Practical Management of Toxicities Associated with Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia

Practical Management of Toxicities Associated with Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia Alfonso Quintás-Cardama, Jorge E. Cortés, Hagop Kantarjian

Abstract The tyrosine kinase inhibitor (TKI) imatinib constitutes the current first-line therapeutic approach for patients with chronic myeloid leukemia. The success of imatinib relies on its potent inhibitory activity against the Bcr-Abl kinase that drives the pathogenesis of this disorder. The vast majority of patients treated with imatinib as a single agent will achieve a complete cytogenetic response. However, a subset of patients will develop imatinib resistance, frequently associated with mutations within the Abl kinase domain. In this setting, treatment with the second-generation TKIs nilotinib and dasatinib has proved highly efficacious. While therapy with these Bcr-Abl TKIs is generally well tolerated, adverse events are common and can result in treatment interruptions that compromise clinical responses. Herein, we discuss some of the toxicities characteristically associated with TKI therapy and provide practical approaches to the clinical management of these adverse effects.

Clinical Lymphoma & Myeloma, Vol. 8, Suppl. 3, S82-S88, 2008 Key words: Bcr-Abl, Dasatinib, Imatinib, Myelosuppression, Nilotinib, Peripheral edema, Pleural effusion

Introduction Chronic myelogenous leukemia (CML) is typically diagnosed in an initial stage termed chronic phase (CP), which is characterized by the overproduction of immature myeloid cells and mature granulocytes in the bone marrow and peripheral blood. In the absence of adequate therapy, CP-CML progresses to an aggressive form of acute leukemia known as blastic phase (BP), usually after transitioning through an accelerated phase (AP). Patients in BP-CML present with a peripheral blood or bone marrow blast percentage of ≥ 30% and are characterized by remarkable resistance to conventional chemotherapeutic agents.1 Before the introduction of imatinib therapy, the median survival of patients in BP-CML was 4-5 months. Imatinib is a tyrosine kinase inhibitor (TKI) that targets a selected array of protein tyrosine kinases, including Abl, Arg (Abl-related gene), platelet-derived growth factor receptor (PDGFR), and KIT.2,3 Therapy with imatinib has been shown to induce a complete cytogenetic response in > 80% of patients with CP-CML after 5 years of follow-up.4 Despite these remarkable results, some patients develop acquired resistance, which is frequently Department of Leukemia, University of Texas M. D. Anderson Cancer Center, Houston Submitted: Nov 8, 2007; Revised: Feb 26, 2008; Accepted: Feb 29, 2008 Address for correspondence: Alfonso Quintás-Cardama, MD, Department of Leukemia, M. D. Anderson Cancer Center, Unit 428, 1515 Holcombe Blvd, Houston, TX 77030 Fax: 713-792-5640; e-mail: [email protected]

associated with point mutations within the kinase domain of Bcr-Abl,5,6 and others exhibit intolerance to imatinib therapy. To overcome this shortcoming, a second generation of Bcr-Abl TKIs, represented by nilotinib and dasatinib, have been developed. Nilotinib and dasatinib have demonstrated remarkable efficacy in patients with CML in all phases after imatinib failure.7,8 Interestingly, these TKIs have shown lack of cross-resistance with imatinib. Results of a series of phase II studies have led to the approval of dasatinib by the US FDA for the treatment of patients with CML after failure of or intolerance to imatinib therapy. Therapy with imatinib, nilotinib, or dasatinib is generally well tolerated but not devoid of adverse events. The most commonly observed toxicities related to TKI therapy in clinical trials of patients with CML include myelosuppression, nausea, diarrhea, fluid retention syndromes, and rash. These toxicities have been observed with all 3 Bcr-Abl TKIs and therefore are considered class-effect adverse events. Conversely, other toxic effects have been ascribed selectively to specific TKIs. This phenomenon is, in all likelihood, the consequence of the distinct spectra of kinase inhibition of each of these agents. Herein, we review the most important TKI-related toxicities encountered in clinical trials of imatinib, nilotinib, and dasatinib in patients with CML and provide practical recommendations for the management of patients receiving therapy with these drugs. It must be emphasized that, in the absence of consensual guidelines for the management of TKI toxicities, the opinions expressed in this article are based on the clinical experience of the authors.

Dr Quintás-Cardama has no relevant relationships to disclose. Dr Cortés has received research support from Novartis Oncology, Bristol-Myers Squibb, Merck, and Wyeth Pharmaceuticals. Dr Kantarjian has received research support from Novartis Oncology, Bristol-Myers Squibb, and MGI Pharma.

