Acute Leukemia - prIME Oncology...Prognostic Impact of NPM1/FLT3-ITD Genotypes From Randomized Patients With Acute Myeloid Leukemia (AML) Treated Within the International RATIFY Study

Acute Leukemia

Richard M. Stone, MDHarvard Medical SchoolBoston, Massachusetts

Outline1. Mutationally Targeted Therapies AML

A. FLT3 inhibition• Upfront with 3+7 chemotherapy: Ancillary data from C10603/RATIFY trial• Upfront with 3+7chemotherapy: Crenolanib and gilteritinib• Upfront with HMA: Quizartinib

B. IDH inhibition: IDH1 and IDH inhibitor, in R/R AML, untreated AML, with HMA , with 3+7

2. Immune-based therapies in AMLA. CAR T-cellB. Targeted therapy with antibodies/antibody-like moleculesC. Checkpoint inhibition

3. Other novel therapies in AMLA. Promoting apoptosisB. E-selectin inhibitor

4. ALL: Antibodies, TKIs ( in PH+) and CAR-T cellsAML, Acute myeloid Leukemia; HMA, hypomethylating agent; IDH, isocitrate dehydrogenase; R/R, relapsed or refractory; CAR, chimeric antigen receptor; TKI, tyrosine kinase inhibitor

AML Therapy for Patients Age <60• Standard induction chemotherapy: “3+7”

• Daunorubicin 60 mg/m2/d ‒ 90 mg/m2/d x 3 ‒ Or idarubicin 12 mg/m2d x 3

• Cytarabine 100 mg/m2/d ‒ 200 mg/m2/d x 7 continuous infusion• Ida plus high-dose ara-C (IA) inferior to standard 3+7 (SWOG 1203 study)• Midostaurin 50 mg bid daily 8 ‒ 21 days for mutation FLT3• ? Add GO 3 mg/m2/d 1, 4, and 7

• Postremission (consolidation) therapy• If ELN adverse or CR2: Allogeneic SCT

– Maybe even DUCB or haploidentical SCT• If ELN favorable: (CBF) cytogenetics, or normal cytogenetics with biallelic CEBPa,

or NPM1 mutation and FLT3 ITD wildtype (or low burden): 4 cycles HiDAC; add midostaurin 50 mg bid daily 8 ‒ 21 for mutation FLT3

• If ELN intermediate: Allogeneic SCT if sibling or MUD, otherwise HiDACIf mutant FLT3, add midostaurin in days 8 through 21 of a consolidation cycle

IA, intra-arterial; SWOG, South West Oncology Group; GO, gemtuzumab ozogamicin; ara-C, cytarabine; Ida, intermediate-dose ara-C; SCT, stem cell transplantation; DUCB, double umbilical cord blood; CBF, core binding factor; MUD, matched unrelated donor; HiDAC, high dose ara-c

Therapy of Older Patients With AMLInduction

• Fit, de novo, likely to benefit: ‒ Daunorubicin 60 mg/m2/d ‒ 90 mg/m2/d x 3d + cytosine arabinoside

100 mg/m2/d ‒ 200 mg/m2/d by IVCI for 7 days Add midostaurin days 8 through 21 if FLT3 mutation ? Add GO 3 mg/m2/d 1, 4, and 7

• Fit, secondary (s/p MDS or with MDS-type cytogenetics): ‒ CPX-351

• Unfit (age >70 ‒ 75, PS >2, comorbid double strand)‒ Hypomethylating agent ‒ Consider 10d decitabine in TP53 mutation‒ Consider fractionated GO as single agent

• Postremission therapy‒ RIC allogeneic SCT if feasible‒ ? Repeat induction for others

IVCI, intravenous continuous infusion; MDS, myelodysplastic syndrome; s/p, status post; PS, performance status; RIC, reduced-intensity conditioning

CPX-351 in High-Risk AMLBackground• CPX-351: Liposomal formulation of

cytarabine and daunorubicin packaged at 5:1 molar ratio

• 1 unit = 1.0 mg cytarabine plus 0.44 mg daunorubicin

• Liposomal encapsulation avoids fluctuating drug ratios

• Preferential uptake & intracellular release in leukemic blasts

• Improved efficacy compared to free drug

CPX-351 in High-Risk AMLCPX-351 Clinical Experience

• Phase I (relapsed / refractory AML): MTD 100 U/m2

• Phase 2: Newly diagnosed older AML– Randomized 2:1 CPX-351 or 7+3– Planned analysis: Secondary AML subset: improved RR (57.6%

vs 31.6%, P = .06), EFS and OS• Phase 3: Untreated high-risk AML 60-75 years

– 309 patients randomized to CPX-351 100 U/m2 days 1, 3 & 5 (n=153) v 7+3 (n=156)

– CPX-351 vs 3+7: CR+CRi (47.7% vs. 33.3%; P=0.016), OS (P=0.005), EFS (P=0.021)

– 60-day mortality favored CPX-351 (13.7 vs 21.2%)Lancet JE, et al. Blood. 2014;123(21):3239-3246. Lancet JE, et al. J Clin Oncol. 2016;34(15 suppl): Abstract 7000.

Phase III Study of Chemotherapy + Midostaurin (PKC412) or Placebo in Newly Diagnosed Patients ≤60 Years of Age

With FLT3-Mutated Acute Myeloid Leukemia (RATIFY)

Midostaurin(50 mg bid, days 1 - 28)

Placebo(bid, days 1 - 28)

Cytarabine(200 mg/m2/d, days 1 - 7)

Daunorubicin(60 mg/m2/d, days 1 - 3)



Cytarabine(200 mg/m2/d, days 1 - 7)

Daunorubicin(60 mg/m2/day, days 1 - 3)

High-dose cytarabine

(3 g/m2/d, q 12 h, days 1, 3, and 5)


High-dose cytarabine

(3 g/m2/day q 12 h, days 1, 3, and 5)


Induction (1 ‒ 2 cycles)

Consolidation*(up to 4 cycles)

Maintenance(up to 12 cycles)

CR CR

R

Patients with newly diagnosed AML

≥18 to <60 years with activating FLT3 mutationsScreening within 48 hours

Stratification by TKD and ITD (ratio <0.7 vs ≥0.7)

(n = 717)

Primary endpoint: OSKey secondary endpoint: EFS* Patients with an HLA-compatible family donor may proceed to

allogeneic HCT ClinicalTrials.gov NCT00651261

Stone R, et al. N Engl J Med. 2017;377(5):454-464.TKD, tyrosine kinase domain; ITD, internal tandem duplication; OS, overall survival; EFS, event-free survival

Kaplan-Meier Analysis of Overall Survival (Not Censored for Transplantation) in RATIFY Showed a 22% Reduction in Risk of Death

With Midostaurin Plus Chemotherapy vs Placebo + Chemotherapy

Stone R, et al. N Engl J Med. 2017;377(5):454-464.

Prognostic Impact of NPM1/FLT3-ITD Genotypes From Randomized Patients With Acute Myeloid Leukemia (AML) Treated Within the International RATIFY Study

Abstract 467

Döhner, K, Thiede C, Larson RA, Prior TW, Marcucci G, Jones D, Krauter J, Heuser M, Lo-Coco F, Ottone T, Nomdedeu J, Mandrekar SJ, Sanford BL, Laumann K, Geyer SM, Klisovic

RB, Wei A, Sierra J, Sanz MA, Brandwein JM, de Witte TM, Jansen JH, Niederwieser D, Appelbaum FR, Medeiros BC, Tallman MS, Schlenk RF, Ganser A, Serve H, Ehninger G,

Amadori S, Cheng Y, Pallaud C, Stone RM, Hartmut D, Bloomfield CD

Overall Survival According to ELN Subgroups

0 20 40 60 80

0.0

0.2

0.4

0.6

0.8

1.0

Logrank p=0.0013+ Censored

0 20 40 60 80

0.0

0.2

0.4

0.6

0.8

1.0

Logrank p=0.0013+ CensoredLog-rank, P = .001

Time, Months Noncensored at HCT

Surv

ival

Pro

babi

lity

NPM1mut/FLT3-ITDlow

NPM1mut/FLT3-ITDhigh

NPM1wt/FLT3-ITDlow

NPM1wt/FLT3-ITDhigh

1 159 86 69 30 02 85 59 49 24 0 3 109 47 38 10 04 75 34 31 13 0

HCT, hematopoietic-cell transplantationKonstanze D, et al. Blood. 2017;130: Abstract 467.

