Best First Line Tyrosine Kinase Inhibitor for Chronic Phase Chronic Myeloid Leukemia in Adults: A Network Meta-Analysis

For many years chronic myeloid leukemia (CML) remained a leukemic subtype in which little improvement was gained with regard to overall survival (OS). Imatinib, the rst tyrosine kinase inhibitor (TKI), completely changed patients’ life expectancy. Although many studies have compared the use of imatinib and more recent TKIs in patients with newly diagnosed chronic phase (CP) CML, they have not established which is the most effective. Since there are no randomised controlled trials (RCTs) that compare head-to-head second- and third-generation TKIs, a network meta-analysis (NMA) is required to identify the best TKI to be preferably used. AP: Accelerated ASCO: Bcr-Abl: Breakpoint Cluster Region - Abelson Gene; BIHAM: Institute of Primary Health Care of Bern; BM: Bone Marrow; BP: Blast Phase; CCyR: Complete Cytogenetic Response; CINeMA: Condence in Network Estimates; CML: Chronic Myeloid Leukemia; CP: Chronic Phase; EHA: European Haematology Association; EMR: Early Molecular Response; ESMO: European Society for Medical Oncology; FISH: Fluorescent in Situ Hybridization; GRADE: Grading of Recommendations Assessment, Development and Evaluation; IRCCS: Istituto di Ricovero e Cura a Carattere Scientico; MMR: Major Molecular Response; MR: Molecular Response; NCCN: National Comprehensive Cancer Network; NMA: Network Meta-Analysis; PFS: Progression-Free Survival; Ph+: Philadelphia Chromosome-Positive; PROSPERO: International Prospective Register of Systematic Reviews; RCT: Randomised Controlled Trial; RoB: Risk of Bias; RT-PCR: Reverse Transcription Polymerase Chain Reaction; OS: Overall Survival; SIE: Italian Society of Hematology; SUCRA: Cumulative Ranking Curve; TKI: Tyrosine Kinase Inhibitor.


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Background For many years, chronic myeloid leukemia (CML) remained a leukemic subtype in which little improvement was gained with regard to overall survival (OS). [1][2][3] Imatinib (Glivec, Novartis), the rst tyrosine kinase inhibitor (TKI), completely changed patients' life expectancy. 4 It was approved in 2001 (in Europe and the USA) for all CML phases and, as its patent has expired, is now available as a generic drug. 5 The third-generation TKI, ponatinib (Iclusig, ARIAD), was approved in the USA in 2012 and in Europe in 2013 for the treatment of adults with CP, AP or BP Ph+ CML who are resistant to, or intolerant of other TKIs, and those with CP, AP or BP Ph+ CML and the T315I mutation known to be involved in resistance to imatinib. 15,16 Although many studies have compared the use of imatinib and more recent TKIs in patients with newly diagnosed Ph+ CP CML, they have not established which is the most effective because they have not always considered the same outcomes and often evaluated them at different times; only some studies provided complete OS and progression-free survival (PFS) data; and the large number of adverse events (AE) are not speci c to a single TKI. [17][18][19][20] Furthermore, the 2017 European Society for Medical Oncology (ESMO) and 2018 National Comprehensive Cancer Network (NCCN) CML guidelines did not make any precise recommendations that would help clinicians decide. [21][22] Otherwise, our previous systematic review and meta-analysis of randomised controlled trials (RCTs) ("First-line imatinib vs second-and third-generation TKIs for chronic phase CML: a systematic review and meta-analysis" by C. Vener et al., PROSPERO Registration No. CRD42016032903) provided complete, updated and precise comparative information concerning the use of TKIs in patients with newly diagnosed adult CP CML in terms of OS and PFS at various time points, clinical and biological response variables, and the most relevant hematological and non-hematological AEs. 23 Biases and the quality of the evidence were assessed using the Cochrane risk of bias tool (RoB) and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) method. 24-25 On the basis of secondary e cacy outcomes, we suggested that patients with newly diagnosed CP CML without co-morbidities should receive second-or third-generation TKIs; however, on the basis of toxicity outcomes, patients with co-morbidities should preferably be treated with imatinib. Unfortunately, we couldn't recommend a speci c newer TKI because there are no head-to-head RCTs between second-and thirdgeneration TKIs, but we could only compare imatinib with newer TKIs considered as a whole. Network meta-analysis (NMA) is a statistical method that allows researchers to compare (indirectly) treatments that have never been compared head-to-head in a trial. 26 For our project, a NMA is therefore required to identify the TKI with the best e cacy-safety pro le to be preferably used.

Methods/design
Review question This systematic review and NMA of RCTs will compare the e cacy and safety of imatinib vs secondgeneration (dasatinib, nilotinib, bosutinib) and third-generation TKIs (ponatinib), considered individually, in adults with newly diagnosed Ph+ CP CML. The evaluated outcomes will be OS, PFS, response, and safety (hematological and non-hematological AEs) (review protocol PROSPERO registration number:

CRD42020190444). 27 This protocol is written in accordance with the guidelines of Preferred Reporting
Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P). The PRISMA-P checklist can be found in Additional le 1.

Searches
To identify the published or unpublished studies of interest we will systematically search for RCTs or quasi-RCTs in the databases PubMed, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL) and ClinicalTrials.gov, from 1990 to 2020. Our search stategy is reported in Additional le 2 (Appendix). We will scan the reference lists of the articles identi ed, recent systematic reviews, metaanalyses and guidelines to identify other pertinent studies. We will also screen the abstracts of the main conferences in the eld (the American Society of Hematology, ASH; the American Society of Clinical Oncology, ASCO; the European Haematology Association, EHA; the Italian Society of Hematology, SIE). We will invite all of the manufacturers of the TKIs in question to provide any unpublished material. No language restrictions will be imposed.