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Table 1 Incidence of Grade 3/4 Cytopenias in Phase II Studies of Imatinib, Nilotinib, or Dasatinib in Patients with Chronic Myeloid Leukemia

Figure 1 Molecular Structures of Imatinib and the Second-Generation Tyrosine Kinase Inhibitors Nilotinib and Dasatinib

Tyrosine Kinase Inhibitor

Imatinib (formerly STI571)

Chronic Myeloid Leukemia Phase Chronic

Accelerated

Blast

Incidence (%) Neutropenia

13

58

64

Thrombocytopenia

8

43

62

Nilotinib Neutropenia 400 mg Twice Daily20-22 Thrombocytopenia

13

18

25

12

27

29

Dasatinib Neutropenia 70 mg Twice Daily23,24 Thrombocytopenia

49

76

82

47

82

84

Imatinib4,21,25 400 mg Daily

Nilotinib

Grade 3/4 Cytopenia

(formerly AMN107)

imatinib and nilotinib have negligible activity the against Src family of kinases. Alternatively, dasatinib is a multikinase inhibitor with potent activity against Bcr-Abl kinase (IC50 < 1 nmol/L) and Src family kinases including Src (IC50 = 0.55 nmol/L), Lck (IC50 = 1.1 nmol/L), Fyn (IC50 = 0.2 nmol/L), and Yes (IC50 = 0.41 nmol/L).15 Dasatinib is also a highly potent ATP competitive inhibitor of c-KIT (IC50 = 13 nmol/L), PDGFR-β (IC50 = 28 nmol/L), Epha2 (IC50 = 17 nmol/L), HER1 (IC50 = 180 nmol/L), and p38 MAP (IC50 = 100 nmol/L) kinases.16 A potential advantage of dasatinib over imatinib and nilotinib is that it binds both the active and inactive conformations of the Bcr-Abl kinase domain.8,15,17 The wider range of kinase inhibition exhibited by dasatinib likely provides the rationale for some off-target side effects observed with this TKI and not with imatinib or nilotinib.

Dasatinib (formerly BMS-354825)

Tyrosine Kinase Inhibitor–Induced Hematologic Toxicity

Kinase Inhibition Spectrum of Tyrosine Kinase Inhibitors in Chromic Myelogenous Leukemia Although imatinib, nilotinib, and dasatinib (Figure 1) are all inhibitors of Abl and PDGFR kinases, they posses distinct inhibitory spectra, which provide the basis for some of the toxicities observed in clinical trials. Initially developed as a protein kinase Cα, imatinib is a small-molecule 2phenylaminopyrimidine derivative that has demonstrated high selectivity as an inhibitor of Abl,2,9 Arg,10 PDGFR,11,12 and KIT.12 The extraordinary activity of imatinib in CML is based on its ability to fit into the canonical adenosine triphosphate (ATP)–binding site of the Abl kinase lining the groove between the N and C lobes. Nilotinib is another phenylaminopyrimidine derivative whose development was based upon the crystal structure of imatinib in complex with Abl kinase.13 Based on crystallographic data, it was inferred that some changes to the imatinib structure were able to be tolerated.5,14 In fact, the replacement of the N-methylpiperazine ring in the imatinib molecule resulted in a compound 20- to 30-fold more potent than imatinib against wild-type bcr-abl, while preserving similar activity against KIT (50% inhibitory concentration [IC50] = 60 nmol/L) and PDGFR (IC50 = 57 nmol/L).13 Importantly,

Incidence of Tyrosine Kinase Inhibitor–Induced Myelosuppression The development of myelosuppression during imatinib therapy was recognized early during the clinical development of this agent, particularly among patients with AP- or BP-CML. In the phase III IRIS (International Randomized Trial of Interferon and STI571) trial involving patients with newly diagnosed CP CML, grade 3 neutropenia (absolute neutrophil count [ANC] < 1 × 109/L) and grade 4 neutropenia (ANC < 0.5 × 109/L) occurred in 11% and 2% of the patients, respectively.18 Grade 3 thrombocytopenia (platelets < 50 × 109/L) and grade 4 thrombocytopenia (platelets < 10 × 109/L) were observed in 7% and 1% of the patients, respectively. In this study, the incidence of grade 3/4 anemia (hemoglobin [Hb] < 8 g/dL) was 3%. The incidence of myelosuppression was higher in patients with AP- or BP-CML, although this was frequently present at the start of CML therapy. In another study including 143 patients receiving imatinib in late CP–CML after interferon (IFN)–α, grade 3/4 myelosuppression, particularly that lasting > 2 weeks, was associated with a lower rate of major (P = .04) or complete (P = .01) cytogenetic responses.19 Based on safety data from phase I studies of nilotinib,7 400 mg twice daily was selected for subsequent phase II studies

