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Financial DisclosureGautam Borthakur, MD
Research Support GSK, Jannsen, Incyte, Eli Lilly
Honoraria Dava Oncology
Advisory Board None
Stock ownership None
Employment No conflict
ATRA and Arsenic Trioxide as Frontline TherapyAcute Promyelocytic Leukemia
Survival ProbabilitiesAPL with ATRA+ ASO3
• Venetoclax potent, orally bioavailable demonstrated single-agent activity in–AML cell lines and primary samples–Heavily pre-treated relapsed/refractory AML
patients• Synergizes with HMA in preclinical models
Venetoclax: selective BCL-2 inhibitor
4DiNardo. Blood 126: abst 327; 2015
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Venetoclax plus DAC/AZA in Rx-naïve AML
• 57 pts median age 75 yr (65-85) Rx with VEN+DAC (n=23), VEN+AZA (n=22), VEN+DAC+AZOLE (n=12)
• Venetoclax 400-1200mg/DOutcome VEN+DAC
(n=23)VEN+AZA
(n=22)V+D+Posa
(n=12)Total N=57)
CR 8(35) 6(27) 0(0) 14( )
CRi 6(26) 7(32) 8(67) 21( )
PR 1(4) --- --- 1( )
ORR 15 (65) 13( 59) 8 (67) 36 (63)
Median response duration 8.4 mos; median survival 15.2 mos
DiNardo. Lancet Oncology (Submitted)
Low-dose ara-C + Venetoclax in Rx-naïve AML ≥ 65 yrs ( updated)
• 61 pts Rx, median age 74 yrs (66-89)
• Ara-C 20mg/m2 SQ daily x 10 and venetoclax 600mg daily
• OR 61%: CR 21%,CRi33%,PR 7%
• 12-mo survival 64%
• Good results in 17 MDS-AML and prior HMA
Wei. Blood 128: abst 102; 2016
Venetoclax+LD-araC in AML. Outcome Venetoclax: Practical Considerations
• Risk for tumor lysis
• Mitigation strategy:
– Allopurinol prophylaxis
– Close attention to phos, LDH, uric acid
– Pre Hydration
– Ramp up dosing: Start at 50- 100 mg a day, increase daily to target 400-600 mg a day
• Look out for prolonged cytopenias: Neutropenia
• Caution with Azoles: drop dose by 50-75%
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Stein E. Blood 126: abst 323; 2015
IDH305 as a Potent, Specific Inhibitor of the IDH1R132 Mutant Protein
• Orally bioavailable1
• Mutant-selective allosteric inhibitor1
• Suppresses 2-HG production and cell proliferation with an IC50 of 24 nM1
• Antitumor activity observed in preclinical models harboring the IDH1 mutation1
• Off-target inhibition of UGT1A1 has been seen in preclinical studies1
2-HG, 2-hydroxyglutarate; Acetyl CoA, acetyl coenzyme A; αKG, alpha-ketoglutarate; Fum, fumarate; IC50, half maximal inhibitory concentration; IDH, isocitrate dehydrogenase; Mal, malate; OAA, oxaloacetate; Suc, succinate.
