Treatment of relapsed or refractory chronic lymphocytic leukemia

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

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

Most patients will have a complete or partial response to initial therapy. However, conventional therapy for CLL is not curative and most patients experience relapse. In addition, many patients will require a change in therapy due to intolerance. The choice of subsequent therapy for patients with progressive disease or intolerance to initial treatment will be reviewed here. The initial treatment of CLL, the use of allogeneic hematopoietic cell transplantation in CLL, and the management of complications of CLL are discussed separately.

●(See "Overview of the treatment of chronic lymphocytic leukemia".)

●(See "Hematopoietic cell transplantation in chronic lymphocytic leukemia".)

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

●(See "Risk of infections in patients with chronic lymphocytic leukemia".)

●(See "Prevention of infections in patients with chronic lymphocytic leukemia".)

EVALUATION PRIOR TO CHANGE IN THERAPY

Patients with BTK inhibitor intolerance — Drug intolerance leads to treatment discontinuation in a sizeable minority of patients on continuous therapy with a Bruton tyrosine kinase (BTK) inhibitor (eg, acalabrutinib, zanubrutinib, ibrutinib) [1]. The management of treatment-emergent adverse effects is individualized. Acalabrutinib and zanubrutinib are better tolerated than ibrutinib.

General guidance for drug holidays and dose reductions is provided in the drug package inserts and can be used to maximize drug benefit. Practical recommendations for the management of adverse events have also been proposed by some expert groups [2,3]. Before switching therapy due to BTK intolerance, we consider the following:

●BTK inhibitors can be continued without dose reductions for most grade 1 or 2 nonhematologic toxicities and for hematologic toxicities less than grade 4. More severe toxicities may respond to a brief drug holiday followed by retreatment at the same dose or a lower dose.

●We usually continue therapy in the setting of bruising or minor bleeding, low grade arthralgia or myalgia, rash, and hypertension that can be controlled with antihypertensive medications.

●Symptom-directed management may improve tolerability and ameliorate these toxicities (eg, topical steroids and/or antihistamines for pruritic rash; acetaminophen for arthralgias/myalgias/headaches; loperamide for diarrhea; antihypertensives for hypertension).

●BTK inhibitors have numerous drug interactions that may necessitate dose adjustments. 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.

●Development of atrial fibrillation does not always necessitate BTK inhibitor discontinuation. Patients with atrial fibrillation should be managed in conjunction with a cardiologist for initial rate and rhythm control with particular attention to drug interactions. BTK inhibitors increase the risk of bleeding, and this risk is further increased when administered to patients on anticoagulation, especially warfarin.

Patients with disease progression

Confirming progression — Progressive disease may be suspected in a patient with CLL who experiences a rising lymphocyte count, enlargement of lymph nodes and/or spleen, and/or worsening cytopenias (table 1). The evaluation of such patients depends in part on the context of these findings:

●Lymphocytosis is commonly seen in patients treated with BTK inhibitors (ibrutinib, acalabrutinib, zanubrutinib) and phosphoinositide 3'-kinase (PI3K) inhibitors (idelalisib, duvelisib) and reflects a redistribution of leukemia cells from lymphoid tissues. Lymphocytosis during the first months of therapy must not be confused with disease progression.

●Lymphocytosis flare and/or small nodal enlargement may be seen when a BTK inhibitor is held, and usually reverses with reinstitution of therapy [4].

●Lymphocytosis and/or nodal enlargement may be seen in the setting of infection.

●Transformation to a more aggressive histologic subtype (Richter transformation) should be suspected in patients with rapid progression of lymphadenopathy, infiltration of uncommon extranodal sites (excluding the bone marrow), development of systemic symptoms (eg, fever, weight loss, night sweats), and/or elevated serum lactate dehydrogenase. (See "Richter transformation in chronic lymphocytic leukemia/small lymphocytic lymphoma".)

Before changing therapy for progressive disease, the diagnosis of CLL must be reconfirmed. This evaluation should rule out disorders that may mimic CLL such as the leukemic phase of mantle cell lymphoma. If therapy with a BTK inhibitor is suspended while investigating disease progression, we try to keep the treatment-free period as brief as possible.

●Cytogenetic and molecular studies – Most cases of CLL can be confirmed by a complete blood count with differential, flow cytometry of the peripheral blood to determine the immunophenotype of circulating lymphocytes, and examination of the peripheral smear. (See "Clinical features and diagnosis of chronic lymphocytic leukemia/small lymphocytic lymphoma".)

Prior to a change in therapy, we perform fluorescence in situ hybridization (FISH) of the peripheral blood to look for del17p (TP53). We also perform mutation analysis of TP53 in all patients. The decision to test for other mutations depends on prior therapy received and whether the patient is a candidate for retreatment. It is important to repeat this testing, as clonal evolution does occur. In contrast, immunoglobulin heavy chain variable (IGHV) mutational status will remain unchanged throughout the course of disease. (See 'Evaluate exposure to prior therapies and response' below.)

●Imaging and/or lymph node biopsy – Imaging is not mandatory unless there is a concern for transformation or need for a symptom-directed investigation. Imaging with ¹⁸F-2-deoxy-2-fluoro-D-glucose labelled positron emission tomography (FDG PET) may also help to select a lymph node for biopsy to confirm suspected histologic transformation. (See "Richter transformation in chronic lymphocytic leukemia/small lymphocytic lymphoma".)

●Bone marrow aspiration and biopsy – A bone marrow aspiration and biopsy may be indicated if cytopenias are present. Patients with anemia should also be evaluated for autoimmune hemolytic anemia. (See "Overview of the complications of chronic lymphocytic leukemia", section on 'Diagnosis'.)

Indications for treatment — Patients with asymptomatic recurrent/progressive CLL do not necessarily require an immediate change in treatment but should be followed closely for the development of symptomatic disease (ie, "active disease" by International Workshop on CLL [iwCLL] criteria) (table 2). In general, the same indications used for first-line therapy are used at the time of relapse or progressive disease. These are presented separately. (See "Overview of the treatment of chronic lymphocytic leukemia", section on 'Indications for treatment ("active disease")'.)

For patients on continuous therapy, such as a BTK inhibitor, we continue treatment as long as there appears to be a clinical benefit and adjust monitoring parameters based on disease tempo. As an example, we would continue treatment with standard monitoring in patients with stable disease. In contrast, continued treatment with more frequent monitoring would be used for those with a small increase in lymph node size or those with small increases in absolute lymphocyte count without thrombocytopenia or anemia. A change in therapy is indicated for those with "active disease" by iwCLL criteria.

CHOICE OF THERAPY — Our choice of subsequent therapy for patients with progressive disease or intolerance to initial treatment is individualized and takes into account multiple factors including prior therapy, response and its duration, and reason for discontinuation; patient and tumor characteristics; patient preference; and goals of therapy (algorithm 1 and table 3).

While we offer guidance, experts differ in their preferred approach and there is no single agreed-upon standard. We always encourage patients to enroll in a well-conducted clinical trial. (See 'Investigational therapies' below.)

Treatment may incorporate one or more of the following targeted agents, often administered as combinations (table 4):

●A covalent Bruton tyrosine kinase (BTK) inhibitor (eg, ibrutinib, acalabrutinib, zanubrutinib)

●The noncovalent BTK inhibitor pirtobrutinib

●The BCL2 inhibitor venetoclax

●A phosphoinositide 3'-kinase (PI3K) inhibitor (eg, idelalisib, duvelisib)

●An anti-CD20 monoclonal antibody (eg, rituximab, obinutuzumab)

With the development of targeted agents, there has been a shift away from the use of traditional chemotherapy agents such as purine analogs (eg, fludarabine, pentostatin) and alkylating agents (eg, chlorambucil, cyclophosphamide, bendamustine).

The following general concepts apply:

●Intolerance versus progression – Symptom-directed management may improve tolerability to maximize duration and therefore benefit of therapy. Patients who discontinue a therapy due to intolerance may be candidates for treatment with a different agent from the same class (eg, acalabrutinib after ibrutinib). Some toxicities are due to off-target effects that may be unique to the particular agent. (See 'Patients with BTK inhibitor intolerance' above.)

●Time-limited versus continuous therapy – Retreatment may be an option for patients who experienced a prolonged treatment-free interval after time-limited therapy (eg, five years after treatment with venetoclax plus obinutuzumab as front-line treatment). It is not an option for progression that occurs on continuous therapy (eg, single-agent BTK inhibitor). For patients on a continuous therapy, aim for a treatment-free interval as short as possible since progression may accelerate when continuous targeted therapies are discontinued.

●Genetics of the CLL clone – del17p, TP53 mutation, and unmutated IGHV (in order of decreasing impact) have been associated with inferior outcomes, particularly with chemoimmunotherapy. Although targeted treatments improve outcomes as compared with chemoimmunotherapy, especially in these subgroups, most studies still show a prognostic role for these factors with targeted agents, in particular with time-limited treatment. No head-to-head comparison of continuous versus fixed-duration treatment is available to firmly establish a preferred treatment option. Mutations of specific genes involved in the relevant pathways (ie, BTK and PLCg2 for covalent BTK inhibitors, BCL2 for BCL2 inhibitors) are associated with resistance towards the respective agent and should be tested for, in particular when re-exposure is considered.

