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A. Epidemiology [4] navigator

  1. Affects primarily >40 year olds (median age is ~53 years)
  2. Accounts for ~10% of all leukemias
  3. 1.5-2 cases per 100,000 population (~2:1 male to female)
  4. Overall, about 4300 new cases per year in USA
  5. Presentation
    1. Fatgiue
    2. Splenomegaly
    3. Weight loss
    4. Leukocytosis in peripheral blood
  6. Stages of Disease
    1. Chronic indolent phase - lasts 3-5 years
    2. Accelerated phase - nearly all patients progress from chronic to accelerated phase
    3. Blast phase
  7. Mean duration from chronic phase to blast crisis is ~4 years
    1. With hydroxyurea, time to death is slightly >3 years
    2. Interferon alpha (IFNa) prolongs mean survival >5 years
    3. Imatinib likely prolongs survival beyond IFNa effect

B. Pathophysiology [2]navigator

  1. Chromosomal Translocation in CML
    1. All cases of CML are associated with production of an oncogenic fusion protein [6]
    2. This fusion protein is produced by translocation of abelson and bcr genes
    3. Translocation event may occur in a CD34+ hemangioblastic progenitor cell [7]
    4. These progenitor cells give rise to bone marrow hematpoietic and endothelial cells
    5. Macroscopic translocations are present in >95% of cases, "Philadelphia Chromosome"
    6. The Philadelphia (Ph) chromosome is a translocation of chromsome (chr) 9 to chr 22
    7. Specifically, the karyotype Ph chr positive CML is t(9;22)(q34;q11)
  2. Molecular Biology of t(9;22)
    1. Abelson Tyrosine Kinase oncogene on chr 9 translocates to BCR on chr 22
    2. BCR (breakpoint cluster region) gene on chr 22 encodes a functional protein
    3. A fusion protein is produced, bcr-abl (increased tyrosine kinase activity)
    4. >99% of CML patients produce a 210K fusion protein
    5. <1% of CML (better prognosis) produce a 190K fusion protein
    6. 20% of adults (3% of children) with acute lymphocytic leukemia (ALL) have Ph chr
    7. These ALL patients produce either a 210K (35%) or a 190K (65%) fusion protein
  3. Activity of Mutant Bcr-Abl Tyrosine Kinase [1,3]
    1. Constitutively active tyrosine kinase activity
    2. Phosphorylates laqrge number of substrates including Ras protein and relatives
    3. Phosphorylates CRK-oncogene-like protein (CKRL)
    4. Direct transforming activity
    5. Blocks apoptotic cell death
  4. Other Chromosome Abnormalities [3]
    1. <5% of cases are Ph negative (>50% of these contain the bcr-abl fusion protein)
    2. BCR fusion to fibroblast growth factor receptor (FGFR1) in BCR-abl negative CML
    3. BCR fusion to platelet derived growth factor receptor (PDGFRA) in atypical CML
    4. TEL-ABL, TEL-JAK2, BCR-JAK2, and PDGFRB fusions all found in atypical CML
    5. Other less common fusions in atypical CML similar to those in CMML
    6. Chromosome 17 abnormalities are poor prognostically
    7. Blast phase and to some extent accelerated phase cells less dependent on bcr-abl
  5. Leukemic Stem Cells [8]
    1. Probably not pluripotent hematopoietic stem cells
    2. Granulocyte-macrophage (GM-) progenitors are likely the leukemic stem cells
    3. GM-progenitors show activated ß-catenin and have improved self-renewal properties
    4. Blockade of ß-catenin pathway with axin reduced GM-progenitor in vitro renewal potential
    5. The GM-progenitor pool is expanded in CML, even moreso in accelerated and blast phase
    6. Bcr-abl does not appear to play a major role in accelerated and blast phase

C. Diagnosisnavigator

  1. Presentation
    1. About 40% of patients are asymptomatic at diagnosis
    2. About 85% of patients with CML are diagnosed in the chronic phase
    3. Fatigue, anorexia, weight loss, diaphoresis, left upper quadrant abdominal pain
    4. Symptoms of hyperviscosity are uncommon
    5. Splenic Enlargement (may be >10cm below left costal margin)
  2. Often found as large number of immature cells on routine blood smear (asymptomatic)
    1. Myelogenous lineage are main cell type
    2. Bizarre appearing eosinophil- and basophil-like cells
  3. Peripheral Blood Findings
    1. White blood counts (WBC) usually >25K/µL (rarely >500K/µL)
    2. Platelet counts increased >350K/µL in ~40% of cases
    3. Basophilia
    4. Reduced leukocyte alkaline phosphatase activity
    5. Presence of all stages of differentiation of myelocyte lineage cells on blood smear
  4. Bone Marrow Findings
    1. Hypercellularity and reduced fat content
    2. Increase in myeloid to erythroid ratios
    3. Increased numbers of megakaryocytes
    4. Blasts and promyelocytes <10% of all cells
    5. If blasts and promyelocytes >10%, then diagnosis is likely acute myelocytic leukemia
  5. Genetic Analysis
    1. Presence of Ph chromosome with appropriate blood smear is diagnostic
    2. Varient Ph chr occur in <5% of cases; all of these make fusion (bcr-abl) protein
    3. Fluorescence in situ hybridization can be used instead of standard chromosome analysis
    4. Southern blot analysis and/or polymerase chain reactions can be used to define fusion

