- © 2006 by American Society of Clinical Oncology
Pregnancy Among Patients With Chronic Myeloid Leukemia Treated With Imatinib
- Patricia Ault,
- Hagop Kantarjian,
- Susan O'Brien,
- Stefan Faderl,
- Miloslav Beran,
- Mary Beth Rios,
- Charles Koller,
- Francis Giles,
- Michael Keating,
- Moshe Talpaz and
- Jorge Cortes
- Address reprint requests to Jorge E. Cortes, MD, Department of Leukemia, M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Unit 428, Houston, TX 77030; e-mail: jcortes{at}mdanderson.org
Abstract
Purpose Imatinib has potential teratogenicity in animals, but the effect of exposure to imatinib during conception and pregnancy in humans is not known.
Patients and Methods The records of all patients with chronic myeloid leukemia (CML) treated with imatinib were reviewed. We report the experience on 19 pregnancies involving 18 patients (10 females and eight males) who conceived while receiving imatinib for the treatment of CML.
Results All female patients discontinued therapy immediately on recognition of pregnancy. Three pregnancies (involving two female patients and one male patient) ended in spontaneous abortion, and one patient had an elective abortion. All other pregnancies were uneventful. Two of the 16 babies had minor abnormalities at or shortly after birth (hypospadias in one baby and rotation of small intestine in one baby) that were surgically repaired. All babies have continued normal growth and development. Among female patients who interrupted therapy, five of nine in complete hematologic remission (CHR) at the time of treatment interruption eventually lost CHR, and six experienced an increase in Philadelphia chromosome–positive metaphases. At a median of 18 months after resuming therapy with imatinib, eight patients had a cytogenetic response (complete in three patients).
Conclusion Although there is no evidence that a brief exposure to imatinib during conception and pregnancy adversely affects the developing fetus, most patients lose their response after treatment interruption. Patients receiving imatinib should be advised to practice adequate contraception.
INTRODUCTION
Imatinib mesylate (STI571, Gleevec, Glivec; Novartis, Basel, Switzerland) is now standard therapy for patients with chronic myeloid leukemia (CML). In chronic phase, a complete cytogenetic (CG) response has been achieved in 40% to 90% of patients treated after experiencing failure with interferon alfa1-4 and in 75% to 90% of patients treated with imatinib as first-line therapy.5-7 High response rates have also been achieved in patients in accelerated or blast phase, although responses are of shorter duration, and CG responses are less frequent than in chronic phase.8-11
Overall, imatinib is well tolerated. Although adverse events may be observed in up to 50% of patients, these are usually mild and manageable.2,6,10,11 Only 2% to 5% of patients have adverse events that require permanent discontinuation of therapy. Although the long-term effects of administration of imatinib are not known, after more than 5 years of follow-up for patients treated in the initial studies, there is no evidence of any long-term adverse clinical consequences of treatment with this agent. However, one area where there is limited information is the potential effect that imatinib may have on the developing fetus. Many young patients are currently being treated with imatinib, and they frequently face the dilemma of conception and pregnancy while receiving imatinib. At the present time, in view of the lack of sufficient information, it is recommended that patients practice contraception while receiving imatinib and that therapy is discontinued if the patient becomes pregnant.
In this report, we present the experience accumulated to date in patients treated with imatinib who conceived children and/or became pregnant while receiving imatinib. This is the first report of a series of patients with such experience.
PATIENTS AND METHODS
From 1999 to May 2005, more than 1,000 patients with CML in any stage of the disease were treated with imatinib at M.D. Anderson Cancer Center (The University of Texas, Houston, TX). The definitions of chronic, accelerated, and blast phases, as well as the definition of interferon alfa failure, were the same used in published studies using imatinib.2,8,9,12 All patients were registered onto studies approved by the institutional review board.
Before treatment was started, patients were given instructions on the administration of imatinib and were advised to avoid acetaminophen, alcohol, grapefruit, and caffeine. All patients were instructed to practice barrier contraception for as long as they were receiving therapy with imatinib. Initial evaluation and follow-up during therapy were performed as previously described.13 Patients were observed for survival at least every 3 months. Drug toxicity was evaluated at each visit and graded according to the National Cancer Institute Common Toxicity Criteria version 2.0. Response criteria were as previously described.14
RESULTS
Eighteen patients (eight men and 10 women) conceived while on therapy with imatinib, resulting in 19 pregnancies. The patients’ characteristics are listed in Table 1.
