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Molecular Response: Closing in on the Target
A Decade of Achievements in Ph+ CML Treatment
Chronic myeloid leukemia (CML) is a cancer of the blood and bone marrow characterized by the presence of an abnormality
called the Philadelphia (Ph) chromosome. The Ph chromosome produces a defective enzyme, known as Bcr-Abl tyrosine kinase,
which is responsible for blocking the signal that tells the body to stop producing certain white blood cells1.
Worldwide, CML is responsible for approximately 10 to 15% of all adult cases of leukemia2, with an incidence of one to two
cases per 100,000 people per year3. Deaths from CML have declined sharply in the years since the introduction of kinase
inhibitors4,5, beginning with Glivec® (imatinib)* in 20016. During this decade of breakthrough, researchers have refined
increasingly sensitive tests to detect ever-diminishing traces of cancer in patients responding to these new medicines 7.
Prior to the molecular era of treatment, many CML patients were monitored by measures of hematologic response – nonspecific blood panels measuring levels of white blood cells. During a hematologic response, patients may still carry a significant
number of Ph+ cells in their bone marrow9.
The first clinical trials of Glivec employed more sensitive tests of cytogenetic
response, in which samples of bone marrow are drawn from patients and cells
containing the Ph chromosome are counted7. Cytogenetic monitoring was
considered the standard treatment measurement in the 1990s when CML was
being treated with less specific therapies, including interferon 8.
Proliferation of Malignant
White Blood Cells
As increasing number of patients participating in clinical trials achieved complete
cytogenetic responses to Glivec (CCyR, no Ph+ cells found), more sensitive tests
had to be used to detect residual levels of Ph+ cells in the body10. Thus, molecular
monitoring of Bcr-Abl levels was introduced. The blood test used to determine
molecular response can detect a single cell containing Bcr-Abl among one
In addition to being more sensitive , the test is simpler and less invasive for
patients than standard cytogenetic tests7.
In the landmark IRISi study that compared Glivec to interferon treatment, molecular
responses were also found to be predictive of better patient outcomes: 100% of Ph+
CML patients who achieved major molecular response (MMR, defined as a
thousand-fold or greater reduction in Bcr-Abl relative to standardized baseline level7)
in the first 12 months treatment survived without disease progression to accelerated
phase or blast crisis for at least five years12. Follow up of those patients is ongoing.
In IRIS, all patients who achieved
MMR in the first 12 months of
treatment remained free of
disease progression
for at least five years.
Today, molecular monitoring with a simple and convenient blood test measures the
deepest level of CML remission – in which traces of leukemia are reduced to nearly undetectable levels – and is taking its place
as a new cornerstone of routine patient management7.
The ENESTndii study is a head-to-head comparison of Glivec, the current standard of care, with Tasigna® (nilotinib)13 – an
inhibitor of Bcr-Abl14 – to see which drug is superior as first-line treatment for adult patients with newly diagnosed Philadelphia
chromosome-positive chronic myeloid leukemia (Ph+ CML) in chronic phase13. 24-month study results showed that treatment
with Tasigna led to higher rates of both major molecular response and complete cytogenetic response compared with Glivec18.
*Known as Gleevec® (imatinib mesylate) tablets in the US, Canada and Israel.
**For more detailed information on Tasigna and Glivec, please see their full Prescribing Information.
Randomized IFN vs. STI571. IRIS is the largest randomized clinical trial of imatinib, in which 1,106 patients were randomized to
receive either imatinib 400 mg/day or a standard regimen of interferon-alfa plus cytarabine. The Phase III trial enrolled 553 patients onto each
treatment arm between June 2000 and January 2001. Of patients originally assigned to interferon-alfa plus cytarabine, 65% crossed over to
imatinib beginning in 2002.
