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• W4294307875 abstract "The incidence of chronic myeloid leukaemia (CML) ranges between 10 and 15 cases/106/year without any major geographic or ethnic differences [1.Hehlmann R. Hochhaus A. Baccarani M. European LeukemiaNet Chronic myeloid leukaemia.Lancet. 2007; 370: 342-350Abstract Full Text Full Text PDF PubMed Scopus (378) Google Scholar]. The median age at diagnosis ranges between 60 and 65 years in Europe, but is considerably lower in countries with a younger population. The prevalence of CML is steadily rising due to the substantial prolongation of survival that has been achieved with targeted therapy [2.Bower H. Björkholm M. Dickman P.W. et al.Life expectancy of patients with chronic myeloid leukemia approaches the life expectancy of the general population.J Clin Oncol. 2016; 34: 2851-2857Crossref PubMed Scopus (472) Google Scholar]. CML in children is rare; biology and treatment strategies in paediatric patients reveal specific aspects [3.Hijiya N. Schultz K.R. Metzler M. et al.Pediatric chronic myeloid leukemia is a unique disease that requires a different approach.Blood. 2016; 127: 392-399Crossref PubMed Scopus (110) Google Scholar]. Therefore, these recommendations are primarily intended for use in adult patients. CML is a disease of haemopoietic stem cells, arising from a translocation t(9;22)(q34;q11), with the shortened chromosome 22, designated as Philadelphia chromosome, 22q-. The translocation leads to a juxtaposition of the ABL1 gene from chromosome 9 and the BCR gene from chromosome 22, resulting in a BCR–ABL1 fusion gene that codes for BCR–ABL1 transcripts and fusion proteins with high tyrosine kinase activity. The molecular pathogenesis of CML is well understood, but the mechanism that leads to the gene translocation is unknown [1.Hehlmann R. Hochhaus A. Baccarani M. European LeukemiaNet Chronic myeloid leukaemia.Lancet. 2007; 370: 342-350Abstract Full Text Full Text PDF PubMed Scopus (378) Google Scholar]. Diagnosis of CML is generally straightforward. In most cases, the diagnosis can be made on the basis of a characteristic blood count and differential (excessive granulocytosis with typical left shift of granulopoiesis). Confirmation of diagnosis is obtained by the identification of the Philadelphia chromosome, 22q- or BCR–ABL1 transcripts, or both, in peripheral blood or bone marrow (BM) cells. In ∼5% of cases the Philadelphia chromosome cannot be detected and confirmation of diagnosis depends on the confirmation of the BCR–ABL1 fusion by either fluorescent in situ hybridisation (FISH) or by reverse transcriptase polymerase chain reaction (RT-PCR). These patients should be treated the same way as Philadelphia-positive (Ph+) patients. Therapeutic response is comparable [4.Hochhaus A. Mahon F.X. le Coutre P. et al.Nilotinib first-line therapy in patients with Philadelphia chromosome-negative/BCR-ABL-positive chronic myeloid leukemia in chronic phase: ENEST1st sub-analysis.J Cancer Res Clin Oncol. 2017; 143: 1225-1233Crossref PubMed Scopus (5) Google Scholar]. In some patients with features of CML, no Philadelphia chromosome or BCR–ABL1 rearrangement can be detected [1.Hehlmann R. Hochhaus A. Baccarani M. European LeukemiaNet Chronic myeloid leukaemia.Lancet. 2007; 370: 342-350Abstract Full Text Full Text PDF PubMed Scopus (378) Google Scholar]. These patients are referred to as Philadelphia-negative (Ph−) and BCR–ABL1 negative, or as atypical CML, according to the World Health Organization (WHO) classification, and represent a separate disease entity [5.Arber D.A. Orazi A. Hasserjian R. et al.The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia.Blood. 2016; 127: 2391-2405Crossref PubMed Scopus (5647) Google Scholar]. Treatment of atypical CML is beyond the scope of these guidelines. BCR–ABL1 positive cells are genetically unstable and are prone to develop multiple and heterogeneous genomic abnormalities, resulting in the transformation of the leukaemic phenotype from chronic to acute, hence leading to the progression from chronic (CP) to accelerated (AP) and blast (BP) phases (Table 1) [5.Arber D.A. Orazi A. Hasserjian R. et al.The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia.Blood. 