Acute Promyelocytic and Other Acute Myeloid Leukemias:

The Slaying of the Old Dragon?

Martin S. Tallman, M.D. Memorial Sloan Kettering Cancer Center

Weill Cornell Medical College 14th Annual Indy Hematology Review

Acute Promyelocytic Leukemia Distinguishing Features

• 10-15% of adult AML • Leukopenia (85%) • Complex coagulopathy • t(15;17) chrom translocation • Sensitivity to anthracyclines • PML-RARα fusion transcript • Differentiation with retinoic acid • Apoptosis with arsenic trioxide

Initial Studies of ATRA in APL

Group Year N CR% D(E)FS% Therapy

Euro. APL 1999 99 94 84 ATRA/DA

GIMEMA 1997 240 95 79 ATRA/Ida

North Am. 1997 172 72 75 Maint.

PETHEMA 1999 123 89 92 No ara-C

GAMLCG 2000 51 92 88 HiDAC

GIMEMA & PETHEMA Study Relapse-free survival

0

0.2

0.4

0.6

0.8

1

0 20 40 60 80 Months

Prob

abili

ty

P <0.0001

High WBC >10,000/µL Intermediate WBC ≤10,000/µL & Plt ≤40,000/µL Low WBC ≤10,000/µL & Plt >40,000/µL

n = 53

n = 49

n = 115 Low risk

Sanz et al. Blood, 2000

Most Important Questions in APL in 2017

1. How can early death rate be reduced?

2. Is ATRA/ATO standard of care?

3. What is best treatment for high-risk disease?

4. Is maintenance needed?

Early Death Rate in APL Population-Based Studies

Study N ED

Jeddi 41 16%

Lehmann 99 31%

Alizadeh 137 14%

McClellan 70 26%

Park 1,400 18%

Jeddi et al. Hematology, 2008; Lehmann et al. Leukemia, 2010; Alizadeh et al. ASH, 2009; McClellan et al. Haematologica, 2012; Park et al. Blood, 2011

Pathogenesis of the Coagulopathy

elastase TAT F1+2 FPA

COAGULATION FIBRINOLYSIS PROTEOLYSIS

ACTIVATION

u-PA plasminogen a-2-antiplasmin D-dimer D-dimer Annexin II

Prevention of Early Death in APL

• Early death as emerged as the major cause of treatment failure

• Start ATRA at first suspicion (based on clinical hx and review of peripheral smear), BEFORE MARROW AND BEFORE DIAGNOSIS CONFIRMED (in ER)

• Frequent plt transfusion to >50,000/µL

• Cryo to maintain fibrinogen >150 mg/dL

• No heparin, although not studied in ATRA era

• No antifibrinolytics

Rodeghiero et al. Blood, 1990; Tallman et al. Leukemia Res, 2004; Sanz et al. Blood, 2008

Important (and Provocative) Concepts in APL

• No treatment modification based on additional cyto abn, therapy-related, FLT3 mutations, CD56, PML isoform, or morphology (M3V)

• Bone marrow not needed on day 14 AND not at CR

– No primary resistance

– No prognostic importance of cyto/molecular genetics when CR1 first achieved at end of induction

• Maybe marrow not needed at diagnosis, if diagnosis unmistakable

Dual Mechanisms of Action of Arsenic Trioxide

Apoptosis Differentiation

RARa release

Caspase activation

Release of cytochrome c from the mitochondria

PML/RARa degradation

Transcription of RARa target genes

Arsenic Trioxide

GIMEMA /SAL/AMLSG-APL0406

Low-risk (wbc<10x109/L)

R

AIDA 2000 (anthracycline-based consolidation)

ATRA + ATO

ATRA + ATO ATRA + Chemo No. of patients 75 79

CR, (%) 75 (100%) 75 (95%)

Induction death 0 4*

Resistant disease 0 0

Induction Outcome

*Differentiation syndrome (2), ischemic CVA (1) and pneumonia (1)

