- 14 Downloads
Imatinib mesylate (Gleevec®, Glivec®) is an orally administered competitive inhibitor of the BCR-ABL tyrosine kinase created by the Philadelphia chromosome (Ph+) in chronic myeloid leukemia (CML).
In patients with newly diagnosed and previously untreated (apart from hydroxyurea and/or anagrelide) CML in the chronic phase, imatinib mesylate 400 mg/day, compared with interferon-α (IFNα) plus cytarabine, resulted in higher hematologic response (HR) and cytogenetic response (CR) rates and fewer patients progressing to the accelerated phase or blast crisis in a large comparative trial. Preliminary results indicate that, compared with IFNα plus cytarabine, imatinib mesylate treatment was associated with similar total costs, but resulted in a higher health-related quality of life (HR-QOL).
Imatinib mesylate was also effective in patients with chronic-phase CML refractory to or intolerant of treatment with IFNα (as 400 mg/day) and in those with blast-crisis or accelerated-phase CML (600 mg/day). In the latter groups, HR and CR rates were lower than those in patients with chronic phase CML.
Imatinib mesylate-associated adverse events were common in clinical trials, but were mostly mild to moderate in severity. The most frequently reported adverse events were superficial edema, nausea, muscle cramps, diarrhea, vomiting, and skin rash. Myelosuppression (thrombocytopenia and neutropenia) was also reported, especially in patients with advanced disease. In patients with previously untreated chronic-phase CML, serious adverse events (both hematologic and nonhematologic) were less common with imatinib mesylate than with IFNα plus cytarabine treatment.
Conclusion: Imatinib mesylate is a valuable therapy for patients with newly diagnosed Ph+ chronic-phase CML. It is better tolerated and produces higher HR, CR and freedom from progressive disease rates than conventional therapy with IFNα plus cytarabine. Preliminary results indicate that, compared with IFNα plus cytarabine, imatinib mesylate treatment was associated with similar total costs, but resulted in a higher HR-QOL. Imatinib mesylate is also effective in patients with accelerated-phase and blast-crisis CML, and patients with chronic-phase CML who have failed IFNα therapy. Given its efficacy and generally manageable adverse event profile, imatinib mesylate offers an important early treatment option for patients with CML.
Imatinib mesylate blocks the tyrosine kinase activity associated with the Abelson (ABL) protein, selectively inhibits the proliferation and survival of leukemia cells expressing break cluster region (BCR)-ABL and suppresses the formation of BCR-ABL-induced tumors in murine models. In vitro studies suggest a synergistic or additive effect when imatinib mesylate is coadministered with other chemotherapy agents, including interferon-α (IFNα), cytarabine, doxorubicin, daunorubicin, and etoposide. Mechanisms of imatinib mesylate resistance include amplification of the BCR- ABL gene, overexpression of BCR-ABL, the development of point mutations in the catalytic domain of BCR-ABL and the development of novel chromosomal aberrations.
Imatinib mesylate is absorbed rapidly and extensively after oral administration; peak plasma concentrations (Cmax) are reached in 2–4 hours and bioavailability is 98%. Mean steady-state Cmax was 2.3 mg/L following administration of imatinib mesylate 400mg once daily to patients with chronic myeloid leukemia (CML). Accumulation is 2- to 3-fold at steady state with once-daily administration. Imatinib mesylate is 95% protein bound, predominantly to albumin and α1-acid glycoprotein. Metabolism is mainly through the action of the cytochrome P450 (CYP) isoform CYP3A4. The main metabolite (N-demethylated piperazine derivative) has similar in vitro potency to the parent compound. In patients with CML, the elimination half-life of imatinib mesylate is 13–16 hours. Excretion is primarily via the feces.
CYP3A4 inducers (e.g. phenytoin) increase the metabolism of imatinib mesylate and CYP3A4 inhibitors (e.g. ketoconazole and erythromycin) decrease it. Imatinib mesylate may inhibit the metabolism of other substrates of CYP3A4 (e.g. simvastatin) as well as substrates of CYP2C9, CYP2D6 and CYP3A4/5.
Oral imatinib mesylate 400 mg/day was more effective than subcutaneous IFNα plus cytarabine in patients with newly diagnosed and previously untreated (apart from hydroxyurea and/or anagrelide) CML in early chronic-phase in a randomized, multicenter, open-label, phase III trial (median treatment duration of 19 months). The estimated 18-month rate of freedom from progression to accelerated-phase or blast-crisis CML was 97% in imatinib mesylate recipients and 92% in IFNα plus cytarabine recipients (p < 0.001). Major cytogenetic response (MCR) rates were 85% and 22%, complete cytogenetic response (CCR) rates were 74% and 9% and complete hematologic response (CHR) rates were 95% and 56%, respectively (all p < 0.001). Molecular response (assessed according to quantitative polymerase chain reaction [PCR]-negativity) occurred in some of the imatinib mesylate recipients who achieved CCR; a >3 log reduction in BCR-ABL/BCR% values was estimated to be achieved in 39% of imatinib mesylate recipients versus 2% of IFNα plus cytarabine recipients (p < 0.001) at 12 months. Preliminary results indicate that, compared with IFNα plus cytarabine, imatinib mesylate treatment was associated with similar total costs, but resulted in a higher health-related quality of life.
Imatinib mesylate 400 mg/day was effective in patients with chronic-phase CML who had failed treatment with IFNα. In the largest phase II trial (median treatment duration of 18 months), MCR was achieved in 60% of patients, CCR in 41% and CHR in 95%. The 18-month estimated progression-free and overall survival rate was 89% and 95%.
In patients with accelerated-phase CML (median treatment duration of 11 months), imatinib mesylate 600 mg/day (n = 119) was effective as shown by the proportion of patients with responses (MCR 28%, CCR 19%, hematologic response [HR] 71%); the estimated 12-month progression-free and overall survival rates were 67% and 78%. Moreover, in patients with myeloid blast-crisis CML (n = 229; median treatment duration 4 months), imatinib was also effective, although the response rate (MCR 16%, CCR 7%, HR 31%) and the estimated median survival time (6.9 months) and the estimated 12-month overall survival rate (32%) were lower than those in the trial in patients with accelerated-phase CML.
The most frequently reported imatinib mesylate-associated nonhematologic adverse events (superficial edema, nausea, muscle cramps, diarrhea, vomiting, and skin rash) were mostly mild to moderate in severity. Grade 3 or 4 hepatotoxicity occurred in <5% of imatinib mesylate recipients.
Myelosuppression (thrombocytopenia and neutropenia) was frequently reported in clinical trials, and was more common in patients with advanced disease. In recipients of imatinib mesylate, the incidence of grade 3 or 4 neutropenia or thrombocytopenia was approximately 2- to 3-fold higher in myeloid blast-crisis or accelerated-phase CML than in chronic-phase CML, and was approximately 2-fold less than that in recipients of IFNα plus cytarabine.
Dosage and Administration
Imatinib mesylate is indicated for the treatment of newly diagnosed patients with Philadelphia chromosome-positive CML. Imatinib mesylate is also indicated for the treatment of patients with CML in blast crisis, accelerated phase, or chronic phase after failure of IFNα.
The recommended dosage of imatinib mesylate is 400 mg/day for patients with chronic-phase CML and 600 mg/day for patients with accelerated-phase or blast-crisis CML. Dosage increases from 400 to 600 mg/day in patients with chronic-phase CML or from 600 to 800 mg/day in patients with accelerated-phase or blast-crisis CML may be considered in disease progression, if a satisfactory HR is not achieved after ≥3 months of treatment, if CR is not achieved after 6–12 months of treatment or if loss of previously achieved HR or CR occurs (in the absence of severe non-leukemia-related neutropenia or thrombocytopenia). The dosage of imatinib mesylate should be adjusted or treatment interrupted if severe neutropenia or thrombocytopenia occurs. If a severe nonhematologic adverse event occurs, imatinib mesylate should be withheld until the event resolves.
- 16.Beran M, Cao X, Estrov Z, et al. Selective inhibition of cell proliferation and BCR-ABL phosphorylation in acute lymphoblastic leukemia cells expressing 190-KD BCR-ABL protein by a tyrosine kinase inhibitor (CGP-57148) [abstract]. Blood 1997 Nov 15; 90 (Suppl. 1, Pt 1): 248aGoogle Scholar
- 25.Branford S, Rudzki Z, Walsh S, et al. High frequency of point mutations clustered within the adenosine triphosphate-binding region of BCR/ABL in patients with chronic myeloid leukemia or Ph-positive acute lymphoblastic leukemia who develop imatinib (STI571) resistance. Blood 2002 May 1; 99(9): 3472–5PubMedCrossRefGoogle Scholar
- 30.Marley SB, Deininger MWN, Davidson RJ, et al. The tyrosine kinase inhibitor STI571, like interferon-alpha, preferentially reduces the capacity for amplification of granulocyte-macrophage progenitors from patients with chronic myeloid leukemia. Exp Hematol 2000 May; 28: 551–7PubMedCrossRefGoogle Scholar
- 32.Druker BJ, Sawyers CL, Capdeville R, et al. Chronic myelogenous leukemia. Hematology (Am Soc Hematol Educ Program) 2001; 87–112Google Scholar
- 37.Novartis Pharmaceuticals Corporation. Gleevec™ imatinib mesylate: full prescribing information. East Hanover (NJ): Novartis, 2002 FebGoogle Scholar
- 39.Reckmann AH, Fischer T, Peng B, et al. Effect of food on STI571 Glivec pharmacokinetics and bioavailability [abstract 1223]. Proceedings of the 37th Annual Meeting of the American Society of Clinical Oncology; 2001 May 12–15; San Francisco, CA; 20 (Pt 1): 307aGoogle Scholar
- 41.O’Brien SG, Peng B, Dutreix C, et al. A pharmacokinetic interaction of Glivec® and simvastatin, a cytochrome 3A4 substrate, in patients with chronic myeloid leukemia [abstract no. 593]. Blood 2001; 98 (11 Pt 1): 141aGoogle Scholar
- 46.Bassi S, Trabacchi E, Bonifazi F, et al. Imatinib (Glivec®) in patients with Ph+ chronic myeloid leukemia in chronic phase after interferon failure: results of a phase II trial of the Italian Cooperative Study Group on CML [abstract no. 3096]. Blood 2002; 100 (Pt 1): 783aGoogle Scholar
- 48.Trabacchi E, Bonifazi F, Bassi S, et al. Imatinib (Glivec®) in patients with Ph+ chronic myeloid leukemia in accelerated/blastic phase (AP/B): results of a phase II trial of the Italian Cooperative Study Group on CML (ICSG on CML) [abstract no. 2295]. Blood 2002; 100 (Pt 1): 584aGoogle Scholar
- 52.Hughes T, Kaeda J, Branford S, et al. Molecular responses to imatinib (STI571) or interferon + Ara-C as initial therapy for CML; results in the IRIS Study [abstract no. 345]. Blood 2002 Nov 16; 100 (Pt 1): 93a–4aGoogle Scholar
- 54.Hahn EA, Sorensen MV, Hudgens SA, et al. Quality of life of patients with chronic phase chronic myeloid leukemia in the IRIS Study of interferon-alpha plus Ara-C vs imatinib (STI571, Glivec®, Gleevec™) [abstractno. 346]. Blood 2002 Nov 16; 100 (Pt 1): 94aGoogle Scholar
- 55.Reed SD, Radeva JI, Glendenning A, et al. Within-trial resource utilization and costs of patients randomized to treatment with imatinib (STI571) versus interferon-alpha (IFN-α) combined with cytarabine (Ara-C) in newly diagnosed patients with chronic myeloid leukemia in chronic phase [abstract no. 698]. Blood 2002 Nov 16; 100 (Pt 1): 187aGoogle Scholar
- 56.Hensley ML, Van Hoomissen IC, Krahnke T, et al. Imatinib in chronic myeloid leukemia (CML): outcomes in >7000 patients treated on expanded access program (EAP) [abstract no. 2328]. 39th Annual Meeting of the American Society of Clinical Oncology; 2003 May 31–Jun 3; Chicago, 579Google Scholar
- 57.Faderl S, Kantarjian HM, Talpaz M. Chronic myelogenous leukemia: update on biology and treatment. Oncology (Huntingt) 1999 Feb; 13(2): 169–80; discussion 181, 184Google Scholar
- 58.National Cancer Institute. Common Toxicity Criteria, Version 2.0 1999 Jun 1 [online]. Available from URL: http://http://ctep.cancer.gov [Accessed 2003 Mar 30]
- 59.Novartis International AG. Data prove Glivec® is superior treatment for patients newly diagnosed with chronic myeloid leukemia [online]. Available from URL: http://http://www.novartis.com [Accessed 2002 Apr 5]
- 60.FDA. FDA approves gleevec for pediatric leukemia treatment [online]. Available from URL: http://http://www.fda.gov [Accessed 2003 Sep 10]
- 64.Silver RT, Woolf SH, Hehlmann R, et al. An evidence-based analysis of the effect of busulfan, hydroxyurea, interferon, and allogeneic bone marrow transplantation in treating the chronic phase of chronic myeloid leukemia: developed for the American Society of Hematology. Blood 1999 Sep 1; 94(5): 1517–36PubMedGoogle Scholar