2016; 127: 2391-2405Crossref PubMed Scopus (5647) Google Scholar, 6.Baccarani M. Deininger M.W. Rosti G. et al.European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013.Blood. 2013; 122: 872-884Crossref PubMed Scopus (1518) Google Scholar]. Table 1 compares the WHO and the European LeukemiaNet (ELN) definitions of CML phases. Of note, the ELN definition has been used in almost all clinical trials assessing the efficacy of tyrosine kinase inhibitors (TKIs) and is recommended as a basis for treatment decisions.Table 1Clinical and haematological criteria for the definition of AP and BP according to WHO [5.Arber D.A. Orazi A. Hasserjian R. et al.The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia.Blood. 2016; 127: 2391-2405Crossref PubMed Scopus (5647) Google Scholar] and ELN [6.Baccarani M. Deininger M.W. Rosti G. et al.European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013.Blood. 2013; 122: 872-884Crossref PubMed Scopus (1518) Google Scholar]Accelerated phaseBlast phaseWHOELNWHOELNSpleenPersisting or increasing splenomegaly unresponsive to therapy–––WBC countPersisting or increasing WBC count (> 10 x 109/L) unresponsive to therapy–––Blast cellsaIn peripheral blood or in BM.10%–19%15%–29%≥ 20%≥ 30%BasophilsaIn peripheral blood or in BM.> 20%> 20%––Platelet count> 1000 x 109/L uncontrolled by therapy–––< 100 x 109/L unrelated to therapyYes––CCA/Ph+Any new clonal aberration during therapyPresent––Additional clonal chromosomal abnormalities in Ph cells at diagnosis that include ‘major route’ abnormalities (second Ph, trisomy 8, isochromosome 17q, trisomy 19), complex karyotype or abnormalities of 3q26.2Extramedullary involvementbExcluding liver and spleen, including lymph nodes, skin, CNS, bone and lung.––PresentPresent‘Provisional’ response- to-TKI criteriaHaematological resistance to the first TKI (or failure to achieve a complete haematological responsecComplete haematological response: WBC < 10 × 109/L; platelet count < 450 × 109/L, no immature granulocytes in the differential and spleen non-palpable. to the first TKI) orAny haematological, cytogenetic or molecular indications of resistance to 2 sequential TKIs orOccurrence of 2 or more mutations in BCR–ABL1 during TKI therapyThe criteria of AP are different, reflecting the difficulty of making the diagnosis of this transitory phase. The criteria of BP differ only for the percent of blast cells. Only one of the listed criteria is sufficient for the diagnosis of AP or BP.AP, accelerated phase; BM, bone marrow; BP, blast phase; CCA/Ph+, clonal chromosome abnormalities in Ph+ cells; CNS, central nervous system; ELN, European LeukemiaNet; Ph, Philadelphia; TKI, tyrosine kinase inhibitor; WBC, white blood cell; WHO, World Health Organization.a In peripheral blood or in BM.b Excluding liver and spleen, including lymph nodes, skin, CNS, bone and lung.c Complete haematological response: WBC < 10 × 109/L; platelet count < 450 × 109/L, no immature granulocytes in the differential and spleen non-palpable. Open table in a new tab The criteria of AP are different, reflecting the difficulty of making the diagnosis of this transitory phase. The criteria of BP differ only for the percent of blast cells. Only one of the listed criteria is sufficient for the diagnosis of AP or BP. AP, accelerated phase; BM, bone marrow; BP, blast phase; CCA/Ph+, clonal chromosome abnormalities in Ph+ cells; CNS, central nervous system; ELN, European LeukemiaNet; Ph, Philadelphia; TKI, tyrosine kinase inhibitor; WBC, white blood cell; WHO, World Health Organization. Progression may be based on BCR–ABL1-dependent factors, e.g. point mutations of the kinase domain, associated with resistance to TKIs, or BCR–ABL1-independent factors, e.g. additional cytogenetic aberrations causing clonal evolution. BM biopsies taken at diagnosis show increased cellularity due to proliferation of the myelopoiesis in all stages of maturation with predominance of mature forms. Basophilia is common, and eosinophils may be prominent. Proportion of blasts vary; but, according to ELN recommendations [6.Baccarani M. Deininger M.W. Rosti G. et al.European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013.Blood. 