ORIGINAL RESEARCH published: 14 July 2022 doi: 10.3389/fonc.2022.892684 Clear Improvement in Real-World Chronic Myeloid Leukemia Survival: A Comparison With Randomized Controlled Trials Claudia Vener 1,2*, Silvia Rossi 3, Pamela Minicozzi 1,4, Rafael Marcos-Gragera 5,6,7, Hélène A. Poirel 8, Marc Maynadié 9, Xavier Troussard 10, Gabriella Pravettoni 2, Roberta De Angelis 3†, Milena Sant 1† and the EUROCARE-6 Working Group 1 Analytical Epidemiology and Health Impact Unit, Department of Research, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Nazionale dei Tumori, Milan, Italy, 2 Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy, 3 Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy, 4 Cancer Survival Group, Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, United Kingdom, 5 Epidemiology Unit and Girona Cancer Registry, Oncology Coordination Plan, Department of Health, Autonomous Government of Catalonia, Catalan Institute of Oncology, Girona Biomedical Research Institute (IdiBGi), Universitat de Girona, Girona, Spain, 6 Biomedical Network Research Centers of Epidemiology and Public Edited by: Health (CIBERESP), Madrid, Spain, 7 Group of Descriptive and Analytical Epidemiology of Cancer, Josep Carreras Leukemia Mario Tiribelli, Research Institute, Girona, Spain, 8 Belgian Cancer Registry, Brussels, Belgium, 9 Côte d'Or Hematological Malignancies University of Udine, Italy Registry, Dijon, France, 10 Basse Normandie Cancer Registry, Centre Hospitalier Universitaire (CHU) de Caen, Normandie, Caen, France Reviewed by: Valentin Garcia-Gutierrez, Ramón y Cajal University Hospital, Tyrosine kinase inhibitors (TKIs) have been improving the prognosis of patients with Spain Ahmet Emre Eskazan, chronic myeloid leukemia (CML), but there are still large differences in survival among Istanbul University-Cerrahp European countries. This raises questions on the added value of results from population- *Correspondence: based studies, which use real-world data, compared to results of randomized controlled Claudia Vener claudia.vener@unimi.it trials (RCTs) involving patients with CML. There are also questions about the extent of the † These authors share last authorship findings on RCTs effectiveness for patients in the general population. We compare survival data extracted from our previous systematic review and meta-analysis of CML RCTs with Specialty section: the latest updated population-based survival data of EUROCARE-6, the widest This article was submitted to Hematologic Malignancies, collaborative study on cancer survival in Europe. The EUROCARE-6 CML survival a section of the journal estimated in patients (15–64 years) diagnosed in 2000–2006 vs. 2007–2013 revealed Frontiers in Oncology that the prognostic improvement highlighted by RCTs was confirmed in real-world Received: 09 March 2022 settings, too. The study shows, evaluating for the first time all European regions, that Accepted: 19 April 2022 Published: 14 July 2022 the optimal outcome figures obtained in controlled settings for CML are also achievable Citation: (and indeed achieved) in real-world settings with prompt introduction of TKIs in daily Vener C, Rossi S, Minicozzi P, clinical practice. However, some differences still persist, particularly in Eastern European Marcos-Gragera R, Poirel HA, Maynadié M, Troussard X, countries, where overall survival values are lower than elsewhere, probably due to a Pravettoni G, De Angelis R, Sant M delayed introduction of TKIs. Our results suggest an insufficient adoption of adequate and the EUROCARE-6 Working Group protocols in daily clinical practice in those countries where CML survival values remain (2022) Clear Improvement in Real- World Chronic Myeloid Leukemia lower in real life than the values obtained in RCTs. New high-resolution population-based Survival: A Comparison With studies may help to identify failures in the clinical pathways followed there. Randomized Controlled Trials. Front. Oncol. 12:892684. Keywords: cancer registries, chronic myeloid leukemia (CML), randomized controlled trials (RCTs), real-world data, doi: 10.3389/fonc.2022.892684 survival, Europe, tyrosine kinase inhibitor (TKI), population-based studies Frontiers in Oncology | www.frontiersin.org 1 July 2022 | Volume 12 | Article 892684 Vener et al. Chronic Myeloid Leukemia Survival HIGHLIGHTS other new treatments (10). There was only a small increase in survival estimates among the elderly, possibly because of the 1. The EUROCARE-6 CML survival estimates revealed that the under-use of imatinib (90% of patients aged 20–59 received prognostic improvement highlighted by RCTs was confirmed in imatinib, 75% of those aged 60–79, and 46% of those aged ≥80) the European real-world setting. and the newer TKIs (13). Furthermore, the cancer registry (CR) 2. There are still large differences in CML survival throughout of Girona showed that the 5-year survival rate in patients with Europe: the prompt introduction of TKIs in daily clinical CML treated with TKIs in 1994–2008 was about 80%, compared practice is undelayable. with 44% among those who were not (14). Population-based studies including all cases occurring in the region covered by a CR reflect the effectiveness of healthcare 1 INTRODUCTION services in controlling the disease and are more likely to highlight socioeconomic disparities potentially associated with cancer The European incidence of chronic myeloid leukemia (CML) survival. People who live in more affluent areas have better was about 1.1/100,000 inhabitants (1), increasing to about 4.0/ access to optimal care than those living in deprived areas, and 100,000 in patients aged 75–99 at the time of diagnosis. The this leads to discrepancies in overall survival (OS) figures (15). disease is characterized by the presence of the BCR-ABL1 fusion Moreover, access to optimal treatment is related to per capita gene located in the Philadelphia (Ph) chromosome and is income and healthcare investments (16). classified as being in a chronic (CP), accelerated (AP), or Clinical practice, particularly in oncological settings, often blastic phase (BP), with the last two phases accounting for relies on randomized controlled trials (RCTs) because they about 4% and 3% of cases, respectively (2, 3) and being provide more detailed information than population-based associated with a worse prognosis (4). studies. However, the amount of data may be overwhelming For many years, CML was associated with a poor life (17), and it can be difficult to determine the health systems’ expectancy (5), but the 2001 introduction of imatinib mesylate, sustainability, in terms of finance and uptake of new practices. As the first tyrosine kinase inhibitor (TKI) and, more recently, of a consequence, oncological organizations have developed second- and third-generation TKIs (dasatinib, nilotinib, frameworks to help clinicians and policymakers quantify the bosutinib, and ponatinib) has profoundly changed the CML real value of new therapies (17–21). Generalizing trial results to curative-intent treatment, previously based on hematopoietic everyday clinical practice is not straightforward because of low stem cell transplantation. TKIs have greatly improved CML overall trial accrual (<5% of all newly diagnosed patients with survival rates and now make it possible to consider CML a cancer) and under-representation by age, gender, disease stage, chronic disease (6–11). Imatinib was approved as first-line co-morbidities, and socioeconomic status. However, despite treatment for all CML phases and is now available as a generic these limitations, approved treatments are frequently offered to drug, as its patent has expired. Dasatinib and nilotinib were patients who would have been ineligible for the related trials, but approved in 2006–2007 as second-line treatments for patients they rarely show the benefits detected in RCTs; furthermore, a resistant to, or intolerant of, previous treatments (including survival advantage detected by RCTs is not always subsequently imatinib): dasatinib in all CML phases and nilotinib only in confirmed in real-life setting. the CP or AP. Since 2010–2011, both have been authorized for This raises questions as to how the results of population- the first-line treatment of newly diagnosed Ph-positive adult based studies using real-world data can add to the results of cases of CP CML. Bosutinib was licensed in the United States in RCTs involving patients with CML and to the findings on the 2012 (and in Europe in 2013) for the treatment of adults with CP, extent of RCTs’ effectiveness for the patient population as a AP, or BP CML who are resistant to, or intolerant of, previous whole. In an attempt to answer these questions, we compared the treatments with one or more TKIs. In December 2017, the survival of patients with CP CML participating in RCTs with the recommendation was extended in the United States to include data from EUROCARE, the widest collaborative population- newly diagnosed adult patients with CP CML. Ponatinib was based study on cancer survival in Europe (22). approved in the United States in 2012 (and in Europe in 2013) for the treatment of adults with CP, AP, or BP CML who are resistant to, or intolerant to, other TKIs and also for the 2 MATERIALS AND METHODS treatment of those with CP, AP, or BP CML who have the T315I mutation, which is known to be involved in resistance to 2.1 Study Design all previous TKIs. We extracted the survival data from the RCTs included in our The 5-year survival estimates for patients with CML increased previous systematic review and meta-analysis comparing first- from 1997 to 2008 throughout Europe (particularly after 2000), line imatinib and second- and third-generation TKIs in adults although with large differences among European countries (10, with newly diagnosed CP CML [International Prospective 12): they increased slightly in Southern Europe, more in the Register of Systematic Review (PROSPERO) Registration No. United Kingdom, and considerably more in Northern, Central, CRD42016032903] (Table 1) (58, 59). and Eastern Europe, although in the latter region, survival Population-based survival data