- Email: [email protected]
Cross-Intolerance With Dasatinib Among Imatinib-Intolerant Patients With Chronic Phase Chronic Myeloid Leukemia
Accepted Manuscript Cross-Intolerance with Dasatinib Among Imatinib-Intolerant Patients with ChronicPhase Chronic Myeloid Leukemia Hanna J. Khoury, Stuart L. Goldberg, Michael J. Mauro, Richard M. Stone, Michael W. Deininger, M. Brigid Bradley-Garelik, Hesham Mohamed, François Guilhot PII:
S2152-2650(16)30016-7
DOI:
10.1016/j.clml.2016.03.004
Reference:
CLML 771
To appear in:
Clinical Lymphoma, Myeloma and Leukemia
Received Date: 14 September 2015 Revised Date:
2 March 2016
Accepted Date: 21 March 2016
Please cite this article as: Khoury HJ, Goldberg SL, Mauro MJ, Stone RM, Deininger MW, BradleyGarelik MB, Mohamed H, Guilhot F, Cross-Intolerance with Dasatinib Among Imatinib-Intolerant Patients with Chronic-Phase Chronic Myeloid Leukemia, Clinical Lymphoma, Myeloma and Leukemia (2016), doi: 10.1016/j.clml.2016.03.004. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Cross-Intolerance with Dasatinib Among Imatinib-Intolerant Patients with Chronic-Phase Chronic Myeloid Leukemia
Hanna J. Khoury,1 Stuart L. Goldberg,2 Michael J. Mauro,3 Richard M. Stone,4
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Michael W. Deininger,5 M. Brigid Bradley-Garelik,6 Hesham Mohamed,6 François Guilhot7
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Division of Hematology, Department of Hematology and Medical Oncology, Winship Cancer
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Institute of Emory University, 1365 Clifton Road NE, Suite C1152, Atlanta, GA 30322, USA [email: [email protected]] 2
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John Theurer Cancer Center at Hackensack University Medical Center, 92 2nd St,
Hackensack, NJ 07601, USA
[email: [email protected]] 3
Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, 1275 York Avenue,
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[email: [email protected]]
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Box 489, New York, NY 10065, USA
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Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA, USA 02115
[email: [email protected]] 5
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Department of Internal Medicine, Huntsman Cancer Institute at the University of Utah, 2000
Circle of Hope Drive #4280, Salt Lake City, UT 84112, USA [email: [email protected]] 6
Bristol-Myers Squibb, 777 Scudders Mill Rd, Princeton, NJ 08536, USA
[email: [email protected]]
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[email: [email protected]] 7
Department of Oncology, Hematology, and Cell Therapy, CHU de Poitiers, CIC Inserm 0802,
Poitiers, France 86021
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[email: [email protected]]
Address for correspondence:
Hanna J. Khoury, MD, 1365 Clifton Road, Suite C1152
Winship Cancer Institute of Emory University, Atlanta, GA 30322
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Phone: 404-778-3932; Fax: 404-778-4755; e-mail contact: [email protected]
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Conflict of Interest Statement HJK has received research support from Bristol-Myers Squibb (BMS), Chemgenex, Genzyme, Novartis, and Wyeth. SLG has received research support from Ariad, BMS, Novartis, and Pfizer, and has acted as a speaker for Ariad, BMS, and Novartis. MJM has received research funding
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from Novartis, and has acted as a consultant for Ariad, BMS, Novartis, and Pfizer. RMS has received research funding from Novartis, and has acted as a consultant for Ariad and BMS. MWD has served as a consultant for BMS and Novartis, and has received research funding from Calistoga and Genzyme. BB-G and HM are employees of BMS.
This analysis was supported by research funding from BMS. StemScientific, an Ashfield
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Company, part of UDG Healthcare plc, funded by BMS, provided medical writing and editorial
Abstract word count: 245
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support.
Tables: 4
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Main text word count: 2928
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Figures: 3
References: 30
Running title: Cross-intolerance with treatments in CML
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Abstract Some patients with chronic myeloid leukemia (CML) are intolerant to first-line imatinib treatment. Our retrospective data analysis of 271 CML imatinib-intolerant patients from
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phase II/III studies examined the extent of cross-intolerance between imatinib and dasatinib. Our results confirm clinical safety and efficacy of dasatinib in imatinib-
intolerant CML patients, suggesting that dasatinib may be a suitable treatment choice for this population.
Background: BCR-ABL inhibitors have improved the prognosis of patients with chronic myeloid leukemia (CML). However, imatinib, the first approved BCR-ABL inhibitor, is discontinued in many patients due to resistance or intolerance. Patients and Methods: This retrospective,
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pooled analysis of phase II/III data explores the extent of cross-intolerance between imatinib
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and dasatinib, a second-generation BCR-ABL inhibitor, in 271 CML imatinib-intolerant patients. Results: Overall, 47 patients (17%) had cross-intolerance to dasatinib based on recurrence of
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grade 3–4 adverse events (AEs). Of 228 patients who discontinued imatinib because of nonhematologic intolerance, 10 (4%) experienced the same severe nonhematologic AEs with
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dasatinib, with 4 (2%) of these patients discontinuing dasatinib due to cross-intolerance. Of 43 patients who discontinued imatinib because of hematologic intolerance, 37 (86%) had recurrence of grade 3–4 hematologic AEs with dasatinib, with 8 (19%) patients discontinuing dasatinib due to cross-intolerance. Among patients taking dasatinib at the optimized dose of 100 mg/day (n = 43), 1 patient (2%) discontinued therapy due to recurrence of nonhematologic AEs, and 3 (7%) discontinued due to recurrence of hematologic AEs. With a median treatment duration of 22 months, estimated rates of progression-free survival (PFS) and overall survival (OS) at 2 years were higher in patients with nonhematologic versus hematologic intolerance to imatinib who switched to dasatinib (PFS: 94% vs 68%, respectively; OS: 98% vs 88%,
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respectively). Conclusion: Dasatinib may be an appropriate treatment option for imatinib-
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intolerant patients with CML, with cross-intolerance resulting in discontinuation in a minority of patients.
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Keywords: Chronic myeloid leukemia, Dasatinib, Drug toxicity, Imatinib
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Introduction Imatinib, the first BCR-ABL inhibitor introduced for the treatment of chronic myeloid
leukemia (CML), was approved by the US Food and Drug Administration for the treatment of interferon-resistant or -intolerant CML in 2001 and newly-diagnosed CML in 2002.1 While
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imatinib is commonly prescribed as a first-line treatment for CML in chronic phase (CML-CP), long-term follow-up with this agent has demonstrated that clinical resistance and intolerance develops in many patients,2,3 often requiring a change in treatment. Therapeutic options in the second-line setting and beyond for patients who have failed imatinib include oral BCR-ABL inhibitors dasatinib, nilotinib, bosutinib, and ponatinib, as well as omacetaxine.4-8 Ponatinib and omacetaxine are the only therapies available to treat patients with a T315I BCR-ABL mutation. Allogeneic stem cell transplant may also be considered in eligible patients with a suitable
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donor.8
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Dasatinib was initially approved for the treatment of all phases of CML and Ph+ acute lymphoblastic leukemia after resistance or intolerance to first-line therapy, including imatinib
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based on the SRC–ABL Tyrosine Kinase Inhibition Activity Research Trial (START) program.4
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Additionally, the phase III randomized trial, Dasatinib versus Imatinib Study in Treatment-Naïve CML Patients (DASISION), demonstrated superior efficacy of dasatinib compared with imatinib as initial therapy.9-12 The primary endpoint of this study, confirmed complete cytogenetic response by 12 months, was achieved in 77% (95% confidence interval [CI]: 71 to 82) of patients treated with dasatinib compared with 66% (95% CI: 60 to 72) taking imatinib. Based on these results, dasatinib was approved for first-line treatment of patients with CML-CP.4,9 Dasatinib is structurally unrelated to imatinib; however, the common molecular target raises the possibility that cross-intolerance, where similar adverse events (AEs) occur with both agents, may arise. To investigate cross-intolerance between imatinib and dasatinib, we assessed the safety, tolerability, and efficacy of dasatinib in patients with imatinib-intolerant
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CML-CP using pooled data from the phase II CA180-013 (START-C) trial and the phase III
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CA180-034 trial.13-18 The presented analysis explores the extent of cross-intolerance between imatinib and dasatinib for hematologic and nonhematologic toxicities.
Study Design and Patient Eligibility
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Patients and Methods
Imatinib-intolerant patients with CML-CP were pooled from 2 international, multicenter clinical trials: CA180-013, a phase II study of dasatinib 70 mg twice daily in 387 patients with resistance (n = 288) or intolerance (n = 99) to imatinib,13,14 and CA180-034, a phase III doseoptimization study in patients with resistance (n = 498) or intolerance (n = 172) to imatinib who
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were randomly assigned to receive dasatinib 100 mg once daily (n = 167), 50 mg twice daily (n = 168), 140 mg once daily (n = 167), or 70 mg twice daily (n = 168).15,17,18 Entry criteria for the
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study populations have been published previously.13-15 Briefly, adult patients with CML-CP and primary or acquired resistance or intolerance to imatinib were included in the trials.13-15 In
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CA180-013, imatinib intolerance was defined as imatinib-related grade ≥3 nonhematologic
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toxicity or imatinib-related grade 4 hematologic toxicity persisting for >7 days.14 In CA180-034, imatinib intolerance was defined as grade ≥3 toxicity considered at least possibly related to imatinib at a dose of ≥400 mg/day, which led to discontinuation of therapy.15 In both studies, dose adjustments were allowed for inadequate response (escalation) and drug-related grade ≥2 nonhematologic toxicity or grade ≥3 hematologic toxicity (dose reduction or interruption).13-15,17,18 Studies were conducted in accordance with the Declaration of Helsinki and approved by local ethics committees or institutional review boards. All patients gave written informed consent.1315,17,18
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Assessments Complete hematologic response (CHR), major cytogenetic response (MCyR), and
complete cytogenetic response (CCyR) were evaluated for up to 2 years. Progression was
defined as increasing white blood cell count, loss of CHR or MCyR, confirmed accelerated/blast
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phase, or death. AEs and other symptoms occurring during dasatinib treatment were collected for the duration of the study and graded according to the Common Terminology Criteria for Adverse Events (CTCAE) v3.0. Cross-intolerance was defined as the recurrence of the same grade 3–4 AEs during dasatinib therapy that had been documented during imatinib therapy. Cross-intolerance data for the dasatinib 100 mg once-daily dose is presented, in addition to the overall population, as 100 mg once daily is the current approved starting dose for patients with
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CML-CP.