IDH305
Glucose
Mitochondrion Cytoplasm
2-HG 2-HG
Citrate
Isocitrate
αKG
SucFum
Mal
OAA
IDH3 IDH2 IDH1
IDH1R132
Citrate
Isocitrate
αKG
Oncogenicpathways
Acetyl CoA
Wei. Blood 128: abst 1073; 2016
Best Overall Response in AML and MDS Patients in the Dose Escalation Phase (IWG Criteria)
BID DoseBOR, n (%)
75 mg(n=3)
150 mg(n=2)
300 mg(n=9)
450 mg (n=10)
550 mg(n=4)
750 mg(n=3)
All Patients(n=31)
CR/CRi 0 1 (50) 4 (44) 3 (30) 2 (50) 0 10 (32)
CR 0 0 3 (33) 2 (20) 2 (50) 0 7 (23)
CRi 0 1 (50) 1 (11) 1 (10) 0 0 3 (10)
PR 0 0 0 0 0 0 0
TF 3 (100) 1 (50) 2 (22) 5 (50) 2 (50) 3 (100) 16 (52)
Unknown 0 0 0 1 (10) 0 0 1 (3)
Not assessed 0 0 3 (33) 1 (10) 0 0 4 (13)
Wei. Blood 128: abst 1073; 2016
AG-221 (IDH2 Inhibitor) in AML
• 198 pts; R140Q (70%); R172k (25%)
• AG-221 starting dose 50mg/D or 30mg BID; highest 600mg/D
• RR AML 138 (70%), unRx 17%,other 6%
• Median response duration 6.9 mosStein E. Blood 126: abst 323; 2015
No Response (%) Total (n=181) RR (n=128)
CR 30 (17) 23 (18)
CRp/CRi 3 + 1 (3) 1 + 1 (2)
Marrow CR 15 (8) 8 (6)
PR 25 (14) 19 (15)
Overall 74 (41) 52 (41)
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Stein E. Blood 126: abst 323; 2015 Stein E. Blood 126: abst 323; 2015
AG-221 (IDH2 Inhibitor) in AML
• 198 pts; R140Q (70%); R172k (25%)
• AG-221 starting dose 50mg/D or 30mg BID; highest 600mg/D
• RR AML 138 (70%), unRx 17%,other 6%
• Median response duration 6.9 mosStein E. Blood 126: abst 323; 2015
No Response (%) Total (n=181) RR (n=128)
CR 30 (17) 23 (18)
CRp/CRi 3 + 1 (3) 1 + 1 (2)
Marrow CR 15 (8) 8 (6)
PR 25 (14) 19 (15)
Overall 74 (41) 52 (41)
Stein E. Blood 126: abst 323; 2015
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Stein E. Blood 126: abst 323; 2015 Stein E. Blood 126: abst 323; 2015
AG-120 (IDH1 inhibitor) in AML
• 87 ps with IDH1-mutated AML
• AG120 100mg BID-1200 mg/D
• Responses: 12 CR (15%), 7 CRi (9%), 1 PR, 7 marrow CR
• 27 / 78 responses= ORR 35%
• IDH1 associated with DNMT3A (67%), NPM1 (24%)
• Phase 2 dose 500mg/D in R-R AML (n=125), unRx AML (n=25), other IDH1 + (n=25)
DiNardo. Blood 126: abst 1306; 2015
AG-120 in AML. Response Durations ( N=27)
DiNardo. Blood 126 : abst 1306; 2015
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Vadastuximab (SGN-33A) with 7+3 in AML
• 42 pts with newly Dx AML; median age 45 yrs (18-65)
• DNR 60mg/m2/D x 3, araC 100mg/m2/D x 7, SGN33A D1 and D4—10 mcg/kg D1 & 4 (n=4) and 10 & 20 mcg/kg D1 and D4
• CR 24 (60%); CRi 7 (18%); OR 31/40 (78%)
• 23/31 (74%) MRD negative
• 30-60 day mortality 0-7%
Erba. Blood 18: abst 211; 2016.
Vadastuximab (SGN-33A) in Older CD33 + AML
• 27 pts; median age 74 yrs (67-89)
• SGN-33A 40mcg/kg
• 6CR (23%), 8 CRi (31%), 5 MLFS (19%)
• ORR 14/26 = 54%
• 60-days mortality 15%
• Median OS ??; 2-yr OS % ??Bixby. Blood 128: abst 613; 2016
Vadastuximab + AZA/DAC in Older AML
•53 pts; median age 75 yrs (60-87)
•AZA/DAC 5 days; SGN-33A 10mcg/kg
•CR 43%, CRi 31%-- OR 73%
•60-day mortality 8%
•Median RFS 9.1 mos, median OS??
Fathi. Blood 128: abst 591; 2016
Sorafenib: A Multi-kinase Inhibitor
Sorafenib• Synonym: BAY 43-9006
• Small molecule - Raf inhibitor
• Also targeting FLT3, VEGFR,
PDGFR, and c-Kit.
• Approved by FDA for renal cell
and hepatocellular carcinoma
• Oral administration: 400 mg bid
• Plasma concentrations:
7.1 mg/L (11 µM)
Sorafenib
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Percentage Change in Marrow Blasts, Baseline =0
Phase 1 Study of Sorafenib in AML/MDS
Borthakur G et al. Haematologica 2011
SORAML Design
Induction I Consolidation Maintenance
DA I SORA
AML
DA II(HAM)
SORA 3 x HiDAC SORA
DA I PLACEBODA II
(HAM)3 x HiDAC
SORA12 months
PLACEBO12 months
PLACEBOPLACEBO
allo SCT:IR with sibling donor
HR with donor
Favorable risk (FR): t(8;21), inv(16); high risk (HR): ≥3 aberrations, monosomy 7 or 5, t(6;9), t(6;11), t(11;19) or insufficient response on day 16 after DAI ( in this case second induction with HAM)Intermediate risk (IR): all cytogenetics not FR or HR
Induction II
Day 16:Response?
