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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 years¹⁷.

Glivec is confirmed as the standard first-line therapy for all CML patients by clinical studies with 5-year follow-up^4-7.

• 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)⁴.
• 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 CML⁸:

• 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)^{26, 27}, these RR factors predict cytogenetic response (CyR) to Glivec therapy for patients with CML⁸. 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%⁴. 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 ²⁸. At 60-month follow-up, estimated rates of event-free survival (EFS) and overall survival (OS) were 83% and 93%, respectively^{5, 6}. 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 category²⁹.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 reproducible³⁰.

Table 1. Calculation and Definition of Disease Relative Risk.Sokal risk was defined based on patients treated with conventional chemotherapy²⁶. Hasford risk was defined based on patients treated with recombinant IFN-α–based regimens²⁷. The calculation of the risk requires use of clinical and haematological data at diagnosis, before any treatment.

Goals of Therapy, Response-Related Prognostic Factors

The goals of therapy in CML are to achieve an optimal response as early as possible. Specifically, the immediate goal of therapy in patients with CML is to stabilise blood counts, achieve a haematological response, and, ideally, to achieve cytogenetic and molecular responses.
Click on image to enlarge.

Table 2. Primary goals of Ph+ CML therapy: complete cytogenetic and molecular response^{31, 32}.

A haematological response (HR) includes reducing platelet counts to < 450 × 10⁹/L and white blood cell (WBC) counts to <10 × 10⁹/L, decreasing the basophil level to <5%, eliminating immature granulocytes from the peripheral blood, and eradicating the signs and symptoms of disease (Table 2)^{8, 33, 34}. Haematological improvement must be maintained for 1 month to qualify as a response.

Cytogenetic response is an important goal of therapy, with PFS benefits for patients. CyR is based on analysis of BM aspirates and the reduction or elimination of Ph+ cells. Achieving a major cytogenetic response (MCyR) (≤35% Ph+ cells) has been associated with improved survival. MCyRs are divided into complete (0% Ph+ cells) and partial (1%-35% Ph+ cells) responses. Achieving a CCyR is associated with the longest survival rate (Table 2)^8,34.

Molecular analytic techniques, such as FISH or RT-PCR, also may be used to detect the presence or absence of BCR-ABL and monitor disease progression³⁵. There is substantial evidence that major reductions in the level of BCR-ABL transcripts correlate with PFS in patients with CML who achieve a CCyR²⁸. For patients receiving therapy for CML, the magnitude of reduction in tumour burden is a key prognostic indicator. Moreover, most patients treated with Glivec achieve a CCyR, thus increasing the importance of molecular monitoring of residual disease to further stratify response to treatment and to promptly detect risk of loss of response^36-38. Major molecular response (MMR) has been defined as a ≥3-log decrease in BCR-ABL:BCR mRNA transcripts as measured by quantitative RT-PCR, or a BCR-ABL:ABL ratio <0.10%; Table 2)^8,34. Undetectable or unquantifiable levels of BCR-ABL constitute a complete molecular response (CMR⁸). The definition of response, however, is evolving based on differences in prognostic value.

Historical Perspective

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