Female Patients
Ten female patients became pregnant while they were receiving therapy with imatinib; one of the patients had a twin pregnancy. At the time they became pregnant, the women had been receiving imatinib for a median of 8 months (range, 1 to 52 months) for CML in chronic (n = 9) or accelerated phase (n = 1). At the time pregnancy was recognized, nine patients had a CHR, with a complete CG response in one patient, partial CG response in three patients, minor CG response in two patients, and no CG response in three patients. One patient had persistent leukocytosis and thrombocytosis. One of these patients had interrupted therapy with imatinib approximately 2 months before conception because of financial reasons. All others had been receiving therapy up to the time of conception and until the pregnancy was identified. Imatinib was immediately discontinued on identification of the pregnancy. The median estimated time of exposure to imatinib from conception to treatment discontinuation was 4 weeks (range, 4 to 9 weeks). During pregnancy, four patients (40%) had an increase in WBC and/or platelets (ie, loss of CHR). Management of CML during pregnancy consisted of hydroxyurea, mostly during the second or third trimesters (n = 3), leukapheresis (n = 1), and interferon alfa (n = 1). These interventions resulted in CHR in one patient. The median total time patients stayed off therapy with imatinib during and after pregnancy was 7 months (range, 1 to 21 months). At the time of delivery or abortion, five patients did not meet criteria for CHR. The cytogenetic response at the time of delivery or abortion included two patients who were 100% Philadelphia chromosome positive, four patients who had a minor CG response, two patients who had a partial CG response, and two patients who had no CG analysis available. Thus, six patients had an increase of Philadelphia chromosome–positive metaphases during pregnancy.
Two patients had a spontaneous abortion shortly after discontinuation of imatinib. There were no other known medical conditions, personal or family history, or other factors of the father or mother that were considered to increase the risk of abortion. One other patient elected to have a therapeutic abortion shortly after the pregnancy was discovered. In the three patients who had abortions, treatment with imatinib was restarted 2 weeks, 4 weeks, and 21 months after the abortion. Seven other pregnancies were carried to term, resulting in the birth of eight babies (one set of twin girls). The median weight of the babies was 5 pounds, 13 ounces (range, 5 pounds, 2 ounces to 6 pounds, 13 ounces; Table 2). One of the babies had hypospadias at the time of birth that was surgically corrected without complications; the baby was otherwise healthy. The other seven babies were all healthy. The median age of the children at the date of this report is 17 months (range, 3 to 53 months), and they all have continued a normal pattern of growth and development.
After the birth of the babies (or the abortion), all patients resumed therapy with imatinib. After a median follow-up time of 18 months (range, 5 to 48 months), nine patients were in CHR, all of who had a CG response (minor, n = 2; partial, n = 3; and complete, n = 3). None of these patients has achieved a major molecular response (ie, BCR-ABL/ABL ratio < 0.05%). One patient never achieved CHR, eventually transformed to blast phase, and died 22 months after delivery.
Male Patients
Among the eight male patients who conceived, one patient conceived twice while receiving imatinib therapy. The patients had been on imatinib for a median of 18 months (range, 4 weeks to 48 months) at the time of conception. The conceptions resulted in the birth of eight healthy babies (five males and three female) and one spontaneous abortion. There were no other identifiable medical conditions, past medical history, or other factors that were known risk factors for the father or mother in the one case of spontaneous abortion. One of the eight babies was born with a mild rotation of the small intestine requiring surgical intervention shortly after birth with no complications reported and requiring no additional management. The median age of the babies is 38 months (range, 3 months to 54 months) at the time of this report, and the growth and development of these babies is reported as normal. None of the patients interrupted therapy with imatinib after the conception. At the time of this report, seven patients (88%) are in CHR, all of them with a complete CG response. One patient developed clonal evolution, progressed to myeloid blast phase, and died 42 months after conception.
DISCUSSION
The management of leukemia in patients who are pregnant and the effect of antineoplastic agents during conception and pregnancy have not been thoroughly investigated. It is estimated that leukemia occurs during the course of pregnancy in approximately one in 75,000 to 100,000 pregnancies.15 Less than 10% of these involve patients with CML. Pregnancy itself does not seem to affect the prognosis of the disease.16 There are two important considerations in the management of a patient with leukemia during pregnancy; these are the mother, who needs optimal cancer therapy, and the developing fetus, who could potentially be affected by the disease and/or the teratogenicity of antineoplastic agents. For male patients, the possible effect cytotoxic agents may have on spermatogenesis and the eventual consequences for the developing fetus should also be considered. Most information on this subject is derived from animal studies. It is common practice to exclude pregnant and lactating patients from studies involving new drugs, particularly antineoplastic agents, and it is rare that the safety of these agents during pregnancy is ever investigated. Therefore, clinical observations are particularly important.
There is limited information regarding the successful management of CML during pregnancy; most of this information is from case reports using leukapheresis,17,18 hydroxyurea,19,20 and interferon.21-23 The effects of imatinib on fertility, pregnancy, and lactation are known mostly from animal studies (Gleevec, product label; Novartis, Basel, Switzerland). Male rats administered imatinib 70 days before mating had a decrease in testicular and epididymal weights and in sperm motility. Imatinib was teratogenic in rats when administered during organogenesis at doses more than 100 mg/kg, which is approximately equivalent to a dose in adults of 800 mg/d based on body-surface area. Female rats administered doses ≥ 45 mg/kg experienced postimplantation loss, with no fetal losses at doses less than 30 mg/kg. At doses more than 100 mg/kg, total fetal loss occurred in all animals. Given this information, patients, both male and female, are advised to practice adequate contraception while on therapy with imatinib and to abstain from breast feeding. According to the product label, patients who are pregnant or become pregnant while on therapy with imatinib should be appraised of the potential hazards to the fetus.
