AML in elderly. D.Selleslag AZ Sint-Jan Brugge, Belgium 14 December 2013

Transcription

1 AML in elderly D.Selleslag AZ Sint-Jan Brugge, Belgium 14 December 2013

2 AML is predominantly a disease of the elderly incidence 2 3/ SEER Cancer Statistics, National Cancer Institute, USA Available at

3 AML in the elderly is associated with poor survival rates SEER Cancer Statistics, National Cancer Institute, USA Available at

4 Poor treatment tolerance Resistant disease

5 Host factors in elderly AML

6 Elderly population is heterogeneous There is no uniform definition of fitness Fitness is a subjective impresssion Choice of therapy is subjective: physician dependent

7 In clinical practice we use performance score to define fitness

8

9 Performance score is more important than age for prediction of day 30 induction mortality r age < 56 yr yr yr > 75 yr PS 0 2 % 11 % 12 % 14 % PS 1 3 % 5 % 16 % 18 % PS 2 2 % 18 % 31 % 50 % PS 3 0 % 29 % 47 % 82 % % PS % 24 % 26 % 32 % Appelbaum et al, Blood, 2006

10 Performance score has limitations Does not differentiate between physical impairment due to Leukemia (reversible with therapy) Comorbidity unrelated to leukemia (irreversible) May fluctuate during diagnostic work up More objective parameters to define fitness are required and should be prospectively validated - geriatric assessment scales - comorbidity scores

11 Treatment of elderly AML

12 Treatment choice and treatment goals are not the same for all elderly AML Treatment intensity Improve QoL Prolong survival Cure Disease biology POOR GOOD Host factors UNFIT FIT

13 Standard treatment options for elderly AML Supportive / palliative are CR 0 % Med OS 2 mts, OS 5 yrs 0 % Low dose Ara C CR %, ED 25 % Med OS 4 mts, OS 5 yrs 0 % Not efficient with unfavourable karyotypes Intensive chemotherapy (3 + 7 induction) CR %, ED % Med OS 10 mts, OS 5 yrs < 15 % Little effect with adverse karyotype

14 LDAC is associated with poor survival in patients with unfavourable cytogenetics AML14 trial comparing LDAC vs HU in patients unfit for intensive treatment LDAC does not provide a survival benefit versus HU in patients with adverse cytogenetics who are ineligible for intensive treatment Burnett AK, et al. Cancer 2007;109:

15 Intensive approach Age, y CR % ED % Cure % < < > < 15

16 Intensive chemotherapy is associated with poor survival in patients with AML aged >60 years Survival is particularly poor in patients with abnormal cytogenetic profiles Knipp S, et al. Cancer 2007;110:345 52

17 Do we have data supporting the choice for intensive or non intensive approach? Limited data EORTC study (1989 )in 60 pts randomized between IC and supportive care We need a large randomized study but the the MRC AML14 study showed that only 8 of 1485 pts were randomized (patient or physician decision)

18 Intensive induction vs supportive care in elderly AML Intensive chemotherapy Palliative therapy Complete remission 58 % 0 % Early death 3/31 18/29 Median survival 21 weeks 11 weeks Survival at 2,5 yrs 17 % 0 % % of days in hospital Lowenberg et al, JCO, 1989 ; 7, 1268

19 How many patients can be treated with IC? Kantarjian, Blood 2010, 116: 4422 Number adverse factors N (%) of patients Mortality Week 8 (%) CR (%) (28%) (40%) Do (23%) not treat 55 intensively or more 38 (9%) MDACC Risk factors Age > = 80 PS = 2 4 Complex karyotype (3 or more abn) Creatinine > 1.3 mg/dl Survival at 2 yrs

20 Intensive chemotherapy: induction What do we know from randomized studies? Standard: with Dauno mg/m2 x 3 AraC mg/m2 CI x yrs: Dauno 90 mg/m2 x 3 : better OS No improvement of OS with addition of 6TG, etoposide new anthracyclins

21 Intensive therapy: post remission What do we know from randomized studies? 1. Consolidation : Consolidation vs no consolidation: never tested (all RCT use some form of consolidation) High vs conventional dose AraC : no advantage Multiple (4 vs 1, 4 vs 3) consolidations : no advantage 2. Maintenance: LD AraC improves remission duration, but not survival