were extracted from the remained lower than elsewhere (10). These improvements were EUROCARE-6 dataset (22). ICD-O-3 (International Classification plausibly linked to the widespread introduction of targeted and of Disease for Oncology, 3rd edition) (60) morphology codes 9863 Frontiers in Oncology | www.frontiersin.org 2 July 2022 | Volume 12 | Article 892684 Vener et al. Chronic Myeloid Leukemia Survival (CML with no cytogenetic information or CML not otherwise associated with BP or AP CML. Therefore, conditional crude OS specified, NOS) and 9875 (CML, BCR-ABL1-positive; Ph+ CML) (i.e., the probability of being alive after 5 years, conditional on according to HAEMACARE (61) groupings were selected. Code surviving 3 years after diagnosis, in brief 5-/3-year OS ratio) was 9876 (Atypical CML, BCR-ABL1-negative; Ph− aCML) was computed on the assumption that patients with CML surviving not included. more than 3 years are not likely to include patients in AP and BP. Quality and completeness of CRs data were evaluated by Relative survival (RS) (64), defined as OS divided by the applying standardized check procedures in conjunction with the expected survival of a comparable group (i.e., of the same age, sex ENCR-JRC technical report, to ensure data comparability (62). and area) from the general population not affected by CML, was At the end of the quality checks of the 101 population-based CRs estimated using the complete approach (65). Expected survival in the EUROCARE-6 database (that provided continuous was estimated using the Ederer II method (66). Conditional incidence data for hematological malignancies from January 1, crude RS was computed in terms of 5-/3-year RS ratio. 2000, to December 31, 2013, with follow-up data up until Standard errors (SEs) of OS and RS were derived by applying December 31, 2014), only 84 with adequate information for Greenwood’s formula (67). SE for conditional survival were the purposes of the study (sufficient time coverage, follow-up calculated with the delta method (63). To obtain two-sided completeness, and morphology accuracy) were selected 95% CIs, the data were logarithmically transformed. The (Supplementary Table 1). statistical significance of survival differences between patients The survival analyses were therefore based on 18,083 eligible diagnosed before and after 2006 (2000–2006 vs. 2007–2013) was CML cases, aged between 15 and 64 (the age selection tested with the Z-test (68). corresponding to the age of patients with CML usually enrolled in RCTs), provided by 84 regional or national CRs in 2.2.3 Comparison Between RCTs and Population- 28 European countries (Table 2). In particular, 8,793 CML cases Based Survival were diagnosed in 2000–2006 and 9,290 CML cases in 2007– We compared both OS, including all causes of death for patients 2013. We have defined the threshold of 2006–2007 because it with CML, and RS, a proxy of cause-specific survival, i.e., corresponds to the introduction of second-generation TKIs discarding competitive causes of mortality other than CML. (dasatinib and nilotinib) in clinical practice (first approval in Because, for RCTs, RS is not available (as they record the 2006–2007). specific cause of death), we estimated the 5-year cause-specific The EUROCARE-6 patient complete selection is reported in survival (i.e., “freedom from death due to advanced CML”) using the Supplementary Material. data extracted from the corresponding RCTs included in the meta-analysis (58, 59). 2.2 Statistical Methods The analyses were made using Review Manager v. 5.3 and SEER*Stat software 8.3.9. 2.2.1 RCT Meta-Analysis Data OS data by follow-up time, number of deaths and hazard ratios (HRs), and cancer-specific mortality were collected through the 3 RESULTS RCTs included in the published meta-analysis (58, 59). The OS data were pooled using the inverse variance method. 3.1 RCTs Results Study heterogeneity was evaluated by calculating the I-squared Many of the RCTs did not report OS at each and every one of the statistic (I2) with little, moderate, and substantial heterogeneity time points, but the patients were closely followed-up (Table 1). being indicated by I2 values of <50%, 50%–75%, and >75%, Only two RCTs reported OS up to 60 months (data not pooled), respectively. Ninety-five percent confidence intervals (CIs) and and only one reported OS up to 72 months. Five-year OS in the two-sided p-values were calculated for each result. ENESTnd (38, 45) study was similar in the imatinib and nilotinib groups [92% vs. 94% for nilotinib of 300 mg (HR = 0.80; 95% CI, 2.2.2 Population-Based Data 0.43–1.50), and 96% for nilotinib of 400 mg (HR = 0.44; 95% CI, Five-year crude OS of CML cases (9863, 9875 ICD-O-3 codes), aged 0.21–0.93)]. Similar results were obtained in the DASISION (23, between 15 and 64, diagnosed in 2000–2006 and 2007–2013, by 32) study comparing imatinib with dasatinib: 5-year OS 90% vs. European region and country, was estimated from the 91% (HR = 1.01; 95% CI, 0.58–1.73). The first follow-up time EUROCARE-6 study dataset. The 64-year threshold was point at which it was possible to analyse pooled OS was 36 determined, considering CML RCTs inclusion criteria and to months (data from three RCTs), but, as it was not clinically make the age of patients more comparable between RCTs relevant, we pooled the HRs roughly extracted from the printed (median age: 50 years; range: 18–91) (Table 1) (58, 59) and OS curves of Radich et al. (33) (36-month of follow-up) and the population-based EUROCARE-6 results (median age: 50 years) ENESTnd (38, 45) and DASISION (23, 32) HRs (60-month (Table 3). The period of diagnosis threshold (pre- and post-2006) follow-up) on the basis of the proportional hazards assumption; was established considering the timing of second-generation TKIs the result was not statistically significant (OS: HR = 0.78; 95% CI, introduction (dasatinib and nilotinib) in clinical practice. 0.54–1.11) (58, 69). As most CRs do not collect data concerning disease phase, we The BFORE study update showed that 5-year OS was similar used conditional survival (63) to select patients who are between bosutinib and imatinib (95% vs. 95%; HR = 0.95; 95% potentially in the CP, thus excluding the short-term mortality CI, 0.45–1.99) (56). Frontiers in Oncology | www.frontiersin.org 3 July 2022 | Volume 12 | Article 892684 Vener et al. Chronic Myeloid Leukemia Survival 3.2 EUROCARE-6 Results 3.3 Comparisons Between RCTs and The numbers of patients with CML eligible for the survival EUROCARE-6 Results analysis are reported by CR (Table 2). The main characteristics The estimated values of 5-year cause-specific survival in the of patients included in survival analysis and the 5-year crude OS ENESTnd study were 97.7% (96.0–99.5%) for nilotinib of 300 values of all CML cases (9863 - CML NOS, 9875 - Ph+ CML mg, 98.5% (97.1–100.0%) for nilotinib 400 mg, 93.8% (90.8– ICD-O-3 codes) are shown by European region and country 96.7%) for imatinib of 400 mg (38, 45). The DASISION study (Table 3). The 9875 - Ph+ CML ICD-O-3 code is scarcely (23, 32) only reported the number of patients who had died of adopted (22%) (Table 2). CML-related causes after 5 years of follow-up: 17/260 in the Comparing OS results between the two periods of diagnosis imatinib arm and 9/259 in the dasatinib arm. The estimated (2000–2006 vs. 2007–2013), a clear increase of OS values was values of 5-year cause-specific survival in CP CML RCTs (58, 59) observed for all European regions and for most countries were quite similar to 5-/3-year conditional crude RS of all CML (Table 3). A marked statistically significant increase was cases estimated in the best ranking countries of the EUROCARE- observed in the pool of all European countries (71.9% for 6 dataset. They are also close to the 5-/3-year conditional crude patients diagnosed in 2000–2006 vs. 84.7% diagnosed in 2007– RS estimates for the European pool (97.2% in 2007–2013) 2013; absolute difference: 12.7%) and in all European areas, with (Supplementary Table 4). higher improvements (>10%) in Eastern Europe (17.6%) and United Kingdom and Ireland (14.7%). Considering each country, the highest significant increases (>20%) were observed for Wales 4 DISCUSSION (21.0%), Slovenia (32.4%), Bulgaria (22.3%), Lithuania (29.5%), and Slovakia (22.8%). Notably, in most Western European The comparison of EUROCARE-6 CML survival estimated in countries, OS of patients diagnosed in 2007–2013 was similar patients diagnosed in 2000–2006 vs. 2007–2013 confirmed that to CP CML OS reported in RCTs (Table 1). the prognostic improvement highlighted by RCTs was verifiable The study evaluated crude 5-/3-year conditional OS of all in real-world settings. In particular, the EUROCARE-6 OS values CML cases (i.e., the probability of being alive after 5 years, in many countries (Table 3) were very similar to CP CML OS conditional on surviving 3 years after diagnosis), likely reported in RCTs (Table 1) (58, 59). Moreover, the same brilliant representing patients with CML in CP, diagnosed in 2000– achievement was observed comparing the estimated values of 5- 2006 and 2007–2013, by European region and country year cause-specific survival in CP CML RCTs (58, 59) with 5-/3- (Table 4). A significant increase was observed in Europe as a year conditional crude RS estimated in almost all European whole (92.9% in 2000–2006 vs. 96.1% in 2007–2013; absolute countries in 2007–2013 (Supplementary Table 4). This means difference: 3.2%) and in all areas except in Northern and Central that the optimal outcome figures obtained in controlled settings Europe, showing that the most substantial 5-year OS increase are achievable (and, indeed, are achieved) in real-world settings, (12.7%, Table 3) was concentrated in the first 3-year prognosis. too. The high concordance between CRs and RCTs survival Notably, countries with more marked delta OS increases results could be explained by the fact that TKIs are responsible of (Slovenia, Lithuania, Bulgaria, and Slovakia; Table 3) showed the quite complete disappearance of AP and BP worse prognosis the highest growth even in the CP (Table 4). Time trends of CML phases. Almost