I’ve just been diagnosed with CML. Could you answer my questions? Sameer Tulpule Royal Hallamshire...

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