Trial Information

A Randomized Prospective Study of Early Intensification Versus Alternating Triple Therapy for Patients With Poor Prognosis Lymphoma

OBJECTIVES:

- Compare the efficacy of early intensification vs alternating triple chemotherapy in
patients with intermediate-grade or immunoblastic lymphoma with poor prognostic
features.

- Compare, in a prospective manner, the cost/benefit ratio of these regimens in these
patients.

- Determine the value of monitoring minimal residual disease detection via in vitro
culture methods and polymerase chain reaction analysis of peripheral stem cell
apheresis products and by longitudinal monitoring of blood and bone marrow samples in
these patients treated with these regimens.

OUTLINE: This is a randomized study. Patients are stratified according to tumor score (3 or
4 vs 5 or 6).

During the first course of induction, patients receive IDSHAP comprising idarubicin (IDA)
and cisplatin IV continuously on days 1-4, cytarabine (ARA-C) IV over 2 hours on day 5, and
methylprednisolone (MePRDL) IV over 15 minutes on days 1-5. During the second course of
induction, patients receive MBIDCOS comprising vincristine, bleomycin, and cyclophosphamide
IV over 15 minutes on day 1, IDA IV continuously and MePRDL IV over 15 minutes on days 1-3,
methotrexate (MTX) IV over 2 hours on day 10, and oral leucovorin calcium every 6 hours on
days 11 and 12. Each course lasts 3 weeks in the absence of disease progression or
unacceptable toxicity.

Patients with stable or responding disease after induction are randomized to 1 of 2
treatment arms.

Arm I

- Patients receive the following 3 courses of early intensification.

- First course: Patients receive ifosfamide (IFF) IV continuously and etoposide
(VP-16) IV over 2 hours every 12 hours on days 1-3. Filgrastim (G-CSF) is
administered subcutaneously (SC) beginning on day 5 and continuing until blood
counts recover and then autologous peripheral blood stem cells (PBSC) are
harvested, selected for CD34 positive cells, and purged in vitro. If more than 5%
of the WBC contains lymphoma cells after induction, then 2 courses of IFF and
VP-16 are administered before PBSC harvest.

- Second course: Patients receive IFF IV continuously on days 1-3, mitoxantrone
(DHAD) IV on day 1, and G-CSF SC as in the first course.

- Third course: Patients receive carmustine IV over 1 hour on day -6, ARA-C and
VP-16 IV every 12 hours on days -5 to -2, and melphalan IV on day -1. PBSC are
reinfused on day 0. G-CSF is administered SC beginning on day 0 and continuing
until blood counts recover. Each course lasts 3 weeks in the absence of disease
progression or unacceptable toxicity.

Arm II

- Patients receive IDSHAP during courses 2 and 5, MBIDCOS during courses 3 and 6, and IFF
and VP-16 IV over 1 hour on days 1-3 and DHAD IV over 15 minutes on day 1 during
courses 1, 4, and 7. Each course lasts 4 weeks in the absence of disease progression or
unacceptable toxicity.

Patients with residual disease after completion of arm I or II treatment undergo
radiotherapy to areas of bulk disease if feasible. Patients on both arms with meningeal
involvement receive ARA-C intrathecally (IT) alternated with MTX every other day until 1
week after clearing of CNS disease and then 2 IT injections during every course of
chemotherapy thereafter. Patients with divergent histology who achieve complete response
after completion of arm I or II treatment receive interferon alfa 3 times a week for 1 year.

Patients are followed at 1 month, every 3 months for 1 year, every 6 months for 1 year, and
then annually for 2 years.

PROJECTED ACCRUAL: A maximum of 136 patients will be accrued for this study within 4 years.