Ir J Med Sci DOI 10.1007/s11845-014-1084-5
ORIGINAL ARTICLE
Pregnancy outcome in chronic myeloid leukemia patients on imatinib therapy A. Mukhopadhyay • S. Dasgupta • U. Kanti Ray F. Gharami • C. K. Bose • S. Mukhopadhyay
•
Received: 22 February 2013 / Accepted: 8 February 2014 Ó Royal Academy of Medicine in Ireland 2014
Abstract Introduction Imatinib is a first-line therapy to treat chronic myeloid leukemia (CML) patients. Materials and methods We selected 22 CML cases of pregnancies and reported 9 accidental and 13 planned pregnancies that were on imatinib therapy. Willing female patients remaining in complete hematological, cytogenetic and major molecular responses for at least 2 years planned for pregnancy and were advised to stop imatinib for 1 month prior to conception and 3 months after conception (first trimester). Willing male patients stopped therapy 1 month prior to conception of their wives. In unplanned cases, all patients were in exposure to imatinib during conception. Twenty-two pregnancies resulted in seven male children and eight female children. There were three spontaneous abortions and four elective abortions along
A. Mukhopadhyay (&) Department of Haemato-Oncology, Netaji Subhas Chandra Bose Cancer Research Institute, 16 A Park Lane, Kolkata 700016, India e-mail: [email protected] S. Dasgupta S. Mukhopadhyay Department of Molecular Biology, Netaji Subhas Chandra Bose Cancer Research Institute, Kolkata, India U. Kanti Ray Department of Pathology and Immunology, Netaji Subhas Chandra Bose Cancer Research Institute, Kolkata, India F. Gharami Department of Clinical Research, Netaji Subhas Chandra Bose Cancer Research Institute, Kolkata, India C. K. Bose Department of Gynaecological Oncology, Netaji Subhas Chandra Bose Cancer Research Institute, Kolkata, India
with one case of hypospadia and another one of mild hydrocephalus. Conclusion We may suggest that planned pregnancy during therapy may be encouraged but imatinib therapy in unplanned pregnancy can cause spontaneous abortion or congenital anomaly. Keywords Unplanned pregnancy Planned pregnancy CML Imatinib Teratogenic effects
Introduction Imatinib inhibits constitutively active BCR-ABL tyrosine kinase in chronic myeloid leukemia (CML). CML is a myeloproliferative disorder that carries the Philadelphia chromosome which results from a reciprocal translocation between the long arms of chromosome 9 and 22, t(9; 22) (q34; q11). The molecular consequence of this translocation is a novel fusion gene, BCR-ABL which encodes a constitutively active protein, tyrosine kinase. The effects of ABL kinase activity have been found to be successfully reversed by a novel molecule STI571 or imatinib mesylate which specifically binds to the ATPbinding site of the BCR-ABL kinase and inhibits it [1, 2]. In chronic phase, a Complete Cytogenetic Response (CCR) has been achieved in 40–90 % of patients treated with imatinib after the failure with interferon alfa [3–8] and also in 75–90 % of patients treated with imatinib as a firstline therapy [8–11]. Overall, imatinib is well tolerated although adverse events may be observed in up to 50 % of patients, which are usually mild and manageable [12–15]. Only 2–5 % of patients have adverse events that require permanent discontinuation of the first-line therapy and need to start the second-line therapy [16].
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The only 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. Most information regarding the reproductive effect of imatinib is derived from pre-clinical animal studies. In a rat model, high doses of imatinib increased embryonic loss and malformations (exencephaly, encephalocele and chemical bone hypoplasia) [17]. At the present time, in view of the lack of sufficient information while receiving imatinib and the therapy is discontinued if the patient becomes pregnant. So this is an unexplored area to focus on the teratogenic effect of imatinib mesylate on the pregnancies of CML patients who are on imatinib therapy. In the present study, female patients were treated with imatinib and conceived children or the wives became pregnant while their husbands were receiving imatinib. In Indian perspective, this is the first report of pregnancy of CML patients on imatinib therapy.
Materials and methods From November 2002 to May 2010, among 800 enrolled CML patients, 22 individuals reported the pregnancies while they (male and female patients) were on imatinib therapy. 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 [12]. Here, we reported the information of 22 pregnancies involving 22 patients (12 females and 10 males) who or their wives conceived while receiving imatinib for the treatment of CML. All patients were in chronic phase except one patient remaining in accelerated phase. In ‘‘planned pregnancy’’ both males and females who were willing to conceive, were instructed to stop the therapy for 1 month when they had planned for pregnancy. Once they or their wives conceived, male patients were advised to start imatinib immediately while female patients were instructed to discontinue the therapy for 1st. trimester (organogenesis period of embryo) and then restart it. In ‘‘unplanned pregnancy’’ the patients who or their wives became pregnant unknowingly, on imatinib therapy, whenever they reported their conception, imatinib was stopped in female patients for rest of the first trimester period then advised to restart it and continue it throughout the pregnancy and male patients were advised to continue it as earlier. So, in unplanned pregnancies, male patients did not withdraw the therapy and their wives conceived when their
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husbands were on imatinib therapy and the female patients discontinued the therapy for 4–9 weeks post conception. But in planned pregnancies male patients discontinued the therapy only for 1 month prior to conception of their wives and the female patients discontinued the treatment for 4 months (1 month before conception and 3 months after conception). Moreover, in planned pregnancies, both male and female patients had been monitored before planning for complete hematological, cytogenetic and major molecular response which could not be possible in unplanned cases.
