Treatment Recommendations

The most complex and controversial aspect of therapy is the treatment algorithm for a patient with previously untreated CML in early chronic phase. The results with imatinib, particularly with higher doses, are excellent. The one major drawback of imatinib treatment is the relatively short follow-up, as this modality has been used for patients with previously untreated chronic-phase CML for only approximately 6 years and as a first line of therapy for approximately 5 years. As the results continue to improve, imatinib would become the preferred therapy for all patients, as it is associated with minimal toxicity and with no treatment-related mortality. If an extrapolation can be made from the IFN-a data, it is reasonable to expect that a significant proportion of patients may be cured with imatinib. Seventy-eight percent of patients who achieve a complete cytogenetic response with IFN-a are alive after 10 years, but only 25-35% of patients achieve this response with IFN-a-based therapy. With imatinib, 80-90% of patients achieve this response. Responses also occur earlier with imatinib, and early responses are associated with an improved long-term outcome. More importantly, the rate of molecular responses is significantly higher with imatinib, suggesting that there are not only more, but better responses with this agent compared to IFN-a. However, the immune modulation that is associated with IFN-a therapy is lacking with imatinib. Immune phenomena are thought to be responsible for the long-term durable cytogenetic and hematologic responses after IFN-a therapy, even in the setting of minimal residual disease (i.e., "functional cures" or dormant state).1062 Allogeneic SCT can be curative in a significant proportion of patients eligible to receive this approach. Besides availability of a donor and age, the major consideration of whether or not to pursue this therapy is the risk of early mortality and the long-term complications. Early mortality is usually lowest among younger patients, particularly those younger than age 20-30 years. Most studies of SCT emphasize the results in the first few years, but late relapses and complications should also be taken into consideration. Extensive chronic GVHD can be seen in as many as 60% of the patients treated,12 and late relapses can occur in some patients.13 All of these issues need to be evaluated when deciding on SCT, and the local experience at the site where the transplant is to be performed needs to be taken into account. When alternative transplant options are being sought, the increased risks and lack of long-term data should be recognized. Matched unrelated transplants may be associated with increased mortality and GVHD, although molecular matching has decreased these risks considerably. Thus, if the local experience is favorable, these transplants could be considered for younger patients.

Nonmyeloablative conditioning regimens have allowed offering transplantation to patients in older age groups or with comorbid conditions. The early mortality is decreased with these transplants, though late complications may be similar to full ablative regimens. These are still relatively new options and there is little long-term data on efficacy and late complications. As longer-term follow-up becomes available regarding the incidence of late relapses and complications, these options may become more standard. Transplantations with alternative donors, such as mismatched and hap-loidentical donors and umbilical cords, should be considered investigational and considered only when other options have failed.

For a patient who has no option for a stem cell transplant, the decision regarding frontline therapy is simple and the treatment of choice is undoubtedly imatinib. More controversial at this time is the proper dose at which treatment should be initiated. The standard dose is 400 mg daily. However, as mentioned earlier, results with higher doses have strongly suggested that these doses are more effective and well tolerated for the majority of patients. Ideally, all patients should be included in clinical trials looking at either highdose imatinib or imatinib-based combinations. Several trials of this nature are currently being performed around the world. For the patient who will not be entered in a clinical trial, although higher doses may be preferred, they may not be practical for financial or other considerations. In such instances, the standard dose can be initiated. Close monitoring is of the outmost importance in such cases, and increasing the dose when response goals are not being met at the desired times should be encouraged.

The decision regarding therapy is more complicated and controversial for young patients who have a fully matched sibling. Results with transplant are best among those younger than age 25-30 years, and SCT should be given consideration. As a patient's age increases, the risks involved with transplantation also increase. For most patients, an initial trial with ima-tinib is probably adequate. However, if the decision is made to start therapy with imatinib, it is important, particularly in the case of the younger patients with an adequate sibling donor, to monitor the patient closely with cytogenetic and molecular monitoring to be certain that the response is progressing as desired.

The proposed ideal goals for patients being treated with imatinib are presented in Table 18.3. For a patient who has not achieved a hematologic response by 3 months, or a minor cytogenetic response by 6 months or partial by 12 months, changing therapies should be strongly considered. What the alternative therapy should be in these cases varies from patient to patient. Increasing the dose of imatinib to 800 mg daily would be the first choice for patients who are being treated with standard dose of imatinib and have had no significant nonhematologic toxicity. If the patient has had hematologic toxicity at the lower doses, the use of hematopoietic growth factors can be considered. For patients who have already been taking higher dose imatinib, and who have the option of an allogeneic stem cell transplant, this option should be considered if the expected 1-year mortality is <40%.

Some scenarios are controversial, and sufficient information may be lacking to make strong recommendations. Patients who achieve a complete cytoge-netic remission but have less than a 3-log reduction in transcript levels have a worse prognosis than those who have at least a 3-log reduction. However, the progression-free survival at 3 years is still 92% and it probably does not justify a change in therapy, particularly when there is a significant risk of mortality or other serious complications. Patients who show an increase in transcript levels after reaching a nadir also pose a dilemma. It has been suggested that a twofold increase may herald the appearance of mutations,63 but this data has not been confirmed by other studies. Also, the short survival proposed for patients with P-loop mutations has not been confirmed in other studies. Thus, at this time, strong recommendations cannot be made based on molecular monitoring alone, particularly when the risks involved with the proposed new therapy are high. The same can be said about the appearance of chromosomal abnormalities in Ph-negative metaphases that occurs in up to 16% of patients. The few instances in which such patients have been diagnosed with myelodysplastic syndromes have been based on soft criteria. Indeed, in many instances these abnormalities may spontaneously disappear. Thus, in the absence of clear data suggesting that these changes affect the long-term outcome of patients, they deserve no more than careful monitoring.

Table 18.3 Recommendations regarding continuation of therapy with imatinib by response at various times after nitiation of imatinib therapy

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