Abstract
Imatinib mesylate (Gleevec, Glivec [Novartis, Basel, Switzerland], formerly referred to as STI571 or CGP57148B) represents the paradigm of a new class of anticancer agents, so-called small molecules. They have a high selectivity against a specific molecular target known to be the cause for the establishment and maintenance of the malignant phenotype. Imatinib is a rationally designed oral signal transduction inhibitor that specifically targets several protein tyrosine kinases, Abl, Arg (Abl-related gene), the stem cell factor receptor (c-KIT), platelet-derived growth factor receptor (PDGF-R), and their oncogenic forms, most notably BCR-ABL. Imatinib has been shown to have remarkable clinical activity in patients with chronic myeloid leukemia (CML) and malignant gastrointestinal stroma tumors (GIST) leading to its approval for treatment of these diseases. Treatment with imatinib is generally well tolerated with a low incidence of severe side effects. The most common adverse events include mild to moderate edema, muscle cramps, diarrhea, nausea, skin rashes, and myelosuppression. Several mechanisms of resistance have been identified. Clonal evolution, amplification, or overexpression of BCR-ABL as well as mutations in the catalytic domain, P-loop, and other mutations have been demonstrated to play a role in primary and secondary resistance to imatinib, respectively. Understanding of the underlying mechanisms of resistance has led to the development of new second- and third-generation tyrosine kinase inhibitors (see chapters on dasatinib, nilotinib, bosutinib, and ponatinib).
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Keywords
- Chronic Myeloid Leukemia
- Imatinib Mesylate
- Chronic Myeloid Leukemia Patient
- Blast Crisis
- Chronic Phase Chronic Myeloid Leukemia
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.
1 Introduction
Chronic myeloid leukemia (CML) is a clonal disorder of the hematopoietic stem cell. The clinical presentation often includes granulocytosis, a hypercellular bone marrow and splenomegaly. The natural course of the disease involves three sequential phases—chronic phase (CP), progressing often through an accelerated phase (AP) into the terminal blast crisis (BC). The duration of CP is several years, while AP and BC usually last only for months. In the past, prior to the introduction of TKIs into the treatment of CML, median survival was in the range of 4–5 years (Hehlmann et al. 2007b; Sawyers 1999).
CML is characterized by the presence of the Philadelphia chromosome (Ph), a unique reciprocal translocation between the long arms of chromosomes 9 and 22, t(9:22), which is present in >90 % of patients with CML and approximately 15–30 % of ALL (Nowell and Hungerford 1960; Rowley 1973). On the molecular level, t(9:22) results in the generation of an oncogene, the BCR-ABL fusion gene, encoding the BCR-ABL protein which has constitutive tyrosine kinase activity (Konopka et al. 1984; Fig. 1).
Its causal role in the development of CML has been demonstrated in vitro as well as in several animal models (Daley et al. 1990; Heisterkamp et al. 1990; Lugo et al. 1990; Voncken et al. 1995).
The pathological effects of BCR-ABL include increased proliferation, protection from programmed cell death, altered stem cell adhesion and possibly genetic instability that leads to disease progression (Deininger and Goldman 1998; Deininger et al. 2000).
Before the introduction of imatinib, standard therapy of CML was interferon-α alone or in combination with cytarabine (ara-C) leading to hematologic remissions in the majority of patients, but major cytogenetic responses—i.e., <35 % Ph+ metaphases—were only seen in 6–25 % of patients (Hehlmann et al. 2007b). The only curative treatment of CML is allogeneic stem cell transplantation from an HLA-compatible donor. However, it is only an option for a part of the patients and still associated with considerable morbidity and mortality (Gratwohl et al. 1998; Hehlmann et al. 2007a).
The presence of BCR-ABL in >90 % of CML patients and the identification of its essential role in the pathogenesis of the disease provided the rationale of targeting this fusion protein for treatment of CML.
In the nineties of the twentieth century, first data of compounds with an effect on tyrosine kinases were published (Levitzky and Gazit 1995). Tyrphostins and other similar compounds were shown to inhibit the ABL- as well as the BCR-ABL tyrosine kinase at micromolar concentrations but had only limited specificity (Anafi et al. 1993a, b; Carlo-Stella et al. 1999). This led to the rational design of further TKI with selective activity against the ABL tyrosine kinase, one of which was a 2-phenylaminopyrimidine called CGP57148B, later called STI571 or imatinib mesylate (Buchdunger et al. 1995, 1996; Druker and Lydon 2000; Druker et al. 1996).
