Chronic Lymphocytic Leukemia

I. What every physician needs to know.

Chronic Lymphocytic Leukemia (CLL) is the most common adult hematologic malignancy in the United States. Underlying the disease is a clonal expansion of functionally incompetent mature B-cells. Often associated are a number of different well-described cytogenetic abnormalities, which may be directly related to disease pathogenesis and can carry prognostic value. The disease has an indolent course, and in its early stages is often asymptomatic. Symptoms develop with the accumulation of large numbers of leukemic cells and result in marrow failure and immune system dysfunction.

II. Diagnostic Confirmation: Are you sure your patient has chronic lymphocytic leukemia?

The formal diagnostic criteria for CLL include: 1) Absolute B-lymphocyte count greater than or equal to 5,000 per microliter, with mainly mature-appearing lymphocytes, and 2) demonstration of clonality and appropriate immunophenotype of these cells by flow cytometry. Staging is most commonly evaluated using the Rai system, ranging from 0 (lymphocytosis only) to 3 and 4 (associated anemia or thrombocytopenia with or without associated lymph node, liver, and spleen enlargement).

A. History Part I: Pattern Recognition:

B. History Part 2: Prevalence:

CLL often has an indolent course, and as many as 25% of cases are discovered incidentally as lymphocytosis on routine lab work. When symptomatic, the most common presentation is lymphadenopathy, in many cases with a prolonged waxing and waning course. Additional presenting signs and symptoms may include hepatosplenomegaly, infection, autoimmune phenomena (immune thrombocytopenic purpura [ITP] and autoimmune hemolytic anemia [AIHA]), and bone marrow failure. Classic “B symptoms” such as weight loss and night sweats are rare but may occur.

The majority of cases of CLL occur in older individuals (median age of 70) with a nearly 2 to 1 male predominance. Incidence is higher in Caucasians than other ethnic groups. The large majority of cases are spontaneous, although a family history of CLL can indicate underlying genetic polymorphisms predisposing to the development of the disease. No clear modifiable risk factors have been identified.

C. History Part 3: Competing diagnoses that can mimic chronic lymphocytic leukemia.

The differential diagnosis of CLL consists primarily of a number of other lymphoproliferative disorders. SLL (small lymphocytic lymphoma) is essentially a manifestation of the same disease process with lymph node involvement but insufficient circulating clonal B-cells to meet diagnostic criteria for CLL. Similarly, B-PLL (B-cell prolymphocytic leukemia) is a closely related disorder that may evolve from CLL or develop de novo. It has a similar presentation except that circulating clonal cells are primarily prolymphocytes, and it carries a worse overall prognosis than CLL.

D. Physical Examination Findings.

Physical exam may reveal lymphadenopathy and occasionally hepatosplenomegaly. Additionally, findings related to associated thrombocytopenia or anemia such as petechiae and conjunctival pallor may be present.

E. What diagnostic tests should be performed?

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

A complete blood count is used to assess the overall number of circulating lymphocytes as well as to assess for associated cytopenias. The most specific and sensitive test to establish the diagnosis of CLL is peripheral flow cytometry. This will show a clonal expansion of cells showing positivity for B-cell associated antigens (CD19, CD23, and dim CD20), low-level surface Ig (K or L), and the T-cell associated antigen CD5. Additionally, Fluorescence in situ hybridization (FISH) cytogenetics should be sent in all patients at diagnosis as well as at relapse, as different cytogenetic patterns carry prognostic value and clonal evolution may alter management.

Additional supporting labs may include immunoglobulin heavy chain variable region (IgVH) mutation analysis, lactate dehydrogenase (LDH), and Beta-2-microglobulin and serum protein electrophoresis (SPEP) which provide prognostic information, as CLL can be associated with amonoclonal gammopathy and hypogammaglobulinemia. HIV (human immunodeficiency virus), HBV (hepatitis B virus), CMV (cytomegalovirus), and HCV (hepatitis C virus) serologies should be drawn prior to chemotherapy as treatment of CLL may worsen these disease processes. In cases with bulky adenopathy, basic metabolic panel (BMP), uric acid, and phosphorus level should be checked due to risk of tumor lysis syndrome.

Bone marrow biopsy is not required for diagnosis or to establish prognosis. However, it is indicated to establish a baseline prior to treatment, to assess response following treatment, and to obtain a new baseline in relapsed cases. Additionally, it may be useful to differentiate cytopenias due to leukemic marrow failure from those due to CLL-related autoimmune phenomena if the cause is unable to be determined through less invasive evaluation.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Imaging is not required to make the diagnosis of CLL, and generally does not affect initial disease management. However, it may be useful to obtain baseline imaging evaluating the extent of lymphadenopathy prior to initiation of treatment to stratify risk of tumor lysis syndrome. The preferred test is a computed tomography (CT) of the neck, chest, abdomen, and pelvis with IV contrast. If a CT is not performed, a standard chest X-ray is recommended. Positron emission tomography (PET) scanning is not routinely used as CLL generally does not have avid uptake of fludeoxyglucose (FDG). It may, however, be indicated in cases of suspected disease transformation to identify potential biopsy sites.

III. Default Management.

Asymptomatic disease can initially be followed with close observation for disease progression. Treatment of CLL is indicated in cases with systemic symptoms (fevers, night sweats, weight loss, painful lymphadenopathy), progressive cytopenias, rapid enlargement of lymph nodes, spleen, liver, refractory autoimmune processes, or with a lymphocyte doubling time of less than 6 months. While not curative, long-term remission can often be achieved with chemotherapy. First-line therapy is fludarabine, cyclophosphamide and rituximab, with an overall response rate of 90%. Ongoing research into newer combinations of novel biologics and chemotherapy agents show promise of good efficacy and favorable toxicity profiles, which may change future diseasemanagement strategies.

Patients with low risk disease or poor performance status may be placed on modified regimens of these agents, or alternatively on chlorambucil. At relapse, patients should be reassessed for potential cytogenetic progression or disease transformation. Therapy in patients with early relapse or certain high-risk cytogenetic mutations may be managed with alternative regimens, including recently approved novel agents targetingthe BCR (B-cell receptor) signalling pathway. However, patients with relapse after a remission lasting at least 3 years without newly acquired high risk mutations should be considered for repeat therapy with their initial regimen.

Complications of therapy include bone marrow suppression, infections, infusion reactions, and rarely tumor lysis syndrome (TLS). Monitoring for cytopenias should be performed with daily CBCs; anemia and thrombocytopenia can be managed with transfusional support, while patients with severe neutropenia should receive pegfilgrastim. Prophylaxis for pneumocystis pneumonia should be initiated with trimethoprim/sulfamethoxazole or atovaquone, and antiviral prophylaxis for herpes simplex virus (HSV) and varicella zoster virus (VZV) with acyclovir or valacyclovir should be instituted; both should be continued for at least 6 months. Supportive measures, including acetaminophen, diphenhydramine, hydrocortisone, and ondansetron may be used for infusion-related reactions and medication side effects. In cases with high disease burden, prophylactic measures for TLS and close monitoring of electrolytes are indicated.

A. Immediate management.

Due to its indolent course, emergent therapy of CLL is rarely necessary. Associated anemia or thrombocytopenia is frequently due to autoimmune destruction as opposed to leukemic bone marrow crowding. In these cases steroid therapy (prednisone 1 milligram/kilogram daily) will often lead to resolution. TLS is rare, but may occur after initiation of treatment or with transformation to a more aggressive neoplasm. Intravenous hydration, allopurinol and/or rasburicase, and careful management of electrolytes are indicated in these cases.

C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

If hospitalized for chemotherapeutic treatment, CBC should be monitored daily for response as well as associated cytopenias that are likely to develop. Additionally, patients with bulky adenopathy should be monitored for TLS with serial BMP, uric acid, and phosphorus levels.

D. Long-term management.

Observation and regular lab monitoring for progression of disease are standard management both for asymptomatic early disease and patients in remission following chemotherapy. Patients with early stage disease should initially be followed expectantly with CBCs every 3 months. Patients with more advanced disease or requiring therapy should be followed as determined by their hematologist/oncologist.

IV. Management with Co-Morbidities.

A. Renal Insufficiency.

May alter chemotherapeutic options for treatment. May place patient at increased risk for TLS during treatment, requiring closer monitoring and treatment.

B. Liver Insufficiency.

May alter chemotherapeutic options for treatment.

C. Systolic and Diastolic Heart Failure.

May alter chemotherapeutic options for treatment.

D. Coronary Artery Disease or Peripheral Vascular Disease.

May alter chemotherapeutic options for treatments. Severe accompanying anemia may exacerbate underlying disease.

E. Diabetes or other Endocrine issues.

Patients requiring steroids for treatment of autoimmune phenomena may require additional hypoglycemic agents to control blood glucose elevations.

