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Gleevec (imatinib mesylate) - 9 indications
Scroll down for information on each indication:
- inoperable and/or metastatic malignant gastrointestinal stromal tumors; approved February 2002
- pediatric patients with Ph+ chronic phase CML whose disease has recurred after stem cell transplant or who are resistant to interferon alpha therapy; approved May 2003
- newly diagnosed Philadelphia positive CML in pediatric patients; approved September 2006
- adult dermafibrosarcoma protuberans (DFSP), adult myelodysplastic syndrome/myeloproliferative diseases (MDS/MPD), adult Ph+ acute lymphoblastic leukemia (ALL) monotherapy, adult aggressive systemic mastocytosis (ASM) and adult hypereosinophilic syndrome/chronic eosinophilic leukemia (HES/CEL); approved October 2006
- pediatric patients with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) in combination with chemotherapy; approved January 2013
General Information
Gleevec (imatinib mesylate) is a kinase inhibitor.
Gleevec is specifically indicated for the following therapeutic conditions:
- Newly diagnosed adult and pediatric patients with Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase
- Patients with chronic myeloid leukemia (CML) in myeloid blast crisis, accelerated phase, or chronic phase, for whom interferon-alpha therapy has failed
- 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 and adjuvant treatment of adult patients following complete gross resection of Kit (CD117) positive GIST
Gleevec is supplied as a tablet for oral administration. Scroll down for recommended dosing/administration for each therapeutic condition.
Mechanism of Action
Gleevec (imatinib mesylate) is a protein-tyrosine kinase inhibitor that inhibits the BCR-ABL tyrosine kinase, the constitutive abnormal tyrosine kinase created by the Philadelphia chromosome abnormality in CML. Imatinib inhibits proliferation and induces apoptosis in BCR-ABL positive cell lines as well as fresh leukemic cells from Philadelphia chromosome positive chronic myeloid leukemia. 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.
Side Effects
Adverse effects associated with the use of Gleevec may include, but are not limited to, the following:
- edema
- nausea
- vomiting
- muscle cramps
- musculoskeletal pain
- diarrhea
- rash
- fatigue
- abdominal pain
Indication 1 - inoperable and/or metastatic malignant gastrointestinal stromal tumors
approved February 2002
Dosing/Administration
Adult Patients With Metastatic and/or Unresectable GIST:
- 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.
Adult Patients With Adjuvant GIST:
- The recommended dose of Gleevec is 400 mg/day for the adjuvant treatment of adult patients following complete gross resection of GIST. In clinical trials, one year of Gleevec and three years of Gleevec were studied. In the patient population defined in Study 2, three years of Gleevec is recommended. The optimal treatment duration with Gleevec is not known.
Clinical Trial Results
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. 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. Median follow up for the combined studies was 37.5 months. There were no observed differences in overall survival between the treatment groups. 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.
Adjuvant Treatment of GIST
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. 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. 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. 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.
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. 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. 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. 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.
Indication 2 - pediatric patients with Philadelphia positive (Ph+) chronic phase CML whose disease has recurred after stem cell transplant or who are resistant to interferon alpha therapy
approved May 2003
Indication 3 - newly diagnosed pediatric patients with Ph+ CML
approved September 2006
Dosing/Administration
The recommended dose is 340 mg/m2 /day (not to exceed 600 mg). Gleevec treatment can be given as a once daily dose or the daily dose may be split into two–one portion dosed in the morning and one portion in the evening.
Clinical Trial Results
One open-label, single-arm study enrolled 14 pediatric patients with Ph+ chronic phase CML recurrent after stem cell transplant or resistant to interferon-alpha therapy. These patients had not previously received Gleevec and ranged in age from 3 to 20 years old. Patients were treated at doses of 260 mg/m2 /day (n = 3), 340 mg/m2 /day (n = 4), 440 mg/m2 /day (n = 5) and 570 mg/m2 /day (n = 2). In the 13 patients for whom cytogenetic data are available, 4 achieved a major cytogenetic response, 7 achieved a complete cytogenetic response rate (CCyR), and 2 had a minimal cytogenetic response. In a second study, 2 of 3 patients with Ph+ chronic phase CML resistant to interferon-alpha therapy achieved a CCyR at doses of 242 and 257 mg/m2 /day.
A total of 51 pediatric patients with newly diagnosed and untreated CML in chronic phase were enrolled in an open-label, multicenter, single-arm Phase 2 trial. Patients were treated with Gleevec 340 mg/m2 /day, with no interruptions in the absence of dose limiting toxicity. Complete hematologic response (CHR) was observed in 78% of patients after 8 weeks of therapy. The complete cytogenetic response rate (CCyR) was 65%, comparable to the results observed in adults. Additionally, partial cytogenetic response (PCyR) was observed in 16%. The majority of patients who achieved a CCyR developed the CCyR between Months 3 and 10 with a median time to response based on the Kaplan-Meier estimate of 6.74 months. Patients were allowed to be removed from protocol therapy to undergo alternative therapy, including hematopoietic stem cell transplantation. Thirty-one children received stem cell transplantation. Of the 31 children, 5 were transplanted after disease progression on study and 1 withdrew from study during first week treatment and received transplant approximately 4 months after withdrawal. Twenty-five children withdrew from protocol therapy to undergo stem cell transplant after receiving a median of 9 twenty-eight day courses (range, 4 to 24). Of the 25 patients 13 (52%) had CCyR and 5 (20%) had PCyR at the end of protocol therapy.
Indications 4 - adult dermafibrosarcoma protuberans (DFSP)
approved October 2006
Dosing/Administration
The recommended dose of Gleevec is 800 mg/day.
Clinical Trial Results
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. An open-label, multicenter, Phase 2 study was conducted testing Gleevec in a diverse population of patients with life threatening diseases associated with Abl, Kit or PDGFR protein tyrosine kinases. This study included 12 patients with DFSP who were treated with Gleevec 800 mg daily (age range, 23 to 75 years). DFSP was metastatic, locally recurrent following initial surgical resection and not considered amenable to further surgery at the time of study entry. A further 6 DFSP patients treated with Gleevec are reported in 5 published case reports, their ages ranging from 18 months to 49 years. The total population treated for DFSP therefore comprises 18 patients, 8 of them with metastatic disease. 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.
Indication 5 - adult myelodysplastic syndrome/myeloproliferative diseases (MDS/MPD)
approved October 2006
Dosing/Administration
Determine PDGFRb gene rearrangements status prior to initiating treatment. The recommended dose of Gleevec is 400 mg/day
Clinical Trial Results
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.
Indication 6 - adult Ph+ acute lymphoblastic leukemia monotherapy
approved October 2006
Dosing/Administration
The recommended dose of Gleevec is 600 mg/day
Clinical Trial Results
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. Complete hematologic response was reached by 19%, Major cytogenetic response (MCyR) by 35%, complete cytogenetic response (CCyR) by 21%.
Indication 7 - adult aggressive systemic mastocytosis (ASM)
approved October 2006
Dosing/Administration
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 cKit 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.
Clinical Trial Results
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.
Indication 8 - adult hypereosinophilic syndrome/chronic eosinophilic leukemia (HES/CEL)
approved October 2006
Dosing/Administration
The recommended dose of Gleevec is 400 mg/day. 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.
Clinical Trial Results
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. In the total patient population (n=176), 107 (61%) had a Complete Hematological Response and 23 (13%) had a Partial Hematological Response.
Indication 9 - pediatric patients with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL)
approved January 2013
Dosing/Administration
The recommended dose of Gleevec to be given in combination with chemotherapy to children with newly diagnosed Ph+ ALL is 340 mg/m2 /day (not to exceed 600 mg). Gleevec treatment can be given as a once daily dose.
Clinical Trial Results
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 safety and effectiveness of Gleevec (340 mg/m2 /day) in combination with intensive chemotherapy was evaluated in a subgroup of patients with Ph+ ALL. The protocol included intensive chemotherapy and hematopoietic stem cell transplant after 2 courses of chemotherapy for patients with an appropriate HLA-matched family donor. There were 92 eligible patients with Ph+ ALL enrolled. 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.