Version May 2024
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 CLL/SLL will be reviewed here. General issues regarding management, including the treatment of relapsed/refractory disease, and the management of complications of CLL/SLL 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 "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 kidney function and electrolytes, alkaline phosphatase, lactate dehydrogenase (LDH), beta-2 microglobulin, direct antiglobulin test (DAT), haptoglobin, and serum immunoglobulin levels. Those with autoimmune hemolytic anemia identified by a positive DAT may benefit from anti-CD20 monoclonal antibodies. (See "Warm autoimmune hemolytic anemia (AIHA) in adults", section on 'Rituximab (alone or added to glucocorticoids)'.)
●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. (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 is tested by Sanger or next-generation sequencing. Testing for del17p, TP53 mutation, and IGHV mutation status is critical for the selection of an appropriate treatment. Testing for CD38 expression and/or ZAP-70 expression are not recommended in clinical practice since IGHV testing is widely available.
●A lymph node biopsy is indicated in patients with suspected histologic transformation to a more aggressive histology (ie, Richter transformation [RT]). RT may be suspected if there is a sudden clinical deterioration characterized by a marked increase in lymphadenopathy at one or more sites, splenomegaly, worsening systemic symptoms (eg, fever, night sweats, weight loss), and/or elevated serum LDH. Imaging with a combined PET/CT scan can be used to determine the preferred biopsy site. (See "Richter transformation in chronic lymphocytic leukemia/small lymphocytic lymphoma", section on 'Image-directed biopsy'.)
●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.
●Those 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/SLL are not cured with conventional therapy.
The goals of therapy are to:
●Improve quality of life
●Prolong overall survival (OS)
Treatment alleviates symptoms and reverses cytopenias.
Some modern treatments have demonstrated improved OS. However, this is a rapidly evolving field, and survival estimates for modern therapies are limited by the short follow-up of trials evaluating these approaches. 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/SLL.
CHOICE OF THERAPY — There is no agreed upon standard front-line treatment regimen, and practice varies.
Our preferred initial therapy is dependent on (algorithm 1):
●Genetic risk stratification of the tumor
●Patient comorbidities and medications
●Patient preference and treatment goals
●Logistics
While we offer guidance, the selection of therapy is individualized based on these factors. The optimal initial treatment of CLL/SLL is the subject of multiple ongoing studies. 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'.)
Assess comorbidities and patient preferences — The treatments used for CLL/SLL differ significantly in associated toxicities and burden of administration. As such, comorbidities, concomitant medications, logistics, and patient preferences weigh substantially in the final treatment decision (table 3).
The main treatment options for most patients are:
●Continuous therapy with a Bruton tyrosine kinase (BTK) inhibitor, either acalabrutinib or zanubrutinib are preferred over ibrutinib.
●Fixed-duration venetoclax plus obinutuzumab, administered over one year.
●Fixed-duration ibrutinib plus venetoclax, administered over 15 months.
Important patient-dependent factors that impact the choice between these options include:
●Comorbidities may overlap with expected toxicities or impact drug metabolism.
•Venetoclax plus obinutuzumab may be preferred over BTK inhibitors in those with cardiovascular disorders, uncontrolled hypertension, and/or a high risk for bleeding (eg, low platelet counts, conditions that require anticoagulation).
•A BTK inhibitor may be preferred over venetoclax plus obinutuzumab in patients with kidney impairment; kidney impairment increases the risk of tumor lysis syndrome (TLS) with venetoclax.
•Ibrutinib plus venetoclax is less preferred in patients with conditions that make them poor candidates for a BTK inhibitor (eg, cardiovascular disorders, uncontrolled hypertension, and/or high risk for bleeding).
●Drug interactions are common with targeted therapies.
•BTK inhibitors should be used with caution in patients on anticoagulation, especially warfarin.
•Venetoclax is avoided in patients on nephrotoxic drugs and those taking a strong CYP3A inhibitor, as both can increase the risk for TLS.
Consultation with a clinical pharmacist may help with identifying and managing interactions. For more detailed information on potential drug-drug interactions, refer to the drug interactions program within UpToDate.
●Treatment burdens differ significantly:
•BTK inhibitors are oral medications given until disease progression or unacceptable toxicity. While toxicity is greatest in the first six months of treatment, it continues for the duration of therapy. Important toxicities include bleeding, atrial fibrillation, and hypertension. Other toxicities include fatigue, rash, infections, and myalgia/arthralgia. Toxicities also play an important role in the selection among BTK inhibitors. (See 'Choice of Bruton tyrosine kinase inhibitor' below.)
•Venetoclax plus obinutuzumab is a more intensive therapy given over one year, followed by a treatment-free period. Those with progression after a prolonged response can be retreated with a second one-year course. As such, in the absence of overall survival (OS) comparisons, it is clinically appropriate to compare second progression-free survival (PFS) in those treated with venetoclax plus obinutuzumab versus first PFS in those treated with a BTK inhibitor, as both of these scenarios are a more accurate reflection of treatment failure.
Venetoclax is an oral medication, and obinutuzumab is intravenous. Treatment initiation requires frequent visits to monitor for TLS. The most common toxicities are neutropenia, thrombocytopenia, anemia, diarrhea, nausea, upper respiratory tract infection, cough, musculoskeletal pain, fatigue, and edema. When administered according to the schedules used in the trials and with risk-based TLS prophylaxis, clinically significant TLS is rare.
•Ibrutinib plus venetoclax is a more intensive therapy given over 15 months, followed by a treatment-free period. Patients with progression after a prolonged response can be retreated with a second course. The few patients with unacceptable toxicity may be candidates for continuous therapy with a BTK inhibitor or with time-limited venetoclax plus rituximab.
Ibrutinib plus venetoclax is an all-oral regimen. Treatment initiation incorporates prophylaxis and monitoring for TLS but is logistically easier than with venetoclax plus obinutuzumab. The most common toxicities are neutropenia, diarrhea, and hypertension. Clinically significant TLS is rare.