D. Staging [1,2,3]navigator

  1. Biphasic or Triphasic Disease
    1. Chronic Phase lasts (3-5 years)
    2. Accelerated Phases (<1 year lifespan)
    3. Blast Crisis (<6 months lifespan)
  2. Chronic Phase divided into Stages 1, 2 and 3 depending on number of symptoms/signs
  3. Poor Prognostic Factors for Chronic Phase Disease [2]
    1. Age >59 years
    2. Platelet count >700,000/µL
    3. Spleen >10cm below costal margin
    4. Blasts >3% in blood or marrow
    5. Basophils >7% in blood or >3% in marrow
    6. Risk group based on number of poor prognostic factors:
    7. Low (hazard ratio <0.8): 0-1 factors
    8. Intermediate (hazard ratio 0.8-1.2): 2 factors
    9. High (hazard ratio >1.2): 3 or more factors
    10. Presence of any characteristics for accelerated phase is high risk
    11. Hazard ratios help determine which kind of therapy to institute after diagnosis
  4. Accelerated Phase
    1. Peripheral blood blasts: >10-15%
    2. Peripheral blasts and promyelocytes >30%
    3. Peripheral basophilia >20% (and/or eosinophilia)
    4. Thrombocytopenia: platelet count <100K/µL
    5. Cytogenetic deterioration (increasing abnormalities)
    6. Spenomegaly
    7. Unexplained fever or bone pain
  5. Blast Crisis
    1. Increase to >30% in bone marrow blasts
    2. About 65% of cases transform to acute myelogenous leukemia (AML)
    3. About 35% of cases transform to acute lymphoblastic leukemia, usually B cell precursor
    4. The AML types depend on chromosomal abnormalities but are usually M2

