I’ve just been diagnosed with CML.Could you answer my questions?

Sameer TulpuleRoyal 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 Wang et al. Genes Chromosomes Cancer. 2001;32:97

Diagnostic Considerations in Chronic Myeloid Leukemia

Karyotyping in CML

1) Allows for the diagnosis of CML2) 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 probeGreen → Abl Probe

Yellow → fusion of Bcr and Abl

Ch 9 Ch 22

Bcr- Ch 22

Abl – Ch 9

Bcr-Abl Fusion

Diagnostic Considerations in Chronic Myeloid Leukemia

Bcr-Abl

Bcr

Abl

cDNAQuantitative RT-PCR

for Bcr-Abl in CML

1) Allows for the diagnosis of CML2) Does not require a bone marrow aspirate for optimal results3) Can quantify the amount of disease

Disease Diagnosis and Monitoring in CML

Test Target Tissue Sensitivity (%)* Use

Cytogenetics Ph chromosome BM 1-10 ▪ Confirm diagnosis of CML▪ Evaluate karyotypic abnormalities other than Ph chromosome (ie, clonal evolution)

FISH Juxtaposition of bcr and abl

PB/BM 0.5-5 ▪ Confirm diagnosis of CML▪ Routine monitoring of cytogenetic response in clinically stable patients▪ Routine measurement of MRD

RT-PCR bcr-abl mRNA PB/BM 0.0001-0.001 ▪ 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

PP P

ADP P

P

PP P

ATP

SIGNALING

Bcr-Abl

Substrate

Effector

ADP = adenosine diphosphate; ATP = adenosine triphosphate; P = phosphate.Savage and Antman. N Engl J Med. 2002;346:683Scheijen 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

PP P

ATP

SIGNALING

Imatinib mesylate

Bcr-Abl

Savage and Antman. N Engl J Med. 2002;346:683.

IRIS 8-Year UpdateOverall Survival (Intent-to-Treat) – Imatinib Arm

Estimated overall survival at 8 years

was 85% (93%, considering only

CML related deaths)

0

10

20

30

40

50

60

70

80

90

100

Alive,%

0 12 24 36 48 60 72 84 96 108

Months Since Randomization

Survival: deaths associated with CML

Overall Survival

% A

live

Most Common Adverse Events (by 5 Years)

All Grade AEs Patients, %

Grade 3/4 AE’s Patients %

Superficial Edema 60 2

Nausea 50 1

Muscle cramps 49 2

Musculoskeletal pain 47 5

Diarrhea 45 3

Rash/skin problems 40 3

Fatigue 39 2

Headache 37 <1

Abdominal pain 37 4

Joint pain 31 3

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 1-2IRIS 8 year update

Imatinib is a Safe Drug....

How often do I need tests

Definitions of Treatment Response

Level of Response Definition

Complete hematological responseNormal CBC and differential, no extramedullary disease

Major cytogenetic response 0-35% Ph-positive metaphases*

- Partial cytogenetic response 1%-35% Ph-positive metaphases*

- Complete cytogenetic response 0% Ph-positive metaphases*

Major molecular response≥ 3-log reduction of BCR-ABL mRNA from baseline

Complete molecular remission Negativity 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

Phase Characteristics

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)

AcceleratedPhase

• 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