Neue zielgerichtete Behandlungsoptionen der neu diagnostizierten FLT3-positiven Akuten Myeloischen Leukämie (AML) Prof. Hartmut Döhner Klinik für Innere Medizin III, Universitätsklinikum Ulm Midostaurin Launch München, 19. Oktober 2017
FLT3 Mutations in AML FLT3 internal tandem duplications (ITD) found in ~25% of younger adult patients; associated with inferior prognosis High mutant-to-wild type ITD allelic ratio ( 0.5) ITD insertion site (JM vs. TK-1 domain) FLT3 tyrosin kinase domain (TKD) mutations in 8%; prognostic impact less well defined Impact for treatment: FLT3 inhibitors in clinical development 1 st generation: Midostaurin, lestaurtinib, sorafenib 2 nd generation: Quizartinib, crenolanib, gilteritinib Allogeneic hematopoietic cell transplantation improves outcome Litzow MR, Blood. 2005;106:3331-32. Whitman SP et al. Absence of the WT allele predicts poor prognosis in adult de novo aml with normal cytogenetics and the internal tandem duplication of FLT3: a cancer and leukemia group B study. Cancer Res. 2001;61(19):7233-9; Thiede C et al. Analysis of FLT3-activating mutations in 979 patients with AML association with FAB subtypes and identification of subgroups with poor prognosis. Blood. 2002;99(12):4326-35; Kottaridis PD et al. Activating ITD mutations of the fms-like tyrosine kinase-3 at complete response and relapse in patients with AML. Blood. 2002;100(7):2393-8; Gale R et al. The impact of FLT3 internal tandem duplication mutant level, number size and interaction with NPM1 mutations in a large cohort of young adult patients with AML. Blood. 2008;111(5):2776-84; Breitenbuecher F et al. Identification of a novel type of ITD mutations in nonjkuxtamembran domains of the FLT3 tyrosine kinase receptor. Blood. 2009;113(17):4074-7; Kayser S et al. Insertion of FLT3 ITD in the tyrosine kinase domain-1 is associated with resistance to chemotherapy and inferior outcome. Blood. 2009;114(12):2386-92; Breitenbuecher F et al. A novel molecular mechanism of primary resistance to FLT3-kinase inhibitors in AML. Blood. 2009;113(17):4063-73; Schlenk RF et al. Differntial impact of allelic ration and insertion site in FLT3-ITD-positive AML with respecht to allegenic transplantation. Blood. 2014;124(23):3441-9; Stone RM et al. Midostaurin plus chemotherapy for AML with FLT3-Mutation. N Engl J Med. 2017;377:354-64.
Number of unique patients with driver mutation Genomic Landscape of Adult AML 500 400 300 20 15 10 5 ELN risk category Favorable Intermediate I Intermediate II Adverse Not available 200 0 100 0 Targeted resequencing of 111 myeloid cancer genes (combined with cytogenetic profiles) in 1540 AML 5236 driver mutations (i.e., fusion genes, copy number alterations, gene mutations) involving 77 loci 6 genes mutated in >10% pts; 13 genes 5-10% pts; 24 genes 2-5% pts; 37 genes <2% pts ELN: European Leukemia Net Papaemmanuil E et al. Genomic Classification and Prognosis in AML. N Engl J Med. 2016;374(23):2209-21.
Driver Mutations with Effect on Overall Survival Adverse Favorable Papaemmanuil E et al. Genomic Classification and Prognosis in AML. N Engl J Med. 2016;374(23):2209-21.
FLT3 Inhibitors in Clinical Development Relative selectivity and potency (IC 50 ) of TKIs against FLT3-ITD 1 st generation TKIs non-selective; unfavorable safety profile; when used as single agent, only transient blast reductions observed 2 nd generation TKIs (quizartinib [AC220], crenolanib, gilteritinib [ASP2215]) more selective and more potent TKI: Tyrosine Kinase Inhibitor, ITD: Internal Tandem Duplication Galanis A et al. Crenolanib: A next generation FLT3 inhibitor. Cancer Res. 2012;72:3660 (abstract); Karaman MW et al. A quantitativ analysis of kinase inhibitor selectivity. Nature Biotechnology. 2008;26(1):127-132; Zarrinkar PP et al. AC220 is a uniquely potent and selective inhibitor of FLT3 for the treatment of AML. Blood. 2009;114(14):2984-2992.
Midostaurin Preclinical Development Midostaurin (PKC412; N-benzoylstaurosporine) is a potent FLT3 (both ITD and TKD) inhibitor; also inhibits PKC, VEGFR, KIT, and PDGFR 1,2 Midostaurin specifically inhibits growth of leukemic cell lines made factor independent by transfection of activating FLT3 mutation (ITD or D835Y) 2 Midostaurin increased survival in a murine BMT model of FLT3-ITD myeloproliferative disorder 3 BMT: Bone Marrow Transplant; PKC: Protein Kinase C; VEGFR: Vascular Endothelial Growth Factor Receptor; PGFR: Platelet-derived Growth Factor Receptor; TKD = Tyrosine Kinase Domain 1 Propper DJ et al. Phase I and pharmacokinetic study of PKC412, an inhibitor of protein kinase C. J Clin Oncol. 2001;19:1485-1492; 2 Weisberg E et al. Inhibition of mutant FLT3 receptors in leukemia cells by the small molecule tyrosine kinase inhibitor PKC412. Cancer Cell. 2002;1:433-443. 3 Kelly LM et al. FLT3 ITD mutation associated with human acute myeloid leukemias induce myeloproliverative disease in a murine bone marrow transplant model. Blood. 2002;99:310-318.
Phase I/II Trials with PKC412 (Midostaurin) PKC412 (75mg TID) in 20 pts with r/r AML & FLT3 mutation 1 >50% reduction in BM blasts in 5/20 (25%), and PB blasts in 14/20 (70%) PKC412 (50/100 mg BID) in 92 pts with r/r AML 2 >50% reduction in BM or PB blasts: FLT3 mut : 25/35 (71%); FLT3 wt : 24/57 (42%) 3+7 induction + PKC412 (100/50 mg BID; continuous vs. intermittent dosing) in 69 pts with newly diagnosed AML 3 BM: Bone Marrow, PB: Peripheral Blood; PKC: Protein Kinase C 1 Stone R et al. Patients with AML and an activating mutation in FLT3 respond to a small-molecule FLT3 tyrosine kinase inhibitor, PKC412. Blood. 2005;105:54-60; 2 Fischer T et al. Phase IIB trial of oral midostaurin (PKC412), the FMS-like tyrosine kinase and multi-targeted kinase inhibitor, in patients with AML or high-risk MDS with either wild-type or mutated FLT3. J Clin Oncol. 2010;28:4339-4345; 3 Stone R et al. Phase IB Study of the FLT3 kinase inhibitor midostaurin with chemotherapy in younger newly diagnosed adult patients with AML. Leukemia. 2012;26:2061-2068.
Phase IB Trial Combining Intensive Chemotherapy with Midostaurin FLT3 mut : CR 12/13 (92%) FLT3 wt : CR 20/27 (74%) FLT3 mut FLT3 wt CR: Complete Remission Stone R et al. Phase IB Study of the FLT3 kinase inhibitor midostaurin with chemotherapy in younger newly diagnosed adult patients with AML. Leukemia. 2012;26:2061-2068
Midostaurin in AML Stone RM et al. N Engl J Med. 2017;377:354-64.
Midostaurin in AML Basel, September 18, 2017 the European Commission (EC) approved midostaurin for two indications: Midostaurin is approved for use in combination with standard daunorubicin and cytarabine induction and high-dose cytarabine consolidation chemotherapy, and for patients in complete response followed by midostaurin single agent maintenance therapy, for adults with newly diagnosed acute myeloid leukemia (AML) who are FLT3 mutation-positive It was also cleared for use as monotherapy for the treatment of adults with aggressive systemic mastocytosis (ASM), systemic mastocytosis with associated hematological neoplasm (SM-AHN) or mast cell leukemia The approval follows a positive opinion issued by the European Medicines Agency's (EMA) Committee for Medicinal Products for Human Use (CHMP) on July 20, 2017 and applies to all 28 EU member states, plus Iceland, Liechtenstein and Norway
Phase III Study of Chemotherapy + Midostaurin (PKC412) or Placebo in Newly Diagnosed Patients 60 Years of Age with FLT3 Mutated Acute Myeloid Leukemia (RATIFY) CALGB, AMLSG, CETLAM, ECOG, EORTC, GIMEMA, NCIC, OSHO, PETHEMA, SAL, SWOG Induction (1-2 cycles) CR Consolidation** (up to 4 cycles) CR Postconsolidation (up to 12 cycles) Patients with newly diagnosed AML 18 to <60 years with activating FLT3 mutations Screening within 48hrs* Stratification by TKD and ITD (ratio <0.7 vs. 0.7) (n=717) R Double blind Midostaurin (50 mg bid, days 8-21) Daunorubicin (60 mg/m 2 /day, days 1-3) Cytarabine (200 mg/m 2 /day, days 1-7) Placebo (bid, days 8-21) Daunorubicin (60 mg/m 2 /day, days 1-3) Cytarabine (200 mg/m 2 /day, days 1-7) Midostaurin (50 mg bid, days 8-21) High-dose cytarabine (3 g/m 2 /day q12h, days 1, 3, and 5) Placebo (bid, days 8-21) High-dose cytarabine (3 g/m 2 /day q12h, days 1, 3, and 5) Midostaurin (50 mg bid, days 1-28) Placebo (bid, days 1-28) * Patients may receive hydroxyurea during screening phase ** Patients with an HLA-compatible family donor may proceed to allogeneic HSCT ClinicalTrials.gov NCT00651261 TKD: Tyrosine Kinase Domain, ITD: Internal Tandem Duplication, OS: Overall Survival, EFS: Event-Free Survival, HSCT: Hematopoietic Stem Cell Transplant Primary endpoint: OS Key secondary endpoint: EFS Stone RM et al. Midostaurin plus chemotherapy for Acute Myeloid Leukemia with FLT3 Mutation. N Engl J Med. 2017;377:354-64.
Key Eligibility Criteria Age 18-60, normal end-organ function Documented AML (non-apl) De novo AML AML with antecedent history of MDS (but no therapy with HMA) Therapy-related AML excluded FLT3 mutation centrally determined prior to enrollment Assessed at one of 9 academic labs around the world Results within 48h Up to 5 days of hydroxyurea allowed prior to start of treatment while awaiting results of mutation analysis APL: Acute Promyelocytic Leukemia, MDS: Myelodysplastic Syndrome, HMA: Hypomethylating Agents
Design Considerations Primary endpoint: Overall survival, not censored for allogeneic transplantation Sample size: 714 evaluable patients HR = 0.78 for OS Power = 84% Type I error rate = 0.025 (1-sided) Final analysis after 509 events (deaths) observed Interim analysis conducted at 50% of events HR: Hazard Ratio, OS: Overall Survival
Revised Analysis Plan Alliance DSMB and CTEP approved the primary analysis of OS to occur with a cut off of April 1, 2015 with 357 events Event rate reached a plateau: 6 events 2014, 3 in 2015. 509 events predicted to occur in 2015 Higher than expected transplant rate: 25% in CR1, 57% overall Increased TKD mutation incidence: 23% Median follow-up time for survivors: 56.7 Months (range: 0.1, 79.2 Months) Critical value to declare statistical significance: 0.0239 (1-sided). DSMB: Data Safety Monitoring Board, CTEP: Cancer Therapy Evaluation Program (of the US National Cancer Institute), OS: Overall Survival, CR: Complete Remission, TKD: Tyrosine Kinase Domain
Consort Diagram Activated May 2008; completed accrual: Oct 2011 screened 3,277 patients Total FLT3 mut : n=896 (27% of screened) Total randomized: n=717 (80% of FLT3 mut ) Midostaurin n=360 Induction 1 n=355 81 received Induction 2 274 completed Induction Consolidation n=231 129 completed Consolidation Maintenance n=120 69 completed Maintenance Placebo n=355 Induction 1 n=354 101 received Induction 2 264 completed Induction Consolidation n=210 103 completed Consolidation Maintenance n=85 51 completed Maintenance
Patient Characteristics Median age (range), years (N = 717) 47.9 (18.0-60.9) Midostaurin (n = 360) 47.1 (19.0-59.8) Placebo (n = 357) P Value 48.6 (18.0-60.9).22 Female sex, n (%) 398 (55.5) 186 (51.7) 212 (59.4).04 FLT3 stratification groups, n (%) 1.00 FLT3-TKD 162 (22.6) 81 (22.5) 81 (22.7) FLT3-ITD allelic ratio < 0.7 341 (47.6) 171 (47.5) 170 (47.6) FLT3-ITD allelic ratio 0.7 214 (29.8) 108 (30.0) 106 (29.7) 34.9 35.6 33.0 Median WBC (range), 10 3 /μl (0.6-421.8) (0.6-421.8) (0.8-329.8).72 Median platelet count (range), 10 3 /μl 50.0 (2.0-461.0) 50.0 (2.0-461.0) 50.0 (8.0-444.0).58 Median ANC (range), per mm 2.2 (0-55.9) 2.2 (0-55.9) 2.3 (0-128.7).65 TKD: Tyrosine Kinase Domain, ITD: Internal Tandem Domain; WBC: White Bloodcell Count, ANC: Absolute Neutrophile Cell Count Stone RM et al. Midostaurin plus chemotherapy for Acute Myeloid Leukemia with FLT3 Mutation. N Engl J Med. 2017;377:354-64.
Patients Surviving, % 100 90 80 70 60 50 40 30 20 10 Overall Survival (Primary Endpoint) Non-censored for Allogeneic HCT 22% reduced risk of death in the midostaurin arm (vs. placebo) Patients, n Midostaurin 360 Placebo 357 4-yr OS: Midostaurin 51%; Placebo: 44% Median (95% CI), months HR (95% CI) P Value b 74.7 (31.5-NE) 0.78 25.6 (0.63-0.96).009 (18.6-42.9) 0 0 12 24 36 48 60 72 84 90 Patients at risk Time, months Midostaurin 360 269 209 181 151 97 37 1 Placebo 357 221 163 147 129 80 30 1 HCT: Hematopoietic Cell Transplant, HR: Hazard Ratio, CI: Confidence Interval, OS: Overall Survival Stone RM et al. Midostaurin plus chemotherapy for Acute Myeloid Leukemia with FLT3 Mutation. N Engl J Med. 2017;377:354-64.
Consistent Effect on OS by FLT3 status (Secondary Endpoint) N HR (95% CI) HR (95% CI) P Value a Overall (stratified) 717 0.78 (0.63-0.96).009 FLT3-ITD high 214 0.80 (0.57-1.12).19 FLT3-ITD low 341 0.80 (0.60-1.11).19 FLT3-TKD 162 0.65 (0.39-1.08).10 0,25 0,5 0,75 1 1,25 Favors midostaurin Favors placebo a P value is one-sided for the overall (stratified) analysis; P values are two-sided for the analyses by FLT3 subgroup. FLT3-ITD-low, FLT3-ITD/-WT allelic ratio < 0.7; FLT3-ITD-high, FLT3-ITD/-WT allelic ratio 0.7. OS: Overall Survival, HR: Hazard Ratio, CI: Confidence Interval; TKD: Tyrosine Kinase Domain, ITD: Internal Tandem Domain Stone RM et al. Midostaurin plus chemotherapy for Acute Myeloid Leukemia with FLT3 Mutation. N Engl J Med. 2017;377:354-64.
Consistent Effect on OS by FLT3 status (Secondary Endpoint) OS: Overall Survival; ITD: Internal Tandem Domain, TKD: Tyrosine Kinase Domain Stone RM et al. Midostaurin plus chemotherapy for Acute Myeloid Leukemia with FLT3 Mutation. N Engl J Med. 2017;377:354-64.
Allogeneic Transplants by Arm By Arm MIDO N=360 PBO N=357 p-value CR1 only, n 100 79 %: 95% CI (28%: 23, 33) (22%: 18, 26) 0.08 Type: Matched-related 47 (47%) 30 (38%) Type: Matched-unrelated 43 (43%) 42 (53%) Type: Other 10 (10%) 7 (9%) Transplant at any time, n 212 196 %: 95% CI (59%: 54, 64) (55%: 50, 60) 0.28 Type: Matched-related 95 (45%) 69 (35%) Type: Matched-unrelated 89 (42%) 108 (56%) Type: Other 28 (13%) 18 (9%) 408 (57%) patients received a transplant MIDO: Midostaurin, PBO: Placebo, CR: Complete Remission, CI: Confidence Interval Stone RM et al. Midostaurin plus chemotherapy for Acute Myeloid Leukemia with FLT3 Mutation. N Engl J Med. 2017;377:354-64.
Impact of Allogeneic HCT in CN-AML Molecular favorable genotypes NPM1 mut / FLT3-ITD neg Molecular unfavorable genotypes incl. FLT3-ITD+ and triple-neg. AML CN-AML: Cytogenetically Normal Acute Myeloid Leukemia, HCT: Hematopoetic Stem Cell Transplantation, ITD: Internal Tandem Duplication Schlenk RF et al. Mutations and Treatment Outcome in Cytogenetically Normal Acute Myeloid Leukemia. N Engl J Med. 2008;358(18):1909-1918.
Patients Surviving, % SCT in CR1 100 90 80 70 60 50 40 30 20 10 0 Patients at risk SCT outside CR1 Overall Survival (OS) Post-Transplant Treatment with Midostaurin increases OS after HCT in CR1 SCT in CR1 SCT outside CR1 Patients, n Median (95% CI), months Midostaurin 101 NE (69.8-NE) Placebo 81 NE (21.8-NE) Midostaurin 112 14.8 (9.1-31.6) Placebo 115 14.4 (10.0-22.7) 0 12 24 36 48 60 72 80 Time, months Midostaurin 101 Placebo 81 Midostaurin 112 Placebo 115 71 50 49 47 63 45 36 37 21 12 5 13 0 0 0 0 a Stratified on FLT3 subtype; 2-sided, log-rank P value. OS: Overall Survival, HCT: Hematopoetic Stem Cell Transplantation, CR: Complete Remission; SCT: Stem Cell Transplantation; NE: Not Reached P Value a Stone RM et al. Midostaurin plus chemotherapy for Acute Myeloid Leukemia with FLT3 Mutation. N Engl J Med. 2017;377:354-64..07.85
Patients, % Most Common Non-Hematologic Grade 3 Events Reported During Treatment 100 Top 20 non-hematologic AEs regardless of attribution 80 P =.84 Midostaurin (n = 355) Placebo (n = 354) 60 P =.60 40 20 P =.35 P =.92 P =.25 P =.82 P =.19 P =.008 P =.53 P =.89 P =.05 P =.32 P =.67 P =.38 P =.14 P =.76 0 a Infection includes the following terms: infection with grade 3/4 neutrophils (ANC < 1.0 10 3 /μl), infections with normal ANC or grade 1/2 neutrophils, infection with unknown ANC, opportunistic infection associated with grade 2 lymphopenia, and other infections. b Fatigue includes asthenia, lethargy, and malaise. c Includes pneumonitis and pulmonary infiltrates. AEs: Adverse Events Stone RM et al. Midostaurin plus chemotherapy for Acute Myeloid Leukemia with FLT3 Mutation. N Engl J Med. 2017;377:354-64.
Patients, % Grade 3 Hematologic Events AEs occurring in 20% of patients regardless of attribution 100 P =.52 P =.86 P =.03 80 60 Midostaurin (n = 355) Placebo (n = 354) 40 20 P =.32 P =.35 0 Thrombocytopenia Neutropenia Anemia Leukopenia Lymphocytopenia AEs: Adverse Events Stone RM et al. Midostaurin plus chemotherapy for Acute Myeloid Leukemia with FLT3 Mutation. N Engl J Med. 2017;377:354-64.
Conclusions Midostaurin, a multi-targeted kinase inhibitor, improves overall survival and event-free survival when added to standard chemotherapy with one-year maintenance in patients aged 18-60 with newly diagnosed ITD and TKD FLT3- mutant AML (RATIFY trial) Results from the AMLSG 16-10 trial (NCT01477606) suggest that midostaurin may also improve outcome in patients aged 60-70 No increase in non-hematologic and hematologic toxicity Midostaurin in combination with standard chemotherapy is the first targeted therapy of AML and will represent the new standard in adult patients with newly diagnosed AML and activating FLT3 mutations An international academic-industry collaborative AML study based on genotype at diagnosis is feasible AML: Acute Myeloid Leukemia, ITD: Internal Tandem Domain, TKD: Tyrosine Kinase Domain
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