●Expected toxicities and patient comorbidities/fitness – Treatment regimens differ significantly in their burden of administration and associated toxicities. When there are several available treatment options, the choice among them is primarily made based on these factors, which are highly dependent upon patient values and preferences (table 4). (See 'Consider treatment burdens and patient comorbidities' below.)

●Candidacy for cellular therapy – Chimeric antigen receptor (CAR)-T cell therapy is an option for fit patients with relapsed or refractory CLL after two or more lines of systemic therapy, including a BTK inhibitor and a BCL2 inhibitor (venetoclax). This population has few therapeutic alternatives, and low-quality evidence suggests that CAR-T cell therapy may produce sustained remissions in a subset. (See 'Chimeric antigen receptor T cells' below.)

Most patients with CLL are not candidates for allogeneic hematopoietic cell transplantation (HCT). However, HCT is a potentially curative treatment option for selected young patients with clinically aggressive relapsed or refractory CLL or for those with high-risk genetic factors. Observational studies suggest that patients in complete remission (CR) at the time of HCT will have a better prognosis. As such, even patients who plan to undergo HCT should be initially treated at the time of relapse to achieve a remission prior to transplant. (See 'Hematopoietic cell transplantation' below.)

●Encourage clinical trials – Most commonly, there is no better therapy to offer a patient than enrollment onto a well-designed, scientifically valid clinical trial. Additional information and instructions for referring a patient to an appropriate research center can be obtained from the United States National Institutes of Health. (See 'Investigational therapies' below.)

Evaluate exposure to prior therapies and response — The management of patients with progressive disease or intolerance should take into account the exposure to other therapies and the quality and duration of response to prior therapy (algorithm 1 and table 3). For those who received a fixed-duration treatment regimen, a response duration significantly less than the median progression-free survival (PFS) expected is a marker of aggressive disease and a predictor of short survival and should lead to a change in therapy rather than retreatment with the prior therapy [5].

Estimating the median PFS for a given treatment is complicated given the paucity of direct comparisons in randomized trials and relatively short follow-up of trials evaluating targeted therapies. We generally consider patients with the following to have early relapse requiring a change in treatment:

●Progression within two to three years of initial treatment with a fixed-duration targeted therapy regimen (eg, venetoclax plus obinutuzumab or ibrutinib plus venetoclax)

●Progression within two to three years of treatment with FCR (fludarabine, cyclophosphamide, and rituximab)

PFS differs greatly by treatment regimen. Data regarding the median PFS of patients following initial treatment that includes a targeted therapy are immature, but prospective trials have reported PFS rates of up to 59 percent at seven years following ibrutinib-based therapy [6]; 78 percent at four years following acalabrutinib [7]; 86 percent at two years following zanubrutinib [8]; 74 percent at four years following venetoclax plus obinutuzumab [9]; and 75 percent at 3.5 years following ibrutinib plus venetoclax [10]. These estimates are not direct comparisons and so cannot accurately compare the efficacy of these agents as first-line therapy, in particular since the patient populations varied greatly with regard to age and fitness.

Prior BTK inhibitor — For patients treated initially with a covalent BTK inhibitor (ie, ibrutinib, acalabrutinib, zanubrutinib), our preferred subsequent therapy depends on the reason for discontinuation (algorithm 1 and table 3):

●Progression on BTK inhibitor – For patients with CLL progressing on a BTK inhibitor and requiring treatment ("active disease"), we suggest venetoclax-based therapy. Venetoclax is highly active and works through a different mechanism of action (BCL2 inhibition). An alternative covalent BTK inhibitor is unlikely to be effective in this setting as acalabrutinib, zanubrutinib, and ibrutinib share a common mode of action (covalent binding to C481 of BTK); by contrast, the noncovalent BTK inhibitor pirtobrutinib has demonstrated activity in this setting and may be an option for patients who have previously received a covalent BTK inhibitor and venetoclax. While idelalisib plus rituximab is approved by regulatory agencies in this setting, its use is limited by toxicities. (See 'BCL2 inhibitors: Venetoclax' below and 'Pirtobrutinib' below.)

After attaining a response, younger patients with a matched donor (related or unrelated) should be evaluated for allogeneic HCT. HCT may be especially attractive in those with higher-risk CLL (eg, del17p, TP53 mutation) and/or progression within five to six years of starting a BTK inhibitor. (See 'Hematopoietic cell transplantation' below.)

●Intolerance to BTK inhibitor – For patients who discontinue a BTK inhibitor due to intolerance, options include treatment with an alternative BTK inhibitor or venetoclax-based therapy. Mutation analysis can help guide the choice; those with mutations in BTK and PLCg2 are unlikely to respond to an alternative covalent BTK inhibitor and are treated with venetoclax-based therapy [11-14]; pirtobrutinib is an option for multiply relapsed disease. For those without a mutation in BTK or PLCg2, a choice is made based on comorbidities and patient preference. (See 'Consider treatment burdens and patient comorbidities' below.)

Prior venetoclax plus obinutuzumab — For patients treated initially with venetoclax plus obinutuzumab or rituximab, our choice of subsequent therapy depends on the timing of relapse (algorithm 1 and table 3):

●Early progression – For patients progressing within a relatively short time (eg, three to five years) after initial treatment with venetoclax plus obinutuzumab, we suggest a BTK inhibitor (eg, ibrutinib, acalabrutinib, zanubrutinib). We suggest acalabrutinib or zanubrutinib rather than ibrutinib. If both are available, the choice depends on individual treatment goals and a desire to balance efficacy and tolerability. The 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, 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). (See '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); however, zanubrutinib is more effective than ibrutinib with deeper responses and improved progression-free survival. (See '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.)

Other experts might offer retreatment with venetoclax-based therapy. Retreatment with venetoclax-based therapy is expected to result in a shorter remission duration as compared to the initial remission, although we do not know what duration of prior remission will allow for meaningful benefit upon retreatment. While idelalisib plus rituximab is approved by regulatory agencies in this setting, its use is limited by toxicities.

After attaining a response, younger patients with a matched donor (related or unrelated) should be evaluated for allogeneic HCT. HCT may be especially attractive in those with higher-risk CLL (eg, del17p, TP53 mutation) and/or progression within five to six years of venetoclax plus obinutuzumab. (See 'Hematopoietic cell transplantation' below.)

●Late progression – For patients with progression more than three to five years following venetoclax plus obinutuzumab, options include retreatment with venetoclax plus an anti-CD20 monoclonal antibody (rituximab or obinutuzumab) or single-agent therapy with a BTK inhibitor. Mutation analysis can help guide the choice; those with mutations in BCL2 are unlikely to achieve a durable response following venetoclax-based therapy and are treated with a BTK inhibitor [15-18]. For those without BCL2 mutation, a choice is made based on comorbidities and patient preference. (See 'Consider treatment burdens and patient comorbidities' below.)

Most prospective trials evaluating BTK inhibitors and PI3K inhibitors did not include patients with prior exposure to venetoclax. Small case series and retrospective studies suggest that BTK inhibitors are effective in this population [19-21]. The largest was an international retrospective study of 188 heavily pretreated patients receiving their next treatment after venetoclax, which reported the following overall response rates (ORR) and median PFS according to class of therapy and exposure to therapies before venetoclax [19]:

●BTK inhibitor (74 patients) – BTK inhibitor naïve (ORR 84 percent; PFS 32 months); BTK inhibitor intolerant (ORR 70 percent; PFS not reached); BTK inhibitor resistant (ORR 50 percent; PFS 4 months)

●CAR-T cells (18 patients) – ORR 67 percent; PFS 9 months

●PI3K inhibitor (17 patients) – ORR 47 percent; PFS 5 months

●Anti-CD20 monoclonal antibody (19 patients) – ORR 32 percent; PFS 2 months

Repeat treatment with venetoclax-based therapy was not evaluated in this study as most patients had received continuous venetoclax monotherapy and not time-limited therapy with venetoclax plus obinutuzumab. A multicenter, international retrospective series reported outcomes following retreatment with venetoclax in 46 patients with relapsed CLL [22]. The most commonly used regimens were venetoclax plus rituximab (48 percent) and single-agent venetoclax (37 percent). Retreatment was started a median of 16 months after the initial regimen was discontinued. Retreatment resulted in an ORR of 79 percent (CR 33 percent; partial response [PR] 46 percent), and the median PFS at retreatment was 25 months (95% CI 17-42 months). Further data regarding the efficacy of BTK inhibitors are described in detail below. (See 'Bruton tyrosine kinase inhibitors' below.)

Prior chemoimmunotherapy — Most patients with progression after initial chemoimmunotherapy should be treated with a BTK inhibitor (eg, ibrutinib, acalabrutinib, or zanubrutinib) or venetoclax-based therapy. Targeted therapies are well established in this setting as this population corresponds with that used in the trials demonstrating efficacy of these agents. The choice between targeted therapies is made based on comorbidities and patient preference (algorithm 1 and table 3). (See 'Consider treatment burdens and patient comorbidities' below.)

Multiply relapsed disease — Treatment of patients with multiply relapsed/refractory CLL with prior exposure to both a BTK inhibitor and venetoclax is individualized. Available options have not been directly compared in a clinical trial, and a choice depends on prior response, comorbidities, and access to cellular therapies. While potentially more toxic, cellular therapies may result in prolonged remissions in a subset of patients.

