US Pharm. 2012;37(5)(Oncology suppl):3-7.
ABSTRACT: The Philadelphia chromosome (Ph) is a cytogenetic abnormality commonly seen in adult patients with acute lymphoblastic leukemia (ALL). The end result of this abnormality is the expression of BCR-ABL fusion proteins. These proteins are constitutively active tyrosine kinases capable of perturbing cell signaling and its homeostasis. Conventional chemotherapy in Ph-positive (Ph+) ALL patients has resulted in frequent relapses and poor overall survival rate. Addition of the tyrosine kinase inhibitor (TKI) imatinib with chemotherapy, however, has substantially improved treatment outcomes of this disease. In this article, clinical literature on TKIs in the treatment of Ph+ ALL will be reviewed.
Acute lymphoblastic leukemia (ALL) is an aggressive neoplastic disease characterized by the presence of lymphoblasts in the blood, bone marrow, spleen, central nervous system (CNS), and other organs.1 The disease is prevalent in both adults and children. In children, current treatment options have brought cure rates exceeding 90%, while in adult patients results have been rather disappointing.1 Initially, adult patients with ALL will also respond to chemotherapy and undergo complete remission; however, the relapse rate is frequent, resulting in poor treatment outcome.1
The Philadelphia chromosome (Ph) is a molecular abnormality that is present in approximately 30% of newly diagnosed cases of adult ALL.2 Unfortunately, occurrence of this disease subtype increases in an age-dependent manner and confers an unfavorable prognosis. Ph results from the translocation of chromosome 9 and 22.2 The translocation produces a fusion gene, BCR-ABL (BCR is breakpoint cluster region gene from chromosome 22, ABL is Abelson tyrosine kinase from chromosome 9). Expression of BCR-ABL results in two different-sized proteins, p190 and p210.2 While p190 protein is exclusively expressed in Ph-positive (Ph+) ALL, p210 protein is predominant in chronic myelogenous leukemia (CML).2
Regardless of their size, both proteins are constitutively active tyrosine kinases capable of aberrant phosphorylation of tyrosine residues of proteins involved in cellular signaling. Perturbation of cell signal pathways (such as Ras, Raf) results in unregulated cell proliferation, decreased apoptosis, and promotion of carcinogenesis.2
Before tyrosine kinase inhibitors (TKIs) were introduced in oncology, treatment of Ph+ ALL with systemic chemotherapy resulted in frequent relapse.2 TKI-based therapy has revolutionized treatment outcomes for this condition and has become the standard of care. In this regard, pharmacists and other health care providers should ensure patient compliance with TKIs, since these agents improve treatment outcomes dramatically. The aims of this article are to educate pharmacists on TKIs in the management of Ph+ ALL in adults (TABLE 1) as well as to summarize recent advances in this area.
TYROSINE KINASE INHIBITORS
Imatinib is an orally active TKI that inhibits the adenosine triphosphate (ATP) binding site of BCR-ABL and prevents conformational shift of the protein to its active state.3 This results in inhibition of proliferation of leukemic cells.3 In addition to BCR-ABL, imatinib inhibits the receptor tyrosine kinases for platelet-derived growth factor (PDGF) and stem cell factor (c-kit).3 Activation of these receptors is believed to be important in disease states, including cancer. Important adverse effects associated with imatinib use include edema, nausea, vomiting, diarrhea, abdominal pain, musculoskeletal pain, muscle cramps, rash, hepatotoxicity, myelosuppression, and fatigue. Growth retardation in children on imatinib therapy has also been reported. Imatinib can cause tumor lysis syndrome and motor impairment while driving a vehicle or operating a machine.3
Imatinib is predominantly metabolized by CYP450 3A4, while other cytochrome enzymes play a minor role in its metabolism.3 Since imatinib is also a potent inhibitor of CYP3A4, it can increase the plasma concentration of therapeutic agents metabolized by CYP3A4. It is therefore important not to take imatinib concurrently with CYP3A4 substrate drug substances.3 Imatinib can also weakly inhibit CYP2D6. As warfarin is metabolized by both CYP3A4 and CYP2D6, patients on imatinib requiring anticoagulation therapy should be placed on heparin instead of warfarin.3
Landmark Clinical Trials Evaluating Imatinib in Patients With Ph+ ALL
At the MD Anderson Cancer Center, 54 patients with de novo Ph+ ALL were treated with imatinib (600 mg/day) concurrently with the hyper-CVAD regimen (fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone with alternating courses of methotrexate and cytarabine).4 During induction, imatinib was administered for 14 days. During courses 2 to 8, imatinib was given continuously. Following 8 courses of intensive chemotherapy, maintenance therapy included imatinib (800 mg/day) along with vincristine and prednisone. Ninety-three percent of patients attained complete remission along with a 3-year overall survival rate of 54%.4 Survival rates in patients who received an identical chemotherapy regimen without imatinib were 15%, suggesting a significant clinical advantage with the addition of imatinib to standard therapy.4
Continuous administration of imatinib (400 mg/day) to a standard chemotherapeutic regimen has resulted in complete remission of 90% (27/30) patients.5 Sixteen patients successfully underwent allogeneic stem cell transplantation (allo-SCT). At 4 years, overall survival was estimated to be 30%.5
In a comparative study, patients receiving imatinib-based chemotherapy (n = 59) were compared with patients who received chemotherapy only (n = 35).6 Imatinib (600 mg/day) was administered in pulses for 7 consecutive days beginning 3 days before each chemotherapy course. After a median follow-up of 5 years, imatinib-treated patients had a significantly lower relapse rate and a better overall survival than patients who received chemotherapy only.6
In a prospective, multicenter trial involving newly diagnosed Ph+ ALL patients, imatinib was administered simultaneously or alternated with identical induction and consolidation chemotherapy.7 Both treatment schedules allowed allo-SCT in a majority of the patients and produced tolerable adverse events, but concurrent imatinib administration with chemotherapy produced greater anticancer effects.7
The same group of researchers studied the long-term outcome of 335 patients on three different treatment schedules of imatinib (600 mg/day).8 Patients in the first cohort received imatinib between induction and first consolidation as well as after the first consolidation therapy. The second cohort was treated with imatinib during the second half of induction chemotherapy and continued until allo-SCT. The third cohort started receiving imatinib with induction chemotherapy and continued until allo-SCT. At 4-year evaluation, overall survival was found to be highest (50%) in patients in the third cohort.8 These findings suggest that imatinib treatment should be started early with prolonged duration.
Findings from the single largest multinational, prospective study on three cohorts of Ph+ ALL patients treated since 1993 are available.9 Patients in Cohort 1 received chemotherapy before introduction of imatinib. Cohort 2 patients were treated with imatinib as consolidation therapy, and Cohort 3 patients received imatinib during phase 2 of the induction regimen.9 Patients who were treated early with imatinib responded better in terms of overall survival, even-free survival, and relapse-free survival. These findings again support the observation of treating Ph+ ALL patients earlier in therapy with imatinib.9
Taken together, these studies emphasize the benefits of imatinib-based therapy in Ph+ ALL. Greater antileukemic effects were achieved with an early introduction of imatinib; hence, this agent is currently a first-line treatment for Ph+ ALL.
Development of resistance has resulted in imatinib’s frequent treatment failure. BCR-ABL–dependent mechanisms of resistance include amplification of the BCR-ABL gene as well as mutations in the ABL kinase domain, the latter being more important from a clinical standpoint. ABL kinase point mutations have been detected in four specific regions—the ATP binding region (P-loop), the contact site, the SH2 (Src homology 2) binding site, and the A-loop.10 Mutations to the P-loop region are a major cause of imatinib resistance.10 The T315I mutation, which substitutes isoleucine for threonine at position 315 of ABL, not only confers resistance to imatinib but also to newer TKIs.11
BCR-independent mechanisms include expression of p-glycoprotein in leukemia cells. Imatinib is a substrate for p-glycoprotein (P-gp) and increased P-gp expression decreases imatinib concentration within cancer cells.12 Cellular uptake of imatinib relies on a subtype of organic cation transporters (OCT-1), and its reduced activity has been seen in patients with CML with inadequate imatinib response.12,13
Independent activation of downstream signaling events by Src family kinases (SFKs) Lyn, HCK, and FGR is another mechanism of imatinib resistance.14 Interestingly, activation of these kinase pathways does not require BCR-ABL inhibition. Dual inhibitors of BCR-ABL and SFKs pathways may overcome this additional problem with imatinib resistance. Stroma-mediated growth has also been observed in murine p190 BCR-ABL ALL cells treated with imatinib. These cells continue to proliferate, although BCR-ABL kinase was inhibited by imatinib and did not require cell-cell contact.15
An Ik6 isoform (Ik6 belongs to the Ikaros family zinc finger 1 proteins associated with lymphocyte development) that lacks DNA binding capacity was detected in 91% of Ph+ ALL patients who were resistant to TKI inhibitors imatinib or dasatinib.16 Aberrant Ik6 expressions were correlated with BCR-ABL transcript levels. Ik6 functions in the lymphocytes, and, when restored, may reduce the number of incidences of TKI treatment resistance.16
Dasatinib is a dual Src/ABL kinase inhibitor that is 300 times more potent than imatinib in cells expressing BCR-ABL.17,18 It can bind to ABL kinase in both active and inactive conformations.18 It also inhibits PDGF receptors and c-kit.17 Dasatinib can overcome most mutations associated with imatinib resistance except T315I.19 Most commonly reported adverse reactions of dasatinib are myelosuppression, fluid retention resulting in pleural and pericardial effusions, headache, dyspnea, skin rash, fatigue, nausea, and hemorrhage.17 Since dasatinib is metabolized by CYP3A4, concurrent administration of a CYP3A4 inhibitor (e.g., ketoconazole) should be avoided.17 In clinical trials, use of proton pump inhibitors or histamine-2 (H2) antagonists along with dasatinib has been shown to decrease the plasma concentration of the latter to a subtherapeutic level. Antacid therapy, 2 hours prior to or 2 hours after the dasatinib dose, may solve this problem.17
In the pivotal study with extensive follow-up, newly diagnosed Ph +ALL patients of 18 years or older were treated with 100 mg dasatinib daily for 14 days of each of 8 treatment cycles of hyper-CVAD.20 Following remission, patients received maintenance treatment of daily dasatinib together with monthly vincristine and prednisone for 2 years, after which dasatinib was administered indefinitely. Thirty-three out of 35 patients (median age of 53 years) attained complete remission. Major adverse events (grade 3 or higher) included hemorrhage and pleural and pericardial effusions. Estimated 2-year survival was calculated to be 64%.20
Nilotinib, an aminopyrimidine derivative, is an orally active TKI that has greater affinity towards ABL kinase than imitanib.21,22 Similar to imatinib, it competitively inhibits the ATP-binding site of BCR-ABL but is 20- to 50-fold more potent than imitanib.22 Interestingly, in vitro nilotinib is effective against 32 out of 33 BCR-ABL mutations.21 Important adverse effects associated with nilotinib use include myelosuppression (anemia, thrombocytopenia, neutropenia), QT prolongation (black box warning), elevated liver enzyme and bilirubin levels, hyperglycemia, elevated lipase/amylase, pancreatitis, electrolyte disturbances, and rash.21 Nilotinib is metabolized by CYP3A4. It inhibits CYP3A4, CYP2C8, CYP2C9, and CYP2D6 and hence may interact with other therapeutic agents metabolized by these enzymes.21 Strong 3A4 inhibitors or inducers should be avoided with nilotinib. To prevent cardiac abnormalities, medications that prolong QT are prohibited with nilotinib. In addition, correction of electrolyte disturbances (e.g., hypokalemia) and periodic monitoring of QT prolongation by ECG are required.21 Nilotinib should be not be taken with food, as food increases nilotinib plasma concentration to a toxic level.21
In a phase I dose escalation study, 119 imatinib-resistant CML and Ph+ ALL patients received nilotinib at a daily oral dose of 50 to 1,200 mg. Although the maximum tolerated dose was determined to be 600 mg twice daily, the recommended dose for phase II studies was set at 400 mg twice daily with an increase to 600 mg twice daily in nonrespondents.23 One out of 10 Ph+ ALL patients with hematologic disease attained partial response, while 1 out of 3 patients with molecular disease achieved a complete molecular remission. Major adverse effects were rashes, elevated bilirubin levels, and myelosuppression. Grade 3 or 4 elevated lipase levels were observed in 6 patients.23 In this trial, although nilotinib’s effects were positive against CML, the drug was of limited value to patients with Ph+ ALL.23
Based on these findings, a phase II, open-label study is currently under way to study the effects of nilotinib in patients with relapsed or refractory Ph+ ALL. Preliminary data indicate that 24% of patients have complete response.24 One patient had hematologic improvement, and stable disease condition was attained in 9 others. Adverse effects observed include thrombocytopenia, neutropenia, hypophosphatemia, and anemia.24
