Chronic Lymphocytic Leukemia (CLL) Treatment & Management

Updated: Jan 30, 2023
  • Author: Mohammad Muhsin Chisti, MD, FACP; Chief Editor: Emmanuel C Besa, MD  more...
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Approach Considerations

Patients with chronic lymphocytic leukemia (CLL) with a low Binet or Rai stage who are asymptomatic should not be offered treatment. Patients with stable low-stage CLL require only periodic follow-up. In multiple studies and a meta-analysis, early initiation of chemotherapy in such cases has failed to show benefit; indeed, it may increase mortality. [33, 34, 35]

Guidelines from the International Workshop on Chronic Lymphocytic Leukemia (iwCLL) provide clinical and laboratory criteria for initiation of primary, second-line, and subsequent-line treatment. [25] Attempts to consolidate major clinical, chromosomal, and serum markers into a single nomogram/model to guide initiation of treatment for CLL are under way, but as of yet these approaches are far from widespread acceptance. [36]

Treatment is indicated for patients whose CLL progresses or who present with symptomatic disease. The iwCLL guidelines define symptomatic or active disease, which comprise the criteria for starting treatment, by the following [2] :

  • Weight loss of at least 10% over 6 months
  • Extreme fatigue (Eastern Cooperative Oncology Group [ECOG] performance status of 2 or more)
  • Fever of at least 38.0°C for 2 or more weeks with no evidence of infection
  • Night sweats for at least 1 month with no evidence of infection
  • Progressive marrow failure (anemia or thrombocytopenia)
  • Autoimmune anemia or thrombocytopenia not responding to glucocorticoids
  • Progressive or symptomatic splenomegaly, or massive splenomegaly (at least 6 cm below the costal margin)
  • Symptomatic or massive lymphadenopathy (at least 10 cm in longest diameter)
  • Progressive lymphocytosis, as defined by an increase of > 50% in 2 months or a doubling time of less than 6 months
  • Symptomatic extranodal involvement, including in the spine

A variety of treatment regimens are used in CLL. Although combination chemotherapy regimens including the nucleoside analogue fludarabine were once the most commonly used first-line therapies, non-chemotherapy regimens are currently preferred in the majority of cases. Recommended biologic agents for first-line therapy include the Bruton tyrosine kinase (BTK) inhibitors, a B-cell lymphoma inhibitor (venetoclax), and monoclonal antibodies. Allogeneic stem cell transplantation is the only known curative therapy. Complete response (CR) is defined by absence of lymphocytosis, lymphadenopathy, and organomegaly, without significant cytopenias.

Treatment selection takes into account the molecular and genetic characteristics of the disease and may comprise monotherapy or combination therapy. Different regimens are recommended for those with a del(17p) or tp53 mutation versus those without those mutations. [5] In addition, different regimens are often recommended for those older than 65 years, or younger than age 65 but with significant comorbidities, versus fit patients who are under 65 years of age. [5]  Fludarabine, cyclophosphamide, and rituximab (FCR) remains a recommended first-line treatment only for fit young patients with IGVH hypermutation, as long-term remissions have been reported in this setting. [6, 7, 4] See also Chronic Lymphocytic Leukemia Treatment Protocols.


Biologic Regimens and Chemotherapy

Biologic agents entered clinical practice for second-line treatment of CLL but have also become preferred agents for first-line therapy. Currently recommended non-chemotherapy regimens for CLL include monotherapy and combination therapy with agents such as Bruton tyrosine kinase (BTK) inhibitors, monoclonal antibodies, and a B-cell lymphoma inhibitor, among others. [5]

Cytostatic Agents

Monotherapy with the alkylating chemotherapy agents, including chlorambucil, had been the first-line therapy for several years. Chlorambucil offers the advantages of oral administration, low cost, and limited toxicity. However, it has an extremely low complete response (CR) rate and is therefore used only for palliative purposes in elderly or debilitated patients. [6, 7]

Bendamustine is an alkylating agent that is administered by intravenous infusion. A phase III trial comparing bendamustine with chlorambucil in treatment-naive patients who were not deemed candidates for more aggressive regimens, such as fludarabine, cyclophosphamide, and rituximab (FCR), showed no difference in overall survival, but complete response was higher with bendamustine than with chlorambucil (21% vs 10%) and progression-free survival (PFS) was longer (21 months vs 9 months). Bendamustine use did not compromise quality of life but did produce greater toxicity. [37] In a German phase II study of bendamustine combined with rituximab in 72 pretreated patients, the overall response rate (ORR) was 59% and PFS was almost 15 months. [38]