Patients that had a prolonged remission after a time-limited treatment regimen (eg, ibrutinib plus venetoclax; venetoclax plus obinutuzumab) may be candidates for retreatment; however, subsequent remissions are likely to be shorter.

The noncovalent BTK inhibitor pirtobrutinib is an oral option that is effective and well tolerated; unlike other BTK inhibitors, it has demonstrated activity in CLL/small lymphocytic lymphoma (SLL) with mutations in BTK and PLCg2. (See 'Pirtobrutinib' below.)

PI3K inhibitors (eg, idelalisib, duvelisib) are also active, oral options, although their use is limited by toxicity. (See 'PI3K inhibitors' below.)

CAR-T cell therapy is a more intensive therapy with substantial potential toxicity and modest activity; some patients with persistent CAR-T cells have experienced remissions lasting over a decade. (See 'Chimeric antigen receptor T cells' below.)

Allogeneic hematopoietic cell transplantation is a potentially curative treatment option for selected young patients with clinically aggressive relapsed or refractory CLL or for those with high-risk genetic factors. (See 'Hematopoietic cell transplantation' below.)

Consider treatment burdens and patient comorbidities — Treatment regimens differ significantly in their rates of CR and measurable residual disease (MRD), time to progression, and associated toxicities (table 4). 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.

Targeted therapies have numerous drug interactions that may necessitate dose adjustments. 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.

When choosing between multiple acceptable treatment options, we consider the following:

●BTK inhibitor (ie, ibrutinib, acalabrutinib, zanubrutinib) – Oral medication administered as continuous therapy. Numerous drug interactions. BTK inhibitors increase the risk for bleeding, atrial fibrillation, and hypertension. Other toxicities include fatigue, rash, infections; myalgia/arthralgia. Acalabrutinib is associated with headaches and diarrhea. When compared with ibrutinib, single-agent acalabrutinib has an overall better tolerability profile with fewer class-associated adverse effects including cardiac toxicity, atrial fibrillation, hypertension, arthralgia, and bleeding [23]. The improvement in tolerability is more narrow for zanubrutinib with less cardiac toxicity, in particular less atrial fibrillation, but similar rates of other toxicities [24].

May be preferred over venetoclax in patients with impaired creatine clearance and in those on strong CYP3A inhibitors due to an increased risk of tumor lysis syndrome (TLS); however, BTK inhibitors are also CYP3A substrates and dose adjustment or avoidance may be warranted, depending on the agent.

●Venetoclax – Oral medication either given as continuous therapy (as a single agent) or for a fixed duration (in combination with an anti-CD20 monoclonal antibody). Requires frequent visits at treatment initiation to monitor for TLS, which is increased in those with renal insufficiency. Avoid use with nephrotoxic drugs and strong CYP3A inhibitors/inducers as they can alter the metabolism of venetoclax and increase the risk for TLS [25]. Other adverse events include fatigue, rash, diarrhea, and infections.

May be preferred over BTK inhibitors in those with cardiovascular disorders, uncontrolled hypertension, and/or a high risk for bleeding (eg, low platelet counts, anticoagulation).

●PI3K inhibitors (ie, idelalisib, duvelisib) – Oral medication administered as continuous therapy. Fatal and/or serious toxicities can be seen, including opportunistic infections, diarrhea or colitis, cutaneous reactions, and pneumonitis. Other toxicities include fatigue and rash. Avoid or dose reduce with strong CYP3A inhibitors/inducers.

Reserved for patients with relapsed/refractory CLL with prior exposure to BTK inhibitors and venetoclax.

SPECIFIC THERAPIES

Bruton tyrosine kinase inhibitors

Acalabrutinib — Acalabrutinib is an oral, selective, irreversible inhibitor of BTK that is active in CLL. In the relapsed setting, acalabrutinib improves PFS when compared with idelalisib plus rituximab or bendamustine plus rituximab. In the treatment-naïve setting, it improves PFS when compared with chlorambucil plus obinutuzumab. In patients with relapsed CLL, acalabrutinib appears to have similar efficacy to ibrutinib, but a better toxicity profile with fewer class-associated adverse effects including cardiac toxicity, atrial fibrillation, hypertension, arthralgia, and bleeding. Extrapolation of studies in previously untreated patients suggests that the addition of obinutuzumab increases efficacy and increases toxicity with higher rates of cytopenias and infections. (See "Selection of initial therapy for symptomatic or advanced chronic lymphocytic leukemia/small lymphocytic lymphoma", section on 'Acalabrutinib'.)

●Regulatory approval and administration – Acalabrutinib is approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for initial and subsequent therapy for adults with CLL at a dose of 100 mg every 12 hours [26]. Treatment is continued until progression or unacceptable toxicity.

●Toxicities – 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.

●Efficacy in relapsed CLL/small lymphocytic lymphoma (SLL) – In a multicenter phase 3 trial (ASCEND), patients with relapsed or refractory CLL were randomly assigned to acalabrutinib (155 patients) or to the physician's choice of idelalisib plus rituximab (119 patients) or bendamustine plus rituximab (36 patients) [27,28]. After a median follow-up of 47 months, acalabrutinib improved PFS (4-year PFS 62 versus 19 percent, HR 0.28; 95% CI 0.20-0.38). Median OS had not been reached in any of the arms. Estimated 4-year OS was numerically higher with acalabrutinib but this difference did not reach statistical significance (4-year OS 78 versus 65 percent, HR 0.69; 95% CI 0.46-1.04); 52 percent of patients on the control arm received acalabrutinib at progression.

Acalabrutinib was better tolerated than idelalisib plus rituximab, with lower rates of discontinuation due to toxicity (23 versus 67 percent). The most common toxicities (all grades) with acalabrutinib were neutropenia (24 percent), headache (23 percent), diarrhea (21 percent), upper respiratory tract infection (20 percent), anemia (18 percent), and cough (18 percent). Additional notable toxicities included atrial fibrillation (8 percent), hypertension (8 percent), and major hemorrhage (3 percent).

While these results support the activity of acalabrutinib in CLL, interpretation is limited by the choice of therapy in the control arm, which did not include some of the more active available targeted therapies (eg, venetoclax, ibrutinib).

●Comparison with ibrutinib – In a multicenter, open-label phase 3 trial (ELEVATE-RR), 533 patients with relapsed CLL with del(17p) or del(11)(q22.3) were randomly assigned to acalabrutinib or to ibrutinib [23,29]. After a median follow-up of 41 months, the two treatments produced similar PFS (median 38 months; HR 1.00, 95% CI 0.79-1.27), a finding that was maintained across prespecified subgroups. Overall survival data are immature with approximately 75 percent of patients alive at last follow-up.

Acalabrutinib resulted in fewer patients with bleeding events (38 versus 51 percent), diarrhea (35 versus 46 percent), arthralgia (16 versus 23 percent), hypertension (9 versus 23 percent), contusion (12 versus 18 percent), and atrial fibrillation (9 versus 16 percent), and higher rates of headache (35 versus 20 percent) and cough (29 versus 21 percent).

Fewer patients assigned to acalabrutinib discontinued treatment due to toxicity (15 versus 22 percent). These lower rates of adverse events are consistent with what has been seen in other trials of acalabrutinib in CLL/SLL [27,30-32].

Zanubrutinib — Zanubrutinib is an oral, selective, irreversible inhibitor of BTK. Where available, it is one of our preferred treatments for relapsed or refractory BTK-naïve CLL/SLL. 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. It has not been directly compared with acalabrutinib in this population.

●Regulatory approval and administration – Zanubrutinib is approved by the US FDA and EMA for initial and subsequent therapy for adults with CLL/SLL at a dose of either 160 mg twice daily or 320 mg once daily. Treatment is continued until progression or unacceptable toxicity.

●Efficacy and comparison with ibrutinib – In a multicenter, open label, phase 3 trial (ALPINE), 652 patients with relapsed or refractory CLL/SLL were randomly assigned to zanubrutinib (160 mg twice daily) or ibrutinib (420 mg once daily) until disease progression [24,33]. After a median follow-up of 29.6 months, zanubrutinib improved overall response rate (84 versus 74 percent) and PFS (78 versus 66 percent at 24 months; HR 0.65, 95% CI 0.49-0.86). OS data are immature. Numerically fewer deaths were reported in the zanubrutinib arm (48 versus 60 deaths), but this difference was not statistically significant (HR for death 0.76, 95% CI 0.51-1.11).

●Toxicities – The most common toxicities include infection, neutropenia, hypertension, diarrhea, anemia, and arthralgia. Serious, potentially life-threatening, toxicities include opportunistic infections, bleeding, arrhythmias, and second primary malignancies.

In ALPINE, those assigned to zanubrutinib had fewer adverse events leading to drug discontinuation (15.4 versus 22.2 percent) and similar treatment-related deaths (10.2 versus 11.1 percent) [24,33]. Zanubrutinib resulted in less cardiotoxicity with fewer cardiac disorders (21 versus 30 percent), less atrial fibrillation/flutter (5.2 versus 13.3 percent), and fewer treatment discontinuations due to cardiac disorders (1 versus 14 patients). These lower rates of cardiac events are consistent with what has been seen in other trials of zanubrutinib in CLL/SLL [8].

There were similar rates of hypertension of any grade (24 versus 23 percent) and grade 3 hypertension (15 versus 14 percent).

