Acute promyelocytic leukemia Laura Cicconi University Tor Vergata - - PowerPoint PPT Presentation

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Acute promyelocytic leukemia Laura Cicconi University Tor Vergata Rome, Italy Acute Myeloid Leukemia Meeting Ravenna, Italy (October 2017) APL. From highly fatal to curable disease Fatal outcome if not recognized and promptly treated

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SLIDE 1

Ravenna, Italy (October 2017)

Acute Myeloid Leukemia Meeting

Laura Cicconi University Tor Vergata Rome, Italy

Acute promyelocytic leukemia

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SLIDE 2
  • Fatal outcome if not recognized and promptly treated
  • Coagulopathy and severe bleeding episodes at onset
  • Recurrent genetic abnormality PML-RARA is unique to

APL and is the target of specific APL therapies

  • Cure rates >90% with target therapies
  • APL. From highly fatal to curable disease
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SLIDE 3

Turning points in APL therapy

t(15;17) J Rowley

ATO° ATO+ATRA

+/-CHT 1980 1990 2000 2010

ATRA*

*All-trans retinoic acid; °arsenic trioxide

Differentiation of blasts. CR with resolution of coagulopathy Cloning of PML-RARA

ATRA+CHT

AIDA (ATRA+IDA) Risk-adapted approaches Most effective single agent in APL (relapsed) >70% CRm in front-line APL

ATO

>95% of cured APL

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SLIDE 4

ATO+ATRA+CHT: 92% ATO+ATRA: 98%

Survival improvement in APL

ATRA+CHT (risk-adapted): >80%

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SLIDE 5

ATO and ATRA synergize for cure

NT RA As RA + As

NT, no treatment. Lallemand-Breitenbach V, et al. J Exp Med. 1999;89:1043-52. Nasr R, et al. Nat Med. 2008;14:1333-42.

5 4 3 2 1

Mice surviving

Duration (days)

40 80 120 160 200 240 280 As RA + As RA Treatment NT

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SLIDE 6

PML-RARA, ATO and ATRA

RARE

Corepressors

NB disruption Repression of RARA target genes

RARA PML RARA PML RARA PML R A R A PML R A R A PML R A R A PML RARA PML

RARA

RING B1 B2 Coiled-Coil DNA LBD

PML

Block of myeloid differentiation

SUM O SUM O SUM O Ub Ub Ub

ATRA ATRA ATRA ATO ATO ATO

APL cure

PML PML

PML/RARA degradation

NB reformation

Coactivators

RARE

Transcriptional reactivation

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SLIDE 7

Synergistic Targeting of PML-RARa in Newly Diagnosed APL

Shen et al. PNAS. 2004, 101(15): 5328-35. Disease free survival N=61

ATRA+ATO ATO ATRA

2 4 6 8 10 12 14 16

After CR After consolidation

ATRA As2O3 ATRA+As2O3

RQ-PCR for PML-RARA

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SLIDE 8

ATO combinations in APL therapy

CHT ATRA ATO

ATRA ATO

  • Can CHT be substituted

by ATO with similar efficacy?

  • Can CHT be minimized by

ATO?

  • 1. Shen, et al. PNAS. 2004.
  • 2. Powell BL, et al. Blood. 2010
  • 3. Iland HJ, et al. Blood. 2012
  • 4. Zhu HH et al. JCO. 2012
  • 1. Estey E, et al. Blood. 2006.
  • 2. Lo-Coco F, et al. NEJM. 2013
  • 3. Burnett AK, et al. Lancet Oncol. 2015
  • 4. Zhu HH et al. NEJM 2016
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SLIDE 9

CHT ATRA ATO

ATO+ATRA+CHT

Australasian APML4 trial

Induction ATRA + ATO + CHT Consolidation (2) ATRA + ATO Maintenance (5) ATRA + LD-CHT

Induction ATRA 45mg/m2/d x36 Idarubicin 12mg/m2/d x4 1 ATO 0.15mg/kg/d x28 9 2 4 6 8 Prednisone 1mg/kg/d x10 36 28 1 ≥10