Genetic risk stratification — Tumor genetic risk stratification impacts prognosis and informs our preferred therapies, as described below.
Del(17p) and/or TP53 mutations (very high risk) — Patients with CLL/SLL with 17p deletion and/or TP53 mutation are at a higher risk of not responding to therapy or experiencing early relapse. While targeted agents have improved outcomes over those achieved with chemoimmunotherapy, del(17p) and TP53 mutation retain their prognostic impact with some targeted therapies, most clearly with venetoclax-based therapies; patients with del(17p) and/or TP53 mutation treated with venetoclax plus obinutuzumab have inferior outcomes when compared with other patients without TP53 alterations [3]. As such, we encourage enrollment in a clinical trial. Outside of a clinical trial, we offer the following approach and adjust based on comorbidities, concomitant medications, patient preference, and logistics.
Preferred options:
●Continuous acalabrutinib
●Continuous zanubrutinib
Alternatives:
●Continuous ibrutinib
●Fixed-duration venetoclax plus obinutuzumab
●Fixed-duration ibrutinib plus venetoclax
For most patients with del(17p) or TP53 mutation, we suggest continuous therapy with acalabrutinib or zanubrutinib (algorithm 1). As described in more detail below, continuous therapy with a BTK inhibitor is highly effective and improves OS over that seen with chemoimmunotherapy in this population. Acalabrutinib and zanubrutinib are preferred over ibrutinib because extrapolation of data from the relapsed setting suggests that they are at least as effective and better tolerated. These two agents have not been compared directly. However, in our practice, if the goal is best efficacy with acceptable toxicity, we offer zanubrutinib. In contrast, if the goal is best tolerability with good efficacy, we offer acalabrutinib. (See 'Choice of Bruton tyrosine kinase inhibitor' below and 'Acalabrutinib' below and 'Zanubrutinib' below and 'Ibrutinib' below.)
Fixed-duration venetoclax plus obinutuzumab is an acceptable alternative, largely based on the extrapolation of data in older adults, patients without del(17p) and TP53 mutation, and those with relapsed disease. It may be preferred in patients who are poor candidates for a BTK inhibitor due to comorbidities (eg, history of atrial fibrillation, moderate hepatic impairment, history of severe bleeding) or concomitant medications (eg, warfarin). Trials of this combination had a limited number of patients with del(17p) or TP53 mutation. However, cross-trial comparisons suggest that efficacy of venetoclax plus obinutuzumab may be decreased in this population. (See 'Venetoclax plus obinutuzumab' below.)
Fixed-duration ibrutinib plus venetoclax is approved for CLL/SLL in Europe. We have the least experience with this combination, especially among patients with del(17p) or TP53 mutation. (See 'Ibrutinib plus venetoclax' below.)
Although approved in Europe for this population, we avoid idelalisib-based regimens in previously untreated CLL due to reports of excessive toxicity. (See "Treatment of relapsed or refractory chronic lymphocytic leukemia", section on 'PI3K inhibitors'.)
No del(17p) and no TP53 mutation
Immunoglobulin heavy chain variable unmutated (high risk) — Patients with immunoglobulin heavy chain variable (IGHV)-unmutated CLL and without del(17p) or TP53 mutation may reasonably choose continuous therapy with acalabrutinib (possibly with obinutuzumab) or zanubrutinib, or fixed-duration venetoclax plus obinutuzumab depending upon comorbidities, concomitant medications, patient preference, and logistics (algorithm 1). (See 'Assess comorbidities and patient preferences' above.)
Preferred options:
●Continuous acalabrutinib as a single agent or with obinutuzumab
●Continuous zanubrutinib
●Fixed-duration venetoclax plus obinutuzumab
●Fixed-duration ibrutinib plus venetoclax
Alternatives:
●Continuous ibrutinib as a single agent or with obinutuzumab
These options have not been directly compared in randomized trials, but all have shown improved PFS when compared with chemoimmunotherapy in this population.
Continuous therapy with a BTK inhibitor improves both PFS and OS over that seen with chemoimmunotherapy in this population. Acalabrutinib and zanubrutinib are preferred over ibrutinib because extrapolation of data from the relapsed setting suggests that they are at least as effective and better tolerated. These two agents have not been compared directly. However, in our practice, if the goal is best efficacy with acceptable toxicity, we offer zanubrutinib. In contrast, if the goal is best tolerability with good efficacy, we offer acalabrutinib. The addition of obinutuzumab to acalabrutinib appears to increase efficacy and increases toxicity with higher rates of cytopenias and infections. As such, we reserve acalabrutinib plus obinutuzumab for young/fit patients without a history of infection. Ibrutinib plus obinutuzumab has not been compared directly versus ibrutinib alone. (See 'Choice of Bruton tyrosine kinase inhibitor' below and 'Acalabrutinib' below and 'Zanubrutinib' below.)
OS data with venetoclax plus obinutuzumab are immature. When compared with BTK inhibitors, venetoclax plus obinutuzumab is a more intensive therapy administered for one year followed by a treatment-free period. Those with progression after a prolonged response can be retreated with a second one-year course. This option may be preferred in patients who are willing to undergo a more intensive therapy in order to attain a treatment-free period and in those who are poor candidates for a BTK inhibitor due to comorbidities (eg, history of atrial fibrillation, moderate hepatic impairment, history of severe bleeding) or concomitant medications (eg, anticoagulants). (See 'Venetoclax plus obinutuzumab' below.)
While fixed-duration ibrutinib plus venetoclax has demonstrated deep responses, it has not been directly compared with venetoclax plus obinutuzumab, and follow-up of clinical trials is short. (See 'Ibrutinib plus venetoclax' below.)
