VOLUME 36 • NUMBER 13 • MAY 1, 2018

JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R T

Dasatinib in Pediatric Patients With Chronic Myeloid

Leukemia in Chronic Phase: Results From a Phase II Trial
Lia Gore, Pamela R. Kearns, Maria Lucia de Martino Lee, Carmino Antonio De Souza, Yves Bertrand, Nobuko
Hijiya, Linda C. Stork, Nack-Gyun Chung, Rocio Cardenas Cardos, Tapan Saikia, Franca Fagioli, Jong Jin Seo,
Judith Landman-Parker, Donna Lancaster, Andrew E. Place, Karen R. Rabin, Mariana Sacchi, Rene Swanink, and
C. Michel Zwaan

Author affiliations and support information

(if applicable) appear at the end of this A B S T R A C T
article.
Purpose
Published at jco.org on March 2, 2018.
Safe, effective treatments are needed for pediatric patients with chronic myeloid leukemia in chronic
Corresponding author: Lia Gore, MD, phase (CML-CP). Dasatinib is approved for treatment of adults and children with CML-CP. A phase I
University of Colorado Anschutz Medical
Campus, Children’s Hospital Colorado,
study determined suitable dosing for children with Philadelphia chromosome–positive (Ph+)
Center for Cancer and Blood Disorders, leukemias.
13123 East 16th Ave, Box B115, Aurora,
Methods
CO 80045; e-mail: Lia.Gore@ucdenver.
edu.
CA180-226/NCT00777036 is a phase II, open-label, nonrandomized prospective trial of patients , 18
years of age receiving dasatinib. There are three cohorts: (1) imatinib-resistant/intolerant CML-CP, (2)
© 2018 by American Society of Clinical
Oncology
imatinib-resistant/intolerant CML in accelerated/blast phase or Ph+ acute lymphoblastic leukemia
(n = 17), and (3) newly diagnosed CML-CP treated with tablets or powder for oral suspension. Major
0732-183X/18/3613w-1330w/$20.00
cytogenetic response . 30% for imatinib-resistant/intolerant patients and complete cytogenetic
response (CCyR) . 55% for newly diagnosed patients were of clinical interest.
Results
Of 113 patients with CML-CP, 14 (48%) who were imatinib-resistant/intolerant and 61 (73%) who
were newly diagnosed remained on treatment at time of analysis. Major cytogenetic response
. 30% was reached by 3 months in the imatinib-resistant/intolerant group and CCyR . 55% was
reached by 6 months in the newly diagnosed CML-CP group. CCyR and major molecular response
by 12 months, respectively, were 76% and 41% in the imatinib-resistant/intolerant group and
92% and 52% in newly diagnosed CML-CP group. Progression-free survival by 48 months was
78% and 93% in the imatinib-resistant/intolerant and newly diagnosed CML-CP groups, re-
spectively. No dasatinib-related pleural or pericardial effusion, pulmonary edema, or pulmonary
arterial hypertension were reported. Bone growth and development events were reported in 4%
of patients.
Conclusion
In the largest prospective trial to date in children with CML-CP, we demonstrate that dasatinib is
a safe, effective treatment of pediatric CML-CP. Target responses to first- or second-line dasatinib
were met early, and deep molecular responses were observed. Safety of dasatinib in pediatric
patients was similar to that observed in adults; however, no cases of pleural or pericardial effusion or
pulmonary arterial hypertension were reported.

J Clin Oncol 36:1330-1338. © 2018 by American Society of Clinical Oncology

larger spleen size, higher peripheral blasts counts,

INTRODUCTION
and lower hemoglobin levels.2 However, there are
conflicting reports about the prognostic relevance
Although chronic myeloid leukemia (CML) ac- of these variables on outcomes in children.3-5
ASSOCIATED CONTENT
counts for , 5% of leukemias and , 1% of all The development of safe and effective
cancers in patients , 20 years of age,1 more ag- therapies for pediatric CML is critical for the
Data Supplement
DOI: https://doi.org/10.1200/JCO.
gressive disease characteristics have been observed successful treatment of this patient population.
2017.75.9597 in pediatric and young adult patients with CML Until recently, the BCR-ABL1–target tyrosine
DOI: https://doi.org/10.1200/JCO.2017. compared with older adults, including higher kinase inhibitor (TKI) imatinib was the only TKI
75.9597 median white blood cell counts, proportionally approved for front-line treatment of pediatric

1330 © 2018 by American Society of Clinical Oncology

 Dasatinib in Children and Adolescents With CML-CP

patients with CML in chronic phase (CML-CP)6; however, 25% to patients with CML-CP resistant to or intolerant of imatinib who received
29% discontinue as a result of poor response or toxicity.7,8 In addition, dasatinib tablets 60 mg/m2 once daily; (2) patients with accelerated- or
there were no approved therapies to treat children with imatinib- blastic-phase CML (CML-AP/BP) or Ph+ acute lymphoblastic leukemia
(ALL) resistant to or intolerant of imatinib who received dasatinib tablets
resistant/intolerant CML-CP. There is also a need for formulations of
80 mg/m2 once daily; and (3) patients with CML-CP newly diagnosed who
TKIs for younger patients who are unable to swallow tablets.9 received either dasatinib tablets 60 mg/m2 once daily or PFOS 72 mg/m2
Dasatinib is a second-generation TKI that is now approved in once daily for $ 12 months; patients were then allowed to switch to tablets.
tablet formulation for the treatment of pediatric patients with PFOS dose was increased by 20% (to 72 mg/m2) to match the exposure of
CML-CP.10 Previously, dosing and safety of dasatinib in pediatric the 60 mg/m2 tablet on the basis of bioavailability data in adults. Detailed
patients were determined in phase I trials.11,12 Here, we present inclusion and exclusion criteria are listed in the Data Supplement.
results from a phase II prospective trial to further evaluate safety Patients could receive dasatinib until disease progression, un-
acceptable toxicity, or patient/physician preference. Patients who dis-
and efficacy of dasatinib tablet and powder for oral suspension continued therapy were followed yearly for survival, effects on growth and
(PFOS) formulations in pediatric patients with CML-CP. development, and effects on bone metabolism up to 5 years after the last
dasatinib dose. The protocol was approved by all institutional review
boards, ethics committees, and national competent authorities at par-
ticipating sites. All patients and/or legal guardians gave written informed
METHODS consent and assent where applicable in accordance with the Declaration of
Helsinki and local guidelines.
Study Design
Study CA180-226 is an ongoing phase II, open-label, non-
randomized, multicenter trial investigating dasatinib in pediatric patients Evaluations
with Philadelphia chromosome–positive (Ph+) leukemia (ClinicalTrials. Primary objectives were to determine major cytogenetic response
gov identifier: NCT00777036). Patients , 18 years of age (the protocol was (MCyR) for patients with imatinib-resistant/intolerant CML-CP, complete
amended 9 months after enrollment started to change inclusion criteria hematologic response (CHR) for patients with imatinib-resistant/intolerant
from , 21 to , 18 years) were enrolled in three cohorts (Fig 1): (1) CML-AP/BP or Ph+ ALL, and complete cytogenetic response (CCyR) for