Result Twenty-two patients (10 men and 12 women) conceived while on therapy with imatinib, resulting in 22 pregnancies. Data are listed in Tables 1 and 2. Female patients Among 12 female patients who became pregnant, 7 patients planned for pregnancy. The time when pregnancy was detected, all seven patients were in Complete Hematological Response (CHR), Complete Cytogenetic Response (CCR) and Major Molecular Response (MMR). Pregnancy of other five female patients were unplanned, among them three had CHR. Out of these three patients, one was in CCR, none was in MMR. Data are listed in Table 2. In ‘‘planned pregnancy’’ imatinib was stopped for 1 month before their planning and restarted after 12 weeks of report of conception and in unplanned pregnancy imatinib was immediately discontinued, on detection of the pregnancy. In case of unplanned pregnancies of female patients the median estimated time of exposure to imatinib from conception to treatment discontinuation was 8 weeks on average (range 6–9 weeks). Immediately after the information of conception, the unplanned pregnant women were advised to stop the imatinib for rest of the first trimester period. During pregnancy, two unplanned patients who were not in CHR had an increase in WBC and/or platelets. At the time of delivery, another two (17 %) patients did not meet criteria for CHR, two (1 unplanned and 1 planned) patients were not fulfilling the criteria for CCR (Table 2). Thus, six patients had an increase of Philadelphia chromosome-positive metaphases during pregnancy. Two patients (1 planned and 1 unplanned) had a spontaneous abortion shortly after discontinuation of imatinib. There were no other known medical conditions, personal or family history, or other factors that were considered to increase the risk of abortion. Three other patients (2 unplanned, 1 planned) were elected to have a therapeutic abortion shortly after the pregnancy was identified due to
Ir J Med Sci Table 1 Individual data of 22 CML patients and their pregnancy outcome ID no.
Age
Sex
Types of pregnancy
Parental data (total interruption of imatinib therapy due to pregnancy)
Interval between exposure and conception
1 st trimester exposure
Pregnancy outcome
CML-436/07
27
F
Planned
18 weeks
6 weeks
Imatinib was stopped
Healthy male child
CML-478/07
25
F
Planned
17 weeks
5 weeks
Imatinib was stopped
Healthy female child
CML-507/08
26
F
Planned
16 weeks
4 weeks
Imatinib was stopped
Spontaneous abortion
CML 554/08
31
F
Planned
16 weeks
4 weeks
Imatinib was stopped
Healthy female child
CML 603/09
33
F
Planned
19 weeks
7 weeks
Imatinib was stopped
Healthy male child
CML-678/10
28
F
Planned
18 weeks
6 weeks
Imatinib was stopped
Healthy female child
CML-764/10
26
F
Planned
17 weeks
5 weeks
Imatinib was stopped
Elective abortion
CML-103/03
26
F
Unplanned
4 weeks
Imatinib was continued at the time of conception
9 weeks
Imatinib was continued at the time of conception Imatinib was continued at the time of his wife’s conception
7 weeks
Spontaneous abortion
5 weeks
Healthy female child
Male child with hypospandium
CML-301/05
31
F
Unplanned
6 weeks
CML-448/07
29
F
Unplanned
9 weeks
CML-517/08
24
F
Unplanned
6 weeks
Continued treatment at the time of conception
7 weeks
Elective abortion
CML-616/09
23
F
Unplanned
5 weeks
Continued treatment at the time of conception
8 weeks
Elective abortion
CML-452/07
29
M
Planned
5 weeks
5 weeks
NA
Healthy male child
CML-566/08
34
M
Planned
6 weeks
6 weeks
NA
Spontaneous abortion
CML-596/08
35
M
Planned
4 weeks
4 weeks
NA
Healthy female child
CML-612/09
33
M
Planned
5 weeks
5 weeks
NA
Healthy male child
CML-653/09
34
M
Planned
5 weeks
5 weeks
NA
Healthy male child
CML-732/10
33
M
Planned
6 weeks
5 weeks
NA
Healthy female child
CML-42/02
24
M
Unplanned
No interruption
Imatinib was continued at the time of his wife’s conception
NA
Elective abortion
CML-210/04
32
M
Unplanned
No interruption
Imatinib was continued at the time of his wife’s conception
NA
Healthy female child
CML-399/06
27
M
Unplanned
No interruption
Imatinib was continued at the time of his wife’s conception
NA
Male child with
Imatinib was continued at the time of his wife’s conception
NA
CML-412/06
27
M
Unplanned
No interruption
mild hydrocephalus Healthy female child
NA Not applicable
abnormal clinical findings of the fetus (Table 1). Five patients who had gone abortions, restarted the treatment with imatinib 2 weeks after their abortions. Seven other pregnancies were carried to term, resulting in the birth of seven babies. There was a hypospadia in one unplanned pregnancy case (Table 1). Other six babies were healthy with average weight of 2.5–3.4 kg (Table 1). Among them, in case of one unplanned pregnancy, the healthy child was born (Table 1). After a median follow-up time of 18 months of restart of imatinib all patients archived CHR with major cytogenetic response.
