 'Del(17p) and/or TP53 mutations (very high risk)' above.)

In two randomized trials (E1912 and FLAIR), ibrutinib plus rituximab improved PFS over that seen with FCR [8,40,41]. The impact on OS is not clear, as an OS benefit was demonstrated in E1912 but not FLAIR [7,8,40,41].

In the phase III ECOG-ACRIN E1912 trial, 529 younger adults (median age 57 years) with previously untreated CLL and without 17p deletion were randomly assigned in a 2:1 ratio to receive ibrutinib plus rituximab (IR) versus six cycles of FCR [8,40]. Patients assigned to IR continued ibrutinib until disease progression or unacceptable toxicity; rituximab was administered during cycles 2 through 7. Those assigned to FCR were allowed to receive ibrutinib as subsequent therapy. At a median follow-up of 5.8 years, ibrutinib plus rituximab resulted in the following:

Superior PFS (78 versus 51 percent at five years, HR 0.37; 95% CI 0.27-0.51). Although not all patients were tested for IGHV mutation status, 29 percent of those tested were IGHV mutated. On subgroup analysis, a PFS benefit was seen in both IGHV unmutated CLL/SLL (75 versus 33 percent at five years; HR 0.27, 95% CI 0.18-0.41) and IGHV mutated CLL/SLL (83 versus 68 percent at five years; HR 0.27, 95% CI 0.11-0.62).

Superior OS (95 versus 89 percent at five years; HR 0.47, 95% CI 0.25-0.89). On subgroup analysis, an OS benefit was seen in IGHV unmutated CLL/SLL (HR 0.35, 95% CI 0.15-0.80) but not in IGHV mutated CLL/SLL (HR 0.72, 95% CI 0.15-3.47).

A lower rate of undetectable MRD at cycle 12 (8 versus 59 percent). Undetectable MRD was associated with superior PFS in patients treated with FCR, but not in patients treated with ibrutinib plus rituximab [50].

A different toxicity profile with lower rates of cytopenias and infectious complications, and higher rates of hypertension, cardiac toxicity, hemorrhagic events, and arthralgia. A numerically higher percentage of patients assigned IR developed second primary cancers other than nonmelanoma skin cancer (13 versus 10 percent).

Longer time on therapy. For those assigned to IR, median time on treatment was 59 months. FCR was given for a mean of five cycles, 67 percent received six cycles.

Among the 175 patients assigned to FCR, 115 (66 percent) remained on surveillance. Among the 354 patients assigned to ibrutinib plus rituximab, 214 (60 percent) remained on ibrutinib, 37 (11 percent) discontinued due to progression or death, 77 (22 percent) discontinued due to adverse events, and 24 (7 percent) withdrew for other reasons. Among those who discontinued ibrutinib for a reason other than progression, median PFS was 25 months.

The randomized phase III FLAIR trial compared six cycles of FCR versus ibrutinib plus rituximab in 771 patients with previously untreated CLL [41]. Initial results are available in abstract form with a median follow-up of 53 months. Ibrutinib plus rituximab improved PFS (median PFS not reached versus 67 months; HR 0.44). This benefit was seen in IGHV unmutated CLL (HR 0.41), but did not reach statistical significance for IGHV mutated CLL. An OS benefit was not seen (HR 1.01).

These results suggest ibrutinib plus rituximab improves PFS and may improve OS over that seen with FCR in younger adults. The benefit is less clear for IGHV-mutated CLL. As described in more detail below, studies suggest that a subset of patients with IGHV-mutated CLL treated with FCR obtain prolonged durable remissions, possibly suggesting cure. As such, FCR is an acceptable alternative in younger patients with IGHV-mutated CLL without del17p and without TP53 mutation who are willing to undergo a more intensive therapy with the potential for long-term disease control. (See 'Fludarabine, cyclophosphamide, and rituximab' below.)

Acalabrutinib-based therapy — Acalabrutinib is an oral, selective, irreversible inhibitor of BTK. In the treatment-naïve setting, acalabrutinib improves PFS when compared with chlorambucil plus obinutuzumab. Acalabrutinib has not been directly compared with other targeted therapies in this setting and there are less long-term data regarding its use. It is approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) as initial or subsequent therapy for adults with CLL with or without obinutuzumab, and we consider single-agent acalabrutinib to be an acceptable treatment in these populations. The addition of obinutuzumab appears to increase efficacy, and increases toxicity with higher rates of cytopenias and infections. As such, we reserve this combination for young/fit patients without a history of infection. Use of acalabrutinib in the relapsed setting, dosing, and administration are discussed separately. (See "Treatment of relapsed or refractory chronic lymphocytic leukemia", section on 'Acalabrutinib'.)

In a multicenter phase 3 trial (ELEVATE TN), 535 older or frail adults with treatment-naïve CLL were randomly assigned 1:1:1 to receive six cycles of acalabrutinib plus obinutuzumab followed by single-agent acalabrutinib, single-agent acalabrutinib alone, or six cycles of chlorambucil plus obinutuzumab [38,45]. Acalabrutinib was continued until progression or unacceptable toxicity. After a median follow-up of 28 months, the following were reported:

PFS – Estimated rates of two-year PFS were 93, 87, and 47 percent, respectively. The acalabrutinib-containing arms improved PFS over that seen with chlorambucil plus obinutuzumab (HR 0.10; 95% CI 0.06-0.17 with obinutuzumab and HR 0.20; 95% CI 0.13-0.30 without obinutuzumab). Four-year follow up presented in abstract form reported 48-month PFS of 87, 78, and 25 percent, respectively.