Enrolled
(N = 145)

Excluded (n = 15)
• Failure to meet study criteria (n = 11)
• Patient withdrawal (n = 2)
• Death (n = 1)
• Other reason (n = 1)

Treated
(n = 130)

Imatinib-resistant/intolerant CML-CP Imatinib-resistant/intolerant Newly diagnosed CML-CP treated

Newly diagnosed CML-CP treated with dasatinib 72 mg/m2
treated with dasatinib tablets CML-AP/BP or Ph+ ALL treated with 2
2 2 with dasatinib tablets 60 mg/m once daily PFOS once daily*
60 mg/m once daily dasatinib tablets 80 mg/m once daily
(n = 51) (n = 33)
(n = 29) (n = 17)

Receiving treatment (n = 14)

Receiving treatment (n = 37) Receiving treatment (n = 24)
Discontinued treatment (n = 15)
Discontinued treatment (n = 14) Discontinued treatment (n = 9)
Progressive disease (n = 5)
Enrollment closed Progressive disease (n = 5) Progressive disease (n = 1)
Patient withdrawal (n = 3)
early as a result of Patient withdrawal (n = 2) Study drug toxicity (n = 1)
Maximum clinical benefit (n = 2)
poor response Maximum clinical benefit (n = 1) Patient withdrawal (n = 1)
Noncompliance with study drug (n = 1) ‡ §
† Other reason (n = 6) Other reason (n = 6)
Other reason (n = 4)

Entered follow-up (n = 14)

Ended follow-up (n = 5)
Entered follow-up (n = 14)
Death (n = 1) Entered follow-up (n = 9)
Ended follow-up (n = 4)
Patient withdrawal (n = 1) Ended follow-up (n = 0)
Patient withdrawal (n = 4)
Lost to follow-up (n = 1)
ǁ
Other reason (n = 2)

Fig 1. CONSORT diagram of study CA180-226. (*)Patients had the option to switch to dasatinib tablets 60 mg/m2 once daily after 1 year of receiving PFOS. (†)Other
includes bone marrow transplant, allogenic bone marrow graft, suboptimal response, and patient lost to follow-up. (‡)Other includes T315I mutation, loss of major
molecular response, investigator decision, loss of complete cytogenetic response (n = 2), and hematopoietic stem cell transplant (n = 2). (§)Other includes hematopoietic
stem cell transplant (n = 2), suboptimal response, second malignancy, and transition to adult hospital (n = 2). (ǁ)Other includes transfer to adult hospital and bone marrow
transplant. CML-AP/BP, chronic myeloid leukemia in accelerated/blast phase; CML-CP, chronic myeloid leukemia in chronic phase; PFOS, powder for oral suspension; Ph+
ALL, Philadelphia chromosome-positive acute lymphoblastic leukemia.

jco.org © 2018 by American Society of Clinical Oncology 1331

 Gore et al

Table 1. Baseline Patient Characteristics

Dasatinib-Treated Patients (n = 113)
Newly Diagnosed CML-CP
Imatinib-Resistant/Intolerant
Characteristic CML-CP (n = 29) Tablets (n = 51) PFOS (n = 33) Total (n = 84)
Age, years, median (range)* 13.77 (1.4-20.1) 12.87 (1.9-17.8) 11.70 (1.8-17.5) 12.33 (1.8-17.8)
Age, years, No. (%)*
,2 1 (3) 1 (2) 1 (3) 2 (2)
$ 2 to , 7 3 (10) 5 (10) 5 (15) 10 (12)
$ 7 to , 12 6 (21) 16 (31) 12 (36) 28 (33)
$ 12 to , 18 17 (59) 29 (57) 15 (45) 44 (52)
Sex, No. (%)
Male 13 (45) 26 (51) 19 (58) 45 (54)
Female 16 (55) 25 (49) 14 (42) 39 (46)
Reason for stopping prior imatinib, No.
Resistance 25 NA NA NA
Intolerance 2 NA NA NA
Undetermined† 2 NA NA NA
Patients with prior therapy, No. (%)
Stem cell transplant 1 (3) 0 0 0
Interferon 4 (14) 1 (2) 0 1 (1)
Hydroxyurea or anagrelide 14 (48) 23 (45) 10 (30) 33 (39)
Chemotherapy‡ 3 (10) 0 0 0
Median time from initial CML diagnosis to first dasatinib dose, 27.66 (3.0-33.9) 0.69 (0-3.5) 0.46 (0.1-1.4) 0.61 (0-3.5)
months (range)

Abbreviations: CML-CP, chronic myeloid leukemia in chronic phase; NA, not applicable; PFOS, powder for oral suspension.
*Two patients with imatinib-resistant/intolerant CML-CP were $ 18 years old and were allowed to continue in study despite not meeting enrollment criteria for age.
†Investigator reported the protocol eligibility criteria with regard to imatinib resistance and/or intolerance were not fully met.
‡Limited to cytostatic and antineoplastic agents.

patients with newly diagnosed CML-CP at any time. MCyR . 30% for this cohort was closed after 17 patients were enrolled. Discussion of
imatinib-resistant/intolerant CML-CP, CHR . 15% for imatinib-resistant/ these data are not included in this report.
intolerant CML-AP/BP or Ph+ ALL, and CCyR . 55% for newly diagnosed Baseline characteristics for the cohorts of CML-CP are in
CML-CP were considered of clinical interest and align with historic re-
Table 1. With $ 24 months of follow-up, 14 patients (48%) with
sponses in pediatric patients with CML-CP.7,8 Secondary objectives
included assessments of safety and evaluation of best cytogenetic and CML-CP resistant to or intolerant of imatinib and 61 patients
hematologic response, time to and duration of response, disease-free (73%) with newly diagnosed CML-CP were still receiving study
survival, progression-free survival (PFS), overall survival (OS), complete treatment. Reasons for exclusion and discontinuation are listed in
molecular response (CMR), and major molecular response (MMR). The Fig 1. Most patients received the protocol-recommended daily dose
description of BCR-ABL1 mutations at baseline (results of which were not of dasatinib (Table 2). Patients who were initiated on PFOS were
available before start of study treatment), progression, treatment failure, or allowed to switch to tablets after receiving PFOS for $ 1 year. Of
end of treatment, and the exploration of the role of mutations as predictors
of response were also secondary objectives. The database lock for this
the 33 patients receiving PFOS, 22 (67%) switched to tablets
analysis was November 2016. Detailed definitions of efficacy outcomes, because of patient preference. Greater than 38% of patients re-
safety assessments, mutational analysis, and statistical methodology can be quired at least one dose interruption, primarily because of dosing
found in the Data Supplement. errors and hematologic toxicity (Table 2). Less than 25% of pa-
tients required dose reductions or escalations.

