impact of age on efficacy and toxicity of nilotinib in ... · treatment of patients with chronic...

Impact of Age on Efficacy and Toxicity of Nilotinib in Patients

With Chronic Myeloid Leukemia in Chronic Phase (CML-CP): ENEST1st Sub-Analysis

Giles FJ, Rea D, Baccarani M, Cross NCP, Steegmann JL, Griskevicius L, le Coutre P, Coriu D, Petrov L, Ossenkoppele

GJ, Mahon F-X, Müller MC, Hellmann A, Porkka K, Brümmendorf TH, Gastl G, Pellegrino A, Dezzani L, Rosti G,

Hochhaus A for the ENEST1st investigators

Abstract 479

• Tyrosine kinase inhibitors (TKIs) are the standard of care for the treatment of patients with chronic myeloid leukemia (CML) and substantially improve the life expectancy of patients with early phase disease1-5

• Unlike all prior therapies, imatinib efficacy in chronic phase CML unaffected by age. Age not a component of the EUTOS score1-5

• The ENEST1st (NCT01061177) study was conducted to further examine the efficacy and toxicity of nilotinib in newly diagnosed CML-CP patients6

• An ENEST1st sub-analysis was conducted to assess the impact of age on molecular response (MR) and adverse events (AEs)

Introduction

1. Cortes J, et al. Cancer. 2003;98:1105–1113.2. Gugliotta G, et al. Blood. 2011;117:5591-5599. 3. Hasford J, et al. Blood. 2011; 118:686-692.4. Latagliata R, et al. Drugs Aging. 2013;30:629-37. 5. Sauselle S, et al. Blood. 2015;126:42-49. 6. Hochhaus A, et al. Leukemia. 2015. [Epub ahead of print]

Giles FJ, et al. Blood. 2015;126: Abstract 479.

Key eligibility criteria:Adults with newly diagnosed CML-CP ≤3 months prior imatinib and/or ≤6 months prior hydroxyurea allowedPh+ or Ph– BCR-ABL1+ CML-CP

Key exclusion criteria:WHO PS>2Known impaired cardiac function History of acute or chronic pancreatitisUncontrolled medical conditions like diabetes, active or uncontrolled infections, acute or chronic liver and renal diseaseImpaired gastrointestinal function

ENEST1st Study Design


Primary endpoint:MR4 at 18 monthsa

Nilotinib 300 mg BIDN = 1089

Nilotinib 300 mg BID

18 months 6 months

ENR

OLL

aMR4 was defined as detectable BCR-ABL1IS ≤ 0.01% or undetectable BCR-ABL1 in cDNA with ≥ 10,000 ABL1transcripts.

• Patients were enrolled from 307 sites in 26 European countries • All 1089 treated patients were included in the sub-analysis • For this subanalysis, patients were stratified according to age

at the time of study entry: – Young patients (18 to 39 years) n = 243 (22%)– Adult patients (40 to 59 years) n = 494 (45%)– Elderly patients (60 to 74 years) n = 300 (27%)– Very elderly patients (≥75 years) n = 52 (5%)

• Molecular responses were assessed every 3 months using RQ-PCR in standardized EUTOS laboratories

• OS and freedom from progression to AP/BP were estimated using Kaplan-Meier product limit estimates according to ITT principles

• Testing for glucose, cholesterol, and lipids was not routinely performed as it was not specified in the study protocol

ENEST1st: Methods


AU, Austria; BE, Belgium; CH, Switzerland; CR, Croatia; CZ, Czech Republic; DE, Denmark; ES, Estonia; GR, Greece; NL, The Netherlands; SK, Slovakia; SV, Slovenia.

Finland4

Sweden33

Norway12

Romania61

DE14

Poland66

CZ 16

Hungary35

AU 17

Germany258

NL 28BE30

France150

Italy154

UK28

GR10

CH 5

Spain100

Bulgaria21

SV 3

Lithuania15

SK 10

Latvia 3

ES 1

Portugal11

CR 4

13 2

12

14

6

57

9

4

8

11

10

13

ENEST1st: Map of Participating Countries and Network of EUTOS MR4

Laboratories (N = 1089 Patients Treated and Monitored)