OS – OS data are immature with estimated two-year OS of 95, 95, and 92 percent, respectively. Estimated 48-month OS was 93, 88, and 88 percent, respectively. OS may be impacted by the administration of acalabrutinib at the time of progression in a majority of patients on the chlorambucil plus obinutuzumab arm.

Toxicities – Grade 3 or greater toxicities were higher in the two obinutuzumab-containing arms (70 and 70 versus 50 percent). Grade 3 or greater infections were more common in the acalabrutinib-containing arms (21, 14, and 8 percent, respectively). The most common adverse events with single-agent acalabrutinib included infection, headache, diarrhea, and nausea. Additional events of clinical interest for acalabrutinib included atrial fibrillation (4 percent), grade 3 or greater hypertension (2 percent), and major bleeding (2 percent).

While these results demonstrate the superiority of acalabrutinib-based therapy over chlorambucil-based therapy in CLL, interpretation is limited by the choice of therapy in the control arm, which did not include targeted therapies (eg, venetoclax, ibrutinib). Additional studies are needed to evaluate the efficacy and toxicity of acalabrutinib compared with other targeted therapies, and inform the sequencing of therapies. This study was not designed to evaluate the impact of adding obinutuzumab to acalabrutinib. On post-hoc analysis, the addition of obinutuzumab to acalabrutinib appears to improve PFS (HR 0.49; 95% CI 0.26-0.95), but also to increase adverse events, including infections, without an improvement in OS. On subgroup analyses, the improved efficacy was not demonstrated in patients with del(17p) or TP53 mutation, although the confidence in these results is limited by small sample size.

Further support for single-agent acalabrutinib comes from longer term follow-up of early phase trials and from extrapolation of data in the relapsed setting in which acalabrutinib appears to have similar efficacy to ibrutinib, but an overall better tolerability profile, including less cardiotoxicity [10]. As an example, in one phase 1/2 trial, 85 of 99 patients with treatment-naïve CLL remained on treatment after a median follow-up of 53 months [51]. Among those who discontinued therapy, six did so because of adverse events and three had disease progression. The majority of patients in this trial had unmutated IGHV (62 percent) and/or TP53 mutation (18 percent).

Zanubrutinib — Zanubrutinib is an oral, selective, irreversible inhibitor of BTK. Zanubrutinib is approved in Europe for the treatment of CLL/SLL. In the United States, CLL/SLL is an off-label indication undergoing regulatory review. In the treatment-naïve setting, zanubrutinib improves PFS when compared with BR. When compared with ibrutinib in the relapsed setting, zanubrutinib improves PFS and has less cardiac toxicity, in particular less atrial fibrillation, but similar rates of other toxicities [11]. Use in relapsed CLL/SLL is discussed in detail separately. (See "Treatment of relapsed or refractory chronic lymphocytic leukemia", section on 'Zanubrutinib'.)

Evidence regarding the efficacy of zanubrutinib in the initial treatment of CLL comes from a multicenter, open label, phase 3 trial (SEQUOIA) that enrolled 590 adults with previously untreated CLL/SLL who were aged 65 years or older, or had comorbidities [39]. The 479 patients without del(17p) were randomly assigned to receive zanubrutinib (160 mg twice daily) or six cycles of BR. The 111 patients with del(17p) were assigned to receive zanubrutinib on a separate study arm. Testing for TP53 mutation was not required. After a median follow-up of 26 months, the following were reported:

PFS – Among those without del(17p), zanubrutinib improved PFS over that seen with BR (estimated two-year PFS 86 versus 70 percent; HR 0.42; 95% CI 0.28-0.63). A PFS benefit with zanubrutinib was seen in most predefined subgroups except in patients with mutated IGHV. Subgroup analysis was limited by small sample size in those with SLL presentation or TP53 mutation.  

OS – OS data are immature with <10 percent deaths in each arm. Among those without del(17p), OS with zanubrutinib and BR were similar (estimated two-year OS 94 versus 95 percent; HR 1.07, 95% CI 0.51-2.22).

Toxicities – Fewer patients assigned to zanubrutinib required dose reduction or treatment discontinuation due to toxicity (8 versus 14 percent required discontinuation due to toxicity). They were also less likely to experience grade 3 or worse neutropenia (11 versus 51 percent) and to require growth factor support (11 versus 58 percent), although rates of grade 3 or worse infection were similar (16 versus 17 percent). Additional events of clinical interest for zanubrutinib included atrial fibrillation (3 percent), grade 3 or greater hypertension (6 percent), and major bleeding (5 percent).

While these results demonstrate the superiority of zanubrutinib over BR, zanubrutinib has not been directly compared with other targeted therapies (eg, venetoclax, ibrutinib) in this setting. Studies evaluating zanubrutinib in relapsed or refractory CLL/SLL are discussed separately. (See "Treatment of relapsed or refractory chronic lymphocytic leukemia", section on 'Zanubrutinib'.)

Venetoclax plus obinutuzumab — Fixed-duration venetoclax plus obinutuzumab is another one of our preferred treatment options for previously untreated CLL (algorithm 1). It is particularly useful for patients with comorbidities (eg, atrial fibrillation, history of severe bleeding) or concomitant medications (eg, anticoagulants) that make them poor candidates for ibrutinib. (See 'Choice of therapy' above.)

