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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Phase II Study of Bexarotene + Sargromastastin as Agents of Differentiation in MDS and AML

Conditions
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Leukemia, Myelodysplastic Syndromes, Myelodysplastic/Myeloproliferative Diseases

Intervention / Treatment
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* Biological: sargramostim
* Drug: bexarotene
* Genetic: cytogenetic analysis
* Genetic: fluorescence in situ hybridization
* Other: flow cytometry
* Other: laboratory biomarker analysis
* Procedure: biopsy


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Bexarotene + GM-CSF<br>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. | Biological: sargramostim<br> <br> Drug: bexarotene<br> <br> Genetic: cytogenetic analysis<br> <br> Genetic: fluorescence in situ hybridization<br> <br> Other: flow cytometry<br> <br> Other: laboratory biomarker analysis<br> <br> Procedure: biopsy<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Response (Complete and Partial) | Response to treatment was assessed after two cycles, according to International Working Group (IWG) criteria. | assessed after 2 cycles, up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Activity as Measured by Change in Peripheral Blood Counts and Changes in Transfusion Requirements | ANC count at baseline and after two cycles were measured and compared. Due to the limited number of clinical responders, the changes in transfusion requirements were not measured. | Baseline and after two cycles | 
| Biological Activity as Measured by in Vivo Induction of Terminal Differentiation of Myeloid Progenitors and in Vivo Changes in Detectable Chromosomal Abnormalities |  | Baseline and 6, 12, 24, and 36 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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refractory anemia with excess blasts, recurrent adult acute myeloid leukemia, untreated adult acute myeloid leukemia, secondary acute myeloid leukemia, de novo myelodysplastic syndromes, previously treated myelodysplastic syndromes, secondary myelodysplastic syndromes, myelodysplastic/myeloproliferative disease, unclassifiable, refractory anemia with ringed sideroblasts, refractory cytopenia with multilineage dysplasia, chronic myelomonocytic leukemia, adult acute myeloid leukemia with 11q23 (MLL) abnormalities, adult acute minimally differentiated myeloid leukemia (M0), adult acute myeloblastic leukemia without maturation (M1), adult acute myeloblastic leukemia with maturation (M2), adult acute myelomonocytic leukemia (M4), adult acute monoblastic leukemia (M5a), adult acute monocytic leukemia (M5b), adult pure erythroid leukemia (M6b), adult erythroleukemia (M6a), adult acute megakaryoblastic leukemia (M7), adult acute myeloid leukemia with t(16;16)(p13;q22), adult acute myeloid leukemia with t(8;21)(q22;q22), adult acute myeloid leukemia with inv(16)(p13;q22)