Imatinib Treatment: Specific Issues Related to Safety, Fertility, and Pregnancy Martee L. Hensley and John M. Ford Imatinib (Gleevec) (formerly STI571) has demonstrated high levels of efficacy in chronic myelogenous leukemia (CML) and gastrointestinal stromal tumors (GIST) and has been used in more than 12,000 patients participating in clinical trials. Experience from clinical trials with imatinib has largely demonstrated the drug to be well tolerated in humans. Common side effects, usually manageable, include nausea, rash, superficial edema, myelosuppression, muscle cramps, and elevated liver transaminases. With longer follow-up and with further experience with the treatment of patients outside of clinical trials, we are able to report on rarer toxicities, the identification of certain predictors of common toxicities, and the clinical experience with male fertility and pregnancy outcomes. Semin Hematol 40(suppl 2):21-25. 2003 Elsevier Inc. All rights reserved. IMATINIB MESYLATE (Gleevec or Glivec, Novartis, Switzerland) (formerly STI571) is an inhibitor of the BCR-ABL tyrosine kinase, the putative cause of chronic myelogenous leukemia (CML). As a targeted therapy for CML, imatinib has demonstrated high levels of efficacy. 6,10,11 Particularly among patients with chronic-phase disease, 8 imatinib achieves higher rates of major and complete cytogenetic responses than other CML therapies. 4 In addition to inhibiting the tyrosine kinase of BCR-ABL, imatinib also inhibits the tyrosine kinases associated with c-abl, ARG, the platelet-derived growth factor receptor (PDGF-r), and c-kit. 1,2,7,9 Initially, there were safety concerns with imatinib because the effect of these other tyrosine kinases on normal cell function was not known. However, in preclinical models, imatinib was well tolerated, with the liver abnormalities identified as a potential concern. Interestingly, imatinib was not found to be either mutagenic or clastogenic. Other notable preclinical features include: imatinib was teratogenic in rats, but not rabbits, and impaired spermatogenesis occurred in rats, dogs, and monkeys. Because of the teratogenicity data in rats, when the imatinib human trials began, it was recommended that effective contraception be used during imatinib therapy to prevent pregnancy. Imatinib has been well tolerated in clinical trials. The more common side effects reported include nausea, rash, superficial edema, myelosuppression, muscle cramps, and elevations in hepatic transaminases. With longer follow-up and experience with the drug, we are able to report on rarer toxicities, identify certain predictors of common toxicities, and describe the clinical experience with male fertility and pregnancy outcomes. Methods Toxicity data and adverse events were collected in phase II and phase III trials of imatinib in CML, and dosing details, efficacy, and tolerability of imatinib in these settings have previously been reported. 5,8,10,11 Clinical trial safety experience is based on 260 patients treated with imatinib for blast crisis in Study 102, 235 patients treated for accelerated phase CML in Study 109, 532 patients treated for chronic-phase CML after failure or intolerance of interferon (IFN) in Study 110, and 553 patients treated in the imatinib arm of Study 106, a randomized trial of front-line treatment for chronic-phase CML comparing imatinib to IFN plus cytarabine. In general, patients with chronic-phase CML were treated with imatinib 400 mg daily, and patients with blast crisis or accelerated-phase CML were treated with imatinib 600 mg daily. Toxicities were graded according to National Cancer Institute Common Toxicity Criteria, version 2.0. 