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Treatment of Chronic Lymphocytic Leukemia


Medical editor Geir Tjønnfjord MD
Hematologist
Oslo University Hospital

General

For chronic lymphocytic leukemia, there is no clear evidence that disease-directed treatment has a life-prolonging effect. The treatment can, however contribute to extending remission and symptom-free periods. This means that treatment is initiated when the disease causes symptoms.  

Indication

The most common indications for anti-leukemic treatment of chronic lymphatic leukemia:

  • bone marrow failure equivalent to Binet's stage C
  • general symptoms such as weight loss and night sweats
  • large symptom-causing tumor
  • troublesome lymph node tumor
  • rapidly progressive lymphocytosis (lymphocyte doubling time < 6 months)
  • autoimmune hemolytic anemia and/or immune-mediated thrombocytopenia, which does not respond to high doses of steroids or is recurring after reduction of treatment intensity.

Goals

  • For the patient to be symptom-free as long as possible.
  • To maintain good quality of life for the patient.

 

 

 

 

 

 

 

Norsk selskap for hematologi. Handlingsprogram for kronisk lymfatisk leukemi [Online] 2005 [hentet 15. april 2007]; tilgjengelig fra: URL: http://www.legeforeningen.no/index.gan?id=84611


Background

Currently, many doctors will recommend that prognostic parameters are surveyed before starting treatment. Some will emphasize these results in choosing treatment, but at present it is unknown whether a risk-adapted treatment strategy is advantageous.

An exception for this may be if del17p exists at the start of treatment. Because these patients are often chemo-refractory, there may be reason to consider alemtuzumab (anti CD52 antibody) as primary treatment. It has not been shown by clinical studies that such an approach to primary treatment provides a gain in survival time.

Chlorambucil monotherapy, fludarabine monotherapy, and fludarabine/cyclophosphamide combination treatment are alternative first line treatments.  

 

Treatment responses to treatment alternatives
Treatment  Complete response Partial response No response/progression
Chlorambucil  8 % 64 % 28 %
Fludarabine 15 % 66 % 19 %
Fludarabine/
cyclophosphamide
39 % 55 %  6 %
Fludarabine/
cyclophosphamide/
rituximab
52 % 43 %  5 %

 

It appears that combination treatment is the most effective as it leads to more responses, more complete responses, and longer disease-free survival than the two other treatment alternatives. However, the total survival is the same for all four treatment alternatives. This is because second line treatment and possible later treatment are also successful, especially in those primarily treated with chlorambucil.

Corticosteroids have traditionally been used in combination with alkylating chemotherapy drugs, such as chlorambucil, for chronic lymphocytic leukemia and other lympho-proliferative diseases. Corticosteroids in addition to chlorambucil do not give a higher response rate, longer remission time, or longer progression-free survival than chlorambucil alone. 

Corticosteroids are not appropriate for treatment of chronic lympocytic leukemia unless there is a special indication for it. Prednisone/prednisolone is indicated for autoimmune hemolytic anemia and immune-mediated thrombocytopenia. It has also been common to initially recommend corticosteroids for treatment of patients with significant anemia, thrombocytopenia, or granulocytopenia, as a result of bone marrow failure (1 mg/kg/day for 2–3 weeks before starting chemotherapy). However, this treatment is not well documented.

Allogeneic stem cell transplant

An allogeneic stem cell transplantation may be a treatment alternative for younger patients, especially patients who are refractory to conventional treatment. The benefits of an allogeneic stem cell transplantation for acute lymphocytic leukemia are not yet clear.


Preparation

  • Provide information about the disease, treatment, and side effects.
  • Evaluate familial donor situation.
  • Consider treatment alternatives.

Implementation

Treatment recommendations

Chlorambucil (6–8 courses)

  • Continual: 0.08–0.12 mg/kg
  • Intermittently:  
    •  10 mg/m2 for 10 days, every 28 days
    •  30 mg/m2 in 4 doses, 1 day every 14 days  
    •  15 mg/m2 for 4 days, every 28 days
  • High continually: 10 mg/m2 until response or toxicity

Fludarabine (6–8 courses) 

  • 40 mg/m2 for 5 days, every 28 days

Fludarabine/ Cyclophosphamide (6–8 courses) 

  • 40 mg/m2 for 3 days, every 28 days
  • 250 mg/m2 for 3 days, every 28 days
  • Possible addition of rituximab recommended as 375 mg/m2 at first course and 500 mg/m2 for subsequent courses.

