1

Re-evaluating the role of dexrazoxane

November 11th

2017

Etienne Brain, Institut CurieHôpital René Huguenin

St Cloud, France

Anthracycline Use and Cardiotoxicity

Anthracyclines and cardiotoxicity

• Anthracyclines remain some of the most widely prescribed and effective anticancer agents1

− Doxorubicin, Epirubicin, Daunorubicin, Idarubicin

• In breast cancer, anthracycline-based regimens achieve higher disease-free and overall survival compared with non-anthracycline-based regimens2

• In childhood cancers, anthracyclines are incorporated in >50% of regimens3

• Anthracycline-induced cardiotoxicity is a multifactorial process1,4,5

• Cardioprotective strategies are available and should be used more pragmatically in routine clinical practice1,4,6

1. Menna P, et al. Expert Opin Drug Saf 2012;11 (Suppl 1):S21-36; 2. Hershman DL, Shao T. Oncology (Williston Park) 2009;23:227-34;

3. Lipshultz SE, Adams MJ. J Clin Oncol 2010;28:1276-81; 4. Hutchkins KK, et al. Br J Clin Pharmacol 2017;83:455-65;

5. Geisberg CA, Sawyer DB. Curr Hypertens Rep 2010;12:404-10; 6. Lipshultz SE, et al. Annu Rev Med 2015;66:161-76

CHF induced by anthracyclines

Felker GE, et al. New Engl J Med 2000;342:1077-1084.

Cause HR (95%CI) P

Idiopathic 1.00

Peripartum 0.31 (0.09-0.98) 0.05

Hypertension 0.74 (0.36-0.52) 0.42

Myocarditis 1.05 (0.67-1.61) 0.82

Connective disease 1.75 (1.02-3.01) 0.04

Ischemic heart 1.52 (1.07-2.17) 0.02

Anthracyclines 3.46 (1.67-7.18) 0.001

HIV 5.86 (3.92-8.77) <0.001

Infiltrative

myocardial disease4.40 (3.04-6.39) <0.001

Median OS if A-related = 1 yr(age: +20%/decade)

Peripartumcardiomyopathy

Idiopathic cardiomyopathy

Cardiomyopathy due to ischemic heart disease

Cardiomyopathy due to doxorubicin therapy

Cardiomyopathy due to infiltrative myocardial disease

Cardiomyopathy due to HIV infection

1.00

0.75

0.50

0.25

0.00

151050Years

Pro

po

rtio

n o

f p

ati

en

ts s

urv

ivin

g

Anthracycline-induced cardiotoxicity

• Anthracycline cardiotoxicity has two components

− Myocyte dysfunction (potentially reversible)

− Cardiomyocyte cell death (irreversible )

• Cardiac damage cannot typically be reversed once it occurs:1,2

− Regeneration of cardiomyocytes is limited3

− Drug therapy can only partially restore normal cardiac function once damage is caused following anthracycline-based treatment3

• Incidence of cardiac damage may be under-estimated:4

− Patients with prior exposure to anthracyclines have an increased lifetime risk of cardiotoxicity and cardiac-related death5,6

− This risk increases with cumulative exposure and duration of survival2,7

− Interaction with baseline CV risk factors is important8

− There is no safe dose of anthracyclines2,9,10

1. Lenihan DJ, Cardinale DM. J Clin Oncol 2012;30:3657-64; 2. Hutchkins KK, et al. Br J Clin Pharmacol 2017;83:455-65; 3. Bergmann O, et al. Science

2009;324:98-102; 4. Ewer MS, et al. Heart Fail Clin 2011;7:363-72; 5. Lipshultz SE, et al. Lancet Oncol 2010;11:950-61; 6. Tukenova M, et al. J Clin Oncol

2010;28:1308-15; 7. Kremer LCM, et al. J Clin Oncol 2001;19:191-6; 8. ZamoranoJl et al. Eur Heart J. 2016 Sep 21;37(36):2768-2801.9. Leger K, et al. Pediatr Blood Cancer 2015;62:123-7; 10. Vejpongsa P, Yeh ETH. J Am Coll Cardiol 2014;64:938-45

2

Cumulative proportion with event

0 200 300 400 700 800 900 1000

Cumulative dose of doxorubicin (mg/m2)

600500100

468172

345110

29692

10328

61

41

203

5912

431151

≤65*>65*

0

0.2

0.4

0.6

0.8

1.0

Hazard ratio (>65:≤65) = 2.2595% CI of (>65:≤65) = (1.04–4.86)Log rank p-value = 0.029Wilcoxon p-value = 0.78

≤65

>65

Doxorubicin, CHF and age

• 630 patients (3 phase III) with 32 CHF

− 26% >550 mg/m²

− >50%: reduction of LVEF <30% w/CT

*Patients at risk

Swain SM, et al. Cancer 2003;97:2869-79.

• HRage 2.25 (1.04–4.86) vs 3.28

(1.4–7.65) if >400 mg/m²

Anthracycline-induced cardiotoxicity is cumulative

• Myocyte injury appears to occur from the first dose1

− Based on cardiac biopsy data2, troponin levels3 and the mathematical relationship4 of the cumulative dose versus incidence of cardiac failure

HF, heart failure

1. Leger K, et al. Pediatr Blood Cancer 2015;62:123-7; 2. Berry G, et al. Ann Oncol 1998;9:711-6; 3. Lipshultz SE, et al. Circulation 1997;96:2641-8; 4. Ewer MS,

et al. J Clin Oncol 1984;2:112-7; 5. Adapted from Feijen EA, et al. J Clin Oncol. 2015;33:3774-80

n=8n=18

n=22n=8

n=3

n=7

Mackay - MDAH

Billingham - Stanford

5%*

Dose (mg/m2)

300

Re

lati

ve

ris

k o

f H

F

30

25

10

20

5

0 500200100

Relative risk of HF following doxorubicin or daunorubicin

treatment (n=7387)5

Cardiac biopsy grade vs cumulative doxorubicin dose (n=158)4

Cumulative doxorubicin dose (mg/m2)

Me

an

bio

ps

y g

rad

e

200–400 401–500 >500

1

2

3

15

1

400

Doxorubicin

Daunorubicin

Mechanisms for anthracycline cardiotoxicity1

• Topoisomerases (TOP)

− TOP2α expressed in tumour cells

− TOP2β expressed ubiquitously

• Anthracyclines target TOP2α and 2β

− Cardiomyocytes express TOP2β not 2α

• Anthracyclines form Fe3+ complexes which drive reactions leading to free radicals

− Free radicals disrupt cellular constituents

− Cellular dysfunction and cell death

1. Sawyer DB NEJM 2013 368(12):1154-6

Decrease risk of CHF

• Infusion (≥6 hr vs shorter)− HR 0.27 (95% CI 0.09-0.81)

• Analogs (epirubicin)− HR 0.36 (95%CI 0.12-1.11)− Efficacy dose/dose?