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Toxicities Associated with TKIs in CML in patients with CML resistant or intolerant to imatinib therapy. In these studies, myelosuppression was the most commonly reported adverse event (Table 1).20-25 Grade 3/4 neutropenia was reported in 13% of the patients in CP, in 18% of the patients in AP, and in 25% of the patients in BP and with Philadelphia chromosome (Ph)–positive acute lymphoblastic leukemia (ALL). The rate of grade 3/4 thrombocytopenia was 12% in patients in CP, 27% in patients in AP, and 29% in patients in BP and with Ph+ ALL.20-22 Similarly, in phase II studies of dasatinib 70 mg twice daily in patients with CP-CML, the incidences of grade 3/4 anemia, neutropenia, and thrombocytopenia were 22%, 49%, and 47%, respectively.25 Grade 3/4 neutropenia or thrombocytopenia in patients in AP and BP ranged between 76% and 82% and 82% and 84%, respectively (Table 1).20-25 However, results from CA180034, in which the efficacy and safety of dasatinib 70 mg twice daily was compared with that of dasatinib 50 mg twice daily, 140 mg once daily, or 100 mg once daily, demonstrated similar efficacy but significantly less cytopenias with the latter dose schedule.26 Myelosuppression in patients with BP-CML receiving standard-dose imatinib (ie, 400 mg daily) usually occurs within the first 2-4 weeks after intiation of therapy, while this is usually observed after approximately 8 weeks in patients with CP-CML treated with imatinib or dasatinib.27 This is believed to be related to the paucity of normal marrow progenitors and their inability to sustain hematopoiesis, which is almost completely reliant upon the malignant Ph+ clone. The elimination of Ph+ progenitors by TKIs renders the bone marrow transiently unable to sustain normal blood production.28 Surprisingly, this has not been the case with the recent experience with bosutinib (SKI-606), another dual Src/Abl inhibitor that is less active against c-KIT, suggesting that the cause of myelosuppression observed with TKIs might be multifactorial, eg, related to the degree of preservation of normal stem cells as well as the effect on c-KIT. A general principle for the management of grade 3/4 neutropenia and/or thrombocytopenia during imatinib therapy for CP CML includes withholding imatinib therapy until recovery of ANC > 1 × 109/L or platelets > 50 × 109/L. Imatinib can then be reinitiated at the same previous dose if the counts recover within 2-4 weeks or at a reduced dose if the time to recovery is > 4 weeks.29 A similar principle can be applied to the management of myelosuppression induced by nilotinib or dasatinib therapy. More difficult is the management of myelosuppression in patients with AP- or BP-CML receiving TKI therapy. Because of the lifethreatening nature of AP-CML, a common approach is to avoid any TKI interruptions if marrow blasts are present and there is no evidence of bleeding or infectious complications. Such a strategy must be implemented with judicious administration of supportive care, including platelet and red blood cell transfusions, growth factors, and antibiotic prophylaxis. Neutropenia. Because grade 3/4 neutropenia results in frequent and, on occasion, protracted treatment interruptions that can compromise the achievement of responses to TKI therapy, the use of growth factors has been investigated as a means to hasten

neutrophil and/or platelet recovery. In a study at M. D. Anderson Cancer Center, 13 patients with CP-CML and grade 3/4 imatinib-induced neutropenia were given granulocyte colonystimulating factor (G-CSF; filgrastim) at doses ranging from 5 μg/kg 1-3 times weekly to 5 μg/kg daily titrated to maintain an ANC ≥ 1 × 109/L.28 The percentage of time off imatinib before and after the administration of G-CSF was 21% versus 6% (P = .0008), respectively. In addition, the response rate to imatinib increased significantly after the start of G-CSF, likely because of a more continuous imatinib administration. In a similar study including 18 patients with AP-CML, therapy with G-CSF or granulocyte-macrophage colony-stimulating factor (GM-CSF) reversed grade 4 neutropenia to grade 1 in 62% of the cases.30 In a recent study that included 122 patients with CP-CML treated with dasatinib, 29% of the patients developed grade 3/4 neutropenia and/or thrombocytopenia. Seven patients received G-CSF at 300 μg daily from 2 days to 7 days weekly, with dosing adjusted to keep an ANC > 1 × 109/L. All patients reached an ANC > 2 × 109/L after a median of 10 days. From dasatinib initiation to G-CSF initiation, patients remained off dasatinib a median of 40% of the total treatment time compared with 24% after G-CSF initiation (P = .07).27 Overall, therapy with G-CSF for TKI-induced neutropenia has proved effective, facilitating a timely and continuous administration of Abl kinase inhibitors. Notably, patients receiving G-CSF did not experience a greater rate of relapse, indicating that myeloid growth factors did not jeopardize the antileukemic effect of TKIs. Thrombocytopenia. The activity of the thrombopoietic cytokine interleukin (IL)–11 (oprelvekin) has been explored to aid the management of TKI-induced thrombocytopenia.27,31,32 One study included 13 patients with CP-CML (n = 11) or APCML (n = 2) who developed grade 3/4 thrombocytopenia.32 Interleukin-11 was administered initially at 10 μg/kg 3 times weekly. Dose escalation was allowed if the patients had no platelet increase > 10 × 109/L above the baseline on ≥ 2 consecutive measurements 1 week apart. Eight patients were receiving imatinib at doses ranging from 300 mg to 800 mg daily; 3 patients were receiving dasatinib 70 mg twice daily; and 2 patients were receiving nilotinib 400 mg twice daily. Eight (62%) of 13 patients had an increase in platelet count, with median peak platelet counts of 102 × 109/L (range, 51-160 × 109/L), including 1 who achieved a normal platelet count. The only significant toxicities observed were grade 4 fatigue (n = 1) and grade 2 peripheral edema (n = 1). In another study, 3 patients who developed dasatinib-induced grade 3/4 thrombocytopenia received IL-11 therapy, 2 of them concomitantly with dasatinib. Two patients reached a platelet count > 100 × 109/L after 94 days and 125 days of IL-11, respectively.27 Although the experience with IL-11 for the treatment of TKI-induced thrombocytopenia is limited, this agent appears to be efficacious and safe in this setting. However, economic considerations and the inconvenience of its subcutaneous administration 2-3 times weekly must be taken into account when prescribing this medication. The thrombopoiesis-stimulating protein AMG-53133 and the oral