Immunoglobulin heavy chain variable mutated (standard risk) — For most patients with IGHV-mutated CLL and without del(17p) or TP53 mutation, we suggest fixed-duration therapy with venetoclax plus obinutuzumab or ibrutinib plus venetoclax rather than continuous therapy with a BTK inhibitor (algorithm 1). This approach is likely to offer a prolonged treatment-free period in this population. Continuous therapy with acalabrutinib or zanubrutinib are reasonable alternatives, especially for those who are poor candidates for venetoclax plus obinutuzumab or ibrutinib plus venetoclax due to kidney impairment, use of nephrotoxic drugs, and/or a strong CYP3A inhibitor. (See 'Assess comorbidities and patient preferences' above.)
Preferred options:
●Fixed-duration venetoclax plus obinutuzumab
●Fixed-duration ibrutinib plus venetoclax
Alternatives:
●Continuous acalabrutinib as a single agent or in combination with obinutuzumab
●Continuous zanubrutinib
●Continuous ibrutinib as a single agent or in combination with obinutuzumab
These options have not been directly compared in randomized trials. Patients with IGHV-mutated CLL/SLL were included in the trials that compared these treatments versus chemoimmunotherapy. In subgroup analyses, patients with IGHV-mutated CLL/SLL have superior outcomes when compared with other patients. The benefits of targeted therapies over chemoimmunotherapy seen in the general population are of lesser magnitude and do not always reach statistical significance in patients with IGHV-mutated CLL, although the studies were not generally powered to detect a difference within this subgroup.
Fixed-duration therapies are more intensive regimens administered for a set time period, followed by a treatment-free period. When compared with other CLL/SLL subgroups, this subgroup is likely to experience a longer treatment-free, and therefore toxicity-free, period following fixed-duration therapy. Those with progression after a prolonged response can be retreated with a second course.
Venetoclax plus obinutuzumab is administered for one year. While follow-up of trials investigating this approach are short, the vast majority of patients will remain off therapy for at least three years [4]. (See 'Venetoclax plus obinutuzumab' below.)
Ibrutinib plus venetoclax is administered for 15 months. It is approved for this indication in Europe but not the United States. While follow-up is short, the vast majority of patients will remain off therapy for at least 2.5 years [5]. (See 'Ibrutinib plus venetoclax' below.)
Continuous therapy with a BTK inhibitor results in prolonged disease control in this population. Acalabrutinib and zanubrutinib are preferred over ibrutinib because extrapolation of data from the relapsed setting suggests that they are at least as effective and better tolerated. These two agents have not been compared directly. However, in our practice, if the goal is best efficacy with acceptable toxicity, we offer zanubrutinib. In contrast, if the goal is best tolerability with good efficacy, we offer acalabrutinib. The addition of obinutuzumab to acalabrutinib appears to increase efficacy and increases toxicity with higher rates of cytopenias and infections. As such, we reserve acalabrutinib plus obinutuzumab for young/fit patients without a history of infection. Ibrutinib plus obinutuzumab has not been compared directly with ibrutinib alone. (See 'Choice of Bruton tyrosine kinase inhibitor' below and 'Acalabrutinib' below and 'Zanubrutinib' below.)
Long-term follow-up of prospective trials have demonstrated that a subset of patients with IGHV-mutated CLL treated with fludarabine, cyclophosphamide, and rituximab obtain prolonged durable remissions [6-9]. However, if fixed-duration therapy is desired, targeted combinations such as venetoclax plus obinutuzumab or ibrutinib plus venetoclax are preferred to chemoimmunotherapy since this approach avoids the potential long-term toxicities of cytotoxic chemotherapy (eg, risk of secondary myelodysplastic syndrome and acute myeloid leukemia), and randomized trials have not demonstrated superiority of fludarabine, cyclophosphamide, and rituximab in this population.
Infectious complications and prophylactic antimicrobials — All patients with CLL/SLL are at an 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".)
BRUTON TYROSINE KINASE INHIBITORS
Choice of Bruton tyrosine kinase inhibitor — The selection of a Bruton tyrosine kinase (BTK) inhibitor (ibrutinib, acalabrutinib, zanubrutinib) is individualized based on available agents, comorbidities, and goals of therapy. All three BTK inhibitors are approved in the United States and 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. These two agents have not been compared directly. However, in our practice, 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 [11,12]. (See "Treatment of relapsed or refractory chronic lymphocytic leukemia", section on 'Acalabrutinib' and 'Acalabrutinib' 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) [13]; 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' below.)
Acalabrutinib
Administration and toxicity — Acalabrutinib is one of our preferred initial therapies for CLL/SLL (algorithm 1). It is administered by mouth at a dose of 100 mg twice daily and continued until disease progression or unacceptable toxicity.
Acalabrutinib can be used as a single agent or in combination with obinutuzumab. Single-agent acalabrutinib can be used for patients of all ages. 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. (See 'Efficacy of acalabrutinib' below.)
Acalabrutinib has several drug interactions that may necessitate avoidance or dose adjustments. As an example, acalabrutinib and other BTK inhibitors are generally avoided in patients on anticoagulation, especially warfarin. For detailed information on potential drug-drug interactions, refer to the drug interactions program within UpToDate. Acalabrutinib should also be avoided in patients with severe liver impairment.
The most common toxicities include anemia, neutropenia, thrombocytopenia, headache, upper respiratory tract infection, and diarrhea. Serious, potentially life-threatening toxicities include opportunistic infections, bleeding, arrhythmias, and second primary malignancies.
As such, acalabrutinib and other BTK inhibitors are generally avoided in patients with cardiovascular disorders, uncontrolled hypertension, and/or a high risk for bleeding (eg, history of major bleeding).
We advise holding acalabrutinib 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.
A rise in the lymphocyte count is expected after beginning therapy and should not be considered a sign of progressive disease in the absence of other features of progression. The lymphocyte count increases dramatically within 24 hours of starting a BTK inhibitor, peaks after one to two months, and then slowly resolves within eight months in most patients.