Nilotinib Efficacy and Safety in Clinical Trials of Newly Diagnosed Ph+ CML Patients. ENESTnd is a Phase III randomized, openlabel, multicenter study comparing the efficacy and safety of nilotinib versus imatinib mesylate, with 846 patients enrolled. Patients were
randomized to receive nilotinib 400 mg twice daily, nilotinib 300 mg twice daily or imatinib mesylate 400 mg daily.
in Ph+
A Decade
Decade of
of Breakthroughs
Achievements in
•IRIS five-year sub-analysis shows that 100% of patients
who achieved MMR at 12 months of Glivec
treatment were free of disease progression12
Tasigna is approved for the treatment
of chronic phase and accelerated
phase Ph+ CML in adult patients
resistant or intolerant to at
least one prior therapy,
including Glivec14
Researchers identify
Glivec as a compound with
activity against the Bcr-Abl
tyrosine kinase15
•Glivec is approved for
the treatment of CML in
blast crisis, accelerated
phase or in chronic
phase after failure of
interferon-alfa therapy6
•Researchers synthesize
•Sprycel is approved for the treatment of
adults with chronic, accelerated
or myeloid or lymphoid
blast phase Ph+ CML
with resistance or
intolerance to prior
therapy including
IRIS study uses
hematologic and
cytogenetic response
as endpoints to
compare Glivec
to interferon as
treatment for
Clinical trials
patients with Ph+
evaluate Tasigna
and Sprycel as a
second-line treatment in patients
with Ph+ CML who
are resistant or
intolerant to at least
one prior therapy,
including Glivec
TOPSiii uses MMR endpoint
to evaluate high-dose Glivec
as initial treatment for
patients with Ph+ CML17
Tyrosine Kinase Inhibitor Optimization and Selectivity Study
ENESTnd, the first registration study to use MMR
as a clinical endpoint for regulatory review,
compares Tasigna to Glivec as initial treatment
for patients with Ph+ CML13
Tasigna and Sprycel are approved for the treatment
of adult patients with newly diagnosed Ph+ CML in
chronic phase14,19
About Tasigna
Tasigna (nilotinib) 200 mg capsules is approved in more than 90 countries for the treatment of chronic
phase and accelerated phase Philadelphia chromosome-positive chronic myelogenous leukemia (Ph+
CML) in adult patients resistant or intolerant to at least one prior therapy, including Glivec. The
effectiveness of Tasigna for this indication is based on hematologic and cytogenetic response rates.
Tasigna (nilotinib) 150 mg capsules is also approved for the treatment of adult patients with newly
diagnosed Ph+ CML in chronic phase. The effectiveness of Tasigna for this indication is based on major
molecular response and cytogenetic response rates at 12 months. The study is ongoing and further data
will be required to determine long-term outcome.
Tasigna Important Safety Information
Tasigna should be taken twice daily at an interval of approximately 12 hours apart and must not be taken
with food. No food should be consumed for two hours before the dose and for at least one hour after the
dose. Avoid grapefruit juice and other foods that are known to inhibit CYP3A4.
Tasigna should not be used in patients who are hypersensitive to nilotinib or any of the excipients.
Treatment with Tasigna has been associated with hematological side effects such as thrombocytopenia,
neutropenia and anemia which was generally reversible and usually managed by withholding Tasigna
temporarily or dose reduction. Complete blood counts should be performed every two weeks for the first
two months and then monthly thereafter as clinically indicated.
Tasigna should be used with caution in patients with uncontrolled or significant cardiac disease (e.g.,
recent heart attack, congestive heart failure, unstable angina or clinically significant bradycardia), as well
as in patients who have or may develop prolongation of QTc. These include patients with abnormally low
potassium or magnesium levels, patients with congenital long QT syndrome, patients taking antiarrhythmic medicines or other drugs that may lead to QT prolongation. Low levels of potassium or
magnesium must be corrected prior to Tasigna administration. Close monitoring for an effect on the QTc
interval is advisable and a baseline electrocardiography is recommended prior to initiating therapy with
Tasigna and as clinically indicated. Uncommon cases (0.1 to 1%) of sudden death have been reported in
clinical studies in patients with significant risk factors.
Tasigna should be used with caution in patients with liver impairment, in patients with a history of
pancreatitis and in patients with total gastrectomy. Patients with rare hereditary problems of galactose
intolerance, severe lactase deficiency or glucose-galactose malabsorption should not use Tasigna.
Tasigna should not be used during pregnancy unless clearly necessary and breast feeding is not
recommended during treatment.
