A Once-Daily Dasatinib Dosing Strategy for Chronic Myeloid Leukemia

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A Once-Daily Dasatinib Dosing Strategy
for Chronic Myeloid Leukemia
George Bryant, ND, ACNP-BC, ANP-BC, AOCNP®
The BCR-ABL inhibitor imatinib is standard first-line therapy for patients with chronic myeloid leukemia (CML) and has
revolutionized treatment of the disease. However, resistance and intolerance to the agent have emerged as major clinical
complications. Dasatinib is the first and only dual BCR-ABL/SRC family kinase inhibitor approved by the U.S. Food and
Drug Administration for the treatment of patients with CML in any phase or Philadelphia chromosome–positive acute
lymphoblastic leukemia who are resistant to or intolerant of imatinib. The agent is well tolerated and has shown clinical
activity in such patients. As with other oral tyrosine kinase inhibitors, nonadherence to the prescribed dasatinib treatment regimen could obstruct a successful outcome. A new recommended dose of 100 mg once daily has been approved
for patients with chronic phase CML. That dosing regimen, combined with appropriate management of dasatinib-related
adverse events, may help patients adhere to their prescribed treatment and achieve maximum therapeutic benefit. This
article highlights recent changes to the dasatinib label, including results with the 100 mg once-daily starting dose for
patients with chronic phase CML, and discusses nursing strategies for the successful management of adverse events in
patients receiving dasatinib.
C
hronic myeloid leukemia (CML) is a clonal myeloproliferative disorder of hematologic stem cells and
accounts for 15% of adult leukemias (Jemal et al.,
2007). CML is characterized by the abnormal multiplication of one or more lines of bone marrow cells,
including myelocytic, erythroblastic, and megakaryocytic cells
(Sawyers, 1999). The disease follows a triphasic course consisting of a relatively benign chronic phase (CP); a transitional,
accelerated phase (AP); and the rapidly fatal blast phase (BP)
(Sawyers). Progression from CP to BP usually occurs within
three to five years if the disease is untreated (Sawyers).
The underlying molecular lesion of CML is the product of
the Philadelphia chromosome (Ph), an aberration that results
from the exchange of genetic material between the BCR and
ABL genes on chromosomes 9 and 22, respectively. The resulting new chromosome produces a BCR-ABL fusion protein that
causes development and progression of CML (Faderl et al., 1999;
Sawyers, 1999). Imatinib (Gleevec®, Novartis Oncology) was
the first BCR-ABL–targeted treatment for CML (Druker et al.,
1996). As a result of its impressive activity and relatively mild
toxicity profile compared to previous treatment options, such
as interferon alpha and cytarabine, imatinib has become the
standard first-line therapy for CP CML and has revolutionized the
treatment of the disease (Soverini, Martinelli, Iacobucci, & Baccarani, 2008). Nonetheless, the therapeutic breakthrough with
tyrosine kinases does not represent a curative strategy for CML.
That would require the selective destruction of mutated stem
cells, a therapeutic modality that currently remains elusive.
316
At a Glance
F Imatinib, a first-line treatment for chronic myeloid leukemia
(CML), is associated with resistance and intolerance, necessitating second-line treatment options.

A new 100 mg once-daily dose of dasatinib, the first available second-line CML treatment, has demonstrated similar
efficacy and improved safety as other doses in patients with
chronic phase CML.

Dasatinib 70 mg twice daily remains the approved dosing
regimen in patients with advanced CML or Philadelphia
chromosome–positive acute lymphoblastic leukemia.
Despite significant improvements in the physical function, wellbeing, and quality of life of patients with CML treated with imatinib (Hahn et al., 2003), resistance and intolerance to this agent
have emerged as substantial clinical issues (Ramirez & DiPersio,
2008). In the pivotal phase III Immediate Risk-Stratification­
George Bryant, ND, ACNP-BC, ANP-BC, AOCNP®, is a nurse practitioner in
the Division of Leukemia and Stem Cell/Bone Marrow Transplant at Barnes
Jewish Hospital in St. Louis, MO. Mention of specific products and opinions
related to those products do not indicate or imply endorsement by the
Clinical Journal of Oncology Nursing or the Oncology Nursing Society. (Submitted June 23, 2008. Accepted for publication September 14, 2008.)