RESULTS Efficacy
Rates of confirmed CHR (cCHR) achieved at any time on
Patients and Treatments treatment were 93% (95% CI, 77.2 to 99.2) and 96% (95% CI, 89.9
In total, 145 patients were enrolled between March 2009 and to 99.3) for patients resistant to or intolerant of imatinib or those
September 2014. Of these, 130 were treated across three cohorts newly diagnosed, respectively. Median time to cCHR was 0.7 months
(Fig 1): 29 with imatinib-resistant/intolerant CML-CP, 17 with (95% CI, 0.5 to 1.8) for patients resistant to or intolerant of imatinib
imatinib-resistant/intolerant CML-AP/BP or Ph+ ALL, and 84 and 1.2 months (95% CI, 0.9 to 1.4) for newly diagnosed patients.
with newly diagnosed CML-CP. Newly diagnosed patients were The cumulative rate of MCyR . 30% was reached as early as
either treated with dasatinib tablets (n = 51) or PFOS for 3 months for patients with imatinib-resistant/intolerant CML-CP,
$ 12 months (n = 33). Given the observed poor response of patients and the cumulative rate of CCyR . 55% was reached as early as
with imatinib-resistant/intolerant CML-AP/BP or Ph+ ALL (CHR 6 months for patients with newly diagnosed CML-CP (Fig 2).
was achieved at any time by one of eight patients with CML-BP and Rapid responses were illustrated by a median time to MCyR of
four of nine patients with Ph+ ALL), and that single-agent TKIs are 3.1 months (95% CI, 2.8 to 4.1) for those in the imatinib-resistant/
now considered substandard of care for this pediatric population, intolerant group and 3.0 months (95% CI, 2.9 to 4.3) for newly

1332 © 2018 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY

 Dasatinib in Children and Adolescents With CML-CP

Table 2. Dasatinib Exposure During Study

Dasatinib-Treated Patients (n = 113)
Newly Diagnosed CML-CP
Imatinib-Resistant/Intolerant
Characteristic CML-CP (n = 29) Tablets (n = 51) PFOS (n = 33) Total (n = 84)
Average daily dose, mg/m2, median (range) 58.18 (35.1-71.7) 58.54 (37.2-77.9) 64.59 (38.3-98.7) 59.84 (37.2-98.7)
Duration of therapy, months, median (range) 49.91 (1.9-90.2) 52.24 (7.6-75.2) 27.40 (0.1-42.0) 42.30 (0.1-75.2)
Relative dose intensity, No. (%)
50 to , 70 3 (10) 2 (4) 6 (18) 8 (10)
70 to , 90 4 (14) 13 (25) 11 (33) 24 (29)
90 to , 110 19 (66) 33 (65) 15 (45) 48 (57)
$ 110 3 (10) 3 (6) 1 (3) 4 (5)
Patients with $ 1 dose interruption, No. (%) 21 (72) 31 (61) 13 (39) 44 (52)
Dosing error 8 (28) 6 (12) 3 (9) 9 (11)
Hematologic toxicity 5 (17) 13 (25) 6 (18) 19 (23)
Nonhematologic toxicity 6 (21) 9 (18) 4 (12) 13 (15)
Other 2 (7) 3 (6) 0 3 (4)
Duration of first interruption, days, median (range) 8 (2-34) 11 (2-35) 11 (4-19) 11 (2-35)
Patients with $ 1 dose reduction, No. (%) 7 (24) 6 (12) 2 (6) 8 (10)
Dosing error 1 (3) 0 0 0
Hematologic toxicity 3 (10) 4 (8) 2 (6) 6 (7)
Nonhematologic toxicity 3 (10) 2 (4) 0 2 (2)
Patients with $ 1 dose escalation, No. (%) 7 (24) 9 (18) 5 (15) 14 (17)
Resistance 4 (14) 7 (14) 3 (9) 10 (12)
Other 3 (10) 2 (4) 1 (3) 3 (4)
No change 0 0 1 (3) 1 (1)
Follow-up, months, median (range) 62.4 (8.0-90.9) 54.3 (16.0-76.6) 32.5 (5.2-42.4) 48.4 (5.2-76.6)

Abbreviations: CML-CP, chronic myeloid leukemia in chronic phase; PFOS, powder for oral suspension.

