Chronic Lymphocytic Leukemia (CLL) 

Updated: Oct 22, 2019
Author: Muhammad A Mir, MD, FACP; Chief Editor: Emmanuel C Besa, MD 

Overview

Practice Essentials

Chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) is a monoclonal disorder characterized by a progressive accumulation of functionally incompetent lymphocytes (see the histologic sample in the image below). CLL is the most common form of leukemia found in adults in Western countries.[1] Some patients die rapidly, within 2-3 years of diagnosis, because of complications from CLL, but most patients survive for 5-10 years.

Peripheral smear from a patient with chronic lymph Peripheral smear from a patient with chronic lymphocytic leukemia, small lymphocytic variety.

See Chronic Leukemias: 4 Cancers to Differentiate, a Critical Images slideshow, to help detect chronic leukemias and determine the specific type present.

Signs and symptoms

Patients with CLL present with a wide range of symptoms and signs. Onset is insidious, and it is not unusual for CLL to be discovered incidentally after a blood cell count is performed for another reason; 25-50% of patients will be asymptomatic at time of presentation.

Signs and symptoms include the following:

  • Enlarged lymph nodes, liver, or spleen
  • Recurring infections
  • Loss of appetite or early satiety
  • Abnormal bruising (late-stage sign)
  • Fatigue
  • Night sweats

See Presentation for more detail.

Diagnosis

Patients with CLL have a higher-than-normal white blood cell count, which is determined by complete blood count (CBC). Peripheral blood flow cytometry is the most valuable test to confirm a diagnosis of CLL. Other tests that may be helpful for diagnosis include bone marrow biopsy and ultrasonography of the liver and spleen. Immunoglobulin testing may be indicated for patients developing repeated infections.

Staging

Two staging systems are used for CLL.

The Rai-Sawitsky staging system categorizes patients into low-, intermediate-, and high-risk groups, as follows:

  • Low risk (formerly stage 0) – Lymphocytosis in the blood and marrow only (25% of presenting population)[2]

  • Intermediate risk (formerly stages I and II) – Lymphocytosis with enlarged nodes in any site or splenomegaly or hepatomegaly (50% of presentation)

  • High risk (formerly stages III and IV) – Lymphocytosis with disease-related anemia (hemoglobin < 11 g/dL) or thrombocytopenia (platelets < 100 x 109/L) (25% of all patients)

The Binet staging system categorizes patients according to the number of lymph node groups involved, as follows:

  • Stage A – Hemoglobin 10 g/dL or higher, platelets 100 × 109/L or higher, and fewer than three lymph node areas involved.

  • Stage B – Hemoglobin and platelet levels as in stage A and three or more lymph node areas involved

  • Stage C – Hemoglobin less than 10 g/dL or platelets less than 100 × 109/L, or both

See Workup for more detail.

Management

Patients with early-stage CLL are not treated with chemotherapy until they become symptomatic or display evidence of rapid progression of disease. Early initiation of chemotherapy has failed to show benefit in CLL and may even increase mortality.

When chemotherapy is initiated, the nucleoside analogue fludarabine is the most commonly used first-line therapy in CLL. Combination regimens have shown improved response rates in several clinical trials and 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)

Other agents used in treatment of CLL, most often for relapsed disease, include the following:

  • Duvelisib
  • Ibrutinib
  • Idelalisib
  • Obinutuzumab
  • Ofatumumab
  • Rituximab
  • Venetoclax

Allogeneic stem cell transplantation is the only known curative therapy for CLL.

See Treatment and Medication for more detail.

Pathophysiology

The cells of origin in most patients with CLL are clonal B cells arrested in the B-cell differentiation pathway, intermediate between pre-B cells and mature B cells. Morphologically, in the peripheral blood, these cells resemble mature lymphocytes.

CLL B-lymphocytes typically show B-cell surface antigens, as demonstrated by CD19, CD20dim, CD21, and CD23 monoclonal antibodies. In addition, they express CD5, which is more typically found on T cells. Because normal CD5+ B cells are present in the mantle zone of lymphoid follicles, B-cell CLL is most likely a malignancy of a mantle zone–based subpopulation of anergic self-reactive cells devoted to the production of polyreactive natural autoantibodies.

CLL B-lymphocytes express extremely low levels of surface membrane immunoglobulin, most often immunoglobulin M (IgM) or IgM/IgD and IgD. Additionally, they also express extremely low levels of a single immunoglobulin light chain (kappa or lambda).

An abnormal karyotype is observed in the majority of patients with CLL. The most common abnormality is deletion of 13q, which occurs in more than 50% of patients. Individuals showing 13q14 abnormalities have a relatively benign disease that usually manifests as stable or slowly progressive isolated lymphocytosis.

