EAST HANOVER, N.J., Dec. 6 /PRNewswire/ -- Data published today in the New England Journal of Medicine underpinned Gleevec(R) (imatinib mesylate)* tablets as a durable and well-tolerated long-term therapy for newly diagnosed adult patients with a form of blood cancer known as Philadelphia chromosome- positive (Ph+) chronic myeloid leukemia (CML).
According to the publication, the five-year overall survival of patients who received Gleevec as initial therapy is higher -- estimated at 95% when excluding deaths from causes unrelated to CML or prior transplantation -- than that in any previously published prospective study of the treatment of CML, a disease with limited survival options before the approval of Gleevec.
Results of the International Randomized Interferon versus STI571 (IRIS) study -- the largest clinical trial ever for this patient population -- showed that responses to therapy with Gleevec continued to increase substantially over five years, while the yearly risk of progression to advanced disease declined to 0.6% in the fifth year.
"These data underscore that Gleevec continues to support positive outcomes in CML with the opportunity for patients to achieve better outcomes the longer they take the therapy," said David Epstein, president and CEO of Novartis Oncology. "The five-year data also show that Gleevec offers very good tolerability as well as an established and predictable safety profile."
The overall survival rate for patients receiving Gleevec was 89% (range 86% to 92%) when considering deaths from all causes. However, when deaths from causes unrelated to CML or prior transplantation are excluded, the overall survival rate was 95% at 60 months.
Before Gleevec was available, about 50% of patients progressed to the more advanced stages of Ph+ CML after only three to five years, and survival was generally short for those patients.
Gleevec has continued to be generally well-tolerated as initial drug therapy for Ph+ CML in chronic phase at the five-year follow-up. With a median follow-up of 60 months, the adverse events were similar to the previously reported profile. Newly occurring or worsening grade 3 or 4 hematologic or biochemical adverse events were infrequent after two and four years of therapy.
Most recently, Gleevec was approved in the European Union (EU) for the treatment of patients with the rare life-threatening blood disorders myelodysplastic syndromes/myeloproliferative diseases (MDS/MPD) and hypereosinophilic syndrome/chronic eosinophilic leukemia (HES/CEL). Gleevec was also recently approved in the EU for adult patients with newly diagnosed Ph+ acute lymphoblastic leukemia (Ph+ ALL) in combination with chemotherapy and as a single agent for patients with relapsed or refractory Ph+ ALL, and in the US for relapsed/refractory Ph+ ALL.
In only five years, Gleevec has now been approved in the EU for six diseases, including two solid tumors and four blood disorders with molecular targets known to be inhibited by the drug. In the US, Gleevec has now been approved for seven diseases, including two solid tumors and five blood disorders with molecular targets known to be inhibited by the drug.
IRIS study details
The International Randomized Interferon versus STI571 (IRIS) study is an open-label Phase III clinical trial enrolling 1,106 newly diagnosed patients with Ph+ CML in chronic phase in 177 centers across 16 countries. There are two arms to the study: one group of patients receiving Gleevec 400 mg per day and another receiving a target dose of interferon (IFN) of 5 MIU/m2/day in combination with Ara-C 20 mg/m2/day for 10 days each month. Because of tolerability reasons, lack of response, or loss of response, 65% of patients in the IFN/Ara-C arm crossed over to the Gleevec arm, whereas only 3% of patients in the Gleevec arm crossed over to the IFN/Ara-C arm.
Cumulative best responses to Gleevec treatment improved dramatically between the first and fifth years of treatment. Over the period, major cytogenetic responses rose from 85% to 92% and complete cytogenetic responses rose from 69% to 87%. Complete hematologic responses rose from 96% to 98%. In a complete hematologic response, the patient's blood cell counts return to normal. Cytogenetic response refers to the disappearance or reduction of the number of Ph+ cells detectable by standard lab methods.
About Gleevec Tablets
Gleevec(R) (imatinib mesylate) tablets are indicated for the treatment of newly diagnosed adult patients with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase. Follow-up is limited. Gleevec tablets are also indicated for the treatment of patients with Ph+ CML in blast crisis, in accelerated phase, or in chronic phase after failure of interferon- alpha (IFN-a) therapy.
Gleevec tablets are also indicated for the treatment of patients with KIT (CD117)-positive unresectable and/or metastatic malignant gastrointestinal stromal tumors (GIST). The effectiveness of Gleevec in GIST is based on objective response rate. There are no controlled trials demonstrating a clinical benefit, such as improvement in disease-related symptoms or increased survival.
Gleevec tablets are also indicated for the treatment of adult patients with unresectable, recurrent and/or metastatic dermatofibrosarcoma protuberans (DFSP), relapsed or refractory Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), certain forms of myelodysplastic/myeloproliferative diseases (MDS/MPD), hypereosinophilic syndrome and/or chronic eosinophilic leukemia (HES/CEL) and aggressive systemic mastocytosis (ASM).