diagnosed patients, and a median time to CCyR of 3.9 months imatinib and seven of 84 newly diagnosed patients (8%) had
(95% CI, 2.8 to 5.6) for patients in the resistant/intolerant CML- progressed at the time of analyses (Data Supplement). Protocol-
CP group and 5.6 months (95% CI, 5.0 to 6.0) for newly diagnosed defined reasons for progression were loss of MCyR (n = 3 in the
patients (Table 3). Cumulative cytogenetic response rates increased imatinib-resistant/intolerant group; n = 4 newly diagnosed pa-
over time through 24 months, the minimum follow-up for this tients), loss of CHR (n = 2 in each group), and development of
analysis (Fig 2). In both cohorts, rates of MCyR increased between CML-BP (n = 2 in the imatinib-resistant/intolerant group; n = 1 in
3 and 12 months and were maintained through 24 months. For the newly diagnosed group). Estimated 48-month PFS was 78%
patients with CML-CP resistant to or intolerant of imatinib, rates and 93% for patients with CML-CP resistant to or intolerant of
of CCyR consistently increased. Median durations of cytogenetic imatinib and patients with newly diagnosed CML-CP, respectively
responses were not reached by the time of analysis (Table 3). (Data Supplement). Similar results were observed for disease-free
Additional assessments were performed to determine the survival (Data Supplement). One death was reported: a patient with
rates of cytogenetic responses at any time, excluding patients with CML-CP resistant to or intolerant of imatinib died of gastroin-
MCyR/CCyR or unknown cytogenetic status at baseline. The testinal bleeding 1 year after stopping dasatinib. This patient had loss
results from these assessments were similar to the results cal- of MCyR before death. There were no deaths reported for patients
culated using the total number of patients in each cohort (Data with newly diagnosed CML-CP. The estimated 48-month OS rate
Supplement). was 96% in the imatinib-resistant/intolerant CML-CP cohort.
Although they were not focal study end points, the cumulative A post hoc analysis of the proportion of patients with BCR-
rates of MMR and CMR were also observed to increase over time in ABL1 # 10% versus . 10% at 3 months was performed for the
all cohorts (Fig 3). By 12 months, MMR was 41% and CMR was newly diagnosed cohort. Of the 77 patients with evaluable tran-
7% for patients with imatinib-resistant/intolerant CML-CP, and by script levels at 3 months, 60 (78%) had BCR-ABL1 # 10% and 17
24 months, MMR was 55% and CMR was 17% (Figs 3A and 3C). (22%) had BCR-ABL1 . 10%. PFS appeared to be higher for newly
MMR and CMR were 52% and 8%, respectively, by 12 months and diagnosed patients with BCR-ABL1 # 10% versus those with BCR-
70% and 21%, respectively, by 24 months for the total newly ABL1 . 10% at 3 months (P , .001; hazard ratio, 0.10; 95% CI,
diagnosed patient population (Figs 3B and 3D). Cohorts in this 0.02 to 0.52); estimated 3-year PFS rates were approximately 97%
study were not designed to be comparative; however, response rates and 82% for patients with BCR-ABL1 # 10% or . 10% at
appeared to be lower for patients taking the PFOS formulation 3 months, respectively.
versus tablets. Median time to MMR was 8.9 months (95% CI, 8.1 BCR-ABL1 mutations were assessed at baseline and at the time
to 11.7) for newly diagnosed patients and was not calculated for the of disease progression, treatment failure, or end of treatment. In
imatinib-resistant/intolerant cohort. the imatinib-resistant/intolerant cohort, six of 27 patients (22%)
Median PFS and OS have not been reached in any cohort. evaluated at baseline had a mutation (E255K, F317L, F359V
Disease is seven of 29 patients (24%) resistant to or intolerant of [n = 2], V379I, Y253H); five were in cCHR. Of nine patients with

jco.org © 2018 by American Society of Clinical Oncology 1333

 Gore et al

A
100

80
MCyR, % (95% CI)

60

40 MCyR >30%
rate of clinical
interest
20

0
3 12 24 3 12 24 3 12 24 3 12 24
Months Imatinib-resistant/ Tablets (n = 51) PFOS (n = 33) Total (n = 84) Fig 2. Cytogenetic responses over time
intolerant for all treated patients. (A) Cumulative rates
CML-CP (n = 29) Newly Diagnosed CML-CP of MCyR and (B) cumulative rates of CCyR.
CCyR, complete cytogenetic response;
CML-CP, chronic myeloid leukemia in chronic
phase; MCyR, major cytogenetic response;
B 100 PFOS, powder for oral suspension.

80
CCyR, % (95% CI)

60 CCyR > 55%

rate of clinical
interest
40

20

0
3 6 12 24 3 6 12 24 3 6 12 24 3 6 12 24
Months Imatinib-resistant/ Tablets (n = 51) PFOS (n = 33) Total (n = 84)
intolerant
CML-CP (n = 29) Newly Diagnosed CML-CP

assessments at end of treatment, three had a mutation (E255K, only. This patient was receiving dasatinib tablets and had cCHR.
F317L, T315A). The patients with the E255K and F317L mutations There were no mutations detected in the seven patients newly
had the same mutation at baseline and end of treatment. No patient diagnosed with CML-CP who were evaluated at end of treatment.
in this cohort had more than one mutation. Mutations in BCR-
ABL1 at T315, F317, and V299 are now considered resistant to
dasatinib,13 which was not fully understood when this trial began. Safety
Of the 78 patients with newly diagnosed CML-CP evaluated at The dasatinib-related adverse events (AEs) of special interest
baseline, one had a P58S mutation that was found in leukemia cells reported in this study are listed in Table 4. There were no occurrences

Table 3. Time To and Duration of Response in Patients Treated With Dasatinib

Median Time to Response* Median Duration of Response*
Patient Group MCyR CCyR MCyR CCyR
Imatinib-resistant/intolerant CML-CP (n = 29) 3.1 (2.8 to 4.1) 3.9 (2.8 to 5.6) NE (54.9 to NE) NE (54.9 to NE)
Newly diagnosed CML-CP
Tablets (n = 51) 3.3 (2.9 to 5.6) 5.7 (3.7 to 6.2) NE (52.7 to NE) NE (49.9 to NE)
PFOS (n = 33) 3.0 (2.8 to 5.0) 5.6 (3.1 to 6.0) NE (NE to NE) NE (NE to NE)
Total (n = 84) 3.0 (2.9 to 4.3) 5.6 (5.0 to 6.0) NE (52.7 to NE) NE (49.9 to NE)

NOTE. Values are months (95% CI).

Abbreviations: CCyR, complete cytogenetic response; CML-CP, chronic myeloid leukemia in chronic phase; MCyR, major cytogenetic response, NE, not estimable,
median not reached; PFOS, powder for oral suspension.
*For patients who had a best response of CCyR or MCyR.

1334 © 2018 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY

 Dasatinib in Children and Adolescents With CML-CP

A B
100 100
90 90 75%
70%
80 80 64%
57%
70 70
52%
MMR (%)

MMR (%)
60 55% 60 45%

50 50
41%
40 40
30 30
Tablets
20 20
PFOS
10 Tablets
10 Total

0 6 12 18 24 30 36 42 48 0 6 12 18 24 30 36 42 48
Months Months
C D
100 100
Tablets
90 90 PFOS
80 80 Total

70 70
CMR (%)

60
CMR (%) 60
50 50 29%
40 40 21%
9%
30 30 10%
17% 8%
20 20
6%
7%
10 Tablets
10

0 6 12 18 24 30 36 42 48 0 6 12 18 24 30 36 42 48
Months Months
Fig 3. Cumulative rates of molecular responses over time for all treated patients. (A, B) MMR for (A) patients with CML-CP resistant to or intolerant of imatinib and (B)
patients with newly diagnosed CML-CP. (C, D) CMR for (C) patients with CML-CP resistant to or intolerant of imatinib and (D) patients with newly diagnosed CML-CP.
Cohorts were not designed to be comparative. There are numerical differences between MMR and CMR in newly diagnosed patients with CML-CP treated with dasatinib
tablets or PFOS, but CIs overlap. CML-CP, chronic myeloid leukemia in chronic phase; CMR, complete molecular response; MMR, major molecular response; PFOS,
powder for oral suspension.