Lo Coco et al. NEJM, 2013

Event-Free Survival Primary objective

98%

84.9%

97.1%

85.6%

p=0.02 p=<0.001

Initial series Final series

Lo Coco et al. NEJM, 2013 and ASH, 2014

ATRA

IDA

ATRA

ATO ATO

APML4

Induction Consolidation Maintenance

ATRA MTX 6MP

APML4 Trial

Iland et al. ASH, 2014

APML4 DFS by Sanz Risk Category

% a

live

and

rela

pse-

free

100

80

60

40

20

0 1 2 3 4 5 6 7 8 0

Years from documented HCR

P [ trend ] = .30

Low 100%

High 95% Intermediate 93%

Iland et al. ASH, 2014

Sanz et al. Blood, 2010; Adès et al. Am J Hematol, 2013; Lo Coco et al. Blood, 2010; Sanz et al. Best Pract Res Clin Haematol, 2003; Iland et al. ASH, 2014

High-Risk APL ATRA + Risk-Adapted Chemo vs APML4

Number Median follow-up

(months)

IDA equivalent

(mg/m2)

AraC

(g/m2)

DFS CIR OS

PETHEMA LPA2005 118 28 122 5.8

82%

14%

79%

European APL2000 74 103 99 22.8 -

7%

88%

GIMEMA AIDA2000 129 59 122 6.3

85%

9%

83%

ALLG

APML4 23 50 48 0

95%

5%

87%

MRD Monitoring

• Low- and intermediate-risk: 1% OS benefit at 5 yrs

• High-risk: 10% OS benefit at 5 years

• Low- and intermediate-risk: MRD monitoring can be reasonably discontinued and pts followed once molecularly negative

• High-risk: continue MRD monitoring every three months for 3 years

Grimwade et al. J Clin Oncol, 2009; Grimwade and Tallman Leukemia Res, 2010

Future Directions

• Decrease early death

• Optimize/refine treatment for high-risk patients

• Novel strategies

–Oral arsenic

Lu et al. Blood, 2006; Au et al. Blood, 2011

Oral Arsenic

• Outcome

– newly dx’d: CHR 100%, CCR 88%, DFS 78%

– Relapsed: CCR and CMR 71%

• Similar bioavailability to IV

• Crosses into CSF about 30% serum level (by itself may not be enough to prevent CNS relapse)

Lu et al. Blood, 2002; Kumana et al. Eur J Clin Pharmacol, 2002; Au et al. Leukemia Res, 2007; Au et al. Blood 2006, 2008, 2011

Overall Survival 1.0

.90

.95

.85

.80 0 10 20 30 40 50 60 70

Time (months)

RIF ATO

P =.18

Ove

rall

Surv

ival

(pro

babi

lity)

Zhu et al. J Clin Oncol, 2013

Future Treatment

APL likely will be treated and cured with all oral therapy (ATRA + oral ATO)

Imagine that!