E. Treatment [1,2] navigator

  1. Response Definitions
    1. Cytogenetic Response
    2. Major Cytogenetic Response - disappearance of Ph+ from >65% of metaphase marrow
    3. Complete Cytogenetic Response - complete reversion to Ph negative status
    4. Complete Hematologic Response - complete normalization of peripheral blood counts
    5. Complete cytogenetic responses predict long-term, relapse-free survival
  2. Treatment Overview [9]
    1. Imatinib (STI-571, Gleevec®) is first line therapy (early and accelerated phases) [10,11]
    2. Second generation kinase inhibitors for relapse after imatinib
    3. Hydroxyurea - cytoreduction therapy, superior to busulfan
    4. Interferon alpha (IFNa) - for early treatment of patients without HLA match
    5. Allogeneic Stem Cell Transplantation - for patients with good HLA match
    6. Accelerated Phase - similar to AML or high dose chemotherapy with marrow transplant
    7. Blast Phase - myeloid treated as AML, lymphoid treated as ALL in most centers
  3. Early Chronic Phase Treatment [1,2]
    1. Cytoreduction therapy often required in the chronic phase
    2. Imatinib 400mg/d provides best responses and is strongly recommended [11,12,13]
    3. Consider imatinib together with or instead of hydroxyurea to control cell counts [14]
    4. Imatinib is superior first line therapy versus high dose IFNa + low dose cytarabine [14]
    5. Dasatanib, another BCR-ABL inhibitor, is also active in first line [9]
    6. Major molecular responses (fall in bcr-abl transcripts by >3 logs) are good prognostics
    7. In complete cytogenic remissions, imatinib induced major molecular responses in 57% compared with 24% with IFNa+cytarabine [15]
    8. Imatinib responses are durable and translate to reductions in mortality [11]
    9. Allogeneic stem cell transplantation has best overall outcomes if HLA matched
  4. Imatinib (STI-571, Gleevec®) [9,11,12,13,15,16]
    1. Orally active, 400mg once daily, specific tyrosine kinase inhibitor
    2. Competitive inhibitor of bcr-abl, PDGF-R, and c-kit tyrosine kinases
    3. Standard first line therapy for CML
    4. At 5 years, 87% of of CML patients had complete cytogenetic responses, 7% showed progressive disease, ~90% survival; drug well tolerated [11]
    5. Well tolerated for treatment of chronic phase, IFNa resistant CML [13]
    6. Complete hematologic responses in 95% of patients at 400mg/d, ~90% at 5 years
    7. Major cytogenetic responses in 60% of patients at 400mg/d
    8. Major molecular responses in 57% of patients with complete cytogenic remissions [15]
    9. Consider switching off of imatinib if no cytogenetic response [17]
    10. Accelerated phase: 63% overall hematologic and 14% complete cytogenetic response
    11. Superior response rates and tolerability for first line treatment of chronic phase CML [14]
    12. Also shows ~16% responses in blast phase of CML and in bcr-abl+ ALL [18]
    13. Also recommended for relapse after stem cell transplantation
    14. Response in Ph+ (Bcr-Abl+) ALL is ~60% with durability usually <16 weeks [18,20]
    15. Nausea (55%), vomiting (~30%), edema (~55%), diarrhea (~35%), muscle cramps, rash
    16. Edema has been problematic, with pleural effusion, ascities, pulmonary edema in 5%
    17. Neutropenia and thrombocytopenia common
    18. About 5% of patients have increases in hepatic transaminase levels; discontinued in 0.5%
    19. Active in chronic myeloproliferative diseases with rearranged PDGF-Rß [21]
  5. Imatinib Resistance [1,25]
    1. ~7% of patients develop progressive, imatinib-resistant disease after 5 years
    2. BCR-ABL amplification and/or point mutations play key role
    3. Point mutations in the ATP binding domain or activation loop of Bcr-Abl protein lead to resistance [19]
    4. Kinases other than BCR-ABL may be involved in later stage disease
    5. Non-kinase related mechanisms may also play a role in imatinib resistance f Second generation kinase inhibitors may be effective (see below)
  6. Dasatinib (Sprycel®) [5,22,25]
    1. Orally active ABL kinase inhibitor which binds to active and inactive forms of ABL
    2. Also inhibits Sarc family kinases including Lyn and Hck and ephrin receptor kinases
    3. Activity against many imatinib-resistant CML cell lines
    4. Complete hematologic remissions in 37 of 40 patients with imatinib-resistant chronic CML
    5. Major hematologic responses in 31/44 accelerated or blast phase imatinib-resistant CML
    6. Myelosuppression (neutropenia and thrombocytopenia) was common (more than imatinib)
    7. Approved in imatinib-resistant CML and Ph+ ALL [5]
    8. Very good efficacy in front line therapy [9]
  7. Nilotinib (Tasigna®) [9,23,25,26]
    1. Orally active competitive inhibitor of BCR-ABL (binds in ATP site)
    2. Approved for CML for patients resistant to or intolerant of imatinib
    3. Active in majority of imatinib-resistant CML cell lines
    4. For 33 blastic-phase CML patients, hematologic response in 13, cytogenic response in 9
    5. Of 46 accclerated phase CML patients, 33 had hematologic and 22 cytogenetic responses
    6. Myelosuppression, rash, and transient indirect hyperbilirubinemia were main side effects
    7. Most patients intolerant of imatinib appear to tolerate nilotinib
    8. Fluid retention is only rare with nilotinib; QT prolongation does occur and should be watched
  8. Interferon alpha (IFNa) [1]
    1. Improves overall survival but is considerably inferior to imatinib
    2. Cytogenetic (<35% Ph+ Cells) and/or hemotologic response to IFNa usually means prolonged survival
    3. IFNa is more effective at high (versus low) doses and may be effective even after BMT
    4. Interferon alpha IFNa may also be used in patients who cannot undergo BMT
    5. IFNa + cytarabine gives more responses than IFNa alone, but is not as well tolerated
    6. IFNa side effects include flu-like symptoms, gastrointestinal effects, depression
    7. IFNa is cost effective if quality of life issues due to side effects are acceptable
    8. Longer acting PEG-interferons under investigation (see below)
    9. IFNa 5MU/m2 per day + low dose cytarabine shows minimal activity after imatinib relapse [14]
  9. Bone Marrow (Stem Cell) Transplantation (BMT)
    1. Allogeneic BMT is preferred in persons <51 years old with HLA matched related donor
    2. Only about 20% of patients with CML are candidates for BMT
    3. BMT should be evaluated at time of diagnosis and performed early in course
    4. BMT should NOT be delayed in eligable patients as it is curative
    5. Marrow cells from HLA-matched sibling or unrelated donor
    6. Outcome with matched sibling donor similar to matched unrelated donor [24]
    7. Main problem with graft versus host disease (GVHD) in unmatched donors
    8. Donor T cells cause GVHD, but there appears to be a benefit from graft versus leukemia
    9. Autologous marrow transplants have increased levels of relapse (less GVHD)
    10. Increasing dose of infused, T-cell depeleted donor cells increases engraftment
    11. Mismatches at HLA-A and HLA-C, but not HLA-D associated with GVHD
  10. Unrelated Donor BMT [24]
    1. Possible graft versus leukemia effect
    2. HLA matched at 6 loci if possible
    3. GVHD increased due to minor histocompatibility antigens with unrelated donor
    4. Clear benefit to early transplant with related donors
    5. Model shows ~5 year survival benefit of early (within 1 year) unrelated transplant
    6. Early versus late transplantation with unrelated donor is beneficial
    7. Overall 5 year survival with unrelated donor is 53-58%
    8. Similar outcomes observed between matched unrelated and sibling donors
    9. Mismatch at HAL-DRB1, age >50, and high body-mass index have poor prognosis in BMT
  11. Childhood CML
    1. Rare disease with most patients Ph negative
    2. Suppression of normal progenitor cells may be due to TNF alpha
    3. Chemotherapy typically induces remission, but relapses are common
    4. Allogeneic Bone Marrow Transplantation (BMT) is most often recommended
    5. Isotretinoin 100mg/sq meter per day po is effective in >50% of patients
    6. Ph+ disease should prompt consideration of imatinib [10]
  12. Other New Agents [2]
    1. Homoharringotonine - plant alkaloid; may be used in IFNa resistant patients
    2. 5-Aza-2'-Deoxycytidine (decitabine) - hypomethylating cytidine analogue, blastic phase
    3. Polyethylene glycol interferon (PEG-IFN) - reduced side effects, increased efficacy
    4. Antisense oligonucleotides targeted to BCR-ABL
    5. Adoptive immunotherapy - T lymphocytes targeted to p210(bcr-abl) protein
  13. With imatinib, 5 year survival is now ~90% [11]