of pleural effusion, pericardial effusion, pulmonary edema,

DISCUSSION
pulmonary hypertension, or pulmonary arterial hypertension
related to dasatinib in pediatric patients with CML-CP. In
patients with imatinib-resistant/intolerant CML-CP and newly CA180-226 is the largest prospective, registrational trial to date in
diagnosed patients, any-grade myalgia or arthralgia occurred in pediatric patients diagnosed with CML. With $ 24 months of
17% and 10%, respectively, and fatigue occurred in 14% and follow-up, high response rates and a favorable safety profile for
11%, respectively. Dasatinib-related pediatric bone growth and dasatinib were demonstrated in patient with imatinib-resistant/
development AEs were grouped together for reporting pur- intolerant CML-CP and those newly diagnosed with CML-CP.
poses. Grade 1/2 events were reported in five of 113 patients This study was designed to explore the most clinically relevant
(4%) with CML-CP. Data on growth and development continue end points for patients with CML at the time the protocol was
to be collected and will be reported once mature. developed in 2008: MCyR and CCyR. Overall, the efficacy of
Dasatinib-related serious AEs were reported in five pa- dasatinib in pediatric patients in this trial was similar to or higher
tients (17%) with imatinib-resistant/intolerant CML-CP and than that historically observed in adults. In a phase III dose-
eight patients (10%) with newly diagnosed CML-CP (Table 4). optimization trial of adults with imatinib-resistant/intolerant
No suspected, unexpected serious adverse reactions were re- CML-CP, 2-year MCyR was 63%17; in pediatric patients treated
ported. There was one dasatinib-related AE leading to dis- in this study, the MCyR rate by 2 years was 90%. Estimated PFS
continuation (grade 3 drug hypersensitivity, which resolved rates at 2 years were similar in adults and pediatric patients with
when the drug was discontinued). Safety assessment of the 17 CML-CP resistant to or intolerant of imatinib (80% and 82%,
pediatric patients with CML-AP/BP or Ph+ ALL was consistent respectively). In adults with newly diagnosed CML-CP from the
with the known safety profile in adults with advanced Ph+ phase III Dasatinib Versus Imatinib Study in Treatment-Naı̈ve
leukemias.14-16 Chronic Myeloid Leukemia Patients (DASISION), the cumulative

jco.org © 2018 by American Society of Clinical Oncology 1335

 Gore et al

Table 4. Dasatinib-Related Adverse Events of Special Interest During This Study

Dasatinib-Treated Patients (n = 113)
Imatinib-Resistant/ Newly Diagnosed CML-CP
Intolerant CML-CP
(n = 29) Tablets (n = 51) PFOS (n = 33) Total (n = 84)
Dasatinib-Related AEs Any Grade Grade 3/4 Any Grade Grade 3/4 Any Grade Grade 3/4 Any Grade Grade 3/4
All AEs 26 (90) 11 (38) 41 (80) 20 (39) 28 (85) 12 (36) 69 (82) 32 (38)
AEs of special interest
Nausea and/or vomiting 9 (31) 0 9 (18) 0 8 (24) 0 17 (20) 0
Myalgia or arthralgia 5 (17) 1 (3) 3 (6) 0 5 (15) 0 8 (10) 0
Fatigue 4 (14) 0 3 (6) 0 6 (18) 0 9 (11) 0
Rash 4 (14) 0 11 (22) 0 5 (15) 0 16 (19) 0
Diarrhea 4 (14) 0 11 (22) 0 4 (12) 0 15 (18) 0
Hemorrhage 3 (10) 0 7 (14) 1 (2) 1 (3) 0 8 (10) 1 (1)
Pediatric bone growth and development 3 (10) 0 1 (2) 0 1 (3) 0 2 (2) 0
Shortness of breath 3 (10) 0 1 (2) 0 1 (3) 0 2 (2) 0
Superficial edema 1 (3) 0 3 (6) 0 3 (9) 0 6 (7) 0
Congestive heart failure or cardiac dysfunction 1 (3) 0 2 (4) 0 0 0 2 (2) 0
Generalized edema 0 0 2 (4) 0 0 0 2 (2) 0
Cardiac disorders 0 0 1 (2) 0 0 0 1 (1) 0
Chest pain 0 0 0 0 1 (3) 0 1 (1) 0
SAEs* 5 (17) 5 (17) 6 (12) 5 (10) 2 (6) 1 (3) 8 (10) 6 (7)
Neutropenia 2 (7) 2 (7) — — — — — —
Anemia 1 (3) 1 (3) — — — — 2 (2) 2 (2)
Left ventricular dysfunction 1 (3) 0 — — — — — —
Abnormal hepatic function 1 (3) 1 (3) — — — — — —
Infection 1 (3) 1 (3) — — — — — —
Overdose 1 (3) 0 — — — — 1 (1)† 0
Febrile neutropenia — — — — — — 1 (1) 1 (1)
Hematochezia — — — — — — 1 (1) 1 (1)
Peripheral edema — — — — — — 1 (1) 0
Drug hypersensitivity — — — — — — 1 (1) 1 (1)
Periorbital cellulitis — — — — — — 1 (1) 1 (1)
Decreased white blood cell count — — — — — — 1 (1) 0
Recurrent leukemia — — — — — — 1 (1) 0
Uterine hemorrhage — — — — — — 1 (1) 0
AEs leading to discontinuation 0 0 0 0 1 (3)‡ 1 (3)‡ 1 (1)‡ 1 (1)‡

NOTE. Values are No. (%)

Abbreviations: dash, no data; AE, adverse event; CML-CP, chronic myeloid leukemia in chronic phase; PFOS, powder for oral suspension; SAE, serious adverse event.
*Patients may have had more than one SAE.
†Grade unknown.
‡Drug hypersensitivity.

