Methotrexate With or Without Cyclophosphamide in Treating Patients With Lymphocytic Leukemia

A Phase II Study of Initial Treatment With Methotrexate in Large Granular Lymphocytic (LGL) Leukemia

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.

Study Overview

• Status: Terminated
• Conditions: Leukemia
• Intervention / Treatment: Drug: Cyclophosphamide; Drug: Methotrexate; Drug: Prednisone

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
• Enrollment (Actual): 59
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Colorado
    • Aurora, Colorado, United States, 80012
      • Aurora Presbyterian Hospital
    • Boulder, Colorado, United States, 80301-9019
      • Boulder Community Hospital
    • Colorado Springs, Colorado, United States, 80933
      • Penrose Cancer Center at Penrose Hospital
    • Denver, Colorado, United States, 80210
      • Porter Adventist Hospital
    • Denver, Colorado, United States, 80220
      • Rose Medical Center
    • Denver, Colorado, United States, 80218
      • Presbyterian - St. Luke's Medical Center
    • Denver, Colorado, United States, 80204
      • St. Anthony Central Hospital
    • Denver, Colorado, United States, 80218
      • St. Joseph Hospital
    • Denver, Colorado, United States, 80224-2522
      • CCOP - Colorado Cancer Research Program
    • Englewood, Colorado, United States, 80110
      • Swedish Medical Center
    • Grand Junction, Colorado, United States, 81502
      • St. Mary's Regional Cancer Center at St. Mary's Hospital and Medical Center
    • Greeley, Colorado, United States, 80631
      • North Colorado Medical Center
    • Lone Tree, Colorado, United States, 80124
      • Sky Ridge Medical Center
    • Longmont, Colorado, United States, 80501
      • Hope Cancer Care Center at Longmont United Hospital
    • Loveland, Colorado, United States, 80539
      • McKee Medical Center
    • Pueblo, Colorado, United States, 81004
      • St. Mary - Corwin Regional Medical Center
    • Thornton, Colorado, United States, 80229
      • North Suburban Medical Center
    • Wheat Ridge, Colorado, United States, 80033
      • Exempla Lutheran Medical Center
  • Georgia
    • Macon, Georgia, United States, 31208
      • Medical Center of Central Georgia
  • Illinois
    • Aurora, Illinois, United States, 60504
      • Rush-Copley Cancer Care Center
    • Chicago, Illinois, United States, 60611-3013
      • Robert H. Lurie Comprehensive Cancer Center at Northwestern University
    • Evanston, Illinois, United States, 60201-1781
      • Evanston Northwestern Healthcare - Evanston Hospital
    • Joliet, Illinois, United States, 60435
      • Joliet Oncology-Hematology Associates, Limited - West
    • Libertyville, Illinois, United States, 60048
      • North Shore Oncology and Hematology Associates, Limited - Libertyville
    • Urbana, Illinois, United States, 61801
      • Carle Cancer Center at Carle Foundation Hospital
    • Urbana, Illinois, United States, 61801
      • CCOP - Carle Cancer Center
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Methodist Cancer Center at Methodist Hospital
    • Michigan City, Indiana, United States, 46360
      • Saint Anthony Memorial Health Centers
  • Iowa
    • Ames, Iowa, United States, 50010
      • McFarland Clinic, PC
    • Mason City, Iowa, United States, 50401
      • Mercy Cancer Center at Mercy Medical Center - North Iowa
    • Sioux City, Iowa, United States, 51101
      • Siouxland Hematology-Oncology Associates, LLP
    • Sioux City, Iowa, United States, 51104
      • St. Luke's Regional Medical Center
    • Sioux City, Iowa, United States, 51104
      • Mercy Medical Center - Sioux City
  • Maryland
    • Baltimore, Maryland, United States, 21231-2410
      • Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
  • Michigan
    • Kalamazoo, Michigan, United States, 49007
      • Bronson Methodist Hospital
    • Kalamazoo, Michigan, United States, 49001
      • Borgess Medical Center
    • Kalamazoo, Michigan, United States, 49007-3731
      • West Michigan Cancer Center
  • Minnesota
    • Burnsville, Minnesota, United States, 55337
      • Fairview Ridges Hospital
    • Coon Rapids, Minnesota, United States, 55433
      • Mercy and Unity Cancer Center at Mercy Hospital
    • Edina, Minnesota, United States, 55435
      • Fairview Southdale Hospital
    • Fridley, Minnesota, United States, 55432
      • Mercy and Unity Cancer Center at Unity Hospital
    • Hutchinson, Minnesota, United States, 55350
      • Hutchinson Area Health Care
    • Litchfield, Minnesota, United States, 55355
      • Meeker County Memorial Hospital
    • Maplewood, Minnesota, United States, 55109
      • Minnesota Oncology Hematology, PA - Maplewood
    • Maplewood, Minnesota, United States, 55109
      • HealthEast Cancer Care at St. John's Hospital
    • Minneapolis, Minnesota, United States, 55407
      • Virginia Piper Cancer Institute at Abbott - Northwestern Hospital
    • Minneapolis, Minnesota, United States, 55415
      • Hennepin County Medical Center - Minneapolis
    • Robbinsdale, Minnesota, United States, 55422-2900
      • Hubert H. Humphrey Cancer Center at North Memorial Outpatient Center
    • Saint Louis Park, Minnesota, United States, 55416
      • CCOP - Metro-Minnesota
    • Saint Louis Park, Minnesota, United States, 55416
      • Park Nicollet Cancer Center
    • Saint Paul, Minnesota, United States, 55102
      • United Hospital
    • Saint Paul, Minnesota, United States, 55101
      • Regions Hospital Cancer Care Center
    • Saint Paul, Minnesota, United States, 55102
      • HealthEast Cancer Care at St. Joseph's Hospital
    • Shakopee, Minnesota, United States, 55379
      • St. Francis Cancer Center at St. Francis Medical Center
    • Waconia, Minnesota, United States, 55387
      • Ridgeview Medical Center
    • Woodbury, Minnesota, United States, 55125
      • Minnesota Oncology Hematology, PA - Woodbury
    • Woodbury, Minnesota, United States, 55125
      • HealthEast Cancer Care at Woodwinds Health Campus
  • Ohio
    • Canton, Ohio, United States, 44710-1799
      • Aultman Cancer Center at Aultman Hospital
    • Lima, Ohio, United States, 45801
      • St. Rita's Medical Center
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033-0850
      • Penn State Cancer Institute at Milton S. Hershey Medical Center
    • Lemoyne, Pennsylvania, United States, 17043
      • Central Pennsylvania Hematology and Medical Oncology Associates, PC
    • Lewistown, Pennsylvania, United States, 17044
      • Lewistown Hospital
    • Philadelphia, Pennsylvania, United States, 19111-2497
      • Fox Chase Cancer Center - Philadelphia
    • Reading, Pennsylvania, United States, 19612-6052
      • McGlinn Family Regional Cancer Center at Reading Hospital and Medical Center
    • State College, Pennsylvania, United States, 16803
      • Mount Nittany Medical Center
  • Wisconsin
    • La Crosse, Wisconsin, United States, 54601
      • Gundersen Lutheran Center for Cancer and Blood
    • Milwaukee, Wisconsin, United States, 53226
      • Medical College of Wisconsin Cancer Center
    • Milwaukee, Wisconsin, United States, 53226
      • Froedtert Hospital and Medical College of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion:

