Chronic Lymphocytic Leukemia (CLL) Treatment & Management

Updated: Oct 22, 2019
  • Author: Muhammad A Mir, MD, FACP; Chief Editor: Emmanuel C Besa, MD  more...
  • Print
Treatment

Approach Considerations

Patients with chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) do not need drug therapy until they become symptomatic or display evidence of rapid progression of disease, as characterized by the following:

  • Weight loss of more than 10% over 6 months
  • Extreme fatigue
  • Fever related to leukemia for longer than 2 weeks
  • Night sweats for longer than 1 month
  • Progressive marrow failure (anemia or thrombocytopenia)
  • Autoimmune anemia or thrombocytopenia not responding to glucocorticoids
  • Progressive or symptomatic splenomegaly
  • Massive or symptomatic lymphadenopathy
  • Progressive lymphocytosis, as defined by an increase of > 50% in 2 months or a doubling time of less than 6 months

Patients with low-risk (Binet A) disease whose CLL is stable require only periodic follow-up. In multiple studies and a meta-analysis, early initiation of chemotherapy has failed to show benefit in CLL; indeed, it may increase mortality. [27, 28] As such, early therapy should be considered only in the setting of a clinical trial.

Attempts to consolidate major clinical, chromosomal, and serum markers into a single nomogram/model are under way. However, as of yet these approaches are far from widespread acceptance. [29]

A variety of treatment regimens are used in CLL. See Chemotherapy Regimens, below, and Chronic Lymphocytic Leukemia Treatment Protocols. These regimens may include nucleoside analogues, alkylating agents, and biologics, often in combination. 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.

Patients with CLL are prone to infections, both common and unusual. Pneumococcal and influenza vaccines are recommended. Growth factors may be used to decrease the duration of neutropenia following chemotherapy.

Next:

Chemotherapy and Biologic Regimens

Nucleoside analogues constitute a class of drugs with major activity against indolent lymphoid malignancies, including CLL. [1] Agents in this class include fludarabine, cladribine, and pentostatin. Fludarabine is the most extensively studied of these nucleoside analogues and is currently the most commonly used first-line therapy in CLL.

It should be noted that many clinical trials in CLL represent a younger population, which can tolerate aggressive chemotherapy regimens to show impressive results. 

Various combination regimens have shown improved response rates in several randomized trials but also have failed to show any survival advantage. Common combination regimens include the following:

  • Fludarabine, cyclophosphamide, and rituximab (FCR) [3, 4]
  • Pentostatin, cyclophosphamide, and rituximab (PCR)
  • Fludarabine, cyclophosphamide, and mitoxantrone (FCM)
  • Cyclophosphamide, vincristine, and prednisone (CVP)
  • Cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)

A study by Robak et al showed that cladribine or fludarabine, in combination with cyclophosphamide, are equally effective in previously untreated progressive CLL. [30] The authors concluded that cladribine or fludarabine and cyclophosphamide are safe first-line regimens for progressive CLL; however, both combinations have unsatisfactory activity in patients with 17p13 (TP53 gene) deletion.

A bendamustine/rituximab combination has had some renewed interest. In a German phase II study of 72 pretreated patients, overall response rate was 59%, and progression-free survival (PFS) was almost 15 months. [31]

The current focus in CLL is on targeted therapies in various combinations. These have already been proven superior to chemoimmunotherapy. At present, chemoimmunotherapy is reserved for young fit patients with favorable CLL features, who account for less than 10% of all CLL cases. However, given the risk of secondary malignancies (eg, myelodysplastic syndromes, acute myeloid leukemia), even those patients may prefer targeted therapy. [32]

Bendamustine

A phase III trial comparing bendamustine with chlorambucil in treatment-naive patients who were not deemed candidates for more aggressive regimens, like FCR, showed no improvement in overall survival, but complete response was higher with bendamustine than with chlorambucil (21% vs 10%) and PFS was longer (21 months vs 9 months). Bendamustine use did not compromise quality of life. [33]

Alemtuzumab

Alemtuzumab is a monoclonal antibody directed at CD52 that is approved for use in CLL as both a first-line agent and for salvage in patients with fludarabine-refractory disease. Alemtuzumab has been shown to be effective in treating CLL with 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.

