Methotrexate With or Without Cyclophosphamide in Treating Patients With Lymphocytic Leukemia

Eastern Cooperative Oncology Group

Status and phase: Terminated; Phase 2

Conditions: Leukemia

Treatments: Drug: Methotrexate; Drug: Cyclophosphamide; Drug: Prednisone

Study type: Interventional

Funder types: NETWORK; NIH

Identifiers

NCT00003910

E5998 (Other Identifier)

CDR0000067089

U10CA021115 (U.S. NIH Grant/Contract)

Details and patient eligibility

About

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.

Full 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.

Enrollment: 59 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

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.

Trial design

Primary purpose: Treatment

Allocation: N/A

Interventional model: Single Group Assignment

Masking: None (Open label)

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59 participants in 1 patient group

Methotrexate (Cy if no response to MTX)

Experimental group

Description:

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.

Treatment:

Drug: Methotrexate

Drug: Cyclophosphamide

Drug: Prednisone