Data supporting the use of venetoclax plus obinutuzumab in previously untreated CLL come from an open-label, phase III trial (CLL14) in which 432 adults (median age 72) with previously untreated CLL and significant comorbidities were randomly assigned to venetoclax plus obinutuzumab versus chlorambucil plus obinutuzumab, each given for a fixed duration of 12 months [21,52]. Venetoclax was started on day 22 of cycle 1 using a five-week dose ramp-up. No crossover was allowed. After a median follow-up of 40 months, when compared with chlorambucil plus obinutuzumab, venetoclax plus obinutuzumab resulted in the following:

Higher ORR (85 versus 71 percent), with more CRs (50 versus 23 percent) and undetectable MRD.

Superior PFS (82 versus 50 percent at 36 months; HR 0.31, 95% CI 0.22-0.44). On preplanned subgroup analysis, this benefit was seen in patients with 17p deletion, TP53 mutation, or both and in patients with IGHV-unmutated CLL, but not among patients with IGHV-mutated CLL. IGHV mutation was identified as a predictive marker for particular benefit of venetoclax over chemotherapy [5]. A PFS benefit was also seen in patients with complex karyotype; venetoclax plus obinutuzumab was equally effective among those with complex karyotype and those without complex karyotype [53].

The majority of patients maintained remission three years following the completion of venetoclax plus obinutuzumab (four-year PFS 74 versus 35 percent; HR 0.33, 95% CI 0.25-0.45) [54].

Similar OS (87 versus 87 percent at 36 months; HR 1.03, 95% CI 0.60-1.75). The median OS has not been reached in either arm and the survival data are immature.

Similar rates of grade 3 or 4 toxicity (79 and 77 percent). Grade 3 or 4 neutropenia and febrile neutropenia occurred in 53 and 5 percent of patients receiving venetoclax plus obinutuzumab, respectively. Growth factors could be administered at the discretion of the treating physician. Tumor lysis syndrome was rare. Quality of life (QOL) measures suggested that use of venetoclax plus obinutuzumab did not impair QOL and resulted in earlier relief of CLL-related symptoms [55].

The acceptable tolerability and improved PFS seen in this study supports a preference for venetoclax plus obinutuzumab over chlorambucil plus obinutuzumab. Further follow-up is needed to assess the durability of remissions and impact on OS. Fixed duration venetoclax plus obinutuzumab has not been directly compared with ibrutinib, continuous venetoclax therapy, or fixed duration venetoclax therapy. Further support for venetoclax is extrapolated from studies in the relapsed setting where venetoclax plus rituximab has demonstrated superior PFS and OS when compared with BR. This is described in more detail separately. (See "Treatment of relapsed or refractory chronic lymphocytic leukemia", section on 'BCL2 inhibitors: Venetoclax'.)

BTK inhibitor plus venetoclax (investigational) — The combination of a BTK inhibitor (ibrutinib or acalabrutinib) plus venetoclax with or without an anti-CD20 monoclonal antibody results in deep responses with a sizeable percentage of patients achieving undetectable measurable residual disease (MRD, also called "minimal residual disease") [12,56-65]. Further study is needed before these combinations should be used in routine practice.

Several phase 2 trials suggest that these combinations can be administered for a fixed duration followed by a treatment-free interval in previously untreated CLL. As examples:

Ibrutinib plus venetoclax – A two cohort multicenter phase 2 study (CAPTIVATE) evaluated two treatment strategies – fixed duration therapy and MRD-guided discontinuation among young/fit patients. Both cohorts were treated with three cycles of ibrutinib monotherapy, followed by combination therapy with ibrutinib plus venetoclax for 12 cycles:

Fixed duration therapy – The 159 patients assigned to the fixed duration cohort discontinued therapy at this point [63]. Response assessment revealed a CR in 55 percent and both a CR and undetectable MRD (uMRD) in the bone marrow in 40 percent. Estimated 24-month PFS and OS were 95 and 98 percent, respectively.

MRD-guided discontinuation – 164 patients were assigned to the MRD-guided discontinuation cohort [62]. In the 86 patients who achieved uMRD, a randomized comparison of placebo versus ibrutinib produced similar one-year disease-free survival (95 versus 100 percent; absolute difference 4.7 percent, 95% CI -1.6 to 10.9). A randomized comparison of ibrutinib with or without venetoclax in the 63 patients without uMRD is pending.

For both of these cohorts, the vast majority of patients categorized at baseline as being at high risk for tumor lysis syndrome (TLS) converted to medium or low TLS risk after the initial three months of ibrutinib.

Ibrutinib, venetoclax, obinutuzumab – The open-label, multicenter CLL2-GIVe trial evaluated the combination of ibrutinib, venetoclax, and obinutuzumab with MRD-guided discontinuation in 41 patients with previously untreated CLL with del(17p) and/or TP53 mutation [64]. Most adverse events (AEs) were low grade and resolved without sequelae. However, there were two fatal AEs (cardiac failure and ovarian carcinoma) and four patients discontinued therapy due to AEs. After 15 cycles of therapy, 59 percent of patients achieved a CR. At final restaging, rates of uMRD were 78 percent in the peripheral blood and 66 percent in the bone marrow. Estimated 24-month PFS and OS were both 95 percent.

Acalabrutinib, venetoclax, obinutuzumab – In another trial, the combination of acalabrutinib, venetoclax, and obinutuzumab resulted in complete remission with uMRD in the bone marrow in 14 of 37 (38 percent) patients with previously untreated CLL by the start of cycle 16 [61].

