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chronic myeloid leukemia (CML, granulocytic leukemia)

Etiology: - acquired defect of clonal origin Epidemiology: - most common myeloproliferative disease - 15-20% of all leukemias - 1-1.5 cases/100,000 population worldwide - median age at diagnosis 5th - 6th decades Pathology: 1) bone marrow shows hyperplasia 2) myelofibrosis in 10-40% of patients Disease stages/progression: - chronic phase (CML-CP) - leukocytosis mainly from neutrophils in various stages of differentiation - blasts < 10%, usually < 2% - absolute basophilia invariably present - some have eosinophilia - hypercellular bone marrow - accelerated phase - 10-19% myeloblasts - blast phase - myeloblasts > 20% [2] Genetics: - Philadelphia chromosome t(9;22)(q34.1;q11.2) BCR/ABL - BCR-ABL fusion gene may inhibit Bcl-xL deamidation - chromosomal translocations involving MSI2, t(7;17)(p15;q23) with HOXA9 & t(7;17)(q32-34;q23) may contribute to disease progression in chronic myeloid leukemia - chromosomal translocation t(4;11)(q21;q23) involving SEPT11 with MLL/HRX may be a cause of chronic myeloid leukemia - chromosomal translocation t(8;9)(p22;p24) involving JAK2 with PCM1 - CSF3R mutation (case report [18]) - other implicated genes: LHX1, AXL Clinical manifestations: - may be asymptomatic - malaise - fatigue - myalgia (case report [18]) - dyspnea - anorexia, early satiety - fever - night sweats - weight loss - abdominal discomfort, abdominal fullness - easy bruising, scattered ecchymoses - bleeding - gout - priapism - hypermetabolism - leukocytosis - splenomegaly in 85% - phases: a) chronic phase (years, the chronic course of the disease) b) accelerated phase (< 1 year) c) blast phase, AML (median survival 6-9 months) Laboratory: 1) complete blood count (CBC) with peripheral blood smear a) WBC generally > 100,000/uL b) granulocytes in all phases of maturation c) thrombocytosis (large & bizarre forms) d) basophilia may be present e) eosinophilia may be present f) anemia if present is mild 2) bone marrow biopsy a) hypercellular bone marrow b) marked myeloid proliferation 3) buffy coat for chronic myelogenous leukemia genotyping - BCR-ABL1 fusion protein in blood/tissue (bcr/abl mRNA by RT-PCR) [2] 4) serum leukocyte alkaline phosphatase is low or absent 5) serum vitamin B12 is increased 6) false positive increase in serum acid phosphatase 7) cytogenetics: a) peripheral blood & bone marrow b) Philadelphia chromosome t(9;22) >95% [9] 8) see ARUP consult [10] 9) flow cytometry not useful Complications: 1) blast transformation 2) leukostasis Differential diagnosis: - leukemoid reaction may be difficult to distinguish from CML in an acutely ill patient [2] Management: 1) treatment with bcr-abl inhibitor all patients at the time of diagnosis even in asymptomatic patients a) imatinib (Gleevec,formerly STI571) [2,3,4,5] - an inhibitor of bcl-abl - may be best single agent - better than interferon alfa plus cytarabine [5] - eradicates Philadelphia chromosome-positive cells; 70% cytogenetic remission during during phase [2] - 89% 5 year survival [2] - all tyrosine kinase inhibitors can prolong QT interval [2] - periodic ECG monitoring [2] b) dasatinib & nilotinib - FDA-approved for imatinib-resistant CML - may be used 1st line instead of imatinib [2] - patients in remission may be eligible for discontinuation of nilotinib after 3 years of therapy [19] c) ponatinib (Iclusig), marketing suspended Dec 2013 d) bosutinib e) the PPAR gamma agonist pioglitazone causes fewer cancer stem cells to remain dormant, thereby rendering them more vulnerable to chemotherapy with imatinib [17] f) benefit of treatment is that a uniformly fatal disease has been changed into a chronic illness [2] g) imatinib + tigecycline may inhibit CML stem cells [20] - CML stem cells insensitive to tyrosine kinase inhibitors but suppressed by inhibitor of oxidative phosphorylation 2) earlier therapy had not appreciably prolonged survival a) hydroxyurea - treatment of choice for: - high blast counts - leukostasis - patients who are candidates for bone marrow transplant - response rates of 85-90% - maintenance therapy is necessary - safe for use with concurrent thrombocytopenia - fewer side effects than busulfan b) busulfan is inferior to hydroxyurea c) interferon alfa 2a or interferon alfa 2b - suppresses the Philadelphia chromosome - may be superior to hydroxyurea (may prolong survival) - 5-10 million units 3-7 times/week - hematologic & cytogenetic response occurs within 3-12 months - addition of cytarabine may be of additional benefit d) fludarabine for CML not responding to other agents 3) allogeneic stem cell transplantation a) reserved for patients with accelerated or blast phase or for patients resistant to bcr-abl inhibitors b) high-dose irradiation followed by transplantation of allogeneic bone marrow from HLA-compatible sibling is the only curative regimen c) studies using HLA-matched unrelated donors are ongoing d) hematologic relapses occur in 10-20% of patients e) long-term disease-free survival is 40-60% 4) anagrelide for thrombocytosis 5) platelet transfusions for thrombocytopenia a) platelet count < 10,000/uL b) bleeding [2] 6) splenectomy a) patients with advanced disease who no longer respond to imatinib b) painful splenomegaly [2] c) thrombocytopenia with high platelet transfusion requirement Notes: - all tyrosine kinase inhibitors for treatment of CML cost ~$100,000/year - multidisciplinary support including social work may be necessary to assist patients in obtaining treatment [2]