Alemtuzumab appears to have a role in consolidation therapy for the elimination of minimal residual disease. [23, 24, 34, 35] 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 CFAR (FCR and alemtuzumab) for high-risk CLL as frontline [36] and salvage treatment. [37] Although the median PFS was 38 months and the median overall survival was not reached in the frontline study, the therapy may be of interest as a regimen to achieve 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 show any improvement in PFS or overall survival. Serious infections developed in 74% of patients at some point during or after treatment. [37] 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 x109 cells. Cytomegalovirus (CMV) polymerase chain reaction (PCR) 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 (2 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 (1 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. We thus continue to recommend 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 its toxicity. [38]

Monoclonal antibodies

Ofatumumab (Arzerra), an anti-CD20 monoclonal antibody, is FDA approved for CLL that is refractory to fludarabine and alemtuzumab. [39] Ofatumumab is also approved for use in combination with chlorambucil for untreated patients with CLL in whom fludarabine-based therapy is inappropriate. [40]

Approval was based on results of a multicenter, randomized, open-label study of 447 patients who were not eligible for fludarabine-based therapy. Median PFS was 22.4 months with combined ofatumumab and chlorambucil treatment vs. 13.1 months with chlorambucil monotherapy (P< 0.001). [41]  In January 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. [42]

In August 2016, ofatumumab’s indication was 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. PFS with ofatumumab plus fludarabine and cyclophosphamide (OFC) was 28.9 months compared with 18.8 months with fludarabine and cyclophosphamide (FC) alone (P=0.0032). The addition of ofatumumab was reported as well tolerated. Median overall survival was 56.4 months in the OFC arm vs. 45.8 months in the FC arm (P=0.1410). [43]  

Obinutuzumab (Gazyva) is another CD20-directed cytolytic monoclonal antibody. It was approved by the FDA in November 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). [44]  Those results effectively ended the use of chlorambucil as monotherapy. [45]

Duvelisib (Copiktra) was approved in September 2018 for relapsed or refractory CLL or SLL in patients who had received at least 2 prior therapies. Approval was based in part on the phase 3 DUO clinical trial (n=319). Patients with relapsed/refractory CLL/SLL were randomized 1:1 to receive duvelisib 25 mg twice-daily or ofatumumab 300 mg on day one, followed by 7 weekly infusions and 4 monthly infusions of 2,000 mg. Duvelisib reduced the risk of disease progression or death by 48% compared with ofatumumab, and more patients responded to duvelisib compared with ofatumumab (73.8% vs 45.3%; P < 0.0001 for both CLL and SLL). The median progression-free survival (PFS) was longer among 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). [46]

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, 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 combination of lumiliximab with FCR. [47]

Combination therapy with monoclonal antibodies

Trials have investigated the combination of monoclonal antibodies with chemotherapeutic agents. Rituximab as a single agent has produced only partial responses of short duration, but it has been used extensively in combination with chemotherapy drugs (eg, fludarabine). Patients with trisomy 12q may express higher levels of CD20, thus making tumor cells more vulnerable to biologics against CD20. [48]

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 been shown to have higher clinical remission rates than fludarabine alone in clinical trials. A prospective, single-arm study of patients treated initially with fludarabine and rituximab reported that median overall survival was 85 months. [49]  After 5 years, 71% of patients were alive and 27% remained free of disease. 

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. [50]  

 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 comon with FCR, but other side-effects, including severe infections, were not increased. [51]

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. [52]  The combination of cyclophosphamide, fludarabine, alemtuzumab, and rituximab (CFAR) is currently under study in clinical trials.

However, the combination of obinutuzumab/chlorambucil was found to be superior to rituximab/chlorambucil in a study of 781 treatment-naive CLL patients. [53]  Median PFS was 27 months in the obinutuzumab/chlorambucil group, compared with 15 months in the rituximab/chlorambucil group; the overall response rate was 78% vs 65%, respectively. At the end of treatment, minimum residual disease (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. [53]

Ibrutinib

In February 2014, the FDA approved ibrutinib for CLL in patients who had received at least one previous therapy. Accelerated approval was based on of 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 ibrutinib 420 mg/day PO until unacceptable toxicity or disease progression. The results show an overall response rate of nearly 58%. 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. [54]

In July 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. [55] 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. [55, 56]

In March 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 to 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 a risk of progression or death that was 84% lower with ibrutinib than with chlorambucil (P< 0.001). Ibrutinib significantly prolonged overall survival (estimated 98% vs 85%) with a relative risk of death that was 84% lower in the ibrutinib group than in the chlorambucil group (P=0.001). [57]

However, hypertension is proving to be an exremely 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 mmHg). New or worsened hypertension was associated with increased risk of major adverse cardiovascular events (hazard ratio 2.17). [58]  Salem et al reported that severe and occasionally fatal cardiac events may occur in patients taking ibrutinib.85

Idelalisib

In July 2014, the FDA approved the oral kinase inhibitor idelalisib for the treatment of relapsed CLL, relapsed follicular B-cell non-Hodgkin lymphoma, and relapsed small lymphocytic lymphoma. [59, 60] 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 (10.7 months) than those who received placebo plus rituximab (5.5 months). [41]

Venetoclax

Venetoclax (Venclexta) was approved by the FDA in April 2016 for patients with CLL with 17p deletion, as detected by an FDA-approved test, who have received at least one prior therapy. It is a selective inhibitor of the B-cell lymphoma 2 (Bcl-2) regulator protein, an antiapoptotic protein.

