Trial Information

STI 571 (GLIVEC) in the Treatment of Philadelphia-chromosome Positive and/or BCR/ABL Rearranged Adult Acute Lymphoblastic Leukemia. GIMEMA LAL 0201.

Imatinib shows a specific activity for the ABL protein- tyrosine kinase at the in vitro and
in vivo level. The compound exerts a direct inhibition on the proliferation of BCR/ABL+ve
cells, in cell lines derived from ALL and CML patients, inducing apoptosis. Induction of
apoptosis by imatinib was observed also in primary samples of leukemic cells obtained from
Ph+ve ALL patients. Since activated BCR/ABL tyrosine kinase is present in nearly all
patients with CML and in 25-30% of those with ALL, these two diseases are the ideal targets
to verify the potential therapeutic activity of this ABL specific tyrosine kinase inhibitor.
So far only limited experiences on the therapeutic benefit of imatinib in ALL patients have
been referred. In one of these studies, all 10 treated patients had received prior
chemotherapeutic treatment for their leukemia. Imatinib was administered as daily oral
therapy and all patients were treated on outpatient basis. Different dosages were tested:
300, 400, 500 mg/day for 28 days. Some responding patients showed prolonged
myelosuppression, but only a minority of these required hospitalization, while other side
effects appeared acceptable. Although these results demonstrated that Imatinib, as a single
agent, is active in BCR/ABL +ve ALL, being able to induce a high response rate, however
these responses appeared to be short. This occurred mainly in patients with advanced
leukemia, thus it could be hypothesized that early relapse, in these patients, may due to a
pre-existing resistance or developed resistance to Imatinib. In vitro studies as well as
limited preclinical experiences are showing enhanced antileukemic effects of Imatinib in
combination with cytotoxic drugs, thus further clinical trials should be aimed to ascertain,
mainly in previously untreated patients, which are the optimal dosage and the best duration
of treatment for maximal therapeutic benefit and to test if this agent, combined with
conventional chemotherapy, could really enhance its antileukemic activity.

The Gimema Group will run two distinct studies among the same protocol to verify the
antileukemic activity and safety of imatinib in Ph+ve and/or BCR/ABL +ve ALL:

Study A: Imatinib as post-consolidation therapy in adult (>=18 and <=60 yrs) ALL patients in
1st CHR; Study B: Imatinib without chemotherapy for remission induction in elderly (>60
years) ALL patients.

This proposal, developed in the framework of the GIMEMA, will include:

1. centralization of all biological samples (bone marrow and peripheral blood) at
diagnosis from all new ALL patients, to identify, in particular, Ph + and/or BCR/ABL +
cases;

2. evaluation of the molecular response to the treatment, and monitoring the molecular
status during the hematological remission in all cases in CR;

3. treatment of all adult patients with the same induction and consolidation treatment
already used in the past by GIMEMA for Ph+ ALL, to have also the possibility of an
historical control versus patients treated before the "imatinib era".

Study A: Imatinib in Ph +ve and/or BCR/ABL +ve adult (age <60 years) ALL patients in first
CHR after induction and consolidation treatment.

Aimed to verify the activity and safety of STI 571 administered after the induction and
consolidation therapy in Ph+ve and/or Bcr/Abl+ve ALL patients in 1st CHR (+CMR). A cohort of
38 patients will be enrolled. All Gimema Centers can join this study. Quantitative Rt-PCR
assay is mandatory before start of Imatinib treatment.

Patients will receive on an out-patients basis Imatinib p.o. at the dosage of 400 mg x
2/daily for 6 months. After completing the 6-months therapy, and in absence of safety
concerns, patients may receive additional therapy with Imatinib, provided that, in the
opinion of investigator, the patient has benefited from treatment.

Study B: Imatinib as induction treatment in newly diagnosed Ph+ and/or Bcr/Abl+ elderly (age
>60 years) ALL patients.

Aimed to verify the activity and safety of Imatinib combined with steroids during the
induction phase in elderly (>60 years) Ph+ve and/or Bcr/Abl+ve ALL patients. A cohort of 53
patients will be enrolled. All Gimema Centers can join this study. The cytogenetic and/or
molecular diagnosis must be obtained within 5 days from diagnosis.

Patients will receive Imatinib p.o at the dosage of 400 mg x 2/daily for 30 days on an
out-patients basis. After completing induction therapy patients may receive additional
therapy with Imatinib, provided that, in the opinion of investigator, the patient benefited
from treatment.