1. health and fitness
2. therapy

H O W
W E
D O
I T
Managing Side Effects of Tyrosine
Kinase Inhibitor Therapy to Optimize
Adherence in Patients with Chronic
Myeloid Leukemia: The Role of the
Midlevel Practitioner
Megan Cornelison, MS, PA-C; Elias J. Jabbour, MD; and Mary Alma Welch, MS, PA-C
ABSTRACT
In the last decade, the development of imatinib, a tyrosine kinase inhibitor, has brought about
unprecedented change in the way newly diagnosed, chronic-phase chronic myeloid leukemia
patients are treated. Two next-generation tyrosine kinase inhibitors, nilotinib and dasatinib, were
initially indicated for imatinib-resistant or imatinib-intolerant chronic myeloid leukemia patients
and recently received approval from the Food and Drug Administration for treatment of newly
diagnosed, chronic-phase chronic myeloid leukemia patients. In comparison with the previous
standards of care, benefits with these three tyrosine kinase inhibitors have included more rapid
response rates, increased survival, and fewer side effects. The improved long-term outcomes have
altered the approach to management of chronic myeloid leukemia from a progressive fatal disease
with a poor prognosis to a chronic condition similar to diabetes or hypertension. Prolonged
survival increases the need for patient education, support, monitoring, and assistance with adverse
event management. Even low-grade side effects can adversely affect patients’ quality of life and,
therefore, require prompt attention to prevent long-term complications or suboptimal outcomes.
New evidence has indicated that patient adherence to tyrosine kinase inhibitor therapy is
essential to successful treatment. Midlevel practitioners can help to optimize outcomes by
educating patients regarding the importance of adherence, performing regular monitoring, helping
patients to understand their test results, and aggressively managing treatment-related side effects.
Chronic myeloid leukemia (CML) is a progressive disease characterized by the overproliferation of myeloid cells, particularly mature granulocytes (neutrophils, eosinophils, and basophils)
and their precursors. About 40% of patients are
asymptomatic at diagnosis and are identified during routine blood testing.1 The majority, however, present with symptoms such as fatigue,
Manuscript submitted May 2, 2011; accepted August 5, 2011.
Correspondence to: Mary Alma Welch, MS, PA-C, University
of Texas, MD Anderson Cancer Center, Department of Leukemia, Unit 428, Houston, TX 77030; telephone: (713) 792-7305;
fax: (713) 794-4297; e-mail: [email protected]
J Support Oncol 2012;10:14 –24
doi:10.1016/j.suponc.2011.08.001
14
© 2012 Elsevier Inc. All rights reserved.
weight loss, night sweats, and abdominal discomfort from an enlarged spleen.2 Approximately
5,000 cases of CML are diagnosed annually in
the United States, and the median age at diagnosis is 68 years.3
The characteristic cytogenetic abnormality of
CML is the Philadelphia chromosome (Ph). It
arises from the reciprocal translocation between
chromosomes 9 and 22, which causes the ABL
gene to fuse with the breakpoint cluster region
(BCR) gene, leading to expression of the oncogenic BCR-ABL tyrosine kinase fusion protein.4
The unregulated activity of the BCR-ABL tyrosine
kinase triggers a cascade of events culminating in
malignant transformation.5,6 Historically, treatment of CML with radiotherapy, busulfan, or hy-
www.SupportiveOncology.net
THE JOURNAL
OF
Drs Cornelison, Jabbour
and Welch are from
University of Texas,
MD Anderson Cancer
Center, Department of
Leukemia, Houston,
Texas.
SUPPORTIVE ONCOLOGY
Cornelison, Jabbour, and Welch
droxyurea was largely unsuccessful.7 Interferon-alfa (IFN-␣) was
introduced in the early 1980s as the first agent to eliminate Ph in
bone marrow cells—termed a “cytogenetic response.”8,9 Cytogenetic response was explored as a clinical end point in a trial of
investigative drugs and categorically defined as complete (no
Ph⫹ metaphases in a sample of 20 metaphase chromosomes),
major (1%-34% Ph⫹ metaphases), minor (35%-79% Ph⫹ metaphases), and no response (80%–100% Ph⫹ metaphases).10
Significant scientific advances have driven the development of tyrosine kinase inhibitor (TKI) therapy for treatment
of patients with CML. Although TKIs provide new opportunities for positive outcomes, treatment results are optimized
when patients adhere to their prescribed therapy.11,12 Adherence is defined as the extent to which patients take medication as prescribed. It is a complex phenomenon, with different
patterns of medication-taking behaviors, ranging from almost
perfect adherence to taking few or none of the prescribed
doses.13 The midlevel practitioner can more readily help
patients remain adherent by understanding the reasons underlying nonadherence. Whereas the study of adherence to
TKI therapy in CML is relatively recent, reasons for nonadherence have been studied extensively in many chronic disease states. A variety of factors have been shown to predict
nonadherence, including those related to the patient (presence of depression, lack of belief in the benefit of medication), the medication (side effects), and the health-care system itself (cost of medication, copayment, or both).13
Side effects related to medication have been consistently
implicated in nonadherence in many illnesses that require
long-term treatment, including tuberculosis, human immunodeficiency virus (HIV) infection, asthma, and hypertension.14 –19 Adverse events (AEs) of TKIs also are associated
with lower adherence.11
Choosing not to take medication to avoid AEs is an example of intentional nonadherence.20 There are also unintentional reasons for nonadherence, such as forgetfulness;
thus, reducing forgetfulness may facilitate adherence.20 One
approach to improving adherence with TKIs, therefore, could
be centered on patient education regarding the importance of
adherence, recognition and prompt reporting of side effects,
and their proactive management. We will briefly summarize
TKI therapies available for treatment of CML, discuss treatment-related AEs, and provide practical advice to assist the
midlevel practitioner (nurse practitioners, physician assistants, and pharmacists) in providing supportive care to their
CML patients, which may improve adherence and, ultimately, optimize outcomes.