The presence of trisomy 12, which is observed in 15% of CLL patients, is associated with atypical morphology and progressive disease. Deletion in the short arm of chromosome 17 has been associated with rapid progression, short remission, and decreased overall survival. 17p13 deletions are associated with loss of function of the tumor suppressor gene p53. Deletions of bands 11q22-q23, observed in 19% of patients, are associated with extensive lymph node involvement, aggressive disease, and shorter survival.

More sensitive techniques have demonstrated abnormalities of chromosome 12. Forty to 50% of patients demonstrate no chromosomal abnormalities on conventional cytogenetic studies. However, 80% of patients will have abnormalities detectable by fluorescence in situ hybridization (FISH). Approximately 2-5% of patients with CLL exhibit a T-cell phenotype.

Studies have demonstrated that the proto-oncogene bcl2 is overexpressed in B-cell CLL.[5] The proto-oncogene bcl2 is a known suppressor of apoptosis (programmed cell death), resulting in a long life for the involved cells. Despite the frequent overexpression of bcl-2 protein, genetic translocations that are known to result in the overexpression of bcl2, such as t(14;18), are not found in patients with CLL.

Studies have shown that this upregulation in bcl2 is related to deletions of band 13q14. Two genes, named miRNA15a and miRNA16-1, are located at 13q14 and have been shown to encode not for proteins, but rather for a regulatory RNA called microRNA (miRNA).[6, 7] These miRNA genes belong to a family of highly conserved noncoding genes throughout the genome whose transcripts inhibit gene expression by causing degradation of mRNA or by blocking transcription of mRNA.

Deletions of miRNA15a and miRNA16-1 lead to overexpression of bcl2 through loss of downregulating miRNAs. Genetic analyses have demonstrated deletion or downregulation of these miRNA genes in 70% of CLL cases.[8]

Wang et al studied the CLL genome and discovered splicing factor 3b (SF3B1) mutations affecting pre-mRNA in 15% of sampled cells, similar to the finding of 20% of myelodysplastic syndrome cells that has been described.[9] At some stage, this may offer tempting therapeutic targets.

Investigations have also identified a number of high-risk genetic features and markers, including the following:

  • Germline immunoglobulin variable heavy chain (IgV H)
  • IgV H V3-21 gene usage
  • Increased CD38 expression
  • Increased Zap70 expression
  • Elevated serum beta-2-microglobulin levels
  • Increased serum thymidine kinase activity
  • Short lymphocyte doubling time (< 6 mo)
  • Increased serum levels of soluble CD23

These features have been associated with rapid progression, short remission, resistance to treatment, and shortened overall survival in patients with CLL.

Germline IgVH has been shown to indicate a poor prognosis. Studies have shown that these patients also have earlier progression of CLL after treatment with chemotherapy.

Zeta-associated peptide of 70 kilodaltons (Zap70) is a cytoplasmic tyrosine kinase whose expression has been associated with a poor prognosis. Cells with germline IgVH often have an increased expression of Zap70; however, studies have shown discordance rates of 10-20% between IgVH mutational status and Zap70 expression levels.

Elevated levels of Zap70 are believed to decrease the threshold for signaling through bcl2, thereby facilitating the antiapoptotic effects of bcl2.

Etiology

As in the case of most malignancies, the exact cause of CLL is uncertain. CLL is an acquired disorder, and reports of truly familial cases are exceedingly rare.[10] A meta-analysis of four genome-wide association studies that included 3100 cases of CLL found multiple risk loci. Several of those loci are in close proximity to genes involved in apoptosis, suggesting a plausible underlying biological mechanism.[11]

Epidemiology

United States statistics

The American Cancer Society estimates that 20,720 new cases of CLL will be diagnosed in the United States in 2019.[12] The true incidence in the US is unknown and is likely higher, as estimates of CLL incidence come from tumor registries, and many cases are not reported.

International statistics

Although the incidence of CLL in Western countries is similar to that of the United States, CLL is extremely rare in Asian countries (ie, China, Japan), where it is estimated to comprise only 10% of all leukemias. However, underreporting and incomplete registry may significantly underestimate the true incidence of CLL in these countries.

Race-, sex-, and age-related demographics

The incidence of CLL is higher among whites than blacks. The incidence of CLL is higher in males than in females, with a male-to-female ratio of 1.7:1.

CLL is a disease that primarily affects the elderly, with the median age of presentation being 72 years. Median age is 58 years in familial cases.[2]

Prognosis

The prognosis of patients with CLL varies widely at diagnosis. Some patients die rapidly, within 2-3 years of diagnosis, because of complications from CLL. Most patients live 5-10 years, with an initial course that is relatively benign but followed by a terminal, progressive, and resistant phase lasting 1-2 years. During the later phase, morbidity is considerable, both from the disease and from complications of therapy.[13, 14]

Prognosis depends on the disease stage at diagnosis as well as the presence or absence of high-risk markers (see Pathophysiology).