- 66.Allan NC, Richards SM, Shepherd PCA. UK Medical Research Council randomised, multicentre trial of interferon-α n1 for chronic myeloid leukaemia: improved survival irrespective of cytogenetic response. UK Medical Research Council’s Working Parties for Therapeutic Trials in Adult Leukaemia. Lancet 1995 Jun 3; 345(8962): 1392–7PubMedCrossRefGoogle Scholar
- 68.Benelux CML Study Group. Randomized study on hydroxyurea alone versus hydroxyurea combined with low-dose interferon-α 2b for chronic myeloid leukemia. Blood 1998 Apr 15; 91(8): 2713–21Google Scholar
- 71.Mauro MJ, Kurilik G, Balleisen S, et al. Myeloid growth factors for neutropenia during imatinib mesylate (STI571) therapy for CML: preliminary evidence of safety and efficacy [abstract no. 584]. Blood 2001; 98: 139aGoogle Scholar
- 75.Hess G, Siegert W, Kolb HJ, et al. A phase II open-label study to investigate the safety profile and potential of imatinib mesylate (Gleevec, STI-571) to restore molecular remissions and chimerism in patients with BCR-ABL-positive CML with minimal residual disease (MRD) post allogeneic BMT/SCT [abstract no. 665]. Blood 2002 Nov 16; 100 (Pt 1): 177a–8aCrossRefGoogle Scholar
- 77.Ullmann AJ, Beck J, Kolbe K, et al. Clinical and laboratory evaluation of patients treated with STI-571 (Gleevec™ after allogeneic and syngeneic stem cell transplantation with relapsed Philadelphia chromosome-positive leukemia [abstract no. 1685]. Blood 2001 Nov 16; 98 (Pt 1): 401aGoogle Scholar
- 78.Soiffer RJ, Galinsky I, DeAngelo D, et al. Imatinib mesylate (Gleevec) for disease relapse following allogeneic bone marrow transplantation [abstract no. 1682]. Blood 2001 Nov 16; 98 (Pt 1): 400aGoogle Scholar
- 79.Pfeifer H, Wassmann B, Scheuring U, et al. ST1571 (Glivec) in the treatment of patients with chronic myeloid leukemia (CML) relapsing after allogeneic stem cell transplantation [abstract no. 0240]. Bone Marrow Transplant 2002 Mar; 29Suppl. 2: S34Google Scholar
- 81.Liesveld JL, Nichols D, Ifthikharuddin JJ, et al. Use of imatinib mesylate in CML patients autografted in the pre-imatinib mesylate era: a single center experience [abstract no. 5471]. Blood 2002 Nov 16; 100 (Pt 2): 473bGoogle Scholar
- 82.Deininger MWN, Schleuning M, Sayer H-G, et al. Allografting after imatinib therapy. No evidence for increased transplant-related mortality and favorable result in patients transplanted in remission. A retrospective study by the EBMT. [abstract no. 3097] Blood 2003; 100 (Pt 1): 783aGoogle Scholar
- 84.O’Dwyer ME, Mauro MJ, Kuyl JM, et al. Preliminary evaluation of the combination of imatinib mesylate (Gleevec) in combination with low dose interferon-alpha for the treatment of chronic phase CML [abstract no. 3513]. Blood 2001 Nov 16; 98: 846aGoogle Scholar
- 85.O’Brien S, Vallance SE, Craddock C, et al. PEGIntron and STI571 combination evaluation study (PISCES) in chronic phase chronic myeloid leukaemia [abstract no. 3512]. Blood 2001 Nov 16; 98: 846aGoogle Scholar
- 86.Druker BJ, Kantarjian HM, Talpaz M, et al. A phase I study of Gleevec (imatinib mesylate) administered concomitantly with cytosine arabinoside (Ara-C) in patients with Philadelphia positive chronic myeloid leukemia (CML) [abstract no. 3511]. Blood 2001 Nov 16; 98: 845a–6aGoogle Scholar
- 87.Cornelissen JJ, Verhoef GEG, Straetmans N, et al. A dose-escalating phase I/II study of imatinib (Glivec) and cytarabin in first chronic phase chronic myeloid leukemia. Blood 2002 Nov 16; 100 (Pt 1): 95aGoogle Scholar
- 88.Hocchaus A, Fischer T, Brummendorf TH. Imatinib (Glivec®) and pegylated interferon (α2a (Pegasys®) phase I/II combination study in chronic phase chronic myelogenous leukemia (CML) [abstract no. 616]. Blood 2002; 100 (Pt 1): 164a–5aGoogle Scholar
- 89.Martine G, Philippe R, Michel T, et al. Imatinib (Gleevec®) and cytarabine (ARA-C) is an effective regimen in Philadephia (Ph)-positive chronic myelogenous leukaemia (CML) chronic phase (CP) patients (pts) [abstract no. 351]. Blood 2002; 100 (Pt 1): 95aGoogle Scholar
- 90.Mauro MJ, O’Dwyer ME, Stone RM, et al. Preliminary evaluation of the combination of imatinib mesylate (Gleevec) with low dose Ara-C as initial therapy for newly diagnosed chronic phase CML [abstract no. 617]. Blood 2002; 100 (Pt 1): 165aGoogle Scholar