Newly diagnosed adult and pediatric patients with Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase.

Patients with Philadelphia chromosome positive chronic myeloid leukemia in blast crisis, accelerated phase, or in chronic phase after failure of interferon-alpha therapy.

Adult patients with relapsed or refractory Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL).

Pediatric patients with newly diagnosed Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) in combination with chemotherapy.

Adult patients with myelodysplastic/myeloproliferative diseases associated with platelet-derived growth factor receptor (PDGFR) gene re-arrangements.

Adult patients with aggressive systemic mastocytosis without the D816V c-Kit mutation or with c-Kit mutational status unknown.

Adult patients with hypereosinophilic syndrome and/or chronic eosinophilic leukemia who have the FIP1L1-PDGFRα fusion kinase (mutational analysis or fluorescence in situ hybridization [FISH] demonstration of CHIC2 allele deletion) and for patients with HES and/or CEL who are FIP1L1-PDGFRα fusion kinase negative or unknown.

Adult patients with unresectable, recurrent and/or metastatic dermatofibrosarcoma protuberans.

Patients with Kit (CD117) positive unresectable and/or metastatic malignant gastrointestinal stromal tumors.

Adjuvant treatment of adult patients following complete gross resection of Kit (CD117) positive GIST.

The prescribed dose should be administered orally, with a meal and a large glass of water. Doses of 400 mg or 600 mg should be administered once daily, whereas a dose of 800 mg should be administered as 400 mg twice a day.

For patients unable to swallow the film-coated tablets, the tablets may be dispersed in a glass of water or apple juice. The required number of tablets should be placed in the appropriate volume of beverage (approximately 50 mL for a 100-mg tablet, and 200 mL for a 400-mg tablet) and stirred with a spoon. The suspension should be administered immediately after complete disintegration of the tablet(s).

For daily dosing of 800 mg and above, dosing should be accomplished using the 400-mg tablet to reduce exposure to iron.

Treatment may be continued as long as there is no evidence of progressive disease or unacceptable toxicity.

The recommended dose of Gleevec is 400 mg/day for adult patients in chronic phase CML and 600 mg/day for adult patients in accelerated phase or blast crisis.

In CML, a dose increase from 400 mg to 600 mg in adult patients with chronic phase disease, or from 600 mg to 800 mg (given as 400 mg twice daily) in adult patients in accelerated phase or blast crisis may be considered in the absence of severe adverse drug reaction and severe non-leukemia related neutropenia or thrombocytopenia in the following circumstances: disease progression (at any time), failure to achieve a satisfactory hematologic response after at least 3 months of treatment, failure to achieve a cytogenetic response after 6 to 12 months of treatment, or loss of a previously achieved hematologic or cytogenetic response.

The recommended dose of Gleevec is 600 mg/day for adult patients with relapsed/refractory Ph+ ALL.

Determine PDGFRb gene rearrangements status prior to initiating treatment.

The recommended dose of Gleevec is 400 mg/day for adult patients with MDS/MPD.

Determine D816V c-Kit mutation status prior to initiating treatment.

The recommended dose of Gleevec is 400 mg/day for adult patients with ASM without the D816V c-Kit mutation. If c-Kit mutational status is not known or unavailable, treatment with Gleevec 400 mg/day may be considered for patients with ASM not responding satisfactorily to other therapies. For patients with ASM associated with eosinophilia, a clonal hematological disease related to the fusion kinase FIP1L1-PDGFRα, a starting dose of 100 mg/day is recommended. Dose increase from 100 mg to 400 mg for these patients may be considered in the absence of adverse drug reactions if assessments demonstrate an insufficient response to therapy.

The recommended dose of Gleevec is 400 mg/day for adult patients with HES/CEL. For HES/CEL patients with demonstrated FIP1L1-PDGFRα fusion kinase, a starting dose of 100 mg/day is recommended. Dose increase from 100 mg to 400 mg for these patients may be considered in the absence of adverse drug reactions if assessments demonstrate an insufficient response to therapy.

The recommended dose of Gleevec is 800 mg/day for adult patients with DFSP.

The recommended dose of Gleevec is 400 mg/day for adult patients with unresectable and/or metastatic, malignant GIST. A dose increase up to 800 mg daily (given as 400 mg twice daily) may be considered, as clinically indicated, in patients showing clear signs or symptoms of disease progression at a lower dose and in the absence of severe adverse drug reactions.

Renal Impairment: Patients with moderate renal impairment (creatinine clearance [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 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 are not recommended.

If a severe non-hematologic adverse reaction develops (such as severe hepatotoxicity or severe fluid retention), Gleevec should be withheld until the event has resolved. Thereafter, treatment can be resumed as appropriate depending on the initial severity of the event.

Dose reduction or treatment interruptions for severe neutropenia and thrombocytopenia are recommended as indicated in Table 1.

Congestive heart failure and left ventricular dysfunction have been reported in patients taking Gleevec. Cardiac adverse reactions were more frequent in patients with advanced age or co-morbidities, including previous medical history of cardiac disease. In an international randomized Phase 3 study in 1106 patients with newly diagnosed Ph+ CML in chronic phase, severe cardiac failure and left ventricular dysfunction were observed in 0.7% of patients taking Gleevec compared to 0.9% of patients taking IFN + Ara-C. In another randomized trial with newly diagnosed Ph+ CML patients in chronic phase that compared Gleevec and nilotinib, cardiac failure was observed in 1.1% of patients in the Gleevec arm and 2.2% of patients in the nilotinib 300 mg twice daily arm and severe (Grade 3 or 4) cardiac failure occurred in 0.7% of patients in each group. Carefully monitor patients with cardiac disease or risk factors for cardiac or history of renal failure. Evaluate and treat any patient with signs or symptoms consistent with cardiac or renal failure.

In a trial of Gleevec versus IFN+Ara-C in patients with the newly diagnosed CML, 1.8% of patients had Grade 3/4 hemorrhage. In the Phase 3 unresectable or metastatic GIST studies, 211 patients (12.9%) reported Grade 3/4 hemorrhage at any site. In the Phase 2 unresectable or metastatic GIST study, 7 patients (5%) had a total of 8 CTC Grade 3/4 hemorrhages; gastrointestinal (GI) (3 patients), intra-tumoral (3 patients) or both (1 patient). Gastrointestinal tumor sites may have been the source of GI hemorrhages. In a randomized trial in patients with newly diagnosed Ph+ CML in chronic phase comparing Gleevec and nilotinib, GI hemorrhage occurred in 1.4% of patients in the Gleevec arm, and in 2.9% of patients in the nilotinib 300 mg twice daily arm. None of these events were Grade 3 or 4 in the Gleevec arm; 0.7% were Grade 3 or 4 in the nilotinib 300 mg twice daily arm. In addition, gastric antral vascular ectasia has been reported in postmarketing experience.

