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Leukemia, Chronic Lymphocytic
Jan Cerny, MD, PhD
image BASICS
DESCRIPTION
  • Chronic lymphocytic leukemia (CLL) is a monoclonal disorder characterized by a progressive accumulation of mature but functionally incompetent lymphocytes.
  • CLL should be distinguished from prolymphocytic leukemia (PLL); based on percentage of prolymphocytes, the disease may be regarded as CLL (<10% prolymphocytes), PLL (>55% prolymphocytes), or CLL/PLL (>10% and <55% prolymphocytes).
  • Small lymphocytic lymphoma is a lymphoma variant of CLL.
  • System(s) affected: hematologic, lymphatic, immunologic
EPIDEMIOLOGY
Incidence
  • With 15,000 to 17,000 new cases reported every year, CLL represents the most common form of leukemia in adults in the United States.
  • In 2013, an estimated 4,580 adults in United States will die from CLL, which makes it the second leading cause of death among adults with leukemia in United States after acute myeloid leukemia (1)[A].
  • Predominant age: CLL primarily affects elderly individuals, median age of diagnosis being 70 years. The incidence continues to rise in those age >55 years.
  • Predominant sex: male > female (1.7:1)
  • The incidence is higher among whites than among African Americans.
ETIOLOGY AND PATHOPHYSIOLOGY
  • The cell of origin in CLL is a clonal B cell arrested in the B-cell differentiation pathway, intermediate between pre-B cells and mature B cells. In the peripheral blood, these cells resemble mature lymphocytes and typically show B-cell surface antigens: CD19, CD20, CD21, and CD23. In addition, they express CD5 (usually found on T cells).
  • The BCL-2 protooncogene is overexpressed in B-CLL. BCL-2 is a known suppressor of apoptosis (programmed cell death), resulting in extremely long life of the affected lymphocytes.
    • Unknown, but genetic mutations leading to disrupted function and prolonged survival of affected lymphocytes are suspected.
Genetics
CLL is an acquired disorder, and reports of truly familial cases are exceedingly rare. CLL has been shown, however, to occur at higher frequency among first-degree relatives of patients with the disease, and several somatic gene mutations have been identified at significantly higher rates among CLL patients.
RISK FACTORS
  • As in the case of most malignancies, the exact cause of CLL is uncertain.
  • Possible chronic immune stimulation is suspected but is still being elucidated.
  • Monoclonal B-cell lymphocytosis: 1% risk progression to CLL
GENERAL PREVENTION
Unknown
COMMONLY ASSOCIATED CONDITIONS
  • Immune system dysregulation is common.
  • Autoimmune hemolytic anemia (AIHA) may accompany CLL.
  • Immune thrombocytopenic purpura (ITP) may accompany CLL.
  • Pure red cell aplasia (PRCA) may accompany CLL.
image DIAGNOSIS
PHYSICAL EXAM
  • Localized or generalized lymphadenopathy
  • Splenomegaly (30-40%)
  • Hepatomegaly (20%)
  • Mucocutaneous bleeding (thrombocytopenia)
  • Skin petechiae (thrombocytopenia)
  • Pallor
DIFFERENTIAL DIAGNOSIS
  • Infectious causes are the following:
    • Bacterial (tuberculosis)
    • Viral (mononucleosis)
  • Malignant causes are the following:
    • Leukemic phase of non-Hodgkin lymphomas
    • Hairy cell leukemia
    • Waldenstrom macroglobulinemia
    • Large granular lymphocytic leukemia
DIAGNOSTIC TESTS & INTERPRETATION
Initial Tests (lab, imaging)
  • CBC with differential shows B cell absolute lymphocytosis with >5,000 B lymphocytes/&mgr;L. The blood smear also shows ruptured lymphocytes (“smudge” cells) and morphologically mature-appearing small lymphocytes.
  • Exam of the blood smear is important in diagnosis of CLL.
  • Diagnosis can be confirmed by immunophenotyping: CLL cells are positive for CD19, CD20, and CD24 as well as CD5. They have low levels of surface membrane immunoglobulin (Ig) M or IgD. The monoclonality is proven by the presence of a single immunoglobulin light chain (&kgr; or &lgr;). FMC7 is absent.
  • CBC shows anemia and/or thrombocytopenia.
  • Plasma &bgr;2-microglobulin may be elevated.