Overall Survival According to ELN Subgroups and Midostaurin Versus Placebo

Forest Plot of Hazard Ratios by Patient Subgroups for OS non-censored at SCTP Value95% CIHazard RatioHazard Ratio (95% CI)No.of PatientsSubgroup

.014(one-sided)

.128(two-sided)

.091(two-sided)

.025(two-sided)

.894(two-sided)

PValue_side

(0.58-0.97)

(0.47-1.10)

(0.24-1.12)

(0.37-0.94)

(0.56-1.93)

CI95

0.75

0.72

0.52

0.59

1.04

HR0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8

<-Midostaurin Better- -Placebo Better->

428

159

85

109

75

Overall

NPM1-MT/ITD-High

NPM1-MT/ITD-Low

NPM1-WT/ITD-High

NPM1-WT/ITD-Low

Konstanze D, et al. Blood. 2017;130: Abstract 467.

Multivariate Analysis for Overall Survival

Two-Sided P valueELN subgroups (NPM1/FLT3-ITD) <.001Treatment (midostaurin vs placebo) .012Allogeneic HCT <.001WBC (≥ vs <50 x109/L) .028Age (difference of 10 years) .335

Sex .689

ELN, European LeukemiaNet; HCT, hematopoietic-cell transplantation; WBC, white blood cell countKonstanze D, et al. Blood. 2017;130: Abstract 467.

Schmalbrock LK, Cocciardi S, Dolnik A, Agrawal M, Theis F, Jahn N, Blätte TJ, Gaidzik VI, Paschka P, Panina E, Fiedler W, Salih HR, Wulf G, Germing U, Lubbert M, Thol F, Heuser

M, Larson RA, Ganser A, Schlenk RF, Stone RM, Döhner H, Konstanze D, Bullinger L

Clonal Evolution of FLT3-ITD Positive AML in Patients Treated With Midostaurin in

Combination With Chemotherapy Within the Ratify (CALGB 10603) and AMLSG 16-10 Trials

Abstract 182

Presence of FLT-ITD Clones at Diagnosis and Relapse

Schmalbrock LK, et al. Blood. 2017;130: Abstract 182.D, diagnosis; R, relapse; *Higher allelic ration

Wang ES, Tallman MS, Stone RM, Walter RB, Karanes C, Jain V, Collins RH

Low Relapse Rate in Younger Patients ≤60 Years Old With Newly Diagnosed FLT3-Mutated Acute

Myeloid Leukemia (AML) Treated With Crenolanib and Cytarabine/Anthracycline Chemotherapy

Abstract 566

Crenolanib is a Highly Selective Type I Tyrosine Kinase Inhibitor of FLT3

Crenolanib Type I inhibitor: Active against both active and inactive conformations

of FLT3 mutations Pan-FLT3 Inhibitor: Active against novel variant FLT3 mutations Overcomes resistance conferring FLT3 mutations, eg. FLT3-D835 High selectivity: No KIT inhibition at clinically achievable levels

(which permits count recovery and no hair depigmentation)

Metabolismonly

Adenosine ring mimic

Binds at the phosphate group

binding region

Kinase-bindingregion

Nonbindingregion

Tarlock et al., EHA, 2017

FLT3 Mutation FLT3 PhosphorylationIC50 (nM)

Juxta-membrane

domain

E573D 1.3L576R 1.4V592A 6.7F594C 6.4F594Y 6.7Y599C 2.1

Kinase 1M664I 2.1N676K 15.9A680V 1.3

Kinase 2(activation

loop)

D835Y 2.4D839E 3.2N841I 2.5

Crenolanib is a pan-FLT3 TKI:Inhibits FLT3 variants at low nM concentration

Crenolanib inhibits FLT3 D835–activating mutations:May overcome resistance to type II TKIs

Smith et al., Leukemia, 2015Ramachandran et al., AACR, 2012

Highly selective for FLT3:No KIT inhibition

Wang ES, et al. Blood. 2017;130: Abstract 566.

Phase II Trial of Crenolanib in Newly Diagnosed FLT3-Mutant AMLGoal: To assess the tolerability and efficacy of crenolanib when administered sequentially with standard induction chemotherapy in patients with newly diagnosed FLT3-mutant AML

Induction(1 - 2 cycles)

Consolidation(up to 4 cycles)

Maintenance(up to 12 cycles)

Newly diagnosed AML with activating FLT3

mutations

Total 44 patients≤60 years old: 29 patients

7+3+

Crenolanib

HiDAC + Crenolanib

Crenolanib

HSCT

Induction Cytarabine 100 mg/m2/CIV, d1- d7 Dnr 90 mg/m2 (<60y) or Ida 12 mg/m2, d1-d3Crenolanib 100 mg tid starting d9

Consolidation Cytarabine 3 g/m2 (<60y) or 1 g/m2 (60y), q12h, 6 dosesCrenolanib 100 mg tid starting d7

Maintenance Crenolanib 100 mg tid continuously

Key Features:• FLT3-ITD or FLT3-TKD• Any FLT3 allelic burden• Physician’s choice of anthracycline• High doses of daunorubicin (90 mg/m2) allowed

in younger patients


High Overall Response Rate

Induction regimenCR/CRi

After Induction 1 Overall Complete Response

Cytarabine + daunorubicin + crenolanibn = 16 11/16 (69%) 13/16 (81%)

Cytarabine + idarubicin + crenolanibn = 13 11/13 (85%) 12/13 (92%)

Total N = 29 22/29 (76%) 24/29 (83%)


91% CR/CRi Patients Achieved FLT3-Negative Status After Treatment

FLT3 Status After Treatment Status Available (n = 23)

FLT3 negative 21 (91%)

FLT3 positive 2 (9%)

24 patients achieved CR/CRi after standard treatment combined with crenolanib. FLT3 analysis was performed after induction or consolidation, and FLT3 data were available in 23 patients.

FLT3 mutation clearance was seen in 21/23 patients, including patients who had variant FLT3 mutations


Overall Survival of Patients

0

20

40

60

80

100

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30Months

Sur

viva

l pro

babi

lity

(%)

Number at risk29 29 26 24 21 18 17 14 13 10 6 3 2 1 1 0

Total of six deaths:• Two refractory (including 1 with complex cytogenetics

and mutant TP53)• Two relapsed (both received <1 week of maintenance)• Two in remission (1 history of cirrhosis with portal

hypertension, 1 post HSCT complication)

• Estimated 1 year OS in Mido arm: ~75%• Estimated 2 year OS in Mido arm: ~60%

Median Age of 47 Years

79%

Median follow-up: 17.6 months(range 4.4 months – 29.6 months)

Median Age of 51 Years

Ove

rall

Surv

ival


Preliminary Results From a Phase 1 Study of Gilteritinib in Combination With Induction and Consolidation Chemotherapy in Subjects With

Newly Diagnosed Acute Myeloid Leukemia (AML)

Abstract 722

Pratz K, Cherry M, Altman JK, Cooper BW, Cruz JC, Jurcic JG, Levis MJ, Lin TL, Perl AE, Podoltsev NA, Schiller G, Liu C, Bahceci E

Antileukemic Response to ≥80 mg/d Gilteritinib in FLT3mut+ Patients by Mutation Type and TKI Status

0

10

20

30

40

50

60

70

80

90

100

FLT3-ITDonly

FLT3-ITD andFLT3-D835

FLT3-D835only

Prop

ortio

n of

Pat

ients

Ach

ievin

g Re

spon

se ,%

Response Rates By FLT3 Mutation Type

CR CRp CRi PR

0

10

20

30

40

50

60

70

80

90

100

TKI Naive Prior TKI Therapy

Prop

ortio

n of

Pat

ients

Ach

ievin

g Re

spon

se, %

Response Rates By TKI StatusCR CRp CRi PR

ORR = 55%CRc = 43%

ORR = 62%CRc = 54%

ORR = 17%CRc = 8%

ORR = 42%CRc = 31%

ORR = 56%CRc = 44%

CRc included patients who achieved complete remission, complete remission with incomplete hematologic recovery, and complete remission with incomplete platelet recovery, ORR included patients in CRc plus patients who achieved PR CR, complete remission; CRc, composite remission (CRc = CR+CRi+CRp;); CRi, complete remission with incomplete hematologic recovery; CRp, complete remission with incomplete platelet recovery; ORR, overall response rate (ORR=CRc+PR); PR, partial remission

N = 141 N = 13 N = 12N = 45 N = 124

Pratz K, et al. Blood. 2017;130: Abstract 722.