References navigator

  1. Hehlmann R, Hachhaus A, Baccarani M. 2007. Lancet. 370(9584):342 abstract
  2. Kurzrock R, Kantarjian HM, Druker BJ, Talpaz M. 2003. Ann Intern Med. 138(10):819 abstract
  3. Goldman JM and Melo JV. 2003. NEJM. 349(15):1451 abstract
  4. Mintzer D and Bagg A. 2001. Am J Med. 2001. 111(6):480 abstract
  5. Dasatinib. 2007. Med Let. 49(1252):6
  6. Stewart AK and Schuh AC. 2000. Lancet. 355(9213):1447 abstract
  7. Gunsillius E, Duba HC, Petzer AL, et al. 2000. Lancet. 355(9216):1688 abstract
  8. Jamieson CHM, Ailles LE, Dylla SJ, et al. 2004. NEJM. 351(7):657
  9. Schiffer CA. 2007. NEJM. 357(3):258 abstract
  10. Imatinib for CML. 2001. Med Let. 43(1106):49 abstract
  11. Druker BJ, Guilhot F, O'Brien SG, et al. 2006. NEJM. 355(23):2408 abstract
  12. Druker BJ, Talpaz M, Resta DJ, et al. 2001. NEJM. 344(14):1031 abstract
  13. Kantargjian H, Sawyers C, Hochhaus A, et al. 2002. NEJM. 346(9):645 abstract
  14. O'Brien SG, Guilhot F, Larson RA, et al. 2003. NEJM. 348(11):994 abstract
  15. Hughes TP, Kaeda J, Branford S, et al. 2003. NEJM. 349(15):1423 abstract
  16. Krause DS and Van Etten RA. 2005. NEJM. 353(2):172 abstract
  17. Marin D, Marktel S, Szydlo R, et al. 2003. Lancet. 362(9384):617 abstract
  18. Druker BJ, Sawyers CL, Kantarjian H, et al. 2001. NEJM. 344(14):1038 abstract
  19. Von Bubnoff N, Schneller F, Peschel C, Duyster J. 2002. Lancet. 359(9305):487 abstract
  20. Hofmann WK, de Vos S, Elashoff D, et al. 2002. Lancet. 359(9305):481 abstract
  21. Apperley JF, Gardembas M, Melo JV, et al. 2002. NEJM. 347(7):481 abstract
  22. Talpaz M, Shah NP, Kantarjian H, et al. 2006. NEJM. 354(24):2531 abstract
  23. Kantarjian H, Giles F, Wunderle L, et al. 2006. NEJM. 354(24):2543
  24. Davies SM, DeFor TE, McGlave PB, et al. 2001. Am J Med. 110(5):339 abstract
  25. Kantarjian HM, Talpaz M, Giles F, et al. 2006. Ann Intern Med. 145(12):913 abstract
  26. Nilotinib. 2008. Med Let. 50(1283):26 abstract