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Patient Characteristics
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Results
A total of 271 patients with imatinib intolerance were included in this analysis (n = 99
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treated patients from CA180-013; n = 172 treated patients from CA180-034). Baseline characteristics are shown in Table 1. The majority of patients (59%) received imatinib therapy for <1 year, while 28% received it for 1 to 3 years, and 13% for >3 years. Median duration of imatinib therapy was 0.8 years (range: 0 to 5.8 years). Median duration of CML at dasatinib initiation was 24 months (range: 1 to 183). Of the 271 patients, 225 (83%) had nonhematologic imatinib intolerance only, 43 (16%) had hematologic imatinib intolerance only, and 3 (1%) had both nonhematologic and hematologic intolerance to imatinib. In the following analyses, these last 3 patients are grouped with patients with nonhematologic intolerance unless otherwise indicated. Details regarding the nature of intolerance were not available in 14 patients with nonhematologic toxicity and 3 patients with hematologic toxicity. Median duration of imatinib
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therapy was 0.7 years (range: 0 to 5.8 years) for patients with nonhematologic intolerance and
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1.8 years (range: 0.1 to 4.9 years) for patients with hematologic intolerance to imatinib. Dasatinib Treatment
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Median duration of dasatinib therapy was 22 months (range: <1 to 31) at the time of analysis. Treatment characteristics are shown in Table 2. Patients were assigned to receive 100 mg once daily (16%), 50 mg twice daily (16%), 140 mg once daily (16%), or 70 mg twice daily (52%). Dose adjustments occurred in a limited number of cases (Table 2). Nonhematologic Intolerance in Patients Treated with Dasatinib
Among imatinib-intolerant CML patients, nonhematologic toxicity was more commonly cited as a reason for discontinuing dasatinib (14%) than hematologic toxicity (7%) or disease
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progression (6%) (Table 2). When examining the most common reasons for imatinib
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intolerance, patients who developed grade 3–4 hepatotoxicity, rash, myalgia/arthralgia, gastrointestinal (GI) toxicity, fluid retention, or pulmonary toxicity with imatinib typically did not
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develop the same grade 3–4 AE with dasatinib (Table 3). A total of 228 patients discontinued imatinib for nonhematologic intolerance, of which 10 (4%) experienced the same grade 3–4
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nonhematologic AE with dasatinib (rash [n = 5], myalgia/arthralgia [n = 2], GI toxicity [n = 2], cardiac toxicity [n = 1]), with a few of these patients (n = 4 [2%]) discontinuing dasatinib due to cross-intolerance. Reasons for discontinuation of dasatinib amongst the 228 patients included grade 3–4 nonhematologic toxicity in 35 patients (15%; n = 4 for the same type of nonhematologic toxicity) and hematologic toxicity amongst 10 patients (4%) (Table 2). For these 45 patients, causes of dasatinib discontinuation and baseline nonhematologic imatinib intolerance are detailed in Supplemental Table 1. There does not seem to be a discernible correlation between the AEs resulting in dasatinib discontinuation and nonhematologic toxicity due to previous imatinib therapy.
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Hematologic Intolerance in Patients Treated with Dasatinib Of the 43 patients who discontinued imatinib for hematologic intolerance, recurrence of the same grade 3–4 hematologic intolerance was observed in 37 (86%) patients treated with dasatinib (Table 3). The majority of recurrence cases (n = 36) involved thrombocytopenia or
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neutropenia, while 1 case consisted of anemia. Nine patients (21%) discontinued dasatinib for grade 3–4 hematologic toxicity (8 for the same type of hematologic toxicity, 1 for a different type of hematologic toxicity), while 3 (7%) discontinued dasatinib for nonhematologic toxicity (Table 2).
Patients Treated with 100 mg Once Daily
Of the 43 imatinib-intolerant patients who were subsequently treated with dasatinib
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100 mg once daily, 8 (19%) had hematologic intolerance only, 34 (79%) had nonhematologic
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intolerance, and 1 (2%) had both hematologic and nonhematologic intolerance to their first-line imatinib therapy. All 8 patients with a history of hematologic intolerance to imatinib experienced
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the same grade 3–4 hematologic toxicity when treated with dasatinib 100 mg once daily; 4/8 (50%) discontinued dasatinib due to hematologic toxicity (n = 3 due to cross-intolerance; n = 1
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due to a different type of hematologic toxicity). Among the 34 patients with nonhematologic intolerance only, 2 patients developed the same grade 3–4 AE (rash), of which 1 discontinued dasatinib for this reason. The patient with both hematologic and nonhematologic imatinib intolerance who was treated with dasatinib 100 mg once daily experienced the same grade 3–4 hematologic toxicity with dasatinib but discontinued dasatinib for another reason. Stratification of All Patients Based on Cytogenetic Response at Start of Dasatinib Therapy Patients were evaluated for efficacy based on CCyR on imatinib and at the start of dasatinib treatment (Table 4). Overall, 11% achieved CCyR on imatinib and had CCyR at the
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start of dasatinib treatment, 18% achieved CCyR on imatinib but did not have CCyR at the start
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of dasatinib treatment, and 63% of patients did not achieve CCyR on imatinib. In the population with nonhematologic intolerance, 73 (32%) had CCyR and 138 (61%) did not have CCyR on imatinib. Six (14%) patients with hematologic intolerance had CCyR and 33 (77%) did not have
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CCyR on imatinib. Cytogenetic response on imatinib was not reported in 8% of patients. Cytogenetic and Molecular Response in All Patients on Dasatinib Therapy
With 2 years of follow-up, 73% of patients had achieved CCyR on dasatinib (Table 4). The median daily dose of dasatinib in patients who achieved CCyR with dasatinib was 99 mg/day, compared with 72 mg/day in patients who did not achieve CCyR with dasatinib. CCyR and major molecular response (MMR) were evaluated in imatinib-intolerant
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patients at the 2-year follow-up, based on cytogenetic response on imatinib and at the start of
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dasatinib (Figure 1A) and based on type of intolerance to imatinib (Figure 1B). Of patients who had CCyR at the start of dasatinib, 90% maintained this response and 53% achieved MMR. Of
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patients with CCyR on imatinib, but not at the start of dasatinib therapy, 84% achieved CCyR and 76% achieved MMR. In patients who received imatinib for >12 months and did not achieve
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CCyR, 50% achieved CCyR on dasatinib and 35% achieved MMR. However, patients who had not achieved CCyR on imatinib and were switched to dasatinib within 12 months of initiating imatinib therapy had CCyR and MMR rates of 77% and 61%, respectively. Among patients with prior hematologic intolerance to imatinib, 44% achieved CCyR and
30% achieved MMR on dasatinib. In contrast, 79% and 60% of patients with prior nonhematologic intolerance to imatinib achieved CCyR and MMR on dasatinib, respectively. Progression-Free Survival and Overall Survival with Dasatinib Therapy Progression-free survival (PFS) and overall survival (OS) at 2 years in imatinib-intolerant patients, stratified by cytogenetic response at the start of dasatinib therapy, are shown in
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Figures 2A and 2B, respectively. Rates of PFS and OS in imatinib-intolerant patients with CCyR
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on imatinib and at the start of dasatinib were 96% and 100%, respectively. The rates for those who had CCyR on imatinib but not at the start of dasatinib were 97% and 98%, respectively. In patients who did not achieve CCyR on imatinib, those with >12 months of imatinib treatment
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had PFS and OS rates of 78% and 96%, respectively. The corresponding rates for patients treated with imatinib for ≤12 months were 92% and 97%, respectively.
PFS and OS, stratified by type of intolerance to imatinib, are shown in Figures 3A and 3B, respectively. Overall rates of PFS and OS at 2 years, regardless of type of intolerance to imatinib, were 90% and 97%, respectively. Patients with nonhematologic intolerance to imatinib had better outcomes (94% PFS and 98% OS) compared with patients with hematologic intolerance to imatinib (68% PFS and 88% OS). Four patients with hematologic imatinib toxicity
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only, 5 patients with nonhematologic imatinib toxicity only, and 1 patient with both transformed
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Discussion
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to accelerated/blast phase disease or died due to progressive disease on study.
In the presented pooled analysis of data from phase II and III studies, 83% of patients
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who were intolerant to imatinib did not have cross-intolerance to dasatinib. Furthermore, with a median treatment duration of 22 months, rates of PFS and OS were high (90% and 97%, respectively), providing evidence of the effectiveness of dasatinib in patients with imatinib intolerance. Our pooled analysis supports the most recent data from trial CA180-034 at 7 years of follow-up, which showed that imatinib-intolerant (and -resistant) patients with CML-CP can experience long-term benefit with dasatinib therapy, particularly if achieving BCR-ABL ≤10% at 3 months.18 Of note, we show that nonhematologic intolerance to imatinib does not necessarily translate to nonhematologic intolerance to dasatinib. Indeed, only 1 patient who received
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dasatinib at a dose of 100 mg once daily discontinued as a result of recurrence of the same
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grade 3–4 nonhematologic AE initially experienced with imatinib. Furthermore, patients who experienced hepatotoxicity with imatinib did not have similar toxicity with dasatinib. These
results are similar to those from a phase II study of nilotinib, in which nonhematologic cross-
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intolerance among patients with CML-CP was rare (1/60 [2%]).19
Forty-five patients with nonhematologic imatinib intolerance discontinued dasatinib therapy due to toxicity in this analysis. There was no clear relationship identified between the type of nonhematologic intolerance to prior imatinib therapy and the AEs on dasatinib that lead to discontinuation. Previous studies have explored potential risk factors associated with dasatinib toxicity.20,21 Consistent with one of these reports, we found 4 patients with rashes on imatinib who discontinued dasatinib due to pleural effusions.20 However, with cross-intolerance
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to imatinib being an unlikely explanation for dasatinib toxicity, additional studies are warranted
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to determine risk factors for dasatinib-related adverse events. Our study shows that recurrence of hematologic intolerance in dasatinib-treated patients
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with previous hematologic intolerance to imatinib was high (37/43 [86%]), with 8 (19%) patients discontinuing dasatinib therapy due to cross-intolerance. Increased inhibition of BCR-ABL–
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driven hematopoiesis or unrelated transduction pathways may contribute to hematologic toxicity; however, this latter possibility is unlikely, as rates of grade 3–4 hematologic toxicities are low (1−5%) in dasatinib-treated patients with solid tumors.22-25 Recurrence was unrelated to dose and may reflect effective inhibition by dasatinib of BCR-ABL–driven hematopoiesis, consistent with a previous study association between imatinib-related cytopenia, cytogenetic and hematologic remission, and high pretreatment BCR-ABL–positive cells measured by fluorescence in situ hybridization.26 Adherence and resistance to tyrosine kinase inhibitors (TKIs) among adolescents and young adults (AYA) with CML have been the focus of several recent studies.27-30 It has also been suggested that TKIs may be better tolerated by AYA patients (aged ≤29 years) than older
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patients (>29 years) with CML.30 In this pooled analysis of dasatinib patients, the age range was
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19 to 84 years. Although there were several patients who fell into this AYA population, there were not enough patients aged ≤29 years to definitively determine if AYA patients with imatinibintolerant CML had lower rates of cross-intolerance to dasatinib. Additional studies would be
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necessary to determine the rate of cross-intolerance to dasatinib in younger versus older patients with CML.