Digital Object Identifier:10.1188/09.CJON.316-323
June 2009 • Volume 13, Number 3 • Clinical Journal of Oncology Nursing
Rate of Adherence (%)
Improves Survival (IRIS) Study of patients with newly diagnosed
CP CML, approximately 25% of patients were initially refractory to imatinib (primary resistance). Relapse and progression
(acquired resistance) occurred in approximately 17% and 7%
of patients after five years of treatment, respectively (Druker
et al., 2006; Hughes & Branford, 2006; O’Brien et al., 2003).
Resistance to imatinib is more common among patients with
advanced-stage CML, and 51% of patients in blast crisis or AP
who initially respond to imatinib therapy eventually relapse
(Jabbour, Cortes, Giles, O’Brien, & Kantarjian, 2007; Lahaye
et al., 2005; Soverini et al., 2006). Imatinib intolerance was
observed in the IRIS trial: 4% of patients discontinued imatinib
as a result of adverse events (AEs) after a median follow-up of
60 months (Druker et al., 2006).
Another concern with oral tyrosine kinase inhibitors as well
as other oral cancer treatments is nonadherence to medication,
particularly with long-term treatments for patients with chronic
conditions, especially in the absence of overt disease (i.e., asymptomatic patients) (Partridge, Avorn, Wang, & Winer, 2002).
Deviating from treatment guidelines can hamper or even prevent
the achievement of therapeutic goals and may result in worsening of disease and death (Osterberg & Blaschke, 2005). Thus, the
importance of adherence to treatment guidelines is clear.
Several factors can contribute to nonadherence, including
numerous psychological variables (Osterberg & Blaschke,
2005), age (Partridge et al., 2002), and a patient’s understanding of the risks and benefits of taking medication (Osterberg
& Blaschke). The complexity of a treatment regimen also can
affect adherence (Claxton, Cramer, & Pierce, 2001; Osterberg
& Blaschke). Claxton et al. confirmed that adherence decreases
with increased dosing frequency per day (see Figure 1). Additionally, the incidence and severity of AEs can have an impact
on adherence (Druker et al., 2006; Hamdan et al., 2007). As
100
90
80
70
60
50
40
30
20
10
mentioned previously, 4% of patients in the IRIS trial discontinued imatinib after five years of follow-up as a result of an
AE (Druker et al., 2006). A retrospective analysis of patients
with CML identified in the medical and pharmacy claims in
the HealthCore Managed Care Database found that imatinib
therapy was suspended in 62 (29%) patients, most often because of anemia (11%) or thrombocytopenia (11%). Treatment
was discontinued permanently by 7% of patients (Hamdan et
al.). Furthermore, the incidence and severity of imatinib-related
AEs increase with higher doses (Druker et al., 2001). Although
a study has not been performed to evaluate the association, a
decreasing adherence rate also is noted (Sun, Fincher, Wang,
Lee, & Buchner, 2007) (see Table 1).
The U.S. Food and Drug Administration’s 2006 approval of
dasatinib (Sprycel®, Bristol-Myers Squibb), a BCR-ABL/SRC
family kinase (SFK) inhibitor, has provided another option
for patients with all phases of CML or those with Ph-positive
acute lymphoblastic leukemia (Ph+ ALL) who are resistant to
or intolerant of imatinib. However, nonadherence remains a
potential barrier to successful treatment. This article discusses
dosing strategies for the successful management of AEs in
patients receiving dasatinib and highlights the 2007 changes
to the dasatinib label, including results with the 100 mg oncedaily starting dose for patients with CP CML, which may help
with adherence.
Nilotinib (Tasigna®, Novartis Pharmaceuticals) is another
tyrosine kinase inhibitor clinically available for patients with
CP or AP CML who are resistant to imatinib (Kantarjian et al.,
2006; le Coutre, 2008). Nilotinib is more potent than its parent
compound, imatinib, but does not target SFKs like dasatinib.