In the last decade, imatinib (Gleevec®; Novartis, Hanover, NJ), a BCR-ABL inhibitor, has revolutionized the treatment of patients with newly diagnosed, chronic-phase CML
(CML-CP). In 2001, imatinib became the first TKI to be
approved by the Food and Drug Administration (FDA), ultimately replacing IFN-␣ as standard therapy.21,22 Since then,
nilotinib (Tasigna®, Novartis) and dasatinib (Sprycel®; Bris-
tol-Myers Squibb, Princeton, NJ)— highly potent next-generation TKIs— have expanded the treatment armamentarium
for CML. Positive phase 2 clinical trial results23,24 led to the
FDA approval of nilotinib in 2007 for the treatment of
CML-CP and accelerated-phase CML in patients resistant to
or intolerant of prior therapy, including imatinib. Dasatinib,
a multikinase inhibitor, also has been studied in patients with
imatinib-resistant CML;25 due to its positive efficacy and
safety profile, it was initially approved by the FDA in 2006 for
the treatment of chronic-, accelerated-, and myeloid- or lymphoid blast–phase CML in patients with resistance or intolerance to prior therapy, including first-line imatinib.
With the use of TKIs, overall survival (OS) of patients
with CML has increased dramatically. From 1975 to 1977, the
5-year OS rate was 24.0%, a rate that increased modestly to
38.9% by 1996 to 1998;26 however, from 1999 to 2006, the
5-year survival rate increased to 56.8%.27 Therefore, unlike
the pre-imatinib era, most patients today survive much longer, at least 5 years after diagnosis. The latest data from the
International Randomized Study of Interferon and STI571
(IRIS) study indicates that the estimated OS at 8 years with
imatinib was 85% (93% when only CML-related deaths and
those prior to stem cell transplant were considered).28 This
improvement in prognosis has given hope to patients with
CML as it is no longer perceived as a rapidly progressive
disease with a poor prognosis; rather, with proper treatment,
CML may be managed in the long term.
More recently, nilotinib and dasatinib have been studied
as first-line treatment of CML. An ongoing phase 3 trial, the
Evaluating Nilotinib Efficacy and Safety in Clinical Trials–
Newly Diagnosed Patients (ENESTnd) study, compares the
efficacy and safety of nilotinib, 300 mg or 400 mg twice daily,
with imatinib, 400 mg once daily, for treatment of newly
diagnosed patients.29 At 12 months, the data indicated the
superiority of nilotinib over imatinib in the rates of major
molecular response (MMR [defined as a ⱖ3-log reduction of
BCR-ABL mRNA]: 44% for 300 mg nilotinib and 43% for
400 mg nilotinib vs 22% for 400 mg imatinib, P ⬍ 0.001 for
both comparisons) and complete cytogenetic response
(CCyR: 80% for 300 mg nilotinib and 78% for 400 mg
nilotinib vs 65% for 400 mg imatinib, P ⬍ 0.001 for both
comparisons); furthermore, patients receiving nilotinib demonstrated a significant improvement in the time to progression to accelerated phase or blast crisis.29 Updated analyses of
this trial at 18 and 24 months30,31 have confirmed the durability of responses with nilotinib and its superiority over
imatinib. More specifically, CCyR was achieved by 85% and
82% of nilotinib-treated patients (receiving 300 and 400 mg
nilotinib, respectively) vs 74% of imatinib-treated patients
(P ⬍ .001 and P ⫽ .017, respectively) at 18 months (24month CCyR data not reported).30 In addition, 66% and 62%
of patients achieved MMR with 300 and 400 mg of nilotinib,
respectively, vs 40% of patients with imatinib (P ⬍ .0001 for
both comparisons) at 18 months, with further increases to
71% and 67% vs 44%, respectively, at 24 months (P ⬍ .0001
for both comparisons).30,31 In June 2010, nilotinib received
VOLUME 10, NUMBER 1 䡲 JANUARY/FEBRUARY 2012
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NEWER STANDARD THERAPIES
15
Managing Side Effects of TKI Therapy to Optimize Adherence in CML Patients
Table 1
Milestone Responses as Suggested by the NCCN Task Force
MILESTONE
(MONTHS)
RESPONSE TYPE
3
Hematologic
(complete)
6
Cytogenetic (partial
or complete)
12
Cytogenetic
(complete)
18
Cytogenetic
(complete)
CRITERIA
Complete normalization of peripheral blood counts with leukocyte count ⬍10 ⫻ 109/l
Platelet count ⬍450 ⫻ 109/l
No immature cells, such as myelocytes, promyelocytes, or blasts, in peripheral blood
No signs and symptoms of disease, with disappearance of palpable splenomegaly
1%–35% Ph⫹ metaphases (1–7 Ph⫹ out of 20 metaphases) or no Ph⫹ metaphases (0 Ph⫹ out of 20
metaphases)
No Ph⫹ metaphases (0 Ph⫹ out of 20 metaphases)
No Ph⫹ metaphases (0 Ph⫹ out of 20 metaphases)
Adapted with permission from O’Brien et al.34
FDA approval as a first-line agent in the treatment of patients
with CML-CP.