The phase II trial included in this pooled analysis reported a CCyR rate of 75% among 99 CML-CP imatinib-intolerant patients who received dasatinib at a dose of 70 mg twice daily.13 In the phase III trial, 670 CML-CP patients with resistance, intolerance, or suboptimal response to imatinib were randomly assigned to 1 of 4 dasatinib regimens, with CCyR rates ranging from 67–73% in the imatinib-intolerant subgroup after 2 years.16
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In the present analysis, CCyR rates in response to dasatinib were high in patients who
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had achieved prior CCyR to imatinib. Furthermore, half of patients who failed to achieve CCyR with imatinib treatment for >12 months achieved CCyR during subsequent dasatinib treatment,
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which suggests that longer duration on a suboptimal dose (due to dose reductions and interruption for intolerance), and consequently, incomplete inhibition of BCR-ABL, may have led
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to the emergence of resistance mechanisms that limited sensitivity to subsequent dasatinib. Increased rates of CCyR and MMR were observed in patients with nonhematologic intolerance to imatinib compared with patients with hematologic intolerance to imatinib. Effects on disease progression and survival followed a similar pattern, with increased 2-year PFS and OS rates in patients with nonhematologic versus hematologic intolerance to imatinib. The reasons for the higher rates of response and survival in patients with nonhematologic intolerance versus hematologic intolerance to imatinib are speculative, but it is possible that frequencies of dose reductions and interruptions and/or primary drug resistance may have been contributing factors. A limitation of this study is that it is a retrospective analysis of prospectively collected data. Additionally, our study focus was to measure cross-intolerance between imatinib and
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dasatinib and, therefore, dasatinib-specific toxicities, such as pleural effusion, were not
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investigated during imatinib therapy in this analysis. However, we found that only 14% of dasatinib-treated patients who were previously imatinib-intolerant discontinued dasatinib
because of any nonhematologic toxicity. Published data regarding dasatinib-related toxicities
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have noted higher pleural effusion rates than reported with imatinib, albeit this nonhematologic AE led to treatment discontinuation in only 6% of dasatinib-treated patients.9-12
Conclusions
In conclusion, these results confirm the safety and efficacy of dasatinib in imatinibintolerant patients with CML-CP. The lack of cross-intolerance with nonhematologic AEs is particularly notable, and although the rate of cross-intolerance with hematologic AEs is high,
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most patients continued with dasatinib therapy. Significant clinical responses were observed in
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patients, even in those with hematologic cross-intolerance, as well as in patients who failed to respond to imatinib after >12 months of treatment. The clinical safety and efficacy of dasatinib in
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CML-CP, in addition to the low rate of discontinuation with dasatinib, support its suitability as an
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appropriate second-line treatment for imatinib-intolerant patients.
Clinical Practice Points •
Introduction of BCR-ABL TKIs for the treatment of CML has resulted in significantly improved response rates and outcomes in many patients; however, resistance or intolerance to first-line imatinib, the first approved BCR-ABL TKI, has limited its use in some
•
Second-generation BCR-ABL TKIs, including dasatinib, are often prescribed for these patients, but cross-intolerance may present another challenge for this population
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•
Presented here is a retrospective, pooled analysis of phase II and III data from 271
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imatinib-intolerant patients with CML who were treated with dasatinib and evaluated for extent of cross-intolerance •
The vast majority of patients (83%) did not have cross-intolerance to dasatinib, based on
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recurrence of grade 3–4 AEs
Of note, nonhematologic intolerance to imatinib did not necessarily translate to nonhematologic intolerance to dasatinib
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High rates of PFS and OS were observed in imatinib-intolerant patients treated with dasatinib
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This analysis presents evidence of clinical safety and efficacy for dasatinib treatment in
agent in this population
Additionally, we provide important information on the recurrence of AEs associated with
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•
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CML patients with imatinib intolerance, supporting the use of dasatinib as a second-line
first-line imatinib use and expand knowledge of factors that may influence the effectiveness
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of second-generation BCR-ABL inhibitors in imatinib-intolerant CML patients
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Acknowledgments
This analysis was supported by research funding from Bristol-Myers Squibb (BMS). Professional medical writing support and editorial assistance was provided by Ami P. Modi, PhD, of StemScientific, an Ashfield Company, part of UDG Healthcare plc, funded by BMS. The authors did not receive financial compensation for authoring the manuscript.
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References Gleevec (imatinib) [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2015.
de Lavallade H, Apperley JF, Khorashad JS, et al. Imatinib for newly diagnosed patients
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2.
with chronic myeloid leukemia: incidence of sustained responses in an intention-to-treat analysis. J Clin Oncol 2008; 26:3358-63. 3.
Deininger M, O'Brien S, Guilhot F, et al. International randomized study of interferon vs STI571 (IRIS) 8-year follow up: sustained survival and low risk for progression or events in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) treated
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with imatinib. Blood 2009; 114(22):abstract 1126.
Sprycel (dasatinib) [prescribing information]. Princeton, NJ: Bristol-Myers Squibb; 2014.
5.
Tasigna (nilotinib) [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals
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Corporation; 2015.
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4.
Bosulif (bosutinib) [prescribing information]. New York, NY: Pfizer Labs; 2014.
7.
Iclusig (ponatinib) [prescribing information]. Cambridge, MA; ARIAD Pharmaceuticals, Inc.;
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6.
2014. 8.
The NCCN Clinical Practice Guidelines in Oncology™ Chronic Myelogenous Leukemia (Version 1.2016). ©2015 National Comprehensive Cancer Network, Inc. All rights reserved. NCCN.org. Accessed January 26, 2016.
9.
Kantarjian H, Shah NP, Hochhaus A, et al. Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 2010; 362:2260-70.
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10. Kantarjian HM, Shah NP, Cortes JE, et al. Dasatinib or imatinib in newly diagnosed chronic-
(DASISION). Blood 2012; 119:1123-9.
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phase chronic myeloid leukemia: 2-year follow-up from a randomized phase 3 trial
11. Jabbour E, Kantarjian HM, Saglio G, et al. Early response with dasatinib or imatinib in
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chronic myeloid leukemia: 3-year follow-up from a randomized phase 3 trial (DASISION). Blood 2014; 123:494-500.
12. Cortes J, Saglio G, MD, Baccarani M, et al. Final study results of the phase 3 dasatinib versus imatinib in newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) trial (DASISION, CA180-056). Presented at ASH Annual Meeting and Exposition; December 6-9, 2014; San Francisco, CA; Abstract 152.
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13. Hochhaus A, Baccarani M, Deininger M, et al. Dasatinib induces durable cytogenetic
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responses in patients with chronic myelogenous leukemia in chronic phase with resistance
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or intolerance to imatinib. Leukemia 2008; 22:1200-6. 14. Hochhaus A, Kantarjian HM, Baccarani M, et al. Dasatinib induces notable hematologic and
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cytogenetic responses in chronic-phase chronic myeloid leukemia after failure of imatinib therapy. Blood 2007; 109:2303-9. 15. Shah NP, Kantarjian HM, Kim DW, et al. Intermittent target inhibition with dasatinib 100 mg once daily preserves efficacy and improves tolerability in imatinib-resistant and -intolerant chronic-phase chronic myeloid leukemia. J Clin Oncol 2008; 26:3204-12. 16. Shah NP, Kim DW, Kantarjian H, et al. Potent, transient inhibition of BCR-ABL with dasatinib 100 mg daily achieves rapid and durable cytogenetic responses and high transformation-free survival rates in chronic phase chronic myeloid leukemia patients with resistance, suboptimal response or intolerance to imatinib. Haematologica 2010; 95:232-40.
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17. Shah NP, Guilhot F, Cortes JE, et al. Long-term outcome with dasatinib after imatinib failure
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in chronic-phase chronic myeloid leukemia: follow-up of a phase 3 study. Blood 2014; 123:2317-24.
18. Shah NP, Rousselot P, Schiffer C, et al. Seven-year follow-up of patients with imatinib-
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resistant or -intolerant chronic-phase chronic myeloid leukemia receiving dasatinib in study CA180-034, final study results. Presented at ASH Annual Meeting and Exposition; December 6-9, 2014; San Francisco, CA; Abstract 520.
19. Cortes JE, Hochhaus A, le Coutre PD, et al. Minimal cross-intolerance with nilotinib in patients with chronic myeloid leukemia in chronic or accelerated phase who are intolerant to imatinib. Blood 2011; 117:5600-6.
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20. de Lavallade H, Punnialingam S, Milojkovic D, et al. Pleural effusions in patients with
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chronic myeloid leukaemia treated with dasatinib may have an immune-mediated
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pathogenesis. Br J Haematol 2008; 14:745-7. 21. Quintás-Cardama A, Kantarjian H, O’Brien S, et al. Pleural Effusion in Patients With
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Chronic Myelogenous Leukemia Treated With Dasatinib After Imatinib Failure. J Clin Oncol 2007; 25:3908-3914.
22. Demetri GD, Lo Russo P, MacPherson IR, et al. Phase I dose-escalation and pharmacokinetic study of dasatinib in patients with advanced solid tumors. Clin Cancer Res 2009; 15:6232-40. 23. Miller AA, Pang H, Hodgson L, et al. A phase II study of dasatinib in patients with chemosensitive relapsed small cell lung cancer (Cancer and Leukemia Group B 30602). J Thorac Oncol 2010; 5:380-4.
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24. Yu EY, Wilding G, Posadas E, et al. Phase II study of dasatinib in patients with metastatic
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castration-resistant prostate cancer. Clin Cancer Res 2009; 15:7421-28.
25. Johnson FM, Agrawal S, Burris H, et al. Phase 1 pharmacokinetic and drug-interaction
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study of dasatinib in patients with advanced solid tumors. Cancer 2010; 116:1582-91. 26. Lima LM, Sampat K, Assouline S, et al. Does pretreatment fluorescence in situ hybridization for BCR-ABL predict imatinib-associated hematologic toxicity in chronic myeloid leukemia? Leuk Lymphoma 2011; 52:1010-16.
27. Sakurai M, Mori T, Karigane D, et al. Unfavorable outcome of chronic myelogenous leukemia in adolescent and young adults treated with tyrosine kinase inhibitors. Int J
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Hematol 2015; 102:342-8.
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28. Kalmanti L, Saussele S, Lauseker M, et al. Younger patients with chronic myeloid leukemia do well in spite of poor prognostic indicators: results from the randomized CML study IV.
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Ann Hematol 2014; 93:71-80.
29. Castagnetti F, Gugliotta G, Baccarani M, et al. Differences among young adults, adults and
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elderly chronic myeloid leukemia patients. Ann Oncol 2015; 26:185-92. 30. Pemmaraju N, Kantarjian H, Shan J, et al. Analysis of outcomes in adolescents and young adults with chronic myelogenous leukemia treated with upfront tyrosine kinase inhibitor therapy. Haematologica 2012; 97:1029-35.