2013; 122: 872-884Crossref PubMed Scopus (1518) Google Scholar], CP disease is associated with < 15% blasts in blood and BM. Megakaryocytes are smaller than normal with hypolobulated nuclei. Moderate to marked reticulin fibrosis is encountered in ∼30% of cases. Pseudo-Gaucher cells and sea-blue histiocytes are usually observed. BM composition undergoes rapid changes during therapy. These consist of reduction of the granulocytic cellularity, normalisation of megakaryopoiesis, regression of fibrosis, lymphocytosis and normalisation of erythropoiesis. The recognition of disease progression from CP to BP is relevant for prognosis and treatment. However, the clinical and morphological boundaries between these stages are sometimes vague. Immunocytology by flow cytometry and histochemistry allow accurate assessment of immature cells and distinction between myeloid (70%–80%) and lymphoid (20%–30%) blast crisis [1.Hehlmann R. Hochhaus A. Baccarani M. European LeukemiaNet Chronic myeloid leukaemia.Lancet. 2007; 370: 342-350Abstract Full Text Full Text PDF PubMed Scopus (378) Google Scholar]. About 50% of patients with CML diagnosed in Europe are asymptomatic. The disease is frequently diagnosed after blood tests are taken for some unrelated reason. At diagnosis, most (90%–95%) CML patients present in CP; initial BP is rare [1.Hehlmann R. Hochhaus A. Baccarani M. European LeukemiaNet Chronic myeloid leukaemia.Lancet. 2007; 370: 342-350Abstract Full Text Full Text PDF PubMed Scopus (378) Google Scholar, 7.Hoffmann V.S. Baccarani M. Hasford J. et al.Treatment and outcome of 2904 CML patients from the EUTOS population-based registry.Leukemia. 2017; 31: 593-601Crossref PubMed Scopus (65) Google Scholar]. The designation of an AP at diagnosis is conflicting but the term should be used during therapy. Common signs and symptoms of CML CP, when present, result from anaemia and splenomegaly. These include fatigue, weight loss, malaise and left upper quadrant fullness or pain. Rare manifestations include bleeding (associated with a low platelet count and/or platelet dysfunction), thrombosis (associated with thrombocytosis and/or marked leukocytosis), gouty arthritis (from elevated uric acid levels), retinal haemorrhages and upper gastrointestinal ulceration (from elevated histamine levels due to basophilia). Leukostatic symptoms (priapism, dyspnoea, drowsiness, loss of coordination, confusion) due to leukaemic cells sludging in the blood vessels are uncommon in CP despite white blood cell (WBC) count often exceeding 100 ×109/L. Splenomegaly is the most consistent physical sign detected in 40%–50% of cases. Hepatomegaly is less common. Extramedullary infiltration (apart from spleen and liver) is rare. Headaches, bone pain, arthralgias, pain from splenic infarction and fever are more frequent with CML transformation [7.Hoffmann V.S. Baccarani M. Hasford J. et al.Treatment and outcome of 2904 CML patients from the EUTOS population-based registry.Leukemia. 2017; 31: 593-601Crossref PubMed Scopus (65) Google Scholar]. On TKI therapy, most patients restore normal haematopoiesis. Transient cytopaenias occur due to delayed recovery of normal haematopoiesis but good efficacy against leukaemia. CML AP might present with non-specific symptoms, worsening anaemia, splenomegaly and organ infiltration; CML BP presents as an acute leukaemia with worsening constitutional symptoms, bleeding, fever and infections. Diagnosis must be confirmed by cytogenetics showing t(9;22)(q34;q11) and by multiplex RT-PCR showing BCR–ABL1 transcripts. In rare cases, BCR–ABL1 juxtaposition can be determined by interphase FISH (iFISH) of blood cells, using dual colour dual fusion probes that allow the detection of BCR–ABL1+ nuclei. Cytogenetic assessment is required because it is necessary to detect additional chromosome abnormalities. Qualitative multiplex RT-PCR is carried out on blood or BM RNA. It identifies the transcript type, either typical e14a2 or e13a2 (also known as b3a2 and b2a2) or atypical variants. Determination of the transcript type is crucial for later monitoring, in particular for the accurate assessment of molecular response. Quantitative RT-PCR (qRT-PCR) measuring BCR–ABL1 transcripts level as BCR–ABL1 % on the International Scale (IS) and BCR–ABL1 mutation