After demonstration of specificity in vitro, in cell-based systems as well as in different animal models, this compound was tested in several phase I and phase II studies (Druker et al. 2001a; Kantarjian et al. 2002a, b). Imatinib was shown to have very high rates of hematologic remissions in CP-CML patients previously treated with interferon-α as well as in advanced stages of the disease. Cytogenetic remissions were achieved in a considerable portion of patients. Based on these good results, imatinib was approved for treatment of CML patients in CP after treatment failure with interferon-α and the advanced stages, i.e., AP and BC (Cohen et al. 2002b).
The phase III (IRIS) trial led to establishment of imatinib as standard for first-line therapy of CP-CML (Cohen et al. 2009; Dagher et al. 2002). Currently, several trials investigate the effect of stopping imatinib in patients reaching a very good long-lasting remission based upon the results of the so-called STIM trial where it could be shown that a part of patients stayed in a very good molecular remission after the end of the therapy (Mahon et al. 2010).
Other molecular targets of imatinib are the stem cell factor receptor (c-KIT) and platelet-derived growth factor receptor (PDGF-R) (Buchdunger et al. 1995, 1996, 2000; Heinrich et al. 2002a, b).
c-KIT is expressed in a variety of human cancers, including germ cell tumors, neuroblastoma, melanoma, small cell lung cancer, breast and ovarian cancers, acute myeloid leukemia, mast cell disorders as well as malignant gastrointestinal stroma tumors (GIST). While in most of these diseases, the exact role of c-KIT expression is not defined in mastocytosis and GISTs activating mutations of c-KIT have been identified.
Based upon data of a single open-label phase II trial and two large phase III trials by the EORTC and SWOG, imatinib received approval for treatment of metastatic/unresectable GIST (Cohen et al. 2009; Dagher et al. 2002). In addition, the role of adjuvant treatment with imatinib after successful resection of primary GIST has been clearly demonstrated and led to the adjuvant label (Joensuu et al. 2012).
Furthermore, imatinib has been successfully used in diseases with aberrant PDGF receptors. They have been shown to deregulate the growth of a variety of cancers, such as GIST; myeloproliferative disorders (Pardanani and Tefferi 2004), e.g., in hypereosinophilic syndrome (FIP1L1/PDGFRα-rearrangement), chronic myelomonocytic leukemia (CMML), harboring the activating translocations involving the PDGF receptor beta locus on chromosome 5q33 (FIP1/PDGFR-translocation); carcinomas; melanoma; gliomas; and sarcomas, including dermatofibrosarcoma protuberans (Barnhill et al. 1996; Greco et al. 2001).
In addition, in several non-malignant diseases, e.g., pulmonary hypertension, and autoimmune disease, the effect of imatinib has been investigated (Hoeper et al. 2013; Moinzadeh et al. 2013).
2 Structure and Mechanisms of Action
Imatinib mesylate is designated chemically as 4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl] aminophenyl] benzamide methanesulfonate. Its molecular formula is C29H31N7O.CH4SO3, and its relative molecular mass is 589.7 (Fig. 2).
Imatinib functions as a specific competitive inhibitor of ATP. It binds with high affinity at the ATP binding site in the inactive form of the kinase domain, blocks ATP binding, and thereby inhibits kinase activity by interrupting the transfer of phosphate from ATP to tyrosine residues on substrate proteins (Cohen et al. 2002a, b, 2005; Lyseng-Williamson and Jarvis 2001; Mauro et al. 2002).
Imatinib selectively inhibits all the ABL tyrosine kinases, including BCR-ABL, cellular homologue of the Abelson murine leukemia viral oncogene product (c-ABL), v-ABL, TEL-ABL, and Abelson-related gene (ARG). In addition, it was found to potently inhibit the tyrosine kinase activity of the α- and β-platelet-derived growth factor receptors (PDGFR) and the receptor for stem cell factor (c-KIT; CD117). The concentrations required for a 50 % kinase inhibition were in the range of 0.025 μM in in vitro kinase assays and approximately 0.25 μM in intact cells. Extensive screening did not show activity against other tyrosine kinases or serine/threonine kinases (Buchdunger et al. 1995, 1996, 2000, 2001; Deininger et al. 2005; Druker and Lydon 2000; Druker et al. 1996; Heinrich et al. 2002a; Okuda et al. 2001; Table 1).