Patients treated (n)EUTOS Laboratories and Contacts

1. Mannheim, Germany: Martin Müller

2. Leipzig, Germany:Thoralf Lange

3. Jena, Germany: Janine Ziermann,Andreas Hochhaus

4. Bordeaux, France: François-Xavier Mahon

5. Bologna, Italy: Michele Baccarani, Gianantonio Rosti

6. Naples, Italy: Fabrizio Pane

7. Turin, Italy: Giuseppe Saglio, Enrico Gottardi

8. London, UK: Letizia Foroni

9. Barcelona, Spain: Dolores Colomer

10. Vienna, Austria: Thomas Lion

11. Prague, Czech Republic: Katerina Polakova Machova

12. Krakow, Poland: Tomasz Sacha

13. Bern, Switzerland: Elisabeth Opplinger-Leibundgut

14. Bucharest, Romania: Daniel Coriu, Rodica Talmaci

Participating EUTOS laboratories

• Patients not in the molecular analysis population were distributed in the age groups as follow• 9 pts in young: 18 to 39 years • 10 pts in adults: 40 to 59 years old • 10 pts in elderly: 60 to 74 years old • 4 pts in very elderly: 75 or more years old

ENEST1st: Patients / Assessment Populations


Screening failure (n = 73)Enrolled (n = 1091)

ITT/safety population (N = 1089)Reason for exclusion:• Did not receive ≥ 1 dose of study drug (n = 2)

Molecular analysis population (n = 1052)Reason for exclusion:

• Typical BCR-ABL1 transcripts not detected at baseline (n = 33)*• Received > 3 mo imatinib therapy prior to enrollment (protocol

violation; n = 4)

Screened (n = 1164)

Young Patients(n = 243)

Adult Patients(n = 494)

Elderly Patients(n = 300)

Very Elderly Patients(n = 52)

ITT, intent-to-treat

ENEST1st: Demographics / Baseline Characteristics


ITT population (N = 1089)Median age (range), years 53 (18-91)Median time since diagnosis (range), mo 0.9 (< 0.1-6.6)a

Prior treatment for CML, n (%) 766 (70.3)Imatinib (< 3 months) 188 (17.3)Hydroxyurea (< 6 months) 576 (52.9)Other 2 (0.2)

Median prior treatment duration (range), mo 0.9 (0.1-7.6)a

EUTOS risk, n (%)Low 900 (82.6)High 94 (8.6)Missing 95 (8.7)

Sokal risk, n (%)Low 377 (34.6)Intermediate 408 (37.5)High 197 (18.1)Missing 107 (9.8)

BCR-ABL1 transcript type, n (%)b2a2 and/or b3a2 1056 (97.0)Otherb 16 (1.5)Inadequate sample, not evaluated, or not reported 17 (1.6)

aOne patient was pretreated with hydroxyurea while awaiting confirmation of CML diagnosis and, therefore, had a longerprior treatment duration than time since diagnosis. Four patients with > 3 mo of prior exposure to imatinib were excluded.

bIncluding e1a2, e19a2, e14a3, e18a2, e8a2, and e13a3.

ENEST1st: Demographics/Baseline Characteristics


aOne patient was pretreated with hydroxyurea while awaiting confirmation of CML diagnosis and, therefore, had a longer prior treatment duration than time since diagnosis. Four patients with > 3 mo of prior exposure to imatinib were excluded.

Figure: EUTOS score at baseline

Young (n = 243)

Adults (n = 494)

Elderly(n = 300)

Very elderly (n = 52)

Median age (range), years 32.0 (18.0, 39.0) 50.0 (40.0, 59.0) 66.0 (60.0, 74.0) 78.0 (75.0, 91.0)

Median time since diagnosis (range), monthsa 0.84 (0.07, 5.86) 0.92 (0.07, 6.61) 0.92 (0.03, 6.41) 0.86 (0.07, 6.02)

Mean (SD) spleen size 5.0 (6.2) 3.22 (4.9) 1.49 (2.8) 1.5 (3.1)

78.283.4 84

88.5

12.87.9 7.3 3.8

9.1 8.7 8.7 7.7

010

20

30

40

50

60

70

80

90

100

Young (n = 243) Adults (n = 494) Elderly (n = 300) Very elderly (n = 52)

Prop

ortio

n of

pat

ient

s (%

) Low High Missing

ENEST1st: Patient Disposition / Treatment Exposure


a Reasons for discontinuation are listed as reported by the investigator. b Withdrawal of consent was due to treatment failure in 2 (1.8%) patients.c Includes discontinuations due to protocol deviation (n = 11), loss to follow-up (n = 9), new cancer therapy (n = 9; CML [n = 7], and endometrial cancer and non-Hodgkin lymphoma [n = 1 each]), administrative problems (n = 4), abnormal test procedure results (n = 4), and death (n = 4). d Excluding periods of drug interruption.