• Liposomal formulations− HR 0.20 (95% CI 0.05-0.75)− HR 0.38 (95%CI 0.24-0.59)

subclinical

• Iron chelating agent dexrazoxane− HR 0.29 (95% CI 0.20-0.44)

• β- and ACE inhibitors

• Replace AC in adjuvant and

metastatic settings

van Dalen EC, et al. Cochrane Database Syst Rev 2006;4:CD005006.

van Dalen EC, et al. Cochrane Database Syst Rev 2008;2:CD003917.

Interstitium Cardiomyocyte

Dexrazoxane partially acts by binding Fe3+ ions

• Dexrazoxane binds Fe3+ before anthracyclines enter cardiomyocytes:1,2

• Binding to Fe3+ prevents the formation of the Fe-anthracycline complex

− Thereby preventing free radical release and cardiac damage

Fe3+

Fe3+

Fe3+

Fe3+

No free radical release

Reduced cardiomyocyte apoptosis

DexrazoxaneDexrazoxaneDexrazoxaneDexrazoxane

1. Hasinoff BB, Herman EH. Cardiovasc Toxicol 2007;7:140-4; 2. Hutchkins KK, et al. Br J Clin Pharmacol 2017;83:455-65

Dexrazoxane binds to topoisomerase IIβ to prevent anthracycline binding

DNA, deoxyribonucleic acid; ROS, reactive oxygen species

Vejpongsa P, Yeh ETH. J Am Coll Cardiol 2014;64:938-45

A A

A A

D

A

A

A A

A

A

ROS

Anthracycline

Dexrazoxane mechanism

Mitochondrialdysfunction

DNA double-strandbreaks

3

Dexrazoxane in EU clinical practice

• First approved in the EU in 1990’s

• Concerns raised about secondary malignancies in 20071 and 20102

− 2011 MHRA initiated a process leading a full risk benefit assessment by EMA

− Dexrazoxane contraindicated in children

− Adult label restricted to patients with advanced/metastatic breast cancer

• Additional new data presented to EMA 2016

− Updated label approved in France and elsewhere in August 2017

1. Tebbi CK, et al. J Clin Oncol. 2007; 25:493-500.

2. Salzer WL, et al. Leukemia. 2010;24:355-70

Cardioxane: Changes to the EU label August 2017

• Paediatric contraindication removed

− For patients expected to receive a cumulative dose of more than 300 mg/m2

of doxorubicin or the equivalent cumulative dose of another anthracycline

• Second primary malignancy

− Updated data, especially in children

• Interference with chemotherapy

− Summary of evidence, indicating most adult and all paediatric studies do not show evidence of interference

− Removed statement that dexrazoxane is not recommended for patients receiving adjuvant treatment

• Early death

− Removed as a safety warning from SmPC as no data to support this is a risk

• The national implementation of changes into the SmPC is almost complete

Clinical Indications for Dexrazoxane as a

Cardioprotective Agent

Dr Robin Jones Royal Marsden NHS Trust

London, UK

Anthracyclines in patients with cancer

• Anthracyclines are drugs of first choice in many cancer types1

• Approximately one-third of breast cancer patients and half of children with cancer are treated with anthracyclines2,3

• Anthracyclines are part of recommended chemotherapy regimens

− for adults with breast cancer:

� HER2 –ve/HER2 +ve disease4

� Advanced/recurrent/metastatic disease4,5

� Inflammatory breast cancer4

− for many childhood cancers

� Hodgkin’s lymphoma6

� Acute lymphoblastic leukaemia7,8

� Acute myelogenous leukaemia9

� Osteosarcoma, Ewing sarcoma & non-rhabdomyosarcoma soft tissue sarcomas10

1. Valcovici M, et al. Arch Med Sci 2016;12:428-35; 2. McGowan JV, et al. Cardiovasc Drugs Ther 2017;31:63-75; 3. Smith LA, et al. BMC Cancer 2010;10:337; 4. NCCN Clinical practice Guidelines in Oncology – Breast Cancer. Version 2.2017;April 6, 2017. Available at www.nccn.org; 5. NICE Clinical guidance [CG81] Advanced breast cancer: diagnosis and treatment. August 2017. Available at www.nice.org.uk/guidance/cg81;

6 NCCN Guidelines: Hodgkin’s Lymphoma 2017 J Natl Compr Canc Netw 2017; 15:608-638. 7 NCCN Guidelines: ALL. August 30, 2017. Available at www.nccn.org; 8. Cooper SL, Brown PA. Pediatr Clin North Am 2015;62:61-73; 9. American Cancer Society 2016. https://www.cancer.org/cancer/leukemia-in-children/treating/children-with-aml.html; 10. Weiss A, et al. Curr Oncol Rep 2014;16:395.;

Potential primary and secondary prevention strategies for cardioprotection

Clinical setting Primary preventionLevel of evidence

Class of recommendation

High-risk profile from genetic testing

Dexrazoxane

Liposomal doxorubicinContinuous infusion

C IIb

Breast cancer

(metastatic >300 mg/m2)Dexrazoxane A I

High-risk paediatric ALL Dexrazoxane A IIa

All patients receiving

anthracyclineβ-blockers, ACE-I, ARB C IIb

Secondary prevention

Abnormal strain/LV function

elevated cardiac biomarkersβ-blockers, ACE-I, ARB B IIa

• Current recommendations for primary prevention are to treat high-risk patients with dexrazoxane, liposomal doxorubicin, or continuous infusion

