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Supplementary Information
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Statistical methods. Cumulative and exposure-adjusted incidence rates of PAD in the pooled Ph+
population and the standard incidence ratio (SIR) analysis.
Supplemental Table 1. Clinical trials from which dasatinib-treated patients who developed PE were
analyzed, with literature references.
Supplemental Table 2. Results of the SIR analysis.
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Statistical methods
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Cumulative and exposure-adjusted incidence rates of PAD with dasatinib were calculated using an
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approach adapted from that described by Giles and colleagues22 in a retrospective pooled analysis of
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2390 patients who received first-line treatment with imatinib, nilotinib, or non-TKI therapy for CML-CP in
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three large trials: International Randomized Study of Interferon and ST1571 (IRIS), Tyrosine Kinase
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Inhibitor Optimization and Selectivity (TOPS) Study, and Evaluating Nilotinib Efficacy and Safety in clinical
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Trials-newly diagnosed patients (ENESTnd). The crude incidence rate was calculated as the number of
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cases divided by the total number of patients included in the analysis. To account for differences in
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duration of dasatinib therapy among treated patients, an exposure-adjusted incidence rate was calculated
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using total dasatinib exposure. Exposure time was calculated for each patient as the time between the
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date of first study drug intake and the last study drug date regardless of PAD occurrence (there were no
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discontinuations due to PAD), death or the end of the reporting period, whichever occurred first.
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For the SIR analysis, the number of cases reported in dasatinib-treated patients was divided by
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the expected number of events reported in the age and gender-specific person-time matched population
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from Truven’s Marketscan Commercial Claims and Medicare Supplemental database.
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Supplemental Table 1. Dasatinib-treated cohorts from clinical trials included in safety database analysis
Trial
Diagnosis
Imatinib
status
Patients,
na,b
Study type
Treatment arm(s)
Median duration
of dasatinib
treatment,
month (range)
Trials of CML patients only
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NCT00101647
(START-A)1
CML-AP
R/I
197
Phase II; Nonrandomized, single
arm
Dasatinib 70 mg BID
13 (0.1−74)
NCT00101816
(START-B)2
CML-MBC
R/I
124
Phase II; Nonrandomized, single
arm
Dasatinib 70 mg BID
4 (0.03−72)
NCT00101660
(START-C)3
CML-CP
R/I
387
Phase II; Nonrandomized, single
arm
Dasatinib 70 mg BID
25 (0.03−75)
NCT00103844
(START-R)4
CML-CP
R
150
Phase II; Randomized,
two arms
Dasatinib 70 mg BID vs
Imatinib 400 mg BID (2:1)
26 (0.2 −71)
NCT00123474 (034)5
CML-CP
R/I
724
Phase III;
Randomized, four
arms
Dasatinib: 50 mg BID vs 70
mg BID vs 100 mg QD vs
140 mg QD
30 (0.07−93)
NCT00481247
(DASISION)6
CML-CP
Newly
diagnosed
519
Phase III;
Randomized, two
arms
Dasatinib 100 mg QD vs
Imatinib 400 mg QD
60 (0.03−73)
NCT01357655 (363)7
CML-CP
Newly
diagnosed
66b
Phase II; Randomized,
two arms
Dasatinib 100 mg QD vs
Dasatinib100 mg QD +
SMO antagonist
19 (0.3−26)
Trials including ALL patients
NCT00103701 (002)8
CML or Ph+ ALL
R/I
84
(10 ALL)
Phase I; Nonrandomized, single
arm
Dasatinib 15–240 mg/d
17 (0.2−91)
NCT00101595
(START-L)2
CML-LBC or Ph+
ALL
R/I
96
(ALL not
given)
Phase II; Nonrandomized, single
arm
Dasatinib 70 mg BID
3 (0.03−31)
NCT00123487 (035)9
CML-AP/BP or
Ph+ ALL
R/I
638
(84 ALL)
Phase III;
Randomized, two
arms
Dasatinib: 70 mg BID vs
140 mg QD
6 (0.03−93)
NCT00529763 (160)10
CML or Ph+ ALL
R/I
121c
(ALL not
given)
Phase II; Nonrandomized, single
arm
Dasatinib 100 mg QD for
CML-CP;
Dasatinib 70 mg BID for
AP/BP ALL
38 (0.3−62)
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Abbreviations: ALL, acute lymphoblastic leukemia; AP, accelerated phase; BID, twice daily; BP, blast phase; CML, chronic myeloid leukemia; CP,
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chronic phase; I, intolerant to imatinib; LBC, lymphoid blast crisis; MBC, myeloid blast crisis; Ph+, Philadelphia chromosome-positive; QD, once
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daily; R, resistant to imatinib; SMO, smoothened gene product.