SCT, stem cell transplant
Röllig C, et al. Lancet. 2015;124: [Epub ahead of print]]
Chemo Rx ± Sorafenib in Younger AML. Outcome
Placebo Sorafenib P
EFS 22 40 .013
RFS 38 56 .017
OS 56 63 .382
Röllig C, et al. Lancet. 2015;124: [Epub ahead of print]
Phase III Study of Chemotherapy +/‐Midostaurinin Newly Diagnosed AML
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″3+7 ″ ± Midostaurin (M) in FLT3-ITD AML (RATIFY)
• 3279 newly Dx pts (age 18-60); 717 with FLT3-mutated AML
• 3+7 +/- midostaurin 50mg BID D8-22; then 4 HDAC +/-midostaurin D8-22; then midostaurin x 1 yr. 55% had SCT (1/2 post CR1)
Stone. Blood 126: abst 6; 2015
Results M (n=360) No M (n=357) P (HR)
-% CR 59 54 .18
-% 5-yr OS 51 43 .007 (.77)
- % 5-yr OS SCTcensored
63 55 .047 (.77)
″3+7 ″ ± Midostaurin (M) in FLT3-ITD AML (RATIFY)
Stone. Blood 126: abst 324; 2015
Practical Issues: FLT3 Inhibitors
• Type 1: Midostaurin, Crenolanib
• Binds active conformation
• Type 2: Quizartinib, Sorafenib, MLN 512
• Binds inactive conformation
• Allosteric: DCC2036
• Continuous dosing important
• Myelosuppression: Quizartinib
• Point mutations e.g. D835: may cause resistance
HyperCVAD+Dasatinib in Ph+ALL. Regimen
2 3 1 4 5 6 7 8
100 70
100
24 months
Hyper-CVAD
MTX-cytarabine
Dasatinib
Vincristine + prednisone
Maintenance phase
Intensive phase
Risk-adapted intrathecal CNS prophylaxis
Ravandi. Blood 126: abst 796; 2015
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HyperCVAD+Dasatinib in Ph+ALL. Landmark Analysis; No ASCT vs. ASCT Practical Aspects: Hyper CVAD+ Dasatinib
• Dasatinib:• 2 weeks in cycle 1
• Uninterrupted subsequently
• Continued indefinitely, preferably post SCT
• Monitor MRD by QPCR for BCR‐ABL
• Consider SCT in CR1
• Older patients:• Lower dasatinib dose
• Lookout for effusions: even late
Mode of Action of BiTE® Antibody Blinatumomab
• Blinatumomab (MT103) is a bispecific T-cell engager (BiTE) antibody designed to direct cytotoxic T cells to CD19 expressing cancer cells
Bargou R., et al. Science 2008;321(5891):974-977.
-CD19antibody
-CD3antibody
VL
VH
VL
Target antigenCD19
CD3
Redirectedlysis
T Cell
TumorCell
BlinatumomabBiTE®
VH
Blinatumomab: Schedule
• CD19 is the earliest B-cell lineage–restricted antigen
• Approval:• Ph negative
• Admit for first cycle
• Cycle: 4 weeks on 2 weeks off
• Induction: up to 2 cycles, Consolidation: 3 cycles
• Induction: 9 μg/d for days 1 to 7, 28 μg/d for days 8 to 28.
• Consolidation: 28 μg/d on days 1 to 28.