ACE-I, angiotensin-converting enzyme inhibitor; ALL, acute lymphoblastic leukaemia; ARB, angiotensin receptor blocker; LV, left ventricularVejpongsa P, Yeh ETH. J Am Coll Cardiol 2014;64:938-45

-18%

-16%

-14%

-12%

-10%

-8%

-6%

-4%

-2%

0%275-399 400-499 500-599 600-699

Me

dia

n d

ec

rea

se fro

m b

as

eli

ne

in

re

sti

ng

LV

EF

Cumulative doxorubicin dose (mg/m2)

FAC Dexrazoxane + FAC

Dexrazoxane preserves LVEF in women with breast cancer

36/40 ptsb

57/61 ptsa

55/57 ptsa

44/45 ptsb

40/45 ptsb

16/20 ptsb

7/8 pts

27/30 pts

Doxorubicin-related cardiotoxicity in 150 women with advanced breast cancer

aP<0.05; bP<0.0001; cP=0.001.FAC, fluorouracil, doxorubicin, and cyclophosphamide; LVEF, left ventricular ejection fraction; pts, patients Speyer JL, et al. J Clin Oncol 1992;10:117-27

4

Pivotal trials in advanced breast cancer1,2

• Patients with advanced breast cancer: randomised to FAC ± dexrazoxane

• Two trials with various study design changes

− Primary analysis combined data from the two studies from patients who were administered treatment in a dexrazoxane: doxorubicin ratio of 10:1

• Outcome measures

− Occurrence of cardiac events defined as one of

� Decline in LVEF (↓ ≥20% from baseline OR ≥ 10% of LLN OR to ≥5% below LLN)

� Development of CHF (manifest by ≥ 2 clinical signs or symptoms)

− Objective response rates (CR, PR)

• Safety outcomes

− All adverse events

− Grade 3/4 toxicity

CHF, congestive heart failure; CR Complete response; FAC, fluorouracil, doxorubicin, and cyclophosphamide. LLN, lower limit of normal at the investigating institution. LVEF left ventricular ejection fraction. PR partial response 1. Swain SM, et al. J Clin Oncol 1997;15:1318-32 2. Swain SM, et al. J Clin Oncol 1997;15:1333-40

Demographics of patients in pivotal breast cancerstudies

Group*, n (%)

Study 088001 Study 088006

Dexrazoxane(n=168)

Placebo(n=181)

Dexrazoxane(n=81)

Placebo(n=104)

Age (median range) 58 (26-84) 56 (25-82) 56 (35-76) 59.5 (23-79)

RaceWhite

BlackOther

124 (74)

30 (18)14 (8)

125 (69)

37 (20)19(11)

72 (89)

5 (6)4 (5)

83 (80)

18 (17)3 (3)

ER status(-) ve

(+) ve

57 (34)

70 (42)

78 (43)

63 (35)

26 (36)

37 (46)

33 (32)

47 (45)

Prior Rx

Radiation

ChemotherapyHormonal

75 (45)

72 (43)88 (52)

71 (39)

63 (35)85 (47)

26 (32)

30 (37)44 (54)

41 (39)

36 (35)50 (48)

DiseaseMeasurable

Non-measureable

141 (84)

27 (16)

152 (84)

29 (16)

54 (67)

27 (33)

69 (66)

35 (34)

• ECOG status and no of disease sites well matched within studies

*n (%) unless otherwise statedCHF, congestive heart failure; CI, confidence interval; ER Estrogen receptor; FAC, fluorouracil, doxorubicin, and cyclophosphamide; HR, hazard ratio 1 Swain SM, et al. J Clin Oncol 1997;15:1318-32

Cardiac outcomes and FAC treatment response in patients with advanced breast cancer ± dexrazoxane

Group, n (%)

Study 088001 Study 088006

DEX(n=168)

Placebo(n=181)

Hazard ratio* P-

value#

DEX(n=81)

Placebo(n=104)

Hazard ratioP-

value#

Patients with

cardiac event25 (15) 57 (31)

2.63

(1.61- 4.27)<0.001 11 (14) 32 (31)

2.00

(1.01-3.96)<0.001

Patients with CHF 0 (0) 15 (8) <0.001 2 (2) 7 (7) 0.30‡

Response rate 46.8 60.5∆= -14%

(-25% to -2%)0.019 53.7 49.3

∆= 4%

(-13% to 22%0.63

Median OS (days) 598 5511.02

(0.80-1.31)0.88 458 553

0.82

(0.59-1.14)0.23

Median PFS

(days)254 260

0.86

(0.68-1.10)0.23 233 249

0.83

(0.60-1.15)0.27

* (95% Confidence interval); # Log rank test unless otherwise stated; ‡ Fisher’s exact test. CHF, congestive heart failure; CI, confidence interval; DEX, dexrazoxane; FAC, fluorouracil, doxorubicin, and cyclophosphamide; HR, hazard ratio; OS, overall survival; PFS, progression free survival Swain SM, et al. J Clin Oncol 1997;15:1318-32

Dexrazoxane protects against FAC-induced cardiac events in patients with advanced breast cancer

0.0

0.2

0.4

0.6

0.8

1.0

300 500 700 900 1100 1300 1500

Cumulative dose of Doxorubicin mg/m2

102 89 36 29 17 10 7 5 353DEX* 2 2

PLA* 199 92 17 7 3 1 1 1 152 1 1

Cu

mu

lati

ve P

rop

ort

ion

Ev

en

t F

ree

Dexrazoxane

Placebo

HR for a cardiac event: 3.5195% CI: 2.15-5.72

p<0.001

*Patients at risk; CI, confidence interval; FAC, fluorouracil, doxorubicin, and cyclophosphamide; HR, hazard ratio Swain SM, et al. J Clin Oncol 1997;15:1333-40

Dexrazoxane protects against FAC-induced cardiac failure in patients with advanced breast cancer

