Similarly, in a randomized, prospective study of 519 patients that compared dasatinib with imatinib, the rate of major molecular response at 12 months was 46% for dasatinib and 28% for imatinib (P < .0001). The rate of major molecular response at 24 months was 64% for dasatinib and 46% for imatinib (P < .0001).[Level of evidence: 1iiDiv] Progression to accelerated-phase CML or blast crisis occurred in 13 patients (5%) on imatinib and in six patients (2.3%) on dasatinib (not statistically different).
Although one of these two studies showed statistically significant decreased rates of progression to accelerated- or blastic-phase CML, which may ultimately translate into improved survival, the follow-up period with nilotinib and dasatinib has not been long enough to detect and confirm this prolonged survival with these agents. The preferred initial treatment for newly diagnosed patients with chronic-phase CML could be any of these specific inhibitors of the BCR/ABL tyrosine kinase.
Higher doses of imatinib mesylate, alternative tyrosine kinase inhibitors (such as dasatinib or nilotinib, and allogeneic SCT) are implemented for suboptimal response or progression and are under clinical evaluation as frontline approaches.[10,11,12,13,14,15,16,17,18] Currently in practice, dose escalation of imatinib is usually the first step taken for suboptimal response, but clinical trials are required to establish the relative efficacy and sequencing of dose escalation, dasatinib, and nilotinib.[15,16] Two studies looked at dose escalation of imatinib in almost 200 previously untreated patients, most of whom were of intermediate Sokal risk; 63% to 73% achieved a major molecular response by 18 to 24 months and only three patients showed progression to advanced phase in these preliminary phase II results.[19,20][Level of evidence: 3iiiDiv] Until randomized studies are performed, it is unclear whether the increased response with increased dosage will translate into longer durations of response or survival advantages.[17,21]
Among the many unanswered questions are the following:
- Will responses on tyrosine kinase inhibitors be durable beyond 10 years, and can we ever stop treatment with them? In a prospective, nonrandomized study, 100 patients in complete molecular remission stopped imatinib after more than 2 years of therapy; by 1 year, 61% of patients relapsed and all responded to the reintroduction of imatinib. Longer follow-up is required to see if some patients maintain a long-term remission after discontinuation of therapy.
- Should the newer tyrosine kinase inhibitors dasatinib or nilotinib replace imatinib as frontline therapy?
- Does time-to-response matter if a good response is obtained eventually?
- Does a good response in a high-risk patient overcome the adverse prognosis of the high-risk features?
- What is the role of allogeneic BMT or SCT for younger, eligible patients and when should it be offered?[13,23,24]
- Should other active agents be added to therapy with tyrosine kinase inhibitors?