Treatment of APL

Objectives

1. Urgency of early recognition and treatment

2. Treatment based on risk stratification

3. Monitoring for relapse

4. Treatment of relapse

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

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

Bleeding in APL

Subcutaneous bleeding

Retinal hemorrhages Intracerebral hemorrhage

Oral mucosal bleeding

Failure 10%

CR 90%

Causes of Induction Mortality in APL

Other DS (6%)

Infection

(30%)

Bleeding (60%)

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%

Prevention of Early Death in APL

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

• Frequent plt transfusion to > 50,000/L

• Cryo to maintain fibrinogen > 150 mg/dL

• No routine heparin

• No routine antifibrinolytics

• No Leukopheresis

CAVEATS for Induction in APL

• Differentiation Syndrome

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

Primary Induction Failure – Rare in APL

• Document Presence of PML/RAR α transcript

for later molecular monitoring

Milestones in the Development of Curative Strategies in APL

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

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

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

0

10

20

30

40

50

60

70

80

90

100

Baseline

N=29 Induction Consolidation

Pa

tie

nts

with

MR

( %

)

48%

86%

Maintenance

90%

Molecular Response to Arsenic Trioxide in

Relapsed APL: US Multicenter Study

Soignet et al. J Clin Oncol, 2001

Shen et al. PNAS, 2004

Disease-Free Survival by Treatment Group

APML - 4

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

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 r

ela

pse

-fre

e

Years from documented HCR

P [ trend ] = .30

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%

≤

≤

APL 0406 Study

Inclusion Criteria

APL0406 Study: Treatment

ATRA + ATO ATRA + Chemo

No. of patients 75 79

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

Induction death 0 4*

Resistant disease 0 0

Induction Outcome

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

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

APL 0406

APL 0406: Overall Survival

MRD Monitoring

• Document molecular CR from marrow after

consolidation

• Low-risk: 1% OS benefit at 5 yrs

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

• 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 pos, treat as

relapse

S0521:Treatment Schema

Disease-Free Survival

Case Study (part 1)

7/11/2012 - 30 yo Latino farm worker

Syncope, SOB

WBC 18,700 , 47% Blasts, Hgb 12, Plt 20,000

Marrow PML-R Fibrinogen 107 PTT > 200

7/14/2012 – Admit to COH

WBC 38,000, plt 13,000 Start ATRA + HU

LDH 5280 Fibrinogen 116 PT+PTT N

7/16/2012 – Start 7+3, Start Decadron

LDH 23,000

7/19/2012 – Intubated for DS, ATRA held

7/22/2012 – Pseudotumor Cerebri Diamox WBC ↓ 2200 → CRh

Case Study (part 2)

• Received 3 cycles consolidation

• IT MTX for CNS Prophylaxis

• Isolated CNS relapse at end of cycle 3

• Marrow + PB molecularly neg

• Triple IT Chemo 2x/ wk

• ATO + ATRA x 2 cycles

• Auto HCT 7/2013

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

0

0 12 24 36 48 60 72 84 96 108

alloHSCT

autoHSCT

Months

Pro

ba

bili

ty

120

Chakrabarty et al. BBMT, 2014

Gemtuzumab Ozogomicin in APL

Study N Disease

Status

CR% Mol CR%

Estey1 19 De novo 84% 100%

LoCoco2 16 Mol. Relapse NA 100%

1Estey et al. Blood, 20022; Lo Coco et al. Blood, 2004

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)

Current Strategies in APL-2015

Induction: ATRA + ATO (+ ida for high-risk) and for older or unable to tolerate anthracyclines or ATRA + ida ATRA 1-2d before ida for low-risk and ATRA 12-24h for high-risk)

CNS and dex prophylaxis for high-risk

Consolidation: ATRA + ATO or ATRA plus anthracyclines for 3 cycles to molecular negativity and intermed-dose ara-C as early consol for high-risk

Maintenance: ATRA +/- low-dose chemo for 1-2 years for high-risk and maybe for low-risk if treated with ATRA+ ida; ? role if PCR neg after consol; if ATRA +ATO for low-risk main not needed

Mol. Monitor: RT-PCR from PB every 3-4 months for 3 yrs for high-risk only (if pt received optimal therapy)

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 (maint) phases of

treatment

• Disease is as sensitive among older adults as younger

• Treatment of relapsed disease (for late relapse highly)

effective

• Autograft is treatment of choice in CR2 not allograft