all patients are diagnosed in CP (or have crude 5-/3-year conditional RS of all CML cases are presented in been quickly brought back to CP), so survival results reported in Supplementary Table 4. Conditional RS values are slightly the whole population are close to those of RCTs. Moreover, the higher than conditional OS values (by 1.1% on average), high concordance between CRs and RCTs survival results could reflecting the limited impact of excluding causes of death other be related to the fact that we compared quite homogeneous than CML in patients aged under 65 at diagnosis. Time trends of groups of patients with CML aged lower than 65 years with conditional RS are quite similar to those estimated for probably few comorbidities. conditional OS. Small significant overall increases were Previous population studies reported similar or inferior estimated in the European pool (94.0% in 2000–2006 vs. 97.2% survival results but estimated only on national or small in 2007–2013; absolute difference: 3.2%) and in all areas but pooled samples. Northern and Central Europe. Swedish CML Registry (779 CMLs, from 2002 to 2010; In Supplementary Tables 2, 3 were reported 5-year crude OS median age, follow-up: 60 years, 61 months) showed 5-year RS and 5-year crude RS, respectively, of CML cases diagnosed in close to 1.0 for those younger than 60 years, 0.9 for those aged 60 2000–2006 and 2007–2013 by European region, country, and to 80 years, and 0.6 for those older than 80 years (70). Swedish morphology code. The differences between OS and RS were Cancer Registry (2,662 CMLs, from 1973 to 2013; median age: 69 small, probably due to the patients’ age selection (15–64 years, years) reported clear improvements in life expectancy over the with negligible competitive mortality). In particular, in study period (71). Swedish Cancer Registry and Swedish Cause of Supplementary Table 2, were compared OS values between Death Registry (CMLs, from 1970 to 2012) showed 5-year OS 9863 CML NOS and 9875 Ph+ CML codes in 2000–2006 and increasing from 0.18 to 0.82, during the study period; between 2007–2013, by areas: in all areas, CML NOS cases showed a lower 2006 and 2012, 5-year RS was close to normal for 40-year-old but OS values in comparison with Ph+ CML, even if differences considerably lower for 80-year-old patients (72). UK’s reduced over time (except for Eastern Europe). Haematological Malignancy Research Network (242 CMLs, Frontiers in Oncology | www.frontiersin.org 4 July 2022 | Volume 12 | Article 892684 Vener et al. Chronic Myeloid Leukemia Survival from 2004 to 2011; median age: 59 years) showed 5-year OS of reimbursement varied greatly between Europe: this could be 78.9% (72.3% to 84.0%) and 5-year RS of 88.6% (81.0% to 93.3%) useful to interpret the different survival outcomes observed by (73). Other national studies are aligned with our survival results countries (Supplementary Table 5). Also to notice that the (74–80). allogeneic bone marrow transplantations medium rate was 0.62 European Treatment and Outcome Study (EUTOS) (2,904 per million for Eastern European countries in comparison with CMLs, from 2008 to 2013; median age, follow-up: 55 years, 29 0.81 per million for other European countries [Supplementary months) showed a 30 months OS of 92% (81). US Surveillance, Table 6, by calendar year from 2000 to 2022 and by country; data Epidemiology, and End Results (SEER) (13,869 CMLs, from provided by the European Society for Blood and Marrow 1975 to 2009) reported lower survival values: 5-year RS ratios Transplantation (EBMT), Chronic Malignancies Working increased from 0.26 in 1975–1989 to 0.36 in 1990–2000 and 0.56 Party (CMWP)]. in 2001–2009 (82). Moreover, SEER (5,138 CMLs, from 2000 to Residual discrepancies can be attributed to different case 2005) showed 5-year OS improvement for all patients during the selection criteria: RCTs select patients on the basis of well- study period (83, 84). Compared with patients diagnosed in defined inclusion and exclusion criteria, and the results cannot 2000, 5-year OS improved among 15–44 years (from 71.6% to be readily extended to the general population, whereas 86.4%), 45–64 years (from 67.5% to 76.3%), 65–74 years (from population-based studies involve unselected patients but often 38.1% to 51.2%), and 75–84 years patients (from 19.2% to lack detail and, in the case of CML, the morphology code might 36.4%) (83). be not very precise. Moreover, RCTs almost always record Population-based studies using real-world survival data reveal cancer-specific mortality, with off-study survival being reported differences from the values observed in RCTs that are often by the investigator after study discontinuation, whereas related to treatment disparities and largely due to different population studies systematically update life status of all socioeconomic conditions. They also provide information registered patients and use RS to make adjustments for general concerning treatment effectiveness in everyday clinical practice mortality by age, gender, and geographical area. without any patient or outcome selection: they are therefore RCTs also generally include patients without comorbidities more representative of what happens in real-life, despite lacking who are younger than those encountered in real-life populations: in clinical details offered by RCTs, particularly in relation to for example, it has been found that the elderly, women, and disease stage at the time of diagnosis and first-line treatments. members of racial and ethnic minorities are less likely to be The findings of RCTs are often used to guide clinical practice enrolled in American cooperative group cancer trials than (particularly in oncology), but patient selection can reduce their patients who are younger, male, and Caucasian (85, 86). applicability to the general population (17, 18, 20, 21). Our previous meta-analysis did not reveal any difference in Conversely, results of population-based CR studies that fully the OS of patients treated with the first- or the new-generation cover the target population are less affected by patient selection TKIs (58, 59). In the only two RCTs for which 5-year OS data are biases, and they provide useful data complementing available [DASISION (23, 32) and ENESTnd (38, 45)], the 60- RCTs outcomes. month OS value was similar in the patients treated with imatinib However, these two information sources need to be integrated and those treated with dasatinib or nilotinib, and similar to and require the use of new study designs and methods of EUROCARE-6 OS data for patients diagnosed in 2007–2013. To analysis. High-resolution population-based studies, which underline that second-generation TKIs introduction time in include representative patients, present more detailed clinical clinical practice (2006–2007) limits a strict comparison with information than that which is routinely collected by population- survival data of previous years, but imatinib can be considered an based CRs: this approach may help to reduce the gap between historical arm because it has been introduced in 2001. Moreover, RCTs and real-world studies (hrstudies.it; https://www.ipaac.eu/ CML survival values under imatinib or second-generation TKIs en/work-packages/wp7/). are fairly superimposable (60 months RCTs OS ≥ 90%, Table 1). In an attempt to quantify the difference between RCTs and We compared the first-line treatment of RCT patients with population-based studies using tangible data, we compared OS newly diagnosed CP CML with all treatment lines administered and cause-specific survival observed in the RCTs included in our to patients with CML from the general population (including a previous systematic review (58), and OS and RS values estimated small percentage of patients with AP and BP CML who have a using EUROCARE-6 (22) cases diagnosed up to age 64 over a different prognosis). Unfortunately, CRs do not routinely collect comparable period of time. It was the first time that this was done information on CML phase and treatment line; thus, it was not for CML, considering all European regions and pooling survival possible to select CP CML cases receiving first-line treatment. To results. Our study shows that CML survival values tend to overcome this drawback, we analyzed 5-/3-year conditional OS become very similar between RCTs and population-based and RS to remove the contribution of BP and AP CML and settings, regardless of the survival analysis methods used. improve estimates comparability. Considering conditional OS However, some differences still persist, in particular in Eastern and RS for patients diagnosed in 2007–2013, population-based European countries, where OS values were lower than elsewhere, CRs survival values were very similar to those observed in especially in the first period of time being considered: this is the RCTs. probably due to a delayed introduction of TKIs in daily clinical Code 9876 (Ph− atypical CML or aCML) was not included but, practice. To underline that the date of the introduction of TKIs as most CRs do not distinguish Ph+ CML and Ph− aCML, and as Frontiers in Oncology | www.frontiersin.org 5 July 2022 | Volume 12 | Article 892684 Vener et al. Chronic Myeloid Leukemia Survival TABLE 1 | Summary of the findings of the RCTs included in the meta-analysis. RCT No. of Median age Males FU Authors, year Journal OS (%) (I/C) patients (range), years (No., %) (months) 12 18 24 36 48 60 72 months months months months months months months 519 I: 49 (18–78) I: 163 (63) 12 Kantarjan H.M. et al., ‡ 99.0/97.0 – – – – – – DASISION* N Engl J Med (D) D: 46 (18–84) D: 144 2010 (23) (56) 18 Shah N. et al., 2010 § - 97.9/96.0 – – – – – (NCT00481247) Blood (24) 24 Kantarjan H.M. et al., § - 98.0/96.0 – – – – – J Clin Oncol 2011 (25) 24 Hochhaus A. et al., § - – – – – – – Blood 2011 (26) 24 Hochhaus A. et al., § - – – – – – – J Clin Oncol 2012 (27) 24 Kantarjian H.M. et al., ‡ - – 95.2/95.3 – – – – Blood 2012 (28) 36 Jabbour E. et al., ‡ - – – 93.2/93.7 – – – Blood 2014 (29) 48 Cortes J.E. et al., § - – – – 92.0/93.0 – – Blood 2013 (30) 60 Cortes J.E. et al., § - – – – – 90.0/91.0 – Blood 2014 (31) 60 