Approval was based on an open-label, multicenter clinical trial of 106 previously treated patients with CLL and 17p deletion in which venetoclax was initiated with a weekly ramp-up schedule starting at 20 mg and increasing up to 50 mg, 100 mg, 200 mg, and finally 400 mg once daily. Treatment was continued with 400 mg/day until disease progression or unacceptable toxicity.

The median time on treatment at the time of evaluation was 12.1 months (range: 0 to 21.5 months). The primary efficacy endpoint, overall response rate (ORR), was 80%. The median time to first response was 0.8 months (range: 0.1 to 8.1 months). Median duration of response (DOR) had not been reached with approximately 12 months of median follow-up. The DOR ranged from 2.9 to 19-plus months. [61]

Lenalidomide

Lenalidomide is an immunomodulatory drug (IMiD) currently approved for use in multiple myeloma and myelodysplastic syndrome with deletion of chromosome 5q. Studies have utilized this medication in treatment of patients with relapsed and refractory CLL. [62] Response rates of 47-38% with complete response rates of 9% and elimination of MRD have also been reported.

Targeted Therapy Combinations

In May 2019, the FDA approved the combination of venetoclax and obinutuzumab for use in patients with previously untreated CLL. [63] The combination needs to be taken for only 1 year; in contrast, standard regimens need to be continued longer, or even indefinitely.

A phase 2 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. [64]  However, this combination is not yet approved for clinical use, and should be limited to clinical trials. [32]

In a randomized, open-label, phase 3 trial in 389 patients with relapsed or refractory CLL, treatment with venetoclax plus rituximab resulted in a 2-year rate of progression-free survival 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 the patients with and without chromosome 17p deletion. [65] 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. [66]

Treatment in elderly patients

Although CLL is common in the elderly, few studies have included older patients, who typically cannot tolerate aggressive chemotherapy regimens.

While chlorambucil is a forgotten drug in the United States, likely primarily due to low cost, it is still used as a first-line agent in elderly, fragile populations in Europe, which make up the bulk of true CLL cases. In the CLL5 study comparing fludarabine with chlorambucil (median age 70 y), while there was significantly higher response rate with fludarabine, progression-free survival (PFS) was similar (19 vs 18 mo). Overall survival was not significantly affected either, although it was 46 months with fludarabine compared with 64 months for chlorambucil. [67]

Two studies have suggested that chlorambucil plus rituximab is safe and effective in older patients with CLL. The studies evaluated the effectiveness of different regimens in patients aged 70 years or older. They compared the effects of chlorambucil, fludarabine, fludarabine plus rituximab (FR), fludarabine with consolidation alemtuzumab, and FR with consolidation alemtuzumab. [68, 69]

Ibrutinib is approved for first-line treatment in elderly patients. Approval was based on the RESONATE-2 study (n=269), which compared ibrutinib to chlorambucil in treatment-naïve patients with CLL who were aged 65 y or older. Statistically significant improvement in PFS and objective response rate was observed with ibrutinib compared with chlorambucil. [57]

Previous
Next:

Transplantation

Allogeneic stem cell transplantation is the only known curative therapy. The optimal timing of transplantation is still being investigated [70] ; however, it is known that delay of transplantation until development of refractory disease results in worse outcomes. However, remember that most patients are elderly and too fragile to consider upfront stem-cell transplantation in first clinical remission.

The effectiveness of nonmyeloablative 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.

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 nonmyeloablative 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.

A study by Michallet et al indicated that patients who had responded to first-line or second-line therapy experienced a longer duration of time until progression, death, or subsequent treatment if they underwent autologous stem cell transplantation instead of observation. [71]

Previous
Next:

Autoimmune Manifestations

Autoimmune manifestations in CLL are myriad, as follows [72] :

  • Positive 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, the most common being bacterial pneumonias.

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. [73]

Prednisone alone, usually in a dose of 20-60 mg daily initially, with subsequent gradual dose reduction, may be useful in patients with 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 pending surgery. Thrombopoietin receptor agonists have been used with some success as in primary ITP. [74]

The previous notion that purine analogs are more prone to result in autoimmune cytopenias has been recently challenged by data from studies such as the UK CLL4 trial. [75]

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.

Occasionally, nonimmune manifestations due to antibodies may occur, such as renal toxicity from monoclonal gammopathy due to CLL. [76]

Previous
Next:

Splenectomy

Refractory splenomegaly and pancytopenia is a common problem 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 the pneumococcus, Haemophilus influenzae, and Neisseria meningitidis.

Previous