Methotrexate With or Without Cyclophosphamide in Treating Patients With Lymphocytic Leukemia

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00003910
Recruitment Status : Terminated
First Posted : January 27, 2003
Results First Posted : May 27, 2013
Last Update Posted : November 24, 2017
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Eastern Cooperative Oncology Group

Brief Summary:

RATIONALE: Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die.

PURPOSE: Phase II trial to study the effectiveness of methotrexate with or without cyclophosphamide in treating patients who have lymphocytic leukemia with neutropenia or anemia.

Condition or disease Intervention/treatment Phase
Leukemia Drug: Cyclophosphamide Drug: Methotrexate Drug: Prednisone Phase 2

Detailed Description:

LGL leukemia is characterized by clonal expansion of cytotoxic T cells. Prominent clinical features include neutropenia, anemia, and rheumatoid arthritis. The terminal effector memory phenotype (CD3+/CD8+/CD57+/CD45RA+/CD62L-) of leukemic LGL suggest a pivotal chronic antigen driven immune response. LGL survival is then promoted by PDGF and IL-15, resulting in global dysregulation of apoptosis and resistance to normal pathways of activation-induced death. These pathogenic features explain why treatment of LGL leukemia is based on immunosuppression therapy. However, no standard therapy has been established due to the absence of large prospective trials.

Oral low dose MTX has been shown to be efficacious in the treatment of neutropenia. However, response to MTX is slow, requiring several months for the neutrophil count to increase above 500/mm3. Also, complete clinical remission may not be achieved until after one year of MTX therapy. Oral Cy has been the primary drug used for the treatment of severe transfusion-dependent anemia. Beneficial clinical effects are seen despite this treatment having no apparent effect on the abnormal LGL clone. Normal hematocrits are maintained after cessation of Cy and these results contrast the effects seen with MTX, in which clinical remissions are often associated with the disappearance of the clone.

This phase II trial undertaken by the Eastern Cooperative Group (ECOG) was initiated to investigate the mechanism of treatment response in patients with LGL leukemia, who need treatment for anemia or neutropenia.

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 59 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Study of Initial Treatment With Methotrexate in Large Granular Lymphocytic (LGL) Leukemia
Actual Study Start Date : July 16, 1999
Actual Primary Completion Date : December 1, 2010
Actual Study Completion Date : March 2012

Arm Intervention/treatment
Experimental: Methotrexate (Cy if no response to MTX)
MTX given orally at 10 mg/m2 in divided doses once weekly. Prednisone was given orally at 1 mg/kg per day for 30 days and then tapered off in the subsequent 24 days. Patients not responding to MTX after 4 months received Cy orally at 100 mg daily in step two with the same prednisone schedule.
Drug: Cyclophosphamide
Patients not responding to MTX after 4 months received Cy orally at 100 mg daily in step two with the same prednisone schedule. In patients showing a partial response, but not a CR, the maximum period of therapy was 1 year.
Drug: Methotrexate
Initial treatment consisted of MTX given orally at 10 mg/m2 in divided doses once weekly.
Drug: Prednisone
Prednisone was given orally at 1 mg/kg per day for 30 days and then tapered off in the subsequent 24 days.

Primary Outcome Measures :
  1. Complete, Partial, and Overall Response Rates of Treatment With MTX, and Also With CY for Patients Failing to Respond to MTX [ Time Frame: Assessed during the first 4 months, then at least every three months for two years. Then every six months until five years after study entry, and every 12 months thereafter until full study stop date. ]
    We will report the overall response rate below. Complete remission requires that all of the following be present for at least four weeks: The patient must have a normal CBC including neutrophil count > 1500/mm3, lymphocyte count< 4000/mm3, hemoglobin > 11 g/dl, and platelet count > 100,000/mm3. In addition, the patient must have a normal LGL count. A complete response will be attained if CD8+ cells were less than 760/mm³. A partial response will be defined as achievement of any one of the following in the absence of CR. The response must last for at least four weeks:In patients being treated for severe neutropenia (less than 500 neutrophils/mm3) an improvement to over 500 neutrophils/mm3 will be considered a partial response, as long as that improvement represents at least a 50% impr

Secondary Outcome Measures :
  1. Clinical Response [ Time Frame: Assessed during the first 4 months of treatment and followed until reaching full study stop date ]

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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No


  • Phenotypic studies from peripheral blood showing CD3+, CD57+ cells greater than 400/mm3 or CD8+ cells greater than 650/mm3 within eight weeks prior to registration
  • Evidence for clonal T-cell receptor gene rearrangement within one year prior to registration
  • At least one of the following: Severe neutropenia less than 500/mm3, neutropenia associated with recurrent infections, symptomatic anemia, or transfusion-dependent anemia
  • Bilirubin ≤ 2.0 mg/dl, SGOT(AST) ≤ 1.5 times normal, and Creatinine ≤ 2.0 mg/dl within 4 weeks prior to registration
  • ECOG performance status of 0-2
  • At least 18 years of age
  • Written informed consent


  • Prior therapy with oral MTX or oral Cy
  • Previous or concurrent malignancies except inactive non-melanoma skin cancer, in situ carcinoma of the cervix, or other cancer if the patient has been disease free for over 5 years
  • Pregnant or breast-feeding for female patients
  • Serious medical illness, other than that treated by the study, which would limit survival to less than 2 years, or psychiatric condition which would prevent informed consent

Note: to be eligible for step 2 of this study, patients were required to have no response after at least 4 months of methotrexate treatment.

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To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00003910

  Show 68 Study Locations
Sponsors and Collaborators
Eastern Cooperative Oncology Group
National Cancer Institute (NCI)
Study Chair: Thomas P. Loughran, MD Milton S. Hershey Medical Center

Responsible Party: Eastern Cooperative Oncology Group Identifier: NCT00003910     History of Changes
Other Study ID Numbers: CDR0000067089
U10CA021115 ( U.S. NIH Grant/Contract )
E5998 ( Other Identifier: ECOG )
First Posted: January 27, 2003    Key Record Dates
Results First Posted: May 27, 2013
Last Update Posted: November 24, 2017
Last Verified: October 2012

Keywords provided by Eastern Cooperative Oncology Group:
stage I chronic lymphocytic leukemia
stage II chronic lymphocytic leukemia
stage III chronic lymphocytic leukemia
stage IV chronic lymphocytic leukemia
T-cell large granular lymphocyte leukemia
LGL clone

Additional relevant MeSH terms:
Leukemia, Lymphoid
Neoplasms by Histologic Type
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Abortifacient Agents, Nonsteroidal
Abortifacient Agents
Reproductive Control Agents
Antimetabolites, Antineoplastic
Dermatologic Agents
Enzyme Inhibitors
Folic Acid Antagonists
Nucleic Acid Synthesis Inhibitors
Anti-Inflammatory Agents