1

Acute Myeloid Leukemia

Guillermo Garcia-Manero

Professor

Department of Leukemia

MD Anderson Cancer Center

Putting the Problem into Perspective

All other sites(~1,445,000)

Leukemias(~ 45,000)

AML

CMLALL

CLL

Other

~ 12,000

Jemal A et al. CA Cancer J Clin 2007; 57: 43-66

~ 5,000

~ 6,000

~ 15,000

Age-Specific Incidence Rates for AML:1995-1999

NCI SEER Program. 1995-1999

0

5

10

15

20

25

30

35

00-04 05-09 10-14 15-19 20-24 25-29 30-34 35-39 40-4445-49 50-54 55-59 60-64 65-69 70-74 75-79 80-84 85+

Ave

rage

an

nu

al r

ate

per

100

,000

Male

Female

All persons

Age

Etiology and Risk Factors

• Chemical exposureBenzene; pesticides

• Other environmental exposuresHair dyes; smoking, non-ionic radiation

• Genetic disordersDown syndrome; Bloom syndrome; Fanconi’s anemia; ataxia-telangectasia; Wiskott-Aldrich

• Prior chemotherapy or XRTAlkylating agents; topoisomerase II inhibitors

Etiology and Risk FactorsAntineoplastic Agents

• Alkylating agents- preceding MDS phase- evolution to AML after 5 to 7 years- chromosome abnormalities: -5, -7

• Topoisomerase II inhibitors- no MDS phase- short latency of 1 to 3 years- monocytic morphology- chromosome abnormalities: 11q23

AML Diagnosis

• ≥ 20% blasts (BM and/or PB)

• IHC stains

- Myeloperoxidase (+) or nonspecific esterase (+)

or butyrate esterase (+)

• Immunophenotype (flow cytometry)

- ≥ 2 myeloid markers (+)

- < 2 lymphoid markers (+)

• Cytogenetic-molecular

Harris N et al. J Clin Oncol 1999; 17: 3835-3849; Cheson BD et al. J Clin Oncol 2003; 21: 4642-4649

2

Expression of Cell-Surface and Cytoplasmic Markers in AML Diagnosis

Stage/Lineage Marker

Percursor CD34, CD38, CD117, CD133, HLA-DR

Granulocytic CD13, CD15, CD16, CD33, CD65, cMPO

Monocytic CD11c, CD14, CD64, lysozyme, CD4, CD11b, CD36, NG2 homologue

Megakaryocytic CD41 (gp IIb/IIIa), CD61 (gp IIIa), CD42(gp 1b)

Erythroid CD235a (glycophorin A)

Döhner H et al. Blood 2010; 115: 453

CD34 and HLA-DR are negative in APL

Byrd JC et al. Blood 2002;100:4325-4336

Pre-Treatment Karyotype as PrognosticFactor in AML (CALGB 8461)

55%

24%

5%

Cytogenetic Risk Groups

MRC SWOG/ECOG CALGBGIMEMA/

AML10German AMLCG

Favorable t(15;17)t(8;21)inv(16)/t(16;16)

t(15;17)t(8;21) (lacking del(9q), complex (i.e. ≥ 3 unrel abn)

t(15;17)t(8;21)inv(16)/t(16;16)inv(16)t(16;16);del(16q)

t(15;17)t(8;21)inv(16)/t(16;16)

t(15;17)t(8;21)inv(16)/t(16;16)

Intermediate normalOther noncomplex

normal+6, +8, -Y, del(12p)

normalother noncomplex

normal-Y

normalother noncomplex

Adverse abn(3q)-5/del(5q)-7complex (≥ 5 unrel abn) (excluding those with favorable changes)

abn(3q),(9q),(11q),(21q),(17p)-5/del(5q)-7/del(7q)t(6;9)t(9;22)complex (≥ 3 unrel abn)

inv(3)/t(3;3)-7t(6;9)t(11;19)+8complex (≥ 3 unrel abn) (excluding those with favorable changes)

other inv(3)/t(3;3)-5/del(5q)-7/del(7q)abn(11q23)del(12p)abn(17p)complex (≥ 3 unrel abn)

AML – WHO Classification (2008)• AML with recurrent genetic abnormalities

- t(8;21)(q22;q22); RUNX1-RUNX1T1- inv(16)(p13.1;q22) or t(16;16)(p13.1;q22); CBFB-MYH11- t(15;17)(q22;q12); PML-RARA- t(9;11)(p22;q23); MLLT3-MLL- t(6;9)(p23;q23); DEK-NUP214- inv(3)(q21;q26.2) or t(3;3)(q21;q26.2); RPN1-EVI1- t(1;22)(p13;q13); RBM15-MKL1- AML with NPM1mut