Cortes J.E. et al., ‡ - – – – – 90.0/91.0 – J Clin Oncol 2016 (32) † 253 I: 50 (19–89) I: 72 (59) 12◦ Radich J.P. et al., ‡ - – – 97.0/97.0 – – – NCT00070499 Blood (D) D: 47 (18–90) D: 74 (60) 2012 (33) 46 I: 60 (38–77) I: 15 (63) 18 Mustjoki S. et al., ‡ - – – – – – – NordCML006* Leukemia (D) D: 54 (29–71) D: 7 (32) 2013 (34) 24 Hjorth-Hansen H. § - – – – – – – (NCT00852566) Blood et al., 2013 (35) 36 Hjorth-Hansen H. Eur J - – – – – – – et al., 2015 (36) ‡ Haematol 846 I: 46 (18–80) I: 158 (56) 12 Larson R.A. et al., § - – – – – – – ENESTnd* J Clin Oncol (N) N300: 47 (18–85) N300: 2010 (37) N400: 47 (18–81) 158 (56) 12 Saglio G. et al, 2010 ‡ - – – – – – – (NCT00471497) N Engl J Med N400: (38) 175 (62) 18 Hughes T.P. et al., § - 96.9/ – – – – – Blood 2010 (39) 98.5 (N300) 99.3 (N400) 24 Kantarjian H.M. et al., ‡ - – 96.3/ – – – – Lancet Oncol 2011 (40) 97.4 (N300) 97.8 (N400) 36 Kantarjian H.M. et al., § - – – 94.0/ – – – Blood 2012 (41) 95.1 (N300) 97.0 (N400) 36 Larson R.A. et al., ‡ - – – 94.0/ – – – Leukemia 2012 (42) 95.1 (N300) 97.0 (N400) 36 Hochhaus A. et al., ‡ - – – – – – – Blood 2013 (43) 48 Hughes T.P. et al., ‡ - – – – 93.3/ – – Blood 2014 (44) 94.3 (N300) 96.7 (N400) 60 Hochhaus A., 2016 ‡ - – – – – 91.7/ – Leukemia (45) 93.7 (Continued) Frontiers in Oncology | www.frontiersin.org 6 July 2022 | Volume 12 | Article 892684 Vener et al. Chronic Myeloid Leukemia Survival TABLE 1 | Continued RCT No. of Median age Males FU Authors, year Journal OS (%) (I/C) patients (range), years (No., %) (months) 12 18 24 36 48 60 72 months months months months months months months (N300) 96.2 (N400) 72 Hochhaus A. et al., § - – – – – – – Blood 2015 (46) 72 Hughes T.P. et al., § - – – – – – 91.4/ Haematologica 2015 (47) 91.6 (N300) 95.8 (N400) † 502 I: 47 (18–89) I: 135 (54) 12 Cortes J.E., 2012 (48) ‡ 97.0/99.0 – – – – – – BELA J Clin Oncol (B) B: 48 (19–91) B: 149 18 Gambacorti-Passerini § - – – – – – – J Clin Oncol (NCT00574873) (60) C., 2011 (49) 24 Brummendorf T.H, ‡ - – 95.0/97.0 – – – – Br J Haematol 2015 (50) 30 Brummendorf T.H., § - – 95.0/97.0 – – – – Haematologica 2012 (51) 30 Gambacorti-Passerini ‡ - – – – – – – Am J Hematol C., 2014 (52) 48 Cortes J.E., 2016 (53) ‡ - – – – – – – Am J Hematol 536 I: 53 (19–84) I: 135 (56) 12 Cortes J.E., 2018 (54) ‡ 97.9/99.6 – – – – – – BFORE* J Clin Oncol (B) B: 52 (18–84) B: 142 18 Gambacorti-Passerini § - 96.6/99.6 – – – – – Blood (NCT02130557) (58) C., 2017 (55) 60 [Brummendorf T.H, § 94.6/94.5 Blood 2020^ (56)] † 307 I: 52 (18–86) I: 92 (61) 12 Lipton J.H, 2016 (57) ‡ - – – – – – – EPIC Lancet Oncol (P) P: 55 (18–89) P: 97 (63) (NCT01650805) RCT, randomized controlled trial; OS, overall survival; FU, follow-up; (−), not evaluated; I/C, imatinib/comparator (B, bosutinib; D, dasatinib; N300, nilotinib of 300 mg; N400, nilotinib of 400 mg; P, ponatinib). *RCT. † Quasi-RCT. ‡ Full paper. § Abstract. ◦ 36-month OS. ^ Updated in 2022. 78.0% of cases are classified as CML NOS (Table 2), some aCML word “myelogenous” is ambiguous for non-hematologists. This cases were inevitably included. This has little impact on our analysis may also explain the considerable difference in the use of code 9875 as 90%–95% of CML diagnoses have the characteristic t(9;22)(q34; between specialized hematological registries and general CRs. CRs q11.2) reciprocal translocation, leading to the Ph chromosome and should correctly code CML morphology by specifying ICD-O-3 to the BCR-ABL1 fusion gene that is the target for specific TKIs (4). 9875 (Ph+ CML) or 9876 (Ph− aCML), the phase of the disease at However, this partly explains why OS values for ICD-O-3 code the time of diagnosis, first-line therapy, and the occurrence of 9863, including CML NOS and (probably) patients with poorer transformation into AP or BP to make a more precise analysis prognosis (such as aCML cases not targeted by TKIs), were, at all possible: one that is potentially comparable with other types of evaluable times and in all evaluable regions, lower compared to the studies. Some strategies should be adopted to avoid CML code values for Ph+ CML for which TKIs are indicated. misuse and to reduce the number of CML NOS cases, such as to plan Code 9875 (Ph+ CML) was hardly used in Northern Europe or specific training courses to increase the precision of coding or to link the United Kingdom and Ireland, and the implausibly small CML population-based data with other available data sources, for number of cases in the other regions/countries considered is example, national health insurance databases, to discover patients attributable to differences in registration criteria or inaccurate really treated with TKIs (87). Unfortunately, 9875 (Ph+ CML) code pathological description. It is also likely that the underuse of code is so underused in CRs in the studied period 2000–2013 not to 9875 for Ph+ CML is due to a bad translation of the ICD-O-3 permit to design a population-based study excluding 9863 code classification: code 9863 refers to “chronic myeloid leukemia, NOS” (CML NOS). and code 9875 refers to “chronic myelogenous leukemia, BCR/ABL A clear improvement in real-world CML survival was observed positive” (Ph+ CML) and, although hematologists normally in European regions and countries comparing EUROCARE-6 with correctly diagnose cases of code 9875 as Ph+ CML, the use of the RCTs OS data. However, some discrepancies with RCTs still Frontiers in Oncology | www.frontiersin.org 7 July 2022 | Volume 12 | Article 892684 Vener et al. Chronic Myeloid Leukemia Survival TABLE 2 | Myeloid malignancies diagnosed in European patients (15–64 years) in 2000–2013 and quality indicators by Cancer Registry (CR). EUROCARE-6 study dataset. Area/Country Cancer registry (CR) Overall period Myeloid malignancies2 2000–2013 of diagnosis1 CML cases included in survival analysis3 Cases % % Not otherwise CML CML NOS CML Ph+ 2000– Microscopically specified (NOS)4 total (9863) cases (9875) cases 2013 Verified (MV) cases (%) (%) Northern DENMARK Denmark 1978–2014 3,404 98.9 1.3 470 122 (26) 348 (74) Europe FINLAND Finland 1978–2013 2,309 90.9 6.9 304 300 (99) 4 (1) ICELAND Iceland 1978–2014 78 98.7 1.3 23 22 (96) 1 (4) NORWAY Norway 1978–2016 2,557 98.9 1.8 312 283 (91) 29 (9) UK and IRELAND Ireland 1994–2012 1,986 98.6 5.7 240 234 (98) 6 (3) Ireland UK-ENGLAND UK-England 1995–2013 15,100 91.1 5.1 3,548 3,449 (97) 99 (3) UK-SCOTLAND UK-Scotland 1978–2013 3,564 95.2 0.8 344 335 (97) 9 (3) UK-WALES UK-Wales 1991–2012 959 76.1 3.1 229 229 (100) 0 (0) Central AUSTRIA Austria 1983–2012 2,629 96.8 4.1 623 541 (87) 82 (13) Europe BELGIUM Belgium 2004–2013 5,727 99.9 1.1 772 426 (55) 346 (45) FRANCE Bas Rhin 1990–2014 698 99.1 1.1 100 16 (16) 84 (84) Basse Normandie, HM 2002–2010 994 93.1 1.5 113 5 (4) 108 (96) Calvados 1990–2014 42 100.0 7.1 2 2 (100) 0 (0) Cote dOr, HM 1990–2014 393 100.0 0.3 53 0 (0) 53 (100) Doubs 1990–2014 436 100.0 0.7 58 2 (3) 56 (97) Gironde, HM 2002–2014 884 100.0 0.2 132 3 (2) 129 (98) Haut-Rhin 1990–2014 511 100.0 1.6 83 24 (29) 59 (71) Herault 1995–2014 729 100.0 0.5 111 30 (27) 81 (73) Isere 1990–2014 791 100.0 0.6 108 12 (11) 96 (89) Loire-Atlantique/ 1991–2014 1,195 100.0 0.8 195 36 (18) 159 (82) Vendé e Manche 1994–2014 45 100.0 4.4 8 8 (100) 0 (0) Somme 1990–2014 435 99.8 0.7 66 10 (15) 56 (85) Tarn 1990–2014 264 100.0 0.4 41 7 (17) 34 (83) GERMANY Bremen 2000–2013 377 98.9 0.5 51 19 (37) 32 (63) Common Cancer 2002–2013 5,493 99.1 3.1 705 442 (63) 263 (37) Registry of 4 Federal States5 Hamburg 1998–2012 587 99.1 2.6 147 131 (89) 16 (11) Rhineland-Palatinate 2004–2012 1,198 93.2 2.1 198 188 (95) 10 (5) Saarland 1993–2012 521 99.6 1.7 77 77 (100) 0 (0) Schleswig-Holstein 2003–2012 1,062 94.5 1.2 158 117 (74) 41 (26) SWITZERLAND Graubunden and 1989–2013 115 100.0 2.6 19 17 (89) 2 (11) Glarus Eastern Switzerland 1981–2013 236 100.0 2.1 51 45 (88) 6 (12) Ticino 2000–2012 219 100.0 1.8 33 15 (45) 18 (55) THE The Netherlands 1989–2013 9,759 99.9 0.6 1,199 152 (13) 1047 (87) NETHERLANDS Southern CROATIA Croatia 2000–2012 1,178 100.0 18.1 265 265 (100) 0 (0) Europe CYPRUS Cyprus 2004–2014 232 100.0 3.0 38 36 (95) 2 (5) ITALY Alto Adige 1995–2010 193 100.0 3.1 17 0 (0) 17 (100) Biella 1995–2010 191 97.9 0.5 12 10 (83) 2 (17) Brescia 1999–2010 290 94.1 9.3 65 65 (100) 0 (0) Catania-Messina-Enna 2003–2013 1,259 99.5 4.7 152 126 (83) 26 (17) Catanzaro 2003–2009 171 90.6 3.5 25 25 (100) 0 (0) Como 2003–2011 238 97.1 2.1 31 31 (100) 0 (0) Ferrara 1991–2011 247 100.0 2.4 26 26 (100) 0 (0) Friuli Venezia Giulia 1995–2010 343 100.0 3.8 75 75 (100) 0 (0) Genova 1986–2010 650 73.1 2.8 57 55 (96) 2 (4) Latina 1996–2012 308 79.5 1.9 43 37 (86) 6 (14) Lodi 2003–2010 129 99.2 5.4 29 28 (97) 1 (3) Mantova 1999–2010 123 100.0 5.7 26 26 (100) 0 (0) Modena 1988–2013 518 99.0 1.2 86 37 (43) 49 (57) Napoli 1996–2013 652 95.7 7.7 75 49 (65) 26 (35) Nuoro 2003–2012 114 100.0 0.0 14 14 (100) 0 (0) Palermo 2003–2013 712 95.2 7.0 95 94 (99) 1 (1) Parma 1978–2014 314 100.0 0.6 44 26 (59) 18 (41) (Continued) Frontiers in Oncology | www.frontiersin.org 8 July 2022 | Volume 12 | Article 892684 Vener et al. Chronic Myeloid Leukemia Survival TABLE 2 | Continued Area/Country Cancer registry (CR) Overall period Myeloid malignancies2 2000–2013 of diagnosis1 CML cases included in survival analysis3 Cases % % Not otherwise CML CML NOS CML Ph+ 2000– Microscopically specified (NOS)4 total (9863) cases (9875) cases 2013 Verified (MV) cases (%) (%) Ragusa 1981–2012 375 99.7 4.3 45 44 (98) 1 (2) Reggio Emilia 1996–2014 407 98.8 1.0 68 30 (44) 38 (56) Romagna 1986–2014 934 99.0 3.5 96 87 (91) 9 (9) Salerno 1996–2010 571 96.1 4.9 77 76 (99) 1 (1) Sassari 1992–2011 209 98.6 1.4 42 42 (100) 0 (0) Siracusa 1999–2012 222 90.5 13.5 27 25 (93) 2 (7) Sondrio 1998–2013 156 84.0 4.5 20 20 (100) 0 (0) Trapani 2002–2010 164 100.0 2.4 33 29 (88) 4 (12) Trento 1995–2010 165 97.6 9.1 39 39 (100) 0 (0) Umbria 1994–2013 692 98.7 4.9 96 96 (100) 0 (0) Varese 1978–2012 348 92.2 12.9 85 83 (98) 2 (2) Veneto 1987–2010 1,244 96.1 2.7 147 145 (99) 2 (1) MALTA Malta 1993–2013 192 99.0 7.8 19 19 (100) 0 (0) PORTUGAL Northern Portugal 2000–2010 939 99.9 3.8 145 124 (86) 21 (14) Southern Portugal 2000–2012 2,055 99.9 7.8 305 262 (86) 43 (14) SLOVENIA Slovenia 1983–2012 1,000 100.0 1.6 102 93 (91) 9 (9) SPAIN Balearic Islands 1988–2012 456 99.8 1.3 65 41 (63) 24 (37) Basque Country 1986–2012 1,163 99.1 6.0 174 131 (75) 43 (25) Canarie 1996–2011 645 99.7 1.6 97 87 (90) 10 (10) Castellon 2004–2012 199 100.0 4.0 30 29 (97) 1 (3) Girona 1994–2014 475 99.8 0.4 64 14 (22) 50 (78) Granada 1985–2012 363 100.0 2.8 51 27 (53) 24 (47) Murcia 1990–2010 492 98.8 4.3 90 90 (100) 0 (0) Navarra 1978–2010 189 98.4 2.1 22 21 (95) 1 (5) Tarragona 1982–2011 336 100.0 3.0 53 35 (66) 18 (34) Eastern BULGARIA Bulgaria 1993–2013 2,899 100.0 8.2 690 690 (100) 0 (0) Europe CZECH Czech Republic 1994–2013 2,975 72.2 25.8 586 468 (80) 118 (20) REPUBLIC ESTONIA Estonia 1978–2012 528 100.0 1.9 88 84 (95) 4 (5) LATVIA Latvia 2000–2013 695 99.9 11.4 146 146 (100) 0 (0) LITHUANIA Lithuania 1993–2012 2,012 99.3 3.6 325 250 (77) 75 (23) POLAND Poland 2001–2013 8,093 95.6 9.8 2,197 2,197 (100) 0 (0) SLOVAKIA Slovakia 1978–2010 2,067 100.0 2.0 311 257 (83) 54 (17) Total 84 CRs 106,419 96.1 4.5 18,083 14,105 (78) 3,978 (22) CML, chronic myeloid leukemia; CR, cancer registry; HM, hematological malignancies; Ph, Philadelphia chromosome. 