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TITLE = GLOBAL, REGIONAL, AND NATIONAL LIFE EXPECTANCY, ALL-CAUSE MORTALITY, AND CAUSE-SPECIFIC MORTALITY FOR 249 CAUSES OF DEATH, 1980-2015: A SYSTEMATIC ANALYSIS FOR THE GLOBAL BURDEN OF DISEASE STUDY 2015 VOLUME = 388 PAGES = 1459–1544 PMID = 27733281 DOI = 10.1016/S0140-6736(16)31012-1, }}Chronic myelogenous leukemia (CML), also known as chronic myeloid leukemia, is a cancer of the white blood cells. It is a form of leukemia characterized by the increased and unregulated growth of myeloid cells in the bone marrow and the accumulation of these cells in the blood. CML is a clonal bone marrow stem cell disorder in which a proliferation of mature granulocytes (neutrophils, eosinophils and basophils) and their precursors is found; characteristic increase in basophils is clinically relevant. It is a type of myeloproliferative neoplasm associated with a characteristic chromosomal translocation called the Philadelphia chromosome.CML is largely treated with targeted drugs called tyrosine-kinase inhibitors (TKIs) which have led to dramatically improved long-term survival rates since 2001. These drugs have revolutionized treatment of this disease and allow most patients to have a good quality of life when compared to the former chemotherapy drugs. In Western countries, CML accounts for 15–25% of all adult leukemias and 14% of leukemias overall (including the pediatric population, where CML is less common).{{TOC limit|3}}

Signs and symptoms

The way CML presents depends on the stage of the disease at diagnosis as it has been known to skip stages in some cases.Most patients (~90%) are diagnosed during the chronic stage which is most often asymptomatic. In these cases, it may be diagnosed incidentally with an elevated white blood cell count on a routine laboratory test. It can also present with symptoms indicative of hepatosplenomegaly and the resulting left upper quadrant pain this causes. The enlarged spleen may put pressure on the stomach causing a loss of appetite and resulting weight loss. It may also present with mild fever and night sweats due to an elevated basal level of metabolism.WEB, Chronic Myelogenous Leukemia Clinical Presentation, Medscape Reference, WebMD, 27 December 2013, 3 January 2014,emedicine.medscape.com/article/199425-clinical#showall, Besa EC, Buehler B, Markman M, Sacher RA, Krishnan K, Some ( 10 × 109/L), unresponsive to therapy

• Persistent or increasing splenomegaly, unresponsive to therapy
• Persistent thrombocytosis (> 1000 × 109/L), unresponsive to therapy
• Persistent thrombocytopenia (

< 100 × 109/L), unrelated to therapy

• ≥ 20% basophils in the peripheral blood
• 10–19% blasts in the peripheral blood and/or bone marrow
• Additional clonal chromosomal abnormalities in Philadelphia (Ph) chromosome-positive (Ph+) cells at diagnosis, including so-called major route abnormalities (a second Ph chromosome, trisomy 8, isochromosome 17q, trisomy 19), complex karyotype, and abnormalities of 3q26.2
• Any new clonal chromosomal abnormality in Ph+ cells that occurs during therapy
• Provisional response-to-TKI criteria
  • Haematological resistance (or failure to achieve a complete haematological response d) to the first TKI
  • Any haematological, cytogenetic, or molecular indications of resistance to two sequential TKIs
  • Occurrence of two or more mutations in the BCR-ABL1 fusion gene during TKI therapy

The patient is considered to be in the accelerated phase if any of the above are present. The accelerated phase is significant because it signals that the disease is progressing and transformation to blast crisis is imminent. Drug treatment often becomes less effective in the advanced stages.

Blast crisis

Blast crisis is the final phase in the evolution of CML, and behaves like an acute leukemia, with rapid progression and short survival. Blast crisis is diagnosed if any of the following are present in a patient with CML:JOURNAL, Karbasian Esfahani M, Morris EL, Dutcher JP, Wiernik PH, 21092684, Blastic phase of chronic myelogenous leukemia, Current Treatment Options in Oncology, 7, 3, 189–99, May 2006, 16615875, 10.1007/s11864-006-0012-y,

• >20% blasts in the blood or bone marrow
• The presence of an extramedullary proliferation of blasts