Participants/population
Adult patient (>= 18 years old) with newly diagnosed (within 6 months) Ph+ CP CML, by peripheral blood or bone marrow (BM) cytogenetics or uorescent in situ hybridization (FISH), or the detection of Bcr-Abl transcript by reverse transcription polymerase chain reaction (RT-PCR); treatment with a TKI prior to study entry is not allowed except for no more than 2 weeks in duration of imatinib; any other medical treatment for CML prior to study entry for longer than 2 weeks is not allowed with the exception of hydroxyurea and/or anagrelide.
Intervention Imatinib, at any dose.

Comparator
Second generation TKIs, dasatinib, nilotinib, bosutinib, at any dose; third generation TKI, ponatinib, at any dose. We will exclude studies with interventions other than TKI, e.g. interferon-a, chemotherapy, stem cell transplantation, or best supportive care.
Types of study to be included initially Published and unpublished RCTs. Trials for which it was unclear whether the method of randomisation provided adequate allocation concealment (quasi-RCTs) and open-label RCTs will be considered, but their quality will be taken into account. We will exclude non-randomised studies.

Data extraction
The full text of the potentially eligible studies will be retrieved and independently assessed for eligibility by two review team members. The same two review authors will independently extract the following information from each study: publication date, study design characteristics, and data on the interventions and control arms. Any disagreement between them over the eligibility of particular studies will be resolved through discussion with a third reviewer. For data not showed, relevant to the NMA, will be requested the authors to provide them.

Risk of bias (quality) assessment
Two review authors will independently assess the RoB of the included studies using the Cochrane risk of bias tool. 24 We will consider the following domains: selection bias (sequence generation, allocation concealment), detection bias (blinding of outcome assessors), performance bias (blinding of participants and personnel), attrition bias (incomplete outcome data), reporting bias. In addition, we will assess the con dence in network meta-analysis estimates by using the new CINeMA tool. 28 Strategy for data synthesis We will provide a narrative synthesis of the ndings from the included studies, structured around the type of intervention, target population characteristics, type of outcome and intervention content.
We will estimate treatment effects from each study by calculating risk ratios (for dichotomous outcomes) and hazard ratios (for OS and PFS) and relative 95% con dence intervals. We will perform standard pairwise meta-analysis and NMA in a frequentist context with a random effect model. We will present results from pairwise meta-analysis and NMA as summary relative effect sizes.
Within each pairwise comparison in standard pairwise meta-analysis, we will assess clinical heterogeneity comparing the data on potential effect modi ers and the presence of statistical heterogeneity by visual inspection of the forest plots and by calculating the I² statistic. 29 An I-squared value smaller than 50% reveals low heterogeneity, I-squared included between 50 and 75% moderate heterogeneity, and I-squared greater than 75% substantial heterogeneity.
Within NMA, we will assume a common estimate for the heterogeneity variance. We will compare the distribution of potential effect modi ers across different pairwise comparisons to assess transitivity across treatment comparisons. We will assess the presence of statistical heterogeneity in the entire network considering the magnitude of the common heterogeneity parameter. We will also evaluate the statistical disagreements between direct and indirect effect sizes, called incoherence, by using local and global approaches. Locally, we will use the loop-speci c approach 30 ; we will use the 'design-by-treatment' Q-statistic in the entire network. 31 We will determine a treatment hierarchy by using the surface under the cumulative ranking curve (SUCRA) and mean ranks. 32 All analyses will be conducted in Stata v. 12.0 statistical software.

Analysis of subgroups or subsets
We will perform a sensitivity analysis considering only low RoB studies. 24 Dissemination plans A scienti c paper will be submitted to a leading journal in this eld.
Details of any existing review of the same topic by the same authors "First-line imatinib vs second-and third-generation TKIs for chronic phase CML: a systematic review and meta-analysis" by C. Vener et al., PROSPERO Registration No. CRD42016032903. 23 Discussion Although many studies have compared the use of imatinib and more recent TKIs in patients with newly diagnosed Ph+ CP CML, they have not established which is the most e cacious. [6][7][8][9]13,14,16 Furthermore, the 2017 ESMO and 2018 NCCN CML guidelines do not make precise recommendations that would help clinicians decide. 21,22 Our previous systematic review and meta-analysis of RCTs provides complete, updated and precise comparative information concerning the use of TKIs in patients with newly diagnosed adult CP CML in terms of OS and PFS at various time points, clinical and biological response variables, and the most relevant hematological and non-hematological AEs. 23 Biases and the quality of the evidence were assessed using the Cochrane risk of bias tool and the GRADE method, 24-25 and the two databases created are available for data sharing purposes.
Unfortunately, we could not recommend a speci c newer TKI because there are no head-to-head RCTs between second-and third-generation TKIs and concluded that a NMA is required. NMA is more powerful method than conventional pairwise meta-analysis because NMA can simultaneously compare multiple treatments, even in absence of head-to-head trials, and rank them according to their e cacy and safety. 33 It should however be noted, that besides cumulative data on OS, PFS, and safety, the choice of the optimal TKI for patients with newly CP CML should always consider AEs and co-morbidities as well as molecular/cytogenetic responses and transformation rates. Abbreviations