 

Presentation

History and Physical Examination

Patients with chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) present with a wide range of symptoms and signs. Onset is insidious, and it is not unusual for CLL to be discovered incidentally after a blood cell count is performed for another reason; 25-50% of patients will be asymptomatic at time of presentation.

Enlarged lymph nodes are the most common presenting symptom, seen in 87% of patients symptomatic at time of diagnosis. A predisposition to repeated infections such as pneumonia, herpes simplex labialis, and herpes zoster may be noted. Early satiety and/or abdominal discomfort may be related to an enlarged spleen.

Mucocutaneous bleeding and/or petechiae may be due to thrombocytopenia. Tiredness and fatigue may be present secondary to anemia; 10% of patients with CLL will present with an autoimmune hemolytic anemia.

Richter syndrome or Richter transformation refers to the transformation of CLL into an aggressive large B-cell lymphoma and is seen in approximately 3-10% of cases. Patients will often present with symptoms of weight loss, fevers, night sweats, muscle wasting, (ie, B symptoms) and increasing hepatosplenomegaly and lymphadenopathy. Treatment remains challenging and prognosis poor, with median survival in months.

Physical examination

In addition to localized or generalized lymphadenopathy, patients may manifest the following:

  • Splenomegaly (30-54% of cases)

  • Hepatomegaly (10-20% of cases)

  • Petechiae

  • Pallor

 

DDx

Diagnostic Considerations

Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are different manifestations of the same disease; SLL is diagnosed when the disease is mainly nodal, and CLL is diagnosed when the disease is seen in the blood and bone marrow. CLL is diagnosed when >5000 monoclonal lymphocytes/mm3 are present for longer than 3 months; the bone marrow usually has more than 30% monoclonal lymphocytes and is either normocellular or hypercellular

Monoclonal B lymphocytosis is a precursor form of CLL that is defined by the following:

  • Monoclonal B cell lymphocytosis of < 5000 monoclonal lymphocytes/mm 3
  • All lymph nodes smaller than 1.5 cm
  • No anemia
  • No thrombocytopenia.

Mantle cell lymphoma can have a clinical presentation very similar to that of CLL, but it is more aggressive. Several features aid in the distinction of mantle cell lymphoma from CLL. Mantle cell lymphoma expresses CD5 and CD19 but not CD23 antigen, which is expressed in CLL. Mantle cell lymphoma typically expresses FMC-7. Importantly, expression of CD20 is bright in mantle cell lymphoma, whereas it is dim in CLL.

Anemia secondary to bone marrow involvement with CLL, splenic sequestration of red blood cells, and autoimmune hemolytic anemia associated with a positive Coombs test are included in the differential diagnosis of a patient with anemia who has CLL. Autoimmune anemia or thrombocytopenia should be distinguished from bone marrow suppression in the staging of CLL.

Another problem to be considered is splenic lymphoma with villous lymphocytes.

Differential Diagnoses

 

Workup

Approach Considerations

In patients with chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL), the complete blood count (CBC) with differential shows absolute lymphocytosis, with more than 5000 B-lymphocytes/µL. Lymphocytosis must persist for longer than 3 months. Clonality must be confirmed by flow cytometry. The presence of a cytopenia caused by clonal bone marrow involvement establishes the diagnosis of CLL regardless of the peripheral B-lymphocyte count.

Patients with fewer than 5000 B-lymphocytes/µL with lymphadenopathy and without cytopenias more likely have small lymphocytic lymphoma (SLL), although this diagnosis should be confirmed by lymph node biopsy.

Patients with a clonal B-cell population less than 5000/µL without lymphadenopathy or organomegaly, cytopenia, or other disease-related symptoms have monoclonal B-lymphocytosis (MBL). MBL will progress to CLL at a rate of 1-2% per year.

Microscopic examination of the peripheral blood smear is indicated to confirm lymphocytosis. It usually shows the presence of smudge cells, depicted in the image below, which are artifacts from lymphocytes damaged during the slide preparation.

Peripheral smear from a patient with chronic lymph Peripheral smear from a patient with chronic lymphocytic leukemia, large lymphocytic variety. Smudge cells are also observed; smudge cells are the artifacts produced by the lymphocytes damaged during the slide preparation.

Large atypical cells, cleaved cells, and prolymphocytes are also often seen on the peripheral smear and may account for up to 55% of peripheral lymphocytes. If this percentage is exceeded, prolymphocytic leukemia (B-cell PLL) is a more likely diagnosis.