Nilotinib is taken orally, and the approved schedule calls for a
twice-daily regimen with a fasting period of at least two hours
before and one hour after each administration. Black-box
warnings explain that QT prolongation and sudden death are
associated with nilotinib, which should be considered prior to
administration (Novartis Pharmaceuticals, 2008).
Dasatinib
One
Two
Three
Four
Medication Doses Daily
Note. Data were pooled from 76 studies from 1986–2000 that reported
adherence as measured with an electronic monitoring device. Mean
adherence was calculated for once-daily, twice-daily, three-times-daily,
and four-times-daily dosing regimens. Vertical lines represent 1 standard
deviation on either side of the mean adherence rate (horizontal bars).
Figure 1. Adherence to Medication According
to Frequency of Doses
Note. From “Adherence to Medication,” by L. Osterberg & T. Blaschke,
2005, New England Journal of Medicine, 353(5), p. 490. Copyright
2005 by the Massachusetts Medical Society. Reprinted with permission.
All rights reserved.
Dasatinib has shown 325-fold greater activity in vitro against
unmutated BCR-ABL compared with imatinib, representing an
enhanced binding affinity that could be important in overcoming resistance in mutated forms of BCR-ABL that have been described (O’Hare et al., 2005). Dasatinib also is effective against
all imatinib-resistant BCR-ABL mutations, which are the most
common causes of imatinib resistance in patients with CML
(Hochhaus, Erben, Ernst, & Mueller, 2007; O’Hare et al.; Shah
et al., 2004). The exception to this is the T315I “gatekeeper”
mutation, which confers a structural modification to BCR-ABL
such that all currently available tyrosine kinase inhibitors are no
longer effective. Furthermore, the activity of dasatinib against
SFKs may contribute to its clinical efficacy, as these kinases have
been implicated in the development and progression of CML
and Ph+ ALL (Hu et al., 2006; Lionberger, Wilson, & Smithgall,
2000; Meyn et al., 2006). Preclinical studies have shown that
dual BCR-ABL/SRC inhibition with dasatinib significantly prolongs the survival of mice with CML compared with BCR-ABL
inhibition alone with imatinib (Hu et al., 2006).
Clinical Journal of Oncology Nursing • Volume 13, Number 3 • Once-Daily Dasatinib for Chronic Myeloid Leukemia
317
Table 1. Adherence Rates by Imatinib Dose
Among Patients With Chronic Myeloid Leukemia
Dose (mg per day)
Adherence Rate (%)
Less than 400
66.9
400 to less than 600
65.7
600 to less than 800
52.1
800 or more
48.1
Note. Sample consisted of patients with chronic myeloid leukemia who
filled imatinib prescriptions at a national retail pharmacy chain from
August 1, 2006, to March 31, 2007. Adherence was measured with the
medication possession ratio (total number of days of medication supplied / number of days from index date to the end of the study period).
Sample size was not stated.
Note. Based on information from Sun et al., 2007.
Efficacy
Dasatinib was approved based on its efficacy demonstrated in
a series of multicenter, open-label, phase II clinical studies (the
START program [SRC/ABL Tyrosine Kinase Inhibition Activity
Research Trials of Dasatinib]) (Cortes et al., 2007; Guilhot, Apperley, Kim, Bullorsky, et al., 2007; Hochhaus, Kantarjian, et al.,
2007; Ottmann et al., 2007). Across the START program, dasatinib was administered orally at a dose of 70 mg twice daily and
showed marked efficacy in heavily pretreated patients. Longerterm results from the studies were reported at the 2007 annual
meeting of the American Society of Hematology (Gambacorti et
al., 2007; Guilhot, Apperley, Kim, Rosti, et al., 2007; Kantarjian,
Rousselot, et al., 2007; Porkka et al., 2007; Stone et al., 2007)
(see Table 2). Hematologic response, achieved when leukocyte
and thrombocyte counts return to normal, were durable in patients taking dasatinib. More importantly, cytogenetic response,
which is a more robust sign of disease remission, was observed
in patients harboring all imatinib-resistant BCR-ABL mutations
except T315I. Importantly, dasatinib showed undiminished
activity in patients with mutations in the P loop, a catalytically
important region of the BCR-ABL kinase domain, which can become highly resistant to imatinib and is associated with a poor
prognosis (Branford et al., 2003).