- AML with biallelic CEBPAmut

• AML with MDS-related changes

• Therapy-related myeloid neoplasms

• AML, NOS (includes FAB, acute myelofibrosis)

• Myeloid sarcoma

• Myeloid proliferations related to Down syndrome

• Blastic plasmacytoid dendritic cell neoplasms

The WHO allows the diagnosis of AML regardless of marrow blasts

Impact of cytogenetic entities recognized in 2008 WHO classification on survival.

Grimwade D et al. Blood 2010;116:354-365

Core Binding Factor (CBF) AML

t(8;21)(q22;q22)inv(16)(p13q22)/

t(16;16)

Incidence 5-10% 5-10%

Molecular RUNX1-ETO CBFb-MYH11

FAB 20-25% of FABM2 FABM4eo

Phenotype (Flow) CD19+, CD56+ (extramedullary disease)

Myelomonocytic

Adverse prognosis ↑ age, ↑ WBC, CD56+, EML/GS, nonwhite

↑ age, ↑ WBC, female (in pts < 60 yrs)

Secondary molecular abnormalities

KITFLT3/D835Y > FLT3/ITDNRAS > KRAS

30-40%2-7%10%

30-40%6-24%30%

Dombret H et al. Curr Op Hematol 2009; 16: 92-97; Schlenk RF et al. J Clin Oncol 2004; 22: 3741; Marcucci G et al. J ClinOncol 2005; 23: 5705; Goyama S and Mulloy JC. Int J Hematol 2011; 94: 126

3

Monosomal Karyotype (MK) in Patients with AML

• MK: ≥ 2 autosomal monosomies or 1 monosomy with structural abnormalities

Perrot A, et al. Blood 2011; 118: 679; Breems DA, et al. J Clin Oncol 2008; 26: 4791

> 60 years ≤ 60 years

Normal Karyotype AML (NK-AML)

• NK = CN (cytogenetically normal) AML

• Approximately 45% of AML

• Heterogeneous group of patients

• Abnormalities in certain genes confer prognostic significance in adult patients

14

• 50 whole genomes + 150 exomes = 200 cases

Recurrently mutated genes: n = 237Significantly mutated genes: n = 23

Cancer Genome Atlas Research Network. N Engl J Med. 2013;368:2059-2074.

Insights Into the AML Genome Mutations in AML and Complementation Groups

Patel JP et al. N Engl J Med 2012; 366: 1079-1089

“Important” Gene Mutations

Mutated Gene Frequency Clinical Significance

NPM1 AML 25-30%CN AML 45-64%Del(9)(q) 35-40%; +8 15%FLT3/ITD 40%IDH 25%

- Predicts for achievement of CR and favorable RFS and OS

- favorable impact regardless of age

CEBPA CN AML 10-18%Del(9)(q) 40%

If biallelic higher CR rate and favorable RFS and OS

KIT CN AML < 10%CBF AML 25-30%

Associated with inferior outcome

Marcucci G et al. J Clin Oncol 2011; 29: 475-486

“Important” Gene MutationsMutated Gene Frequency Clinical Significance

FLT3-ITD AML 20%CN AML 28-34%

- Inferior outcome especially when high mutant/allelic ratio- Available inhibitors

FLT3-TKD AML 5-10%CN AML 11-14%Inv(16) 14-24%

- Controversial significance

IDH1, IDH2 AML 15-20% - Limited prognosticsignificance- Available inhibitors

Marcucci G et al. J Clin Oncol 2011; 29: 475-486

4

Molecular Prognosis in CN AML

NPM1 without FLT3 ITD Other Genotypes except CEBPA

Schlenk R et al. N Engl J Med 2008; 358:1909 ; Marcucci G et al. J Clin Oncol 2011; 29: 475

HSCT = ChemoHSCT > Chemo

Correlation of Cytogenetic and Molecular Data in AML with Clinical Data (ELN)

INTERMEDIATE-II

UNFAVORABLE

INTERMEDIATE-I

FAVORABLE

Döhner H, et al. Blood. 2010;115(3):453-474

NPM1mut/FLT3-ITDmut

NPM1wt/FLT3-ITDmut

NPM1wt/FLT3-ITDwt

t(9;11); MLLT3-MLLOther (neither favorable nor adverse)

inv(3) or t(3;3); RPN1-EVI1t(6;9); DEK-NUP214t(v;11); MLL rearranged-5 or del(5q); -7; abnl(17p); complex CG

