Presentation on theme: "I’ve just been diagnosed with CML. Could you answer my questions? Sameer Tulpule Royal Hallamshire Hospital Sheffield."— Presentation transcript:
I’ve just been diagnosed with CML. Could you answer my questions? Sameer Tulpule Royal Hallamshire Hospital Sheffield
What now? Leukemia Can be cured
Fast Facts Rare disease 1 to 1.5 new cases per 100,000 population per year Rare in young adults under 19 years Not inherited – cannot pass down to kids
How did I get it? In almost all cases there are no identifiable predisposing causes Radiation is the only clearly established external factor predisposing to development of CML Benzene is implicated only on an anecdotal basis
What is CML Wang et al. Genes Chromosomes Cancer. 2001;32:97
Diagnostic Considerations in Chronic Myeloid Leukemia Karyotyping in CML 1) Allows for the diagnosis of CML 2) Requires a bone marrow aspirate for optimal metaphases Demonstrating the presence of the t(9;22) or its gene product is absolutely essential in diagnosing a patient with CML
FISH in CML Red → Bcr probe Green → Abl Probe Yellow → fusion of Bcr and Abl Ch 9Ch 22 Bcr- Ch 22 Abl – Ch 9 Bcr-Abl Fusion
Diagnostic Considerations in Chronic Myeloid Leukemia Bcr-Abl Bcr Abl cDNA Quantitative RT-PCR for Bcr-Abl in CML 1) Allows for the diagnosis of CML 2) Does not require a bone marrow aspirate for optimal results 3) Can quantify the amount of disease
Disease Diagnosis and Monitoring in CML TestTargetTissueSensitivity (%)*Use Cytogenetics Ph chromosomeBM1-10▪ Confirm diagnosis of CML ▪ Evaluate karyotypic abnormalities other than Ph chromosome (ie, clonal evolution) FISH Juxtaposition of bcr and abl PB/BM0.5-5▪ Confirm diagnosis of CML ▪ Routine monitoring of cytogenetic response in clinically stable patients ▪ Routine measurement of MRD RT-PCR bcr-abl mRNAPB/BM ▪ Routine measurement of MRD ▪ Determine the breakpoints of the 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
Normal Bcr-Abl Signaling* The kinase domain activates a substrate protein, eg, PI3 kinase, by phosphorylation This activated substrate initiates a signaling cascade culminating in cell proliferation and survival PPP ADP P P PPP ATP SIGNALING Bcr-Abl Substrate Effector ADP = adenosine diphosphate; ATP = adenosine triphosphate; P = phosphate. Savage and Antman. N Engl J Med. 2002;346:683 Scheijen and Griffin. Oncogene. 2002;21:3314.
Imatinib Mesylate: Mechanism of Action* Imatinib mesylate occupies the ATP binding pocket of the Abl kinase domain This prevents substrate phosphorylation and signaling A lack of signaling inhibits proliferation and survival P PPP ATP SIGNALING Imatinib mesylate Bcr-Abl Savage and Antman. N Engl J Med. 2002;346:683.
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) A l i v e, % MonthsSinceRandomization Survival:deathsassociatedwithCML OverallSurvival % Alive
Most Common Adverse Events (by 5 Years) All Grade AEs Patients, % Grade 3/4 AE’s Patients % Superficial Edema602 Nausea501 Muscle cramps492 Musculoskeletal pain475 Diarrhea453 Rash/skin problems403 Fatigue392 Headache37<1 Abdominal pain374 Joint pain313 IRIS Study: Most Frequently Reported AEs Only Serious Adverse Events (SAEs) were collected after 2005 Grade 3/4 adverse events decreased in incidence after years 1-2 IRIS 8 year update Imatinib is a Safe Drug....
How often do I need tests
Definitions of Treatment Response Level of ResponseDefinition Complete hematological response Normal CBC and differential, no extramedullary disease Major 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 baseline Complete molecular remissionNegativity by RT-PCR * Cytogenetic response is based on analysis of at least 20 metaphases Deininger, 2005; National Comprehensive Cancer Network, 2007.
Do I need repeated Bone marrows? Usually only at diagnosis No Part of trial If there is loss of response
CML – Phases of Disease PhaseCharacteristics Chronic Phase Indolent course, often asymptomatic and found incidentally on routine physical exam Predominance of mature white blood cells Approximately 90% of patients are diagnosed at this stage Median survival is 4–7 years (pre-tyrosine kinase inhibitor [TKI] therapy) Accelerated Phase Transition generally occurs over a period of 1 year or more. Duration is 6 months to 1 year Associated with progressive leukocytosis, thrombocytosis or thrombocytopenia, basophilia, increased blasts, splenomegaly, fever, bone pain Clonal evolution may be present Blast Phase Lasts only a few months – survival is poor if untreated Associated with increasing blasts (>20%), progressive splenomegaly despite treatment, and clonal evolution National Comprehensive Cancer Network, 2007; National Cancer Institute, 2007; Calabretta & Perrotti, 2004; Cortes et al., 2006.
Summary Rare disease Potentially curable disease Good long term survival Imatinib has a good safety profile