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Treatment of APL

M a t t h e w M e i, M .D .A s s is t a n t P ro f e s s o r

C it y o f H o p e C o m p re h e n s iv e C a n c e r C e n t e r

Disclosures

• I have nothing to disclose

Objectives

1. Urgency of early recognition and treatment

2. Treatment based on risk stratification

3. Monitoring for relapse

4. Treatment of relapse

5. Long-term toxicities

Acute Promyelocytic Leukemia

Distinguishing Features

• 10-15% of adult AML

• Leukopenia (85%)

• Complex coagulopathy

• t(15;17) chrom translocation

• Sensitivity to anthracyclines

• PML-RAR fusion transcript

• Differentiation with retinoic acid

• Apoptosis with arsenic trioxide

Bleeding in APL

Oral mucosal bleeding Subcutaneous bleeding

Retinal hemorrhages Intracerebral hemorrhage

Early Death Rate in APLPopulation-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

Molecular Basis of

Leukemogenesis in APL

• RAR fuses to PML

• Increased affinity for nuclear co-repressor protein complex (N-coR)

• Histone deacetylase alters chromatin conformation inhibiting transcription

• Retinoic acid (RA) induces release of N-coR permitting transcription

RAR

PML

N-CoR

mSin3

HD

RARE

RAR

PML

N-CoR

mSin3

HD

RARE

RA

Grignani et al. Nature, 1998

Milestones in the Development of

Curative Strategies in APL

1957 1973 1985 1990’s 1997 2000’s 2009

Initial

Description,

Highly Fatal

DaunorubicinATRA

ArsenicATRA + Chemo

ATRA + ArsenicHighly Curable

0.0

0.2

0.4

0.6

0.8

1.0

0 5 10 15 20Years

DF

S

ECOG Data

Pre-ATRA era

1973-1989

Tallman et al. Blood, 2002Years

0.0

0.2

0.4

0.6

0.8

1.0

0 2 3 4 6

OS

WBC < 10,000/L

WBC 10-50,000/L

WBC > 50,000/L

51

P = .14

APL2000

Kelaidi et al. J Clin Oncol, 2009

All-trans Retinoic Acid

• Natural vitamin A derivative

• Induces leukemic promyelocytes to differentiate in vitro

• Induces CR in almost all pts with APL as single agent

• No imposition of marrow aplasia

At diagnosis Day 12 Day 37

Arsenic Trioxide

• Single most active agent in APL

• Single-agent CR rate very high in frontline and relapsed setting

• Dual mechanism (differentiation at lower dose, apoptosis at higher dose)

• Biggest concerns are QTc prolongation and elevated LFTs

Molecular Response to Arsenic Trioxide in

Relapsed APL: US Multicenter Study

0

10

20

30

40

50

60

70

80

90

100

Baseline

N=29Induction Consolidation

Pati

en

ts w

ith

MR

(%

)

48%

86%

Maintenance

90%

Soignet et al. J Clin Oncol, 2001

Prevention of Early Death in APL

• ATRA at first suspicion (based on clinical hxand review of peripheral smear), before marrow and before diagnosis is confirmed

• Frequent platelet transfusions to > 50,000/L

• Cryoprecipitate to maintain fibrinogen > 150 mg/dL

• No routine heparin

• No routine antifibrinolytics

• No leukopheresisRodeghiero et al. Blood, 1990; Tallman et al. Leukemia Res, 2004; Sanz et al. Blood, 2008

Risk Stratification

Treatment is primarily based on risk stratification.

Risk stratification is easy

Initial WBC > 10 = high risk (probably needs some

chemotherapy besides just ATRA + ATO)

Initial WBC ≤ 10 = standard risk (induce with ATRA +

ATO)

Caveats for Induction in APL

• Differentiation Syndrome – steroid

prophylaxis built a number of the regimens

• Do NOT do marrow on Day 14 or Day 21!

– Cytogenetic / molecular positivity on day 28

does NOT mean treatment failure.

• Initial rise in WBC with rising neutrophils

represents differentiation of the malignant

clone, not true count recovery

• Newly diagnosed APL

• Age 18 - 70 years

• WBC ≤10 x 109/L

• WHO performance status ≤ 2

APL 0406 Study

Trial designed to assess a non-inferiority margin difference

between the group proportions of 5%

Inclusion Criteria

APL0406 Study: Treatment

R Estey et al, Blood 2006

Lo Coco et al. NEJM, 2013

Induction

ATR

ATO

Consolidation

4 weeks on / 4 weeks off

2 weeks on / 2 weeks off

Induction Consolidation Maintenance

ATR ATR ATRATR ATR

MTX + 6MPIDA IDA IDAMTZChemo

Arm

ATO

arm

ATO ATO ATO ATO

Until CR 3 monthly cycles 2 years

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)