F. Malignancy.

It is not uncommon for CLL to be discovered in the context of a second malignancy. Patients should be encouraged to undergo age appropriate cancer screening and take steps to lower cancer risk, such as smoking cessation.

G. Immunosuppression (HIV, chronic steroids, etc).

Both CLL as well as its treatment can lead to further immune system dysfunction. Patients should be screened and treated for chronic viral illnesses (HIV, HBV, HCV) prior to starting treatment as chemotherapy can lead to further immunosuppression and worsening of these diseases. Antimicrobial prophylaxis is indicated in certain cases as above.

H. Primary Lung Disease (COPD, Asthma, ILD).

May alter chemotherapeutic options for treatments. Severe accompanying anemia may exacerbate underlying disease.

I. Gastrointestinal or Nutrition Issues.

Chemotherapeutic regimens may cause gastrointestinal (GI) upset, diarrhea and other symptoms. Supportive treatment with anti-emetics and other agents is appropriate.

J. Hematologic or Coagulation Issues.

Anemia and thrombocytopenia are common complications of both the disease and chemotherapeutic treatment. Many cases may be autoimmune phenomenon treated with steroids as above. Other cases may require transfusional support.

K. Dementia or Psychiatric Illness/Treatment.

Depression is not uncommon in patients diagnosed with cancer thus patients should be screened and treated if a diagnosis is confirmed.

V. Transitions of Care.

A. Sign-out considerations While Hospitalized.

Increased risk for infection should be communicated. Response to steroid, transfusion, or granulocyte stimulating factor support of cytopenias should be monitored. Complications of treatment, including tumor lysis syndrome, should be communicated.

B. Anticipated Length of Stay.

Admissions strictly for CLL management are uncommon. Length of admission for disease complications is dependent on severity and response to treatment of these issues or other comorbid conditions.

C. When is the Patient Ready for Discharge.

Admissions strictly for CLL management are uncommon. Discharge is based primarily on management of complications or comorbid conditions.

D. Arranging for Clinic Follow-up.

Patients should be referred for follow-up with a hematologist/oncologist. Timing is dependent on disease stage and treatment. For uncomplicated, early stage diagnoses, initial follow-up in 2-4 weeks is appropriate. All patients should have flow cytometry and FISH cytogenetics performed at initial diagnosis to establish diagnosis and prognosis. Additionally, a CBC should be available for review at the clinic’s follow-up.

E. Placement Considerations.

No specific discharge needs are generally required.

F. Prognosis and Patient Counseling.

CLL in general has a very indolent course. However, the disease is not curable and the goal of therapy is preventing complications relating to the disease. Risk of progression and overall survival are primarily related to cytogenetics and stage at presentation. Because of immune dysfunction, patients are at elevated risk for infections and secondary malignancies, and should take age-appropriate steps to decrease these risks, including smoking cessation, vaccination and cancer screening.

VI. Patient Safety and Quality Measures.

A. Core Indicator Standards and Documentation.

None

B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.

Standard prophylaxis measures are appropriate in most cases. In cases complicated by disease or treatment-related cytopenias, neutropenic isolation precautions and/or avoidance of chemoprophylaxis for venous thromboembolism (VTE) due to severe thrombocytopenia may be indicated. Standard vaccinations should be encouraged, particularly in patients undergoing treatment due to potential immunosuppression. Age-appropriate cancer screening and steps such as smoking cessation should be encouraged as immune system dysfunction places patients at elevated risk for development of a second malignancy.

VII. What's the Evidence?

Horner, MJ, Ries, LAG, Krapcho, M. “SEER Cancer Statistics Review, 1975-2006, National Cancer Institute”.

Robak, T, Dmoszynska, A, Solal-Celigny, P. “(2010) Rituximab plus fludarabine and cyclophosphamide prolongs progression-free survival compared with fludarabine and cyclophosphamide alone in previously treated chronic lymphocytic leukemia”. J Clin Oncol. vol. 28. 2010. pp. 1756-1765.

Hallek, M, Cheson, BD, Catovsky, D. “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. vol. 111. 2008. pp. 5446-5456.

Cramer, P, Langerbeins, P, Eichhorst, B, Hallek, M. “Advances in first-line treatment of chronic lymphocytic leukemia: current recommendations on management and first-line treatment by the German CLL Study Group (GCLLSG)”. European Journal of Haematology. 2015.

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Chronic Lymphocytic Leukemia