Peripheral blood flow cytometry is the most valuable test to confirm a diagnosis of chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL). It confirms the presence of circulating clonal B-lymphocytes expressing CD5, CD19, CD20(dim), CD 23, and an absence of FMC-7 staining.

Consider obtaining serum quantitative immunoglobulin levels in patients developing repeated infections, because monthly intravenous immunoglobulin administration in patients with low levels of immunoglobulin G (IgG) (< 500 mg) may be beneficial in reducing the frequency of infectious episodes.

The differential diagnosis (see DDx) of CLL includes several other entities, such as hairy cell leukemia, which is moderately positive for surface membrane immunoglobulins of multiple heavy-chain classes and is typically negative for CD5 and CD21.

Prolymphocytic leukemia has a typical phenotype that is positive for CD19, CD20, and surface membrane immunoglobulin; one half will be negative for CD5. Large granular lymphocytic leukemia has a natural killer (NK) cell phenotype (CD2, CD16, and CD56) or a T-cell immunotype (CD2, CD3, and CD8). The pattern of positivity for CD19, CD20, and the T-cell antigen CD5 is shared only by mantle cell lymphoma; these cells generally do not express CD23.

Splenic lymphoma with villous lymphocytes is strongly positive for surface immunoglobulin, and positive for FMC-7, CD22, CD79b, and DBA-44. Follicular lymphoma is also strongly positive for surface immunoglobulin, positive for FMC-7, CD22, CD10, CD79b, and weak CD23.

Bone marrow aspiration and biopsy with flow cytometry is not required in all cases of CLL. However, it may be necessary in selected cases to establish the diagnosis and to assess other complicating features such as anemia and thrombocytopenia.

Liver/spleen ultrasonographic studies may demonstrate splenomegaly in patients with CLL. CT scanning of the chest, abdomen, or pelvis is generally not required for staging purposes in CLL. However, be careful to not miss lesions such as obstructive uropathy or airway obstruction that are caused by lymph node compression on organs or internal structures.

Serum free light chain (FLC) assays remain a research tool. Monoclonal and polyclonal abnormalities have been detected in half the patients and appear to be associated with poor time to first treatment.[15]

Chromosomal Testing

Although not necessary for the diagnosis or staging of CLL, additional molecular testing now exists that may help predict prognosis or clinical course.[16, 17, 18, 19] The National Comprehensive Cancer Network regards the following tests as informative (but not essential) for determining prognosis, therapy, or both in CLL[20] :

  • Fluorescence in situ hybridization (FISH) to detect +12; del(11q); del(13q); del(17p)
  • TP53 sequencing
  • CpG-stimulated metaphase karyotype for complex karyotype
  • Molecular analysis to detect immunoglobulin heavy chain region (IgV H) mutation status
  • If IgV testing is not available, determination of CD38 and ZAP-70 expression by flow cytometry, methylation, or immunohistochemistry as surrogate markers

However, a systematic review and meta-analysis by Parikh and colleagues recommended that FISH and IGVH status be performed as standard clinical tests for all patients with newly diagnosed CLL patients in those countries with the resources to do so. These authors argue that use of these tests allows the application of powerful, recently developed prognostic indices to CLL cases.[21]

Favorable prognostic findings include the following[20] :

  • FISH - Deletion in the long arm of chromosome 13 [del(13q)] as a sole abnormality
  • TP53 - Wild-type
  • IgV H -  >2% mutation

Unfavorable prognostic findings include the following[20] :

  • FISH - Deletion in the short arm of chromosome 17 [del(17p)] or the long arm of chromosome 11 [del(11q)] 
  • TP53 - Mutated
  • IgV H -  ≤2% mutation
  • Complex karyotype -  ≥3 unrelated chromosome abnormalities in more than one cell on karyotype

In addition to a worse prognosis, patients with del(17p) tend to have resistance to therapy with alkylating agents and purine analogues, while those with del(11q) typically have bulky lymphadenopathy at presentation. The poor prognosis seen with del(17p) and del(11q) are independent of the patient's stage at presentation. Patients with these abnormalities may benefit from treatment with the monoclonal antibody alemtuzumab.[22, 23, 24]

None of the poor prognostic markers has been validated as an indication to initiate treatment in asymptomatic patients.[2]

MicroRNA analysis remains a research tool. miR-181b levels appear to decrease in blood samples of patients whose disease is progressive.[25]

Bone Marrow Aspiration and Biopsy

Bone marrow aspiration and biopsy with flow cytometry is not required in all cases of CLL, but it may be necessary in selected cases to establish the diagnosis and to assess other complicating features such as anemia and thrombocytopenia. For example, bone marrow examination may be necessary to distinguish between thrombocytopenia of peripheral destruction (in the spleen) and that due to marrow infiltration.