Outcome in Younger (A,C,E; age 18 to 60 years) and Elderly (B,D,F; age > 60 years) Patients with AML by ELN Categories

Röllig C et al. JCO 2011;29:2758-2765

2017 European LeukemiaNet (ELN) Recommendations for AML

Risk Category Genetic Lesion

Favorable t(8;21)(q22;q22); RUNX1-RUNX1T1

inv(16)(p13.1q22); CBFB-MYH11

Mutated NPM1 without FLT3-ITD or with FLT3-ITDlow

Biallelic mutated CEBPA

Intermediate Mutated NPM1 and FLT3-ITDhigh

Wild type NPM1 without FLT3-ITD or with FLT3-ITDlow

t(9;11)(p21.3;q23.3); MLLT3-KMT2A

Cytogenetic abnormalities not classified as favorable or adverse

Adverse t(6;9)(p23;q34.1); DEK-NUP214

t(v;11q23.3); KMT2A rearranged

t(9;22)(q34.1;q11.2); BCR-ABL1

inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2); GATA2,MECOM(EVI1)

-5 or del(5q); -7; -17/abn(17p)

Complex karyotype (≥3), monosomal karyotype

Wild type NPM1 and FLT3-ITDhigh

Mutated RUNX1

Mutated ASXL1

Mutated TP53

Döhner H, et al. Blood. 2017;129(4):424-447.

* Low, low allelic ratio (<0.5); high, high allelic ratio (≥0.5)

Molecular Markers and Response

Patel JP et al. N Engl J Med 2012; 366: 1079-1089

ECOG E1900 trial – HD daunorubicin was associated with an improved rateof survival among patients with mutant DNMT3A (in UVA also mutant MLL and

NPM1)

Mutant DNTM3A or NPM1, or MLL translocation

WT DNTM3A and NPM1, and no MLL translocation

44%

25%

35%

39%

Lestaurtinib Midostaurine MLN-518

AC220Sunitinib Sorafenib

FLT3 kinase inhibitors

Prescott H, Expert Opinion Emerg Drugs, 2011, In press

5

Rollig C, et al. Lancet Oncology, 2015, 16 (16), 1691-1699

(A)EFS, (B) RFS, and (C)OS

(B)censored and not censored for AlloSCTRATIFY Schema

R

A

N

D

O

M

I

Z

E

DNR

ARA-C

Midostaurin

DNR

ARA-C

Placebo

HidAC

Midostaurin

HidAC

Placebo

Midostaurin

MAINTENANCE

12 months

Placebo

MAINTENANCE

12 months

Stratify*

FLT3

ITD

or

TKD

FLT3 WILD

TYPE not

eligible for

enrollment

X 4

X 4

CR

CR

P

R

E

-

R

E

G

I

S

T

E

R

F

L

T

3

S

C

R

E

E

N

Stratification: TKD; ITD with allelic ratio <0.7 ‘vs’ ≥0.7

Stone R, et al. ASH 2015, Abstract #6

Complete Response Rates

MIDO

(N=360)

PBO

(N=357)p *

CR by day 60 212 191

Rate 59% 53% 0.15

Time to CR, median (range) 35 days (20-60) 35 days (20-60)

CR in

induction/consolidation**239 211

Rate 66% 59% 0.045

Time to CR, median (range) 37 days (20-99) 36 days (20-112)

* 2-sided Fisher’s Exact p

** includes all CRs reported within 30 days of ending protocol therapy27

Overall Survival (Primary Endpoint)23% reduced risk of death in the Mido arm

• Median OS: Mido 74.7 (31.7-NE); PBO 25.6 (18.6-42.9) months

NE: not estimable

* controlled for FLT3 subtype (TKD, ITD-Low, ITD-High)

Arm 4-year Survival

MIDO 51.4% (95%CI: 46, 57)

PBO 44.2% (95%CI: 39, 50)

+ Censor

Hazard Ratio*: 0.771-sided log-rank p-value*: 0.0074

28

IDH mutations lead to 2HG production

• Wild-type IDH1 and IDH2 are NADP+ dependent metabolic enzymes that catalyze isocitrate to αKG

• IDH Mutations cause a reverse reaction that reduces αKG to 2HG via conversion of NADPH to NADP+