1 CRs period of diagnosis refers to overall data sent by each cancer registry. 2 International Classification of Disease for Oncology, 3rd edition (ICD-O-3) codes for myeloid malignancies: 9740-9742, 9800-9801, 9805-9809, 9840, 9860-9861, 9863, 9865-9867, 9869-9876, 9891, 9895-9898, 9910-9911, 9920, 9930-9931, 9945-9946, 9950, 9960-9964, 9966, 9975, 9980, 9982-9987, 9989, 9991-9992. 3 ICD-O-3 codes of CML cases eligible for the survival analysis: 9863 (CML with no cytogenetic information, CML NOS) and 9875 (Ph+, BCR/ABL1-positive CML). 4 Myeloid NOS cases ICD-O-3 codes: 9800, 9801, 9805, and 9860. 5 Four Federal States: Brandenburg, Mecklenburg-Western Pomerania, and the Free States of Saxony and Thuringia. CRs with national coverage are in bold. remain. Our results suggest an insufficient adoption of adequate M. Sekerija (National CR); Cyprus: P. Pavlou (National CR); Czech protocols in daily clinical practice in countries where CML survival Republic: L. Dušek (National CR); Denmark: H. Storm (National values still remain lower in real-life than those obtained in RCTs. In CR); Estonia: M. Mägi; K. Innos* (National CR); Finland: N. Malila; future works, it will be of interest to focus on populations usually J. Pitkäniemi (National CR); France: M. Velten (Bas Rhin CR); X. excluded from RCTs, such as older patients, or with comorbidities Troussard (Basse Normandie, Haematological Malignancies CR); and other cancers. A.M. Bouvier; V. Jooste* (Burgundy, Digestive CR); A.V. Guizard (Calvados, General CR); G. Launoy (Calvados, Digestive CR); S. Dabakuyo Yonli (Cote dOr, Gynaecologic (Breast) CR); M. EUROCARE-6 WORKING GROUP Maynadié (Cote dOr, Haematological Malignancies CR); A.S. Woronoff (Doubs CR); J.B. Nousbaum (Finistere, Digestive CR); Austria: M. Hackl (National CR); Belgium: E. Van Eycken G. Coureau (Gironde, General CR); A. Monnereau* (Gironde, (National CR); Bulgaria: Z. Valerianova (National CR); Croatia: Haematological Malignancies CR); I. Baldi (Gironde, Central Frontiers in Oncology | www.frontiersin.org 9 July 2022 | Volume 12 | Article 892684 Vener et al. Chronic Myeloid Leukemia Survival TABLE 3 | Five-year crude overall survival of CML cases (15–64 years) (9863, 9875 ICD-O-3 codes)1 diagnosed in 2000–2006 and 2007–2013 by European region and country. EUROCARE-6 study dataset. Country/Area Total cases Median age Male M 2000–2006 2007–2013 Absolute p- 2000–2013 (years) % difference value N at N5 OS 95%CI N at N5 OS 95%CI start start Northern Europe 1,109 48 621 56.0 534 438 80.5 77.2 83.9 575 314 89.2 86.4 92.2 8.8** <0.001 (4 CRS) Denmark 470 48 267 56.8 225 186 80.8 75.8 86.1 245 135 88.7 84.0 93.6 7.9* 0.028 Finland 304 49 175 57.6 165 135 80.0 74.1 86.3 139 73 86.0 79.8 92.6 6.0 0.187 Iceland 23 45 18 78.3 11 9 – – – 12 6 – – – – – Norway 312 48 161 51.6 133 108 80.5 74.0 87.5 179 100 91.8 87.7 96.0 11.3** 0.005 UK and Ireland 4,361 49 2,555 58.6 2,001 1,488 72.2 70.3 74.2 2,360 1,187 86.9 85.3 88.4 14.7** <0.001 (4 CRs) Ireland 240 52 141 58.8 117 97 79.5 72.5 87.2 123 58 90.7 85.3 96.5 11.2* 0.017 England 3548 48 2080 58.6 1596 1167 70.9 68.7 73.2 1952 982 86.5 84.8 88.2 15.5** <0.001 Scotland 344 50 210 61.0 166 139 83.1 77.6 89.0 178 87 87.8 82.1 93.7 4.6 0.263 Wales 229 50 124 54.1 122 85 67.2 59.4 76.1 107 60 88.2 81.7 95.2 21.0** <0.001 Central Europe 5,103 50 2,958 58.0 2,186 1,829 82.6 81.0 84.2 2,917 1,407 88.5 87.1 89.9 5.9** <0.001 (25 CRs) Austria 623 51 379 60.8 347 262 74.6 70.2 79.4 276 146 84.2 79.6 89.1 9.5** 0.005 Belgium 772 50 437 56.6 201 176 87.0 82.5 91.8 571 282 92.0 89.5 94.6 5.0 0.066 France (13 CRs 1070 50 628 58.7 444 394 88.5 85.6 91.5 626 321 92.1 89.5 94.7 3.6 0.076 Pool) Germany (6 CRs 1336 50 786 58.8 597 502 82.6 79.6 85.7 739 312 85.7 82.7 88.8 3.2 0.150 Pool) Switzerland (3CRs 103 50 60 58.3 51 47 90.2 82.4 98.7 52 26 85.8 74.4 99.0 −4.4 0.561 Pool) The Netherlands 1199 49 668 55.7 546 448 80.4 77.1 83.8 653 320 87.2 84.2 90.2 6.7** 0.003 Southern Europe 3,167 49 1,855 58.6 1,738 1,396 78.1 76.2 80.1 1,429 816 86.9 85.0 88.8 8.8** <0.001 (44 CRs) Cyprus 38 49 28 73.7 10 9 – – – 28 19 – – – – – Croatia 265 52 166 62.6 154 100 59.7 52.5 68.0 111 25 68.6 57.7 81.5 8.8 0.220 Italy (29 CRs Pool) 1647 50 950 57.7 906 752 81.3 78.8 83.9 741 441 88.3 85.8 90.8 7.0** <0.001 Malta 19 40 12 63.2 12 9 – – – 7 2 – – – – – Portugal (2 CRs 450 49 253 56.2 254 191 74.0 68.8 79.6 196 121 82.9 77.5 88.6 8.9* 0.025 Pool) Slovenia 102 49 65 63.7 54 35 59.3 47.5 73.9 48 30 91.7 84.2 99.8 32.4** <0.001 Spain (CRs Pool) 646 47 381 59.0 348 300 83.6 79.8 87.6 298 178 90.3 86.7 94.0 6.7* 0.014 Eastern Europe 4,343 51 2,376 54.7 2,334 1,351 55.3 53.3 57.3 2,009 754 72.8 70.6 75.1 17.6** <0.001 (7 CRs) Bulgaria 690 53 374 54.2 390 174 41.3 36.7 46.5 300 106 63.6 58.0 69.7 22.3** <0.001 Czech Republic 586 50 329 56.1 336 228 66.1 61.2 71.3 250 81 75.0 68.5 82.2 9.0* 0.039 Estonia 88 50 54 61.4 53 30 54.7 42.8 69.9 35 19 69.0 54.5 87.3 14.2 0.186 Latvia 146 50 82 56.2 67 40 56.7 46.0 69.9 79 28 63.8 52.8 77.1 7.1 0.414 Lithuania 325 49 173 53.2 179 92 49.1 42.3 57.0 146 73 78.7 71.9 86.1 29.5** <0.001 Poland 2197 50 1195 54.4 1105 669 57.8 55.0 60.8 1092 384 74.3 71.2 77.6 16.5** <0.001 Slovakia 311 50 169 54.3 204 118 55.4 49.0 62.7 107 63 78.2 70.3 86.9 22.8** <0.001 European Pool 18,083 50 10,365 57.3 8,793 6,502 71.9 71.0 72.9 9,290 4478 84.7 83.9 85.5 12.7** <0.001 (84 CRs) CI, confidence interval; CML, chronic myeloid leukemia; CR, cancer registry; ICD-O-3, International Classification of Disease for Oncology, 3rd edition; M, male; N at start, number of CML cases alive at the beginning of the period; N5, number of CML cases alive at 5 years from diagnosis; OS, overall survival. 1 ICD-O-3 codes of CML cases eligible for the survival analysis: 9863 (CML with no cytogenetic information, CML NOS) and 9875 (Ph+, BCR/ABL1-positive CML). Survival estimates are not provided for strata including fewer than 10 cases. **p-value <0.01 and *p-value <0.05. In bold European regions and statistically significant p values. Nervous System CR); K. Hammas (Haut-Rhin CR); B. Tretarre Saxony-Anhalt, Thüringen)]; A. Nennecke (Hamburg CR); J. (Herault CR); M. Colonna (Isere CR); S. Plouvier (Lille Area CR); T. Kieschke (Lower Saxony CR); S. Zeissig (Rhineland-Palatinate D’Almeida (Limousin CR); F. Molinié; A. Cowppli-Bony (Loire- CR); B. Holleczek (Saarland CR); A. Katalinic* (Schleswig- Atlantique/Vendée CR); S. Bara (Manche CR); C. Schvartz (Marne- Holstein CR); Iceland: H. Birgisson (National CR); Ireland: D. Ardennes, Thyroid CR); G. Defossez (Poitou-Charentes CR); B. Murray; P.M. Walsh (National CR); Italy: G. Mazzoleni; F. Lapô t re-Ledoux (Somme CR); P. Grosclaude (Tarn CR); Vittadello (Alto Adige CR); F. Cuccaro (Barletta-Andria-Trani Germany: S. Luttmann (Bremen CR); R. Stabenow [Common CR CR); R. Galasso (Basilicata CR); G. Sampietro (Bergamo CR); S. of 4 Federal States (Brandenburg, Mecklenburg-West Pomerania, Rosso (Biella CR); M. Magoni (Brescia CR); M. Ferrante (Catania- Frontiers in Oncology | www.frontiersin.org 10 July 2022 | Volume 12 | Article 892684 Vener et al. Chronic Myeloid Leukemia Survival TABLE 4 | Conditional crude 5-/3-year overall survival1 of CML cases (15–64 years) (9863, 9875 ICD-O-3 codes)2 diagnosed in 2000–2006 and 2007–2013 by European region and country. EUROCARE-6 study dataset. Country/Area 2000–2006 2007–2013 Absolute difference p-value N3 N5 5-/3-year 95%CI N3 N5 5-/3-year 95%CI Northern Europe (4 CRS) 470 438 95.7 93.9 97.6 475 314 96.4 94.3 98.5 0.7 0.642 Denmark 199 186 94.2 91.0 97.6 199 135 93.8 89.7 98.1 −0.4 0.873 Finland 143 135 96.4 93.3 99.5 114 73 96.0 91.7 100.6 −0.3 0.907 Iceland 9 9 – – – 10 6 – – – – – Norway 119 108 97.3 94.3 100.4 152 100 100.0 100.0 100.0 2.7 0.079 UK and Ireland (4 CRs) 1,641 1,488 92.9 91.6 94.2 1,872 1,187 97.2 96.2 98.1 4.3** <0.001 Ireland 105 97 93.0 88.1 98.1 99 58 98.6 95.8 101.4 5.6 0.057 England 1293 1167 92.6 91.1 94.0 1537 982 97.3 96.3 98.4 4.8** <0.001 Scotland 146 139 94.5 90.9 98.3 144 87 95.1 90.6 99.9 0.6 0.832 Wales 97 85 94.3 89.5 99.3 92 60 96.6 92.0 101.4 2.3 0.497 Central Europe (25 CRs) 1,937 1,829 96.3 95.4 97.1 2,372 1,407 96.0 95.0 97.0 −0.2 0.719 Austria 280 262 96.3 94.0 98.6 252 146 93.9 90.2 97.7 −2.4 0.274 Belgium 185 176 96.7 94.1 99.3 471 282 98.2 96.5 99.8 1.5 0.344 France (13 CRs Pool) 415 394 97.3 95.7 98.9 523 321 96.6 94.6 98.6 −0.7 0.588 Germany (6 CRs Pool) 529 502 96.3 94.7 97.9 545 312 95.2 92.9 97.5 −1.1 0.453 Switzerland (3 CRs Pool) 50 47 95.8 90.3 101.7 42 26 91.9 81.5 103.6 −3.9 0.535 The Netherlands 478 448 95.2 93.3 97.2 539 320 95.7 93.6 97.9 0.5 0.725 Southern Europe (44 CRs) 1,509 1,396 94.3 93.2 95.5 1,209 816 97.2 96.1 98.4 2.9** 0.001 Cyprus 10 9 – – – 27 19 – – – – – Croatia 116 100 87.6 81.5 94.2 59 25 91.9 81.5 103.7 4.3 0.510 Italy (29 CRs Pool) 799 752 95.3 93.8 96.8 624 441 97.6 96.2 99.1 2.3* 0.028 Malta 10 9 – – – 3 2 – – – – – Portugal (2 CRs Pool) 219 191 93.5 90.2 97.0 173 121 96.0 92.7 99.5 2.5 0.301 Slovenia 41 35 86.5 76.1 98.2 44 30 100.0 100.0 100.0 13.5* 0.016 Spain (CRs Pool) 314 300 95.7 93.5 98.0 279 178 97.4 95.1 99.7 1.7 0.313 Eastern Europe (7 CRs) 1,636 1,351 86.6 84.9 88.4 1,295 754 93.4 91.6 95.1 6.7** <0.001 Bulgaria 241 174 78.2 72.7 84.0 195 106 95.1 91.3 99.0 17.0** <0.001 Czech Republic 256 228 92.5 89.2 95.9 144 81 93.5 88.0 99.2 1.0 0.771 Estonia 39 30 80.6 68.6 94.6 29 19 86.4 73.1 102.0 5.8 0.556 Latvia 49 40 82.6 72.4 94.3 52 28 92.7 83.3 103.2 10.1 0.180 Lithuania 121 92 82.2 75.3 89.8 122 73 95.0 90.4 99.9 12.8** 0.004 Poland 791 669 88.0 85.7 90.4 665 384 92.6 90.1 95.2 4.6** 0.010 Slovakia 139 118 88.3 82.9 94.0 88 63 95.0 89.6 100.7 6.7 0.093 European Pool (84 CRs) 7,193 6,502 92.9 92.3 93.5 7,223 4,478 96.1 95.5 96.7 3.2** <0.001 CI, confidence interval; CML, chronic myeloid leukemia; CR, cancer registry; ICD-O-3, International Classification of Disease for Oncology, 3rd edition. N3 and N5, number of CML cases alive at 3 and 5 years from diagnosis, respectively. 