Consolidation #2 Consolidation #1 ATRA 45mg/m2/d x28

1

ATO 0.15mg/kg/d x28

1 28 28

ATRA 45mg/m2/d x21 ATO 0.15mg/kg/d x25

1 7 15 21 29 35 1 5 8 12 15 19 22 26 29 33

Maintenance ATRA 45mg/m2/d x14 MTX 5-15mg/m2/wk x11 6-MP 50-90mg/m2/d x76

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SLIDE 10

ATO+ATRA+CHT

Australasian APML4 trial

20 40 60 80 100

% alive and relapse−free

1 2 3 4 5 6 7 8

Years from documented HCR

Number at risk

APML4 APML3 HR = 0.21, 95% CI: 0.07 − 0.59, P−value = 0.001 2−year DFS: 97% vs 86%, 5−year DFS: 95% vs 79%

HR = 0.21 (95% CI: 0.07 - 0.59) P = .001 Disease-free survival

APML3

APML4

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SLIDE 11

ATO combinations in APL therapy

CHT ATRA ATO

ATRA ATO

  • Can CHT be substituted

by ATO with similar efficacy?

  • Can CHT be minimized by

ATO?

  • 1. Shen, et al. PNAS. 2004.
  • 2. Powell BL, et al. Blood. 2010
  • 3. Iland HJ, et al. Blood. 2012
  • 4. Zhu HH et al. JCO. 2012
  • 1. Estey E, et al. Blood. 2006.
  • 2. Lo-Coco F, et al. NEJM. 2013
  • 3. Burnett AK, et al. Lancet Oncol. 2015
  • 4. Zhu HH et al. NEJM 2016
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SLIDE 12

ATRA + ATO ± GO. MDACC Long-term follow-up

Estey et al., Blood 2006; Abaza Y, et al. Blood 2017

ATRA ATO

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SLIDE 13

Median F/U 47.6 months, Range 2.7 – 159.7 months

Disease-free survival

ATRA + ATO ± GO. MDACC Long-term follow-up

Abaza Y, et al. Blood 2017

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GIMEMA-SAL-AMLSG MRC – AML 17

ATO+ATRA+/- minimal CHT Randomized Studies

ATRA ATO

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SLIDE 15

R

Estey et al. Blood 2006 Lo-Coco et al. Blood 2010

Induction

ATRA ATO

Consolidation

ATO ATO ATO ATO

Induction Consolidation Maintenance

ATRA

MTX + 6MP IDA IDA IDA MTZ Chemo arm ATO arm

ATO+ATRA in low-intermediate risk APL

GIMEMA-SAL-AMLSG APL0406 trial

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SLIDE 16

Arm A (ATO+ATRA) at 72 months: 96.6% (CI95%: 93.4-99.9) Arm B (ATRA+IDA) at 72 months: 77.4% (CI95%: 70.2-85.4)

APL0406: Updated and extended series

276 pts; Follow-up 67 mos

APL2017 conference; G.Avvisati

Event-free survival

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SLIDE 17

Gray test 0.0001

Arm A (ATO+ATRA) at 72 months: 1.7% (CI95%: 0 - 4) Arm B (ATRA+IDA) at 72 months: 15.5% (CI95%: 9 - 22)

APL0406: Updated and extended series

276 pts; Follow-up 67 mos

APL2017 conference; G.Avvisati

Cumulative incidence of relapse

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SLIDE 18

Event ATRA-ATO AIDA

Induction Death

4

Death in CR

2 5

Molecular resistance

2

Relapses

2 17

Secondary AML

1 Total 4 29

Events in APL0406 protocol

APL2017 conference; G.Avvisati

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SLIDE 19

Burnett AK, et al. Lancet Oncol 2015;16: 1295–305

Induction

  • ATO 0.3 mg/kg days 1-5 in week 1

followed by ATO 0.25 mg/kg twice a week for 7 weeks

  • ATRA 45 mg/m2/d 9 weeks

Consolidation (4 courses)

  • ATO 0.3 mg/kg days 1-5 in week 1

followed by ATO 0.25 mg/kg twice a week for 3 weeks

  • ATRA 45 mg/m2/d 2 weeks on 2

weeks off High-risk patients GO 6 mg/m2 as a single infusion within the first 4 days (on day 1 if possible and on day 4 if necessary).