0.0

0.2

0.4

0.6

0.8

1.0

300 500 700 900 1100 1300 1500

Cumulative dose of Doxorubicin mg/m2

102 92 42 31 20 11 7 7 359DEX* 2 2

PLA* 199 92 19 7 6 1 1 1 157 1 1

Cu

mu

lati

ve P

rop

ort

ion

Wit

ho

ut

CH

F

Dexrazoxane

Placebo

1

HR for cardiac failure: 13.0595% CI: 3.72 - 46.0

p<0.001

CHF Congestive Heart FailureSwain SM, et al. J Clin Oncol 1997;15:1333-40

Grade 3 and 4 toxicities following FAC chemotherapy in patients with advanced breast Ca ± dexrazoxane

0

20

40

60

80

100

Pa

tie

nts

(%

)

Dexrazoxane

Placebo

*

* p=0.007

FAC, fluorouracil, doxorubicin, and cyclophosphamide Swain SM, et al. J Clin Oncol 1997;15:1318-32

5

Impact of dexrazoxane upon overall survival after FAC in patients with advanced breast cancer

HR for survival (P:D) = 1.02

95% CI: 0.8-1.31

p = 0.88

HR for survival (P:D) = 0.82

95% CI: 0.59-1.14

p = 0.23

0.0

0.2

0.4

0.6

0.8

1.0

Cu

mu

lati

ve

Pro

po

rtio

n S

urv

ivin

g

0.0

0.2

0.4

0.6

0.8

1.0

0 400 800 1200 1600 2000

Cu

mu

lati

ve

Pro

po

rtio

n S

urv

ivin

g

0 400 800 1200 1600 2000

81 63 39 10 616DEX*

104 90 44 19 530PLA*

27

70 1

166 145 105 31 13 251DEX*

181 159 67 32 1947PLA* 1

76 4 1

111 9

Days Days

Dexrazoxane

Placebo

Dexrazoxane

Placebo

Study #88001 Study #88006

CI, confidence interval; FAC, fluorouracil, doxorubicin, and cyclophosphamide; HR, hazard ratio Swain SM, et al. J Clin Oncol 1997;15:1318-32

Evidence of dexrazoxane as a cardioprotectant in other clinical settings

• Although dexrazoxane is currently only licensed in adults for use in patients

with advanced or metastatic breast cancer, its efficacy as a cardioprotectant

has been demonstrated in several clinical trials in other cancer types:

− Ewing sarcomas1

− Soft tissue sarcomas2

− Childhood acute lymphoblastic leukaemia3 and Hodgkin’s lymphoma4

− Small cell lung cancer5

− Non-Hodgkin’s Lymphoma6

• In most trials, dexrazoxane does not appear to interfere with anthracycline anti-tumour efficacy

1. Wexler, LH, et al. J Clin Oncol 1996;14:362–72; 2. Lopez M, et al. J Clin Oncol 1998;16:86-92; 3. Lipshulz SE, et al. N Engl J Med 2004;351:145-53; 4. Chow EJ, et al. Blood 2016;128:696 04; 5. Feldman JE, et al. ASCO 1992;11:993; 6. Limat S, et al. J Clin Pharm Ther 2014; 39: 168-174

Dexrazoxane reduces the risk of developing short-term subclinical cardiotoxicity in sarcoma patients*

Control Dexrazoxane

-16

-12

-8

-4

0

Ch

an

ge in

LV

EF

(p

erc

en

tag

e p

oin

ts)

0 210 310 360 410

Cumulative doxorubicin dose (mg/m2)

0 210 310 360 4100

10

20

30

40

50

LV

EF

(%)

60

70

Cumulative doxorubicin dose (mg/m2)

n=18 n=20 n=13 n=17 n=10 n=17 n=5 n=10n=8 n=15

Dexrazoxane treated

patients had smaller declines in LVEF per

100 mg/m2 of doxorubicin (1.0% vs

2.7%, p=0.02)

Dexrazoxane treated

patients received higher median

cumulative doses of doxorubicin (410 vs

310 mg/m2, p<0.05)

*Thirty-eight previously untreated patients ≤25 years of age with one of the Ewing sarcoma family of tumours receiving up to 410 mg/m2 of doxorubicin . Adapted from Wexler, LH, et al. J Clin Oncol 1996;14:362–72

Impact of dexrazoxane upon dose limiting cardiotoxicity in sarcoma patients

Dexrazoxane-treated patients experienced less subclinical cardiotoxicity vs. controls (22% vs 67%, p<0.01)P

ati

en

ts w

ith

ou

t d

os

e-l

imit

ing

ca

rdio

tox

icit

y (

%)

Cumulative doxorubicin dose (mg/m2)

100

40

300100

80

60

Control

Dexrazoxane

200 400

20

0

0

Dose-limiting cardiotoxicity defined as a reduction in LVEF to less than 45%, a decrease in LVEF of greater than 20 percentage points from baseline, or evidence of clinical congestive heart failure. Median potential follow-up duration: 39 months for all patients (37 months for dexrazoxane-treated patients and 40 months for controls) Adapted from: Wexler LH, et al. J Clin Oncol 1996;14:362-72

LV ejection fraction following high doses of epirubicinin breast Ca and soft tissue sarcoma ± dexrazoxane1

• Randomised trial to evaluate the cardioprotective effect of dexrazoxane in patients treated with high-dose epirubicin

• Patients with breast cancer (n=95) or STS (n=34) received epirubicin ±dexrazoxane

• Age range 26-72 years

− Median: Dex = 58, Control =55

• Anti-tumour response rates, time to progression, and survival did not significantly differ between the two arms

Linear regression analysis p=0.0001

LV

EF

(%

)

Cumulative epirubicin dose (mg/m2)

800

50

20

40

10

00 1200400

80

70

60

30Epirubicin (n=62)

Dexrazoxane + epirubicin (n=59)

LVEF: left ventricular ejection fraction; STS: soft tissue sarcoma Lopez M, et al. J Clin Oncol 1998;16:86-92

