Thomas A. Gossel, R.Ph., Ph.D., Professor Emeritus, Ohio Northern University, Ada, Ohio
continuing education for pharmacists
New Chronic Myeloid Leukemia Drugs:
Bosulif, Iclusig, and Synribo
Volume XXXI, No. 7
Dr. Thomas A. Gossel has no relevant financial relationships to disclose.
Goal.
The goal of this lesson is to provide information on chronic my-eloid leukemia and its treatment with three new-molecular entity drugs: bosutinib (Bosulif®),pona-tinib (Iclusig®), and omacetaxine
(Synribo™).
Objectives.
At the completion of this activity, the participant will be able to:1. recognize signs and symp-toms, 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 therapeu-tic uses for the drugs and projected benefits over other approved medi-cations for CML;
5. list adverse effects and toxic-ity, significant drug-drug interac-tions; and
6. demonstrate an understand-ing of important counselunderstand-ing infor-mation 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 chil-dren. 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 pharma-cotherapy.
Leukemia
Leukemia is a cancer of white blood cells that develops in my-eloid tissue (bone marrow). Large numbers of cancerous cells accu-mulate 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 lympho-blastic 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 (throm-bocytes). They are formed in bone marrow by primitive (immature) cells called stem cells that continu-ally 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) Distributor Dosage Form Med Guide* Name
Bosutinib (Bosulif) Pfizer Labs 100, 500 mg tabs No Ponatinib (Iclusig) Ariad 15, 45 mg tabs Yes
Pharmaceuticals
Omacetaxine (Synribo) Teva 3.5 mg
Pharmaceuticals dose vials No
offspring cells remain as stem cells, while others go through a series of maturing stages (precursor or blast cells). Blast cells are new, imma-ture 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 myelo-proliferative 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. Dur-ing cell division, some of the DNA from chromosome #9 is transferred to chromosome #22. The resulting abnormal chromosome is termed the Philadelphia (Ph) chromo-some (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) chromo-somes direct the bone marrow to manufacture an enzyme called tyrosine kinase. The resulting Bcr-Abl tyrosine kinase, an onco-genic fusion protein, bypasses the normal cell regulatory processes and leads to an overproduction of myeloid stem cells. These abnor-mal 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 pres-ents in three stages: chronic phase, accelerated (intermediate) phase, and blast crisis, based on pathol-ogy and clinical presentation. The initial (chronic) phase is relatively benign and characterized by well-differentiated 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 mar-row blasts ≥5 percent, basophils >20 percent and a platelet count of 1000 x 103/mm3, or higher despite
adequate therapy. As the abnor-mal 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 chal-lenge 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 pres-ent, 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 ad-vanced into the accelerated phase and 10 percent into blast crisis when diagnosed. Among patients initially diagnosed in the chronic phase, the accelerated phase is her-alded 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 accelera-tion. 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. Be-fore the advent of tyrosine kinase inhibitor (TKI) therapy, the me-dian 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 hy-droxyurea (Hydrea). Both busulfan and hydroxyurea controlled the he-matologic manifestations of CML, but neither modified the clinical course of the cancer. In patients with chronic-phase CML, busulfan and hydroxyurea therapy were as-sociated 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 cy-togenetic (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 hy-droxyurea 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, includ-ing 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 patho-genesis of CML led to a search for specific inhibitors. The most signifi-cant advancement in treatment of CML was achieved with introduc-tion in 2001 of imatinib (Gleevec). Imatinib revolutionized the treat-ment of Philadelphia-positive (Ph+) CML and established targeted Bcr-Abl 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 phos-phorylation 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 initiat-ed 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 front-line therapy. Imatinib thus became the first TKI to be approved for the treatment of CML and is currently indicated as initial pharmacother-apy for all phases of newly diag-nosed CML.
At the same time, however, ap-proximately 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, cyto-genetic, and molecular assessments at specific time points constitutes primary resistance to imatinib. Decreasing response after hav-ing 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 re-sistance 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 identifica-tion of mutaidentifica-tions in the tyrosine kinase domain as the most com-mon mechanism of resistance. This was soon followed by development of new agents with higher bind-ing 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 stud-ied 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 achiev-ing 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, treat-ment 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 effec-tive salvage therapy, redefined the CML treatment algorithm. Nearly
all patients are now offered thera-py with imatinib at diagnosis, and for those who experience failure with therapy, a second-generation TKI is indicated. With this ap-proach, 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 at-tempts at treatment discontinu-ation 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 In-formation leaflet (package insert), Medication Guide when available, and other published reference sources for more detailed informa-tion.