Several novel agents are currently being evaluated for the treatment of Ph+ ALL. Ponatinib is an orally active multikinase inhibitor that is capable of inhibiting BCR-ABL even in the presence of T135I mutation.25 Interim results of an on-going phase I dose escalation study with ponatinib are available. Nine patients with advanced Ph+ leukemia, including 3 patients with Ph+ ALL, were included in the study.26 Two patients in this category attained major cytogenetic responses. At the time of this report, patients were treated with daily doses up to 60 mg of ponatinib. Dose-limiting toxicities include elevated pancreatic enzymes and pancreatitis.26
Bosutinib, a dual Src/ABL kinase inhibitor, when administered at a dose of 400 to 600 mg/day was well tolerated in patients with leukemia, including Ph+ ALL patients who were intolerant or resistant to imatinib.27 The study was originally planned for a year but later was extended to patients with favorable response to bosutinib treatment.27 During the time of this report, patients with blast-phase CML and ALL achieved a complete hematologic response rate of 15%. The experimental agent causes gastrointestinal adverse effects and rash.27
INNO-406, another oral dual ABL/Lyn kinase inhibitor, was administered to 9 Ph+ ALL patients who were intolerant or resistant to imatinib at a dose of 30 mg/day to 480 mg twice daily.28 The maximal tolerated dose was determined to be 240 mg twice daily.28 Grade 3/4 adverse events included elevation of liver enzymes and bilirubin, thrombocytopenia, and acute renal failure. Both bosutinib and INNO-406 are not active against T315I mutants of imatinib treatment.27,28 XL-228, another novel dual Src/ABL inhibitor, is currently being evaluated in a phase I trial.29
MK-0457 is a small-molecule aurora kinase and Janus kinase-2 inhibitor with antileukemic properties.30 This agent inhibits cells expressing T315I BCR-ABL mutations.30 Three patients including one with Ph+ ALL were treated with 5-day continuous IV infusion of MK-0457. In the Ph+ ALL patient who received MK-0457 at a rate of 20 mg/m2/h attained a peak plasma concentration of 1 mM along with inhibition of pCrkL, a substrate of BCR-ABL kinase.30 No major adverse effect was reported. Another aurora kinase inhibitor, danusertib, has also been shown to inhibit BCR-ABL kinases, including those with T315I mutations.31
Sorafenib, an orally active multikinase inhibitor approved to treat hepatocellular and renal cell carcinoma, has been shown to inhibit BCR-ABL kinase activity. In one study, sorafenib induced apoptosis in cells expressing T315I.32 It also inhibited BCR-ABL kinase activity. Rahmani et al reported that sorafenib inhibits BCR-ABL by down-regulating downstream targets (e.g., STAT5).33
Fingolimod, a drug recently approved for the treatment of multiple sclerosis, is an activator of protein phosphatase 2A (PP2A).34 Inhibition of PP2A is necessary for BCR-ABL mediated leukemogenesis. Thus, fingolimod opens a new area of research for a cure of leukemia. Fingolimod impaired the clonogenicity of imatinib/dasatinib–sensitive or –resistant p190/p120 BCR-ABL in leukemia cell lines.34
Another TKI, DCC-2036, inhibits ABL both in switch-on and switch-off states by a non–ATP-competitive mechanism and hence avoids steric hindrance with T315I.35 In vitro studies and studies using animal models have thus far produced encouraging results.35
TKI-based regimens are considered standard of therapy for Ph+ ALL. Despite some successes, development of resistance and adverse effects remain major challenges associated with the use of these agents. Novel agents with unique pharmacologic properties are needed to enhance treatment efficacy.
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32. Kurosu T, Ohki M, Wu N, et al. Sorafenib induces apoptosis specifically in cells expressing BCR/ABL by inhibiting its kinase activity to activate the intrinsic mitochondrial pathway. Cancer Res. 2009;69:3927-3936.
33. Rahmani M, Nguyen TK, Dent P, et al. The multikinase inhibitor sorafenib induces apoptosis in highly imatinib mesylate-resistant bcr/abl+ human leukemia cells in association with signal transducer and activator of transcription 5 inhibition and myeloid cell leukemia-1 down-regulation. Mol Pharmacol. 2007;72:788-795.
34. Neviani P, Santhanam R, Oaks JJ, et al. FTY720, a new alternative for treating blast crisis chronic myelogenous leukemia and Philadelphia chromosome-positive acute lymphocytic leukemia. J Clin Invest. 2007;117:2408-2421.
35. Van Etten RA, Chan WW, Zaleskas VM, et al. Switch pocket inhibitors of the ABL tyrosine kinase: distinct kinome inhibition profiles and in vivo efficacy in mouse models of CML and B-lymphoblastic leukemia induced by BCR-ABL T315I. Blood. 2008;112:A576.
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