The current focus in CLL is on targeted therapies in various combinations, which are discussed below. These have already been proven superior to chemoimmunotherapy. Moreover, the risk of secondary malignancies (eg, myelodysplastic syndromes, acute myeloid leukemia) with chemoimmunotherapy further strengthens the argument for targeted therapy. [39]

Bruton tyrosine kinase inhibitors

Bruton tyrosine kinase (BTK) leads to downstream activation of B-cell survival pathways, including nuclear factor-kB (NF-kB), which helps prevent apoptosis and promotes survival of B-cells. BTK inhibitors block this pathway and therefore promote destruction of the leukemic cells. The first-generation BTK inhibitor ibrutinib and the second-generation inhibitors acalabrutinib and zanubrutinib are approved for both first-line and subsequent therapy of CLL.

Second-generation BTK inibitors have proved successful for treatment of CLL in patients with ibrutinib intolerance, but have not been effective in CLL refractory to ibrutinib. However, third-generation BTK inhibitors, currently under investigation, are showing promise in overcoming BTK inhibitor resistance. [40]


In 2014, the FDA approved the BTK inhibitor ibrutinib (Imbruvica) for CLL in patients who had received at least one previous therapy. Accelerated approval was based on a clinical study of 48 previously treated participants. On average, participants were diagnosed with CLL 6.7 years prior to the study and had received four previous therapies. All study participants received oral ibrutinib 420 mg/day until unacceptable toxicity or disease progression. The overall response rate was nearly 58% and the estimated PFS at 26 months was 75%. At the time of the study, the duration of response ranged from 5.6 to 24.2 months. An improvement in survival or disease-related symptoms has not been established. [41]

Also in 2014, the FDA approved an expanded indication for ibrutinib for the treatment of CLL patients with a deletion in chromosome 17, which is associated with poor response to standard treatments. [42] Approval of the expanded indication was based on an analysis of a subgroup of 127 CLL patients with 17p deletion from the RESONATE study, in which patients treated with ibrutinib experienced a 75% reduction in the risk of disease progression or death. [42, 43]

In 2016, the FDA further expanded the indication for ibrutinib to include treatment-naïve patients. Approval was based on the RESONATE-2 study (n=269) that compared ibrutinib with chlorambucil in treatment-naïve patients with CLL who were 65 years of age or older. During a median follow-up of 18.4 months, PFS was significantly longer with ibrutinib than with chlorambucil (median, not reached vs 18.9 mo), with risk of progression or death 84% lower with ibrutinib than with chlorambucil (P< 0.001). Ibrutinib significantly prolonged overall survival (estimated 98% vs 85%); relative risk of death was 84% lower in the ibrutinib group than in the chlorambucil group (P=0.001). [44]

The CLL12 trial, published in 2022, showed that ibrutinib prolonged survival in Binet stage A patients who had not received prior treatment for CLL. Statistically, ibrutinib did not increase overall toxicity compared with no treatment. [45] However, the clinical recommendation for first-line therapy in early-stage CLL remains to "watch and wait". [46]

Unfortunately, hypertension has proved to be an extremely common adverse event in patients taking ibrutinib. In a study of 562 consecutive patients treated with ibrutinib for B-cell malignancies, Dickerson et al found that new hypertension developed in 71.6% of patients and existing hypertension worsened in an additional 6.7% of patients over a median of 30 months. Of the new hypertension cases, 17.7% were high-grade (blood pressure > 160/100 mm Hg). New or worsened hypertension was associated with increased risk of major adverse cardiovascular events (hazard ratio 2.17). [47]

Other severe and occasionally fatal cardiac events that may occur in patients taking ibrutinib include supraventricular and ventricular arrhythmias, heart failure, and conduction disorders. [48] Development of atrial fibrillation (AF), particularly in elderly patients, typically necessitates starting anticoagulation, which also increases bleeding risk. [2]

Resistance to ibrutinib has been reported, and the mechanisms of resistance are only partially understood. It is frequently due to BTK mutations at the ibrutinib binding site that interfere with the binding of ibrutinib, or to gain-of-function mutations in PLCG2 that cause the pathway to be activated without BTK interaction. Whole-exome sequencing in patients with resistance identified a cysteine-to-serine mutation in BTK at the binding site. In some cases, both mutations occur together. Some initial studies have also suggested that BTK inhibitor therapy can lead to clonal selection and expansion. [49] [50] Patients who experienced relapse of CLL were significantly more likely to have acquired a mutation of BTK or PLGC2. [2] Analysis for potential mutations may also serve as a guide to further targeted interventions for these patients prior to relapse.

