• Dose-limiting toxicity [ Designated as safety issue: Yes ]
• Toxicity profile [ Designated as safety issue: Yes ]
• Maximum tolerated dose [ Designated as safety issue: Yes ]
• Clinical response rate [ Designated as safety issue: No ]
• Duration of response [ Designated as safety issue: No ]
• Anti-DT388IL3 antibodies at days 1, 15, and 30 [ Designated as safety issue: No ]
• Serum DT388IL3 levels and half-life [ Designated as safety issue: No ]
• Leukemia blast interleukin-3 receptor density at baseline [ Designated as safety issue: No ]
• Acute myeloid leukemia (AML) progenitor sensitivity to DT388IL3 [ Designated as safety issue: No ]
• Correlation of response to treatment with disease type (relapsed/refractory or poor-risk de novo AML or high-risk myelodysplastic syndromes) [ Designated as safety issue: No ]

• Dose-limiting toxicity
• Toxicity profile
• Maximum tolerated dose
• Clinical response rate
• Duration of response
• Anti-DT388IL3 antibodies at days 1, 15, and 30
• Serum DT388IL3 levels and half-life
• Leukemia blast interleukin (IL)-3 receptor density at baseline
• Acute myeloid leukemia (AML) progenitor sensitivity to DT388IL3
• AML type (relapsed/refractory vs poor risk-de novo)
• Blast cell gene expression at baseline

RATIONALE: Combinations of biological substances in DT388IL3 fusion protein may be able to carry cancer killing substances directly to the cancer cells.

PURPOSE: This phase I/II trial is studying the side effects and best dose of DT388IL3 fusion protein and to see how well it works in treating patients with acute myeloid leukemia or myelodysplastic syndromes.

OBJECTIVES:

• Determine the maximum tolerated dose of DT_388IL3 fusion protein in patients with refractory or relapsed or poor-risk acute myeloid leukemia (AML) or high-risk myelodysplastic syndromes (MDS).
• Define the dose-limiting toxicities of this regimen in these patients.
• Measure the pharmacokinetics of this regimen in these patients.
• Measure the immune responses in patients treated with this regimen.
• Evaluate response and correlate with disease type (relapsed/refractory or poor-risk de novo AML or high-risk MDS), pretreatment marrow blast percentage, and leukemia blast interleukin-3 receptor density.

OUTLINE: This is a phase I, multicenter, dose-escalation study followed by a phase II, open-label study.

• Phase I: Patients receive DT_388IL3 IV over 15 minutes daily for 5 days in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of DT_388IL3 until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.

• Phase II: An additional 15 patients receive DT_388IL3 at the MTD as in phase I. Patients undergo serum and blast collection periodically for laboratory studies, including analysis of expression of interleukin-3 receptors and anti-DT_388IL3 antibodies at baseline. Samples are also analyzed by immunoenzyme assays and flow cytometry.

After completion of study treatment, patients are followed periodically for up to 5 years.

PROJECTED ACCRUAL: A total of 50 patients will be accrued for this study.

• Leukemia
• Myelodysplastic Syndromes

• Biological: DT(388)IL3 fusion protein
• Genetic: gene expression analysis
• Genetic: protein expression analysis
• Other: flow cytometry
• Other: immunoenzyme technique
• Other: laboratory biomarker analysis

DISEASE CHARACTERISTICS:

• Diagnosis of 1 of the following:

  • Histologically or morphologically confirmed acute myeloid leukemia (AML), meeting 1 of the following criteria:

    • Relapsed or refractory AML after treatment with ≥ 1 prior conventional induction therapy

      • Patients in early first relapse must not have a matched donor available and/or be ineligible for allogeneic stem cell transplantation

    • Poor-risk AML, as defined by any of the following criteria:

      • Treatment-related AML, unless associated with favorable cytogenetics (e.g., inversion 16, t[16;16], t[8;21], t[15;17]), and ineligible for stem cell transplantation
      • Antecedent hematological disease (e.g., myelodysplastic syndromes, myelofibrosis, or polycythemia vera) that evolved to AML (≥ 20% blasts) and ineligible for stem cell transplantation
      • De novo AML (must be > 70 years of age)
      • AML with unfavorable cytogenetics (e.g., abnormalities of chromosomes -7, -5, 7q-, or 5q-; complex [≥ 3] abnormalities; or abnormalities of 11q23, excluding t[9;11], t[9;22], inversion 3, t[3;3], and t[6;9]), regardless of age, and ineligible for allogeneic stem cell transplantation

  • High-risk myelodysplastic syndromes diagnosed by morphologic, histochemical, or cell surface marker criteria

    • Resistant or intolerant to chemotherapy
    • Ineligible for or unwilling to undergo immediate allogeneic stem cell transplantation
• Bone marrow index (i.e., percent cellularity × percent blasts) ≤ 40% at time of treatment
• No active CNS leukemia

PATIENT CHARACTERISTICS:

• ECOG performance status 0-2
• Bilirubin ≤ 1.5 mg/dL
• ALT and AST < 2.5 times upper limit of normal
• Albumin ≥ 3 mg/dL
• Creatinine ≤ 1.5 mg/dL
• LVEF ≥ 50%
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for 2 weeks after completion of study treatment
• No complicated medical or psychiatric problems that would preclude study compliance
• No concurrent serious uncontrolled infection or disseminated intravascular coagulation
• No myocardial infarction within the past 6 months
• No allergies to diphtheria toxin
• No requirement for oxygen

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• No other concurrent antineoplastic drugs
• No concurrent radiotherapy
• No concurrent corticosteroids as antiemetics
• No concurrent hematopoietic growth factors (e.g., epoetin alfa, interleukin-11, filgrastim [G-CSF], or sargramostim [GM-CSF])
• No concurrent intravenous immunoglobins