Treatment

The only curative treatment for CML is a bone marrow transplant or an allogeneic stem cell transplant.WEB, Chronic Myelogenous Leukemia Treatment & Management, Medscape Reference, WebMD, 27 December 2013, 4 January 2014,emedicine.medscape.com/article/199425-treatment#showall, Besa EC, Buehler B, Markman M, Sacher RA, Krishnan K, Other than this there are four major mainstays of treatment in CML: treatment with tyrosine kinase inhibitors, myelosuppressive or leukapheresis therapy (to counteract the leukocytosis during early treatment), splenectomy and interferon alfa-2b treatment. Due to the high median age of patients with CML it is relatively rare for CML to be seen in pregnant women, despite this, however, chronic myelogenous leukemia can be treated with relative safety at any time during pregnancy with the cytokine interferon-alpha.JOURNAL, Shapira T, Pereg D, Lishner M, How I treat acute and chronic leukemia in pregnancy, Blood Reviews, 22, 5, 247–59, September 2008, 18472198, 10.1016/j.blre.2008.03.006,

Chronic phase

In the past, antimetabolites (e.g., cytarabine, hydroxyurea), alkylating agents, interferon alfa 2b, and steroids were used as treatments of CML in the chronic phase, but since the 2000s have been replaced by Bcr-Abl tyrosine-kinase inhibitorsBOOK, Kufe DW, Pollack RE, Weichselbaum RR, 2003, Holland-Frei Cancer Medicine, Tyrosine Kinase Inhibitors: Targeting Considerations, NCBI bookshelf book, 6th, B.C. Decker, Hamilton, Ontario, 978-1-55009-213-4,www.ncbi.nlm.nih.gov/books/NBK13641/, October 27, 2012, etal, registration,archive.org/details/cancermedicine60002unse, drugs that specifically target BCR-ABL, the constitutively activated tyrosine kinase fusion protein caused by the Philadelphia chromosome translocation. Despite the move to replacing cytotoxic antineoplastics (standard anticancer drugs) with tyrosine kinase inhibitors sometimes hydroxyurea is still used to counteract the high leukocyte counts encountered during treatment with tyrosine kinase inhibitors like imatinib; in these situations it may be the preferred myelosuppressive agent due to its relative lack of leukemogenic effects and hence the relative lack of potential for secondary haematologic malignancies to result from treatment.WEB, Chronic Myelogenous Leukemia, Medscape Reference, WebMD, 27 December 2013, 3 January 2014,emedicine.medscape.com/article/199425-medication#showall, Besa EC, Buehler B, Markman M, Sacher RA, Krishnan K, IRIS, an international study that compared interferon/cytarabine combination and the first of these new drugs imatinib, with long-term follow up, demonstrated the clear superiority of tyrosine-kinase-targeted inhibition over existing treatments.JOURNAL, DeAngelo DJ, Ritz J, 1761631, Imatinib therapy for patients with chronic myelogenous leukemia: are patients living longer?, Clinical Cancer Research, 10, 1 Pt 1, 1–3, January 2004, 14734443, 10.1158/1078-0432.CCR-1218-3,clincancerres.aacrjournals.org/content/10/1/1.full.pdf, free,

Imatinib

The first of this new class of drugs was imatinib mesylate (marketed as Gleevec or Glivec), approved by the US Food and Drug Administration (FDA) in 2001. Imatinib was found to inhibit the progression of CML in the majority of patients (65–75%) sufficiently to achieve regrowth of their normal bone marrow stem cell population (a cytogenetic response) with stable proportions of maturing white blood cells. Because some leukemic cells (as evaluated by RT-PCR) persist in nearly all patients, the treatment has to be continued indefinitely. Since the advent of imatinib, CML has become the first cancer in which a standard medical treatment may give to the patient a normal life expectancy.JOURNAL, Gambacorti-Passerini C, Antolini L, Mahon FX, Guilhot F, Deininger M, Fava C, Nagler A, Della Casa CM, Morra E, Abruzzese E, D’Emilio A, Stagno F, le Coutre P, Hurtado-Monroy R, Santini V, Martino B, Pane F, Piccin A, Giraldo P, Assouline S, Durosinmi MA, Leeksma O, Pogliani EM, Puttini M, Jang E, Reiffers J, Valsecchi MG, Kim DW, 6, Multicenter independent assessment of outcomes in chronic myeloid leukemia patients treated with imatinib, Journal of the National Cancer Institute, 103, 7, 553–61, April 2011, 21422402, 10.1093/jnci/djr060, free,