CCyR rate by 2 years was 86%18; the rate in newly diagnosed Achieving early molecular response (EMR) has been associ-
pediatric patients treated in the present study was 94%. Estimated ated with improved long-term outcomes in adults and pediatric
2-year PFS rates were similar in newly diagnosed adults and pe- patients with CML treated with TKIs.5,20 For newly diagnosed
diatric patients (94% and 95%, respectively). pediatric patients treated with dasatinib in this study, 78% achieved
The results described here in patients treated with first-line BCR-ABL1 # 10% at 3 months. In the French National Phase IV
dasatinib are promising compared with results previously reported Trial, 63% achieved this same milestone with imatinib.21 This
in pediatric patients treated with first-line imatinib. The French Na- comparison is consistent with results observed in newly diagnosed
tional Phase IV Trial (n = 44), a prospective study of newly diagnosed adults treated with dasatinib versus imatinib (84% v 64%, re-
pediatric patients with CML-CP treated with imatinib 260 mg/m2 spectively).22 Such observed differences between dasatinib and
daily, reported CCyR and MMR rates at 12 months of 61% and 31%, imatinib may be relevant given the emerging evidence that early,
respectively.7 In a study of patients , 18 years of age and treated with deep response is of clinical relevance in CML. In newly diagnosed
high-dose imatinib (340 mg/m2 daily), 51% achieved CCyR and 30% patient populations treated with dasatinib or imatinib, a significant
achieved MMR at 12 months.8 CCyR by 12 months was reported to be association between EMR and PFS was observed.21,22 In contrast,
72% in newly diagnosed patients , 22 years of age receiving imatinib EMR was not correlated with improved outcomes in pediatric
340 mg/m2 daily.19 Newly diagnosed pediatric patients treated with patients treated with high-dose imatinib.23
dasatinib in this study had CCyR and MMR rates by 12 months of 92% In adults, more patients receiving dasatinib achieved EMR than
and 52%, respectively. MMR is currently considered a more relevant those receiving imatinib; EMR has been shown to predict improved
objective of CML therapy, and findings in this trial support that deep long-term survival outcomes and deep molecular responses, currently
and durable molecular remissions are achievable at high levels in a requirement for consideration in TKI discontinuation and dis-
pediatric patients with CML-CP treated with dasatinib. continuation trials.20 Our data suggest a possible role for front-line

1336 © 2018 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY

 Dasatinib in Children and Adolescents With CML-CP

dasatinib in achieving earlier and deeper responses in pediatric pa- tablets and PFOS; however, this trial was not designed to compare
tients, although long-term studies would be needed to prove supe- cohorts. A population pharmacokinetic analysis is ongoing to
riority in survival. Permanent discontinuation of TKIs is a key unmet, evaluate dasatinib PFOS exposure in pediatric patients. Dasatinib
and currently unstudied, need in the treatment of pediatric CML. was shown to be safe and well tolerated in pediatric patients at
Efficacy of dasatinib in patients with imatinib-resistant/intolerant doses up to 120 mg/m2, with no maximum tolerated dose iden-
CML-CP in our study is of particular interest because all but two tified in a phase I study.12
patients were resistant to imatinib. Long-term data from this trial and This trial was not designed to compare results between co-
others, as well as randomized trials, are needed to confirm the best horts, dasatinib treatment in children versus adults, or dasatinib
front-line TKI for pediatric patients. versus imatinib in pediatric patients. Similarities and differences
TKI cost should also be considered when choosing a front-line described here were based on data from separate trials with dif-
TKI. With the introduction of generic imatinib in the United ferences in methodology, patient population, and geographic
States, imatinib is expected to have a lower initial cost than distribution, which limit interpretation.
dasatinib.24 However, the total cost of dasatinib versus imatinib Overall, dasatinib treatment produced early, deep, and durable
over a patient’s life may be less. Our data and data from other responses of clinical importance in this largest prospective trial of
reports suggest that patients receiving dasatinib are more likely to pediatric patients with CML-CP to date. Target responses were met
achieve early and deep responses and may be eligible for TKI as early as 3 and 6 months for patients with imatinib-resistant/
discontinuation.20 Additionally, nonadherence is associated with intolerant CML-CP or newly diagnosed CML-CP, respectively.
increased health care costs,25 and complex treatment regimens Safety of dasatinib was consistent with that reported in adults,
have been shown to decrease adherence.26 except that no cases of pleural or pericardial effusion or pulmonary
Dasatinib has been shown to be better tolerated than imatinib arterial hypertension were observed in pediatric patients. These
in adults with CML-CP,22 and there is some evidence, including results support dasatinib as a safe and effective first- or second-line
results described here, that suggest better tolerability of dasatinib option for the treatment of pediatric CML-CP.
versus imatinib in children.7 There were no reported pleural ef-
fusion or pulmonary hypertension events in pediatric patients
from this trial or from the phase I study.12 In contrast, dasatinib- AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS
related pleural effusion was reported in 28% of adults with OF INTEREST
newly diagnosed and imatinib-resistant/intolerant CML-CP, and
dasatinib-related pulmonary hypertension was reported in 5% of Disclosures provided by the authors are available with this article at
jco.org.
newly diagnosed adults and 2% adults with imatinib-resistant/
intolerant CML-CP.22,27 It is possible that the pediatric patients in
this study had fewer or no cardiopulmonary comorbidities that
AUTHOR CONTRIBUTIONS
would predispose them to the events seen in adults. It is also
important to investigate potential effects of dasatinib on growth
Conception and design: Lia Gore, Pamela R. Kearns
and development in pediatric patients. Follow-up is ongoing to Provision of study materials or patients: Lia Gore, C. Michel Zwaan
characterize the safety of chronic dasatinib use, because pediatric Collection and assembly of data: Lia Gore, Carmino Antonio De Souza,
patients may live for many decades with CML. This will include Yves Bertrand, Nobuko Hijiya, Linda C. Stork, Nack-Gyun Chung, Rocio
assessment of growth and puberty, once the data are more mature. Cardenas Cardos, Franca Fagioli, Jong Jin Seo, Judith Landman-Parker,
Long-term follow-up is essential, considering late toxicities of TKIs Andrew E. Place, C. Michel Zwaan
have been observed in case reports.2,5,28 Data analysis and interpretation: Lia Gore, Maria Lucia de Martino Lee,
Nobuko Hijiya, Tapan Saikia, Donna Lancaster, Andrew E. Place, Karen R.
A bioequivalence study conducted in adults demonstrated that Rabin, Mariana Sacchi, Rene Swanink, C. Michel Zwaan
the bioavailability of dasatinib PFOS was 19% lower than that of Manuscript writing: All authors
dasatinib tablets,29 which led to the use of 72 mg/m2 dasatinib Final approval of manuscript: All authors
PFOS in this study. Results reported here were similar between Accountable for all aspects of the work: All authors

