Risk Stratification in AML. Michelle Geddes Feb 27, 2014

Transcription

1 Risk Stratification in AML Michelle Geddes Feb 27, 2014

2 Objectives Outline the challenges in post-remission therapy for AML Review etiology of disease escape mechanisms from therapy Evaluate prognostic factors in AML including predictors of relapse and treatment related mortality

3 Strategy for treatment of AML 80% of patients under 60 achieve remission Majority relapse and median survival without post-remission therapy is 4-8 months

4 Survival of 1213 adult de novo AML patients on the CALGB 8461 study Byrd J C et al. Blood 2002;100:

5 Prognostic Factors in AML Cytogenetics Age Performance status (Karnofsky <60%) Therapy-related leukemias Secondary leukemias Response to initial therapy MDR 1 resistant phenotype Obesity

6 Pathophysiology of AML Class I - Mutations in signal transduction pathways giving proliferative advantages to leukemic clones i.e. ITD, mutations of TKD of C-KIT or FLT3, NRAS Class II - Mutations affecting transcription factors or cofactors impairing differentiation i.e. NPM1, CEBPA, WT1ASXL1 Abnormalities in epigenetic regulation IDH1, IDH2, TET2 hypermethylation, MLL encodes a histone demethylase

7 Mechanisms of resistance in AML Subpopulation of rare cancer stem cells can persist and result in relapse Selection of resistant clones with acquired genetic or epigenetic alterations conferring improved cell survival Growth factors Cell cycle proteins Cell death mechanisms Drug efflux mechanisms Signalling pathways Role of immune system control is being investigated and this concept is a factor in allogeneic HCT

8 Future new strategies in treatment of Examples: AML? Sorafenib in patients with FLT3 ITD and TKD Azacytidine in patients with MLL abnormalities In the interim - better identification of patients who benefit from high dose therapy/allogeneic transplantation?

9 Effect of Age on Outcomes in AML A) all patients B) Patients selected to undergo induction chemotherapy Blood 2009; 113:4179.

10 Age is a marker for high risk disease features Median age of AML patients 68y Definition of elderly generally 55y or 60y OS after induction 40-60% in most series; 5y survival 6% in those >65y and 2% in age >75% Age alone is not a strong predictor, but associated with higher TRM and disease features: Higher incidence of high risk cytogenetics Lower incidence of favourable cytogenetics Higher multidrug resistance Higher comorbidities and poor performance status

11 Pretreatment risk score in newly diagnosed AML predicts induction TRM TRM score >60y 60y N % N % 0-3 7/ / / / / Calculation of score: 0 (age < 61 years) + 2 (age 61 to 70 years) + 4 (age 71 years) + 0 (PS = 0) + 2 (PS = 1) + 4 (PS > 1) + 0 (platelets < 50) + 1 (platelets 50). JCO November 20, 2011 vol. 29 no

12 Higher risk of treatment failure in older patients with poor pretreatment predictors of relapse Cytogenetic risk and age can predict relapse in older patients however when modelled show AUCs of 0.65 and 0.59, respectively Multivariable models only yielded an AUC of 0.72 (predictive ability closer to coin flip than certainty) - removal of age as covariate from such models had no effect Newer genetic and molecular abnormalities may improve prediction of outcome pretreatment Argues for importance of both pre-treatment and posttreatment data i.e. MRD to assess risk of disease resistance JCO November 10, 2013 vol. 31 no

13 Effect of performance status on TRM Strong predictor of outcome in clinical trials and reflects comorbidities Can change rapidly i.e. if sepsis Combined with age can predict TRM Age ECOG TRM <50 < < < <3 13 >79 <3 30 < > Cancer 2001; 92:1059

14 Therapy-related AML 10-20% of all AML cases Shorter median survival than de novo AML, MDS, or MDS/MPN 90% clonal chromosomal problem, often adverse cytogenetic profile Cytogenetics remain strongest prognostic factor and are classified as per de novo AML Therapy-related t(15;17) AML has excellent outcomes and treated as per de novo APL Intermediate and poor cytogenetic risk patients do worse than de novo AML patients in these risk groups

15 Therapy-related AML Post alkylating agents (chlorambucil, melphalan) and RT 5y latency MDS, abnormalities of chromosomes 5, 7, 8 Risk increases with age Post topoisomerase II inhibitors (etoposide, anthracyclines ie doxo/daunorubicin) 1-3y latency 11q23, often myelomonocytic or monocytic; some APL Risk stable across age groups Chemo plus radiation increased risk

16 Outcomes in therapy-related CBF mutation AML are poorer than in de novo CBF AML Multivariate analysis showed trend for worse outcomes with secondary AML status; age-matched control analysis showed significant worse survival in secondary CBF AML patients Cancer 2009; 115(14):

17 Antecedent hematologic disorders Heterogeneous group of patients with prior MDS or MPNs 25-40% of elderly AML patients Range of prior therapies can include chemo for heme or other cancers Often prior transfusion iron load, infection colonization, bleeding High incidence of splenomegaly or organ dysfunction Outcomes with chemotherapy poor (LFS<10%) and few patients are transplant candidates options depend on comorbidities/performance status and potential for allohct

18 Cytogenetic risk groups predict outcomes in AML Byrd J C et al. Blood 2002;100:

19 Karyotype predicts outcomes in AML by WHO 2008 Patients in MRC AML10, MRC AML12, MRC AML15 Grimwade Hematology 2009

20 MRC Cytogenetic Risk Groups Risk Group (% AML) Abnormalities 10y Overall Survival (%) Favourable (16%) Alone or in combination with additional mutations: t(8;21) inv(16); t(16;16) t(15;17) - considered separately Normal karyotype (40%) 38 Intermediate (20%) Not favourable or unfavourable 33 del (5q); add (5q); del (7q); add (7q); monosomies 5 or 7 inv(3); t(3;3) t(6;11); t(10;11); t(9;22); 17p abnormalities or monosomy 17; Complex karyotypes 4 abn 11q23 abnormalities excluding t(9;11) and t(11;19) abnormalities of 3q excluding t(3;5) Blood. 2010;116(3):354

21 JCO C-kit abnormalities can clarify prognosis in Core Binding Factor Leukemias ckit mutations change prognosis to intermediate risk in CBF mutated disease CR rates same but 6x higher relapse rate if mutated ckit, 5y OS 74% vs 32% JCO August 20, 2006 vol. 24 no. 24

22 Monosomy karyotype 2 autosomal monosomies or a single autosomal monosomy with 1 or more structural abnormalities 10% of AML patients Low rate of CR after induction (48%) and <5% 4y overall survival In the MRC dataset of almost 6000 patients, 94% of monosomy karyotypes are included with adverse risk J Clin Oncol. 2008;26(29):4791 Blood. 2012;119(2):551

23 Cytogenetic risk groups in patients >60y Cytogenetics impact outcomes especially in high risk disease Trisomy 8 in patients >60y not undergoing transplant has 9% 5y overall survival Cytogenetic Risk Group Frequency CR (%) 5y Overall Survival (%) Favourable Intermediate Poor Blood. 2001;98(5):1312

24 AML with t(15;17) Fusion protein PML/RARα Retinoic acid receptor - nuclear receptor regulates and controls cell differentiation and proliferation Novel DNA binding protein, abnormal fusion protein blocks myeloid differentiation

25 Prognostic Factors in apml modern age of ATRA-based Rx WBC <10 and plts >40 low risk Relapse free survival 98% WBC < 10 and plts <40 intermediate risk Relapse free survival 89% WBC >10 high risk Relapse free survival 70%

26 Dilemma What to do with the normal cytogenetics patients?

27 Molecular Testing in AML 40-50% of AML samples have normal karyotype FLT3, NPM1, KIT, CEBPA, TET2 recurrent mutations by targeted sequencing DNMT3A and IDH1 found more recently by massive parallel sequencing Even with SNP arrays and CGH studies 25% no mutations seen Blood 2011; 118(20):5593

28 FLT3 ITD and mutation FLT3 is a receptor tyrosine kinase on hematopoietic cells ITD lead to inframe insertions in juxtamembrane region TKD mutations in activation loop Lead to constitutive activation, higher WBC

29 Kaplan-Meier survival plots of older patients with cytogenetically normal, primary acute myeloid leukemia according to FLT3 mutational status. Whitman S P et al. Blood 2010;116:

30 Role of NPM1 in normal cytogenetics AML NPM1 mutations result in aberrant nucleophosmin expression in leukemic cell cytoplasm of leukemic cells 1/3 of all AML, better prognosis Possible founder mutation in AML Mutation disturbs hematopoiesis, 85% normal cyto Found in all leukemia stem cells, precedes FLT3 Mutually exclusive of CEBPA mutations Biological and clinical features minimally affected by other chromosomes/dysplasia CEBPA transcription factor myelopoiesis Mutation leads to truncated protein or impaired DNA binding, dimerization Schlenk R et al. N Engl J Med 2008;358: , Blood 2011; 117(4):1109

31 European LeukemiaNet Prognostic Predictors Cytogenetics/molecular (non APL): Favorable - inv(16), t(8;21), NPM1+ and FLT3-, Mutated CEBPA with normal karyotype Intermediate-1 - Normal karyotype with either: NPM1+ FLT3-ITD+, NPM1- and FLT3-ITD+, or NPM1-FLT3- ITD- Intermediate-2- t(9;11) MLLT3-MLL, other cytogenetic abnormalities not favorable or unfavorable Unfavorable del 5(q), -5q, -7, inv(3), t(3;3), t(6;9), t(v;11) with MLL rearrangement, 17p abnormality, complex ( 3) Blood. 2010;115(3):453

32 Cancer Genome Atlas Research Network Whole genome sequencing in 50 AML patients compared genome in blast cells vs. skin cells Detects amplifications, deletions, gene fusion Less sensitive Exome capture and sequencing in 150 AML patients (detects abnormalities in 1% of genome) More sensitive but may not detect structural abn RNA expression profiling in 197 pts, RNA sequencing for 179 pts, mirna 194 pts, BeadChip profiling for 192 pts, SNP arrays on 100 pts N Engl J Med 2013; 368:

33 Cancer Genome Atlas Research Network On average only 13 mutations found in AML genome Average of 5 are in genes that are recurrently mutated 23 genes had higher than expected mutation prevalence Driver mutation found in every patient; less complex genetic abnormalities than other cancers sequenced to date N Engl J Med 2013; 368:

34 Characterization of Mutations Cancer Genome Atlas Research Network The Cancer Genome Atlas Research Network. N Engl J Med 2013;368:

35 Organization of Mutations in AML Cancer Genome Atlas Research Network FLT3, DNMT3A, and NPM1 coexist freq -may be a new AML subtype Many samples had mutations both in NPM1 and DNMT3A (P< ) or in NPM1 and FLT3 (P< ) Clusters in mrna, mirna, and DNA methylation A number of mutually exclusive genes were seen The Cancer Genome Atlas Research Network. N Engl J Med 2013;368:

36 GEP and methylation patterns Myeloid differentiation signal is highly correlated with gene expression signature Distinct expression patterns for APL, RUNX1-RUNX1T1 and triple mutants. Strongest methylation patterns were in the CPG-sparse regions

37 Role of Molecular Testing in AML Currently we have FLT3, NPM1 and C-KIT available. CEBPA testing coming (?biallelic) Role of additional molecular testing for prognostication and eventually therapeutic molecular targets

38 Role of Chemotherapy in AML Induce remission: Goal to reduce tumour burden from leukemia cells to below 10 9 Blasts<5%, Hb 100, platelets 100, neuts >1 Followed by remission consolidation x2-4 cycles

39 Disease detection in AML Morphology Cytogenetics Flow cytometry Molecular testing

40 Minimal Residual Disease in AML Multicolour flow cytometry (MFC) can detect a LAIP in 85% of patients at diagnosis Residual disease by MFC after consolidation associated with high risk of survival HOVON/Swiss prospective multinational trial in young AML: patients in CR with MRD >-/1% after induction are at high risk of relapse in multivariate analysis

41 Landmark analysis of different P values for relapse with various minimal residual disease cut points at 3 time points Cycle 1 N=164 Cycle 2 N=183 Line = p 0.05 Post Consolidation N=121 Terwijn M et al. JCO 2013;31:

42 Survival in relation to MFC MRD testing after induction for AML in Calgary OS of AML Patients by Response to Induction, When Not Treated with First Remission BMT (n=84) % OS logrank p< Months CR (n=55) MRD (n=17) NR (n=12) 5y RFS in CR 27.7% vs MRD 18.8% (p=0.66) In MRD group vs. CR group: Age >60y in 41% vs 35% 2 ry leukemia 14% vs 14% Cytogenetic risk MRD vs CR: 41% vs 71% int risk 35 vs 16% favourable risk 24% vs 13% high risk Griffiths, Liew et al ASH abstract 2012

43 MRD in Calgary compared to effect of age and cytogenetic risk Griffiths, Liew et al ASH abstract 2012

44 Effect of MRD positivity on older patients in CR after induction. HR, 2.05; 95% CI, 1.52 to 2.75; P <.001 HR 1.85; 95% CI ; P< patients in CR after induction chemotherapy: 51% had no MRD detected by MFC, 49% were MRD positive Median times to relapse 8.5 vs 17.1 months Suggestion of higher cytogenetic risk in MRD + patients Freeman S D et al. JCO 2013;31:

45 Other factors associated with prognosis Comorbidity scores Leukemia stem cell frequency Common lab parameters Bone marrow microenvironment

46 Chemo vs Transplant in Intermediate Risk patients Three large meta-analyses of >600 patients with AML and intermediate risk Those genetically assigned to matched related donor HCT had superior 4y DFS Approximately 12% better overall survival Less relapse but more treatment-related mortality Unrelated donor outcomes similar to sib donors with more GVHD but less relapse

47 AML OS by Risk Group, Donor Status Cornelissen J J et al. Blood 2007;109:

48 Do prognostic factors influence therapy? Evidence for allogeneic transplantation in high risk disease Better survival in monosomy karyotype Improved outcomes in FLT3 disease; role for allotransplant in other adverse risk mutations?

49 Questions?