Protocol Number: 97-C-0178

Title:

Fludarabine Treatment of Chronic Lymphocytic Leukemia: c-DNA Microarray Gene Expression Analysis, and Pre-Clinical Bone Marrow Transplant/Immunotherapy Studies

Number:

97-C-0178

Summary:

Fludarabine is the most active agent for the treatment of chronic lymphocytic leukemia (CLL), with up to a 79% response rate in previously untreated patients. However, advanced stage CLL patients treated with fludarabine have only a 33 month disease-free survival; fludarabine does not represent a curative modality for CLL. Because attempts to combine fludarabine with other chemotherapeutic agents have resulted in increased toxicity, single agent fludarabine currently represents the treatment of choice for advanced stage CLL. As such, we have designed this protocol to better understand the genetic basis of CLL, and to develop new transplantation therapies for CLL patients.

A new technology utilizing cDNA microarrays now permits the simultaneous quantitation of the expression of thousands of genes; this methodology can evaluate defined cellular pathways, and also discover novel genes influencing cell biology. Using cDNA microarray gene expression analysis on lymphocytes from CLL, we seek to identify genes associated with CLL pathogenesis, and genes associated with either clinical sensitivity or resistance to fludarabine. In addition to improving our understanding of the pathogenesis of CLL, these molecular studies may identify new therapeutic targets in CLL, and may help to identify those CLL patients most likely to respond to fludarabine.

This study also focuses on the pre-clinical development of bone marrow transplantation and cellular immunotherapy approaches in fludarabine-treated CLL patients. Allogeneic bone marrow transplantation represents a curative treatment modality in CLL; unfortunately, most CLL patients are not candidates for alloBMT because of increased age and a lack of HLA-matched donors. Because allogeneic donor T cells mediate both the beneficial GVL effect and detrimental graft-versus-host disease (GVHD), prior attempts to separate GVL from GVHD have been largely unsuccessful. Utilizing murine models, we have shown that CD8+ T cells of Tc2 phenotype (cytolytic effectors secreting Type II cytokines) mediated a GVL effect without inducing ongoing GVHD; we have also shown that Tc2 cells prevented graft rejection without inducing GVHD. Allogeneic Tc2 cells may thus represent a population capable of expanding the application of allogeneic immunotherapy in CLL patients. As a step towards clinical translation, we have developed techniques for generating human Tc2 cells. We will now evaluate the generation Tc2 cells in the setting of fludarabine treatment of CLL. In addition, we will further characterize the immunosuppressive effects of fludarabine, and develop CLL purging methodologies which will be needed for future autologous BMT and T cell immunotherapy protocols in CLL.

Sponsoring Institute:

National Cancer Institute (NCI)

Recruitment Detail

Type: Active Accrual Of New Subjects

Gender: Male & Female

Referral Letter Required: No

Population Exclusion(s): None

Eligibility Criteria:

INCLUSION CRITERIA:

Low, Intermediate or High-Risk Category of CLL, using the Modified Three-Stage Rai Staging System.

Patients in the intermediate risk group should have evidence of active disease as demonstrated by at least one of the following criteria: a) massive or progressive splenomegaly or lymphadenopathy; b) presence of weight loss greater than 10% over the preceding 6 months; c) constitutional symptoms of extreme fatigue, night sweats or recurrent fever of greater than 100 degrees F (documented fevers must be occurring without evidence of specific infection); d) progressive lymphocytosis with an increase of greater than 50% over a 2 month period, or an anticipated doubling time of less than 6 months.

Patients with a diagnosis of CLL who do not meet the eligibility criteria for receiving fludarabine (are not intermediate- or high-risk CLL), can enroll on the protocol for the purpose of donating cellular products. Such patients will not receive fludarabine chemotherapy. At a later date, if it is documented that the patient does meet the criteria, then the patient may receive fludarabine (after discussion with the Principal Investigator); in such patients, all of the criteria listed must be met prior to starting fludarabine.

In a limited number of cases, patients with low-risk CLL may be initiated on fludarabine treatment. For example, individuals who are candidates for bone marrow transplantation may be started on fludarabine as an induction regimen prior to transplantation. Additionally, some low-risk patients may be started on fludarabine for psychological reasons (patient insistence on starting chemotherapy prior to disease progression). However, it must be stressed that low-risk CLL patients will be discouraged from initiating chemotherapy except in these specific cases.

Age greater than or equal to 18 years of age.

Patients must have received no prior cytotoxic therapy.

ECOG performance status of 0 to 2.

Required initial laboratory tests: BUN and Creatinine values must be less than or equal to 1.5 times the normal values; alternatively, patients with creatinine clearance of greater than 50 ml per minute will also be eligible. AST and ALT values must be less than or equal to 2.0 times normal values; patients with laboratory values greater than these levels may be enrolled on the protocol (after a specific approval from the Principal Investigator) if the values are due to a known, pre-existing liver disease. Bilirubin must be less than or equal to 2.0 mg/dl. In addition, patients must be negative for the Direct Coomb's test.

The patient must be competent to sign an informed consent, and sign the protocol consent form.

EXCLUSION CRITERIA:

Patients must not be pregnant or breastfeeding.

No patients with active autoimmune hemolytic anemia (AIHA; as indicated by a positive direct Coombs test) or immune thrombocytopenia (ITP) shall be enrolled. Patients with a history of prior steroid therapy to control either AIHA or ITP will be eligible, provided they do not require maintenance corticosteroids, do not have evidence of active autoimmune disease, and have a negative Direct Coomb's Test.

Any patient with a medical condition that requires chronic use of corticosteroids shall not be enrolled.

Special Instructions: Currently Not Provided

Keywords:

Genetics

Bone Marrow Transplantation

Immunosuppression

T Lymphocytes

Marrow Purging

Recruitment Keywords:

None

Conditions:

Chronic Lymphocytic Leukemia

Investigational Drug(s):

None

Investigational Device(s):

None

Contacts:

CSSC
Clinical Studies Support Center/NCI
164 Rollins Avenue
2nd FLoor
Rockville, MD 20852
Phone: (888) 624-1937
Fax: (301) 881-8239

Electronic Address: ncicssc@mail.nih.gov

Citations:

Clinical staging of chronic lymphocytic leukemia

Fludarabine phosphate in the treatment of chronic lymphocytic leukemia

A randomized comparison of fludarabine and chlorambucil for patients with previously untreated chronic lymphocytic leukemia

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