A retrospective population-based cohort study of patients with CLL treated with ibrutinib demonstrated an increased risk of death in patients concomitantly receiving a CYP3A inducer; death in those cases was most commonly due to CLL progression. Although the mechanisms are not completely understood, this phenomenon may be partly attributed to lower levels of ibrutinib in patients exposed to CYP3A inducers. [51]


In 2019, the FDA approved the BTK inhibitor acalabrutinib (Calquence) for treatment of adults with CLL and SLL. Acalabrutinib is an irreversible BTK inhibitor and is more selective than ibrutinib. Approval was based on two randomized controlled trials in patients with CLL: ELEVATE-TN and ASCEND. In ELEVATE-TN, which included 535 patients with previously untreated CLL, PFS was significantly longer with acalabrutinib as monotherapy or in combination with obinutuzumab, as compared with obinutuzumab plus chlorambucil. In ASCEND, which included 310 patients with relapsed or refractory CLL after at least one prior systemic therapy, PFS was significantly longer with acalabrutinib than with idelalisib or bendamustine plus a rituximab product. [52] In a 4-year follow-up of ELEVATE-TN, the efficacy and safety of acalabrutinib plus obinutuzumab and acalabrutinib monotherapy were maintained, with low rates of treatment discontinuation. [53]

Another study compared acalabrutinib 200 mg once daily versus 100 mg twice daily in 99 patients with treatment-naive CLL. The  ORR was found to be 97%. The twice-daily dosing group showed better trough BTK occupancy levels, suggesting that twice-daily dosing may be more favorable. [54]

However, resistance to acalabrutinib has been reported, with genetic mutations that are similar to those reported with ibrutinib. [2] Moreover, in a study comparing first-line CLL therapy with alcalabrutinib versus ibrutinib, patients receiving acalabrutinib monotherapy were 89% more likely to start a next-line treatment than patients treated with ibrutinib. This study used time to next treatment as a clinically meaningful surrogate measure for disease progression. [55]

Adverse effects of acalabrutinib include diarrhea, headaches, neutropenia, thrombocytopenia, and pneumonia. Hypertension and AF have also been reported, but less commonly than with ibrutinib, suggesting that acalabrutinib may be tried in patients with a history of intolerance to ibrutinib. Although ibrutinib and acalabrutinib have comparable efficacy and rates of PFS, acalabrutinib is typically preferred due to its more favorable adverse effect profile, particularly with regard to cardiovascular effects. [2]


Zanubrutinib is a second-generation, irreversible BTK inhibitor with higher specificity than ibrutinib. In January 2023, the FDA granted accelerated approval for zanubrutinib to treat patients with CLL or SLL. [56]

Approval was based on the phase III SEQUOIA and ALPINE trials. In SEQUOIA, 479 treatment-naïve patients received either zanubrutinib until disease progression/unacceptable toxicity or bendamustine plus rituximab for 6 cycles. Median PFS was not reached in the zanubrutinib arm and was 33.7 months in the bendamustine plus rituximab arm. In a separate, nonrandomized SEQUOIA cohort of 110 patients with a 17p deletion who received zanubrutinib, the overall response rate (ORR) was 88% and the median duration of response (DoR) was not reached over the 25-month follow-up period. [56]

In ALPINE, which compared zanubrutinib with ibrutinib in 652 patients with relapsed or refractory CLL/SLL, the ORR was 80% in the zanubrutinib arm vs 73% in the ibrutinib arm. Like the SEQUOIA cohort, the median DoR was not reached in either arm over the 14-month follow-up period. Median PFS was not reached in the zanubrutinib arm and was 35 months in the ibrutinib group. [56]

Common adverse effects of zanubrutinib include petechiae and contusions. Cardiovascular effects, including AF, are less frequent with zanubrutinib than with ibrutinib and its overall toxicity profile is more favorable. [2, 57]  


Venetoclax (Venclexta) is a BH3 mimetic that is a selective inhibitor of the B-cell lymphoma 2 (Bcl-2) regulator protein, an antiapoptotic protein. [58] It was approved by the FDA in 2016 for patients with CLL with 17p deletion, as detected by an FDA-approved test, who have received at least one prior therapy. Venetoclax is typically given weekly in a dose ramp-up regimen over 4-5 weeks until the maximum dose of 400 mg is reached. Patients take 400 mg daily indefinitely, until disease progression or adverse effects occur. [2]