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Table 1 Baseline Characteristics in Imatinib-Intolerant CML-CP Patients From Two Second-
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Line Dasatinib Studies (n = 271)
Median age (range), years
56 (19–84)
Median time from diagnosis of CML to start of dasatinib (range), months
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Prior imatinib dose, n (%) 400–600 mg/day > 600 mg/day Other
Median duration of imatinib therapy (range), years Imatinib therapy duration, n (%)
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<1 year
> 3 years Other prior therapy, n (%)
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1–3 years
24 (1–183)
249 (92) 20 (7) 2 (<1) 0.8 (0–5.8)
159 (59) 76 (28) 36 (13)
91 (34)
Interferon-α
37 (14)
Stem cell transplantation
14 (5)
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Chemotherapy
Category of imatinib intolerance, n (%) Nonhematologic only
225 (83)
Hematologic only
43 (16)
Both
3 (1)
Abbreviations: CML = chronic myeloid leukemia; CML-CP = chronic phase chronic myeloid leukemia.
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Median duration of dasatinib therapy (range), months Median daily dose of dasatinib (range), mg Dasatinib dose, n (%) 100 mg once daily
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Table 2. Dasatinib Treatment
22 (<1–31)
95 (10–152)
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43 (16)
50 mg twice daily
43 (16)
140 mg once daily
44 (16)
70 mg twice daily
141 (52)
Dasatinib dose adjustments, n (%) Interruption
223 (82)
Reduction
184 (68)
Discontinuation
121 (45)
Disease progression
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Hematologic toxicity
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Reasons for discontinuing dasatinib therapy, n (%)
Nonhematologic toxicity
16 (6) 19 (7) 38 (14)
Reasons for discontinuing dasatinib in patients with hematologic
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imatinib intolerance (n = 43), n (%)
9 (21)
Nonhematologic toxicity
3 (7)
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Hematologic toxicity
Reasons for discontinuing dasatinib in patients with nonhematologic imatinib intolerancea (n = 228), n (%) Hematologic toxicity
10 (4)
Nonhematologic toxicity
35 (15)
a
Three patients had both hematologic and nonhematologic intolerance to imatinib; these patients are
included in the nonhematologic intolerance group but did not discontinue dasatinib for toxicity. One patient who discontinued imatinib because of nonhematologic intolerance discontinued dasatinib for both hematologic and nonhematologic reasons and is included in both of these categories of reasons for discontinuing dasatinib therapy.
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Table 3 Intolerance to Imatinib and Recurrence During Dasatinib Therapya
Cause of intolerance
Discontinued imatinib for grade 3–4 AE
Nonhematologic intolerance 90
Same grade 3–4 AE on dasatinib
5 (4 possible cases)
48
0
19
2
15
2 (2 possible cases)
9
(1 possible cases)
9
(2 possible cases)
6
0
5
0
2
0
1
0
1
1
1
0
1
0
Hemorrhagic conjunctivitis
1
0
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Rash
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Patients, n
Hepatotoxicity
Hypotension
1
0
Nausea
1
0
Paresthesia
1
0
Keratoconjunctivitis sicca
1
0
Nephritis
1
0
Weight gain
1
0
Not specified
14
(3 possible cases)
Total
228
10 (12 possible cases)
1
1
Myalgia/arthralgia Gastrointestinal toxicity Fluid retention Pulmonary toxicity Bone pain Fatigue
Cardiac toxicity
Asthenia
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Arthritis
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Allergic reaction
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Neuropathy
Hematologic intolerance Anemia
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1
1
Neutropenia
12
12
Neutropenia + thrombocytopenia
6
Thrombocytopenia
20
Not specified
3
Total
43
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Leukopenia + thrombocytopenia
5
18
(2 possible cases)
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37 (2 possible cases)
All intolerant patients
271
Abbreviation: AE = adverse event. a
47 (14 possible cases)
Three patients had both hematologic and nonhematologic intolerance to imatinib; these patients are
included in the nonhematologic intolerance group. Four patients had grade 3–4 cytopenia at the start of
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dasatinib treatment.
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Table 4 Cytogenetic Response in Imatinib-Intolerant Patients
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CyR on imatinib, n (%) CCyR on imatinib
79 (29)
Non-complete CyR on imatinib
171 (63)
CyR on imatinib not reported
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21 (8)
CyR on dasatinib, n (%)
Prior CCyR on imatinib and at start of dasatinib
30 (11)
Prior CCyR on imatinib but not at start of dasatinib
49 (18)
Prior non-complete CyR on imatinib and CCyR at start of dasatinib Prior non-complete CyR on imatinib and at start of dasatinib
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Prior non-complete CyR on imatinib and undetermined CyR at start of dasatinib
6 (2) 164 (61) 1 (<1) 19 (7)
Prior CyR on imatinib not reported and undetermined CyR at start of dasatinib
2 (<1)
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Prior CyR on imatinib not reported and non-complete CyR at start of dasatinib
CCyR status on dasatinib, n (%)
199 (73)
Patients who did not achieve CCyR on dasatinib
72 (27)
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Patients who achieved CCyR on dasatinib
Daily dose of dasatinib based on CCyR status on dasatinib, median (range), mg Patients who achieved CCyR on dasatinib
99 (25, 152)
Patients who did not achieve CCyR on dasatinib
72 (10, 147)
Abbreviations: CCyR = complete cytogenetic response; CyR = cytogenetic response.
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Figure Legends Figure 1 CCyR and MMR at 2 Years
(a) Imatinib-intolerant patients were stratified by cytogenetic response on imatinib and at start of
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dasatinib. Cytogenetic response on imatinib was reported in 250 patients; the 21 patients in whom cytogenetic response on imatinib was not reported are not included in this analysis. (b) Patients were stratified by type of intolerance to imatinib. Three patients had both hematologic and nonhematologic intolerance to imatinib; these patients are included in the nonhematologic intolerance group. CCyR = complete cytogenetic response; MMR = major molecular response.
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Figure 2 Kaplan-Meier Analyses of (a) PFS and (b) OS Stratified by Cytogenetic Response
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Imatinib-intolerant patients were stratified by cytogenetic response at start of dasatinib. Cytogenetic response on imatinib was reported in 250 patients; the 21 patients in whom
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cytogenetic response on imatinib was not reported are not included in this analysis.
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CCyR = complete cytogenetic response; OS = overall survival; PFS = progression-free survival.
Figure 3 Kaplan-Meier Analyses of (a) PFS and (b) OS Stratified by Type of Intolerance Patients were stratified by type of intolerance (hematologic vs nonhematologic) to imatinib. Three patients had both hematologic and nonhematologic intolerance to imatinib; these patients are included in the nonhematologic intolerance group. OS = overall survival; PFS = progressionfree survival.
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dasatinib discontinuation Causes of nonhematologic imatinib intolerance at baseline Patient Arthralgia Myalgia Arthralgia Myalgia
Bone pain
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2
Indigestion
Arthralgia Myalgia
4
Asthenia
5 6
Bronchiolitis Fluid retention
7
Gastrointestinal toxicity
8
Gastrointestinal toxicity
9
Gastrointestinal toxicity
10
Gastrointestinal toxicity
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12
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11
Causes of on-study dasatinib discontinuation
Nonhematologic adverse events
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Supplemental table 1 Causes of baseline nonhematologic imatinib intolerance and on-study
Hepatotoxicity
Hepatotoxicity
13 14 15
Hepatotoxicity Hepatotoxicity Hepatotoxicity
16
Keratoconjunctivitis sicca
17 18 19
Neuropathy Pulmonary toxicity Pulmonary toxicity
20
Rash
21
Rash
Paresthesia Persistent cough Pulmonary edema QTC prolongation Rash Pain Depressive syndrome impairment Pneumonitis Stomach pain Diarrhea Gastritis Headache Muscular pain Diarrhea Muscle and joint pain Rash Stomach pain Vomiting Pleural effusion Pneumonia Pleural effusion Abdominal pain Dysgeusia Headache Nausea Chest discomfort Shortness of breath Hypersensitivity pneumonitis Musculoskeletal pain extended Prolong QTC interval Dilated cardiomyopathy-left ventricular systolic dysfunction Pleural effusion Pleural effusion Thrombus embolism Acne Face edema Adult respiratory distress syndrome
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Rash
23 24 25 26
Rash Rash Rash Rash
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Rash
28 29 30 31 32 33 34 35
Rash Rash Rash Rash Rash Rash Rash Unspecified
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Cardiac functional rhythm EBV associated B-cell lympholiferative disorder Pleural effusion Cardiac infarction Congestive heart failure Dyspnea Fever Headache Rash (cutaneous) Left ventricular diastolic dysfunction Neuropathy Pleural effusion Pleural effusion Pleural effusion Rash Shortness of breath Pulmonary edema (recurrent) Hematologic adverse events
Rash
6
Rash
7 8 9 10
Rash Rash Unspecified Unspecified
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5
Pancytopenia
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2 3 4
Arthralgia Myalgia Asthenia Hepatotoxicity Rash
1
Thrombopenia Neutropenia 6G/DL hemoglobin Neutropenia Thrombopenia Neutropenia Thrombopenia Thrombocytopenia Thrombocytopenia Anemia Cytopenia
28
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90
CCyR on imatinib and at start of dasatinib (n=30)
SC
53
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CCyR on imatinib but not at start of dasatinib (n=49)
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61
50
No prior CCyR on imatinib >12 months (n=62)
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76
77
No prior CCyR on imatinib ≤12 months (n=109)
0
84
35
20
40 60 Patients, %
80
100
CCyR MMR
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44
SC
Hematologic intolerance to imatinib (n=43)
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CCyR
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Nonhematologic intolerance to imatinib (n=228)
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30
79
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60
0
20
40
60
Patients, %
80
100
MMR
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100 90
SC
70 60
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50 40
2-year PFS
30
CCyR on imatinib and at start of dasatinib (n=30)
96%
CCyR on imatinib but not at start of dasatinib (n=49)
97%
No prior CCyR and imatinib >12 months (n=62)
78%
No prior CCyR and imatinib ≤12 months (n=109)
92%
20 10 0 6
9
12
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3
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Months
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0
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% Not progressed
80
15
18
21
24
27
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100 90 80
SC
60 50 40
0 0
98%
No prior CCyR and imatinib >12 months (n=62)
96%
No prior CCyR and imatinib ≤12 months (n=109)
97%
3
6
9
12
15
Months
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10
CCyR on imatinib but not at start of dasatinib (n=49)
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20
100%
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30
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2-year OS
CCyR on imatinib and at start of dasatinib (n=30)
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% Alive
70
18
21
24
27
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100
SC
90
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70 60 50 40 30 20
2-year PFS
Hematologic intolerance to imatinib (n=43)
68%
Nonhematologic intolerance to imatinib (n=228)
94%
0 6
9
TE
3
EP
0
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10
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% Not progressed
80
12
15 Months
18
21
24
27
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100
SC
90 80
50 40 30 20
M AN U
60
2-year OS
Hematologic intolerance to imatinib (n=43)
10
88%
0 6
9
12
TE
3
EP
0
98%
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Nonhematologic intolerance to imatinib (n=228)
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% Alive
70
Months
15
18
21
24
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S2152-2650(16)30016-7
DOI:
10.1016/j.clml.2016.03.004
Reference:
CLML 771
To appear in:
Clinical Lymphoma, Myeloma and Leukemia
Received Date: 14 September 2015 Revised Date:
2 March 2016
Accepted Date: 21 March 2016
Please cite this article as: Khoury HJ, Goldberg SL, Mauro MJ, Stone RM, Deininger MW, BradleyGarelik MB, Mohamed H, Guilhot F, Cross-Intolerance with Dasatinib Among Imatinib-Intolerant Patients with Chronic-Phase Chronic Myeloid Leukemia, Clinical Lymphoma, Myeloma and Leukemia (2016), doi: 10.1016/j.clml.2016.03.004. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Cross-Intolerance with Dasatinib Among Imatinib-Intolerant Patients with Chronic-Phase Chronic Myeloid Leukemia
Hanna J. Khoury,1 Stuart L. Goldberg,2 Michael J. Mauro,3 Richard M. Stone,4
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Michael W. Deininger,5 M. Brigid Bradley-Garelik,6 Hesham Mohamed,6 François Guilhot7
1
Division of Hematology, Department of Hematology and Medical Oncology, Winship Cancer
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Institute of Emory University, 1365 Clifton Road NE, Suite C1152, Atlanta, GA 30322, USA [email: [email protected]] 2
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John Theurer Cancer Center at Hackensack University Medical Center, 92 2nd St,
Hackensack, NJ 07601, USA
[email: [email protected]] 3
Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, 1275 York Avenue,
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[email: [email protected]]
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Box 489, New York, NY 10065, USA
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Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA, USA 02115
[email: [email protected]] 5
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Department of Internal Medicine, Huntsman Cancer Institute at the University of Utah, 2000
Circle of Hope Drive #4280, Salt Lake City, UT 84112, USA [email: [email protected]] 6
Bristol-Myers Squibb, 777 Scudders Mill Rd, Princeton, NJ 08536, USA
[email: [email protected]]
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[email: [email protected]] 7
Department of Oncology, Hematology, and Cell Therapy, CHU de Poitiers, CIC Inserm 0802,
Poitiers, France 86021
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[email: [email protected]]
Address for correspondence:
Hanna J. Khoury, MD, 1365 Clifton Road, Suite C1152
Winship Cancer Institute of Emory University, Atlanta, GA 30322
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Phone: 404-778-3932; Fax: 404-778-4755; e-mail contact: [email protected]
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Conflict of Interest Statement HJK has received research support from Bristol-Myers Squibb (BMS), Chemgenex, Genzyme, Novartis, and Wyeth. SLG has received research support from Ariad, BMS, Novartis, and Pfizer, and has acted as a speaker for Ariad, BMS, and Novartis. MJM has received research funding
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from Novartis, and has acted as a consultant for Ariad, BMS, Novartis, and Pfizer. RMS has received research funding from Novartis, and has acted as a consultant for Ariad and BMS. MWD has served as a consultant for BMS and Novartis, and has received research funding from Calistoga and Genzyme. BB-G and HM are employees of BMS.
This analysis was supported by research funding from BMS. StemScientific, an Ashfield
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Company, part of UDG Healthcare plc, funded by BMS, provided medical writing and editorial
Abstract word count: 245
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support.
Tables: 4
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Main text word count: 2928
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Figures: 3
References: 30
Running title: Cross-intolerance with treatments in CML
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Abstract Some patients with chronic myeloid leukemia (CML) are intolerant to first-line imatinib treatment. Our retrospective data analysis of 271 CML imatinib-intolerant patients from
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phase II/III studies examined the extent of cross-intolerance between imatinib and dasatinib. Our results confirm clinical safety and efficacy of dasatinib in imatinib-
intolerant CML patients, suggesting that dasatinib may be a suitable treatment choice for this population.
Background: BCR-ABL inhibitors have improved the prognosis of patients with chronic myeloid leukemia (CML). However, imatinib, the first approved BCR-ABL inhibitor, is discontinued in many patients due to resistance or intolerance. Patients and Methods: This retrospective,
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pooled analysis of phase II/III data explores the extent of cross-intolerance between imatinib
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and dasatinib, a second-generation BCR-ABL inhibitor, in 271 CML imatinib-intolerant patients. Results: Overall, 47 patients (17%) had cross-intolerance to dasatinib based on recurrence of
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grade 3–4 adverse events (AEs). Of 228 patients who discontinued imatinib because of nonhematologic intolerance, 10 (4%) experienced the same severe nonhematologic AEs with
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dasatinib, with 4 (2%) of these patients discontinuing dasatinib due to cross-intolerance. Of 43 patients who discontinued imatinib because of hematologic intolerance, 37 (86%) had recurrence of grade 3–4 hematologic AEs with dasatinib, with 8 (19%) patients discontinuing dasatinib due to cross-intolerance. Among patients taking dasatinib at the optimized dose of 100 mg/day (n = 43), 1 patient (2%) discontinued therapy due to recurrence of nonhematologic AEs, and 3 (7%) discontinued due to recurrence of hematologic AEs. With a median treatment duration of 22 months, estimated rates of progression-free survival (PFS) and overall survival (OS) at 2 years were higher in patients with nonhematologic versus hematologic intolerance to imatinib who switched to dasatinib (PFS: 94% vs 68%, respectively; OS: 98% vs 88%,
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respectively). Conclusion: Dasatinib may be an appropriate treatment option for imatinib-
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intolerant patients with CML, with cross-intolerance resulting in discontinuation in a minority of patients.
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Keywords: Chronic myeloid leukemia, Dasatinib, Drug toxicity, Imatinib
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Introduction Imatinib, the first BCR-ABL inhibitor introduced for the treatment of chronic myeloid
leukemia (CML), was approved by the US Food and Drug Administration for the treatment of interferon-resistant or -intolerant CML in 2001 and newly-diagnosed CML in 2002.1 While
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imatinib is commonly prescribed as a first-line treatment for CML in chronic phase (CML-CP), long-term follow-up with this agent has demonstrated that clinical resistance and intolerance develops in many patients,2,3 often requiring a change in treatment. Therapeutic options in the second-line setting and beyond for patients who have failed imatinib include oral BCR-ABL inhibitors dasatinib, nilotinib, bosutinib, and ponatinib, as well as omacetaxine.4-8 Ponatinib and omacetaxine are the only therapies available to treat patients with a T315I BCR-ABL mutation. Allogeneic stem cell transplant may also be considered in eligible patients with a suitable
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donor.8
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Dasatinib was initially approved for the treatment of all phases of CML and Ph+ acute lymphoblastic leukemia after resistance or intolerance to first-line therapy, including imatinib
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based on the SRC–ABL Tyrosine Kinase Inhibition Activity Research Trial (START) program.4
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Additionally, the phase III randomized trial, Dasatinib versus Imatinib Study in Treatment-Naïve CML Patients (DASISION), demonstrated superior efficacy of dasatinib compared with imatinib as initial therapy.9-12 The primary endpoint of this study, confirmed complete cytogenetic response by 12 months, was achieved in 77% (95% confidence interval [CI]: 71 to 82) of patients treated with dasatinib compared with 66% (95% CI: 60 to 72) taking imatinib. Based on these results, dasatinib was approved for first-line treatment of patients with CML-CP.4,9 Dasatinib is structurally unrelated to imatinib; however, the common molecular target raises the possibility that cross-intolerance, where similar adverse events (AEs) occur with both agents, may arise. To investigate cross-intolerance between imatinib and dasatinib, we assessed the safety, tolerability, and efficacy of dasatinib in patients with imatinib-intolerant
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CML-CP using pooled data from the phase II CA180-013 (START-C) trial and the phase III
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CA180-034 trial.13-18 The presented analysis explores the extent of cross-intolerance between imatinib and dasatinib for hematologic and nonhematologic toxicities.
Study Design and Patient Eligibility
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Patients and Methods
Imatinib-intolerant patients with CML-CP were pooled from 2 international, multicenter clinical trials: CA180-013, a phase II study of dasatinib 70 mg twice daily in 387 patients with resistance (n = 288) or intolerance (n = 99) to imatinib,13,14 and CA180-034, a phase III doseoptimization study in patients with resistance (n = 498) or intolerance (n = 172) to imatinib who
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were randomly assigned to receive dasatinib 100 mg once daily (n = 167), 50 mg twice daily (n = 168), 140 mg once daily (n = 167), or 70 mg twice daily (n = 168).15,17,18 Entry criteria for the
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study populations have been published previously.13-15 Briefly, adult patients with CML-CP and primary or acquired resistance or intolerance to imatinib were included in the trials.13-15 In
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CA180-013, imatinib intolerance was defined as imatinib-related grade ≥3 nonhematologic
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toxicity or imatinib-related grade 4 hematologic toxicity persisting for >7 days.14 In CA180-034, imatinib intolerance was defined as grade ≥3 toxicity considered at least possibly related to imatinib at a dose of ≥400 mg/day, which led to discontinuation of therapy.15 In both studies, dose adjustments were allowed for inadequate response (escalation) and drug-related grade ≥2 nonhematologic toxicity or grade ≥3 hematologic toxicity (dose reduction or interruption).13-15,17,18 Studies were conducted in accordance with the Declaration of Helsinki and approved by local ethics committees or institutional review boards. All patients gave written informed consent.1315,17,18
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Assessments Complete hematologic response (CHR), major cytogenetic response (MCyR), and
complete cytogenetic response (CCyR) were evaluated for up to 2 years. Progression was
defined as increasing white blood cell count, loss of CHR or MCyR, confirmed accelerated/blast
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phase, or death. AEs and other symptoms occurring during dasatinib treatment were collected for the duration of the study and graded according to the Common Terminology Criteria for Adverse Events (CTCAE) v3.0. Cross-intolerance was defined as the recurrence of the same grade 3–4 AEs during dasatinib therapy that had been documented during imatinib therapy. Cross-intolerance data for the dasatinib 100 mg once-daily dose is presented, in addition to the overall population, as 100 mg once daily is the current approved starting dose for patients with
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CML-CP.