Important Safety Information(1)
Hematologic Disorders
For Ph+ CML, severe (NCI Grades 3/4) lab abnormalities-including neutropenia (3%-48%), anemia (<1%-42%), thrombocytopenia (<1%-33%), and hepatotoxicity (3%-6%)-and severe adverse experiences (NCI Grades 3/4), including severe fluid retention (eg, pleural effusion, pulmonary edema, and ascites) and superficial edema (1.8%-11%), hemorrhage (1%-19%), and musculoskeletal pain (2%-9%) were reported among adults 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. Patients should be weighed and monitored regularly for signs and symptoms of edema, which can be serious or life-threatening. There have also been reports, including fatalities, of cardiac tamponade, cerebral edema, increased intracranial pressure, papilledema, and gastrointestinal (GI) perforation.
In HES/CEL patients, instances of Grade 3 leukopenia, neutropenia, lymphopenia, and anemia were reported.
In patients with HES and cardiac involvement, cases of cardiogenic shock/left ventricular dysfunction have been associated with the initiation of Gleevec therapy. The condition was reported to be reversible with the administration of systemic steroids, circulatory support measures and temporarily withholding Gleevec. MDS/MPD and ASM may be associated with high eosinophil levels. Monitoring should therefore be considered in patients with HES/CEL, and in patients with MDS/MPD or ASM associated with high eosinophil levels.
Solid Tumors
For GIST, severe (NCI Grades 3/4) lab abnormalities (400 mg/day; 600 mg/day)-including neutropenia (10%; 11%) anemia (3%; 9%) thrombocytopenia (0%; 1%) and hepatotoxicity (3%; 8%) and severe adverse experiences (NCI Grades 3/4), including severe fluid retention [eg, pleural effusion, and ascites (3%; 8%)], superficial edema (6%; 5%), hemorrhage (6%; 11%), abdominal pain (11%; 4%), nausea (6%; 4%), diarrhea (3%; 7%), and musculoskeletal pain (6%; 1%) were reported among Gleevec patients. Patients should be weighed and monitored regularly for signs and symptoms of edema, which can be serious or life-threatening. There have also been reports, including fatalities, of cardiac tamponade, cerebral edema, increased intracranial pressure, papilledema, and gastrointestinal (GI) perforation.
Some patients with GIST (5%) were reported to have severe GI bleeds or intratumoral bleeds. GI tumor sites may have been the source of GI bleeds.
For DFSP, severe (NCI Grades 3/4) lab abnormalities included anemia(17%), thrombocytopenia (17%), neutropenia (8%), and hepatotoxicity (8%).
Important Safety Information(1)
Severe congestive heart failure and left ventricular dysfunction have occasionally been reported in patients taking Gleevec. Most of the patients with reported cardiac events have had other co-morbidities 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.
Bullous dermatologic reactions (e.g., erythema multiforme and Stevens- Johnson syndrome) have been reported. In some cases, the reaction recurred upon rechallenge. Several post-marketing reports described cases in which patients tolerated reintroduction of Gleevec after resolution or improvement of the bullous reaction. In these instances, Gleevec was resumed at a lower dose with or without supportive care.
Dose adjustments may be necessary due to hepatotoxicity, other non- hematologic adverse events, or hematologic adverse events.
Therapy with Gleevec was discontinued for adverse events in 3% to 5% of adult patients with Ph+ CML or Kit+ GIST. None of the 5 patients in the ASM study discontinued Gleevec due to drug-related adverse events or abnormal laboratory values.
Gleevec is metabolized by the CYP3A4 isoenzyme and is an inhibitor of CYP3A4, CYP2D6, and CYP2C9. Dosage of Gleevec tablets should increase by at least 50% and clinical response should be carefully monitored in patients receiving Gleevec tablets with a potent CYP3A4 inducer such as rifampin or phenytoin. Examples of commonly used drugs that may significantly interact with Gleevec include acetaminophen, warfarin, erythromycin, and phenytoin. (Please see full prescribing information for other potential drug interactions).
For daily dosing of 800mg and above, dosing should be accomplished using the 400mg tablets to reduce exposure to iron.
Patients with severe hepatic impairment should be treated at a starting dose of 300 mg/day and should be closely monitored.
Women of childbearing potential should be advised to avoid becoming pregnant while taking Gleevec tablets. Because of the potential for serious adverse reactions in nursing infants, women should be advised to avoid breast- feeding while taking Gleevec tablets.
Use of Gleevec tablets is contraindicated in patients with hypersensitivity to imatinib or to any other component of Gleevec tablets.