Interactions

disease interactions

Related

buffy coat chromosomal translocation t9q34.1:22q11 (Philadelphia chromosome; bcr/abl) chronic myelogenous leukemia genotyping chronic myeloid leukemia (CML) blast crisis leukocyte alkaline phosphatase (LAP)

Specific

Philadelphia chromosome-positive chronic myeloid leukemia (CML)

General

chronic leukemia chronic myeloproliferative disorder myeloid leukemia

References

  1. Mayo Internal Medicine Board Review, 1998-99, Prakash UBS (ed) Lippincott-Raven, Philadelphia, 1998, pg 432-434
  2. Medical Knowledge Self Assessment Program (MKSAP) 11, 14, 15, 16, 17, 19. American College of Physicians, Philadelphia 1998, 2006, 2009, 2012, 2015, 2022 - Medical Knowledge Self Assessment Program (MKSAP) 19 Board Basics. An Enhancement to MKSAP19. American College of Physicians, Philadelphia 2022
  3. Journal Watch 21(9):72, 2001 Druker BJ et al, Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 344:1031, 2001 PMID: 11287972 - Druker BJ et al, Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med 344:1038, 2001 PMID: 11287973 - Goldman JM & Melo JV Targeting the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 344:1084, 2001 PMID: 11287980
  4. Journal Watch 22(7):53, 2002 Kantarjian H et al, Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N Engl J Med 346:645, 2002 PMID: 11870241 - Savage DG & Antman KH, Imatinib mesylate--a new oral targeted therapy. N Engl J Med 346:683, 2002 PMID: 11870247
  5. Journal Watch 23(8):63-64, 2003 O'Brien SG et al, Imatinib compared with interferon and low-dose cytarabine for newly diagnoses chronic-phase chronic myeloid leukemia N Engl J Med 348:994, 2003 PMID: 12637609 Pegg K & Mackinnon S, Imatinib mesylate -- the new standard for treatment of chronic myeloid leukemia N Engl J Med 348:1048, 2003 PMID: 12637616
  6. Druker BJ et al, Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med 2006, 355:3408 PMID: 17151364 - Strebhardt K & Ullrich A. Another look at imatinib mesylate. N Engl J Med 2006, 355:2481 PMID: 17151370
  7. Geriatric Review Syllabus, 7th edition Parada JT et al (eds) American Geriatrics Society, 2010 - Geriatric Review Syllabus, 8th edition (GRS8) Durso SC and Sullivan GN (eds) American Geriatrics Society, 2013
  8. WHO Classification of Tumours. Tumors of Haematopoietic and Lymphoid Tissues. Jaffe et al. IARC Press 2001
  9. Geriatrics at your Fingertips, 13th edition, 2011 Reuben DB et al (eds) American Geriatric Society
  10. ARUP Consult: Chronic Myelogenous Leukemia - CML The Physician's Guide to Laboratory Test Selection & Interpretation https://www.arupconsult.com/content/chronic-myelogenous-leukemia
