Updates in Treatment Strategies for Acute Leukemia. Alexander Perl, MD Assistant Professor, Hematology/Oncology University of Pennsylvania 1/22/2016

Transcription

1 Updates in Treatment Strategies for Acute Leukemia Alexander Perl, MD Assistant Professor, Hematology/Oncology University of Pennsylvania 1/22/2016

2 What is happening to standard of care in 2017? AML treatment no longer is one size fits all Who benefits from something other than 7&3 More intensive induction vs. standard (younger patients) Vorinostat + HiDAC/idarubicin vs. 7&3 Liposomal induction chemo (older patients) CPX-351 Targeted agents added to induction FLT3 inhibitors Making low intensity therapy more effective HMA Novel agents (SGN33A, venetoclax, others) Combining HMA + novel agents

3 Therapy selection in older patients low intensity treatment/su pportive care only/hospice Slide from Jeff Lancet, with permission

4 CPX nm bilamellar liposomes 5:1 molar ratio of cytarabine to daunorubicin 1 unit = 1.0 mg cytarabine plus 0.44 mg daunorubicin Lancet J et al. J Clin Oncol. 2016;34:(suppl; abstr 7000).

5

6 Response rate and early mortality favor CPX-351 over 7&3 in older patients age >60 CPX-351 (n=153) 7 & 3 (n=156) Lancet JE et al. Blood. 2016;128:906a.

7 Overall survival and post-hsct survival improved by CPX-351 in Secondary AML Lancet JE et al. J Clin Oncol. 2016;34:(suppl; abstr 7000); Lancet JE et al. Blood. 2016;128:906a.

8 Genomic Classification and Prognosis in AML Paparmmanuil E et al. NEJM. 2016;374:

9 TP53 Mutations and Prognosis Paparmmanuil E et al. NEJM. 2016;374:

10 TP53 and Decitabine in AML NA = not applicable; PD = progressive disease; PR = partial remission; SD = stable disease. Welch JS et al. N Engl J Med. 2016;375:

11 Vadastuximab (SGN33a) + Hypomethylating Agent in Frontline Older AML LFS = leukemia-free state. Fathi, et al. Blood. 2016;128:591a.

12 Phase 1/2 Trial of Venetoclax + LDAC in Treatment-Naïve Patients Age 65 With AML Ph1: LDAC 20 mg BID x d escalating doses of VEN, repeat q28d RP2D= VEN 600 mg/d (61 pts treated) Median age 74, 40% with antecedent hematologic disorder Wei A, et al. Blood. 2016;128:102a.

13 Crenolanib Phase II Trial in Newly Diagnosed FLT3 mutant AML Induction (1-2 cycles) Treatment naive AML with activating FLT3 mutations 7+3 (cytarabine + daunorubicin) + crenolanib 7+3 (cytarabine + idarubicin) + crenolanib CR/CRi Consolidation (up to 4 cycles) HiDAC + crenolanib and/or BMT Maintenance (up to 12 cycles) crenolanib Key Design Elements: 2 cohorts: A. Daunorubicin/cytarabine + crenolanib 100 mg TID B. Idarubicin/cytarabine + crenolanib 100 mg TID Eligibility criteria: No upper age limit Secondary AML (post MDS) included Any FLT3 allelic burden Very similar design to phase 3 midostaurin + frontline chemo (RATIFY) trial presented at ASH Wang et al., Proc. ASH: abstract 1071

14 Crenolanib Phase II Trial in Newly Diagnosed FLT3 mutant AML Induction (1-2 cycles) Treatment naive AML with activating FLT3 mutations 7+3 (cytarabine + daunorubicin) + crenolanib 7+3 (cytarabine + idarubicin) + crenolanib CR/CRi Consolidation (up to 4 cycles) HiDAC + crenolanib and/or BMT Maintenance (up to 12 cycles) crenolanib Key Design Elements: 2 cohorts: A. Daunorubicin/cytarabine + crenolanib 100 mg TID B. Idarubicin/cytarabine + crenolanib 100 mg TID Eligibility criteria: No upper age limit Secondary AML (post MDS) included Any FLT3 allelic burden Characteristics Total (n=38) Age (yr), median [range] 58 [19 75] De novo AML 33 (87%) Secondary AML 5 (13%) WBC count (unit/µl), median [range] Mutations 32,500 [2, ,800] 100,000 9 (24%) FLT3-ITD only 28 (74%) Very similar design to phase 3 midostaurin + frontline chemo (RATIFY) trial presented at ASH FLT3-ITD and TKD 3 (8%) FLT3-TKD only 7 (18%) Wang et al., Proc. ASH: abstract 1071

15 Clinical Response Rate in 32 Evaluable Patients Induction Chemotherapy Regimen CR after Induction 1 Overall Complete Response Cytarabine + Daunorubicin (n=23) 17/23 (75%) 19/23 (83%) Cytarabine + Idarubicin (n=9) 9*/9 (100%) 9/9 (100%) Total (n=32) 26/32 (81%) 28/32 (88%) 26 (81%) patients achieved CR/CRi after first induction. 6% (2/32) induction mortality 16 (42%) patients were bridged to transplant. 28/28 patients who entered CR had full count recovery by day Wang et al., Proc. ASH: abstract 1071

16 Clinical Response Rate in 32 Evaluable Patients Induction Chemotherapy Regimen CR after Induction 1 Overall Complete Response RATIFY After induction 1 n=360 RATIFY Overall Complete Response Cytarabine + Daunorubicin (n=23) 17/23 (75%) 19/23 (83%) Cytarabine + Idarubicin (n=9) 9*/9 (100%) 9/9 (100%) Total (n=32) 26/32 (81%) 28/32 (88%) 59% 66% 26 (81%) patients achieved CR/CRi after first induction. induction mortality 2/32 (6%) 16 (42%) patients were bridged to transplant. 28/28 patients who entered CR had full count recovery by day Wang et al., Proc. ASH: abstract 1071

17 Overall Survival (n=38) 100 ARO-006 OS Months Number at risk Median follow-up: 6 months (range months) There have been no relapses among patients who entered CR 17 Wang et al., Proc. ASH: abstract 1071

18 ARO-006 OS Overall Survival (n=38) Arm 4-year Survival MIDO 51.4% (95%CI: 46, 57) PBO 44.2% (95%CI: 39, 50) Months Number at risk Median follow-up: 6 months (range months) There have been no relapses among patients who entered CR RATIFY (C10603) study Stone RM, et al. ASH 2016, abstract 6 18 Wang et al., Proc. ASH: abstract 1071

19 Gilteritinib (ASP2215) ASP2215 Conc. (nm) ASP2215 Conc. (nm) Type 1 FLT3 tyrosine kinase inhibitor, also inhibits AXL Active against FLT3 WT, ITD, D835, and gatekeeper (F691L) mutations Administered once daily First in Human Phase 1/2 Eligibility: Adult ( 18 years) subjects with AML who relapsed after, or are refractory to, induction or salvage treatment irrespective of FLT3 mutation status Demographics (n=252): median age 62 (21-90), FLT3+ 76% (87% FLT3-ITD, 6% FLT3-TKD, 6% both) median prior tx=2, 28% s/p transplant, 27% prior FLT3 TKI FBS indicates fetal bovine serum; FLT3, fms-related tyrosine kinase 3; ITD, internal tandem duplications; P-FLT3, phosphorylated fms-related tyrosine kinase 3; WT, wild type.

20 Proportion of Patients Achieving Response (%) Antileukemic Response to 80 mg/day Gilteritinib in FLT3 mut+ Patients by Mutation Type and TKI Status Proportion of Patients Achieving Response (%) Response Rates By FLT3 Mutation Type CR CRp CRi PR ORR=55% CRc=43% ORR=62% CRc=54% ORR=17% CRc=8% FLT3-ITD FLT3-ITD and FLT3-D835 only FLT3-D835 only N=141 N=13 N= Response Rates By TKI Status CR CRp CRi PR ORR=56% CRc=44% TKI Naive N=124 ORR=42% CRc=31% Prior TKI Therapy N=45 Perl AE et al. Blood 2016; 128: 1069a, submitted

21 Overall Survival in FLT3 mut+ Patients Treated With Gilteritinib (N=191)* Gilteritinib 80 mg/day in FLT3 mut+ Patients Median OS: 31 weeks (range: weeks) Median Duration of Response: 20 weeks (range: weeks) Median Time to Best Response: 7.2 weeks (range: weeks) OS, overall survival. Perl AE et al. Blood 2016; 128: 1069a, submitted

22 Updates in ALL therapy Ph+ Use of TKI-intensive regimens with *less* myleosuppressive agents decreases induction mortality in adults and increases overall survival Is transplant still mandatory in optimal responders? What about immunotherapy? Use of pediatric-inspired regimens C10403 Phase 2 trial (borrowed from COG AALL0232) 2% induction mortality 2 year OS 79%/EFS 66% Long term f/u awaited Adult ALL now segregated into AYA (age <35) middle age adult (35-60) older adult /elderly (>60) Stock W, et al. J Clin Oncol 2014 (suppl); 796a Chalandon Y, et al. Blood Jun 11;125(24):

23 Ross ME, et al. Blood Oct 15;102(8):2951-9

24 Ph-Like (BCR-ABL1-like) B-ALL BCR-ABL1(-) subgroup with similar gene expression profile and poor outcome to chemo High incidence of kinase activating mutations, esp. gene fusions JAK, PDGFR, ABL, FLT3, CSF1R, others High frequency of B-lineage transcription factor mutations IZKF1, EBF1, PAX5, others Roberts KG, et al. N Engl J Med Sep 11;371(11):

25 Mutations activating signal transduction occur in ~60% of adult B-ALL 14/18 Ph-like were CRLF2 fusions PH-like= 20% of cases PH+ = 37% of cases Tasian SK, et al Leukemia. 2017

26 Ph-like adult ALL shows poor survival Ph-like adults Roberts, KG et al. J Clin Oncol Nov 21 Jain N, et al. Blood 2016 Dec 5.

27 Current approach to B-ALL New B-ALL dx Age <40 Age (fit) Age >70 (or comorbidity) AYA tx, MRD directed therapy Chemo +/- blina if suboptimal response depth, consider HSCT with pre/post TKI maintenance if Ph+ r/o Ph+ (and Ph-like): Low intensity +/- TKI based (as appropriate)

28 Current approach to B-ALL New B-ALL dx Age <40 Age (fit) Age >70 (or comorbidity) AYA tx, MRD directed therapy Chemo +/- blina if suboptimal response depth, consider HSCT with pre/post TKI maintenance if Ph+ r/o Ph+ (and Ph-like): Low intensity +/- TKI based (as appropriate) Clinical trials examining frontline blinatumomab and/or TKI if Ph-like

29 We re finally getting somewhere! AML therapy is improving Novel agents likely to be approved soon Combinations of low intensity + novel agents promising ALL therapy is improving Better chemotherapy for young adults Immunotherapy (blinatumomab, CART19, ADC s) New and potentially actionable targets in Ph-like ALL

30

31 Backup slides

32 Better targeted therapy for FLT3 mut + AML Lots happening: Crenolanib + frontline chemo ph2 (interim data: ASH 2016) Gilteritinib (ASP2215) ph 1/2 (final data: ASH2016) Ph3 quizartinib + frontline chemo enrolling Ph2 frontline gilteritinib + frontline chemo enrolling Ph3 data from quizartinib (AC220) vs. salvage coming soon Ph3 data from gilteritinib vs. salvage coming soon PH3 gilteritinib vs. placebo post HSCT maintenance to open

33 Demographics (n=38) Characteristics 60 yrs (n=23) > 60 yrs (n=15) Total (n=38) Age (yr), median [range] 48 [19 60] 68 [61 75] 58 [19 75] AML De novo 21 (91%) 12 (80%) 33 (87%) saml 2 (9%) 3 (20%) 5 (13%) WBC count (unit/µl), median [range] 41,350 [3, ,800] 26,460 [2, ,100] 32,500 [2, ,800] 100,000 5 (22%) 1 (7%) 6 (16%) 200,000 2 (5%) 1 (3%) 3 (8%) Mutations FLT3 + ITD 18 (78%) 10 (67%) 28 (74%) FLT3 + TKD 3 (13%) 4 (27%) 7 (18%) FLT3 + ITD and TKD 2 (9%) 1 (7%) 3 (8%) 33 Wang et al., Proc. ASH: abstract 1071

34 AG221 and AG120 Conclusions Drugs were generally well-tolerated Most frequent TEAEs were GI events Both agents induce durable responses in patients with RR-AML: ORR 37% for AG221; 35% for AG-120 Median response duration 5.6 months (AG-120) & 6.9 months (AG221) Prolonged treatment possible in patients with stable disease Target inhibition (2HG reduction) universal not predictive of response depth or reduction in IDH mutation burden Differentiation of leukemia cells prosed mechanism of action Randomized phase 3 study of AG-221 vs conventional care regimens initiated (IDHENTIFY trial; NCT )

35 IDH inhibitors for AML Molecular profiling and relationship with clinical response in patients with IDH1 mutation-positive hematologic malignancies receiving AG-120, a first-in-class potent inhibitor of mutant IDH1, in addition to data from the completed dose escalation portion of the phase 1 study Safety and Efficacy of AG-221, a Potent Inhibitor of Mutant IDH2 That Promotes Differentiation of Myeloid Cells in Patients with Advanced Hematologic Malignancies: Results of a Phase 1/2 Trial Courtney DiNardo 1, Stéphane de Botton 2, Daniel A Pollyea 3, Eytan M Stein 4, Amir T Fathi 5, Gail J Roboz 6, Robert Collins 7, Ronan T Swords 8, Ian W Flinn 9, Jessica K Altman 10, Martin S Tallman 4, Hagop Kantarjian 1, Sung Choe 11, Hua Liu 11, Malia Prahl 11, Bin Wu 11, Katharine Yen 11, Sam Agresta 11, Richard M Stone 12 Eytan M. Stein, Courtney DiNardo, Jessica K. Altman, Robert Collins, Daniel J. DeAngelo, Hagop M. Kantarjian, Mikkael A. Sekeres, Amir T. Fathi, Ian W. Flinn, Arthur E. Frankel, Ross L. Levine, Bruno C. Medeiros, Manish R. Patel, Daniel Pollyea, Gail J. Roboz, Richard M. Stone, Ronan T. Swords, Martin S. Tallman, Katharine Yen, Eyal C. Attar, Qiang Xu, Alessandra Tosolini, Jay M. Mei, Anjan Thakurta, Robert D. Knight, and Stéphane De Botton ASH 2015 abstract #1306 ASH 2015 abstract #323

36 Isocitrate Dehydrogenase (IDH) Mutations as a Target in AML IDH is an enzyme of the citric acid cycle Mutant IDH produces 2- hydroxyglutarate (2-HG), which alters DNA methylation and leads to a block in cellular differentiation AG-221 is a selective, oral, potent inhibitor of the mutant IDH2 enzyme AG120-is a selective, oral, potent inhibitor of mutant IDH1 enzyme Tumor Cell AML, acute myeloid leukemia; IDH, isocitrate dehydrogenase; 2-HG, 2-hydroxyglutarate; midh2, mutated IDH

37 Study Design & study population Dose Escalation Completed Advanced heme malignancies with IDH2 mutation Continuous 28 day cycles Cumulative daily doses of mg Expansion Phase I completed (n=25 pts per arm) RR-AML age 60, or any age if relapsed post-bmt RR-AML age <60, excluding pts relapsed post-bmt Untreated AML pts age 60 who decline standard of care Any hematologic malignancy ineligible for other arms Phase 2 Ongoing AG mg PO QD RR-AML (N 125) For AG-120 Phase 1/2 study: dose escalation from mg Total N=87 Age in years, median (range) 68 (36 89) Men/women, n 45/42 Diagnosis, a n (%) R/R AML 68 (78) MDS/Other 10 (12) Untreated AML 8 (9) ECOG performance status, b n (%) 0 19 (22) 1 50 (58) 2 16 (18) IDH1 mutation-positive c 78 No. of prior chemotherapy regimens, median (range) 2 (0 5) Prior transplant, n (%) 18 (21) Abnormal 37 cytogenetics at screening, d n (%) 44 (51) Age (years), median (range) 69 (19 100) Gender, % M/F 56/44 IDH2 mutation, n (%) R (70) R (24) ECOG PS, n (%) (77) 2 41 (20) Diagnosis, n (%) RR-AML 159 (76) Untreated AML 24 (11) MDS 14 (7) Other 12 (6) Prior chemotherapy regimens (R/R 2 (1-6) AML)

38 Adverse Events ( 15% of patients) of any attribution AG120 (IDH1) AG221 (IDH2) AE (n=87) Grade 3, n (%) No MTD defined at 1200 mg/d, cohort expansion at 500 mg qd No deaths from attributed to study drug DLT s: Gr3 QT increase (800 mg, n=1) Gr3 rash (1200 mg, n=1) All grades, n (%) 1 AE 65 (75) 78 (90) Fatigue 6 (7) 25 (29) Diarrhea 1 (1) 23 (26) Nausea 3 (3) 21 (24) Pyrexia 3 (3) 21 (24) Leukocytosis 7 (8) 18 (21) Peripheral edema - 17 (20) Vomiting 2 (2) 16 (18) Febrile neutropenia 16 (18) 16 (18) Anemia 13 (15) 15 (17) Constipation 1 (1) 14 (16) Decreased appetite 1 (1) 14 (16) Dyspnea 5 (6) 14 (16) Dose-escalation ended; MTD not reached Cohort expansion at 100 mg/d Any Grade AE (n=209) % Nausea 32 2 Diarrhea 28 3 Fatigue 28 6 Hyperbilirubinemia Decreased appetite 27 3 Febrile neutropenia Dyspnea 23 5 Pyrexia 23 4 Cough 22 0 Vomiting 20 1 Constipation 19 < 1 Anemia Peripheral edema 18 2 Thrombocytopenia Drug-related grade 5 SAEs: Grade 3 atrial flutter (1), cardiac tamponade (1), pericardial effusion (1), respiratory failure (1)

39 AG120 (IDH1) ORR, n (%) (95% CI) Clinical Responses Total N=78 27 (35%) (24%, 46%) CR, n (%) 12 (15%) CRp, n (%) 7 (9%) PR, n (%) 1 (1%) mcr/mlfs, n (%) 6 (8%) CRi, n (%) 1 (1%) SD, n (%) 40 (51%) PD, n (%) 7 (9%) NE, n (%) 4 (5%) Overall Response (CR, CRp, CRi, mcr, PR) RR-AML (n = 159) 59 (37%) [95%CI: 30%, 45%] All (N = 209) 79 (38%) [31%, 45%] CR, 39complete response; CRp, CR with incomplete platelet recovery; CRi, CR with incomplete hematologic recovery; mcr, marrow CR; PR, partial response; SD, stable disease; PD, progressive disease CR AG221 (IDH2) 29 (18%) [95%CI: 13%, 25%] 37 (18%) [13%, 24%] CRp 1 (1%) 3 (1%) CRi 3 (2%) 3 (1%) mcr 9 (6%) 14 (7%) PR 17 (11%) 22 (11%) SD 72 (45%) 96 (46%) PD 10 (6%) 11 (5%) Not evaluable 18 (11%) 23 (11%) Overall response by IDH mutation: R140Q 36% / R172K 42%

40 AG120 (IDH1) AG221 Treatment Durations 27 patients who met protocol defined responses of CR/CRp/mCR/PR to AG120 Duration of treatment and best overall response (dose escalation patients, n=78) AG221 (IDH2) CR CRp CRi Responders to AG221 (CR, CRp, CRi, mcr, PR): n=59 Median Tx duration: 6.8 months (range: ) mcr PR SD PD NE/Missing Treatment Duration (months)

41 Frequency AG120 AG221 IDH1 variant allele frequency (VAF) and 2HG level in 14 patients who achieved CR or CRp. 2HG remain suppressed even at disease progression, following repsonse Majority of patients with CR treated to date at Memorial Sloan Kettering Cancer Center do not have appreciable decrease in IDH2 VAF 0.6 Pretreatment Response Pt_001 Pt_003 Pt_006 Pt_010 Pt_018 Pt_030 Patients Courtesy of Drs. Ross Levine and Alan Shih, MSKCC a Patients with best response CR or CRp, data unavailable for CRi; bone marrow mononuclear cells; only on-treatment samples included; 5 patients discontinued for transplant < 106 days: 2 CR and 3 CRp; b Bone marrow samples; 1 patient excluded due to missing 2-HG level at baseline Persistent VAF during blast reduction response suggests differentiation of IDH mutant AML in response to IDH inhibition

42 Ph+ ALL: Current approach Untreated Ph+ ALL TKI + minimal chemo MRD(+) MRD assessment Post-remission chemo + TKI +/- blinatumomab MRD assessment MRD(-) HSCT MRD(+/-) MRD(+) TKI maintenance

43 CR rate 53/53= 100% Induction mortality=0 Age >65 Ph+ older patients now fare better than Ph(-) Dasatinib + steroids/vcr CR rate 67/71= 96% Induction mortality=4% Age >55 Dasatinib + low intensity chemo Foa R, et al. Blood Dec 15;118(25): Rousselot P, et al. Blood Aug 11;128(6):

44 Middle age and older= high risk ALL E2993: High risk = Age >35 WBC >100 if B-ALL, >30 if T-ALL Sive JI, et al. Br J Haematol May;157(4): Goldstone AH, et al. Blood Feb 15;111(4):

45 Ph+ ALL over the years ( ) UKALLXII/E2993: DVAP/CyAraC6MP + allohsct GRAALL: Imatinib + hypercvad +/- HSCT vs. auto/chemo + TKI maintenance autopsct (MMR or MRD(-)) allohsct TKI + less chemo chemo TKI + more chemo Fielding AK, et al. Blood Feb 6;123(6): Chalandon Y, et al. Blood Jun 11;125(24):

46 Proportion of Patients Achieving Response (%) Proportion of Patients Achieving Response (%) Antileukemic Activity of Gilteritinib in relapsed/refractory AML Response in FLT3 mut+ and FLT3 WT Patients (N=249) Response in FLT3 mut+ Patients by Gilteritinib Dose (N=191) CR CRp CRi PR Gilteritinib 80 mg/day: CRc (CR+CRp+CRi)=41% ORR=67% ORR=52% ORR=49% CRc=37% ORR=38% CRc=42% ORR=55% CRc=46% ORR=47% CRc=39% ORR=60% CRc=30% ORR=50% CRc= CRc= ORR=12% CRc=9% ORR=14% CRc=7% 0 FLT3 WT (N=58) FLT3 mut+ (N=191) 0 20 mg n=14 40 mg n=8 80 mg 120 mg 200 mg n=12 n=56 n= mg n= mg n=2 Perl AE et al. Blood 2016; 128: 1069a, submitted