The ongoing Dasatinib vs Imatinib in Patients with Newly
Diagnosed Chronic-Phase CML (DASISION) study compares the efficacy and safety of dasatinib, 100 mg once daily,
with imatinib, 400 mg once daily, as first-line treatment in
CML-CP.32 Results demonstrated that by 12 months dasatinib, when compared with imatinib, was associated with significantly higher and faster rates of CCyR (77% vs 66%,
respectively; P ⫽ .007) and MMR (46% vs 28%, respectively;
P ⬍ .0001).32 Updated analyses comparing dasatinib and
imatinib at 18 months revealed significantly greater rates of
CCyR (78% vs 70%, respectively; P ⫽ .0366) and MMR
(57% vs 41%, respectively; P ⫽ .0002).33 Dasatinib received
FDA approval for the treatment of newly diagnosed CML-CP
patients in October 2010.
PATIENT RESPONSE TO TKI THERAPY
Response to TKI therapy is assessed by hematologic, cytogenetic, and molecular monitoring methods; and response
milestones have been suggested by the National Comprehensive Cancer Network (NCCN) Task Force (Table 1).34
Achieving milestone responses confirms the patient’s optimal
response to therapy; failure to achieve milestones, or a suboptimal response, may indicate nonadherence to treatment or
resistance to therapy. Careful assessment of AEs and tolerability are paramount as patients experiencing AEs have lower
adherence rates and may have stopped or considered stopping
therapy.11,35 Helping patients identify and manage their side
effects is an important part of patient management that may
optimize patient adherence and lead to improved responses.
TKI-ASSOCIATED SIDE EFFECTS AND
THEIR MANAGEMENT
Side Effects
The different side-effect profiles for imatinib, nilotinib,
and dasatinib should be considered when initiating treatment
and monitoring patients. The most common all-grade AEs,
not including hematologic abnormalities, in newly diagnosed
16
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CML patients who have received imatinib, nilotinib, or dasatinib in clinical studies (as listed in the respective prescribing information for each agent) are found in Tables 2– 4. Most
AEs are of mild or moderate severity (grade 1 or 2).36 –38
The most commonly reported grade 1 or 2 AEs experienced in 5 years of follow-up of newly diagnosed CML patients treated with imatinib as first-line therapy were edema,
muscle cramps, diarrhea, nausea, musculoskeletal pain, rash or
other skin problems, abdominal pain, fatigue, joint pain, and
headache.39 Grade 3 or 4 AEs included neutropenia, thrombocytopenia, anemia, and elevated liver enzymes.
The comparison of nilotinib vs imatinib as first-line therapy in the ENESTnd study revealed lower rates of nausea,
diarrhea, vomiting, muscle spasm, and edema with either dose
of nilotinib than with imatinib.29 Conversely, rates of rash,
headache, pruritus, and alopecia were higher with nilotinib at
either dose than with imatinib. More events of increased
levels of liver enzymes were observed with nilotinib than with
imatinib therapy, although fewer events of decreased phosphate and increased creatinine were reported in nilotinib- vs
imatinib-treated patients.29 A lower rate of neutropenia with
either dose of nilotinib vs imatinib (12% and 10% vs 20%,
respectively) was observed. Comparable rates of grade 3/4
thrombocytopenia (nilotinib 10% and 12% vs imatinib 9%)
and anemia (nilotinib 3% and 3% vs imatinib 5%) were
reported, and such events occurred within the first 2
months.29 QTcF prolongation ⬎500 msec has not been
observed in either nilotinib arm. The safety profile of
nilotinib as first-line therapy remained unchanged at 24
months, confirming the favorable tolerability of this
agent.30,40
The safety profile differs for nilotinib when it is administered as second-line therapy. In CML-CP patients with at
least 6 months of follow-up, grade 3/4 elevations in liver
enzymes (lipase 15%, bilirubin 9%) occurred infrequently and
were not clinically significant for most patients; 10% of nilotinib-treated CML-CP patients experienced hypophosphatemia. Cardiac toxicity, observed as QTcF prolongation
⬎500 msec, was reported in 1% of patients. The most comTHE JOURNAL
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Cornelison, Jabbour, and Welch
Table 2
Table 3
Common Adverse Reactions Reported in Newly
Diagnosed CML Clinical Trials of Imatinib 400 mg
Once Daily (ⱖ10% of Patients)37
Most Frequently Reported Nonhematologic Adverse
Reactions with Nilotinib 300 mg Twice Daily
(Regardless of Relationship to Study Drug) in
Patients with Newly Diagnosed CML-CP (ⱖ10%
of Patients)38
PREFERRED TERM
Fluid retention
Superficial edema
Other fluid retention reactionsa
Nausea
Muscle cramps
Musculoskeletal pain
Diarrhea
Rash and related terms
Fatigue
Headache
Joint pain
Abdominal pain
Nasopharyngitis
Hemorrhage
GI hemorrhage
CNS hemorrhage
Myalgia
Vomiting
Dyspepsia
Cough
Pharyngolaryngeal pain
Upper respiratory tract infection
Dizziness
Pyrexia
Weight increased
Insomnia
Depression
Influenza
Bone pain
Constipation
Sinusitis
a
ALL GRADES (%)
(N ⫽ 551)
GRADES 3/4 (%)
(N ⫽ 551)
62
60
7
50
49
47
45
40
39
37
31
37
31
29
2
⬍1
24
23
19
20
18
21
19
18
16
15
15
14
11
11
11
2.5
1.5
1.3
1.3
2.2
5.4
3.3
2.9
1.8
0.5
2.5
4.2
0
1.8
0.5
0
1.5
2
0
0.2
0.2
0.2
0.9
0.9
2
0
0.5
0.2
1.6
0.7
0.2
Other fluid retention reactions include pleural effusion, ascites, pulmonary edema, pericardial effusion, anasarca, edema aggravated, and fluid retention not otherwise specified.
