1. health and fitness
2. disease

continuing education for pharmacists
Volume XXXI, No. 7
New Chronic Myeloid Leukemia Drugs:
Bosulif, Iclusig, and Synribo
Thomas A. Gossel, R.Ph., Ph.D., Professor Emeritus, Ohio Northern University, Ada, Ohio
Dr. Thomas A. Gossel has no relevant
financial relationships to disclose.
Goal. The goal of this lesson is to
provide information on chronic myeloid leukemia and its treatment
with three new-molecular entity
drugs: bosutinib (Bosulif®), ponatinib (Iclusig®), and omacetaxine
(Synribo™).
Objectives. At the completion of
this activity, the participant will be
able to:
1. recognize signs and symptoms, and key features of chronic
myeloid leukemia (CML) including
prevalence;
2. identify the new drugs by
generic name, trade name and
chemical name when relevant;
3. select the indication(s),
pharmacologic action(s) and clinical
applications for each drug;
4. identify important therapeutic uses for the drugs and projected
benefits over other approved medications for CML;
5. list adverse effects and toxicity, significant drug-drug interactions; and
6. demonstrate an understanding of important counseling information to convey to patients and/or
their caregivers.
Introduction
An estimated 5,430 men and
women in the United States were
diagnosed with chronic myeloid
leukemia (CML) in 2012 with a
typical-age at diagnosis between
55 and 65 years. CML accounts for
about 15 percent of new leukemia
cases in adults. It is rare in children. While these figures may not
appear overwhelming when aligned
with morbidity and mortality data
characteristic of more invasive
cancers, CML represents a cancer
that can be effectively treated and
all but eliminated in most patients
with early diagnosis and pharmacotherapy.
Leukemia
Leukemia is a cancer of white
blood cells that develops in myeloid tissue (bone marrow). Large
numbers of cancerous cells accumulate because they multiply out
of control or because they survive
much longer than normal cells, or
both. With leukemia, the cancerous
cells fill the marrow and spill out
into the blood. There are several
types of leukemia: acute lymphoblastic leukemia (ALL), chronic
lymphocytic leukemia (CLL), acute
myeloid leukemia (AML) and
chronic myeloid leukemia (CML).
In acute leukemia, bone marrow
cells are immature and are unable
to function normally. The number
of abnormal cells increases rapidly.
In chronic leukemia, cells are more
mature and can carry out some of
their normal functions, and the
number of abnormal cells increases
more slowly. Most leukemias arise
from cells that normally develop
into white blood cells (the word
leukemia is derived from a Greek
word that means “white blood”).
Blood cells normally comprise
about 40 percent of blood volume
and are divided into three major
types: erythrocytes (red blood cells;
RBCs), leukocytes (white blood
cells; WBCs) and platelets (thrombocytes). They are formed in bone
marrow by primitive (immature)
cells called stem cells that continually divide to produce new cells.
There are two types of stem cells:
myeloid and lymphoid cells. Some
Table 1
New drugs for treatment of chronic myeloid leukemia
Generic (Proprietary) Name
Bosutinib (Bosulif)
Ponatinib (Iclusig)
Omacetaxine (Synribo)
Distributor
Dosage Form
Pfizer Labs
Ariad
Pharmaceuticals
Teva
Pharmaceuticals 100, 500 mg tabs
15, 45 mg tabs
No
Yes
3.5 mg singledose vials
No
*Medication Guide availability information at time of publishing
Med Guide*
offspring cells remain as stem cells,
while others go through a series of
maturing stages (precursor or blast
cells). Blast cells are new, immature blood cells of any type before
forming into mature blood cells.
