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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


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%


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)


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


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


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


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


″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


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.


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


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


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.


Published by AAAS


Fig. 3 Persistent fevers in patients with high tumor burden after infusion with 19-28z CAR+ T cells.


Published by AAAS

gautam borthakur, mdcme.uthscsa.edu/courses/panao/2017/online syllabus...gautam borthakur, md...

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