No hay notas en la diapositiva.
[slide 12] The Ph Chromosome and the bcr-abl Gene The Ph chromosome is the result of a reciprocal translocation, t(9;22)(q34;q11), between the long arms of chromosomes 9 and 22. A segment of the abl gene (Abelson mouse leukaemia proto-oncogene) on chromosome 9q34 coding for a non-receptor tyrosine kinase is translocated to the bcr gene (breakpoint cluster region) on chromosome 22q11 to form an abnormal hybrid bcr-abl gene. 1 The bcr-abl gene is transcribed into a hybrid messenger RNA; the translation product of this RNA is an abnormal fusion protein tyrosine kinase. The abl gene, which spans exons 2 through 11 on chromosome 9, encodes native tyrosine kinase (145 kDa). Wild-type Abl (or c- abl ) kinase has normal signal transduction activity in a non-malignant cell. During the translocation between chromosomes 9 and 22, the breakpoint in the abl gene fragment usually occurs 5 ' of exon 2. In contrast, the breakpoint site on the bcr gene may vary (eg, between exons b1 and b2, b3, or b4), resulting in fusion gene products of varying lengths, which in turn code for fusion protein tyrosine kinases of different molecular masses: 185/190 kDa, 210 kDa, and 230 kDa (not shown), all with tyrosine kinase activity. The Bcr portion of the protein interferes with the regulatory component of the Abl kinase activity, resulting in kinase activity that is constitutively activated. The p210Bcr-Abl fusion protein tyrosine kinase is expressed primarily in CML, the p190Bcr-Abl primarily in Ph+ ALL, and the p230Bcr-Abl in a subset of patients with CML. 1-4 References 1. Pasternak G, Hochhaus A, Schultheis B, et al. Chronic myelogenous leukemia: molecular and cellular aspects. J Cancer Res Clin Oncol . 1998;124:643-660. 2. Sawyers CL. Chronic myeloid leukemia. N Engl J Med . 1999;340:1330-1340. 3. Faderl S, Talpaz M, Estrov Z, et al. The biology of chronic myeloid leukemia. N Engl J Med . 1999;341: 164-172. 4. Melo JV. The diversity of BCR-ABL fusion proteins and their relationship to leukemia phenotype. Blood . 1996;88:2375-2384.
[slide 11] Prevalence of the Ph Chromosome in Haematological Malignancies The Ph chromosome is also seen in leukaemias other than CML. About 5% of childhood ALL, 15% to 30% of adult ALL, and 2% of cases of AML are Ph chromosome – positive (Ph+). 1-3 In some patients with CML, the Ph chromosome may not be detectable by cytogenetic analysis. For those cases, molecular techniques such as Southern blotting, fluorescence in situ hybridisation (FISH), and reverse transcriptase polymerase chain reaction (RT-PCR) can be used to detect the presence of the bcr-abl gene. 4 References 1. Faderl S, Kantarjian HM, Talpaz M. Chronic myelogenous leukemia: update on biology and treatment. Oncology (Huntingt). 1999;13:169-180. 2. Pasternak G, Hochhaus A, Schultheis B, et al. Chronic myelogenous leukemia: molecular and cellular aspects. J Cancer Res Clin Oncol . 1998;124:643-660. 3. Sawyers CL. Chronic myeloid leukemia. N Engl J Med . 1999;340:1330-1340. 4. Faderl S, Talpaz M, Estrov Z, et al. Chronic myelogenous leukemia: biology and therapy. Ann Intern Med . 1999;131:207-219.
