Goodbye to accelerated phase of chronic myeloid leukaemia

Goodbye to accelerated phase of chronic myeloid leukaemia | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Goodbye to accelerated phase of chronic myeloid leukaemia Qian Jiang, Sen Yang, Xiao-shuai Zhang, Robert Gale, Xiaojun Huang This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4554542/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 04 Dec, 2024 Read the published version in Leukemia → Version 1 posted 9 You are reading this latest preprint version Abstract Whether there is really a distinct accelerated phase (AP) at diagnosis in chronic myeloid leukemia (CML) in the context of tyrosine kinase-inhibitor (TKI)-therapy and whether co-variates identified as characterizing AP are simply adverse co-variates for outcomes, we studied 2,122 consecutive subjects in chronic phase (CP, n = 1,837) or AP (n = 285) according to the European LeukemiaNet (ELN) classification. AP subjects with increased basophils only had similar transformation-free survival (TFS) and survival compared with CP subjects in ELTS intermediate-risk. AP subjects with increased blasts only had worse TFS but similar survival compared with CP subjects in the ELTS high-risk; AP subjects with decreased platelets only, similar TFS but worse survival. Proportions of CP and AP subjects meeting the 2020 ELN TKI-response milestones were similar. However, worse outcomes were only seen in AP subjects failing to meet ELN milestones. Findings were similar using the 2022 International Consensus Classification (ICC) criteria replacing decreased platelets with additional cytogenetic abnormalities. Our data support the 2022 WHO classification of CML eliminating AP. We suggest adding a very high-risk cohort to the ELTS score including people with increased blasts or decreased platelets and dividing CML into 2 phases: CP and acute phase. Health sciences/Diseases/Haematological diseases/Haematological cancer/Leukaemia/Chronic myeloid leukaemia Health sciences/Risk factors Chronic myeloid leukemia accelerated phase chronic phase. Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction There is considerable recent controversy whether CML is a bi- or tri-phasic disease; chronic (CP) and blast phase (BP) with or without an accelerated phase (AP).( 1 ) From a biological perspective chronic phase CML is best considered a preleukaemia wherein the cells differentiate normally with no evidence of uncontrolled proliferation. CP cells do not spontaneously form myeloid colonies in vitro and blood granulocyte concentration increases appropriately in infections and cycles in rare persons with cyclical neutropenia. In untreated CP CML the concentration of blood granulocytes reaches an apogee and does not increase further. ( 2 – 5 ) In gene expression profiling (GEP) the pattern of expression suggests 2 phases where CP CML cells and normal CD34-positive cells have similar patterns.( 6 ) It is estimated the abnormal granulocyte mass can be explained by as few as 2–4 extra late cell divisions. Clinically, CML was initially divided into 2 phases: CP versus terminal, blast or not chronic phases.( 7 ) The suggestion of an AP was based on identifying co-variates associated with an increased risk of transforming to BP. These co-variates differ between different AP classifications.( 4 , 8 , 9 ) Moreover, in the context of tyrosine kinase-inhibitor (TKI)-therapy this increased transformation risk is modest. Also, people classified as presenting in AP receive the same TKI-therapy as those presenting in CP. Based on these considerations AP was removed from the World Health Organization (WHO) 2022CML classification.( 3 ) However the 2020 European Leukemia Net (ELN) recommendations, 2022 International Consensus Classification (ICC) and 2024 National Comprehensive Cancer Guidelines retain AP phase CML.( 4 , 5 ) We interrogated data from 2122 subjects with CML presenting in CP (n = 1837) or AP (n = 285) using definitions in the ELN 2020 criteria and 2053 subjects presenting in CP (n = 1748) or AP (n = 305) using the 2022 ICC criteria. We found most subjects classified as AP had outcomes like those of subjects in CP defined as intermediate- or high-risk in the European Treatment and Outcome Study (EUTOS) Long-Term Survival (ELTS) risk score. About 25 percent, those with increased blasts only or with decreased platelets had worse transformation-free survival (TFS) or survival but not both. However, these worse outcomes were only in subjects failing to meet the 2020 ELN TKI-therapy-response criteria. Proportions of CP and AP subjects meeting the 2020 ELN TKI-response milestones were similar. These data indicate co-variates used to identify AP do not identify a distinct phase but are predictors of the likelihood of response to TKI-therapy. Our conclusions support the 2022 WHO CML classification removing AP. We conclude CML should be divided into CP and terminal, acute or not chronic phases without an intermediate AP. Subjects and Methods Subjects We interrogated data from consecutive subjects ≥ 18 years with CML initially presenting with AP and CP at Peking University People’s Hospital from January, 2006 to June, 2023. Criteria of ELN 2020 for subjects initially presenting with AP included ≥ 1 of the followings: ( 1 ) blood or bone marrow blasts ≥ 15% but < 30%; ( 2 ) blood basophils ≥ 20%; and ( 3 ) platelet concentration < 100 × 10E + 9/L unrelated to therapy.( 5 ) The ICC 2022 AP criteria include ≥ 1 of the followings: ( 1 ) bone marrow or blood blasts 10–19%; ( 2 ) blood basophils ≥ 20%; and ( 3 ) presence of additional clonal cytogenetic abnormalities in Ph-chromosome-positive cells (ACA) including second Ph-chromosome, trisomy 8, isochromosome 17q, trisomy 19, complex karyotype or abnormalities of 3q26.2.( 4 ) Demographic and clinical co-variates including age, sex, complete blood count (CBC) parameters, spleen size below costal margin, comorbidity(ies), ACA in Ph-positive cells including a 2nd Ph, trisomy 8, isochromosome 17q, trisomy 19, complex cytogenetics and/or abnormalities of 3q26.2. Outcomes were abstracted from the medical record. The study was approved by the Ethics Committee of Peking University People’s Hospital and subjects gave written informed consent consistent with precepts of the Declaration of Helsinki. Treatment, monitoring and evaluation Treatment, monitoring and evaluation followed the ELN recommendations.( 5 , 10 , 11 ) For persons in CP the ELTS score at diagnosis was calculated as described.( 12 ) Bone marrow cytogenetic analyses used G-banding. Blood samples were used to analyze BCR::ABL1 transcript type at diagnosis. During TKI-therapy, BCR::ABL1 transcript levels were analyzed by quantitative real-time polymerase chain reaction (qRT-PCR) with an ABL1 control and converted to international scales ( BCR::ABL1 IS ) using our laboratory-specific conversion factor of 0.65 validated at the Institute of Medical and Veterinary Science International Reference Laboratory when the value (IS) was < 10%.( 13 ) Screening for BCR::ABL1 mutation was done in subjects with a sub-optimal, warning or failure responses according to the ELN recommendations.( 5 , 10 , 11 ) The last follow-up was 30, September, 2023. Statistical analysis Descriptive statistics were used to summarize co-variates. Categorical variables were reported as percentages and counts. Continuous variables were reported as medians and ranges or interquartile range (IQR). Pearson Chi-square test was used to analyze categorical variables. Student’s t (normal distribution) or Mann-Whitney U (non-normal distribution) tests were used to analyze continuous variables. Transformation was defined as blood or bone marrow blasts ≥ 30% (ELN criteria) or ≥ 20% (ICC criteria).( 4 , 5 ) Transformation-free survival (TFS) was calculated from TKI-therapy start to the date of transformation, death or censored at a transplant or last follow-up. Survival was calculated from TKI-therapy start to death from any cause or censored at a transplant or last follow-up. Probabilities of TFS and survival were calculated by the Kaplan-Meier method and compared by log-rank test. Subjects were censored at a transplantation, death or last follow-up. Uni- and multi-variable analyses were conducted to explore the co-variates associated with therapy responses and outcomes. Potentially prognostic co-variates included age, sex, WBC counts, haemoglobin concentration (HGB), disease phase, ACA in Ph-positive cells and co-morbidity(ies). Co-variates correlated at P < 0.20 were included in multi-variable analyses, and variance inflation factors (VIFs) was estimated to check for multi-collinearity amongst co-variates relevant to outcomes and responses to TKIs. 2-sided P < 0.05 was considered significant. SPSS 22.0 (SPSS, Chicago, IL) and R version 4.0.2 (R Core Team, Vienna, Austria) were used for analysis and graphing. Results Subjects diagnosed by the ELN 2022 recommendations Data from 2,296 consecutive CP (n = 1,991) and AP (n = 305) persons were interrogated (Fig. 1 ). 23 subjects were exclude because the age at diagnosis was < 18 years old, 22 subjects with an interval from diagnosis to start of TKI therapy ≥ 6 months, 26 with a BCR::ABL transcript other than e14a2 or e13a2 , 3 with the duration of TKI-therapy < 3 months and 100 with irregular response monitoring and/or loss to follow-up. 2,122 subjects (CP; n = 1,837; AP; n = 285) were evaluable for analyses. 