In a phase 3 trial (GLOW), ibrutinib plus venetoclax improved PFS over that seen with chlorambucil plus obinutuzumab in previously untreated CLL. The combination of a BTK inhibitor plus venetoclax has not been directly compared with fixed duration venetoclax plus obinutuzumab or continuous BTK inhibitor therapy.

In an open-label, phase 3 trial (GLOW), 211 older or frail adults with previously untreated CLL without del(17p) or TP53 mutation were randomly assigned to ibrutinib plus venetoclax or chlorambucil plus obinutuzumab [66]. Ibrutinib was administered as a single agent for three cycles, followed by 12 cycles of ibrutinib plus venetoclax. Chlorambucil plus obinutuzumab was administered for six standard 28-day cycles. After a median follow-up of 28 months:

Ibrutinib plus venetoclax improved PFS (median not reached versus 21 months, 24-month PFS 84 versus 44 percent; HR 0.22, 95% CI 0.13-0.36) and rates of uMRD in the bone marrow at three months after the end of treatment by next-generation sequencing (52 versus 17 percent). OS was immature (11 versus 12 deaths).

Among the 26 patients who were at high risk of tumor lysis syndrome (TLS) at the start of ibrutinib treatment, all but two converted to medium or low risk prior to starting venetoclax.

The most common grade 3 or greater treatment-emergent adverse events were neutropenia (35 percent), diarrhea (10 percent), and hypertension (8 percent) among those treated with ibrutinib plus venetoclax, and neutropenia (50 percent), thrombocytopenia (20 percent), infections (11 percent), and TLS (6 percent) among those treated with chlorambucil plus obinutuzumab. There were nine treatment-related deaths. There were seven deaths in the ibrutinib plus venetoclax arm, four due to cardiac or sudden death.

Chemoimmunotherapy — Clinically fit patients with IGHV-mutated CLL and without 17p deletion or TP53 mutation may reasonably choose treatment with targeted therapy or chemoimmunotherapy depending upon their values and preferences (algorithm 1).

If chemoimmunotherapy is chosen, the preferred regimen depends on clinical fitness. In order of decreasing efficacy and increasing tolerability, options include:

Fludarabine, cyclophosphamide, and rituximab (see 'Fludarabine, cyclophosphamide, and rituximab' below)

BR (see 'Bendamustine plus rituximab' below)

Chlorambucil plus obinutuzumab (see 'Chlorambucil-based therapy' below)

We do not offer maintenance after chemoimmunotherapy. While some studies have shown that maintenance with an anti-CD20 monoclonal antibody improves PFS, an overall survival benefit has not been demonstrated and there are concerns about associated prolonged immune suppression [67-70].

Fludarabine, cyclophosphamide, and rituximab — Fludarabine, cyclophosphamide, and rituximab (FCR (table 5)) is an acceptable initial treatment option for younger patients with IGHV-mutated CLL without 17p deletion or TP53 mutation (algorithm 1). FCR is not appropriate for patients with 17p deletion or TP53 mutation. In addition, targeted therapy is preferred over FCR in IGHV-unmutated CLL due to improved PFS and OS demonstrated in a randomized trial [8]. (See 'Efficacy in younger patients' above.)

Most older patients will not tolerate FCR largely due to cumulative myelosuppression, infections, or other adverse events [71]. Some experts offer a regimen labeled "FCR-lite," which has a higher dose of rituximab, but somewhat lower doses of fludarabine and cyclophosphamide [72,73]. Other experts have used pentostatin, cyclophosphamide, and rituximab (PCR) based on initial reports of improved tolerability that was not confirmed in a randomized trial [74]. We do not use "FCR-lite" or PCR and instead offer other treatments (eg, BR or targeted therapy) to patients unlikely to tolerate full doses of FCR.

Support for FCR in patients with IGHV-mutated CLL is based on long-term follow-up of single-arm trials and the randomized CLL8 trial described below showing deep responses and prolonged remissions in this population, and a subgroup analysis of the randomized trial with short follow-up described above suggesting that this population may not derive additional benefit from ibrutinib [8]. (See 'Efficacy in younger patients' above.)

Several nonrandomized phase II trials have evaluated FCR in previously untreated patients [72,75-80]. Long-term results are available for 300 patients initially treated with FCR combination therapy as part of one of these prospective phase II trials (median follow-up 12.8 years) [42-44]. Median PFS and OS were 6.4 and 12.7 years, respectively. On multivariate analysis, inferior outcomes were seen in those with IGHV-unmutated CLL and in those with del(17p). Relapses beyond seven years were uncommon in the 35 patients with IGHV-mutated CLL that had achieved undetectable MRD. The most common causes of death were CLL (58 percent), other cancers (18 percent), Richter transformation (15 percent), and infection in remission (7 percent). The risk of late infection for the first and second years were 10 and 4 percent with rates of <1.5 percent per year for subsequent years.

Additional data come from 408 patients treated with FCR as part of the randomized CLL8 trial comparing FCR versus fludarabine plus cyclophosphamide in previously untreated CLL, and followed for a median of 5.9 years [24,81]. The median PFS was 57 months overall. On subgroup analysis, estimated five-year PFS after FCR was 67, 33, and 15 percent for those with IGHV-mutated CLL, IGHV-unmutated CLL, and 17p deletion, respectively.