Gleevec is sometimes associated with GI irritation. Gleevec should be taken with food and a large glass of water to minimize this problem. There have been rare reports, including fatalities, of GI perforation.

In patients with hypereosinophilic syndrome with occult infiltration of HES cells within the myocardium, cases of cardiogenic shock/left ventricular dysfunction have been associated with HES cell degranulation upon 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.

Myelodysplastic/myeloproliferative disease and systemic mastocytosis may be associated with high eosinophil levels. Consider performing an echocardiogram and determining serum troponin in patients with HES/CEL, and in patients with MDS/MPD or ASM associated with high eosinophil levels. If either is abnormal, consider prophylactic use of systemic steroids (1-2 mg/kg) for one to two weeks concomitantly with Gleevec at the initiation of therapy.

Bullous dermatologic reactions, including erythema multiforme and Stevens-Johnson syndrome, have been reported with use of Gleevec. In some cases of bullous dermatologic reactions, including erythema multiforme and Stevens-Johnson syndrome reported during postmarketing surveillance, a recurrent dermatologic reaction was observed upon rechallenge. Several foreign postmarketing reports have described cases in which patients tolerated the reintroduction of Gleevec therapy after resolution or improvement of the bullous reaction. In these instances, Gleevec was resumed at a dose lower than that at which the reaction occurred and some patients also received concomitant treatment with corticosteroids or antihistamines.

Clinical cases of hypothyroidism have been reported in thyroidectomy patients undergoing levothyroxine replacement during treatment with Gleevec. Monitor TSH levels in such patients.

Cases of Tumor Lysis Syndrome (TLS), including fatal cases, have been reported in patients with CML, GIST, ALL, and eosinophilic leukemia receiving Gleevec. The patients at risk of TLS are those with tumors having a high proliferative rate or high tumor burden prior to treatment. Monitor these patients closely and take appropriate precautions. Due to possible occurrence of TLS, correct clinically significant dehydration and treat high uric acid levels prior to initiation of Gleevec.

Motor vehicle accidents have been reported in patients receiving Gleevec. Advise patients that they may experience side effects, such as dizziness, blurred vision, or somnolence during treatment with Gleevec. Recommend caution when driving a car or operating machinery.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The majority of Gleevec-treated patients experienced adverse reactions at some time. Gleevec was discontinued due to drug-related adverse reactions in 2.4% of patients receiving Gleevec in the randomized trial of newly diagnosed patients with Ph+ CML in chronic phase comparing Gleevec versus IFN+Ara-C, and in 12.5% of patients receiving Gleevec in the randomized trial of newly diagnosed patients with Ph+ CML in chronic phase comparing Gleevec and nilotinib. Gleevec was discontinued due to drug-related adverse reactions in 4% of patients in chronic phase after failure of interferon-alpha therapy, in 4% of patients in accelerated phase and in 5% of patients in blast crisis.

A variety of adverse reactions represent local or general fluid retention, including pleural effusion, ascites, pulmonary edema, and rapid weight gain with or without superficial edema. These reactions appear to be dose related, were more common in the blast crisis and accelerated phase studies (where the dose was 600 mg/day), and are more common in the elderly. These reactions were usually managed by interrupting Gleevec treatment and using diuretics or other appropriate supportive care measures. These reactions may be serious or life threatening.

Adverse reactions, regardless of relationship to study drug, that were reported in at least 10% of the Gleevec-treated patients are shown in Tables 2, 3, and 4.

Cytopenias, and particularly neutropenia and thrombocytopenia, were a consistent finding in all studies, with a higher frequency at doses greater than or equal to 750 mg (Phase 1 study). The occurrence of cytopenias in CML patients was also dependent on the stage of the disease.

In patients with newly diagnosed CML, cytopenias were less frequent than in the other CML patients (see Tables 5, 6, and 7). The frequency of Grade 3 or 4 neutropenia and thrombocytopenia was between 2- and 3-fold higher in blast crisis and accelerated phase compared to chronic phase (see Tables 4 and 5). The median duration of the neutropenic and thrombocytopenic episodes varied from 2 to 3 weeks, and from 2 to 4 weeks, respectively.

These reactions can usually be managed with either a reduction of the dose or an interruption of treatment with Gleevec, but may require permanent discontinuation of treatment.

Severe elevation of transaminases or bilirubin occurred in approximately 5% of CML patients (see Tables 6 and 7) and were usually managed with dose reduction or interruption (the median duration of these episodes was approximately 1 week). Treatment was discontinued permanently because of liver laboratory abnormalities in less than 1.0% of CML patients. One patient, who was taking acetaminophen regularly for fever, died of acute liver failure. In the Phase 2 GIST trial, Grade 3 or 4 SGPT (ALT) elevations were observed in 6.8% of patients and Grade 3 or 4 SGOT (AST) elevations were observed in 4.8% of patients. Bilirubin elevation was observed in 2.7% of patients.

The overall safety profile of pediatric patients treated with Gleevec in 93 children studied was similar to that found in studies with adult patients, except that musculoskeletal pain was less frequent (20.5%) and peripheral edema was not reported. Nausea and vomiting were the most commonly reported individual adverse reactions with an incidence similar to that seen in adult patients. Most patients experienced adverse reactions at some time during the study. The incidence of Grade 3/4 events across all types of adverse reactions was 75%; the events with the highest Grade 3/4 incidence in CML pediatric patients were mainly related to myelosuppression.

Pediatric and young adult patients with very high risk ALL, defined as those with an expected 5 year event-free survival (EFS) less than 45%, were enrolled after induction therapy on a multicenter, non-randomized cooperative group pilot protocol. The study population included patients with a median age of 10 years (1 to 21 years), 61% of whom were male, 75% were white, 7% were black, and 6% were Asian/Pacific Islander. Patients with Ph+ ALL (n = 92) were assigned to receive Gleevec and treated in 5 successive cohorts. Gleevec exposure was systematically increased in successive cohorts by earlier introduction and more prolonged duration.

The safety of Gleevec given in combination with intensive chemotherapy was evaluated by comparing the incidence of Grade 3 and 4 adverse events, neutropenia (less than 750/mcL) and thrombocytopenia (less than 75,000/mcL) in the 92 patients with Ph+ ALL compared to 65 patients with Ph- ALL enrolled on the trial who did not receive Gleevec. The safety was also evaluated comparing the incidence of adverse events in cycles of therapy administered with or without Gleevec. The protocol included up to 18 cycles of therapy. Patients were exposed to a cumulative total of 1425 cycles of therapy, 778 with Gleevec, and 647 without Gleevec. The adverse events that were reported with a 5% or greater incidence in patients with Ph+ ALL compared to Ph- ALL or with a 1% or greater incidence in cycles of therapy that included Gleevec are presented in Table 8.

In older patients (greater than or equal to 65 years old), with the exception of edema, where it was more frequent, there was no evidence of an increase in the incidence or severity of adverse reactions. In women there was an increase in the frequency of neutropenia, as well as Grade 1/2 superficial edema, headache, nausea, rigors, vomiting, rash, and fatigue. No differences were seen that were related to race but the subsets were too small for proper evaluation.

The adverse reactions were similar for Ph+ ALL as for Ph+ CML. The most frequently reported drug-related adverse reactions reported in the Ph+ ALL studies were mild nausea and vomiting, diarrhea, myalgia, muscle cramps, and rash. Superficial edema was a common finding in all studies and were described primarily as periorbital or lower limb edemas. These edemas were reported as Grade 3/4 events in 6.3% of the patients and may be managed with diuretics, other supportive measures, or in some patients by reducing the dose of Gleevec.

Adverse reactions, regardless of relationship to study drug, that were reported in at least 10% of the patients treated with Gleevec for MDS/MPD in the Phase 2 study, are shown in Table 9.

All aggressive systemic mastocytosis (ASM) patients experienced at least one adverse reaction at some time. The most frequently reported adverse reactions were diarrhea, nausea, ascites, muscle cramps, dyspnea, fatigue, peripheral edema, anemia, pruritus, rash, and lower respiratory tract infection. None of the 5 patients in the Phase 2 study with ASM discontinued Gleevec due to drug-related adverse reactions or abnormal laboratory values.

The safety profile in the HES/CEL patient population does not appear to be different from the safety profile of Gleevec observed in other hematologic malignancy populations, such as Ph+ CML. All patients experienced at least one adverse reaction, the most common being GI, cutaneous and musculoskeletal disorders. Hematological abnormalities were also frequent, with instances of CTC Grade 3 leukopenia, neutropenia, lymphopenia, and anemia.

Adverse reactions, regardless of relationship to study drug, that were reported in at least 10% of the 12 patients treated with Gleevec for DFSP in the Phase 2 study are shown in Table 10.

Clinically relevant or severe laboratory abnormalities in the 12 patients treated with Gleevec for DFSP in the Phase 2 study are presented in Table 11.

Adverse reactions, regardless of relationship to study drug, that were reported in at least 10% of the patients treated with Gleevec are shown in Table 12.

Overall the incidence of all grades of adverse reactions and the incidence of severe adverse reactions (CTC Grade 3 and above) were similar between the two treatment arms except for edema, which was reported more frequently in the 800 mg group.

Clinically relevant or severe abnormalities of routine hematologic or biochemistry laboratory values were not reported or evaluated in the Phase 3 GIST trials. Severe abnormal laboratory values reported in the Phase 2 GIST trial are presented in Table 13.

In Study 1, the majority of both Gleevec and placebo-treated patients experienced at least one adverse reaction at some time. The most frequently reported adverse reactions were similar to those reported in other clinical studies in other patient populations and include diarrhea, fatigue, nausea, edema, decreased hemoglobin, rash, vomiting, and abdominal pain. No new adverse reactions were reported in the adjuvant GIST-treatment setting that had not been previously reported in other patient populations, including patients with unresectable and/or malignant metastatic GIST. Drug was discontinued for adverse reactions in 57 patients (17%) and 11 patients (3%) of the Gleevec and placebo-treated patients, respectively. Edema, GI disturbances (nausea, vomiting, abdominal distention, and diarrhea), fatigue, low hemoglobin, and rash were the most frequently reported adverse reactions at the time of discontinuation.

In Study 2, discontinuation of therapy due to adverse reactions occurred in 15 patients (8%) and 27 patients (14%) of the Gleevec 12-month, and 36-month treatment arms, respectively. As in previous trials the most common adverse reactions were diarrhea, fatigue, nausea, edema, decreased hemoglobin, rash, vomiting, and abdominal pain.

Adverse reactions, regardless of relationship to study drug, that were reported in at least 5% of the patients treated with Gleevec are shown in Table 14 (Study 1) and Table 15 (Study 2). There were no deaths attributable to Gleevec treatment in either trial.

Estimated 1%-10%: palpitations, pericardial effusion

Estimated 0.1%-1%: congestive cardiac failure, tachycardia, pulmonary edema

Estimated 0.01%-0.1%: arrhythmia, atrial fibrillation, cardiac arrest, myocardial infarction, angina pectoris

Estimated 1%-10%: flushing, hemorrhage

Estimated 0.1%-1%: hypertension, hypotension, peripheral coldness, Raynaud’s phenomenon, hematoma, subdural hematoma

Estimated 1%-10%: blood creatine phosphokinase (CPK) increased, blood amylase increased

Estimated 0.1%-1%: blood lactate dehydrogenase (LDH) increased

Estimated 1%-10%: dry skin, alopecia, face edema, erythema, photosensitivity reaction, nail disorder, purpura

Estimated 0.1%-1%: exfoliative dermatitis, bullous eruption, psoriasis, rash pustular, contusion, sweating increased, urticaria, ecchymosis, increased tendency to bruise, hypotrichosis, skin hypopigmentation, skin hyperpigmentation, onychoclasis, folliculitis, petechiae, erythema multiforme, panniculitis (including erythema nodosum)

Estimated 0.01%-0.1%: vesicular rash, Stevens-Johnson syndrome, acute generalized exanthematous pustulosis, acute febrile neutrophilic dermatosis (Sweet’s syndrome), nail discoloration, angioneurotic edema, leucocytoclastic vasculitis

Estimated 1%-10%: abdominal distention, gastroesophageal reflux, dry mouth, gastritis

Estimated 0.1%-1%: gastric ulcer, stomatitis, mouth ulceration, eructation, melena, esophagitis, ascites, hematemesis, chelitis, dysphagia, pancreatitis

Estimated 0.01%-0.1%: colitis, ileus, inflammatory bowel disease

Estimated 1%-10%: weakness, anasarca, chills

Estimated 0.1%-1%: malaise

Estimated 1%-10%: pancytopenia, febrile neutropenia, lymphopenia, eosinophilia

Estimated 0.1%-1%: thrombocythemia, bone marrow depression, lymphadenopathy

Estimated 0.01%-0.1%: hemolytic anemia, aplastic anemia

Estimated 0.1%-1%: hepatitis, jaundice

Estimated 0.01%-0.1%: angioedema

Estimated 0.1%-1%: sepsis, herpes simplex, herpes zoster, cellulitis, urinary tract infection, gastroenteritis

Estimated 0.01%-0.1%: fungal infection

Estimated 1%-10%: weight decreased, decreased appetite

Estimated 0.1%-1%: dehydration, gout, increased appetite, hyperuricemia, hypercalcemia, hyperglycemia, hyponatremia, hyperkalemia, hypomagnesemia

Estimated 1%-10%: joint swelling

Estimated 0.1%-1%: joint and muscle stiffness, muscular weakness, arthritis

Estimated 1%-10%: paresthesia, hypesthesia

Estimated 0.1%-1%: syncope, peripheral neuropathy, somnolence, migraine, memory impairment, libido decreased, sciatica, restless leg syndrome, tremor

Estimated 0.1%-1%: renal failure acute, urinary frequency increased, hematuria, renal pain

Estimated 0.1%-1%: breast enlargement, menorrhagia, sexual dysfunction, gynecomastia, erectile dysfunction, menstruation irregular, nipple pain, scrotal edema

Estimated 1%-10%: epistaxis

Estimated 0.1%-1%: pleural effusion

Estimated 0.01%-0.1%: interstitial pneumonitis, pulmonary fibrosis, pleuritic pain, pulmonary hypertension, pulmonary hemorrhage

Estimated 0.1%-1%: hypothyroidism, hyperthyroidism

Estimated 1%-10%: conjunctivitis, vision blurred, orbital edema, conjunctival hemorrhage, dry eye

Estimated 0.1%-1%: vertigo, tinnitus, eye irritation, eye pain, scleral hemorrhage, retinal hemorrhage, blepharitis, macular edema, hearing loss, cataract

The following additional adverse reactions have been identified during post approval use of Gleevec. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Gleevec will increase plasma concentration of CYP3A4 metabolized drugs (e.g., triazolo-benzodiazepines, dihydropyridine calcium channel blockers, certain HMG-CoA reductase inhibitors, etc.). Use caution when administering Gleevec with CYP3A4 substrates that have a narrow therapeutic window.

Use caution when administering Gleevec with CYP2D6 substrates that have a narrow therapeutic window.

Gleevec can cause fetal harm when administered to a pregnant woman based on human and animal data. There are no clinical studies regarding use of Gleevec in pregnant women. There have been postmarket reports of spontaneous abortions and congenital anomalies from women who have been exposed to Gleevec during pregnancy. Reproductive studies in rats have demonstrated that imatinib mesylate induced teratogenicity and increased incidence of congenital abnormalities following prenatal exposure to imatinib mesylate at doses equal to the highest recommended human dose of 800 mg/day based on BSA. Advise women to avoid pregnancy when taking Gleevec. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus.

The background risk of major birth defects and miscarriage for the indicated population is not known; however, in the U.S. general population, the estimated background risk of major birth defects of clinically recognized pregnancies is 2% to 4% and of miscarriage is 15% to 20%.

In embryo-fetal development studies in rats and rabbits, pregnant animals received oral doses of imatinib mesylate up to 100 mg/kg/day and 60 mg/kg/day, respectively, during the period of organogenesis.

In rats, imatinib mesylate was teratogenic at 100 mg/kg/day (approximately equal to the maximum human dose of 800 mg/day based on BSA), the number of fetuses with encephalocoele and exencephaly was higher than historical control values and these findings were associated with missing or underdeveloped cranial bones. Lower mean fetal body weights were associated with retarded skeletal ossifications.

In rabbits, at doses 1.5 times higher than the maximum human dose of 800 mg/day based on BSA, no effects on the reproductive parameters with respect to implantation sites, number of live fetuses, sex ratio or fetal weight were observed. The examinations of the fetuses did not reveal any drug related morphological changes.

In a pre- and postnatal development study in rats, pregnant rats received oral doses of imatinib mesylate during gestation (organogenesis) and lactation up to 45 mg/kg/day. Five animals developed a red vaginal discharge in the 45 mg/kg/day group on Days 14 or 15 of gestation, the significance of which is unknown since all females produced viable litters and none had increased post-implantation loss. Other maternal effects noted only at the dose of 45 mg/kg/day (approximately one-half the maximum human dose of 800 mg/day based on BSA) included an increased number of stillborn pups and pups dying between postpartum Days 0 and 4. In the F1 offspring at this same dose level, mean body weights were reduced from birth until terminal sacrifice and the number of litters achieving criterion for preputial separation was slightly decreased. There were no other significant effects in developmental parameters or behavioral testing. F1 fertility was not affected but reproductive effects were noted at 45 mg/kg/day, including an increased number of resorptions and a decreased number of viable fetuses. The no-observed-effect level (NOEL) for both maternal animals and the F1 generation was 15 mg/kg/day.

Imatinib and its active metabolite are excreted into human milk. Because of the potential for serious adverse reactions in breastfed infants from Gleevec, advise a lactating woman not to breastfeed during treatment and for 1 month after the last dose.

Based on data from 3 breastfeeding women taking Gleevec, the milk:plasma ratio is about 0.5 for imatinib and about 0.9 for the active metabolite. Considering the combined concentration of imatinib and active metabolite, a breastfed infant could receive up to 10% of the maternal therapeutic dose based on body weight.

Test pregnancy status in females with reproductive potential prior to the initiation of treatment with Gleevec.

In the unresectable or metastatic GIST study, 16% of patients were older than 65 years. No obvious differences in the safety or efficacy profile were noted in patients older than 65 years as compared to younger patients, but the small number of patients does not allow a formal analysis.

The effect of hepatic impairment on the pharmacokinetics of both imatinib and its major metabolite, CGP74588, was assessed in 84 patients with cancer with varying degrees of hepatic impairment at imatinib doses ranging from 100 mg to 800 mg.

In vivo, imatinib inhibits tumor growth of BCR-ABL transfected murine myeloid cells as well as BCR-ABL positive leukemia lines derived from CML patients in blast crisis.

Imatinib is also an inhibitor of the receptor tyrosine kinases for platelet-derived growth factor (PDGF) and stem cell factor (SCF), c-Kit, and inhibits PDGF- and SCF-mediated cellular events. In vitro, imatinib inhibits proliferation and induces apoptosis in GIST cells, which express an activating c-Kit mutation.

The pharmacokinetics of Gleevec have been evaluated in studies in healthy subjects and in population pharmacokinetic studies in over 900 patients. The pharmacokinetics of Gleevec are similar in CML and GIST patients.

Following oral administration in healthy volunteers, the elimination half-lives of imatinib and its major active metabolite, the N-demethyl derivative (CGP74588), are approximately 18 and 40 hours, respectively.

Typically, clearance of imatinib in a 50-year-old patient weighing 50 kg is expected to be 8 L/h, while for a 50-year-old patient weighing 100 kg the clearance will increase to 14 L/h. The inter-patient variability of 40% in clearance does not warrant initial dose adjustment based on body weight and/or age but indicates the need for close monitoring for treatment-related toxicity.

Similar findings were observed in patients receiving 400 to 1200 mg/day Gleevec concomitantly with enzyme-inducing anti-epileptic drugs (EIAED) (e.g., carbamazepine, oxcarbamazepine, phenytoin, fosphenytoin, phenobarbital, and primidone). The mean dose normalized AUC for imatinib in the patients receiving EIAED’s decreased by 73% compared to patients not receiving EIAED.

Concomitant administration of Gleevec and St. John’s Wort led to a 30% reduction in the AUC of imatinib.

Gleevec will increase plasma concentration of other CYP3A4 metabolized drugs (e.g., triazolo-benzodiazepines, dihydropyridine calcium channel blockers, certain HMG-CoA reductase inhibitors, etc.).

Because warfarin is metabolized by CYP2C9 and CYP3A4, patients who require anticoagulation should receive low-molecular weight or standard heparin instead of warfarin.

In a study of fertility, male rats were dosed for 70 days prior to mating and female rats were dosed 14 days prior to mating and through to gestational Day 6. Testicular and epididymal weights and percent motile sperm were decreased at 60 mg/kg, approximately three-fourths the maximum clinical dose of 800 mg/day based on BSA. This was not seen at doses less than or equal to 20 mg/kg (one-fourth the maximum human dose of 800 mg). The fertility of male and female rats was not affected.

Fertility was not affected in the preclinical fertility and early embryonic development study although lower testes and epididymal weights as well as a reduced number of motile sperm were observed in the high dose males rats. In the preclinical pre- and postnatal study in rats, fertility in the first generation offspring was also not affected by imatinib mesylate.

It is important to consider potential toxicities suggested by animal studies, specifically, liver, kidney, and cardiac toxicity and immunosuppression. Severe liver toxicity was observed in dogs treated for 2 weeks, with elevated liver enzymes, hepatocellular necrosis, bile duct necrosis, and bile duct hyperplasia. Renal toxicity was observed in monkeys treated for 2 weeks, with focal mineralization and dilation of the renal tubules and tubular nephrosis. Increased blood urea nitrogen (BUN) and creatinine were observed in several of these animals. An increased rate of opportunistic infections was observed with chronic imatinib treatment in laboratory animal studies. In a 39 week monkey study, treatment with imatinib resulted in worsening of normally suppressed malarial infections in these animals. Lymphopenia was observed in animals (as in humans). Additional long-term toxicities were identified in a 2-year rat study. Histopathological examination of the treated rats that died on study revealed cardiomyopathy (both sexes), chronic progressive nephropathy (females) and preputial gland papilloma as principal causes of death or reasons for sacrifice. Non-neoplastic lesions seen in this 2-year study which were not identified in earlier preclinical studies were the cardiovascular system, pancreas, endocrine organs, and teeth. The most important changes included cardiac hypertrophy and dilatation, leading to signs of cardiac insufficiency in some animals.

A total of 1106 patients were randomized from 177 centers in 16 countries, 553 to each arm. Baseline characteristics were well balanced between the two arms. Median age was 51 years (range, 18 to 70 years), with 21.9% of patients greater than or equal to 60 years of age. There were 59% males and 41% females; 89.9% Caucasian and 4.7% black patients. At the cut-off for this analysis (7 years after last patient had been recruited), the median duration of first-line treatment was 82 and 8 months in the Gleevec and IFN arm, respectively. The median duration of second-line treatment with Gleevec was 64 months. Sixty percent of patients randomized to Gleevec are still receiving first-line treatment. In these patients, the average dose of Gleevec was 403 mg ± 57 mg. Overall, in patients receiving first line Gleevec, the average daily dose delivered was 406 mg ± 76 mg. Due to discontinuations and cross-overs, only 2% of patients randomized to IFN were still on first-line treatment. In the IFN arm, withdrawal of consent (14%) was the most frequent reason for discontinuation of first-line therapy, and the most frequent reason for cross over to the Gleevec arm was severe intolerance to treatment (26%) and progression (14%).

The primary efficacy endpoint of the study was progression-free survival (PFS). Progression was defined as any of the following events: progression to accelerated phase or blast crisis (AP/BC), death, loss of CHR or MCyR, or in patients not achieving a CHR an increasing WBC despite appropriate therapeutic management. The protocol specified that the progression analysis would compare the intent to treat (ITT) population: patients randomized to receive Gleevec were compared with patients randomized to receive IFN. Patients that crossed over prior to progression were not censored at the time of cross-over, and events that occurred in these patients following cross-over were attributed to the original randomized treatment. The estimated rate of progression-free survival at 84 months in the ITT population was 81.2% [95% CI: 78, 85] in the Gleevec arm and 60.6% [56, 65] in the IFN arm (p less than 0.0001, log-rank test), (Figure 1). With 7 years follow up there were 93 (16.8%) progression events in the Gleevec arm: 37 (6.7%) progression to AP/BC, 31 (5.6%) loss of MCyR, 15 (2.7%) loss of CHR or increase in WBC and 10 (1.8%) CML unrelated deaths. In contrast, there were 165 (29.8%) events in the IFN+Ara-C arm of which 130 occurred during first-line treatment with IFN-Ara-C. The estimated rate of patients free of progression to accelerated phase (AP) or blast crisis (BC) at 84 months was 92.5% [90, 95] in the Gleevec arm compared to the 85.1%, [82, 89] (p less than or equal to 0.001) in the IFN arm, (Figure 2). The annual rates of any progression events have decreased with time on therapy. The probability of remaining progression free at 60 months was 95% for patients who were in complete cytogenetic response (CCyR) with molecular response (greater than or equal to 3 log reduction in BCR-ABL transcripts as measured by quantitative reverse transcriptase polymerase chain reaction) at 12 months, compared to 89% for patients in CCyR but without a major molecular response and 70% in patients who were not in CCyR at this time point (p less than 0.001).

Physical, functional, and treatment-specific biologic response modifier scales from the FACT-BRM (Functional Assessment of Cancer Therapy - Biologic Response Modifier) instrument were used to assess patient-reported general effects of interferon toxicity in 1,067 patients with CML in chronic phase. After one month of therapy to 6 months of therapy, there was a 13% to 21% decrease in median index from baseline in patients treated with IFN, consistent with increased symptoms of IFN toxicity. There was no apparent change from baseline in median index for patients treated with Gleevec.

An open-label, multicenter, randomized trial (Gleevec versus nilotinib) was conducted to determine the efficacy of Gleevec versus nilotinib in adult patients with cytogenetically confirmed, newly diagnosed Ph+ CML-CP. Patients were within 6 months of diagnosis and were previously untreated for CML-CP, except for hydroxyurea and/or anagrelide. Efficacy was based on a total of 846 patients: 283 patients in the Gleevec 400 mg once daily group, 282 patients in the nilotinib 300 mg twice daily group, 281 patients in the nilotinib 400 mg twice daily group.

Median age was 46 years in the Gleevec group and 47 years in both nilotinib groups, with 12%, 13%, and 10% of patients greater than or equal to 65 years of age in Gleevec 400 mg once daily, nilotinib 300 mg twice daily and nilotinib 400 mg twice daily treatment groups, respectively. There were slightly more male than female patients in all groups (56%, 56%, and 62% in Gleevec 400 mg once daily, nilotinib 300 mg twice daily and nilotinib 400 mg twice-daily treatment groups, respectively). More than 60% of all patients were Caucasian, and 25% were Asian.

The primary data analysis was performed when all 846 patients completed 12 months of treatment or discontinued earlier. Subsequent analyses were done when patients completed 24, 36, 48, and 60 months of treatment or discontinued earlier. The median time on treatment was approximately 61 months in all three treatment groups.

The primary efficacy endpoint was major molecular response (MMR) at 12 months after the start of study medication. MMR was defined as less than or equal to 0.1% BCR-ABL/ABL % by international scale measured by RQ-PCR, which corresponds to a greater than or equal to 3 log reduction of BCR-ABL transcript from standardized baseline. Efficacy endpoints are summarized in Table 19.

Twelve patients in the Gleevec arm progressed to either accelerated phase or blast crises (7 patients within first 6 months, 2 patients within 6 to 12 months, 2 patients within 12 to 18 months and 1 patient within 18 to 24 months) while two patients on the nilotinib arm progressed to either accelerated phase or blast crisis (both within the first 6 months of treatment).

By 60 months, MMR was achieved by 60% of patients on Gleevec and 77% of patients on nilotinib.

Median overall survival was not reached in either arm. At the time of the 60-month final analysis, the estimated survival rate was 91.7% for patients on Gleevec and 93.7% for patients on nilotinib.

Effectiveness was evaluated primarily on the basis of the rate of hematologic response, reported as either complete hematologic response, no evidence of leukemia (i.e., clearance of blasts from the marrow and the blood, but without a full peripheral blood recovery as for complete responses), or return to chronic phase CML. Cytogenetic responses were also evaluated. Median duration of treatment was 18 months with 45% of patients treated for greater than or equal to 24 months (maximum = 35 months). Efficacy results are reported in Table 20. Response rates in accelerated phase CML were higher for the 600 mg dose group than for the 400 mg group: hematologic response (75% vs 64%), confirmed and unconfirmed major cytogenetic response (31% vs 19%).

Effectiveness was evaluated primarily on the basis of rate of hematologic response, reported as either complete hematologic response, no evidence of leukemia, or return to chronic phase CML using the same criteria as for the study in accelerated phase. Cytogenetic responses were also assessed. Median duration of treatment was 4 months with 21% of patients treated for greater than or equal to 12 months and 10% for greater than or equal to 24 months (maximum = 35 months). Efficacy results are reported in Table 20. The hematologic response rate was higher in untreated patients than in treated patients (36% vs 22%, respectively) and in the group receiving an initial dose of 600 mg rather than 400 mg (33% vs 16%). The confirmed and unconfirmed major cytogenetic response rate was also higher for the 600-mg dose group than for the 400-mg dose group (17% vs 8%).

The median time to hematologic response was 1 month. In late chronic phase CML, with a median time from diagnosis of 32 months, an estimated 87.8% of patients who achieved MCyR maintained their response 2 years after achieving their initial response. After 2 years of treatment, an estimated 85.4% of patients were free of progression to AP or BC, and estimated overall survival was 90.8% [88.3, 93.2]. In accelerated phase, median duration of hematologic response was 28.8 months for patients with an initial dose of 600 mg (16.5 months for 400 mg). An estimated 63.8% of patients who achieved MCyR were still in response 2 years after achieving initial response. The median survival was 20.9 [13.1, 34.4] months for the 400 mg group and was not yet reached for the 600 mg group (p = 0.0097). An estimated 46.2% [34.7, 57.7] vs 65.8% [58.4, 73.3] of patients were still alive after 2 years of treatment in the 400 mg vs 600 mg dose groups, respectively. In blast crisis, the estimated median duration of hematologic response is 10 months. An estimated 27.2% [16.8, 37.7] of hematologic responders maintained their response 2 years after achieving their initial response. Median survival was 6.9 [5.8, 8.6] months, and an estimated 18.3% [13.4, 23.3] of all patients with blast crisis were alive 2 years after start of study.

Efficacy results were similar in men and women and in patients younger and older than age 65. Responses were seen in black patients, but there were too few black patients to allow a quantitative comparison.

A total of 48 Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) patients with relapsed/refractory disease were studied, 43 of whom received the recommended Gleevec dose of 600 mg/day. In addition 2 patients with relapsed/refractory Ph+ ALL received Gleevec 600 mg/day in a Phase 1 study.

Confirmed and unconfirmed hematologic and cytogenetic response rates for the 43 relapsed/refractory Ph+ ALL Phase 2 study patients and for the 2 Phase 1 patients are shown in Table 21. The median duration of hematologic response was 3.4 months and the median duration of MCyR was 2.3 months.

Pediatric and young adult patients with very high risk ALL, defined as those with an expected 5-year event-free survival (EFS) less than 45%, were enrolled after induction therapy on a multicenter, non-randomized cooperative group pilot protocol.

There were 50 patients with Ph+ ALL assigned to cohort 5 all of whom received Gleevec plus chemotherapy; 30 were treated exclusively with chemotherapy and Gleevec and 20 received chemotherapy plus Gleevec and then underwent hematopoietic stem cell transplant, followed by further Gleevec treatment. Patients in cohort 5 treated with chemotherapy received continuous daily exposure to Gleevec beginning in the first course of post induction chemotherapy continuing through maintenance cycles 1 through 4 chemotherapy. During maintenance cycles 5 through 12, Gleevec was administered 28 days out of the 56 day cycle. Patients who underwent hematopoietic stem cell transplant received 42 days of Gleevec prior to HSCT, and 28 weeks (196 days) of Gleevec after the immediate post transplant period. The estimated 4-year EFS of patients in cohort 5 was 70% (95% CI: 54, 81). The median follow-up time for EFS at data cutoff in cohort 5 was 40.5 months.

An open-label, multicenter, Phase 2 clinical trial was conducted testing Gleevec in diverse populations of patients suffering from life-threatening diseases associated with Abl, Kit or PDGFR protein tyrosine kinases. This study included 7 patients with MDS/MPD. These patients were treated with Gleevec 400 mg daily. The ages of the enrolled patients ranged from 20 to 86 years. A further 24 patients with MDS/MPD aged 2 to 79 years were reported in 12 published case reports and a clinical study. These patients also received Gleevec at a dose of 400 mg daily with the exception of three patients who received lower doses. Of the total population of 31 patients treated for MDS/MPD, 14 (45%) achieved a complete hematological response and 12 (39%) a major cytogenetic response (including 10 with a CCyR). Sixteen patients had a translocation, involving chromosome 5q33 or 4q12, resulting in a PDGFR gene re-arrangement. All of these patients responded hematologically (13 completely). Cytogenetic response was evaluated in 12 out of 14 patients, all of whom responded (10 patients completely). Only 1 (7%) out of the 14 patients without a translocation associated with PDGFR gene re-arrangement achieved a complete hematological response and none achieved a major cytogenetic response. A further patient with a PDGFR gene re-arrangement in molecular relapse after bone marrow transplant responded molecularly. Median duration of therapy was 12.9 months (0.8 to 26.7) in the 7 patients treated within the Phase 2 study and ranged between 1 week and more than 18 months in responding patients in the published literature. Results are provided in Table 22. Response durations of Phase 2 study patients ranged from 141+ days to 457+ days.

One open-label, multicenter, Phase 2 study was conducted testing Gleevec in diverse populations of patients with life-threatening diseases associated with Abl, Kit or PDGFR protein tyrosine kinases. This study included 5 patients with ASM treated with 100 mg to 400 mg of Gleevec daily. These 5 patients ranged from 49 to 74 years of age. In addition to these 5 patients, 10 published case reports and case series describe the use of Gleevec in 23 additional patients with ASM aged 26 to 85 years who also received 100 mg to 400 mg of Gleevec daily.

Cytogenetic abnormalities were evaluated in 20 of the 28 ASM patients treated with Gleevec from the published reports and in the Phase 2 study. Seven of these 20 patients had the FIP1L1-PDGFRα fusion kinase (or CHIC2 deletion). Patients with this cytogenetic abnormality were predominantly males and had eosinophilia associated with their systemic mast cell disease. Two patients had a Kit mutation in the juxtamembrane region (one Phe522Cys and one K509I) and four patients had a D816V c-Kit mutation (not considered sensitive to Gleevec), one with concomitant CML.

Of the 28 patients treated for ASM, 8 (29%) achieved a complete hematologic response and 9 (32%) a partial hematologic response (PHR) (61% overall response rate). Median duration of Gleevec therapy for the 5 ASM patients in the Phase 2 study was 13 months (range, 1.4 to 22.3 months) and between 1 month and more than 30 months in the responding patients described in the published medical literature. A summary of the response rates to Gleevec in ASM is provided in Table 23. Response durations of literature patients ranged from 1+ to 30+ months.

Gleevec has not been shown to be effective in patients with less aggressive forms of systemic mastocytosis (SM). Gleevec is therefore not recommended for use in patients with cutaneous mastocytosis, indolent systemic mastocytosis (smoldering SM or isolated bone marrow mastocytosis), SM with an associated clonal hematological non-mast cell lineage disease, mast cell leukemia, mast cell sarcoma or extracutaneous mastocytoma. Patients that harbor the D816V mutation of c-Kit are not sensitive to Gleevec and should not receive Gleevec.

One open-label, multicenter, Phase 2 study was conducted testing Gleevec in diverse populations of patients with life-threatening diseases associated with Abl, Kit or PDGFR protein tyrosine kinases. This study included 14 patients with Hypereosinophilic Syndrome/Chronic Eosinophilic Leukemia (HES/CEL). HES patients were treated with 100 mg to 1,000 mg of Gleevec daily. The ages of these patients ranged from 16 to 64 years. A further 162 patients with HES/CEL aged 11 to 78 years were reported in 35 published case reports and case series. These patients received Gleevec at doses of 75 mg to 800 mg daily. Hematologic response rates are summarized in Table 24. Response durations for literature patients ranged from 6+ weeks to 44 months.

Dermatofibrosarcoma Protuberans (DFSP) is a cutaneous soft tissue sarcoma. It is characterized by a translocation of chromosomes 17 and 22 that results in the fusion of the collagen type 1 alpha 1 gene and the PDGF B gene.

Twelve of these 18 patients either achieved a complete response (7 patients) or were made disease free by surgery after a partial response (5 patients, including one child) for a total complete response rate of 67%. A further 3 patients achieved a partial response, for an overall response rate of 83%. Of the 8 patients with metastatic disease, five responded (62%), three of them completely (37%). For the 10 study patients with the PDGF B gene rearrangement, there were 4 complete and 6 partial responses. The median duration of response in the Phase 2 study was 6.2 months, with a maximum duration of 24.3 months, while in the published literature it ranged between 4 weeks and more than 20 months.

Two open-label, randomized, multinational Phase 3 studies were conducted in patients with unresectable or metastatic malignant GIST. The two study designs were similar allowing a predefined combined analysis of safety and efficacy. A total of 1640 patients were enrolled into the two studies and randomized 1:1 to receive either 400 mg or 800 mg orally daily continuously until disease progression or unacceptable toxicity. Patients in the 400 mg daily treatment group who experienced disease progression were permitted to crossover to receive treatment with 800 mg daily. The studies were designed to compare response rates, progression-free survival and overall survival between the dose groups. Median age at patient entry was 60 years. Males comprised 58% of the patients enrolled. All patients had a pathologic diagnosis of CD117 positive unresectable and/or metastatic malignant GIST.

The primary objective of the two studies was to evaluate either progression-free survival (PFS) with a secondary objective of overall survival (OS) in one study or overall survival with a secondary objective of PFS in the other study. A planned analysis of both OS and PFS from the combined datasets from these two studies was conducted. Results from this combined analysis are shown in Table 26.

Median follow up for the combined studies was 37.5 months. There were no observed differences in overall survival between the treatment groups (p = 0.98). Patients who crossed over following disease progression from the 400 mg/day treatment group to the 800 mg/day treatment group (n = 347) had a 3.4 month median and a 7.7 month mean exposure to Gleevec following crossover.

One open-label, multinational Phase 2 study was conducted in patients with Kit (CD117) positive unresectable or metastatic malignant GIST. In this study, 147 patients were enrolled and randomized to receive either 400 mg or 600 mg orally every day for up to 36 months. The primary outcome of the study was objective response rate. Tumors were required to be measurable at entry in at least one site of disease, and response characterization was based on Southwestern Oncology Group (SWOG) criteria. There were no differences in response rates between the 2 dose groups. The response rate was 68.5% for the 400 mg group and 67.6% for the 600 mg group. The median time to response was 12 weeks (range was 3 to 98 weeks) and the estimated median duration of response is 118 weeks (95% CI: 86, not reached).

In the adjuvant setting, Gleevec was investigated in a multicenter, double-blind, placebo-controlled, randomized trial involving 713 patients (Study 1). Patients were randomized one to one to Gleevec at 400 mg/day or matching placebo for 12 months. The ages of these patients ranged from 18 to 91 years. Patients were included who had a histologic diagnosis of primary GIST, expressing KIT protein by immunochemistry and a tumor size greater than or equal to 3 cm in maximum dimension with complete gross resection of primary GIST within 14 to 70 days prior to registration.

Recurrence-free survival (RFS) was defined as the time from date of randomization to the date of recurrence or death from any cause. In a planned interim analysis, the median follow up was 15 months in patients without a RFS event; there were 30 RFS events in the 12-month Gleevec arm compared to 70 RFS events in the placebo arm with a hazard ratio of 0.398 (95% CI: 0.259, 0.610), p less than 0.0001. After the interim analysis of RFS, 79 of the 354 patients initially randomized to the placebo arm were eligible to cross over to the 12-month Gleevec arm. Seventy-two of these 79 patients subsequently crossed over to Gleevec therapy. In an updated analysis, the median follow-up for patients without a RFS event was 50 months. There were 74 (21%) RFS events in the 12-month Gleevec arm compared to 98 (28%) events in the placebo arm with a hazard ratio of 0.718 (95% CI: 0.531-0.971) (Figure 3). The median follow-up for OS in patients still living was 61 months. There were 26 (7%) and 33 (9%) deaths in the 12-month Gleevec and placebo arms, respectively with a hazard ratio of 0.816 (95% CI: 0.488-1.365).

A second randomized, multicenter, open-label, Phase 3 trial in the adjuvant setting (Study 2) compared 12 months of Gleevec treatment to 36 months of Gleevec treatment at 400 mg/day in adult patients with KIT (CD117) positive GIST after surgical resection with one of the following: tumor diameter greater than 5 cm and mitotic count greater than 5/50 high power fields (HPF), or tumor diameter greater than 10 cm and any mitotic count, or tumor of any size with mitotic count greater than 10/50 HPF, or tumors ruptured into the peritoneal cavity. There were a total of 397 patients randomized in the trial with 199 patients on the 12-month treatment arm and 198 patients on the 36-month treatment arm. The median age was 61 years (range, 22 to 84 years).

RFS was defined as the time from date of randomization to the date of recurrence or death from any cause. The median follow-up for patients without a RFS event was 42 months. There were 84 (42%) RFS events in the 12-month treatment arm and 50 (25%) RFS events in the 36-month treatment arm. Thirty-six months of Gleevec treatment significantly prolonged RFS compared to 12 months of Gleevec treatment with a hazard ratio of 0.46 (95% CI: 0.32, 0.65), p less than 0.0001 (Figure 4).

The median follow-up for overall survival (OS) in patients still living was 48 months. There were 25 (13%) deaths in the 12-month treatment arm and 12 (6%) deaths in the 36-month treatment arm. Thirty-six months of Gleevec treatment significantly prolonged OS compared to 12 months of Gleevec treatment with a hazard ratio of 0.45 (95% CI: 0.22, 0.89), p = 0.0187 (Figure 5).