Chronic Lymphocytic Leukemia (CLL)

CLL is a disorder of morphologically mature but immunologically less mature lymphocytes and is manifested by progressive accumulation of these cells in the blood, bone marrow, and lymphatic tissues. In this disorder, lymphocyte counts in the blood are usually greater than or equal to 5,000/mm3 with a characteristic immunophenotype (CD5- and CD23-positive B cells).
As assays have become more sensitive for detecting monoclonal B-CLL–like cells in peripheral blood, researchers have detected a monoclonal B-cell lymphocytosis in 3% of adults older than 40 years and 6% in adults older than 60 years. Such early detection and diagnosis may falsely suggest improved survival for the group and may unnecessarily worry or result in therapy for some patients who would have remained undiagnosed in their lifetime, a circumstance known in the literature as overdiagnosis or pseudodisease. (NCi)

There are 2 general types of CLL based on whether the disease affects B cells or T cells:
• B-cell CLL. More than 95% of people with CLL have the B-cell type. And, about 1% of people with B-cell leukemia have a type called B-cell prolymphocytic leukemia (PLL).
• T-cell prolymphocytic leukemia. The T-cell type of CLL is now called T-cell prolymphocytic leukemia. About 1% of people with CLL have the T-cell type.
However, even between these 2 types of CLL, there are several subtypes that differ genetically. This means that the disease may act differently based on the genetic subtype. (ASCO)

Clinical Evaluation   Staging   Treatment  

Incidence and Mortality

Estimated new cases and deaths from CLL in the United States in 2018:
• New cases: 20,940. • Deaths: 4,510.

Prognosis and Survival

In two selected series of more than 900 patients followed prospectively for a median of 5 to 7 years, overt CLL requiring chemotherapy occurred in 7% of patients. In a database analysis and for up to 77 months before diagnosis, almost all patients with a diagnosis of CLL had prediagnostic B-cell clones that were identified in peripheral blood when available.

For patients with progressing CLL, treatment with conventional doses of chemotherapy is not curative; selected patients treated with allogeneic stem cell transplantation have achieved prolonged disease-free survival. Antileukemic therapy is frequently unnecessary in uncomplicated early disease.
The median survival for all patients ranges from 8 to 12 years in older trials with data from the 1970s through the 1990s. There is, however, a large variation in survival among individual patients, ranging from several months to a normal life expectancy. Treatment must be individualized based on the clinical behavior of the disease.

As found in one report, CLL occurs primarily in middle-aged and elderly adults, with increasing frequency in successive decades of life.
The clinical course of this disease progresses from an indolent lymphocytosis without other evident disease to one of generalized lymphatic enlargement with concomitant pancytopenia. Complications of pancytopenia, including hemorrhage and infection, represent a major cause of death in these patients.
Immunological aberrations, including Coombs-positive hemolytic anemia, immune thrombocytopenia, and depressed immunoglobulin levels may all complicate the management of CLL.
Prognostic factors that may help predict clinical outcome include cytogenetic subgroup, immunoglobulin mutational status, ZAP-70, and CD38. (Refer to the Prognostic Factors section in the Stage Information for Chronic Lymphocytic Leukemia section of this summary for more information.)
Patients who develop an aggressive high-grade non-Hodgkin lymphoma, usually diffuse large B-cell lymphoma and termed a Richter transformation, have a poor prognosis.
Patients with CLL are also at increased risk for other malignancies, even before therapy. A population-based analysis of almost 2 million cancer patients in the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) database suggests that cancer-specific survival for patients with pre-existing CLL who subsequently develop colorectal and breast cancer is significantly lower (hazard ratio [HR], 1.46; P < .001 for colorectal cancer and HR, 1.41; P = .005 for breast cancer) than cancer-specific survival for patients with colorectal and breast cancer who do not have antecedent CLL, after adjusting for age, sex, race, and disease stage, and excluding CLL-related deaths.

Risk Factors

The cause of CLL is unknown. There is no evidence that exposure to radiation, chemicals, or chemotherapy increases a person’s risk of developing CLL. However, the following factors may raise a person’s risk of developing CLL:

• Family history. Although it is uncommon, having more than 1 close relative with CLL or some other lymph-related cancer may be linked with an increased risk of CLL. People with a first-degree relative with CLL, such as a parent, sibling, or child, are 2 to 4 times more likely to develop the disease.

• Age. CLL is most common in older adults, is rare in young adults, and hardly ever develops in children. About 90% of people diagnosed with CLL are older than 50. The average age of people diagnosed with CLL is 71.

• Gender. Men develop CLL more often than women.

• Race/Ethnicity. B-cell CLL is more common in people of Russian and European descent, and hardly ever develops in people from China, Japan, or Southeast Asian countries. It also occurs commonly in black people. The reason(s) for these differences is not known.

