Treatment
Historical Perspective
Interferon Alfa
Interferon alfa is a member of a naturally occurring family of proteins that is produced in response to cell division and viral stimuli. Although the precise mechanism of action in CML is unclear, this agent has a variety of known biological effects, including inhibition of cell growth, regulation of cytokine expression, and immune modulation.1 Clinical trials with IFN-α showed both haematological and cytogenetic responses, which correlated with the phase of the disease.2 Haematological responses have been observed in up to 50%-80% of patients with early chronic-phase CML2-5 and complete cytogenetic responses (CCyRs) have been reported in approximately 8%-38% of such patients, with a median time to cytogenetic response of 12-18 months.3,5-9
In late chronic- and advanced-phase CML, IFN-α has only modest activity. HRs can be obtained, but cytogenetic responses are infrequent and transient.2,10-12 Patients who achieve a major cytogenetic response (MCyR) with IFN-α experience a prolonged duration of the chronic phase and extended survival3, with 5-year survival rates of approximately 50%12. The 10-year survival rate from first CCyR with IFN-α therapy ranged from 62% to 82%, with low-risk patients surviving the longest13. Improved survival with IFN-α compared with chemotherapy has been shown in randomised studies and in a meta-analysis.7-10,13 Treatment with IFN-α in combination with cytarabine (Ara-C) has resulted in a higher rate of MCyR and longer survival than treatment with IFN-α alone.5,9-10,14 The addition of Ara-C seems to increase toxicity.5
Despite some favourable results early in the course of CML disease, there is no evidence of a cure with IFN-α as a single agent or in combination with other agents. For patients in the accelerated phase of CML, no improvement in response rates is observed.11 Minimal residual disease remains detectable by polymerase chain reaction (PCR)1,5 however, there is a correlation between low levels of minimal residual disease and continuing remission.16 Most patients ultimately develop resistance to IFN-α and die from the disease. Toxicity is fairly common with IFN-α therapy. Patients may experience a mild-to-moderate flu-like syndrome, and chronic adverse events may include fatigue, weight loss, depression, insomnia, and cognitive dysfunction, as well as gastrointestinal discomfort, neurological and psychiatric disorders, renal dysfunction, and pancytopaenia1. Discontinuation of therapy because of intolerance is common, especially in patients older than 60 years. Approximately 18%-27% of patients stop IFN-α because of severe drug-induced toxicity,5,7 and more than 50% of patients require dose reduction.1,5
References:
1. Faderl S, Kantarjian HM, Talpaz M. Chronic myelogenous leukemia: update on biology and treatment. Oncology (Williston Park).1999;13:169-180; discussion 181, 184.
2. Cortes JE, Talpaz M, Kantarjian H. Chronic myelogenous leukemia: a review. Am J Med. 1996;100:555-570.
3. Kantarjian HM, Smith TL, O'Brien S, Beran M, Pierce S, Talpaz M. Prolonged survival in chronic myelogenous leukemia after cytogenetic response to interferon-alpha therapy. The Leukemia Service. Ann Intern Med. 1995;122:254-261.
4. Faderl S, Talpaz M, Estrov Z, Kantarjian HM. Chronic myelogenous leukemia: biology and therapy. Ann Intern Med. 1999;131:207-219.
5. Guilhot F, Chastang C, Michallet M, et al. Interferon alfa-2b combined with cytarabine versus interferon alone in chronic myelogenous leukemia. French Chronic Myeloid Leukemia Study Group. N Engl J Med. 1997;337:223-229.
6. Ozer H, George SL, Schiffer CA , et al. Prolonged subcutaneous administration of recombinant alpha 2b interferon in patients with previously untreated Philadelphia chromosome-positive chronic-phase chronic myelogenous leukemia: effect on remission duration and survival: Cancer and Leukemia Group B study 8583. Blood. 1993;82:2975-2984.
7. Hehlmann R, Heimpel H, Hasford J, et al. Randomized comparison of interferon-alpha with busulfan and hydroxyurea in chronic myelogenous leukemia. The German CML Study Group. Blood. 1994;84:4064-4077.
8. Ohnishi K, Ohno R, Tomonaga M, et al. A randomized trial comparing interferon-alpha with busulfan for newly diagnosed chronic myelogenous leukemia in chronic phase. Blood. 1995;86:906-916.
9. Long-term follow-up of the Italian trial of interferon-alpha versus conventional chemotherapy in chronic myeloid leukemia. The Italian Cooperative Study Group on Chronic Myeloid Leukemia. Blood. 1998;92:1541-1548
10. Sawyers CL. Chronic myeloid leukemia. N Engl J Med. 1999;340:1330-1340.
11. Kantarjian HM, Keating MJ, Estey EH, et al. Treatment of advanced stages of Philadelphia chromosome-positive chronic myelogenous leukemia with interferon-alpha and low-dose cytarabine. J Clin Oncol. 1992;10:772-778.
12. Sacchi S, Kantarjian HM, O'Brien S, et al. Long-term follow-up results of alpha-interferon-based regimens in patients with late chronic phase chronic myelogenous leukemia. Leukemia. 1997;11:1610-1616.
13. Bonifazi F, de Vivo A, Rosti G, et al. Chronic myeloid leukemia and interferon-alpha: a study of complete cytogenetic responders. Blood. 2001;98:3074-3081.
14. 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.
15. Hochhaus A, La Rosee P. Imatinib therapy in chronic myelogenous leukemia: strategies to avoid and overcome resistance. Leukemia. 2004;18:1321-1331.
16. Hochhaus A, Reiter A, Saussele S, et al. Molecular heterogeneity in complete cytogenetic responders after interferon-alpha therapy for chronic myelogenous leukemia: low levels of minimal residual disease are associated with continuing remission. German CML Study Group and the UK MRC CML Study Group. Blood. 2000;95:62-66.