Zanubrutinib resulted in a higher rate of neutropenia (29 versus 24 percent), yet similar rates of grade 3 or greater infections (27 versus 28 percent). Major bleeding occurred with similar frequency in the two arms (3.7 versus 4.3 percent).

Ibrutinib — Ibrutinib is an oral irreversible inhibitor of Bruton tyrosine kinase (BTK) and an option for patients with relapsed or refractory ibrutinib-naïve CLL. It is well tolerated and produces sustained remissions in a majority of patients [34-39]. While there is some evidence that progression-free survival (PFS) and overall survival (OS) are shorter in subgroups with del(17p) or del(11q) [39-41], for patients with del(17p), the outcomes with ibrutinib treatment are much better than for chemotherapy-based treatment [42]. In patients with relapsed CLL, we prefer acalabrutinib or zanubrutinib since they have at least similar efficacy to ibrutinib, but better toxicity profiles, in particular with less cardiotoxicity. (See 'Acalabrutinib' above and 'Zanubrutinib' above.)

●Regulatory approval and administration – Ibrutinib is approved by the US FDA and the EMA for both previously treated as well as previously untreated patients with CLL. Treatment is continued until progression or unacceptable toxicity. Administration and use as initial therapy are described separately.

●Efficacy and toxicity in relapsed CLL/SLL – The efficacy of ibrutinib in relapsed/refractory CLL was demonstrated in a multicenter, open-label randomized trial (RESONATE) that compared ibrutinib versus ofatumumab in 391 patients with relapsed/refractory CLL/SLL [43-47]. Ibrutinib led to a clear improvement in PFS (59 versus 3 percent at three years, median 44 versus 8.1 months, hazard ratio [HR] 0.15; 95% CI 0.113-0.196) and demonstrated improved OS (median 68 versus 65 months, HR 0.81; 95% CI 0.60-1.09) despite extensive cross-over. Ibrutinib resulted in more diarrhea, pyrexia, and nausea and lower rates of cough and infusion-related reaction. Ibrutinib also had higher than expected rates of hypertension (21 percent), atrial fibrillation (12 percent), and major hemorrhage (10 percent).

In a multicenter, single-arm trial of ibrutinib in 144 patients with relapsed/refractory CLL/SLL with del(17p), the overall response rate (ORR) was 83 percent (10 percent complete) at a median follow-up of 28 months [48]. Estimated rates of PFS and OS at two years were 63 and 75 percent, respectively. Richter transformation occurred in 17 patients, 11 of which transformed within the first six months. Toxicities were similar to those seen in other trials of ibrutinib.

Case reports and a retrospective analysis have also reported high response rates when ibrutinib is used after venetoclax-based therapy [19-21]. (See 'Prior venetoclax plus obinutuzumab' above.)

●Impact of adding rituximab – The addition of rituximab may shorten time to response but without improved PFS [49,50]. In a randomized phase 2 trial, 208 patents with relapsed CLL or treatment-naïve high-risk CLL were randomly assigned to receive ibrutinib with or without rituximab [49]. After a median follow-up of 36 months, the two treatment arms had similar ORR (92 percent each), PFS (HR 1.16; 95% CI 0.55-2.44), and OS (HR 0.75; 95% CI 0.28-2.02). The addition of rituximab resulted in a quicker time to complete response (CR; median 12 versus 22 months) and lower levels of minimal residual disease.

●Combination therapy – While initial reports suggest improved clinical outcomes when ibrutinib is added to classical chemoimmunotherapy (eg, bendamustine plus rituximab [BR]), it is not known whether this combination improves on outcomes seen with single-agent ibrutinib or whether it allows for the earlier discontinuation of ibrutinib therapy [51-55]. While initial reports suggest deep responses when ibrutinib is given in combination with venetoclax, further study is needed before this combination should be used in routine practice. (See "Selection of initial therapy for symptomatic or advanced chronic lymphocytic leukemia/small lymphocytic lymphoma", section on 'Ibrutinib plus venetoclax'.)

Pirtobrutinib — Pirtobrutinib is an oral, noncovalent (reversible) BTK inhibitor. Initial studies suggest that pirtobrutinib is effective and well tolerated, although it has not been directly compared with other agents.

Since they do not require binding to the BTK C481 residue, noncovalent BTK inhibitors like pirtobrutinib are active in patients with BTK C481 mutations commonly seen in those progressing on a covalent (irreversible) BTK inhibitor, such as ibrutinib, acalabrutinib, or zanubrutinib. In contrast, CLL progressing on a noncovalent BTK inhibitor exhibits other mutations in BTK or PLCg2, some of which also confer resistance to covalent BTK inhibitors, highlighting the importance of this pathway for efficacy [56].

●Regulatory approval and administration – Pirtobrutinib is approved by the FDA for treatment of adults with CLL/SLL who have received at least two prior lines of therapy, including a BTK inhibitor and a BCL2 inhibitor. The usual dose is 200 mg once daily. Treatment is continued until progression of unacceptable toxicity.

●Efficacy and toxicity – In a phase 1/2 trial of the noncovalent BTK inhibitor pirtobrutinib in 317 patients CLL/SLL (BRUIN), the 247 patients with prior exposure to a BTK inhibitor had an overall response rate (including partial response with lymphocytosis) of 82 percent and median progression-free survival of 19.6 months [57,58]. On subgroup analysis, response rates of 70 to 80 percent were seen in those with prior exposure to a BTK inhibitor plus venetoclax, progression on the prior BTK inhibitor, and BTK C481 mutation. A lower response rate was seen in those with PLCg2 mutation (10 of 18 patients, 56 percent).

Pirtobrutinib was well tolerated, and few patients discontinued therapy due to toxicity (2.8 percent). The most common adverse events were infection (71 percent), bleeding (43 percent), and neutropenia (33 percent). Adverse events of particular interest with BTK inhibitors included hypertension (14 percent), atrial fibrillation and flutter (3.8 percent), and major hemorrhage (2.2 percent).

These results illustrate the activity of a noncovalent BTK inhibitor in CLL/SLL previously exposed to a covalent BTK inhibitor, including CLL/SLL with BTK C481 mutation, and those with refractory disease.

BCL2 inhibitors: Venetoclax — Venetoclax is an oral, selective, small molecule inhibitor of BCL2 and one of our preferred treatments for patients with relapsed or refractory CLL, especially for those progressing after a BTK inhibitor. The combination of venetoclax plus rituximab improved PFS and OS when compared with bendamustine plus rituximab in a randomized trial. The combination of venetoclax plus obinutuzumab offers a time-limited treatment option, as studied in treatment-naïve patients. Deep responses can be achieved by combining a BTK inhibitor with venetoclax. Use of venetoclax plus ibrutinib is discussed in more detail separately. (See "Selection of initial therapy for symptomatic or advanced chronic lymphocytic leukemia/small lymphocytic lymphoma", section on 'Ibrutinib plus venetoclax'.)

●Regulatory approval – Venetoclax is approved by the FDA and EMA for the treatment of patients with CLL [59,60].

●Administration and tumor lysis syndrome prophylaxis – Venetoclax is started at 20 mg daily and increased gradually over five weeks to a final daily dose of 400 mg. If used, anti-CD20 monoclonal antibodies are not started concurrently with venetoclax (ie, obinutuzumab is started before venetoclax, rituximab is started after venetoclax).

With this dose escalation schedule, approximately 6 percent of patients will develop tumor lysis syndrome (TLS) (table 5). The patient's risk of TLS must be estimated prior to the initiation of therapy to guide management:

•Hypouricemic agents (allopurinol or rasburicase, depending on TLS risk category) are started two to three days prior to the initiation of venetoclax. All patients require laboratory monitoring for TLS (potassium, uric acid, phosphorus, calcium, creatinine), aggressive hydration, and correction of any electrolyte disturbances and elements of reversible renal failure. The risk of TLS increases with tumor mass and renal dysfunction. Venetoclax has not been studied in patients with severe renal impairment (creatinine clearance <30 mL/min and patients on dialysis).

•Patients at low risk for TLS (ie, all lymph nodes <5 cm and absolute lymphocyte count [ALC] <25 x 10⁹/L) may be managed as outpatients with oral hydration (1.5 to 2 liters), allopurinol, and frequent laboratory studies (pre-dose, 6 to 8 hours, and 24 hours).

•Patients at medium risk for TLS (ie, any lymph node 5 cm to <10 cm or ALC ≥25 x 10⁹/L) can be managed in either the outpatient or inpatient setting depending on comorbidities. Hospitalization is preferred for patients with creatinine clearance <80 mL/min and allows for frequent monitoring and supplementation of oral intake with intravenous fluids. Allopurinol is used as the hypouricemic agent.

•Patients at high risk for TLS (ie, any lymph node ≥10 cm or any lymph node ≥5 cm and an ALC ≥25 x 10⁹/L) should be hospitalized at the time of the first doses at the 20 mg and 50 mg level. This allows for more frequent laboratory studies (pre-dose, 4, 8, 12, and 24 hours) and the administration of both oral (1.5 to 2 liters) and intravenous (150 to 200 mL/hour as tolerated) fluids. While most patients receive allopurinol as the hypouricemic agent, rasburicase is preferred if uric acid is elevated at baseline.