Patients, n (%)Safety

population (N = 1089)

Completed ≥ 24 mo of treatment 881 (80.9)Discontinued treatmenta 208 (19.1)

AEs 117 (10.7)

Withdrew consentb 27 (2.5)

Disease progression/treatment failure 17 (1.6)

Abnormal laboratory value 6 (0.6)

Otherc 41 (3.8)

Median duration of exposure (25th-75th percentile), daysd 722 (691-734)

Median dose intensity (25th-75th percentile), mg/day 600 (588-600)

ENEST1st: Treatment Exposure by Age Group


13.2

15.4 15.3

11.5

6.2 6.16.7

9.69.9

8.1 8

5.8

0

2

4

6

8

10

12

14

16

18

Young (n = 243) Adults (n = 494) Elderly (n = 300) Very Elderly (n = 52)

1 dose reduction 2 dose reductions >2 dose reductions

Prop

ortio

n of

pat

ient

s (%

)

ENEST1st: Rates of MMR, MR4, and MR4.5 at 3, 12, 18, and 24 Months


Patie

nts,

%a

Primary endpoint

56.3

30.8

15.3

65.8

38.4

20.9

61.2

40.4

22.0

At 3 mo At 12 mo At 18 mo At 24 mo

29.7

6.31.9

MR4

MR4.5

MMR

MMR, major molecular response (BCR-ABL1IS ≤ 0.1%); MR4.5, detectable BCR-ABL1IS ≤ 0.0032% or undetectable BCR-ABL1in cDNA with ≥ 32,000 ABL1 transcripts.a Molecular analysis population (n = 1052)

ENEST1st: Cumulative Incidence of MMR, MR4, and MR4.5


MMRMR4

MR4.5

68.9%

77.2% 80.4%

37.1%

48.7%55.2%

20.7%

31.7%38.6%

100

Cum

ulat

ive

Inci

denc

e of

Res

pons

e, %

a

Time Since Study Entry, mo

90

80

70

60

50

40

30

20

10

00 3 6 9 12 15 18 21 24

By 12 mo By 18 mo By 24 mo

a Molecular analysis population (n = 1052).

ENEST1st: Cumulative Rates of MR4 by 6, 12, 18, and 24 Months by Age Group


12.4

28.8

42.1

50.2

16.2

39.2

49.8

57.1

15.9

39.8

52.957.4

12.5

39.643.8

47.9

0.0

10.0

20.0

30.0

40.0

50.0

60.0

70.0

80.0

90.0

100.0

6 months 12 months 18 months 24 months

Time Since Study Entry


Prop

ortio

n of

pat

ient

s (%

)

ENEST1st: Cumulative Rates of MR4.5 by 6, 12, 18, and 24 Months by Age Group


5.2

15.9

27.5

35.6

6.2

21.8

33.2

39.4

6.9

22.1

32.9

39.8

2.1

25.0

31.3

37.5

0.0

10.0

20.0

30.0

40.0

50.0

60.0

70.0

80.0

90.0

100.0

6 months 12 months 18 months 24 months

Time Since Study Entry


Prop

ortio

n of

pat

ient

s (%

)

ENEST1st: Landmark Analysis: Cumulative Incidence of MR4 by BCR-ABL1IS Levels at 3 Months (n = 783)


Time Since Study Entry, mo

70

60

50

40

20

10

0 9 12 15 18 210

30

24

80

90

100

63

Cum

ulat

ive

Inci

denc

e of

MR

4 , %

By 12 mo By 24 moBy 18 mo

47.0%

59.0%67.6%

8.3%

0%

20.0%24.1%

0% 0%

BCR-ABL1IS ≤ 1% at 3 mo (n = 615)

BCR-ABL1IS > 1% to ≤ 10% at 3 mo(n = 145)

BCR-ABL1IS > 10% at 3 mo (n = 23)

ENEST1st Landmark Analysis: Cumulative Incidence of MR4.5 by BCR-ABL1IS Levels at 3 Months

Giles FJ, et al. Blood. 2015;126: Abstract 479.Time Since Study Entry, mo

70

60

50

40

20

10

0 9 12 15 18 210

30

24

80

90

100

63

Cum

ulat

ive

Inci

denc

e of

MR

4.5 ,

%

By 12 mo By 24 moBy 18 mo

26.5%

39.5%47.0%

4.1%9.0%

14.5%

0%0%0%

BCR-ABL1IS ≤ 1% at 3 mo (n = 615)

BCR-ABL1IS > 1% to ≤ 10% at 3 mo(n = 145)

BCR-ABL1IS > 10% at 3 mo (n = 23)

ENEST1st: Most Frequent Adverse Events by Age Groupa


aAEs reported in ≥ 10% of patients at any grade in any groupALT, alanine aminotransferase

21.4 21

14.8 14.8 13.6 13.6 12.811.1 10.7 10.3 10.3

24.9

17.4

8.9 9.3

16.815 15.4

9.9 10.57.3

11.9

17.3

8.310.3 9.3

18.315

13.7

36.3 5.7

8

11.5

7.73.8

5.8

17.315.4

5.8

1.93.8 3.8

13.5

0

10

20

30

40

Prop

ortio

n of

pat

ient

s (%

)

Young (n=243) Adults (n=494) Elderly (n=300) Very Elderly (n=52)

ENEST1st: Adverse Events by Age Group


11.5

3.7

2.10.8 0.8 0.8

0 0.4 0.4

10.5

4.3

1.21.6

0.2

5.3

0.4

4.5

0.8

14.3

5

1.3 1.71

10

0.7

4.3

1.7

11.5

0 0

3.8

0

13.5

7.7 7.7

1.9

0

2

4

6

8

10

12

14

16

Pro

porti

on o

f pat

ient

s (%

)

Young (n=243) Adults (n=494) Elderly (n=300) Very Elderly (n=52)

ENEST1st: Cardiovascular Adverse Events by Age Group


Young (n = 243)

Adults(n = 494)

Elderly (n = 300)

Very elderly (n = 52)

P value by Fisher's Exact

Test*Cardiovascular events 2 (0.8%) 26 (5.3%) 30 (10%) 7 (13.5%) <.0001Ischemic heart disease (IHD) 1 (0.4%) 14 (2.8%) 17 (5.7%) 5 (9.6%) .0002

Peripheral arterial occlusive disease 1 (0.4%) 9 (1.8%) 9 (3.0%) 1 (1.9%) .12

Ischemic cerebrovascular event 0 4 (0.8%) 4 (1.3%) 1 (1.9%) .19

Overall test is significant at

P < .05

*P values provided are nominal, post hoc, and provided for descriptive purpose only; no multiplicity adjustments were made

• 6 patients (0.6%) (2 in young patient group and 4 in adult patient group) progressed to AP/BP on study

• 13 patients (1.2%) died on study (5 in adult patients group, 5 in elderly patients group and 3 in very elderly patients group)

• 1 patient died of CMLb

• 12 patients died due to other causes, including infections (n = 4), secondary cancers (n = 3), heart failure (n = 2), and one each due to pulmonary embolism, cerebral infarction, and thrombocytopenia considered not due to CML

ENEST1st: Progression and Survival


KM-estimated rate at 24 mo, % (95% CI) ITT population(N = 1089)

Freedom from progression to AP/BPa 99.4 (98.7-99.7) Overall survival 98.9 (98.0-99.4)

KM, Kaplan-Meier. aFreedom from progression to AP/BC considered only transformation events (deaths unrelated to CML were excluded).bLaboratory data to confirm progression to AP/BP not provided by the investigator.

• According to the EUTOS score, high-risk CML more frequent among younger patients

• Molecular response rates and rates of progression to AP/BP were comparable across age groups

• The distribution of some AEs was significantly different depending on age

• Understanding of variations in disease characteristics and TKI AE profiles in terms of patient age may help in improving CML therapy

ENEST1st Sub-Analysis on Age Effect Conclusions


impact of age on efficacy and toxicity of nilotinib in ... · treatment of patients with chronic...

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