3 We reviewed the clinical trial databases, augmenting the safety data with results from longer term treatment and from Novartis Clinical Safety and Epidemiology reports with a special focus on rare, severe toxicities (grade 3 or 4 rash), delayed toxicities (late liver dysfunction), and issues related to fertility and pregnancy outcomes. Results Overview of Imatinib Safety From Phase II Trials The side effect profile of imatinib therapy in CML was largely outlined by the safety data from the phase II trials. Study 102 was a phase II study for patients with CML blast crisis. The first 37 patients were treated with a dose of 400 mg/d, and the subsequent 223 were treated with a dose of 600 mg/d. In addition, within-patient dose escalation was permitted (from 400 to 600 mg, or from 600 to 800 mg, respectively) for patients who failed to respond or progressed at their starting dose. Study 109 was a phase II trial for patients with accelerated-phase CML in which the first 77 patients were treated at 400 mg/d and the From the Department of Oncology Clinical Research, Novartis Pharmaceuticals, Basel, Switzerland. Address correspondence to John M. Ford, MD, Novartis Pharma AG, Postfach, CH 4002 Basel, Switzerland. 2003 Elsevier Inc. All rights reserved. 0037-1963/03/4002-2005$30.00/0 doi:10.1053/shem.2003.50038 Seminars in Hematology, Vol 40, No 2, Suppl 2 (April), 2003: pp 21-25 21
22 Hensley and Ford Table 1. Adverse Experiences in Greater Than 10% of Patients During Phase II Leukemia Studies (102, 109, and 110) Preferred Term (% of patients) Study 102 Myeloid Blast Crisis (n 260) Study 109 Accelerated Phase (n 235) Study 110 Chronic Phase All Grades Grade 3/4 All Grades Grade 3/4 All Grades Grade 3/4 Nausea 70 4 71 5 60 2 Fluid retention 71 12 73 6 66 3 Superficial edemas 67 5 71 4 64 2 Other fluid retention events 22 8 10 3 7 2 Muscle cramps 27 0.8 42 0.4 55 1 Diarrhea 42 4 55 4 43 2 Vomiting 54 4 56 3 32 1 Hemorrhage 52 19 44 9 22 2 CNS hemorrhage 7 5 2 0.9 1 1 Gastrointestinal hemorrhage 8 3 5 3 2 0.4 Musculoskeletal pain 43 9 46 9 35 2 Rash 35 5 44 4 42 3 Headache 27 5 30 2 34 0.2 Fatigue 29 3 41 4 40 1 Arthralgia 25 4 31 6 36 1 Dyspepsia 11 0 21 0 24 0 Myalgia 8 0 22 2 25 0.2 Weight increase 5 0.8 14 3 30 5 Pyrexia 41 7 39 8 17 1 Abdominal pain 31 6 33 3 29 0.6 Cough 14 0.8 26 0.9 17 0 Dyspnea 14 4 20 7 9 0.6 Anorexia 14 2 17 2 6 0 Constipation 15 2 15 0.9 6 0.2 Nasopharyngitis 8 0 16 0 18 0.2 Night sweats 12 0.8 14 1 10 0.2 Pruritus 8 1 13 0.9 12 0.8 Epistaxis 13 3 13 0 5 0.2 Hypokalemia 13 4 8 2 5 0.2 Petechiae 10 2 5 0.9 1 0 Pneumonia 12 6 8 6 3 0.8 Weakness 12 3 9 3 7 0.2 Upper respiratory tract infection 3 0 9 0.4 15 0 Dizziness 11 0.4 12 0 13 0.2 Insomnia 10 0 13 0 13 0.2 Sore throat 8 0 11 0 11 0 Ecchymosis 11 0.4 6 0.9 2 0 Rigors 10 0 11 0.4 8 0 Asthenia 5 2 11 2 6 0 Influenza 0.8 0.4 6 0 10 0.2 subsequent 158 were treated with 600 mg, again with the allowance for within-patient dose escalation. Patients with chronic-phase CML who were refractory or intolerant to IFN therapy were treated in Study 110, with all 532 patients starting at a dose of 400 mg/d. Dose escalation to 600 mg and if needed, up to 800 mg was permitted in patients who failed to respond. Nonhematologic adverse events occurring in greater than 10% of patients with advanced disease treated in these three studies are shown in Table 1. While grade 3 and 4 nonhematologic events were relatively uncommon, side effects of any grade that occurred relatively frequently, and were considered potentially clinically important included nausea, vomiting, diarrhea, superficial edema (including both periorbital and peripheral edema), muscle cramps, maculopapular rash, fatigue,and headache. While uncommon, two events were felt to be potentially clinically important: severe fluid retention and hemorrhage. Less than 5% of patients experienced excessive, central fluid retention, which manifested itself as congestive heart failure, pleural effusion, ascites, pericardial effusion, and pulmonary edema. Grade 3 or 4 hemorrhage occurred in 2% to