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aTotal
number of patients enrolled.
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bEntry
criteria for the studies typically included Eastern Cooperative Oncology Group (ECOG) performance status 0–2 (except for CA180-002,
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START-C, and START-R trials, which required ECOG 0–1), with a history of PAD or known PAD risk factors. Dasatinib clinical trials in this
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analysis permitted patients with uncontrolled diabetes, with the exception of CA180-002.
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cEstimated
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enrollment (to be completed October 2015).
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References:
1. Guilhot F, Apperley J, Kim D-W, Bullorsky EO, Baccarani M, Roboz GJ et al. Dasatinib induces significant hematologic and cytogenetic
responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in accelerated phase. Blood 2007; 109: 4143–4150.
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2. Cortes J, Rousselot P, Kim D-W, Ritchie E, Hamerschlak N, Coutre S et al. Dasatinib induces complete hematologic and cytogenetic
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responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in blast crisis. Blood 2007; 109: 3207–3213.
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3. Hochhaus A, Kantarjian HM, Baccarani M, Lipton JH, Apperley JF, Druker BJ et al. Dasatinib induces notable hematologic and
cytogenetic responses in chronic-phase chronic myeloid leukemia after failure of imatinib therapy. Blood 2007; 109: 2303–2309.
4. Kantarjian H, Pasquini R, Hamerschlak N, Rousselot P, Holowiecki J, Jootar S et al. Dasatinib or high-dose imatinib for chronic-phase
chronic myeloid leukemia after failure of first-line imatinib: a randomized phase 2 trial. Blood 2007; 109: 5143–5150.
5. Shah NP, Kantarjian HM, Kim D-W, Réa D, Dorlhiac-Llacer PE, Milone JH et al. Intermittent target inhibition with dasatinib 100 mg once
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daily preserves efficacy and improves tolerability in imatinib-resistant and -intolerant chronic-phase chronic myeloid leukemia. J Clin Oncol
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2008; 26: 3204–3212.
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6. Kantarjian H, Shah NP, Hochhaus A, Cortes J, Shah S, Ayala M et al. Dasatinib versus imatinib in newly diagnosed chronic-phase chronic
myeloid leukemia. N Engl J Med 2010; 362: 2260–2270.
7. Trudel GC, Paliwal P, Lainas I. Dasatinib plus SMO antagonist versus dasatinib alone for treating patients (pts) with newly diagnosed
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Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia in chronic phase (CML-CP): Design of CA180-363, a phase II open-
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label randomized trial. J Clin Oncol 2012; 30 (Suppl 15): (abstract TPS6634).
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8. Talpaz M, Shah NP, Kantarjian H, Donato N, Nicoll J, Paquette R et al. Dasatinib in imatinib-resistant Philadelphia chromosome-positive
leukemias. N Engl J Med 2006; 354: 2531–2541.
9. Kantarjian H, Cortes J, Kim D-W, Dorlhiac-Llacer P, Pasquini R, DiPersio J et al. Phase 3 study of dasatinib 140 mg once daily versus 70
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mg twice daily in patients with chronic myeloid leukemia in accelerated phase resistant or intolerant to imatinib: 15-month median follow-
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up. Blood 2009; 113: 6322–6329.
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10. Huang XJ, Hu JD, Li JY, Jin J, Meng FY, Shen ZX et al. Study on efficiency and safety of dasatinib in Chinese patients with chronic
myelogenous leukemia who are resistant or intolerant to imatinib. Zhonghua Xue Ye Xue Za Zhi 2012; 33: 889–895 (in Chinese).
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Supplemental Table 2. Results of the standard incidence ratio (SIR) analysis
Event
PAD
Comparator
Observed
Expected
SIR (95% CI)
General population
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19.7
0.56 (0.31, 1.01)
CML population
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42.7
0.26 (0.14, 0.46)
64 For this SIR analysis, the number of cases reported in dasatinib-treated patients was divided by the expected number of events reported in the age
65 and gender-specific person-time matched population from Truven’s Marketscan Commercial Claims and Medicare Supplemental database.
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