In 2019, the FDA approved the combination of venetoclax and obinutuzumab for use in patients with previously untreated CLL. [59] The combination needs to be taken for only 1 year; in contrast, standard regimens need to be continued longer, or even indefinitely. [60]

In a randomized, open-label, phase III trial in 389 patients with relapsed or refractory CLL, treatment with venetoclax plus rituximab resulted in  2-year PFS of 84.9%, compared with 36.3% in patients treated with bendamustine plus rituximab (hazard ratio for progression or death, 0.17; 95% confidence interval [CI], 0.11 to 0.25; P< 0.001). The benefit of venetoclax-rituximab was maintained across all clinical and biologic subgroups, including patients with and without chromosome 17p deletion. [61] Study patients received venetoclax for up to 2 years, plus rituximab for the first 6 months; or bendamustine plus rituximab for 6 months. In a post-treatment study, on median follow-up of 36 months, PFS and overall survival remained superior with venetoclax-rituximab, demonstrating the feasibility of this fixed-duration regimen. [62]

A phase II study of the combination of ibrutinib and venetoclax in 80 previously untreated high-risk and older patients with CLL reported that after 12 cycles, 88% of patients had complete remission or complete remission with incomplete count recovery, and 61% of patients had remission with undetectable minimal residual disease (MRD). [63] In the phase III GLOW trial, ibrutinib-venetoclax demonstrated significantly higher PFS and more sustained treatment responses as first-line CLL treatment in older patients, particularly in those with comorbidities, compared with chlorambucil-obinutuzumab. [64] However, there is still insufficient evidence to recommend ibrutinib-venetoclax as a standard first-line therapy in the elderly. Adverse effects include neutropenia, diarrhea, and hypertension.

A phase II trial reports promising results with a three-drug combination of venetoclax, acalabrutinib, and obinutuzumab, with 83% of patients showing undetectable MRD at a median follow-up of 35 months. The trial involved 68 patients with previously untreated high-risk CLL. [65]

Resistance to venetoclax may occur through Richter transformation to diffuse large B-cell lymphoma or recurrence of CLL. Richter transformation has been associated with BCL2 mutations that prevent the binding of venetoclax to BCL2 domains; BTG1 mutations; upregulation of clones that express a convoluted kayotype; mutations in cyclin-dependent kinase genes; and the enhanced expression of BCL-XL and MCL1, which are anti-apoptotic. [49]


Pirtobrutinib is a highly selective and reversible BTK inhibitor that received accelerated approval for use in mantle cell lymphoma in 2023. Its use in CLL is currently under investigation in clinical trials.

In a clinical trial published in 2021, 323 patients with a history of treated B-cell malignancies, including 121 patients with CLL/SLL, were treated with pirtobrutinib across seven dose levels. The ORR was found to be 62%, and the ORR was similar even in patients with a history of BTK inhibitor resistance. [66] These results provide hope that physicians may soon have a BTK inhibitor that can be used in patients with a history of resistance or intolerance to BTK inhibitors.

The most commonly reported adverse effects were diarrhea, fatigue, and neutropenia. Of note, cardiac arrhythmias, including AF and atrial flutter, were not observed, and the vast majority of patients in the study tolerated the medication well; only 1% discontinued treatment because of a treatment-related adverse event. [66]

Monoclonal antibodies

The following monoclonal antibodies are approved for use in CLL:

  • Obinutuzumab
  • Ofatumumab
  • Alemtuzumab

Other monoclonal antibodies in development that are undergoing study in CLL include hLL1, epratuzumab, and lumiliximab. Despite promising results in a phase I/II trial of lumiliximab, a phase III trial comparing FCR with and without lumiliximab in patients with relapsed CLL was stopped early when an interim analysis failed to show sufficient efficacy of the FCR-lumiliximab combination. [67]


Obinutuzumab (Gazyva) is a CD20-directed cytolytic monoclonal antibody. It was approved by the FDA in 2013 for previously untreated CLL in combination with chlorambucil. Obinutuzumab is the first drug with a breakthrough therapy designation to receive FDA approval. This designation means that obinutuzumab has the potential to offer a substantial improvement over available therapies for patients with serious or life-threatening diseases.