1 The crude 5-/3-year conditional overall survival is the probability of being alive after 5 years, conditional on surviving 3 years after diagnosis. 2 ICD-O-3 codes of CML cases eligible for the survival analysis: 9863 (CML with no cytogenetic information, CML NOS) and 9875 (Ph+, BCR/ABL1-positive CML). Survival estimates are not provided for strata including fewer than 10 cases. **p-value <0.01 and *p-value <0.05. In bold European regions and statistically significant p values. Messina-Enna CR); A. Sutera Sardo (Catanzaro CR); M.L. Gambino L. Mangone (Reggio Emilia CR); F. Falcini (Romagna CR); R. (Como CR); P. Ballotari; E. Giacomazzi (Cremona and Mantova Cavallo (Salerno CR); D. Piras (Sassari CR); A. Madeddu; F. Bella CR); S. Ferretti (Ferrara CR); A. Caldarella; G. Manneschi (Firenze- (Siracusa CR); A.C. Fanetti (Sondrio CR); S. Minerba (Taranto CR); Prato CR); G. Gatta*; M. Sant*; P. Baili*; F. Berrino*; L. Botta; A. G. Candela; T. Scuderi (Trapani CR); R.V. Rizzello (Trento CR); F. Trama; R. Lillini; A. Bernasconi; S. Bonfarnuzzo; C. Vener; F. Stracci (Umbria CR); G. Tagliabue (Varese CR); M. Rugge (Veneto Didonè; P. Lasalvia; G. Del Monego; M.C. Magri; L. Buratti CR); A. Brustolin (Viterbo CR); Latvia: S. Pildava (National CR); (Fondazione IRCCS Istituto Nazionale dei Tumori, Milan); D. Lithuania: G. Smailyte (National CR); Malta: M. Azzopardi Serraino; L. Dal Maso (Friuli Venezia Giulia CR); R. Capocaccia* (National CR); Norway: T.B. Johannesen* (National CR); Poland: (Epidemiologia e Prevenzione Board); R. De Angelis*; E. Demuru; C. J. Didkowska; U. Wojciechowska (National CR); M. Bielska-Lasota* Di Benedetto; S. Rossi*; M. Santaquilani; S. Venanzi (Istituto (National Institute of Public Health-National Institute of Hygiene- Superiore di Sanità, Rome); R.A. Filiberti (Genova CR); S. National Research Institute, Warsaw); Portugal: A. Pais (Central Iacovacci (Latina CR); V. Gennaro (Liguria, mesotheliomas CR); Portugal CR); J.L. Pontes (Northern Portugal CR); A. Miranda A.G. Russo (Lodi CR); G. Spagnoli (Modena CR); L. Cavalieri d’Oro (Southern Portugal CR); Slovakia: C. Safaei Diba (National CR); (Monza and Brianza CR); M. Fusco; M.F. Vitale (Napoli CR); M. Slovenia: V. Zadnik; T. Zagar (National CR); Spain: C. Sá nchez- Usala (Nuoro CR); F. Vitale (Palermo CR); M. Michiara (Parma Contador Escudero; P. Franch Sureda (Balearic Islands, Mallorca CR); G. Chiranda (Piacenza CR); G. Cascone; E. Spata (Ragusa CR); CR); A. Lopez de Munain; M. De-La-Cruz (Basque Country CR); Frontiers in Oncology | www.frontiersin.org 11 July 2022 | Volume 12 | Article 892684 Vener et al. Chronic Myeloid Leukemia Survival M.D. Rojas, A. Aleman (Canary Islands CR); A. Vizcaino (Castellon designed the study and data quality checks; RM-G, HP, MM, XT, CR); R. Marcos-Gragera (Girona CR); M.J. Sanchez (Granada CR); and GP provided advice and revised the results. EUROCARE-6 M.D. Chirlaque (Murcia CR); M. Guevara Eslava*; E. Ardanaz Working Group collected, prepared, and transmitted raw data (Navarra CR); J. Galceran; M. Carulla (Tarragona CR); for the study database; corrected data after quality controls; and Switzerland: Y. Bergeron (Fribourg CR); C. Bouchardy (Geneva checked the results of the analyses. All authors contributed to the CR); S. Mohsen Mousavi (Graubünden and Glarus CR); S. Mohsen article and approved the submitted version. Mousavi (Eastern Switzerland CR); A. Bordoni (Ticino CR); The Netherlands: O. Visser* (National CR); UK-England: J. Rashbass (National CR); UK-Northern Ireland: A. Gavin* (National CR); UK-Scotland: D. Morrison (National CR); UK-Wales: D. W. FUNDING Huws* (National CR).*EUROCARE Steering Committee This study was funded by the Compagnia di San Paolo, the Cariplo Foundation and the European Commission (grant DATA AVAILABILITY STATEMENT number 801520 HP-JA-2017, Innovative Partnership for Action Against Cancer, iPAAC Joint Action). The sources of The datasets presented in this article are not readily available. See the funding played no role in designing the study, collecting, EUROCARE-6 Collaborative Group Rules (http://www. analyzing, or interpreting the data, writing the report, or eurocare.it). Requests to access the datasets should be directed deciding whether or not to submit the article for publication. to http://www.eurocare.it. This research was (partially) funded by Italian Ministry of Health “Ricerca Corrente” funds. ETHICS STATEMENT Ethical review and approval was not required for the study on ACKNOWLEDGMENTS human participants in accordance with the local legislation and institutional requirements. Written informed consent from the We would like to thank Simone Bonfarnuzzo for his assistance participants’ legal guardian/next of kin was not required to and Christine Gislason for revising the language of the paper. participate in this study in accordance with the national legislation and the institutional requirements. SUPPLEMENTARY MATERIAL AUTHOR CONTRIBUTIONS The Supplementary Material for this article can be found online at: CV designed and carried out the study and analyzed the data; SR https://www.frontiersin.org/articles/10.3389/fonc.2022.892684/ and PM did quality controls and analyzed the data; RA and MS full#supplementary-material REFERENCES 7. Druker BJ, Tamura S, Buchdunger E, Ohno S, Segal GM, Fanning S, et al. Effects of a Selective Inhibitor of the Abl Tyrosine Kinase on the Growth of 1. Sant M, Allemani C, Tereanu C, De Angelis R, Capocaccia R, Visser O, et al. Bcr-Abl Positive Cells. Nat Med (1996) 2:561–6. doi: 10.1038/nm0596-561 Incidence of Hematologic Malignancies in Europe by Morphologic Subtype: 8. Buchdunger E, Zimmermann J, Mett H, Meyer T, Müller M, Druker BJ, et al. Results of the HAEMACARE Project. Blood (2010) 116:3724–34. doi: Inhibition of the Abl Protein-Tyrosine Kinase In Vitro and In Vivo by a 2- 10.1182/blood-2010-05-282632 Phenylaminopyrimidine Derivative. Cancer Res (1996) 56:100–4. 2. Björkholm M, Ohm L, Eloranta S, Derolf A, Hultcrantz M, Andersson JST, 9. Druker BJ. Perspectives on the Development of a Molecularly Targeted Agent. et al. Success Story of Targeted Therapy in Chronic Myeloid Leukemia: A Cancer Cell (2002) 1:31–6. doi: 10.1016/S1535-6108(02)00025-9 Population-Based Study of Patients Diagnosed in Sweden From 1973 to 2008. 10. Sant M, Minicozzi P, Mounier M, Anderson LA, Brenner H, Holleczek B, et al. JCO (2011) 29:2514–20. doi: 10.1200/JCO.2011.34.7146 Survival for Haematological Malignancies in Europe Between 1997 and 2008 3. Hoffmann VS, Baccarani M, Hasford J, Lindoerfer D, Burgstaller S, Sertic D, by Region and Age: Results of EUROCARE-5, a Population-Based Study. et al. The EUTOS Population-Based Registry: Incidence and Clinical Lancet Oncol (2014) 15:931–42. doi: 10.1016/S1470-2045(14)70282-7 Characteristics of 2904 CML Patients in 20 European Countries. Leukemia 11. Francis S, Lucas C, Lane S, Wang L, Watmough S, Knight K, et al. A (2015) 29:1336–43. doi: 10.1038/leu.2015.73 Population Study Showing That the Advent of Second Generation Tyrosine 4. Swerdlow SH, Campo E, NL H, Jaffe ES, Pileri SA, Stein H, et al. WHO Kinase Inhibitors has Improved Progression-Free Survival in Chronic Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, Myeloid Leukaemia. Leuk Res (2013) 37:752–8. doi: 10.1016/ France: IARC Press (2008). j.leukres.2013.04.003 5. Silver RT, Woolf SH, Hehlmann R, Appelbaum FR, Anderson J, Bennett C, et al. 12. De Angelis R, Minicozzi P, Sant M, Dal Maso L, Brewster DH, Osca-Gelis G, An Evidence-Based Analysis of the Effect of Busulfan, Hydroxyurea, Interferon, et al. Survival Variations by Country and Age for Lymphoid and Myeloid and Allogeneic Bone Marrow Transplantation in Treating the Chronic Phase of Malignancies in Europe 2000-2007: Results of EUROCARE-5 Population- Chronic Myeloid Leukemia: Developed for the American Society of Hematology. Based Study. EJC (2015) 51:2254–68. doi: 10.1016/j.ejca.2015.08.003 Blood (1999) 94:1517–36. 