Imatinib: Safety, Fertility, and Pregnancy 23 Table 2. Patients (%) With Newly Occurring or Worsening Grade 3/4 Laboratory Abnormalities in Phase II Leukemia Studies Laboratory Parameters (% of patients) Study 102 Myeloid Blast Crisis (n 260) Study 109 Accelerated Phase (n 235) Study 110 Chronic Phase Grade 3 Grade 4 Grade 3 Grade 4 Grade 3 Grade 4 Hematologic parameters Anemia 41 11 34 6 6 1 Neutropenia 16 48 23 36 27 8 Thrombocytopenia 29 33 31 13 19 1 Biochemistry parameters Creatinine 1 1.5 0 1.3 0 0.2 0 Bilirubin 1 3.8 0 2.1 0 0.8 0 Alkaline phosphatase 1 4.6 0 5.1 0.4 0.2 0 AST 1 1.9 0 3.0 0 2.3 0 ALT 1 2.3 0.4 3.8 0 1.9 0 19% of patients, with the higher incidence occurring among patients treated for blast crisis. Gastrointestinal (GI) hemorrhage occurred in 3% to 5% of patients but was considered drug-related in 0% to 2%, and severe in less than 1.5%. Thrombocytopenia, concomitant use of nonsteroidal anti-inflammatory drugs, and history of gastric ulcer were contributing factors to the development of GI hemorrhage. Cerebral hemorrhages were also observed, but were more likely to occur in patients with advanced CML in the setting of rapid disease progression with thrombocytopenia. The potential clinical importance of edema and hemorrhage led to an analysis of potential predictors of these two adverse events. While higher drug exposure (measured by patients imatinib steady-state plasma concentration) was associated with increased risk of developing edema in univariate analysis, in multivariate analysis, this association was not independent of older patient age and female gender as risks for edema. Similarly for hemorrhage, higher drug exposure was associated with increased hemorrhage risk in univariate analysis, but in multivariate analysis was not independent of older age, platelet count, concomitant medications (antacids, antifungals, antivirals, paracetamol), and advanced disease stage. It is notable that the concomitant medication use is also confounded by disease stage and with conditions that may predispose to hemorrhage such as peptic ulcer. Hematologic and biochemical toxicities observed in the phase II studies are summarized in Table 2. Greater levels of myelosuppression were seen in blast crisis and accelerated-phase patients than among patients with late chronic-phase CML. Imatinib Safety Profile in Early-Stage CML Study 106 was a randomized trial of imatinib versus IFN plus low-dose cytarabine for patients with newly diagnosed CML without prior treatment except hydroxyurea. Efficacy data from this study show that patients assigned to the imatinib arm were approximately five times more likely to achieve complete cytogenetic response and had longer time to progression than patients assigned to IFN plus cytarabine. 4 In terms of safety, two types of comparisons are useful for putting the use of imatinib as front-line therapy of CML in perspective. Compared with previously treated CML patients from Study 110, patients on Study 106 experienced less nausea of any grade (42.5% v 60%) and less vomiting of any grade (14.7% v 32%), a difference that may be partly attributed to the more common intake of food with the imatinib therapy and/or to the fact that patients on Study 106 were earlier in their disease course. Myelosuppression was also less profound in Study 106 than in Study 110 (Table 3). Notably, grade 4 neutropenia was seen in only 2% of imatinib-treated patients on Study 106 versus 8% of patients on Study 110. Grade 4 thrombocytopenia occurred in less than 1% of patients on both studies. Focus on Toxicities of Special Interest in Study 106 The incidence of selected toxicities is detailed in Table 4. Because of the known risk of fluid retention, there was concern regarding the development of Table 3. Myelosuppression in CML Studies 106 and 110 Grade Study 106 Early Chronic Phase (n 551) Study 110 Late Chronic Phase Neutropenia 3 11% 25% 4 2% 8% Thrombocytopenia 3 7% 16% 4 1% 1% Anemia 3 3% 4% 4 1% 1%
24 Hensley and Ford Table 4. Incidence of Selected Toxicities Observed Among Patients Treated With Imatinib or Interferon Plus Cytarabine on Study 106 Preferred Term Glivec IFN Cytarabine Conjunctival hemorrhage 6 (1.1%) 2 (0.4%) Glaucoma 2 (0.4%) 2 (0.4%) Zoster 9 (1.6%) 4 (0.8%) Seizure 2 (0.4%) 6 (1.1%) Increased menstrual bleeding 14 (2.5%) 12 (2.3%) Gynecomastia 1 (0.2%) 1 (0.2%) Pulmonary edema 4 (0.7%) 5 (0.9%) Pleural effusion 1 (0.2%) 4 (0.8%) Exfoliative dermatitis 3 (0.5%) 1 (0.2%) glaucoma, seizure, pulmonary edema, and pleural effusion with imatinib treatment. Such potentially serious events were not observed more frequently among patients in the imatinib arm of Study 106, compared with patients on the IFN arm. Similarly, the known risk of mild rash with imatinib