• Defined by cytogenetic and molecular interactions

• Intensified induction may be important

• Less intensive chemotherapy consolidation under study

• Increased importance of minimal residual disease

• Expanded availability of allogeneic transplantation

• Novel strategies for older patients

• Incorporation of novel agents

Acute Myeloid Leukemia State-of-the-Art 2017

14% Other adverse 5% MLL-PTD

12% FLT-ITD/ NPM1 wt

INTERMEDIATE 21% CEBPα mut (biallelic)/ FLT3-ITD neg 3%

NPM1 mut/ FLT3-ITD neg/WT1 wt 18%

Inv(16)/t(16;16)/ CBFB-MYH11 5%

3% inv(3)/t(3;3)/EVI-1

t(8;21)/RUNX1-RUNX1-T1 8%

t(15;17)/PML-RARA 11%

ADVERSE 34% FAVORABLE

45%

Grimwade Hematology Am Soc Hematol Educ Program, 2009

Distribution of Cytogenetically and Molecularly Defined Risk Groups in AML

Gene Incidence Associations Impact

FLT3-ITD 25% NPM1 Unfavorable

NPM1 33% FLT3 Favorable

dCEBPα 8% FLT3 Favorable

C-KIT 15% CBF Unfavorable [in t(8;21), but less clear

in inv(16)]; 1D816 worse than others

IDH1 and 2 22% NPM1 Favorable

Gene Mutations Clinically Important in Everyday Practice Today

1Yui et al. ASH abstr 2785, 2016

Multivariate Risk Classification For FLT3-ITD-neg,

Intermediate Risk AML

• Group 1 (favorable): IDH2/NPM1 mutant

• Group 3 (poor-risk): TET2, PHF6, ASXL1, MLL-PTD mutations

• Group 2: all others

Patel et al. New Engl J Med, 2012

P<0.001

Cytogentic Classification Mutations Overall

Risk

Inversion (16), t(8:21) Any

Favorable

Normal Karyotype or Intermediate Risk

Cytogenetic Lesions

FLT3-ITD negative

NPM1 and IDH1/2 mutant

FLT3-ITD negative

ASXL1, MLL-PTD, PHF6 and TET2-wildtype

Intermediate FLT3-ITD

negative or positive CEBPA mutant

FLT3-ITD positive

MLL-PTD, TET2, DNMT3A R882, and

trisomy 8 negative

FLT3-ITD negative

TET2, MLL-PTD, ASXL1, PHF6 mutant

Unfavorable FLT3-ITD positive

TET2, MLL-PTD, DNMT3A R882 mutant

or trisomy 8

Unfavorable Any

Revised AML Risk Stratification Based on Integrated Mutational Profiling

Patel et al. New Engl J Med, 2012

Remission Induction and Escalated Daunorubicin Dose in AML

• DNR 90 mg benefits patients with any cytogenetic risk, and with FLT3-ITD, DNMT3A, or NPM1, including age 50-60.

• Whether or not dauno 60=90 mg dose requires further studies • DNR 90 mg standard for all patients up to age 60-65

• CRs after third attempt uncommon and short-lived

Fernandez et al. NEJM 2009, Patel et al. NEJM 2012;

Burnett et al Blood, 2015; Luskin et al. Blood, 2015; Zarabi et al. ASH, 2016

• Do we need 4 cycles? Probably not, but I do it

• Do we need 3g/m2 of Ara-C? Probably not, but I do it

• Do we need high-dose Ara-C? Probably not, but I do it

Consolidation Questions Remain Unanswered

Induction Consolidation

DA ± GO vs

ADE ± GO vs

FLAG-Ida ± GO

MACE-MiDAC ± GO vs

HiDAC ± GO (3.0 vs 1.5 mg/m2)

Burnett et al. J Clin Oncol, 2013

MRC AML15

Burnett et al. J Clin Oncol, 2013

100

75

50

25

0 1 2 3 4 5

Cumulative Incidence

of Relapse

%

0 Years

6

n=328 1.5g/m²

n=326 3g/m²

7 8

51%

60%

MRC: AML 15

p = 0.06

Less Intensive Consolidation 3g/m2 vs 1.5g/m2 Ara-C

Burnett et al. J Clin Oncol, 2013

100

75

50

25

0 1 2 3 4 5

Relapse Free

Survival %

0 Years

6

n=328 1.5g/m²

n=326 3g/m²

7 8

34%

42%

MRC: AML 15

p = 0.1

Less Intensive Consolidation 3g/m2 vs 1.5g/m2 Ara-C

Condensed vs Standard Schedule of HiDAC Consolidation

• HiDAC 3 gms/m2 twice daily D1,3,5 (G on D10) vs HiDAC 3 gms/m2 twice daily D1,2,3 (G on D8) (Third cohort 3 gms/m2 D1,3 5 without G)

• Time to count recovery shorter with D1,2,3 (median 4 days)

• Rates of infection lower with D1,2,3

• Days in hospital and plts transfusion reduced with D1,2,3

• RFS and OS not different

Jaramillo et al. ASH abstr 337, 2016

Relapse-free and Overall Survival According to Consolidation Schedule

Jaramillo et al. ASH abstr 337, 2016

Minimal Residual Disease

• Detected by increasingly sensitive techniques (immunophenotyping, PCR, sequencing)

