impact of age on efficacy and toxicity of nilotinib in ... · treatment of patients with chronic...
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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
Giles FJ, et al. Blood. 2015;126: Abstract 479.
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
Giles FJ, et al. Blood. 2015;126: Abstract 479.
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)
Giles FJ, et al. Blood. 2015;126: Abstract 479.
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
Giles FJ, et al. Blood. 2015;126: Abstract 479.
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
Giles FJ, et al. Blood. 2015;126: Abstract 479.
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
Giles FJ, et al. Blood. 2015;126: Abstract 479.
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
Giles FJ, et al. Blood. 2015;126: Abstract 479.
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
Giles FJ, et al. Blood. 2015;126: Abstract 479.
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
Giles FJ, et al. Blood. 2015;126: Abstract 479.
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
Giles FJ, et al. Blood. 2015;126: Abstract 479.
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
Giles FJ, et al. Blood. 2015;126: Abstract 479.
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
Young (n = 233) Adults (n = 482) Elderly (n = 289) Very elderly (n = 48)
Prop
ortio
n of
pat
ient
s (%
)
ENEST1st: Cumulative Rates of MR4.5 by 6, 12, 18, and 24 Months by Age Group
Giles FJ, et al. Blood. 2015;126: Abstract 479.
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
Young (n = 233) Adults (n = 482) Elderly (n = 289) Very elderly (n = 48)
Prop
ortio
n of
pat
ient
s (%
)
ENEST1st: Landmark Analysis: Cumulative Incidence of MR4 by BCR-ABL1IS Levels at 3 Months (n = 783)
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 , %
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
Giles FJ, et al. Blood. 2015;126: Abstract 479.
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
Giles FJ, et al. Blood. 2015;126: Abstract 479.
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
Giles FJ, et al. Blood. 2015;126: Abstract 479.
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
Giles FJ, et al. Blood. 2015;126: Abstract 479.
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
Giles FJ, et al. Blood. 2015;126: Abstract 479.