For the CLL population as a whole, ORRs and CR rates with FCR are approximately 95 and 40 to 70 percent, respectively [75,76]. Most patients with CR have no detectable disease on flow cytometry at the end of therapy, a finding that has been associated with longer remission duration [50]. The estimated four-year failure-free survival is 70 percent.

Treatment-related mortality is 1 to 3 percent. Additional toxicities with FCR include cytopenias, infections, nausea, vomiting, and hair loss. Approximately half of patients will have severe (grade 3/4) neutropenia, but major infections occur in less than 5 percent of cycles. Less common side effects of cyclophosphamide can include hemorrhagic cystitis, bladder carcinogenesis, impairment of fertility, leukemogenesis, and, with prolonged high dose therapy, interstitial pulmonary fibrosis. Anti-CD20 monoclonal antibodies can be associated with hepatitis B reactivation and the rare late complication of progressive multifocal leukoencephalopathy. (See "General toxicity of cyclophosphamide in rheumatic diseases" and "Hepatitis B virus reactivation associated with immunosuppressive therapy" and "Progressive multifocal leukoencephalopathy (PML): Epidemiology, clinical manifestations, and diagnosis".)

Long-term toxicity with fludarabine-based regimens appears to be limited to myelotoxicity and infectious complications [82]. The use of fludarabine as a single agent is associated with autoimmune hemolytic anemia, a complication that may be less common if cyclophosphamide and/or rituximab are included. We avoid fludarabine-based regimens in patients with a history of autoimmune hemolytic anemia or autoimmune thrombocytopenia. (See "Risk of infections in patients with chronic lymphocytic leukemia" and "Prevention of infections in patients with chronic lymphocytic leukemia", section on 'Purine analog therapy'.)

Bendamustine plus rituximab — The combination of BR has efficacy and tolerability intermediate to fludarabine- and chlorambucil-based treatments and has been used for patients with decreased renal function or other comorbidities. BR is an acceptable initial treatment option for older (eg, >65 years) patients with IGHV-mutated CLL and without 17p deletion or TP53 mutation (algorithm 1). BR is not appropriate for patients with 17p deletion or TP53 mutation. In addition, targeted therapy is preferred over BR in IGHV-unmutated CLL due to improved PFS and OS demonstrated in a randomized trial. (See 'Efficacy in older patients' above.)

BR is well tolerated and appears to have similar efficacy to ibrutinib in patients with IGHV-mutated CLL, based on a subgroup analysis of the randomized trial described above [7]. As described below, BR is slightly less effective but better tolerated than FCR [83]. BR is preferred to single-agent bendamustine based on single-arm trials that demonstrate higher response rates when rituximab is added to bendamustine and extrapolation of trials that have demonstrated superior survival when rituximab is added to fludarabine-based therapy in CLL [84-87]. While bendamustine-based therapy has demonstrated superior response rates when compared with chlorambucil-based therapy, a survival benefit has not been demonstrated [85-87].

In a multicenter, open-label trial, 564 adults with previously untreated CLL without del(17p) and without significant comorbidities were randomly assigned to FCR versus BR [83]. The two treatment arms were balanced for measured prognostic variables except there were significantly more patients with unmutated IGHV assigned to BR. Cytopenias and infections were the most common toxicities in both arms and were more pronounced in patients older than 65 years. FCR resulted in more cases of severe neutropenia (84 versus 59 percent) and infections (39 versus 25 percent). There were 19 treatment-related deaths; 13 with FCR and 6 with BR. Despite being associated with more severe toxicities and dose reductions, FCR improved PFS (median 55 versus 42 months). At a median follow-up of 37 months, this PFS benefit has not yet translated into an improvement in OS, which was approximately 92 percent at three years in the study population as a whole. In contrast to those with unmutated IGHV, patients with mutated IGHV had superior median PFS following treatment with FCR (not reached versus 43 months) or BR (55 versus 34 months).

Chlorambucil-based therapy — Chlorambucil-based therapy is not commonly used for the initial treatment of CLL because randomized trials of targeted agents (eg, ibrutinib, acalabrutinib, venetoclax plus obinutuzumab) have demonstrated similar tolerability and superior efficacy in patients with del17p, TP53 mutation, or IGHV-unmutated CLL. (See 'Ibrutinib-based therapy' above and 'Venetoclax plus obinutuzumab' above.)

Chlorambucil plus obinutuzumab is an alternative to targeted therapy for older or frail adults with IGHV-mutated CLL (algorithm 1). This combination is well tolerated and appears to have similar efficacy to venetoclax plus obinutuzumab or ibrutinib-based therapy in patients with IGHV-mutated CLL, based on subgroup analyses of the randomized trials described above [21,22]. (See 'Venetoclax plus obinutuzumab' above.)

While chlorambucil plus obinutuzumab is likely less effective than FCR in younger patients, inferiority has not been confirmed in older patients [84,88-90]. In addition, while bendamustine-based therapy has demonstrated superior response rates when compared with chlorambucil-based therapy, a survival benefit has not been demonstrated [85-87].

Chlorambucil has been administered as a single agent or in combination with an anti-CD20 monoclonal antibody (eg, obinutuzumab, ofatumumab, rituximab). The addition of an anti-CD20 monoclonal antibody deepens responses and improves PFS, but is also associated with infusion-related reactions and hematologic toxicity. The addition of obinutuzumab has demonstrated an OS benefit, whereas trials of rituximab and ofatumumab have not demonstrated an OS benefit.