Consider a lymph node biopsy if lymph node(s) begin to enlarge rapidly in a patient with known CLL, to assess the possibility of transformation to a high-grade lymphoma. When such transformation is accompanied by fever, weight loss, and pain, it is termed Richter syndrome.

Staging

Two staging systems are in common use for CLL: the modified Rai staging in the United States and the Binet staging in Europe. Neither is completely satisfactory, and both have often been modified. Because of its historical precedent and wide use, the Rai-Sawitsky system is described first, followed by the Binet. See also Chronic Lymphocytic Leukemia Staging.

These CLL staging systems have been unable to provide information regarding disease progression due to its heterogeneity.

After successful treatment of immune cytopenias, CLL may be down-staged,

Rai-Sawitsky staging system

The original 5-stage Rai-Sawitsky staging system[26] was revised in 1987 to a simpler 3-stage system. The revised Rai staging system divides patients into low-, intermediate-, and high-risk groups, as follows:

  • Low risk (formerly stage 0) – Lymphocytosis in the blood and marrow only (25% of presenting population)[2]

  • Intermediate risk (formerly stages I and II) – Lymphocytosis with enlarged nodes in any site or splenomegaly or hepatomegaly (50% of presentation)

  • High risk (formerly stages III and IV) – Lymphocytosis with disease-related anemia (hemoglobin < 11 g/dL) or thrombocytopenia (platelets < 100 x 109/L) (25% of all patients)

Binet staging system

The Binet stages are as follows:

  • Stage A – Hemoglobin greater than or equal to 10 g/dL, platelets greater than or equal to 100 × 109/L, and fewer than 3 lymph node areas involved.

  • Stage B – Hemoglobin and platelet levels as in stage A and 3 or more lymph node areas involved

  • Stage C – Hemoglobin less than 10 g/dL or platelets less than 100 × 109/L, or both

 

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.

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]

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]

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]

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.

 

Guidelines

Guidelines Summary

Guidelines Contributor: Karen Seiter, MD Professor, Department of Internal Medicine, Division of Oncology/Hematology, New York Medical College

Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia (CLL) have been issued by the following organizations:

  • National Comprehensive Cancer Network (NCCN)[20]

  • International Workshop on Chronic Lymphocytic Leukemia (IWCLL)[16]

  • European Society of Medical Oncology (ESMO)[77]

Diagnosis and Staging

All three guidelines are in agreement that the diagnosis of CLL requires the presence of ≥5 × 109/L B lymphocytes in the peripheral blood and the clonality of the circulating B lymphocytes should be confirmed by flow cytometry. The IWCLL guidelines also require persistence of lymphocytosis for longer than 3 months, while NCCN and ESMO do not.[20, 16, 77]

For adequate immunophenotyping to establish diagnosis by flow cytometry, the NCCN recommends using the cell surface markers kappa/lambda, CD19, CD20, CD5, CD23, and CD10. If flow is used to establish the diagnosis, cytospin for cyclin D1, or fluorescence in situ hybridization (FISH) for t(11;14); t(11q;v) should also be included.[20]

The NCCN recommends proceeding with lymph node biopsy if diagnosis is not established by flow cytometry. Diagnosis on lymph node biopsy requires immunophenotyping of CD3, CD5, CD10, CD20, CD23, and cyclin D1.[20]

ESMO guidelines note that leukaemia cells are characteristically small, mature-appearing lymphocytes with a narrow border of cytoplasm and a dense nucleus lacking discernible nucleoli, and having partially aggregated chromatin. Larger, atypical lymphocytes or prolymphocytes cannot exceed 55%.[77]

The IWCLL guidelines also allow for the diagnosis of CLL in the presence of a cytopenia caused by clonal bone marrow involvement regardless of the peripheral B-lymphocyte count.[16]

Additional tests recommended prior to initiation of treatment include:

  • FISH to detect cytogenetic abnormalities, in particular a deletion of chromosome 17 [del(17p)], 13[del(13q)] and 11 [del(11q)] and trisomy of chromosome12[20, 16, 77]

  • Molecular analysis to detect IGHV mutation status[16, 20]

  • Determination of CD38 and ZAP-70 expression by flow cytometry or immunohistochemistry[20]

  • TP53 sequencing [20]

  • Prior to chemoimmunotherapy, alemtuzumab or allogeneic stem cell transplantation, testing for hepatitis B and C viruses, cytomegalovirus (CMV), and human immunodeficiency virus(HIV)[16, 77]

  • Unilateral bone marrow aspirate and biopsy[16, 77] ; however, most oncologists in the United States do not consider bone marrow analysis to be required

The NCCN considers the following essential in the workup of patients diagnosed with CLL[20] :

  • Physical exam with attention to node-bearing areas, including Waldeyer ring, and measurement of size of liver and spleen

