Bexarotene and GM-CSF in Treating Patients With Myelodysplastic Syndrome or Acute Myeloid Leukemia

Johns Hopkins Medicine

Status and phase: Completed; Phase 2

Conditions: Leukemia; Myelodysplastic/Myeloproliferative Diseases; Myelodysplastic Syndromes

Treatments: Biological: sargramostim; Genetic: fluorescence in situ hybridization; Procedure: biopsy; Drug: bexarotene; Other: flow cytometry; Other: laboratory biomarker analysis; Genetic: cytogenetic analysis

Study type: Interventional

Funder types: Other; NIH

Identifiers

NCT00425477

JHOC-J0675

P30CA006973 (U.S. NIH Grant/Contract)

J0675 CDR0000525989

JHOC-NA_00003076

Details and patient eligibility

About

RATIONALE: Bexarotene may help cancer or abnormal cells become more like normal cells, and to grow and spread more slowly. Colony-stimulating factors, such as GM-CSF, may increase the number of immune cells found in bone marrow or peripheral blood. Giving bexarotene together with GM-CSF may be an effective treatment for myelodysplastic syndrome (MDS) or acute myeloid leukemia.

PURPOSE: This phase II trial is studying how well giving bexarotene together with GM-CSF works in treating patients with MDS or acute myeloid leukemia.

Full description

OBJECTIVES:

Primary

• Assess the clinical response in patients with myelodysplastic syndromes or acute myeloid leukemia treated with bexarotene and sargramostim (GM-CSF).

Secondary

• Determine the clinical activity of this regimen, in terms of transfusion requirements, in these patients.
• Determine the biological activity of this regimen, in terms of biological markers and cytogenetic abnormalities, in these patients.
• Assess the toxicity profile of this regimen in these patients.

OUTLINE: Patients receive oral bexarotene and sargramostim (GM-CSF) subcutaneously on days 1-28. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

Blood and bone marrow samples are collected at baseline and after 1 or 2 courses of study therapy. Samples are examined by flow cytometry for laboratory studies, including biological markers, and by fluorescent in situ hybridization (FISH) for cytogenetic changes.

After completion of study treatment, patients are followed periodically for 6 months.

PROJECTED ACCRUAL: A total of 18 patients will be accrued for this study.

Enrollment: 26 patients

Sex: All

Ages: 18 to 120 years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

DISEASE CHARACTERISTICS:

• Diagnosis (confirmed by bone marrow aspirate and/or biopsy) of 1 of the following:

  • Myelodysplastic syndromes of 1 of the following cell types:

    • Refractory anemia (RA) with ringed sideroblasts
    • Refractory cytopenia with multilineage dysplasia (RCMD)
    • RCMD and ringed sideroblasts
    • RA with excess blasts-1
    • RA with excess blasts-2
    • Myelodysplastic syndromes, unclassified
    • Chronic myelomonocytic leukemia

  • Relapsed or refractory acute myeloid leukemia (AML), meeting 1 of the following criteria:

    • Recurrent genetic abnormalities (11q23 [MLL] abnormalities)

    • Multilineage dysplasia

    • Therapy-related AML

    • Not otherwise categorized, including any of the following:

      • M0 minimally differentiated
      • M1 without maturation
      • M2 with maturation
      • M4 myelomonocytic leukemia
      • M5 monoblastic/monocytic leukemia
      • M6 erythroid leukemia
      • M7 megakaryoblastic leukemia

• Newly diagnosed untreated AML allowed provided patient does not qualify for or refused potentially curative intensive chemotherapeutic regimens

• No RA with 5q-syndrome

• No peripheral leukemia with blast count > 30,000/mm³ (uncontrolled with hydroxyurea)

• Relatively stable bone marrow function for > 7 days (i.e., no WBC doubling to > 10,000/mm^3)

• No acute promyelocytic leukemia

• No clinical symptoms of active CNS disease (if CNS disease is suspected, patient must have lumbar puncture with negative cytology)

PATIENT CHARACTERISTICS:

• ECOG performance status 0-2
• Creatinine ≤ 2.0 mg/dL
• Bilirubin ≤ 1.6 mg/dL (unless secondary to hemolysis)
• AST and ALT ≤ 4 times upper limit of normal (unless disease related)
• Hemoglobin ≥ 8 g/dL (transfusions allowed)
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective barrier contraception
• No untreated positive blood cultures or progressive infection as assessed by radiographic studies
• No history of intolerance to sargramostim (GM-CSF)

PRIOR CONCURRENT THERAPY:

• Recovered from prior therapy

• At least 2 weeks since prior treatment for myeloid disorder, including any of the following:

  • Chemotherapy
  • Hematopoietic growth factors
  • Biologic therapy (e.g., monoclonal antibodies)

• Hydroxyurea for patients with WBC > 10,000/mm^3 allowed

• No concurrent vitamin A supplementation

• No concurrent gemfibrozil

Trial design

Primary purpose: Treatment

Allocation: N/A

Interventional model: Single Group Assignment

Masking: None (Open label)

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26 participants in 1 patient group

Bexarotene + GM-CSF

Experimental group

Description:

BEX and GM-CSF were administered in 4 week cycles. BEX was given orally with food daily for 28 days at the FDA-approved dose for treatment of CTCL of 300 mg/m2 and GM-CSF was given at a daily dose of 125 µg/m2 subcutaneously for 28 days.

Treatment:

Other: laboratory biomarker analysis

Drug: bexarotene

Genetic: cytogenetic analysis

Biological: sargramostim

Procedure: biopsy

Genetic: fluorescence in situ hybridization

Other: flow cytometry