• IDH1 and IDH2 Mutations occur in 15-20% of patients with AML

Yen, KE, Oncogene, 2010, 29, 6409-17

Duration of treatment

and best overall

response in all

response-evaluable

patients as of 1 May

2015 (n=158)

Treatment durationa:

3-month = 61.2%

6-month = 48.7%

Median = 5.6 months

AG221

Stein E, et al. ASH 2015

6

IDH mutations, BCL-2 Dependence and ABT-199

VENETOCLAX BINDS TO AND INHIBITS OVEREXPRESSED BCL-2

Venetoclax Binds to and Inhibits Overexpressed BCL-2

Venetoclax

BH3-only

BAX BAK BCL-2 BCL-2

Mitochondria

An Increase in BCL-2 Expression Allows the Cancer

Cell to Survive

Mitochondria

Pro-apoptotic Proteins

(BAX, BAK)

Anti-apoptotic Proteins(BCL-2)

21Apoptosis is Initiated

Apoptosome

APAF-1

Cytochorome C

Active Caspase

Procaspase

Mitochondria

3

The large # of pro-apoptotic molecules bound and sequestered by BCL2 has cancer cells “primed” for cell death; apoptosis initiated after displacement by ABT199

Konopleva et al , ASH 2014

IDH Mutations and BCL2-Dependence

CR/CRi

IDH1/IDH2 mutation, FLT3 WT or TKD

IDH1/IDH2 mutation, FLT3 ITD

ABT-199 (Venetoclax) for R/R AML:• 28 evaluable patients, 11 (35%) with IDH1/2 mutations. • > 50% patients had clinical benefit including 6 CR/CRi; 4 were IDH mutants• Another 4 IDH mutants with MLFS or PR

Sekeres MA et al. Blood 2009;113:28

Time from Diagnosis to Treatment (TDT)

≤ or 5 days: AML Patients ≥ 60 years

Favorable by TDT

Intermediate by TDT Unfavorable by TDT

Favorable

Intermediate

Unfavorable

Initial Evaluation

• Patient-specific Induction mortality- Age- Comorbidities- Performance status

• Disease-specific Resistance- Cytogenetic-molecular- AHD (MDS)- MDR phenotype?

AML Treatment (Non-APL)

• Induction- cytarabine plus anthracycline

• Postremission therapy- chemotherapy- allo/auto HSCT

• Recommendations may differ by- Age (< 60 y vs. ≥ 60 y) ± PS- Karyotype/genotype

AML Induction Therapy

• Infusional cytarabine (100-200 mg/m2) over 24 hrs daily x 7 days

7 PLUS 3

• Anthracycline *- Daunorubicin 60-90 mg/m2 iv daily x 3- Idarubicin 12 mg/m2 iv daily x 3

Patients < 60 Years

* Fernandez HF et al. N Engl J Med 2009; 361: 1249-1259; Pautas C et al. J Clin Oncol 2010; 28: 808-814

7

AML Induction Therapy(Patients < 60 Years)

• HD daunorubicin prolongs survival *- patients < 50 yrs- favorable/intermediate CG- Absence of FLT3-ITD

• Extension of 3+7 → 3+10

• Addition of 3rd drug

• G/GM priming

• MDR modulators

NO DIFFERENCE

* Fernandez HF et al. N Engl J Med 2009; 361: 1249-1259

High-Dose Cytarabine in Induction(Patients < 60 Years)

• Studies:- SWOG (1996) and HOVON (2011) suggest no- Metaanalysis of 4 randomized trails (2006) suggests yes

- EORTC-GIMEMA (2011) suggests yes (for pts ≤ 45 yrs)

• Common issues:- higher mortality/toxicity despite survival

benefit (in some)Weick JK et al. Blood 1996; 88: 2841-2851; Löwenberg B et al. N Engl J Med 2011; 364: 1027-1036; Kern W and Estey E. Cancer 2006; 107: 116; Willemze R et al. Blood 2011; 118: abs 257

Simplified Classification of AML• AML sensitive to conventional chemotherapy

• CBF leukemias (without c-KIT mutation)

• Diploid AML with NPM1 and CEBPmutation (without FLT3 mutation)

• Others (younger patients without AHD)?