0

10

20

30

40

50

60

70

IND I CONS II CONS III CONS

0

10

20

30

40

50

60

70

IND I CONS II CONS III CONS

Grade 3-4 neutropenia >15 dGrade 3-4 thrombocytopenia >15 d

ATO Chemo

p= <.0001

p= <.0001

p= <.0001

45

69

4

13

4

46

2

10

p= <.0004

p= .0001

p= .0185 p= .011735

62

54

25

44

17

3

p= <.0001

APL 0406: Hematologic Toxicity


APL 0406: Other Toxicities

Toxicity ATRA+ATO ATRA+Chemo P value

QTc prolongation1,% 13 0 0.0005

Hepatic toxicity1

(Grade 3-4), %57 5 <0.0001

Leukocytosis2

(>10x109/L), %47 24 0.007

1. Managed with temporary discontinuation and dose

modification of ATO

2. Hydroxyurea 500 mg qid if WBC <50K and 1 g qid if >50K

100

75

50

25

0

0 12 24 36 48 60

Months from diagnosis

Event-

free s

urv

ival pro

babili

ty 100

75

50

25

0

Dis

ease-f

ree s

urv

ival pro

babili

ty97.1%

85.6%

ATRA+ATO

ATRA+Chemo

ATRA+ATO

ATRA+Chemop=0.02 p=0.14

97.1%

90.3%

0 12 24 36 48 60

Months after CR

Event-free Survival

APL 0406

Disease-free Survival

Type of event

Relapse

Death in CR

ATRA+ATO

2

1

ATRA+Chemo

5

3


APL 0406: Overall Survival

100

75

50

25

00 12 24 36 48 60

Months from diagnosis

Overa

ll surv

ival pro

babili

ty

98.7%

91.1%

ATRA+ATO

ATRA+Chemop=0.02


APL 0406 – Long-term

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

After initial 2013 publication, more patients were enrolled

(total n = 276).

OS at 50 months was 99.2% vs. 92.6% (p = 0.0073)

EFS at 50 months was 97.3% vs. 80% (p < 0.003)

ATRA + ATO is clear standard of care for newly

diagnosed standard risk APL.

Platzbecker U, et al. J Clin Onc 2016.

AML17

Randomized phase 3 trial of ATRA + ATO vs. ATRA

+ chemotherapy for newly diagnosed APL

– Patients with high risk disease receiving ATRA +

ATO only could receive one dose of gemtuzumab

ozogamicin

235 patients, 57 high risk

Grimwade et al. J Clin Oncol, 2009; Grimwade and Tallman Leukemia Res, 2010 Burnett AK, et al. Lancet Oncol 2015.

AML17

ATRA + chemotherapy arm – induction /

consolidation regimen as per low-risk arm of

AIDA2000

ATRA + ATO

• Induction: ATRA 45 mg/m2 until remission, ATO

0.3 mg/kg D1-5, then twice weekly on weeks 2-8

• Consolidation: ATRA 45 mg/m2 D1-14, ATO 03.

mg/kg D1-5, twice weekly on weeks 2-4

• Gemtuzumab ozogamicin 6 mg/m2 on D1 for high-

risk in ATRA + ATO patientsGrimwade et al. J Clin Oncol, 2009; Grimwade and Tallman Leukemia Res, 2010

Burnett AK, et al. Lancet Oncol 2015.

AML17 results

Burnett AK, et al. Lancet Oncol 2015.

AML17

Conclusions:

• Relapse rate lower with ATRA + ATO.

• Overall survival unchanged in either low-risk or

high-risk cohort.

• Toxicities decreased overall with ATRA + ATO.

• QOL unchanged.

Update at ASH 2016 confirmed above findings.

Grimwade et al. J Clin Oncol, 2009; Grimwade and Tallman Leukemia Res, 2010 Burnett AK, et al. Lancet Oncol 2015.


Randomized trial for newly diagnosed APL patients.

481 patients enrolled

Two randomizations:

• ATO consolidation (yes/no)

• Maintenance (ATRA alone vs. ATRA + 6-MP/MTX)

Powell BL, et al. Blood 2010.

North American Intergroup C9710


Fairly sizeable advantage realized with addition of ATO

consolidation in high and low risk disease for disease-

free and event-free survival.

OS not different but p-value 0.059 (86% vs. 81% at 3

years)

Not enough events to evaluate the differential effect of

maintenance therapy (p-value for PFS 0.11)




Australasian Leukaemia and Lymphoma Group

Single-arm phase 2 trial with 124 patients, median follow-

up for 2 years.

Both low and high-risk patients were included.

APML4

Iland H, et al. Blood 2012.

