Favorable outcome with STI571 (imatinib mesylate) and allogeneic stem cell transplantation in a case of Ph+ chemorefractory acute lymphocytic leukaemia

Abstract

Summary:We present a patient with a Philadelphia chromosome positive (Ph+) acute lymphocytic leukaemia (ALL) refractory to standard induction chemotherapy. Treatment with the ABL-specific tyrosine kinase inhibitor STI571 (Glivec, Gleevec, imatinib mesylate) resulted in a complete haematologic and cytogenetic remission. Allogeneic stem cell transplantation from an unrelated donor could be undertaken while the patient was in STI571-induced complete remission from the leukaemia. At present, the patient has a 15-month posttransplantation follow-up and is in stable molecular remission as evaluated by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) for the BCR/ABL fusion gene transcript. The Philadelphia chromosome, t(9;22), is found in about 5% of children with ALL but in 15-25% of adults with ALL. The t(9;22) translocation results in a fusion of the oncogene ABL on chromosome 9 with the BCR (breakpoint cluster region) on chromosome 22. The hybrid gene is expressed, with the gene product being a protein of p190 or p210 in size that has tyrosine kinase activity. The t(9;22) translocation with the deregulated tyrosine kinase activity of the BCR/ABL-fusion protein is known to be the causative molecular event in chronic myelogenous leukaemia (CML). 1 The presence of a t(9;22) translocation in ALL is associated with a poor prognosis and a high risk of relapse. 2 Here we report a female patient who presented with chemo- Treatment with the novel ABL-specific tyrosine kinase inhibitor STI571 (Glivec, Gleevec, imatinib mesylate), a drug that has remarkable activity in CML, 3 resulted in a rapid clearance of the blast cells and an allogeneic stem cell transplantation procedure could be performed during complete remission of the leukaemia. Case reportA 43-year-old female was referred to our hospital in January 2000 with a 1-month history of night sweats, weight loss and tiredness. The physical examination was unremarkable and there were no hepatosplenomegaly or palpable lymph nodes. The initial laboratory evaluation revealed haemoglobin 123 g/l, white cell count 100 ϫ 10 9 /l, platelet count 263 ϫ 10 9 /l, and 80% blast cells in the blood smear. A bone marrow aspirate showed 73% blast cells, with morphology compatible with an acute lymphocytic leukaemia. The immunophenotype, established by flow cytometry, was consistent with a pre-B-ALL (CD10 + , CD19 + , CD34 + , HLA-DR + , S Ϫ Ig Ϫ ). Cytogenetic examination revealed a Philadelphia translocation and the karyotype was 46,XX,t(9;22)(14(/45,XX,-21)(3(/46,XX)(4). Presence of the BCR/ABL fusion gene was demonstrated using quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) giving a product corresponding to p190. The leukaemia did not respond to three courses of standard induction chemotheraphy. The patient withstood the three courses without any major complication. The induction courses consisted of ABCDV (ara-C 3 g/m 2 b.i.d., days 1-3; betamethasone, 20 mg/m 2 , days 1-5; cyclophosphamide 600 mg/m 2 , day 1, daunorubicin 30 mg/m 2 , days...

Changes in Therapy for Solid Tumors: Potential for Overcoming Drug Resistance In Vivo with Molecular Targeting Agents

“…In comparison with traditional chemotherapy, imatinib has a surprisingly high complete hematologic response rate of 95% as well as a complete cytogenetic response rate of 60%. 6 Imatinib is also effective in the treatment of Ph1-positive acute lymphoid leukemia (ALL) 7 and gastrointestinal stromal tumor (GIST), although the effectiveness is not as pronounced as that against CML. It has also been shown to be effective against small-cell lung cancer cell lines targeted to c-kit, and against platelet-derived growth factor (PDGF)-driven tumor models, including glioblastoma and dermatofibrosarcoma protuberans.…”