Novartis Tasigna(R) Trial Shows Superior Results to Gleevec(R) in Patients With Early-Stage Chronic Myeloid Leukemia
EAST HANOVER, N.J., Dec. 8 /PRNewswire/ — In a large Phase III clinical trial, TasignaÃ‚® (nilotinib) 200 mg capsules demonstrated greater efficacy over GleevecÃ‚® (imatinib mesylate) tablets* in the treatment of adult patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) in chronic phase(1).
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In the first head-to-head comparison of these two oral therapies as initial treatment for this life-threatening blood cancer, Tasigna results showed statistically significant improvement over Gleevec in every measure of efficacy, including major molecular response (MMR), complete cytogenetic response (CCyR) and prevention of progression to accelerated or blastic phase(1). The new data were presented as a late breaker abstract at the 51st annual meeting of the American Society of Hematology (ASH), held in December, in New Orleans, USA.
At 12 months, significantly fewer patients progressed to accelerated or blastic phase on Tasigna 300 mg twice daily than on Gleevec 400 mg once daily (2 patients vs. 11 patients)(1), demonstrating a statistically significant improvement in disease control(1). In the study, Tasigna was well tolerated. Fewer patients discontinued due to adverse events from the Tasigna 300 mg twice daily arm of the study compared to the Gleevec 400 mg once daily arm. No patients in the study had prolongation of QT interval >500 milliseconds(1). No sudden deaths occurred with either treatment(2).
“The outstanding rates of response observed with Tasigna, combined with the very low rate of disease progression, strongly indicate that patients who begin their treatment with Tasigna may have long-term improvement of progression-free survival,” said Giuseppe Saglio, University of Turin, San Luigi Hospital, Orbassano-Torino, Italy, a member of the study management committee. “The efficacy results and tolerability of Tasigna should support its use in newly diagnosed Ph+ CML patients.”
With Tasigna 300 mg twice daily, the rate of MMR at 12 months was twice that of patients receiving Gleevec 400 mg once daily (44% vs. 22%, p < 0.0001)(1). In addition, 80% of patients achieved CCyR with Tasigna versus 65% with Gleevec 400 mg once daily (p < 0.0001)(1). Responses were achieved faster in the Tasigna group than in the Gleevec group(1).
MMR was defined in the study as reduction in the level of the abnormal Bcr-Abl protein to less than or equal to 0.1% of the pre-treatment level based on an internationally agreed standard(1). This can be interpreted to mean that for every 1,000 cells containing Bcr-Abl that were present in the blood at the start of therapy, only one cell was present at the 12-month follow-up. CCyR indicates that no CML cells containing the diagnostic Ph chromosome can be seen in a sample of bone marrow taken from the patient.
“Novartis is pioneering research targeting the molecular origin of Ph+ CML, which has led to treatments of unprecedented effectiveness and safety,” said David Epstein, President and CEO of Novartis Oncology and Novartis Molecular Diagnostics. “Considering the already low rates of progression to advanced disease and the excellent long-term survival of patients on Gleevec, the efficacy and safety profile of Tasigna at 12 months is fantastic news and brings promise for further improving the outcomes of patients with Ph+ CML.”
Tasigna is a potent and selective inhibitor of the Bcr-Abl protein that causes production of cancer cells in Ph+ CML(2,3). Upon initial reports of resistance in the Gleevec registration trials, Novartis scientists created a new molecule, Tasigna, just a year after the launch of Gleevec. The first clinical trials began just 21 months after discovery. The drug received its first regulatory approval in the second-line indication in 2007.
Novartis plans to file worldwide applications for approval of Tasigna as a treatment for adult patients with newly diagnosed Ph+ CML. Tasigna is currently approved in more than 80 countries including the European Union, United States and other countries for the treatment of adult patients with Ph+ CML in chronic phase or accelerated phase who are resistant or intolerant to prior treatment including Gleevec.
The clinical trial, Evaluating Nilotinib Efficacy and Safety in Clinical Trials of Newly Diagnosed Ph+ CML Patients (ENESTnd), is a Phase III randomized, open-label, multicenter trial comparing the efficacy and safety of Tasigna versus Gleevec in adult patients with newly diagnosed Ph+ CML in chronic phase(1). It is the largest global randomized comparison of two oral therapies ever conducted in newly diagnosed Ph+ CML patients. Designed to detect a difference in MMR between Tasigna and Gleevec after 12 months of treatment, it is also the first registration study in which molecular traces of a key biomarker specific to Ph+ CML have been used as a primary endpoint for regulatory review. The trial’s secondary endpoints included CCyR, as well as progression to accelerated or blastic phase, and overall survival.
ENESTnd is being conducted at 220 global sites with 846 patients enrolled. Patients were randomized to receive Tasigna 400 mg twice daily (n = 281), Tasigna 300 mg twice daily (n = 282) or Gleevec 400 mg once daily (n = 283). The primary endpoint was MMR at 12 months; a secondary endpoint was CCyR by 12 months(1). Planned follow-up is for five years(2). Patients on the Gleevec treatment arm who had suboptimal response or treatment failure will be able to escalate dose and/or switch to Tasigna via a protocol extension.
Samples for molecular response were evaluated by a single reference laboratory. The blood test used to determine molecular response can detect a single cell containing traces of Bcr-Abl in up to one million normal blood cells(4). In addition to being simpler and less invasive for patients, the test has a much greater sensitivity than standard cytogenetic tests, which require a sample of bone marrow to be drawn for visual detection of cells containing the Ph chromosome(5).
All patients had a minimum of 12 months of treatment or discontinued early; the median follow-up was 14 months. Overall, 84%, 82% and 79% of patients remained in the study on Tasigna 300 mg twice daily, Tasigna 400 mg twice daily and Gleevec 400 mg once daily, respectively.
Rates of MMR at 12 months were statistically higher for patients in the Tasigna 300 mg twice daily group compared with Gleevec 400 mg once daily (44% vs. 22%, p < 0.0001) and also for Tasigna 400 mg twice daily compared with Gleevec 400 mg once daily (43% vs. 22%, p < 0.0001). Among patients who achieved MMR, median time to MMR was faster for Tasigna 300 mg twice daily (5.7 months) and Tasigna 400 mg twice daily (5.8 months) compared with Gleevec 400 mg once daily (8.3 months). Molecular response was assessed by polymerase chain reaction (PCR) at baseline, monthly for three months, and every three months thereafter.
Rates of CCyR by 12 months were significantly higher for Tasigna at 300 mg twice daily compared with Gleevec 400 mg once daily (80% vs. 65%, p < 0.0001) and for Tasigna 400 mg twice daily compared with Gleevec 400 mg once daily (78% vs. 65%, p = 0.0005). Overall, progression to advanced disease was lower for Tasigna 300 mg twice daily (2 patients) and Tasigna 400 mg twice daily (1 patient) compared with Gleevec 400 mg once daily (11 patients).
Both Tasigna and Gleevec were well tolerated overall. Rates of discontinuation due to adverse events or laboratory abnormalities were 7% for Tasigna 300 mg twice daily, 11% for Tasigna 400 mg twice daily, and 9% for Gleevec 400 mg once daily.
About Ph+ CML
CML is a disease in which the body produces cancerous white blood cells. Almost all patients with CML have an abnormality known as the Philadelphia chromosome, which produces a protein called Bcr-Abl. Bcr-Abl causes malignant white blood cells to proliferate(6). Worldwide, CML is responsible for approximately 10% to 15% of all adult cases of leukemia(7), with an incidence of one to two cases per 100,000 people per year(8).
Tasigna has been approved in more than 80 countries for the treatment of chronic phase and accelerated phase Ph+ CML in adult patients resistant or intolerant to at least one prior therapy, including Gleevec. The effectiveness of Tasigna for this indication is based on confirmed hematologic and unconfirmed cytogenetic response rates. There are no controlled trials demonstrating a clinical benefit, such as improvement in disease-related symptoms or increased survival.
Tasigna important safety information
WARNING: QT PROLONGATION AND SUDDEN DEATHS
Tasigna prolongs the QT interval. Sudden deaths have been reported in patients receiving nilotinib. Tasigna should not be used in patients with hypokalemia, hypomagnesemia, or long QT syndrome. Hypokalemia or hypomagnesemia must be corrected prior to Tasigna administration and should be periodically monitored. Drugs known to prolong the QT interval and strong CYP3A4 inhibitors should be avoided. Patients should avoid food 2 hours before and 1 hour after taking dose. A dose reduction is recommended in patients with hepatic impairment. ECGs should be obtained to monitor the QTc at baseline, seven days after initiation, and periodically thereafter, as well as following any dose adjustments.
Do not use in patients with hypokalemia, hypomagnesemia, or long QT syndrome.
Warnings and precautions
Treatment with Tasigna can cause Grade 3/4 thrombocytopenia, neutropenia, and anemia. Complete blood counts should be performed every two weeks for the first 2 months and then monthly thereafter, or as clinically indicated. Myelosuppression was generally reversible and usually managed by withholding Tasigna temporarily or dose reduction.
Tasigna prolongs the QT interval. ECGs should be performed at baseline, seven days after initiation, periodically as clinically indicated, and following dose adjustments. Correct hypokalemia or hypomagnesemia prior to administration and monitor periodically.
Significant prolongation of the QT interval may occur when Tasigna is inappropriately taken with food, and/or strong CYP3A4 inhibitors and/or medicinal products with a known potential to prolong QT. Therefore, co-administration with food must be avoided and concomitant use with strong CYP3A4 inhibitors and/or medicinal products with a known potential to prolong QT should be avoided. The presence of hypokalemia and hypomagnesemia may further enhance this effect.
There were sudden deaths reported in the safety population and in the expanded access program. Ventricular repolarization abnormalities may have contributed to their occurrence.
Elevated serum lipase
Caution is recommended in patients with a history of pancreatitis. Check serum lipase levels monthly or as clinically indicated.
Serum bilirubin and hepatic transaminases
The use of Tasigna may result in elevations in bilirubin, AST/ALT, and alkaline phosphatase. Hepatic function tests should be checked monthly or as clinically indicated.
Tasigna can cause hypophosphatemia, hypokalemia, hyperkalemia, hypocalcemia, and hyponatremia. Correct electrolyte abnormalities prior to initiating Tasigna and monitor periodically during therapy.
Nilotinib exposure is increased in patients with impaired hepatic function. A lower starting dose is recommended for patients with mild to severe hepatic impairment and QT interval should be monitored closely.
The concomitant use of QT prolonging drugs and strong inhibitors or inducers of CYP3A4 should be avoided as they may affect serum concentration of Tasigna.
Concomitant strong CYP3A4 inhibitors
The concomitant use of strong CYP3A4 inhibitors or anti-arrhythmic drugs (including, but not limited to amiodarone, disopyramide, procainamide, quinidine, and sotalol) and other drugs that may prolong QT interval (including, but not limited to chloroquine, halofantrine, clarithromycin, haloperidol, methadone, moxifloxacin, bepridil, and pimozide) should be avoided. Should treatment with any of these agents be required, it is recommended that therapy with Tasigna be interrupted. If interruption of treatment with Tasigna is not possible, patients who require treatment with a drug that prolongs QT or strongly inhibits CYP3A4 should be closely monitored for prolongation of the QT interval, and a dose reduction to 1/2 the daily dose is recommended (400 mg once daily). If the strong inhibitor is discontinued, a washout period should be allowed before Tasigna is adjusted upward to the indicated dose. Close monitoring for prolongation of the QT interval is indicated for patients who cannot avoid strong CYP3A4 inhibitors. Grapefruit products and other foods that are known to inhibit CYP3A4 should also be avoided.
Concomitant strong CYP3A4 inducers
The concomitant use of strong CYP3A4 inducers should be avoided (including, but not limited to, dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital). Patients should also refrain from taking St John’s Wort. If patients must be co-administered a strong CYP3A4 inducer, the dose of Tasigna may need to be increased, depending on patient tolerability. If the strong inducer is discontinued, the Tasigna dose should be reduced to the indicated Tasigna dose. Tasigna is a competitive inhibitor of CYP3A4, CYP2C8, CYP2C9, CYP2D6, and UGT1A1. In vitro studies also suggest that nilotinib may induce CYP2B6, CYP2C8, and CYP2C9, and decrease the concentrations of drugs which are eliminated by these enzymes. Single-dose administration of Tasigna to healthy subjects did not change the pharmacokinetics and pharmacodynamics of warfarin (a CYP2C9 substrate). The ability of Tasigna to induce metabolism has not been determined in vivo. Caution should be exercised when co-administering Tasigna with substrates for these enzymes that have a narrow therapeutic index. Tasigna inhibits human P-glycoprotein. If Tasigna is administered with drugs that are substrates of Pgp, increased concentrations of the substrate are likely and caution should be exercised.
Food increases blood levels of Tasigna. Patients should avoid food 2 hours before and at least 1 hour after the dose is taken.
Since the capsules contain lactose, Tasigna is not recommended for patients with rare hereditary problems of galactose intolerance, severe lactase deficiency with a severe degree of intolerance to lactose-containing products, or of glucose-galactose malabsorption.
Use in pregnancy
There are no adequate and well controlled studies of Tasigna in pregnant women. However, Tasigna may cause fetal harm when administered to a pregnant woman. Women of child-bearing potential should avoid becoming pregnant while taking Tasigna and should be advised of the potential hazard to the fetus if they do.
In chronic phase patients, the most commonly reported adverse reactions (>10%) were rash (33%), pruritus (29%), nausea (31%), fatigue (28%), headache (31%), constipation (21%), diarrhea (22%), and vomiting (21%). The most common (>10%) Grade 3/4 adverse reactions were thrombocytopenia (28%), neutropenia (28%), elevated lipase (15%), and hyperglycemia (11%). In accelerated phase patients, the most commonly reported adverse reactions (>10%) were rash (28%), pruritus (20%), and constipation (18%). The most common (>10%) Grade 3/4 adverse reactions were thrombocytopenia (37%), neutropenia (37%), anemia (23%), and elevated lipase (17%). Other serious adverse reactions included pneumonia, febrile neutropenia, leukopenia, intracranial hemorrhage, and pyrexia (Grade 3/4: 2%).
Dose adjustments or modifications
Tasigna may need to be temporarily withheld and/or dose reduced for QT prolongation, hematological toxicities that are not related to underlying leukemia, clinically significant moderate or severe nonhematologic toxicities, laboratory abnormalities, or concomitant use of strong CYP3A4 inhibitors. With concomitant use of strong CYP3A4 inducers, the dose of Tasigna may need to be increased, depending on patient tolerability.
For Grade 3 to 4 lipase elevations, dosing should be withheld, and may be resumed at 400 mg once daily. For Grade 3 to 4 bilirubin elevations, dosing should be withheld, and may be resumed at 400 mg once daily.
If possible, consider alternative therapies. If Tasigna must be administered to patients with hepatic impairment, a lower starting dose is recommended in patients with hepatic impairment and QT interval should be monitored. The following dose reduction should be considered:
For patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment, an initial dosing regimen of 400 mg in the morning and 200 mg in the evening (12 hours apart) per day followed by dose escalation to 400 mg twice daily based on patient tolerability should be considered. For patients with severe hepatic impairment (Child-Pugh Class C), a starting dose of 200 mg twice daily followed by a sequential dose escalation to 400 mg in the morning and 200 mg in the evening (12 hours apart) per day and then to 400 mg twice daily based on patient tolerability should be considered.
Other patients in whom Tasigna should be used with caution
Tasigna should not be used during pregnancy. Sexually active female patients should use effective contraception during treatment. Women should not breast feed while taking Tasigna. The safety and effectiveness of Tasigna in pediatric patients have not been established.
GleevecÃ‚® (imatinib mesylate) tablets are indicated for the treatment of newly diagnosed adult patients with Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) in the chronic phase (CP). Gleevec is also indicated for the treatment of patients with Ph+ CML in blast crisis (BC), accelerated phase (AP), or in CP after failure of interferon-alpha therapy.
Gleevec important safety information
Gleevec is often associated with edema and occasionally severe fluid retention. Patients should be weighed and monitored regularly for signs and symptoms of fluid retention, which can be serious or life-threatening.
Cytopenias have been reported. Complete blood counts should be performed weekly for the first month, biweekly for the second month, and periodically thereafter as clinically indicated (for example, every 2-3 months).
Dose adjustments may be necessary due to hepatotoxicity, other nonhematologic adverse reactions, or hematologic adverse reactions.
In Ph+ CML trials,** severe (NCI Grades 3/4) lab abnormalities–including neutropenia (3.6%-48%), anemia (1%-42%), thrombocytopenia (<1%-33%), and hepatotoxicity (approx 5%)–and severe adverse reactions (NCI Grades 3/4), including hemorrhage (1.8%-19%), fluid retention (eg, pleural effusion, pulmonary edema, and ascites) (2.5%-11%) and superficial edema (1.5%-6%), and musculoskeletal pain (2%-9%) were reported among patients receiving Gleevec. Severe fluid retention appears to be dose-related, was more common in the advanced phase studies (where the dosage was 600 mg/day), and is more common in the elderly.
Severe congestive heart failure and left ventricular dysfunction have occasionally been reported. Most of the patients with reported cardiac events have had other comorbidities and risk factors, including advanced age and previous medical history of cardiac disease. Patients with cardiac disease or risk factors for cardiac failure should be monitored carefully, and any patient with signs or symptoms consistent with cardiac failure should be evaluated and treated.
Hepatotoxicity, occasionally severe, may occur. Assess liver function before initiation of treatment and monthly thereafter or as clinically indicated. Monitor liver function when combined with chemotherapy known to be associated with liver dysfunction. A 25% decrease in the recommended dose should be used for patients with severe hepatic impairment.
Patients with moderate renal impairment (CrCL = 20-39 mL/min) should receive a 50% decrease in the recommended starting dose, and future doses can be increased as tolerated. Doses greater than 600 mg/day are not recommended in patients with mild renal impairment (CrCL = 40-59 mL/min). For patients with moderate renal impairment, doses greater than 400 mg/day are not recommended. Gleevec should be used with caution in patients with severe renal impairment.
In the newly diagnosed CML trial, 2% of patients had (NCI Grades 3/4) hemorrhage.
There have also been reports, including fatalities, of cardiac tamponade, cerebral edema, acute respiratory failure, and gastrointestinal (GI) perforation.
Bullous dermatologic reactions (eg, erythema multiforme and Stevens-Johnson syndrome) have also been reported. In some cases, the reaction recurred upon rechallenge. Several postmarketing reports describe patients able to tolerate the reintroduction of Gleevec at a lower dose with or without concomitant corticosteroids or antihistamines following resolution or improvement of the bullous reaction.
Clinical cases of hypothyroidism have been reported in thyroidectomy patients undergoing levothyroxine replacement during treatment with Gleevec. TSH levels should be closely monitored in such patients.
Consider potential toxicities–specifically liver, kidney, and cardiac toxicity, and immunosuppression from long-term use.
Fetal harm can occur when administered to a pregnant woman; therefore, women of childbearing potential should be advised to not become pregnant while taking Gleevec tablets and to avoid breast-feeding while taking Gleevec tablets because of the potential for serious adverse reactions in nursing infants. Sexually active female patients taking Gleevec should use adequate contraception. If the patient does become pregnant while taking Gleevec, the patient should be advised of the potential hazard to the fetus.
Gleevec is metabolized by the CYP3A4 isoenzyme and is an inhibitor of CYP3A4, CYP2D6, and CYP2C9. Dosage of Gleevec should increase by at least 50%, and clinical response should be carefully monitored, in patients receiving Gleevec with a potent CYP3A4 inducer such as rifampin or phenytoin. Examples of commonly used drugs that may significantly interact with Gleevec include ketoconazole, acetaminophen, warfarin, erythromycin, and phenytoin. (Please see full Prescribing Information for other potential drug interactions.)
For daily dosing of 800 mg and above, dosing should be accomplished using the 400-mg tablet to reduce exposure to iron.
Common side effects of Gleevec tablets
The majority of adult patients with Ph+ CML who received Gleevec in clinical studies experienced adverse reactions at some time, but most were mild to moderate in severity. The most frequently reported adverse reactions (all Grades) were superficial edema (60%-74%), nausea (50%-73%), diarrhea (43%-57%), musculoskeletal pain (38%-49%), rash and related terms (36%-47%), muscle cramps (28%-62%), and vomiting (23%-58%).**^
Supportive care may help management of some mild-to-moderate adverse reactions. However, in some cases, either a dose reduction or interruption of treatment with Gleevec may be necessary.
Gleevec tablets should be taken with food and a large glass of water to minimize GI irritation. Gleevec tablets should not be taken with grapefruit juice and other foods known to inhibit CYP3A4.
Patients should be informed to take Gleevec exactly as prescribed, not to change their dose or stop taking Gleevec unless they are told to do so by their doctor. If patients miss a dose, they should be advised to take their dose as soon as possible unless it is almost time for their next dose, in which case the missed dose should not be taken. A double dose should not be taken to make up for any missed dose.
**Numbers indicate the range of percentages in 4 studies among adult patients with newly diagnosed Ph+ CML and patients in BC, AP, and CP after failure of interferon-alpha therapy.
^ For more detailed study information, please see full Prescribing Information.
The foregoing release contains forward-looking statements that can be identified by terminology such as “to file,” “may,” “should,” “potential,” “promise,” “plans,” “will,” or similar expressions, or by express or implied discussions regarding potential new indications or labeling for Tasigna or regarding potential future revenues from Tasigna or Gleevec. You should not place undue reliance on these statements. Such forward-looking statements reflect the current views of management regarding future events, and involve known and unknown risks, uncertainties and other factors that may cause actual results with Tasigna or Gleevec to be materially different from any future results, performance or achievements expressed or implied by such statements. There can be no guarantee that Tasigna will be submitted or approved for any additional indications or labeling in any market. Nor can there be any guarantee that Tasigna or Gleevec will achieve any particular levels of revenue in the future. In particular, management’s expectations regarding Tasigna and Gleevec could be affected by, among other things, unexpected clinical trial results, including unexpected new clinical data and unexpected additional analysis of existing clinical data; unexpected regulatory actions or delays or government regulation generally; the company’s ability to obtain or maintain patent or other proprietary intellectual property protection; competition in general; government, industry and general public pricing pressures; the impact that the foregoing factors could have on the values attributed to the Novartis Group’s assets and liabilities as recorded in the Group’s consolidated balance sheet, and other risks and factors referred to in Novartis AG’s current Form 20-F on file with the US Securities and Exchange Commission. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those anticipated, believed, estimated or expected. Novartis is providing the information in this press release as of this date and does not undertake any obligation to update any forward-looking statements contained in this press release as a result of new information, future events or otherwise.
Located in East Hanover, New Jersey, Novartis Pharmaceuticals Corporation is an affiliate of Novartis AG, which provides healthcare solutions that address the evolving needs of patients and societies. Focused solely on healthcare, the Novartis Group offers a diversified portfolio to best meet these needs: innovative medicines, preventive vaccines, diagnostic tools, cost-saving generic pharmaceuticals and consumer health products. The Novartis Group is the only company with leading positions in each of these areas. In 2008, the Group’s continuing operations achieved net sales of USD 41.5 billion and net income of USD 8.2 billion. Approximately USD 7.2 billion was invested in R&D activities throughout the Group. Headquartered in Basel, Switzerland, Novartis Group companies employ approximately 99,000 full-time-equivalent associates and operate in more than 140 countries around the world. For more information, please visit http://www.us.novartis.com.
*Known as GlivecÃ‚® (imatinib) outside the US, Canada and Israel.
(1) Saglio G, Kim DW, Issaragrisil S, Philipp le Coutre, et al. Nilotinib Demonstrates Superior Efficacy Compared with Imatinib in Patients with Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase: Results from the International Randomized Phase III ENESTnd Trial. Abstract #LBA-1. American Society of Hematology 2009 Annual Meeting.
(2) Novartis data on file.
(3) Tasigna (nilotinib) Prescribing Information. East Hanover, New Jersey, USA: Novartis Pharma. http://www.pharma.us.novartis.com/product/pi/pdf/tasigna.pdf.
(4) Kurzrock R, Talpaz M. The Molecular Pathology of Chronic Myelogenous Leukaemia. Br J Haematol. 1991 Oct; 79 Suppl 1:34-7.
(5) NCCN Practice Guidelines in Oncology – v.1.2010. Chronic Myelogenous Leukemia.
(6) National Cancer Institute. General Information About Chronic Myelogenous Leukemia (PDQ). http://www.cancer.gov/cancertopics/pdq/treatment/CML/patient/. Accessed March 2009.
(7) American Cancer Society. Detailed Guide: CML. What are the key statistics about CML? (Sept 2008 revision) Available at: http://www.cancer.org/docroot/CRI/content/CRI_2_4_1x_What_Are_the_Key_Statistics_About_Chronic_Myeloid_Leukemia_CML.asp?rnav=cri. Accessed April 2009.
(8) Central European Leukemia Study Group. About CML. [Cited 2009 Jan 13] Available from: http://www.cml-info.com/de/healthcare-professionals/about-cml.html.
(9) GleevecÃ‚® (imatinib mesylate) tablets prescribing information. East Hanover, NJ: Novartis Pharmaceuticals Corporation; November 2008.
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