• Dose intensification of chemotherapy may be helpful

• Chemo-resistant AML

• AML with adverse cytogenetics

• AML with FLT3-ITD

• Others (older patients, younger patients with t-AML and/or AHD)

• New agents are neededHills, RK, et al. The Lancet Oncology, 2014; 15(9), 986

Gemtuzumab Ozogamycin in induction Therapy

Meta-analysis of 5 Randomized Trials

• 5:1 molar ratio of cytarabine to daunorubicin is optimal in in vitro and in vivo AML models

• 100-nm bilamellar liposomes

• CPX-351 liposomes deliver 5:1 molar ratio for >24 h

• CPX-351 accumulates and persists in the bone marrow

• Selective uptake of CPX-351 by leukemia blasts and intracellular drug release

Lancet JE et al. Blood. 2014;123:3239-3246.

Cytarabine/Daunorubicin Liposome: CPX 351 Overall Survival Was Greater in the CPX-351 Arm Compared to the 7+3 Arm

Kaplan-Meier Curve for Overall Survival

ITT Analysis Population

CPX-351

7+3

104/153

132/156

9.56 (6.60, 11.86)

5.95 (4.99, 7.75)

Events/N Median Surv. (95% CI)

122

110

92

77

79

56

62

43

46

31

34

20

21

12

16

7

11

3

5

2

153

156

1

0CPX-351

7+3

6 9 12 15 18 21 24 27 30 33 360 3

Months from Randomization

100

80

60

40

20

0

Su

rviv

al (%

)

Hazard Ratio = 0.69

p-value = 0.005

8

Assessment of Response

• Marrow at d 7-10:- assess blasts and cellularity- if hypoplastic (cellularity < 20% and blasts < 5-10%) rpt marrow in 7-14 d

- if blasts: donor search/salvage Rx

• Goal: complete remission:- ANC > 1,000/mcl- Plts ≥ 100,000/mcl- Marrow blasts < 5%

• Molecular CR only matters in APL

AML Postremission Therapy

Better-risk karyotype

HiDAC 3g/m2 over 3h q12 d 1,3,5 x 4 *OR

HiDAC x 1-2 auto HSCT

Intermediate-risk karyotype

Matched sibling or auto HSCT

OR

HiDAC 3g/m2 over 3h q12 d 1,3,5 x 4 *OR

Clinical trial

Poor-risk karyotype

AHD

t-AML

Clinical trial

OR

Allo HSCT/alternative donor HSCT

NCCN Practice Guidelines in Oncology – v.1.2008 * Mayer RJ et al. N Engl J Med 1994; 331: 896-903

Indications for Allo SCT in CR1

Genotype MSD Alternative

Favorable No No

+ KIT Possible Possible

Intermediate Possible Possible

+ FLT3/ITD Yes Yes

+ NPM1 w/o FLT3/ITD or IDH1 No No

+ CEBPA* w/o FLT3/ITD or IDH1 No No

Unfavorable Yes Yes

* Biallelic mutations only

Modified from Rowe JM, Tallman MS. Blood 2010; 116: 3147-3156

AML Survival ExpectationsECOG 1973-1997

Tallman M et al. Blood 2005;106:1154-1163

All Patients Age ≤ 55 yrs Age > 55 yrs

AML Therapy for Patients ≥ 60 Yrs

• Assess performance status, comorbidities and karyotype

• Preferably, obtain karyotype/molecular profile prior to therapy

• Standard induction not appropriate - pts ≥ 70 - 75 yrs- poor PS (> 2) - poor risk karyotype

AML Induction Therapy(Patients ≥ 60 Years)

• Ara-C + Anthracycline induction - PS 0-2; no significant comorbidities; absence of unfavorable disease features

• Alternative approaches- intermediate intensity therapy (clofarabine)- low-intensity therapy (hypomethylating

agents; low dose cytarabine)- best supportive care (hydrea, transfusions)- palliative care

9

Postremission Surveillance

• CBC and platelets- every 1-3 months x 2 years- then every 3-6 months x 3 years

• Marrow- only if hemogram becomes abnormal- no routine surveillance recommended

• Minimal residual disease- only in the context of clinical trials

MRD: Available Techniques• Quantification of MRD provides an estimate of the reduction of

disease burden, reflecting:

• the inherent leukemia biology

• drug-resistance mechanisms

• the adequacy of the treatment, and

• other host-drug interactions influencing the response.