Efficacy of acalabrutinib — In the treatment-naïve setting, acalabrutinib improves PFS when compared with chlorambucil plus obinutuzumab. Acalabrutinib has not been directly compared with other targeted therapies as initial therapy; however, extrapolation of data from the relapsed setting suggests that acalabrutinib has similar efficacy to ibrutinib but an overall better tolerability profile, including less cardiotoxicity [10]. (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 [11,14,15]. Acalabrutinib was continued until progression or unacceptable toxicity.
●Progression-free survival – The estimated four-year PFS with acalabrutinib plus obinutuzumab (87 percent) and acalabrutinib alone (78 percent) were higher than that seen with chlorambucil plus obinutuzumab (25 percent). Subgroup analyses included:
•In immunoglobulin heavy chain variable (IGHV)-unmutated CLL/SLL, the estimated four-year PFS were 86, 77, and 4 percent, respectively.
•In IGHV-mutated CLL/SLL, the estimated four-year PFS were 89, 81, and 62 percent, respectively.
Among the 61 patients with 17p deletion or TP53 mutation, the estimated five-year PFS in the two acalabrutinib-containing arms was 71 versus 18 percent with chlorambucil plus obinutuzumab.
●Overall survival – Overall survival (OS) data are immature with estimated four-year OS of 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.
ELEVATE-TN 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 (hazard ratio [HR] 0.49; 95% CI 0.26-0.95) without an improvement in OS. On subgroup analyses, the improved efficacy with obinutuzumab was not demonstrated in patients with del(17p) or TP53 mutation, although the confidence in these results is limited by a small sample size.
Among patients treated with single-agent acalabrutinib in ELEVATE-TN, the most common toxicities were infection (74 percent), bleeding (42 percent), diarrhea (40 percent), and headache (38 percent) [11,14]. Additional events of clinical interest included atrial fibrillation/flutter (4 percent), grade ≥3 hypertension (2.8 percent), and major bleeding (2.8 percent). The addition of obinutuzumab increased the rate of grade ≥3 toxicities (70 versus 50 percent), including neutropenia (31 versus 11 percent) and infection (24 versus 16 percent).
Zanubrutinib
Administration and toxicity — Zanubrutinib is one of our preferred initial therapies for CLL/SLL (algorithm 1). It is administered by mouth (either 160 mg twice daily or 320 mg once daily) and continued until disease progression or unacceptable toxicity.
Zanubrutinib has numerous drug interactions that may necessitate avoidance or dose adjustments. As an example, zanubrutinib and other BTK inhibitors are generally avoided in patients on anticoagulation, especially warfarin. For more detailed information on potential drug-drug interactions, refer to the drug interactions program within UpToDate. Dose reductions are also needed for severe liver impairment.
The most common toxicities include bleeding, upper respiratory tract infection, diarrhea, arthralgias, and cardiac events. As such, zanubrutinib and other BTK inhibitors are generally avoided in patients with cardiovascular disorders, uncontrolled hypertension, and/or a high risk for bleeding (eg, history of major bleeding).
We advise holding zanubrutinib 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.
A rise in the lymphocyte count is expected after beginning therapy and should not be considered a sign of progressive disease in the absence of other features of progression. The lymphocyte count increases dramatically within 24 hours, peaks after one to two months, and then slowly resolves within eight months in most patients.
Efficacy of zanubrutinib — In the treatment-naïve setting, zanubrutinib improves PFS when compared with bendamustine plus rituximab (BR). Zanubrutinib has not been directly compared with other targeted therapies as initial therapy; however, 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 [13]. (See "Treatment of relapsed or refractory chronic lymphocytic leukemia", section on 'Zanubrutinib'.)
A multicenter, open-label, phase 3 trial (SEQUOIA) enrolled 590 adults with previously untreated CLL/SLL who were aged 65 years or older or had comorbidities [16]. The 479 patients without del(17p) were randomly assigned to receive zanubrutinib (at a dose of 160 mg twice daily) or six cycles of bendamustine plus rituximab. 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:
●Progression-free survival – Among those without del(17p), zanubrutinib improved PFS over that seen with bendamustine plus rituximab (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 a small sample size in those with SLL presentation or TP53 mutation.
Those with del(17p) treated with zanubrutinib had an estimated 18-month PFS of 89 percent [17].
●Overall survival – OS data are immature with <10 percent deaths in each arm. Among those without del(17p), OS with zanubrutinib and bendamustine plus rituximab were similar (estimated two-year OS 94 versus 95 percent; HR 1.07; 95% CI 0.51-2.22).
Among patients treated with zanubrutinib in SEQUOIA, the most common toxicities were bleeding (44 percent), upper respiratory tract infection (17 percent), diarrhea (14 percent), arthralgia (14 percent), and cardiac events (14 percent) [16]. Additional events of clinical interest included atrial fibrillation (3 percent), grade ≥3 hypertension (6 percent), and major bleeding (5 percent). When compared with chemotherapy, zanubrutinib was less likely to require dose reduction or treatment discontinuation due to toxicity.
Ibrutinib
Administration and toxicity — Ibrutinib is a highly effective treatment for CLL/SLL. However, if a BTK inhibitor is selected for initial therapy, we prefer acalabrutinib or zanubrutinib rather than ibrutinib, as they appear to be at least as effective and better tolerated (algorithm 1). (See 'Choice of Bruton tyrosine kinase inhibitor' above.)
Ibrutinib can be used as a single agent or in combination with obinutuzumab. Single-agent ibrutinib can be used for patients of all ages. Ibrutinib plus obinutuzumab has not been compared directly versus ibrutinib alone and is expected to have increased toxicity, including higher rates of cytopenias and infections. As such, we reserve this combination for young/fit patients without a history of infection. Most experts do not add rituximab; while it may shorten time to response, benefits in PFS or OS have not been demonstrated [18,19].