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Alfonso Quintás-Cardama et al nonpeptide thrombopoietin receptor agonist eltrombopag34 constitute appealing options for the treatment of TKI-induced thrombocytopenia that warrant future investigation. Anemia. A systematic investigation of the prognostic significance of anemia during imatinib therapy in 338 patients with CP-CML (150 patients after IFN failure and 188 with newly diagnosed CML) showed that 230 (68%) of the patients developed anemia.35 By multivariate analysis, a starting Hb level < 12 g/dL, age ≥ 60 years, female sex, higher imatinib dose, and intermediate/high Sokal risk score were associated with increased probability of developing anemia with imatinib therapy. Forty-four percent of patients with anemia received treatment with 40,000 units of recombinant human erythropoietin (rHuEPO) once weekly. Increments in the Hb level of ≥ 2 g/dL were observed in 68% of the patients treated with rHuEPO, with remarkable tolerance.35 Similarly, 60% of the patients with CP-CML who developed anemia while receiving dasatinib therapy had increments in the Hb level of ≥ 2 g/dL after treatment with rHuEPO.27 It is worth mentioning that rHuEPO has been reported to promote resistance in imatinib-treated K562 cells in vitro, although similar results have not been observed in vivo.36 However, the Centers for Medicare and Medicaid Services declined the use of erythropoietic-stimulating agents for patients with CML. Overall, cytopenias occur in a significant proportion of patients with CML receiving TKI therapy. This complication can be readily managed and overcome by means of growth factor support. Far from interfering with the antileukemic activity of TKIs, growth factor administration in the context of TKI-induced myelosuppression allows for a more continuous administration of these agents, thus maximizing the treatment exposure and probability of response.

Tyrosine Kinase Inhibitor–Induced Nonhematologic Toxicity After 5 years of follow-up, the most frequently reported nonhematologic adverse events with imatinib therapy were edema (including peripheral and periorbital edema; 60%), muscle cramps (49%), diarrhea (45%), nausea (50%), musculoskeletal pain (47%), rash and other skin toxicities (40%), fatigue (39%), headache (37%), and joint pain (31%; Table 2).4 The most commonly encountered grade 3/4 nonhematologic toxicity was elevated liver enzymes in 5% of the patients. In general, newly occurring or worsening grade 3/4 nonhematologic toxicities were infrequent after 4 years of therapy. Peripheral Edema The development of peripheral edema is one of the most common toxicities associated with TKI use. Among patients treated with imatinib, peripheral edema has been reported in > 50% of patients; this toxicity is clearly dose related.3,37 Perhaps the most frequent form of this complication is the development of periorbital edema, which is typically more pronounced in the morning. Periorbital edema is frequently associated with lower-

Table 2 Incidence of Selected Nonhematologic Toxicities in Patients with Chronic-Phase Chronic Myeloid Leukemia Treated with Imatinib, Nilotinib, or Dasatinib Imatinib 400 mg Daily (%)

Nilotinib 400 mg Twice Daily (%)

Dasatinib 70 mg Twice Daily (%)

Peripheral Edema

55.5

<4

18

Pleural Effusion

<1

<1

19

Congestive Heart Failure

<1

NR

NR

Elevated Transaminases

43.2

6

60

Nonhematologic Toxicity (All Grades)

