4 Fast FactsRare disease 1 to 1.5 new cases per 100,000 population per yearRare in young adults under 19 yearsNot inherited – cannot pass down to kids
5 How did I get it?In almost all cases there are no identifiable predisposingcausesRadiation is the only clearly established external factorpredisposing to development of CMLBenzene is implicated only on an anecdotal basis
6 What is CML Wang et al. Genes Chromosomes Cancer. 2001;32:97
7 Diagnostic Considerations in Chronic Myeloid Leukemia Demonstrating the presence of the t(9;22) or its gene product isabsolutely essential in diagnosing a patient with CMLKaryotyping in CML1) Allows for the diagnosis of CML2) Requires a bone marrow aspirate foroptimal metaphases
8 Yellow → fusion of Bcr and Abl FISH in CMLBcr- Ch 22Ch 9Ch 22Abl – Ch 9Bcr-Abl FusionRed → Bcr probeGreen → Abl ProbeYellow → fusion of Bcr and Abl
9 Diagnostic Considerations in Chronic Myeloid Leukemia Bcr-AblBcrAblcDNAQuantitative RT-PCRfor Bcr-Abl in CML1) Allows for the diagnosis of CML2) Does not require a bone marrow aspirate foroptimal results3) Can quantify the amount of disease
10 Disease Diagnosis and Monitoring in CML TestTargetTissueSensitivity (%)*UseCytogeneticsPh chromosomeBM1-10▪ Confirm diagnosis of CML▪ Evaluate karyotypicabnormalities other than Phchromosome (ie, clonalevolution)FISHJuxtaposition of bcr and ablPB/BM0.5-5▪ Routine monitoring ofcytogenetic response inclinically stable patients▪ Routine measurement ofMRDRT-PCRbcr-abl mRNA▪ Determine the breakpoints ofthe fusion genes*Number of leukemic cells detectable per 100 cells.BM = bone marrow; FISH = fluorescence in situ hybridization; PB = peripheral blood; MRD = minimal residual disease; RT-PCR = reverse transcriptase polymerase chain reaction.Wang et al. Genes Chromosomes Cancer. 2001;32:97
11 Normal Bcr-Abl Signaling* The kinase domain activates a substrate protein, eg, PI3 kinase, by phosphorylationThis activated substrate initiates a signaling cascade culminating in cell proliferation and survivalSubstrateBcr-AblEffectorPPADPBcr-Abl is a disregulated tyrosine kinase protein capable of both auto- and substrate phosphorylation.Highly plastic structure with both open (active) and closed (autoinhibited) stages.State is regulated both intramolecularly and by other proteins.Bcr-Abl signaling begins when adenosine triphosphate (ATP) binds to the kinase domain. This allows the binding of the substrate to be phosphorylated. Following phosphate transfer, the phosphosubstrate is competent to bind to and activate downstream effector molecules.PATPPPPSIGNALINGADP = adenosine diphosphate; ATP = adenosine triphosphate; P = phosphate.Savage and Antman. N Engl J Med. 2002;346:683Scheijen and Griffin. Oncogene. 2002;21:3314.Hantschel O, Superti-Furga G. Regulation of the c-Abl and Bcr-Abl tyrosine kinases. Nat Rev Mol Cell Biol. 2004;5:33-44.Savage DG, Antman KH. Imatinib mesylate–a new oral targeted therapy. N Engl J Med. 2002;346:Scheijen B, Griffin JD. Tyrosine kinase oncogenes in normal hematopoiesis and hematological disease. Oncogene. 2002;21:
12 Imatinib Mesylate: Mechanism of Action* Imatinib mesylate occupies the ATP binding pocket of the Abl kinase domainThis prevents substrate phosphorylation and signalingA lack of signaling inhibits proliferation and survivalBcr-AblPATPAt the molecular level, imatinib mesylate targets a specific part of the tyrosine kinase region of Bcr-Abl.Imatinib mesylate is an ATP-mimetic agent that binds Bcr-Abl with greater affinity than ATP at its ATP-binding site.The tyrosine kinase activity of Bcr-Abl is dependent on its ATPase activity.Bcr-Abl–bound imatinib mesylate prevents ATP binding and hydrolysis and hence the tyrosine kinase action of Bcr-Abl.This blocks the downstream substrate of Bcr-Abl, which is dependent on phosphorylation for activation.This in turn blocks downstream signal transduction pathways activated by Bcr-Abl.Imatinib mesylateSIGNALINGSavage and Antman. N Engl J Med. 2002;346:683.Savage DG, Antman KH. Imatinib mesylate–a new oral targeted therapy. N Engl J Med. 2002;346:Scheijen B, Griffin JD. Tyrosine kinase oncogenes in normal hematopoiesis and hematological disease. Oncogene. 2002;21:
13 IRIS 8-Year Update Overall Survival (Intent-to-Treat) – Imatinib Arm Estimated overall survival at 8 years was 85%(93%, considering only CML related deaths)123456789Alive,%MonthsScRadmzur:wCLO% Alive13
14 IRIS Study: Most Frequently Reported AEs Imatinib is a Safe Drug....IRIS Study: Most Frequently Reported AEsMost Common Adverse Events (by 5 Years)All Grade AEs Patients, %Grade 3/4 AE’s Patients %Superficial Edema602Nausea501Muscle cramps49Musculoskeletal pain475Diarrhea453Rash/skin problems40Fatigue39Headache37<1Abdominal pain4Joint pain31Only Serious Adverse Events (SAEs) were collected after 2005Grade 3/4 adverse events decreased in incidence after years 1-2IRIS 8 year update
16 Definitions of Treatment Response Level of ResponseDefinitionComplete hematological responseNormal CBC and differential, no extramedullary diseaseMajor cytogenetic response0-35% Ph-positive metaphases*- Partial cytogenetic response1%-35% Ph-positive metaphases*- Complete cytogenetic response0% Ph-positive metaphases*Major molecular response≥ 3-log reduction of BCR-ABL mRNA from baselineComplete molecular remissionNegativity by RT-PCR* Cytogenetic response is based on analysis of at least 20 metaphasesDeininger, 2005; National Comprehensive Cancer Network, 2007.
17 Do I need repeated Bone marrows? NoUsually only at diagnosisPart of trialIf there is loss of response
18 CML – Phases of Disease Phase Characteristics Chronic Indolent course, often asymptomatic and found incidentally on routine physical examPredominance of mature white blood cellsApproximately 90% of patients are diagnosed at this stageMedian survival is 4–7 years (pre-tyrosine kinase inhibitor [TKI] therapy)AcceleratedTransition generally occurs over a period of 1 year or more. Duration is 6 months to 1 yearAssociated with progressive leukocytosis, thrombocytosis or thrombocytopenia, basophilia, increased blasts, splenomegaly, fever, bone painClonal evolution may be presentBlastLasts only a few months – survival is poor if untreatedAssociated with increasing blasts (>20%), progressive splenomegaly despite treatment, and clonal evolutionNational Comprehensive Cancer Network, 2007;National Cancer Institute, 2007; Calabretta & Perrotti, 2004; Cortes et al., 2006.
19 Summary Rare disease Potentially curable disease Good long term survivalImatinib has a good safety profile