  • Performance status determination

  • B symptoms assessment

  • Complete blood count and comprehensive metabolic panel

For staging, all three guidelines recommend use of either the Rai system or the Binet system.[20, 16, 77]

Treatment

The guidelines are in agreement that patients with early-stage CLL should not be treated with chemotherapy until they become symptomatic or display evidence of rapid progression of disease.[20, 16, 77]

Patients at low risk and intermediate risk (ie, Rai stages 0-II) who have no indications for treatment should be observed. Blood cell counts and clinical examinations should be performed every 3–12 months. Indications for treatment include the following:

  • Significant disease-related symptoms (eg, fatigue, night sweats, weight loss, fever without infection)

  • Threatened end-organ function

  • Progressive bulky disease

  • Progressive anemia

  • Progressive thrombocytopenia

Therapy recommendations for patients at high risk (ie, Rai stages III-IV) and progressive cytopenia are based on the following:

  • Patient age
  • Patient comorbidities
  • Presence or absence of del(17p)
  • Presence or absence of TP53 mutations

For first-line treatment of CLL without del(17p) or TP53 mutations, NCCN category 1 recommendations (based on high-level evidence, with uniform NCCN consensus that the intervention is appropriate) are as follows[20] :

  • Patients < 65 years, without significant comorbidities: FCR (fludarabine, cyclophosphamide, rituximab)

  • Patients ≥65 years, and younger patients with significant comorbidities: Chlorambucil plus obinutuzumab or ibrutinib

For treatment of CLL with del(17p) or TP53 mutations, the NCCN recommends the following[20] :

  • First-line therapy: Ibrutinib (preferred)

  • Post–first-line maintenance therapy: Consider lenalidomide for high-risk patients

  • Relapsed/refractory disease therapy: Ibrutinib (category 1), venetoclax plus rituximab (category 1); other preferred regimens are idelalisib plus rituximab and monotherapy with venetoclax

  • Post–second-line therapy (ie, for patients with complete or partial response to relapsed/refractory therapy): Lenalidomide, ofatumumab

The ESMO guidelines note that patients with del(17p) have a poor response to fludarabine and short survival and instead recommend initial treatment with alemtuzumab or allogeneic stem cell transplantation. ESMO guidelines also recommend allogeneic stem cell transplantation in patients with very-high-risk p53 mutation and/or refractory disease.[77]

 

Medication

Medication Summary

Chlorambucil (an alkylating agent) and fludarabine (a purine nucleoside analogue that acts as an antimetabolite) are commonly used in the treatment of chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL). Purine analogues, fludarabine in particular, are very active against CLL. Ibrutinib is indicated for CLL including patients who are treatment-naïve or have been previously treated. It is also indicated for patients who carry a deletion in chromosome 17 [del(17p) CLL), which is associated with poor responses to standard treatment.

Fludarabine produces remissions in a significant proportion of patients. It appears to induce apoptosis in malignant lymphocytes upon exposure.

Biologic agents are increasingly used in the treatment of CLL, typically in combination with chemotherapeutic agents. These biologic agents include several monoclonal antibodies (eg, rituximab), the P13K inhibitor duvelisib, and the Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib.

Antineoplastic Agents

Class Summary

Antineoplastic agents act by inhibiting the key factors responsible for neoplastic transformation of cells.

Pentostatin (Nipent)

Pentostatin inhibits adenosine deaminase, resulting in deoxyadenosine and deoxyadenosine 5+-triphosphate accumulation that may inhibit DNA or RNA synthesis, causing cell death.

Chlorambucil (Leukeran)

Chlorambucil is a nitrogen mustard derivative with bifunctional alkylating activity. It forms intrastrand crosslinks, interfering with DNA replication and RNA transcription and translation.

Fludarabine (Fludara)

A nucleotide analogue of vidarabine, fludarabine is converted to 2-fluoro-ara-A, which enters the cell and is phosphorylated to form active metabolite 2-fluoro-ara-ATP, which inhibits DNA synthesis. Inhibits DNA polymerase and ribonucleotide reductase as well as DNA primase and DNA ligase I.

Alemtuzumab

Alemtuzumab is a humanized monoclonal antibody against CD52, an antigen found on B-cells, T-cells, and almost all CLL cells. It binds to the CD52 receptor of the lymphocytes, which slows the proliferation of leukocytes. Indicated as a single agent for treatment of B-cell chronic lymphocytic leukemia (B-CLL).

Rituximab (Rituxan, Truxima)

Rituximab is a humanized murine monoclonal antibody against CD20, an antigen found on B-cells. This agent binds CD20 on lymphocytes and induces apoptosis as well as initiating complement-mediated killing of bound cells. Because CLL B-cells have low levels of CD20 expression, increased doses of rituximab may be necessary. It is available as an IV formulation.