Approval of obinutuzumab was based on a pivotal phase III trial in 356 patients (mean age, 73 y) with previously untreated CLL, in which median PFS was significantly better in patients who received obinutuzumab in combination with chlorambucil than in those treated with chlorambucil alone (23 vs 11.1 mo; P< 0.0001). [68] Those results effectively ended the use of chlorambucil as monotherapy. [69]

In 2019, the FDA approved the use of obinutuzumab in combination with ibrutinib for previously untreated CLL or SLL. This was the first approval for a non-chemotherapy combination regimen for treatment-naïve patients with CLL/SLL.The approval was supported by the phase III iLLUMINATE trial, in which ibrutinib plus obinutuzumab proved superior to chlorambucil plus obinutuzumab. [70] The GAUGUIN trial also demonstrated the efficacy of obinutuzumab in CLL, with a median PFS of 10.7 months. [2]


Ofatumumab (Arzerra), an anti-CD20 monoclonal antibody, was approved by the FDA in 2010 for CLL that is refractory to fludarabine and alemtuzumab. [71] It has an increased binding affinity to CD20 and greater complement-dependent cytotoxicity relative to ritixumab, making it more favorable for cells expressing low levels of CD20. [2] Ofatumumab is also approved for use in combination with chlorambucil for untreated patients with CLL in whom fludarabine-based therapy is inappropriate. [72, 73]

In 2016, ofatumumab’s indication was expanded to include extended treatment as a single agent for patients who are in complete or partial response after at least two lines of therapy for recurrent or progressive CLL. [74] Also in 2016, ofatumumab’s indication was further expanded to include use in combination with fludarabine and cyclophosphamide in relapsed CLL. Approval was based on the COMPLEMENT 2 international trial (N = 365) in patients with relapsed CLL, in which the addition of ofatumumab to fludarabine and cyclophosphamide was associated with improved PFS. [75] However, for commercial reasons, the manufacturer withdrew obatumumab from non-US markets in 2018, limiting its availability outside the United States to compassionate use programs for patients currently benefiting from the drug. [76] Ofatumumab is now primarily used for multiple sclerosis.


Alemtuzumab is a monoclonal antibody directed at CD52. Alemtuzumab has been shown to be effective in treating CLL with high-risk genetic markers, including the p53 mutations [del(17p13.1)]. This is in contrast to rituximab, which is not effective in p53 mutation–bearing CLL. Although very effective in clearing the bone marrow of disease, alemtuzumab has shown only limited activity in clearing bulky lymphadenopathy. However, alemtuzumab appears to have a role in consolidation therapy for the elimination of MRD. [29, 30, 77, 78] In one study, 38% of patients treated with alemtuzumab consolidation after induction chemotherapy had molecular disease remission. Of note, three patients in this study developed Epstein-Barr virus–positive large B-cell lymphoma; two of these lymphomas resolved spontaneously and the third responded to cidofovir and immunoglobulin.

Two phase II studies have evaluated aggressive treatment with FCR and alemtuzumab for high-risk CLL as frontline [79] and salvage treatment. [80] Although the median PFS was 38 months and the median overall survival was not reached in the frontline study, this regimen may be of interest as means of achieving complete response in the 17p deletion CLL population before allogeneic stem cell transplantation, in selected patients with excellent performance status.

In pretreated patients, when used as salvage and compared with FCR, the addition of alemtuzumab to FCR did not improve PFS or overall survival. Serious infections developed in 74% of patients at some point during or after treatment. [80] The German CLL Study Group prematurely closed a phase III trial involving alemtuzumab consolidation due to severe infections in the alemtuzumab arm; however, this has not been seen in other studies to date.

Antiviral prophylaxis and prophylactic antibiotics for Pneumocystis jiroveci are recommended for patients receiving alemtuzumab during and for 2-4 months after treatment, or until their CD4 count exceeds 250 × 109 cells. Cytomegalovirus (CMV) polymerase chain reaction (PCR) testing is also recommended to monitor for CMV reactivation. If CMV is detected, alemtuzumab should be discontinued, and appropriate treatment initiated until CMV becomes undetectable.

A 2012 Cochrane Database review including five randomized controlled trials (845 patients) failed to show improvement in survival or PFS when alemtuzumab was compared with rituximab (two trials). PFS (but not overall survival) was improved when alemtuzumab was compared with chlorambucil, at the price of increased CMV infections in the alemtuzumab arm (one trial). In two other trials reviewed, alemtuzumab was superior to no therapy for overall survival in one trial but one of the two trials had to be closed prematurely due to severe infections in the alemtuzumab group. [81] The findings support continued recommendation of alemtuzumab only for those patients with p53 mutation (p17) and those in whom a fludarabine-based regimen has failed, and not as a first-line agent due to the high rate of infections and other serious adverse events.