Impact of dexrazoxane upon the incidence of myocardial injury (troponin T elevation*) in children with ALL1

N=76 N=55 N=74 N=51 N=59 N=41N=82 N=64 N=77 N=61 N=62 N=45

0

10

20

30

40

50

OverallPre-

Treatment 0-60 61-120 121-180 181-240

Days of doxorubicin treatment

cT

nT

ele

va

ted

sa

mp

les

(%

)

p=0.771 p=0.999

p=0.058

p<0.001

p<0.001p<0.001

Doxorubicin Dexrazoxane/Doxorubicin

*cTnT, cardiac troponin T1. Lipshultz SE, et al. NEJM 2004;351:145-53

6

16 year follow-up of children with haematologicmalignancies treated in the COG-P9404, -P9425 and -P9426 studies1

Characteristics Dexrazoxane No Dexrazoxane P value

Left ventricular function, % n=51 n=42

Fractional shortening 35 ± 4 33 ± 5 0.09

Ejection fraction 61 ± 6 57 ± 7 0.02

LV remodelling (TD ratio) 0.18 ± 0.04 0.18 ± 0.05 0.41

Blood biomarker, pg/mL n=43 n=35

N-terminal proBNP 45 ± 39 65 ± 56 0.06

BNP 11 ± 11 18 ± 15 0.02

cTnT. cTnl All undetectable -

Multivariate analysis confirmed differences persist after adjusting for sex, current age, age at diagnosis, race/ethnicity and original COG trial

1. Chow EJ, et al. Blood 2016;128:696Original studies: P9404 (ALL; n=537): P9425 (intermediate/high-risk Hodgkin lymphoma; n=216): P9426 (low-risk Hodgkin lymphoma; n=255)

Change in LVEF after doxorubicin based chemotherapy (CAV) for small cell lung cancer ± dexrazoxane1

6.87.5 7.1

13.5

1.42

0.1

1.5

0

2

4

6

8

10

12

14

16

150mg 300mg 400mg 600mg

Me

an

dro

p i

n L

VE

F (

%)

Cumulative doxorubicin dose/m2

Control (n=62) Dexrazoxane (n=43)

p=0.003 p=0.07 p=0.028 p=0.09

Median age in each treatment arm was 66.0 years

CAV, Cyclophosphamide / Doxorubicin / Vincristine. LVEF: left ventricular ejection fraction;1. Feldman JE, et al. ASCO 1992;11:993

Cardiac outcomes and tumour response after doxorubicin chemotherapy for SCLC ± dexrazoxane1

29

8

12

56

12

5

13

55

0

10

20

30

40

50

60

Cardiac events CHF Complete Response Partial Response

Pa

tie

nts

(%

)

Clinical Outcome

Control (n=62) Dexrazoxane (n=43)

p=0.029 p=NS p=NS p=NS

Median time to treatment failure was 183 days in both groups

1. Feldman JE, et al. ASCO 1992;11:993

Cardiotoxicity in patients with aggressive NHL treated with (R)CHOP ± dexrazoxane1

• Retrospective analysis of patients treated with (R)CHOP

− Period 1 (n=98) pre-dexrazoxane

− Period 2 (n=82) after the introduction of dexrazoxane

− 45% of patients received dexrazoxane in period 2

• Lower age and dexrazoxane use were linked with cardioprotection:

− Age < 60 years. HR: 0.4 [0.17–0.9]; p=0.03

− Dexrazoxane. HR: 0.1 [0.01–0.75]; p=0.02

0

5

10

15

20

25

30

35

Cardiac events Clinical CHF

Pa

tie

nts

(%

)

5- year cumulative risks of cardiac events during the two periods of the

study

First period

Second period

p=0.006

P=0.01

CHF, congestive heart failure; HR, hazard ratio; NHL, non-Hodgkin’s lymphoma; (R)CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisolone with or without rituximab. Cardiac event defined as either a decline in resting left ventricular ejection fraction (LVEF) <50%, a decline in LVEF of >= 20% from baseline or as clinical evidence of CHF.1.Limat S, et al. J Clin Pharm Ther 2014;39:168-74.

Note In this study dexrazoxane was administered at ratio to doxorubicin of 20:1 to patients who had received > 200mg/m2 of doxorubicin

The use of dexrazoxane is recommended in international guidelines

• ASCO guidelines:1

− The use of dexrazoxane should be considered in patients with metastatic breast cancer and other malignancies, for patients who have received more than 300 mg/m2 doxorubicin who may benefit from continued doxorubicin-containing therapy.

− Cardiac monitoring should continue in patients receiving doxorubicin

• ESMO guidelines:2

− To minimize cardiotoxicity, the use of liposome-encapsulated doxorubicin and the use of an appropriate cardioprotectant regimen (as dexrazoxane, BB, ACE-inhibitors, AT1-antagonists) should be considered and planned in all patients at high risk of cardiotoxicity

ACE, angiotensin-converting enzyme; ASCO, American Society of Clinical Oncology; AT1, angiotensin-1; BB, beta-blocker; ESMO, European Society for Medical Oncology. 1. Hensley ML, et al. J Clin Oncol 2009;27:127-45; 2. Curigliano G, et al. Ann Oncol 2012;23 (Suppl 7):vii155-66.

