noted to have cytogenetics aconsistent chromosomal abnormality - - PowerPoint PPT Presentation

 First human cancer

noted to have aconsistent chromosomal abnormality

 Spectacular success

• f Glivec

 Mother of

cytogenetics

 Era of targeted

therapy

0.8 Imatinib 276 14 1990-2000 960 357 1982-1989 365 266 1975-1981 132 127 1965-1975 123 122 Year Total Dead 1.0 0.6 0.4 0.2 0.0 Proportion Surviving Years From Referral 3 6 9 12 15 90%

The University of Texas M. D. Anderson Cancer Center database.

Parameter Historical Perspective (Until 2000) Modern Perspective (Since 2000) Course Fatal Indolent Prognosis Poor Excellent

• Median survival, yrs

3-6 ≥ 25*

• Frontline treatment

Allogeneic SCT, interferon alfa Imatinib Second-line treatment Not established Allogeneic SCT, novel TKIs

Faderl S, et al. N Engl J Med. 1999;131:207-219. Druker BJ, et al. N Engl J Med. 2001;344:1031-1037. *extrapolated from imatinib mesylate Kaplan-Meyer data.

 Much of the practice guidelines in CML

is IRIS TRIAL driven.

 Use of Glivec as the first line agent  The decline of Haemopoietic stem cell

transplant

 Pleasant surprises: late responses and

annual risk of progression decreases with time

All annual event rates include loss of CHR, MCyR, AP/BC, and death during treatment

Annual Event Rates Over Time

2 4 6 8 10 1 2 3 4 5 6 Year Annual Rates (%)

Hochhaus A, et al. ASH 2007. Abstract 25.

Hochhaus A, et al. ASH 2007. Abstract 25.

Patients with chronic-phase CML (N = 1106) Imatinib 400 mg/day* (n = 553) Interferon alfa 5 million U/m2 daily + Cytarabine 20 mg/m2 10 days/mo (n = 553) Imatinib (n = 364) Crossover to Imatinib† (n = 359) Crossover to Interferon† (n = 14) Interferon alfa/ Cytarabine (n = 13)

*Increased stepwise to 400 mg BID allowed if no CHR at 3 months or > 65% Ph+ cells at 12 months.

†Permitted for no CHR at 6 months, no MCyR at 12 months, loss of response, or treatment intolerance.

 Incidence (0.39-0.9

per 100,000)

 7% to 15% of all adult

leukemias

 Prevalence

increasing because

• f marked

improvement in treatment results

 Age  Financial considerations  Compliances  Infrastructure and manpower  others

 Most Asian CML patients have younger

age of onset

 Pregnancy  Long period of treatment  Compliance issue  ?more transplant option

182 patients: mean age of presentation 35 years ( Compared to 44 in western studies) SCNg and P kuperan Malaysian J Path01 1990; 12 (2): l l l Overall median age(36-46); USA (65)

Money is not

everything –it’s the only thing

 Malaysia: US 6948  Spore: US 30000  Indonesia: US 2271  Thailand: US 3737  USA: US 50000  Impossible for majority of Malaysian CML

patients to afford glivec

 If not for the hugely successful patient

assistance program, Glivec will not be available for >90% of CML patients.

 700 patients (300 private and 400

govern)

 Around 100 patients from East Malaysia.

 Very few patients can afford 2nd

generation TKI. No assistance program to date.

 Care of BMT patients can be very costly

if they develop severe GVHD.

 Follow up monitoring tests (esp

cyto/molecular tests are pricey)

[Pix]

 Outside the major towns, diagnostic,

medical and supportive facilities may be lacking.

 Problems especially acute in inland part

• f East Malaysia

 Cytogenetic services  Molecular services: qPCR –not routine

services.

 Mutation analysis  Still lots of room for improvement  Differences between research and

routine services

 Steady improvement over the years  Haematology departments  More trainees  Active Malaysian Society of

Haematology

 Still room to grow (30 clinical Haem/28

million)

 Not sufficient for the growing population

• f 25 million

 7 active centers (6 Uni/govern; 1 private)

 1174 HSCT bet 1987 and 2006

 BMT rate relatively low

 Usual considerations: efficacy, safety,

cost, compliance etc

 Need ministry of health endorsement  Tripartite: MOS, MSH, Academy of

Medicine

 Lack of cyto/molecular testing  Lack of BMT facilities  Availability of Glivec and second

generation TKI

 No mutation studies  HSCT might be difficult to organize  Patient compliance

At diagnosis

 Cytogenetic study and BCR/ABL

qualitative study

 BM aspirate and biopsy

 Glivec is still the standard of care for

CML (despite the sexy stories of second generation TKI)

 Withdrawal of BMS—hard to secure

dasatinib

Monitoring

 Haematological response (review

diagnosis if no response)

 Cytogenetic study at 6 months and 12

months (expect PCyR -6m and CCR at 12m)

 Molecular study (optional) at 18mth  Failures warrant assessment by

haematologists.

Chronic phase

 Imatinib (300-400mg)  BMT  Clinical trials

Failures( resistance relapse)

 More imatinib  Nilotinib  BMT

Accelerated phase /blast crisis

 Imatinib/nilotinib/dasatinib +/- chemo  BMT  trial

 At diagnosis/initiation of TKI  Failures during monitoring  Potential BMT cases/post BMT care  At 1 year mark

 From university/specialist center: ard 80%

CCR at 1 year mark

 From community hospital: ard 60%

reported.

 Specialist care/review is important  Fear of cytopenia lead to under dosing  Patient compliance issue

Provide

• ptimal care to
• ur patients

despite finite (limited ) resources

 What is the appropriate treatment strategy in

the setting of imatinib resistance or failure?

 Treatment resistances--- combinations TKI,

combining with chemo. T315I problem. Safety and efficacy?

 What is the appropriate role of

transplantation in CML?

 Lack of cure--Strategies to eradicate minimal

residue disease (MRD)

• >attacking leukemic stem cells with

…immune mechanisms etc