Dasatinib, nilotinib, radotinib, bosutinib, and asciminib

To overcome imatinib resistance and to increase responsiveness to TK inhibitors, four novel agents were later developed. The first, dasatinib, blocks several further oncogenic proteins, in addition to more potent inhibition of the BCR-ABL protein, and was approved in 2007, by the U.S. Food and Drug Administration (FDA) to treat CML in people who were either resistant to or intolerant of imatinib. A second TK inhibitor, nilotinib, was approved by the FDA for the same indication. In 2010, nilotinib and dasatinib were also approved for first-line therapy, making three drugs in this class available for treatment of newly diagnosed CML. In 2012, radotinib joined the class of novel agents in the inhibition of the BCR-ABL protein and was approved in South Korea for people resistant to or intolerant of imatinib. Bosutinib received US FDA and EU European Medicines Agency approval on 4 September 2012, and 27 March 2013, respectively for the treatment of adults with Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML) with resistance, or intolerance to prior therapy.{{cn|date=April 2022}}Asciminib (Scemblix) was approved for medical use in the United States in October 2021.PRESS RELEASE, FDA approves Novartis Scemblix (asciminib), with novel mechanism of action for the treatment of chronic myeloid leukemia, Novartis,www.novartis.com/news/media-releases/fda-approves-novartis-scemblix-asciminib-novel-mechanism-action-treatment-chronic-myeloid-leukemia, 29 October 2021,

Treatment-resistant CML

While capable of producing significantly improved responses compared with the action of imatinib, neither dasatinib nor nilotinib could overcome drug resistance caused by one particular mutation found to occur in the structure of BCR-ABL1 known as the T315I mutation (in other words, where the 315th amino acid is mutated from a threonine residue to an isoleucine residue).{{cn|date=April 2022}} Two approaches were developed to the treatment of CML as a result:In 2007, Chemgenex released results of an open-label Phase 2/3 study (CGX-635-CML-202) that investigated the use of a non BCR-ABL targeted agent omacetaxine, administered subcutaneously (under the skin) in patients who had failed with imatinib and exhibited T315I kinase domain mutation.JOURNAL, Jabbour E, Cortes JE, Giles FJ, O’Brien S, Kantarjian HM, Current and emerging treatment options in chronic myeloid leukemia, Cancer, 109, 11, 2171–81, June 2007, 17431887, 10.1002/cncr.22661, 10.1.1.605.7683, 46509746, JOURNAL, Kimura S, Ashihara E, Maekawa T, New tyrosine kinase inhibitors in the treatment of chronic myeloid leukemia, Current Pharmaceutical Biotechnology, 7, 5, 371–9, October 2006, 17076652, 10.2174/138920106778521532, This is a study which is ongoing through 2014.WEB, Homoharringtonine (Omacetaxine Mepesuccinate) in Treating Patients With Chronic Myeloid Leukemia (CML) With the T315I BCR-ABL Gene Mutation, database record, ClinicalTrial.gov,clinicaltrials.gov/ct2/show/results/NCT00375219, October 27, 2012, In September 2012, the FDA approved omacetaxine for the treatment of CML in the case of resistance to other chemotherapeutic agents.PRESS RELEASE, October 26, 2012, FDA approves Synribo for chronic myelogenous leukemia, US Food and Drug Administration,www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm325895.htm, October 27, 2012, PRESS RELEASE, September 4, 2012, FDA approves new orphan drug for chronic myelogenous leukemia, US Food and Drug Administration,www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm318160.htm, October 27, 2012, Independently, ARIAD pharmaceuticals, adapting the chemical structures from first and second-generation TK inhibitors, arrived at a new pan-BCR-ABL1 inhibitor which showed (for the first time) efficacy against T315I, as well as all other known mutations of the oncoprotein. The drug, ponatinib, gained FDA approval in December 2012 for treatment of patients with resistant or intolerant CML. Just as with second-generation TK inhibitors, early approval is being sought to extend the use of ponatinib to newly diagnosed CML also.{{citation needed|date=December 2012}}