• 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

Exclusion:

• 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of Patients With Complete or Partial Response to Treatment With MTX	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% improvement.	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.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of Patients With Complete or Partial Response to Treatment of CY Among Patients Failing to Respond to MTX	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% improvement.	Assessed during the first 4 months of treatment and followed until reaching full study stop date

Collaborators and Investigators

• Sponsor: Eastern Cooperative Oncology Group
• Collaborators: National Cancer Institute (NCI)
• Investigators: Study Chair: Thomas P. Loughran, MD, Milton S. Hershey Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): September 15, 1999
• Primary Completion (Actual): December 1, 2010
• Study Completion (Actual): March 1, 2012

Study Registration Dates

• First Submitted: November 1, 1999
• First Submitted That Met QC Criteria: January 26, 2003
• First Posted (Estimated): January 27, 2003

Study Record Updates

• Last Update Posted (Actual): July 5, 2023
• Last Update Submitted That Met QC Criteria: June 20, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Keywords: 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: Neoplasms by Histologic Type; Neoplasms; Leukemia; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-Inflammatory Agents; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Dermatologic Agents; Reproductive Control Agents; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Folic Acid Antagonists; Cyclophosphamide; Prednisone; Methotrexate
• Other Study ID Numbers: CDR0000067089; U10CA021115 (U.S. NIH Grant/Contract); E5998 (Other Identifier: ECOG)