Single-agent ibrutinib is administered by mouth at a dose of 420 mg once daily and continued until disease progression or unacceptable toxicity. Dose adjustments are needed for liver impairment. Most experts do not add rituximab; while the addition of rituximab may shorten time to response, benefits in PFS or OS have not been demonstrated [18,19]. The combination of ibrutinib plus venetoclax is discussed separately. (See 'Venetoclax plus obinutuzumab' below.)
Ibrutinib has numerous drug interactions that may necessitate avoidance or dose adjustments. For more detailed information on potential drug-drug interactions, refer to the drug interactions program within UpToDate.
Toxicity with ibrutinib is greatest during the first six cycles of treatment [20]. After six cycles, patients experience cumulative toxicity, although at a lower rate. Common toxicities include infection, bleeding, diarrhea, and headache. Additional toxicities of clinical interest include arrythmias, hypertension, infections, and bleeding. Pneumonitis and second primary malignancies are uncommon toxicities of ibrutinib [21,22]. Rare cases of hemophagocytic lymphohistiocytosis have been reported after exposure to ibrutinib [23].
Because of these toxicities, ibrutinib and other BTK inhibitors are generally avoided in patients with cardiovascular disorders, uncontrolled hypertension, and/or a high risk for bleeding (eg, history of major bleeding). (See "Cardiotoxicity of cancer chemotherapy agents other than anthracyclines, HER2-targeted agents, and fluoropyrimidines", section on 'BTK inhibitors'.)
We advise 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.
A rise in the lymphocyte count is expected after beginning therapy and should not be considered a sign of progressive disease in the absence of other features of progression. The lymphocyte count increases dramatically within 24 hours of starting a BTK inhibitor, peaks after one to two months, and then slowly resolves within eight months in most patients [24].
Efficacy of ibrutinib — Multiple randomized trials have compared ibrutinib-based therapy versus various chemotherapy regimens in older and younger adults with CLL/SLL. All have demonstrated improved PFS, while some have demonstrated improved OS. In subgroup analyses, the improvement in PFS seen in the general population is of lesser magnitude and does not always reach statistical significance in patients with IGHV-mutated CLL. Ibrutinib has not been directly compared with other targeted therapies for the initial treatment of CLL/SLL.
Very few patients with del(17p) or TP53 mutation were included in the studies below. Additional experience in this group comes from small single-arm trials [19,25-29].
●Ibrutinib plus rituximab versus fludarabine, cyclophosphamide, and rituximab – Two randomized phase 3 trials (ECOG-ACRIN E1912 [30,31] and FLAIR [32]) compared ibrutinib plus rituximab versus six cycles of fludarabine, cyclophosphamide, and rituximab in a combined 1300 patients with previously untreated CLL.
In both trials, ibrutinib plus rituximab improved PFS (HR 0.37 and 0.44). In ECOG-ACRIN E1912, 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). In FLAIR, the PFS benefit was seen in IGHV-unmutated CLL (HR 0.41) but did not reach statistical significance for IGHV-mutated CLL.
In ECOG-ACRIN E1912, ibrutinib plus rituximab also improved OS (95 versus 89 percent at five years; HR 0.47; 95% CI 0.25-0.89) in the population as a whole and 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). In FLAIR, an OS benefit was not seen (HR 1.01).
●Ibrutinib versus ibrutinib plus rituximab versus bendamustine plus rituximab – A randomized phase 3 trial (Alliance A041202) compared single-agent ibrutinib versus ibrutinib plus rituximab versus six cycles of bendamustine plus rituximab in 547 older adults with previously untreated CLL [18].
Single-agent ibrutinib improved PFS over that seen with bendamustine plus rituximab (estimated two-year PFS 87 versus 74 percent; HR 0.39; 95% CI 0.26-0.58). On subgroup analysis, this benefit was seen in those with or without del17p; however, the benefit lost statistical significance among those with methylated ZAP-70 (a marker that is strongly associated with the presence of mutated IGHV). The addition of rituximab to ibrutinib increased complete response rates (12 versus 26 percent) but not PFS (HR 1.00; 95% CI 0.62-1.62).
OS data are immature, but there is no hint for a difference in the full population as of yet, although this study allowed crossover, which limits the ability to detect an OS advantage.
●Ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab – A randomized phase 3 trial (iLLUMINATE) compared ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab in 229 mostly older adults with previously untreated CLL [33].
Ibrutinib plus obinutuzumab prolonged PFS (30-month PFS 79 versus 31 percent; HR 0.23; 95% CI 0.15-0.37). The estimated 30-month OS was similar between the arms (86 versus 85 percent), although crossover was allowed upon progression.
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 complete response (19 percent) and undetectable measurable residual disease (35 percent) compare favorably with those seen with single-agent ibrutinib in other trials.
●Ibrutinib versus chlorambucil – A randomized phase 3 trial (RESONATE-2) compared single-agent ibrutinib versus up to 12 cycles of chlorambucil in 269 older adults with previously untreated CLL [34-37]. Ibrutinib improved PFS (seven-year PFS 59 versus 9 percent; HR 0.15; 95% CI 0.10-0.22). On subgroup 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. Ibrutinib also improved OS (five-year OS 83 versus 68 percent; HR 0.45; 95% CI 0.28-0.74).
VENETOCLAX PLUS OBINUTUZUMAB
Administration and toxicity — Fixed-duration venetoclax plus obinutuzumab is one of our preferred initial therapies for CLL/SLL (algorithm 1). It is particularly useful for patients who are poor candidates for a Bruton tyrosine kinase (BTK) inhibitor due to comorbidities (eg, atrial fibrillation, history of severe bleeding) or concomitant medications (eg, anticoagulants). (See 'Choice of therapy' above.)