The new dasatinib prescribing information includes results
from a randomized study (START-R trial) comparing dasatinib
(70 mg twice daily) with high-dose imatinib (800 mg per day) for
the treatment of patients with CP CML who were resistant to firstline imatinib (400–600 mg per day). At a median follow-up of 15
months, complete cytogenetic responses were achieved in 40%
of patients (n = 101) treated with dasatinib compared with 16%
of patients (n = 49) treated with high-dose imatinib (Kantarjian,
Pasquini, et al., 2007; Shah et al., 2006). The median time-totreatment-failure was not yet reached for dasatinib and was 3.5
months for high-dose imatinib (95% confidence interval 3.3–3.8)
(Kantarjian, Pasquini, et al.). Overall risk-benefit assessment
significantly favored dasatinib for patients with CP CML who are
resistant to conventional doses of imatinib (Bristol-Myers Squibb
Company, 2008; Kantarjian, Pasquini, et al.; Shah et al., 2006).
Tolerability
Most AEs observed across clinical trials with dasatinib were
mild to moderate (grade 1 or 2) and resolved spontaneously or
with appropriate management (Shah et al., 2007). An article
titled, “Practical Management of Dasatinib for Maximum Patient Benefit” on pages 329–335 describes AEs associated with
dasatinib and their effective management. Although the AEs
typically resolve with dose interruption or reduction, they can
recur upon rechallenging with dasatinib. No evidence exists of
cumulative toxicity with long-term therapy (Hochhaus, Kantarjian, et al., 2007), and dasatinib had a similar tolerability profile
in patients who were resistant to or intolerant of imatinib (Cortes et al., 2007). The rate of dasatinib discontinuation because
of drug-related AEs was 9% in CP, 0% in AP, 11% during myeloid
blast crisis, and 2% during lymphoid blast crisis. This low rate
of discontinuation indicates that dasatinib is not cross-intolerant
with imatinib (Cortes et al.; Guilhot, Apperley, Kim, Bullorsky,
et al., 2007; Hochhaus, Kantarjian, et al.).
Table 2. Efficacy of Dasatinib 70 mg Twice Daily in Phase II Clinical Studies
CHR
Trial
MCyR
CCyR
n
Follow-Up (Months)
n
%
n
%
n
%
Chronic phase (START-C)
387
15.2
351
91
230
59
189
49
Accelerated phase (START-A)
174
14.1
78
45
67
39
55
32
Myeloid blast phase (START-B)
109
12 or morea
NR
NR
36
33
28
26
Lymphoid blast phase (START-B)
48
12 or morea
NR
NR
25
52
22
46
Ph+ ALL (START-L)
46
12 or more
15
33
26
57
25
54
a
Minimum follow-up
CCyR—complete cytogenetic response; CHR—complete hematologic response; MCyR—major cytogenetic response; NR—not reported; Ph+ ALL—
Philadelphia chromosome–positive acute lymphoblastic leukemia; START—SRC/ABL Tyrosine Kinase Inhibition Activity Research Trials of Dasatinib
Note. Based on information from Gambacorti et al., 2007; Guilhot, Apperley, Kim, Rosti, et al., 2007; Kantarjian, Rousselot, et al., 2007; Porkka et al.,
2007; Soverini et al., 2006; Stone et al., 2007.
a
318
June 2009 • Volume 13, Number 3 • Clinical Journal of Oncology Nursing
Table 3. Phase III Dose-Optimization Study of Dasatinib in Patients With Chronic Phase
Chronic Myelogenous Leukemia (CA180-034)a
Incidence of Adverse Events (%)
Responses (%)
CHR
MCyR
CCyR
Pleural Effusion
(Any Grade)
Neutropenia
(Grade 3 or 4)
Thrombocytopenia
(Grade 3 or 4)
100 mg once daily (n = 165)
90
59
41
10
34
22
50 mg twice daily (n = 167)
92
54
42
16
46
34
140 mg once daily (n = 163)
86
56
44
20
43
40
70 mg twice daily (n = 167)
87
55
45
18
43
38
DoSe
Minimum follow-up was six months.