mon grade 3/4 hematologic abnormalities were neutropenia
(29%) and thrombocytopenia (29%).23 This safety profile
appears to remain unchanged during 24 months of
follow-up.41
In the comparison of first-line therapy with dasatinib vs
imatinib in the DASISION study, the most common nonhematologic adverse reactions (ie, nausea, vomiting, muscle
inflammation, rash, fluid retention, and headache) were more
frequent with imatinib than dasatinib. Fluid retention was
reported for 42% of patients treated with imatinib and 19% of
patients treated with dasatinib; fluid retention events included superficial edema (36% of imatinib-treated patients
and 9% of dasatinib-treated patients) and pleural effusion
(0% of imatinib-treated patients and 10% of dasatinib-treated
patients).32 Comparable rates of grade 3/4 neutropenia with
VOLUME 10, NUMBER 1 䡲 JANUARY/FEBRUARY 2012
PREFERRED TERM
ALL GRADES (%)
(N ⫽ 279)
GRADES 3/4 (%)
(N ⫽ 279)
36
28
19
19
19
19
15
15
15
14
14
13
12
12
12
11
10
10
10
⬍1
3
⬍1
0
1
⬍1
⬍1
⬍1
0
⬍1
⬍1
0
1
⬍1
0
⬍1
0
0
0
Rash
Headache
Fatigue
Nasopharyngitis
Nausea
Pruritus
Abdominal pain upper
Arthralgia
Constipation
Diarrhea
Myalgia
Upper respiratory tract infection
Abdominal pain
Back pain
Cough
Asthenia
Alopecia
Muscle spasm
Pyrexia
dasatinib vs imatinib (21% vs 20%, respectively), a higher
rate of thrombocytopenia with dasatinib vs imatinib (19% vs
10%, respectively), and comparable rates of anemia with
dasatinib vs imatinib (10% vs 7%, respectively) were observed.42 Three-fourths of the severe hematologic side effects
occurred within the first 4 months in DASISION. Cardiac
toxicity measured as QTc ⬎500 msec occurred in 0.4% of
patients receiving dasatinib as first-line therapy.32 Analysis of
safety at 18 months revealed that the safety profile of dasatinib as a first-line agent is relatively unchanged with longer
follow-up; however, 12% of patients in the dasatinib arm
developed pleural effusion with ⬍1% grade 3/4.33
Nonhematologic toxicity was minimal for dasatinib administered as a second-line agent. Pleural effusion was observed in 17% of dasatinib-treated patients; three cases were
of grade 3 severity, and there were no cases of grade 4 severity.
Grade 3/4 hypophosphatemia was observed in 10% of
CML-CP patients. Grade 3/4 neutropenia and thrombocytopenia occurred in 61% and 56%, respectively, of patients
treated with dasatinib.25
Management of Adverse Events
Recently updated clinical practice guidelines from the
NCCN provide specific recommendations for the management of AEs associated with imatinib, nilotinib, and dasatinib
(Tables 5–7).43 Generally, grade 3/4 AEs are addressed via
www.SupportiveOncology.net
17
Managing Side Effects of TKI Therapy to Optimize Adherence in CML Patients
Table 4
Adverse Reactions Reported in ⱖ10% of Newly
Diagnosed Patients with CML-CP in Clinical Study
with Dasatinib 100 mg Once Daily36
PREFERRED TERM
Fluid retention
Pleural effusion
Superficial localized edema
Generalized edema
Congestive heart failure/cardiac
dysfunctiona
Pericardial effusion
Pulmonary hypertension
Pulmonary edema
Diarrhea
Headache
Musculoskeletal pain
Rashb
Nausea
Fatigue
Myalgia
Hemorrhagec
Gastrointestinal bleeding
Other bleedingd
CNS bleeding
Vomiting
Muscle inflammation
ALL GRADES (%)
(N ⫽ 258)
GRADES 3/4 (%)
(N ⫽ 258)
23
12
10
3
2
1
⬍1
0
0
⬍1
2
1
⬍1
18
12
12
11
9
8
6
6
2
5
0
5
4
⬍1
0
0
⬍1
0
0
0
0
⬍1
0
1
1
0
0
0
0
a
Includes cardiac failure (acute and congestive), cardiomyopathy, diastolic dysfunction,
ejection fraction decreased, and left ventricular dysfunction.
b
Includes erythema, erythema multiforme, rash (generalized, macular, papular, pustular,
and vesicular), and skin exfoliation.
c
Adverse reaction of special interest with ⬍10% frequency.
d
Includes conjunctival, ear, eye, sclera, uterine, and vaginal hemorrhages; ecchymosis;
epistaxis; gingival bleeding; hematoma; hematuria; hemoptysis; intra-abdominal hematoma; and petechiae.
dose interruption followed by resumption of treatment at a
reduced dose after resolution of toxicity; the time frame of
recovery of individual patients guides dosing decisions. Dose
reduction and temporary discontinuation of imatinib, nilotinib, and dasatinib have been used effectively to treat events
of neutropenia and thrombocytopenia in the clinical trial
setting.23,25,44 The management of hematologic AEs is described in the NCCN Guidelines for Chronic Myelogenous
Leukemia.43
Common mild or moderate AEs are addressed via specific
treatments or supportive care. Patients who suffer from gastrointestinal (GI) upset with imatinib or dasatinib can be
advised to take the medicine with a meal and a large glass of
water;43 in our practice, we have used split dosing as an
acceptable method for reducing GI discomfort. Another effective strategy recommended in our practice is taking the
imatinib or dasatinib dose prior to going to bed. Since the
pharmacokinetic profile of nilotinib dictates that it should be
taken on an empty stomach,45 nausea associated with nilo-
18
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tinib is managed with supportive care;43 in our experience,
this AE is reduced with an antiemetic such as ondansetron
(Zofran®; GlaxoSmithKline, Brentford, UK).
