DT388IL3 Fusion Protein 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.

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