• Most studied in patients with NPM1 mutation and CBF AMLs

• Complex due to genetic heterogeneity and multiple subclones

• Has prognostic implications following chemotherapy and before allogeneic transplantation

• Will rapidly become incorporated in routine clinical practice

Ivey et al. N Engl J Med, 2016

Minimal Residual Disease (by PCR) in Standard-Risk AML

100

75

50

25

0 0 1 2 3 4 5

Years since Entry

Sur

viva

l (%

) MRD-negative 73%

MRD-positive 24%

P<0.001

Overall Survival

100

75

50

25

0 0 1 2 3 4 5

Years since Remission

Rel

apse

(%)

MRD-negative 34%

MRD-positive 86%

P<0.001

Relapse in All Patients

Equivalent Post-Transplant Outcomes for Pre-transplant AML MRD (by FC) and Active AML

Araki et al. J Clin Oncol, 2016

Active disease Remission (MRD–) Remission (MRD+)

Active disease Remission (MRD–) Remission (MRD+)

Survival Landmarked from Time of Transplant

• CPX-351 median OS not reached vs 10.25 months for 7+3 – HR of 0.46 favoring CPX-351 (P=0.0046) – Cox proportional hazards HR, including transplant as a time-dependent

covariate, was 0.51 (95% CI, 0.35–0.75; P=0.0007), favoring CPX-351

CI, confidence interval; HR, hazard ratio; OS, overall survival.

Median follow-up: - CPX-351 = 531 days (96-983) - 7+3 = 442 days (316-650)

Lancet et al. ASH, 2016

RATIFY (C10603) Trial 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

PRE-REGISTER

FLT3 SCREEN

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

Stone et al. ASH abstr 6, 2015

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

Arm 4-year Survival MIDO 51.4% (95%CI: 46, 57) PBO 44.2% (95%CI: 39, 50)

+ Censor

Hazard Ratio*: 0.77 1-sided log-rank p-value*: 0.0074

Stone et al. ASH abstr 6, 2015

0

10

20

30

40

50

60

70

80

90

100

Response in FLT3mut+ Patients by Gilteritinib Dose (N=191)

n=10 300 mg

Prop

ortio

n of

Pat

ients

Ach

ievin

g Re

spon

se (%

)

n=12 n=56 n=89 80 mg 120 mg 200 mg

n=2 450 mg

n=8 40 mg

n=14 20 mg

ORR=67%

ORR=47%

ORR=60% ORR=55%

ORR=38%

ORR=14%

ORR=50%

CRc=42%

CRc=39%

CRc=30% CRc=46%

CRc=0

CRc=7%

CRc=0

0

10

20

30

40

50

60

70

80

90

100

Response in FLT3mut+ and FLT3WT Patients (N=249)

CR CRp CRi PR

Antileukemic Activity of Gilteritinib

Gilteritinib ≥80 mg/day: CRc (CR+CRp+CRi)=41% ORR=52%

Prop

ortio

n of

Pat

ients

Ach

ievin

g Re

spon

se (

%)

FLT3mut+ (N=191)

FLT3WT (N=58)

ORR=12%

CRc=9%

ORR=49%

CRc=37%

Perl et al. ASH abstr 1069, 2016

Binds to CD33 antigen

Complex is internalized and traffics to lysosome

PBD dimer is released

PBD dimer crosslinks DNA

DNA repair failed

Apoptotic cell death

Vadastuximab Talirine (SGN-CD33A; 33A) Proposed Mechanism of Action

Anti-CD33 antibody, engineered cysteines to enable uniform site-specific conjugation Cleavable dipeptide linker, highly stable in circulation Pyrrolobenzodiazepine (PBD) dimer, binds DNA with high intrinsic affinity