3 Preclinical Data
In vitro studies demonstrated specific inhibition of myeloid cell lines expressing BCR-ABL without killing the parental cell lines from which they were derived (Deininger et al. 1997; Druker et al. 1996; Gambacorti-Passerini et al. 1997). Continuous treatment with imatinib inhibited tumor formation in syngeneic mice as well as in a nude mouse model after inoculation of BCR-ABL-expressing cells in a dose-dependent manner, treated intraperitoneally or with oral administration of STI571, respectively (Druker et al. 1996; le Coutre et al. 1999). Activity on primary CML cells could be demonstrated, and a >90 % reduction of BCR-ABL-expressing colonies in colony-forming assays from peripheral blood or bone marrow from CML patients was achieved at a concentration of imatinib of 1 μM while normal colonies did not show growth inhibition (Deininger et al. 1997; Druker et al. 1996; Gambacorti-Passerini et al. 1997).
4 Clinical Data in CML
4.1 Phase I Trials
In 1998, a phase I clinical trial with imatinib was initiated. This study was a dose escalation trial designed to determine the maximally tolerated dose, with clinical benefit as a secondary endpoint. 83 patients with CP CML who had failed standard therapy with interferon-α (IFN-α) or were intolerant to it were enrolled. One-third of patients had signs of early progression to AP. They received escalating oral doses of imatinib, ranging from 25 to 1,000 mg/day. Clinical features of patients were typical of the disease. Dose-limiting toxicity was not reached, although a higher frequency of severe toxicities was encountered at imatinib doses >750 mg/day. The most common adverse events were nausea (43 %), myalgia (41 %), edema (39 %), and diarrhea (25 %). After 29 patients were enrolled, therapeutic doses of 300 mg or more per day were reached. 53 of 54 patients achieved a complete hematologic response, reaching normal blood counts typically within four weeks of treatment. 51 of these 53 patients maintained normal blood counts after one year of therapy. Furthermore, these patients had a 31 % rate of major cytogenetic responses (MCyR; <35 % Ph+ metaphases) and a 13 % rate of complete cytogenetic responses (CCyR; eradication of Ph+ bone marrow cells) (Druker 2008; Druker et al. 2001b).
In another phase I trial, patients with myeloid and lymphoid blast crisis and patients with relapsed or refractory Ph+ lymphoblastic leukemia (ALL) were treated with daily doses of 300–1,000 mg of imatinib. 55 % of patients with myeloid blast crisis responded to therapy (45 % of patients with <5 % blasts in the bone marrow, and 11 % reached a complete remission with full recovery of peripheral blood counts, respectively) but only in 18 % response was maintained longer than one year.
Of 20 patients with Ph+ ALL or lymphoid blast crisis, 70 % responded, 20 % reached a complete hematologic remission. Nevertheless, all but one relapsed between days 45 and 117 (Druker et al. 2001a).
Based on the results of the phase I trials, the use of imatinib was expanded to large phase II and phase III clinical trials.
4.2 Phase II Studies
Three open-label, single-arm phase II studies using imatinib as a single agent were conducted in patients with Ph+ CML in three clinical settings: CML-CP after IFN-α failure or with intolerance to the drug, CML-AP, and CML-BC. Imatinib was administered orally once daily. Initially, all patients received 400 mg/day. Early in the study, however, the imatinib dose was increased to 600 mg daily for CML-AP and CML-BC trials. Patients with resistant or progressive disease receiving a dose of 400 or 600 mg/day could receive doses of 600 or 800 mg daily (administered as 400 mg twice daily).
In 532 patients with CP CML who had failed IFN-α therapy, 95 % of patients reached a complete hematologic response, with CCR rates of 41 % and major cytogenetic remission (MCR) of 60 %. The estimated rates of freedom from progression to accelerated or blastic phase and overall survival at 6 years were 61 and 76 %, respectively (Druker 2008; Hochhaus et al. 2008; Kantarjian et al. 2002a).