Study Design and Treatment• Phase I study (NCT02236013):

– Multicenter, open-label, 3+3 design– Enrollment began in January 2015

and is ongoing– Adult patients aged ≥18 years with

newly diagnosed AML were enrolled

• Dose-escalation cohorts of 40, 80, and 120 mg/day gilteritinib with 3 – 6 patients per cohort

• More than 20 patients in the dose-expansion cohort, including ≥15 FLT3Mut+ patients

*Gilteritinib was initially administered on days 1 – 14, but the schedule was later changed to administration on days 4 – 17 due to DLTs in the 40 mg/day dose cohort.

Patients aged ≥18 years with newly diagnosed AML

Maintenance (up to 26 cycles)Gilteritinib (once daily)

DLT

Obs

erva

tionRemission induction (1 – 2 cycles)

Cytarabine (100 mg/m2,d 1 – 7)+

Idarubicin (12 mg/m2, d 1 – 3)+

Gilteritinib (once daily, d 1 – 14 or 4 – 17*)

Consolidation (1 – 3 cycles) Cytarabine (1.5 g/m2 q 12 h, d 1, 3, and 5)

+Gilteritinib (once daily, d 1 – 14)

Dos

e Es

cala

tion


Response Parameter*, n (%)FLT3Mut+

n = 21†

CR 19 (90.5)

CRp 1 (4.8)

CRi 1 (4.8)

PR 0

CRc‡ 21 (100)

Antileukemic Response: FLT3Mut+


CR, complete remission; CRc, composite complete remission; CRi, complete remission with incomplete hematologic recovery; CRp, complete remission with incomplete platelet recovery; FLT3, fms-like tyrosine kinase 3; Mut+, mutation-positive; PR, partial remission; WT, wildtype*Response parameters were defined according to the International Working Group Criteria for AML (Cheson B, et al. J Clin Oncol. 2003;21(24):4642–4649).†Two patients were excluded from the response analysis population: one patient was excluded due to favorable cytogenetic status and one patient was excluded due to refusal to undergo a bone marrow biopsy and withdrawal of consent.‡CRc included patients who achieved CR, CRp, and CRi.

Response Parameter*, n (%)FLT3WT

n = 23†

CR 9 (39.1)

CRp 0

CRi 5 (21.7)

PR 3 (13.0)

CRc 14 (60.9)

Antileukemic Response: FLT3WT


*Response parameters were defined according to the International Working Group Criteria for AML (Cheson B, et al. J Clin Oncol. 2003;21(24):4642–4649).†Two patients with favorable cytogenetic status were excluded from the response analysis population.

The Combination of Quizartinib With Azacitidineor Low Dose Cytarabine Is Highly Active in

Patients (Pts) With FLT3-ITD Mutated Myeloid Leukemias: Interim Report of a Phase I/II Trial

Swaminathan M, Kantarjian HM, Daver N, Borthakur G, Ohanian M, Kadia T, DiNardoCD, Jain N, Estrov Z, Ferrajoli A, Garcia-Manero G, Konopleva M, Andreeff M,

Pemmaraju N, Jabbour EJ, Wierda WG, Ravandi F, Pinsoy MR, Cortes JE

Abstract 723

Quizartinib (AC220)• Second-generation class II RTK inhibitor

• Principal target organs in animal studies were bone marrow and lymphoid organs

• DLT: QTcF prolongation

• In phase I and II studies, composite complete response rate (CRc) ~50% among patients with FLT3-ITD

• Dose-finding study (30 mg v 60 mg): – Similar CRc– Higher ORR (71% v 61%), remission duration (20 wk v 4 wk) and OS

(25.4 wks v 20.7 wks) with 60 mg

Swaminathan M, et al. Blood. 2017;130: Abstract 723.

Quizartinib + Azacitidine or Low-Dose CytarabineStudy Design

MDS, CMML, or AMLFLT3-ITD and one of the following:• Age ≥60 years with previously untreated

disease• Age ≥18 years with refractory or relapsed

disease with ≤1 prior treatment regimen (ie, 1st salvage)

• Any age who received HMA and progressed to AML

Physician’s Choice

N = 61

Quizartinib +

AZA

Quizartinib +

LDAC

N = 37

N = 24

• (CR+CRi+PR+HI)• Secondary endpoints: CRc (CR+CRp+CRi); overall survival and relapse-free survival


Quizartinib + Azacitidine or Low-Dose Cytarabine Response to Therapy

Best ResponseN (%)

Q+AZA Q+LDAC Total

CR 8 (22) 2 (8) 10 (16)

CRp 2 (5) 5 (21) 7 (12)

Cri 15 (41) 7 (29) 22 (36)

CRc (CR+CRp+Cri) 25 (68) 14 (58) 39 (64)

OR (CRc+HI+PR) 26 (70) 16 (67) 42 (69)

NR 9 (24) 8 (33) 17 (28)

60-day mortality 2 (5) 0 (0) 2 (3)


AML: FLT3i – Conclusion• Understand role of FLT3i + low-dose chemotherapy:

‒ SWOG unfit, older: azacytidine vs aza/midostaurin vs aza/nivolumab (phase II/III) (FLT3 mut or WT)

• Understand role of specific v nonspecific TKI + chemo in upfront patients‒ Chemo + mido vs chemo + crenolanib in upfront mutant

FLT3 AML

• Understand role of specific FLT3i single-agent rx in advanced mutant FLT3 AML‒ Results of dealer’s choice vs quizartinib and dealer’s choice

vs gilteritinib trials awaitedSwaminathan M, et al. Blood. 2017;130: Abstract 723.

ARO-021: Phase III Comparison of Crenolanib With Midostaurinin Combination With Chemotherapy

R1:1Newly diagnosed

FLT3-mutated AML

Eligibility N = 510Cytarabine/

Daunorubicin+

Crenolanib

Consolidation +

Crenolanib

Crenolanibmaintenance

Cytarabine/Daunorubicin

+Midostaurin

Consolidation +

Midostaurin

MidostaurinMaintenance

Secondary Endpoints• Overall survival• Relapse-free survival• Composite complete remission rate• Duration of response

Primary Endpoint• Event-free survival


IDH1 and IDH2 MUTATIONS• IDH mutations occur in ~20% of patients with AML

– Most (~85%) occur in diploid or +8 de novo AML– Higher prevalence with increased patient age– Enriched in certain molecularly and

karyotypically defined populations (eg, normal karyotype, mutant-NPM1 AML)

• “Hot-Spot” mutations in enzymatic active site– IDH1-R132, IDH2-R140 or IDH2-R172

• Often considered “founder mutations”– IDH mutations are ancestral in 20% of IDH1 cases

and 35% of IDH2 cases• Can be acquired at time of progression

– 10% - 15% of AML from MDS– 20% - 25% of AML from MPN

Swaminathan M, et al. Blood. 2017;130: Abstract 723.Dang L, et al. Trends Mol Med. 2010;16(9):387-397. Chou WC, et al. Leukemia. 2011;25(2):246-253. Molenaar RJ, et al. Leukemia. 2015;29(11):2134-2142.

Enasidenib Monotherapy is Effective and Well-Tolerated in Patients with Previously Untreated Mutant-IDH2 (mIDH2) Acute Myeloid Leukemia (AML)

Pollyea DA, Tallman MS, De Botton S, DiNardo CD, Kantarjian HM, Collins RH, Stein AS, Xu Q, Tosolini A, Gupta I, Agresta VS, Stein EM

Abstract 638

Older Patients With Previously Untreated IDH2-Positive AML Were Eligible to Enroll in Phase I of the Pivotal Study

• Patients: ‒ Untreated mIDH2 AML‒ ECOG PS 0 - 2‒ Not candidates for standard

treatment

• Enasidenib dosing:‒ Dose-escalation: 50 mg/day –

650 mg/day‒ Expansion phase: 100 mg qd‒ Continuous 28-day treatment

cycles *NCT01915498 Data cutoff: 1 Sept 2017

ECOG PS, Eastern Cooperative Oncology Group performance status

All Patients in AG221-C-001

N = 345

Previously Untreated AML

N = 38

R/R AML: n = 281MDS: n = 17Other: n = 9

A subgroup of older patients with previously untreated mIDH2 AML received enasidenib monotherapy in the phase I portions of the AG221-C-001 study*

Pollyea DA, et al. Blood. 2017;130: Abstract 638.

ResponsePreviously Untreated

mIDH2 AMLN = 38

Overall response (CR, CRi/CRp, PR, MLFS), n (%) 12 (32)ORR 95%CI 17.5%, 48.7%Best response, n (%)CR 7 (18)CRi/CRp 1 (3)PR 2 (5)MLFS 2 (5)

Stable Disease*, n (%) 18 (47)Disease Progression, n (%) 1 (3)Not evaluable, n (%) 7 (18)

*Failure to achieve a response but not meeting criteria for progressive disease for a period of ≥8 weeksData cutoff: 1 Sept 2017CRi/CRp, CR with incomplete neutrophil or platelet recovery; MLFS, morphologic leukemia-free state; ORR, overall response rate

• Median number of enasidenib treatment cycles: 6.5 (range 1 - 35)


Treatment Duration, Response and Disposition

Data cutoff: 1 Sept 2017AE, adverse event; ID, investigator decision; NE, not evaluable; NR, not reached; PD, progressive disease; PV, protocol violation; SD, stable disease; WC, withdrew consent

WCWCWCDeathIDPD

AEID

WCPD

DeathOther

PDAE

PDPD

AEDeath

PDPDPDPD

PDPDDeath

OtherPD

TransplantPD

IDPD

TransplantPV

AEPatient decision

OngoingOngoing

Ongoing

0 6 12 18 24 30 36

CR Non-CR response SD PD NE

Treatment duration (months)

Indi

vidu

al P

atie

nts

Previously Untreated mIDH2 AML

N = 38Follow-up time, median months (range) 8.6 (0.5 – 34.3)Time to first response, median months (range) 1.9 (1.0 – 3.8)Time to best response, median months (range) 3.7 (1.0 – 12.9)Time to CR, median months (range) 5.6 (3.4 – 12.9)Duration of response, median months [95%CI] 12.2 [7.4, NR]Duration of CR, median months [95%CI] NR [3.7, NR]


Overall Survival

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

0 6 12 18 24 30 36

Months

Surv

ival

Median OS NR [95%CI 10.4 months, NR]

Data cutoff: 1 Sept 2017

Overall Survival: Responders

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

0 6 12 18 24 30 36

Months

Surv

ival Median OS 11.3 months [95%CI 5.7, 17.0]

Overall Survival


Ivosidenib (AG-120) in Mutant IDH1 AML and Advanced Hematologic Malignancies: Results of a

Phase 1 Dose Escalation and Expansion Study

Abstract 725

DiNardo CD, De Botton S, Stein EM, Roboz GJ, Mims AS, Pollyea DA, Swords R, Altman JK, Collins RH, Mannis GN, Uy GL, Donnellan W, Pigneux A, Fathi AT, Stein AS, Erba HP, Prince GT,

Foran JM, Traer E, Stuart RK, Arellano ML, Slack JL, Sekeres MA, Yen K, Kapsalis SM, Liu H, Goldwasser M, Agresta S, Attar EC, Tallman MS, Stone RM, Kantarjian HM

Study Design and ObjectivesDose escalation (n = 78)

Enrollment completeDose expansion (n = 180)

Enrollment complete: 500 mg qd in continuous 28-day cycles

Single-Arm, Open-Label, Phase I, Multicenter Trial Study

Untreated AML not eligible for SOC, n = 252

Other non-AML mIDH1 R/R advanced hematologic malignancies, n = 113

Other R/R AML not eligible for arm 1, n = 184

Patients with mIDH1+ advanced hematologic

malignanciesOral ivosidenib daily in

continuous 28-day cycles

Doses included 100 mg bid, 300, 500, 800, 1200 mg qd

R/R AML in 2nd+ relapse, relapse after SCT, refractory to induction or reinduction, or relapse within 1 year, n = 1261

ClinicalTrials.gov NCT02074839. DLTs, dose limiting toxicities; MTD, maximum tolerated dose; RP2D, recommended phase II dose

Study objectivesPrimary Safety and tolerability, MTD and/or RP2D, clinical activity mIDH1 R/R AML enrolled in

expansion arm 1Secondary DLTs, pharmacokinetics and pharmacodynamics (including 2-HG), preliminary clinical

activity in advanced hematologic malignanciesExploratory Determination of comutations and mIDH1 variant allele frequency (VAF)

DiNardo CD, et al. Blood. 2017;130: Abstract 725.

• CRh = 6 patients with investigator-assessed responses of CRi/CRp and 5 with MLFS

Response in R/R AML

Data cutoff: 12May2017. CRh, CR with partial hematologic recovery; CRp, CR with incomplete platelet recovery; CRi, CR with incomplete hematologic recovery; NA, not assessed; ORR, objective response rate; PD, progressivbe

Primary R/R AML Set – n = 125CR+CRh rate, n (%) [95% CI] 38 (30.4%) [22.5, 39.3]

Time to CR/CRh, median (range) months 2.7 (0.9, 5.6)Duration of CR/CRh, median [95% CI] months 8.2 [5.5, 12.0]

CR rate, n (%) [95% CI] 27 (21.6%) [14.7, 29.8]Time to CR, median (range) months 2.8 (0.9, 8.3)Duration of CR, median [95% CI] months 9.3 [5.6, 18.3]

CRh rate, n (%) 11 (8.8%)

Overall Response Rate, n (%) [95% CI] 52 (41.6%) [32.9, 50.8]Time to first response, median (range) months 1.9 (0.8, 4.7)Duration of response, median [95% CI] months 6.5 [4.6, 9.3]

Best responseCR, n (%) 27 (21.6)CRi or CRp, n (%) 16 (12.8)MLFS, n (%) 9 (7.2)SD, n (%) 44 (35.2)PD, n (%) 13 (10.4)NA, n (%) 16 (12.8)


41

Transfusion Independence in Primary R/R AML SetPatients Who Were Dependent at Baseline

Post-baseline transfusion independence defined as no transfusion for at least one 56-day period.

P la te le t(n = 6 9 )

R B C(n = 6 8 )

0

2 0

4 0

6 0

8 0

1 0 0P

os

t-b

as

eli

ne

tra

ns

fus

ion

ind

ep

en

de

nc

e,

%100

7 1 .47 5 .0

5 8 .3

8 4 .6

5 0 .0

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 vera ll

1 5 .4

3 9 .7

1 6 .7

3 9 .1


Genetic Profiling and Deep IDH1 Mutation Clearance to ≤0.04% in Ivosidenib (AG-120)-Treated Patients With

Mutant IDH1 Relapsed or Refractory and Untreated AML

Stone RM, Choe S, Zhang V, Marteyn B, Penard-Lacronique V, Wang V, DiNardo CD, Stein EM, Fathi AT, Tallman MS, Kantarjian HM, Attar EC, Wu B, de Botton S

Abstract 2684

R/R AML (n = 73) Untreated AML (n = 23)

Best Response (n) n

Mutation Clearance

n (%)

No Mutation

Clearance n (%) Best Response (n) n

Mutation Clearance

n (%)

No Mutation

Clearance n (%)

CR+CRh 34 7 (21) 27 (79) CR+CRh 9 5 (56) 4 (44)CR 25 7 (28) 18 (72) CR 5 3 (60) 2 (40)CRh 9 0 9 (100) CRh 4 2 (50) 2 (50)

Others 39 0 39 (100) Others 14 0 14 (100)Non-CR+CRhrespondersa 7 0 7 (100)

Non-CR+CRh respondersa 5 0 5 (100)

Nonresponders 32 0 32 (100) Nonresponders 9 0 9 (100)P valueb .003 P valueb .004

Stone RM, et al. Blood. 2017;130: Abstract 2684.

Ivosidenib Induces Deep Molecular Remissions in AML Patients with Best Overall Response of CR or CRh (BMMCs)

Data cutoff: May 12, 2017aDefined as patients with best overall response of CRi, CRp, MLFS, or PR who do not meet criteria for CR or CRh. bp-value is based on Fisher’s exact test comparing IDH1 mutation clearance in patients with best overall response of CR+CRh to patients with Other (non-CR+CRh responders and non-responders)

1 P .001 by Fisher’s exact test; (Sung - Lists all RTK pathway genes that are assayed in BWH)2 All detected FLT3 mutations were FLT3-TKD

12

By-Subject VAF of Known/Likely Co-Occurring Mutations at Baseline by Response to Ivosidenib Treatment (R/R AML at 500 mg QD (Bone Marrow, N = 142, NGS)

Stone RM, et al. Blood. 2017;130: Abstract 2684.

Mutant Isocitrate Dehydrogenase (mIDH) Inhibitors, Enasidenib or Ivosidenib, in Combination With Azacitidine (AZA):

Preliminary Results of a Phase 1b/2 Study in Patients With Newly Diagnosed Acute Myeloid Leukemia (AML)

DiNardo CD, Stein AS, Fathi AT, Montesinos P, Odenike O, Kantarjian HM, Stone RM, Koralek DO, Oostendorp J, Gong J, Gupta I, Vyas P

Abstract 639

Overall Response RatesOverall response rate (ORR): CR + CRi/CRp + PR + MLFS (IWG 2003)

Enasidenib + AZA: • ORR: 4 of 6

– In the enasidenib 100 mg + AZA arm, the best responses on-study were 2 CRs; 1 pt had PD

– In the enasidenib 200 mg + AZA arm, 1 pt achieved PR, 1 had MLFS, and 1 maintained SD

Ivosidenib 500 mg + AZA:• ORR: 8 of 11

– 4 pts achieved CR – 1 pt achieved CRi, 1 pt achieved PR, 2 pts had MLFS, and 3 pts maintained SD

Data cutoff: Sep 1, 2017MR, morphologic relapse after CR/CRi/CRpDiNardo CD, et al. Blood. 2017;130: Abstract 639.

Ivosidenib or Enasidenib Combined With Standard Induction Chemotherapy Is Well Tolerated and Active in

Patients With Newly Diagnosed AML With an IDH1 or IDH2 Mutation: Initial Results From a Phase I Trial

Stein EM, DiNardo CD, Mims AS, Savona MR, Pratz K, Stein AS, Fathi AT, Stone RM, Pollyea DA, Odenike O, Löwenberg B, Döhner H, Schiller G, Gupta IV, Nabhan S,

Zhang V, Almon C, Cooper M, Tallman MS

Abstract 726

Ivosidenib (AG-120) + CT Enasidenib (AG-221) + CT

Response, n (%)All

n = 30De Novo

n = 21sAMLn = 9

All n = 50

De novo n = 27

sAMLn = 23

CR+CRi/CRp 23 (77) 19 (91) 4 (44) 31 (62) 18 (67) 13 (57)

CR 19 (63) 15 (71) 4 (44) 25 (50) 16 (59) 9 (39)

CRi/CRp 4 (13) 4 (19) - 6 (12) 2 (7) 4 (17)

MLFS 1 (3) - 1 (11) 10 (20) 4 (15) 6 (26)

PR 2 (7) 1 (5) 1 (11) - - -

Persistent disease 2 (7) 1 (5) 1 (11) 5 (10) 2 (7) 3 (13)

NE 2 (7) - 2 (22) 4 (8) 3 (11) 1 (4)

Persistent disease, stable disease + disease progression

Best Overall Response Summary

Best response from any time on study is shown

Data cut 01AUG2017

Stein EM, et al. Blood. 2017;130: Abstract 726.

IDH1 Inhibitors: Conclusions1. Enasidenib is approved for R/R IDH2-mutant AML

2. Ivosidenib likely will be approved for R/R IDH1-mutant AML

3. Possible role for these ‘differentiating agents” as single agents in chemotherapy unfit mutant-IDH AML

4. The drugs can be given safely with AZA in chemotherapy-unfit IDH-mutant AML: Phase II/III HMA +/- IDHi trials underway

5. The drugs can be given safely with 3+7 in chemo in chemotherapy-fit IDH-mutant AML: Phase III trial planned


Phase I Trial of CD123-Specific CAR-T Cells in AML and BPDCN (#811)

• Patients with relapsed/refractory AML or blastic plasmacytoid dendritic cell neoplasm (BPDCN) were eligible

• Exclusion criteria included active CNS disease, active infections, active GVHD post-alloSCT

• In six patients with AML with 4 - 7 prior lines of therapy and prior allSCT, there were 2 CR/CRi, 1 MLFS, 2 SD, and 1 PD at day 28 of treatment

• A CR was attained in the patient with BPDCN

• Grade 1/2 CRS (n = 4) and grade 1/2 neurotoxicity (dizziness [n = 3], headache [n = 7], somnolence [n = 3]) were observed


Flotetuzumab: CD123 x CD3 Bispecific DART Protein (#637)

• DART bispecific platform– Multiple applications across different diseases– Predictable manufacturability– Long-term stability– Optimal variable light and heavy chain pairing

allows for tighter conformation and closer proximity between effector (CD3+) cells and target (CD123+) cells

• Ability to tailor half-life and valency• Flotetuzumab (MGD006/S80880) mode of action:

redirected T-cell killing of CD123+ Cells

“Anti-CD123” Anti-CD3

Tumor Cell T CellTarget

Cell Killing

• Activation• Cytokine release• Expansion• Differentiation

CD123 x CD3 DART

Tumor Cell


• Rapid responses after single cycle of therapy in majority of patients who respond (cycles ≤2)

• Antileukemic activity observed in 8/14 patients (57%)

• Objective response rate (CR/CRi/MLF/PR): 6/14 patients (43%)

• CR/CRi Rate: 4/14 (28%)

MDSAML AML AML AML

AML

AML

AML AML AML AML AML AML AML

Cohort 2: 100500 ng/kg/dayCohort 2a: 30100500 ng/kg/dayCohort 3: 30100 700ng/kg/dayCohort 7: 30100 500ng/kg/dayCohort 8: 30100 700ng/kg/day

Treatment Group

4 Days On/3 Days Off

7 Days On

CRm, molecular CR;SD/OB,stable disease/other anti-leukemic benefit

SD/OB SD/OB

PRMLF1 CRi1 CRi2 CR3 CRm4

TFTF

TF

TF

TF TF

Antileukemic Activity at Threshold Dose ≥500 ng/kg†


Phase 2 Study of Combination of Cytarabine, Idarubicin, and Nivolumab for Initial Therapy

of Patients With Newly Diagnosed Acute Myeloid Leukemia

Ravandi F, Daver N, Garcia-Manero G, Benton CB, Thompson PA, Borthakur G, Kadia T, Boddu PC, Alvarado Y, Jabbour EJ, Konopleva M,

Takahashi K, Kornblau S, DiNardo CD, Estrov Z, Flores W, Basu S, Allison J, Sharma P, Pierce S, Brandt M, Pike A, Cortes JE, Kantarjian HM

Abstract 815

Phase II Study of Nivolumab + IA in Patients With Newly Diagnosed AML

Key Eligibility Criteria

• AML by WHO criteria (APL excluded), high-risk MDS (≥10% blasts)

• Ages 18 – 60 (Patients over 60 who are very fit may be enrolled)

• Ps 0, 1, 2

• Adequate cardiac, renal, and hepatic function

Regimen

• Patients received cytarabine and idarubicin as induction/consolidation

• Nivolumab 3 mg/kg, q2w, was started on day 24, and continued for a total of one year.

Ravandi F, et al. Blood. 2017;130: Abstract 815.

Characteristics N = 35

Median age54 years(range, 26-65)

-7/7q-/-5/complex 14 (40%)

RiskFavorableIntermediatePoor

5 (14%)16 (46%)14 (40%)

Efficacy N = 35

CRCRp/CriPRNR

21 (62%)5 (14%)1 (3%)4 (11%)

Median OS 15.8 months

Median EFS 8.3 months

Median RFS (in CR)

17.3 months

In Nonresponders, CD4+ T effector cells exhibited an exhausted phenotype (PD1+TIM3+)

Suspected irAEs N = 35

Rash 2 (6%)

Colitis 2 (6%)

Pancreatitis 1 (3%)

Cholecystitis 1 (3%)

Ravandi F, et al. Blood. 2017;130: Abstract 815

Phase II Study of Nivolumab + IA in Patients With Newly Diagnosed AML

IA + Nivolumab – Comparison to IA

Overall Survival Event-Free Survival Remission Duration*

* Censored for death in CRRavandi F, et al. Blood. 2017;130: Abstract 815.

Nivolumab (Nivo) With Azacytidine (AZA) in Patients (pts) With Relapsed Acute Myeloid Leukemia (AML) or Frontline Elderly AML

Daver N, Garcia-Manero G, Basu S, Cortes JE, Farhad Ravandi F, Jabbour EJ, Assi R, Brandt M, Pierce S, Gordon T, Pemmaraju N, Andreeff M, Ning J, Kornblau S, Kadia T, Flores W, Matthews J, DiNardo CD, Borthakur G, Konopleva M, Allison J, Sharma P,

Kantarjian HM

Abstract 1345

Nivolumab (Anti-PD1 mAb) With 5-Azacytidine for Relapsed AML and Front-Line Elderly AML

• AML or Biphenotypic or Bilineage:

‒ Refractory or relapsed

• AML post-MDS/CMML:

‒ Progressing after MDS/CMML therapy

‒ Regardless prior AML therapy

Phase I (3+3 design) N = 6-12• 28 day – Cycles:‒ 5-Aza: IV/SC D1-725 50 75 mg/m2

‒ Nivolumab: IV on D1 & D150.1 0.3 1 3 mg/kg

Phase II • Relapse (N = 70) ‒ 28 day – Cycles:‒ 5-Aza: RP2D mg/m2

IV/SC D1-7‒ Nivolumab: RP2D mg/kg

IV on D1 & D15 X4 cycles or until CR then D1 once

•Relapsed (N = 70/70)•Front line (N = 15/40)

Phase I• Primary Objective: ‒ MTD & RP2D

• Secondary objectives:‒ Safety

• Phase I/II, open-label, single-arm study

Phase II• Primary Objective: ‒ ORR (CR, CRi, PR, HI

& morphologic LFS) per IWG 2003 criteria

• Secondary objectives:‒ DOR, DFS & OS

Patients at MTD

Daver N, et al. Blood. 2017;130: Abstract 1345.

Relapsed/Refractory N = 70

Median age 70 years(range, 22-90)

-7/-5/complex cytogenetics 24 (34%)

Prior therapies 2(range, 1-7)

Prior regimensHMA-basedHiDAC-basedInt-dose cytarabine-basedTargeted therapy

47272234

Daver N, et al. Blood. 2017;130: Abstract 1345.

Grade 2 - 4 irAEs in 15 patients:• Pneumonitis (N = 11)• Nephritis (n = 6)• Skin rash (n = 3)• Transaminitis (n = 2)2 cases of irAE-related death

Efficacy in frontline AML (>65)Evaluable = 12• CR/CRi/PR in 8 /12(66%)• Enrollment ongoing

In relapsed/refractory AML• ORR, 33%• CR/CRi/PR, 16 (23%)• Median OS, 10.6 months

Phase Ib/II Trial of Nivolumab Plus Azacitidinein Patients With AML

AZA+Nivo in Relapsed AMLOS (censored for SCT) by response (N = 70) OS AZA+Nivo versus historical HMA-combo

censored for SCT (Salvage 1, N = 32)

Salvage 1Median Age: 72 yearsSecondary AML: 42%

Adverse cytogenetics: 35%Daver N, et al. Blood. 2017;130: Abstract 1345.

p < .001

p < .001

Phase 1/2 Study of Venetoclax With Low-Dose Cytarabine in Treatment-Naive, Elderly Patients With Acute Myeloid Leukemia Unfit for Intensive

Chemotherapy: 1-Year Outcomes

Abstract 890

Wei A, Strickland SA, Roboz GJ, Hou J-Z, Fiedler W, Lin TL, Walter RB, Enjeti A, Chyla B, Popovic R, Fakouhi K, Shah P, Dunbar M, Xu T, Mabry M, Hayslip J

VEN 600 mg PO QD on days 1 – 28*LDAC 20 mg/m2 SC QD on days 1 – 10

(28-day cycles)

PRIMARY OBJECTIVES: safety, PK, MTD, ORR, TTP, and RP2D SECONDARY OBJECTIVES: response rates (CR, CRi, PR, and MLFS), DOR, and OS

*VEN dosed from D2–28 on cycle 1.ClinicalTrials.gov ID number: NCT02287233.

DOR, duration of response; MTD, maximum tolerated dose; PK, pharmacokinetics; SC, subcutaneously; TTP, time to progression; VEN, venetoclax

1-year outcomes presented: VEN 600 mg + LDAC

N = 61: phase I (n = 8) + phase II (n = 53)

Phase I: RP2D

Phase I/II: VEN + LDAC in Elderly Patients With AML

Wei A, et al. Blood. 2017;130: Abstract 890.

VEN600 mg (N = 61)

Intermediate(n = 37)

Adverse(n = 19)

No priorHMA

(n = 44)

PriorHMA

(n = 17)

62% 76% 47% 66% 53%100%

90%

80%

70%

60%

50%

40%

30%

20%

10%

0%

2%

3%

2%

36%

26%

41%

35%

32%

16%

34%

32%

41%

12%

CR + CRi

CR CRi PR

41%

11%

2°AML

(n = 27)

52%

AML Response Rates

Median time to response – 1 month

(range: <1 month – 9.5 months)

Median time to best response – 2.6 months

(range: <1 month – 14.4 months)

Data cutoff date: 15 AUG 2017Wei A, et al. Blood. 2017;130: Abstract 890.

Cytogenetics ORR (CR + CRi) Median OS, mo

Intermediate riskn = 37 28 (76%) 15.7

Adverse riskn = 19 9 (47%) 5.7

Molecular Subgroups

NPM1n = 7* 7 (100%) NR

CEBPAbiallelicn = 3 3 (100%) NR

Chromatin-spliceosome

n = 2215 (68%) 11.4

TP53-aneuploidy n = 20 10 (50%) 6.5

*Four of the 7 NPM1 patients have FLT3 mutations (3: ITD, 1: TKD).

Outcomes According to Molecular Drivers of AML

Data cutoff date: 15 AUG 2017.

1.0

0.8

0.6

0.4

0.2

0.00 5 10 15 20 25 30

OS, monthsSu

rviv

ing

Censored observation

OS in PatientsNPM1

CEBPAbiallelic

Chromatin-spliceosome

TP53-aneuploidy

Wei A, et al. Blood. 2017;130: Abstract 890.

GMI-1271 Improves Efficacy and Safety of Chemotherapy in R/R and Newly Diagnosed Older Patients with AML: Results of a Phase

1/2 Study

Abstract 894

DeAngelo DJ, Jonas BA, Liesveld JL, Bixby DL, Advani AS, Marlton P, O'Dwyer M, Magnani JL, Thackray HM, Becker PS

GMI-1271, an E-Selectin Antagonist, Disrupts the Relationship Between Tumor Cells and Bone Marrow Microenvironment

E-selectin:• Constitutively expressed in the bone

marrow microvasculature• Binds to the E-selectin ligand on AML

cells• Promotes cell-adhesion-mediated drug

resistance (CAMDR) of leukemic cell

GMI-1271, an E-selectin antagonist:• Inhibits activation of cancer survival

pathways (eg, NF-KB), disrupting CAMDR within bone marrow microenvironment

• Protects normal HSCs by enhancing quiescence and ability for self renewal

• Reduces chemotherapy-associated mucositisDeAngelo DJ, et al. Blood. 2017;130: Abstract 894.

Phase I/II Study Schema

MEC Induction: mitoxantrone (10 mg/m2/d IV), etoposide (100 mg/m2/d IV), cytarabine (1000 mg/m2/d IV over 60 mins) for 5 daysMEC Consolidation: same, for 4 days

7+3 Induction: cytarabine (200 mg/m2 continuous infusion x 7d), idarubicin (12 mg/m2 x 3d). Day 15 optional reinduction of 5+2 of same IDAC Consolidation: cytarabine (2 g/m2/d IV over 3 hrs QD for 5d), OR cytarabine (1.5 g/m2/dose IV over 3 hrs, BID QOD for 6 doses)

GMI-1271: 5, 10, or 20 mg/kg q 12 hrs in phase I. RP2D was 10 mg/kg

ClinicalTrials.gov identifier: NCT02306291DeAngelo DJ, et al. Blood. 2017;130: Abstract 894.

Demographics – Older Newly Diagnosed Patients

N = 25Age, median (range) 67 (60-79)Newly diagnosed, All

de novo 12 (48)Secondary AML 13 (52)

ELN Risk Category

Favorable 3 (12)Intermediate 7 (28)Adverse 12 (48)Unknown 3 (12)

DeAngelo DJ, et al. Blood. 2017;130: Abstract 894.

Overall Survival and Remission Duration– Older Newly Diagnosed Patients

• Censored at last known follow-up• Median follow-up is 10.5 months

• 10/25 (40%) have proceeded to HSCT• Median EFS is 11.3 months

DeAngelo DJ, et al. Blood. 2017;130: Abstract 894

Ove

rall

Surv

ival

, %

Dur

atio

n of

Rem

issi

on, %

ALL: Current ApproachPH-Negative - Younger

Pediatric-like prescription or HyperCVADAdd rituximab in CD20Testing addition of blina or ino early in prescription

PH-Negative - Older: Larson or hyperCVADPh-Positive - Younger: TKI plus chemotherapy (eg, ponat +hyperCVAD)Ph-Positive - Older

TKI plus steroidsOptions for Relapse: ino, blina, CAR

DeAngelo DJ, et al. Blood. 2017;130: Abstract 894

Steroid + Ponatinib monotherapy inPh-Positive ALL. Overall Resultsat w36 ( 9 mths)

Parameter N (%)CHR* 38/42** (90)CKR 17/19 (90)Deep CMR 11/19 (57)Deep CMR*** at least one time(undetectable)

20/24

Martinelli et al, ASH 2017

Inotuzumab Ozogamicin in Combination With Bosutinib for Patients With Relapsed or

Refractory Ph+ ALL or CML in Lymphoid Blast Phase

Abstract 143

Jain N, Cortes JE, Ravandi F, Konopleva M, Alvarado Y, Kadia T, Wierda, WG, Borthakur G, Naqvi K, Pemmaraju N, DiNardo CD, Daver N, Yilmaz M, Patel K,

Linderman DB, Garris R, Jabbour EJ, Kantarjian HM

Inotuzumab

D1: 0.8 mg/m2

D8: 0.5 mg/m2

D15: 0.5 mg/m2

Bosutinib daily (3 dose levels)DL1: 300 mgDL2: 400 mgDL3: 500 mg

Bosutinib continuously daily starting C1D1 until PD or toxicity

D1: 0.5 mg/m2

D8: 0.5 mg/m2

D15: 0.5 mg/m2

*After CR / CCyR / MRD neg: 1.0 mg/m2 q4 wks

Cycle 2-6*Cycle 1

Treatment Schema

Each cycle is 4 weeks

Jain N, et al. Blood. 2017;130: Abstract 143.

Overall Responses (N = 16)Parameter N (%)

ORR 13/16 (81)CR 8/16 (50)CRp 3/16 (19) CRi 2/16 (12)

CCyR 12/13 (92)MMR 11/13 (85)CMR 8/13 (62) Flow neg 9/13 (69)

Jain N, et al. Blood. 2017;130: Abstract 143.

Role of Remission Status and Prior Transplant in Optimizing Survival Outcomes Following Allogeneic Hematopoietic Stem Transplantation in Patients who

Received Inotuzumab Ozogamicin for Relapsed / Refractory Acute Lymphoblastic Leukemia

Kebriaei P. Stelljes M, DeAngelo DJ, Goekbuget N, Kantarjian HM, Advani AS, Merchant A, Stock W, Wang T, Zhang H, Loberiza F, Vandendries E, Marks D

Abstract 886

Methods: Patient Population

ALL, acute lymphoblastic leukemia; HSCT, hematopoietic stem cell transplant; R/R ALL, relapsed/refractory acute lymphoblastic leukemia

Patients• R/R ALL patients enrolled in either study

and treated with inotuzumab• Proceeded to allogeneic HSCT

Study 1010: 24 patients included

Study 1022: 77 patients includedStudy 1022 (INO-VATE)

Phase III trial (NCT01564784)Aug 2012–Jan 2017

N = 164

Study 1010Phase I/II trial (NCT01363297)

Aug 2011–Jan 2016N = 72

Analysis included 101 patients treated with inotuzumab ozogamicin who then proceeded to HSCT

Kebriaei P, et al. Blood. 2017;130: Abstract 886.

Post-Transplant OS: All HSCT

CI, confidence interval; HR, hazard ratio; INO, inotuzumab ozogamicin; OS, overall survival; ST, standard therapy

CensoredINO (n = 101, Events = 58)Median OS 9.2 (95% CI 5.1, -)ST (n = 31, Events = 17)Median OS 14.2 (95% CI 11.4, 25.0)

HR (unstratified) INO vs ST: 1.234 (95% CI 0.664, 2.295)P = .7767 (one-sided, unstratified)

* *+ +

+ + **

10131

6127

4821

378

163

113

42

00

No. of RiskINOST

12-mo Probability(95% CI)

24-mo Probability(95% CI)

INO 45.1 (35.2,54.5) 41.4 (31.5,51.0)

ST 64.8 (44.1,79.4) 34.1 (15.3,54.0)


Surv

ival

Pro

babi

lity

Time, Months0 5 10 15 20 25 30 35

100

80

60

40

20

0

Safety Outcomes: VOD• 19 (18.8%) patients in the inotuzumab group experienced veno-

occlusive disease (VOD) post-transplant; 5 of these cases were fatal– 1 cycle: 7% – 2 cycles: 20% – 3 cycles: 19% – 4–6 cycles: 24% – ≤2 vs ≥3 cycles: 16% vs 21%

• Median time from follow-up SCT to VOD was 15.0 days (range, 3–57 days)

• No difference was seen in median time from last dose to transplant between patients who experienced VOD and those who did not

ALL, acute lymphoblastic leukemia; SCT, stem cell transplant


Chimeric Antigen Receptor (CAR)

Abbreviations: CAR, chimeric antigen receptor; GMP, good manufacturing practice; TCR, T-cell receptor

• ELIANA is a single-arm global study with centralized manufacturing of tisagenlecleucel• 25 sites in 11 countries across North America, Europe, Australia, and Asia

Global, Multicenter ELIANA Trial: ALL Registration Study

FPFV=8 APR 2015Data cutoff: 23 NOV 2016

Buechner J, at al. Haematologica. 2017;102(s2): Abstract S476.

ELIANA: Primary Efficacy AnalysisParameter Efficacy Analysis Seta

n = 63Primary endpoint % (n/N) 95% CI POverall remission rate (CR + CRi) within 3 months 83 (52/63) (71-91) <.001d

Best overall response, %b

CR 63

CRi 19

Secondary endpointBest overall response of CR or CRi within 3 months with MRD-negativec BM 83 (71-91) <.001d

Primary efficacy analysis consistent with interim analysis where primary endpoint was met

a Patients infused with CTL019 ≥3 months prior to data cutoff. b The response was unknown in 6 patients. c MRD negative = MRD <0.01%. d Nominal P value presented to test null hypothesis of overall remission rate <20% for comparison with historical control.


CTL019: Efficacy Outcomes in ALL Studies

RFS• 12 mo: 60% (95% CI, 48-75)• 24 mo: 53% (95% CI, 39-70)

24 patients in continuous remission ≥1 year, 19 without further therapy

7 patients proceeded to HSCT, 1 to DLI• 2 relapses after SCT

Duration of Response in B2202 and B2101J


Other CAR-T Cell Constructs in ALL: KTE-C19 and JCAR017

JCAR017 explored in a phase I study for pediatric and young adult patients with relapsed/refractory CD19-positive ALL (N = 45)2

• MRD-negative CR rate was 93%• Severe CRS: 23%

KTE-C19: anti-CD19 CAR T cell therapy; tested in phase I ZUMA-3 and ZUMA-4 trials in adult and pediatric relapsed/refractory ALL1

• 82% (9/11) achieved CR/CRi• 100% responders tested negative for MRD• 38% (5/13) of patients experienced ≥grade 3 CRS

1. Shah BD, et al. Blood. 2017;130: Abstract 2803. 2. Gardner R, et al. Blood. 2016;128: Abstract 219.

Shah BD, Stock W, Wierda WG, Oluwole O, Holmes H, Schiller GJ, Topp MS, Kersten MJ, Houot R, Boissel N, Mojadidi M, Xue A, Mardiros A, Jiang Y, Shen T,

Aycock JS, Stout S, Wiezorek JS, Jain R

Phase 1 Results of ZUMA-3: KTE-C19, an Anti-CD19 Chimeric Antigen Receptor (CAR) T Cell

Therapy, in Adult Patients With Relapsed/Refractory Acute Lymphoblastic

Leukemia (R/R ALL)Abstract 888

85

• Approximately 50% of new ALL cases occur in adults aged ≥20 y1

– Although ≈50% of adult ALL patients may achieve long-term survival,2 outcomes for patients with R/R ALL are poor3,4

• The KTE-C19 CAR construct demonstrated an ORR of 82% and a CR rate of 54% in patients with refractory large B-cell lymphomas after a single infusion of CAR-T cells5

• Promising early efficacy and manageable toxicity were also reported with KTE-C19 in adult patients with R/R ALL6

• Here, we report updated safety and efficacy data from patients with R/R ALL in the ZUMA-3 trial (NCT02614066)

Background

Shah BD, et al. Blood. 2017;130: Abstract 888.

86

ZUMA-3 Treatment Schema

Day 0Day −4 Day 28

First Disease Assessmentb

KTE-C19 Infusion

Conditioning Chemotherapy

Leukapheresis

Bridging Therapya


87

Summary of Treatment-Emergent and KTE-C19–Related AEs

TEAE,a n (%)

2 × 106

Dose Groupn = 6

1 × 106

Dose Groupn = 14

0.5 × 106

Dose Groupn = 9

OverallN = 29

Any TEAE 6 (100) 14 (100) 9 (100) 29 (100)Grade 3 1 (17) 5 (36) 2 (22) 8 (28)Grade 4 4 (67) 9 (64) 5 (56) 18 (62)Grade 5 1 (17) 0 (0) 1 (11) 2 (7)

Any KTE-C19–relatedTEAE

6 (100) 14 (100) 9 (100) 29 (100)

Grade 3 2 (33) 6 (43) 4 (44) 12 (41)Grade 4 2 (33) 7 (50) 3 (33) 12 (41)Grade 5 1 (17) 0 (0) 0 (0) 1 (3)

• 2 patients who received KTE-C19 died during the study due to AEs

–1 due to multiorgan failure secondary to CRS on study Day 6, as previously reported1

–1 due to cerebrovascular accident not related to KTE-C19 treatment on study Day 48

• No cases of cerebral edema


Best Overall Response With 8 Weeks of Follow-Up2 × 106 Dose

Group n = 6

1 × 106 Dose Groupn = 14

0.5 × 106

Dose Groupn = 4

OverallN = 24

CR Rate (CR + CRi), n (%) 4 (67) 10 (71) 3 (75) 17 (71)CR 3 (50) 10 (71) 3 (75) 16 (67)CRi 1 (17) 0 0 1 (4)

Blast-free hypoplastic/aplastic BM, n (%) 0 2 (14) 0 2 (8)

• 88% (21/24) of all patients treated had undetectable MRDa

- 100% of CR/CRi/blast-free hypoplastic/aplastic BM- 2 patients with unconfirmed CR/CRi were also MRD-

• 67% (2/3) CR rate for patients with Ph+ disease • 4 patients have relapsed, with a time to relapse ranging from 130 to 234 days: 1 CD19-

aMRD negativity was defined as <0.01% B lymphoblasts in BM by multicolor flow cytometry.BM, bone marrow; CR, complete remission; CRi, CR with incomplete blood count recovery; MRD, minimal residual disease; ORR, objective response rate; Ph+, Philadelphia-chromosome positiveShah BD, et al. Blood. 2017;130: Abstract 888.

Autologous vs Allogeneic CAR-T Cell TherapyVarious approaches to CAR-T Cell Therapy

ASH 2017: Phase I results of UCART19 in adults with CD19+ R/R B-ALL Benjamin R, et al. ASH 2017, Abstract 887

Conclusions

New drugs approved in AML 20171. Midostaurin: w/induction chemo, FLT3 mutant upfront2. Enasidenib: single agent, R/R IDH2 mutant3. CPX-351: upfront in secondary AML4. Gemtuzumab: w/chemo, CD33+ upfront or single-agent

relapsed CD33+5. ? 2018, Ivosidenib: single agent, R/R IDH1 mutant

Drugs to watch in AML include venetoclax, GMI-1271, ICPI

ALL: Use of BITE, ADC, and CART changing the approach

Acknowledgements• Clinical Team at DFCI:

– Dan DeAngelo, Martha Wadleigh, David Steensma, Jackie Garcia, Goyo Abel , Eric Winer, Marlise Luskin

– Ilene Galinsky, NP

– Andrian Penicaud, PA, Kat Edmonds , NP, Sarah Cahill, PA, Mary Girard, PA, Sioban Creedon, NP

• BMT Team: Alyea, Antin, Armand, Cutler, Ho, Koreth, Soiffer

• DFHCC Team: Avigan, Rosenblatt, Amrein, Fathi, Brunner, Hobbs

• Scientific Team at Dana-Farber/Harvard Cancer Center

– Ben Ebert; Andy Lane, Coleman Lindsley,Jim Griffin; Tony Letai, David Weinstock, David Frank , Kim Stegmeir, Donna Neuberg, Tom Look, S Armstrong, T Graubet

• Worldwide Collaborators

– Alliance: R Larson, G Marcucci, W Blum, G Uy, G Roboz, S. Mandrekar

– Worldwide:,C Schiffer, T Fischer, H Dohner, K Dohner, C Thiede, R Schlenk, and others.

• Slides

– Daver, E Stein, C Dinardo, B Medeiros, E Wang, D Pollyea, A Wei, C Rollig, K Dohner, J Cortes D DeAngelo, M Davids, K Pratz, D Steensma

Documents

Acute Leukemia - prIME Oncology...Prognostic Impact of NPM1/FLT3-ITD Genotypes From Randomized Patients With Acute Myeloid Leukemia (AML) Treated Within the International RATIFY Study