Trial Information

A Randomized Trial for Patients With Acute Myeloid Leukemia or High Risk Myelodysplatic Syndrome Aged 60 or Over

OBJECTIVES:

- Compare the response rate, survival, quality of life, and supportive care requirements
with intensive versus nonintensive chemotherapy in older patients with acute myeloid
leukemia or high risk myelodysplastic syndrome.

- Compare response achievement, response duration, survival, toxicity and supportive care
requirements with differing doses of daunorubicin and cytarabine in these patients
receiving intensive chemotherapy.

- Determine the efficacy of PSC 833 in enhancing the effects of daunorubicin in these
patients receiving intensive chemotherapy.

- Compare relapse rate, deaths in complete remission, disease free survival, and survival
with short versus long intensive chemotherapy in these patients.

- Compare response achievement, response duration, survival, toxicity, quality of life,
and resource use with hydroxyurea versus cytarabine in these patients receiving low
dose chemotherapy.

- Determine response achievement, response duration, survival, toxicity, quality of life,
and supportive care requirements with the addition of tretinoin to the nonintensive
chemotherapy in these patients.

- Assess the correlation between P-gp and BCL-2 in family members and treatment outcomes
and other prognostic factors in these patients with these treatment regimens.

OUTLINE: This is a randomized, multicenter study. Patients are randomized or electively
assigned to either intensive or nonintensive chemotherapy*.

Intensive chemotherapy

- Induction therapy: Patients are randomized to 1 of 6 treatment arms. Patients receive 2
courses of chemotherapy comprising 1 of 2 daunorubicin doses, 1 of 2 cytarabine doses,
thioguanine, and with or without PSC 833.

Patients receive daunorubicin IV once daily on days 1-3 with cytarabine IV twice daily and
oral thioguanine once daily on days 1-10 during course 1. Treatment repeats in approximately
31 days as in course 1 except cytarabine and thioguanine are given only on days 1-8.

- Arm I: Patients receive higher dose of daunorubicin, lower dose of cytarabine, and
thioguanine.

- Arm II: Patients receive higher dose of daunorubicin, higher dose of cytarabine, and
thioguanine.

- Arm III: Patients receive lower dose of daunorubicin, lower dose of cytarabine, and
thioguanine.

- Arm IV: Patients receive lower dose of daunorubicin, higher dose of cytarabine, and
thioguanine.

- Arm V: Patients receive treatment as in arm III in combination with continuous infusion
of PSC 833 beginning day 1.

- Arm VI: Patients receive treatment as in arm IV in combination with continuous infusion
of PSC 833 beginning on day 1.

Patients with refractory disease after the first course of induction chemotherapy may
continue with the intensive protocol arm or enter the nonintensive arm*. Patients who do not
achieve complete remission after completion of induction chemotherapy are removed from
study. Patients in complete remission after induction therapy receive consolidation therapy.

- Consolidation therapy: Patients in complete remission after induction are randomized to
either short or long consolidation.

- Short consolidation: Patients receive mitoxantrone IV on days 1-3 and cytarabine
IV over 2 hours twice daily on days 1-3.

- Long consolidation: Patients complete short consolidation and then receive
idarubicin IV over 5 minutes once daily on days 1 and 3, cytarabine IV over 2
hours twice daily and etoposide IV over 1 hour once daily on days 1-3.

Non-intensive chemotherapy*

- Patients are randomized to 1 of 4 treatment arms.

- Arm I: Patients receive oral hydroxyurea as necessary to control WBC count until
treatment failure.

- Arm II: Patients receive hydroxyurea as in arm I and oral tretinoin daily for up
to 16 weeks.

- Arm III: Patients receive low dose cytarabine subcutaneously twice daily on days
1-10 every 28 days for a minimum of 4 courses.

- Arm IV: Patients receive cytarabine as in arm III plus oral tretinoin daily for up
to 16 weeks.

NOTE: *Patients with liver function test > 2 times upper limit of normal are not eligible
for nonintensive randomization

Quality of life is assessed at study entry, and then at 1, 3, and 6 months.

Patients are followed at one year.

PROJECTED ACCRUAL: Approximately 2,000 patients (1,200 to intensive arm and 800 to
nonintensive arm) will be accrued for this study over 5 years.