13. Wiggins CL, Harlan LC, Nelson HE, Stevens JL, Willman CL, Libby EN, et al. 6. Druker BJ, Talpaz M, Resta DJ, Peng B, Buchdunger E, Ford JM, et al. Efficacy Age Disparity in the Dissemination of Imatinib for Treating Chronic Myeloid and Safety of a Specific Inhibitor of the BCR-ABL Tyrosine Kinase in Chronic Leukemia. Am J Med (2010) 123:764.e1–9. doi: 10.1016/j.amjmed.2010.03.018 Myeloid Leukemia. N Engl J Med (2001) 344:1031–7. doi: 10.1056/ 14. Osca-Gelis G, Puig-Vives M, Saez M, Gallardo D, Lloveras N, Guá rdia R, et al. NEJM200104053441401 Is Survival in Myeloid Malignancies Really Improving? A Retrospective 15 Frontiers in Oncology | www.frontiersin.org 12 July 2022 | Volume 12 | Article 892684 Vener et al. Chronic Myeloid Leukemia Survival Year Population-Based Study. Leuk Lymphoma (2015) 56:896–902. doi: (DASISION, CA180-056). Blood (ASH Annu Meeting Abstracts) (2014) 124 10.3109/10428194.2014.947610 (21):152. doi: 10.1182/blood.V124.21.152.152 15. Marmot M. Fair Society, Healthy Lives. The Marmot Review. Strategic Review 32. Cortes JE, Saglio G, Kantarjian HM, Baccarani M, Mayer J, Boqué C, et al. of Health Inequalities in England Post-2010. Available at: http://www. Final 5-Year Study Results of DASISION: The Dasatinib Versus Imatinib instituteofhealthequity.org (Accessed Nov 11, 2021). Study in Treatment-Naïve Chronic Myeloid Leukemia Patients Trial. J Clin 16. Baili P, Di Salvo F, Marcos-Gragera R, Siesling S, Mallone S, Santaquilani M, Oncol (2016) 34(20):2333–40. doi: 10.1200/JCO.2015.64.8899 et al. Age and Case Mix-Standardised Survival for All Cancer Patients in 33. Radich JP, Kopecky KJ, Appelbaum FR, Kamel-Reid S, Stock W, Malnassy G, Europe 1999-2007: Results of EUROCARE-5, a Population-Based Study. Eur J et al. A Randomized Trial of Dasatinib 100 Mg Versus Imatinib 400 Mg in Cancer (2015) 51:2120–9. doi: 10.1016/j.ejca.2015.07.025 Newly Diagnosed Chronic-Phase Chronic Myeloid Leukemia. Blood (2012) 17. Del Paggio JC. Deconstructing Clinical Trials-Help From Oncology Value 120(19):3898–905. doi: 10.1182/blood-2012-02-410688 Frameworks. JAMA Oncol (2017) 3:1306–7. doi: 10.1001/jamaoncol.2017.1312 34. Mustjoki S, Richter J, Barbany G, Ehrencrona H, Fioretos T, Gedde-Dahl T, 18. Chandra A, Shafrin J, Dhawan R. Utility of Cancer Value Frameworks for et al. Impact of Malignant Stem Cell Burden on Therapy Outcome in Newly Patients, Payers, and Physicians. JAMA (2016) 315:2069–70. doi: 10.1001/ Diagnosed Chronic Myeloid Leukemia Patients. Leukemia (2013) 27(7):1520– jama.2016.4915 6. doi: 10.1038/leu.2013.19 19. Hellmann MD, Kris MG, Rudin CM. Medians and Milestones in Describing 35. Hjorth-Hansen H, Richter J, Stenke L, Ehrencrona H, Gjertsen BT, Gedde- the Path to Cancer Cures: Telling “Tails”. JAMA Oncol (2016) 2:167–8. doi: Dahl T, et al. Dasatinib Treatment Induces Fast and Deep Responses in Newly 10.1001/jamaoncol.2015.4345 Diagnosed Chronic Myeloid Leukemia (CML) Patients in Chronic Phase: 20. Vera-Badillo FE, Napoleone M, Krzyzanowska MK, Alibhai SMH, Chan AW, Clinical Results From a Randomised Phase-2 Study (Nordcml006). Blood Ocana A, et al. Bias in Reporting of Randomised Clinical Trials in Oncology. (ASH Annu Meeting Abstracts) (2013) 122(21):4032. doi: 10.1182/ Eur J Cancer (2016) 61:29–35. doi: 10.1016/j.ejca.2016.03.066 blood.V122.21.4032.4032 21. Tannock IF, Amir E, Booth CM, Niraula S, Ocana A, Seruga B, et al. Relevance 36. Hjorth-Hansen H, Stenke L, Söderlund S, Dreimane A, Ehrencrona H, Gedde- of Randomised Controlled Trials in Oncology. Lancet Oncol (2016) 17:e560– Dahl T, et al. Dasatinib Induces Fast and Deep Responses in Newly Diagnosed 7. doi: 10.1016/S1470-2045(16)30572-1 Chronic Myeloid Leukaemia Patients in Chronic Phase: Clinical Results From 22. EUROCARE Survival of Cancer Patients in Europe. Available at: http://www. a Randomised Phase-2 Study (Nordcml006). Eur J Haematol (2015) 94 eurocare.it (Accessed Nov 11, 2021). (3):243–50. doi: 10.1111/ejh.12423 23. Kantarjian HM, Shah NP, Hochhaus A, Cortes J, Shah S, Ayala M, et al. 37. Larson RA, Le Coutre PD, Reiffers J, Hughes TP, Saglio G, Edrich P, et al. Dasatinib Versus Imatinib in Newly Diagnosed Chronic-Phase Chronic Comparison of Nilotinib and Imatinib in Patients (Pts) With Newly Myeloid Leukemia. N Engl J Med (2010) 362(24):2260–70. doi: 10.1056/ Diagnosed Chronic Myeloid Leukemia in Chronic Phase (CML-CP): NEJMoa1002315 ENESTnd Beyond One Year. J Clin Oncol (ASCO Annu Meeting Abstracts) 24. Shah N, Kantarjian HM, Hochhaus A, Cortes JE, Bradley-Garelik MB, Zhu C, (2010) 28(15):6501. doi: 10.1200/jco.2010.28.15_suppl.6501 et al. Dasatinib Versus Imatinib in Patients With Newly Diagnosed Chronic 38. Saglio G, Kim DW, Issaragrisil S, le Coutre P, Etienne G, Lobo C, et al. Myeloid Leukemia in Chronic Phase (CML-CP) in the DASISION Trial: 18- Nilotinib Versus Imatinib for Newly Diagnosed Chronic Myeloid Leukemia. Month Follow-Up. Blood (ASH Annu Meeting Abstracts) (2010) 116(21):206. N Engl J Med (2010) 362(24):2251–9. doi: 10.1056/NEJMoa0912614 doi: 10.1182/blood.V116.21.206.206 39. Hughes T, Hochhaus A, Saglio G, Kim DW, Jootar S, Le Coutre PD, et al. ENESTnd 25. Kantarjian HM, Shah NP, Cortes JE, Baccarani M, Bradley-Garelik MB, ZhuA update: Continued Superiority of Nilotinib Versus Imatinib in Patients with C, et al. Dasatinib or Imatinib (IM) in Newly Diagnosed Chronic Myeloid Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase (CML-CP). Leukemia in Chronic Phase (CML-CP): Two-Year Follow-Up From Blood (ASH Annual Meeting Abstracts) (2010) 116(21). [Abstract 207]. DASISION. J Clin Oncol (ASCO Annu Meeting Abstracts) (2011) 29 40. Kantarjian HM, Hochhaus A, Saglio G, De Souza C, Flinn IW, Stenke L, et al. (15):6510. doi: 10.1200/jco.2011.29.15_suppl.6510 Nilotinib Versus Imatinib for the Treatment of Patients With Newly 26. Hochhaus A, Saglio G, Chuah C, Pavlovsky C, Bradley Garelick MB, Lambert Diagnosed Chronic Phase, Philadelphia Chromosome-Positive, Chronic A, et al. Dasatinib and Imatinib-Induced Reductions in BCR-ABL Transcript Myeloid Leukaemia: 24-Month Minimum Follow-Up of the Phase 3 Levels Below 10% at 3 Months Are Associated With Improved Responses in Randomised ENESTnd Trial. Lancet Oncol (2011) 12(9):841–51. doi: Patients With Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase 10.1016/S1470-2045(11)70201-7 (CML-CP): Analysis of Molecular Response Kinetics in the DASISION Trial. 41. Kantarjian HM, Kim DW, Issaragrisil S, Clark RE, Reiffers J, Nicolini FE, et al. [Abstract]. Blood (ASH Annu Meeting Abstracts) (2011) 118(21):2767. doi: Enestnd 4-Year (Y) Update: Continued Superiority of Nilotinib vs Imatinib in 10.1182/blood.V118.21.2767.2767 Patients (Pts) With Newly Diagnosed Philadelphia Chromosome-Positive (Ph 27. Hochhaus A, Shah N, Cortes JE, Baccarani M, Bradley-Garelik MB, Dejardin +) Chronic Myeloid Leukemia in Chronic Phase (CML-CP). [Abstract]. Blood D, et al. Dasatinib Versus Imatinib (IM) in Newly Diagnosed Chronic Myeloid (ASH Annu Meeting Abstracts) (2012) 120(21):1676. doi: 10.1182/ Leukemia in Chronic Phase (CML-CP): DASISION 3-Year Follow-Up. J Clin blood.V120.21.1676.1676 Oncol (ASCO Annu Meeting Abstracts) (2012) 30(15):6504. doi: 10.1200/ 42. Larson RA, Hochhaus A, Hughes TP, Clark RE, Etienne G, Kim DW, et al. jco.2012.30.15_suppl.6504 Nilotinib vs Imatinib in Patients With Newly Diagnosed Philadelphia 28. Kantarjian HM, Shah NP, Cortes JE, Baccarani M, Agarwal MB, Undurraga Chromosome-Positive Chronic Myeloid Leukemia in Chronic Phase: MS, et al. Dasatinib or Imatinib in Newly Diagnosed Chronic-Phase Chronic ENESTnd 3-Year Follow-Up. Leukemia (2012) 26(10):2197–203. doi: Myeloid Leukemia: 2-Year Follow-Up From a Randomized Phase 3 Trial 10.1038/leu.2012.134 (DASISION). Blood (2012) 119(5):1123–9. doi: 10.1182/blood-2011-08- 43. Hochhaus A, Saglio G, Larson RA, Kim DW, Etienne G, Rosti G, et al. 376087 Nilotinib Is Associated With a Reduced Incidence of BCR-ABL Mutations vs 29. Jabbour E, Kantarjian HM, Saglio G, Steegmann JL, Shah NP, Boqué C, et al. Imatinib in Patients With Newly Diagnosed Chronic Myeloid Leukemia in Early Response With Dasatinib or Imatinib in Chronic Myeloid Leukemia: 3- Chronic Phase. Blood (2013) 121(18):3703–8. doi: 10.1182/blood-2012-04- Year Follow-Up From a Randomized Phase 3 Trial (DASISION). Blood (2014) 423418 123(4):494–500. doi: 10.1182/blood-2013-06-511592 44. Hughes TP, Saglio G, Kantarjian HM, Guilhot F, Niederwieser D, Rosti G, 30. Cortes JE, Hochhaus A, Kim DW, Shah NP, Mayer J, Rowlings P, et al. Four- et al. Early Molecular Response Predicts Outcomes in Patients With Year (Yr) Follow-Up of Patients (Pts) With Newly Diagnosed Chronic Chronic Myeloid Leukemia in Chronic Phase Treated With Frontline Myeloid Leukemia in Chronic Phase (CML-CP) Receiving Dasatinib or Nilotinib or Imatinib. Blood (2014) 123(9):1353–60. doi: 10.1182/blood- Imatinib: Efficacy Based on Early Response. Blood (ASH Annu Meeting 2013-06-510396 Abstracts) (2013) 122(21):653. doi: 10.1182/blood.V122.21.653.653 45. Hochhaus A, Saglio G, Hughes TP, Larson RA, Kim DW, Issaragrisil S, et al. 31. Cortes JE, Saglio G, Baccarani M, Kantarjian HM, Mayer J, Boqué C, et al. Long-Term Benefits and Risks of Frontline Nilotinib vs Imatinib for Chronic Final Study Results of the Phase 3 Dasatinib Versus Imatinib in Newly Myeloid Leukemia in Chronic Phase: 5-Year Update of the Randomized Diagnosed Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Trial ENESTnd Trial. Leukemia (2016) 30(5):1044–54. doi: 10.1038/leu.2016.5 Frontiers in Oncology | www.frontiersin.org 13 July 2022 | Volume 12 | Article 892684 Vener et al. Chronic Myeloid Leukemia Survival 46. Hochhaus A, Saglio G, Hughes TP, Larson RA, Taningco L, Deng W, et al. Common Procedure for European Cancer Registries - Version 1.1. Impact of Treatment With Frontline Nilotinib (NIL) vs Imatinib (IM) on Luxembourg: Publications Office of the European Union (2018). Sustained Deep Molecular Response (MR) in Patients (Pts) With Newly 63. Janssen-Heijnen ML, Gondos A, Bray F, Hakulinen T, Brewster DH, Brenner Diagnosed Chronic Myeloid Leukemia in Chronic Phase (CML-Cp). Blood H, et al. Clinical Relevance of Conditional Survival of Cancer Patients in (ASH Annu Meeting Abstracts) (2015) 126(23):2781. doi: 10.1182/ Europe: Age-Specific Analyses of 13 Cancers. J Clin Oncol (2010) 28:2520–8. blood.V126.23.2781.2781 doi: 10.1200/JCO.2009.25.9697 47. Hughes T, Larson RA, Kim DW, Issaragrisil S, Le Coutre PD, Lobo C, et al. 64. Rossi S, Baili P, Capocaccia R, Caldora M, Carrani E, Minicozzi P, et al. The Efficacy and Safety of Nilotinib vs Imatinib in Patients With Newly Diagnosed EUROCARE-5 Study on Cancer Survival in Europe 1999-2007: Database, Chronic Myeloid Leukemia in Chronic Phase: 6-Year Follow-Up of Quality Checks and Statistical Analysis Methods. Eur J Cancer (2015) 51 ENESTND. Haematologica (EHA-European Hematol Assoc Library) (2015) (15):2104–19. doi: 10.1016/j.ejca.2015.08.001 100480:P228. 65. Brenner H, Gefeller O, Hakulinen T. Period Analysis for ‘Up-Todate’ Cancer 48. Cortes JE, DW K, Kantarjian HM, Brümmendorf TH, Dyagil I, Griskevicius L, Survival Data: Theory, Empirical Evaluation, Computational Realisation and et al. Bosutinib Versus Imatinib in Newly Diagnosed Chronic-Phase Chronic Applications. Eur J Cancer (2004) 40:326–35. doi: 10.1016/j.ejca.2003.10.013 Myeloid Leukemia: Results From the BELA Trial. J Clin Oncol (2012) 30 66. Ederer F, Axtell LM, Cutler SJ. The Relative Survival: A Statistical (28):3486–92. doi: 10.1200/JCO.2011.38.7522 Methodology. Natl Cancer Inst Monogr (1961) 6:101–21. 