Acute Myeloid Leukemia: State of the Art in 2018

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1 Acute Myeloid Leukemia: State of the Art in 2018 Harry P. Erba, MD, PhD Professor, Department of Medicine Director, Leukemia Program Duke University Durham, NC

2 Treatment Paradigm of Adults with AML Fit for intensive chemotherapy Induction chemotherapy CR Consolidation chemotherapy CR Allo HSCT AML Dx Refractory Relapse Salvage Therapy Unfit for intensive chemotherapy Azacitidine Decitabine LD Cytarabine Gemtuzumab ozogamicin response Maintenance

3 Probability ECOG E1900 (Treatment Naïve AML, < Age 60 Years): Overall Survival 1.0 All Patients (N = 647) DNR 90 mg/m 2 /day x 3 + Cytarabine 100 mg/m 2 /day x 7 DNR 45 mg/m 2 /day x course to CR Sibling Donor Allogeneic HSCT High-dose Cytarabine x 2 cycles Observation Gemtuzumab Ozogamicin 6 mg/m 2 x1 Auto HSCT Log Rank P = Induction Treatment DNR 45 mg/m 2 /day DNR 90 mg/m 2 /day N = 327 N = 330 CR 57% CR 71% Month Fernandez HF, et al. N Engl J Med. 2009; 361(13):

4 Benefit of High Dose Daunorubicin in Induction Therapy for Adults < Age 60 Years with FLT3 ITD + AML Overall Survival DNR 90 DNR 45 CR rate 70% 48% Median OS 15.2 mo 10.1 mo OS at 4 years 28% 17% Luskin MR, et al. (Update ECOG 1900). Blood 2016

5 No Benefit of Daunorubicin 90 vs 60 mg/m 2 in Induction Therapy for Younger AML Patient CR rate DA60 75% DA90 73% Burnett A, et al. (UK NCRI AML 17) Blood. April 1, 2015

6 Higher Daunorubicin Exposure Benefits FLT3 Mutated AML ITD and TKD At 3 years DNR 90 DNR 60 HR P CIR 44% 60% RFS 45% 33% OS 54% 34% Burnett A, et al. (UK NCRI AML 17). Blood 2016; 128 (3): 449.

7 S1203: Overall survival (N = 261, deaths = 99) IA (N = 261, deaths = 96) IA+V (N = 216, deaths = 88) IA+V versus IA p value = 0.60 IA+V versus 7+3 p value = 0.67 IA versus 7+3 p value = 0.92 Garcia-Manero G. et al. ASH Years since randomization

8 Fractionated GO Improves EFS in Adult AML Patients 280 patients with treatment naïve de novo AML, age % intermediate risk karyotype, 3% favorable risk, 18% FLT3 ITD+ Induction: DNR 60 mg/m 2 /d x 3 and Ara-C 200 mg/m 2 /d x 7 +/- GO 3 mg/m 2 d 1, 4, 7 Consolidation: DNR 60 mg/m 2 d 1 and Ara-C 1 gram/m 2 q12 hr d 1-4 +/- GO 3 mg/m 2 d 1 DA DA+GO CR rate 75% 81% EFS, 2 years 17% 41% RFS, 2 years 23% 50% OS, median 19 months 34 months Longer duration of both neutropenia and thrombocytopenia in DA+GO 3 cases of VOD/SOS, 2 fatal. No VOD following allo HSCT (only 6 pt) Castaigne S, et al. Leukemia 2012;379:

9 Addition of Fractionated GO to Induction and Consolidation Improves Event-free and Overall Survival EFS OS Castaigne S, et al. Lancet 2012; 379:

10 Forest Plot of Event Free Survival (ALFA 0701) Castaigne S, et al. Lancet 2012; 379:

11 RATIFY (CALGB 10603): Chemotherapy + Midostaurin or Placebo Newly Diagnosed Patients < 60 Years With FLT3-Mutated AML Induction Consolidation x 4 Maintenance ND AML FLT3-ITD / TKD+ (Mutation Screening Within 48 Hours) Age years 3277 subjects screened; 896 FLT3 mutation positive; 717 randomized (80% selection bias) n = 717 R 1:1 Daunorubicin Cytarabine plus Placebo Daunorubicin Cytarabine plus Midostaurin High-Dose Cytarabine plus Placebo High-Dose Cytarabine plus Midostaurin Placebo Midostaurin Collaboration with 13 international cooperative groups; 225 sites from 17 countries Alliance, SWOG, ECOG, NCIC CTG, GIMEMA, EORTC, AMLSG, SAL, OSHO, PETHEMA, CETLAM 9 academic FLT3 screening laboratories worldwide Stone RM, et al. N Engl J Med. 2017;377:

12 RATIFY (CALGB 10603): Overall Survival Median OS OS Subgroup Analysis 51% 44% Toxicity No difference in early mortality Higher rate of rash and GI toxicity with mido Stone RM, et al. N Engl J Med. 2017;377:

13 Phase 3 Study of CPX-351 Versus 7+3 in Older Patients With Newly Diagnosed High-Risk AML Key eligibility Previously untreated Aged years Able to tolerate intensive therapy PS 0-2 CPX-351 n = 153 Stratifications Therapy-related AML AML with history of MDS with and without prior HMA therapy AML with history of CMML De novo AML with MDS karyotype Aged years Aged years 7+3 n = 156 Induction CPX mg/100 mg per m 2 IV days 1, 3, 5 Cytarabine 100 mg/m 2 /day x 7 plus daunorubicin 60 mg/m 2 /day x 3 Lancet JF et al. J Clin Oncol. 2018; 36: Reinduction CPX-351 days 1 and 3 OR 5+2 Induction (1-2 cycles) Primary endpoint: Overall survival Patients in CR or CRi: Consolidation (1-2 cycles) Follow-up Death or 5 years Consolidation CPX mg/65 mg per m 2 IV days 1, 3 Cytarabine 100 mg/m 2 /day x 5 plus daunorubicin 60 mg/m 2 /day x 2

14 Patients, % Patients, % CPX-351 Versus 7+3 for Secondary AML: 30-Day and 60-Day Mortality Rates % % % % CPX Deaths 30 Days 0 CPX Deaths 60 Days Deaths Secondary to Progressive AML Deaths Secondary to Adverse Event Lancet JE et al. J Clin Oncol. 2016; 34(suppl): 7000.

15 Phase 3 Study of CPX-351 Vs 7+3 in High-Risk AML: Response Rate CPX-351 (n = 153) 7+3 (n = 156) 60 P =.016 P = % Patients, % a % 25.6% 33.3% 0 Odds ratio (95% CI) CR CR + CRi 1.69 (1.03, 2.78) 1.77 (1.11, 2.81) Lancet JF et al. J Clin Oncol. 2018; 36:

16 Survival, % CPX-351 Improves Survival Among Older, High-Risk AML Kaplan-Meier Curve for OS: ITT Analysis Population Lancet JF et al. J Clin Oncol 2018; 36:

17 Delayed Recovery of ANC and Platelet Count with CPX-351 Compared with 7+3 in Older, High Risk AML Patients receiving 1 induction ANC 500/mcL Platelets 50,000/mcL CPX CPX n = 58 n = 34 n = 58 n = 34 Median, days Patients receiving 2 inductions n = 15 n = 18 n = 15 n = 18 Median, days Lancet JE et al. J Clin Oncol. 2016; 34(suppl): 7000.

18 Induction Therapy for Adult AML (Fit for chemotherapy, age agnostic) Prior leukemogenic therapy Antecedent MDS or MDS/MPN Cytogenetic Risk FLT3 mutation CBF AML Intermediate risk FLT3 Mutated Secondary AML Poor risk karyotype DNR / Ara-C + GO DNR / AraC + midostaurin CPX 351

19 Barriers to Incorporating Recently Approved Agents into AML Therapy Labeled indication may be too restrictive or too permissive Extrapolation of clinical trial data to other populations History of drug development Value of EFS benefit Clinician preferences/beliefs regarding AML therapy Cost of new agents and inpatient payments Lack of data on combination therapies TAT for cytogenetic and mutation analysis

20 Treatment Paradigm of Adults with AML Fit for intensive chemotherapy Induction chemotherapy CR Consolidation chemotherapy CR Allo HSCT AML Dx Refractory Relapse Salvage Therapy Unfit for intensive chemotherapy Azacitidine Decitabine LD Cytarabine Gemtuzumab ozogamicin response Maintenance

21 AML-001 Study of Aza vs CCR in Older AML: Overall Survival a ITT population. b Median follow-up for OS was 24.4 months, with 193 deaths in AZA arm (80.1%) and 201 deaths in the CCR arm (81.4%). c Stratified by ECOG PS and cytogenetic risk. Dombret H et al. Blood. 2015; 126:

22 GO vs BSC in Older Treatment Naïve AML: EORTC/GIMEMA AML 19 All Patients Favorable/Intermediate Risk Karyotype Poor Risk Karyotype GO 6 mg/m 2 day 1, 3 mg/m 2 day 8 followed by 2 mg/m 2 q month x 8 GO CR rate 27% Median overall survival: GO 4.9 months, BSC 3.6 months Decreased survival benefit with lower CD33 expression Amadori S et al. J Clin Oncol 2016; 34: 972

23 Phase Ib VEN + HMA: Patient Characteristics Characteristic N=145* Median age (range), years 74 (65 86) Male, n (%) 81 (56) ECOG Performance Score, n (%) 0 32 (22) 1 90 (62) 2 23 (16) Baseline bone marrow blasts, n (%) 30% 44 (30) 31 50% 48 (33) >50% 53 (37) Median months on study (range) 8.9 ( ) Baseline hydroxyurea use, n (%) 14 (10) * Includes 11 patients treated with 1200 mg of venetoclax Cytogenetic risk groups defined in 2014 NCCN guidelines, version 2 Site reported data; to be confirmed by central laboratory Key Characteristic N=145* Age 75 years, n (%) 62 (43) Cytogenetics, n (%) Intermediate risk 74 (51) Poor risk 71 (49) Mutation, n (%) FLT3 14 (10) IDH 1/2 22 (15) TP53 16 (11) Secondary AML, n (%) 36 (25) Data cutoff was July 7, 2017 median months of follow up was 15.6 DiNardo CD et al. EHA Annual Congress. 2018

24 Phase Ib VEN + HMA in AML: Treatment-Emergent AE AEs in 25% of patients Any grade Grade 3/4 Any event, n (%) 145 (100) 141 (97) Nausea 88 (61) 2 (1) Diarrhea 76 (52) 7 (5) Constipation 70 (48) 2 (1) Febrile neutropenia 63 (43) 63 (43) Fatigue 54 (37) 8 (6) Hypokalemia 49 (34) 15 (10) Decreased appetite 48 (33) 3 (2) Decreased WBC count 45 (31) 45 (31) Vomiting 44 (30) 0 Platelet count decreased 42 (30) 35 (24) Anemia 40 (28) 36 (25) Cough 41 (28) 0 Peripheral edema 41 (28) 0 No Clinical or Laboratory Evidence of TLS Serious AEs in 3% of patients N = 145 Any event, n (%) 102 (70) Febrile neutropenia 46 (32) Pneumonia 17 (12) Bacterial Infection 9 (6) Lung Infection 7 (5) Sepsis 6 (4) Hypotension 5 (3) Mental Status Changes 4 (3) Gastrointestinal Hemorrhage 4 (3) Mucosal Inflammation 4 (3) Patient Disposition Deaths, n (%) N=145* 30 days after Ven start 5 (3) 60 days after Ven start 11 (8) DiNardo CD et al. European Hematology Association Congress 2018, Stockholm, Sweden.

25 R a te o f R e s p o n s e (% ) Phase Ib VEN + HMA in AML: Response Rates by Treatment Patients (%) with CR/CRi shown at the top of each bar * Includes 11 patients that received 1200 mg venetoclax A ll D o s e s * V e n m g V e n m g A z a D e c A z a D e c N = n = 2 9 n = 3 1 n = 3 7 n = 3 7 O t h e r R D M L F S P R C R i C R DiNardo CD et al. European Hematology Association Congress 2018, Stockholm, Sweden.

26 R a te o f R e s p o n s e (% ) Phase Ib VEN + HMA in AML: Response Rates by Patient Subgroups C y t o g e n e t ic R is k A M L A g e Patients (%) with CR/CRi shown at the top of each bar O t h e r R D M L F S P R C R i C R In t r m e d P o o r D e n o v o 2 o < n = 7 4 n = 7 1 n = n = 3 6 n = 8 3 n = 6 2 DiNardo CD et al. European Hematology Association Congress 2018, Stockholm, Sweden.

27 O v e r a ll S u r v iv a l (% ) Phase Ib VEN + HMA in AML: Overall Survival Median Months of Survival (95% CI) Ven 400 mg NR (11.0 NR) All Patients 17.5 (12.3 NR) Ven 800 mg 17.5 (10.3 NR) V e n m g A ll P a tie n t s V e n m g P a t ie n t s a t R is k A ll p a t ie n t s M o n t h s S in c e F ir s t D o s e V e n m g V e n m g DiNardo CD et al. European Hematology Association Congress 2018, Stockholm, Sweden. 2

28 Standard Therapy for Unfit AML Have single agent HMA or LoDAC been replaced by venetoclax combination based on results of phase Ib studies? If so, why?

29 Treatment Paradigm of Adults with AML Fit for intensive chemotherapy Induction chemotherapy CR Consolidation chemotherapy CR Allo HSCT AML Dx Refractory Relapse Salvage Therapy Unfit for intensive chemotherapy Azacitidine Decitabine LD Cytarabine Gemtuzumab ozogamicin response Maintenance

30 Phase III Study of Elacytarabine vs Investigator Choice for Rel/Ref AML Prior Regimen 1 9% 2 60% >3 31% Investigator Choice: HiDAC MEC FLAG FLAG/IDA LoDAC Azacitidine Decitabine Hydroxyurea Supportive care Roboz G et al. J Clin Oncol. 2014; 32:

31 Enasidenib in Patients With IDH2 Mutations: Responses Parameter Relapsed or Refractory AML Enasidenib 100 mg/d (n = 109) All Doses (N = 176) ORR, % [n/n] 95% CI 38.5% (42/109) [ ] 40.3% (71/176) [ ] Best response CR, n (%) [95% CI] 22 (20.2) [ ] 34 (19.3) [ ] CRi or CRp, n (%) 7 (6.4) 12 (6.8) PR, n (%) 3 (2.8) 11 (6.3) MLFS, n (%) 10 (9.2) 14 (8.0) SD, n (%) 58 (53.2) 85 (48.3) PD, n (%) 5 (4.6) 9 (5.1) NE, n (%) 2 (1.8) 3 (1. 7) Time to first response (mo), median (range) 1.9 ( ) 1.9 ( ) Duration of response (mo), median [95%CI] 5.6 [ ] 5.8 [ ] Time to CR (mo), median (range) 3.7 ( ) 3.8 ( ) Duration of CR (mo), median [95%CI] 8.8 [5.3, NR] 8.8 [6.4, NR] Overall response by IDH mutation type: R140Q 36% / R172K 42% Stein EM et al. Blood. 2017;130:

32 Enasidenib in R/R AML Patients With IDH2 Mutations: OS R/R AML Patients Treated at all Doses (N = 176) Median Overall Survival : 9.3 months (95% CI 8.2, 10.9) Stein EM et al. Blood. 2017;130:

33 Enasidenib in R/R IDH2m+ AML: OS by Best Response R/R AML Patients (N =176) Median OS (95% CI) CR 19.7 mo (11.6-NE) Non-CR Response 13.8 mo ( ) No Response 7.0 mo ( ) Stein EM et al. Blood. 2017;130:

34 Enasidenib-induced Differentiation of IDH2-R140Q Clone Screening 37% BM Blasts Cycle 1 d 15 Evidence of Cellular Differentiation Cycle 3 d 1 4% BM Blasts Blasts Promyelocytes Mature Granulocytes Lymphocytes Stein EM et al. Blood. 2017;130:

35 IDH Differentiation Syndrome (IDH-DS): Analysis of the Phase I/II Enasidenib Study 33 of 281 (11.7%) of enasidenib-treated patients had possible/probable IDH-DS Fathi A et al. JAMA Oncol. 2018; 4(8):

36 2-HG ng/ml midh2 VAF IDH2 Inhibition: 2-HG, VAF, and Response 1.0x10 5 Baseline 2-HG levels and baseline midh2 VAF were similar for responding and nonresponding patients 80 Number of Patient Samples 1.0x x x x10 1 CR R NR R140 R172 Plasma 2-HG (ng/ml) at baseline in 125 efficacy-evaluable R/R AML patients with baseline 2-HG data Amatangelo MD, et al. Blood. 2017;130: PM BM CR R140 PM BM R R PM BM NR NR R172 Baseline midh2 VAF from PB or BM in R/R AML patient samples

37 Co-mutational Burden and N-RAS Mutation are Associated with Lack of Response to Enasidenib in Relapsed / Refractory IDH2m+ AML Amatangelo MD, et al. Blood. 2017;130:

38 Ivosidenib in R/R IDH1m AML: Baseline Demographics Characteristic R/R AML 500 mg (n=179) Characteristic R/R AML 500 mg (n=179) Women / men, n 89 / 90 Age in years, median (range) Age category, n (%) < to < ECOG PS at baseline, n (%) De novo AML, n (%) Secondary AML, n (%) 67.0 (18 87) 47 (26.3) 92 (51.4) 40 (22.3) 36 (20.1) 99 (55.3) 42 (23.5) 2 (1.1) 120 (67.0) 59 (33.0) No. of prior therapies, median (range) 2.0 (1 6) Prior AML therapy outcomes, n (%) Relapsed after transplant In 2nd or later relapse Refractory to initial induction/reinduction therapy Relapsed 1 year of initial therapy In first relapse Other Cytogenetic risk status by investigator, n (%) Intermediate Poor Unknown/missing 43 (24.0) 26 (14.5) 106 (59.2) 17 (9.5) 15 (8.4) 5 (2.8) 105 (58.7) 50 (27.9) 24 (13.4) Pollyea D. et al. European Hematology Association Congress 2018, Stockholm, Sweden. Abstract S1560

39 Ivosidenib in R/R IDH1m AML: Adverse Events Leukocytosis Grade 3 leukocytosis (WBC > 100,000) reported in 14/179 patients (8%) Managed with hydroxyurea None were fatal ECG QT prolongation Grade 3 QT prolongation reported in 18/179 patients (10%) Study drug was reduced in 2 patients and held in 13 patients (all grades) None were fatal QT prolonging medications such as antifungals and fluoroquinolone antiinfectives were allowed on study with monitoring IDH differentiation syndrome (IDH-DS) All grade reported in 19/179 patients (10.6%) Resolved in 17 patients Grade 3 IDH-DS in 9 (5.0%) 7/19 IDH-DS patients had co-occurring leukocytosis No instances of IDH-DS led to dose reduction, permanent treatment discontinuation, or death Managed with corticosteroids and diuretics, and hydroxyurea if accompanied by leukocytosis Best response for the 19 patients with IDH-DS: Best Response CR CRh CRi/CRp MLFS SD NE n= Pollyea D. et al. European Hematology Association Congress 2018, Stockholm, Sweden. Abstract S1560

40 Ivosidenib in R/R IDH1m AML: Response R/R AML 500 mg (n=179) CR+CRh rate, n (%) [95% CI] 57 (31.8) [25.1, 39.2] Time to CR/CRh, median (range) months Duration of CR/CRh, median [95% CI] months 2.0 (0.9, 5.6) 8.2 [5.6, 12.0] CR rate, n (%) [95% CI] 43 (24.0) [18.0, 31.0] Time to CR, median (range) months 2.8 (0.9, 8.3) Duration of CR, median [95% CI] months 10.1 [6.5, 22.2] CRh rate, n (%) 14 (7.8) Duration of CRh, median [95% CI] months 3.6 [1.0, 5.5] R/R AML 500 mg (n=179) Overall Response Rate, n (%) [95% CI] 75 (41.9) [34.6, 49.5] Time to first response, median (range) months Duration of response, median [95% CI] months Best response, n (%) 1.9 (0.8, 4.7) 6.5 [5.5, 10.1] CR 43 (24.0) CRi or CRp 21 (11.7) MLFS 11 (6.1) SD 68 (38.0) PD 15 (8.4) NA 21 (11.7) Pollyea D. et al. European Hematology Association Congress 2018, Stockholm, Sweden. Abstract S1560

41 S u r v iv a l p r o b a b ilit y Ivosidenib in R/R IDH1m AML: OS by Best Response 1.0 C R + C R h 0.9 N o n -C R /C R h re s p o n d e rs 0.8 N o n -re s p o n d e rs 0.7 O v e ra ll C e n s o re d O v e r a ll s u r v iv a l (m o n th s ) N u m b e r o f p a tie n ts a t r is k : Months Overall survival, median [95% CI] CR+CRh Non-CR/CRh responders 18.8 [14.2, NE] 9.2 [6.7, 10.8] Non-responders 4.7 [3.7, 5.7] All 9.0 [7.1, 10.0] Overall follow-up, median (range) 15.3 ( ) C R + C R h N o n -C R /C R h r e s p o n d e rs N o n -r e s p o n d e rs Non-CR/CRh responders include CRi, CRp, and MLFS who are not CRh Non-responders = all others including those with best responses of SD, PD, or not evaluable Pollyea D. et al. European Hematology Association Congress 2018, Stockholm, Sweden. Abstract S1560

42 P o s t-b a s e lin e tra n s fu s io n in d e p e n d e n c e, % Ivosidenib in R/R IDH1m AML: Transfusion Independence C R C R h N o n -C R /C R h re s p o n d e rs N o n -re s p o n d e rs O v erall P la te le t (n = 9 1 ) Transfusion independence was observed across all response categories in R/R AML 500 mg Patients Who Were Dependent at Baseline. Post-baseline transfusion independence defined as no transfusion for at least one 56-day period R B C (n = 9 7 ) Pollyea D. et al. European Hematology Association Congress 2018, Stockholm, Sweden. Abstract S1560

43 Ivosidenib in R/R IDH1m AML: Exposure-adjusted Incidence of Febrile Neutropenia and Grade 3 Infections Best response CR CRh Non-CR/CRh responders Nonresponders Overall (n=43) (n=14) (n=18) (n=104) (n=179) All grade febrile neutropenia 2.0 [1.0, 3.8] 3.7 [1.4, 9.8] 6.1 [2.7, 13.5] 12.1 [8.8, 16.5] 5.9 [4.5, 7.6] Grade 3 infections 2.6 [1.5, 4.6] 6.4 [3.1, 13.5] 13.1 [7.6, 22.6] 21.3 [16.8, 27.0] 10.2 [8.4, 12.4] Incidence rate reported as 100 patients / month [95% CI], calculated as total number of specific AEs / total person exposure time in months x 100 * for all patients with the same best overall response Pollyea D. et al. European Hematology Association Congress 2018, Stockholm, Sweden. Abstract S1560

44 Treatment of Rel/Ref AML with IDH Mutations Responses and goals of therapy Chemotherapy vs IDHm inhibitor

45 Thank You!