A faster dose escalation has been used for selected patients at experienced centers with close inpatient monitoring [61]. TLS may occur on resumption of venetoclax after treatment interruption. Thus, the risk of TLS should be reassessed if the dose interruption lasted more than one week during the dose escalation phase, or more than two weeks after completion of the dose escalation phase. 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".)

●Decision to add an anti-CD20 monoclonal antibody – Data regarding the efficacy and safety of venetoclax come from single-arm prospective trials that have reported high response rates with single-agent therapy or in combination with rituximab or obinutuzumab, and from a randomized trial that demonstrated a PFS and OS advantage for venetoclax plus rituximab over bendamustine plus rituximab [62-68]. Nonrandomized comparisons have had mixed results with some suggesting higher CR rates when venetoclax is combined with rituximab or obinutuzumab and others reporting no clear benefit from the addition of an anti-CD20 monoclonal antibody [66-69].

As more data accumulate and experience with combination therapy expands, our contributors differ in their use of venetoclax for relapsed CLL. Some prefer to use venetoclax as a single agent, especially for those wanting an all-oral regimen, while others offer venetoclax in combination with rituximab or obinutuzumab based on cross-trial comparisons that suggest deeper responses with combination therapy and the ability to administer a time-limited course (24 months) in patients without TP53 mutation or 17p deletion. We anticipate that our approach will evolve as we gain more experience with combination therapy.

●Toxicities – The most common short-term toxicities include neutropenia, thrombocytopenia, anemia, diarrhea, nausea, upper respiratory tract infection, cough, musculoskeletal pain, fatigue, and edema. Serious, potentially life-threatening toxicities include tumor lysis syndrome and infections. Long-term venetoclax exposure may also influence the clonal dynamics of non-CLL cells, which may manifest as cytopenias in the setting of BAX mutations in myeloid cells [70].

●Efficacy in relapsed/refractory CLL/SLL

•Following ibrutinib – An interim analysis of a multicenter, phase 2, open-label study evaluated the efficacy of venetoclax in 91 patients with heavily pretreated CLL who relapsed after or were refractory to ibrutinib [64]. The ORR was 65 percent (9 percent complete) and similar among patients with and without high-risk genetic abnormalities (eg, del17p or TP53 mutations). After a median follow-up of 14 months, estimated PFS and OS at 12 months were 75 and 91 percent. Median PFS was 25 months. In a separate report of this trial, venetoclax was associated with a similar response rate (67 percent ORR, <1 percent complete) and estimated PFS at 12 months (79 percent) among 36 patients with relapse after idelalisib [71].

•Patients with 17p deletion – An international, single-arm phase 2 trial evaluated venetoclax in 153 patients with relapsed or refractory CLL with 17p deletion and 5 patients with previously untreated CLL with 17p deletion [63,65]. Most patients were hospitalized for the initial dose, and all received TLS prophylaxis and a gradual dose escalation as recommended in the package insert. At a median follow-up of 27 months, the ORR was 77 percent (20 percent complete) with a median time to first response of one month (range 0.5 to 4.4 months) and an estimated median duration of response of 33 months. At two years, estimated PFS and OS were 54 and 73 percent, respectively. There were 53 deaths on study; 44 were due to disease progression, one was deemed possible due to treatment, and the rest were deemed unrelated.

•Venetoclax plus rituximab superior to bendamustine plus rituximab (BR) – In an international, open-label, phase 3 trial (the MURANO trial), 389 patients with relapsed or refractory CLL were randomly assigned to six months of BR or to two years of venetoclax plus six months of rituximab [67,72,73]. Cross-over to venetoclax was not allowed at the time of progression. After a median follow-up of 59 months, venetoclax plus rituximab improved PFS (median 54 versus 17 months; HR 0.19; 95% CI 0.15-0.26) and OS (82 versus 62 percent at 5 years; HR 0.40; 95% CI 0.26-0.62). The benefit was maintained in several subgroup analyses, including patients with high-risk disease and older adults. The most common toxicities of any grade with venetoclax were neutropenia (61 percent), diarrhea (40 percent), nausea (21 percent), anemia (16 percent), fatigue (18 percent), upper respiratory tract infection (22 percent), and thrombocytopenia (13 percent). Serious adverse events were seen in 46 percent and fatal adverse events occurred in 5 percent.

Patients assigned to venetoclax plus rituximab were more likely to achieve undetectable minimal residual disease (uMRD), a status predictive of superior PFS and OS [73,74]. Of the 83 patients who attained uMRD after venetoclax plus rituximab, 32 (39 percent) remained with uMRD at five years from the start of treatment, while 28 (34 percent) had confirmed MRD conversion without progression and 23 (30 percent) had progressive disease. At first progression, an at least partial response was attained following retreatment with venetoclax-based therapy in 13 of 18 patients (72 percent) and following treatment with ibrutinib in 14 of 14 patients (100 percent) [73]. These longer-term results confirm the PFS and OS benefit of venetoclax plus rituximab in this population and demonstrate prolonged remissions following a time-limited course of therapy.

Nonrandomized studies have reported prolonged treatment-free periods in patients achieving deep remission following limited duration venetoclax plus rituximab with retreatment upon progression [75].

•Venetoclax plus obinutuzumab – The combination of venetoclax plus obinutuzumab has demonstrated superior response rates and PFS when compared with chlorambucil plus obinutuzumab in the treatment-naïve population [76]. Small prospective studies have also demonstrated deep responses in patients with relapsed CLL [68]. The use of venetoclax plus obinutuzumab for the initial treatment of CLL is discussed in detail separately. (See "Selection of initial therapy for symptomatic or advanced chronic lymphocytic leukemia/small lymphocytic lymphoma", section on 'Venetoclax plus obinutuzumab'.)

PI3K inhibitors

Idelalisib — Idelalisib is an oral inhibitor of phosphoinositide 3'-kinase (PI3K) delta that has shown activity in patients with relapsed or refractory CLL, although its use may be limited by toxicity [77-79]. We reserve PI3K inhibitors for patients with relapsed/refractory CLL with prior exposure to BTK inhibitors and venetoclax.

●Regulatory approval – Idelalisib is approved by the US FDA for the treatment of patients with relapsed CLL, in combination with rituximab, for whom rituximab alone would be considered appropriate therapy due to other comorbidities [80]. Trials of idelalisib included some patients with significant comorbidities, including cardiac and renal dysfunction [81]. Approval by the EMA is for patients who have received at least one prior therapy.

●Administration and warnings – The starting dose is 150 mg twice daily, and suggested dose reductions for toxicities are provided in the package insert. The following should be noted:

•Idelalisib is associated with an increase in opportunistic infections and the manufacturer suggests prophylaxis for Pneumocystis jirovecii pneumonia (PJP) and monitoring for cytomegalovirus. (See "Risk of infections in patients with chronic lymphocytic leukemia", section on 'Phosphatidylinositol 3-kinase inhibitors' and "Prevention of infections in patients with chronic lymphocytic leukemia", section on 'Bruton tyrosine kinase inhibitors'.)

•Idelalisib carries boxed warnings regarding an increased risk of fatal and/or serious hepatotoxicity, diarrhea, colitis, intestinal perforation, and pneumonitis. The package insert also includes warnings about severe cutaneous reactions, hypersensitivity reactions, and neutropenia. Idelalisib has also resulted in hypertriglyceridemia, hyperglycemia, alanine aminotransferase (ALT) elevations, and aspartate aminotransferase (AST) elevations [82]. Hepatic function should be evaluated prior to and during treatment. Hepatotoxicity may be more common among younger patients and those without prior therapy [83].

•In addition to early-onset mild diarrhea, there are a few patients with a severe, wasting diarrhea due to histologically proven colitis, which is poorly understood. Colitis usually occurs after more than eight months of therapy and the overall incidence of severe (grade 3 or worse) colitis is low. Management is not clear, but usually treatment is paused, and systemic or local corticosteroids used. After recovery, many patients tolerate restarting idelalisib at a lower dose (eg, 100 mg twice daily).

•The lymphocyte count typically increases dramatically within 24 hours of starting idelalisib plus rituximab, peaks during the second week of therapy, and usually resolves by week 12.

When compared with those reported in the trials leading to approval, patients treated in routine practice tend to be older, have more comorbidities, and more complications, especially infectious complications [84]. Idelalisib is administered with rituximab, which may result in the following major toxicities:

•Infusion reactions (ie, fevers, rigors, and hypotension). (See "Infusion-related reactions to therapeutic monoclonal antibodies used for cancer therapy".)

•Infections related to immunosuppression. (See "Secondary immunodeficiency induced by biologic therapies", section on 'Monoclonal antibodies to B cells'.)

•Hepatitis B virus reactivation among patients positive for hepatitis B surface antigen (HBsAg) or antibodies against hepatitis B core antigen (anti-HBc). (See "Hepatitis B virus reactivation associated with immunosuppressive therapy".)

•Rarely, JC virus infection can result in potentially fatal progressive multifocal leukoencephalopathy. (See "Progressive multifocal leukoencephalopathy (PML): Epidemiology, clinical manifestations, and diagnosis".)

●Efficacy and toxicity in relapsed/refractory CLL/SLL – In randomized phase 3 trials, the addition of idelalisib improved PFS and OS, but increased severe toxicity when added to rituximab [81,85], ofatumumab [86], or the combination of bendamustine plus rituximab [87].

