Drug therapy for chronic myeloid leukaemia

Question: In patients with recently diagnosed and minimally treated chronic myeloid leukaemia (CML) who are considered suitable for systemic induction and maintenance therapy during the chronic phase, does the use of interferon (IFN) prolong survival compared with busulphan or hydroxyurea? Perspectives: Evidence was selected and reviewed by a working group of five haematologist, three of whom serve with the Hematological Cancer Disease Site Group (DSG) of the Cancer Care Ontario Practice Guidelines Initiative. The present practice guideline has been reviewed and discussed by the Hematological Cancer DSG, which comprises haematologists, medical oncologists, and radiation oncologists. Community representatives did not participate in the development of this report, but will in future reports. Guideline approval requires participation by community representatives. Outcomes: The primary outcome of interest is survival. Adverse effects and quality of life are also considered. Results: Quality of Evidence. The working group found 1 published meta-analysis of individual patient data and 9 reports of eligible randomised controlled trials (RCTS). The practice guideline recommendation is based primarily on the meta-analysis of individual patient data from 7 randomised controlled trials. Benefits. The choice of drug therapy requires balancing the best quality of life on the one hand with prolongation of life on the other. A recently published meta-analysis of individual patient data found that IFN reduced the relative annual death rate of Philadelphia-positive (Ph-positive) patients by 30% compared with any chemotherapy. When compared with hydroxyurea, IFN reduced the annual death rate by 26%, which translates into a 12% absolute improvement in survival at 5 years (46.5% for hydroxyurea vs. 58.6% for IFN, log rank p = 0.001). A French trial found that the combination of interferon and cytarabine provides the greatest prolongation of life: 3-year survival for combination treatment was 86% as compared with 79% for IFN alone (p = 0.02). In 3 trials, busulphan was found to be less effective than other treatment alternatives in prolonging survival; it should not be used as initial treatment. Hydroxyurea is well tolerated, and indirect evidence suggests that, when it is used according to the more intense protocols described in the literature, survival may be comparable to that with IFN. Harms. Discontinuation of medication owing to side effects occurred in 20% of patients taking IFN, in 7% of patients taking busulphan, and in 0.3% of patients taking hydroxyurea. Side effects of IFN were multiple: influenza-like syndrome in 25% of cases, gastrointestinal symptoms in 15%, and other symptoms (haematologic, hepatic, neurologic, dermatologic, and psychiatric) in less than 10% of the patients. Practice Guideline: Recommended therapy for patients with recently diagnosed and minimally treated chronic myeloid leukaemia (CML): Patients being considered for bone marrow transplantation. Hydroxyurea is the preferred therapy when transplantation is to be carried out soon after diagnosis. Interferon, alone or combined with cytarabine (see first two subpoints in "Patients not being considered for transplantation"), may be used to determine prognosis when this knowledge is needed to assist with a decision regarding transplantation. Busulphan should not be used. Patients not being considered for transplantation. Combined therapy with interferon and cytarabine offers the best chance of prolonging survival, but is associated with increased adverse effects as compared with other alternatives. Interferon given as a single agent is the second choice, after combined therapy (interferon and cytarabine), with respect to prolonging survival. Hydroxyurea is the preferred single agent for those wishing to minimise side effects and to preserve quality of life. Patients considering single-agent therapy should be counselled regarding the comparison between interferon and hydroxyurea, with respect to side effects and influence on survival. For patients with CML who are elderly or who have limiting medical conditions, hydroxyurea is the treatment of choice. Available trial results do not provide evidence to guide therapy for patients in this age group; most trials restrict entry to those 70 years and under. General recommendation regarding administration of therapy: When treating patients, the doses and aims of therapy should follow closely those described in the literature (for example, hydroxyurea is given in sufficient dosage to reduce the white cell count to less than 10 × 10⁹/L, and interferon is given to the maximum tolerated dose or to a white cell count of 2-5 × 10⁹/L). Recommendations regarding busulphan: Busulphan should not be used as primary therapy for any patient in chronic phase with CML. Busulphan should not be used prior to transplantation. Busulphan may be effective in some patients during the accelerated phase.