  • Serum protein electrophoresis (some patients may have monoclonal gammopathy)
  • Lactate dehydrogenase (LDH) may be elevated (due to disease activity or to AIHA).
  • Hypogammaglobulinemia
  • In cases associated with AIHA, labs consistent with hemolysis may be present (elevated LDH, total bilirubin; reticulocyte count does not have to be elevated due to bone marrow infiltration).
  • Liver/spleen ultrasound may demonstrate organomegaly and may also detect enlarged abdominal lymph nodes.
  • CT scan of chest/abdomen/pelvis typically is not necessary for staging. However, it may help to identify compression of organs or internal structures from enlarged lymph nodes.
  • Positron emission tomography (PET) scan might be helpful to guide biopsy if Richter transformation is suspected (see below).
Follow-Up Tests & Special Considerations
Frequency and type of follow-up depend on severity of symptoms as well as risk factors (see “Prognosis”).
Diagnostic Procedures/Other
  • Although bone marrow biopsy has its prognostic value (diffuse infiltration is a risk factor), it is not done routinely.
  • Consider a lymph node biopsy if lymph node(s) begins to enlarge rapidly in a patient with known CLL to assess the possibility of transformation to a high-grade lymphoma (Richter syndrome), especially when accompanied by fever, weight loss, and pain.
Test Interpretation
  • A bone marrow aspirate usually shows >30% lymphocytes.
  • Cytogenetic (fluorescence in situ hybridization) may show chromosomal changes, which are prognostic (i.e., del[13q], del[11q], del[17p], trisomy 12, and del[6q]).
  • SF3B1 mutation is associated with rapid disease progression and shorter survival in CLL (2)[A].
image TREATMENT
GENERAL MEASURES
Patients with frequent infections associated with hypogammaglobulinemia are likely to benefit from monthly infusions of intravenous immunoglobulin (IVIG).
MEDICATION
First Line
  • Most patients are asymptomatic and do not need active treatment unless they have generalized (so-called B) symptoms, progressive marrow failure, AIHA or thrombocytopenia, progressive splenomegaly, massive lymphadenopathy, or progressive lymphocytosis (increase >50% in 2 months or a doubling time of <6 months).
  • P.603

  • Low-risk disease, Rai stage 0, and Binet stage A require only periodic follow-up.
  • Intermediate-risk group, Rai stages I and II, and Binet stage B could be observed until evidence of disease progression or development of symptoms.
  • Treatment should be initiated in high-risk patients, Rai stage III and IV, and Binet stage C.
  • Early treatment in low-risk group is not recommended.
  • Three main groups of drugs used are alkylating agents (chlorambucil and, recently, bendamustine), purine analogues (fludarabine and pentostatin), and monoclonal antibodies (rituximab and alemtuzumab).
  • Single-agent (fludarabine, bendamustine, or chlorambucil) or combination regimens commonly used
  • Fludarabine-based regimens are FC (in combination with cyclophosphamide), FR (fludarabine + rituximab), and FCR (fludarabine + cyclophosphamide + rituximab).
  • FCR is the widely used regimen of choice if patient can tolerate it.
  • Steroids (prednisone) are useful in patients with autoimmune manifestations of CLL (e.g., AIHA, ITP).
Second Line
  • Combinations of chemotherapeutic agents that patient did not fail yet. Occasionally, some patients can be retreated with a drug used previously.
  • Ibrutinib, is a Bruton tyrosine kinase (BTK) inhibitor from a novel class of agents, which has a high level of activity in CLL (3)[A].
  • Newer agents, like ofatumumab (novel anti-CD20), lenalidomide, and others, have shown promising activity.
  • Alemtuzumab (anti-CD52) has shown activity in relapsed and refractory disease.
  • Consider splenectomy (surgery/radiation) if massive splenomegaly causes significant anemia and thrombocytopenia.
  • Allogenic and autologous stem cell transplant can be considered in high-risk and younger patients (limited data available).
ISSUES FOR REFERRAL
  • Surgical consultation for splenectomy in selected patients
  • Bone marrow transplant in young patients with refractory disease (however, still considered experimental therapy)
    • Allogeneic hematopoietic stem cell transplant (HSCT) with nonmyeloablative conditioning offers lower treatment-related mortality and may be appropriate for certain patients.
ADDITIONAL THERAPIES
Patients requiring therapy who are high-risk for tumor lysis syndrome should be given allopurinol to prevent uric acid nephropathy.