Of note, the license for alemtuzumab was withdrawn in 2012, but it has continued to be available internationally through compassionate programs and is being used to treat multiple sclerosis. However, its use in CLL has been progressively less prevalent, given the introduction of targeted treatment regimens.

Combination therapy with monoclonal antibodies

Rituximab as a single agent has produced only partial responses of short duration, but it has been used extensively in combination with other biologic agents (ibrutinib, venetoclax, lenalidomide) and chemotherapy drugs (eg, fludarabine). Patients with trisomy 12q may express higher levels of CD20, thus making tumor cells more vulnerable to biologics against CD20. [82]

Fludarabine has been shown to downregulate CD55 and CD59; these are proteins involved in complement resistance, and their loss enhances the action of rituximab. Fludarabine combined with rituximab has produced higher clinical remission rates than fludarabine alone in clinical trials. In a prospective, single-arm study of patients treated initially with fludarabine and rituximab, median overall survival was 85 months. After 5 years, 71% of patients were alive and 27% remained free of disease. [83]

The combination of fludarabine and cyclophosphamide with rituximab (FCR) has shown to produce better clinical response rates than those seen with either fludarabine or fludarabine and cyclophosphamide (FC) in salvage therapy for patients with previously treated CLL. A study by Robak et al in 552 patients with previously treated CLL found that after a median follow-up of 25 months, median PFS was 30.6 months with FCR versus 20.6 months with FC. In addition, patients receiving FCR demonstrated significantly better event-free survival, response rate, complete response rate, duration of response, and time to new CLL treatment or death. [84]  

A study in treatment-naive patients with CD20-positive CLL found that 3 years after randomization, PFS was 65% with FCR versus 45% with FC. Overall survival was 87% versus 83%, respectively. Grade 3 and 4 neutropenia and leukocytopenia were more common with FCR, but other adverse effects, including severe infections, were not increased. [85]

A phase III study in patients with previously treated CLL found that fludarabine plus alemtuzumab (n=168) resulted in longer PFS than did fludarabine alone (n=167; median 23.7 months versus 16.5 months, P=0·0003). Overall survival was also superior with the combination. [86] However, a study of the combination of cyclophosphamide, fludarabine, alemtuzumab, and rituximab (CFAR) as salvage therapy for heavily pretreated patients with CLL found that although CFAR produced good response rates, there was no benefit in survival outcomes and CFAR was associated with a high rate of infectious complications. [87]

The combination of obinutuzumab with chlorambucil was found to be superior to rituximab/chlorambucil in a study of 781 treatment-naive CLL patients. [88] Median PFS was 27 months in the obinutuzumab/chlorambucil group, compared with 15 months in the rituximab/chlorambucil group; the ORRs were 78% vs 65%, respectively. At the end of treatment, MRD in bone marrow was 19.5% in patients who received obinutuzumab/chlorambucil, versus 2.6% in patients who received rituximab/chlorambucil, and MRD in blood was 37.7% and 3.3%, respectively. [88]

Phosphoinositide 3-kinase inhibitors

Phosphatidylinositol 3-kinase (PI3K) is one of the tyrosine kinases that play a role in B-cell receptor (BCR) signaling. [2] The PI3K inhibitors idelalisib and duvelisib are approved for treatment of relapsed CLL, but have high rates of adverse effects (ie, infections and autoimmune complications). Thus, these agents are typically used only if the less toxic therapies are no longer effective.


In 2014, the FDA approved the oral kinase inhibitor idelalisib (Zydelig) for the treatment of relapsed CLL, relapsed follicular B-cell non-Hodgkin lymphoma, and relapsed SLL. [89, 90] Idelalisib works by promoting apoptosis in the CLL cells without affecting alternative immune pathways, including T-cells and natural killer cells. [2] The drug was approved for the relapsed CLL indication for use in combination with rituximab. Approval was based on a placebo-controlled study in 220 patients in which patients treated with idelalisib plus rituximab showed significantly longer PFS than those who received placebo plus rituximab (10.7 vs 5.5 months, respectively). [73] It has also proved effective in patients with bulky lymphadenopathy or treatment-refractory disease. The most commonly observed adverse effects include pneumonia, neutropenic fever, and diarrhea. [2]


Duvelisib (Copiktra) was approved in 2018 for relapsed or refractory CLL or SLL in patients who had received at least two prior therapies. Approval was based in part on the phase III DUO clinical trial (n=319), in which duvelisib reduced the risk of disease progression or death by 48% compared with ofatumumab, and more patients responded to duvelisib than to ofatumumab (73.8% vs 45.3%; P < 0.0001 for both CLL and SLL). The median PFS was longer in those treated with duvelisib (13.3 vs 9.9 months; P < 0.0001), including in patients with the del(17p) mutation (12.7 vs 9.0 months; P = 0.0011). Overall survival (OS) was similar between the 2 treatment cohorts (P = 0.48) [91] . The most commonly observed adverse effects include hematologic toxicities, transaminitis, diarrhea, and opportunistic infections. [2]


