Treatment Options for Chronic Lymphocytic Leukemia

Chemotherapy for Chronic Lymphocytic Leukemia

The two most commonly used types of chemotherapeutic agents for the treatment of chronic lymphocytic leukemia (CLL) are:

  • Alkylating agents
  • Purine nucleoside analogues

Alkylating Agents

A category of anticancer drugs called alkylating agents have been the mainstay of chemotherapy for CLL for the past 40 years and are usually reserved for CLL patients who have had no prior treatment. The two most commonly used alkylating agents for chronic lymphocytic leukemia are:

  • Chlorambucil (Leukeran)

  • Cyclophosphamide (Cytoxan) - This drug is often used in combination with other drugs (combination chemotherapy) in CLL patients with Rai stage II, III, or IV disease. Examples of commonly used combination drug regimens for CLL include:

    • CVP - cyclophosphamide + vincristine + prednisone
    • CHOP - cyclophosphamide + doxorubicin + vincristine + prednisone
    • fludarabine + cyclophosphamide

Prednisone, a potent anti-inflammatory corticosteroid drug, is sometimes given in combination with alkylating agents for the treatment of autoimmune hemolytic anemia (AIHA) and/or idiopathic thrombocytopenia that can occur as complications of CLL.

One drawback of using alkylating agents in patients with CLL is that it increases the risk for developing secondary acute myelogenous leukemia (AML) by about 2 to 3 fold.

Bendamustine (Treanda) Approved for Chronic Lymphocytic Leukemia

In March 2008, the U.S. Food and Drug Administration approved an alkylating agent manufactured by Cephalon Inc. called bendamustine hydrochloride (Treanda) for the treatment of chronic lymphocytic leukemia (CLL). In clinical trials, patients with CLL who were treated with bendamustine (Treanda) had a median disease progression-free survival time of 18 months, compared with 6 months for patients who were treated with chlorambucil.

The FDA-approved labeling for bendamustine recommends that the drug be adminstered on the first and second days of a 28-day treatment cycle, with the treatment repeated for up to six cycles. Patients who receive bendamustine must be carefully monitored for both hematologic and non-hematologic toxicities.

Serious side-effects of bendamustine may include:

  • Myelosuppresssion in most patients - a decrease in blood counts due to toxicity of the chemotherapeutic agent
  • Infections such as sepsis and pneumonia
  • Adverse infusion reactions
  • Allergic reactions including anaphalaxis
  • Tumor lysis syndrome - A side-effect of chemotherapy which results when the tumor is "lysed" or destroyed. It is characterized by symptoms of kidney failure due to excessive amounts of calcium, phosphate,and potassium being released by dying tumors
  • Severe skin reactions

Less serious side-effects of bendamustine therapy may include:

  • Nausea
  • Vomiting
  • Diarrhea
  • Mild skin rashes
  • Itching

Purine Nucleoside Analogues

Purine nucleoside analogues are a class of anti-cancer drugs that have been found to be highly effective for the treatment of CLL. Examples of purine nucleoside analogues that may be used for the treatment of CLL include:

  • Fludarabine (Fludara)
  • Pentostatin (Nipent)
  • Cladribine (Leustatin)

Fludarabine is the most commonly used purine nucleoside analogue for the treatment of chronic lymphocytic leukemia. It is also the drug of choice for patients with refractory CLL who do not respond favorably to initial treatment with alkylating agents. Purine nucleoside analogues may be used alone (monotherapy) or in combination with other drugs in the management of patients with CLL.

Of the various purine nucleoside analogues available, doctors have had the most experience with fludarabine which is the most commonly used in patients with CLL. Studies have shown that:

  • Fludarabine monotherapy for CLL is very effective with most patients achieving a positive response to the drug.

  • Fludarabine monotherapy is also very effective for the treatment of patients with relapsed CLL.

  • Fludarabine has been found to be more effective than chlorambucil in studies comparing response rates and disease-free time intervals in patients with CLL.

  • Studies have also shown that fludarabine monotherapy is more effective than combination chemotherapy with CHOP or CVP in previously untreated CLL patients.

  • Fludarabine has also been found to be very effective when used in combination with an alkylating agent (e.g., cyclophosphamide) or a monoclonal antibody (rituximab) in patients with CLL.

Potential complications of fludarabine therapy include the risk of developing severe autoimmune hemolytic anemia as well as an increased risk for opportunistic infections such as Pneumocystis carinii pneumonia and Herpes virus infections. Patients with CLL who are being treated with fludarabine and corticosteroids (e.g., prednisone) are also usually treated with a prophylactic antibiotic (e.g., sulfmethoxazole/trimethoprim) and an antiviral agent (e.g., acyclovir) to prevent opportunistic infections.

A study published in 2002 in the Journal of Clinical Oncology (Volume 20; pages 3878-3884) reported that patients with CLL who were treated with fludarabine and chlorambucil were at increased risk for developing myelodysplastic syndromes (MDS) and/or acute myelogenous leukemia (AML). The increased risk for developing MDS and/or AML has not, however, been reported in clinical trials using combinations of:

  • fludarabine and cyclosphosphamide
  • cladribine and cyclophosphamide
  • cladribine and chlorambucil
Side-Effects of Chemotherapy

A drawback of chemotherapy for the treatment of cancer is that it can produce a variety of undesired side-effects. The side-effects of chemotherapy vary depending upon the type of drug(s) used, the dosage, and the length of time that the chemotherapy is administered. In general, common side-effects of cancer chemotherapy may include:

  • Hair loss
  • Mucositis - inflammation of the lining of the mouth and gastrointestinal tract, which can be very painful.
  • Increased susceptibility to infections
  • Increased susceptibility to bleeding and bruising
  • Fatigue and general loss of energy
  • Nausea and vomiting
  • Loss of appetite

The side-effects of cancer chemotherapy are temporary and usually disappear after treatment has been completed. A variety of strategies are available to better control the side-effects of chemotherapy and patients should discuss with their oncologist the various options that can be used to minimize or reduce these adverse side-effects.