• Agent Orange. The U.S. Department of Veterans Affairs lists CLL as a disease associated with exposure to Agent Orange, a chemical used during the Vietnam War.

• Monoclonal B-cell lymphocytosis. This is a condition in which people have higher than usual levels of lymphocytes. But, these levels are not high enough to classify as CLL. There is a slight risk that monoclonal B-cell lymphocytosis can turn into CLL.



The following tests may be used to diagnose CLL:

• Blood tests. A person may have CLL if the blood contains too many white blood cells. People with CLL may have low levels of red blood cells and platelets.

• Bone marrow aspiration and biopsy. CLL is usually diagnosed with blood tests because the cancerous cells are easily found in the blood. A bone marrow biopsy is usually not needed to diagnose CLL, but it may be done before beginning treatment. For some patients, a bone marrow aspiration and biopsy may help determine prognosis. It may also provide more information about the reasons that other blood counts are abnormal.

• CT scans can also help find out if CLL is in other organs, such as the spleen. If a person has no symptoms when diagnosed, a CT scan is generally not needed. When it is needed, it is usually done only before treatment and at the end of treatment.

• Flow cytometry and cytochemistry. These tests are used to distinguish CLL from other kinds of leukemia, which can also involve lymphocytes. Both tests can be done from a blood sample. Flow cytometry, also called immunophenotyping, is the most important test to confirm a diagnosis of CLL.

• Genomic and molecular testing. Testing the leukemia cells for specific genes, proteins, chromosome changes, and other factors unique to the leukemia. Because CLL cells divide very slowly, looking at the chromosomes often is less useful than using tests to find specific genetic mutations or changes. Fluorescence in situ hybridization (FISH) assays and other genetic tests, such as polymerase chain reaction, are used to find genetic changes.

Some of the genetic changes that occur in CLL include:
        • The deletion of the long arm of chromosome 13 [del(13q)], which is found in about half of patients.
        • An extra copy of chromosome 12 (trisomy 12)
        • del(11q)
        • del(17p)
        • NOTCH1 mutations
        • SF3B1 mutations
        • TP53 abnormalities
        • MYD88 mutations
        • IGVH, which may be important whether it is changed or unchanged

Results of genetic and molecular testing can determine how quickly the disease will progress and will help decide your treatment options. For example, people with del(17p) are more likely to have difficult-to-treat leukemia and some treatments may work better than others for these patients.


People with CLL may have anemia from low levels of red blood cells, more infections because they do not have enough white blood cells, and bruise or bleed easily because of a low level of platelets.
Most often, CLL is diagnosed when too many abnormal lymphocytes are found in the blood, also known as lymphocytosis. However, the same disease can occur when the abnormal lymphocytes are mostly in the lymph nodes but not in the blood. This is called small lymphocytic lymphoma, but it behaves very similarly to CLL. (ASCO)

Confusion with other diseases may be avoided by determination of cell surface markers. CLL lymphocytes coexpress the B-cell antigens CD19 and CD20 along with the T-cell antigen CD5. This coexpression only occurs in one other disease entity, mantle cell lymphoma. CLL B cells express relatively low levels of surface-membrane immunoglobulin (compared with normal peripheral blood B cells) and a single light chain (kappa or lambda). CLL is diagnosed by an absolute increase in lymphocytosis and/or bone marrow infiltration coupled with the characteristic features of morphology and immunophenotype, which confirm the characteristic clonal population.

The differential diagnosis must exclude hairy cell leukemia and Waldenström macroglobulinemia. (Refer to the PDQ summaries on Hairy Cell Leukemia and Adult Non-Hodgkin Lymphoma Treatment for more information.) Waldenström macroglobulinemia has a natural history and therapeutic options similar to CLL, with the exception of hyperviscosity syndrome associated with macroglobulinemia as a result of elevated immunoglobulin M. Prolymphocytic leukemia (PLL) is a rare entity characterized by excessive prolymphocytes in the blood with a typical phenotype that is positive for CD19, CD20, and surface-membrane immunoglobulin and negative for CD5. These patients demonstrate splenomegaly and poor response to low-dose or high-dose chemotherapy.

Cladribine (2-chlorodeoxyadenosine) appears to be an active agent (60% complete remission rate) for patients with de novo B-cell prolymphocytic leukemia.[Level of evidence: 3iiiDiv] Alemtuzumab (campath-1H), an anti-CD52 humanized monoclonal antibody, has been used for 76 patients with T-cell prolymphocytic leukemia after failure of prior chemotherapy (usually pentostatin or cladribine) with a 51% response rate (95% confidence interval, 40%–63%) and median time to progression of 4.5 months (range, 0.1–45.4 months).[Level of evidence: 3iiiDiv] These response rates have been confirmed by other investigators. Patients with CLL who show prolymphocytoid transformation maintain the classic CLL phenotype and have a worse prognosis than PLL patients.

