Acute Myeloid Leukemia

Transcription

1 Average annual rate per 100,000 Acute Myeloid Leukemia Guillermo Garcia-Manero Professor Department of Leukemia MD Anderson Cancer Center Putting the Problem into Perspective All other sites (~1,445,000) Leukemias (~ 45,000) ~ 12,000 ~ 5,000 ~ 6,000 ~ 15,000 AML CML ALL CLL Other Jemal A et al. CA Cancer J Clin 2007; 57: Age-Specific Incidence Rates for AML: Etiology and Risk Factors Male Female All persons Age Chemical exposure Benzene; pesticides Other environmental exposures Hair dyes; smoking, non-ionic radiation Genetic disorders Down syndrome; Bloom syndrome; Fanconi s anemia; ataxia-telangectasia; Wiskott-Aldrich Prior chemotherapy or XRT Alkylating agents; topoisomerase II inhibitors NCI SEER Program Etiology and Risk Factors Antineoplastic Agents Alkylating agents - preceding MDS phase - evolution to AML after 5 to 7 years - chromosome abnormalities: -5, -7 Topoisomerase II inhibitors - no MDS phase - short latency of 1 to 3 years - monocytic morphology - chromosome abnormalities: 11q23 AML Diagnosis 20% blasts (BM and/or PB) IHC stains - Myeloperoxidase (+) or nonspecific esterase (+) or butyrate esterase (+) Immunophenotype (flow cytometry) - 2 myeloid markers (+) - < 2 lymphoid markers (+) Cytogenetic-molecular Harris N et al. J Clin Oncol 1999; 17: ; Cheson BD et al. J Clin Oncol 2003; 21:

2 Expression of Cell-Surface and Cytoplasmic Markers in AML Diagnosis Stage/Lineage Percursor Granulocytic Monocytic Marker CD34, CD38, CD117, CD133, HLA-DR CD13, CD15, CD16, CD33, CD65, cmpo CD11c, CD14, CD64, lysozyme, CD4, CD11b, CD36, NG2 homologue Megakaryocytic CD41 (gp IIb/IIIa), CD61 (gp IIIa), CD42 (gp 1b) Erythroid CD235a (glycophorin A) CD34 and HLA-DR are negative in APL Pre-Treatment Karyotype as Prognostic Factor in AML (CALGB 8461) 55% 24% 5% Döhner H et al. Blood 2010; 115: 453 Byrd JC et al. Blood 2002;100: Favorable Intermediate Adverse Cytogenetic Risk Groups MRC SWOG/ECOG CALGB t(15;17) t(8;21) inv(16)/t(16;16) normal Other noncomplex abn(3q) -5/del(5q) -7 complex ( 5 unrel abn) (excluding those with favorable changes) t(15;17) t(8;21) (lacking del(9q), complex (i.e. 3 unrel abn) normal +6, +8, -Y, del(12p) abn(3q),(9q),(11q), (21q),(17p) -5/del(5q) -7/del(7q) t(6;9) t(9;22) complex ( 3 unrel abn) t(15;17) t(8;21) inv(16)/t(16;16) inv(16)t(16;16); del(16q) normal other noncomplex inv(3)/t(3;3) -7 t(6;9) t(11;19) +8 complex ( 3 unrel abn) (excluding those with favorable changes) GIMEMA/ AML10 t(15;17) t(8;21) inv(16)/t(16;16) normal -Y other German AMLCG t(15;17) t(8;21) inv(16)/t(16;16) normal other noncomplex inv(3)/t(3;3) -5/del(5q) -7/del(7q) abn(11q23) del(12p) abn(17p) complex ( 3 unrel abn) AML WHO Classification (2008) AML with recurrent genetic abnormalities - t(8;21)(q22;q22); RUNX1-RUNX1T1 - inv(16)(p13.1;q22) or t(16;16)(p13.1;q22); CBFB-MYH11 - t(15;17)(q22;q12); PML-RARA - t(9;11)(p22;q23); MLLT3-MLL - t(6;9)(p23;q23); DEK-NUP214 - inv(3)(q21;q26.2) or t(3;3)(q21;q26.2); RPN1-EVI1 -The t(1;22)(p13;q13); WHO allows RBM15-MKL1 the diagnosis of AML - AML with NPM1 mut - AML with regardless biallelic CEBPA of marrow blasts mut AML with MDS-related changes Therapy-related myeloid neoplasms AML, NOS (includes FAB, acute myelofibrosis) Myeloid sarcoma Myeloid proliferations related to Down syndrome Blastic plasmacytoid dendritic cell neoplasms Impact of cytogenetic entities recognized in 2008 WHO classification on survival. Core Binding Factor (CBF) AML t(8;21)(q22;q22) inv(16)(p13q22)/ t(16;16) Incidence 5-10% 5-10% Molecular RUNX1-ETO CBFb-MYH11 FAB 20-25% of FABM2 FABM4eo Phenotype (Flow) Adverse prognosis Secondary molecular abnormalities KIT FLT3/D835Y > FLT3/ITD NRAS > KRAS CD19+, CD56+ (extramedullary disease) age, WBC, CD56+, EML/GS, nonwhite 30-40% 2-7% 10% Myelomonocytic age, WBC, female (in pts < 60 yrs) 30-40% 6-24% 30% Grimwade D et al. Blood 2010;116: Dombret H et al. Curr Op Hematol 2009; 16: 92-97; Schlenk RF et al. J Clin Oncol 2004; 22: 3741; Marcucci G et al. J Clin Oncol 2005; 23: 5705; Goyama S and Mulloy JC. Int J Hematol 2011; 94: 126 2