Dexrazoxane in adults with cancer: from evidence to practice

Dexrazoxane is the first clinically effective cardioprotective agent for adults with metastatic breast cancer receiving anthracyclines1

Patients should not be denied optimal treatment because of concerns for cardiotoxicity

There is strong evidence to consider the use of dexrazoxane in other clinical settings2–6 on a case by case basis

1. Doroshow JH. Curr Pharm Biotechnol 2012;13:1949-56; 2. Wexler, LH, et al. J Clin Oncol 1996;14:362–72; 3. Lopez M, et al. J Clin Oncol1998;16:86-92; 4. Lipshulz SE, et al. N Engl J Med 2004;351:145-53; 5. Limat S, et al. J Clin Pharm Ther 2014; 39: 168-174 Feldman JE, et al. ASCO 1992;11:993

7

Cardioprotection in Elderly Patients

Steven E. Lipshultz, MDKarmanos Cancer Institute

Wayne State University School of Medicine

Detroit, MI

There is an increasing incidence of cancer in the elderly population1

• Cancer is primarily a disease of older people, with adults aged ≥65 years accounting for 65.2% of the total cancer prevalence in the UK2

*All cancers excluding non-melanoma skin cancer: 1993-20141. Cancer Research UK. Trends over time for cancer incidence by age. March 2017 2. Office for National Statistics. Cancer Registration Statistics, England: 2015. May 2017

European age-standardised incidence rates per 100,000 population, by age, UK*1

0 to 24 25 to 49 50 to 74 75+

Successful treatment of cancer is determined by the balance between oncologic efficacy and toxicity/late effects as measured by quality of life for a patient and their family

over a lifespan

Lipshultz SE, Sallan SE. J Clin Oncol 1993;11:1199-203

Factors associated with increased risk of anthracycline-induced cardiotoxicity

• The degree and progression of anthracycline-related toxicity varies

widely among individuals1

• Suggests a genetic predisposition and the presence of modifiable and

non-modifiable risk factors1

• However, some patients appear to

be more vulnerable than others, independent of these risk factors1

Risk factors1,2

• A high cumulative dose of

anthracyclines

• Female gender

• Age > 65 years or < 4 years

• Concomitant treatments (such

as radiation therapy and

trastuzumab)

• The presence of pre-existing

cardiovascular disease and

comorbidities (hypertension,

obesity, physical inactivity)

1. Lipshultz SE, et al. Annu Rev Med 2015;66:161-76 2. Volkova M, Russell R. Curr Cardiol Rev 2011;7:214-20

The risk of anthracycline-induced cardiotoxicity increases with age1

• Median survival of adult patients with anthracycline-induced cardiomyopathy is approximately 1 year1

• Age is an independent risk factor

− 20% increase in risk for each decade of life1

• Patients ≥ 65 years have a two-fold increased risk of developing

anthracycline-induced CHF compared with younger patients2,3

• Cardiotoxicity of anthracyclines is dose-dependent and can occur at any

time in the treatment course with acute, subacute, and late-onset presentations4

CHF, chronic heart failure1. Felker GM, et al. N Engl J Med 2000;342:1077-84; 2. Aapro M, et al. Ann Oncol 2011;22:257-267; 3. Swain SM, et al. Cancer 2003;97:2869-79; 4. Vachhani P, et al. Leuk Res Rep 2017;7:36-9

Dashed lines are the upper and lower 95% CI from the predicted mean +/- 2 SE of the mean.

End of Dox

DCM RCMNormal

Normal

Long-term follow-up is essential to see if an early doxorubicin “Hit” results in late cardiotoxicity associated with progressive cardiovascular morbidity and mortality1–11

20-year survivors6–11

> 8-fold increased CV mortality

> 4-fold increased sudden death

10-fold increased atherosclerosis

5-fold increased myocardial infarction

↑ CV mortality from 15 to 25 years after doxorubicin

30-year survivors6–11

> 3-fold higher anthracycline–associated CV mortality

15-fold higher rates of heart failure

10-fold higher rate of other CV disease

9-fold higher rate of stroke

CV, cardiovascular; DCM, dilated cardiomyopathy; Dox, doxorubicin; RCM, restricted cardiomyopathy1. Lipshultz SE, et al. J Clin Oncol 2005;23:2629-36; 2. Lipshultz SE, et al. J Clin Oncol 2010;8:1276-81; 3. Lipshultz SE, et al. NEJM 2004;351:145-53; 4. Lipshultz SE, et al.

NEJM 1995;332: 1738-43; 5. Lipshultz SE, et al. NEJM 1991; 324:808-15; 6. Mertens AC, et al. J Clin Oncol 2001;19:3163-72; 7. Mulrooney DA, et al. BMJ. 2009; 339: b4606; 8. Möller TR, et al. J Clin Oncol 2001;19:3173-81; 9. Tukenova M, et al. J Clin Oncol 2001;28:1308-15; 10. Armstrong GT, et al. J Clin Oncol 2009;27:2328-38; 11. Oeffinger KC, et

al. NEJM 2006;355:1572-82

Left ventricular contractility (health of heart muscle cells) progressively worsens over time

8

2

30 35 40 45

NCI CCSS: age-specific cumulative incidence of four major cardiac outcomes in 10,724 5-year survivors compared to 3,159 siblings1

Coronary Artery Disease Arrhythmia

Valvular Disease Heart Failure

1. Armstrong GT, et al. J Clin Oncol 2013;31:3673-80

0

4

6

8

10

26

Cu

mu

lati

ve In

cid

en

ce (

%)

0

2

4

6

8

10

26 30 35 40 45Cu

mu

lati

ve In

cid

en

ce (

%)

RTNo RTSibling

RTNo RTSibling

P <0.001

P <0.001

30 35 40 450

2

4

6

8

26

RT +anthracyclineAnthracycline aloneRT aloneNo RT or anthracyclineSibling

P <0.001

Cu

mu

lati

ve In

cid

en

ce (

%)

15

10

5

026 30 35 40 45

Cu

mu

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cid

en

ce (

%)

Age (years)Age (years)

RTNo RTSibling

P <0.001

NCI CCSS survivor lifetime cause-specific mortality1

Varies by disease:

• Loss to 28%

• 18 years lost life

• 43 years expectancy

1.00

0.75

0.50

0.25

0.005 15 25 35 45 55 65 75 85

1.00

0.75

0.50

0.25

0.005 15 25 35 45 55 65 75 85

Background mortalityExcess other causes of mortalityExcess subsequent cancer, cardiac, pulmonary, and external causes of mortalityLate-recurrence mortality

Lif

eti

me

mo

rta

lity

pro

ba

bil

ity

Lif

eti

me

mo

rta

lity

pro

ba

bil

ity

Time since diagnosis, y

Time since diagnosis, y

Overall mortality: 5-y cancer survivorsOverall mortality: general U.S. population