Rituximab-hyaluronidase (Rituxan Hycela)

The SC product is combined with hyaluronidase human, which increases subcutaneous tissue permeability. It is indicated, in combination with fludarabine and cyclophosphamide (FC), for treatment of adults with previously untreated and previously treated CLL.

Ofatumumab (Arzerra)

Ofatumumab is an anti-CD20 human monoclonal antibody that inhibits B-cell activation in early stages. It is indicated for CLL refractory to fludarabine and alemtuzumab, for previously untreated CLL in combination with chlorambucil, as extended treatment (as a single agent) for patients who are in complete or partial response after at least 2 lines of therapy for recurrent or progressive CLL, and for refractory CLL in combination with fludarabine and cyclophosphamide.

Obinutuzumab (Gazyva)

Obinutuzumab is a CD20-directed cytolytic antibody, which, upon binding to CD20, mediates B-cell lysis. Mediation may be through engagement of immune effector cells, by directly activating intracellular death-signaling pathways, and/or by activation of the complement cascade. The CD20 antigen is expressed on the surface of pre–B cells and mature B lymphocytes. The immune effector cell mechanisms include antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis. It is indicated for previously untreated CLL in combination with chlorambucil.

Ibrutinib (Imbruvica)

Ibrutinib is a Bruton's tyrosine kinase (BTK) inhibitor that forms a covalent bond with a cysteine residue in the BTK active site, leading to inhibition of BTK enzymatic activity. BTK is a signaling molecule of the B-cell antigen receptor (BCR) and cytokine receptor pathways. It is indicated for CLL including patients who are treatment-naïve or have been previously treated. It is also indicated for patients who carry a deletion in chromosome 17 (del 17p CLL), which is associated with poor responses to standard treatment.

Idelalisib (Zydelig)

Idelalisib is a phosphoinositide 3-kinase (PI3K) delta inhibitor. Idelalisib induces apoptosis and inhibits proliferation in cell lines derived from malignant B cells and in primary tumor cells; also inhibits several cell- signaling pathways, including B cell receptor (BCR) signaling and the CXCR4 and CXCR5 signaling, which are involved in trafficking and homing of B cells to the lymph nodes and bone marrow. It is indicated relapsed chronic lymphocytic leukemia (CLL).

Venetoclax (Venclexta)

Venetoclax is a selective inhibitor of the B-cell lymphoma 2 (Bcl-2) regulator protein, an antiapoptotic protein. Overexpression of Bcl-2 has been demonstrated in CLL cells where it mediates tumor cell survival and has been associated with resistance to chemotherapeutic agents. It is indicated for patients with CLL as monotherapy or in combination with obinutuzumab or rituximab.

Duvelisib (Copiktra)

Selective oral small molecule inhibitor of PI3K-delta and PI3K-gamma. Inhibiting PI3K induces growth inhibition and reduces viability in cell lines derived from malignant B cells and in primary CLL tumor cells. It is indicated for adults with relapsed/refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) after at least 2 prior therapies.

 

Questions & Answers

Overview

What is chronic lymphocytic leukemia (CLL)?

What are the signs and symptoms of chronic lymphocytic leukemia (CLL)?

How can chronic lymphocytic leukemia (CLL) diagnosed?

What are the staging systems for chronic lymphocytic leukemia (CLL)?

How is chronic lymphocytic leukemia (CLL) managed?

What is the role of clonal B cells in the pathophysiology of chronic lymphocytic leukemia (CLL)?

What is the role of genetics in the pathogenesis of chronic lymphocytic leukemia (CLL)?

What is the role of proto-oncogene bcl2 in the pathophysiology of chronic lymphocytic leukemia (CLL)?

What is the role of miRNA15a and miRNA16-1 in the pathophysiology of chronic lymphocytic leukemia (CLL)?

What are high-risk genetic markers in chronic lymphocytic leukemia (CLL)?

What are poor prognostic indicators for chronic lymphocytic leukemia (CLL)?

What causes chronic lymphocytic leukemia (CLL)?

What is the incidence of chronic lymphocytic leukemia (CLL) in the US?

What is the global incidence of chronic lymphocytic leukemia (CLL)?

Which patient groups are at higher risk for chronic lymphocytic leukemia (CLL)?

What is the prognosis of chronic lymphocytic leukemia (CLL)?

Presentation

Which history is characteristic of chronic lymphocytic leukemia (CLL)?

Which physical findings are characteristic of chronic lymphocytic leukemia (CLL)?

DDX

How is chronic lymphocytic leukemia (CLL) diagnosed?

How is mantel cell lymphoma differentiated from chronic lymphocytic leukemia (CLL)?

What are the differential diagnoses for Chronic Lymphocytic Leukemia (CLL)?