22 EORTC/HOVON AML-9: DFS from 2 nd Randomization Lowenberg, JCO, No AraC LD AraC Logrank P = (years) O N Number of patients at risk : April 99 Induction Consolidation Maintenance R: LD Ara vs no LD AraC No AraC AraC

23 EORTC- HOVON AML-9: OS from 2 nd Randomization April LD AraC Logrank P = No AraC 0 (years) O N Number of patients at risk : No AraC AraC

24 Relapse Non relapse mortality Leukemia free survival Overall survival Farag et al, BBMT 2011

25

26

27 Can we wait for the karyotype? Delay of chemotherapy (< 5 vs > 5 days) does not influence survival in AML > 60 yrs and WBC < /mm3 Sekeres, M. A. et al. Blood 2009;113:28 36

28 Investigational therapies for elderly AML

29 New agents Hypomethylating agents Azacytidine Decitabine Clofarabine Gemtuzumab Flt3 inhibitors Quizartinib Volasertib CPX351..

30 Clofarabine is a Purine Nucleoside analogue N NH 2 N N NH 2 N N NH 2 N N NH 2 N HO N O N Cl HO N O N F HO N O HO N Cl HO N O F N HO HO deoxyadenosine cladribine HO HO fludarabine clofarabine Clofarabine: registered for relapsed ALL < 21 yrs

31 Clofarabine (Genzyme, Sanofi) Very active as monotherapy in AML Relapsed AML: CR 50 % Dose: 40 mg/m2 x 5 days Elderly AML not eligible for IC: CR 45 %, OS 1 yr for CR pts Dose : 30 (20) mg/m2 x 5 days (Kantarjian, Burnett, JCO 2010) High CR also in unfavourable cytogenetics Disappointing results in randomized studies: Will clofarabine ever be commercialized?

32 Burnett et al, ASH 2012

33 Burnett et al, ASH 2012

34 DNA hypermethylation is reversible Normal M M M Hypomethylating agents Expressed DNA methyl transferase M M M M M M M M M Cancer MDS Silencing of regulatory genes (e.g. tumor suppressor genes) Courtesy of Issa, JP

35 Hypomethylating Cytosine Analogs NH 2 NH 2 NH 2 NH 2 N CH 3 N CH 3 CH 3 N N N N N O N O N O N O Ribose Deoxyribose Cytosine 5-methyl-cytosine 5-aza-cytidine 5-aza-2 -deoxycytidine (azacitidine) (decitabine) Vidaza (Celgene) Dacogen (J&J) FDA /EMA approved FDA/EMA approved

36 Interphase = G1 +S + G2 S G1 G2 M

37 AZA 001: phase III survival study Treatment continued until relapse, unacceptable adverse events, disease progression MDS Int2 High (n = 358) Randomization AZA 75 mg/m 2 /day SC for 7 days every 28 days (n = 179) Investigator selection of Conventional Care Regimens Convential care regimens (n = 179) Best supportive care only Low dose cytarabine (20 mg/m 2 /day for 14 days every days) Standard chemotherapy (7 + 3) Fenaux P, et al. Lancet Oncol. 2009;10:

38 AZA-001 post hoc analysis: OS in pts with 20 30% blasts (WHO AML) Patients surviving (%) months 24.5 months Azacitidine (n=55) CCR (n=58) 0 p = Time from randomisation (months) Fenaux P, et al. Poster presentation at ASH 2008, San Francisco, CA, USA 38

39 AZA-001: OS in patients who achieved HI as best response 100 Azacitidine CCR Patients surviving (%) months Median not reached CR is not required for survival benefit 0 0 p< Time from randomisation (months) List AF, et al. Oral presentation at ASCO 2008, Chicago, IL, USA 39

40 Vidaza EU Label 2008 Vidaza is indicated for: Int-2 / High-risk MDS (IPSS) CMML with 10 29% marrow blasts without MPD WHO-classified AML with 20 30% blasts and multilineage dysplasia not eligible for HSCT So far no approval for AML > 30 % blasts 40

41 AML- AZA 001(Celgene) Stratification Based on cytogenetics

42 Decitabine vs Treatment of Choice in elderly AML (DACO-016) N = 485 CR + CRp 17.8 % vs 7.8 % p = No difference in safety Kantarjian et al. J Clin Oncol. 2012; 30(21):

43 OS Protocol-specified 2009 clinical cutoff analysis (396 deaths) Kantarjian et al. J Clin Oncol. 2012; 30(21):

44 OS Ad hoc mature (2010) analysis (446 deaths) Significant Survival Benefit for decitabine Kantarjian et al. J Clin Oncol. 2012; 30(21):

45 DACOGEN (decitabine) : EU label Adult patients 65 years Newly diagnosed de novo or secondary AML according to WHO classification (> 20% blasts) Not candidate for standard induction chemotherapy EU registration since September 2012 No FDA approval for AML Belgian reimbursement since 1 December 2013 PS 2 or more Significant comorbidities (HCT-CI) Secondary AML Poor cytogenetics or molecular features Stop if no response after 4 cycles 45 45

46

47 Human Mouse

48 Gemtuzumab Relapsed or refractory AML CR = 25 %, remission duration 6 mths Side effects Hepatotoxicity, Myelosuppression No mucositis, no alopecia, no cardiotoxicity Elderly AML Postconsolidation: no improvement of survival in elderly AML with 3 doses GO 6 mg/m2 (Blood, 2010, HOVON) Unfit elderly: Low dose AraC +/ GO: more CR, but no survival benefit (Burnett, Leukemia, 2013) Fit elderly: Intensive chemo +/ GO

49 1 Castaigne et al, Lancet 2012; 2 Burnett et al, JCO 2012; 3 Amadori et al, JCO 2013 (in press)

50 Quizartinib (Astellas, Ambit)

51 Quizartinib: efficacy > 60 yrs, refractory to or relapsed < 1 year after first line CT (Martinelli, ASCO 2013) Flt3 ITD + (110) Flt3 ITD (44) CRc = CR + Cri + CRp 57 % 36 % HSCT 10 % 2 % Median CRc 12.1 wks 10.8 wks duration Median OS 25.3 wks 19.1 wks Survival > 12 mths 15 % 14 %

52 Quizartinib : next step: phase III

53 Polo like Kinase 1: key regulator of mitosis and interesting target for treatment Prometaphase Spindle Assembly Metaphase Centrosome Maturation Mitotic exit Prophase Plk1 Anaphase Mitotic entry Interphase Telophase CytoKinesis

54 Volasertib phase II study (Boehringer)

55 Maertens et al, ASH 2012

56 Kantarjian et al, Lancet Oncol 2012; Cortes et al, Lancet Oncol 2013; Stuart et al, ASCO 2010; Fehninger et al, Blood 2011

57 Tosedostat depletes amino acid pool in neoplastic cells Selective depletion of AA in cancer cells Oral compound, well tolerated, first in class

58 Case study 58

59 Patient characteristics 78 yrs old male Date of diagnosis: November 2010 Presentation: dyspnea, weakness for 2 weeks Performance status: ECOG PS 2 Medical history: ischaemic heart disease with 2 stents hypertension 59

60 Lab findings PB counts: Hb 8.1 g/dl WBC 2.3 x 10 9 /L ANC 1.2 x 10 9 /L Platelets 63 x 10 9 /L BM aspirate Blasts 41 % Karyotyping complex: -5,-7,+8 Classification FAB: AML WHO: AML 60

61 How would you treat this patient? Standard induction chemotherapy Supportive care only Low dose chemotherapy: hydroxyurea or low dose AraC Azacitidine Decitabine Other Treatment decision: randomisation in AZA- AML-001: azacitidine 75 mg/m2 SC for 7 days every 28 days 61

62 Treatment outcome Treatment started on 30/11/2010 Best response : PR achieved between cycles 5-6 Response duration: PR maintained for 24 months ECOG PS: improved from 2 to 1 between cycles 3-4 Transfusion independence achieved at cycle 4 Gradual loss of response from 24 th cycle AZA stopped in April 2013 after 28 cycles Died in June 2013 with pneumonia 62

63 63

64 Cure is cool, but survival also 64