The most frequent Grade 3 or 4 adverse events for Tasigna were primarily hematological in nature and
included neutropenia and thrombocytopenia. Elevations seen in bilirubin, liver function tests, lipase
enzymes and blood sugar were mostly transient and resolved over time. These cases were easily
managed and rarely led to discontinuation of treatment. Pancreatitis was reported in less than 1% of
cases. The most frequent non-hematologic drug-related adverse events were rash, pruritus, nausea,
fatigue, headache, alopecia, myalgia, constipation and diarrhea. Most of these adverse events were mild
to moderate in severity.
About Glivec
Glivec is approved in more than 110 countries, including the US, EU and Japan, for the treatment of all
phases of Ph+ CML. Glivec is also approved in the US, EU and other countries for the treatment of
patients with KIT (CD117)-positive gastrointestinal tumors (GIST), which cannot be surgically removed
and/or have already spread to other parts of the body (metastasized). In the US and EU, Glivec is
approved for the post-surgery treatment of adult patients following complete surgical removal of KIT
(CD117)-positive gastrointestinal stromal tumors.
Not all indications are available in every country and indications may differ.
Glivec Important Safety Information
Glivec can cause fetal harm when administered to a pregnant woman. Women should not become
pregnant, and should be advised of the potential risk to the unborn child.
Glivec is often associated with edema (swelling) and serious fluid retention. Studies have shown that
edema (swelling) tended to occur more often among patients who are 65 and older or those taking higher
doses of Glivec.
Cytopenias (reduction or lack of certain cell elements in blood circulation), such as anemia, have
occurred. If the cytopenia is severe, your doctor may reduce your dose or temporarily stop your treatment
with Glivec.
Severe congestive heart failure and left ventricle dysfunction have been reported, particularly in patients
with other health issues and risk factors. Patients with heart disease or risk factors will be monitored and
treated for the condition.
Severe liver problems (hepatotoxicity) may occur. Cases of fatal liver failure and severe liver injury
requiring liver transplants have been reported with both short-term and long-term use of Glivec.
Bleeding may occur. Severe gastrointestinal (GI) bleeding has been reported in patients with Ph+ CML
and KIT+ GIST. GI tumor sites may be the cause of this bleeding.
In patients with hypereosinophilic syndrome (a condition with increased eosinophils, which are a type of
white blood cell), e.g., HES, MDS/MPD, or ASM and heart involvement, cases of heart disease
(cardiogenic shock/left ventricular dysfunction) have been associated with the initiation of Glivec therapy.
Skin reactions, such as fluid-filled blisters, have been reported with the use of Glivec.
Clinical cases of hypothyroidism (reduction in thyroid hormones) have been reported in patients taking
levothyroxine replacement with Glivec.
Long-term use may result in potential liver, kidney, and/or heart toxicities; immune system suppression
may also result from long-term use.
GI perforation (small holes or tears in the walls of the stomach or intestine), in some cases fatal, has been
Growth retardation has been reported in children taking Glivec. The long-term effects of extended
treatment with Glivec on growth in children are unknown.
Cases of tumor lysis syndrome (TLS), which refers to a metabolic and electrolyte disturbance caused by
the breakdown of tumor cells, have been reported and can be life-threatening in some cases.
Almost all patients treated with Glivec experience side effects at some time. Some common side effects
you may experience are fluid retention, muscle cramps or pain and bone pain, abdominal pain, loss of
appetite, vomiting, diarrhea, decreased hemoglobin, abnormal bleeding, nausea, fatigue and rash.
Glivec is sometimes associated with stomach or intestinal irritation. Glivec should be taken with food and
a large glass of water to minimize this problem. There have been rare reports, including deaths, of
stomach or intestinal perforation (a small hole or tear).
If you are experiencing any of the mentioned side effects, please be sure to speak with your doctor
Do not take any other medications without talking to your doctor or pharmacist first, including Tylenol
(acetaminophen); herbal products (St. John’s wort, Hypericum perforatum); Coumadin (warfarin sodium);
rifampin; erythromycin; metoprolol; ketoconazole; and Dilantin (phenytoin). Taking these with Glivec may
affect how they work, or affect how Glivec works.
You should also tell your doctor if you are taking or plan to take iron supplements. Patients should also
avoid grapefruit juice and other foods that may affect how Glivec works.
1. National Cancer Institute. General Information About Chronic Myelogenous Lukemia (PDQ).
http://www.cancer.gov/cancertopics/pdq/treatment/CML/patient/. Accessed September 2009.
2. American Cancer Society. Detailed Guide: CML. What are the key statistics about CML? (Sept
2008 revision) Available at:
hronic_Myeloid_Leukemia_CML.asp?rnav=cri. Accessed April 2009.
3. Central European Leukemia Study Group. About CML. [Cited 2009 Jan 13] Available from:
4. American Cancer Society. Cancer Facts and Figures 2001.
http://www.cancer.org/downloads/STT/F&F2001.pdf. Accessed September 2009.
5. American Cancer Society. Cancer Facts and Figures 2009.
http://www.cancer.org/downloads/STT/500809web.pdf. Accessed September 2009.
6. Glivec (imatinib) prescribing information. Basel, Switzerland: Novartis International AG; March
7. National Comprehensive Cancer Network (NCCN): Clinical Practice Guide-lines in Oncology:
chronic myeloid leukemia, V.1.2010.
8. Hehlmann R, Heimpel H, et al. Randomized comparison of interferon-alpha with busulfan and
hydroxyurea in chronic myelogenous leukemia. The German CML Study Group. Blood. 1994 84:
9. Sessions J. Chronic Myeloid Leukemia in 2007. http://www.amcp.org/data/jmcp/pages%2047.pdf. Accessed September 2009.
10. Jabbour E, Cortes J, Kantarjian H, et al. Molecular Monitoring in Chronic Myeloid Leukemia
Response to Tyrosine Kinase Inhibitors and Prognostic Implications. Cancer. DOI
10.1002/cncr.23427. Published online 17 March 2008.
11. Kurzrock R, Talpaz M. The molecular pathology of chronic myelogenous leukaemia. Br J
Haematol. 1991 Oct; 79 Suppl 1:34-7.
12. Druker BJ, Guilhot F, O’Brien SG, et al. Five-Year Follow-up of Patients Receiving Imatinib for
Chronic Myeloid Leukemia. N Engl J Med. 2006; 355(23):2408-2517.
13. A Study of Imatinib Versus Nilotinib in Adult Patients With a Suboptimal Cytogenetic Response
With Philadelphia Chromosome Positive (Ph+) Chronic Myelogenous Leukemia in Chronic Phase
(CML-CP) (ENEST). http://clinicaltrials.gov/ct2/show/NCT00519090?term=ENEST&rank=2.
Accessed September 2009.
14. Tasigna (nilotinib) European Summary of Characteristics. Novartis AG.
15. Sherbenou DW, Druker BJ. Applying the discovery of the Philadelphia chromosome. J. Clin.
Invest. 117(8): 2067-2074 (2007). doi:10.1172/JCI31988.
16. Giles F, et al. A Phase I/II Study of AMN107, a Novel Aminopyrimidine Inhibitor of Bcr-Abl, on a
Continuous Daily Dosing Schedule in Adult Patients (pts) with Imatinib-Resistant Advanced
Phase Chronic Myeloid Leukemia (CML) or Relapsed/Refractory Philadelphia Chromosome
(Ph+) Acute Lymphocytic Leukemia (ALL). Presented at the 2004 American Society of
Hematology Annual Meeting.
17. Cortes J. First report of the TOPS study: A randomized phase III trial of 400mg vs 800mg imatinib
in patients with newly diagnosed, previously untreated CML in chronic phase using molecular
endpoints. Abstract. 13th Congress of the European Hematology Association, Bella Center,
Copenhagen, Denmark, June 12-15, 2008.
18. Hughes T, et al. ENESTnd Update: Continued Superiority of Nilotinib Versus Imatinib In Patients
with Newly Diagnosed Chronic Myeloid Leukemia In Chronic Phase (CML-CP). 52nd Annual
Meeting of the American Society of Hematology. Abstract No. 207. December 6, 2010.
19. Sprycel (dasatinib) European Summary of Characteristics. Bristol-Myers Squibb.