Vaccination

In 2005, encouraging but mixed results of vaccination were reported with the BCR/ABL1 p210 fusion protein in patients with stable disease, with GM-CSF as an adjuvant.JOURNAL, Bocchia M, Gentili S, Abruzzese E, Fanelli A, Iuliano F, Tabilio A, Amabile M, Forconi F, Gozzetti A, Raspadori D, Amadori S, Lauria F, 26816784, 6, Effect of a p210 multipeptide vaccine associated with imatinib or interferon in patients with chronic myeloid leukaemia and persistent residual disease: a multicentre observational trial, Lancet, 365, 9460, 657–62, 2005, 15721470, 10.1016/S0140-6736(05)17945-8,art.torvergata.it/bitstream/2108/41872/3/Bocchia.pdf, 2108/41872, free,

Prognosis

Before the advent of tyrosine kinase inhibitors, the median survival time for CML patients had been about 3–5 years from time of diagnosis.WEB, Chronic Myelogenous Leukemia, Medscape Reference, WebMD, 27 December 2013, 3 January 2014,emedicine.medscape.com/article/199425-overview#showall, Besa EC, Buehler B, Markman M, Sacher RA, Krishnan K, With the use of tyrosine kinase inhibitors, survival rates have improved dramatically. A 2006 follow-up of 553 patients using imatinib (Gleevec) found an overall survival rate of 89% after five years.JOURNAL, Druker BJ, Guilhot F, O’Brien SG, Gathmann I, Kantarjian H, Gattermann N, Deininger MW, Silver RT, Goldman JM, Stone RM, Cervantes F, Hochhaus A, Powell BL, Gabrilove JL, Rousselot P, Reiffers J, Cornelissen JJ, Hughes T, Agis H, Fischer T, Verhoef G, Shepherd J, Saglio G, Gratwohl A, Nielsen JL, Radich JP, Simonsson B, Taylor K, Baccarani M, So C, Letvak L, Larson RA, 6, Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia, The New England Journal of Medicine, 355, 23, 2408–17, December 2006, 17151364, 10.1056/NEJMoa062867, 21772851, free, A 2011 followup of 832 patients using imatinib who achieved a stable cytogenetic response found an overall survival rate of 95.2% after 8 years, which is similar to the rate in the general population. Fewer than 1% of patients died because of leukemia progression.

Epidemiology

United Kingdom

CML accounts for 8% of all leukaemias in the UK, and around 680 people were diagnosed with the disease in 2011.WEB, Chronic myeloid leukaemia (CML) statistics,www.cancerresearchuk.org/cancer-info/cancerstats/types/leukaemia-cml/, Cancer Research UK, 28 October 2014,

United States

The American Cancer Society estimates that in 2014, about 5,980 new cases of chronic myeloid leukemia were diagnosed, and about 810 people died of the disease. This means that a little over 10% of all newly diagnosed leukemia cases will be chronic myeloid leukemia. The average risk of a person getting this disease is 1 in 588. The disease is more common in men than women, and more common in whites than African-Americans. The average age at diagnosis is 64 years, and this disease is rarely seen in children.WEB, What are the key statistics about chronic myeloid leukemia?,www.cancer.org/cancer/leukemia-chronicmyeloidcml/detailedguide/leukemia-chronic-myeloid-myelogenous-key-statistics, cancer.org, American Cancer Society, 6 January 2015, 9 February 2015,www.cancer.org/cancer/leukemia-chronicmyeloidcml/detailedguide/leukemia-chronic-myeloid-myelogenous-key-statistics," title="web.archive.org/web/20150209010230www.cancer.org/cancer/leukemia-chronicmyeloidcml/detailedguide/leukemia-chronic-myeloid-myelogenous-key-statistics,">web.archive.org/web/20150209010230www.cancer.org/cancer/leukemia-chronicmyeloidcml/detailedguide/leukemia-chronic-myeloid-myelogenous-key-statistics, dead,

References

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External links

{{Medical resourcesC181}}205.1}}9875|3}}| OMIM = | OMIM_mult =| MedlinePlus = 000570| eMedicineSubj = med| eMedicineTopic = 371| DiseasesDB = 2659| MeshID = D015464}}

• Chronic Myelogenous Leukemia Treatment at the US National Cancer Institute
• Chronic Myelocytic Leukemia (CML) at Merck Manual of Diagnosis and Therapy Professional Edition

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