Elevated Serum Lipase

0

9

0

Rash

33.9

22

22

Nausea

43.7

13

19

Fatigue

34.5

16

28

Headache

31.2

<4

34

Muscle Cramps

38.3

<4

NR

Abbreviation: NR = not reported

extremity edema. Interestingly, the incidence of peripheral edema associated with nilotinib was significantly less than that observed with imatinib. This was suggested to reflect the greater activity of the latter against PDGFR.13 Interestingly, therapy with dasatinib, a potent PDGFR inhibitor (IC50 = 28 nmol/L),15 resulted in periorbital edema in 5%-10% and peripheral edema in 10%-27% of patients, but none experienced grade 3/4 toxicity.8 Like other TKI-induced toxicities, peripheral edema tends to improve over time. Moderate forms of edema can be managed by limiting the salt intake and administration of low-dose loop diuretics such as furosemide (eg, 20 mg orally daily) with potassium and magnesium supplementation and close electrolyte monitoring. More severe cases of periorbital edema resulting in visual impairment might require imatinib interruption and, in selected cases, surgery.38 Periorbital edema might be improved by elevation of the head during sleep, diuretics, and skin-tightening agents (eg, topical Preparation H® or lanolin, avoiding contact with conjunctiva). Pleural Effusion Pleural effusion is an extremely rare complication of imatinib or nilotinib therapy. However, it has been reported relatively frequently in phase I and II studies of dasatinib. Pleural effusion has been reported in 14%-30% of patients receiving dasatinib, with a higher incidence among patients with AP- and BP-CML. Studies have reported that pleural effusion occurred in 19% of patients with CP-CML and in 28% of the patients with myeloid BP-CML.23,39 In a recent analysis, pleural effusion was documented in 48 (35%) of 138 patients with CML enrolled in phase II trials in dasatinib, being more frequent among patients in AP CML (50%) and BP-CML (33%) than in those in CP-CML (29%).40 Thus, patients receiving dasatinib therapy must be monitored for the development of early manifestations of fluid retention (eg, dry cough, dyspnea), which might

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Toxicities Associated with TKIs in CML Figure 2 Dasatinib-Induced Pleural Effusion A

B

(A) Chest radiograph of a patient with CP-CML receiving dasatinib 70 mg twice daily. (B) Dasatinib was interrupted, and oral prednisone 60 mg daily was started, which resulted in complete resolution of the pleural effusion within 72 hours.

herald the development of pleural effusion. When established, the management of this complication is predicated upon its extension and/or clinical severity. Mild effusions need careful monitoring, whereas moderate-sized effusions will require dasatinib interruption and loop diuretics. The administration of pulse steroids might hasten the resolution of the pleural effusion but generally only if dasatinib therapy is discontinued (Figure 2).40 A typical course would be prednisone 40-60 mg daily for 3-5 days. It is possible that part of the beneficial effect of steroids might be related to decreasing dasatinib levels

precipitously. Patients with large recurrent large effusions might require thoracentesis, a temporary pleuroperitoneal shunt (eg, Denver shunt), and/or chemical pleurodesis. When the effusion has resolved, dasatinib may be resumed at a reduced dose. Dasatinib doses of ≤ 100 mg once daily appear to be safer than higher doses administered on a twice-daily schedule.26 If appropriate management of the pleural effusion is instituted in a timely fashion, most patients can continue dasatinib therapy. Cardiac Toxicity The relatively high incidence of peripheral edema and dyspnea associated with imatinib therapy raised the clinical suspicion that imatinib therapy could be associated with the development of left ventricular dysfunction and/or frank congestive heart failure (CHF) in patients without previous history of heart disease. Clinical findings of CHF have recently been reported in 10 patients receiving imatinib, and preclinical studies revealed that imatinib-treated mice can develop left ventricular contractile dysfunction and cellular abnormalities suggestive of a toxic myopathy secondary to imatinib-induced activation of the endoplasmic reticulum stress response and cell death.41 However, close examination of 6 imatinib trials, comprising 2327 patients who received imatinib monotherapy, including 1995 patients with CML, showed that only 12 (0.5%) had developed CHF possibly related to imatinib exposure.42 Similarly, CHF was reported as being drug related in < 1% of the patients included in the IRIS trial.4 Data on cardiac toxicity related to nilotinib therapy is anecdotal and limited to sporadic cases of QT interval prolongation and rare episodes of pericardial effusion and atrial fibrillation.7 Preliminary data suggest that a subset of patients who develop dasatinibinduced pleural effusion exhibit elevations in right ventricular systolic pressure.27 The management of cardiac occurrences, although they are rare, is based on close observation and prompt intervention with TKI discontinuation, echocardiographic monitoring, and aggressive therapy with diuretics, angiotensinconverting enzyme inhibitors, and β blockers. Hepatic Toxicity Abnormalities in liver function tests (LFTs) have been relatively frequent in patients with CML treated with TKIs, particularly among patients with advanced CML, in whom leukemic liver infiltration makes it difficult to discern the exact role of TKIs in the development of hepatic toxicity. Typically, TKI-induced hepatic toxicity consists of grade 1 elevation of transaminases usually during the first months of therapy, although bilirubin level elevations and cases of late-onset liver dysfunction have also been reported.4 Although hepatic toxicity has been reported in approximately 60% of patients treated with imatinib or dasatinib, grade 3/4 events occur in < 3% of cases.4,23 Elevations of bilirubin (generally unconjugated) levels without elevations of transaminase levels have been reported in 14% of patients receiving nilotinib.7 Our approach to the management of hepatic toxicity consists of strict avoidance of any hepatic toxins, particularly alcohol and acetaminophen, and monitoring of aminotransferases and bilirubin levels at

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Alfonso Quintás-Cardama et al baseline every week for the first month and every 3 months after initiation of TKI therapy. In the event of grade 1/2 hepatic toxicity, TKI therapy can be continued under close monitoring. Therapy with TKIs must be interrupted if grade 3/4 hepatic toxicity ensues, but this can be resumed at the same dose when LFTs decrease to ≤ grade 1. In cases of recurrent grade 3/4 hepatic toxicity, TKI therapy is usually terminated. The mechanisms whereby TKIs induce hepatic toxicity are currently unknown, but liver biopsies have shown features consistent with TKI-induced hypersensitivity. The presence of significant inflammatory changes supports recent results demonstrating that corticosteroid therapy might result in prompt resolution of imatinib-induced hepatotoxicity.43 Rash The development of a maculopapular rash secondary to imatinib therapy has been reported in ≤ 34% of patients (grade 3/4 in 2%),18 whereas the incidence in patients treated with nilotinib or dasatinib is approximately 20% (grade 3/4 in < 1%).7,25 In a multivariate analysis, female sex and the daily dose of imatinib were independent risk factors for the development of imatinib-induced rash.44 Tyrosine kinase inhibitor–induced rash is typically mild, and most patients do not require discontinuation of therapy; most cases are self-limited despite continued therapy. In the event of grade 3/4 rash, systemic cortiscosteroid therapy with prednisone 1 mg/kg daily is necessary with or without topical triamcinolone acetonide 0.1% ointment for the palliation of symptoms. When the rash resolves, the TKI dose with which to resume therapy must be predicated on the clinical situation on a case-by-case basis. Rare cases of Stevens-Johnson syndrome have been described associated with imatinib therapy.45-48 This occurrence mandates immediate interruption of imatinib and initiation of systemic steroid therapy (eg, prednisone 1 mg/kg daily). Interestingly, some of these patients can be rechallenged with low-dose imatinib (eg, 100 mg daily) followed by slow steroid tapering and closely monitored dose escalation of imatinib.47,48 Nonetheless, given the lack of cross-reactivity between imatinib and other TKIs, we consider it safer to terminate imatinib therapy and, upon resolution of the acute event, to start a different TKI. Rashes with TKIs have been anecdotally reported to follow or be exacerbated by sun exposure (photosensitivity).

Conclusion Therapy with TKIs for patients with CML is generally well tolerated. This is supported by the long-term follow-up of patients treated with imatinib. The second-generation Abl kinase inhibitors nilotinib and dasatinib have also shown that, in addition to their remarkable activity after failure of imatinib therapy, their toxicity profile is excellent, with most related toxicities being self-limited and manageable. Although all TKIs currently employed in the treatment of CML exhibit overlapping toxicities, the confirmation of the safety of the second-generation TKIs will require a longer follow-up. Tyrosine kinase inhibitor–related toxicities are more frequent in patients with AP-CML. This subset of patients must be closely

monitored, and the risk-benefit ratio of TKI therapy must be carefully considered. An important aspect to bear in mind when managing TKI-induced toxicities is that responses have been observed in a significant proportion of cases with TKI doses well below their determined maximal tolerated doses. This provides flexibility for dose reductions and schedule modifications while still providing therapeutic levels of the drug. Special attention should be paid to potentially life-threatening toxicities such as myelosuppression, particularly during the first months of therapy, and pleural effusion in patients treated with dasatinib. Prompt and judicious management of these complications allows for the continuation of TKI therapy in most patients.

