A European population-based registry was designed to provide robust information on the epidemiology and characteristics of CML. All cases of newly diagnosed CML in a sample of almost 93 million adults in 20 European countries were registered. These data allow results of prospective trials to be generalized to most countries. The Evaluating Nilotinib Efficacy and Safety in Clinical Trials as First-Line Treatment (ENEST1st) study included more than 1000 persons with newly diagnosed chronic phase CML. For the first time deep molecular response at 18 months was evaluated as the primary endpoint. Molecular responses were monitored by the EUTOS network of 14 standardized laboratories. Results show a favourable impact of gradual dose-adjustment based on the adverse events profile of nilotinib (2).
Risk of developing peripheral arterial occlusive disease (PAOD) whilst receiving TKIs was evaluated in three phase-3 studies. Nilotinib was associated with higher rates of PAOD compared with imatinib. These data suggest baseline assessment of risk of developing PAOD in persons scheduled to receive nilotinib followed by careful monitoring and appropriate interventions (3).
Treatment for CML has evolved from chemotherapy to interferon-α (IFNα) and finally to TKIs such as imatinib. Unfortunately, imatinib therapy is unlikely to eradicate the most immature leukemia cells (CML stem cells) from which the disease developed. This likely accounts for the substantial relapse rate observed when imatinib is stopped even in persons with no detectable leukaemia by molecular techniques. Interferon alpha (IFNα), unlike imatinib, preferentially targets CML stem cells. A small proportion of persons with CML treated with IFNα do not have leukemia relapse after discontinuing therapy. The mechanisms by which IFNα exerts this anti-leukemia effect is poorly-understood. Activation of leukemia specific immunity may have a role (4).
Serial quantification of BCR-ABL1 mRNA transcript levels is important in monitoring response to TKIs in persons with CML. However, there is substantial variability in reporting of results from different laboratories. Consequently, an international scale (IS) for reporting results has been proposed. Accurate definition of deep molecular responses is increasingly important to optimize therapy and to facilitate comparisons of data sets. Detailed laboratory recommendations, developed by the EUTOS project, may accomplish these goals (5).
Assessment of response 3 months after beginning TKI-therapy is an important tool to predict therapy-efficacy. In this final article from Leukemia an added advantage of calculating the slope of the decline of BCR-ABL1 transcripts is reported. These data suggest persons at risk of CML progression can be precisely identified by the absence of at least a half-log reduction of BCR-ABL1 transcripts at 3 months. Confirmation of these data are, of course, needed, but this approach may help further optimize TKI-therapy (6).
Robert Peter Gale MD, PhD, DSc(hc), FACP and Andreas Hochhaus MD
Editors-in-Chief, Leukemia