1133 (62%) CP subjects were male. Median age was 40 years (Interquartile Range [IQR], 30–52 years) (Table 1 ). 1209 (66%), 453 (25%) and 175 (10%) were classified as ELTS low-, intermediate- and high-risk. With a median follow-up of 53 months (IQR, 27–84 months), 101 (6%) subjects transformed to BP and 50 (3%) died. 7-year probabilities of TFS and survival were 91% (89, 92%) and 95% (93, 96%). At last follow-up 392 subjects (27%) receiving initial imatinib-therapy switched to 2nd -generation TKI (2G-TKI) (n = 333; 85%), 3rd-generation TKI (3G-TKI) (n = 53; 14%) or chemotherapy (n = 6; 2%). 99 subjects (26%) receiving initial 2G-TKI therapy switched to imatinib (n = 36; 36%), a 2G-TKI (n = 42; 43%), a 3G-TKI (n = 18; 18%) or chemotherapy (n = 3; 3%) because of therapy failure (n = 64, 65%), adverse events (n = 9; 9%) or subject preference (n = 26; 26%). Table 1 Subject baseline co-variates by ELN criteria. CP (n = 1837) AP (n = 285) P -value Age, years, median (Interquartile range, IQR) 40 (30, 52) 42 (31, 54) 0.06 Male, n (%) 1133 (62) 181 (64) 0.58 ELTS risk score, n (%) Low 1209 (66) Intermediate 453 (25) High 175 ( 10 ) AP criteria Basophils > 20% 204 (71) Blasts > 15% and < 30% 37 ( 13 ) Platelets < 100 × 10E + 9/L ≥ 2 criteria 31 ( 11 ) 13 ( 5 ) 1st TKI-therapy < 0.001 Imatinib 1452 (79) 188 (66) 2G-TKI 385 (21) 97 (34) Types of 2G-TKIs Nilotinib 257 (67) 68 (70) Dasatinib 63 (16) 21 (22) Flumatinib Radotinib 51 ( 13 ) 15 ( 4 ) 8 ( 8 ) 0 (0) Follow-up, months, median (IQR) 53 (27, 84) 49 (25, 96) 0.97 Abbreviations: ELN, European LeukemiaNet; CP, chronic phase; AP, accelerated phase; IQR, interquartile range; ELTS, European Treatment and Outcome Study (EUTOS) Long-Term Survival; 2G-TKI, 2nd -generation tyrosine kinase-inhibitor (TKI). 181 subjects (64%) classified as AP at diagnosis were male. Median age was 42 years (IQR, 31–54 years). 204 (71%), 37 (13%), 31 (11%) and 13 (5%) subjects were classified as AP based on increased basophils only, increased blasts only, decreased platelets only and ≥ 2 features (Table 1 ). With a median follow-up of 49 months (IQR, 25–96 months), 42 (15%) subjects transformed to BP and 25 (9%) died. 7-year probabilities of TFS and survival were 84% (79, 89%) and 91% (86, 95%). At last follow-up, 68 subjects (36%) receiving initial imatinib-therapy switched to a 2G-TKI (n = 63, 93%), a 3G-TKI (n = 3, 4%) or chemotherapy (n = 2, 3%). 33 subjects (34%) receiving initial 2G-TKI therapy switched to imatinib (n = 3, 9%), a 2G-TKI (n = 22, 67%), a 3G-TKI (n = 7, 21%) or chemotherapy (n = 1, 3%) because of therapy failure (n = 26, 79%), adverse events (n = 4, 12%) or subject preference (n = 3, 9%). Comparison of outcomes Comparisons by AP subjects at diagnosis by defining criteria and CP subjects by ELTS risk cohort are displayed in Fig. 2 . (There were too few AP subjects defined by ≥ 2 criteria for this analysis). We used uni- and multi-variable analyses to explore co-variates associated with TFS and survival (Table 2 ). There were no multi-collinearity interactions (VIFs = 1.0 ~ 1.8) between potential predictive co-variates including disease phase, sex, age, haemoglobin, WBC and platelet concentrations, ACA in Ph-chromosome-positive cells or co-morbidity(ies). In multi-variable analyses the ELTS low-, intermediate- and high-risk cohorts were used as the reference cohort. AP subjects with increased basophils only had comparable TFS and survival compared with CP subjects in the ELTS intermediate-risk cohort. AP subjects with increased blasts only had worse TFS (HR = 2.2 [1.1, 4.5]; P = 0.03) but similar survival (HR = 1.5 [0.5, 4.6]; P = 0.50) compared with CP subjects in the ELTS high-risk cohort. AP subjects with decreased platelets only had similar TFS (HR = 1.9 [0.9, 4.2]; P = 0.10) but worse survival (HR = 2.7 [1.0, 7.3]; P = 0.04) compared with ELTS high-risk cohort. Table 2 Multi-variable analyses of outcomes by ELN criteria. TFS Survival HR (95% CI) P -value HR (95% CI) P -value Disease phase CP Risk Low (ref) Intermediate 2.0 (1.3, 3.3) 0.003 1.7 (0.9, 3.3) 0.13 High 3.7 (2.2, 6.4) < 0.001 3.7 (1.8, 7.6) 20% 1.9 (1.1, 3.4) 0.03 2.2 (1.0, 4.7) 0.04 Blasts > 15% and < 30% 8.2 (4.1, 16.3) < 0.001 5.4 (1.8, 16.2) 0.003 Platelets < 100 × 10E + 9/L 7.2 (3.5, 14.9) < 0.001 10.0 (4.0, 25.2) 20% 0.9 (0.5, 1.7) 0.84 1.3 (0.6, 2.8) 0.47 Blasts > 15% and < 30% 4.0 (2.0, 8.0) < 0.001 3.2 (1.1, 9.7) 0.04 Platelets < 100 × 10E + 9/L 3.6 (1.7, 7.5) < 0.001 6.0 (2.3, 15.3) < 0.001 Disease phase CP Risk Low 0.3 (0.2, 0.5) < 0.001 0.3 (0.1, 0.6) 20% 0.5 (0.3, 1.0) 0.04 0.6 (0.3, 1.3) 0.21 Blasts > 15% and < 30% 2.2 (1.1, 4.5) 0.03 1.5 (0.5, 4.6) 0.50 Platelets < 100 × 10E + 9/L 1.9 (0.9, 4.2) 0.10 2.7 (1.0, 7.3) 0.04 Age (10 years) 1.3 (1.1, 1.5) 0.01 Male (ref. female) Initial imatinib-therapy (ref. 2G-TKI) 0.7 (0.5, 1.1) 0.10 0.7 (0.4, 1.2) 0.17 WBC (× 10E + 11/L) 0.9 (0.8, 1.1) 0.37 Haemoglobin (g/dL) 0.9 (0.8, 1.0) 0.01 0.9 (0.8, 1.0) 0.004 ACA (ref. none) 1.9 (1.0, 3.7) 0.05 2.2 (0.9, 5.0) 0.07 Co-morbidity (ref. none) 1.4 (0.8, 2.3) 0.22 Abbreviations: ELN, European LeukemiaNet; TFS, transformation-free survival; HR, hazard ratio; CP, chronic phase; AP, accelerated phase; 2G-TKI, 2nd -generation tyrosine kinase-inhibitor (TKI); WBC, white blood cell; ACA, additional cytogenetic abnormality. We did sensitivity analyses in subjects receiving initial imatinib therapy (n = 1638) or initial 2G-TKI therapy (n = 471) using the ELN AP criteria ( Supplement Figs. 1 and 2 and Supplement Tables 1 and 2 ). Subjects In the initial imatinib cohort AP with increased basophils only had similar outcomes compared with CP subjects in the ELTS intermediate-risk cohort. AP subjects with increased blasts only or decreased platelets only had similar outcomes compared with CP subjects in ELTS high-risk cohort. In the 2G-TKI cohort AP subjects with increased basophils only had similar outcomes compared with CP subjects in the ELTS low- and intermediate-risk cohorts. Subjects with increased blasts only had worse TFS HR = 3.4 [1.0, 11.3]; P = 0.05) but similar survival (HR = 0.0 [0.0, ∞]; P = 1.00; there was no death in this cohort) compared with CP subjects in ELTS high-risk cohort. AP subjects with decreased platelets only had worse TFS (HR = 4.6 [1.4, 15.3]; P = 0.01) and worse survival (HR = 9.0 [1.9, 41.5]; P = 0.01) compared with CP subjects in ELTS high-risk cohort. ELTS risk score predicts outcomes in AP subjects 241 evaluable AP subjects were classified as ELTS low- (n = 74), intermediate- (n = 74) and high-risk (n = 93). The distribution of ELTS risk in AP subjects classified by increased basophils only, increased blasts only and decreased platelets only are displayed in Fig. 3 . 73 subjects (41%) with increased basophils were classified as low-, 61 (34%) as intermediate- and 44 (25%) as ELTS high-risk. 2 subjects with increased blasts only were classified as ELTS intermediate- and 32 as high-risk. 1 subject with decreased platelets only was classified as low-, 11 as intermediate- and 17 as ELTS high-risk. There was significant difference in outcomes between the 3 risk cohorts (P = 0.01 ~ < 0.001). Comparison of outcomes by ELN milestones There was no difference in proportions of subjects meeting optimal, warning and failure at 3, 6 and 12 months according to the ELN response milestones criteria between CP and AP cohorts. However, AP subjects with increased blasts only or decreased platelets only had higher failure rate at 3 months ( P = 0.03) and high non-optimal rates at 6 months ( P = 0.06). When subjects with increased basophils only were re-classified into CP ELTS risk cohort the remaining AP subjects showed higher rate of meeting warning and/or failure response milestones at 3 ( P = 0.01) and 6 ( P = 0.08) months (Fig. 4 ). AP subjects achieving optimal and warning response showed similar outcomes to CP subjects. However, AP subjects with a failure milestone had significantly worse TFS (3-month, P = 0.027; 6-month, P = 0.204; 12-months, P = 0.189) and/or survival (3-month, P = 0.118; 6-month, P = 0.057; 12-months, P = 0.056) than CP subjects (Fig. 5 ). Subjects diagnosed by the ICC 2022 criteria Data from 2,052 consecutive CP (n = 1,748) and AP (n = 305) persons were interrogated according to the ICC criteria. The above analyses were repeated in subjects classified as AP using the 2022 ICC criteria. Subject co-variates were shown in the Supplement Fig. 3 –9 and Table 1 –6. In multi-variable analyses AP subjects with increased basophils only had comparable TFS and survival compared with CP subjects in the ELTS intermediate-risk cohort. AP subjects with increased blasts only had similar survival but worse TFS (HR = 2.0 [1.0, 3.7]; P = 0.04) compared with CP subjects in ELTS high-risk cohort. AP subjects with ACA only or ≥ 2 features had comparable TFS and survival compared with CP subjects in ELTS high-risk cohort. There were significant differences in the proportion of subjects achieving 2020 ELN response milestones at 3 months but not at 6 months and thereafter between CP and AP subjects. Overall, the outcomes of AP subjects classified by the 2022 ICC 2022 criteria were like those classified by the 2020 ELN criteria. Discussion CML was initially divided into 2 phases: CP versus terminal, blast or not CP. The suggestion of a 3rd AP phase was a late addition.