Large granular lymphocyte (LGL) leukemia is characterized by lymphocytosis with a natural killer cell immunophenotype (CD2, CD16, and CD56) or a T-cell immunophenotype (CD2, CD3, and CD8). These patients often have neutropenia and a history of rheumatoid arthritis. The natural history is indolent, often marked by anemia and splenomegaly. This condition appears to fit into the clinical spectrum of Felty syndrome. A characteristic genetic finding in almost 50% of the patients with T-cell LGL involves mutations in the signal transducer and activator of the transcription 3 gene (STAT 3). Therapy includes low doses of oral cyclophosphamide or methotrexate, cyclosporine, and treatment of the bacterial infections acquired during severe neutropenia.


Stage Information for CLL

Staging is useful in chronic lymphocytic leukemia (CLL) to predict prognosis and also to stratify patients to achieve comparisons for interpreting specific treatment results. Anemia and thrombocytopenia are the major adverse prognostic variables.

CLL has no standard staging system. The Rai staging system and the Binet classification are presented below. A National Cancer Institute (NCI)-sponsored working group has formulated standardized guidelines for criteria related to eligibility, response, and toxic effects to be used in future clinical trials in CLL.

Rai Staging System

Stage 0
Stage 0 CLL is characterized by absolute lymphocytosis (>15,000/mm3) without adenopathy, hepatosplenomegaly, anemia, or thrombocytopenia.

Stage I
Stage I CLL is characterized by absolute lymphocytosis with lymphadenopathy without hepatosplenomegaly, anemia, or thrombocytopenia.

Stage II
Stage II CLL is characterized by absolute lymphocytosis with either hepatomegaly or splenomegaly with or without lymphadenopathy.

Stage III
Stage III CLL is characterized by absolute lymphocytosis and anemia (hemoglobin <11 g/dL) with or without lymphadenopathy, hepatomegaly, or splenomegaly.

Stage IV
Stage IV CLL is characterized by absolute lymphocytosis and thrombocytopenia (<100,000/mm3) with or without lymphadenopathy, hepatomegaly, splenomegaly, or anemia.

Binet Classification

Clinical stage A
Clinical stage A CLL is characterized by no anemia or thrombocytopenia and fewer than three areas of lymphoid involvement (Rai stages 0, I, and II).
*[Note: Lymphoid areas include cervical, axillary, inguinal, and spleen.]

Clinical stage B
Clinical stage B CLL is characterized by no anemia or thrombocytopenia with three or more areas of lymphoid involvement (Rai stages I and II).

Clinical stage C
Clinical stage C CLL is characterized by anemia and/or thrombocytopenia regardless of the number of areas of lymphoid enlargement (Rai stages III and IV).

The Binet classification integrates the number of nodal groups involved with the disease with bone marrow failure. Its major benefit derives from the recognition of a predominantly splenic form of the disease, which may have a better prognosis than in the Rai staging, and from recognition that the presence of anemia or thrombocytopenia has a similar prognosis and does not merit a separate stage.
Neither system separates immune from nonimmune causes of cytopenia. Patients with thrombocytopenia or anemia or both, which is caused by extensive marrow infiltration and impaired production (Rai III/IV, Binet C) have a poorer prognosis than patients with immune cytopenias.
The International Workshop on CLL has recommended integrating the Rai and Binet systems as follows: A(0), A(I), A(II); B(I), B(II); and C(III), C(IV).
The NCI-sponsored working group has published guidelines for the diagnosis and treatment of CLL in both clinical trial and general practice settings.[3] Use of these systems allows comparison of clinical results and establishment of therapeutic guidelines.

Reference [3] Hallek M, Cheson BD, Catovsky D, et al.: Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood 111 (12): 5446-56, 2008. [PMC free article: PMC2972576] [PubMed: 18216293]

Prognostic factors

New prognostic markers are now available to the clinician and investigator. The use of these markers to stratify patients in clinical trials, to help assess the need for therapy, and to help select the type of therapy continues to evolve.
Prospective trials to verify and establish the role of these prognostic markers are ongoing. No large multivariable analyses exist as yet to test the relative power of these individual prognostic variables. Prognostic indices are under evaluation and will require prospective validation. The new prognostic markers include the following:

• Immunoglobulin variable region heavy chain gene (IgVH) mutation. The finding of significant numbers of mutations in this region is associated with a median survival in excess of 20 to 25 years. The absence of mutations is associated with a median survival of 8 to 10 years.

• ZAP-70. ZAP-70 has been proposed as a surrogate for the mutational status. ZAP-70 positivity for previously untreated and asymptomatic patients (>30%) is associated with a more unfavorable median survival (6–10 years), while a negative ZAP-70 is associated with a median survival of more than 15 years.
A prospective evaluation of these markers in a randomized study of fludarabine-based chemotherapy (E2997 [NCT00003764]) failed to show any difference in response rates, response duration, progression-free survival, or overall survival (OS).