[slide 23] Chemotherapy Is Only Palliative in the Treatment of CML Hydroxyurea, an inhibitor of DNA synthesis, and busulfan, an alkylating agent, have been the oral chemotherapeutic agents of choice for CML. These agents may induce complete haematological response in up to 90% of patients with CML in chronic phase, however, cytogenetic responses are rare and disease progression is not affected. Thus, these agents are generally considered to be palliative. 1-5 Of the 2 chemotherapeutic agents, hydroxyurea is more effective than busulfan. Therapy with hydroxyurea is associated with a superior outcome to busulfan (5-year survival 44% vs 32%, respectively) with a significantly longer median survival (58 months vs 45 months, P =.008, respectively). 3,6 Hydroxyurea is generally better tolerated than busulfan; the side-effects associated with hydroxyurea are rare and mild and include nausea, vomiting, diarrhoea, and mucosal and dermal ulcerations. 3,7,8 References 1. Faderl S, Kantarjian HM, Talpaz M. Chronic myelogenous leukemia: update on biology and treatment. Oncology (Huntingt). 1999;13:169-180. 2. The Italian Cooperatitive Study Group on Chronic Myeloid Leukemia. Interferon alfa-2a compared with conventional chemotherapy for the treatment of chronic myeloid leukemia. N Engl J Med. 1994;330:820-825. 3. Hehlmann R, Heimpel H, Hasford J, et al, and the German CML Study Group. Randomized comparison of interferon- with busulfan and hydroxyurea in chronic myelogenous leukemia. Blood. 1994;84:4064-4077. 4. Allan NC, Richards SM, Shepherd PCA, on behalf of the UK Medical Research Council’s Working Parties for Therapeutic Trials in Adult Leukaemia. UK Medical Research Council randomised, multicentre trial of interferon- n1 for chronic myeloid leukaemia: improved survival irrespective of cytogenetic response. Lancet. 1995;345:1392-1397. 5. Ohnishi K, Ohno R, Tomonaga M, et al, and the Kouseisho Leukemia Study Group. A randomized trial comparing interferon- with busulfan for newly diagnosed chronic myelogenous leukemia in chronic phase. Blood. 1995;86:906-916. 6. Silver RT, Woolf SH, Hehlmann R, et al. An evidence-based analysis of the effect of busulfan, hydroxyurea, interferon, and allogeneic bone marrow transplantation in treating the chronic phase of chronic myeloid leukemia: developed for the American Society of Hematology. Blood . 1999;94:1517-1536. 7. Sawyers CL. Chronic myeloid leukemia. N Engl J Med . 1999;340:1330-1340. 8. Hill JM, Meehan KR. Chronic myelogenous leukemia. Curable with early diagnosis and treatment. Postgrad Med . 1999;106:149-152,157-159.
[slide 26] Bcr-Abl as a Therapeutic Target for CML The Bcr-Abl fusion protein, the product of the Ph chromosome, fulfills the criteria for an ideal molecular target in cancer because it is present in 95% of patients with CML. Extensive research has shown that Bcr-Abl is the unique pathophysiological cause of CML. Bcr-Abl tyrosine kinase activity is constitutively increased in CML cells, affecting numerous signal transduction pathways that are essential for leukaemic transformation, including increased cellular proliferation, anti-apoptotic effects, and adhesion defects. Imatinib is a specific tyrosine kinase inhibitor of the Bcr-Abl fusion protein. 1 Reference 1. Druker BJ, Tamura S, Buchdunger E, et al. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat Med . 1996;2:561-566.
[slide 27] Mechanism of Action of Imatinib Imatinib is a potent inhibitor of Bcr-Abl fusion tyrosine kinase. Imatinib acts specifically by inhibiting the binding site for ATP to the Abl kinase, thus blocking the phosphorylation of tyrosine residues on substrate protein. 1 Blocking the binding of ATP inactivates the Abl kinase because it cannot transfer phosphate to its substrate. By inhibiting phosphorylation, imatinib prevents the activation of signal transduction pathways that induce the leukaemic transformation processes that cause CML. Reference 1. Goldman JM, Melo JV. Targeting the Bcr-Abl tyrosine-kinase in chronic myeloid leukemia. N Engl J Med . 2001;344:1084-1086.
[slide 69] Imatinib: Conclusions 1 Imatinib is effective as first-line therapy in newly diagnosed chronic phase CML. Imatinib induces outstanding rates of rapid haematological and cytogenetic responses compared with IFN- + Ara-C. Imatinib is superior to IFN- + Ara-C. Sixty-nine percent of patients achieved a complete cytogenetic response with imatinib compared with 7% on IFN- + Ara-C therapy. Imatinib is generally well tolerated. Patients on imatinib enjoy better quality of life than patients on IFN- + Ara-C. Imatinib should now be considered as the standard first-line therapy for CML. The remaining questions that need to be answered are as follows: Long-term survival The effectiveness of doses above 400mg (several trials are underway) The effectiveness of combinations with IFN- or chemotherapy The role of transplantation versus imatinib Reference 1. Data on file. Novartis Pharma AG, Basel, Switzerland.