Chlorambucil plus obinutuzumab – As described above, when compared with chlorambucil plus obinutuzumab, fixed duration venetoclax plus obinutuzumab or ibrutinib-based therapy deepens responses and improves PFS among patients with IGHV-unmutated CLL or TP53 deletion/mutation, but not among patients with IGHV-mutated CLL [21,22]. Another phase III trial of 781 adults (median age 73 years) with previously untreated CLL assigned initial therapy in a 1:1:1 randomization to single-agent chlorambucil, chlorambucil plus rituximab, or chlorambucil plus obinutuzumab with the following results [3]:

The addition of rituximab to chlorambucil resulted in superior ORR (67 versus 30 percent) and CR (8 versus 0 percent) rates and a higher rate of severe (grade 3/4) neutropenia (25 versus 15 percent) but similar rates of infection (11 versus 14 percent). At a median follow-up of 18.7 months, rituximab improved PFS (median 16 versus 11 months; HR 0.44; 95% CI 0.34-0.57). This did not translate into an OS benefit (HR 0.6; 95% CI 0.39-1.11).

The addition of obinutuzumab to chlorambucil resulted in even higher CR rates with some patients having no evidence of MRD, a result that was not seen after rituximab plus chlorambucil in this study. The addition of obinutuzumab to chlorambucil improved PFS (median 27 versus 11 months; HR 0.18; 95% CI 0.13-0.24) and OS (HR 0.41; 95% CI 0.23-0.74). The most common severe (grade 3/4) toxicities with obinutuzumab were infusion-related reactions (21 percent), neutropenia (34 percent), and thrombocytopenia (12 percent). Infection rates were not increased.

When compared with rituximab plus chlorambucil, the combination of obinutuzumab plus chlorambucil increased ORR (78 versus 65 percent) and CR rates (21 versus 7 percent). However, it should be noted that the combination of obinutuzumab plus chlorambucil was associated with more severe adverse events overall (70 versus 55 percent), and more infusion-related reactions (20 versus 4 percent) and thrombocytopenia (10 versus 3 percent), than was rituximab plus chlorambucil. At a median follow-up of 18.7 months, obinutuzumab improved median PFS (26.7 versus 15.2 months; HR 0.39; 95% CI 0.31-0.49). Further follow-up is needed to evaluate OS.

Chlorambucil plus ofatumumab – In a phase III trial (COMPLEMENT 1), 447 adults (median age 69 years) with previously untreated CLL not considered eligible for fludarabine-based therapy were randomly assigned to ofatumumab plus chlorambucil versus chlorambucil alone, each for up to 12 cycles [91,92]. The addition of ofatumumab resulted in a higher ORR (82 versus 69 percent) and CR (14 versus 1 percent) rate, and longer PFS (median 23 versus 15 months, HR 0.61; 95% CI 0.49-0.76). At the final analysis, the two treatment groups had similar five-year survival rates (69 versus 66 percent; HR 0.88, 95% CI 0.65-1.17). Despite premedication, at least one symptom of infusion reaction was seen in 67 percent of patients, and 10 percent had severe (grade 3/4) infusion reaction. There were no fatal infusion reactions. Other toxicities included neutropenia, weakness, headache, leukopenia, herpes simplex, lower respiratory tract infection, arthralgia, and upper abdominal pain. There was no difference in the number of patients with adverse events leading to withdrawal of treatment (13 percent).

Single-agent chlorambucil is relatively well tolerated in older adults. In a phase III trial, 193 older adults (median age 70) with an Eastern Cooperative Oncology Group (ECOG) performance status 2 or better, and symptomatic, previously untreated CLL were randomly assigned to single-agent treatment with either fludarabine or chlorambucil [90]. After a median follow-up of 42 months, patients assigned to chlorambucil had the following outcomes when compared with those assigned to fludarabine:

Lower ORR (51 versus 72 percent) and CR (zero versus 7 percent) rates.

Similar PFS (median 18 versus 19 months), a nonsignificant trend toward longer OS with chlorambucil (64 versus 46 months), and a significantly higher proportion of patients who were retreated with either chlorambucil or fludarabine for disease progression (77 versus 50 percent).

Lower rates of severe (grade 3/4) myelotoxicity (23 versus 42 percent), but similar rates of severe infection (4 versus 8 percent) and all infections (32 versus 26 percent).

An analysis of 663 patients enrolled onto successive trials of initial therapy in CLL demonstrated a survival benefit for fludarabine compared with chlorambucil among patients younger than 70 years (HR 0.7, 95% CI 0.5-0.9), but not in those over 70 years (HR 1.0, 95% CI 0.6-1.7) [84].

Together, these studies suggest that the outcomes after initial therapy differ with age. While fludarabine-based therapy results in superior response rates, a survival benefit compared to single-agent chlorambucil therapy has yet to be confirmed in this older population.

We give chlorambucil in a pulsed intermittent dose schedule (eg, a single oral dose of 0.8 mg/kg every four weeks). An alternative schedule uses chlorambucil 0.5 mg/kg on days 1 and 15 each of six 28-day cycles [3]. The chlorambucil dose is modified based on laboratory studies to prevent the development of significant anemia, neutropenia, and/or thrombocytopenia, which are the main toxicities associated with its use [93]. Other less common adverse effects of chlorambucil include infertility, seizures, hepatotoxicity, hypersensitivity, drug fever, pulmonary fibrosis, and interstitial pneumonia.