The most common toxicities with venetoclax plus obinutuzumab are neutropenia, thrombocytopenia, anemia, diarrhea, nausea, upper respiratory tract infection, cough, musculoskeletal pain, fatigue, and edema. When administered according to the schedules used in the trials and with risk-based prophylaxis, tumor lysis syndrome (TLS) is rare.
Venetoclax plus obinutuzumab is administered over one year and followed by a treatment-free period. Those with progression after a prolonged response can be retreated with a second one-year course.
Treatment with venetoclax plus obinutuzumab is logistically complicated and follows a strict dose escalation schedule that begins with several doses of obinutuzumab prior to initiation and dose escalation of venetoclax [38]. (See "Treatment of relapsed or refractory chronic lymphocytic leukemia", section on 'BCL2 inhibitors: Venetoclax'.)
Important specific considerations for venetoclax include:
●Venetoclax is avoided in patients with severe kidney impairment (creatinine clearance <30 mL/min and patients on dialysis), those on nephrotoxic drugs, and those taking a strong CYP3A inhibitor, as these can increase the risk for TLS. For more detailed information on potential drug-drug interactions, refer to the drug interactions program within UpToDate.
●Venetoclax can cause life-threatening TLS. All patients should receive TLS prophylaxis and 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), as described in more detail separately. (See "Treatment of relapsed or refractory chronic lymphocytic leukemia", section on 'BCL2 inhibitors: Venetoclax'.)
Obinutuzumab can be associated with infusion-related reactions, hepatitis B virus (HBV) 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'.)
●Hepatitis B virus reactivation – All patients should be screened for HBV prior to starting treatment. Patients with evidence of prior HBV 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 – There is a small but increased risk of progressive multifocal leukoencephalopathy (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".)
Rare cases of severe, sometimes fatal, disseminated intravascular coagulation (DIC) have been reported in patients treated with obinutuzumab [39].
Efficacy of venetoclax plus obinutuzumab — Data supporting the use of venetoclax plus obinutuzumab in previously untreated CLL come from two open-label phase 3 trials that evaluated this combination in young, fit patients (GAIA-CLL13 [38]) and those with significant comorbidities (CLL14 [40,41]). In both trials, venetoclax plus obinutuzumab deepened responses and improved progression-free survival (PFS) over that seen with chemoimmunotherapy.
In subgroup analyses, the improvement in PFS seen in the general population was of lesser magnitude and did not reach statistical significance in patients with immunoglobulin heavy chain variable (IGHV)-mutated CLL. Further follow-up is needed to assess the durability of remissions and impact on overall survival (OS), although most patients remain in remission for three years following the completion of therapy [4]. Very few patients with del(17p) or TP53 mutation were included in the studies below. Additional experience in this group comes from small, single-arm trials [42,43]. Venetoclax plus obinutuzumab has not been directly compared with other targeted therapies for the initial treatment of CLL/SLL.
In the GAIA-CLL13 trial, 926 younger adults with minimal comorbidities and without 17p deletion or TP53 mutation were randomly assigned to one of four time-limited therapies [38]:
●Venetoclax plus rituximab for 12 cycles
●Venetoclax plus obinutuzumab for 12 cycles
●Venetoclax plus obinutuzumab plus ibrutinib for 12 cycles, followed by single-agent ibrutinib in those with detectable measurable residual disease (MRD; also called "minimal residual disease")
●Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab or bendamustine plus rituximab for six cycles
Key outcomes included:
●When compared with chemoimmunotherapy, venetoclax plus obinutuzumab improved PFS (three-year PFS 87.7 versus 75.5 percent) and achievement of undetectable MRD (uMRD) at 15 months (86.5 versus 52 percent). The addition of ibrutinib resulted in a small incremental benefit in these outcomes (three-year PFS 90.5 percent, uMRD 92.2 percent) and an increase in grade 3 and 4 infection (21.2 versus 13.2 percent). Venetoclax plus rituximab did not improve PFS or uMRD over that seen with chemoimmunotherapy. Data on OS are immature.
●In patients with unmutated IGHV, the three-year PFS was higher among patients treated with venetoclax plus obinutuzumab (82.9 percent) and venetoclax, obinutuzumab, plus ibrutinib (86.6 percent) versus chemoimmunotherapy (65.5 percent); PFS with venetoclax plus rituximab (76.4 percent) was not superior to chemoimmunotherapy.
●In patients with mutated IGHV, improvements in the three-year PFS were numerically higher in the obinutuzumab-containing arms but did not reach statistical significance: venetoclax plus obinutuzumab (93.6 percent), venetoclax, obinutuzumab, plus ibrutinib (96 percent), venetoclax plus rituximab (87 percent), and chemoimmunotherapy (89.9 percent).
In the CLL14 trial, 432 adults 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 [3,4,40,41,44,45]. Key outcomes included:
●Venetoclax plus obinutuzumab improved PFS, and most patients maintained remission for three years following the completion of venetoclax plus obinutuzumab (four-year PFS 74 versus 35 percent; hazard ratio [HR] 0.33; 95% CI 0.25-0.45). A PFS benefit was seen in patients with 17p deletion, TP53 mutation, or both and in patients with complex karyotype or IGHV-unmutated CLL, but not among patients with IGHV-mutated CLL.
In patients with unmutated IGHV, the two-year PFS was higher with venetoclax plus obinutuzumab (two-year PFS 89.4 versus 51 percent).
In patients with mutated IGHV, the two-year PFS was numerically higher with venetoclax plus obinutuzumab but did not reach statistical significance (two-year PFS 90.3 versus 85.6 percent).
●OS rates were similar in the two arms (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, or the survival data are immature.
●Rates of grade 3 or 4 toxicity were similar in the two arms (79 and 77 percent). In those receiving venetoclax plus obinutuzumab, grade 3 or 4 neutropenia and febrile neutropenia occurred in 53 and 5 percent, respectively. Growth factors could be administered at the discretion of the treating clinician. TLS was rare. Quality of life measures suggested that the use of venetoclax plus obinutuzumab did not impair quality of life and resulted in earlier relief of CLL-related symptoms [45].
