AML: How to characterize and treat elderly patients non fit for standard chemotherapy

Transcription

1 m1 AML: How to characterize and treat elderly patients non fit for standard chemotherapy Clinic for Medicine III University Hospital Munich Campus Grosshadern AMLCG study group Karsten Spiekermann, MD

2 Slide 1 m1 Name oben links: Diesen Namen müssen wir flexibel verändern können! Bitte als zugänglichen Text formatieren. Außerdem ist der RICHTIGE Namen um Augenblick: Medizinische Klinik und Poliklinik III - Großhadern Klinikum der Universität München Logos oben rechts: Diese Logos müssen wir flexibel verändern können! Bitte als verschiebbare / veränderbare Symbole in den Master integrieren. mkrych, 6/13/2005

3 Main topics 4 facts about AML and age How to characterize elderly AML patients How to treat AML in the elderly

4 I. AML is a curable disease APL-sudy AMLCG JCO 2003

5 II. The incidence of AML dramatically increases with age - All age: 2.3/100,000 -Age 60: 13.7/100,000 -Median age: years old

6 III. The cure rate decreases with age Swedish Acute Leukemia Registry N=2767 non APL Juliusson G Blood 2009

7 IV. Reasons for poor results in elderly Biology of the disease (Therapeutic resistance) Genetics MDR overexpression Treatment related mortality (TRM) Poor performance status Comorbidity Impaired organ function Age Reluctance of physicians to treat elderly patients with intensive chemotherapy protocols

8 Complex therapeutic decisions in elderly AML Medical fitness Age Comorbidity Organ function Performance status Cognitive function Leukemia Biology Karyotype Molecular genetics Growth kinetics AHD Patient preference QoL Hospitalization Family/partner Therapeutic Options Physician experience and attitude Decision: Benefit from standard chemotherapy?

9 Therapeutic decisions in elderly AML Medical fitness Age Comorbidity Organ function Performance status Cognitive function Leukemia Biology Karyotype Molecular genetics Growth kinetics AHD Patient preference QoL Hospitalization Family/partner Therapeutic Options Physician experience and attitude Decision: Benefit from standard chemotherapy?

10 Age: Most important decision tool to define patients fit for intensive chemotherapy Swedish Acute Leukemia Registry Juliusson G Blood 2009

11 Performance status predicts outcome in elderly, but not younger AML patients PS>2: MRC (Wheatly, 2009), ALFA (Malfusion, 2008) MDACC (Kantarjian 2006), SWOG (Appelbaum, 2006) 5 SWOG-trials: S9034, S9500, S9031, S9333, S0112 (N=968) Appelbaum F Blood 2006

12 Therapeutic decisions in elderly AML Medical fitness Age Comorbidity Organ function Performance status Cognitive function Leukemia Biology Karyotype Molecular genetics Growth kinetics AHD Patient preference QoL Hospitalization Family/partner Therapeutic Options Physician experience and attitude Decision: Benefit from standard chemotherapy?

13 Unfavorouble karyotype AML: no cure by conventional chemotherapy!

14 Unfavorouble karyotype AML: dramatic increase with age

15 Age + Medical fitness + Leukemia biology Predictive prognostic models for patients treated with intensive chemotherapy AMLCG (Buechner, 2009) ALFA: (Malfusion, 2008) AMLSG (Fröhling, 2006) MRC (Wheatly, 2009) Age >75 years PS>2 58% High-risk cytogenetics (WBC>50 109/L) 15% Malfusion, 2008

16 Therapeutic decisions in elderly AML Medical fitness Age Comorbidity Organ function Performance status Cognitive function Leukemia Biology Karyotype Molecular genetics Growth kinetics AHD Patient preference QoL Hospitalization Family/partner Therapeutic Options Physician experience and attitude Decision: Benefit from standard chemotherapy?

17 Patient physician agreement: Chance of cure in elderly AML (>60yrs) 89% 74% N=43, Dana-Farber Cancer Institute (DFCI) or the Minneapolis Veterans Administration Medical Center (MVAMC) Sekeres MA Leukemia 2004

18 Therapeutic decisions in elderly AML Medical fitness Age Comorbidity Organ function Performance status Cognitive function Leukemia Biology Karyotype Molecular genetics Growth kinetics AHD Patient preference QoL Hospitalization Family/partner Therapeutic Options Physician experience and attitude Decision: Benefit from standard chemotherapy?

