Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outline
Published Results
Related Publications
Trial Contact Information
Registry Information

Alternate Title

Fludarabine With or Without Cyclophosphamide in Treating Patients With Chronic Lymphocytic Leukemia

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase III	Treatment	Closed	18 and over	NCI	ECOG-2997 CALGB-10103, SWOG-E2997, NCT00003764, E2997

Objectives

1. Compare the efficacy of fludarabine with or without cyclophosphamide in terms of complete remission rate and overall survival in patients with previously untreated B cell chronic lymphocytic leukemia (CLL).
2. Compare the toxicities of these 2 regimens in this patient population.
3. Determine whether the expression of proteins specifically implicated in the regulation of DNA damage induced apoptosis of lymphoid cells (i.e., p53; mdm2; GST; Bcl-2; Mcl-1; Bax; p27; and caspase-3) correlates with response to chemotherapy in these patients.
4. Determine whether there is a relationship between clinical response or resistance and differential expression of genes in the CLL cells either at initiation of therapy or following relapse and progression.
5. Correlate mutations in immunoglobulin heavy chain variable region genes with clinical response or resistance in this patient population.

Entry Criteria

Disease Characteristics:

• Diagnosis of chronic lymphocytic leukemia (CLL) of any stage as defined by the following:
  • Peripheral blood absolute lymphocyte count greater than 5,000/mm³ within 14 days prior to study
  • Lymphocytes must be small to moderate size with no more than 55% prolymphocytes, atypical lymphocytes, or lymphoblasts morphologically
  • Phenotypically characterized as B-CLL



• Must have one of the following characteristics indicating need for chemotherapy:
  • Progressive marrow failure (hemoglobin less than 10 g/dL and/or platelet count less than 100,000/mm³)
  • Progressive lymphocytosis with an increase of more than 50% over a 2 month period or anticipated doubling time of less than 6 months
  • Massive (i.e., greater than 6 cm below left costal margin) or progressive splenomegaly
  • Massive nodes or clusters (i.e., greater than 10 cm in longest diameter) or progressive adenopathy
  • At least 10% weight loss within 6 months of study
  • Extreme fatigue
  • Fevers greater than 100.5 degrees F for 2 weeks without evidence of infection
  • Night sweats without evidence of infection



• No autoimmune anemia or autoimmune thrombocytopenia

Prior/Concurrent Therapy:

Biologic therapy:

• Not specified

Chemotherapy:

• No prior cytotoxic chemotherapy

Endocrine therapy:

• No prior steroid treatment for CLL

Radiotherapy:

• Not specified

Surgery:

• Not specified

Patient Characteristics:

Age:

• 18 and over

Performance status:

• ECOG 0-2

Life expectancy:

• Not specified

Hematopoietic:

• See Disease Characteristics

Hepatic:

• Bilirubin no greater than 2 mg/dL unless secondary to tumor

Renal:

• Creatinine no greater than 2.0 mg/dL
• Creatinine clearance at least 40 mL/min if creatinine is greater than 1.5 mg/dL

Other:

• No other prior or concurrent malignancy within the past 2 years except basal cell carcinoma of the skin or carcinoma in situ of the cervix
• No active infection requiring oral or intravenous antibiotics
• Not pregnant or nursing
• Fertile patients must use effective contraception

Expected Enrollment

A total of 280 patients will be accrued for this study over 2 to 2.5 years.

Outline

This is a randomized, multicenter study. Patients are stratified according to stage of disease (O-II vs III-IV). Patients are randomized to one of two treatment arms.

• Arm I: Patients receive fludarabine IV over 30 minutes on days 1-5.



• Arm II: Patients receive fludarabine as in arm I plus cyclophosphamide IV over 1 hour on day 1.

Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

Patients are followed every 3 months for 2 years and then every 6 months until disease progression.

Flinn IW, Neuberg DS, Grever MR, et al.: Phase III trial of fludarabine plus cyclophosphamide compared with fludarabine for patients with previously untreated chronic lymphocytic leukemia: US Intergroup Trial E2997. J Clin Oncol 25 (7): 793-8, 2007.[PUBMED Abstract]

Grever MR, Lucas DM, Dewald GW, et al.: Comprehensive assessment of genetic and molecular features predicting outcome in patients with chronic lymphocytic leukemia: results from the US Intergroup Phase III Trial E2997. J Clin Oncol 25 (7): 799-804, 2007.[PUBMED Abstract]

Grever MR, Dewald GW, Neuberg DS, et al.: Select high risk genetic features predict earlier progression following chemotherapy in chronic lymphocytic leukemia: prospective randomized trial (Intergroup E2997) to evaluate justification for risk-adapted therapy. [Abstract] J Clin Oncol 24 (Suppl 18): A-6521, 342s, 2006.

Flinn IW, Kumm E, Grever MR, et al.: Fludarabine and cyclophosphamide produces a higher complete response rate and more durable remissions than fludarabine in patients with previously untreated CLL: Intergroup trial E2997. [Abstract] Blood 104 (11): A-475, 2004.

Grever MR, Lucas DM, Dewald GW, et al.: Outcome of treatment with fludarabine versus fludarabine and cyclophosphamide in chronic lymphocytic leukemia (CLL) is adversely impacted by high risk genetic features: results from ECOG 2997. [Abstract] Blood 104 (11 Pt 1): A-3487, 2004.

Dewald GW, Paietta E, Goloubeva O, et al.: Correlation of interphase fluorescence in situ hybridization (FISH) anomalies with cell morphology and immunophenotyping in chronic lymphocytic leukemia (B-CLL). [Abstract] Blood 100 (11 pt 1): A-2334, 2002.

Trial Contact Information

Trial Lead Organizations

Eastern Cooperative Oncology Group

Ian Flinn, MD, PhD, Protocol chair(Contact information may not be current)		Ph: 410-614-5542 Email: iflinn@jhmi.edu

Cancer and Leukemia Group B

Michael Grever, MD, Protocol chair		Ph: 614-293-8724 Email: michael.greever@osumc.edu

Southwest Oncology Group

Mohamad Hussein, MD, Protocol chair		Ph: 216-445-6830; 800-862-7798 Email: husseim@ccf.org

Registry Information
Official Title		Phase III Randomized Trial of Fludarabine and Cyclophosphamide Versus Fludarabine for Previously Untreated Chronic Lymphocytic Leukemia
Trial Start Date		1999-12-23
Registered in ClinicalTrials.gov		NCT00003764
Date Submitted to PDQ		1999-01-29
Information Last Verified		2004-04-26
NCI Grant/Contract Number		CA21115

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