analysis are not required at baseline. Baseline mutational analysis in patients with newly diagnosed CML CP is not advised, as this has not been proven to provide information on optimal treatment selection and to predict therapeutic outcome. Recommendations for the baseline diagnostic work-up are summarised in Table 2 [V, A].Table 2Recommendations for diagnostic work-up, assessment of response and monitoringBaseline (diagnostic work-up)To assess the responseTo monitor the response and the treatmentBlood counts and differentialYesEvery 15 days until a CHR without significant cytopaenias has been achievedEvery 3 monthsBM, cytologyYesNoNoBM, karyotypeYesAt 3 and 6 monthsThen every 6 months until CCyR has been achievedBlood, iFISHNoNoOnly if cytogenetics of BM metaphases cannot be analysed or is normal and molecular response cannot be assessedBlood, RT-PCR (qualitative)YesNoNoBlood, qRT-PCR (quantitative, BCR–ABL %)NoEvery 3 monthsEvery 4–6 weeks in first year after treatment discontinuationMutational analysisOnly in AP or BPNoOnly in the case of failureAP, accelerated phase; BM, bone marrow; BP, blast phase; CCyR, complete cytogenetic response; CHR, complete haematological response; iFISH, interphase fluorescent in situ hybridisation; qRT-PCR: quantitative RT-PCR; RT-PCR, reverse transcriptase polymerase chain reaction. Open table in a new tab AP, accelerated phase; BM, bone marrow; BP, blast phase; CCyR, complete cytogenetic response; CHR, complete haematological response; iFISH, interphase fluorescent in situ hybridisation; qRT-PCR: quantitative RT-PCR; RT-PCR, reverse transcriptase polymerase chain reaction. The relative risk of a patient with CML can be calculated using simple clinical and haematological data provided that they were collected before any treatment. The Sokal score has been developed in the chemotherapy era and the Euro score in the interferon alpha (IFNα) era, with survival as the endpoint for both. The chance of achieving a complete cytogenetic response (CCyR) after 18 months of TKI therapy can be estimated with the European Treatment and Outcome Study (EUTOS) score. The EUTOS Long-Term Survival (ELTS) score for patients on TKI therapy considers CML-related deaths only (Table 3) [III, A] [8.Pfirrmann M. Baccarani M. Saussele S. et al.Prognosis of long-term survival considering disease-specific death in patients with chronic myeloid leukemia.Leukemia. 2016; 30: 48-56Crossref PubMed Scopus (176) Google Scholar]. Despite randomised first-line trials employing different scores, the intrinsic risk of early acceleration or blast crisis in low-risk patients is low with all available TKIs.Table 3Calculation of the relative risk of a patient with CML using clinical and haematological data obtained before any treatment [8.Pfirrmann M. Baccarani M. Saussele S. et al.Prognosis of long-term survival considering disease-specific death in patients with chronic myeloid leukemia.Leukemia. 2016; 30: 48-56Crossref PubMed Scopus (176) Google Scholar]SokalEUROEUTOSELTSAge (years)0.116 (age - 43.4)0.666 when age > 50N/A0.0025 × (age/10)3Spleen sizeaSpleen size is measured by manual palpation and expressed as maximum distance perpendicular from costal margin. (cm)0.345 × (spleen - 7.51)0.042 × spleen4 × spleen0.0615 × spleenPlatelet count (×109/L)0.188 × [(platelets/700)2 - 0.563]1.0956 when platelets ≥ 1500N/A0.4104 × (platelets/1000)−0.5Blood blast cells (%)0.887 × (blast cells - 2.10)0.0584 × blast cellsN/A0.1052 × blast cellsBlood basophils (%)N/A0.20399 when basophils > 3%7 × basophilsBlood eosinophils (%)N/A0.0413 × eosinophilsN/ARelative riskExponential of the totalTotal × 1000TotalTotalLow< 0.8≤ 780≥ 87≤ 1.5680Intermediate0.8–1.2781–1480N/A1.5680–2.2185High≥ 1.2≥ 1480≥ 87≥ 2.2185EndpointSurvivalSurvivalCCyRCML-specific survivalCCyR, complete cytogenetic response; CML, chronic myeloid leukaemia; ELTS, EUTOS Long-Term Survival; EUTOS, European Treatment and Outcome Study; N/A, not applicable.a Spleen size is measured by manual palpation and expressed as maximum distance perpendicular from costal margin. Open table in a new tab CCyR, complete cytogenetic response; CML, chronic myeloid leukaemia; ELTS, EUTOS Long-Term Survival; EUTOS, European Treatment and Outcome Study; N/A, not applicable. Major route cytogenetic aberrations (+8, iso(17q), +19, +22q-), chromosome 3 aberrations and BM fibrosis at diagnosis have been associated with an unfavourable outcome after imatinib therapy [9.Fabarius A. Leitner A. Hochhaus A. et al.Impact of additional cytogenetic aberrations at diagnosis on prognosis of CML: long-term observation of 1151 patients from the randomized CML Study IV.Blood. 