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Patient Characteristics
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Results
A total of 271 patients with imatinib intolerance were included in this analysis (n = 99
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treated patients from CA180-013; n = 172 treated patients from CA180-034). Baseline characteristics are shown in Table 1. The majority of patients (59%) received imatinib therapy for <1 year, while 28% received it for 1 to 3 years, and 13% for >3 years. Median duration of imatinib therapy was 0.8 years (range: 0 to 5.8 years). Median duration of CML at dasatinib initiation was 24 months (range: 1 to 183). Of the 271 patients, 225 (83%) had nonhematologic imatinib intolerance only, 43 (16%) had hematologic imatinib intolerance only, and 3 (1%) had both nonhematologic and hematologic intolerance to imatinib. In the following analyses, these last 3 patients are grouped with patients with nonhematologic intolerance unless otherwise indicated. Details regarding the nature of intolerance were not available in 14 patients with nonhematologic toxicity and 3 patients with hematologic toxicity. Median duration of imatinib
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therapy was 0.7 years (range: 0 to 5.8 years) for patients with nonhematologic intolerance and
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1.8 years (range: 0.1 to 4.9 years) for patients with hematologic intolerance to imatinib. Dasatinib Treatment
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Median duration of dasatinib therapy was 22 months (range: <1 to 31) at the time of analysis. Treatment characteristics are shown in Table 2. Patients were assigned to receive 100 mg once daily (16%), 50 mg twice daily (16%), 140 mg once daily (16%), or 70 mg twice daily (52%). Dose adjustments occurred in a limited number of cases (Table 2). Nonhematologic Intolerance in Patients Treated with Dasatinib
Among imatinib-intolerant CML patients, nonhematologic toxicity was more commonly cited as a reason for discontinuing dasatinib (14%) than hematologic toxicity (7%) or disease
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progression (6%) (Table 2). When examining the most common reasons for imatinib
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intolerance, patients who developed grade 3–4 hepatotoxicity, rash, myalgia/arthralgia, gastrointestinal (GI) toxicity, fluid retention, or pulmonary toxicity with imatinib typically did not
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develop the same grade 3–4 AE with dasatinib (Table 3). A total of 228 patients discontinued imatinib for nonhematologic intolerance, of which 10 (4%) experienced the same grade 3–4
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nonhematologic AE with dasatinib (rash [n = 5], myalgia/arthralgia [n = 2], GI toxicity [n = 2], cardiac toxicity [n = 1]), with a few of these patients (n = 4 [2%]) discontinuing dasatinib due to cross-intolerance. Reasons for discontinuation of dasatinib amongst the 228 patients included grade 3–4 nonhematologic toxicity in 35 patients (15%; n = 4 for the same type of nonhematologic toxicity) and hematologic toxicity amongst 10 patients (4%) (Table 2). For these 45 patients, causes of dasatinib discontinuation and baseline nonhematologic imatinib intolerance are detailed in Supplemental Table 1. There does not seem to be a discernible correlation between the AEs resulting in dasatinib discontinuation and nonhematologic toxicity due to previous imatinib therapy.
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Hematologic Intolerance in Patients Treated with Dasatinib Of the 43 patients who discontinued imatinib for hematologic intolerance, recurrence of the same grade 3–4 hematologic intolerance was observed in 37 (86%) patients treated with dasatinib (Table 3). The majority of recurrence cases (n = 36) involved thrombocytopenia or
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neutropenia, while 1 case consisted of anemia. Nine patients (21%) discontinued dasatinib for grade 3–4 hematologic toxicity (8 for the same type of hematologic toxicity, 1 for a different type of hematologic toxicity), while 3 (7%) discontinued dasatinib for nonhematologic toxicity (Table 2).
Patients Treated with 100 mg Once Daily
Of the 43 imatinib-intolerant patients who were subsequently treated with dasatinib
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100 mg once daily, 8 (19%) had hematologic intolerance only, 34 (79%) had nonhematologic
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intolerance, and 1 (2%) had both hematologic and nonhematologic intolerance to their first-line imatinib therapy. All 8 patients with a history of hematologic intolerance to imatinib experienced
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the same grade 3–4 hematologic toxicity when treated with dasatinib 100 mg once daily; 4/8 (50%) discontinued dasatinib due to hematologic toxicity (n = 3 due to cross-intolerance; n = 1
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due to a different type of hematologic toxicity). Among the 34 patients with nonhematologic intolerance only, 2 patients developed the same grade 3–4 AE (rash), of which 1 discontinued dasatinib for this reason. The patient with both hematologic and nonhematologic imatinib intolerance who was treated with dasatinib 100 mg once daily experienced the same grade 3–4 hematologic toxicity with dasatinib but discontinued dasatinib for another reason. Stratification of All Patients Based on Cytogenetic Response at Start of Dasatinib Therapy Patients were evaluated for efficacy based on CCyR on imatinib and at the start of dasatinib treatment (Table 4). Overall, 11% achieved CCyR on imatinib and had CCyR at the
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start of dasatinib treatment, 18% achieved CCyR on imatinib but did not have CCyR at the start
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of dasatinib treatment, and 63% of patients did not achieve CCyR on imatinib. In the population with nonhematologic intolerance, 73 (32%) had CCyR and 138 (61%) did not have CCyR on imatinib. Six (14%) patients with hematologic intolerance had CCyR and 33 (77%) did not have
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CCyR on imatinib. Cytogenetic response on imatinib was not reported in 8% of patients. Cytogenetic and Molecular Response in All Patients on Dasatinib Therapy
With 2 years of follow-up, 73% of patients had achieved CCyR on dasatinib (Table 4). The median daily dose of dasatinib in patients who achieved CCyR with dasatinib was 99 mg/day, compared with 72 mg/day in patients who did not achieve CCyR with dasatinib. CCyR and major molecular response (MMR) were evaluated in imatinib-intolerant
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patients at the 2-year follow-up, based on cytogenetic response on imatinib and at the start of
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dasatinib (Figure 1A) and based on type of intolerance to imatinib (Figure 1B). Of patients who had CCyR at the start of dasatinib, 90% maintained this response and 53% achieved MMR. Of
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patients with CCyR on imatinib, but not at the start of dasatinib therapy, 84% achieved CCyR and 76% achieved MMR. In patients who received imatinib for >12 months and did not achieve
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CCyR, 50% achieved CCyR on dasatinib and 35% achieved MMR. However, patients who had not achieved CCyR on imatinib and were switched to dasatinib within 12 months of initiating imatinib therapy had CCyR and MMR rates of 77% and 61%, respectively. Among patients with prior hematologic intolerance to imatinib, 44% achieved CCyR and
30% achieved MMR on dasatinib. In contrast, 79% and 60% of patients with prior nonhematologic intolerance to imatinib achieved CCyR and MMR on dasatinib, respectively. Progression-Free Survival and Overall Survival with Dasatinib Therapy Progression-free survival (PFS) and overall survival (OS) at 2 years in imatinib-intolerant patients, stratified by cytogenetic response at the start of dasatinib therapy, are shown in
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Figures 2A and 2B, respectively. Rates of PFS and OS in imatinib-intolerant patients with CCyR
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on imatinib and at the start of dasatinib were 96% and 100%, respectively. The rates for those who had CCyR on imatinib but not at the start of dasatinib were 97% and 98%, respectively. In patients who did not achieve CCyR on imatinib, those with >12 months of imatinib treatment
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had PFS and OS rates of 78% and 96%, respectively. The corresponding rates for patients treated with imatinib for ≤12 months were 92% and 97%, respectively.
PFS and OS, stratified by type of intolerance to imatinib, are shown in Figures 3A and 3B, respectively. Overall rates of PFS and OS at 2 years, regardless of type of intolerance to imatinib, were 90% and 97%, respectively. Patients with nonhematologic intolerance to imatinib had better outcomes (94% PFS and 98% OS) compared with patients with hematologic intolerance to imatinib (68% PFS and 88% OS). Four patients with hematologic imatinib toxicity
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only, 5 patients with nonhematologic imatinib toxicity only, and 1 patient with both transformed
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Discussion
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to accelerated/blast phase disease or died due to progressive disease on study.
In the presented pooled analysis of data from phase II and III studies, 83% of patients
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who were intolerant to imatinib did not have cross-intolerance to dasatinib. Furthermore, with a median treatment duration of 22 months, rates of PFS and OS were high (90% and 97%, respectively), providing evidence of the effectiveness of dasatinib in patients with imatinib intolerance. Our pooled analysis supports the most recent data from trial CA180-034 at 7 years of follow-up, which showed that imatinib-intolerant (and -resistant) patients with CML-CP can experience long-term benefit with dasatinib therapy, particularly if achieving BCR-ABL ≤10% at 3 months.18 Of note, we show that nonhematologic intolerance to imatinib does not necessarily translate to nonhematologic intolerance to dasatinib. Indeed, only 1 patient who received
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dasatinib at a dose of 100 mg once daily discontinued as a result of recurrence of the same
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grade 3–4 nonhematologic AE initially experienced with imatinib. Furthermore, patients who experienced hepatotoxicity with imatinib did not have similar toxicity with dasatinib. These
results are similar to those from a phase II study of nilotinib, in which nonhematologic cross-
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intolerance among patients with CML-CP was rare (1/60 [2%]).19
Forty-five patients with nonhematologic imatinib intolerance discontinued dasatinib therapy due to toxicity in this analysis. There was no clear relationship identified between the type of nonhematologic intolerance to prior imatinib therapy and the AEs on dasatinib that lead to discontinuation. Previous studies have explored potential risk factors associated with dasatinib toxicity.20,21 Consistent with one of these reports, we found 4 patients with rashes on imatinib who discontinued dasatinib due to pleural effusions.20 However, with cross-intolerance
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to imatinib being an unlikely explanation for dasatinib toxicity, additional studies are warranted
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to determine risk factors for dasatinib-related adverse events. Our study shows that recurrence of hematologic intolerance in dasatinib-treated patients
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with previous hematologic intolerance to imatinib was high (37/43 [86%]), with 8 (19%) patients discontinuing dasatinib therapy due to cross-intolerance. Increased inhibition of BCR-ABL–
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driven hematopoiesis or unrelated transduction pathways may contribute to hematologic toxicity; however, this latter possibility is unlikely, as rates of grade 3–4 hematologic toxicities are low (1−5%) in dasatinib-treated patients with solid tumors.22-25 Recurrence was unrelated to dose and may reflect effective inhibition by dasatinib of BCR-ABL–driven hematopoiesis, consistent with a previous study association between imatinib-related cytopenia, cytogenetic and hematologic remission, and high pretreatment BCR-ABL–positive cells measured by fluorescence in situ hybridization.26 Adherence and resistance to tyrosine kinase inhibitors (TKIs) among adolescents and young adults (AYA) with CML have been the focus of several recent studies.27-30 It has also been suggested that TKIs may be better tolerated by AYA patients (aged ≤29 years) than older
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patients (>29 years) with CML.30 In this pooled analysis of dasatinib patients, the age range was
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19 to 84 years. Although there were several patients who fell into this AYA population, there were not enough patients aged ≤29 years to definitively determine if AYA patients with imatinibintolerant CML had lower rates of cross-intolerance to dasatinib. Additional studies would be
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necessary to determine the rate of cross-intolerance to dasatinib in younger versus older patients with CML.
