Leukemia, Myelodysplastic/Myeloproliferative Diseases, Myelodysplastic Syndromes
Conditions
Keywords
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)
Brief summary
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
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.
Interventions
BIOLOGICALsargramostim
DRUGbexarotene
GENETICcytogenetic analysis
GENETICfluorescence in situ hybridization
OTHERflow cytometry
OTHERlaboratory biomarker analysis
PROCEDUREbiopsy
Sponsors
National Cancer Institute (NCI)
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 120 Years
Healthy volunteers
No
Inclusion 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Response (Complete and Partial) | assessed after 2 cycles, up to 2 years | Response to treatment was assessed after two cycles, according to International Working Group (IWG) criteria. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Activity as Measured by Change in Peripheral Blood Counts and Changes in Transfusion Requirements | Baseline and after two cycles | 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. |
| 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 | — |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Bexarotene + GM-CSF 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. | 26 |
| Total | 26 |
Baseline characteristics
| Characteristic | Bexarotene + GM-CSF |
|---|---|
| Age, Continuous | 72 years |
| Region of Enrollment United States | 26 participants |
| Sex: Female, Male Female | 7 Participants |
| Sex: Female, Male Male | 19 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 3 / 26 |
| other Total, other adverse events | 7 / 26 |
| serious Total, serious adverse events | 7 / 26 |
Outcome results
Primary
Clinical Response (Complete and Partial)
Response to treatment was assessed after two cycles, according to International Working Group (IWG) criteria.
Time frame: assessed after 2 cycles, up to 2 years
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Bexarotene + GM-CSF | Clinical Response (Complete and Partial) | SD (stable disease) | 4 Participants |
| Bexarotene + GM-CSF | Clinical Response (Complete and Partial) | PR (partial remission) | 0 Participants |
| Bexarotene + GM-CSF | Clinical Response (Complete and Partial) | HI (hematologic improvement) | 4 Participants |
| Bexarotene + GM-CSF | Clinical Response (Complete and Partial) | PD (progressive disease) | 5 Participants |
Secondary
Biological Activity as Measured by in Vivo Induction of Terminal Differentiation of Myeloid Progenitors and in Vivo Changes in Detectable Chromosomal Abnormalities
Time frame: Baseline and 6, 12, 24, and 36 weeks
Population: Due to the limited number of clinical responders, this research assay was not done.
Secondary
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.
Time frame: Baseline and after two cycles
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Bexarotene + GM-CSF | Clinical Activity as Measured by Change in Peripheral Blood Counts and Changes in Transfusion Requirements | ANC at baseline | 524 neutrophils/mm^3 | Standard Error 95 |
| Bexarotene + GM-CSF | Clinical Activity as Measured by Change in Peripheral Blood Counts and Changes in Transfusion Requirements | ANC after 2 cycles | 931 neutrophils/mm^3 | Standard Error 244 |