noted to have cytogenetics aconsistent chromosomal abnormality - PowerPoint PPT Presentation

 First human cancer  Mother of noted to have cytogenetics aconsistent chromosomal abnormality  Spectacular success  Era of targeted of Glivec therapy

Year Total Dead 1.0 Imatinib 276 14 1990-2000 960 357 0.8 1982-1989 365 266 90% Proportion Surviving 1975-1981 132 127 1965-1975 123 122 0.6 0.4 0.2 0.0 0 3 6 9 12 15 Years From Referral The University of Texas M. D. Anderson Cancer Center database.

Parameter Historical Perspective Modern Perspective (Until 2000) (Since 2000) Course Fatal Indolent Prognosis Poor Excellent  Median survival, yrs ≥ 25* 3-6 Allogeneic SCT,  Frontline treatment Imatinib interferon alfa Second-line treatment Not established Allogeneic SCT, novel TKIs *extrapolated from imatinib mesylate Kaplan-Meyer data. Faderl S, et al. N Engl J Med. 1999;131:207-219. Druker BJ, et al. N Engl J Med. 2001;344:1031-1037.

 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

Annual Event Rates Over Time 10 Annual Rates (%) 8 6 4 2 0 1 2 3 4 5 6 Year All annual event rates include loss of CHR, MCyR, AP/BC, and death during treatment Hochhaus A, et al. ASH 2007. Abstract 25.

Imatinib Imatinib (n = 364) 400 mg/day* (n = 553) Crossover to Imatinib † Patients with (n = 359) chronic-phase CML Crossover to Interferon alfa (N = 1106) 5 million U/m 2 daily + Interferon † (n = 14) Cytarabine 20 mg/m 2 10 Interferon alfa/ days/mo Cytarabine (n = 553) (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. Hochhaus A, et al. ASH 2007. Abstract 25.

 Incidence (0.39-0.9 per 100,000)  7% to 15% of all adult leukemias  Prevalence increasing because of 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 2 nd 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 of 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 of 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 optimal care to our 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