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

Phase 2
18 Years
Not Enrolling

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Trial Information

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

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.

Inclusion Criteria


- 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

- At least one of the following: Severe neutropenia less than 500/mm3, neutropenia
associated with recurrent infections, symptomatic anemia, or transfusion-dependent

- 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

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.

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Complete, Partial, and Overall Response Rates of Treatment With MTX, and Also With CY for Patients Failing to Respond to MTX

Outcome Description:

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

Outcome 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.

Safety Issue:


Principal Investigator

Thomas P. Loughran, MD

Investigator Role:

Study Chair

Investigator Affiliation:

Milton S. Hershey Medical Center


United States: Federal Government

Study ID:




Start Date:

July 1999

Completion Date:

March 2012

Related Keywords:

  • Leukemia
  • 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
  • Leukemia
  • Leukemia, Lymphoid



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