Umbralisib is a dual inhibitor of PI3K and casein kinase 1 (CK1) epsilon. [2] The UNITY-CLL study, which analyzed umbralisib in combination with ublituximab (the U2 regimen) demonstrated superior PFS versus standard of care chemoimmunotherapy in patients with treatment-naive and refractory CLL. [92] However, updated findings from the UNITY-CLL trial continued to show a possible increased risk of death in patients receiving umbralisib, and the FDA determined that the risks of treatment with umbralisib outweigh its benefits. Consequently, the drug’s manufacturer voluntarily withdrew umbralisib from the market for the approved uses in marginal zone lymphoma and follicular lymphoma. [93]


Lenalidomide is an immunomodulatory drug approved for use in multiple myeloma, myelodysplastic syndrome with deletion of chromosome 5q, and certain lymphomas. In phase II trials, lenalidomide demonstrated efficacy in CLL that is relapsed or refractory to previous treatments that included fludarabine, although better results were reported with first-line use of lenalidomide. [94] In 2013, however, the FDA halted a clinical trial of single-agent lenalidomide for the first-line treatment of CLL due to increased risk of death as compared with single-agent chlorambucil. Lenalidomide should not be used for treatment of CLL outside of a clinical trial. [95]

Chimeric antigen receptor (CAR) T-cell therapy

CAR T-cell therapy is a novel treatment in which the patient's T-cells are collected from a blood sample and transformed in the laboratory so that they will recognize a specific antigen (eg, CD19) on the surface of cancer cells, attack the cancer cells, and proliferate in vivo. The CAR T-cells are then grown in large quanitity and infused into the patient. [96] For more information, see Cancer Immunotherapy with Chimeric Antigen Receptor (CAR) T-Cells.

Due to weak response levels and brief remission periods, clinical developments focusing on individual CAR T-cell monotherapy have slowed down. [49] However, Gauthier et al reported encouraging success with CAR T-cell therapy combined with ibrutinib in 19 patients with ibrutinib-refractory CLL. In the trial, 61% of patients achieved marrow remission, with undetectable MRD; in that subset, the 1-year overall survival probability was 86%, and PFS probabilitiy was 59%. The treatment was well tolerated, with low severity of cytokine release syndrome. [97]

Full remission of CLL has been reported in approximately a quarter of patients treated with CAR T-cell therapy. In 2022, Melenhorst et al reported decade-long remission of CLL in two patients who had achieved complete remission with CAR T-cell therapy in 2010. The patients continued to show detectable levels of CAR T-cells, but the cell population had evolved from consisting primarily of killer T-cells to consisting primarily—in one of the patients, exclusively—of proliferative CD4-positive CAR T-cells, with continuing capability of destroying leukemia cells. [98]

Treatment in elderly patients

While chlorambucil is a neglected drug in the United States, due to very low rates of objective response and inferior results compared with newer biologic agents, in Europe it is still used as a first-line agent in elderly, fragile populations, which make up the bulk of true CLL cases. In the CLL5 study comparing fludarabine with chlorambucil (median age of 70 years), while there was a significantly higher response rate with fludarabine, PFS was similar (19 vs 18 months). Overall survival was not significantly affected either, although it was 46 months with fludarabine compared with 64 months for chlorambucil. [99]

Prospective and retrospective studies have shown that chlorambucil plus rituximab is safe and effective in older patients with CLL. [100, 101] For example, in the retrospective GIMEMA study, which used that combination as front-line treatment in 102 elderly (≥65 years) and/or unfit patients with CLL, estimated survival rates were 86.1% (95% CI 79.4–93.5%) after 48 months and 81.2% (95% CI 72.4–91.2%) after 60 months. [100]

Ibrutinib is approved for first-line treatment in elderly patients. Approval was based on the RESONATE-2 study (n=269), which compared ibrutinib with chlorambucil in treatment-naïve patients with CLL who were aged 65 years or older. Statistically significant improvement in PFS and objective response rate was observed with ibrutinib compared with chlorambucil. [44]



Allogeneic stem cell transplantation is the only known curative therapy for CLL. The optimal timing of transplantation is still being investigated [102] ; however, delay of transplantation until development of refractory disease is known to result in worse outcomes. Nevertheless, most patients are elderly and too fragile for upfront stem-cell transplantation to be considered in their first clinical remission. Thus, the targeted and biologic agents remain the first-line treatment in patients who meet criteria for treatment.