The phase II trial included in this pooled analysis reported a CCyR rate of 75% among 99 CML-CP imatinib-intolerant patients who received dasatinib at a dose of 70 mg twice daily.13 In the phase III trial, 670 CML-CP patients with resistance, intolerance, or suboptimal response to imatinib were randomly assigned to 1 of 4 dasatinib regimens, with CCyR rates ranging from 67–73% in the imatinib-intolerant subgroup after 2 years.16
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In the present analysis, CCyR rates in response to dasatinib were high in patients who
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had achieved prior CCyR to imatinib. Furthermore, half of patients who failed to achieve CCyR with imatinib treatment for >12 months achieved CCyR during subsequent dasatinib treatment,
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which suggests that longer duration on a suboptimal dose (due to dose reductions and interruption for intolerance), and consequently, incomplete inhibition of BCR-ABL, may have led
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to the emergence of resistance mechanisms that limited sensitivity to subsequent dasatinib. Increased rates of CCyR and MMR were observed in patients with nonhematologic intolerance to imatinib compared with patients with hematologic intolerance to imatinib. Effects on disease progression and survival followed a similar pattern, with increased 2-year PFS and OS rates in patients with nonhematologic versus hematologic intolerance to imatinib. The reasons for the higher rates of response and survival in patients with nonhematologic intolerance versus hematologic intolerance to imatinib are speculative, but it is possible that frequencies of dose reductions and interruptions and/or primary drug resistance may have been contributing factors. A limitation of this study is that it is a retrospective analysis of prospectively collected data. Additionally, our study focus was to measure cross-intolerance between imatinib and
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dasatinib and, therefore, dasatinib-specific toxicities, such as pleural effusion, were not
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investigated during imatinib therapy in this analysis. However, we found that only 14% of dasatinib-treated patients who were previously imatinib-intolerant discontinued dasatinib
because of any nonhematologic toxicity. Published data regarding dasatinib-related toxicities
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have noted higher pleural effusion rates than reported with imatinib, albeit this nonhematologic AE led to treatment discontinuation in only 6% of dasatinib-treated patients.9-12
Conclusions
In conclusion, these results confirm the safety and efficacy of dasatinib in imatinibintolerant patients with CML-CP. The lack of cross-intolerance with nonhematologic AEs is particularly notable, and although the rate of cross-intolerance with hematologic AEs is high,
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most patients continued with dasatinib therapy. Significant clinical responses were observed in
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patients, even in those with hematologic cross-intolerance, as well as in patients who failed to respond to imatinib after >12 months of treatment. The clinical safety and efficacy of dasatinib in
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CML-CP, in addition to the low rate of discontinuation with dasatinib, support its suitability as an
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appropriate second-line treatment for imatinib-intolerant patients.
Clinical Practice Points •
Introduction of BCR-ABL TKIs for the treatment of CML has resulted in significantly improved response rates and outcomes in many patients; however, resistance or intolerance to first-line imatinib, the first approved BCR-ABL TKI, has limited its use in some
•
Second-generation BCR-ABL TKIs, including dasatinib, are often prescribed for these patients, but cross-intolerance may present another challenge for this population
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•
Presented here is a retrospective, pooled analysis of phase II and III data from 271
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imatinib-intolerant patients with CML who were treated with dasatinib and evaluated for extent of cross-intolerance •
The vast majority of patients (83%) did not have cross-intolerance to dasatinib, based on
•
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recurrence of grade 3–4 AEs
Of note, nonhematologic intolerance to imatinib did not necessarily translate to nonhematologic intolerance to dasatinib
•
High rates of PFS and OS were observed in imatinib-intolerant patients treated with dasatinib
•
This analysis presents evidence of clinical safety and efficacy for dasatinib treatment in
agent in this population
Additionally, we provide important information on the recurrence of AEs associated with
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•
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CML patients with imatinib intolerance, supporting the use of dasatinib as a second-line
first-line imatinib use and expand knowledge of factors that may influence the effectiveness
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of second-generation BCR-ABL inhibitors in imatinib-intolerant CML patients
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Acknowledgments
This analysis was supported by research funding from Bristol-Myers Squibb (BMS). Professional medical writing support and editorial assistance was provided by Ami P. Modi, PhD, of StemScientific, an Ashfield Company, part of UDG Healthcare plc, funded by BMS. The authors did not receive financial compensation for authoring the manuscript.
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1.
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References Gleevec (imatinib) [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2015.
de Lavallade H, Apperley JF, Khorashad JS, et al. Imatinib for newly diagnosed patients
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2.
with chronic myeloid leukemia: incidence of sustained responses in an intention-to-treat analysis. J Clin Oncol 2008; 26:3358-63. 3.
Deininger M, O'Brien S, Guilhot F, et al. International randomized study of interferon vs STI571 (IRIS) 8-year follow up: sustained survival and low risk for progression or events in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) treated
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with imatinib. Blood 2009; 114(22):abstract 1126.
Sprycel (dasatinib) [prescribing information]. Princeton, NJ: Bristol-Myers Squibb; 2014.
5.
Tasigna (nilotinib) [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals
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Corporation; 2015.
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4.
Bosulif (bosutinib) [prescribing information]. New York, NY: Pfizer Labs; 2014.
7.
Iclusig (ponatinib) [prescribing information]. Cambridge, MA; ARIAD Pharmaceuticals, Inc.;
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6.
2014. 8.
The NCCN Clinical Practice Guidelines in Oncology™ Chronic Myelogenous Leukemia (Version 1.2016). ©2015 National Comprehensive Cancer Network, Inc. All rights reserved. NCCN.org. Accessed January 26, 2016.
9.
Kantarjian H, Shah NP, Hochhaus A, et al. Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 2010; 362:2260-70.
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10. Kantarjian HM, Shah NP, Cortes JE, et al. Dasatinib or imatinib in newly diagnosed chronic-
(DASISION). Blood 2012; 119:1123-9.
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phase chronic myeloid leukemia: 2-year follow-up from a randomized phase 3 trial
11. Jabbour E, Kantarjian HM, Saglio G, et al. Early response with dasatinib or imatinib in
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chronic myeloid leukemia: 3-year follow-up from a randomized phase 3 trial (DASISION). Blood 2014; 123:494-500.
12. Cortes J, Saglio G, MD, Baccarani M, et al. Final study results of the phase 3 dasatinib versus imatinib in newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) trial (DASISION, CA180-056). Presented at ASH Annual Meeting and Exposition; December 6-9, 2014; San Francisco, CA; Abstract 152.
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13. Hochhaus A, Baccarani M, Deininger M, et al. Dasatinib induces durable cytogenetic
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responses in patients with chronic myelogenous leukemia in chronic phase with resistance
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or intolerance to imatinib. Leukemia 2008; 22:1200-6. 14. Hochhaus A, Kantarjian HM, Baccarani M, et al. Dasatinib induces notable hematologic and
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cytogenetic responses in chronic-phase chronic myeloid leukemia after failure of imatinib therapy. Blood 2007; 109:2303-9. 15. Shah NP, Kantarjian HM, Kim DW, et al. Intermittent target inhibition with dasatinib 100 mg once daily preserves efficacy and improves tolerability in imatinib-resistant and -intolerant chronic-phase chronic myeloid leukemia. J Clin Oncol 2008; 26:3204-12. 16. Shah NP, Kim DW, Kantarjian H, et al. Potent, transient inhibition of BCR-ABL with dasatinib 100 mg daily achieves rapid and durable cytogenetic responses and high transformation-free survival rates in chronic phase chronic myeloid leukemia patients with resistance, suboptimal response or intolerance to imatinib. Haematologica 2010; 95:232-40.
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17. Shah NP, Guilhot F, Cortes JE, et al. Long-term outcome with dasatinib after imatinib failure
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in chronic-phase chronic myeloid leukemia: follow-up of a phase 3 study. Blood 2014; 123:2317-24.
18. Shah NP, Rousselot P, Schiffer C, et al. Seven-year follow-up of patients with imatinib-
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resistant or -intolerant chronic-phase chronic myeloid leukemia receiving dasatinib in study CA180-034, final study results. Presented at ASH Annual Meeting and Exposition; December 6-9, 2014; San Francisco, CA; Abstract 520.
19. Cortes JE, Hochhaus A, le Coutre PD, et al. Minimal cross-intolerance with nilotinib in patients with chronic myeloid leukemia in chronic or accelerated phase who are intolerant to imatinib. Blood 2011; 117:5600-6.
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20. de Lavallade H, Punnialingam S, Milojkovic D, et al. Pleural effusions in patients with
TE
chronic myeloid leukaemia treated with dasatinib may have an immune-mediated
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pathogenesis. Br J Haematol 2008; 14:745-7. 21. Quintás-Cardama A, Kantarjian H, O’Brien S, et al. Pleural Effusion in Patients With
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Chronic Myelogenous Leukemia Treated With Dasatinib After Imatinib Failure. J Clin Oncol 2007; 25:3908-3914.
22. Demetri GD, Lo Russo P, MacPherson IR, et al. Phase I dose-escalation and pharmacokinetic study of dasatinib in patients with advanced solid tumors. Clin Cancer Res 2009; 15:6232-40. 23. Miller AA, Pang H, Hodgson L, et al. A phase II study of dasatinib in patients with chemosensitive relapsed small cell lung cancer (Cancer and Leukemia Group B 30602). J Thorac Oncol 2010; 5:380-4.
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24. Yu EY, Wilding G, Posadas E, et al. Phase II study of dasatinib in patients with metastatic
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castration-resistant prostate cancer. Clin Cancer Res 2009; 15:7421-28.
25. Johnson FM, Agrawal S, Burris H, et al. Phase 1 pharmacokinetic and drug-interaction
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study of dasatinib in patients with advanced solid tumors. Cancer 2010; 116:1582-91. 26. Lima LM, Sampat K, Assouline S, et al. Does pretreatment fluorescence in situ hybridization for BCR-ABL predict imatinib-associated hematologic toxicity in chronic myeloid leukemia? Leuk Lymphoma 2011; 52:1010-16.
27. Sakurai M, Mori T, Karigane D, et al. Unfavorable outcome of chronic myelogenous leukemia in adolescent and young adults treated with tyrosine kinase inhibitors. Int J
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Hematol 2015; 102:342-8.
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28. Kalmanti L, Saussele S, Lauseker M, et al. Younger patients with chronic myeloid leukemia do well in spite of poor prognostic indicators: results from the randomized CML study IV.
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Ann Hematol 2014; 93:71-80.
29. Castagnetti F, Gugliotta G, Baccarani M, et al. Differences among young adults, adults and
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elderly chronic myeloid leukemia patients. Ann Oncol 2015; 26:185-92. 30. Pemmaraju N, Kantarjian H, Shan J, et al. Analysis of outcomes in adolescents and young adults with chronic myelogenous leukemia treated with upfront tyrosine kinase inhibitor therapy. Haematologica 2012; 97:1029-35.
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Table 1 Baseline Characteristics in Imatinib-Intolerant CML-CP Patients From Two Second-
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Line Dasatinib Studies (n = 271)
Median age (range), years
56 (19–84)
Median time from diagnosis of CML to start of dasatinib (range), months
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Prior imatinib dose, n (%) 400–600 mg/day > 600 mg/day Other
Median duration of imatinib therapy (range), years Imatinib therapy duration, n (%)
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<1 year
> 3 years Other prior therapy, n (%)
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1–3 years
24 (1–183)
249 (92) 20 (7) 2 (<1) 0.8 (0–5.8)
159 (59) 76 (28) 36 (13)
91 (34)
Interferon-α
37 (14)
Stem cell transplantation
14 (5)
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Chemotherapy
Category of imatinib intolerance, n (%) Nonhematologic only
225 (83)
Hematologic only
43 (16)
Both
3 (1)
Abbreviations: CML = chronic myeloid leukemia; CML-CP = chronic phase chronic myeloid leukemia.
