Mitomycin and Mitoxantrone in Treating Patients With Acute Myelogenous Leukemia

OBJECTIVES: I. Determine whether a single mitomycin C treatment will suppress expression of
one or more proteins associated with the multidrug resistance phenotype in leukemia cells of
patients with refractory acute myelogenous leukemia. II. Determine the maximum tolerated dose
of a combination of mitomycin C followed 72 hours later by a single dose of mitoxantrone in
patients with acute myelogenous leukemia with GM-CSF support. III. Determine the toxicity
profile and pharmokinetics for these combinations of mitomycin C and mitoxantrone. IV.
Determine the ability of this regimen to induce complete response in patients with primary
resistant or refractory acute myelogenous leukemia.

OUTLINE: Patients receive mitomycin C by IV bolus on day 1 of treatment. Patients receive
mitoxantrone beginning on day 4. One patient each is entered at the first and second dose
levels. Dose escalation of mitoxantrone continues in the absence of toxicity. If the patient
experiences toxicity at level 1 or 2, then 2 additional patients are entered at that tier.
Three patients are entered at all subsequent tiers. At these tiers, if no toxicity is
observed, escalation continues. If 1 of the 3 patients experiences toxicity, an additional 3
patients are enrolled at the same dose. If none of these additional patients experiences
toxicity, escalation continues; however, if 1 patient has toxicity, the trial is stopped. If
2 or more have toxicities, the dose is de-escalated. If 2 or more of the original 3 patients
have toxicities, the dose is de-escalated. On day 15, patients are treated with sargramostim
(GM-CSF) intravenously over 4 hours if the bone marrow is free of residual leukemia; GM-CSF
treatment continues until the ANC is greater than 1,500/mm3 for 3 consecutive days.

PROJECTED ACCRUAL: For the pilot study of mitomycin C modulation of multidrug resistance
proteins, 12 patients will be accrued. For the phase I study of mitomycin C and mitoxantrone,
at least 17 patients will be entered.

DISEASE CHARACTERISTICS: Acute myelogenous leukemia, either de novo or secondary (evolving
from myelodysplastic syndrome, myeloproliferative syndrome, or previous treatment for
malignancies other than leukemia) OR Refractory anemia with excess blasts in transformation
Patient is at least 60 years old and at least one of the following is true: Failed one
induction attempt or First or greater relapse OR Patient is 18-59 years old without an
acceptable allogeneic donor and no autologous marrow for transplant and at least one of the
following is true: Failed 2 separate induction attempts, or Second or greater relapse, or
Resistant relapse, or Relapsed post transplant Prior treatment with anthracyclines or
mitoxantrone required Cumulative daunorubicin dose less than 400/m2 required

PATIENT CHARACTERISTICS: Age: 18 and over Performance status: Karnofsky 70%-100% (50% if
hospitalized) Hematopoietic: Not specified Hepatic: Total direct bilirubin no greater than
2.0 mg/dL SGOT and SGPT no greater than 3 x normal Alkaline phosphatase no greater than 3 x
normal No active hepatitis Renal: Not specified Cardiovascular: No myocardial infarction
within last 6 months No congestive heart failure Ejection fraction greater than 50%
(measured by MUGA or 2-D Echo) Pulmonary: No severe chronic obstructive pulmonary disease
Other: No active infection or antimicrobiologically stabilized infection Not pregnant

PRIOR CONCURRENT THERAPY: Biologic therapy: Not specified Chemotherapy: See Disease
Characteristics Endocrine therapy: Not specified Radiotherapy: Not specified Surgery: Not
specified