Treatment for recurrence

There are no clear recommendations regarding treatment for recurrence after first line treatment. If the need for further treatment appears after 2 years or more, there are good chances that first line treatment can achieve a new response. No response or early recurrence indicates that alternative treatment regimens should be tried. 

For chlorambucil resistance, the next obvious choice is a fludarabin treatment regimen. If fludarabin monotherapy was used as first line treatment, an alternative is combination treatment supplemented with monoclonal antibody (rituximab (anti-CD20 antibody) or alemtuzumab). Newer clinical studies indicate that fludarabin resistance is associated with very poor prognosis and experimental treatment including allogeneic stem cell transplantation should be considered for these patients. 

At present, an allogeneic stem cell transplantation should only take place within evaluable clinical studies.

Splenectomy

Certain patients have significant splenomegaly and lymphocyte infiltration in the bone marrow with relatively moderate lymphocytosis in the blood. In these patients, the spleen can cause troublesome local symptoms or cause anemia and thrombocytopenia due to hypersplenism. In these situations, a splenectomy is a good treatment alternative. A splenectomy may also be worth trying with immune hemolysis or thrombocytopenia which responds poorly to adequate steroid doses.

Infections

Patients with chronic lymphocytic leukemia often have an increased tendency for infections which may be due to granulocytopenia or, more frequently, hypogammaglobulinemia. In these patients with serious infection complications, which are reasonable to believe are secondary to gammaglobulinemia (infections with capsule-covered bacteria), there is a documented effect from prophylaxis substitution treatment with gammaglobulin. It is important to be aware that many patients have significant hypogammaglobulinemia without infection tendencies. In these patients, there is no indication for substitution treatment.


Follow-up

After treatment is finished, a formalized evaluation of the treatment response should be performed based on NCI criteria. As a minimum, this involves a complete clinical examination with emphasis on lymph nodes, the liver, and spleen.

Determination of hemoglobin, leukocytes, granulocytes, lymphocytes, and thrombocytes in blood should be done a few weeks after concluded treatment. Additionally, a bone marrow examination should be performed, preferably with both aspirate and biopsy.

Response criteria (NCI)
Criterion Complete response Partial response Progressive disease
Symptoms None               None  
Lymph nodes Nodes > 50% reduction > 50% increase or new manifestations
Liver/spleen Not palpable > 50% reduction > 50% increase or new manifestations
Hemoglobin > 11 g/dl

> 11 g/dl or 50% improvement

 
Granulocytes > 1,5 x 109/l > 1,5 x 109/l or 50 % improvement  
Lymfocytes < 4 x 109/l > 50% reduction

> 50 % increase

Thrombocytes > 100 X 109/l >100 x 109/l or 50% improvement  
BM-aspirate < 30 % lymfocytes    
BM-biopsy No infiltrates Nodular infiltrates  

Some doctors will also include a CT of the abdomen and thorax in this type of response evaluation, but outside of clinical studies, the clinical benefit to be obtained from these procedures is doubtful.

Thereafter, the patient is checked at regular intervals (individually adapted) with patient history, clinical examination, and certain laboratory parameters as mentioned above.

The indication for re-treating will usually be the same as for primary treatment.

Transformation to aggressive B-cell lymphoma (Richter's syndrome)

Some patients with chronic lymphocytic leukemia over years exhibit an increasing number of promyelocytes with declining treatment response. This is not actually a transformation, but a more rapid selection of clones over time which is less sensitive to treatment. Richter's syndrome occurs in 3-5% of patients with chronic lymphatic leukemia. The disease profile is characterized by rapid growth of one or more lymph nodes accompanied by systemic manifestations such as fever and/or weight loss. A histological examination of the affected lymph node is similar to that of large-cell B-cell lymphoma.


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