Workup

What is the role of a complete blood count (CBC) with differentials in the diagnosis of chronic lymphocytic leukemia (CLL)?

What is the role of peripheral blood smear in the diagnosis of chronic lymphocytic leukemia (CLL)?

What is the role of serum quantitative immunoglobulin measurement in the evaluation of chronic lymphocytic leukemia (CLL)?

How are prolymphocytic leukemia and splenic lymphoma differentiated from chronic lymphocytic leukemia (CLL)?

What is the role of bone marrow aspiration and biopsy in the evaluation of chronic lymphocytic leukemia (CLL)?

What is the role of imaging in the evaluation of chronic lymphocytic leukemia (CLL)?

Which tests does the NCCN consider informative in the evaluation of chronic lymphocytic leukemia (CLL)?

What are potential prognostic markers for chronic lymphocytic leukemia (CLL)?

How is bone marrow aspiration and biopsy used in the evaluation of chronic lymphocytic leukemia (CLL)?

What are the staging systems for chronic lymphocytic leukemia (CLL)?

What is the Rai-Sawitsky staging system for chronic lymphocytic leukemia (CLL)?

What is the Binet staging system for chronic lymphocytic leukemia (CLL)?

Treatment

When is chemotherapy indicated in the treatment of chronic lymphocytic leukemia (CLL)?

What is included in the treatment of chronic lymphocytic leukemia (CLL)?

Which chemotherapy and biologic regimens are used in the treatment of chronic lymphocytic leukemia (CLL)?

What is the role of bendamustine in the treatment of chronic lymphocytic leukemia (CLL)?

What is the role of alemtuzumab in the treatment of chronic lymphocytic leukemia (CLL)?

What is the role of ofatumumab (Arzerra) in the treatment of chronic lymphocytic leukemia (CLL)?

What is the role of obinutuzumab (Gazyva) in the treatment of chronic lymphocytic leukemia (CLL)?

What is the role of duvelisib (Copiktra) in the treatment of chronic lymphocytic leukemia (CLL)?

Which monoclonal antibodies are being investigated for the treatment of chronic lymphocytic leukemia (CLL)?

What is the role of combination therapies with monoclonal antibodies in the treatment of chronic lymphocytic leukemia (CLL)?

What is the role of ibrutinib in the treatment of chronic lymphocytic leukemia (CLL)?

What is the role of idelalisib in the treatment of chronic lymphocytic leukemia (CLL)?

What is the role of venetoclax in the treatment of chronic lymphocytic leukemia (CLL)?

What is the role of lenalidomide in the treatment of chronic lymphocytic leukemia (CLL)?

How is the role of combination venetoclax and obinutuzumab in the treatment of chronic lymphocytic leukemia (CLL)?

How is chronic lymphocytic leukemia (CLL) managed in elderly patients?

What is the role of allogeneic stem cell transplantation in the treatment of chronic lymphocytic leukemia (CLL)?

What are autoimmune manifestations in chronic lymphocytic leukemia (CLL)?

What is the prevalence of autoimmune manifestations in chronic lymphocytic leukemia (CLL)?

What is the role of prednisone in the treatment of chronic lymphocytic leukemia (CLL)?

What causes hyperviscosity syndrome in chronic lymphocytic leukemia (CLL) cause?

What is the role of splenectomy in the treatment of chronic lymphocytic leukemia (CLL)?

Guidelines

What are the ESMO diagnostic guidelines for chronic lymphocytic leukemia (CLL)?

Which organizations have published guidelines for diagnosing and treating chronic lymphocytic leukemia (CLL)?

What are the diagnostic guidelines for chronic lymphocytic leukemia (CLL)?

What are National Comprehensive Cancer Network (NCCN) recommendations for further testing when the diagnosis of chronic lymphocytic leukemia (CLL) is not established by flow cytometry?

What are the IWCLL diagnostic guidelines for chronic lymphocytic leukemia (CLL)?

What testing is recommended prior to initiating treatment for chronic lymphocytic leukemia (CLL)?

What are the NCCN recommendations for the workup of chronic lymphocytic leukemia (CLL)?

What are the indications for treatment of low or intermediate risk chronic lymphocytic leukemia (CLL)?

What is the basis for treatment recommendations for high risk chronic lymphocytic leukemia (CLL)?

What are NCCN treatment recommendations for chronic lymphocytic leukemia (CLL) without del(17p) or TP53 mutations?

What are NCCN treatment recommendations for chronic lymphocytic leukemia (CLL) with del(17p) or TP53 mutations?

Medications

Which medications are used in the treatment of chronic lymphocytic leukemia (CLL)?

Which medications in the drug class Antineoplastic Agents are used in the treatment of Chronic Lymphocytic Leukemia (CLL)?