ATO + ATRA vs. AIDA

UK NCRI - AML 17 trial

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SLIDE 20

AML 17 APL Randomisation: Updated Outcomes

Outcome AIDA ATRA+ATO HR/OR & CI p-value CR 91% 96% 0.46 (0.17-1.27) 0.13 Molecular negaAvity 90% 93% 0.67 (0.27-1.66) 0.4 30-day mortality 6% 4% 0.72 (0.23-2.31) 0.6 Resistant disease 3% 0% 0.14 (0.02-0.97) 0.05 60-day mortality 9% 5% 0.55 (0.21-1.43) 0.2 5-year survival 87% 93% 0.61 (0.27-1.35) 0.2 5-year EFS 79% 93% 0.38 (0.19-0.77) 0.007 5-year Frank RFS 87% 97% 0.33 (0.13-0.85) 0.02 5-year Molecular RFS* 77% 98% 0.19 (0.09-0.41) <.0001 5-year CIDCR 2% 2% 1.72 (0.18-16.6) 0.6 5-year CIHR 10% 1% 0.16 (0.05-0.48) 0.001 5-year CIMR* 21% 0% 0.12 (0.05-0.30) <.0001 5-year CITAML 1% 0% 0.15 (0.003-7.48) 0.3

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SLIDE 21

UK NCRI - AML17 trial. Outcomes

Molecular relapse free survival Cumulative incidence of relapse

Burnett AK, et al. Lancet Oncol 2015;16: 1295–305

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SLIDE 22

ATO-ATRA toxicity profile

ATRA-chemo ATRA-ATO Differentiation syndrome 15-20% 20-25% Myelosuppression 60-100% 20% Infections, GI toxicity +++ + Hyperleukocytosis 5% 10-40% Hepatic toxicity (AST/ALT) 5-10% 10-40% Cardiac toxicity 2-5% 10% t-MN and t-AL 2-5% ? Other malignancies ?

Long-term

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SLIDE 23

Incidence of differentiation syndrome

APL0406 AML17

22% 26% 22% 25%

P= ns P= ns

Lo-Coco et al, NEJM 2013; Burnett et al, Lancet Oncol 2015

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SLIDE 24

Hematologic toxicity

(APL0406)

Grade 3-4 thrombocytopenia >15 days Grade 3-4 neutropenia >15 days 20 40 60 80 100

Induction 1st cons 2nd cons 3rd cons

ATRA-ATO ATRA-CHT

20 40 60 80 100

Induction 1st cons 2nd cons 3rd cons

ATRA-ATO ATRA-CHT

P<0.0001 P<0.0001 P<0.0001 P<0.0001 P<0.0001 P<0.0001 P<0.0001 P<0.0001

Platzbecker et al., JCO 2016

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SLIDE 25

FUO and infections (APL0406)

5 10 15 20 25 30 35 40 45 50 Induction 1st Cons 2nd Cons 3rd Cons ATRA+ATO ATRA+CHT p= <.0001 p= <.0001 p= ns

Supportive care (AML17)

Lo-Coco et al, NEJM 2013; Burnett et al, Lancet Oncol 2015

Infections, supportive care and hospitalization

p= ns

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SLIDE 26

ATO-ATRA toxicity profile

ATRA-chemo ATRA-ATO Differentiation syndrome 15-20% 20-25% Myelosuppression 60-100% 20% Infections, GI toxicity +++ + Hyperleukocytosis 5% 10-40% Hepatic toxicity (AST/ALT) 5-8% 10-40% Cardiac toxicity 2-5% 10% t-MN and t-AL 2-5% ? Other malignancies ?

Long-term

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SLIDE 27
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SLIDE 28

Is there room for improvement?

