Trial Information

FAB LMB 96 -- TREATMENT OF MATURE B-CELL LYMPHOMA/LEUKAEMIA: A SFOP LMB 96/CCG 5961/UKCCSG NHL 9600 COOPERATIVE STUDY

OBJECTIVES:

- Confirm the previously found excellent survival for low-risk patients (Group A) with
B-cell lymphoma/leukemia treated with the LMB 89 regimen.

- Verify that good event-free survival is retained in intermediate-risk patients (Group
B) when the dose of cyclophosphamide (CTX) or the number of CTX-containing regimens is
reduced.

- Verify that good event-free survival is retained in high-risk patients (Group C)
despite reduction in doses during consolidation therapy and a reduced number of
maintenance courses, and, for patients with CNS involvement, additional intravenous and
intrathecal methotrexate in place of cranial irradiation.

- Monitor survival and event-free survival of all patients registered prior to the first
chemotherapy course.

- Compare the survival and event-free survival of Group C patients with CNS involvement
against results from those treated on the LMB 89 study.

- Compare event-free survival and survival of patients with large cell and Burkitt's and
Burkitt's-like lymphoma.

- Monitor the long-term toxicity in patients treated on this study, including fertility,
cardiotoxicity, and secondary malignancy.

- Characterize further the biology of childhood small non-cleaved cell lymphoma with
respect to drug resistance (i.e., topoisomerase II and MDR activity), viral association
(i.e., Epstein-Barr virus, human immunodeficiency virus, human herpesvirus 6), and
specific breakpoint translocations (i.e., IgH and C-myc) per companion study CCG-B944.

- Characterize further the biology of childhood mature B-cell lymphoma per UKCCSG
studies.

OUTLINE: This is a randomized study. Patients are stratified according to participating
group (UKCCSG vs SFOP vs CCG), histology (large cell vs small non-cleaved cell), risk group
(Group A vs Group B vs Group C). Stage III Group B patients are further stratified according
to Murphy stage (stages I/II vs III vs III/IV) and by LDH (less than twice normal vs twice
normal or higher). Group C patients are further stratified based on presence of CNS disease
(yes vs no).

Patients with resected stage I and resected abdominal-only stage II disease are treated on
the Group A Regimen. Patients with unresected stage I/II, stage III, or CNS-negative stage
IV disease with fewer than 25% blasts in bone marrow are treated on the Group B Regimen.
Patients with 25% or more blasts in bone marrow or with CNS involvement (i.e., L3 blasts in
CSF, cranial nerve palsy, clinical spinal cord compression, isolated intracerebral mass, or
parameningeal cranial or spinal extension) are treated on the Group C Regimen.

The following acronyms are used:

- ARA-C Cytarabine, NSC-63878

- CF Leucovorin calcium, NSC-3590

- COP CTX/VCR/PRED (or PRDL)

- COPAD CTX/VCR/PRED (or PRDL)/DOX

- COPADM CTX/VCR/PRED (or PRDL)/DOX/MTX

- CTX Cyclophosphamide, NSC-26271

- CYM ARA- C/MTX

- CYVE ARA-C/VP-16

- DOX Doxorubicin, NSC-123127

- G-CSF Granulocyte Colony-Stimulating Factor (Amgen), NSC-614629

- HC Hydrocortisone, NSC-10483

- HD High Dose

- MTX Methotrexate, NSC-740

- PRDL Prednisolone, NSC-9900

- PRED Prednisone, NSC-10023

- TIT Triple Intrathecal Chemotherapy (IT MTX/IT HC/IT ARA-C)

- VCR Vincristine, NSC-67574

- VP-16 Etoposide, NSC-141540

Group A Regimen (Low-Risk Patients)

- Induction: Patients receive COPAD: VCR IV on days 1 and 6, oral PRED (or IV) twice
daily on days 1-5, then tapered over 3 days, CTX IV over 15 minutes every 12 hours on
days 1-3, and DOX IV over 6 hours on day 1 starting after the first CTX dose. G-CSF SC
is administered until hematopoietic recovery beginning on day 7. Patients receive a
second course beginning on day 21.

Group B Regimen (Intermediate-Risk Patients)

- Induction 1: Patients receive CTX IV over 15 minutes on day 1, VCR IV on day 1, and
oral PRED on days 1-7, and MTX IT and HC IT on day 1. Patients with responding disease
proceed with COPADM. Patients with no response proceed to treatment on arm I of the
Group C Regimen.

- COPADM 1: Patients receive VCR IV on day 8, oral PRED twice daily on days 8-12, then
tapered over 3 days, MTX IV over 3 hours on day 8, oral CF every 6 hours for 12 doses
beginning 24 hours after start of MTX, CTX IV over 15 minutes every 12 hours on days
9-11, and DOX IV over 6 hours on day 9 beginning after the first CTX dose. G-CSF is
administered as in the Group A Regimen. MTX IT and HC IT are given on days 9 and 13.

- Group B patients are randomized to 1 of 4 treatments following recovery and disease
assessment:

Arm I:

- Induction 2 (begins no sooner than 16 days after start of COPADM 1): Patients receive
COPADM 2 according to the same schedule as in COPADM 1 in Induction 1 except CTX is
increased. G-CSF is administered as in the Group A Regimen. Patients receive MTX IT and
HC IT on days 2 and 6.

- Consolidation: Patients receive CYM: MTX IV over 3 hours on day 1, oral CF every 6
hours for a maximum of 12 doses beginning 24 hours after the start of MTX, and ARA-C IV
over 24 hours on days 2-6. Patients receive TIT: MTX IT on day 2, HC IT on days 2 and
7, and ARA-C IT on day 7.

- Response is assessed upon recovery with resection of residual masses. If histology is
negative patients proceed to a second course of CYM. If histology is positive patients
proceed to CYVE on arm I of the Group C Regimen.

- Maintenance: Patients receive COPADM 3 as in COPADM 1 in Induction 1, except CTX IV is
administered over 30 minutes on days 2 and 3, and MTX IT and HC IT are administered on
day 2.

Arm II:

- Induction 2: Patients receive COPADM 2 as in arm I of the Group B Regimen. G-CSF is
administered as in the Group A Regimen. MTX IT and HC IT are administered as in
Induction 1.

- Consolidation: Patients receive CYM, TIT, and response assessment as in arm I of the
Group B Regimen.

- Maintenance: Patients receive no maintenance therapy.

Arm III:

- Induction 2: Patients receive COPADM 2 as in COPADM 1 in Induction 1. G-CSF is
administered as in the Group A Regimen. Patients receive MTX IT and HC IT as in
Induction 1.

- Consolidation: Patients receive CYM, TIT, and response assessment as in arm I of the
Group B Regimen.

- Maintenance: Patients receive COPADM 3 as in arm I of the Group B Regimen. Patients
receive MTX IT and HC IT on day 2.

Arm IV:

- Induction 2: Patients receive COPADM 2 as in COPADM 1 in Induction 1. G-CSF is
administered as in the Group A Regimen. Patients receive MTX IT and HC IT as in
Induction 1.

- Consolidation: Patients receive CYM, TIT, and response assessment as in arm I of the
Group B Regimen.

- Maintenance: Patients receive no maintenance therapy.

Group C Regimen (High-Risk Patients)

- Induction: Patients receive COP as in Induction 1 of the Group B Regimen, TIT on days
1, 3, and 5, and oral CF every 12 hours on days 2 and 4. Tumor response is evaluated on
day 7 and treatment decisions are made as in Induction 1 of the Group B Regimen.
Patients receive COPADM 1 as in COPADM 1 in Induction 1 of the Group B Regimen except
HD MTX IV is given over 4 hours on day 1. G-CSF is administered as in the Group A
Regimen. TIT is given on days 2, 4, and 6. Patients receive COPADM 2 as in COPADM 2 in
arm I of the Group B Regimen, Induction 2 except HD MTX IV is given over 4 hours on day
1. G-CSF is administered as in the Group A Regimen. Patients receive TIT on days 2, 4,
and 6.

- Patients are randomized to 1 of 2 treatment arms upon recovery and disease assessment:

Arm I:

- Consolidation: Patients receive CYVE: ARA-C IV on days 1-5, and VP-16 IV over 2 hours
on days 2-5. G-CSF is administered as in the Group A Regimen. For patients with CNS
disease: MTX IT and HC IT on day 1, 6 hours prior to initiation of ARA-C, HD MTX IV
over 4 hours, about day 18, oral CF every 6 hours for a maximum of 12 doses, beginning
24 hours after starting MTX, and TIT prior to beginning CF.

- Response is assessed upon recovery with resection of residual masses. Patients with a
complete response receive a second course of CYVE (no HD MTX/CF), beginning 1 week
after HD MTX.

- Maintenance (28 days between courses):

- Course 1: Patients receive COPADM as in arm I Maintenance in the Group B Regimen,
except HD MTX is administered as in Group C Induction, and TIT is given on day 2
replacing MTX IT and HC.

- Course 2: Patients receive CYVE: ARA-C IV every 12 hours on days 1-5, and VP-16 IV
over 90 minutes on days 1-3.

- Course 3: Patients receive COPAD as in Group B Induction 1, except CTX IV is
administered over 30 minutes on days 1 and 2.

- Course 4: Patients receive treatment identical to Course 2.

Arm II:

- Consolidation: Patients receive Mini-CYVE: ARA-C IV on days 1-5, and VP-16 IV over 1
hour on days 2-5. G-CSF is administered as in the Group A Regimen. For patients with
CNS disease: MTX IT and HC IT as in arm I in the Group C Regimen, and HD MTX, CF, and
TIT as in arm I in the Group C Regimen.

- Response is assessed upon recovery with resection of residual masses. Patients with a
complete response receive a second course of CYVE (no HD MTX and CF) beginning 1 week
after HD MTX.

- Maintenance: Patients receive COPADM and TIT as in arm I of the Group C Regimen in
Course 1 for 1 course only.

Patients are followed every 3 months for 6 months, every 6 months for 2.5 years, and then
annually thereafter.

PROJECTED ACCRUAL: A total of 900 patients will be accrued for this study within 5 years.
Yearly accrual is expected to be 20 Group A patients, 115 Group B patients, and 45 Group C
patients.