For patients in BC and with Ph+ ALL, the studies confirmed the results of the phase I trial. Response rates were also high; however, relapses were seen frequently. The majority of patients in BC relapsed during the first year of treatment. Hematologic responses were observed in 52 % of patients (n = 260) with myeloid BC, with a median response duration of 10 months. Interestingly, 48 % of patients in this trial developed new cytogenetic abnormalities during treatment, demonstrating clonal evolution (Druker et al. 2001a; Ottmann et al. 2002; Sawyers et al. 2002).
The efficacy in patients with AP CML was intermediate between CP and BC. Of 181 patients with AP, 82 % showed a hematologic response, 53 % reached a CHR which was sustained in 69 %. Major cytogenetic remissions were seen in 24 % of patients with a CCR rate of 17 % (Talpaz et al. 2002).
The treatment results in advanced phase CML and Ph+ ALL underline the necessity of combination therapies with conventional chemotherapy as well as the use of second-generation tyrosine kinase inhibitors.
The results of the phase I and phase II trials led to the approval by the Food and Drug Administration (FDA) of imatinib for the treatment of CML in advanced phase and after failure of IFN therapy (Cohen et al. 2002b; Deininger et al. 2005; Druker 2008).
4.3 Phase III Study (IRIS Trial)
In a landmark phase III study, the International Randomized Study of Interferon and STI571 (IRIS) trial, imatinib and the combination of IFN plus cytarabine were compared in newly diagnosed CP CML patients. More than 1,000 patients were accrued in less than 7 months. 553 patients were randomized to each of the two treatments, imatinib at 400 mg per day or interferon-α plus Ara-C. There were no significant differences in prognostic or clinical features between the two treatment arms. After a median follow-up of 19 months, patients randomized to imatinib had significantly better results for CHR, MCR, and CCR, as well as progression-free survival than patients treated with interferon-α plus Ara-C (O’Brien et al. 2003a, b).
The remarkable superiority of imatinib led to early disclosure of study results. Thereafter, most patients were crossed over from interferon-α plus Ara-C to the imatinib arm.
The IRIS trial is now a long-term follow-up study of patients who received imatinib as initial therapy. After a follow-up of 5 years, the overall survival for newly diagnosed CP patients treated with imatinib was 89 %. An estimated 93 % of imatinib-treated patients remain free from disease progression to the AP or BC. The estimated annual rate of treatment failure was 3.3 % in the first year, 7.5 % in year two, 4.8 % in year three, 1.5 % in year four, and 0.9 % in year five. The progression rate did not increase over time (Druker et al. 2006; Fig. 3).
Most of the side effects of imatinib were mild to moderate, with the most common being edema, muscle cramps, diarrhea, nausea, skin rashes, and myelosuppression (Druker et al. 2006). Quality of life was far better in patients treated with imatinib (Hahn et al. 2003). Rates of hematologic and cytogenetic responses are shown in Table 2. A recent update at 7 years showed an estimated overall survival of 86 and of 94 % considering only CML-related deaths, respectively. The estimated EFS at 7 years was 81 % and the estimated rate without progression to AP or BC is 93 %. A CCR was achieved by 456 of 553 (82 %) of patients on first-line imatinib (O’Brien et al. 2008).
Monitoring of residual disease by quantitative RT-PCR in complete cytogenetic responders showed that the risk of disease progression was inversely correlated with the reduction of BCR-ABL mRNA compared with pre-therapeutic levels (Hughes et al. 2003). The rates of major molecular remissions as well as the depth of molecular responses increase over time with a downward trend of relapse (O’Brien et al. 2008).
Investigation of pharmacokinetics in the imatinib-treated patients showed a correlation between imatinib trough plasma concentrations with clinical responses, EFS and adverse events. Patient with high imatinib exposure had better rates of CCR, major molecular responses, and event-free survival (Larsen et al. 2008).
The results of the IRIS trial have led to FDA approval of imatinib for first-line treatment of patients with CP CML in 2002 (Cohen et al. 2002b, 2005; Druker et al. 2001b).
