OBJECTIVES:

• Determine the toxic effects and pharmacokinetics of MS-275 in patients with poor-risk hematologic malignancy.
• Determine whether this drug induces changes in hematologic differentiation, in terms of changes in morphology, cell surface marker expression, and acetylation status, in these patients.
• Determine whether this drug induces clinical response in these patients.

OUTLINE: This is a dose-escalation study.

Patients receive oral MS-275 on days 1, 8, 15, and 22. Courses repeat every 6 weeks in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of MS-275 until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which at least 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.

PROJECTED ACCRUAL: Approximately 25-30 patients will be accrued for this study.

DISEASE CHARACTERISTICS:

• One of the following histologically confirmed diagnoses:

  • Acute myeloid leukemia (AML)

    • Newly diagnosed de novo AML in patients over 60 years old with the following poor-risk features:

      • Antecedent hematologic disorder
      • Complex karyotype or other adverse cytogenetics
      • Stem cell immunophenotype
    • AML arising from myelodysplastic syndromes (MDS)
    • Secondary AML
    • Relapsed or refractory AML, including primary induction failure

  • MDS

    • Poor-risk, defined as the following:

      • International Performance Score at least 1.5
      • More than 10% marrow blasts
      • Cytopenias in at least 2 lineages
    • Refractory anemia with excess blasts (RAEB)
    • RAEB in transformation
    • Chronic myelomonocytic leukemia

  • Acute lymphoblastic leukemia (ALL)

    • Newly diagnosed de novo ALL in patients over 60 years old with the following poor-risk features:

      • Complex karyotype or other adverse cytogenetics
      • Mixed lineage immunophenotype
    • Relapsed or refractory ALL, including primary induction failure

  • Chronic myelogenous leukemia (CML)

    • CML in accelerated phase or blast crisis
    • Interferon-refractory CML in chronic phase

  • Multiple myeloma (MM)

    • Relapsed or refractory, including prior autologous stem cell transplantation

  • Acute promyelocytic leukemia

    • Prior treatment with tretinoin
    • Ineligible for arsenic trioxide
    • No evidence of active coagulopathy

    • Low-risk for developing clinically significant coagulopathy during study

      • Low tumor burden by marrow aspiration at time of relapse
      • No prior coagulation-related sequelae (deep vein thrombosis, pulmonary embolism, or CNS thrombosis or bleed)
• Failure after primary induction therapy or relapse after complete remission allowed if patient received no more than 3 courses of prior induction/reinduction therapy
• Not eligible for curative stem cell transplantation
• No hyperleukocytosis with at least 50,000/mm^3 leukemic blasts
• No active CNS leukemia
• No plasma cell leukemia
• No amyloidosis resulting in major organ dysfunction

PATIENT CHARACTERISTICS:

Age:

• 18 and over

Performance status:

• ECOG 0-2

Life expectancy:

• Not specified

Hematopoietic:

• See Disease Characteristics
• No disseminated intravascular coagulation
• No hyperviscosity

Hepatic:

• AST/ALT no greater than 2 times normal
• Alkaline phosphatase no greater than 2 times normal
• Bilirubin no greater than 1.5 times normal

Renal:

• Creatinine no greater than 1.5 times normal
• No uncorrected hypercalcemia

Cardiovascular:

• See Disease Characteristics
• LVEF at least 45% by MUGA or echocardiogram

• No intrinsic impaired cardiac function, including any of the following:

  • Myocardial infarction within the past 3 months
  • Prior severe coronary artery disease
  • Cardiomyopathy
  • Congestive heart failure

Other:

• No active uncontrolled infection
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• See Disease Characteristics
• At least 1 week since prior growth factors (epoetin alfa, filgrastim [G-CSF], sargramostim [GM-CSF], interleukin [IL]-3, or IL-11)
• At least 4 weeks since prior autologous stem cell transplantation
• No prior allogeneic stem cell transplantation
• No concurrent immunotherapy

Chemotherapy:

• See Disease Characteristics
• At least 3 weeks since prior chemotherapy and recovered
• At least 24 hours since prior hydroxyurea or mercaptopurine for prevention of leukostasis
• No concurrent chemotherapy

Endocrine therapy:

• Not specified

Radiotherapy:

• At least 2 weeks since prior emergency radiotherapy to large soft tissue or lytic bony lesions for MM
• No concurrent radiotherapy

Surgery:

• Not specified

Other:

• At least 24 hours since other prior noncytotoxic agents for prevention of leukostasis
• No other concurrent antitumor therapy