• Chromosomal abnormalities by fluorescent in situ hybridization (FISH). FISH chromosomal abnormalities were associated with prognosis in retrospective and prospective studies and clonal evolution has been seen over time.
13q- is favorable (with a 17-year median OS in a prospective study).
Trisomy 12 and 11q- have less favorable prognoses (with a 9- to 11-year median OS in a prospective study).
In particular, 17p- is associated with mutated TP53 and with poor response rates and short duration of response to the standard therapeutic options.
17p- is associated with the most unfavorable prognosis (with a 7-year median OS in one prospective trial).
The combination of adverse cytogenetics such as 11q- or 17p- (suggesting a worse prognosis) with ZAP-70 negativity (suggesting a better prognosis) in the same patients resulted in a poor prognosis. These findings emphasize the need for prospective studies of combinations of these prognostic markers.

• CD38 immunophenotype. CD38 positivity (>30%) correlates with a worse prognosis, but there is a 30% false-positive rate and a 50% false-negative rate using IgVH mutational status as the gold standard for prognosis.

Other prognostic factors include:

• Stage. (Refer to the Rai staging system section and the Binet classification section of this summary for more information.)

• Positron emission tomography-computed tomography (PET-CT) scan results. Of 432 patients retrospectively reviewed, 209 patients had a maximum standardized uptake value (SUVmax) of 5 or higher. Eighty percent of these patients had histologically aggressive CLL or Richter syndrome, and both of these entities had equally worse prognoses. If the SUVmax was 10 or higher, the 5-year OS rate was only 30%.

• Lymphocyte doubling time (doubling of the white blood cell count in excess of 1 year implies a favorable prognosis).

• Beta-2-microglobulin (higher levels imply a worse prognosis).



Treatment Option Overview for CLL

Treatment of chronic lymphocytic leukemia (CLL) ranges from periodic observation with treatment of infectious, hemorrhagic, or immunologic complications to a variety of therapeutic options, including steroids, alkylating agents, purine analogs, combination chemotherapy, monoclonal antibodies, and transplant options.
Because this disease is generally not curable, occurs in an elderly population, and often progresses slowly, it is most often treated in a conservative fashion. In asymptomatic patients, treatment may be deferred until the patient becomes symptomatic as the disease progresses. Since the rate of progression may vary from patient to patient, with long periods of stability and sometimes spontaneous regressions, frequent and careful observation is required to monitor the clinical course.

A meta-analysis of randomized trials showed no survival benefit for immediate versus delayed therapy for patients with early-stage disease, nor for the use of combination regimens incorporating an anthracycline compared with a single-agent alkylator for advanced-stage disease.[Level of evidence: 1iiA]
A variety of clinical factors, including the immunoglobulin variable region heavy chain (IgVH) gene mutation, chromosomal abnormalities by fluorescent in situ hybridization analysis or cytogenetics, beta-2-microglobulin, and lymphocyte doubling time may be helpful in predicting progression of disease.

Infectious complications in advanced disease are in part a consequence of the hypogammaglobulinemia and the inability to mount a humoral defense against bacterial or viral agents.
Herpes zoster represents a frequent viral infection in these patients, but infections with Pneumocystis carinii and Candida albicans may also occur. The early recognition of infections and the institution of appropriate therapy are critical to the long-term survival of these patients.
A randomized study of intravenous immunoglobulin (400 mg/kg every 3 weeks for 1 year) in patients with CLL and hypogammaglobulinemia produced significantly fewer bacterial infections and a significant delay in onset of first infection during the study period. There was, however, no effect on survival. Routine chronic administration of intravenous immunoglobulin is expensive, and the long-term benefit (>1 year) is unproven.

Second malignancies and treatment-induced acute leukemias may also occur in a small percentage of patients. Transformation of CLL to diffuse large cell lymphoma (Richter syndrome) carries a poor prognosis with a median survival of less than 1 year, though 20% of the patients may live more than 5 years after aggressive combination chemotherapy. (Refer to the PDQ summary on Adult Non-Hodgkin Lymphoma Treatment for more information.)

Autoimmune hemolytic anemia and/or thrombocytopenia can occur in patients with any stage of CLL. Initial therapy involves corticosteroids with or without alkylating agents (fludarabine can worsen the hemolytic anemia). It is frequently advisable to control the autoimmune destruction with corticosteroids, if possible, before administering marrow-suppressive chemotherapy because the patients may be difficult to transfuse successfully with either red blood cells or platelets.
Alternate therapies include high-dose immune globulin, rituximab, cyclosporine, azathioprine, splenectomy, and low-dose radiation therapy to the spleen. Tumor lysis syndrome is an uncommon complication (presenting in 1 out of 300 patients) of chemotherapy for patients with bulky disease.