Fluid retention is commonly associated with imatinib and
dasatinib. Patients taking imatinib who have peripheral
edema or generalized fluid retention should be weighed and
monitored closely; salt restriction may be helpful, and control
with diuretics can be useful,43 although diuretic therapy is
usually ineffective at treating periorbital edema. Imatinibrelated fluid retention is generally mild and does not require
dose reduction, treatment interruption, or discontinuation.29,46 Dasatinib-induced pleural effusions are potentially
serious and require prompt diagnosis and treatment. For patients with grade 2-3 pleural effusion, dasatinib therapy
should be discontinued; a short course of diuretics or use of an
oral steroid, such as prednisone 20 mg/day three times daily,
should be administered.43,47 Patients should be educated to
report symptoms of chest pain, dyspnea, and dry cough as
soon as they occur.48 If pleural effusion is confirmed by X-ray,
treatment interruption is suggested until the AE improves to
grade ⬍1; oral steroids can quickly reduce symptoms. A lower
dasatinib dose should be used when treatment is resumed. The
use of diuretics also may be helpful.48 Comorbid conditions
(autoimmune disease, hypertension, cardiovascular disease)
may play a role in the development of pleural effusions.
Patients with these conditions, therefore, may need closer
monitoring.46
Most cases of skin toxicity are mild to moderate in severity and
appear soon after treatment begins.46 Topical or systemic steroids
are used to treat skin reactions; in the rare event of a severe case,
dose reduction, interruption, or discontinuation is recommended.34
TKI-related muscle cramps and musculoskeletal pain may be
treated with increased fluid intake, administration of calcium
and potassium supplements, and tonic water, which is suggested because of its quinine content. Other side effects, such
as diarrhea and headache, are also managed with supportive
care43 and symptomatic treatment. Nonsteroidal anti-inflammatory drugs (NSAIDs) are effective for treatment of headache; adjusting the timing of the TKI dose is also an appropriate management strategy in the treatment of headache.
Special considerations in using nilotinib and dasatinib are
related to QT interval prolongation. The prescribing information for these agents recommends that they should be
avoided or employed with caution in patients with hypokalemia, hypomagnesemia, or long QT syndrome. Hypokalemia
or hypomagnesemia must be corrected prior to administration
of nilotinib or dasatinib, and drugs known to prolong the QT
interval should be avoided.36,38 Nilotinib, specifically, should
not be used with strong CYP3A4 inhibitors. Electrocardiograms should be conducted before starting nilotinib, 7 days
after initiation of therapy, with any dose changes, and regularly during treatment.38
The development of imatinib intolerance in patients with
CML is rare at the 400-mg dose, occurring in ⬍1% of patients
in the IRIS trial.21,39 Only 5% of patients discontinued due to
toxicity after 6 years of follow-up.49 Dose-escalation studies
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Cornelison, Jabbour, and Welch
Table 5
Management of Select Side Effects Associated with Imatinib Treatment of CML-CP
Hematologic
Nonhematologic—Specific
interventions (Grade 2
or 3 severity)
Nonhematologic—Grade 4
Nonhematologic — Liver
● Grade 3/4 neutropenia (absolute neutrophil count [ANC] ⬍1,000/mm3): Dose interruption until ANC ⱖ1,500/
mm3
● Grade 3/4 thrombocytopenia (platelet count ⬍50,000/mm3):
Dose interruption until platelet count ⱖ75,000/mm3
Growth factors can be used in combination with imatinib for patients with resistant neutropenia.
● Diarrhea: Supportive care
● Edema: Diuretics, supportive care
● Fluid retention (pleural effusion, pericardial effusion, edema, and ascites): Diuretics, supportive care, dose
reduction, interruption, or discontinuation. Consider echocardiogram to check left ventricular ejection
fraction.
● GI upset: Take medication with a meal and large glass of water
● Muscle cramps: Calcium supplement, tonic water
● Rash: Topical or systemic steroids, dose reduction, interruption, or discontinuation
If any of the grade 2 or 3 toxicities are not responsive to symptomatic measures, treat as grade 4.
Hold drug until grade 1 or better, then consider resuming dose at 25%–33% dose reduction (not less than 300
mg). Consider change to dasatinib, nilotinib, or clinical trial.
● Grade 2: Hold drug until grade ⱕ1. Resume at 25%–33% dose reduction (not less than 300 mg). Evaluate for
other hepatotoxic drugs that may be contributing to toxicity, including acetaminophen. Consider change to
dasatinib, nilotinib, or clinical trial.
● Grade 3/4: Consider change to dasatinib, nilotinib, or clinical trial.
Adapted with permission from the NCCN Clinical Practice Guidelines in Oncology for Chronic Myelogenous Leukemia, V.1.2012.43 © 2011 National Comprehensive Cancer Network, Inc. All
rights reserved. The NCCN Guidelines and illustrations herein may not be reproduced in any form for any purpose without the express written permission of the NCCN. To view the most
recent and complete version of the NCCN Guidelines, go online to NCCN.org. National Comprehensive Cancer Network®, NCCN®, NCCN Guidelines™, and all other NCCN content are
trademarks owned by the National Comprehensive Cancer Network, Inc.
Table 6
Management of Select Side Effects Associated with Nilotinib Treatment of CML-CP
QT Interval prolongation
Hematologic
Nonhematologic—Specific
interventions (Grade 2
or 3 severity)
Nonhematologic—Grade 4
Nonhematologic—Liver
ECGs with a QTc ⬎480 msec: Hold drug.