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Median duration of dasatinib therapy (range), months Median daily dose of dasatinib (range), mg Dasatinib dose, n (%) 100 mg once daily
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Table 2. Dasatinib Treatment
22 (<1–31)
95 (10–152)
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43 (16)
50 mg twice daily
43 (16)
140 mg once daily
44 (16)
70 mg twice daily
141 (52)
Dasatinib dose adjustments, n (%) Interruption
223 (82)
Reduction
184 (68)
Discontinuation
121 (45)
Disease progression
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Hematologic toxicity
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Reasons for discontinuing dasatinib therapy, n (%)
Nonhematologic toxicity
16 (6) 19 (7) 38 (14)
Reasons for discontinuing dasatinib in patients with hematologic
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imatinib intolerance (n = 43), n (%)
9 (21)
Nonhematologic toxicity
3 (7)
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Hematologic toxicity
Reasons for discontinuing dasatinib in patients with nonhematologic imatinib intolerancea (n = 228), n (%) Hematologic toxicity
10 (4)
Nonhematologic toxicity
35 (15)
a
Three patients had both hematologic and nonhematologic intolerance to imatinib; these patients are
included in the nonhematologic intolerance group but did not discontinue dasatinib for toxicity. One patient who discontinued imatinib because of nonhematologic intolerance discontinued dasatinib for both hematologic and nonhematologic reasons and is included in both of these categories of reasons for discontinuing dasatinib therapy.
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Table 3 Intolerance to Imatinib and Recurrence During Dasatinib Therapya
Cause of intolerance
Discontinued imatinib for grade 3–4 AE
Nonhematologic intolerance 90
Same grade 3–4 AE on dasatinib
5 (4 possible cases)
48
0
19
2
15
2 (2 possible cases)
9
(1 possible cases)
9
(2 possible cases)
6
0
5
0
2
0
1
0
1
1
1
0
1
0
Hemorrhagic conjunctivitis
1
0
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Rash
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Patients, n
Hepatotoxicity
Hypotension
1
0
Nausea
1
0
Paresthesia
1
0
Keratoconjunctivitis sicca
1
0
Nephritis
1
0
Weight gain
1
0
Not specified
14
(3 possible cases)
Total
228
10 (12 possible cases)
1
1
Myalgia/arthralgia Gastrointestinal toxicity Fluid retention Pulmonary toxicity Bone pain Fatigue
Cardiac toxicity
Asthenia
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Arthritis
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Allergic reaction
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Neuropathy
Hematologic intolerance Anemia
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1
1
Neutropenia
12
12
Neutropenia + thrombocytopenia
6
Thrombocytopenia
20
Not specified
3
Total
43
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Leukopenia + thrombocytopenia
5
18
(2 possible cases)
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37 (2 possible cases)
All intolerant patients
271
Abbreviation: AE = adverse event. a
47 (14 possible cases)
Three patients had both hematologic and nonhematologic intolerance to imatinib; these patients are
included in the nonhematologic intolerance group. Four patients had grade 3–4 cytopenia at the start of
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dasatinib treatment.
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Table 4 Cytogenetic Response in Imatinib-Intolerant Patients
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CyR on imatinib, n (%) CCyR on imatinib
79 (29)
Non-complete CyR on imatinib
171 (63)
CyR on imatinib not reported
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21 (8)
CyR on dasatinib, n (%)
Prior CCyR on imatinib and at start of dasatinib
30 (11)
Prior CCyR on imatinib but not at start of dasatinib
49 (18)
Prior non-complete CyR on imatinib and CCyR at start of dasatinib Prior non-complete CyR on imatinib and at start of dasatinib
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Prior non-complete CyR on imatinib and undetermined CyR at start of dasatinib
6 (2) 164 (61) 1 (<1) 19 (7)
Prior CyR on imatinib not reported and undetermined CyR at start of dasatinib
2 (<1)
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Prior CyR on imatinib not reported and non-complete CyR at start of dasatinib
CCyR status on dasatinib, n (%)
199 (73)
Patients who did not achieve CCyR on dasatinib
72 (27)
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Patients who achieved CCyR on dasatinib
Daily dose of dasatinib based on CCyR status on dasatinib, median (range), mg Patients who achieved CCyR on dasatinib
99 (25, 152)
Patients who did not achieve CCyR on dasatinib
72 (10, 147)
Abbreviations: CCyR = complete cytogenetic response; CyR = cytogenetic response.
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Figure Legends Figure 1 CCyR and MMR at 2 Years
(a) Imatinib-intolerant patients were stratified by cytogenetic response on imatinib and at start of
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dasatinib. Cytogenetic response on imatinib was reported in 250 patients; the 21 patients in whom cytogenetic response on imatinib was not reported are not included in this analysis. (b) Patients were stratified by type of intolerance to imatinib. Three patients had both hematologic and nonhematologic intolerance to imatinib; these patients are included in the nonhematologic intolerance group. CCyR = complete cytogenetic response; MMR = major molecular response.
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Figure 2 Kaplan-Meier Analyses of (a) PFS and (b) OS Stratified by Cytogenetic Response
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Imatinib-intolerant patients were stratified by cytogenetic response at start of dasatinib. Cytogenetic response on imatinib was reported in 250 patients; the 21 patients in whom
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cytogenetic response on imatinib was not reported are not included in this analysis.
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CCyR = complete cytogenetic response; OS = overall survival; PFS = progression-free survival.
Figure 3 Kaplan-Meier Analyses of (a) PFS and (b) OS Stratified by Type of Intolerance Patients were stratified by type of intolerance (hematologic vs nonhematologic) to imatinib. Three patients had both hematologic and nonhematologic intolerance to imatinib; these patients are included in the nonhematologic intolerance group. OS = overall survival; PFS = progressionfree survival.
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dasatinib discontinuation Causes of nonhematologic imatinib intolerance at baseline Patient Arthralgia Myalgia Arthralgia Myalgia
Bone pain
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2
Indigestion
Arthralgia Myalgia
4
Asthenia
5 6
Bronchiolitis Fluid retention
7
Gastrointestinal toxicity
8
Gastrointestinal toxicity
9
Gastrointestinal toxicity
10
Gastrointestinal toxicity
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12
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3
11
Causes of on-study dasatinib discontinuation
Nonhematologic adverse events
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Supplemental table 1 Causes of baseline nonhematologic imatinib intolerance and on-study
Hepatotoxicity
Hepatotoxicity
13 14 15
Hepatotoxicity Hepatotoxicity Hepatotoxicity
16
Keratoconjunctivitis sicca
17 18 19
Neuropathy Pulmonary toxicity Pulmonary toxicity
20
Rash
21
Rash
Paresthesia Persistent cough Pulmonary edema QTC prolongation Rash Pain Depressive syndrome impairment Pneumonitis Stomach pain Diarrhea Gastritis Headache Muscular pain Diarrhea Muscle and joint pain Rash Stomach pain Vomiting Pleural effusion Pneumonia Pleural effusion Abdominal pain Dysgeusia Headache Nausea Chest discomfort Shortness of breath Hypersensitivity pneumonitis Musculoskeletal pain extended Prolong QTC interval Dilated cardiomyopathy-left ventricular systolic dysfunction Pleural effusion Pleural effusion Thrombus embolism Acne Face edema Adult respiratory distress syndrome
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Rash
23 24 25 26
Rash Rash Rash Rash
27
Rash
28 29 30 31 32 33 34 35
Rash Rash Rash Rash Rash Rash Rash Unspecified
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Cardiac functional rhythm EBV associated B-cell lympholiferative disorder Pleural effusion Cardiac infarction Congestive heart failure Dyspnea Fever Headache Rash (cutaneous) Left ventricular diastolic dysfunction Neuropathy Pleural effusion Pleural effusion Pleural effusion Rash Shortness of breath Pulmonary edema (recurrent) Hematologic adverse events
Rash
6
Rash
7 8 9 10
Rash Rash Unspecified Unspecified
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5
Pancytopenia
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2 3 4
Arthralgia Myalgia Asthenia Hepatotoxicity Rash
1
Thrombopenia Neutropenia 6G/DL hemoglobin Neutropenia Thrombopenia Neutropenia Thrombopenia Thrombocytopenia Thrombocytopenia Anemia Cytopenia
28
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90
CCyR on imatinib and at start of dasatinib (n=30)
SC
53
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CCyR on imatinib but not at start of dasatinib (n=49)
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61
50
No prior CCyR on imatinib >12 months (n=62)
AC C
76
77
No prior CCyR on imatinib ≤12 months (n=109)
0
84
35
20
40 60 Patients, %
80
100
CCyR MMR
ACCEPTED MANUSCRIPT
44
SC
Hematologic intolerance to imatinib (n=43)
RI PT
CCyR
D
Nonhematologic intolerance to imatinib (n=228)
M AN U
30
79
AC C
EP
TE
60
0
20
40
60
Patients, %
80
100
MMR
RI PT
ACCEPTED MANUSCRIPT
100 90
SC
70 60
M AN U
50 40
2-year PFS
30
CCyR on imatinib and at start of dasatinib (n=30)
96%
CCyR on imatinib but not at start of dasatinib (n=49)
97%
No prior CCyR and imatinib >12 months (n=62)
78%
No prior CCyR and imatinib ≤12 months (n=109)
92%
20 10 0 6
9
12
D
3
TE
Months
EP
0
AC C
% Not progressed
80
15
18
21
24
27
RI PT
ACCEPTED MANUSCRIPT
100 90 80
SC
60 50 40
0 0
98%
No prior CCyR and imatinib >12 months (n=62)
96%
No prior CCyR and imatinib ≤12 months (n=109)
97%
3
6
9
12
15
Months
D
10
CCyR on imatinib but not at start of dasatinib (n=49)
TE
20
100%
EP
30
M AN U
2-year OS
CCyR on imatinib and at start of dasatinib (n=30)
AC C
% Alive
70
18
21
24
27
RI PT
ACCEPTED MANUSCRIPT
100
SC
90
M AN U
70 60 50 40 30 20
2-year PFS
Hematologic intolerance to imatinib (n=43)
68%
Nonhematologic intolerance to imatinib (n=228)
94%
0 6
9
TE
3
EP
0
D
10
AC C
% Not progressed
80
12
15 Months
18
21
24
27
RI PT
ACCEPTED MANUSCRIPT
100
SC
90 80
50 40 30 20
M AN U
60
2-year OS
Hematologic intolerance to imatinib (n=43)
10
88%
0 6
9
12
TE
3
EP
0
98%
D
Nonhematologic intolerance to imatinib (n=228)
AC C
% Alive
70
Months
15
18
21
24
27