CCyR—complete cytogenetic response; CHR—complete hematologic response; MCyR—major cytogenetic response
Note. Based on information from Bristol-Myers Squibb Company, 2008.
a
New Dasatinib Dosage
Although dasatinib 70 mg twice daily was the chosen dose in
the phase II study, results of a phase III dose-optimization study
have led to the approval of a new dasatinib dose in patients with
CP CML (Shah et al., 2007). In that study, 670 patients with CP
CML who were resistant to or intolerant of imatinib were randomized to receive dasatinib 100 mg once daily, 50 mg twice daily,
140 mg once daily, or 70 mg twice daily. Similar hematologic and
cytogenetic responses were observed across all four arms (see
Table 3). A difference was found, however, in safety profiles: The
100 mg once-daily dose was associated with reduced incidence
of grade 3 or 4 cytopenias and pleural effusions, suggesting that
this dosing regimen is more tolerable than the 70 mg twice-daily
schedule. Overall, the results of the study indicate that the 100
mg once-daily regimen offers a more favorable risk-benefit assessment compared with twice-daily dasatinib.
Based on the findings, 100 mg once-daily dasatinib (administered in the morning or evening) is now the recommended
starting dose for patients with CP CML who are resistant to or
intolerant of imatinib. The reduced frequency of serious AEs
associated with the once-daily treatment regimen may improve
patient adherence. Data show that fewer treatment interruptions,
dose reductions, and discontinuations were associated with the
100 mg once-daily dose compared with the 70 mg twice-daily
dose (Shah et al., 2007). One additional advantage of dasatinib
with respect to adherence is the lack of a fasting requirement,
which is necessary with nilotinib. Studies of adherence with
antiviral and bisphosphonate agents have reported that patients
had difficulty adhering to fasting requirements and that hunger
from such requirements is a primary cause of nonadherence (da
Silveira, Drachler, Leite, & Pinheiro, 2003; Gallant & Block, 1998;
Papaioannou, Kennedy, Dolovich, Lau, & Adachi, 2007). The recommended dose for patients with advanced-phase CML (i.e., AP
and BP CML) and Ph+ ALL remains 70 mg twice daily.
Management of Adverse Events
Although most AEs that occur with dasatinib are mild to moderate, pleural effusion, cytopenias, and cardiac abnormalities
must be managed promptly to ensure that patients can remain
on therapy and achieve maximum therapeutic benefit. Additionally, patients should be informed of the AEs that can arise during
therapy and educated about the benefits of early reporting, in
addition to adhering to their prescribed treatment regimens
(Partridge et al., 2002).
Across all clinical trials of dasatinib, the most commonly occurring nonhematologic grade 3 or 4 AEs were fluid retention
(8%), hemorrhage (6%), pleural effusion (5%), dyspnea (4%),
diarrhea (3%), and fatigue (2%) (Bristol-Myers Squibb Company,
2008). Those AEs generally occurred at comparable rates in all
phases of CML; however, the incidences of grade 3 or 4 neutropenia (73.6% versus 46%), thrombocytopenia (75.4% versus
41%), and anemia (58% versus 18%) were higher in patients with
advanced-phase CML or Ph+ ALL.
During dasatinib treatment, patients should be monitored
closely for signs and symptoms of cytopenias and pleural effusions. Recommended monitoring and management techniques
for patients with these and other dasatinib-related AEs are listed
in Table 4 (Bristol-Myers Squibb Company, 2008; National Comprehensive Cancer Network, 2008). Cytopenias can be related
to the disease (particularly in the advanced phase) and may be
an indication of therapeutic benefit. In such cases, treatment
with dasatinib should not be interrupted and dose escalation
may be warranted (National Comprehensive Cancer Network,
2008). (Also see “Practical Management of Dasatinib for Maximum Patient Benefit” on pages 329–335.)
