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

• to evaluate the activity and toxicity of imatinib in the treatment of Ph+ acute lymphoblastic leukemia;
• to evaluate the molecular response to the treatment, and to monitor the molecular status of remission in all cases achieving or not a molecular response.

The GIMEMA has activated a network to centralize all biological samples (bone marrow and peripheral blood) at diagnosis from all new ALL patients. This will permit to identify, in particular, Ph + and/or BCR/ABL + cases within 5 days from diagnosis, thus permitting to treat these patients according to different programs on the basis of the presence of Ph chromosome.

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.

Inclusion Criteria:

• Patients with Ph +ve and/or BCR/ABL +ve ALL, either in 1st CHR (independently from the molecular status) for study A, or at diagnosis and untreated for study B;
• Age >18 years and <60 for study A, >60 for study B;
• Written voluntary informed consent.

Exclusion Criteria:

• Patients of childbearing potential without a negative pregnancy test prior to the initiation of study. Barrier contraceptive precautions are to be used throughout the trial in both sexes;
• Pretreatment with steroids for more than 10 days in study B;
• Serum bilirubin and creatinine values >3 the upper limit of normal range;
• SGOT and SGPT values >3 the upper limit of the normal range;
• Patients who had received any other investigational agent within 4 weeks before the enrollment;
• Patients with cardiovascular diseases grade >3 according to the New York Heart Association (see Appendix 1);
• Patients with a history of non compliance to medical regimen or who are considered potentially unreliable;
• Patients with moderate/severe mood or psychiatric disorders;
• Concomitant neoplasia.