  11. FDA News Release: Dec. 14, 2012 FDA approves Iclusig to treat two rare types of leukemia http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm332252.htm - Cortes JE et al. Ponatinib in refractory Philadelphia chromosome-positive leukemias. N Engl J Med 2012 Nov 29; 367:2075. PMID: 23190221
  12. Le Gouill S, Talmant P, Milpied N, Daviet A et al Fluorescence in situ hybridization on peripheral-blood specimens is a reliable method to evaluate cytogenetic response in chronic myeloid leukemia. J Clin Oncol. 2000 Apr;18(7):1533-8 PMID: 10735902
  13. Goldman JM. Initial treatment for patients with CML. Hematology Am Soc Hematol Educ Program. 2009:453-60. PMID: 20008231
  14. Marin D. Current status of imatinib as frontline therapy for chronic myeloid leukemia. Semin Hematol. 2010 Oct;47(4):312-8. PMID: 20875547
  15. Radich JP. The biology of chronic myelogenous leukemia progression: who, what, where, and why? Hematol Oncol Clin North Am. 2011 Oct;25(5):967-80, v. PMID: 22054729
  16. Kantarjian H, O'Brien S, Jabbour E et al Improved survival in chronic myeloid leukemia since the introduction of imatinib therapy: a single-institution historical experience. Blood. 2012 Mar 1;119(9):1981-7 PMID: 22228624
  17. Prost S et al. Erosion of the chronic myeloid leukaemia stem cell pool by PPAR-gamma agonists. Nature 2015 Sep 17; 525:380. PMID: 26331539 - Holyoake T and Vetrie D.Cancer: Repositioned to kill stem cells. Nature 2015 Sep 17; 525:328 PMID: 26331538
  18. Fathi AT, Graubert TA, Kulkarni NM et al Case 37-2016 - An 86-Year-Old Woman with Leukocytosis and Splenomegaly. N Engl J Med 2016; 375:2273-2282. December 8, 2016 PMID: 27959687 http://www.nejm.org/doi/full/10.1056/NEJMcpc1509539
  19. Nelson R FDA Updates Labeling for Nilotinib: Treatment Can Be Stopped. Medscape - Dec 22, 2017. https://www.medscape.com/viewarticle/890566
  20. O'Neil A. Evidence for New Method of Eradicating Residual CML Precursors. Targeting mitochondrial oxidative phosphorylation may help prevent CML relapse. MedPage Today. Jan 31, 2018 https://www.medpagetoday.com/reading-room/asco/hematologic-malignancies/70855
  21. Cortes J, Kantarjian H. How I treat newly diagnosed chronic phase CML. Blood. 2012 Aug 16;120(7):1390-7. Review. PMID: 22613793 Free PMC Article
  22. Jabbour E, Kantarjian H. Chronic myeloid leukemia: 2018 update on diagnosis, therapy and monitoring. Am J Hematol 2018 Mar; 93:442 PMID: 29411417 Free article
  23. Chronic Myelogenous Leukemia (PDQ): Treatment http://www.cancer.gov/cancertopics/pdq/treatment/CML/HealthProfessional