About 1% of morphologic CLL cases express T-cell markers (CD4 and CD7) and have clonal rearrangements of their T-cell receptor genes. These patients have a higher frequency of skin lesions, more variable lymphocyte shape, and shorter median survival (13 months) with minimal responses to chemotherapy.

Computed tomographic (CT) scans have a very limited role in following patients after completion of treatment; the decision to treat for relapse was determined by CT scan or ultrasound in only 2 of 176 patients in three prospective trials for the German CLL Study Group.

Treatment Options for Stage 0 CLL

Because of the indolent nature of stage 0 chronic lymphocytic leukemia (CLL), treatment is not indicated.
The French Cooperative Group on CLL randomly assigned 1,535 patients with previously untreated stage A disease to receive either chlorambucil or no immediate treatment and found no survival advantage for immediate treatment with chlorambucil.[Level of evidence: 1iiA]
A meta-analysis of six trials of immediate versus deferred therapy with chlorambucil (including the aforementioned trial by the French Cooperative Group) showed no difference in overall survival at 10 years.[Level of evidence: 1iiA]
Whether immediate therapy with the nucleoside analogs or other newer strategies will be superior to a watchful waiting approach is uncertain.


Treatment for Stage I, II, III, and IV CLL

Clearance of Minimal Residual Disease
The improvements in response rates from more intensive regimens have maximized the clearance of minimal residual disease (MRD).
In one prospective trial of 493 patients, clearance of MRD was an independent predictor of overall survival (OS) by multivariate analysis.
The surrogate endpoint of clearance of residual disease, while prognostic, did not show improved survival in a randomized prospective trial.

The necessary study would include patients who fail to completely clear the marrow with induction therapy and randomly assign them to further alternative treatment versus the same treatment later at relapse, looking at OS as the primary endpoint.

Choice of Treatment Options

In the absence of randomized trials comparing the new B-cell receptor inhibitors and bcl-2 inhibitors to the new monoclonal antibodies and to more conventional chemotherapeutic agents, the following general principles may provide a sequencing for available therapeutic options:

• Despite many other options, asymptomatic or minimally affected patients with chronic lymphocytic leukemia (CLL) are often offered observation outside the context of a clinical trial. Therapy often begins when patients develop profound cytopenias, or when they become symptomatic enough that quality of life is substantially impacted, such as with enlarging bulky lymphadenopathy or debilitating symptoms.
• Because no curative therapy has been found, a recommendation is that initial therapy maximize efficacy (with improvement of OS), while introducing the least overall toxicity, both short term and long term.
• Standard chemotherapeutic agents, such as fludarabine, bendamustine, cyclophosphamide, and chlorambucil, induce mutational damage to the genome that can manifest as more aggressive and refractory phenotypes upon relapse and can induce second malignancies.
- Avoiding alkylators and purine analogues also prevents prolonged cytopenias and the recurrent, long-lasting, and sometimes fatal infections seen after therapy with these agents.
- Avoiding chemotherapeutic agents upfront, when possible, is a new paradigm of sequencing therapy for CLL.
• Of the new biologic agents, only ibrutinib (the Bruton tyrosine kinase inhibitor) is U.S. Food and Drug Administration (FDA)-approved on its own for first-line use in all newly diagnosed patients with CLL, who require therapy.

Treatment options:
1. Observation.
Outside of the context of a clinical trial, treatment for asymptomatic or minimally affected patients with CLL is observation. No data exist as yet to suggest any harm with a delay in therapy until the patient becomes symptomatic or develops serious cytopenias despite growth factor support. Because the rate of progression may vary from patient to patient, with long periods of stability and sometimes spontaneous regressions, frequent and careful observation is required to monitor the clinical course. One nomogram to predict time-to-first treatment relies on the number of lymph node sites, size of cervical lymph nodes, lactate-dehydrogenase level, the immunoglobulin variable region heavy chain (IgVH) mutational status, and the presence of 11q- or 17p- deletion established by fluorescence in situ hybridization (FISH) analysis.