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 bendamustine plus rituximab. This is described in more detail separately. (See "Treatment of relapsed or refractory chronic lymphocytic leukemia", section on 'BCL2 inhibitors: Venetoclax'.)
IBRUTINIB PLUS VENETOCLAX
Clinical use — Fixed-duration ibrutinib plus venetoclax is an option for the initial treatment of CLL/SLL and is approved for this indication in Europe but not the United States (algorithm 1). (See 'Choice of therapy' above.)
Ibrutinib plus venetoclax is administered over 15 months and followed by a treatment-free period. Those with progression after a prolonged response can be retreated with a second course of ibrutinib plus venetoclax. Those with unacceptable toxicity may be candidates for continuous therapy with a Bruton tyrosine kinase (BTK) inhibitor or with time-limited venetoclax plus rituximab. Fixed-duration ibrutinib plus venetoclax has not been directly compared with measurable residual disease (MRD)-guided ibrutinib plus venetoclax. MRD-guided treatment does not have regulatory approval, and it is not known whether using MRD assessments to extend the duration of therapy will improve outcomes.
While trials have studied other combinations of BTK inhibitors plus venetoclax with or without an anti-CD20 monoclonal antibody (eg, venetoclax, obinutuzumab, and ibrutinib; venetoclax, obinutuzumab, and acalabrutinib), use of these other combinations is considered investigational.
Efficacy and toxicity — 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 MRD (uMRD) [46-57]. Studies of ibrutinib plus venetoclax have demonstrated improved progression-free survival (PFS) and overall survival (OS) when compared with chemoimmunotherapy. The ibrutinib lead-in prior to starting venetoclax also appears to decrease the risk of tumor lysis syndrome (TLS).
●Fixed-duration ibrutinib plus venetoclax – An open-label, randomized phase 3 trial (GLOW) compared ibrutinib plus venetoclax versus chlorambucil plus obinutuzumab in 211 older or frail adults with previously untreated CLL without del(17p) or TP53 mutation [58,59]. 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 46 months:
•Ibrutinib plus venetoclax improved PFS (3.5-year PFS 75 versus 25 percent; HR 0.21, 95% CI 0.14-0.33) and OS (3.5-year OS 88 versus 78 percent; HR 0.49, 95% CI 0.26-0.91). It resulted in deeper responses with a higher percentage of uMRD in the bone marrow at three months after the end of treatment by next-generation sequencing (52 versus 17 percent). The vast majority of patients treated with ibrutinib plus venetoclax did not require subsequent treatment at 3.5 years (94 percent of those with mutated immunoglobulin heavy chain variable [IGHV], 91 percent of those with unmutated IGHV; time to next therapy HR 0.16, 95% CI 0.07-0.33).
•Among the 26 patients who were at high risk of 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 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, with four deaths due to cardiac or sudden death.
●MRD-guided ibrutinib plus venetoclax – An open-label, randomized phase 3 trial (Flair) compared MRD-guided ibrutinib plus venetoclax versus fludarabine, cyclophosphamide, and rituximab (FCR) in 523 adults with previously untreated CLL without del(17p) [60]. Ibrutinib was given as a single agent for two cycles, followed by ibrutinib plus venetoclax administered for two to six years. The duration of combination therapy was double the time taken to achieve uMRD defined using repeat assessments of flow cytometry of the peripheral blood and bone marrow with a detection limit of 1x10-5. FCR was administered for six standard 28-day cycles. After a median follow-up of 44 months:
•The percentage of patients who were able to discontinue ibrutinib plus venetoclax due to MRD stopping rules increased with time: 24 months (29 percent), 36 months (58 percent), and 60 months (78 percent).
•Ibrutinib plus venetoclax improved PFS (3-year PFS 97.2 versus 76.8 percent; HR 0.13, 95% CI 0.07-0.24) and OS (3-year OS 98 versus 93 percent; HR 0.31, 95% CI 0.15-0.67). On subgroup analysis, PFS benefit was more prominent in those with unmutated IGHV (3-year PFS 98 versus 71; HR 0.07, 95% CI 0.02-0.19) and did not reach statistical significance in those with mutated IGHV (3-year PFS 94 versus 89 percent; HR 0.54, 95% CI 0.21-1.38).
•FCR resulted in more cytopenias and secondary malignancies. Ibrutinib plus venetoclax resulted in more cardiac toxicity (eg, serious cardiac events 11 versus 0.4 percent). There were seven deaths attributed to treatment: six in the FCR arm (infections, secondary cancers, and sudden unexplained or cardiac death), and one in the ibrutinib plus venetoclax arm (sudden unexplained or cardiac death).
Fixed-duration ibrutinib plus venetoclax has not been directly compared with MRD-guided ibrutinib plus venetoclax. MRD-guided treatment does not have regulatory approval, and it is not known whether using MRD assessments to extend the duration of therapy will improve outcomes. In particular, patients with mutated IGHV were less likely to achieve MRD negativity in all ibrutinib plus venetoclax datasets but still have superior PFS as compared to those with unmutated IGHV.
●Ibrutinib, venetoclax, and obinutuzumab – An open-label, randomized phase 3 trial (GAIA-CLL13) compared the following time-limited therapies in 926 young, fit patients without 17p deletion or TP53 mutation [38]:
•Venetoclax plus rituximab
•Venetoclax plus obinutuzumab
•Venetoclax plus obinutuzumab plus ibrutinib
•Chemoimmunotherapy with FCR or bendamustine plus rituximab
Key outcomes included:
•When compared with chemoimmunotherapy, venetoclax plus obinutuzumab plus ibrutinib improved PFS (three-year PFS 90.5 versus 75.5 percent) and achievement of uMRD at 15 months (92.2 versus 52 percent). When compared with venetoclax plus obinutuzumab alone, there was a small incremental benefit in these outcomes (three-year PFS 90.5 versus 87.7 percent, uMRD 92.2 versus 86.5 percent) and an increase in grade 3 and 4 infection (21.2 versus 13.2 percent). Data on OS are immature.
•In patients with unmutated IGHV, the three-year PFS was higher among patients treated with venetoclax plus obinutuzumab (82.9 percent) and venetoclax, obinutuzumab, plus ibrutinib (86.6 percent) versus chemoimmunotherapy (65.5 percent).
•In patients with mutated IGHV, improvements in PFS were numerically higher in the obinutuzumab-containing arms but did not reach statistical significance: venetoclax plus obinutuzumab (93.6 percent), venetoclax, obinutuzumab, plus ibrutinib (96 percent), venetoclax plus rituximab (87 percent), and chemoimmunotherapy (89.9 percent).
●Acalabrutinib, venetoclax, obinutuzumab – In a phase 2 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 [52].
CHEMOIMMUNOTHERAPY — Chemoimmunotherapy was widely used for the treatment of CLL/SLL prior to the development of targeted therapies. However, targeted therapies are preferred over chemoimmunotherapy in all patients with CLL/SLL given their efficacy and superior side effect profiles. Chemotherapy may be considered in resource-limited settings without access to targeted therapies. Chemoimmunotherapy is not appropriate for patients with CLL/SLL with del(17p) and/or TP53 mutation and much less efficacious in patients with unmutated immunoglobulin heavy chain variable.
If chemoimmunotherapy is chosen, the preferred regimen depends on clinical fitness [61]. In order of decreasing efficacy and increasing tolerability, options include:
●Fludarabine, cyclophosphamide, and rituximab
●Bendamustine plus rituximab
●Chlorambucil plus obinutuzumab
Studies comparing these regimens to targeted therapies are described in the sections above.
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/small lymphocytic lymphoma (CLL/SLL) is an extremely heterogeneous disease. 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 4). (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 comorbidities, medications, and tumor genetic features (eg, 17p deletion, TP53 mutation, immunoglobulin heavy chain variable [IGHV] mutation) that impact treatment. (See 'Pretreatment evaluation' above.)
●Goals of therapy and prognosis – Patients with CLL/SLL are not cured with conventional therapy. Treatment alleviates symptoms, reverses cytopenias, and is given with the overall goals of improving quality of life and prolonging overall survival. (See 'Goals of therapy' above.)
●Assess comorbidities and patient preference – The treatments used for CLL/SLL differ significantly in associated toxicities and burden of administration. As such, comorbidities, concomitant medications, logistics, and patient preferences weigh substantially in the final treatment decision (table 3). (See 'Assess comorbidities and patient preferences' above.)
The main treatment options are:
•Continuous therapy with a Bruton tyrosine kinase (BTK) inhibitor, either acalabrutinib or zanubrutinib
•Fixed-duration venetoclax plus obinutuzumab
●Genetic risk stratification – Our preferred initial therapy depends on a genetic risk stratification of the tumor (algorithm 1) and is then adjusted for comorbidities and patient preference:
•17p deletion and/or TP53 mutation – For most patients with del(17p) or TP53 mutation, we suggest continuous therapy with a BTK inhibitor rather than fixed-duration venetoclax plus obinutuzumab or ibrutinib plus venetoclax (Grade 2C) (algorithm 1). (See 'Del(17p) and/or TP53 mutations (very high risk)' above.)
Acalabrutinib and zanubrutinib appear to be at least as effective and better tolerated than ibrutinib. These two agents have not been compared directly. However, in our practice, if the goal is best efficacy with acceptable toxicity, we offer zanubrutinib. In contrast, if the goal is best tolerability with good efficacy, we offer acalabrutinib. (See 'Choice of Bruton tyrosine kinase inhibitor' above and 'Acalabrutinib' above and 'Zanubrutinib' above.)
Fixed-duration venetoclax plus obinutuzumab or ibrutinib plus venetoclax are acceptable alternatives. Venetoclax plus obinutuzumab may be preferred in patients who are poor candidates for a BTK inhibitor due to comorbidities (eg, history of atrial fibrillation, moderate hepatic impairment, history of severe bleeding) or concomitant medications (eg, warfarin). (See 'Venetoclax plus obinutuzumab' above.)
•Immunoglobulin heavy chain variable unmutated (without 17p deletion or TP53 mutation) – Patients with IGHV-unmutated CLL and without del(17p) or TP53 mutation may reasonably choose continuous therapy with acalabrutinib or zanubrutinib or fixed-duration venetoclax plus obinutuzumab or ibrutinib plus venetoclax depending upon comorbidities, concomitant medications, patient preference, and logistics. These options have not been directly compared in randomized trials, but all have shown improved progression-free survival when compared with chemoimmunotherapy in this population. (See 'Immunoglobulin heavy chain variable unmutated (high risk)' above.)
•Immunoglobulin heavy chain variable mutated (without 17p deletion or TP53 mutation) – For most patients with IGHV-mutated CLL and without del(17p) or TP53 mutation, we suggest fixed-duration therapy with venetoclax plus obinutuzumab or ibrutinib plus venetoclax rather than continuous therapy with a BTK inhibitor (Grade 2C). This approach is likely to offer a prolonged treatment-free period in this population. Continuous therapy with acalabrutinib or zanubrutinib are reasonable alternatives, especially for those who are poor candidates for venetoclax plus obinutuzumab due to kidney impairment, use of nephrotoxic drugs, and/or a strong CYP3A inhibitor. (See 'Immunoglobulin heavy chain variable mutated (standard risk)' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Michael J Keating, MD, who contributed to earlier versions of this topic review.
آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟