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BlinatumomabResponses After Two Cycle: Prespecified Groups Blinatumomab: Single Agent Phase 2 Study
Topp Et al. Lancet Oncology, Volume 16, 2015, 57–66
MRD negative status among CR/CRh: 82%
Blinatumomab: Practical Issues
• Prephase: Reduces CRS Risk, in high volume disease• Dexamethasone 10–24 mg/m2 /day (for up to 5 days) for bone-
marrow blasts> 50%, PB blasts of ≥15 000 cells per μL, or elevated lactate dehydrogenase
• Prephase stopped 3 days prior to Blina
• Stepwise dosing in cycle 1 (Reduce CRS Risk)• 9 μg/day for 1 week, then 28 μg/day for 3 weeks • Dexamethasone (20 mg) premedication within 1 h before
treatment initiation and before the dose step in cycle one (minimize infusion reaction)
• Do not flush line: risk of overdose
• Change bag every 48 hrs
Blinatumomab: Practical Issues
• CNS prophylaxis: Triple intrathecal priror to each cycle
• CNS reaction• Altered mental status, seizure, neuropathy: Levetiracetum for seizure• Hold Blina for grade 3 symptoms• Consider steroid (Dexamethasone 8 mg IV every 8 hours for 3 days,
then taper over 4 additional day)• Can resume once resolved to grade 1-2
• Cytokine release syndrome• Mostly resolved with steroids• IL-6 antibody (Tocilizumab)• Will discuss with CAR-T cell
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41
41
• The antibody-antigen complex is rapidly internalized upon binding to CD22
• Calicheamicin is released inside the tumor cell- Calicheamicin is more
potent than other cytotoxic chemotherapeutic agents
• Calicheamicin binds to DNA, inducing double-stranded DNA breaks
• Development of DNA breaks is followed by apoptosis of the tumor cell
CD22
Inotuzumab ozogamicin
Internalization
Tumor Cell
Nucleus
Calicheamicin binds to DNA
Inotuzumab in ALL. Mechanisms of Action
Jabbour. Blood 126: abst 83;2015
Blinatumomab in ALL MRD-positive• 116 pts (median age 45 yr; range 18-76) with
ALL in CR but MRD ≥ 0.1% post ≥ 3 intensive courses; 35% in ≥ CRD2
• Blinatumomab 15 mcg/m2/D x 4 wks Q 6 wks x 4
• 88 pts (78%) MRD-negative post Cycle 1
Parameter No. % MRD negative
-CRD1 75 82
-CRD 2/3 39/2 71/50
-MRD10-1 -1 9 67
-MRD10-3 – 10-1 97 80Gokbuget. Blood. 2014; 124: Abst # 379
Blinatumomab in ALL MRD-positive• Median follow-up 29 mos, Median OS 36 mos
• 90 (78%) received allo-SCT
Median (mos)
Overall MRD negative
MRD positive
P-value
OS 36 40 12 0.001
RFS 19 35 7 0.002
DOR NR NR 15 0.015
Gokbuget. Blood. 2015; 126: Abst # 680
• No difference in OS (HR=1.39; p=0.37) and RFS (HR=0.89; p=0.73) between allo-SCT vs no allo-SCT
Blinatumomab in Refractory-Relapse ALL
• 189 pts Rx with blina 28mcg CI/D x 4 wks Q 6 wks
• Median OS 5.9 mo; Median RFS 6.1 mo
• Toxicities: CNS
Response No. (%)
-CR 63(33)
-CRh 18(10)
-CR+CRh 81(43)
-No marrow blasts 17(9)
Topp. Lancet Oncol. 2015;16:57-66
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Basic Design Chimeric Antigen Receptor T Cells CD19-Targeted T Cells Rapidly Induce Molecular Remissions in Adults with Chemotherapy-Refractory Acute
Lymphoblastic Leukemia
by Renier J. Brentjens, Marco L. Davila, Isabelle Riviere, Jae Park, Xiuyan Wang, Lindsay G. Cowell, Shirley Bartido, Jolanta Stefanski, Clare Taylor, Malgorzata Olszewska, Oriana Borquez-Ojeda, Jinrong Qu, Teresa Wasielewska, Qing He, Yvette Bernal, Ivelise V. Rijo, Cyrus Hedvat, Rachel Kobos, Kevin Curran, Peter
Steinherz, Joseph Jurcic, Todd Rosenblat, Peter Maslak, Mark Frattini, and Michel Sadelain
Sci Transl MedVolume 5(177):177ra38-177ra38
March 20, 2013
Published by AAAS
Fig. 1 Rapid antitumor effects mediated by 19-28z T cells.
Renier J. Brentjens et al., Sci Transl Med 2013;5:177ra38
Published by AAAS
Fig. 2 Cytokine release and T cell persistence were increased in patients with high tumor burdens.
Renier J. Brentjens et al., Sci Transl Med 2013;5:177ra38
Published by AAAS
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Fig. 3 Persistent fevers in patients with high tumor burden after infusion with 19-28z CAR+ T cells.
Renier J. Brentjens et al., Sci Transl Med 2013;5:177ra38
Published by AAAS