SURGERY/OTHER PROCEDURES
  • Splenectomy in selected patients with splenomegaly and refractory cytopenia
  • Radiation (if compression symptoms from bulky lymphadenopathy)
INPATIENT CONSIDERATIONS
Admission Criteria/Initial Stabilization
No specific criteria but due to complications of disease (e.g., AIHA) or of therapy (e.g., febrile neutropenia) or significant tumor lysis syndrome after initiation of chemotherapy
image ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Patient Monitoring
Patients with low-risk CLL and/or patients in remission
  • CBC with differential (lymphocytosis) every 3 to 6 months, LDH, &bgr;2-microglobulin, IgG level
  • Physical exam (lymphadenopathy, splenomegaly)
DIET
  • Ensure adequately balanced calorie/vitamin intake.
  • Follow weight.
PATIENT EDUCATION
Leukemia and Lymphoma Society has educational pamphlets: http://www.webmd.com/cancer/tc/leukemia-topic-overview.
PROGNOSIS
There are two staging systems used: the Rai in the United States and the Binet in Europe. Neither is completely satisfactory.
  • Rai staging system
    • Stage 0: lymphocytosis only; median survival of 120 months
    • Stage I: lymphocytosis and adenopathy; median survival of 95 months
    • Stage II: lymphocytosis and splenomegaly and/or hepatomegaly; median survival of 72 months
    • Stage III: lymphocytosis and anemia (hemoglobin <10 g/dL); median survival of 30 months
    • Stage IV: lymphocytosis and thrombocytopenia (platelets <100 × 109/L); median survival of 30 months
  • Binet staging system
    • Stage A: hemoglobin ≥10 g/dL, platelets 100 × 109, and <3 lymph node areas involved (Rai stages 0, I, and II); survival >120 months
    • Stage B: Hemoglobin and platelet levels as in stage A and 3 or more lymph node areas involved (Rai stages I and II); survival is 61 months.
    • Stage C: Hemoglobin <100 g/L, platelets <100 × 109, or both (Rai stages III and IV); survival is 32 months.
  • Adverse risk factors
    • Advanced Rai or Binet stage
    • Peripheral lymphocyte doubling time <12 months
    • Diffuse marrow infiltration
    • Increased number of prolymphocytes or cleaved cells
    • Poor response to chemotherapy
    • High &bgr;2-microglobulin and thymidine kinase levels and low micro RNAs (miRNAs)
    • Abnormal karyotyping: deletion 17p (del[17p] P53 mutation or deletion) and del(11q)
    • New IgVH unmutated status (expression of ZAP-70 >20% or CD38 >30% evaluated by immunophenotyping are surrogate markers)
    • NOTCH1 mutation (also associated with unmutated IgVH)
REFERENCES
1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin. 2013;63(1):11-30.
2. Wan Y, Wu CJ. SF3B1 mutations in chronic lymphocytic leukemia. Blood. 2013;121(23):4627-4634.
3. Advani RH, Buggy JJ, Sharman JP, et al. Bruton tyrosine kinase ibrutinib (PCI-32765) has significant activity in patients with relapsed/refractory B-cell malignancies. J Clin Oncol. 2013;31(1):88-94.
Additional Reading
&NA;
  • Chiorazzi N, Rai KR, Ferrarini M. Chronic lymphocytic leukemia. N Engl J Med. 2005;352(8):804-815.
  • National Comprehensive Cancer Network guidelines: http://www.nccn.org/
  • Shanafelt TD, Kay NE. Comprehensive management of the CLL patient: a holistic approach. Hematology Am Soc Hematol Educ Program. 2007:324-331.
Codes
&NA;
ICD10
  • C91.10 Chronic lymphocytic leuk of B-cell type not achieve remis
  • C91.11 Chronic lymphocytic leukemia of B-cell type in remission
  • C91.12 Chronic lymphocytic leukemia of B-cell type in relapse
Clinical Pearls
&NA;
  • CLL represents the most common form of leukemia in adults in the United States.
  • Predominant age: CLL primarily affects elderly individuals, median age of diagnosis being 70 years. The incidence continues to rise in those age >55 years.
  • Clinical monitoring of asymptomatic and low-risk patients is a reasonable approach (“watch and wait”).
  • High-risk patients, bulky disease, or patients who fail fludarabine- and rituximab-based therapies have typically poor prognosis and may require intensive therapies, including allogeneic transplantation.
  • Median survival is 3 to 10 years, depending on stage.