Here we report on 18 patients (eight men and 10 women) who conceived while receiving imatinib. Three of the 19 pregnancies ended in spontaneous abortions (16%; 95% CI, 3% to 40%), including two (20%) of the 10 pregnancies (95% CI, 3% to 56%) in female patients. This rate is somewhat higher than the reported rate of spontaneous abortions in the general population of approximately 10% to 15%, which occur most frequently between the seventh and 12th weeks of pregnancy.24 Thus, it is possible that the brief exposure to imatinib may slightly increase the risk of a spontaneous abortions. In addition, two (13%) of the 16 babies (95% CI, 2% to 38%) born from these patients had minor complications at the time of or shortly after birth (one baby had hypospadias, and one had a mild rotation of the small intestine). With the constraints of a small series, this could represent a higher frequency than expected of congenital abnormalities. In addition, the possible role the exposure to anagrelide and hydroxyurea may have had on the occurrence of hypospadias cannot be determined. hypospadias occurs embryologically during urethral development between the eighth and 20th weeks of gestation in approximately one in 300 males.25 Neonatal intestinal obstruction occurs in one in 1,500 live births and may result from a variety of causes including intrinsic developmental defects, abnormalities of peristalsis, and insults in utero after the formation of normal bowel.26 All other babies in our series have continued normal growth and development to date. The exposure to imatinib was minimal in all cases after conception. There have been isolated case reports with similar favorable outcomes.27,28
The advice for patients who are receiving imatinib and want to become pregnant is difficult. Interrupting therapy for a period of time before stopping contraception could be considered. However, it is unclear what the duration of this interruption should be, and both the half-life of imatinib and the half-life of the sperm and ova that have been exposed to imatinib before stopping therapy have to be considered. In addition, the implications of such an interruption of therapy on the outcome of the disease are not clear. In a recent report,29 two patients who were in complete CG and molecular remission that was sustained for several months interrupted therapy to become pregnant, and both had a CG relapse as early as 3 months after discontinuation of therapy. In this regard, it is troublesome that, of the 10 female patients who interrupted therapy because of pregnancy, only three have achieved a CG response after a median of 18 months of therapy after delivery or abortion. Thus, patients who want to interrupt therapy to become pregnant should be advised of the risk of suboptimal response or relapse even if they have achieved a complete molecular remission. To our knowledge, there are three instances in which continuation of imatinib throughout the pregnancy has been reported. These pregnancies resulted in the birth of babies with no congenital defects, although two of the babies had low birth weight.30,31
We conclude that conception among patients with CML while receiving imatinib may result in normal pregnancies. A possible effect on miscarriages and other birth abnormalities cannot be ruled out. In the absence of more detailed and specific information in this regard, the recommendation should continue to be that patients should practice adequate methods of contraception, preferably barrier, while on therapy with imatinib and that physicians not administer imatinib to patients during pregnancy or lactation.
Authors' Disclosures of Potential Conflicts of Interest
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
| Authors | Employment | Leadership | Consultant | Stock | Honoraria | Research Funds | Testimony | Other |
|---|---|---|---|---|---|---|---|---|
| Hagop Kantarjian | Novartis Pharmaceuticals (C); Bristol-Myers Squibb (C); MGI (C) | |||||||
| Susan O' | BrienEnzon (B); Berlex (B); Genentech (B); IDEC (B) | Berlex (C); Genentech (C); IDEC (C) | ||||||
| Charles Koller | Novartis Pharmaceuticals (C) | |||||||
| Francis Giles | Novartis Pharmaceuticals (C) | |||||||
| Moshe Talpaz | Novartis Pharmaceuticals (B) | Novartis Pharmaceuticals (C) | ||||||
| Jorge Cortes | Novartis Pharmaceuticals (C) |
Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C) ≥ $100,000 (N/R) Not Required
Author Contributions
Conception and design: Patricia Ault, Hagop Kantarjian, Jorge Cortes
Provision of study materials or patients: Hagop Kantarjian, Susan O'Brien, Stefan Faderl, Miloslav Beran, Mary Beth Rios, Charles Koller, Michael Keating, Jorge Cortes
Collection and assembly of data: Patricia Ault, Susan O'Brien, Stefan Faderl, Miloslav Beran, Mary Beth Rios, Charles Koller, Michael Keating, Jorge Cortes
Data analysis and interpretation: Patricia Ault, Hagop Kantarjian, Mary Beth Rios, Jorge Cortes
Manuscript writing: Patricia Ault, Hagop Kantarjian, Jorge Cortes
Final approval of manuscript: Patricia Ault, Hagop Kantarjian, Susan O'Brien, Stefan Faderl, Miloslav Beran, Mary Beth Rios, Charles Koller, Francis Giles, Michael Keating, Moshe Talpaz, Jorge Cortes
Characteristics of Patients Conceiving While on Therapy With Imatinib
Outcome of Pregnancy From Patients Who Conceived While Receiving Imatinib
Footnotes
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Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
- Received October 24, 2005.
- Accepted December 19, 2005.