Common Side Effects of Gleevec Tablets(1)
The majority of adult patients with Ph+ CML who received Gleevec in clinical studies experienced adverse events at some time. Most adverse events were mild to moderate in severity. The most frequently reported adverse events (all Grades) were superficial edema (58%-74%), nausea (47%-73%), muscle cramps (28%-62%), vomiting (21%-58%), diarrhea (39%-57%), musculoskeletal pain (38%- 49%), and rash related terms (36%-47%).**++
The most frequently reported drug-related adverse events reported in the Ph+ ALL studies were mild nausea, vomiting, diarrhea, myalgia, muscle cramps and rash, which were easily manageable. Superficial edemas were also a common finding in all studies and were described primarily as periorbital or lower limb edemas. However, these edemas were rarely severe and may be managed with diuretics, other supportive measures, or in some patients by reducing the dose of Gleevec.
Frequently reported adverse events (all Grades) in the seven MDS/MPD patients assessed were nausea (57%); diarrhea and muscle cramps (43% each); anemia, fatigue, arthralgia, and periorbital edema (29% each).
All ASM patients experienced at least one adverse event at some time. The most frequently reported adverse events were diarrhea, nausea, ascites, muscle cramps, dyspnea, fatigue, peripheral edema, anemia, pruritis, rash and lower respiratory tract infection.
All HES/CEL patients experienced at least one adverse event, the most common being gastrointestinal, cutaneous and musculoskeletal disorders, and hematological abnormalities.
The majority of adult patients who received Gleevec in the GIST study experienced adverse events at some time. Most adverse events were mild to moderate in severity. The most frequently reported adverse events (all Grades, 400 mg/day; 600 mg/day) were superficial edema (81%; 77%), diarrhea (59%; 70%), nausea (63% 74%), fatigue (48%; 53%), muscle cramps (47%; 58%), abdominal pain (40%; 37%), rash and related terms (38%; 53%), vomiting (38%; 55%), musculoskeletal pain (37%; 30%), and hemorrhage (26%; 34%)+
Frequently reported adverse events (all Grades) in the 12 DFSP patients assessed include nausea and fatigue (42% each); periorbital, peripheral and eye edema (33% each); diarrhea, vomiting, rash, increased lacrimation, and anemia (25% each); face edema, pyrexia, exertional dyspnea, rhinitis and anorexia (17% each).
Supportive care may help management of some mild to moderate adverse events so that prescribed dose can be maintained whenever possible, however in some cases, either a reduction of the dose or an 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.
Disclaimer
The foregoing release contains forward-looking statements that can be identified by terminology such as "estimated," "opportunity," or similar expressions, or by express or implied discussions regarding the long-term impact of a patient's use of Gleevec or potential future sales of Gleevec. Such forward-looking statements involve known and unknown risks, uncertainties and other factors that may cause actual results with Gleevec to be materially different from any future results, performance or achievements expressed or implied by such statements. There can be no guarantee regarding the long-term impact of a patient's use of Gleevec. Nor can there be any guarantee regarding potential future sales of Gleevec. In particular, management's expectations regarding Gleevec could be affected by, among other things, unexpected clinical trial results, including additional analysis of Gleevec clinical data, and new 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; and other risks and factors referred to in the Company'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 this information as of this date and does not undertake any obligation to update any forward-looking statements contained in this document as a result of new information, future events or otherwise.
About Novartis
Novartis Pharmaceuticals Corporation researches, develops, manufactures and markets leading innovative prescription drugs used to treat a number of diseases and conditions, including central nervous system disorders, organ transplantation, cardiovascular diseases, dermatological diseases, respiratory disorders, cancer and arthritis. The company's mission is to improve people's lives by pioneering novel healthcare solutions.
Located in East Hanover, New Jersey, Novartis Pharmaceuticals Corporation is an affiliate of Novartis AG -- a world leader in pharmaceuticals and consumer health. In 2005, the Group's businesses achieved sales of USD 32.2 billion and pro forma net income of USD 6.1 billion. The Group invested approximately USD 4.8 billion in R&D. Headquartered in Basel, Switzerland, Novartis Group companies employ approximately 99,000 people and operate in over 140 countries around the world. For further information please consult http://www.novartis.com/.
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* Known as Glivec(R) (imatinib) outside the U.S., Canada and Israel
** Numbers indicate the range of percentages in 4 studies among adult
patients with Ph+ CML in blast crisis, accelerated phase, and chronic
phase.
++ For more detailed study information, please see full prescribing
information for Gleevec.
(1) Gleevec(R) (imatinib mesylate) tablets prescribing information. East
Hanover, NJ: Novartis Pharmaceuticals Corporation; 2006.