The effectiveness of non-myeloablative transplantation has shown that there is a graft-versus-leukemia effect in CLL. Autologous transplantation after high-dose conditioning has not been shown to provide a survival advantage and is not recommended outside the setting of a clinical trial. A study by Michallet et alindicated that patients who had responded to first-line or second-line therapy were more likely to experience 5-year event-free survival (EFS) if they underwent autologous stem cell transplantation instead of observation (5-year EFS rates were 42% vs 24%, respectively); however, transplantation had no effect on overall survival. [103]

Alemtuzumab is being investigated for use in hematopoietic stem cell transplantation (HSCT). This agent may play an important role in the elimination of MRD in patients undergoing autologous transplantation, while, at the same time, the lack of CD52 on hematopoietic stem cells prevents interference with stem cell collection. The addition of alemtuzumab to non-myeloablative conditioning regimens for allogeneic HSCT appears to decrease the incidence of graft versus host disease (GVHD), but it may be associated with increased rates of cytomegalovirus reactivation.


Treatment of Complications

Autoimmune manifestations in CLL are myriad, as follows [104] :

  • Positive direct antiglobulin test (DAT; Coombs test) without autoimmune hemolytic anemia (AIHA)
  • AIHA
  • Immune thrombocytopenia (ITP)
  • Pure red cell aplasia
  • Autoimmune neutropenia
  • Cold agglutinin disease
  • Paraneoplastic pemphigus
  • Neuropathies
  • Evans syndrome

Up to 25% of patients with CLL demonstrate autoimmune anemia, thrombocytopenia, or both. Simultaneously, immune incompetence is present, characterized by a progressive profound hypogammaglobulinemia, predisposing patients to a number of infections, especially bacterial pneumonias, as well as sepsis and meningitis. Common pathogens include Streptococcus pneumoniae, Staphylococcus aureus, and Haemophilus influenzae. Viral infections, such as from herpes zoster and herpes simplex, may also occur. Infections account for nearly half of all deaths in patients with CLL. 

Yearly influenza and pneumococcal vaccination every 5 years is indicated; however, live vaccines should not be given to patients with CLL. Growth factors may be used to decrease the duration of neutropenia following chemotherapy. Patients experiencing frequent bacterial infections associated with hypogammaglobulinemia are likely to benefit from monthly infusions of intravenous immunoglobulin (IVIG). Studies of prophylactic IVIG in patients with CLL have not demonstrated a survival benefit, but have shown a significant decrease in the occurrence of major infections and a significant reduction in clinically documented infections. [105]

Prednisone alone, usually in a dose of 20-60 mg daily initially, with subsequent gradual dose reduction, may be useful in patients with autoimmune hemolytic anemia (AIHA). Rituximab, alone or as part of a combination regimen, can be very effective in eliminating the B-cell clone that induces autoimmune disorders, particularly for patients with autoimmune thrombocytopenia. IVIG can be used as a short-term measure in patients who have severe thrombocytopenias or in patients anticipating surgery. Thrombopoietin receptor agonists have been used with some success, as in primary immune thrombocytopenia. [106] The previous notion that purine analogs such as fludarabine are more prone to result in autoimmune cytopenias has been challenged by data from studies such as the Leukemia Research Foundation Chronic Lymphocytic Leukaemia Trial 4 (LRF CLL4). [107]

Occasionally, nonimmune manifestations due to antibodies may occur in CLL. For example, glomerulonephritis due to monoclonal gammopathy has been reported in patients with CLL. [108, 109]

Extremely high white blood cell counts (> 300,000/µL) may produce a hyperviscosity syndrome with altered central nervous system function and/or respiratory insufficiency. Leukocytapheresis and urgent therapy with prednisone and chemotherapy may be required. Virtually all patients requiring therapy should also be given allopurinol to prevent uric acid nephropathy and should be monitored for development of tumor lysis syndrome.




Refractory splenomegaly and pancytopenia are not uncommon in patients with advanced CLL. Occasionally, these patients require splenectomy. Substantial improvements in hemoglobin and platelet counts are observed in up to 90% of patients undergoing splenectomy. All patients with CLL who are to undergo splenectomy should be immunized at least 1 week in advance against pneumococcus, Haemophilus influenzae, and Neisseria meningitidis.