Disease free survival rates for patients with CML (chronic myeloid leukaemia) have increased, thanks to earlier diagnosis, better supportive care, and more effective therapies, such as SCT and IFN-α based treatments. The introduction of signal transduction inhibitors, particularly Glivec, is the most exciting new therapeutic approach to the treatment of CML.
Because disease free survival rates have increased, managed care is a critical issue for patients and for physicians treating CML. Goals in managing the treatment of CML are twofold. First, the aim is to normalize peripheral blood counts down to normal levels (the haematologic response), and second, to eliminate or reduce the degree of the Ph chromosome (known as the cytogenetic and molecular response). Regular RQ-PCR monitoring with selective bone marrow cytogenetic analysis and mutation screening provides the critical information required for clinical decision-making in CML.
Achieving a cytogenetic response — reducing or eliminating the Ph chromosome — and increasing survival is the ultimate goal in treating CML. Major cytogenetic responses, in which 65% or more of leukaemic cells with this genetic abnormality are eliminated, are strongly associated with prolonged patient survival. Although long-term survival data are not yet available, the tyrosine kinase inhibitor Imatinib, which targets the molecular cause of CML, induces higher rates of cytogenetic response than reported historical data for all other drug therapies, including IFN-α. In addition, Imatinib can induce these responses in advanced stages of disease when other therapies are ineffective. It is expected that with longer follow-up of patients treated with Imatinib, these high cytogenetic response rates will translate into a significant survival advantage. The presence of a cytogenetic response predicts a favorable therapeutic outcome for the patient and, conversely, worsening or loss of a response may warn of future relapse. Therefore, regular monitoring of cytogenetic responses is a crucial component of CML therapy. This is rather important, as cytogentics is further able to provide information on additional cytogenetic abnomralities, which are known to be of prognostic value. Whether monitored by classical cytogenetics or by the more sensitive emerging techniques of FISH, the clinical information that is provided by monitoring cytogenetic responses should form the basis for optimizing therapy.
In addition to cytogenetics, Quantitation of BCR-ABL mRNA is emerging as the standard of care to monitor the status of chronic myeloid leukemia (CML). The amount of BCR-ABL transcript in the peripheral blood, measured as a ratio of BCR-ABL to a control gene, provides an estimate of the number of terminally differentiated PH+ cells. Serial studies in which the level of BCR-ABL is tracked in individual patients suggest that it is a good estimate of the total leukemic cell mass. A temporary interruption to imatinib therapy is typically associated with a steady increase in BCR-ABL level, as well as patients developing mutations in the kinase domain of BCR-ABL almost always have a significant rise in the BCR-ABL level consistent with proliferation of resistant leukemic cells. The level of BCR-ABL is also a good predictor of PFS. In the IRIS study, serial RQ-PCR assays indicated that the log reduction in BCR-ABL, measured from the standardized baseline, was a good predictor of subsequent response and risk of progression. The achievement of MMR (≥3 log reduction) by 12 months in the IRIS trial was associated with 100% probability of transformation-free survival at 60 months. MMR was achieved by 40% in the IRIS trial by 12 months and by 55% and 75% at 24 and 44 months, respectively. It is not yet known whether achieving MMR at an earlier time-point by using an increased imatinib dose leads to an improved PFS. Anyway, in both the IRIS and the TIDEL trial molecular response at 3 months proved to be a good predictor of achievement of MMR by 24 months. Another approach to molecular monitoring is to measure the level of BCR-ABL once CCR is achieved, rather than at 3 monthly intervals from the start of therapy, however, taking into account that using this approach the predictive value of the early molecular response will not be realized. In addition, patients not achieving a CCR by 6 months are at higher risk to develop resistance and are therefore most likely to benefit from close molecular monitoring at these early time points.
International Standardization of Molecular Monitoring
The development of an international scale for quantification of BCR-ABL transcript levels is obviously warranted. This would enable molecular responses to be compared in trials assessing different drug regimens where the RQ-PCR assays have been performed in different laboratories using various techniques. It would further allow the clinician relying on RQ-PCR results from a local laboratory to determine with confidence whether their patient had achieved MMR. A consensus meeting in October 2005 at the NIH in Bethesda proposed the establishment of an international scale (IS) that could be applied at individual centers. It was agreed that the IS would be relyed to the MMR level, which would be expressed as a value of 0.1%. The process for the local laboratory to convert their in-house results to the IS involves i) adoption of the consensus principles established by the Bethesda group; ii) testing a set of reference standards to establish a laboratory-specific conversion factor; and iii) multiplying all local BCR-ABL values by the conversion factor to express the results according to the IS. To test the accuracy of this approach, a set of clinical samples assayed in the local laboratory would then need to be sent to an international reference laboratory to verify that the conversion factor provided an accurate conversion.
In summary, the recent developments in treatments and monitoring for CML have provided physicians and patients with more complicated treatment decisions (see ELN Treatment Recommendations)