As an example, when compared with rituximab plus placebo, the combination of idelalisib plus rituximab led to a clear improvement in PFS (median 19.4 versus 6.5 months), and a more modest improvement in OS (median 41 versus 35 months; HR 0.8 [95% CI 0.5-1.1]) despite extensive cross-over [81,85]. However, at least one grade 3 or greater toxicity occurred in 74 percent of patients receiving idelalisib, 54 percent of patients receiving placebo, and >90 percent of patients in the extension study, with neutropenia and pneumonia being the most common. Febrile neutropenia was reported in 6 percent. More common, but less severe, toxicities included fever, fatigue, nausea, chills, and diarrhea. The frequency of diarrhea increased with longer exposure to idelalisib. Severe elevations in hepatic aminotransferase levels were described (ALT in 9 percent, AST in 6 percent); most resolved upon holding idelalisib and none resulted in permanent drug discontinuation. There were several cases of PJP pneumonia (5 cases), fungal infection (22 cases), cytomegalovirus (2 cases), and progressive multifocal leukoencephalopathy (1 case). None of the patients with PJP pneumonia had received PJP prophylaxis.

Patients who have received venetoclax may be unlikely to achieve a durable response with idelalisib; in one international retrospective study of patients with relapsed or refractory CLL who discontinued venetoclax-based therapy for any reason, those treated with a PI3K inhibitor had an ORR of 47 percent and a median PFS of five months [19].

Duvelisib — Duvelisib is an oral inhibitor of PI3K delta and gamma isoforms that has shown activity in small nonrandomized studies of patients with multiply relapsed CLL/SLL and superior PFS when compared with ofatumumab in a multicenter randomized trial [88-92]. However, duvelisib has substantial toxicity; increased risk of death and serious side effects were highlighted in an FDA warning in June 2022 [93], and more safety concerns were raised for PI3K inhibitors as a class in April 2022 [94]. We reserve the use of duvelisib for patients with multiply relapsed disease, usually after treatment with ibrutinib and venetoclax, with or without prior chemoimmunotherapy.

●Regulatory approval – Duvelisib is approved by the US FDA as a single agent for the treatment of patients with relapsed CLL/SLL who have received at least two prior therapies [88].

●Administration – The starting dose is 25 mg administered orally twice a day until progression or unacceptable toxicity. Suggested dose reductions for toxicities are provided in the package insert in addition to dose adjustments for patients taking CYP3A inhibitors/inducers.

●Toxicity – Fatal and/or serious toxicities can be seen, including opportunistic infections, diarrhea or colitis, cutaneous reactions, and pneumonitis.

Hepatic function and blood counts must be monitored for hepatotoxicity and neutropenia. The prescribing information recommends prophylaxis for PJP pneumonia and suggests that clinicians consider the use of prophylactic antivirals to prevent cytomegalovirus infection and reactivation. (See "Risk of infections in patients with chronic lymphocytic leukemia", section on 'Duvelisib' and "Prevention of infections in patients with chronic lymphocytic leukemia", section on 'Bruton tyrosine kinase inhibitors'.)

Lymphocytosis is expected during the first few weeks of therapy and may persist for several weeks.

●Efficacy – While duvelisib can achieve partial responses in most patients, survival may be worse due to increased treatment-related deaths.

In a multicenter trial (DUO), 319 patients with relapsed or refractory CLL/SLL were randomly assigned to receive duvelisib (25 mg twice daily until progression) or a finite course of ofatumumab [91,95]. Crossover to the alternative therapy was allowed at the time of progression and more than half of patients assigned to ofatumumab received duvelisib at progression. Duvelisib resulted in a higher ORR (74 versus 45 percent) and superior median PFS (13.3 versus 9.9 months, HR 0.52). A subset analysis demonstrated a benefit in all patient populations, including those with 17p deletion and/or TP53 mutation. In the final OS analysis with a median follow-up of 63 months, OS was worse with duvelisib; however, these findings did not reach statistical significance (median OS 52 versus 63 months; HR 1.09, 95% CI 0.79-1.51) [93]. Patients receiving duvelisib had more deaths due to adverse events, serious adverse events, grade ≥3 adverse events, and treatment modifications due to adverse events.

Duvelisib has not been directly compared with other targeted agents, such as idelalisib (which inhibits PI3K delta and not gamma), ibrutinib (which inhibits BTK), or venetoclax (which inhibits BCL2). While indirect comparisons are complicated by differences in study populations and other biases, indirect data suggest duvelisib has similar toxicities to idelalisib and may result in shorter remissions and different toxicities than ibrutinib and venetoclax.

Chimeric antigen receptor T cells — The CD19-directed chimeric antigen receptor (CAR)-T cell therapy lisocabtagene maraleucel (liso-cel) is an option for fit patients with relapsed or refractory CLL/SLL after two or more lines of systemic therapy, including a BTK inhibitor and a BCL2 inhibitor (venetoclax). This population has few therapeutic alternatives, and low-quality evidence suggests that liso-cel may produce sustained remissions in a subset. However, treatment is associated with substantial toxicity, and the manufacturing process is complex and expensive. As such, the decision to proceed with CAR-T cell therapy is individualized and highly dependent on an estimation of complication risk and the needs and wishes of the patient.

CAR-T cells are genetically modified ex vivo, expanded in a production facility, and then infused back into the patient as therapy. Prior to reinfusion, patients receive a lymphodepleting chemotherapy preparative/conditioning regimen (ie, fludarabine plus cyclophosphamide). Trials have allowed for additional "bridging" therapy for disease control during the manufacturing process.

Toxicity in CLL/SLL appears to be greater than in diffuse large B cell lymphoma. CAR-T cells can have serious and potentially fatal complications, including neurologic events and cytokine release syndrome (CRS), which is a severe systemic response (eg, high fever, flu-like symptoms, hypotension, mental status changes) to the activation and proliferation of CAR-T cells. There are also reports of T cell malignancies after CAR-T cell therapy. These complications are described in more detail separately. (See "Cytokine release syndrome (CRS)" and "Immune effector cell-associated neurotoxicity syndrome (ICANS)" and "Diffuse large B cell lymphoma (DLBCL): Second or later relapse or patients who are medically unfit", section on 'Chimeric antigen receptor T cell therapy'.)

Data regarding the efficacy of CAR-T cell therapy in CLL/SLL are limited to single-arm, prospective trials with variable response rates and duration of response [96-106]; some patients with persistent CAR-T cells have experienced remissions lasting over a decade [106].

A multicenter, open-label, single-arm phase 1/2 trial (TRANSCEND CLL 004) evaluated liso-cel in patients with relapsed/refractory CLL/SLL after at least two prior lines of therapy (median five), including a BTK inhibitor [105]. Key findings included:

●Leukapheresis was performed in 137 patients, and a safety analysis included the 117 patients that received liso-cel. The median time from leukapheresis to infusion was 36 days. Although manufacturing was successful in 96 percent and bridging therapy was allowed, several patients experienced disease progression before infusion, leading to ineligibility or death, resulting in a drop-out rate of 15 percent. Safety and efficacy analyses were performed on an "as treated" population rather than "intention-to-treat".

●There were five deaths within 90 days of liso-cel infusion, one of which was attributed to liso-cel (macrophage activation syndrome).

●Most patients had CRS with 67 percent requiring tocilizumab and/or corticosteroids. Grade 3 CRS occurred in 9 percent, and there were no grade 4 or 5 CRS.

●Neurologic events occurred in 45 percent of patients, and 33 percent required tocilizumab and/or corticosteroids for a neurologic event. Grade 3 or 4 neurologic events occurred in 19 percent, and there were no grade 5 neurologic events.

●Other notable adverse events included prolonged cytopenias (54 percent), grade 3 or greater infection (17 percent), hypogammaglobulinemia (15 percent), and tumor lysis syndrome (11 percent).

●The primary efficacy analysis focused on the 49 patients refractory to both BTK inhibition and BCL2 inhibition who received a target dose of 100 x 10⁶ CAR-positive viable T-cells (target dose 2). In this population, 9 of 49 patients (18 percent) achieved a complete response (CR) or remission (including with incomplete marrow recovery), and the median duration of response was 35.5 months (not reached in those with a CR or remission). An 18 percent CR or remission rate was also reported for the broader population of 96 patients treated with liso-cel and evaluable for efficacy.

These results suggest that CAR-T cell therapy is modestly effective in this difficult to treat population with CLL/SLL refractory to both BTK inhibition and BCL2 inhibition. This served as the basis for accelerated approval of liso-cel by the US Food and Drug Administration for treatment of adults with relapsed or refractory CLL/SLL after two or more lines of systemic therapy including a BTK inhibitor and a BCL2 inhibitor [107].

Another cohort included 32 evaluable patients with relapsed or refractory CLL/SLL enrolled on a clinical trial of a different CD19-directed CAR-T cells [104]. Patients had received a median of 3.5 prior therapies; nine had received a BTK inhibitor, and one had received venetoclax. A majority (72 percent) had unmutated IGHV, and nine patients (28 percent) had mutated TP53 or 17p deletion. Key findings included:

●Grade 3 or higher CRS developed in nine patients, and grade 3 or higher neurotoxicity developed in three patients. There were no treatment-related deaths.