4. Kalmanti L, Saussele S, Lauseker M, et al: 8. Giona F, Putti MC, Micalizzi C, et al: Long-term
REFERENCES Younger patients with chronic myeloid leukemia do results of high-dose imatinib in children and adoles-
well in spite of poor prognostic indicators: Results cents with chronic myeloid leukaemia in chronic
1. Howlader N, Noone AM, Krapcho M, et al from the randomized CML study IV. Ann Hematol 93: phase: The Italian experience. Br J Haematol 170:
(eds): Previous version: SEER Cancer Statistics Re- 71-80, 2014 398-407, 2015
view, 1975-2013. http://seer.cancer.gov/csr/1975_ 5. Hijiya N, Schultz KR, Metzler M, et al: Pediatric 9. Lam MS: Extemporaneous compounding of
2013/ chronic myeloid leukemia is a unique disease that re- oral liquid dosage formulations and alternative drug
2. Hijiya N, Millot F, Suttorp M: Chronic myeloid quires a different approach. Blood 127:392-399, 2016 delivery methods for anticancer drugs. Pharmaco-
leukemia in children: Clinical findings, management, 6. Novartis Pharmaceuticals: Gleevec (imatinib) therapy 31:164-192, 2011
and unanswered questions. Pediatr Clin North Am [package insert]. East Hanover, NJ, Novartis Phar- 10. Bristol-Myers Squibb: Sprycel (dasatinib)
62:107-119, 2015 maceuticals, 2016 [package insert]. Princeton, NJ, Bristol-Myers Squibb,
3. Pemmaraju N, Kantarjian H, Shan J, et al: 7. Millot F, Baruchel A, Guilhot J, et al: Imatinib is 2017
Analysis of outcomes in adolescents and young effective in children with previously untreated 11. Aplenc R, Blaney SM, Strauss LC, et al: Pedi-
adults with chronic myelogenous leukemia treated chronic myelogenous leukemia in early chronic atric phase I trial and pharmacokinetic study of dasa-
with upfront tyrosine kinase inhibitor therapy. Hae- phase: Results of the French national phase IV trial. tinib: A report from the children’s oncology group
matologica 97:1029-1035, 2012 J Clin Oncol 29:2827-2832, 2011 phase I consortium. J Clin Oncol 29:839-844, 2011

jco.org © 2018 by American Society of Clinical Oncology 1337

 Gore et al

12. Zwaan CM, Rizzari C, Mechinaud F, et al: in chronic phase chronic myeloid leukemia patients 24. Padula WV, Larson RA, Dusetzina SB, et al:
Dasatinib in children and adolescents with relapsed with resistance, suboptimal response or intolerance Cost-effectiveness of tyrosine kinase inhibitor treat-
or refractory leukemia: Results of the CA180-018 to imatinib. Haematologica 95:232-240, 2010 ment strategies for chronic myeloid leukemia in
phase I dose-escalation study of the Innovative 18. Kantarjian HM, Shah NP, Cortes JE, et al: chronic phase after generic entry of imatinib in the
Therapies for Children with Cancer Consortium. Dasatinib or imatinib in newly diagnosed chronic- United States. J Natl Cancer Inst 108:djw003, 2016
J Clin Oncol 31:2460-2468, 2013 phase chronic myeloid leukemia: 2-Year follow-up 25. de Almeida MH, Fogliatto L, Couto D: Im-
13. National Comprehensive Cancer Network: from a randomized phase 3 trial (DASISION). Blood portance of adherence to BCR-ABL tyrosine-
The NCCN Clinical Practice Guidelines in Oncology 119:1123-1129, 2012 kinase inhibitors in the treatment of chronic myeloid
Chronic Myeloid Leukemia version 2. 2017. https:// 19. Champagne MA, Fu CH, Chang M, et al: leukemia. Rev Bras Hematol Hemoter 36:54-59,
www.nccn.org/professionals/physician_gls/pdf/cml.pdf Higher dose imatinib for children with de novo 2014
14. Kantarjian H, Cortes J, Kim DW, et al: Phase 3 chronic phase chronic myelogenous leukemia: A 26. Hirji I, Gupta S, Goren A, et al: Chronic myeloid
study of dasatinib 140 mg once daily versus 70 mg twice report from the Children’s Oncology Group. Pediatr leukemia (CML): Association of treatment satisfac-
daily in patients with chronic myeloid leukemia in Blood Cancer 57:56-62, 2011 tion, negative medication experience and treatment
accelerated phase resistant or intolerant to imatinib: 15- 20. Baccarani M, Deininger MW, Rosti G, et al: restrictions with health outcomes, from the patient’s
Month median follow-up. Blood 113:6322-6329, 2009 European LeukemiaNet recommendations for the perspective. Health Qual Life Outcomes 11:167,
15. Saglio G, Hochhaus A, Goh YT, et al: Dasatinib management of chronic myeloid leukemia: 2013. 2013
in imatinib-resistant or imatinib-intolerant chronic Blood 122:872-884, 2013 27. Shah NP, Rousselot P, Schiffer C, et al:
myeloid leukemia in blast phase after 2 years of 21. Millot F, Guilhot J, Baruchel A, et al: Impact of Dasatinib in imatinib-resistant or -intolerant chronic-
follow-up in a phase 3 study: Efficacy and tolerability early molecular response in children with chronic phase, chronic myeloid leukemia patients: 7-Year
of 140 milligrams once daily and 70 milligrams twice myeloid leukemia treated in the French Glivec phase follow-up of study CA180-034. Am J Hematol 91:
daily. Cancer 116:3852-3861, 2010 4 study. Blood 124:2408-2410, 2014 869-874, 2016
16. Lilly MB, Ottmann OG, Shah NP, et al: 22. Cortes JE, Saglio G, Kantarjian HM, et al: Final 28. Gore L, DeGregori J, Porter CC: Targeting
Dasatinib 140 mg once daily versus 70 mg twice daily 5-year study results of DASISION: The Dasatinib developmental pathways in children with cancer:
in patients with Ph-positive acute lymphoblastic Versus Imatinib Study in Treatment-Naı̈ve Chronic What price success? Lancet Oncol 14:e70-e78, 2013
leukemia who failed imatinib: Results from a phase 3 Myeloid Leukemia Patients Trial. J Clin Oncol 34: 29. ClinicalTrials.gov: Pharmacokinetic study
study. Am J Hematol 85:164-170, 2010 2333-2340, 2016 comparing blood levels of dasatinib in healthy
17. Shah NP, Kim D-W, Kantarjian H, et al: Potent, 23. Giona F, Saglio G, Santopietro M, et al: Early participants who received the tablet formulation
transient inhibition of BCR-ABL with dasatinib response does not predict outcome in children and with those who received liquid and tablet-
100 mg daily achieves rapid and durable cytogenetic adolescents with chronic myeloid leukaemia treated dispersed formulations. https://clinicaltrials.gov/
responses and high transformation-free survival rates with high-dose imatinib. Br J Haematol, 2016 ct2/show/NCT01392703