Chronic Myeloid Leukemia
CML (sometimes called chronic
myelogenous leukemia, chronic
granulocytic leukemia or chronic
myelocytic leukemia) is a myeloproliferative cancer that develops
due to a problem that most likely
starts within a single stem cell in
the bone marrow, resulting in an
acquired genetic mutation. During cell division, some of the DNA
from chromosome #9 is transferred
to chromosome #22. The resulting
abnormal chromosome is termed
the Philadelphia (Ph) chromosome (at the molecular level, an
oncogene known as Bcr-Abl), and
is responsible for CML initiation
by causing a clonal expansion of
Bcr-Abl-expressing hematopoietic
stem cells. An oncogene is genetic
material that, when mutated or
expressed at high levels, helps turn
a normal cell into a cancerous one.
These mutant (changed) chromosomes direct the bone marrow to
manufacture an enzyme called
tyrosine kinase. The resulting
Bcr-Abl tyrosine kinase, an oncogenic fusion protein, bypasses the
normal cell regulatory processes
and leads to an overproduction of
myeloid stem cells. These abnormal cells multiply and mature to
develop into near-normal white
cells, mainly neutrophils, basophils
and eosinophils (collectively called
granulocytes). Large numbers of
these granulocytes that are formed
in the bone marrow spill into the
blood. The Ph chromosome is not
passed from parent to child; thus,
CML is not an inherited cancer.
CML Progression. CML presents in three stages: chronic phase,
accelerated (intermediate) phase,
and blast crisis, based on pathology and clinical presentation. The
initial (chronic) phase is relatively
benign and characterized by welldifferentiated leukemic cells. While
the malignant cells have a slight
growth advantage, they retain
a nearly normal differentiation
capacity.
In chronic-phase CML, the
white blood cell count might be
elevated, versus neutrophil and
platelet functions that typically
remain normal.
Within five years of diagnosis,
the chronic phase will be followed
by progression to the accelerated
phase or on to the terminal blast
crisis. The accelerated phase shows
a peripheral blood pattern of marrow blasts ≥5 percent, basophils
>20 percent and a platelet count of
1000 x 103/mm3, or higher despite
adequate therapy. As the abnormal cells accumulate in the bone
marrow and blood, it is difficult for
cells in the marrow to survive and
manufacture enough normal blood
cells. The accelerated phase may
persist three to 18 months.
Approximately 25 percent of
patients may transition directly
from the chronic phase into blast
crisis. In this third phase the
condition rapidly worsens and
behaves like an acute leukemia.
Many immature blast cells develop
and fill much of the bone marrow
and cause worsening of symptoms.
Blast crisis is the remaining challenge in the management of CML.
This phase is usually defined by
the presence of extramedullary
blastic infiltrates of ≥30 percent
leukemic blasts in peripheral blood
or marrow. Blast cells are not
typically found in circulating blood
of healthy individuals. Death is
common within three to six months
after a patient enters this final
phase.
Most patients (85 percent) are
diagnosed with CML while in the
chronic phase. Symptoms, if present, are mild with as many as 45
percent of patients discovered after
routine blood tests while still
asymptomatic. Approximately 5
percent of patients will have advanced into the accelerated phase
and 10 percent into blast crisis
when diagnosed. Among patients
initially diagnosed in the chronic
phase, the accelerated phase is heralded by increased symptoms and
greater need for more intensive
therapy to control their disease.
Symptomatic patients may
present with fatigue, weakness,
bleeding, sweating, and weight
loss. Splenomegaly may induce
feelings of early satiety and left
upper quadrant pain or mass,
and suggests disease acceleration. Leukocytosis, anemia and
thrombocytosis are common.
Hepatomegaly may occasionally
be found. Lymphatic disease and
bone marrow malignancies are rare
in early CML, but become more
common later in the disease and
are associated with poor prognosis.
Very rarely, CML develops into a
condition called myelofibrosis, at
which time the bone marrow can no
longer make red cells, white cells
or platelets because it is replaced
by scar tissue (fibrosis).
History of CML Therapy. Before the advent of tyrosine kinase
inhibitor (TKI) therapy, the median survival time for patients with
CML was about four years. Until
then, standard treatment for CML
consisted of either the alkylating
agent busulfan (Busulfex, Myleran)
or the ribonucleotide inhibitor hydroxyurea (Hydrea). Both busulfan
and hydroxyurea controlled the hematologic manifestations of CML,
but neither modified the clinical
course of the cancer. In patients
with chronic-phase CML, busulfan
and hydroxyurea therapy were associated with a median survival of
44 and 56 months, respectively.
Interferon-alpha (IFNα; Intron
A, Roferon-A) was introduced in
the 1980s and improved overall
survival. It became the standard
of care for CML until the advent
of TKI therapy. Treatment with
IFNα yielded complete hematologic
response in 50 to 80 percent of
previously untreated patients with
chronic-phase CML. A positive cytogenetic (cell production) response
was achieved in 40 to 60 percent
of patients, including complete
cytogenetic response (defined as no
detectable Ph chromosomes in at
least 20 bone marrow metaphases)
in 5 to 25 percent of patients with
chronic-phase CML. The results
of numerous randomized clinical
trials comparing IFNα and hydroxyurea or busulfan showed
that IFNα improved survival more
than chemotherapeutic agents.
Unfortunately, IFNα has minimal
activity in CML that has advanced
to the accelerated or blastic phase.
Moreover, it is also associated with
significant adverse effects, including flu-like symptoms, fever, chills,
myalgias, fatigue, depression,
neuropathy, diarrhea, memory loss,
immune-mediated complications
and myelosuppression.
Tyrosine Kinase Inhibitors.
Realization of the critical role that
tyrosine kinase plays in the pathogenesis of CML led to a search for
specific inhibitors. The most significant advancement in treatment of
CML was achieved with introduction in 2001 of imatinib (Gleevec).
Imatinib revolutionized the treatment of Philadelphia-positive (Ph+)
CML and established targeted BcrAbl inhibitors as the standard of
care. The drug is a small-molecule
TKI that binds to the adenosine
triphosphate binding site of the Abl
enzyme. This prevents the phosphorylation of a critical residue
necessary for substrate binding
and kinase activity. Imatinib also
inhibits the activity of several
other tyrosine kinases.
A prospective, randomized,
phase III trial (the International
Randomized Study of Interferon
versus STI571 [IRIS]), was initiated in 2000 to compare single-agent
imatinib with IFNα plus low-dose
cytarabine (Depocyt, etc.) therapy
in treatment-naïve patients with
early chronic-phase CML. The
outcome of the IRIS trial resulted
in a fundamental change in the
treatment protocol for CML and
established imatinib as its frontline therapy. Imatinib thus became
the first TKI to be approved for the
treatment of CML and is currently
indicated as initial pharmacotherapy for all phases of newly diagnosed CML.
At the same time, however, approximately 30 percent of patients
will discontinue imatinib therapy
because of intolerance, or pri-
mary or acquired resistance. In the
treatment of CML, failure to meet
defined goals for hematologic, cytogenetic, and molecular assessments
at specific time points constitutes
primary resistance to imatinib. Decreasing response after having achieved these goals is defined
as secondary resistance. Initial
estimates of primary resistance
were 15 to 24 percent at 18 months
of follow-up, and for secondary resistance were 7 to 15 percent. More
recent estimations, however, are
that approximately 40 percent of
patients are at a risk of losing the
complete cytogenetic response that
had been achieved.
Following the lead of imatinib,
a second generation of TKIs was
developed shortly after imatinib
failure was identified. An initial
important step was the identification of mutations in the tyrosine
kinase domain as the most common mechanism of resistance. This
was soon followed by development
of new agents with higher binding affinity to Bcr-Abl even in the
presence of most known mutants.
Two of these agents, dasatinib
(Sprycel) and nilotinib (Tasigna),
have been most extensively studied and have received regulatory
approval for use as second-line (i.e.,
salvage) therapy among patients
with resistance or intolerance to
imatinib, with more than half
(53 to 93 percent) of them achieving a major cytogenetic response.
Unfortunately, some patients also
develop resistance or intolerance to
dasatinib and/or nilotinib. Prior to
approval of the three new drugs to
be discussed subsequently, treatment options were few for patients
previously treated with imatinib,
followed by dasatinib and/or
nilotinib. Therefore, alternative
treatments are needed for patients
with chronic-phase CML who have
received treatment with and have
become resistant to or intolerant of
multiple TKIs.
The excellent results obtained
with imatinib when used as initial
therapy, and availability of effective salvage therapy, redefined the
CML treatment algorithm. Nearly
all patients are now offered therapy with imatinib at diagnosis, and
for those who experience failure
with therapy, a second-generation
TKI is indicated. With this approach, the median survival for
CML patients will probably exceed
20 years.
Among the most intriguing
clinical questions remaining in the
management of CML is whether
patients can eventually discontinue
therapy and be cured. The current
recommendation is to continue
therapy indefinitely. Early attempts at treatment discontinuation among patients with CML
suggested that most patients
experienced relapse.
The New Drugs
Drugs discussed subsequently
are new-molecular entity drugs
indicated to treat CML (Table 1).
The discussion provides a brief
introduction to the drugs and is
not intended to extend beyond an
overview of the topic. The reader
is, therefore, encouraged to consult
each product’s full Prescribing Information leaflet (package insert),
Medication Guide when available,
and other published reference
sources for more detailed information.
Bosutinib (Bosulif)
Bosulif (BAH-su-lif) was approved
for treatment of adult patients with
chronic, accelerated, or blast phase
Ph+ CML with resistance or intolerance to prior therapy, including
imatinib.
Mechanism of Action. Bosutinib inhibits the Bcr-Abl kinase
(tyrosine kinase) that promotes
CML. It also inhibits other kinases.
Efficacy. Efficacy was assessed in a single clinical trial
that enrolled 546 adult patients
with chronic-, accelerated- or
blast-phase CML. All subjects had
disease that progressed after treatment with imatinib or imatinib
followed by dasatinib and/or nilotinib, or who could not tolerate the
adverse effects of prior therapy. All
patients in the trial received Bosulif. Thirty-three percent of patients
Table 2
Examples of inhibitors
and inducers of CYP3A
isoenzymes
Inhibitors
Strong: ritonavir, indinavir, nelfinavir, saquinavir, ketoconazole,
boceprevir, telaprevir, itraconazole,
voriconazole, posaconazole, clarithromycin, telithromycin, nefazodone,
conivaptan
Moderate: fluconazole, darunavir,
erythromycin, diltiazem, atazanavir,
aprepitant, amprenavir, fosamprevir,
crizotinib, imatinib, verapamil, ciprofloxacin, grapefruit juice
Inducers
Strong: rifampin, phenytoin, carbamazepine, St. John’s Wort, rifabutin,
phenobarbital
Moderate: bosentan, nafcillin, efavirenz, modafinil, etravirine
with accelerated CML previously
treated with at least imatinib had
blood counts that returned to normal range (complete hematologic
response) and 55 percent achieved
normal blood counts without evidence of leukemia (overall hematologic response) within the first 48
weeks of treatment. Meanwhile, 15
percent and 28 percent of patients
with blast-phase CML achieved
a complete hematologic response
and overall hematologic response,
respectively.
Adverse Reactions. In
clinical trials, the most common
adverse reactions (incidence >20
percent) were diarrhea, nausea,
thrombocytopenia, vomiting, abdominal pain, rash, anemia, fever
and fatigue.
Warnings, Precautions and
Contraindications. Warnings
and precautions are:
• Gastrointestinal toxicity (diarrhea, nausea, vomiting, abdominal pain): monitor and manage as
necessary. Withhold, reduce dose,
or discontinue Bosulif.
• Myelosuppression (thrombocytopenia, anemia, neutropenia):
monitor blood counts and manage
as necessary.
• Hepatic toxicity (elevated
liver enzymes and bilirubin): monitor liver enzymes at least monthly
for the first three months and as
needed. Withhold, reduce dose, or
discontinue Bosulif.
• Fluid retention (pericardial
and pleural effusion, pulmonary
and peripheral edema): monitor patients and manage using standard
of care treatment. Withhold, reduce
dose, or discontinue Bosulif.
• Embryofetal toxicity: the drug
may cause fetal harm. Females of
reproductive potential should avoid
becoming pregnant while being
treated with Bosulif.
The only contraindication is
hypersensitivity to Bosulif. Anaphylactic shock occurred in <0.2
percent of patients in clinical trials.
Drug Interactions. CYP3A
inhibitors and inducers: avoid concurrent use of Bosulif with strong
or moderate CYP3A inhibitors and
inducers (Table 2).
Proton pump inhibitors: may
decrease bosutinib drug levels.
Consider short-acting antacids or
H2-antagonists in place of proton
pump inhibitors, with dosing separated by more than two hours.
Dosing. Daily doses of 500 mg
orally should be taken with food.
Continue treatment with Bosulif
until disease progression or patient
intolerance. If a dose is missed beyond 12 hours, the patient should
skip the missed dose and take the
usual prescribed dose on the following day. Dose escalation to 600 mg
daily can be considered in patients
who do not reach complete hematologic response by Week 8 or complete cytogenetic response by Week
12, and who do not have significant
adverse reactions. Starting doses
should be reduced to 200 mg daily
in case of hepatic impairment, and
300 mg daily for renal impairment.
Patient Counseling Information. Specific points for counseling as listed in the Prescribing
Information leaflet are summarized
in Table 3.
Ponatinib (Iclusig)
Iclusig (eye-CLUE-sig) received
FDA approval for treatment of
adult patients with chronic-phase,
accelerated phase and blast-crisis
CML that is resistant or intolerant
to prior TKI therapy or Ph+ ALL
that is resistant or intolerant to
prior TKI therapy. These indications are based on response rate.
There are no studies verifying
improvement in disease-related
symptoms or increased survival
with the drug.
Mechanism of Action. Ponatinib is a TKI and inhibitor of other
kinases.
Efficacy. Efficacy was evaluated in a single clinical trial of 449
patients with various phases of
CML and Ph+ ALL. All patients
received Iclusig. Effectiveness was
demonstrated by a reduction in
the percentage of cells expressing
the Ph chromosome genetic mutation, a major cytogenetic response
(MCyR). Fifty-four percent of all
patients and 70 percent of patients
with the T3151 mutation achieved
MCyR. The median duration of
MCyR had not been reached at the
time of approval.
In accelerated- and blast-crisis
CML and Ph+ ALL, the drug’s
effectiveness was determined by
the number of patients who experienced a normalization of white
blood cell counts or had no evidence
of leukemia (major hematologic response or MaHR). Results showed:
• 52 percent of patients with
accelerated-phase CML experienced MaHR for a median duration
of 9.5 months;
• 31 percent of patients with
blast-crisis CML achieved MaHR
for a median duration of 4.7
months;
• 41 percent of patients with
Ph+ ALL achieved MaHR for a
median duration of 3.2 months.
Adverse Reactions. The most
common non-hematologic adverse
reactions (≥20 percent) were hypertension, rash, abdominal pain,
fatigue, headache, dry skin, constipation, joint pain, nausea and
fever. Hematologic adverse reactions included thrombocytopenia,
anemia, neutropenia, lymphopenia
and leukopenia.
Warnings, Precautions and
Contraindications. Warnings
and precautions are:
• Congestive heart failure:
monitor patients for signs or symptoms of congestive heart failure
and treat as clinically indicated.
• Hypertension (including
confusion, headache, chest pain,
shortness of breath, and hypertensive crisis): monitor for high blood
pressure and treat as clinically
indicated.
• Pancreatitis: monitor serum
lipase monthly; interrupt or discontinue Iclusig.
• Hemorrhage: interrupt
Iclusig for serious or severe hemorrhage.
• Fluid retention: monitor for
fluid retention; interrupt, reduce,
or discontinue Iclusig.
• Cardiac arrhythmias (especially bradyarrhythmias): monitor
for symptoms of arrhythmias.
• Myelosuppression: thrombocytopenia, neutropenia, and anemia may require dose interruption
or reduction. Monitor complete
blood counts every two weeks for
three months and then monthly
and as clinically indicated. Interrupt Iclusig for absolute neutrophil
count <1000/mm3 or thrombocytopenia <50,000/mm3.
• Tumor lysis syndrome:
ensure adequate hydration and
correct high uric acid levels prior to
initiating therapy with Iclusig
• Compromised wound healing
and gastrointestinal perforation:
interrupt therapy for at least one
week prior to major surgical procedures.
• Embryofetal toxicity: can
cause harm. Advise women of potential risk to a fetus.
• A Boxed Warning advises on
the risk of arterial thrombosis and
hepatotoxicity.
There are no contraindications listed for Iclusig.
Drug Interactions. Strong
CYP3A inhibitors (Table 2): reduce
Iclusig dose if co-administration
cannot be avoided.
Dosing. The recommended
dose and schedule is 45 mg given
once daily, with or without food.
Table 3
Patient counseling information*
BosulifIclusig Synribo
Alopeciax
Bleeding, hemorrhage x x
Compromised wound healing x
Congestive heart failure, x
cardiac arrhythmias
Dosing, administration x x
Drug interactions x
Fatiguex
Fluid retention x x
Gastrointestinal problemsxxx
Hyperglycemiax
Hypertensionx
Lactose content x
Liver problems x x
Low blood cell counts, x x x
myelosuppression
Other adverse reactions x
Pancreatitisx
Pregnancy, breastfeedingxxx
Rashx
Thrombosis,x
thromboembolism
*Specific counseling points in each product’s Prescribing Information leaflet (package insert).
These are minimum counseling points. Additional information may be included as deemed
appropriate.
Tablets should be swallowed whole.
Continue treatment as long as
there is no evidence of disease
progression or unacceptable toxicity. Modify or interrupt dosing for
hematologic and non-hematologic
toxicity.
Patient Counseling Information. An FDA-approved Medication Guide must be dispensed
with Iclusig. Specific points for
counseling as listed in the Prescribing Information leaflet are summarized in Table 3.
Omacetaxine (Synribo)
Homoharringtonine (HHT) is a
natural alkaloid obtained from the
evergreen tree Cephalotaxus harringtonia, which is native to China.
Its antileukemic activity was first
demonstrated in China in the
1970s, and studies in the United
States confirmed its usefulness
in CML. At one point, HHT was
considered the most effective drug
treatment for this disease after
failure of IFNα; however, the clini-
cal development of HHT in CML
came to a halt with introduction of
imatinib. Investigation continued,
however.
Omacetaxine is a semisynthetic
form of HHT, and its activity in
imatinib-resistant CML has established this agent for the second
time as a valuable option in management of CML. Synribo (sin-RIbo) is FDA approved for treatment
of adult patients with chronic- or
accelerated-phase CML with resistance and/or intolerance to two or
more TKIs. This indication is based
upon response rate. There are no
trials verifying an improvement
in disease-related symptoms or
increased survival with the drug.
Mechanism of Action. The
mechanism of action of omacetaxine has not been fully elucidated
but includes inhibition of protein
synthesis, and is independent of
direct Bcr-Abl binding. Its mechanism differs from TKIs. In vitro,
the drug reduces protein levels of
the Bcr-Abl oncoprotein.
Efficacy. Efficacy was evaluated using a combined cohort of
patients whose cancer progressed
after previous treatment with two
or more TKIs. All participants were
treated with Synribo. Its efficacy
in chronic-phase CML was demonstrated by a reduction in the
percentage of cells expressing the
Ph+ mutation. Fourteen out of 76
patients achieved a reduction in an
average time of 3.5 months. The
median length of the reduction was
12.5 months.
In accelerated-phase CML,
Synribo’s effectiveness was determined by the number of patients
who experienced normalization in
white blood cell counts or had no
evidence of leukemia (major hematologic response; MaHR). Results
showed five out of 35 patients (14.3
percent) achieved MaHR in an
average time of 2.3 months. The
median duration of MaHR in these
patients was 4.7 months.
Adverse Reactions. In chronic- and accelerated-phase CML,
the most common adverse reactions (frequency ≥20 percent) were
thrombocytopenia, anemia, neutropenia, diarrhea, nausea, fatigue,
weakness, injection site reactions,
fever, infection and lymphopenia.
Warnings, Precautions and
Contraindications. Warnings
and precautions are:
• Myelosuppression: severe and
fatal thrombocytopenia, neutropenia and anemia. Monitor hematologic parameters frequently.
• Bleeding: severe thrombocytopenia and increased risk of
hemorrhage. Fatal cerebral hemorrhage and severe, non-fatal gastrointestinal hemorrhage.
• Hyperglycemia: glucose
intolerance and hyperglycemia
including hyperosmolar non-ketotic
hyperglycemia.
• Embryofetal toxicity: can
cause fetal harm. Advise females
of reproductive potential to avoid
pregnancy.
There are no contraindications listed for Synribo.
Drug Interactions. Omacetaxine is not a substrate of CYP450
enzymes or P-glycoprotein in vitro.
Based on the findings from in vitro
studies, no clinical drug interaction trials were warranted.
Preparation and Administration Precautions. Synribo should
be reconstituted and administered
in a healthcare facility. The drug
is an antineoplastic product. Follow special handling and disposal
procedures. Avoid contact with the
skin. If Synribo comes into contact
with skin, immediately and thoroughly wash affected area with
soap and water.
Dosing. Starting dose for
induction is 1.25 mg/m2 subcutaneously twice daily for 14 consecutive
days every 28 days. Repeat cycles
every 28 days until hematologic
response is seen. For maintenance,
administer 1.25 mg/m2 twice daily
for seven consecutive days every 28
days. Treatment should be continued as long as patients are benefitting from therapy.
Patient Counseling Information. Specific points for counseling as listed in the Prescribing
Information leaflet are summarized
in Table 3.
Overview and Summary
Evolution of understanding the
pathophysiology and management
of CML has been rapid and immense during the past 50 years.
Medical science has advanced from
identifying a common cytogenetic
abnormality to translating this
finding into treatment strategies
that have altered the natural history of the disease. With improved
treatment options available, CML
outcomes may continue to be improved.
The author, the Ohio Pharmacists Foundation and the Ohio Pharmacists Association
disclaim any liability to you or your patients
resulting from reliance solely upon the information contained herein. Bibliography for
additional reading and inquiry is available
upon request.
This lesson is a knowledge-based CE activity and
is targeted to pharmacists in all practice settings.
Program 0129-0000-13-007-H01-P
Release date: 7-15-13
Expiration date: 7-15-16
CE Hours: 1.5 (0.15 CEU)
The Ohio Pharmacists Foundation Inc. is
accredited by the Accreditation Council
for Pharmacy Education as a provider of
continuing pharmacy education.
continuing education quiz
Please print.
Program 0129-0000-13-007-H01-P
0.15 CEU
Name________________________________________________
Address_____________________________________________
New Chronic Myeloid Leukemia Drugs:
Bosulif, Iclusig, and Synribo
City, State, Zip______________________________________
Email_______________________________________________
1. In 2012, the typical age at CML diagnosis was between:
a. 35 and 45.
c. 55 and 65.
b. 45 and 55.
d. 65 and 75.
2. All of the following are correct about CML EXCEPT:
a. it is a myeloproliferative cancer.
b. it is also called chronic granulocytic leukemia.
c. some DNA is transferred from chromosome #22 to #9.
d. the chronic phase of CML is relatively benign.
3. The Philadelphia chromosome directs bone marrow to
manufacture which of the following enzymes?
a. Tyrosine kinase
c. Threonine kinase
b. Thymidine kinase d. Tryptophan kinase
4. Most patients with CML are diagnosed at which of
the following levels?
a. Acute phase
c. Accelerated phase
b. Chronic phase
d. Blast crisis
5. Historically, standard treatment of CML consisted
of which of the following ribonucleotide inhibitor
drugs?
a. Hydroxyurea
c. Interferon-alpha
b. Busulfan
d. Methotrexate
Completely fill in the lettered box corresponding to
your answer.
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*Obtain NABP e-Profile number at www.MyCPEmonitor.net.
Birthdate____________
(MMDD)
Return quiz and payment (check or money order) to
Correspondence Course, OPA,
2674 Federated Blvd, Columbus, OH 43235-4990
7. The IRIS trial established which of the following
drugs as front-line therapy for CML?
a. Dasatinib
c. Nilotinib
b. Imatinib
d. Bosutinib
8. Bosutinib is approved for treating all of the following
leukemias EXCEPT:
a. acute phase Ph+ CML. c.accelerated phase Ph+ CML.
b. chronic phase Ph+ CML.d.blast crisis Ph+ CML.
9. Which of the following is a contraindication to using
Bosulif?
a. Elevated liver enzymes
b. Myelosuppression
c. Hypersensitivity to bosutinib
d. No contraindication listed
10. Patients receiving ponatinib should be counseled on
the drug’s potential for causing all the following EXCEPT:
a. bleeding.
c. fluid retention.
b. dementia.
d. myelosuppression.
11. The recommended dose for ponatinib is:
a. 5 mg once daily.
c. 45 mg once daily.
b. 25 mg twice daily. d. 75 mg twice daily.
6. Adverse effects associated with interferon-alpha
include all of the following EXCEPT:
a. depression.
c. myelosuppression.
b. fever.
d. splenomegaly.
1.
2.
3.
4.
5.
NABP e-Profile ID*__________________________________
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[d]
[d]
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[d]
 I am enclosing $5 for this month’s quiz made payable
to: Ohio Pharmacists Association.
1. Rate this lesson: (Excellent) 5 4 3 2 1 (Poor)
2. Did it meet each of its objectives?  yes  no
If no, list any unmet_______________________________
3. Was the content balanced and without commercial bias?
 yes  no
4. Did the program meet your educational/practice needs?
 yes  no
5. How long did it take you to read this lesson and complete the quiz? ________________
6. Comments/future topics welcome.
12. A potential drug interaction with ponatinib is with:
a. ketoconazole.
c. St. John’s Wort.
b. verapamil.
d. nafcillin.
13. The semisynthetic form of homoharringtonine is:
a. imatinib.
c. ponatinib.
b. bosutinib.
d.omacetaxine.
14. The drug label that carries a Boxed Warning advising about the risk of arterial thrombosis is:
a. Gleevec.
c. Iclusig.
b. Bosulif.
d.Synribo.
15. The method of administration for Synribo is:
a. orally.
c. intramuscularly.
b. subcutaneously.
d.intravenously.
To receive CE credit, your quiz must be received no later than July 15,
2016. A passing grade of 80% must be attained. Quizzes are uploaded
to the CPE Monitor. CE statements of credit will not be mailed. Send
inquiries to [email protected].
july 2013