References 1. Sokal JE, Baccarani M, Russo D, et al. Staging and prognosis in chronic myelogenous leukemia. Semin Hematol 1988; 25:49-61. 2. Druker BJ, Tamura S, Buchdunger E, et al. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat Med 1996; 2:561-6. 3. Druker BJ, Sawyers CL, Kantarjian H, et al. Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome [published erratum in: N Engl J Med 2001; 345:232]. N Engl J Med 2001; 344:1038-42. 4. Druker BJ, Guilhot F, O’Brien SG, et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med 2006; 355:2408-17. 5. Schindler T, Bornmann W, Pellicena P, et al. Structural mechanism for STI571 inhibition of Abelson tyrosine kinase. Science 2000; 289:1938-42. 6. Kantarjian H, Sawyers C, Hochhaus A, et al. Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N Engl J Med 2002; 346:645-52. 7. Kantarjian H, Giles F, Wunderle L, et al. Nilotinib in imatinib-resistant CML and Philadelphia chromosome–positive ALL. N Engl J Med 2006; 354:2542-51. 8. Talpaz M, Shah NP, Kantarjian H, et al. Dasatinib in imatinib-resistant Philadelphia chromosome–positive leukemias. N Engl J Med 2006; 354:2531-41. 9. Buchdunger E, Zimmermann J, Mett H, et al. Inhibition of the Abl protein-tyrosine kinase in vitro and in vivo by a 2-phenylaminopyrimidine derivative. Cancer Res 1996; 56:100-4. 10. Okuda K, Weisberg E, Gilliland DG, et al. ARG tyrosine kinase activity is inhibited by STI571. Blood 2001; 97:2440-8. 11. Carroll M, Ohno-Jones S, Tamura S, et al. CGP 57148, a tyrosine kinase inhibitor, inhibits the growth of cells expressing BCR-ABL, TEL-ABL, and TEL-PDGFR fusion proteins. Blood 1997; 90:4947-52. 12. Buchdunger E, Cioffi CL, Law N, et al. Abl protein-tyrosine kinase inhibitor STI571 inhibits in vitro signal transduction mediated by ckit and platelet-derived growth factor receptors. J Pharmacol Exp Ther 2000; 295:139-45. 13. Weisberg E, Manley PW, Breitenstein W, et al. Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl [published erratum in: Cancer Cell 2005; 7:399]. Cancer Cell 2005; 7:129-41. 14. Nagar B, Bornmann WG, Pellicena P, et al. Crystal structures of the kinase domain of c-Abl in complex with the small molecule inhibitors PD173955 and imatinib (STI-571). Cancer Res 2002; 62:4236-43. 15. Lombardo LJ, Lee FY, Chen P, et al. Discovery of N-(2-chloro-6methyl- phenyl)-2-(6-(4-(2-hydroxyethyl)- piperazin-1-yl)-2-methylpyrimidin-4- ylamino)thiazole-5-carboxamide (BMS-354825), a dual Src/Abl kinase inhibitor with potent antitumor activity in preclinical assays. J Med Chem 2004; 47:6658-61. 16. Lee F, Lombardo L, Camuso A, et al. BMS-354825 potently inhibits multiple selected oncogenic tyrosine kinases and possesses broad spectrum antitumor activities in vitro and in vivo. Proc Am Assoc Cancer Res 2005; 46:159 (Abstract 675). 17. Shah NP, Tran C, Lee FY, et al. Overriding imatinib resistance with a novel ABL kinase inhibitor. Science 2004; 305:399-401. 18. O'Brien SG, Guilhot F, Larson RA, et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase

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Toxicities Associated with TKIs in CML chronic myeloid leukemia. N Engl J Med 2003; 348:994-1004. 19. Sneed TB, Kantarjian HM, Talpaz M, et al. The significance of myelosuppression during therapy with imatinib mesylate in patients with chronic myelogenous leukemia in chronic phase. Cancer 2004; 100:116-21. 20. Ottmann O, Kantarjian H, Larson R, et al. A phase II study of nilotinib, a novel tyrosine kinase inhibitor administered to imatinib resistant or intolerant patients with chronic myelogenous leukemia (CML) in blast crisis (BC) or relapsed/refractory Ph+ acute lymphoblastic leukemia (ALL). Blood 2006; 108:528a (Abstract 1862). 21. le Coutre P, Bhalla K, Giles F, et al. A phase II study of nilotinib, a novel tyrosine kinase inhibitor administered to imatinib-resistant and -intolerant patients with chronic myelogenous leukemia (CML) in chronic phase (CP). Blood 2006; 108:53a (Abstract 165). 22. Kantarjian HM, Gattermann N, Hochhaus A, et al. A phase II study of nilotinib a novel tyrosine kinase inhibitor administered to imatinib-resistant or intolerant patients with chronic myelogenous leukemia (CML) in accelerated phase (AP). Blood 2006; 108:615a (Abstract 2169). 23. Cortes J, Rousselot P, Kim DW, et al. Dasatinib induces complete hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in blast crisis. Blood 2007; 109:3207-13. 24. Guilhot F, Apperley J, Kim DW, et al. Dasatinib induces significant hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in accelerated phase. Blood 2007; 109:4143-50. 25. Hochhaus A, Kantarjian HM, Baccarani M, et al. Dasatinib induces notable hematologic and cytogenetic responses in chronic-phase chronic myeloid leukemia after failure of imatinib therapy. Blood 2007; 109:2303-9. 26. Shah N, Kim DW, Kantarjian HM, et al. Dasatinib 50 mg or 70 mg BID compared to 100 mg or 140 mg QD in patients with CML in chronic phase (CP) who are resistant or intolerant to imatinib: one-year results of CA180034. J Clin Oncol 2007; 25(18 suppl):358s (Abstract 7004). 27. Quintas-Cardama A, Kantarjian HM, Nicaise C, et al. Cytopenias in patients (pts) with chronic myelogenous leukemia (CML) in chronic phase (CP) treated with dasatinib (Sprycel®): clinical features and management, including outcome after hematopoietic growth factor therapy. Blood 2006; 108:613a (Abstract 2163). 28. Quintas-Cardama A, Kantarjian H, O’Brien S, et al. Granulocyte–colony-stimulating factor (filgrastim) may overcome imatinib-induced neutropenia in patients with chronic-phase chronic myelogenous leukemia. Cancer 2004; 100:2592-7. 29. Deininger MW, O’Brien SG, Ford JM, et al. Practical management of patients with chronic myeloid leukemia receiving imatinib. J Clin Oncol 2003; 21:1637-47. 30. Mauro M, Kurilik G, Balleisen S, et al. Myeloid growth factors for neutropenia during imatinib mesylate (STI571) therapy for CML: preliminary evidence of safety and efficacy. Paper presented at: the 43rd Annual Meeting of the American Society of Hematology; December 7-11, 2001; Orlando, FL. Abstract 584. 31. Ault P, Kantarjian H, Welch MA, et al. Interleukin 11 may improve thrombocytopenia associated with imatinib mesylate therapy in chronic

