Trial Information

Treatment for Newly Diagnosed Patients With Stage III/IV Non-Hodgkin Lymphoma-Study XIII (A Therapeutic Pilot Study)

The overall objective of this research study is to determine the toxicity and feasibility of
administration of an intensified, multi-agent chemotherapy regimen for children with stages
III and IV non-Hodgkin lymphoma (NHL), lymphoblastic histiotype. The planned pilot therapy
includes major modifications of our best previous treatments for patients with T-cell acute
lymphoblastic leukemia (ALL) that may improve the disease-free survival of these children
and adolescents. Ultimately, it is intended to propose this therapy for further evaluation
in the setting of a patient population large enough to evaluate its efficacy.

Secondary objectives are:

- To determine the toxicity of high-dose methotrexate (HDMTX) given prior to the
induction/consolidation phase of therapy and of repeated induction treatment (weeks
16-21) in patients with advanced stage NHL, lymphoblastic histiotype.

- To determine the toxicity and feasibility of administration of continuation therapy
which include additional drug pairs not used in the St. Jude Total XI-ALL study.

- To estimate the complete response (CR) rate and event-free survival (EFS) in children
with stage III/IV lymphoblastic NHL after treatment with this intensified multiagent
chemotherapy. Pooling of data from this study with that gained from treatment of
patients with T-ALL on the Total XIII and XIII B studies, with appropriate
stratification, will facilitate this aim.

- To compare plasma and cerebrospinal fluid concentrations of VP-16 after 1 hour of
administration. The data obtained here will be pooled for analysis with that from Total
XIII and Total XIII B studies

- To assess serially whether the frequency of specific HPRT mutations in are related to
cumulative dose of etoposide, or plasma AUC of etoposide, etoposide catechol, or both

- To assess the degree of bone marrow infiltration at the time of diagnosis and serially
during remission using and comparing morphologic, immunologic and molecular methods. In
the absence of morphologically detected tumor cells, we will estimate the frequency of
minimal residual disease (MRD) during remission using immunologic and molecular
methods. The data obtained here will be pooled for analysis with that obtained from
T-cell ALL cases treated on Total XIII and Total XIII B ALL studies.

- Because similar studies are being conducted for patients with T-ALL on the Total XIII
and Total XIII B ALL studies, we will pool data from the present study with that from
T-cell ALL cases treated on Total XIII and Total XIII B ALL studies and correlate
detection of lymphoblasts in bone marrow or cerebrospinal fluid (CSF) with subsequent
clinical course (complete remission duration).

- To evaluate the sensitivity of neoplastic cells at diagnosis to anticancer drugs. This
evaluation will be limited to patients with bone marrow involvement or viable tumor
samples at diagnosis. Information obtained from this aim will complement that obtained
from patients with T-ALL in the Total XIII and Total XIII B ALL studies.

Details of Treatment Plan:

Pre-Induction Chemotherapy

Methotrexate 200 mg/m2/hr IV push, then 800 mg/m2 IV over 24 hours

Induction

Induction Chemotherapy uses several chemotherapy drugs to kill cancer cells in the body and
lasts 6 to 8 weeks.

Prednisone 40 mg/m2/day PO, days 1-29, Vincristine 1.5 mg/m2/week IV, days 1, 8, 15, 22,
Daunomycin 25 mg/m2/week IV, days 1, 8, L-asparaginase 10,000 Units/m2 IM days 2, 4, 6, and
8 Etoposide 300 mg/m2 IV Days 22, 25, 29, Cytarabine 300 mg/m2 IV Days 22, 25, 29 For
infants less than 12 months of age, Vincristine dosage is 0.05 mg/kg/dose. CNS Therapy

All patients will receive triple IT therapy on days 1, 22, and 43. Patients with known CNS
disease will receive additional IT treatments until 2 consecutive CSF studies are normal.
Children with cranial nerve palsies will receive local irradiation to the base of the skull.

Consolidation:

HDMTX 2 g/m2 days 44 and 51. Mercaptopurine 75 mg/m2 PO daily, for 14 days. ITMHA will be
given into spinal fluid (IT) the day before first HDMTX dose.

Continuation

Continuation: Continuation therapy lasts 120 weeks. The following drugs will be given in
different two-drug combinations during this treatment:

Weeks:

1 VP-16 + Cyclo, 2* 6-MP + MTX, 3 MTX + Ara-C, 4 Dex + VCR, 5 VP-16 + Cyclo, 6 6-MP + HDMTX,
7 VP-16 + Ara-C, 8 Dex + VCR 9 VP-16 + Cyclo, 10 6-MP + MTX, 11 MTX + Ara-C, 12 Dex + VCR,
13 VP-16 + Cyclo, 14* 6-MP + HDMTX, 15 VP-16 + Ara-C

IT MHA (MTX, hydrocortisone, Ara-C, dose age dependent, given one day before HDMTX. IT MHA
(every 4 weeks) for patients with CNS 2 or 3 status. Reinduction therapy (same as initial
induction treatment, except that only one dose of VP-16/ara-C will be given on day 22) will
be given from weeks 16 to 21.

Dosages, Schedules and Routes VP-16: 300 mg/m2 IV over 1 hour; once a week,
Cyclophosphamide: 300 mg/m2 IV push; once a week, Mercaptopurine (6-MP): 75 mg/m2 PO; daily
x 7, Methotrexate (MTX): 40 mg/m2 IM or IV once a week; only IM after CNS radiation,
Cytarabine (Ara-C) 300 mg/M2 IV push; once a week, Dexamethasone (Dex): 8 mg/m2 PO; in 3
divided doses daily x 7, Vincristine (VCR) 1.5 mg/m2 IV; once a week (max 2 mg)
L-Asparaginase, (L-ASP): 10,000 U/m2 IM; every 4 weeks x 9, HDMTX: 2 g/m2 IV over 2 hours;
every 8 weeks x 7 (same leucovorin rescue as used in consolidation phase)