High Complete Remission Rate and Promising Outcome by Combination of Imatinib and Chemotherapy for Newly Diagnosed BCR-ABL-Positive Acute Lymphoblastic Leukemia.

Abstract

The BCR-ABL gene rearrangement resulting from Philadelphia chromosome occurs in up to 30% of adult acute lymphoblastic leukemia (ALL), and its presence is known to be the most adverse prognostic factor for ALL. Because long-term survival cannot be achieved by conventional chemotherapy alone, there is a clear medical need for alternative treatment approaches. As a novel agent for this disease, imatinib, a selective inhibitor of BCR-ABL protein kinase, has been the subject of eager anticipation. Previous findings that single-agent treatment induced response in more than 50% of patients, but that the response was not durable, prompted us to plan a phase 2 study to evaluate the efficacy and feasibility of imatinib-combined chemotherapy for newly diagnosed BCR-ABL-positive ALL. In the Japan Adult Leukemia Study Group (JALSG) ALL202 study, screening for BCR-ABL was performed in all patients at presentation, and those with positive BCR-ABL were treated with imatinib-combined chemotherapy. For remission induction therapy, imatinib was administered from day 8 to day 63 in combination with daunorubicin, cyclophosphamide, vincristine (VCR) and prednisolone (PSL). Consolidation therapy consisted of an odd course (C1) comprising high-dose methotrexate and high-dose cytarabine and an even course (C2) with single-agent imatinib for 28 days. C1 and C2 were alternated for 4 cycles each. After the completion of the consolidation therapy, patients received maintenance therapy consisting of VCR, PSL and imatinib up to 2 years from the date they had attained CR. The daily dose of imatinib used in this study was 600mg. Allogeneic hematopoietic stem cell transplantation (HSCT) was recommended if a human leukocyte antigen (HLA)-identical sibling donor was available, and was allowed from an alternative donor. Between September 2002 and January 2005, 80 patients with a median age of 48 years (range, 15 to 63 years) were entered into the trial. Remission induction therapy resulted in complete remission (CR) in 77 (96.2%) patients, resistant disease in one, and early death in two. Polymerase chain reaction (PCR) negativity was confirmed for 50.0% at the end of remission induction therapy. Severe toxicity was not different from that observed with conventional chemotherapy. Twenty-one (26.2%) required interruption of imatinib during the remission induction course, but none of the patients had to withdraw from the study at any time because of adverse events. Relapse occurred in 20 patients after median CR duration of 5.2 months. Allogeneic HSCT was performed for 46 patients, 36 of whom underwent transplantation in their first CR. The 2-year event-free and overall survival (OS) rates were estimated to be 44.9%, and 57.9%, respectively, both of which were significantly better than those for our historical controls treated with chemotherapy alone (p<0.0001 and p=0.0002). The probability for OS at 2 years was 51.5% for those who underwent allogeneic HSCT, and 84.2% for those who did not. These results showed that imatinib-combined regimen is effective and feasible for newly diagnosed BCR-ABL-positive ALL. Although longer follow-up is required to determine its overall effect on survival, this treatment clearly has a major potential for the treatment of BCR-ABL-positive ALL.