2. Ibrutinib. Ibrutinib is a selective irreversible inhibitor of Bruton tyrosine kinase, a signaling molecule located upstream in the B-cell receptor-signaling cascade. Trials of previously untreated patients and of patients with relapsed or refractory CLL showed durable responses to the oral agent in phase I and II studies.[Level of evidence: 3iiiDiii]
A phase Ib–II trial (NCT01105247) of 85 patients with relapsed or refractory CLL showed a 26-month progression-free survival (PFS) rate of 75% and included patients with 17p- or unmutated IgVH FISH testing.[Level of evidence: 3iiiDiii] Patients who discontinued ibrutinib early because of disease progression or drug intolerance had very poor outcomes, which were mainly attributable to very poor pre-existing prognostic factors.
A prospective, randomized trial of 391 patients with relapsed or refractory CLL or small lymphocytic lymphoma compared ibrutinib with ofatumumab. With a median follow-up of 9.4 months, the 12-month OS favored ibrutinib (90% vs. 81%) (hazard ratio [HR], 0.43; P = .005).[Level of evidence: 1iiA] Similar outcomes were seen for patients whose disease was resistant to purine analogues or who had a chromosome 17p deletion.
A prospective, randomized trial of 269 previously untreated patients who were aged 65 years or older compared ibrutinib with chlorambucil. With a median follow-up of 18 months, the 2-year OS favored ibrutinib (98% vs. 85%) (HR, 0.16; 95% CI, 0.05–0.56; P = .001).[Level of evidence: 1iiA]
A prospective, randomized trial of 578 previously treated patients compared ibrutinib plus bendamustine plus rituximab with bendamustine plus rituximab. With a median follow-up of 17 months, PFS favored the ibrutinib-combination arm at 18 months (79% vs. 24%) (HR, 0.20; 95% confidence interval [CI], 0.15–0.27; P = .0001).[Level of evidence: 1iDiii]
These randomized trials establish the rationale for first-line use of ibrutinib in patients with CLL, especially for high-risk patients with 17p- disease. These trials also establish the use of ibrutinib for patients with relapsed disease.

Bruton tyrosine kinase in the B-cell receptor-signaling cascade

Bruton tyrosine kinase in the B-cell receptor-signaling cascade

3. Rituximab. Rituximab is a murine anti-CD20 monoclonal antibody. When used alone, higher doses of rituximab or increased frequency or duration of therapy is required for comparable responses to those seen for other indolent lymphomas.

4. Obinutuzumab. Obinutuzumab is a human anti-CD20 monoclonal antibody.
In a randomized prospective trial (NCT01010061), 781 previously untreated patients with coexisting medical problems were randomly assigned to chlorambucil and obinutuzumab versus chlorambucil and rituximab versus chlorambucil alone. The median PFS was best for the obinutuzumab arm (26.7 months) versus the rituximab arm (16.3 months) versus chlorambucil alone (11.1 months) (HR, 0.18; 95% CI, 0.13–0.24; P < .001) for obinutuzumab and chlorambucil versus chlorambucil alone; for rituximab and chlorambucil versus chlorambucil alone (HR, 0.44; 95% CI, 0.34–0.57; P < .001). The 2-year OS was significantly improved for the obinutuzumab arm (91%) versus chlorambucil alone (80%) (HR, 0.41; 95% CI, 0.23–0.74; P = .002). Patients who received obinutuzumab did not have improved survival compared with those who received rituximab alone.[Level of evidence: 1iiA]

5. Ofatumumab. Ofatumumab is a human anti-CD20 monoclonal antibody.
A prospective, randomized trial of 447 patients who were previously untreated compared ofatumumab plus chlorambucil with chlorambucil alone. With a median follow-up of 2 years, median PFS favored the ofatumumab arm at 22.4 months versus 13.1 months (HR, 0.57; 95% CI, 0.45–0.72; P = .0001) but with no difference in OS.[Level of evidence: 1iiDiii]
A prospective trial of 474 previously treated patients who attained partial or complete remission to second- or third-line chemotherapy were randomly assigned to 2 years of maintenance therapy with ofatumumab versus observation. With a median follow-up of 19 months, median PFS favored the ofatumumab maintenance arm at 29.4 months versus 15.2 months (HR, 0.50; 95% CI, 0.38–0.66; P < .0001) but with no difference in OS.[Level of evidence: 1iiDiii]

6. Venetoclax. Venetoclax is a highly selective inhibitor of BCL2.
In a phase I dose escalation study, 56 previously treated patients received venetoclax, resulting in a 79% response rate, including patients with adverse prognosis resistant to fludarabine or with 17p deletion.[Level of evidence: 3iiiDiv]
These data led to FDA approval for use in relapsed disease.

7. Idelalisib. Idelalisib is an oral inhibitor of the delta isoform of the phosphatidylinositol 3-kinase, which is located in the B-cell receptor-signaling cascade.
In a randomized, double-blind, prospective trial (NCT01539512), 220 patients treated mainly with fludarabine-based regimens and who had coexisting medical problems, such as renal dysfunction, received rituximab and idelalisib versus rituximab and placebo. With a median follow-up of less than 1 year, the PFS rate at 24 weeks favored the rituximab and idelalisib arm (93%) versus the rituximab and placebo arm (46%) (HR, 0.15; 95% CI, 0.08–0.28; P < .001), and the OS rate at 1 year was significantly better for the rituximab and idelalisib arm (92%) versus the rituximab and placebo arm (80%) (HR, 0.28; 95% CI, 0.09–0.86; P = .02).[Level of evidence: 1iA] In 64 previously untreated patients, the combination of idelalisib plus rituximab resulted in a PFS rate of 83% at 3 years.[Level of evidence: 3iiiDiii]

8. Oral alkylating agents with or without corticosteroids.
The French Cooperative Group on CLL randomly assigned 1,535 patients with previously untreated stage A disease to receive either chlorambucil or no immediate treatment and found no survival advantage for chlorambucil.[Level of evidence: 1iiA] A meta-analysis of six trials of immediate versus deferred therapy with chlorambucil (including the aforementioned trial by the French Cooperative Group) showed no difference in OS at 10 years.[Level of evidence: 1iiA]

9. Purine analogs.
Several randomized trials have compared the purine analogs with chlorambucil; with cyclophosphamide, doxorubicin, and prednisone; or with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) in previously untreated patients. All of these trials showed higher or equivalent response rates for the purine analog, and most showed an improvement in PFS; one reached significance in OS favoring fludarabine.[Level of evidence: 1iiDiii]

A comparison of chlorambucil versus fludarabine, after 15 years' median follow-up, showed patients with improved median OS with fludarabine at 63 versus 59 months (P = .04) and an improved percentage of patients alive at 8 years (31% vs. 19%, P = .04).[Level of evidence: 1iiA] All of the trials demonstrated higher toxic effects with the purine analogs, especially granulocytopenic infections, herpes infections, autoimmune hemolytic anemia, and persistent thrombocytopenia. The increased risk of infection may persist for months or years after treatment with a purine analog.

Although empiric evidence is lacking, some investigators recommend prophylaxis with trimethoprim-sulfa during therapy and for 6 to 12 months afterwards to prevent pneumocystis infection. In a similar way, other investigators employ prophylaxis (e.g., acyclovir) for the herpes viruses. Purine analogs cause less hair loss or nausea than combination chemotherapy, including alkylators and anthracyclines.

10. Bendamustine. Bendamustine is a cytotoxic agent with bifunctional properties of an alkylator and a purine analog. In previously treated and untreated patients, bendamustine with rituximab has shown response rates around 70% to 90%.[Level of evidence: 3iiiDiii]
In a randomized comparison with chlorambucil in 319 previously treated patients, bendamustine showed a better response rate (68% vs. 31%, P < .0001) and PFS (21.6 months vs. 8 months) with a median follow-up of 35 months.[Level of evidence: 1iiDiii] The German CLL Study Group compared bendamustine plus rituximab versus fludarabine plus cyclophosphamide plus rituximab (FCR) as first-line therapy in patients with CLL who required therapy. With a 36-month median follow-up, the median PFS was better for FCR (53.7 months vs. 43.2 months) (HR, 1.58; 95% CI, 1.25–2.07; P = .001), but there was no difference in OS at 3 years (91% vs. 92%, not significant).[Level of evidence: 1iiDiii]

11. Lenalidomide. Lenalidomide is an oral immunomodulatory agent with response rates of more than 50%, with or without rituximab, for patients with previously treated and untreated disease.[Level of evidence: 3iiiDiv] Prolonged, lower-dose approaches and attention to prevention of tumor lysis syndrome are suggested with this agent. Combination therapy and long-term toxicities from using lenalidomide (such as increased myelodysplasia, as seen in myeloma patients) remain undefined for patients with CLL.

12. Combination chemotherapy.
Combination chemotherapy was used in a trial of 817 patients that compared FCR with fludarabine plus cyclophosphamide (FC) and at a median follow-up of 5.9 years showed improved OS at 6 years for the rituximab combination (69% vs. 62%) (HR, 0.68; 95% CI, 0.54–0.89; P = .001).[Level of evidence: 1iiA] FCR has never been compared with watchful waiting up front in asymptomatic or minimally affected patients. The improvements in response rates from more intensive regimens have maximized the clearance of MRD. However, the surrogate endpoint of MRD clearance has not been proven to be a valid surrogate for improved survival in a randomized, prospective trial; the necessary study would take patients who fail to completely clear the marrow with induction therapy and randomly assign them to further alternative treatment versus the same treatment later at relapse looking at OS as the primary endpoint. A cumulative incidence of 6% to 8% for myelodysplasia is seen at 5 to 7 years in patients who received FC, with or without rituximab.

Other combination chemotherapy regimens include the following:
◦ FCR.
◦ Fludarabine plus rituximab as seen in the CLB-9712 (NCT00003248) and CLB-9011 trials.
◦ FC versus FCR.
◦ Pentostatin plus cyclophosphamide plus rituximab as seen in the MAYO-MC0183 (NCT00201721) trial, for example.
◦ Ofatumumab plus FC.
◦ CVP: cyclophosphamide plus vincristine plus prednisone.
◦ CHOP: cyclophosphamide plus doxorubicin plus vincristine plus prednisone.
◦ FC versus fludarabine as seen in the E2997 (NCT00003764) trial and the LRF-CLL4 (NCT00004218) trial, for example.
◦ Fludarabine plus chlorambucil as seen in the CLB-9011 trial, for example.
A meta-analysis of ten trials compared combination chemotherapy (before the availability of rituximab) with chlorambucil alone and showed no difference in OS at 5 years.[Level of evidence: 1iiA]

13. Involved-field radiation therapy. Relatively low doses of radiation therapy will affect an excellent response for months or years. Sometimes radiation therapy to one nodal area or the spleen will result in abscopal effect (i.e., the shrinkage of lymph node tumors in untreated sites).

