Definitions, methodological and statistical issues for phase 3 clinical trials in chronic myeloid leukemia: a proposal by the European LeukemiaNet

Abstract

The treatment policy of chronic myeloid leukemia (CML), particularly with tyrosine kinase inhibitors, has been influenced by several recent studies that were well designed and rapidly performed, but their interpretation is of some concern because different end points and methodologies were used. To understand and compare the results of the previous and future studies and to translate their conclusion into clinical practice, there is a need for common definitions and methods for analyses of CML studies. A panel of experts was appointed by the European LeukemiaNet with the aim of developing a set of definitions and recommendations to be used in design, analyses, and reporting of phase 3 clinical trials in this disease. IntroductionApplied statistics are important tools in medical evaluations. The relevance of statistical designs and statistical results in trials is based on concise definitions regarding diagnosis, management, and treatment strategies. The choice of adequate statistical tests depends on the parameters to be analyzed and on specific end points.After the initial descriptions of chronic myeloid leukemia (CML) more than 160 years ago, little progress was made in its treatment for more than a century. 1 Survival prolongation was first achieved with drugs, such as hydroxyurea. 1 Then, major improvements were obtained with allogeneic hematopoietic stem cell transplantation. First priority at that time was to analyze survival.The understanding of the pathogenesis of CML began with the discovery of the Philadelphia (Ph) chromosome followed later on by the recognition of its molecular counterpart, the BCR-ABL fusion gene. In CML, clinical trials performed during the past 2 to 3 decades have profoundly improved the outcome of patients with CML. 2 In Europe, the coordinators of national CML Study Groups (European Investigators on CML) joined forces to perform European trials and long-term observations, 3 to conduct common meta-analyses, 4,5 and to elaborate new prognostic scores. 6,7 With the advents of IFN-␣ and of tyrosine kinase inhibitors (TKIs), analyses of treatment response moved more into focus.Thus, the relationship between responses and survival became of particular interest. The cytogenetic outcome is usually considered as a reliable surrogate marker for survival in CML, 7,8 whereas the relationship between molecular response and survival is still under investigation. 9 Molecular response is probably more relevant to the issue of treatment discontinuation without relapse and cure. 10 On the other hand, because of the recent improvement of survival offered by the use of TKIs, other diseases and deaths from causes other than CML progression have become more frequent in CML patients. Analysis of survival may include these new parameters. Quality of life and compliance have also to be considered in the context of this chronic disease with an expected long duration of treatment.Consequently, statistical methods in addition to Kaplan-Meier (KM) 11 analyses and initial Cox regression models 12 should be a...

Deep molecular responses achieved in patients with CML-CP who are switched to nilotinib after long-term imatinib

“…An AE of any grade that requires a switch in therapy may be considered a competing risk event for the achievement of response on that TKI, 18 and management of AEs arising on TKI therapy is recommended according to current guidelines. 19 Proper adherence to therapy is essential, as nonadherence can contribute to a reduced ability to achieve molecular responses, a loss of CCyR, and the occurrence of AEs.…”

Imatinib results in better outcomes than HLA-identical sibling transplants in young persons with newly diagnosed chronic-phase chronic myelogenous leukemia

“…This is because our definition of survival is similar to 'alternative treatment-free survival', which is a reasonable approach to assess the usefulness of a study-treatment according to current recommendations. 6 As indicated, there was no substantial change in our conclusions whether or not subjects in the imatinib cohort were censored when they were switched to alternative therapies after failing imatinib. Our transplant results are comparable to those of large series.…”

“…4,5 Outcomes' analyses were based mostly on European LeukemiaNet criteria. 6 Lefttruncated and right-censored methods were used to account for differences in interval from diagnosis to starting therapy 7 and results confirmed by analysis without using left truncation (definitions of left-truncated method and adjusted survival probability were given in Supplementary Table 2). Left-truncated Cox proportional hazards regression models were used to evaluate the relative risk of subjects receiving imatinib versus a transplant.…”

Donor lymphocyte infusions to leukemic bone lesions are therapeutically effective in a Ph+ ALL patient with post-HSCT relapse

“…In addition, trephine biopsy staining was used for determination of lymphocyte sub-sets (CD8, CD56, and CD3) and for blast cells including Ki67 positivity as was detailed elsewhere (Klimczak & Lange, 2000). Molecular karyotyping, fluorescence in situ hybridization (FISH) analysis (9;22 translocation), and detailed enumeration of e1a2 bcr/abl transcripts were done using a standardized RT-PCR approach, as outlined in Baccarani et al (2009) and Guilhot et al (2012). Marrow cell gene expression analysis of interferon (IFN)-, interleukin (IL)-17, RORt, and Notch1 was performed using real-time PCR (primers and probes were purchased from Life Technologies, Foster City, CA); all expression levels were normalized with respect to four housekeeping genes (i.e.…”