●The overall response rate and CR rate were 44 and 28 percent, respectively. After a median follow-up of 32 months, the median overall survival was 64 months. Median progression-free survival was longer in those attaining CR (40 versus 1 month). Outcomes did not differ by patient age, number of prior therapies, or genetic findings.

It is not known how subtle structural differences in various CAR-T constructs directed against the same antigen may impact efficacy or toxicity. While other CD19-directed CAR-T cell therapies have regulatory approval for other indications, they have not been approved for CLL/SLL.

Hematopoietic cell transplantation — Patients with CLL are generally older adults with a median age greater than 70 years, and due to the relatively benign course of the disease in the majority of patients, only selected patients are candidates for intensive treatments such as HCT. The determination of transplant eligibility should be made based on a risk-benefit assessment and the needs and wishes of the patient. (See "Determining eligibility for allogeneic hematopoietic cell transplantation".)

The ideal timing of HCT in CLL is unknown and transplants should be carried out in the context of a clinical trial whenever possible. Which patients may be candidates for HCT is changing with advances in targeted therapies and our knowledge of who might respond to these therapies. A conceptual framework for determining HCT candidacy has been proposed by the European Research Initiative on CLL and European Society for Blood and Marrow Transplantation [108]. This framework identifies patients with CLL resistant to chemoimmunotherapy and resistant to a BTK inhibitor and/or BCL2 inhibitor as having particularly high-risk disease ("high risk-II" disease) that might be suitable for HCT.

HCT may also be appropriate for young patients with relapsed or refractory CLL already exposed to a BTK inhibitor and venetoclax [109]. HCT may also be considered for patients with histologic transformation to a more aggressive histology. (See "Hematopoietic cell transplantation in chronic lymphocytic leukemia".)

There have been no randomized trials comparing allogeneic HCT versus non-HCT based strategies in CLL. Retrospective studies and small prospective trials have reported outcomes following HCT conducted in highly selected patient populations prior to the widespread use of targeted agents [110-114]. Conditioning regimen, donor source, and other details of care vary. As examples:

●A retrospective study of 68 patients with high-risk CLL who underwent reduced intensity conditioning followed by unrelated cord blood transplantation reported three year rates of relapse (16 percent), nonrelapse mortality (39 percent), PFS (45 percent), and OS (54 percent) [113].

●Another retrospective study of 117 patients with CLL who underwent haploidentical donor transplantation reported five year cumulative incidences of relapse (26 percent), nonrelapse mortality (44 percent), PFS (31 percent), and OS (38 percent) [114].

●A prospective trial of nonmyeloablative conditioning followed by allogeneic HCT in 90 patients with poor-risk CLL as defined by primary refractory disease, initial relapse within 12 months, relapse after autologous HCT, or progressive disease in the presence of unfavorable genetic features reported 10 year rates of relapse (46 percent), nonrelapse mortality (20 percent), and OS (51 percent) [115-117].

Limited data suggest that prior exposure to targeted therapy does not impact outcomes following HCT [118,119]. As an example, a multicenter, retrospective study of 65 patients with CLL and prior exposure to at least one targeted therapy reported two year rates of relapse (27 percent), nonrelapse mortality (13 percent), PFS (63 percent), and OS (81 percent) [118]. This study included patients with prior exposure to ibrutinib, venetoclax, and idelalisib, and a majority also had prior chemoimmunotherapy. In multivariate analysis, HCT comorbidity index score of one or greater was associated with inferior PFS. In contrast, PFS did not appear to be impacted by the number or types of targeted therapies used, the timing of targeted therapy, the depth of response in those with responding disease, or the presence of high-risk disease characteristics (eg, TP53 mutation, del17p).

The decision to proceed with HCT is highly dependent upon patient values and preferences. Patients with different values and preferences will make different choices.

PALLIATION OF SYMPTOMS — Most patients can be successfully treated with targeted therapies, and those with resistant disease should be encouraged to participate in clinical trials. Therapies directed at the palliation of symptoms alone should be reserved for those where other options are not available.

Anti-CD20 monoclonal antibodies and corticosteroids may offer a short-lived partial response (PR) with only moderate toxicity. Splenectomy may be useful in patients with splenomegaly and profound cytopenias unresponsive to other therapies. Radiation therapy to the spleen or other bulky lymphoid tissue is an option for patients with bulky disease compromising critical structures. Leukapheresis is seldom used in CLL.

Anti-CD20 monoclonal antibodies — When used as single agents, anti-CD20 monoclonal antibodies (rituximab, ofatumumab, obinutuzumab) are usually well tolerated and can result in short-lived PRs.

●Rituximab – Single-agent rituximab produces PRs when used as a single agent for the treatment of refractory CLL; these responses are short lived with a median response time of 20 weeks [120-122]. Rituximab may also be combined with corticosteroids for palliation. A prospective trial of rituximab plus high-dose methylprednisolone in 14 patients with fludarabine-refractory CLL, 21 percent of whom had previously received rituximab, reported an overall response rate (ORR) of 93 percent with a median time to progression of 15 months [123].

●Obinutuzumab – Small prospective studies have demonstrated the efficacy of single-agent obinutuzumab in CLL [124,125]. In a phase I/II study of obinutuzumab in 23 patients with relapsed/refractory CLL, 14 patients (61 percent) had a documented response [124]. The estimated median PFS and duration of response were 11 and 9 months, respectively. In a second study, the ORR was 42 percent among the 64 patients with relapsed/refractory CLL treated with single-agent obinutuzumab [126].

●Ofatumumab – Single-agent ofatumumab has demonstrated PR rates of approximately 50 percent in patients with relapsed or refractory CLL [127-133]. With appropriate premedication, infusion reactions are seen in approximately 44 percent of patients receiving their first infusion and decreased in number and intensity with subsequent infusions [127,128]. The most common severe (grade 3/4) toxicities include thrombocytopenia (9 percent), neutropenia (6 percent), anemia (3 percent), and infections (9 percent). Although ofatumumab has been withdrawn from the Canadian and European markets and its use in CLL has been decreasing, it is available in the United States.

The major toxicities of anti-CD20 antibodies include:

●Infusion reactions (ie, fevers, rigors, and hypotension). (See "Infusion-related reactions to therapeutic monoclonal antibodies used for cancer therapy".)

●Infections related to immunosuppression. (See "Secondary immunodeficiency induced by biologic therapies", section on 'Monoclonal antibodies to B cells'.)

●Hepatitis B virus reactivation among patients positive for hepatitis B surface antigen (HBsAg) or antibodies against hepatitis B core antigen (anti-HBc). (See "Hepatitis B virus reactivation associated with immunosuppressive therapy".)

●Rarely, JC virus infection can result in potentially fatal progressive multifocal leukoencephalopathy. (See "Progressive multifocal leukoencephalopathy (PML): Epidemiology, clinical manifestations, and diagnosis".)

Corticosteroids — Corticosteroids, such as prednisone, have been administered as single agents in CLL, usually in an initial dose of 20 to 60 mg/day by mouth, with dose reduction occurring in a graduated fashion thereafter [134]. With steroid therapy alone, one-third of patients have shrinkage of lymph nodes and reduction in splenic size. An increase in the lymphocyte count often occurs in the first one to two months of treatment, followed by a subsequent decline. A shift of lymphocytes from lymphoid organs and bone marrow into the blood is thought to be responsible for this initial increase in blood lymphocyte count.

The major indication for corticosteroids in CLL is in the management of antibody-mediated (autoimmune) anemia and thrombocytopenia, which improve in approximately two-thirds of patients. Three to six months of treatment are usually required for achievement of clinical response. (See "Overview of the complications of chronic lymphocytic leukemia", section on 'Autoimmune hemolytic anemia'.)

In addition to psychiatric, metabolic (eg, hyperglycemia), gastrointestinal, and musculoskeletal toxicities, a major side effect of chronic corticosteroid therapy in patients with CLL is increased susceptibility to infections. (See "Major adverse effects of systemic glucocorticoids".)

High-dose corticosteroids have been used in CLL as salvage therapy in patients with end-stage or treatment-resistant disease. Usual starting doses of dexamethasone are 40 mg/day orally on days 1 through 4, 9 through 12, and 17 through 20, every 28 days [135,136]. An alternative is methylprednisolone 1 g/m² daily for five days [137,138]. Clinical responses can occasionally be gratifying, although toxicity in the form of susceptibility to infection is common and troublesome, often requiring dose reduction.

Splenectomy — Most patients with CLL who develop splenomegaly and profound cytopenia will initially respond to chemoimmunotherapy. However, some patients, especially those with advanced disease, will demonstrate marked splenomegaly along with cytopenias refractory to treatment [139-142]. Splenectomy is preferred for the management of these patients since it provides long-term benefit. Splenic irradiation can achieve a temporary improvement in blood counts in patients that are not surgical candidates.

A number of reports have demonstrated the hematologic and survival benefits of splenectomy in patients with splenomegaly, often massive and with mechanical symptoms, and/or cytopenias unresponsive to chemotherapy [139-146]. Platelet count increments on the order of 50,000/microL and hemoglobin concentration increments of >2 g/dL can be achieved in up to 80 to 90 percent of patients and improvement in absolute neutrophil count in 60 percent. Improvements in hemoglobin and neutrophil counts appear to correlate with splenic weight. In addition, a case-control retrospective analysis reported a trend toward improved survival among Rai stage IV patients undergoing splenectomy [144]. Perioperative mortality (9 percent) is more common in patients with a preoperative performance status ≥2 (table 6).