ECG should be obtained to monitor the QTc at baseline, 7 days after initiation and periodically thereafter as
well as following any dose adjustments.
● Grade 3/4 neutropenia (ANC ⬍1,000/mm3): Dose interruption until ANC ⱖ1,000/mm3
● Grade 3/4 thrombocytopenia (platelet count ⬍50,000/mm3):
Dose interruption until platelet count is ⱖ50,000/mm3
Growth factors can be used in combination with nilotinib for patients with resistant neutropenia and
thrombocytopenia.
● Headache, nausea, diarrhea: Supportive care
● Rash: Topical or systemic steroids, dose reduction, interruption, or discontinuation
If any of the grade 2 or 3 toxicities are not responsive to symptomatic measures, treat as grade 4.
Hold drug until grade 1 or better, and then resume at reduced dose level (400 mg once daily). If clinically
appropriate, consider escalating dose to 300–400 mg twice daily, depending on starting dose.
● Elevated serum levels of lipase, amylase, bilirubin, and/or hepatic transaminases (grade ⱖ3): Hold drug until
serum levels return to grade ⱕ1. Resume nilotinib at 400 mg once daily.
Adapted with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines™) for Chronic Myelogenous Leukemia V.1.2012.43 © 2011 National Comprehensive Cancer
Network, Inc. All rights reserved. The NCCN Guidelines and illustrations herein may not be reproduced in any form for any purpose without the express written permission of the NCCN. To
view the most recent and complete version of the NCCN Guidelines, go online to NCCN.org. National Comprehensive Cancer Network®, NCCN®, NCCN Guidelines™, and all other NCCN content
are trademarks owned by the National Comprehensive Cancer Network, Inc.
suggest a positive relationship between dose and toxicity.50,51
Discontinuation or interruption of imatinib was necessary in
19%-31% of patients following dose escalation to 600 or 800
mg in clinical trials, mostly as a result of myelosuppression.42,44 However, in one clinical study of high-dose (800
mg) imatinib in which patients were previously treated with
imatinib 400-600 mg, 61% of patients discontinued due to
disease progression or no response and 18% discontinued due
to intolerance, mostly nonhematologic toxicity.25 In the case
of imatinib intolerance (recurrence of nonhematologic tox-
icity despite dose reduction or symptom management), a
change to nilotinib or dasatinib should be considered. As the
experience with treatment of nilotinib and dasatinib in newly
diagnosed patients accumulates, an understanding of intolerance to these medications will be gained.
VOLUME 10, NUMBER 1 䡲 JANUARY/FEBRUARY 2012
www.SupportiveOncology.net
Keys to Successful Management of CML
During the initial workup for CML and at each follow-up
visit after initiation of therapy, practitioners have many opportunities to educate patients and foster a strong patient–
19
Managing Side Effects of TKI Therapy to Optimize Adherence in CML Patients
Table 7
Management of Select Side Effects Associated with Dasatinib Treatment of CML-CP
Hematologic
Nonhematologic—Specific
interventions (Grade 2
or 3 severity)
Nonhematologic—Grade 4
● Grade 4 neutropenia (ANC ⬍500/mm3): Dose interruption until ANC ⱖ1000/mm3
● Grade 3– 4 thrombocytopenia (platelet count ⬍50,000/mm3):
Dose interruption until platelet count is ⱖ50,000/mm3
Growth factors can be used in combination with dasatinib for patients with resistant neutropenia and
thrombocytopenia.
● Fluid retention (ascites, edema, and pleural and pericardial effusion): Diuretics, supportive care
● Pleural/pericardial effusion: Diuretics, dose interruption. If the patients has significant symptoms, consider
short course of steroids (prednisone 20 mg/day x 3)
● Headache, diarrhea: Supportive care
● GI upset: Take medication with a meal and large glass of water.
● Rash: Topical or systemic steroids, dose reduction, interruption, or discontinuation
If any of the grade 2 or 3 toxicities are not responsive to symptomatic measures, treat as grade 4.
Hold drug until grade 1 or better, and then consider resuming at reduced dose level depending on the severity
of the initial event, or change to nilotinib or imatinib.
Adapted with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines™) for Chronic Myelogenous Leukemia V.1.2012.43 © 2011 National Comprehensive Cancer
Network, Inc. All rights reserved. The NCCN Guidelines and illustrations herein may not be reproduced in any form for any purpose without the express written permission of the NCCN. To
view the most recent and complete version of the NCCN Guidelines, go online to NCCN.org. National Comprehensive Cancer Network®, NCCN®, NCCN Guidelines™, and all other NCCN content
are trademarks owned by the National Comprehensive Cancer Network, Inc.
practitioner relationship. Patient education regarding treatment and symptom management is a vital aspect of caring for
the patient with CML and should begin immediately at diagnosis.52 Every treatment option should involve an explanation of risks and benefits to engage and empower the patient
to participate fully in his or her health care. Patients also must
be given clear instruction on how and when to take their
medications. For example, nilotinib must be taken on an
empty stomach, with no food 2 hours before and 1 hour after
the dose. One simple strategy that can be recommended is
taking nilotinib at 10:00 a.m. and 10:00 p.m.; however, a goal
of the practitioner is to guide each patient to successfully
incorporate the medications into his or her personal routines
and schedules. Potential drug interactions with TKIs also
must be discussed in-depth so that all medications are taken
into account, even over-the-counter medications, herbal supplements, and dietary interactions (eg, grapefruit juice). A
comprehensive review of likely drug interactions with TKIs
has been published recently53 that may aid the practitioner in
this process.
It is essential that patients understand the importance of
reporting symptoms to their practitioners in a timely manner.
Some patients may be reluctant to report side effects because
they may fear that their therapy may be interrupted or their
dose will be lowered.54 Practitioners can explain that side
effects can be managed through supportive care or with a brief
interruption of therapy. If a dose reduction is necessary,
midlevel practitioners can reassure patients that the adjustment is reasonable and that the treatment can still be effective. Again, patients must be reminded that they should not
wait to report their symptoms as these symptoms can become
more severe or treatment-limiting.54 Finally, it is essential
that practitioners evaluate patient adherence at each clinic
visit.12,43 In our practice, adherence is determined during the
patient interview with questions regarding dosing (eg, at what
time[s] are they taking their medication and how are they
20
www.SupportiveOncology.net
taking their medication), with pill counts performed only
infrequently.
The following case report illustrates successful AE management of a patient initially treated with imatinib:
This 64-year-old man was diagnosed with Ph⫹ CML-CP.
He began imatinib therapy, 400 mg twice daily, and quickly
developed grade 1 periorbital edema, loose stools, and a slight
elevation in bilirubin; he was reassured that these are common side effects of imatinib. Within 3 months, he achieved
CCyR. After 1 year of therapy, he began experiencing a
grade 3 skin rash covering 30%-60% of his body. Imatinib
was suspended, and he was treated with topical and oral
steroids until the rash completely resolved. Because the rash
disappeared quickly, imatinib was restarted at the same dose.
The grade 3 rash recurred within 2 weeks, and therapy was
held and steroids restarted. Once the rash resolved to grade
1, imatinib was restarted at the reduced dose of 400 mg once
daily. The patient initially tolerated this dose well and
achieved an MMR after 33 months. After 4 years on therapy
(of which 2.5 years involved the lower dose), the grade 3
rash recurred after he incurred a slight sunburn. This time,
it was accompanied by significant facial edema of uncertain
etiology, but both the rash and facial edema responded to oral
steroids. Imatinib was discontinued until the rash resolved to
grade 1. After several attempts to restart imatinib, which
rapidly resulted in a recurrent rash, the patient was considered to be intolerant to imatinib. His therapy was changed to
nilotinib, 400 mg twice daily. Six years after diagnosis, he is
maintaining an MMR and is tolerating the nilotinib well.
Dose interruption has been explored as a potential management strategy for patients receiving TKI therapy. A retrospective analysis presented at the American Society of Hematology annual meeting in 2009 suggested that weekend
treatment interruption during dasatinib therapy allows for the
continuation of treatment for patients with side effects.55
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Cornelison, Jabbour, and Welch
However, until large-scale prospective studies prove the safety
of alternative dosing schemas, patients should continue to
take therapy as directed by their health-care provider.
THE ROLE OF MIDLEVEL PRACTITIONERS IN
TREATMENT SUCCESS
As a result of the success of TKI therapy, CML is now
treated as a serious, chronic disease and most patients can
expect long-term, event-free survival. Data from head-tohead studies comparing nilotinib vs imatinib and dasatinib vs
imatinib have revealed that nilotinib and dasatinib are more
effective than imatinib for newly diagnosed patients with
CML-CP with respect to cytogenetic and molecular responses,29,32 suggesting that long-term outcomes for patients
will improve. Today, patients are expected to require lifelong
therapy. It is during this treatment era that practitioners play
a pivotal role in maximizing the quality and duration of
response by educating patients on the importance of adherence and by managing side effects aggressively and effectively.
Poor adherence to medication in chronic noncancer illnesses is a common problem in clinical practice.56 Rates of
adherence and persistence (the duration from treatment initiation to discontinuation) with oral cancer therapies vary
widely, ranging 16%–100% in adult patients;57 these disparate reports are due in part to differences in definitions and
methods of measurement for adherence and persistence.
Counseling patients regarding the importance of adherence
has been shown to have a significant and sustained positive
impact on patients taking antiretroviral medications for
HIV.58 A Cochrane report recently provided a synthesis of
systematic reviews that evaluated the effects of various interventions to promote medication adherence. Among the interventions that showed promise for improving adherence was
education delivered together with self-management skills
training, counseling, or support.59 A retrospective analysis of
adherence to TKI therapy for CML also has shown a correlation between patient adherence and patient counseling by a
nurse or a hematologist.60 Patient education includes discussion of medication schedules and incorporation of prompts
(mechanical or relationship-assisted) that will help to reduce
patient forgetfulness.20,61 Patients’ success may therefore depend, in part, on their understanding of the treatment plan,
knowing the medication regimen, being committed to following it, and having the resources to be adherent.61
The following is a case study which illustrates the management of patient adherence:
A 24-year-old woman was diagnosed with Ph⫹ CML-CP and
treated with imatinib, 400 mg daily for 5 months, when she was
referred to a specialty center for grade 2 pancytopenia. At that
time, she was in complete hematologic response (CHR) and
Ph⫹ in 11/20 cells sampled by bone marrow cytogenetics. Her
dose was reduced by 50%, and she continued on imatinib 200
mg daily with complete resolution of pancytopenia, stable CHR,
and partial cytogenetic response for 10 months. Her dose was
increased back to imatinib 400 mg daily, and 3 months later,
although she retained her CHR, she showed no improvement in
VOLUME 10, NUMBER 1 䡲 JANUARY/FEBRUARY 2012
cytogenetic response after 17 months of imatinib therapy. Her
therapy was switched to dasatinib 100 mg daily; however, she
immediately began to complain of grade 3 bone pain and headaches unalleviated by supportive measures. Her dose was thus
reduced by 50%, and she continued on dasatinib 50 mg daily
with complete resolution of AEs for 6 months. At this time it
was determined that she had achieved a major cytogenetic response (MCyR). Three months later, she retained her MCyR
without achieving a CCyR. Her lack of improvement prompted
the midlevel provider to investigate adherence. When this was
explored, she reported low-grade malaise, depressed mood, frustration with lack of cytogenetic improvement, and pregnancy
concerns that were barriers to adherence and, thus, also barriers
to optimal outcome. The patient was counseled on the natural
history of CML and its prognosis and the importance of adherence and its effect on optimal outcome and was supported in her
pregnancy concerns. Dasatinib was increased to the full 100 mg
daily. Supportive care initiatives were reviewed with the patient
by the midlevel provider, including likely side effects and their
appropriate management, using scheduled NSAIDs combined
with proton pump inhibitors to manage low-grade bone pain,
vasodilators for migraine headaches, and tramadol for pain
unalleviated by NSAIDs. She was reassured that clinic staff
could work with her to manage her concerns should she experience these symptoms again and counseled to avoid missed
doses due to AEs. She returned to the clinic 3 months later, with
grade 1 bone pain and headache that were intermittent and
manageable with supportive measures, 100% adherence, and
attainment of a CCyR, after 29 months of therapy.