ADMINISTRATION CONSIDERATIONS — Administration considerations for ibrutinib, venetoclax, and monoclonal antibodies are presented here. Considerations for acalabrutinib are presented separately. (See "Treatment of relapsed or refractory chronic lymphocytic leukemia", section on 'Acalabrutinib'.)

Ibrutinib — The starting dose of ibrutinib is 420 mg orally once daily, and suggested dose reductions for toxicities are provided in the package insert. Ibrutinib is metabolized by the liver; dose adjustments are needed for liver impairment [94]. Ibrutinib has numerous drug interactions that may necessitate dose adjustments. For more detailed information on potential drug-drug interactions, refer to the Lexicomp drug interactions program within UpToDate. (See "Chemotherapy nephrotoxicity and dose modification in patients with kidney impairment: Molecularly targeted agents and immunotherapies", section on 'Ibrutinib'.)

Patients taking ibrutinib have an increased risk of bleeding, although the mechanism is not well understood [95-97]. Bleeding rates have been estimated at 21 bleeding events per 100 patient-years and 3 major bleeding events per 100 patient-years [97]. Fatal bleeding events have occurred in the setting of concomitant risk factors (trauma, anticoagulant use, antiplatelet agents). Caution is advised when a patient is on warfarin or other anticoagulants. We recommend holding ibrutinib for three to seven days before and after surgery to mitigate the risk of perioperative bleeding. Platelet transfusions may lessen bleeding risk if urgent surgery cannot be delayed.

Reported cardiovascular toxicities include supraventricular arrhythmias, ventricular arrhythmias, conduction disorders, heart failure, and hypertension. Atrial fibrillation and other arrhythmias are reported in up to 10 percent of patients [98-102]. The UK CLL Forum has published a good practice paper that provides additional guidance regarding cardiovascular complications with Bruton tyrosine kinase inhibitors [103]. (See "Cardiotoxicity of cancer chemotherapy agents other than anthracyclines, HER2-targeted agents, and fluoropyrimidines", section on 'BTK inhibitors'.)

Pneumonitis and second primary malignancies are uncommon toxicities of ibrutinib [104,105]. Rare cases of hemophagocytic lymphohistiocytosis have been reported after exposure to ibrutinib [106].

The lymphocyte count increases dramatically within 24 hours of starting ibrutinib, peaks after one to two months, and then slowly resolves within eight months in the majority of patients [107].

The optimal length of treatment (months, years, life-long) has not been established, but licensed standard of care based on clinical trial evidence is to continue treatment until progressive disease or unacceptable adverse events. Ongoing trials are evaluating ibrutinib-containing combination therapy with the hope of a treatment-free period in patients achieving deep responses. (See 'BTK inhibitor plus venetoclax (investigational)' above.)

Venetoclax — Venetoclax can cause life-threatening tumor lysis syndrome (TLS). All patients should receive TLS prophylaxis and should be monitored to allow for the early detection of TLS. The specific prophylaxis measures used depend upon the patient's estimated risk of TLS, which differs according to tumor burden (lymph node size and absolute lymphocyte count). Risk stratification, prophylaxis, and the diagnosis and management of TLS is presented in more detail separately. (See "Tumor lysis syndrome: Prevention and treatment" and "Tumor lysis syndrome: Pathogenesis, clinical manifestations, definition, etiology and risk factors" and "Treatment of relapsed or refractory chronic lymphocytic leukemia", section on 'BCL2 inhibitors: Venetoclax'.)

The dose of venetoclax is gradually increased following a strict dose escalation schedule, which is provided in the package insert along with dose modifications for adverse reactions, and important drug interactions. Venetoclax has not been studied in patients with severe renal impairment (creatinine clearance <30 mL/min and patients on dialysis).

Venetoclax may cause fetal harm and should be avoided in pregnancy. For additional administration considerations and information about toxicity, see the package instructions.

Anti-CD20 monoclonal antibodies — Anti-CD20 monoclonal antibodies (eg, rituximab, obinutuzumab, ofatumumab) can be associated with infusion-related reactions, hepatitis B virus reactivation, and other complications. The following administration considerations are of particular importance. For additional guidance, see the package instructions.

Infusion reactions – Premedication is mandatory to minimize infusion reactions. This is described in more detail separately. (See "Infusion-related reactions to therapeutic monoclonal antibodies used for cancer therapy", section on 'Obinutuzumab' and "Infusion-related reactions to therapeutic monoclonal antibodies used for cancer therapy", section on 'Ofatumumab' and "Infusion-related reactions to therapeutic monoclonal antibodies used for cancer therapy", section on 'Rituximab'.)

Hepatitis B virus reactivation – All patients should be screened for hepatitis B prior to starting treatment. Patients with evidence of prior hepatitis B infection should be monitored for clinical and laboratory signs of reactivation during therapy and for several months after completion of therapy. This is described in more detail separately. (See "Hepatitis B virus reactivation associated with immunosuppressive therapy".)

Immunosuppression – Anti-CD20 monoclonal antibodies target B cells and can lead to secondary immunodeficiency. (See "Secondary immunodeficiency induced by biologic therapies", section on 'Monoclonal antibodies to B cells'.)

Progressive multifocal leukoencephalopathy (PML) – There is a small, but increased risk of PML with the use of anti-CD20 monoclonal antibodies. PML typically presents with subacute neurologic deficits, including altered mental status, visual symptoms, paralysis, and ataxia. (See "Progressive multifocal leukoencephalopathy (PML): Epidemiology, clinical manifestations, and diagnosis".)