2011; 118: 6760-6768Crossref PubMed Scopus (217) Google Scholar] and are considered warning signs. The three commercially available TKIs for the front-line treatment of CML are imatinib, dasatinib and nilotinib (Figure 1); options for first-line therapy in CML CP are imatinib 400–800 mg/day, nilotinib 300 mg twice daily or dasatinib 100 mg/day. TKI selection should be based on treatment goals, age and comorbidities and should take into consideration the adverse event (AE) profile of the available drugs. With all three TKIs, overall survival (OS) after 5 years is 85%–95% [I, A]. So far, no significant survival difference between imatinib and second generation inhibitors has been observed. Imatinib mesylate was the first TKI to receive approval for the treatment of patients with CML CP. It acts via competitive inhibition at the adenosine triphosphate (ATP)-binding site of the BCR–ABL1 oncoprotein, which results in the inhibition of phosphorylation of proteins involved in cell signal transduction. It efficiently inhibits the BCR–ABL1 kinase, but, among others, also blocks the platelet-derived growth factor (PDGF) receptors and the KIT tyrosine kinase. The International Randomised Study of Interferon and STI571 (IRIS) study is considered a landmark clinical trial for CML treatment with TKIs. A total of 1106 patients in CML CP were randomised to receive imatinib 400 mg/day or IFNα plus low-dose cytarabine. After a median follow-up of 19 months, outcomes for patients receiving imatinib were significantly better than in those treated with IFNα plus cytarabine, notably the rates of CCyR (74% versus 9%, P < 0.001), and freedom from progression to AP or BP at 12 months (99% versus 93%, P < 0.001) [10.O'Brien S.G. Guilhot F. Larson R.A. et al.Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia.N Engl J Med. 2003; 348: 994-1004Crossref PubMed Scopus (2994) Google Scholar]. Responses to imatinib were also durable: in a 10-year follow-up of the IRIS study, the estimated event-free survival rate was 79.6%, and the OS rate was 83.3% [11.Hochhaus A. Larson R.A. Guilhot F. et al.Long-term outcomes of imatinib treatment for chronic myeloid leukemia.N Engl J Med. 2017; 376: 917-927Crossref PubMed Scopus (705) Google Scholar]. Other strategies for front-line therapy include using higher doses of imatinib or combining a TKI with an additional agent, such as IFNα. In the German CML IV study, patients with tolerance- and response-adapted high-dose imatinib achieved deep molecular remission (DMR) more quickly than patients on standard-dose imatinib [12.Hehlmann R. Müller M.C. Lauseker M. et al.Deep molecular response is reached by the majority of patients treated with imatinib, predicts survival, and is achieved more quickly by optimized high-dose imatinib: results from the randomized CML-Study IV.J Clin Oncol. 2014; 32: 415-423Crossref PubMed Scopus (254) Google Scholar, 13.Kalmanti L. Saussele S. Lauseker M. et al.Safety and efficacy of imatinib in CML over a period of 10 years: data from the randomized CML-study IV.Leukemia. 2015; 29: 1123-1132Crossref PubMed Scopus (193) Google Scholar]. A recent meta-analysis revealed an advantage of high-dose imatinib with regard to achievement of major molecular response (MMR) at 12 months of therapy [14.Hoffmann V.S. Hasford J. Deininger M. et al.Systematic review and meta-analysis of standard dose imatinib vs. high dose imatinib and 2nd generation tyrosine kinase inhibitors for chronic myeloid leukemia.J Cancer Res Clin Oncol. 2017; 143: 1311-1318Crossref PubMed Scopus (12) Google Scholar]. IFNα has re-emerged as an interesting therapeutic option in CML with the advent of PEGylated formulations (with polyethylene glycol PEG) requiring less frequent administration, improved efficacy and tolerability. In the French SPIRIT trial, patients were randomised to receive imatinib 400 or 600 mg/day, imatinib 400 mg/day plus PEG-IFNα-2a, or imatinib 400 mg/day plus subcutaneous cytarabine. At 12 months, rates of CCyR were similar among the 4 groups. The imatinib plus PEG-IFNα-2a-treated group obtained higher rates of MMR and DMR [15.Preudhomme C. Guilhot J. Nicolini F.E. et al.Imatinib plus peginterferon alfa-2a in chronic myeloid leukemia.N Engl J Med. 2010; 363: 2511-2521Crossref PubMed Scopus (324) Google Scholar]. PEGylated IFNα in combination with dasatinib appeared to improve molecular response rates in a single-armed phase II study with historical controls [16.Hjorth-Hansen H. Stentoft J. Richter J. et al.Safety and efficacy of the combination of pegylated interferon-α2b and dasatinib in newly diagnosed chronic-phase chronic myeloid leukemia patients.Leukemia. 2016; 30: 1853-1860Crossref PubMed Scopus (52) Google Scholar]. IFNα maintenance after TKI therapy may help to bridge to treatment-free remission (TFR) [17.Burchert A. Saussele S. Eigendorff E. et al.Interferon alpha 2 maintenance therapy may enable high rates of treatment discontinuation in chronic myeloid leukemia.Leukemia. 2015; 29: 1331-1335Crossref PubMed Scopus (47) Google Scholar]. In all, despite lack of registration, PEGylated IFNα is promising as an agent to increase the proportion of patients that may discontinue (see Table 4), but must still be considered investigational.Table 4Minimum requirements for treatment-free remission [40.Hughes T.P. Ross D.M. Moving treatment-free remission into mainstream clinical practice in CML.Blood. 2016; 128: 17-23Crossref PubMed Scopus (244) Google Scholar]Institutional requirements for safe supervision of TFR:1. Availability of high quality internationally standardised, accurate, sensitive qRT-PCR laboratory2. Rapid turn-around of PCR test results—within 4 weeks3. Capacity to provide PCR tests every 4–6 weeks, when required4. Structured follow-up established to enable rapid intervention if BCR-ABL1 is risingGreen criteria, which support treatment-free remission:1. Institutional criteria met2. Sokal-Score at diagnosis non-high3. Typical b2a2- or b3a2-BCR–ABL1 transcripts, or atypical transcripts which can be quantified over a 4.5 log dynamic range4. Chronic phase disease5. Optimal response to first-line therapy6. Duration of TKI therapy > 5 years7. MR4.5 reached8. Duration of deep molecular response (MR4 or MR4.5) (standardised lab) > 2 yearsMR, molecular response; PCR, polymerase chain reaction; qRT-PCR, quantitative reverse transcriptase PCR; TFR, treatment-free remission; TKI, tyrosine kinase inhibitor.Republished from [40.Hughes T.P. Ross D.M. Moving treatment-free remission into mainstream clinical practice in CML.Blood. 2016; 128: 17-23Crossref PubMed Scopus (244) Google Scholar] with permission of the American Society of Hematology; permission conveyed through Copyright Clearance Center, Inc. Open table in a new tab MR, molecular response; PCR, polymerase chain reaction; qRT-PCR, quantitative reverse transcriptase PCR; TFR, treatment-free remission; TKI, tyrosine kinase inhibitor. Republished from [40.Hughes T.P. Ross D.M. Moving treatment-free remission into mainstream clinical practice in CML.Blood. 2016; 128: 17-23Crossref PubMed Scopus (244) Google Scholar] with permission of the American Society of Hematology; permission conveyed through Copyright Clearance Center, Inc. Dasatinib is an oral, second generation multikinase TKI that is 350 times more potent than imatinib in vitro and inhibits multiple kinases including Src-family members. The DASISION trial was a phase III randomised study comparing dasatinib 100 mg/day to imatinib 400 mg/day in 519 newly diagnosed patients with CML. Patients assigned to dasatinib achieved confirmed CCyR at 12 months more often than those on imatinib (77% versus 66%, P < 0.007). A 5-year follow-up showed that dasatinib induced more rapid and deeper responses at early time points compared with imatinib. At 3 months, a higher proportion of patients treated with dasatinib achieved BCR–ABL1 transcripts <10% on the IS (84% versus 64%, P < 0.0001). Meeting this threshold in either arm predicted for better progression-free survival (PFS) and OS. Transformations to CML AP or CML BP were fewer in patients treated with dasatinib versus imatinib at 5 years (4.6% versus 7.3%) [18.Kantarjian H. Shah N.P. Hochhaus A. et al.Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia.N Engl J Med. 2010; 362: 2260-2270Crossref PubMed Scopus (1264) Google Scholar, 19.Cortes J.E. Saglio G. Kantarjian H.M. et al.Final 5-year study results of DASISION: the dasatinib versus imatinib study in treatment-naïve chronic myeloid leukemia patients trial.J Clin Oncol. 2016; 34: 2333-2340Crossref PubMed Scopus (556) Google Scholar]. Nilotinib is a structural analogue of imatinib. Compared with imatinib, the in vitro affinity for the BCR-ABL1 ATP-binding site is 30- to 50-fold higher. In the ENESTnd study, two doses of nilotinib (300 or 400 mg twice daily) were compared with imatinib 400 mg/day. The primary endpoint, MMR rate at 12 months, was achieved at higher rates for both doses of nilotinib compared with imatinib (44% and 43% versus 22%, P < 0.001). The cumulative incidence of CCyR by 24 months was 87% and 85% with nilotinib 300 mg twice daily, and 400 mg twice daily, respectively, and 77% with imatinib 400 mg/day (P < 0.001). By 5 years, the cumulative incidences of MMR by 60 months were 77%, 77% and 60%, respectively (P < 0.0001). The incidences of DMR with BCR–ABL1 transcripts [IS] ≤ 0.0032% (equivalent to a 4.5 log reduction) by 72 months were 56%, 55% and 33%, respectively (P < 0.0001). The incidences of transformation to AP or BP were 3.9%, 2.1%, and 7.4%, respectively (P = 0.06 and 0.003, respectively). The estimated 5-year survival rates were 94%, 96%, and 92%, respectively. While nilotinib was superior to imatinib across all Sokal score categories in inducing higher rates of CCyR and MMR, the advantage in reducing the rates of transformation was more pronounced in patients with intermediate- and high-Sokal-risk CML. The rates of transformations were 1%, 1% or 0% in Sokal low-risk patients treated with nilotinib 300 mg twice daily, 400 mg twice daily or imatinib 400 mg/day. The rates were 2%, 1% or 10% among patients with intermediate Sokal risk and 9%, 5% or 11% among patients with high Sokal risk [20.Saglio G. Kim D.W. Issaragrisil S. et al.Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia.N Engl J Med. 2010; 362: 2251-2259Crossref PubMed Scopus (1354) Google Scholar, 21.Hochhaus A. Saglio G. Hughes T.P. et al.Long-term benefits and risks of frontline nilotinib vs imatinib for chronic myeloid leukemia in chronic phase: 5-year update of the randomized ENESTnd trial.Leukemia. 2016; 30: 1044-1054Crossref PubMed Scopus (529) Google Scholar]. Therapy goals should be discussed with the patient and defined before the selection of the first-line drug. With all three TKIs licensed for first-line therapy, survival chances are similar [I, A]. However, the chance to achieve DMR with an option to discontinue therapy is higher with dasatinib and nilotinib as compared with imatinib [V, C]. This may be particularly relevant for young female patients with a wish to become pregnant and for all patients with a long life expectancy. Risk of transformation to AP and BP is lower in Sokal non-low-risk patients using dasatinib or nilotinib [I, A]. The use of generic imatinib may be considered to reduce cost of therapy substantially, but also for its safety profile, particularly in elderly patients [22.Padula W.V. Larson R.A. Dusetzina S.B. et al.Cost-effectiveness of tyrosine kinase inhibitor treatment strategies for chronic myeloid leukemia in chronic phase after generic entry of imatinib in the United States.J Natl Cancer Inst. 2016; 108 (pii: djw003.)Crossref PubMed Scopus (76) Google Scholar]. In some countries imatinib may be mandatory for first-line use on cost-effectiveness/reimbursement grounds. However, many different forms of generic imatinib are being commercialised worldwide and precise information on the tolerance and efficacy of each of these different compounds are rare. Recent results from a randomised study (ClinicalTrials.gov Identifier: NCT02130557)" @default.
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• W4294307875 title "Chronic myeloid leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up" @default.
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