Trial Information

Standard Chemotherapy (CHOP Regimen) Versus Sequential High-Dose Chemotherapy With Autologous Stem Cell Transplantation in Patients With Newly Diagnosed Aggressive Non-Hodgkin's Lymphomas and Poor Prognostic Factors: A Randomized Phase III Study (MISTRAL)

OBJECTIVES:

- Compare the efficacy of sequential high-dose chemotherapy and autologous peripheral
blood stem cell transplantation with standard chemotherapy (cyclophosphamide,
doxorubicin, vincristine, and prednisone) in patients with newly diagnosed aggressive
non-Hodgkin's lymphoma and poor prognostic factors.

- Compare the toxic effects of these 2 regimens in these patients.

- Compare the response rates and overall survival of patients treated with these
regimens.

OUTLINE: This is a randomized, multicenter study. Patients are randomized to one of two
treatment arms.

- Arm I: Patients receive standard chemotherapy comprising cyclophosphamide, doxorubicin,
vincristine, and prednisone (CHOP). Patients receive cyclophosphamide IV over 30
minutes, doxorubicin IV, and vincristine IV on day 1. Patients receive oral prednisone
daily on days 1-5. Treatment repeats every 21 days for 6-8 courses. Patients with bulky
disease at diagnosis or residual disease after chemotherapy receive radiotherapy 30-60
days after initiation of the last course of CHOP.

- Arm II: Patients receive 5 regimens of chemotherapy administered in sequence.

- Regimen A : Patients receive CHOP as in Arm I.

- Regimen B: Three weeks after starting regimen A, patients receive high-dose
cyclophosphamide IV over 24 hours on day 1. Patients without initial bone marrow
involvement receive filgrastim (G-CSF) subcutaneously (SC) daily beginning on day
3 and continuing until autologous peripheral blood stem cells (PBSC) are
harvested. PBSC are harvested on days 13-15 or when blood counts recover. Patients
with initial bone marrow involvement do not undergo harvest of PBSC at this time,
but receive G-CSF SC daily.

- Regimen C: Two to three weeks after high-dose cyclophosphamide, patients receive
vincristine IV and high-dose methotrexate IV over 6 hours on day 2. Patients
receive leucovorin calcium IV every 6 hours on days 3-5 beginning 24 hours after
initiation of the methotrexate infusion.

- Regimen D: Within 1-2 weeks after the administration of methotrexate in regimen C,
patients receive methylprednisolone IV followed 6 hours later by high-dose
etoposide IV over 10 hours on day 1. Patients receive methylprednisolone IV on day
2. Patients without initial bone marrow involvement receive G-CSF SC daily
beginning on day 3 and continuing until blood counts recover. Patients with
initial bone marrow involvement receive G-CSF SC daily until autologous PBSC are
harvested. PBSC are harvested on days 10-14 or when blood counts recover.

- Regimen E: Myeloablative therapy and autologous PBSC transplantation begin 16-40
days after the administration of etoposide. Patients receive mitoxantrone IV over
1 hour every 2 hours for 3 doses on day 2 and melphalan IV over 30 minutes on day
5. PBSC are reinfused on day 6 beginning at least 24 hours after the
administration of melphalan. Patients receive G-CSF SC or by continuous infusion
beginning on day 7.

Patients with bulky disease at diagnosis or residual disease after chemotherapy receive
radiotherapy 30-100 days after PBSC transplantation.

Patients at high risk of developing CNS disease receive prophylactic intrathecal
chemotherapy. Patients may receive cytarabine, methotrexate, and hydrocortisone or
methotrexate and hydrocortisone every 1-2 weeks for 6 courses.

Patients are followed every 3 months for 2 years, every 6 months for 3 years, and then
annually thereafter.

PROJECTED ACCRUAL: Approximately 400 patients will be accrued for this study within 4-5
years.