Bosutinib (Bosulif)
Bosulif (BAH-su-lif) was approved for treatment of adult patients with chronic, accelerated, or blast phase Ph+ CML with resistance or intol-erance to prior therapy, including imatinib.
Mechanism of Action. Bosu-tinib inhibits the Bcr-Abl kinase (tyrosine kinase) that promotes CML. It also inhibits other kinases.
Efficacy. Efficacy was as-sessed in a single clinical trial that enrolled 546 adult patients with chronic-, accelerated- or blast-phase CML. All subjects had disease that progressed after treat-ment with imatinib or imatinib followed by dasatinib and/or nilo-tinib, or who could not tolerate the adverse effects of prior therapy. All patients in the trial received Bosu-lif. Thirty-three percent of patients
with accelerated CML previously treated with at least imatinib had blood counts that returned to nor-mal range (complete hematologic response) and 55 percent achieved normal blood counts without evi-dence of leukemia (overall hemato-logic 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, ab-dominal pain, rash, anemia, fever and fatigue.
Warnings, Precautions and Contraindications. Warnings and precautions are:
• Gastrointestinal toxicity (di-arrhea, nausea, vomiting, abdomi-nal pain): monitor and manage as necessary. Withhold, reduce dose, or discontinue Bosulif.
• Myelosuppression (thrombo-cytopenia, anemia, neutropenia): monitor blood counts and manage
as necessary.
• Hepatic toxicity (elevated liver enzymes and bilirubin): moni-tor 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 pa-tients 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. Ana-phylactic shock occurred in <0.2 percent of patients in clinical trials.
Drug Interactions. CYP3A inhibitors and inducers: avoid con-current 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 sepa-rated 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 be-yond 12 hours, the patient should skip the missed dose and take the usual prescribed dose on the follow-ing day. Dose escalation to 600 mg daily can be considered in patients who do not reach complete hemato-logic response by Week 8 or com-plete 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 Infor-mation. Specific points for coun-seling 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 indica-tions are based on response rate. There are no studies verifying improvement in disease-related symptoms or increased survival with the drug.
Mechanism of Action. Pona-tinib is a TKI and inhibitor of other kinases.
Efficacy. Efficacy was evalu-ated 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 muta-tion, 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 expe-rienced a normalization of white blood cell counts or had no evidence of leukemia (major hematologic re-sponse or MaHR). Results showed: • 52 percent of patients with accelerated-phase CML experi-enced 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 hy-pertension, rash, abdominal pain, fatigue, headache, dry skin, con-stipation, joint pain, nausea and fever. Hematologic adverse reac-tions included thrombocytopenia, anemia, neutropenia, lymphopenia and leukopenia.
Table 2
Examples of inhibitors
and inducers of CYP3A
isoenzymes
Inhibitors
Strong: ritonavir, indinavir,
nel-finavir, saquinavir, ketoconazole, boceprevir, telaprevir, itraconazole, voriconazole, posaconazole, clarithro-mycin, telithroclarithro-mycin, nefazodone, conivaptan
Moderate: fluconazole, darunavir,
erythromycin, diltiazem, atazanavir, aprepitant, amprenavir, fosamprevir, crizotinib, imatinib, verapamil, cipro-floxacin, grapefruit juice
Inducers
Strong: rifampin, phenytoin,
carba-mazepine, St. John’s Wort, rifabutin, phenobarbital
Moderate: bosentan, nafcillin,
Warnings, Precautions and Contraindications. Warnings and precautions are:
• Congestive heart failure: monitor patients for signs or symp-toms of congestive heart failure and treat as clinically indicated.
• Hypertension (including confusion, headache, chest pain, shortness of breath, and hyperten-sive crisis): monitor for high blood pressure and treat as clinically indicated.
• Pancreatitis: monitor serum lipase monthly; interrupt or discon-tinue Iclusig.
• Hemorrhage: interrupt Iclusig for serious or severe hemor-rhage.
• Fluid retention: monitor for fluid retention; interrupt, reduce, or discontinue Iclusig.
• Cardiac arrhythmias (espe-cially bradyarrhythmias): monitor for symptoms of arrhythmias.