14. Alemtuzumab. Alemtuzumab, the monoclonal antibody directed at CD52, shows activity in the setting of chemotherapy-resistant disease or high-risk untreated patients with 17p deletion or p53 mutation. As a single agent, the subcutaneous route of delivery for alemtuzumab is preferred to the intravenous route in patients because of the similar efficacy and decreased adverse effects, including less acute allergic reactions that were shown in some nonrandomized reports.

In a combination regimen, subcutaneous alemtuzumab plus fludarabine (with or without cyclophosphamide) or intravenous alemtuzumab plus alkylating agents have resulted in excess infectious toxicities and death, with no compensatory improvement in efficacy in three phase II trials and one randomized trial.[80-82][Level of evidence: 3iiiDiv]; [Level of evidence: 1iiDiii]

In a randomized prospective study, 335 previously treated patients received intravenous alemtuzumab plus fludarabine versus fludarabine alone. With a median follow-up of 30 months, the combination of fludarabine plus intravenous alemtuzumab had better PFS, with a median of 23.7 months versus 16.5 months (HR, 0.61; 95% CI, 0.47–0.80; P = .0003); and better OS, with a median not reached, versus 52.9 months (HR, 0.65; 95% CI, 0.45–0.94; P = .021).[Level of evidence: 1iiA] Profound and long-lasting immunosuppression has been seen, which mandates monitoring for reactivation of cytomegalovirus and prophylaxis for pneumocystis and herpes virus infections. Antibiotic prophylaxis includes trimethoprim and sulfamethoxazole, itraconazole, and acyclovir (or ganciclovir) for asymptomatic cytomegalovirus viremia.

15. Bone marrow and peripheral stem cell transplantations. Bone marrow and peripheral stem cell transplantations are under clinical evaluation.

In a prospective randomized trial, 241 previously untreated patients younger than 66 years with advanced-stage disease received induction therapy with a CHOP-based regimen followed by fludarabine. Complete responders (105 patients) were randomly assigned to undergo autologous stem cell transplantation (ASCT) or observation, while the other 136 patients were randomly assigned to receive dexamethasone, high-dose aracytin, and cisplatin reinduction followed by either ASCT or FC. Although the 3-year event-free survival (EFS) favored ASCT in complete responders, there was no difference in OS in any of the randomized comparisons.[Level of evidence: 1iiDi]

Patients with adverse prognostic factors are very likely to die from CLL. These patients are candidates for clinical trials that employ high-dose chemotherapy and immunotherapy with myeloablative or nonmyeloablative allogeneic peripheral stem cell transplantation. Although most patients who attain complete remission after ASCT eventually relapse, a survival plateau for allogeneic stem cell support suggests an additional graft-versus-leukemia effect. A series (NCT00281983) of 90 patients with relapsed or refractory CLL who underwent ASCT reported a 58% 6-year OS rate and a 38% 6-year EFS rate, which included those patients with the worst prognostic factors (such as TP53 gene mutation).[Level of evidence: 3iiiD] Patients who relapse after ASCT may respond well and durably to salvage regimens.

16. Autologous T cells directed at specific antigen targets. Autologous T cells were modified by a lentiviral vector to incorporate antigen receptor specificity for the B-cell antigen CD19 and then infused into a previously treated patient. A dramatic response lasting 6 months has prompted larger trials of this concept.[Level of evidence: 3iiiDiv] Ongoing clinical trials are testing the concept of T cells directed at specific antigen targets with engineered chimeric–antigen receptors (termed CARs).



Treatment for Recurrent or Refractory CLL

In a phase II trial of 300 patients, after previous therapy with rituximab and combination chemotherapy, duration of first remission of fewer than 3 years was a poor prognostic factor. Repeat treatment with the same regimen was often successful when applied to patients with a first remission of more than 3 years.

Clinical trials are appropriate and should be considered when possible.
In small studies, response rates of more than 40% have been reported for lenalidomide and flavopiridol.[Level of evidence: 3iiiDiv]
The addition of the BCL2 anti-sense oligonucleotide oblimersen to FC improved complete response rates in a randomized study of 241 patients with relapsed disease.[Level of evidence: 1iiDiv]
Bone marrow and peripheral stem cell transplantations are under clinical evaluation.