led to concern about more severe skin adverse events. Exfoliative rash was observed in 0.5% of patients in Study 106, and the incidence of exfoliative rash across all studies was approximately 1:500. Preclinical data and the observance of elevated liver transaminases on phase II trials meant that liver toxicity was carefully monitored on Study 106. Grade 2 elevations in AST/ALT were observed in 6.7% of imatinib patients versus 17.6% of patients in the IFN plus cytarabine group, and the incidence of new grade 3 or 4 events was 4.2% versus 7.1%, respectively. In general, AST/ALT elevations occurred relatively early and resolved over 14 to 21 days with drug withdrawal, allowing imatinib to be restarted in most cases. In contrast, with longer follow-up, there have been reports of seven patients with late-onset liver toxicity, occurring 293 to 541 days after initiation of imatinib therapy. These late events were manifested by elevations of AST/ALT in all seven patients and elevations of bilirubin in four of seven. With withdrawal of imatinib therapy, these resolved to grade 1 or less in a median of 73 days (range, 42 to 126). Of the four patients who were subsequently rechallenged with imatinib, two had recurrences of the transaminase elevation while the other two did not. Severe, exfoliative rashes (grade 3 to 4) have been reported in 19 patients with CML (approximately 1:500 patients of the 12,000 treated with imatinib from all studies). The events have generally occurred early in the treatment course. Two of the 19 patients were described as having Stevens-Johnson syndrome. One of these two patients with multiple medical problems and multiple concurrent medications died. The treating physician attributed the Stevens-Johnson syndrome to allopurinol. The second patient was treated with corticosteroids and rechallenged with imatinib successfully. Male Fertility and Pregnancies Among Patients Treated With Imatinib Preclinical safety data showed that imatinib was teratogenic in rats, but not rabbits. These observations led to the recommendation that women taking imatinib use appropriate methods of contraception. There was no evidence that imatinib was clastogenic or mutagenic, thus imatinib is not felt to be genotoxic, and spermatozoa are expected to be qualitatively normal. However, spermatogenesis was impaired in rats, dogs, and monkeys. This observation raised concern that men treated with imatinib may have reduced sperm counts. Clinical experience thus far has not shown this to be true. Although sperm counts were not required for assessment of toxicities in Study 106, inadequate sperm counts have not been reported. One patient was found to have a low-normal sperm count during an infertility work-up. With continued imatinib therapy, the count improved somewhat and conception occurred without medical intervention. A second patient had a normal sperm count while taking imatinib prior to banking sperm. In addition, among men being treated on clinical trials, there are reports of 13 pregnancies in the partners of men on imatinib, providing additional support that spermatogenesis is not impaired. Five additional pregnancies in partners of men taking imatinib have been reported from patients treated outside of clinical trials. The outcomes of these pregnancies are detailed in Table 5. Despite the recommendation not to conceive while undergoing imatinib therapy, there are reports of 26 pregnancies that have occurred (15 in clinical trials, 11 in nonclinical trials) among women taking imatinib. Pregnancy outcomes are detailed in Table 6. Only one patient restarted imatinib while continuing Table 5. Outcomes of Pregnancies Among Partners of Men Treated With Imatinib Clinical trials 13 pregnancies in partners of male patients on imatinib: 8 chronic-phase CML (400 mg); 4 accelerated CML (600 mg); 1 GIST (800 mg) 4 normal infants 2 pregnancies ongoing 2 therapeutic abortion on social grounds (normal abortus) 1 spontaneous abortion 1 death in utero at 13 weeks 3 no information Nonclinical trial spontaneous reports 5 pregnancies with limited information (4 ongoing) Abbreviation: GIST, gastrointestinal stromal tumor.
