Poor accrual

RATIONALE: Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. It is not yet known if homoharringtonine is more effective than hydroxyurea for chronic myelogenous leukemia that has not responded to interferon alfa.

PURPOSE: Randomized phase III trial to compare the effectiveness of homoharringtonine with that of hydroxyurea in treating patients who have chronic myelogenous leukemia that has not responded to interferon alfa.

OBJECTIVES: I. Compare the overall survival of interferon alfa refractory chronic myelogenous leukemia patients treated with homoharringtonine to those treated with hydroxyurea. II. Compare the time to progression of these patients treated with these two drugs. III. Estimate the complete and major cytogenetic response and describe the serial cytogenetics of these patients treated with these two drugs.

OUTLINE: This is a randomized study. Patients are randomized to receive one of two treatments. Arm I: Induction: Patients receive homoharringtonine IV continuously over 24 hours daily for 14 days. Induction continues every 28 days for a maximum of 6 courses or until hematopoietic recovery. Maintenance: Patients receive homoharringtonine IV continuously over 24 hours daily for 5 days. Treatment repeats every 28 days. Arm II: Induction: Patients receive oral hydroxyurea daily for 28 days until acceptable blood counts are achieved. Maintenance: Patients receive oral hydroxyurea daily every 28 days to maintain acceptable blood counts. Treatment in both arms continues for a minimum of 6 courses in the absence of disease progression or unacceptable toxicity. Patients are followed every 6 months for a maximum of 10 years.

PROJECTED ACCRUAL: A total of 480 patients (240 per arm) will be accrued for this study within 4 years.

1. Documentation of Disease:

   1.1 Diagnosis of Chronic Myelogenous Leukemia (CML) in chronic phase. Patients in either accelerated or blastic phases are not eligible. Clonal cytogenetic evolution alone does not exclude patients. See Appendix I for definitions of accelerated and blastic phases of CML.

   1.2 Patients in whom a Philadelphia chromosome [t(9;22)] is not detectable by cytogenetic studies are eligible if they meet one of the following criteria:

   • BCR/ABL protein detectable by immunoblotting
   • BCR/ABL rearrangement detectable by Southern blot analysis
   • Polymerase chain reaction (PCR) positive fusion transcripts for BCR/ABL
   • BCR/ABL translocation present by fluorescence in situ hybridization (FISH).

2. Prior Treatment:

   2.1 No previous therapy with homoharringtonine (HHT)

   2.2 No more than six months cumulative (<180 days) of prior hydroxyurea (HU) therapy. However, patients may not have received more than 60 days of HU treatment after failing interferon. Patients with previous intolerance or failure to respond to HU are not eligible.

   2.3 Patients must have failed an adequate trial (5M units/m2/day) of alpha-Interferon (IFN) or IFN/ara-C to be eligible, as defined below (any ONE of the following):

   • Failure to achieve a complete hematologic response after 6 months of IFN therapy.
   • Failure to achieve any cytogenetic response (i.e., still 100% Ph+) after 12 months of IFN therapy.
   • Intolerable adverse effects of IFN therapy after at least one month of IFN treatment. Significant documented toxicity of ≥ grade 3 (using NCI Common Toxicity Criteria guidelines) due to IFN is required.
   • Loss of a prior hematologic remission or cytogenetic response to IFN.
   • A two-fold increase in WBC count when compared to WBC count when IFN therapy was initiated.

3. Age ≥ 16 years

4. Patients with uncontrolled tachyarrhythmias (such as, atrial fibrillation, paroxysmal supraventricular tachycardia, and ventricular tachycardias not adequately controlled) are not eligible.

5. Non-pregnant and non-nursing. Treatment under this protocol would expose an unborn child to significant risks. Women and men of reproductive potential should agree to use an effective means of birth control.