Radiation therapy — The major indication for radiation therapy in CLL is the presence of large, bulky lymphoid masses causing compression symptoms, especially if the CLL has been unresponsive to other treatments [147]. CLL lymphocytes are extremely radiation sensitive [148,149]; treatment usually results in a rapid shrinkage of lymphoid masses. However, in most cases the benefits have been only temporary and/or used in a palliative setting [150].

In one study, 52 patients with stages II to IV CLL were treated with a median splenic irradiation dose of 7 gray (Gy), given in weekly treatments of 1 Gy [151]. Clinical response was noted in 82 percent, with a median remission duration of nine months (range: 3 to 24 months). Since splenic irradiation does not usually result in long-term control, splenectomy is the preferred option if the patient is in a satisfactory clinical state.

Management of complications — Patients with CLL commonly develop complications associated with their intrinsic immune dysfunction resulting in immunodeficiency and autoimmune disorders. The most common complications are infection, anemia, and thrombocytopenia. Rare but potentially life-threatening complications include leukostasis, tumor lysis syndrome, and second cancers. These are discussed in more detail separately. (See "Overview of the complications of chronic lymphocytic leukemia" and "Prevention of infections in patients with chronic lymphocytic leukemia" and "Risk of infections in patients with chronic lymphocytic leukemia".)

INVESTIGATIONAL THERAPIES — Most commonly, there is no better therapy to offer a patient than enrollment onto a well-designed, scientifically valid, peer-reviewed clinical trial. Additional information and instructions for referring a patient to an appropriate research center can be obtained from the United States National Institutes of Health.

Many agents are under active investigation. These include novel agents (eg, additional noncovalent Bruton tyrosine kinase [BTK] inhibitors, BTK degraders [152]), combinations of agents already used in CLL, and agents approved for other diseases.

We await results of these studies before incorporating medications not approved for CLL. Specifically, lenalidomide should not be used for patients with CLL outside of a clinical trial. While initial studies reported moderate activity for lenalidomide [153-156], some studies have been terminated due to toxicity concerns and excess deaths [157].

We also do not use the anti-CD52 monoclonal antibody alemtuzumab for patients with CLL. While partial responses may be seen in approximately one-third of patients, use is limited by toxicities that include infusion-related side effects, myelosuppression, and infections [158-170].

The logistical and clinical complications of autologous chimeric antigen receptor (CAR)-T cells have led to efforts to create off-the-shelf CAR products. As an example, CAR-natural killer (NK) cell therapy derived from umbilical cord blood (UCB) is an investigational allogeneic product that does not require full histocompatibility (HLA) matching. In a phase 1/2 study of UCB-derived CAR-NK cells, infusion was not associated with cytokine release syndrome, neurotoxicity, or graft-versus-host disease [171]. Three of five patients with CLL/small lymphocytic lymphoma achieved a complete response.

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 5^th to 6^th 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 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

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

●Basics topics (see "Patient education: Chronic lymphocytic leukemia (CLL) (The Basics)" and "Patient education: Tumor lysis syndrome (The Basics)")

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

SUMMARY AND RECOMMENDATIONS

●Evaluation prior to change in therapy – Most patients with chronic lymphocytic leukemia (CLL) will have a response to initial therapy. However, conventional therapy is not curative, and most patients experience relapse. In addition, many patients will require a change in therapy due to intolerance.

Drug intolerance leads to treatment discontinuation in a sizeable minority of patients on continuous therapy with a Bruton tyrosine kinase (BTK) inhibitor (eg, ibrutinib, acalabrutinib, zanubrutinib). Before switching therapy due to BTK intolerance, we consider drug holidays, dose adjustments, and symptom-directed management in an effort to maximize drug benefit. (See 'Patients with BTK inhibitor intolerance' above.)

Progressive disease may be suspected due to a rising lymphocyte count, enlargement of lymph nodes and/or spleen, and/or worsening cytopenias (table 1). Before changing therapy for progressive CLL, the diagnosis must be reconfirmed. Most cases of relapsed CLL can be confirmed by a complete blood count with differential, flow cytometry of the peripheral blood to determine the immunophenotype of circulating lymphocytes, and examination of the peripheral smear. (See 'Confirming progression' above.)

●Indications for treatment – Patients with recurrent/progressive CLL do not necessarily require immediate treatment but should be followed closely for the development of symptomatic disease (ie, "active disease") (table 2), which necessitates intervention. For patients on continuous therapy, such as a BTK inhibitor, we continue treatment as long as there appears to be a clinical benefit and adjust monitoring parameters based on disease tempo. (See 'Indications for treatment' above.)

●Choice of therapy – Our choice of subsequent therapy for patients with progressive disease or intolerance to initial treatment is individualized and takes into account prior therapy, response, and reason for discontinuation; patient and tumor characteristics; patient preference; and goals of therapy (algorithm 1 and table 3). Patients with CLL experience serial relapses and many will be treated with all available agents at some point during their disease course (table 4). A preferred order for their use has not been established. (See 'Choice of therapy' above.)

•Prior BTK inhibitor – For patients treated initially with a BTK inhibitor (ie, ibrutinib, acalabrutinib, zanubrutinib), our preferred subsequent therapy depends on the reason for discontinuation (see 'Prior BTK inhibitor' above):

For patients with CLL progressing on a BTK inhibitor and requiring treatment (ie, with "active disease"), we suggest venetoclax-based therapy rather than an alternative BTK inhibitor or a phosphoinositide 3'-kinase (PI3K) inhibitor (Grade 2C). Venetoclax is highly active and works through a different mechanism of action (BCL2 inhibition). (See 'BCL2 inhibitors: Venetoclax' above.)

After attaining a response, younger patients with a matched donor (related or unrelated) should be evaluated for allogeneic hematopoietic cell transplantation (HCT). (See 'Hematopoietic cell transplantation' above.)

For patients who discontinue a BTK inhibitor due to intolerance, options include treatment with an alternative BTK inhibitor or venetoclax-based therapy. Mutation analysis can help guide the choice; those with mutations in BTK and PLCg2 are unlikely to respond to an alternative covalent BTK inhibitor and are treated with venetoclax-based therapy; in contrast, the noncovalent BTK inhibitor pirtobrutinib has demonstrated activity in this setting and may be an option for multiply relapsed disease. For those without a mutation in BTK or PLCg2, a choice is made based on comorbidities and patient preference. (See 'Consider treatment burdens and patient comorbidities' above.)

•Prior venetoclax plus obinutuzumab – For patients treated initially with venetoclax plus obinutuzumab, our choice of subsequent therapy depends on the timing of relapse (see 'Prior venetoclax plus obinutuzumab' above):

For patients progressing within three to five years after initial treatment with venetoclax plus obinutuzumab, we suggest a BTK inhibitor rather than retreatment with venetoclax-based therapy or a PI3K inhibitor (Grade 2C). Where available, we suggest acalabrutinib or zanubrutinib rather than ibrutinib (Grade 2B). When compared with ibrutinib, 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). The improvement in tolerability is more narrow for zanubrutinib (ie, less cardiac toxicity, in particular less atrial fibrillation, but similar rates of other toxicities); however, zanubrutinib is more effective than ibrutinib with deeper responses and improved progression-free survival. (See 'Bruton tyrosine kinase inhibitors' above.)

After attaining a response, younger patients with a matched donor (related or unrelated) should be evaluated for allogeneic HCT. (See 'Hematopoietic cell transplantation' above.)

For patients with progression more than three to five years following venetoclax plus obinutuzumab, options include retreatment with venetoclax plus an anti-CD20 monoclonal antibody (rituximab or obinutuzumab) or single-agent therapy with a BTK inhibitor. Mutation analysis can help guide the choice; those with mutations in BCL2 are unlikely to achieve a durable response following venetoclax-based therapy and are treated with a BTK inhibitor. For those without BCL2 mutation, a choice is made based on comorbidities and patient preference. (See 'Consider treatment burdens and patient comorbidities' above.)

•Prior chemoimmunotherapy – Most patients with progression after initial chemoimmunotherapy should be treated with a BTK inhibitor or venetoclax-based therapy; a choice between these is made based on comorbidities and patient preference.

•Multiply relapsed disease – Patients with multiply relapsed/refractory CLL with prior exposure to both a BTK inhibitor and venetoclax may respond to systemic treatment with the noncovalent BTK inhibitor pirtobrutinib or to a PI3K inhibitor (eg, idelalisib, duvelisib). Fit patients may also be candidates for the CD19-directed chimeric antigen receptor T cell therapy lisocabtagene maraleucel. (See 'Pirtobrutinib' above and 'PI3K inhibitors' above and 'Chimeric antigen receptor T cells' above.)

●Other therapies – We reserve PI3K inhibitors for patients with relapsed/refractory CLL with prior exposure to BTK inhibitors and venetoclax. (See 'PI3K inhibitors' above.)

For those seeking palliation of symptoms, anti-CD20 monoclonal antibodies and corticosteroids may offer short-lived partial responses with only moderate toxicity. Splenectomy, obtained either surgically or via splenic irradiation, may be useful in patients with splenomegaly and profound cytopenias unresponsive to chemotherapy. Radiation therapy is an option for patients with bulky disease compromising critical structures. (See 'Palliation of symptoms' above.)

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