Chronic Myeloid Leukemia (CML): A Model Disease for Utilizing Evidence Based Guidelines in a Decade of Progress.
Authors: Silver Richard T. , Baccarani Michele , Vandris Katherine , Guilhot Francois , Simonsson Bengt , Hochhaus Andreas , Hehlmann Rudiger ,   the European LeukemiaNet6
Published: October 2019

The importance of evidence-based guidelines (EBG), including CML, has been long recognized and supported by the American Society of Hematology (ASH). The extraordinary progress in treating CML with imatinib is well known, yet there remains need for alternative treatment for imatinib (IM) resistant disease. This mandated an up-to-date evaluation of current treatment results and methods for quantifying treatment effects. The European LeukemiaNet therefore assembled 19 experts from 9 countries in Europe, the USA, and Australia to recommend new guidelines for evaluating the treatment of CML. Eight members of the current committee were also members of the prior ASH committee of 1998. We also examined progress in evidence-based CML trials since the last (1998) ASH guidelines publication. A computerized Medline search of relevant literature since 1998 was conducted together with pertinent abstracts presented in 2004 and 2005 at ASH, ASCO, and European and International Society meetings. The new major conclusions are: the initial treatment recommended for nearly all CML patients is IM 400mg/d (for very young patients with an appropriate HLA match, allo HSCT may be considered). Failure is defined as no hematologic response (HR) at 3 mos, incomplete HR, or no cytogenetic response (CgR) at 6 mos, less than partial CgR at 12 mos (Ph>35%), less than complete CgR at 18 mos, and loss of HR or CgR or the appearance of IM resistant BCR-ABL mutations with a major increase of the IC50 to IM. Suboptimal response is defined as incomplete HR at 3 mos, less than partial CgR at 6 mos, less than complete CgR at 12 mos, less than major molecular response (MMolR) at 18 mos, loss of MMolR, BCR-ABL mutations with a minor increase of IC50 to IM, or additional chromosome abnormalities. In this event, a dose increase of IM, allo HSCT, dasatinib, or investigational agents are recommended. The importance of regular molecular monitoring for BCR-ABL transcripts is stressed. We compared the data of the EBG of 1998 with those of 2006. Older data (1998) often did not include relevant information such as age, physical findings, duration of follow up, and long-term survival. In general, sample sizes were small, and treatment protocols were not adhered to systematically. External review committees did not exist and committee members felt personally challenged if their opinions, not evidence-based, disagreed with the majority. Based on evidence, an overall superiority of allo HSCT compared to interferon-based regimens could not be demonstrated. Studies of the past 8 years have substantially corrected the deficiencies of the past. Shared decision-making between patient and physician remains critical. The current guidelines represent an important achievement of the European LeukemiaNet, reflect improved scientific quality of CML trials, and are a splendid example of international cooperation.