( 14 ) These terms are confusing. The biology of CML suggests 2 phases, CP and terminal, advanced or not CP. Also, not everyone in whom CML transforms from a preleukaemia to leukaemia has increased blasts making blast phase (BP) an inaccurate descriptor. Further complicating the terminology are different definitions of AP, the impact of TKI-therapy where few people transform to a terminal phase and where initial therapy of people presenting in either CP or AP is similar. The strongest predictors of CML-related survival in people presenting in CP is response to TKI-therapy, to clinical co-variates art diagnosis which correlate with several laboratory coo-variates at diagnosis. As we describe above, co-variates purportedly identifying a AP also align with likelihood of response to TKI-therapy response rather than compromising a distinct phase of CML. We addressed the controversy of whether there is an AP of CML by interrogating data obtained at diagnosis in a large cohort of subjects with CP or with AP classified using the 2020 ELN and 2022 ICC criteria. We found most AP subjects, those with increased basophils only, had TFS and survival like those of CP subjects in the ELTS intermediate- and high-risk cohorts. AP subjects with increased blasts only or decreased platelets only had either worse TFS or survival but not both compared with the high-risk ELTS cohort. These worse outcomes were seen only for subjects failing to meet the 2020 ELN TKI-therapy-response milestones. These data suggest increased blasts only or decreased platelets only are predictive co-variates for TKI-therapy-response and not a distinct phase of CML and supporting the 2022 WHO classification eliminating AP as a phase of CML. Our study limitations. First, it is single-centre and retrospective. 2nd, few subjects received initial 2G-TKI-therapy. 3rd, we had too few subjects to evaluate those meeting ≥ 2 AP criteria. 4th, we did not monitor therapy compliance in all subjects. Last, we studied people with AP at diagnosis, not those presenting in CP and evolving to AP. However, we suggest our conclusions also apply here and that people developing prior AP features have failed TKI-therapy and are no longer in CP.. Based on our data we suggest 2 changes to CML nomenclature. 1st, eliminating AP based on the biology of CML and on our clinical data. 2nd, we suggest changing the name of the leukaemia phase of CML to terminal, acute or not CP rather than BP. We also suggest updating the EUTOS ELTS risk score classification to consider a very high-risk cohort with increased blasts and/or decreased platelets We acknowledge our conclusions and suggestions are controversial and welcome comments.. Declarations Acknowledgments We thank medical staff and patients’ participants. RPG acknowledges support from the National Institute of Health Research (NIHR) Biomedical Research Centre funding scheme. Funding Funded, in part, by the National Nature Science Foundation of China (No. 81970140 and No. 82370161). Author Contributions QJandX-JH designed the study. QJ, SY and X-SZ collected and analyzed the data. QJ, SY, X-SZ, RPG and X-JH prepared the typescript. All authors approved the final typescript, take responsibility for the content and agreed to submit for publication. Conflict of Interest RPG is a consultant to BeiGene Ltd., Fusion Pharma LLC, LaJolla NanoMedical Inc., Mingsight Parmaceuticals Inc. and CStone Pharmaceuticals; advisor to Antegene Biotech LLC, Medical Director, FFF Enterprises Inc.; partner, AZAC Inc.; Board of Directors, Russian Foundation for Cancer Research Support; and Scientific Advisory Board: StemRad Ltd. Ethics Approval Approve by the Ethics Committee of People’s Hospital Beijing compliant with precepts the Helsinki Declaration. References Berman E, Shah NP, Deninger M, Altman JK, Amaya M, Begna K, et al. CML and the WHO: Why? J Clin Oncol. 2023:Jco2301689. Kantarjian HM, Tefferi A. Classification of accelerated phase chronic myeloid leukemia in the era of the BCR::ABL1 tyrosine kinase inhibitors: A work in progress. Am J Hematol. 2023;98(9):1350-3. Khoury JD, Solary E, Abla O, Akkari Y, Alaggio R, Apperley JF, et al. 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A Cancer and Leukemia Group B study. Leuk Lymphoma. 1992;7(1-2):63-8. Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127(20):2391-405. Cortes JE, Talpaz M, O'Brien S, Faderl S, Garcia-Manero G, Ferrajoli A, et al. Staging of chronic myeloid leukemia in the imatinib era: an evaluation of the World Health Organization proposal. Cancer. 2006;106(6):1306-15. Baccarani M, Deininger MW, Rosti G, Hochhaus A, Soverini S, Apperley JF, et al. European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood. 2013;122(6):872-84. Baccarani M, Cortes J, Pane F, Niederwieser D, Saglio G, Apperley J, et al. Chronic myeloid leukemia: an update of concepts and management recommendations of European LeukemiaNet. J Clin Oncol. 2009;27(35):6041-51. Pfirrmann M, Baccarani M, Saussele S, Guilhot J, Cervantes F, Ossenkoppele G, et al. Prognosis of long-term survival considering disease-specific death in patients with chronic myeloid leukemia. Leukemia. 2016;30(1):48-56. Qin YZ, Jiang Q, Jiang H, Li JL, Li LD, Zhu HH, et al. Which method better evaluates the molecular response in newly diagnosed chronic phase chronic myeloid leukemia patients with imatinib treatment, BCR-ABL(IS) or log reduction from the baseline level? Leuk Res. 2013;37(9):1035-40. Kantarjian HM, Dixon D, Keating MJ, Talpaz M, Walters RS, McCredie KB, et al. Characteristics of accelerated disease in chronic myelogenous leukemia. Cancer. 1988;61(7):1441-6. Additional Declarations There is NO conflict of interest to disclose. Supplementary Files APCPsupplementfigureandtable0518rpgv1.docx Cite Share Download PDF Status: Published Journal Publication published 04 Dec, 2024 Read the published version in Leukemia → Version 1 posted Editorial decision: revise 10 Jul, 2024 Review # 2 received at journal 09 Jul, 2024 Review # 1 received at journal 25 Jun, 2024 Reviewer # 2 agreed at journal 21 Jun, 2024 Reviewer # 1 agreed at journal 14 Jun, 2024 Reviewers invited by journal 10 Jun, 2024 Editor assigned by journal 10 Jun, 2024 Submission checks completed at journal 10 Jun, 2024 First submitted to journal 09 Jun, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4554542","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":312810762,"identity":"c0a0055d-12d9-4ac0-92f8-998199ecedc1","order_by":0,"name":"Qian Jiang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA+ElEQVRIiWNgGAWjYBACxmYwJcHAwN7AwMADRHzEa+E5ANHCRrx9EglgLQwEtTC3Mz97+KXMQt5c8nXig7c5djJsDMwPH91gsMvD7TA2c2OZcxKGO2fnbjacuy0Z6DA2Y+MchuRiPH4xk5Zsk2DccDt3mzTvNmagFh426RyGA4kNOLWwfwNpsd9w8+z237zb6onRwmMm+bFNInHDDaAVvNsOE6WlTJrhnETyhjO5myXnbjvOw8YM8otBMk4thv3Ht0n+KKuz3XD87MYPb7dV2/OzNz98nFNhh1sLUIIZNfqYQYQBDvVAIA9y3A8SYnwUjIJRMApGIAAA22VMgbXvBOwAAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0001-7131-0522","institution":"Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease","correspondingAuthor":true,"prefix":"","firstName":"Qian","middleName":"","lastName":"Jiang","suffix":""},{"id":312810763,"identity":"8be503d0-9626-4e54-8de3-4de422f7d53a","order_by":1,"name":"Sen Yang","email":"","orcid":"","institution":"Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease","correspondingAuthor":false,"prefix":"","firstName":"Sen","middleName":"","lastName":"Yang","suffix":""},{"id":312810764,"identity":"f5a00a84-16de-474b-a1ec-8feb205f11bb","order_by":2,"name":"Xiao-shuai Zhang","email":"","orcid":"https://orcid.org/0000-0001-5405-0802","institution":"Peking University People's Hospital, Peking University Institute of Hematology","correspondingAuthor":false,"prefix":"","firstName":"Xiao-shuai","middleName":"","lastName":"Zhang","suffix":""},{"id":312810765,"identity":"035cac4a-00be-4aa9-a783-acc295b79158","order_by":3,"name":"Robert Gale","email":"","orcid":"","institution":"Hammersmith Hospital, Imperial College London","correspondingAuthor":false,"prefix":"","firstName":"Robert","middleName":"","lastName":"Gale","suffix":""},{"id":312810766,"identity":"960fb4a5-3cdb-445c-8946-5031e70bcac5","order_by":4,"name":"Xiaojun Huang","email":"","orcid":"https://orcid.org/0000-0002-2145-6643","institution":"Peking University People's Hospital, Peking University Institute of Hematology,Peking-Tsinghua Center for Life Sciences, State Key Laboratory of Natural and Biomimetic Drugs","correspondingAuthor":false,"prefix":"","firstName":"Xiaojun","middleName":"","lastName":"Huang","suffix":""}],"badges":[],"createdAt":"2024-06-09 16:45:15","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4554542/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4554542/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41375-024-02486-2","type":"published","date":"2024-12-04T05:00:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":59090874,"identity":"d21ecad0-f17b-4cf7-b423-40768ebfcf87","added_by":"auto","created_at":"2024-06-26 08:55:06","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":220923,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eStudy flow chart in subjects by ELN criteria.