Drug Interactions
Because dasatinib is a CYP3A4 substrate, use of CYP3A4 inhibitors (e.g., ketoconazole) during dasatinib treatment should
be avoided, as it may increase exposure to dasatinib (see pages
329–335). If co-administration is unavoidable, toxicity should be
monitored closely and dose reduction of 20–40 mg daily should
be considered (Bristol-Myers Squibb Company, 2008). Furthermore, CYP3A4 inducers (e.g., rifampin) may decrease dasatinib
plasma concentrations. In clinical trials, co-administration of
dasatinib with rifampin resulted in a five-fold decrease in dasatinib plasma concentrations. In patients who require CYP3A4
Clinical Journal of Oncology Nursing • Volume 13, Number 3 • Once-Daily Dasatinib for Chronic Myeloid Leukemia
319
Table 4. Monitoring and Management of Hematologic and Nonhematologic Adverse Events
Adverse Event
Cytopenias
(neutropenia,
thrombocytopenia)
Monitoring Recommendation
Phase of Disease
Management Techniques
Because cytopenias usually occur
within the first one or two months
of treatment, particular care should
be taken during that time. Also, because cytopenias tend to occur more
frequently in patients with advanced
disease (probably because of a high
incidence of pancytopenia prior to
starting therapy), care should be taken in such cases as well. Complete
blood counts should be performed
weekly for the first two months and
monthly thereafter or as clinically
indicated.
Chronic phase
• Stop dasatinib until absolute neutrophil count (ANC) is 1.0 x
109/L or higher and platelets are 50 x 109/L or higher.
• Resume treatment with dasatinib at the original starting dose
if recovery occurs in seven days or less.
• If platelets are lower than 25 x 109/L or recurrence of ANC is
lower than 0.5 x 109/L for more than seven days, repeat step 1
and resume dasatinib at a reduced dose of 80 mg once daily
(second episode) or discontinue (third episode).
Advanced
disease
• Check if cytopenia is related to leukemia.
• If unrelated to leukemia, stop dasatinib until ANC is 1.0 x
109/L or higher and platelets are 20 x 109/L or higher, and resume at the original starting dose.
• If cytopenia recurs, repeat step 1 and resume dasatinib at a
reduced dose of 50 mg twice daily (second episode) or 40 mg
twice daily (third episode).
• If cytopenia is related to leukemia, consider a dose escalation
to 100 mg twice daily.
Congestive
heart failure
or cardiac
dysfunction
Exercise caution when treating
patients who have or may develop
QTc prolongation. Monitor for any
changes in QTc.
Any
Hypokalemia or hypomagnesemia should be corrected prior to
dasatinib administration. Temporarily interrupt dasatinib administration and monitor the patient carefully until symptoms resolve.
Diarrhea
Question patients during therapy.
Grade 3
For mild to moderate adverse events, use antidiarrheal medications. In case of nausea, patients can benefit from eating after
initial fasting periods.
Grade 4
In the case of severe gastrointestinal adverse events that are not
responsive to therapy, dose should be withheld. Following resolution of the event, a dose reduction may be prudent (not less than
300 mg).
Gastrointestinal
bleeding
Perform regular blood count testing
(weekly for the first two months
of treatment). Patients should be
informed of the importance of notifying their physicians of any bleeding or bruising. Patients requiring
anticoagulants are at increased risk,
and extra care should be taken to
monitor them.
Any
Dasatinib dose modifications may be performed when patients
experience thrombocytopenia (previously described). In case of
severe gastrointestinal hemorrhages, treatment must be interrupted, and transfusion may be appropriate.
Gastrointestinal
upset
Symptoms may include nausea,
belching, heartburn, cramping, and
abdominal distention.