Formulation – Several rituximab biosimilars are licensed and may be used for the treatment of CLL. Most studies have utilized intravenous administration of rituximab. A subcutaneous formulation (rituximab-hyaluronidase) that uses a fixed dose and a shorter administration time is available for patients who have tolerated intravenous administration [108,109]. We await further data regarding the feasibility and tolerability of this formulation before incorporating it into the routine care of patients with CLL.

Rare cases of severe, sometimes fatal disseminated intravascular coagulation (DIC) have been reported in patients treated with obinutuzumab [110].

Infectious complications and prophylactic antimicrobials — All patients with CLL are at increased risk for infections. Pathogens of concern vary depending on the treatment regimen used. The use of prophylactic antimicrobials depends on the planned treatment regimen and its associated immune dysfunction. This is discussed in more detail separately. (See "Risk of infections in patients with chronic lymphocytic leukemia" and "Prevention of infections in patients with 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. Additionally, immunocompromised patients are candidates for a modified vaccination schedule (figure 1), other preventive strategies (including pre-exposure prophylaxis), and the early initiation of COVID-directed therapy. 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.)

Beyond the Basics topics (see "Patient education: Chronic lymphocytic leukemia (CLL) in adults (Beyond the Basics)" and "Patient education: Hematopoietic cell transplantation (bone marrow transplantation) (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

Indications for treatment – Chronic lymphocytic leukemia (CLL) is an extremely heterogeneous disease and most patients do not require treatment at the time of diagnosis. Therapy is indicated for patients with disease-related complications, termed "active disease" by the International Workshop on CLL (iwCLL) (table 6). (See "Overview of the treatment of chronic lymphocytic leukemia", section on 'Indications for treatment ("active disease")'.)

Pretreatment evaluation – A pretreatment evaluation is performed to determine the extent of disease, patient performance status, comorbidities, and laboratory parameters (eg, 17p deletion, TP53 mutation, IGHV mutation) that have an impact on treatment. (See 'Pretreatment evaluation' above.)

Goals of therapy – Patients with CLL are not cured with conventional therapy. Treatment alleviates symptoms and reverses cytopenias, and is given with the overall goals of improving quality of life and prolonging overall survival (OS). Median OS is approximately 5 to 15 years from start of front-line therapy depending on disease features, patient characteristics, and treatment choice. (See 'Goals of therapy' above.)

There is no agreed-upon standard front-line treatment regimen and practice varies. While OS rates with the different available regimens are similar, they differ in rates of complete remission, time to progression, and associated toxicities. A choice between these therapies is made based on patient and tumor characteristics and goals of therapy. (See 'Initial treatment options' above.)

Treatment regimens and outcomes may differ between younger and older adults, mostly due to the accumulation of comorbidities with age. Instead of using an arbitrary age cutoff to define "older" and "younger," physicians should use clinical judgment to assess the physiologic age of the patient and likelihood that the patient will be able to tolerate more or less intensive treatment regimens. (See 'Risk stratification and assessment of fitness' above.)

Risk stratified initial therapy – Our preferred initial therapy depends on a genetic risk stratification of the tumor and an assessment of patient fitness (algorithm 1):

17p deletion and/or TP53 mutation – Patients with 17p deletion and/or TP53 mutation are at high risk of either not responding to initial treatment with chemoimmunotherapy, or relapsing soon after achieving remission, and should be encouraged to participate in clinical trials. For these patients, we recommend initial treatment with targeted therapy (eg, Bruton tyrosine kinase [BTK]-inhibitor-based therapy or venetoclax-based therapy) rather than chemoimmunotherapy, regardless of patient age (Grade 1B). (See 'Del(17p) and/or TP53 mutations (very high risk)' above.)

IGHV unmutated (without 17p deletion or TP53 mutation) – For these patients, we suggest targeted therapy rather than chemoimmunotherapy (Grade 2B). Targeted agents are preferred due to a clear improvement in progression-free survival (PFS), with a demonstrated OS benefit in some trials. (See 'IGHV unmutated (high risk)' above.)

The choice among targeted agents is strongly dependent on patient comorbidities and preferences. We have longer-term data regarding the efficacy and toxicity of ibrutinib-based therapy. BTK inhibitors are oral therapies given continuously until progression. While response rates are high, few patients achieve undetectable measurable residual disease (MRD). In contrast, undetectable MRD can be achieved by the majority of patients treated with a fixed duration of venetoclax plus obinutuzumab. (See 'Targeted agents' above.)

IGHV mutated (without 17p deletion or TP53 mutation) – For these patients, OS appears to be similar regardless of whether chemoimmunotherapy or targeted therapy is used. Long-term follow-up of prospective trials have demonstrated that a subset of patients with IGHV-mutated CLL treated with chemoimmunotherapy obtain prolonged durable remissions, possibly suggesting cure. (See 'IGHV mutated (standard risk)' above.)

If chemoimmunotherapy is chosen, the preferred regimen depends on clinical fitness. In order of decreasing efficacy and increasing tolerability, options include:

-Fludarabine, cyclophosphamide, and rituximab (see 'Fludarabine, cyclophosphamide, and rituximab' above)

-Bendamustine plus rituximab (see 'Bendamustine plus rituximab' above)

-Chlorambucil plus obinutuzumab (see 'Chlorambucil-based therapy' above)

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

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Topic 83749 Version 90.0

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