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4554542/v1/742fa076c3332bb3e9bd12d8.jpg"},{"id":59091448,"identity":"713e8350-bff7-4a44-947e-8d3f1152a963","added_by":"auto","created_at":"2024-06-26 09:03:06","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":283187,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eComparisons of outcomes between CP with different ELTS risk cohorts and AP subgroups in subjects by ELN criteria\u003c/strong\u003e.\u003c/p\u003e","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4554542/v1/fb5e09cf74c742283158f539.jpg"},{"id":59090875,"identity":"fb13a04f-2a82-45bc-9506-1cbc627ca2a6","added_by":"auto","created_at":"2024-06-26 08:55:06","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":615992,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eComparisons of outcomes between AP subjects divided by ELTS score by ELN criteria\u003c/strong\u003e.\u003c/p\u003e","description":"","filename":"Figure3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4554542/v1/008126c3afd73e98e150820e.jpg"},{"id":59091447,"identity":"db5e0a6f-607c-451d-b49e-621238dc25e6","added_by":"auto","created_at":"2024-06-26 09:03:06","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":189876,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eThe monitoring milestones of BCR-ABL1 transcript levels by the IS at 3, 6, and 12 months in subjects by ELN criteria (A. comparison between CP and AP; B. comparison between AP subgroups; C. comparison between revised-CP [CP subjects and AP subjects with increased basophils] and revised-AP [AP subjects with increased blasts or decreased platelets])\u003c/strong\u003e.\u003c/p\u003e","description":"","filename":"Figure4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4554542/v1/f7d0fa3bbbce86d5cd41dce3.jpg"},{"id":59090879,"identity":"855dcf58-3d4d-43d4-9daf-6c31e04749b8","added_by":"auto","created_at":"2024-06-26 08:55:06","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":569169,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eComparisons of outcomes between CP and AP at 3, 6, 12 months in subjects by ELN criteria\u003c/strong\u003e.\u003c/p\u003e","description":"","filename":"Figure5.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4554542/v1/492cc9c1ecac710917e45f23.jpg"},{"id":70645520,"identity":"75eb861b-55e2-40ba-a3dc-d945f01d28dd","added_by":"auto","created_at":"2024-12-05 08:09:25","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2591028,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4554542/v1/5b3d89df-5612-4e22-a27c-ace44b34ead0.pdf"},{"id":59090876,"identity":"422f9dda-9d57-4335-a2ac-ea84aeb90acb","added_by":"auto","created_at":"2024-06-26 08:55:06","extension":"docx","order_by":9,"title":"","display":"","copyAsset":false,"role":"supplement","size":1517470,"visible":true,"origin":"","legend":"","description":"","filename":"APCPsupplementfigureandtable0518rpgv1.docx","url":"https://assets-eu.researchsquare.com/files/rs-4554542/v1/b9e02955be285046332dcd3b.docx"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e conflict of interest to disclose.","formattedTitle":"Goodbye to accelerated phase of chronic myeloid leukaemia","fulltext":[{"header":"Introduction","content":"\u003cp\u003eThere is considerable recent controversy whether CML is a bi- or tri-phasic disease; chronic (CP) and blast phase (BP) with or without an accelerated phase (AP).(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) From a biological perspective chronic phase CML is best considered a \u003cem\u003epreleukaemia\u003c/em\u003e wherein the cells differentiate normally with no evidence of uncontrolled proliferation. CP cells do not spontaneously form myeloid colonies \u003cem\u003ein vitro\u003c/em\u003e and blood granulocyte concentration increases appropriately in infections and cycles in rare persons with cyclical neutropenia. In untreated CP CML the concentration of blood granulocytes reaches an apogee and does not increase further. (\u003cspan additionalcitationids=\"CR3 CR4\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e) In gene expression profiling (GEP) the pattern of expression suggests 2 phases where CP CML cells and normal CD34-positive cells have similar patterns.(\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e) It is estimated the abnormal granulocyte mass can be explained by as few as 2\u0026ndash;4 extra late cell divisions.\u003c/p\u003e \u003cp\u003eClinically, CML was initially divided into 2 phases: CP \u003cem\u003eversus\u003c/em\u003e terminal, blast or not chronic phases.(\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e) The suggestion of an AP was based on identifying co-variates associated with an increased risk of transforming to BP. These co-variates differ between different AP classifications.(\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e) Moreover, in the context of tyrosine kinase-inhibitor (TKI)-therapy this increased transformation risk is modest. Also, people classified as presenting in AP receive the same TKI-therapy as those presenting in CP. Based on these considerations AP was removed from the World Health Organization (WHO) 2022CML classification.(\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) However the 2020 European Leukemia Net (ELN) recommendations, 2022 International Consensus Classification (ICC) and 2024 National Comprehensive Cancer Guidelines retain AP phase CML.(\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eWe interrogated data from 2122 subjects with CML presenting in CP (n\u0026thinsp;=\u0026thinsp;1837) or AP (n\u0026thinsp;=\u0026thinsp;285) using definitions in the ELN 2020 criteria and 2053 subjects presenting in CP (n\u0026thinsp;=\u0026thinsp;1748) or AP (n\u0026thinsp;=\u0026thinsp;305) using the 2022 ICC criteria. We found most subjects classified as AP had outcomes like those of subjects in CP defined as intermediate- or high-risk in the European Treatment and Outcome Study (EUTOS) Long-Term Survival (ELTS) risk score. About 25 percent, those with increased blasts only or with decreased platelets had worse transformation-free survival (TFS) or survival but not both. However, these worse outcomes were only in subjects failing to meet the 2020 ELN TKI-therapy-response criteria. Proportions of CP and AP subjects meeting the 2020 ELN TKI-response milestones were similar. These data indicate co-variates used to identify AP do not identify a distinct phase but are predictors of the likelihood of response to TKI-therapy. Our conclusions support the 2022 WHO CML classification removing AP. We conclude CML should be divided into CP and terminal, acute or not chronic phases without an intermediate AP.\u003c/p\u003e"},{"header":"Subjects and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eSubjects\u003c/h2\u003e \u003cp\u003eWe interrogated data from consecutive subjects\u0026thinsp;\u0026ge;\u0026thinsp;18 years with CML initially presenting with AP and CP at Peking University People\u0026rsquo;s Hospital from January, 2006 to June, 2023. Criteria of ELN 2020 for subjects initially presenting with AP included\u0026thinsp;\u0026ge;\u0026thinsp;1 of the followings: (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) blood or bone marrow blasts\u0026thinsp;\u0026ge;\u0026thinsp;15% but \u0026lt;\u0026thinsp;30%; (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) blood basophils\u0026thinsp;\u0026ge;\u0026thinsp;20%; and (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) platelet concentration\u0026thinsp;\u0026lt;\u0026thinsp;100 \u0026times; 10E\u0026thinsp;+\u0026thinsp;9/L unrelated to therapy.(\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e) The ICC 2022 AP criteria include\u0026thinsp;\u0026ge;\u0026thinsp;1 of the followings: (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) bone marrow or blood blasts 10\u0026ndash;19%; (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) blood basophils\u0026thinsp;\u0026ge;\u0026thinsp;20%; and (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) presence of additional clonal cytogenetic abnormalities in Ph-chromosome-positive cells (ACA) including second Ph-chromosome, trisomy 8, isochromosome 17q, trisomy 19, complex karyotype or abnormalities of 3q26.2.(\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e) Demographic and clinical co-variates including age, sex, complete blood count (CBC) parameters, spleen size below costal margin, comorbidity(ies), ACA in Ph-positive cells including a 2nd Ph, trisomy 8, isochromosome 17q, trisomy 19, complex cytogenetics and/or abnormalities of 3q26.2. Outcomes were abstracted from the medical record. The study was approved by the Ethics Committee of Peking University People\u0026rsquo;s Hospital and subjects gave written informed consent consistent with precepts of the Declaration of Helsinki.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eTreatment, monitoring and evaluation\u003c/h2\u003e \u003cp\u003eTreatment, monitoring and evaluation followed the ELN recommendations.(\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e) For persons in CP the ELTS score at diagnosis was calculated as described.(\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e) Bone marrow cytogenetic analyses used G-banding. Blood samples were used to analyze \u003cem\u003eBCR::ABL1\u003c/em\u003e transcript type at diagnosis. During TKI-therapy, \u003cem\u003eBCR::ABL1\u003c/em\u003e transcript levels were analyzed by quantitative real-time polymerase chain reaction (qRT-PCR) with an \u003cem\u003eABL1\u003c/em\u003e control and converted to international scales (\u003cem\u003eBCR::ABL1\u003c/em\u003e\u003csup\u003e\u003cem\u003eIS\u003c/em\u003e\u003c/sup\u003e) using our laboratory-specific conversion factor of 0.65 validated at the Institute of Medical and Veterinary Science International Reference Laboratory when the value (IS) was \u0026lt;\u0026thinsp;10%.(\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e) Screening for \u003cem\u003eBCR::ABL1\u003c/em\u003e mutation was done in subjects with a sub-optimal, warning or failure responses according to the ELN recommendations.(\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e) The last follow-up was 30, September, 2023.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eDescriptive statistics were used to summarize co-variates. Categorical variables were reported as percentages and counts. Continuous variables were reported as medians and ranges or interquartile range (IQR). Pearson Chi-square test was used to analyze categorical variables. Student\u0026rsquo;s t (normal distribution) or Mann-Whitney U (non-normal distribution) tests were used to analyze continuous variables. Transformation was defined as blood or bone marrow blasts\u0026thinsp;\u0026ge;\u0026thinsp;30% (ELN criteria) or \u0026ge;\u0026thinsp;20% (ICC criteria).(\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e) Transformation-free survival (TFS) was calculated from TKI-therapy start to the date of transformation, death or censored at a transplant or last follow-up. Survival was calculated from TKI-therapy start to death from any cause or censored at a transplant or last follow-up. Probabilities of TFS and survival were calculated by the Kaplan-Meier method and compared by log-rank test. Subjects were censored at a transplantation, death or last follow-up.\u003c/p\u003e \u003cp\u003eUni- and multi-variable analyses were conducted to explore the co-variates associated with therapy responses and outcomes. Potentially prognostic co-variates included age, sex, WBC counts, haemoglobin concentration (HGB), disease phase, ACA in Ph-positive cells and co-morbidity(ies). Co-variates correlated at \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.20 were included in multi-variable analyses, and variance inflation factors (VIFs) was estimated to check for multi-collinearity amongst co-variates relevant to outcomes and responses to TKIs. 2-sided \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered significant. SPSS 22.0 (SPSS, Chicago, IL) and R version 4.0.2 (R Core Team, Vienna, Austria) were used for analysis and graphing.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eSubjects diagnosed by the ELN 2022 recommendations\u003c/h2\u003e \u003cp\u003eData from 2,296 consecutive CP (n\u0026thinsp;=\u0026thinsp;1,991) and AP (n\u0026thinsp;=\u0026thinsp;305) persons were interrogated (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). 23 subjects were exclude because the age at diagnosis was \u0026lt;\u0026thinsp;18 years old, 22 subjects with an interval from diagnosis to start of TKI therapy\u0026thinsp;\u0026ge;\u0026thinsp;6 months, 26 with a \u003cem\u003eBCR::ABL\u003c/em\u003e transcript other than \u003cem\u003ee14a2\u003c/em\u003e or \u003cem\u003ee13a2\u003c/em\u003e, 3 with the duration of TKI-therapy\u0026thinsp;\u0026lt;\u0026thinsp;3 months and 100 with irregular response monitoring and/or loss to follow-up. 2,122 subjects (CP; n\u0026thinsp;=\u0026thinsp;1,837; AP; n\u0026thinsp;=\u0026thinsp;285) were evaluable for analyses.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e1133 (62%) CP subjects were male. Median age was 40 years (Interquartile Range [IQR], 30\u0026ndash;52 years) (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). 1209 (66%), 453 (25%) and 175 (10%) were classified as ELTS low-, intermediate- and high-risk. With a median follow-up of 53 months (IQR, 27\u0026ndash;84 months), 101 (6%) subjects transformed to BP and 50 (3%) died. 7-year probabilities of TFS and survival were 91% (89, 92%) and 95% (93, 96%). At last follow-up 392 subjects (27%) receiving initial imatinib-therapy switched to 2nd -generation TKI (2G-TKI) (n\u0026thinsp;=\u0026thinsp;333; 85%), 3rd-generation TKI (3G-TKI) (n\u0026thinsp;=\u0026thinsp;53; 14%) or chemotherapy (n\u0026thinsp;=\u0026thinsp;6; 2%). 99 subjects (26%) receiving initial 2G-TKI therapy switched to imatinib (n\u0026thinsp;=\u0026thinsp;36; 36%), a 2G-TKI (n\u0026thinsp;=\u0026thinsp;42; 43%), a 3G-TKI (n\u0026thinsp;=\u0026thinsp;18; 18%) or chemotherapy (n\u0026thinsp;=\u0026thinsp;3; 3%) because of therapy failure (n\u0026thinsp;=\u0026thinsp;64, 65%), adverse events (n\u0026thinsp;=\u0026thinsp;9; 9%) or subject preference (n\u0026thinsp;=\u0026thinsp;26; 26%).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSubject baseline co-variates by ELN criteria.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCP (n\u0026thinsp;=\u0026thinsp;1837)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAP (n\u0026thinsp;=\u0026thinsp;285)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge, years, median\u003c/p\u003e \u003cp\u003e(Interquartile range, IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e40 (30, 52)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e42 (31, 54)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.06\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1133 (62)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e181 (64)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.58\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eELTS risk score, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1209 (66)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIntermediate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e453 (25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHigh\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e175 (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAP criteria\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBasophils\u0026thinsp;\u0026gt;\u0026thinsp;20%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e204 (71)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBlasts\u0026thinsp;\u0026gt;\u0026thinsp;15% and \u0026lt;\u0026thinsp;30%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e37 (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePlatelets\u0026thinsp;\u0026lt;\u0026thinsp;100\u0026thinsp;\u0026times;\u0026thinsp;10E\u0026thinsp;+\u0026thinsp;9/L\u003c/p\u003e \u003cp\u003e\u0026ge;\u0026thinsp;2 criteria\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e31 (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e)\u003c/p\u003e \u003cp\u003e13 (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1st TKI-therapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eImatinib\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1452 (79)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e188 (66)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2G-TKI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e385 (21)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e97 (34)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTypes of 2G-TKIs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNilotinib\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e257 (67)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e68 (70)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDasatinib\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e63 (16)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e21 (22)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFlumatinib\u003c/p\u003e \u003cp\u003eRadotinib\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e51 (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e)\u003c/p\u003e \u003cp\u003e15 (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8 (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e)\u003c/p\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFollow-up, months, median (IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e53 (27, 84)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e49 (25, 96)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.97\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eAbbreviations: ELN, European LeukemiaNet; CP, chronic phase; AP, accelerated phase; IQR, interquartile range; ELTS, European Treatment and Outcome Study (EUTOS) Long-Term Survival; 2G-TKI, 2nd -generation tyrosine kinase-inhibitor (TKI).\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e181 subjects (64%) classified as AP at diagnosis were male. Median age was 42 years (IQR, 31\u0026ndash;54 years). 204 (71%), 37 (13%), 31 (11%) and 13 (5%) subjects were classified as AP based on increased basophils only, increased blasts only, decreased platelets only and \u0026ge;\u0026thinsp;2 features (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). With a median follow-up of 49 months (IQR, 25\u0026ndash;96 months), 42 (15%) subjects transformed to BP and 25 (9%) died. 7-year probabilities of TFS and survival were 84% (79, 89%) and 91% (86, 95%). At last follow-up, 68 subjects (36%) receiving initial imatinib-therapy switched to a 2G-TKI (n\u0026thinsp;=\u0026thinsp;63, 93%), a 3G-TKI (n\u0026thinsp;=\u0026thinsp;3, 4%) or chemotherapy (n\u0026thinsp;=\u0026thinsp;2, 3%). 33 subjects (34%) receiving initial 2G-TKI therapy switched to imatinib (n\u0026thinsp;=\u0026thinsp;3, 9%), a 2G-TKI (n\u0026thinsp;=\u0026thinsp;22, 67%), a 3G-TKI (n\u0026thinsp;=\u0026thinsp;7, 21%) or chemotherapy (n\u0026thinsp;=\u0026thinsp;1, 3%) because of therapy failure (n\u0026thinsp;=\u0026thinsp;26, 79%), adverse events (n\u0026thinsp;=\u0026thinsp;4, 12%) or subject preference (n\u0026thinsp;=\u0026thinsp;3, 9%).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eComparison of outcomes\u003c/h2\u003e \u003cp\u003eComparisons by AP subjects at diagnosis by defining criteria and CP subjects by ELTS risk cohort are displayed in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. (There were too few AP subjects defined by \u0026ge;\u0026thinsp;2 criteria for this analysis). We used uni- and multi-variable analyses to explore co-variates associated with TFS and survival (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). There were no multi-collinearity interactions (VIFs\u0026thinsp;=\u0026thinsp;1.0\u0026thinsp;~\u0026thinsp;1.8) between potential predictive co-variates including disease phase, sex, age, haemoglobin, WBC and platelet concentrations, ACA in Ph-chromosome-positive cells or co-morbidity(ies). In multi-variable analyses the ELTS low-, intermediate- and high-risk cohorts were used as the reference cohort. AP subjects with increased basophils only had comparable TFS and survival compared with CP subjects in the ELTS intermediate-risk cohort. AP subjects with increased blasts only had worse TFS (HR\u0026thinsp;=\u0026thinsp;2.2 [1.1, 4.5]; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.03) but similar survival (HR\u0026thinsp;=\u0026thinsp;1.5 [0.5, 4.6]; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.50) compared with CP subjects in the ELTS high-risk cohort. AP subjects with decreased platelets only had similar TFS (HR\u0026thinsp;=\u0026thinsp;1.9 [0.9, 4.2]; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.10) but worse survival (HR\u0026thinsp;=\u0026thinsp;2.7 [1.0, 7.3]; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.04) compared with ELTS high-risk cohort.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eMulti-variable analyses of outcomes by ELN criteria.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eTFS\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003eSurvival\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHR (95% CI)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e-value\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eHR (95% CI)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e-value\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDisease phase\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCP Risk\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLow \u003cb\u003e(ref)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIntermediate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.0 (1.3, 3.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.003\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.7 (0.9, 3.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.13\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHigh\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.7 (2.2, 6.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3.7 (1.8, 7.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBasophils\u0026thinsp;\u0026gt;\u0026thinsp;20%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.9 (1.1, 3.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.03\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.2 (1.0, 4.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.04\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBlasts\u0026thinsp;\u0026gt;\u0026thinsp;15% and \u0026lt;\u0026thinsp;30%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8.2 (4.1, 16.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5.4 (1.8, 16.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.003\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePlatelets\u0026thinsp;\u0026lt;\u0026thinsp;100\u0026thinsp;\u0026times;\u0026thinsp;10E\u0026thinsp;+\u0026thinsp;9/L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7.2 (3.5, 14.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10.0 (4.0, 25.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDisease phase\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCP Risk\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.5 (0.3, 0.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.003\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.6 (0.3, 1.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.13\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIntermediate \u003cb\u003e(ref)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHigh\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.8 (1.1 3.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.2 (1.0, 4.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.04\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBasophils\u0026thinsp;\u0026gt;\u0026thinsp;20%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.9 (0.5, 1.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e0.84\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.3 (0.6, 2.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.47\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBlasts\u0026thinsp;\u0026gt;\u0026thinsp;15% and \u0026lt;\u0026thinsp;30%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.0 (2.0, 8.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3.2 (1.1, 9.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.04\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePlatelets\u0026thinsp;\u0026lt;\u0026thinsp;100\u0026thinsp;\u0026times;\u0026thinsp;10E\u0026thinsp;+\u0026thinsp;9/L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.6 (1.7, 7.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6.0 (2.3, 15.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDisease phase\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCP Risk\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.3 (0.2, 0.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.3 (0.1, 0.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIntermediate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.5 (0.3, 0.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.5 (0.2, 1.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.04\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHigh \u003cb\u003e(ref)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBasophils\u0026thinsp;\u0026gt;\u0026thinsp;20%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.5 (0.3, 1.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.6 (0.3, 1.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.21\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBlasts\u0026thinsp;\u0026gt;\u0026thinsp;15% and \u0026lt;\u0026thinsp;30%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.2 (1.1, 4.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.03\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.5 (0.5, 4.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.50\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePlatelets\u0026thinsp;\u0026lt;\u0026thinsp;100\u0026thinsp;\u0026times;\u0026thinsp;10E\u0026thinsp;+\u0026thinsp;9/L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.9 (0.9, 4.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e0.10\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.7 (1.0, 7.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.04\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (10 years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.3 (1.1, 1.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.01\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale (ref. female)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInitial imatinib-therapy (ref. 2G-TKI)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.7 (0.5, 1.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.7 (0.4, 1.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.17\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWBC (\u0026times;\u0026thinsp;10E\u0026thinsp;+\u0026thinsp;11/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.9 (0.8, 1.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHaemoglobin (g/dL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.9 (0.8, 1.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.9 (0.8, 1.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.004\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eACA (ref. none)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.9 (1.0, 3.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.2 (0.9, 5.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.07\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCo-morbidity (ref. none)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.4 (0.8, 2.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.22\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eAbbreviations: ELN, European LeukemiaNet; TFS, transformation-free survival; HR, hazard ratio; CP, chronic phase; AP, accelerated phase; 2G-TKI, 2nd -generation tyrosine kinase-inhibitor (TKI); WBC, white blood cell; ACA, additional cytogenetic abnormality.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eWe did sensitivity analyses in subjects receiving initial imatinib therapy (n\u0026thinsp;=\u0026thinsp;1638) or initial 2G-TKI therapy (n\u0026thinsp;=\u0026thinsp;471) using the ELN AP criteria (\u003cb\u003eSupplement\u003c/b\u003e Figs.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e and \u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e and \u003cb\u003eSupplement\u003c/b\u003e Tables\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e and \u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Subjects In the initial imatinib cohort AP with increased basophils only had similar outcomes compared with CP subjects in the ELTS intermediate-risk cohort. AP subjects with increased blasts only or decreased platelets only had similar outcomes compared with CP subjects in ELTS high-risk cohort. In the 2G-TKI cohort AP subjects with increased basophils only had similar outcomes compared with CP subjects in the ELTS low- and intermediate-risk cohorts. Subjects with increased blasts only had worse TFS HR\u0026thinsp;=\u0026thinsp;3.4 [1.0, 11.3]; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.05) but similar survival (HR\u0026thinsp;=\u0026thinsp;0.0 [0.0, \u0026infin;]; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1.00; there was no death in this cohort) compared with CP subjects in ELTS high-risk cohort. AP subjects with decreased platelets only had worse TFS (HR\u0026thinsp;=\u0026thinsp;4.6 [1.4, 15.3]; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.01) and worse survival (HR\u0026thinsp;=\u0026thinsp;9.0 [1.9, 41.5]; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.01) compared with CP subjects in ELTS high-risk cohort.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eELTS risk score predicts outcomes in AP subjects\u003c/h2\u003e \u003cp\u003e241 evaluable AP subjects were classified as ELTS low- (n\u0026thinsp;=\u0026thinsp;74), intermediate- (n\u0026thinsp;=\u0026thinsp;74) and high-risk (n\u0026thinsp;=\u0026thinsp;93). The distribution of ELTS risk in AP subjects classified by increased basophils only, increased blasts only and decreased platelets only are displayed in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. 73 subjects (41%) with increased basophils were classified as low-, 61 (34%) as intermediate- and 44 (25%) as ELTS high-risk. 2 subjects with increased blasts only were classified as ELTS intermediate- and 32 as high-risk. 1 subject with decreased platelets only was classified as low-, 11 as intermediate- and 17 as ELTS high-risk. There was significant difference in outcomes between the 3 risk cohorts (P\u0026thinsp;=\u0026thinsp;0.01\u0026thinsp;~\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eComparison of outcomes by ELN milestones\u003c/h2\u003e \u003cp\u003eThere was no difference in proportions of subjects meeting optimal, warning and failure at 3, 6 and 12 months according to the ELN response milestones criteria between CP and AP cohorts. However, AP subjects with increased blasts only or decreased platelets only had higher failure rate at 3 months (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.03) and high non-optimal rates at 6 months (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.06). When subjects with increased basophils only were re-classified into CP ELTS risk cohort the remaining AP subjects showed higher rate of meeting warning and/or failure response milestones at 3 (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.01) and 6 (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.08) months (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). AP subjects achieving optimal and warning response showed similar outcomes to CP subjects. However, AP subjects with a failure milestone had significantly worse TFS (3-month, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.027; 6-month, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.204; 12-months, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.189) and/or survival (3-month, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.118; 6-month, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.057; 12-months, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.056) than CP subjects (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003eSubjects diagnosed by\u003c/b\u003e \u003cb\u003ethe\u003c/b\u003e \u003cb\u003eICC 2022 criteria\u003c/b\u003e\u003c/p\u003e \u003cp\u003eData from 2,052 consecutive CP (n\u0026thinsp;=\u0026thinsp;1,748) and AP (n\u0026thinsp;=\u0026thinsp;305) persons were interrogated according to the ICC criteria. The above analyses were repeated in subjects classified as AP using the 2022 ICC criteria. Subject co-variates were shown in the \u003cb\u003eSupplement\u003c/b\u003e Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e\u0026ndash;9 \u003cb\u003eand\u003c/b\u003e Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e\u0026ndash;6. In multi-variable analyses AP subjects with increased basophils only had comparable TFS and survival compared with CP subjects in the ELTS intermediate-risk cohort. AP subjects with increased blasts only had similar survival but worse TFS (HR\u0026thinsp;=\u0026thinsp;2.0 [1.0, 3.7]; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.04) compared with CP subjects in ELTS high-risk cohort. AP subjects with ACA only or \u0026ge;\u0026thinsp;2 features had comparable TFS and survival compared with CP subjects in ELTS high-risk cohort.\u003c/p\u003e \u003cp\u003eThere were significant differences in the proportion of subjects achieving 2020 ELN response milestones at 3 months but not at 6 months and thereafter between CP and AP subjects. Overall, the outcomes of AP subjects classified by the 2022 ICC 2022 criteria were like those classified by the 2020 ELN criteria.\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eCML was initially divided into 2 phases: CP \u003cem\u003eversus\u003c/em\u003e terminal, blast or not CP. The suggestion of a 3rd AP phase was a late addition.(\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e) These terms are confusing. The biology of CML suggests 2 phases, CP and terminal, advanced or not CP. Also, not everyone in whom CML transforms from a preleukaemia to leukaemia has increased blasts making blast phase (BP) an inaccurate descriptor. Further complicating the terminology are different definitions of AP, the impact of TKI-therapy where few people transform to a terminal phase and where initial therapy of people presenting in either CP or AP is similar.\u003c/p\u003e \u003cp\u003eThe strongest predictors of CML-related survival in people presenting in CP is response to TKI-therapy, to clinical co-variates art diagnosis which correlate with several laboratory coo-variates at diagnosis. As we describe above, co-variates purportedly identifying a AP also align with likelihood of response to TKI-therapy response rather than compromising a distinct phase of CML.\u003c/p\u003e \u003cp\u003eWe addressed the controversy of whether there is an AP of CML by interrogating data obtained at diagnosis in a large cohort of subjects with CP or with AP classified using the 2020 ELN and 2022 ICC criteria. We found most AP subjects, those with increased basophils only, had TFS and survival like those of CP subjects in the ELTS intermediate- and high-risk cohorts. AP subjects with increased blasts only or decreased platelets only had either worse TFS or survival but not both compared with the high-risk ELTS cohort. These worse outcomes were seen only for subjects failing to meet the 2020 ELN TKI-therapy-response milestones. These data suggest increased blasts only or decreased platelets only are predictive co-variates for TKI-therapy-response and not a distinct phase of CML and supporting the 2022 WHO classification eliminating AP as a phase of CML.\u003c/p\u003e \u003cp\u003eOur study limitations. First, it is single-centre and retrospective. 2nd, few subjects received initial 2G-TKI-therapy. 3rd, we had too few subjects to evaluate those meeting\u0026thinsp;\u0026ge;\u0026thinsp;2 AP criteria. 4th, we did not monitor therapy compliance in all subjects. Last, we studied people with AP at diagnosis, not those presenting in CP and evolving to AP. However, we suggest our conclusions also apply here and that people developing prior AP features have failed TKI-therapy and are no longer in CP..\u003c/p\u003e \u003cp\u003eBased on our data we suggest 2 changes to CML nomenclature. 1st, eliminating AP based on the biology of CML and on our clinical data. 2nd, we suggest changing the name of the leukaemia phase of CML to terminal, acute or not CP rather than BP. We also suggest updating the EUTOS ELTS risk score classification to consider a very high-risk cohort with increased blasts and/or decreased platelets We acknowledge our conclusions and suggestions are controversial and welcome comments..\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments \u0026nbsp;\u003c/strong\u003eWe thank medical staff and patients’ participants. \u0026nbsp; RPG acknowledges support from the National Institute of Health Research (NIHR) Biomedical Research Centre funding scheme.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding \u0026nbsp;\u003c/strong\u003eFunded, in part, by the National Nature Science Foundation of China (No. 81970140 and No. 82370161).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions \u0026nbsp;\u0026nbsp;\u003c/strong\u003eQJandX-JH designed the study. \u0026nbsp;QJ, SY and X-SZ collected and analyzed the data. \u0026nbsp;QJ, SY, X-SZ, RPG and X-JH prepared the typescript. \u0026nbsp;All authors approved the final typescript, take responsibility for the content and agreed to submit for publication.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest \u0026nbsp;\u003c/strong\u003eRPG is a consultant to BeiGene Ltd., Fusion Pharma LLC, LaJolla NanoMedical Inc., Mingsight Parmaceuticals Inc. \u0026nbsp;and CStone Pharmaceuticals; advisor to Antegene Biotech LLC, Medical Director, FFF Enterprises Inc.; partner, AZAC Inc.; Board of Directors, Russian Foundation for Cancer Research Support; and Scientific Advisory Board: StemRad Ltd.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics Approval \u0026nbsp;\u0026nbsp;\u003c/strong\u003eApprove by the Ethics Committee of People’s Hospital Beijing compliant with precepts the Helsinki Declaration.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eBerman E, Shah NP, Deninger M, Altman JK, Amaya M, Begna K, et al. CML and the WHO: Why? J Clin Oncol. 2023:Jco2301689.\u003c/li\u003e\n\u003cli\u003eKantarjian HM, Tefferi A. Classification of accelerated phase chronic myeloid leukemia in the era of the BCR::ABL1 tyrosine kinase inhibitors: A work in progress. Am J Hematol. 2023;98(9):1350-3.\u003c/li\u003e\n\u003cli\u003eKhoury JD, Solary E, Abla O, Akkari Y, Alaggio R, Apperley JF, et al. The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms. Leukemia. 2022;36(7):1703-19.\u003c/li\u003e\n\u003cli\u003eArber DA, Orazi A, Hasserjian RP, Borowitz MJ, Calvo KR, Kvasnicka HM, et al. International Consensus Classification of Myeloid Neoplasms and Acute Leukemias: integrating morphologic, clinical, and genomic data. Blood. 2022;140(11):1200-28.\u003c/li\u003e\n\u003cli\u003eHochhaus A, Baccarani M, Silver RT, Schiffer C, Apperley JF, Cervantes F, et al. European LeukemiaNet 2020 recommendations for treating chronic myeloid leukemia. Leukemia. 2020;34(4):966-84.\u003c/li\u003e\n\u003cli\u003eRadich JP, Dai H, Mao M, Oehler V, Schelter J, Druker B, et al. Gene expression changes associated with progression and response in chronic myeloid leukemia. Proc Natl Acad Sci U S A. 2006;103(8):2794-9.\u003c/li\u003e\n\u003cli\u003eSilver RT, Karanas A, Dear KB, Weil M, Brunner K, Haurani F, et al. Attempted prevention of blast crisis in chronic myeloid leukemia by the use of pulsed doses of cytarabine and lomustine. A Cancer and Leukemia Group B study. Leuk Lymphoma. 1992;7(1-2):63-8.\u003c/li\u003e\n\u003cli\u003eArber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127(20):2391-405.\u003c/li\u003e\n\u003cli\u003eCortes JE, Talpaz M, O\u0026apos;Brien S, Faderl S, Garcia-Manero G, Ferrajoli A, et al. Staging of chronic myeloid leukemia in the imatinib era: an evaluation of the World Health Organization proposal. Cancer. 2006;106(6):1306-15.\u003c/li\u003e\n\u003cli\u003eBaccarani M, Deininger MW, Rosti G, Hochhaus A, Soverini S, Apperley JF, et al. European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood. 2013;122(6):872-84.\u003c/li\u003e\n\u003cli\u003eBaccarani M, Cortes J, Pane F, Niederwieser D, Saglio G, Apperley J, et al. Chronic myeloid leukemia: an update of concepts and management recommendations of European LeukemiaNet. J Clin Oncol. 2009;27(35):6041-51.\u003c/li\u003e\n\u003cli\u003ePfirrmann M, Baccarani M, Saussele S, Guilhot J, Cervantes F, Ossenkoppele G, et al. Prognosis of long-term survival considering disease-specific death in patients with chronic myeloid leukemia. Leukemia. 2016;30(1):48-56.\u003c/li\u003e\n\u003cli\u003eQin YZ, Jiang Q, Jiang H, Li JL, Li LD, Zhu HH, et al. Which method better evaluates the molecular response in newly diagnosed chronic phase chronic myeloid leukemia patients with imatinib treatment, BCR-ABL(IS) or log reduction from the baseline level? Leuk Res. 2013;37(9):1035-40.\u003c/li\u003e\n\u003cli\u003eKantarjian HM, Dixon D, Keating MJ, Talpaz M, Walters RS, McCredie KB, et al. Characteristics of accelerated disease in chronic myelogenous leukemia. Cancer. 1988;61(7):1441-6.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"leukemia","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"leu","sideBox":"Learn more about [Leukemia](http://www.nature.com/leu/)","snPcode":"41375","submissionUrl":"https://mts-leu.nature.com/cgi-bin/main.plex","title":"Leukemia","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Chronic myeloid leukemia, accelerated phase, chronic phase.","lastPublishedDoi":"10.21203/rs.3.rs-4554542/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4554542/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eWhether there is really a distinct accelerated phase (AP) at diagnosis in chronic myeloid leukemia (CML) in the context of tyrosine kinase-inhibitor (TKI)-therapy and whether co-variates identified as characterizing AP are simply adverse co-variates for outcomes, we studied 2,122 consecutive subjects in chronic phase (CP, n = 1,837) or AP (n = 285) according to the European LeukemiaNet (ELN) classification. AP subjects with increased basophils only had similar transformation-free survival (TFS) and survival compared with CP subjects in ELTS intermediate-risk. AP subjects with increased blasts only had worse TFS but similar survival compared with CP subjects in the ELTS high-risk; AP subjects with decreased platelets only, similar TFS but worse survival. Proportions of CP and AP subjects meeting the 2020 ELN TKI-response milestones were similar. \u0026nbsp;However, worse outcomes were only seen in AP subjects failing to meet ELN milestones. Findings were similar using the 2022 International Consensus Classification (ICC) criteria replacing decreased platelets with additional cytogenetic abnormalities. Our data support the 2022 WHO classification of CML eliminating AP. We suggest adding a very high-risk cohort to the ELTS score including people with increased blasts or decreased platelets and dividing CML into 2 phases: CP and acute phase.\u003c/p\u003e","manuscriptTitle":"Goodbye to accelerated phase of chronic myeloid leukaemia","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-06-26 08:55:01","doi":"10.21203/rs.3.rs-4554542/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"revise","date":"2024-07-10T11:41:47+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"This content is not available.","date":"2024-07-09T18:05:30+00:00","index":2,"fulltext":"This content is not available."},{"type":"editorInvitedReview","content":"This content is not available.","date":"2024-06-25T12:25:46+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2024-06-21T20:17:16+00:00","index":2,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2024-06-14T07:42:57+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewersInvited","content":"","date":"2024-06-10T18:59:27+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-06-10T10:06:04+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-06-10T10:05:54+00:00","index":"","fulltext":""},{"type":"submitted","content":"Leukemia","date":"2024-06-09T16:44:21+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"leukemia","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"leu","sideBox":"Learn more about [Leukemia](http://www.nature.com/leu/)","snPcode":"41375","submissionUrl":"https://mts-leu.nature.com/cgi-bin/main.plex","title":"Leukemia","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"ec56b04b-6baa-42b4-a52a-d4668a0cec2f","owner":[],"postedDate":"June 26th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":33068746,"name":"Health sciences/Diseases/Haematological diseases/Haematological cancer/Leukaemia/Chronic myeloid leukaemia"},{"id":33068747,"name":"Health sciences/Risk factors"}],"tags":[],"updatedAt":"2024-12-05T08:09:16+00:00","versionOfRecord":{"articleIdentity":"rs-4554542","link":"https://doi.org/10.1038/s41375-024-02486-2","journal":{"identity":"leukemia","isVorOnly":false,"title":"Leukemia"},"publishedOn":"2024-12-04 05:00:00","publishedOnDateReadable":"December 4th, 2024"},"versionCreatedAt":"2024-06-26 08:55:01","video":"","vorDoi":"10.1038/s41375-024-02486-2","vorDoiUrl":"https://doi.org/10.1038/s41375-024-02486-2","workflowStages":[]},"version":"v1","identity":"rs-4554542","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4554542","identity":"rs-4554542","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}