Any
• Antiemetics for nausea and vomiting
• Intensive fluid management
• Dasatinib should be taken with a meal or a large glass of water.
Headache
Symptoms may include head pain,
blurred vision, nausea, vomiting,
impaired hearing, irritability, and
malaise.
Any
Pain relief (e.g., nonsteroidal anti-inflammatory drugs, acetaminophen)
Pleural effusion
Symptoms suggestive of pleural effusion, such as dyspnea or dry cough,
should be evaluated by chest x-ray.
Severe pleural effusion may require
thoracentesis and oxygen therapy.
Grade 3
Standard management approach is to use diuretics or dose interruption. If patient has significant symptoms, a short course of steroids can be administered; when resolved, reduce one dose level.
Grade 4
Hold dasatinib until grade 1 or better, then consider resuming at
decreased dose level.
Symptoms may include itching,
swelling, and change in color.
Any
• Apply topical or systemic steroids.
• Dasatinib dose should be reduced, interrupted, or discontinued.
Rash
Note. Based on information from National Comprehensive Cancer Network, 2008.
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June 2009 • Volume 13, Number 3 • Clinical Journal of Oncology Nursing
inducers, alternate agents with lower enzyme induction potential should be used, if possible; however, if the use of a CYP3A4
inducer is necessary, dasatinib dose escalation in 20 mg increments is recommended (Bristol-Myers Squibb Company).
The solubility of dasatinib is pH-dependent, according to
preclinical data, suggesting that concomitant administration of
dasatinib and antacids could decrease the absorption of dasatinib (Bristol-Myers Squibb Company, 2008). Therefore, antacids
should be taken at least two hours before or after dasatinib
administration (Bristol-Myers Squibb Company). The use of proton pump inhibitors should be avoided entirely as it is likely to
reduce exposure to dasatinib. Antacids should be used in place
of proton pump inhibitors (Bristol-Myers Squibb Company).
Additionally, dasatinib may affect the plasma concentration
of certain drugs. Caution should be used when administering
CYP3A4 substrates that have a narrow therapeutic index during
concomitant dasatinib treatment (Bristol-Myers Squibb Company, 2008). The article on pages 329–335 offers a listing of drugs
whose plasma concentrations may be altered by dasatinib.
Special Populations
Dasatinib is not recommended for use by women who are
pregnant or who are contemplating pregnancy; women should
not breast-feed while taking dasatinib (Bristol-Myers Squibb
Company, 2008). Although no differences have been observed
in the safety and efficacy of dasatinib in clinical studies between
patients who were older than 65 years and those who were
younger, some older patients may have greater sensitivity to
dasatinib (Bristol-Myers Squibb). Additionally, the safety and efficacy of dasatinib have not been established in patients younger
than 18 years (Bristol-Myers Squibb Company).
Conclusion
Imatinib resistance and intolerance have emerged as significant clinical issues in the treatment of CML and Ph+ ALL. Dasatinib is highly effective in patients with CML who are resistant
to or intolerant of imatinib, and it offers a positive prospect for
such patients. The new 100 mg once-daily dosing regimen for
patients with CP CML may benefit treatment adherence through
simpler dosing and improved tolerability. Additionally, appropriate management of AEs associated with treatment may help
patients adhere to their prescribed treatment regimens, thus
ensuring that patients achieve maximum therapeutic benefit.
The author takes full responsibility for the content of this article
but thanks Jonathan C. Maher and Josh Collis of Gardiner-Caldwell
U.S., supported by Bristol-Myers Squibb Company, for medical
writing support. The author served on Millennium Pharmaceuticals, Inc., and Celgene Corporation speakers bureaus. The content
of this article has been reviewed by independent peer reviewers
to ensure that it is balanced, objective, and free from commercial
bias. No financial relationships relevant to the content of this
article have been disclosed by the author, planners, independent
peer reviewers, or editorial staff.
Author Contact: George Bryant, ND, ACNP-BC, ANP-BC, AOCNP®, can be
reached at gbryant@dom.wustl.edu, with copy to editor at CJONEditor@
ons.org.
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