• Myelosuppression: thrombo-cytopenia, neutropenia, and ane-mia may require dose interruption or reduction. Monitor complete blood counts every two weeks for three months and then monthly and as clinically indicated. Inter-rupt Iclusig for absolute neutrophil count <1000/mm3 or
thrombocyto-penia <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 proce-dures.
• Embryofetal toxicity: can cause harm. Advise women of po-tential risk to a fetus.
• A Boxed Warning advises on the risk of arterial thrombosis and hepatotoxicity.
There are no contraindica-tions 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.
Tablets should be swallowed whole. Continue treatment as long as there is no evidence of disease progression or unacceptable toxic-ity. Modify or interrupt dosing for hematologic and non-hematologic toxicity.
Patient Counseling Infor-mation. An FDA-approved Medi-cation Guide must be dispensed with Iclusig. Specific points for counseling as listed in the Prescrib-ing Information leaflet are summa-rized in Table 3.
Omacetaxine (Synribo)
Homoharringtonine (HHT) is a natural alkaloid obtained from the evergreen tree Cephalotaxus har-ringtonia, 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, theclini-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 es-tablished this agent for the second time as a valuable option in man-agement of CML. Synribo (sin-RI-bo) is FDA approved for treatment of adult patients with chronic- or accelerated-phase CML with resis-tance 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 omacetax-ine has not been fully elucidated but includes inhibition of protein synthesis, and is independent of direct Bcr-Abl binding. Its mecha-nism differs from TKIs. In vitro, the drug reduces protein levels of the Bcr-Abl oncoprotein.
Table 3
Patient counseling information*
Bosulif Iclusig Synribo
Alopecia x
Bleeding, hemorrhage x x
Compromised wound healing x
Congestive heart failure, x
cardiac arrhythmias Dosing, administration x x Drug interactions x Fatigue x Fluid retention x x Gastrointestinal problems x x x Hyperglycemia x Hypertension x Lactose content x Liver problems x x
Low blood cell counts, x x x
myelosuppression
Other adverse reactions x
Pancreatitis x
Pregnancy, breastfeeding x x x
Rash x
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.
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 author, the Ohio Pharmacists Founda-tion and the Ohio Pharmacists AssociaFounda-tion disclaim any liability to you or your patients resulting from reliance solely upon the infor-mation 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.
The Ohio Pharmacists Foundation Inc. is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.
Efficacy. Efficacy was evalu-ated 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 dem-onstrated 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 deter-mined by the number of patients who experienced normalization in white blood cell counts or had no evidence of leukemia (major hema-tologic 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 chron-ic- and accelerated-phase CML, the most common adverse reac-tions (frequency ≥20 percent) were thrombocytopenia, anemia, neutro-penia, diarrhea, nausea, fatigue, weakness, injection site reactions, fever, infection and lymphopenia.
Warnings, Precautions and Contraindications. Warnings and precautions are:
• Myelosuppression: severe and fatal thrombocytopenia, neutrope-nia and anemia. Monitor hemato-logic parameters frequently.
• Bleeding: severe thrombo-cytopenia and increased risk of hemorrhage. Fatal cerebral hemor-rhage and severe, non-fatal gastro-intestinal 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 contraindica-tions listed for Synribo.
Drug Interactions. Omace-taxine is not a substrate of CYP450
enzymes or P-glycoprotein in vitro. Based on the findings from in vitro studies, no clinical drug interac-tion trials were warranted. Preparation and Administra-tion PrecauAdministra-tions. Synribo should be reconstituted and administered in a healthcare facility. The drug is an antineoplastic product. Fol-low special handling and disposal procedures. Avoid contact with the skin. If Synribo comes into contact with skin, immediately and thor-oughly wash affected area with soap and water.
Dosing. Starting dose for induction is 1.25 mg/m2
subcutane-ously 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 contin-ued as long as patients are benefit-ting from therapy.
Patient Counseling Infor-mation. Specific points for coun-seling 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 im-mense 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 his-tory of the disease. With improved treatment options available, CML outcomes may continue to be im-proved.continuing education quiz
New Chronic Myeloid Leukemia Drugs:
Bosulif, Iclusig, and Synribo
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1. In 2012, the typical age at CML diagnosis was be-tween:
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
6. Adverse effects associated with interferon-alpha include all of the following EXCEPT:
a. depression. c. myelosuppression. b. fever. d. splenomegaly.
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 EX-CEPT:
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.
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 advis-ing 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.
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