Trial Information

Treatment Optimization Trial in Chronic Myeloid Leukemia (CML) - Randomized Controlled Comparison of Imatinib vs. Imatinib/Interferon-alpha vs. Imatinib/Low-Dose AraC vs. Interferon-alpha Standard Therapy and Determination of the Role of Allografting in Newly Diagnosed Chronic Phase

OBJECTIVES:

- Compare the hematologic, cytogenetic, and molecular response rates in patients with
newly diagnosed chronic phase chronic myelogenous leukemia treated with imatinib
mesylate alone or with interferon alfa or low-dose cytarabine vs interferon alfa
standard therapy.

- Compare the group-dependent, progression-free and overall survival and time to
progression in patients treated with these regimens.

- Compare the efficacy of allogeneic stem cell transplantation vs imatinib mesylate-based
therapy in patients eligible for transplantation.

- Compare the efficacy of reduced-intensity conditioning vs standard conditioning in
patients over 45 years of age.

- Determine the time to and duration of hematologic, cytogenetic, and molecular responses
and correlate these factors in patients treated with these regimens.

- Compare the short- and long-term adverse effects of these regimens in these patients.

- Compare the presentation, duration, and responses to therapy of accelerated and blastic
phases in patients treated with these regimens.

- Determine the survival of high-risk patients after early allografting.

- Determine the influence of pre-transplantation therapies on the outcome of allogeneic
stem cell transplantation in these patients.

OUTLINE: This is a randomized, multicenter, pilot study. Patients are stratified according
to participating center. Patients with low- to intermediate-risk disease are randomized to 1
of 4 treatment arms. Patients with high-risk disease are randomized to 1 of 3 treatment arms
with imatinib mesylate-based regimens.

- Arm I: Patients receive oral imatinib mesylate once daily for up to 12 months in the
absence of disease progression or unacceptable toxicity.

- Arm II: Patients receive oral imatinib mesylate as in arm I. Patients also receive
interferon alfa subcutaneously (SC) 3 times a week beginning at least 3 months after
the start of imatinib mesylate.

- Arm III: Patients receive oral imatinib mesylate as in arm I. Patients also receive
cytarabine SC up to twice daily for 5 days monthly beginning at least 3 months after
the start of imatinib mesylate.

- Arm IV: After initial cytoreduction with hydroxyurea, patients receive interferon alfa
SC daily with or without hydroxyurea. In the absence of a complete response after 3
months, patients may also receive low-dose cytarabine SC once daily. Treatment
continues for up to 21 months.

Patients who fail interferon alfa therapy are crossed over to receive imatinib mesylate.

Patients who fail therapy with imatinib mesylate and are eligible for an allogeneic
transplantation are stratified according to availability of donor (HLA-identical related vs
unrelated), status, and participating center. Patients are randomized to receive an
allogeneic transplantation or continue any salvage therapy.

Patients who are not eligible for allogeneic transplantation receive hydroxyurea and
cytarabine or high-dose chemotherapy with autologous stem cell rescue followed by
interferon- or imatinib mesylate-based therapy.

Patients over 45 years of age are further randomized to receive an age-adjusted standard
conditioning regimen or reduced intensity preparative regimen (mini transplantation) prior
to allogeneic transplantation.

Patients are followed every 6 months for 3 years and then annually thereafter.

PROJECTED ACCRUAL: A total of 1,600 patients (400 per treatment arm) will be accrued for
this study within 4-5 years.