CML Management
Prognosis
Before the introduction of Glivec® (imatinib), the therapeutic options for chronic myeloid leukaemia (CML) included allogeneic stem-cell transplantation (SCT), interferon-alfa (IFN-α) administration, or chemotherapy with hydroxyurea or busulfan, as well as experimental therapy. The outlook for patients with CML has improved over time due to earlier diagnosis, better supportive care, and improved therapeutic options, including IFN-α and SCT. In the decade preceding the molecular era, median survival time of patients doubled to 5-7 years, with up to 50% of patients alive at 5 years.1
Glivec is confirmed as the standard first-line therapy for all CML patients by clinical studies with 5-year follow-up.2-5
- An 89% overall survival at 5 years with Glivec exceeds that of all other CML therapies, with <5% of deaths related to CML.
- An estimated 98% of patients in chronic-phase CML have had a best response of CHR, and an estimated 92% of patients have had a best response of major cytogenetic response with Glivec
- Late responses to Glivec occur and responses are durable.
- Annual risk of progression is decreasing with time.
The annual rate of progression to advanced phases of CML (accelerated phase/blast crisis) at year 5 declined to 0.6% (from 1.5% in year 1).- Increasing the daily dose of Glivec to 600 or 800 mg may be considered for patients in the absence of severe adverse drug reaction and severe non-leukaemia-related neutropaenia or thrombocytopaenia in certain circumstances, including disease progression, failure to achieve response within prespecified time points, or loss of response (refer to SmPC for further details). 2
- Overall risk of progression to advanced phase is low and is associated with the degree of response, regardless of when achieved.
Continuing follow-up of CML patients in the clinical trials of Glivec is providing evidence of a long-term survival advantage relative to previously available pharmacotherapies for CML, particularly when Glivec is administered in the chronic phase.
Prognostic Factors Associated With Outcomes in Philadelphia Chromosome-Positive (Ph+) CML
There are 2 sets of prognostic factors that can be considered in patients with CML:6
- Baseline factors are those that can be identified before treatment begins, including phase of disease and relative risk (RR) of progression and death.
- Response-related factors are those that can be identified during treatment.
Baseline Prognostic Factors for Systemic Therapy
The phase of disease influences the quality and duration of response expected as well as overall survival, ie, better results are expected in chronic and accelerated phases of CML than in accelerated and blast-crisis phases of CML, respectively. Risk scores ranging from low to intermediate to high have been calculated based on a series of prognostic factors (Table 1).
Although the risk definitions developed by Sokal and Hasford were derived from patients treated with chemotherapy and IFN-α, respectively (Table 1)7,8 these RR factors predict cytogenetic response (CyR) to Glivec therapy for patients with CML.6 Median follow-up of 30 months among patients who received Glivec as first-line therapy in the International Randomised Interferon versus STI571 (IRIS) trial yielded a best-observed complete cytogenetic response (CCyR) rate of 79%, as well as an estimated 30-month progression-free survival (PFS) rate of 88%.2 Patients with a CCyR and a >3-log reduction in their BCR-ABL transcript level at 12 months had a 100% probability of remaining progression free at 24 months.9 At 60-month follow-up, estimated rates of event-free survival (EFS) and overall survival (OS) were 83% and 93%, respectively.3,4 Rates of estimated survival at 42 months were consistently high among chronic-phase patients in all Sokal risk groups (high, 92%; medium, 93%; low, 97%) (NS), suggesting that once CCyR is achieved, rates of survival do not significantly differ by risk category.10 According to initial reports from the European LeukemiaNet CML Registry of 1460 BCR-ABL–positive patients with CML, the proportion of cytogenetic remissions with Glivec therapy at month 12 indicates that the results of the IRIS trial are reproducible.11
Table 1. Calculation and Definition of Disease Relative Risk.Sokal risk was defined based on patients treated with conventional chemotherapy.7 Hasford risk was defined based on patients treated with recombinant IFN-α–based regimens.8 The calculation of the risk requires use of clinical and haematological data at diagnosis, before any treatment.
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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. Glivec Summary of Product Characteristics [SMPC]. Basel, Switzerland: Novartis Pharma AG; 2006.
3. Druker BJ, Guilhot F, O'Brien S, Larson RA, on behalf of the IRIS. Long-term benefits of imatinib (IM) for patients newly diagnosed with chronic myelogenous leukemia in chronic phase (CML-CP): the 5-year update from the IRIS study [abstract]. J Clin Oncol. 2006;24:338s. Abstract 6506. Oral presentation.
4. Druker BJ, Guilhot F, O'Brien SG, et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med. 2006;355:2408-2417.
5. Baccarani M, Guilhot F, Larson RA, G. OBS, Druker B, IRIS obot. on behalf of the IRIS Study Group. Outcomes by cytogenetic and molecular response at 12 and 18 months of imatinib in patients with newly diagnosed chronic myeloid leukemia (CML) in chronic phase (CP) in the IRIS trial [abstract]. Blood. 2006;108:606a. Abstract 2138.
6. Baccarani M, Saglio G, Goldman J, et al. Evolving concepts in the management of chronic myeloid leukemia. Recommendations from an expert panel on behalf of the European LeukemiaNet. Blood. 2006;108:1809-1820.
7. Sokal JE, Cox EB, Baccarani M, et al. Prognostic discrimination in "good-risk" chronic granulocytic leukemia. Blood. 1984;63:789-799.
8. Hasford J, Pfirrmann M, Hehlmann R, et al. A new prognostic score for survival of patients with chronic myeloid leukemia treated with interferon alfa. Writing Committee for the Collaborative CML Prognostic Factors Project Group. J Natl Cancer Inst. 1998;90:850-858.
9. Hughes TP, Kaeda J, Branford S, et al. Frequency of major molecular responses to imatinib or interferon alfa plus cytarabine in newly diagnosed chronic myeloid leukemia. N Engl J Med. 2003;349:1423-1432.
10.Simonsson B. Beneficial effects of cytogenetic and molecular response on long-term outcomes in patients with newly diagnosed chronic myeloid leukemia in chronic phase treated with imatinib: Update from the IRIS study [abstract]. Blood. 2005;106:52a. Abstract 166.
11. Hasford J, Rosti G, Baccarani M, et al. The European Leukemia Net CML Registry--objectives, achievements and first results [abstract]. Blood. 2006;108:279b. Abstract 4781.