Affiliations
Lia Gore, University of Colorado School of Medicine/Children’s Hospital Colorado, Aurora, CO; Pamela R. Kearns, University of
Birmingham, Birmingham, West Midlands; Donna Lancaster, Royal Marsden Hospital, Sutton, Surrey, United Kingdom; Maria Lucia de
Martino Lee, Support Group for Children and Adolescents with Cancer; Carmino Antonio De Souza, University of Campinas, São Paulo,
Brazil; Yves Bertrand, L’Institut d’Hématologie et d’Oncologie Pédiatrique, Lyon, France; Nobuko Hijiya, Ann and Robert H. Lurie
Children’s Hospital of Chicago, and Northwestern University Feinberg School of Medicine, Chicago, IL; Linda C. Stork, Oregon Health &
Science University, Portland, OR; Nack-Gyun Chung, The Catholic University of Korea, Seoul St. Mary’s Hospital; Jong Jin Seo, University
of Ulsan College of Medicine, and Asan Medical Center, Seoul, Republic of Korea; Rocio Cardenas Cardos, Instituto Nacional De
Pediatria, Mexico City, Mexico; Tapan Saikia, Prince Aly Khan Hospital, Mumbai, India; Franca Fagioli, Regina Margherita Hospital,
Turin, Italy; Judith Landman-Parker, Hôpital Enfants Armand-Trousseau, Paris, France; Andrew E. Place, Dana-Farber/Boston
Children’s Cancer and Blood Disorders Center, Boston, MA; Karen R. Rabin, Texas Children’s Cancer Center, and Baylor College of
Medicine, Houston, TX; Mariana Sacchi and Rene Swanink, Bristol-Myers Squibb, Princeton, NJ; C. Michel Zwaan, Erasmus MC-Sophia
Children’s Hospital, Rotterdam, Netherlands; Pamela R. Kearns and C. Michel Zwaan, Innovative Therapies for Children with Cancer
Consortium, European Union.
Support
Supported by Bristol-Myers Squibb.
Prior Presentation
Presented in part at the ASCO Annual Meeting, Chicago, IL, June 2-6, 2017; and the European Hematology Association 22nd
Congress, Madrid, Spain, June 22-25, 2017.

nnn

1338 © 2018 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY

 Dasatinib in Children and Adolescents With CML-CP

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Dasatinib in Pediatric Patients With Chronic Myeloid Leukemia in Chronic Phase: Results From a Phase II Trial
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are
self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more
information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/site/ifc.
Lia Gore Tapan Saikia
Stock or Other Ownership: ARIAD (I), Amgen, Sanofi, Celgene, Clovis Consulting or Advisory Role: Dr. Reddy’s laboratory
Oncology, Ignyta (I)
Honoraria: Amgen, Novartis, Bristol-Myers Squibb Franca Fagioli
Consulting or Advisory Role: Celgene, Novartis, ProEd Communications, No relationship to disclose
Roche, Amgen, Medscape Jong Jin Seo
Patents, Royalties, Other Intellectual Property: Patent held for diagnostic Research Funding: Bristol-Myers Squibb
discovery and treatment response methodology tools in the use of MR
spectroscopy for leukemia. Judith Landman-Parker
Travel, Accommodations, Expenses: Amgen, Roche, Novartis, Bristol- Research Funding: Boehringer Ingelheim (Inst), Bristol-Myers Squibb
Myers Squibb (Inst), Novartis (Inst), Takeda (Inst)

Pamela R. Kearns Donna Lancaster

Honoraria: Celgene No relationship to disclose
Consulting or Advisory Role: Bristol-Myers Squibb, Genzyme Andrew E. Place
Research Funding: Pfizer (Inst) Consulting or Advisory Role: Abbvie
Maria Lucia de Martino Lee Research Funding: Karyopharm Therapeutics
Honoraria: Shire Farmaceutica Brasil, Zodiac Pharma Travel, Accommodations, Expenses: Abbvie
Consulting or Advisory Role: Shire Farmaceutica Brasil, Zodiac Pharma Karen R. Rabin
Speakers’ Bureau: Shire Farmaceutica Brasil, Zodiac Pharma Consulting or Advisory Role: Adaptive Biotechnologies Corporation
Travel, Accommodations, Expenses: Amgen Brasil, Shire Farmaceutica Travel, Accommodations, Expenses: Adaptive Biotechnologies
Brasil Corporation
Carmino Antonio De Souza Mariana Sacchi
No relationship to disclose Employment: Bristol-Myers Squibb
Yves Bertrand Rene Swanink
Consulting or Advisory Role: Jazz Pharmaceuticals Employment: Bristol-Myers Squibb
Nobuko Hijiya Stock or Other Ownership: Bristol-Myers Squibb
Honoraria: Novartis, Amgen Honoraria: Bristol-Myers Squibb
Consulting or Advisory Role: Novartis, Amgen C. Michel Zwaan
Travel, Accommodations, Expenses: Amgen, Kite Pharma Honoraria: Novartis
Linda C. Stork Consulting or Advisory Role: Celgene (Inst)
Research Funding: Bristol-Myers Squibb Speakers’ Bureau: Novartis
Research Funding: Pfizer (Inst), Jazz Pharmaceuticals (Inst), Sanofi (Inst),
Nack-Gyun Chung Bristol-Myers Squibb (Inst)
No relationship to disclose Travel, Accommodations, Expenses: Jazz Pharmaceuticals
Rocio Cardenas Cardos
No relationship to disclose

jco.org © 2018 by American Society of Clinical Oncology

 Gore et al

Acknowledgment

We thank the patients who participated in this study and the clinical study teams. We thank Dr. Yousif Matloub for his work developing
this study and Eric Bleickardt for clinical development contributions to this study. Medical writing and editorial support were provided by
Samantha L. Dwyer and Andrea Lockett of StemScientific, an Ashfield Company (Lyndhurst, NJ), and were funded by Bristol-Myers
Squibb.

© 2018 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY