{"entity":{"id":"cml-chronic-phase","kind":"cancer","name":"Chronic myeloid leukaemia, chronic phase","aka":["CML-CP","Chronic-phase CML","Newly diagnosed Ph-positive CML","BCR::ABL1-positive chronic phase"],"tldr":"Chronic-phase chronic myeloid leukaemia is the disease that imatinib turned from fatal into manageable: a daily pill blocks the BCR::ABL1 protein that drives it. Blood tests track the leukaemia gene to a millionth, newer pills such as asciminib (ASC4FIRST) reach deeper responses faster, and patients with years of undetectable disease can try stopping.","summary":"The Philadelphia chromosome, t(9;22), fuses BCR to ABL1 and produces a constitutively active tyrosine kinase; in chronic phase the marrow overproduces mature granulocytes with fewer than 10 percent blasts (WHO) and the disease is symptomless in half of patients, found on a routine blood count. Response is measured by quantitative PCR for BCR::ABL1 on the International Scale, with ELN milestones of 10 percent or less at three months, 1 percent or less at six months and 0.1 percent or less (major molecular response) at twelve months; failure to reach them prompts kinase domain mutation testing and a switch of drug.\n\nIRIS (2003) randomised 1,106 newly diagnosed patients to imatinib or interferon plus cytarabine: complete cytogenetic response at 18 months in 76 percent versus 14 percent, and at ten years 83 percent of imatinib patients were alive, most without progression. Second-generation inhibitors dasatinib (DASISION), nilotinib (ENESTnd) and bosutinib (BFORE) produce faster and deeper responses without a survival advantage, at the cost of pleural effusions, vascular events and liver toxicity respectively. Asciminib, which binds the myristoyl pocket rather than the ATP site, beat investigator-selected inhibitors in ASC4FIRST (2024): major molecular response at 48 weeks in 67.7 percent against 49.0 percent, and 69.3 percent against 40.2 percent for imatinib, with fewer side effects, earning accelerated approval for newly diagnosed disease in October 2024.\n\nResistance through kinase domain mutations is handled by switching: ponatinib or asciminib for T315I, and the third-generation olverembatinib in China; allogeneic transplant is reserved for failure of several inhibitors. Treatment-free remission is now a goal: EURO-SKI found about half of patients with at least three years of therapy and a year of deep molecular response stayed in remission two years after stopping. The unsolved problems are the residual stem cell pool that keeps the other half relapsing, cardiovascular toxicity over decades of therapy, and the price and access gap that leaves patients in low-income countries on older drugs or none.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Chronic_myelogenous_leukemia","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Chronic_myelogenous_leukemia"},{"label":"NCCN Guidelines: Chronic Myeloid Leukemia","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1427"}],"tags":["subtype-page"],"related":[],"cancers":[],"sections":[],"technologies":["kinase-inhibitors","mrd-kinetics-models","cytogenetics-fish"],"targets":["bcr-abl"],"drugs":[],"companies":[],"institutions":[],"pathways":["bcr-abl1-signalling","cml-signalling"],"terms":["molecular-response","philadelphia-chromosome","tki-term","mrd"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-iris-imatinib-nejm-2003","paper-druker-imatinib-phase1-nejm-2001"],"journals":[],"dependsOn":[],"notes":[],"group":"haematologic","burden":"About 95 percent of people with chronic myeloid leukaemia are diagnosed in chronic phase; on a tyrosine kinase inhibitor their life expectancy is close to that of the general population, and about half of those who reach a deep, stable molecular response can stop treatment.","subtypes":["Newly diagnosed chronic phase, low ELTS risk","Newly diagnosed chronic phase, high ELTS risk","Chronic phase resistant or intolerant to first tyrosine kinase inhibitor","Chronic phase with T315I mutation (ponatinib, asciminib, olverembatinib)","Chronic phase in sustained deep molecular response (treatment-free remission candidate)","Chronic phase in pregnancy or in children"],"biomarkers":["BCR::ABL1 transcript by quantitative PCR on the International Scale","ELTS and Sokal risk scores","Karyotype and additional chromosomal abnormalities","BCR::ABL1 kinase domain mutations (T315I and others)","Depth of molecular response (MR4, MR4.5) for stopping","Cardiovascular risk profile before nilotinib or ponatinib"],"standardOfCare":[{"setting":"Newly diagnosed chronic phase","approach":"Imatinib 400 mg daily, a second-generation inhibitor (dasatinib, nilotinib, bosutinib) chosen by comorbidity and treatment goal, or asciminib (ASC4FIRST); PCR at 3, 6 and 12 months against ELN milestones.","refs":["imatinib","dasatinib","nilotinib","bosutinib","asciminib","nct04971226","nct05456191","molecular-response"],"guideline":{"version":"NCCN Guidelines: Chronic Myeloid Leukemia","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1427"}},{"setting":"Resistance or intolerance","approach":"Switch inhibitor guided by kinase domain mutation testing; ponatinib or asciminib for T315I; radotinib or olverembatinib where approved; allogeneic transplant after failure of two or more inhibitors.","refs":["ponatinib","asciminib","olverembatinib","radotinib","nct06423911","nct03459534","nct05384587","allogeneic-hsct"],"guideline":{"version":"NCCN Guidelines: Chronic Myeloid Leukemia","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1427"}},{"setting":"Sustained deep molecular response","approach":"Attempt treatment-free remission after at least three to five years of therapy and two years of MR4 or better, with monthly PCR for six months; restart on loss of major molecular response.","refs":["mrd","molecular-response","mrd-kinetics-models"],"guideline":{"version":"NCCN Guidelines: Chronic Myeloid Leukemia","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1427"}}],"stateOfArt":["Life expectancy in chronic-phase CML on tyrosine kinase inhibitors approaches that of the general population.","Asciminib gives the highest first-line molecular response rates yet reported with the fewest side effects.","About half of patients who reach a deep, stable response can stop treatment and stay in remission."],"history":[{"year":1960,"title":"Nowell and Hungerford describe the Philadelphia chromosome","refs":["philadelphia-chromosome"]},{"year":1990,"title":"BCR-ABL shown to cause leukaemia in mice","refs":["bcr-abl"]},{"year":1998,"title":"Imatinib enters the clinic: remissions in nearly every chronic-phase patient","refs":["imatinib"]},{"year":2003,"title":"IRIS: imatinib beats interferon plus cytarabine","refs":["imatinib"]},{"year":2006,"title":"Dasatinib and nilotinib approved for resistant disease, later first line","refs":["dasatinib","nilotinib"]},{"year":2012,"title":"Ponatinib approved, covering T315I","refs":["ponatinib"]},{"year":2018,"title":"EURO-SKI: half of patients stopping treatment stay in remission","refs":["molecular-response"]},{"year":2024,"title":"ASC4FIRST: asciminib approved for newly diagnosed chronic phase","refs":["asciminib","nct04971226"]}],"pipeline":["asciminib","olverembatinib","radotinib","nct04971226","nct05456191","nct06423911","nct06163430"],"openProblems":["The leukaemic stem cells that survive kinase inhibition and cause relapse after stopping.","Cardiovascular toxicity over decades on second- and third-generation inhibitors.","Access to any tyrosine kinase inhibitor, and to PCR monitoring, in low-income countries."],"parent":"cml"},"route":"/cancers/cml-chronic-phase/","neighbours":{"technology":[{"id":"allogeneic-hsct","kind":"technology","name":"Allogeneic stem cell transplantation","route":"/technologies/allogeneic-hsct/"},{"id":"cytogenetics-fish","kind":"technology","name":"Cytogenetics and FISH","route":"/technologies/cytogenetics-fish/"},{"id":"mrd-kinetics-models","kind":"technology","name":"Residual disease kinetics (BCR-ABL halving and ctDNA slopes)","route":"/technologies/mrd-kinetics-models/"},{"id":"kinase-inhibitors","kind":"technology","name":"Small-molecule kinase inhibitors","route":"/technologies/kinase-inhibitors/"}],"target":[{"id":"bcr-abl","kind":"target","name":"BCR::ABL1 (Philadelphia chromosome)","route":"/targets/bcr-abl/"}],"pathway":[{"id":"bcr-abl1-signalling","kind":"pathway","name":"BCR::ABL1 (Philadelphia chromosome)","route":"/pathways/bcr-abl1-signalling/"},{"id":"cml-signalling","kind":"pathway","name":"Chronic myeloid leukaemia (KEGG map)","route":"/pathways/cml-signalling/"}],"term":[{"id":"mrd","kind":"term","name":"Minimal / molecular residual disease (MRD)","route":"/terms/mrd/"},{"id":"molecular-response","kind":"term","name":"Molecular response (MMR, MR4, treatment-free remission)","route":"/terms/molecular-response/"},{"id":"philadelphia-chromosome","kind":"term","name":"Philadelphia chromosome (Ph+, BCR::ABL1)","route":"/terms/philadelphia-chromosome/"},{"id":"tki-term","kind":"term","name":"Tyrosine kinase inhibitor (TKI)","route":"/terms/tki-term/"}],"paper":[{"id":"paper-druker-imatinib-phase1-nejm-2001","kind":"paper","name":"First imatinib trial: a pill that switched off the enzyme driving chronic myeloid leukaemia","route":"/key-papers/paper-druker-imatinib-phase1-nejm-2001/"},{"id":"paper-iris-imatinib-nejm-2003","kind":"paper","name":"IRIS: imatinib versus interferon plus cytarabine as first treatment for chronic myeloid leukaemia","route":"/key-papers/paper-iris-imatinib-nejm-2003/"}],"drug":[{"id":"asciminib","kind":"drug","name":"Asciminib","route":"/drugs/asciminib/"},{"id":"bosutinib","kind":"drug","name":"Bosutinib","route":"/drugs/bosutinib/"},{"id":"dasatinib","kind":"drug","name":"Dasatinib","route":"/drugs/dasatinib/"},{"id":"imatinib","kind":"drug","name":"Imatinib","route":"/drugs/imatinib/"},{"id":"nilotinib","kind":"drug","name":"Nilotinib","route":"/drugs/nilotinib/"},{"id":"olverembatinib","kind":"drug","name":"Olverembatinib","route":"/drugs/olverembatinib/"},{"id":"ponatinib","kind":"drug","name":"Ponatinib","route":"/drugs/ponatinib/"},{"id":"radotinib","kind":"drug","name":"Radotinib","route":"/drugs/radotinib/"}],"trial":[{"id":"nct06163430","kind":"trial","name":"A Phase 1/2 Clinical Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Efficacy of TERN-701 in Participants With Chronic Myeloid Leukemia (CARDINAL)","route":"/trials/nct06163430/"},{"id":"nct03459534","kind":"trial","name":"A Phase 3 Study for the Efficacy and Safety of Radotinib in CP-CML Patients With Failure or Intolerance to Previous TKIs","route":"/trials/nct03459534/"},{"id":"nct04971226","kind":"trial","name":"A Study of Oral Asciminib Versus Other TKIs in Adult Patients With Newly Diagnosed Ph+ CML-CP","route":"/trials/nct04971226/"},{"id":"nct05456191","kind":"trial","name":"A Study to Investigate Tolerability and Efficacy of Asciminib (Oral) Versus Nilotinib (Oral) in Adult Participants (≥18 Years of Age) With Newly Diagnosed Philadelphia Chromosome Positive Chronic Myelogenous Leukemia in Chronic Phase (Ph+ CML-CP)","route":"/trials/nct05456191/"},{"id":"nct05384587","kind":"trial","name":"Asciminib Monotherapy, With Dose Escalation, for 2nd and 1st Line Chronic Myelogenous Leukemia","route":"/trials/nct05384587/"},{"id":"nct06423911","kind":"trial","name":"Study of Olverembatinib (HQP1351) in Patients With CML-CP","route":"/trials/nct06423911/"}],"cancer":[{"id":"cml","kind":"cancer","name":"Chronic myeloid leukaemia (CML)","route":"/cancers/cml/"},{"id":"all-paediatric-ph-positive","kind":"cancer","name":"Philadelphia chromosome-positive acute lymphoblastic leukaemia in children (Ph-positive ALL)","route":"/cancers/all-paediatric-ph-positive/"}]}}