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Chemotherapy: Hydroxyurea and Busulfan

Before the introduction of Glivec^® (imatinib), the oral chemotherapeutic agents hydroxyurea (an inhibitor of deoxyribonucleic acid [DNA] synthesis) and busulfan (an alkylating agent) were the drugs of choice for patients who were not stem-cell transplantation (SCT) candidates or who were intolerant of or refractory to interferon alfa (IFN-α). Hydroxyurea and busulfan were also used before SCT. Although haematological responses (HRs) have been reported in up to 90% of patients with newly diagnosed chronic myeloid leukaemia (CML) who were treated with these agents, they rarely induce a cytogenetic response and disease progression is not affected^{3, 39}.

Hydroxyurea is generally better tolerated than busulfan and is more effective: 5-year survival rates are 44% versus 32%, respectively, with a significantly longer median survival of 58 months versus 45 months⁴⁰. Because neither drug inhibits the progression of CML, these agents are considered palliative therapy for symptoms caused by leukocytosis^{3, 39}.

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 modulation¹⁷. Clinical trials with IFN-α showed both haematological and cytogenetic responses, which correlated with the phase of the disease²². Haematological responses have been observed in up to 50%-80% of patients with early chronic-phase CML^{22, 31, 39, 41} 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^3,41-45.

In late chronic- and advanced-phase CML, IFN-α has only modest activity. HRs can be obtained, but cytogenetic responses are infrequent and transient^3,22,46,47. Patients who achieve a major cytogenetic response (MCyR) with IFN-α experience a prolonged duration of the chronic phase and extended survival³¹, with 5-year survival rates of approximately 50%⁴⁷. The 10-year survival rate from first CCyR with IFN-α therapy ranged from 62% to 82%, with low-risk patients surviving the longest³². Improved survival with IFN-α compared with chemotherapy has been shown in randomised studies and in a meta-analysis^{3, 32, 43-45}. 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^{3, 41, 45, 48}. The addition of Ara-C seems to increase toxicity⁴¹.

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 observed⁴⁶. Minimal residual disease remains detectable by polymerase chain reaction (PCR)⁴⁹; however, there is a correlation between low levels of minimal residual disease and continuing remission⁵⁰. 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 pancytopaenia¹⁷. 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^{41, 43}, and more than 50% of patients require dose reduction^{17, 41}.

Stem-cell Transplantation

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