Late effects account for 30% of lifetime mortality probability

Loss in life expectancy of 10.4 y

1. Yeh JM, et al. Ann Intern Med. 2010;152:409-17

Doxorubicin cardiotoxicity is multifaceted and requires targeted multi-agent cardioprotection1

Dexrazoxane prevents anthracycline binding

to TOP IIβ

1. Lipshultz SE, et al. Nat Rev Clin Oncol 2013;10:697-710

Light micrographs showing protective effect of dexrazoxane against doxorubicin-induced cardiac lesions1

Toluidine stain, x 400. Myocardial vacuolization and myofibrillar loss are less severe in rats treated with dexrazoxane/DOX 12 mg/kg (C) and dexrazoxane/DOX 7 mg/kg (D) than in rats treated with 12 mg/kg DOX (A) or 7 mg/kg DOX (B) alone

DEX, dexrazoxane; DOX, doxorubicin1. Herman EH,… Lipshultz SE, et al. Cancer Chemother Pharmacol 2001;48:297-304

Mitochondrial abnormalities are greatest at the extremes of age

• Both children and the elderly are at higher risk of diminished mitochondrial function

• Like paediatric patients, elderly individuals have less mitochondrial

reserve respiratory capacity

• Ageing:1

− impairs mitochondrial function by affecting both the capacity and the

control of oxidative phosphorylation

− reduces the fidelity of myocardial mtDNA resulting in a reduction of

maximal respiratory capacity

− sensitises the heart to acute and chronic stress, lowering the threshold

of damage it can endure

1. Desler C, et al. J Aging Res 2012;2012:192503

Anthracycline-treated cancer survivors have significantly more mitochondrial DNA mutations or polymorphisms than healthy controls1

• Cancer survivors (n=167):

− 64 sequence variants identified

in 51 of 167 patients screened

(avg = 0.31 sequence

variants/patient; 30% of patients ≥ 1 change)

• Healthy controls (n=56):

− 8 sequence variants in 7 of 56

patients (avg = 0.14 sequence

variants/patient; 12.5% patients ≥ 1 change, p=0.008)

Primer Set Mutation & Location N Total4 T4216C*

T4218C

C4242T

T4336C*

4

1

7

2

14

5 C4312T*

T4330G*

A4529T

1

1

1

3

13 A8248G

G8269A

9-base deletion at 8271ο

1

2

6

9

14 T9950Cο

A10005G

T10034C*

A10042G

T10084Cο

A10086G*

A10097G

T10115Cο

2

1

1

1

2

1

1

1

10

15 A10398G*, ο

C10400T*

T10463C*

6

3

6

15

17 C14766Tο 1 1

18 C15885T*

A15907G*

A15924G*, ο

G15928A*

T deletion, bp 15940-15944

A15954G

1

2

5

1

2

1

12

*Potentially pathologic; οοοοpolymorphism; *,οοοο Both

1. Lipshultz SE, et al. ASCO 2010

9

Variable N DOXMedian (range)

N DEX/DOXMedian (range)

P

mtDNA copies/cell 27 1106.3 (144.2-6746.8) 35 310.5 (15.3-1859.2) 0.001

CI Activity

(OD/mg x 103)

25 10.5 (5.0-31.3) 33 11.7 (5.0-41.4) 0.97

CIV Activity

(OD/mg x 103)

25 9.8 (5.0-20.1) 34 8.1 (4.7-23.4) 0.40

There is accelerated mitochondrial aging with doxorubicin, which is attenuated by dexrazoxane1

NCI DFCI Protocol 05-336:Mitochondrial function in 10-year ALL survivors

Results: Significantly higher number of mtDNA copies/cell in the DOX group compared to the DEX/DOX group

ALL, acute lymphoblastic leukaemia; CI, complex 1 – oxidative phosphorylation (OXPHOS) NADH; CIV, complex IV - oxidative phosphorylation (OXPHOS) cytochrome c oxidase activity; DEX, dexrazoxane; DOX, doxorubicin; mtDNA, mitochondrial DNA; OD, optical density 1. Lipshultz SE. Cancer 2016;122:946-53

Dexrazoxane blocks pathologic remodelling1,2

Dexrazoxane

NCI DFCI ALL 9501 Cohort:

LV thickness to dimension ratio

in patients treated with

doxorubicin

MaleFemale

*p-value ≤ 0.05 vs. Dexrazoxane +ALL, acute lymphoblastic leukaemia; LV, left ventricular; NCI DFCI, National Cancer Institute Dana-Farber Cancer Institute 1. Lipshultz SE et al. Nat Rev Clin Oncol 2013;10:697-710; 2. Lipshultz SE, et al. Lancet Oncol 2010;11:950-961

Dexrazoxane allows doxorubicin dose escalation without cardiotoxicity1

5.0

-2.5

-7.5

2.5

0.0

-5.0

0 20 40 60

Time from enrolment (weeks)

Both Groups Not Significantly Different from Normal

• No heart failure or clinical evidence of cardiotoxicity (≥ grade 3)

− Grade 1/2 LV dysfunction occurred in five patients

− Four had transient effects

− Grade 3 elevation of cardiac troponin in one patient

• No effect of dexrazoxane upon chemotherapy response rates

− All pilots exceeded expectations based on historical controls

600 mg/m2 doxorubicinNormal + 450 mg/m2 doxorubicin

Z s

co

re

LV fractional shortening

Study: NCI COG P9754

DOX: doxorubicin; LV, left ventricular1. Schwartz CL, … Lipshultz SE. Pediatr Blood Cancer 2016;63:54-61; 2. Lipshultz ER, et al. Am Soc Clin Oncol Educ Book. 2017;37:799-806. Oral presentation at the 2017 ASCO Annual meeting; Chicago, IL 2–6 June 2017.