Novel Treatments For AML Agent Target Mechanism Comment Status

Vadastuximab CD33 Immunoconjugate Phase I trial comb with 7 + 3; CR 60%, CRi18%,

74% MRD neg; CR/CRi 54% in older treat-naïve; CR/CRi 73%

with HMA

Alternative schedule w/ single day dosing

underway

Entospletinib SYK SYK inhibitor Phase I/II in untreated AML then chemo; CR in 11q23

rearranged pt

Phase II underway

Selinexor XPO1 Inhibits nuclear transport protein

exportin

1.Combined with chemo: ORR 60%in R/R AML

2. Phase I comb with DAC: ORR81%

Lower dose being explored

Eltrombopag TPO receptor

TPO receptor agonist Shortens plt recovery (mean peak plts 719,000, max

1,935,000), reduces plt transf

Accruing

Venetoclax BCL2 BCL2 inhibitor Phase 1/2 trial + LoDAC in untreated older pts; ORR 75%;

CR/CRi 70%

Phase I/II trial underway

Erba ASH abstr 211, 2016; Bixby ASH abstr 590, 2016; Fathi ASHabstr 591, 2016; Walker ASH abstr 2831, 2016; Wang ASH abstr 212, 2016; Bhatnager ASH abstr 1651, 2016; Mukherjee ASH abstr 447, 2016; Wei ASH abstr 102, 2016

Role of IDH in Malignancy

• IDH is critical metabolic enzyme in the citric acid cycle

• IDH1 in cytoplasm and IDH2 in mitochondria

• Cancer-associated IDHm produces 2-hydroxyglutarate (2-HG) and blocks normal cellular differentiation

Response

44

RR-AML (n = 159)

Untreated AML

(n = 24) MDS

(n = 14) All

(N = 209) Overall Response (CR, CRp, CRi, mCR, PR)

59 (37%) [95%CI: 30%,

45%] 10 (42%)

[22%, 63%] 7 (50%)

[23%, 77%] 79 (38%)

[31%, 45%]

CR 29 (18%)

[95%CI: 13%, 25%]

4 (17%) [5%, 37%]

3 (21%) [5%, 51%]

37 (18%) [13%, 24%]

CRp 1 (1%) 1 (4%) 1 (7%) 3 (1%)

CRi 3 (2%) 0 0 3 (1%)

mCR 9 (6%) 1 (4%) 3 (21%) 14 (7%)

PR 17 (11%) 4 (17%) 0 22 (11%)

SD 72 (45%) 9 (38%) 6 (43%) 96 (46%)

PD 10 (6%) 1 (4%) 0 11 (5%)

Not evaluable 18 (11%) 4 (17%) 1 (7%) 23 (11%)

• Overall response by IDH mutation type: R140Q 36% / R172K 42%

CR, complete response; CRp, CR with incomplete platelet recovery; CRi, CR with incomplete hematologic recovery; mCR, marrow CR; PR, partial response; SD, stable disease; PD, progressive disease

Stein et al. ASH abstr, 2015

Differentiation Syndrome

• 21 days of AG-221 at 100 mg daily • Fever, oxygen requirement • Normal BAL

Courtesy Dr. Stephane De Botton

• Dexamethasone 10 mg BID for 15 days • Resolution of clinical symptoms • Patient achieves a complete remission

How I Treat AML-2017

• Induction: dauno 90 mg/m2/d x 3d (or ida) + ara-C 100 mg/m2/d x 7d c.i. + targeted agent (HMA or novel agents in older adults or if not fit); LP for monocytic lineage or WBC > 40,000

• Consol: multiple cycles (3-4) of HiDAC in younger pts fav-risk, NK FLT3-/NPM+, or dCEBPα; 3-4 for CBF; no clear role in older adults (can give 1-2 cycles at 1-1.5 gm/m2) + targeted agent

• Allogeneic HCT for intermed- and high-risk (consider alternative donor if no sib); consider in CBF [esp t(8;21) with c-KIT]; not FLT3-/NPM1+ (esp if IDH+) or dCEBPα+; RIC for older adults

• No maintenance (except ? APL) except targeted agent

• Relapse: reinduction chemo + targeted agent or targeted agent alone

Paschka et al. J Clin Oncol, 2006; Schlenk et al. NEJM, 2008; Green et al. J Clin Oncol, 2010; Dohner et al. Blood, 2010

Coombs, Tallman, Levine. Nat Rev Clin Oncol, 2015

Coombs, Tallman, Levine. Nat Rev Clin Oncol, 2015