5 Treatment Recommendations for the Use of Imatinib in Chronic Phase CML
Based upon the results achieved in the phase I, II, and III trials with imatinib, expert panels of the European Leukemia Net and the NCCN have developed guidelines for monitoring and treatment of CP-CML with imatinib (http://www.nccn.org/professionals/physician_gls/PDF/cml.pdf; Baccarani et al. 2013; http://www.nccn.org/professionals/physician_gls/PDF/cml.pdf; Table 3).
In case of suboptimal response, imatinib dosage should be increased and the option of allogeneic stem cell transplantation should be considered. In addition, in patients with failure of imatinib therapy, second- and third-generation tyrosine kinase inhibitors such as dasatinib, nilotinib, bosutinib or ponatinib have been approved (see according chapters). Further, TKI are currently under investigation.
6 Imatinib in Combination with Other Drugs
In order to further optimize the efficacy of imatinib in CML, a number of approaches have been investigated in phase II trials. Increase in the dose of imatinib monotherapy to 800 mg/d in CP-CML has shown earlier complete cytogenetic responses but is associated with more side effects. However, the importance of faster responses has not been clear yet (Cortes et al. 2003). In addition, imatinib in combination with other agents, such as interferon-α, cytarabine, and homoharringtonine, has been examined. Patients treated with combination therapy reached faster cytogenetic remission, but also experienced higher rates of toxicity, in particular myelotoxicity (Baccarani et al. 2003, 2004; Gardembas et al. 2003). Several major phase III trials have been initiated which compare standard dose imatinib with increased doses and combinations with cytarabine or interferon. In these trials, the induction of faster cytogenetic as well as molecular remissions could be shown in patients receiving higher dosages of imatinib. However, the increased dosage if imatinib as well as when used in combination with cytarabine was more toxic than standard dose (Hehlmann et al. 2011; Preudhomme et al. 2010).
7 Imatinib: Other Targets
Other molecular targets of imatinib are the platelet-derived growth factor receptor (PDGF-R) and the stem cell factor receptor (c-KIT) (Buchdunger et al. 1995, 2000; Heinrich et al. 2002a).
Aberrant PDGF receptors have been shown to deregulate the growth of a variety of cancers, such as myeloproliferative disorders (Pardanani and Tefferi 2004), e.g., in hypereosinophilic syndrome (FIP1L1/PDGFR-rearrangment) (Jovanovic et al. 2007), CMML involving the 5q33 translocations (Jovanovic et al. 2007), carcinomas, melanoma, gliomas, and sarcomas, including dermatofibrosarcoma protuberans (Barnhill et al. 1996; Greco et al. 2001).
c-KIT is expressed in a variety of human malignancies, including germ cell tumors, neuroblastoma, melanoma, small cell lung cancer, breast and ovarian cancer, acute myeloid leukemia, mast cell disorders and malignant GIST.
In most of these diseases, the exact role of c-KIT expression is not defined in mastocytosis and GISTs activating mutations of c-KIT have been identified (Heinrich et al. 2003a, b).
In approximately 60 % of cases of GIST, there are mutations in c-kit 105 in the juxtamembrane domain. In most of the remaining cases, mutations in exon 13 and exon 9 have been found. The mutations lead to constitutive activation of the receptor without its ligand (Lux et al. 2000). Imatinib was investigated in 147 patients with histologically and immunohistochemically confirmed metastatic and/or unresectable GIST in a single, open-label trial involving one European center and three centers in the United States. Seventy-three patients were randomized to receive 400 mg of imatinib daily, and 74 patients received 600 mg daily. An objective response was confirmed in 56 patients with an overall response rate for the combined study arms of 38 % (95 % confidence interval, 30–46 %). All responses were partial responses. Adverse events were similar to CML patients and included edema, fluid retention, nausea, vomiting, diarrhea, myalgia, skin rash, bone marrow suppression, bleeding, and elevations in aspartate aminotransferase, alanine aminotransferase, or bilirubin. Gastrointestinal bleeding or intratumoral hemorrhage occurred in seven patients (5 %) and was not correlated with thrombocytopenia or tumor bulk. The pharmacokinetics of imatinib in GIST patients were similar to those of CML patients (Demetri 2002; Demetri et al. 2002). Imatinib mesylate at a recommended dose of 400 or 600 mg daily was approved by the United States FDA for the treatment of malignant metastatic and/or unresectable GISTs in 2001 (Dagher et al. 2002).