Although evaluation of long-term medication adherence
in CML is relatively new, several studies with shorter follow-up have been published. The Adherence Assessment
with Gleevec: Indicators and Outcomes (ADAGIO) study12
assessed adherence using multiple measures at baseline and at
90 days, including self-report, proportion of patient visits
kept, and pill count. The perceptions of physicians and third
parties regarding patient adherence were also captured. Patients reported that their adherence to imatinib was good and
that they were vigilant in keeping clinic appointments. Physicians and third parties (spouse or family member) also considered adherence to imatinib to be high. Other assessments,
however, revealed significantly poorer outcomes: one-third of
patients were considered to be nonadherent, as defined by
having a positive response to any one of four questions on the
Basel Assessment of Adherence Scale. By pill count, only
14.2% of subjects took 100% of the prescribed imatinib.12
A second study investigated adherence to imatinib over 3
months in 87 patients using a microelectronic monitoring
device (an electronic device fitted into the medication bottle
cap that recorded each time the bottle was opened).11 All
patients had achieved CCyR before participating in the study
and were at a median of 5 years from diagnosis. The median
adherence rate was high (98%) but ranged from a low of 24%
of medication taken to a high of 104% of medication taken.
Approximately one-quarter of patients had adherence ⱕ90%,
www.SupportiveOncology.net
21
Managing Side Effects of TKI Therapy to Optimize Adherence in CML Patients
and 14% had adherence ⱕ80%. Achieving a molecular response at 18 months was strongly associated with good adherence to therapy during the 3-month study period. Assessment of
response since initiation of imatinib treatment demonstrated no
complete molecular responses (CMRs: defined as undetectable
levels of BCR-ABL transcripts) in patients whose adherence was
ⱕ90%, and no MMRs were observed when adherence was
ⱕ80%.11 The authors concluded that poor adherence is the
primary reason that some patients do not obtain adequate molecular responses with imatinib therapy.11 In the same study,
adherence rates were lower in patients with side effects of asthenia, nausea, muscle cramps, and bone or joint pain and in
patients who took imatinib independently of meals. These results suggest that common side effects of imatinib therapy negatively influence medication adherence. In a study designed to
define symptom burden over the course of the disease, CML
patients indicated that fatigue, pain, and nausea led them to stop
or to consider interruption or reduction of dose or dose frequency
during treatment.35
Since some patients fail to continue taking their medication when side effects become uncomfortable and distressing,
midlevel practitioners and other health-care providers play a
vital role in educating patients about the need to promptly
report side effects. In turn, aggressive management to minimize treatment-related side effects may help patients maintain treatment. Management of treatment-related side effects
to improve adherence is suggested in conditions, such as HIV
infection, that require chronic treatment.62– 64
The patient case report discussed previously illustrates the
crucial role health-care providers play in managing and reassuring patients about mild side effects and supporting them
through the treatment of more serious reactions requiring
dose interruptions or reductions. Furthermore, as patients
have been educated on the importance of adherence with
medication, it is important to provide counsel on the safety of
temporary interruptions to manage side effects and, ultimately, to be able to continue treatment. Awareness of the
timing and definitions of therapeutic milestones, such as hematologic response, cytogenetic response, and molecular response, may help to identify patients who are experiencing
intolerance, nonadherent, or not responding optimally to
treatment. Patients often find these concepts hard to grasp,
and through consistent and repeated communication and
education, practitioners can make a substantial difference in
guiding patients through lifelong management of CML. The
case report also illustrates the successful approach of dose
reduction and temporary interruption in a patient who was
intolerant to standard dosing and how these treatment modifications can be successful at managing difficult cases.
A future goal of CML therapy is to cure CML and thus be
able to discontinue treatment; however, a high rate of relapse is
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Many advances have been made in the treatment of CML,
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facilitate adherence by preventing adverse effects on patient
quality of life, treatment interruptions, or long-term complications. A proactive approach by midlevel practitioners can do
much to ensure optimal outcomes in the treatment of CML.
Acknowledgments: Financial support for medical editorial assistance was provided by Novartis Pharmaceuticals. We thank Mariana Ovnic, PhD, and Patricia
Segarini, PhD, of Percolation Communications for their medical editorial assistance.
Conflict of Interest Disclosures: Ms Cornelison and Ms Welch have no
competing interests. Dr Jabbour has received honoraria from Bristol-Myers
Squibb and Novartis Oncology.
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