19 Definition of fit patients varies with age Swedish Acute Leukemia Registry Δ: 35 vs 75% Δ: 2 vs 45% Juliusson G Leukemia 2006

20 Overall survival in health care regions, grouped according to remission intention (RI) rate Juliusson G Leukemia 2006

21 Therapeutic decisions in elderly AML Medical fitness Age Comorbidity Organ function Performance status Cognitive function Leukemia Biology Karyotype Molecular genetics Growth kinetics AHD Patient preference QoL Hospitalization Family/partner Therapeutic Options Physician experience and attitude Decision: Benefit from standard chemotherapy?

22 Intensive Chemotherapy in elderly AML

23 Intensive chemotherapy (3+7) is superior to a watch & wait strategy in AML % Löwenberg JCO 1989

24 AML is a potentially curable disease in elderly medically fit AML No Age limit All cytogenics Büchner JCO 2008

25 Therapy in medically non-fit AML

26 A Comparison of Low-Dose Cytarabine and Hydroxyurea for Acute Myeloid Leukemia and High-Risk Myelodysplastic Syndrome in Patients Not Considered Fit for Intensive Treatment Burnett Cancer 2007;109: Definition of not fit not considered fit by the local investigator for the intensive treatment. No specific criteria for defining such patients were used, except that patients aged <70 years should have a documented comorbidity that precluded chemotherapy.

27 AML MRC14: Overall survival according to karyotype (N=217) Favourable/intermediate Unfavourable Standard: Low dose AraC+supportive care Burnett Cancer, 2007

28 A randomized phase 3 study of tipifarnib compared with best supportive care, including hydroxyurea, in the treatment of newly diagnosed acute myeloid leukemia in patients 70 years or older Jean-Luc Harousseau Blood 2009;114: N=457 Median age: contries, 115 sites (W/E Europe) Recruitment Definition of not fit Newly diagnosed AML who either were not fit for or not willing to receive induction chemotherapy

29 Reasons for not treating with intensive protocols Decision by: Patient: 13% Physician: 65% Both: 22% Reasons: Age alone 32% comorbidity 24% disease biology 3% combination 28% Harousseau Blood, 2009

30 Results Median survival BSC 109d Tipifarnib 107d Early death (30d) BSC 17% Tipifarnib 21% Harousseau Blood, 2009

31 Prognostic variables in 70+ unfit AML HR Age >75 vs. < ECOG 2 vs Unfavourable Yes vs. No Cytogenetics BM blasts >50% vs. <50% Harousseau Blood, 2009

32 Innovative treatment options

33 Most promising alternative therapies Clofarabine CLASSIC II-trial; Erba ASCO 2009 #7062 Monotherapy in patients unlikely to benefit CR-Rate: 38%, median OD 9.5 months Azacytidine VIVEDEP-study: Raffoux ASH 2009 #763 Combination AZA, VPA, ATRA CR-rate: 22%, median OS 12.4 months FLT3 PTK inhibitors Harousseau Blood, 2009

34 Therapeutic decisions in elderly AML Medical fitness Age Comorbidity Organ function Performance status Cognitive function Leukemia Biology Karyotype Molecular genetics Growth kinetics AHD Patient preference QoL Hospitalization Family/partner Therapeutic Options Physician experience and attitude Decision: Benefit from standard chemotherapy?

35 Defining the benefit from therapy in elderly AML Age Medical fitness Leukemia biology Patient preferences Geriatric assessment Clinical judgement GoGo Slow Go NoGo Intensive Chemotherapy Clinical trial trial Best supportive care care +/- +/-cytoreduction Symptom control

36 AMLCG: Approach to elderly (70+) patients with AML register Observation period days (diagnostics, geriatric assessment, supportive care) Clinical course Risk factors improvement No No complex Karyotype ECOG<3 Stable, progress Intent of of Rx Rx cure palliation Therapy Intensive chemotherapy Supportive Care +/- +/-AraC Clinical study

37 Thank you very much for your attention!