APML4

INDUCTION CONSOLIDATION (1) MAIN

ATRA D 1-35 ATRA D 1-28 ATRA, 6-MP

IDA D 2,4,6,8 ATO D 1-28 MTX

ATO D 9-36

CONSOLIDATION (2)PRED D 1-10

ATRA D 1-7, 15-21, 29-35

ATO D 1-5, 8-12, 22-26, 29-33

Iland H et. al, Blood 2012

APML4

DFS by Sanz Risk Category

0

20

40

60

80

100

% r

ela

pse−

fre

e

0 1 2 3 4 5 6 7 8Years from documented HCR

Number at risk

32 31 30 22 12 8 3 1 0Low

60 58 57 46 32 15 8 2 0Inter

19 18 18 12 8 6 2 0 0High

Low

Intermediate

High

P−value (trend) = 0.30

2−year relapse−free rate: 100%, 97%, 95%, 5−year: 100%, 93%, 95%% a

live a

nd

rela

pse

-fre

e 100-

80-

60-

40-

20-

0-

1 2 3 4 5 6 7 80

Years from documented HCR

P [ trend ] = .30

Low 100%

High 95%

Intermediate

93%

APML4

2015 update (5-year data):

5-yr OS 94% overall (high-risk 87%)

5-yr DFS 95%

5-yr EFS 90%

3 patients relapsed between the interim 2-year

analysis and the 5-year update.

Grimwade et al. J Clin Oncol, 2009; Grimwade and Tallman Leukemia Res, 2010 Iland H et. al, Lancet Oncol 2015.

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 Medianfollow-up

(months)

IDAequivalent

(mg/m2)

AraC

(g/m2)

DFS CIR OS

PETHEMA

LPA2005118 28 122 5.8 82%

14% 79%

European

APL200074 103 99 22.8 - 7% 88%

GIMEMA

AIDA2000129 59 122 6.3 85% 9% 83%

ALLG

APML423 50 48 0 95% 5% 87%

MRD Monitoring

• Document molecular CR from marrow after consolidation

(slightly more sensitive than PB by 1.5 logs)

• Unclear benefit in low-risk disease

• Potential benefit in high-risk disease, never prospectively

validated, but treatment of molecular relapse is easier than

hematologic relapse

• Monitor from PB q3 mo. for 2 yrs for high-risk, age >60,

therapy interruptions or intolerance

• Low-risk: may not be necessary

• If pos PCR, repeat in 2-4 weeks; if persistent positive, treat

as relapse Grimwade et al. J Clin Oncol, 2009; Grimwade and Tallman

Leukemia Res, 2010; Grimwade Best Pract Res Clin

Haematol 2015

Relapsed APL

• Molecular relapse

– ATO x 2 cycles

– Autograft in CR2

• Morphologic relapse

– ATO x 2 cycles: CR 85%

– Autograft in CR2: 5-yr DFS 70-80%

• Isolated CNS relapse

– ATO crosses into CNS 30-50% serum levels

– ATO x 2 cycles, IT MTX/ara-C, autograft

Lo Coco Blood, 1999 and 2004; Esteve Leukemia, 2007, Estey Blood, 2002; Meloni Blood,1997; de Botton

J Clin Oncol, 2005; Thomas Haematologica, 2006; Kohno Int J Hem, 2008, Kharfan-Dabaja BBMT, 2007;

Au J Clin Oncol 2000; Knipp Leuk Res, 2007; Sanz Blood, 2009

Adjusted Probability of Overall Survival

APL in CR2

1.0

0.8

0.6

0.4

0.2

00 12 24 36 48 60 72 84 96 108

alloHSCTautoHSCT

Months

Pro

babili

ty

120

Chakrabarty et al. BBMT, 2014

Late Toxicities

3-5% death rate in CR reported in PETHEMA and

European APL trials1,2

– Heart failure, secondary malignancies, especially

as historical APL regimens have included a lot

of anthracycline

Possible late toxicities with ATO – hypertension,

DM, arrhythmia3

1Sanz MA, et al. Blood 2008 2Ades L, et al. Blood 2010.3Shetty AV, et al. ASH 2014.

ASH 2016 Updates

Two trials for high risk patients:

1) APL2006 – Induction with ATRA + ida 12mg/m2 x

3 days + ara-C 200 mg/m2 x 7 days (7+3)

– Randomization between consolidation chemotherapy with

or without ATO, ara-C later removed from ATO arm due to

toxicity, results ultimately comparable

2) SWOG/Alliance/ECOG S0535 – Untreated high-risk

patients, GO 9 mg/m2 on D1, ATRA + ATO until

remission. Consolidation ATO x 2, ATRA + dauno x 2,

GO x 2, maintenance ATRA + 6MP/MTX

– 3y EFS 79%

Lu et al. Blood, 2002; Kumana et al. Eur J Clin Pharmacol, 2002;

Au et al. Leukemia Res, 2007; Au et al. Blood 2006 and 2008

Provocative Thoughts Regarding

Treatment of APL

• Current therapy is directed at less chemo and can be cured

with NO chemo

• Current strategies focus early (ED) and late (maintenance)

phases of treatment

• Disease is as sensitive among older adults as younger

• Risk stratification is very simple

• Treatment of relapsed disease is highly effective

• Autograft is treatment of choice in CR2 not allograft

ONY AML WHERE…

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