myelogenous leukemia. Leuk Res 2004; 28:613-8. 32. Aribi AM, Kantarjian H, Ault P, et al. The effect of interleukin-11 (oprelvekin, Neumega®) on thrombocytopenia associated with tyrosine kinase inhibitors (TKI) in patients with chronic myeloid leukemia (CML). Blood 2006; 108:609a (Abstract 2148). 33. Bussel JB, Kuter DJ, George JN, et al. AMG 531, a thrombopoiesisstimulating protein, for chronic ITP [published erratum in: N Engl J Med 2006; 355:2054]. N Engl J Med 2006; 355:1672-81. 34. Jenkins JM, Williams D, Deng Y, et al. Phase 1 clinical study of eltrombopag, an oral, non- peptide thrombopoietin receptor agonist. Blood 2007; 109:4739-41. 35. Cortes J, O’Brien S, Quintas A, et al. Erythropoietin is effective in improving the anemia induced by imatinib mesylate therapy in patients with chronic myeloid leukemia in chronic phase. Cancer 2004; 100:2396-402. 36. Kirschner KM, Baltensperger K. Erythropoietin promotes resistance against the Abl tyrosine kinase inhibitor imatinib (STI571) in K562 human leukemia cells. Mol Cancer Res 2003; 1:970-80. 37. Druker BJ, Talpaz M, Resta DJ, et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 2001; 344:1031-7. 38. Fraunfelder FW, Solomon J, Druker BJ, et al. Ocular side-effects associated with imatinib mesylate (Gleevec®). J Ocul Pharmacol Ther 2003; 19:371-5. 39. Cortes J, Rousselot P, Kim DW, et al. Dasatinib induces complete hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in blast crisis. Blood 2007; 109:3207-13. 40. Quintas-Cardama A, Kantarjian HM, Munden R, et al. Pleural effusion in patients (pts) with chronic myelogenous leukemia (CML) treated with dasatinib after imatinib failure. Blood 2006; 108:614a (Abstract 2164). 41. Kerkelä R, Grazette L, Yacobi R, et al. Cardiotoxicity of the cancer therapeutic agent imatinib mesylate. Nat Med 2006; 12:908-16. 42. Hatfield A, Owen S, Pilot PR. In reply to ‘Cardiotoxicity of the cancer therapeutic agent imatinib mesylate.’ Nat Med 2007; 13:13; author reply 15-6. 43. Ferrero D, Pogliani EM, Rege-Cambrin G, et al. Corticosteroids can reverse severe imatinib-induced hepatotoxicity. Haematologica 2006(6 suppl); 91:ECR27. 44. Valeyrie L, Bastuji-Garin S, Revuz J, et al. Adverse cutaneous reactions to imatinib (STI571) in Philadelphia chromosome-positive leukemias: a prospective study of 54 patients. J Am Acad Dermatol 2003; 48:201-6. 45. Hsiao LT, Chung HM, Lin JT, et al. Stevens-Johnson syndrome after treatment with STI571: a case report. Br J Haematol 2002; 117:620-2. 46. Vidal D, Puig L, Sureda A, et al. Sti571-induced Stevens-Johnson Syndrome. Br J Haematol 2002; 119:274-5. 47. Pavithran K, Thomas M. Imatinib induced Stevens-Johnson syndrome: lack of recurrence following re-challenge with a lower dose. Indian J Dermatol Venereol Leprol 2005; 71:288-9. 48. Mahapatra M, Mishra P, Kumar R. Imatinib-induced Stevens-Johnson syndrome: recurrence after re-challenge with a lower dose. Ann Hematol 2007; 86:537-8.

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