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SLIDE 29

Open areas of investigation

  • 1. Early death in “real-life” APL
  • 2. Improve patient QoL: oral arsenic formulations
  • 3. Optimal management of high-risk disease
  • 4. Biologic basis of ATO resistance
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SLIDE 30
  • 1. Early death

Clinical trials vs. “real-life”data

Recent trials

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SLIDE 31

0% 5% 10% 15% 20% 25% 30% 29,00% 17,30% 26,00% 11,00% 21,80% 17,00% 9,60% 20,00% 10,00% 11,90% 19,40% 14,70% 4,90% 6,80% 4,80%

ATO-based PopulaAon based : ATRA+CHT 17% 5.5% （n=758)

Early death

Clinical trials vs. “real-life”data

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SLIDE 32

2.Oral arsenic

m

ATO+ATRA vs. RIF+ ATRA Chinese APL Cooperative Group

Zhu H et al. JCO 2013;31:4215-4221 * Mitoxantrone was added at a dose of 1.4 mg/m2/day on 5 days 4, 5, 6, 7, and 8 (if WBC >10 x 109/L start

  • n day 1).

ATRA = all-trans retinoic acid; ATO = arsenic trioxide; RIF = Realgar-Indigo naturalis formula; HA = homoharringtonine and cytarabine; DA = daunorubicin and cytarabine; MA = mitoxantrone and cytarabine *

Randomized comparison of oral arsenic derivaAve vs. IV ATO

Chemotherapy

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SLIDE 33

Zhu H et al. JCO 2013;31:4215-4221

n = 114; CR 113; Relapse 1; Death in CR 1 n = 117; CR 114; Relapse 1 3-year OS 99.1% (95% CI, 97.2% to 99.9%) 3-year OS 96.6% (95% CI, 93.0% to 99.8%

Oral arsenic

m

ATO+ATRA vs. RIF+ ATRA

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SLIDE 34

12 24 36 48 60 20 40 60 80 100

Time (months) OS (%)

100% (4ys) F/U 48m(42-53m)

Medical costs: 4,675$ Median hospital stay: 15 months

Oral arsenic

ATRA+ oral ATO. Non-high risk

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SLIDE 35
  • 3. High-risk APL

ATO/ATRA-based trials

20 40 60 80 100 1 2 3 4 5 6 7 8

Years from documented HCR

Number at risk

WCC<=10 WCC>10 HR = 1.21, 95% CI: 0.13 − 10.8, P−value = 0.87 2−year relapse−free rate: 98% vs. 95%, 5−year relapse−free rate: 96% vs. 95%

Years from documented HCR

WCC ≤ 10 96% WCC > 10 95%

HR = 1.21 (95% CI: 0.13 - 10.8) P = .87

Iland HJ, et al. Blood. 2012 DFS OS

Burnett AK, et al. Lancet Oncol 2015

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SLIDE 36

Pan-European randomized trial in high-risk APL (APOLLO trial )

High-risk APL

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SLIDE 37
  • 4. ATO resistance

Role of PML mutations

Jeanne M., et al, Cancer Cell 2010; Lehmann-Che et al, NEJM 2014; Iaccarino et al, BJH 2016

*

B2 PML RARA

A216V (2) A216T (1) L217F (1) S220G (1)

  • PML mutations within the B2 domain of PML/RARA confer ATO

resistance and can be found in up to 40% of relapsed/refractory APL

  • Mutations have been described also in normal PML allele and have

been proposed as additional mechanism associated with ATO resistance

C212A (1)

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SLIDE 38

Conclusions

  • ATO-ATRA has become the standard of care in newly

diagnosed low/intermediate risk APL

  • ATO-ATRA+CHT can be a curative option for high-

risk disease but deserves futher investigation

  • Early death remains the major obstacle to APL cure
  • Despite the low rate of relapses, resistance to ATO should

be futher investigated

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SLIDE 39
  • M. Divona
  • C. Ciardi
  • A. Ferrantini
  • S. Lavorgna
  • T. Ottone
  • V. Alfonso
  • L. Iaccarino
  • G. Falconi
  • E. Fabiani

Acknowledgements

Prof F. Lo Coco Prof MT Voso Prof W. Arcese

  • Prof. A Venditti
  • Prof. F Buccisano
  • M. Consalvo
  • P. Panetta
  • P. Curzi
  • D. Fraboni