Ravandi F and Jorgensen J. JNCCN, 2012, 10(8), 1029

Also, Next Generation Sequencing

(A) RFS and (B) OS by cytogenetic status at CR and cytogenetic risk at diagnosis

Chen Y, et al. JCO 2011;29:2507-2513

MRD Assessment – Flow Cytometry

Terwijn M et al. JCO 2013;31:3889-3897

Effect of MRD Status by FC on Patients in

CR after course 1

Freeman S D et al. JCO 2013;31:4123-4131

10

Agents to Eradicate MRD

• Monoclonal antibodies

• SGN-CD33A, AMG-330, SL-140

• Demethylating agents

• Oral azacytidine

• Check-point inhibitors

• Nivolumab

• Small molecule inhibitors

• FLT3 Kinase inhibitors, IDH inhibitors, ABT-199

• Vaccines

• CAR-T cells

AML Salvage

• No defined standard

• Determine by age and remission duration

• Remission durations ≥ 12 mos:- CR ~ 60%- re-induce; clinical trial; HSCT in CR2

• Remission durations < 12 mos:- CR ~ 10-20%- clinical trial; best supportive care for older pts

Representative Salvage Chemotherapy Regimens (NCCN)

• Cladribine + cytarabine + GCSF ±mitoxantrone or idarubicin

• High-dose cytarabine + anthracycline

• Fludarabine + cytarabine + GCSF ± idarubicin

• Mitoxantrone + etoposide + cytarabine (MEC)

Strongly consider clinical trial in AML relapse

Wierzbowska A et al. Eur J Haematol 2008; 80: 115-126; Montillo M et al. Am J Hematol 1998; 58: 105-109; Parker JE et al. Br J Haematol 1997; 99: 939-944; Amadori S et al. J Clin Oncol 1991; 9: 1210-1214

Prognostic Markers of AML in First Relapse

667 pts (non-APL) in first Relapse

RFI and CG (0-5)Age (0-2)Previous SCT (2)

Low score=high OS

Breems DA et al. J Clin Oncol 2005; 23: 1969

% OS1-y 5-y %CR2

70 46 85

49 18 6016 4 34

Ding L et al. Nature. 2012;441:506-510.

Clonal Evolution of AML by Molecular Profiling Acute Promyelocytic Leukemia

• Incidence 10-15% (FAB M3)- higher in hispanics (20-25%) and with ↑ BMI

• Median age at Dx 40 yrs

• Coagulopathy and hemorrhage

• Promyelocytes:- strongly MPO (+); multiple Auer rods- CD9 (+), CD13 (+), CD33 (+), CD34 (-), HLA-DR (-)

• Translocation t(15;17) with PML/RAR- fusion transcripts

11

Acute Promyelocytic Leukemia

Two morphologic variants

Hypergranular

• 80% of APL

• “faggot cells”

Microgranular (M3v)

• 20% of APL

• WBC

Model of PML-RARA-mediated Transcriptional Repression, RA-induced Activation, and Differentiation

Therapy

Ablain J , de The H Blood 2011; 117: 5795-5802

Early Death Rate in APL (SEER Data)

• 1400 pts with APL Dx 1992-2007

• Death rate 17.3% (age ≥ 55 yrs 24.2%, p<.0001)

• 3-yr overall survival (age ≥ 55 yrs 47%, p<.0001) - 55% if Dx 1992-1995- 66% if Dx 1996-2002- 70% if Dx 2002-2007

• Cox proportional hazards model- only diagnostic time peroid and age were significant

for survival

Park JH et al. Blood 2011; 118: 1248

Randomized Trial - Treatment

REstey et al, Blood 2006

Ravandi et al. JCO 2009

Lo-Coco et al, Blood 2010

Induction

ATRA

ATO

Until CR

Consolidation

ATO ATO ATO ATO

4 weeks on / 4 weeks off

2 weeks on / 2 weeks off

Induction Consolidation Maintenance

ATRA ATRA ATRAATRA ATRA

MTX + 6MPIDA IDA IDAMTZ

Until CR 2 years3 monthly cycles

Chemo

Arm

ATO

arm

ATRA+ ATO - Event-free SurvivalPrimary endpoint

Even

t-fr

ee s

urv

ival

pro

bab

ilit

y

Months from diagnosis

97.1%

85.6%

p = 0.02ATRA+ATO

ATRA+Chemo

Lo-Coco F, et al. N Engl J Med. 2013 ;369(2):111-21

Overa

ll s

urv

ival

pro

bab

ilit

y

Months from diagnosis

98.7%

91.1%

p = 0.02ATRA+ATO

ATRA+Chemo

ATRA + ATO - Overall Survival

Lo-Coco F, et al. N Engl J Med. 2013 ;369(2):111-21

12

ATRA + ATO – Longer follow-up

Platzbecker U, et al. JCO 2016