Imatinib: Safety, Fertility, and Pregnancy 25 Table 6. Pregnancy Outcomes Among Women Treated With Imatinib Clinical trials 15 pregnancies in female patients on imatinib for 5-65 weeks, detected at 5-22 weeks of gestation 14 chronic-phase CML (400 mg); 1 blast crisis (600 mg) 9 elective, therapeutic abortions 1 spontaneous abortion 2 on-going 3 proceeded to term 2 normal infants (1 in a blast crisis patient on Glivec for 30 weeks) blast crisis patient stopped imatinib at week 22, then had blast crisis relapse, restarted imatinib to control blast crisis, then delivered normal infant 1 hypospadias Nonclinical trial spontaneous reports 11 pregnancies in female patients on imatinib for 5-80 weeks, detected at 5-23 weeks of gestation 5 chronic phase CML (400 mg); 3 accelerated phase (600 mg); 1 GIST (200 mg); 2 unknown 2 therapeutic abortions (one because of hydrocephalus, congenital heart defect, 2-vessel cord) 4 spontaneous abortions 2 ongoing 3 no information to carry the pregnancy to term. In this patient, who was being treated for blast crisis CML, the imatinib was stopped at the time the pregnancy was diagnosed (approximately 22 weeks gestation), but restarted when the blast crisis relapsed. The patient continued imatinib with adequate control of blast crisis and ultimately delivered a normal infant. The pregnancy outcome data must be interpreted with extreme caution. Reports are anecdotal and thus the data may suffer from reporting bias. Although two normal infants have been born, this information is not sufficient to alter recommendations that women being treated with imatinib use effective forms of contraception throughout treatment. In the event of inadvertent conception on imatinib therapy, decisions will need to be highly individualized. Women must be apprised of the preclinical data showing teratogenicity, and they must be aware of the risk of disease progression during the time that imatinib must be stopped if the patient elects to continue the pregnancy. There are no data that show continued imatinib therapy during pregnancy can be recommended. Conclusions Continued follow-up of large cohorts of patients confirms that imatinib therapy is generally well tolerated. Side effects of nausea, vomiting, and myelosuppression are less common and less severe among patients treated in earlier stages of disease. Delayed liver toxicity occurs rarely, but may require permanent discontinuation of imatinib treatment. To date, there is no objective evidence of impaired spermatogenesis in men. Women treated with imatinib should be aware of the potential teratogenicity of imatinib, and should be counseled to use effective contraceptive methods throughout treatment. References 1. Buchdunger E, Cioffi CL, Law N, et al: Abl protein-tyrosine kinase inhibitor STI571 inhibits in vitro signal transduction mediated by c-kit and platelet-derived growth factor receptors. J Pharmacol Exp Ther 295:139-145, 2000 2. Buchdunger E, Zimmerman J, Mett H, et al: Inhibition of the Abl protein-tyrosine kinase in vitro and in vivo by a 2-phinylaminopyrimidine derivative. Cancer Res 56:100-104, 1996 3. Cancer Therapy Evaluation Program: Common Toxicity Criteria, version 2.0. CDTD, NCI, NIH, DHSS. March 1998 (http://ctep.info.nih.gov/ctc3.htm) 4. O Brien SG, Guilhot F, Larson RA, et al: Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 348: 994-1004, 2003 5. 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. N Engl J Med 344:1038-1042, 2001 6. Druker BJ, Talpaz M, Resta DJ, et al: Clinical efficacy and safety of an abl-specific tyrosine kinase inhibitor as targeted therapy for chronic myeloid leukemia. N Engl J Med 344: 1031-1037, 2001 7. Heinrich MC, Griffith JD, Druker BJ, et al: Inhibition of c-kit receptor tyrosine kinase activity by STI 571, a selective tyrosine kinase inhibitor. Blood 96:925-932, 2000 8. Kantarjian H, Sawyers C, Hochhaus A, et al: Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N Engl J Med 346:645-652, 2002 9. Okuda K, Weisberg E, Gilliland DG, et al: ARG tyrosine kinase activity is inhibited by STI571. Blood 97:2440-2448, 2001 10. Sawyers CL, Hochhaus A, Feldman E, et al: Imatinib induces hematologic and cytogenetic responses in patients with chronic myelogenous leukemia in myeloid blast crisis: results of a phase II study. Blood 99:3530-3539, 2002 11. Talpaz M, Silver RT, Druker BJ, et al: Imatinib induces durable hematologic and cytogenetic responses in patients with accelerated phase chronic myeloid leukemia: Results of a phase II study. Blood 99:1928-1937, 2002