49. Gambacorti-Passerini C, Cortes JE, Kim DW, Kantarjian H, Khattry N, Lipton 67. Greenwood M. The Natural Duration of Cancer (Report on Public Health and JH, et al. Bosutinib (BOS) Versus Imatinib (IM) in Patients (Pts) With Medical Subjects No. 33). London, UK: His Majesty’s Stationery Office (1926). Chronic Phase Chronic Myeloid Leukemia (CP CML) in the BELA Trial: 68. Parkin DM, Hakulinen T. Cancer Registration: Principles and Methods. 18-Month Follow-Up. J Clin Oncol (ASCO Annu Meeting Abstracts) (2011) 29 Analysis of Survival. IARC Sci Publ (1991) 95:159–76. (15):6509. doi: 10.1200/jco.2011.29.15_suppl.6509 69. Parmar MK, Torri V, Stewart L. Extracting Summary Statistics to Perform 50. Brümmendorf TH, Cortes JE, De Souza CA, Guilhot F, Duvillié L, Pavlov D, Meta-Analyses of the Published Literature for Survival Endpoints. Stat Med et al. Bosutinib Versus Imatinib in Newly Diagnosed Chronic-Phase Chronic (1998) 17(24):2815–28. doi: 10.1002/(SICI)1097-0258(19981230)17:24<2815:: Myeloid Leukaemia: Results From the 24-Month Follow-Up of the BELA AID-SIM110>3.0.CO;2-8 Trial. Br J Haematol (2015) 168(1):69–81. doi: 10.1111/bjh.13108 70. Höglund M, Sandin F, Hellström K, Björeman M, Björkholm M, Brune M, 51. Brümmendorf TH, Gambacorti-Passerini C, Lipton J, Tee GY, Casado LF, et al. Tyrosine Kinase Inhibitor Usage, Treatment Outcome, and Prognostic Zaritskey A, et al. Bosutinib Versus Imatinib in Newly Diagnosed Chronic- Scores in CML: Report From the Population-Based Swedish CML Registry. Phase Chronic Myeloid Leukaemia: 30-Month Update of the BELA Trial. Blood (2013) 122(7):1284–92. doi: 10.1182/blood-2013-04-495598 Haematologica (EHA-European Hematol Assoc Meeting Abstracts) (2012) 97 71. Bower H, Björkholm M, Dickman PW, Höglund M, Lambert PC, Andersson (s1):0587. TML. Life Expectancy of Patients With Chronic Myeloid Leukemia 52. Gambacorti-Passerini C, JE C, JH L, Dmoszynska A, Wong RS, Rossiev V, Approaches the Life Expectancy of the General Population. J Clin Oncol et al. Safety of Bosutinib Versus Imatinib in the Phase 3 BELA Trial in Newly (2016) 34(24):2851–7. doi: 10.1200/JCO.2015.66.2866 Diagnosed Chronic Phase Chronic Myeloid Leukemia. Am J Hematol (2014) 72. Gunnarsson N, Sandin F, Höglund M, Stenke L, Björkholm M, Lambe M, et al. 89(10):947–53. doi: 10.1002/ajh.23788 Population-Based Assessment of Chronic Myeloid Leukemia in Sweden: 53. Cortes JE, Jean Khoury H, Kantarjian H, Brümmendorf TH, Mauro MJ, Striking Increase in Survival and Prevalence. Eur J Haematol (2016) 97 Matczak E, et al. Long-Term Evaluation of Cardiac and Vascular Toxicity in (4):387–92. doi: 10.1111/ejh.12743 Patients With Philadelphia Chromosome-Positive Leukemias Treated With 73. Smith AG, Painter D, Howell DA, Evans P, Smith G, Patmore R, et al. Bosutinib. Am J Hematol (2016) 91(6):606–16. doi: 10.1002/ajh.24360 Determinants of Survival in Patients With Chronic Myeloid Leukaemia 54. Cortes JE, Gambacorti-Passerini C, Deininger MW, Mauro MJ, Chuah C, Kim Treated in the New Era of Oral Therapy: Findings From a UK Population- DW, et al. Bosutinib Versus Imatinib for Newly Diagnosed Chronic Myeloid Based Patient Cohort. BMJ Open (2014) 4(1):e004266. doi: 10.1136/bmjopen- Leukemia: Results From the Randomized BFORE Trial. J Clin Oncol (2018) 36 2013-004266 (3):231–7. doi: 10.1200/JCO.2017.74.7162 74. Schmidt S, Wolf D, Thaler J, Burgstaller S, Linkesch W, Petzer A, et al. First 55. Gambacorti-Passerini C, Deininger MW, Mauro MJ, Chuah C, Kim DW, Annual Report of the Austrian CML Registry. Wien Klin Wochenschr (2010) Dyagil I, et al. Bosutinib vs Imatinib for Newly Diagnosed Chronic Myeloid 122(19-20):558–66. doi: 10.1007/s00508-010-1450-x Leukaemia (CML) in the BFORE Trial: 18-Month Follow-Up. Blood (ASH 75. Castagnetti F, Di Raimondo F, De Vivo A, et al. A Population-Based Study of Annu Meeting Abstracts) (2017) 130(1):896. doi: 10.1182/ Chronic Myeloid Leukemia Patients Treated With Imatinib in First Line. Am J blood.V130.Suppl_1.896.896 Hematol (2017) 92(1):82–7. doi: 10.1002/ajh.24591 56. Brümmendorf TH, Cortes JE, Milojkovic D, Gambacorti-Passerini C, Clark 76. Daskalakis M, Feller A, Noetzli J, Bonadies N, Arndt V, Baerlocher GM, et al. RE, le Coutre PD, et al. Bosutinib (BOS) Versus Imatinib for Newly Diagnosed Potential to Improve Therapy of Chronic Myeloid Leukemia (CML), Chronic Phase (CP) Chronic Myeloid Leukemia (CML): Final 5-Year Results Especially for Patients With Older Age: Incidence, Mortality, and Survival From the Bfore Trial. Blood (ASH Annu Meeting Abstracts) (2020) 136(1):41. Rates of Patients With CML in Switzerland From 1995 to 2017. Cancers doi: 10.1182/blood-2020-137393 (2021) 13(24):6269. doi: 10.3390/cancers13246269 57. Lipton JH, Chuah C, Guerci-Bresler A, Rosti G, Simpson D, Assouline S, et al. 77. Faber E, Mužıḱ J, Koza V, Demečková E, Voglová J, Demitrovičová L, et al. Ponatinib Versus Imatinib for Newly Diagnosed Chronic Myeloid Leukaemia: Treatment of Consecutive Patients With Chronic Myeloid Leukaemia in the An International, Randomised, Open-Label, Phase 3 Trial. Lancet Oncol Cooperating Centres From the Czech Republic and the Whole of Slovakia (2016) 17(5):612–21. doi: 10.1016/S1470-2045(16)00080-2 After 2000- a Report From the Population-Based CAMELIA Registry. Eur J 58. Vener C, Banzi R, Ambrogi F, Ferrero A, Saglio G, Pravettoni G, et al. First- Haematol (2011) 87(2):157–68. doi: 10.1111/j.1600-0609.2011.01637.x Line Imatinib Versus 2nd and 3rd Generation TKIs for Chronic Phase CML: 78. Thielen N, Visser O, Ossenkoppele G, Janssen J. Chronic Myeloid Leukemia Systematic Review and Meta-Analysis. Blood Adv (2020) 4(12):2723–35. doi: in the Netherlands: A Population-Based Study on Incidence, Treatment, and 10.1182/bloodadvances.2019001329 Survival in 3585 Patients From 1989 to 2012. Eur J Haematol (2016) 97 59. Vener C, Ferrero A, Banzi R, Pistotti V, Del Giovane C, Sant M, et al. Available (2):145–54. doi: 10.1111/ejh.12695 at: http://www.crd.york.ac.uk/PROSPERO/ (Accessed Nov 11, 2021). 79. Nicolini FE, Alcazer V, Cony-Makhoul P, Heiblig M, Morisset S, Fossard G, 60. Fritz A, Percy C, Jack A, Shanmugaratnam K, Sobin L, Parkin DM, et al. et al. Long-Term Follow-Up of De Novo Chronic Phase Chronic Myelogenous International Classification of Disease for Oncology (ICD-O), 3rd Edn. Geneva: Leukemia Patients on Front-Line Imatinib. Exp Hematol (2018) 64:97–105.e4. World Health Organization (2000). doi: 10.1016/j.exphem.2018.05.003 61. HAEMACARE Working Group. Manual for Coding and Reporting 80. Penot A, Preux PM, Le Guyader S, Collignon A, Herry A, Dufour V, et al. Haematological Malignancies. Tumori (2010) 96(4):i–A32. Incidence of Chronic Myeloid Leukemia and Patient Survival: Results of Five 62. Martos C, Crocetti E, Visser O, Rous B. Giusti F and the Cancer Data Quality French Population-Based Cancer Registries 1980-2009. Leuk Lymphoma Checks Working Group. A Proposal on Cancer Data Quality Checks. In: One (2015) 56(6):1771–7. doi: 10.3109/10428194.2014.974046 Frontiers in Oncology | www.frontiersin.org 14 July 2022 | Volume 12 | Article 892684 Vener et al. Chronic Myeloid Leukemia Survival 81. Hoffmann VS, Baccarani M, Hasford J, Castagnetti F, Di Raimondo F, Casado 87. Haematological Malignancies in Belgium 2004-2018, in: Belgian Cancer LF, et al. Treatment and Outcome of 2904 CML Patients From the EUTOS Registry, Brussels (2021). Belgian Cancer Registry - Publications (Accessed Population-Based Registry. Leukemia (2017) 31(3):593–601. doi: 10.1038/ Dec 22, 2021). leu.2016.246 82. Chen Y, Wang H, Kantarjian H, Cortes J. Trends in Chronic Myeloid Conflict of Interest: The authors declare that the research was conducted in the Leukemia Incidence and Survival in the United States From 1975 to 2009. absence of any commercial or financial relationships that could be construed as a Leuk Lymphoma (2013) 54(7):1411–7. doi: 10.3109/10428194.2012.745525 potential conflict of interest. 83. Brunner AM, Campigotto F, Sadrzadeh H, Drapkin BJ, Chen YB, Neuberg DS, et al. Trends in All-Cause Mortality Among Patients With Chronic Myeloid Publisher’s Note: All claims expressed in this article are solely those of the authors Leukemia: A Surveillance, Epidemiology, and End Results Database Analysis. and do not necessarily represent those of their affiliated organizations, or those of Cancer (2013) 119(14):2620–9. doi: 10.1002/cncr.28106 the publisher, the editors and the reviewers. Any product that may be evaluated in 84. Srour SA, Devesa SS, Morton LM, Check DP, Curtis RE, Linet MS, et al. this article, or claim that may be made by its manufacturer, is not guaranteed or Incidence and Patient Survival of Myeloproliferative Neoplasms and endorsed by the publisher. Myelodysplastic/Myeloproliferative Neoplasms in the United States, 2001- 12. Br J Haematol (2016) 174(3):382–96. doi: 10.1111/bjh.14061 Copyright © 2022 Vener, Rossi, Minicozzi, Marcos-Gragera, Poirel, Maynadie,́ 85. Al-Refaie WB, Vickers SM, Zhong W, Parsons H, Rothenberger D, Troussard, Pravettoni, De Angelis, Sant and the EUROCARE-6 Working Group. Habermann EB, et al. Cancer Trials Versus the Real World in the United This is an open-access article distributed under the terms of the Creative Commons States. Ann Surg (2011) 254(3):438–43. doi: 10.1097/SLA.0b013e318 Attribution License (CC BY). The use, distribution or reproduction in other forums is 22a7047 permitted, provided the original author(s) and the copyright owner(s) are credited and 86. Murthy VH, Krumholz HM, Gross CP. Participation in Cancer Clinical Trials: that the original publication in this journal is cited, in accordance with accepted Race-, Sex-, and Age-Based Disparities. JAMA (2004) 291(22):2720–6. doi: academic practice. No use, distribution or reproduction is permitted which does not 10.1001/jama.291.22.2720 comply with these terms. Frontiers in Oncology | www.frontiersin.org 15 July 2022 | Volume 12 | Article 892684