Following approval, two open-label, controlled, multicenter, randomized phase III studies were performed by the EORTC (N = 946) and the other by SWOG (N = 746). Both studies compared imatinib at a dosage of 400 mg/day and 800 mg/day, respectively. Combined analysis of the two studies was prospectively defined by both groups. Objective responses were achieved in >50 % of patients receiving either imatinib dose. Median PFS was approximately 20 months and median OS was approximately 49 months, respectively. In the combined analysis, 347 patients crossed over to imatinib 800 mg/day at the time of progression according to the protocol. Median OS after crossover was 14.3 months (Blanke et al. 2008; Heinrich et al. 2008).
After approval of imatinib in metastatic GIST, the role of adjuvant treatment after successful resection was investigated. The ACOSOG Z9001 trial could demonstrate a significantly improved recurrence-free survival following surgical resection of primary GIST, resulting in the adjuvant label for imatinib. An improved 5-year RFS and overall survival by extending the duration of adjuvant imatinib treatment to 3 years could be shown in a further large phase III trial (Joensuu et al. 2012).
8 Side Effects/Toxicity
Hematologic side effects of imatinib are shown in Tables 4 and 5. Grade 3 or 4 neutropenia, thrombocytopenia, or anemia was seen in all phase II trials and the phase III study. While grade 3/4 neutropenia occured in first-line treatment of CP CML in about 17 %, in accelerated and blastic phase, it could be detected in approximately 60 % of patients. In addition, in advanced phase, CML thrombocytopenia and anemia are more frequently than in CP-CML (first or second line).
Typical non-hematologic side effects in phase II trials of imatinib in CML are shown in Table 4 (Cohen et al. 2002b, 2005; Guilhot 2004). In the IRIS trial, most of the side effects of imatinib were mild to moderate, with the most common being edema, muscle cramps, diarrhea, nausea, skin rashes, and myelosuppression as shown in Table 5 (Druker et al. 2006; O’Brien et al. 2003b).
Recently, it has been suggested that imatinib may cause cardiotoxicity (Kerkela et al. 2006). However, a preexisting condition predisposing to congestive heart failure (CHF) could not be excluded in these patients. Furthermore, a follow-up examination of the Novartis database of imatinib clinical trials including >5,600 years of exposure to imatinib found an incidence of CHF in imatinib recipients of 0.2 % cases per year with a possible or probable relationship to the drug. In the IRIS trial, the incidence of cardiac failure and left ventricular dysfunction was estimated at 0.04 % per year in the imatinib arm compared to 0.75 % in interferon-a- and ara-C-treated patients (Hatfield et al. 2007).
In an early trial in GIST, adverse events were similar to CML patients and included edema, fluid retention, nausea, vomiting, diarrhea, myalgia, skin rash, bone marrow suppression, bleeding, and elevations in aspartate aminotransferase, alanine aminotransferase, or bilirubin. Gastrointestinal bleeding or intratumoral hemorrhage occurred in 7 patients (5 %) and was not correlated with thrombocytopenia or tumor bulk. Other non-hematologic side effects included fatigue and gastrointestinal complaints which were usually mild to moderate. The most common laboratory abnormality was anemia. Fluid retention and skin rash were reported more often in patients treated with 800 mg/day. Based upon these data, escalation of imatinib dosing up to 800 mg/day for patients with progressive disease was approved (Blanke et al. 2008; Heinrich et al. 2008).
9 Clinical Pharmacology and Drug Interactions
Imatinib AUC is dose proportional at the recommended daily dose range of 400 and 600 mg. Within 7 days, approximately 81 % of the dose is eliminated, 68 % in feces, and 13 % in urine.
Cytochrome P450 (CYP3A4) is the major enzyme responsible for imatinib metabolism, and both imatinib and CGP74588 appear to be potent in vitro CYP2D6 inhibitors. Imatinib plasma concentrations may be altered when the drug is administered with inhibitors or inducers of CYP3A4. When CYP3A4 inhibitors, e.g., itroconazole, ketoconazole, erythromycin, or clarithromycin, are co-administered with imatinib, its metabolization may be decreased. CYP3A4 inducers, such as dexamethasone, phenytoin, rifampicin, carbamazepine, phenobarbital, may increase imatinib metabolism. Furthermore, increased plasma concentrations of drugs which are substrates of CYP3A4, e.g., simvastatin, cyclosporine and others, may be the result of imatinib use (Cohen et al. 2002b, 2005; Lyseng-Williamson and Jarvis 2001; Mauro et al. 2002).
In a small number of children with Ph+ ALL imatinib, plasma levels as well as of its metabolite CGP74588 were measured. Imatinib plasma levels were similar to those in adult patients. However, AUC of CGP74588 was only 5–24 % of the parent drug’s AUC, and it was eliminated much faster than in adults indicating a lesser role of the metabolite in antileukemic activity (Marangon et al. 2009).
In the phase-III-(IRIS) trial, the correlation of imatinib pharmacokinetics and the response to treatment as well as to side effects could be shown (Larsen et al. 2008).
10 Biomarkers
10.1 CML
-
Disease progression and imatinib resistance
Resistance to imatinib includes de novo resistance and relapse after an initial response. The frequent and durable responses in CP-CML are caused by the selective inhibition of BCR-ABL by imatinib. In accelerated and blastic phase CML as well as in Ph+ ALL, the combination of high numbers of proliferating tumor cells and genomic instability may lead to secondary genetic alterations, independent of BCR-ABL (von Bubnoff et al. 2003). In the majority of patients who respond to imatinib and then relapse, reactivation of the BCR-ABL tyrosine kinase could be shown. This indicates that BCR-ABL-dependent mechanisms either prevent imatinib from reaching its target or render the target insensitive to BCR-ABL. In the former category are mechanisms such as increased drug efflux through the multidrug resistance gene or protein binding of imatinib while the latter include mutations in the catalytic domain, the P-loop, and other mutations (Druker 2008; Gorre et al. 2001). Over 70 point mutations have been demonstrated to play a role in primary and secondary resistance to imatinib, respectively (Hochhaus et al. 2011; Fig. 4).
Gene amplification or overexpression of BCR-ABL as reason for resistance is seen occasionally (Shah et al. 2008; Shah and Sawyers 2003).
Understanding the underlying mechanisms of resistance has led to the development and investigation of new second- and third-generation tyrosine kinase inhibitors (Mueller 2009; Schiffer 2007) (see chapters bosutinib, dasatinib, nilotinib, and ponatinib).
10.2 GIST
Other molecular targets of imatinib are the platelet-derived growth factor receptor (PDGF-R) and the stem cell factor receptor (c-KIT) (Buchdunger et al. 1995, 2000; Heinrich et al. 2002a).
In GISTs, activating mutations of c-KIT and PDGF-R have been identified (Heinrich et al. 2003a, b).
In approximately 60 % of cases of GIST, there are mutations in c-kit 105 in the juxtamembrane domain. In most of the remaining cases, mutations in exon 13 and exon 9 have been found. The mutations lead to constitutive activation of the receptor without its ligand (Lux et al. 2000). The mutational status is being used for the choice and duration of adjuvant therapy. In case of a PDGF-RA D842V mutation, no adjuvant therapy is indicated. In the presence of wild-type kit, the situation has to be discussed on an individual base. In exon-11 and all mutations except exon-9 mutations, adjuvant therapy should be performed with 400 mg imatinib while in the presence of exon-9-mutations, 800 mg/d should be used (Joensuu et al. 2012).
11 Summary and Perspectives
The development of imatinib mesylate resembles the progress made in molecular biology over the past 30 years and has changed the landscape of cancer treatment leading toward causative treatment not only of CML and GIST but also for other malignancies.
After identification of the critical role of BCR-ABL in the pathogenesis of CML, less than 15 years went by until the development of imatinib which is now the standard of care for patients in CP CML. It has specific activity against a limited number of targets and has been shown to be highly effective not only in CML but also in other hematologic malignancies and solid tumors such as GIST. Side effects of treatment are mild to moderate. The understanding of mechanisms of resistance and disease progression has further lead to the development of second- and third-generation tyrosine kinase inhibitors.
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Waller, C.F. (2014). Imatinib Mesylate. In: Martens, U. (eds) Small Molecules in Oncology. Recent Results in Cancer Research, vol 201. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-54490-3_1
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