Dexrazoxane facilitates the high cumulative dose of doxorubicin in patients with sarcoma1

• Heavily pretreated patients with sarcoma (median age 54 yrs;

range 18–68 yrs) received

dexrazoxane in dose escalation from 450 to 750 mg/m2 of

doxorubicin

• Patients were able to receive a median of 750 mg/m2 doxorubicin

• In all patients with benefit to the treatment, there was no need to discontinue doxorubicin due to cardiotoxicity

Cumulative anthracycline dosage

Cumulative dose per person

2000

1500

1000

500

0

Cu

mu

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ve a

nth

racyclin

e d

ose

Dexrazoxane co-administration

1. Schuler MK et al. BMC Cancer 2016:16:619

No dexrazoxane

The impact of dexrazoxane upon cardiac outcomes in anthracycline-treated ‘older’ patients with advanced/metastatic breast cancer1

1. Marty M, et al. Ann Oncol 2006;17:614–622

Dexrazoxane administered at both 20:1 (dox) and 10:1 (epi) in this study

Survival (months) Cumulative dose (mg/m2)

Control

Control

Dexrazoxane

% c

ard

iac e

ven

t-fr

ee s

urv

ival Dexrazoxane

% c

ard

iac e

ven

t-fr

ee s

urv

ival

The impact of dexrazoxane upon cardiac autonomic nervous system dysfunction in epirubicin-based adjuvant chemotherapy-treated breast cancer patients with diabetes

• All patients* exhibited decreased heart rate variability after epirubicin treatment,

suggesting that epirubicin impaired cardiac ANS activity

• However, this decrease was attenuated in patients receiving dexrazoxane,

indicating that dexrazoxane ameliorated the ANS dysfunction induced by epirubicin

Chemo, chemotherapy alone; Chemo+DRZ, chemotherapy+dexrazoxane group; DRZ, dexrazoxane; HF, high frequency; HRV, heart rate variability; LF, low frequency; Post-C, postchemotherapy; Pre-C, prechemotherapy; pNN50, percentage of the number of pairs of adjacent normal-to-normal interval difference

by >50 milliseconds; RHR,resting heart rate; RMSSD, root mean square of differences between adjacent normal-to-normal intervals; SDANN, standard deviation of the average of all normal-to-normal intervals; SDNN, standard deviation of all normal-to-normal intervals.

Patient age range: chemo alone: 55.25±±±±3.75 yrs; chemo+DRZ: 53.82±±±±4.99 yrs.∗∗∗∗P<0.05 versus respective prechemotherapy.† P<0.05, compared to Chemo.

Parameter Chemo (n=52) Chemo + DRZ (n=51)

Pre-C Post-C Pre-C Post-C

RHR 75.04 ± 12.63 92.47 ± 14.55* 77.86 ± 14.36* 84.37 ± 12.22*†

SDNN 121.02 ± 7.67 63.75 ± 5.43* 122.73 ± 6.25 92.37 ± 5.37*†

SDANN 103.29 ± 6.59 55.96 ± 3.86* 104.84 ± 7.22 73.27 ± 5.84*†

RMSSD 26.3 ± 4.65 13.04 ± 3.4* 26.00 ± 5.82 18.13 ± 3.82*†

pNN50 7.18 ± 1.17 2.62 ± 1.16* 7.33 ± 1.16 4.80 ± 1.20*†

LF 407.71 ± 28.52 235.27 ± 27.95* 410.53 ± 30.72 305.20 ± 28.93*†

HF 208.13 ± 25.94 80.12 ± 22.90* 202.27 ± 26.31 118.24 ± 20.04*†

LF/HF 1.99 ± 0.26 3.25 ± 1.22* 2.07 ± 0.35 2.63 ± 0.40*†

1. Sun F, et al. Medicine (Baltimore) 2016;95:e5228

10

The effects of dexrazoxane in high-risk patients with newly diagnosed or relapsed AML1

• A case series of 6 patients (aged 55–71 years) with newly diagnosed or

relapsed AML at high risk for cardiovascular morbidity

• All patients were treated with dexrazoxane in conjunction with

anthracycline-containing induction/ re-induction chemotherapy regimens

• No patient died from cardiac complications

• Three patients had eventual improvement in their LVEF post dexrazoxane

– all three patients underwent optimal heart failure management

AML, acute myeloid leukaemia; LVEF, left ventricular ejection failure1. Vachhani P, et al. Leuk Res Rep 2017;7:36-39

Strategies to reduce accelerated cardiovascular aging

• Dexrazoxane reduces anthracycline-related accelerated cardiac ageing

• All patients with cancer are at increased risk of cardiotoxicity regardless

of therapy

• Screening recommendations should apply to all cancer patients for

assessment of global risk of premature cardiovascular disease

• Modifiable risk factors should be actively managed

• Screening for genetic susceptibilities that place patients at high risk for

anthracycline cardiotoxicity, i.e. hemochromatosis gene mutations, may inform treatment decisions

• Encourage the use of dexrazoxane before anthracycline dosing for patients at higher risk of cardiotoxicity

Conclusions

• Cardiovascular-related health burden will increase as this expanding

population ages

• Cardiotoxicity associated with cancer therapeutics can be pervasive,

persistent, and progressive but missed clinically

• Persistent mitochondrial damage may relate to lifespan cardiotoxicity

• Dexrazoxane treatment before anthracycline dose is cardioprotective and

reduces cardiotoxicity

• Dexrazoxane allows anthracycline dose escalation without cardiotoxicity

• Tailored cardioprotective therapies (cocktails) are needed and may be

unique

Questions

Re-evaluating the role of dexrazoxane

November 11th

2017

Preparation and administration of Cardioxane®

For full details see Summary of Product Characteristics

Reconstitution

Dissolve the contents of each vial in 25ml of water for injections. Shake gently to dissolve the vial contents

Dilution

Each vial should be diluted prior to infusion using either Ringer lactate or 0.16M Sodium lactate (25ml or 100ml). It is preferable to use

solutions with a high pH.Cardioxane® is for single use only. Reconstituted and subsequently diluted Cardioxane® should be used immediately or within 4 hours if

stored between 2ºC and 8ºC.

Dosage and administration

Cardioxane® is administered by a short intravenous infusion (15 minutes), approximately 30 minutes prior to anthracycline

administration at a dose equal to 10 times either the doxorubicin-equivalent dose or the epirubicin-equivalent doseFor persons with moderate to

severe renal impairment administer 50% of normal dose