The diagnosis of monoclonal B-lymphocytosis, instead of CLL, requires the following: An absolute increase in the clonal B-lymphocytes (but < 5.0 x 109 /L) in the peripheral blood of an otherwise healthy adult; absence of lymphadenopathy or organomegaly (as defined by physical examination and CT scans), cytopenias, or disease related symptoms. 1% to 2% of patients with monoclonal B-lymphocytosis develop CLL per year.
The diagnosis of small lymphocytic lymphoma (SLL), which is the same disease as CLL except that SLL is not associated with a peripheral blood lymphocytosis > 5 x 109/L at diagnosis, requires biopsy proven involvement of lymphadenopathy and/or splenomegaly due to SLL.
The staging system used for treatment planning for CLL at BCCA is the modified Rai system (Hallek, Guidelines for the diagnosis and treatment of CLL, Blood 2008;111:5446-56). It identifies three risk groups.
Treatment is not recommended for asymptomatic patients merely because of lymphocytosis, splenomegaly or lymphadenopathy. An elevated white blood cell count, even to markedly high levels, does not require treatment by itself as long as the hemoglobin and platelet count remain satisfactory, the patient does not become symptomatic and the lymphocyte doubling time remains greater than 6 months. Treatment should be considered for patients who develop one or more of the following, due to the CLL.
- Symptomatic splenomegaly
- Symptomatic lymphadenopathy
- Lymphocyte doubling time < 6 months
- Autoimmune hemolytic anemia
- Autoimmune thrombocytopenia
- Otherwise unexplained fatigue or constitutional symptoms sufficient to interfere with work or normal daily activity
Treatment of advanced stage small lymphocytic lymphoma (SLL) is identical to that of CLL. Additional guidance on choice of treatment and integration of hematopoietic stem cell transplantation is available on the Leukemia/Bone Marrow Transplant (BMT) Program website.
All patients should receive the immunizations recommended in Appendix III.
The BC Cancer Agency maintains current Chemotherapy Protocols.
a) CLL without immune mediated hemolysis or immune mediated thrombocytopenia
1. CLL without 11q or 17p deletion: fludarabine + rituximab (LYFLUDR). Note that rituximab is not included in the initial 1-2 cycles if the total WBC is markedly elevated (see protocol).
The combination of fludarabine + rituximab provides the best balance of tolerability and improved progression free and overall survival (Byrd, Blood 2003;101:6-14; Byrd, Blood 2005:105:49-53).
2. CLL with 11q deletion: fludarabine + cyclophosphamide + rituximab (FCR) which may overcome the negative prognostic impact of this cytogenetic abnormality. (see review, Ding, ASH Education BookDecember 4, 2010 vol. 2010 no.1 p90-92)
CLL with 17p deletion: 17p deleted CLL is often resistant to both fludarabine + rituximab and fludarabine + cyclophosphamide + rituximab. A patient with CLL with 17p deletion should be discussed with a senior hematologist/oncologist in the Lymphoma Tumor Group and may be a candidate for early assessment for allogeneic hematopoietic stem cell transplantation.
b) CLL with immune mediated hemolysis or thrombocytopenia
Prednisone, given in high daily doses, > 40 mg/day, is the drug of choice for the initial two to four weeks of management of patients with CLL-associated hemolytic anemia or thrombocytopenia. The acute CLL-related immune mediated cell destruction should be stopped or at least well controlled before additional chemotherapy is started, usually after prednisone has been given for 2-3 weeks. After control of the immune mediated cell destruction is established the prednisone can be tapered and stopped and treatment with CVP + rituximab (LYCVPR) used for at least two cycles before switching to fludarabine + rituximab (LYFLUDR) to conclude the treatment. Folic acid supplementation should be given to patients with active hemolysis.
2. Supportive Measures
Allopurinol (300 mg/day by mouth) is necessary prophylactically only when a rapid lysis of large numbers of lymphocytes is anticipated (initial WBC >200.0 x 10 9 /L). It should also be employed in patients with chronic hyperuricemia, gout or significant renal dysfunction. Patients with hypogammaglobinemia and repeated infections should be assessed for possible use of intravenous gammaglobulin.
Involved field radiation is an effective treatment for localized SLL and for symptomatic or cosmetically disturbing focal lymphadenopathy for all stages of SLL/CLL. Radiation of the spleen is ordinarily not useful and may cause worsening of pancytopenia.
Occasionally, removal of the spleen may prove helpful in CLL. The most common situations that may require elective splenectomy are symptomatic splenomegaly or hemolytic anemia or autoimmune thrombocytopenia uncontrolled by chemotherapy. This procedure should only be carried out with sophisticated hematologic support. Pneumococcal, hemophilus influenza and meningococcal vaccines should be given to patients as far in advance of splenectomy as possible (see Appendix III).
5. Secondary Chemotherapy
CLL which is refractory to fludarabine + rituximab may respond to agents such as chlorambucil, cyclophosphamide (with or without vincristine and prednisone) or bendamustine (bendamustine requires CAP approval). Rituximab can be added to secondary chemotherapy if the patient’s CLL has not demonstrated refractoriness to it (ie. non-response or progression within 6 months of receiving a rituximab-containing regimen). CLL that cannot be controlled with fludarabine, alkylating agents and rituximab and is free of bulky (> 5 cm) lymphadenopathy may respond well to alemtuzumab, a monoclonal antibody directed against the CD52 antigen. Its use should be discussed with a member of the Lymphoma Tumor Group and requires special authorization.
Hallek, Guidelines for the diagnosis and treatment of LL, Blood 2008;111:5446-56