3 Monosomal Karyotype (MK) in Patients with AML MK: 2 autosomal monosomies or 1 monosomy with structural abnormalities > 60 years 60 years Normal Karyotype AML (NK-AML) NK = CN (cytogenetically normal) AML Approximately 45% of AML Heterogeneous group of patients Abnormalities in certain genes confer prognostic significance in adult patients Perrot A, et al. Blood 2011; 118: 679; Breems DA, et al. J Clin Oncol 2008; 26: Insights Into the AML Genome 50 whole genomes exomes = 200 cases Recurrently mutated genes: n = 237 Significantly mutated genes: n = 23 Mutations in AML and Complementation Groups Cancer Genome Atlas Research Network. N Engl J Med. 2013;368: Patel JP et al. N Engl J Med 2012; 366: Important Gene Mutations Mutated Gene Frequency Clinical Significance NPM1 AML 25-30% CN AML 45-64% Del(9)(q) 35-40%; +8 15% FLT3/ITD 40% IDH 25% CEBPA CN AML 10-18% Del(9)(q) 40% KIT CN AML < 10% CBF AML 25-30% - Predicts for achievement of CR and favorable RFS and OS - favorable impact regardless of age If biallelic higher CR rate and favorable RFS and OS Associated with inferior outcome Important Gene Mutations Mutated Gene Frequency Clinical Significance FLT3-ITD AML 20% CN AML 28-34% FLT3-TKD AML 5-10% CN AML 11-14% Inv(16) 14-24% - Inferior outcome especially when high mutant/allelic ratio - Available inhibitors - Controversial significance IDH1, IDH2 AML 15-20% - Limited prognostic significance - Available inhibitors Marcucci G et al. J Clin Oncol 2011; 29: Marcucci G et al. J Clin Oncol 2011; 29:

4 Molecular Prognosis in CN AML Correlation of Cytogenetic and Molecular Data in AML with Clinical Data (ELN) FAVORABLE INTERMEDIATE-I NPM1 mut /FLT3-ITD mut NPM1 wt /FLT3-ITD mut NPM1 wt /FLT3-ITD wt NPM1 without FLT3 ITD Other Genotypes except CEBPA HSCT > Chemo HSCT = Chemo Schlenk R et al. N Engl J Med 2008; 358:1909 ; Marcucci G et al. J Clin Oncol 2011; 29: 475 INTERMEDIATE-II UNFAVORABLE Döhner H, et al. Blood. 2010;115(3): t(9;11); MLLT3-MLL Other (neither favorable nor adverse) inv(3) or t(3;3); RPN1-EVI1 t(6;9); DEK-NUP214 t(v;11); MLL rearranged -5 or del(5q); -7; abnl(17p); complex CG Outcome in Younger (A,C,E; age 18 to 60 years) and Elderly (B,D,F; age > 60 years) Patients with AML by ELN Categories 2017 European LeukemiaNet (ELN) Recommendations for AML Risk Category Favorable Intermediate Adverse Genetic Lesion t(8;21)(q22;q22); RUNX1-RUNX1T1 inv(16)(p13.1q22); CBFB-MYH11 Mutated NPM1 without FLT3-ITD or with FLT3-ITD low Biallelic mutated CEBPA Mutated NPM1 and FLT3-ITD high Wild type NPM1 without FLT3-ITD or with FLT3-ITD low t(9;11)(p21.3;q23.3); MLLT3-KMT2A Cytogenetic abnormalities not classified as favorable or adverse t(6;9)(p23;q34.1); DEK-NUP214 t(v;11q23.3); KMT2A rearranged t(9;22)(q34.1;q11.2); BCR-ABL1 inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2); GATA2,MECOM(EVI1) -5 or del(5q); -7; -17/abn(17p) Complex karyotype ( 3), monosomal karyotype Wild type NPM1 and FLT3-ITD high Mutated RUNX1 Mutated ASXL1 Mutated TP53 * Low, low allelic ratio (<0.5); high, high allelic ratio ( 0.5) Röllig C et al. JCO 2011;29: Döhner H, et al. Blood. 2017;129(4): Molecular Markers and Response ECOG E1900 trial HD daunorubicin was associated with an improved rate of survival among patients with mutant DNMT3A (in UVA also mutant MLL and NPM1) FLT3 kinase inhibitors Lestaurtinib Midostaurine MLN-518 Mutant DNTM3A or NPM1, or MLL translocation WT DNTM3A and NPM1, and no MLL translocation 44% 25% 35% 39% Patel JP et al. N Engl J Med 2012; 366: Sunitinib Sorafenib AC220 Prescott H, Expert Opinion Emerg Drugs, 2011, In press 4

5 (A)EFS, (B) RFS, and (C)OS (B)censored and not censored for AlloSCT P R E - R E G I S T E R F L T 3 S C R E E N Stratify* FLT3 ITD or TKD R A N D O M I Z E RATIFY Schema DNR ARA-C Midostaurin DNR ARA-C Placebo CR CR HidAC Midostaurin HidAC Placebo X 4 X 4 Midostaurin MAINTENANCE 12 months Placebo MAINTENANCE 12 months FLT3 WILD TYPE not eligible for enrollment Stratification: TKD; ITD with allelic ratio <0.7 vs 0.7 Rollig C, et al. Lancet Oncology, 2015, 16 (16), Stone R, et al. ASH 2015, Abstract #6 Complete Response Rates MIDO (N=360) PBO (N=357) CR by day Rate 59% 53% 0.15 p * Overall Survival (Primary Endpoint) 23% reduced risk of death in the Mido arm Arm 4-year Survival MIDO 51.4% (95%CI: 46, 57) PBO 44.2% (95%CI: 39, 50) + Censor Time to CR, median (range) 35 days (20-60) 35 days (20-60) CR in induction/consolidation** Rate 66% 59% Time to CR, median (range) 37 days (20-99) 36 days (20-112) * 2-sided Fisher s Exact p ** includes all CRs reported within 30 days of ending protocol therapy 27 Hazard Ratio*: sided log-rank p-value*: Median OS: Mido 74.7 (31.7-NE); PBO 25.6 ( ) months NE: not estimable * controlled for FLT3 subtype (TKD, ITD-Low, ITD-High) 28 IDH mutations lead to 2HG production Wild-type IDH1 and IDH2 are NADP+ dependent metabolic enzymes that catalyze isocitrate to αkg AG221 Duration of treatment and best overall response in all response-evaluable patients as of 1 May 2015 (n=158) IDH Mutations cause a reverse reaction that reduces αkg to 2HG via conversion of NADPH to NADP+ Treatment duration a : 3-month = 61.2% 6-month = 48.7% Median = 5.6 months IDH1 and IDH2 Mutations occur in 15-20% of patients with AML Yen, KE, Oncogene, 2010, 29, Stein E, et al. ASH

6 1 IDH mutations, BCL-2 Dependence and ABT-199 An Increase in BCL-2 Expression VENETOCLAX Allows BINDS the TO Cancer AND INHIBITS Cell OVEREXPRESSED to Survive BCL-2 Pro-apoptotic Proteins (BAX, BAK) Anti-apoptotic Proteins (BCL-2) 2 Venetoclax Binds to and Inhibits Overexpressed BCL-2 Venetoclax BH3-only 3 Apoptosome APAF-1 Cytochorome C Apoptosis is Initiated Active Caspase Procaspase IDH Mutations and BCL2-Dependence CR/CRi IDH1/IDH2 mutation, FLT3 WT or TKD IDH1/IDH2 mutation, FLT3 ITD BAX BAK BCL-2 BCL-2 Mitochondria Mitochondria Mitochondria The large # of pro-apoptotic molecules bound and sequestered by BCL2 has cancer cells primed for cell death; apoptosis initiated after displacement by ABT199 Konopleva et al, ASH 2014 ABT-199 (Venetoclax) for R/R AML: 28 evaluable patients, 11 (35%) with IDH1/2 mutations. > 50% patients had clinical benefit including 6 CR/CRi; 4 were IDH mutants Another 4 IDH mutants with MLFS or PR Time from Diagnosis to Treatment (TDT) or 5 days: AML Patients 60 years Initial Evaluation Favorable Intermediate Unfavorable Intermediate by TDT Favorable by TDT Unfavorable by TDT Patient-specific Induction mortality - Age - Comorbidities - Performance status Disease-specific Resistance - Cytogenetic-molecular - AHD (MDS) - MDR phenotype? Sekeres MA et al. Blood 2009;113:28 AML Treatment (Non-APL) Induction - cytarabine plus anthracycline Postremission therapy - chemotherapy - allo/auto HSCT Recommendations may differ by - Age (< 60 y vs. 60 y) ± PS - Karyotype/genotype AML Induction Therapy Patients < 60 Years Infusional cytarabine ( mg/m 2 ) over 24 hrs daily x 7 days 7 PLUS 3 Anthracycline * - Daunorubicin mg/m 2 iv daily x 3 - Idarubicin 12 mg/m 2 iv daily x 3 * Fernandez HF et al. N Engl J Med 2009; 361: ; Pautas C et al. J Clin Oncol 2010; 28:

7 Survival (%) AML Induction Therapy (Patients < 60 Years) HD daunorubicin prolongs survival * - patients < 50 yrs - favorable/intermediate CG - Absence of FLT3-ITD Extension of Addition of 3 rd drug NO DIFFERENCE G/GM priming MDR modulators * Fernandez HF et al. N Engl J Med 2009; 361: High-Dose Cytarabine in Induction (Patients < 60 Years) Studies: - SWOG (1996) and HOVON (2011) suggest no - Metaanalysis of 4 randomized trails (2006) suggests yes - EORTC-GIMEMA (2011) suggests yes (for pts 45 yrs) Common issues: - higher mortality/toxicity despite survival benefit (in some) Weick JK et al. Blood 1996; 88: ; Löwenberg B et al. N Engl J Med 2011; 364: ; Kern W and Estey E. Cancer 2006; 107: 116; Willemze R et al. Blood 2011; 118: abs 257 Simplified Classification of AML AML sensitive to conventional chemotherapy CBF leukemias (without c-kit mutation) Diploid AML with NPM1 and CEBP mutation (without FLT3 mutation) Others (younger patients without AHD)? Dose intensification of chemotherapy may be helpful Chemo-resistant AML AML with adverse cytogenetics AML with FLT3-ITD Others (older patients, younger patients with t-aml and/or AHD) New agents are needed Gemtuzumab Ozogamycin in induction Therapy Meta-analysis of 5 Randomized Trials Hills, RK, et al. The Lancet Oncology, 2014; 15(9), 986 Cytarabine/Daunorubicin Liposome: CPX 351 5:1 molar ratio of cytarabine to daunorubicin is optimal in in vitro and in vivo AML models 100-nm bilamellar liposomes CPX-351 liposomes deliver 5:1 molar ratio for >24 h CPX-351 accumulates and persists in the bone marrow Selective uptake of CPX-351 by leukemia blasts and intracellular drug release Overall Survival Was Greater in the CPX-351 Arm Compared to the 7+3 Arm 100 CPX Kaplan-Meier Curve for Overall Survival ITT Analysis Population CPX Events/N 104/ /156 Hazard Ratio = 0.69 p-value = Median Surv. (95% CI) 9.56 (6.60, 11.86) 5.95 (4.99, 7.75) Months from Randomization Lancet JE et al. Blood. 2014;123:

8 Assessment of Response Marrow at d 7-10: - assess blasts and cellularity - if hypoplastic (cellularity < 20% and blasts < 5-10%) rpt marrow in 7-14 d - if blasts: donor search/salvage Rx Goal: complete remission: - ANC > 1,000/mcl - Plts 100,000/mcl - Marrow blasts < 5% Molecular CR only matters in APL AML Postremission Therapy Better-risk karyotype Intermediate-risk karyotype Poor-risk karyotype AHD t-aml HiDAC 3g/m 2 over 3h q12 d 1,3,5 x 4 * OR HiDAC x 1-2 auto HSCT Matched sibling or auto HSCT OR HiDAC 3g/m 2 over 3h q12 d 1,3,5 x 4 * OR Clinical trial Clinical trial OR Allo HSCT/alternative donor HSCT * NCCN Mayer RJ Practice et al. N Engl Guidelines J Med 1994; in 331: Oncology v Indications for Allo SCT in CR1 Genotype MSD Alternative Favorable No No + KIT Possible Possible Intermediate Possible Possible + FLT3/ITD Yes Yes + NPM1 w/o FLT3/ITD or IDH1 No No + CEBPA* w/o FLT3/ITD or IDH1 No No AML Survival Expectations ECOG All Patients Age 55 yrs Age > 55 yrs Unfavorable Yes Yes * Biallelic mutations only Modified from Rowe JM, Tallman MS. Blood 2010; 116: Tallman M et al. Blood 2005;106: AML Therapy for Patients 60 Yrs Assess performance status, comorbidities and karyotype Preferably, obtain karyotype/molecular profile prior to therapy Standard induction not appropriate - pts yrs - poor PS (> 2) - poor risk karyotype AML Induction Therapy (Patients 60 Years) Ara-C + Anthracycline induction - PS 0-2; no significant comorbidities; absence of unfavorable disease features Alternative approaches - intermediate intensity therapy (clofarabine) - low-intensity therapy (hypomethylating agents; low dose cytarabine) - best supportive care (hydrea, transfusions) - palliative care 8

9 Postremission Surveillance CBC and platelets - every 1-3 months x 2 years - then every 3-6 months x 3 years Marrow - only if hemogram becomes abnormal - no routine surveillance recommended Minimal residual disease - only in the context of clinical trials MRD: Available Techniques Quantification of MRD provides an estimate of the reduction of disease burden, reflecting: the inherent leukemia biology drug-resistance mechanisms the adequacy of the treatment, and other host-drug interactions influencing the response. Also, Next Generation Sequencing Ravandi F and Jorgensen J. JNCCN, 2012, 10(8), 1029 (A) RFS and (B) OS by cytogenetic status at CR and cytogenetic risk at diagnosis Chen Y, et al. JCO 2011;29: MRD Assessment Flow Cytometry Effect of MRD Status by FC on Patients in CR after course 1 Terwijn M et al. JCO 2013;31: Freeman S D et al. JCO 2013;31:

10 Agents to Eradicate MRD Monoclonal antibodies SGN-CD33A, AMG-330, SL-140 Demethylating agents Oral azacytidine Check-point inhibitors Nivolumab Small molecule inhibitors FLT3 Kinase inhibitors, IDH inhibitors, ABT-199 Vaccines CAR-T cells No defined standard AML Salvage Determine by age and remission duration Remission durations 12 mos: - CR ~ 60% - re-induce; clinical trial; HSCT in CR2 Remission durations < 12 mos: - CR ~ 10-20% - clinical trial; best supportive care for older pts Representative Salvage Chemotherapy Regimens (NCCN) Cladribine + cytarabine + GCSF ± mitoxantrone or idarubicin High-dose cytarabine + anthracycline Fludarabine + cytarabine + GCSF ± idarubicin Mitoxantrone + etoposide + cytarabine (MEC) Prognostic Markers of AML in First Relapse 667 pts (non-apl) in first Relapse % OS 1-y 5-y %CR Strongly consider clinical trial in AML relapse Wierzbowska A et al. Eur J Haematol 2008; 80: ; Montillo M et al. Am J Hematol 1998; 58: ; Parker JE et al. Br J Haematol 1997; 99: ; Amadori S et al. J Clin Oncol 1991; 9: RFI and CG (0-5) Age (0-2) Previous SCT (2) Low score=high OS Breems DA et al. J Clin Oncol 2005; 23: 1969 Clonal Evolution of AML by Molecular Profiling Acute Promyelocytic Leukemia Incidence 10-15% (FAB M3) - higher in hispanics (20-25%) and with BMI Median age at Dx 40 yrs Coagulopathy and hemorrhage Promyelocytes: - strongly MPO (+); multiple Auer rods - CD9 (+), CD13 (+), CD33 (+), CD34 (-), HLA-DR (-) Translocation t(15;17) with PML/RAR- fusion transcripts Ding L et al. Nature. 2012;441:

11 Event-free survival probability Overall survival probability Acute Promyelocytic Leukemia Two morphologic variants Model of PML-RARA-mediated Transcriptional Repression, RA-induced Activation, and Differentiation Therapy Hypergranular 80% of APL faggot cells Microgranular (M3v) 20% of APL WBC Ablain J, de The H Blood 2011; 117: Early Death Rate in APL (SEER Data) 1400 pts with APL Dx Death rate 17.3% (age 55 yrs 24.2%, p<.0001) 3-yr overall survival (age 55 yrs 47%, p<.0001) - 55% if Dx % if Dx % if Dx Cox proportional hazards model - only diagnostic time peroid and age were significant for survival Park JH et al. Blood 2011; 118: 1248 ATO arm R Chemo Arm Randomized Trial - Treatment Induction ATO ATRA Until CR Estey et al, Blood 2006 Ravandi et al. JCO 2009 Lo-Coco et al, Blood 2010 Consolidation ATO ATO ATO ATO 4 weeks on / 4 weeks off 2 weeks on / 2 weeks off Induction Consolidation Maintenance IDA IDA MTZ IDA ATRA ATRA ATRA ATRA Until CR 3 monthly cycles MTX + 6MP ATRA 2 years ATRA+ ATO - Event-free Survival Primary endpoint 97.1% ATRA + ATO - Overall Survival 98.7% 91.1% 85.6% p = 0.02 ATRA+ATO ATRA+Chemo p = 0.02 ATRA+ATO ATRA+Chemo Lo-Coco F, et al. N Engl J Med ;369(2): Months from diagnosis Lo-Coco F, et al. N Engl J Med ;369(2): Months from diagnosis 11

12 ATRA + ATO Longer follow-up Platzbecker U, et al. JCO