Male patients Among 10 male patients whose wives conceived while they were on imatinib treatment, 6 pregnancies were planned in which cases male patients were advised to interrupt treatment for 1 month and they restarted imatinib immediately after conception of their wives. All six planned pregnancies were in CHR, CCR and MMR (Tables 1 and 2). Other four patients were on treatment while their wives became pregnant accidentally. In unplanned pregnancy imatinib continued uninterruptedly. In unplanned pregnancy
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Ir J Med Sci Table 2 Dose of imatinib therapy and status of disease of 22 CML patients before pregnancy and after their child birth lD no.
Sex
Age
Types of pregnancy
At the time of conception
At the time of termination of pregnancy
Imatinib dose (mg/d)
CHR
CCR
MMR
CHR
CCR
MMR Yes
CML-436/07
F
27
Planned
400
Yes
Yes
Yes
Yes
Yes
CML-478/07
F
25
Planned
300
Yes
Yes
Yes
Yes
Yes
Yes
CML-507/08
F
26
Planned
400
Yes
Yes
Yes
No
No
No
CML 554/08
F
31
Planned
400
Yes
Yes
Yes
Yes
Yes
Yes
CML 603/09
F
33
Planned
400
Yes
Yes
Yes
Yes
Yes
No
CML-678/10
F
28
Planned
400
Yes
Yes
Yes
Yes
Yes
Yes
CML-764/10 CML-103/03
F F
26 26
Planned Unplanned
400 400
Yes Yes
Yes Yes
Yes No
Yes No
Yes No
Yes No
CML-301/05
F
31
Unplanned
400
Yes
No
No
Yes
No
No
CML-448/07
F
29
Unplanned
400
Yes
No
No
No
No
No
CML-517/08
F
24
Unplanned
600
No
No
No
No
No
No
CML-616/09
F
23
Unplanned
600
No
No
No
No
No
No
CML-452/07
M
29
Planned
400
Yes
Yes
Yes
NA
NA
NA
CML-566/08
M
34
Planned
400
Yes
Yes
Yes
NA
NA
NA
CML-596/08
M
35
Planned
400
Yes
Yes
Yes
NA
NA
NA
CML-612/09
M
33
Planned
400
Yes
Yes
Yes
NA
NA
NA
CML-653/09
M
34
Planned
400
Yes
Yes
Yes
NA
NA
NA
CML-732/10
M
33
Planned
400
Yes
Yes
Yes
NA
NA
NA
CML-42/02
M
24
Unplanned
800
No
No
No
NA
NA
NA
CML-210/04
M
32
Unplanned
600
Yes
No
No
NA
NA
NA
CML-399/06
M
27
Unplanned
600
No
No
No
NA
NA
NA
CML-412/06
M
27
Unplanned
400
Yes
Yes
No
NA
NA
NA
CHR Complete hematological response CCR Complete cytogenetic response MMR Major molecular response NA Not applicable
incidentally two patients were in complete hematological response and among them one was in complete cytogenetic response. One patient was in accelerated phase. There was one spontaneous abortion (planned pregnancy) and one elective abortion (unplanned pregnancy) (Table 1). The conceptions resulted in the birth of eight babies (four female and four male babies of average weight of 2.5–3.5 kg). Among them, one baby (unplanned pregnancy) was born with mild hydrocephalus (Table 1). There was no other identifiable congenital anomaly or adverse medical condition at the time of birth (Table 1).
Discussion Imatinib, used primarily for CML, has demonstrated that tyrosine kinase inhibitors can have a wide therapeutic window and herald the era of targeted cancer and noncancer disease therapy [18]. Imatinib mesylate has become a standard first-line therapy in Chronic Myeloid Leukemia, both in chronic phase and also in accelerated phase, though the response is of shorter duration in the latter.
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There does not seem to be any long-term consequences of its use, even though evidences are not available for more than 5 years (median value). But there is very limited data as far as the effects on pregnancy are concerned. It is very difficult for the patients who become pregnant, while on treatment, to balance the risk to the fetus of continuing imatinib versus the risk to the mother of interrupting treatment. From the fetal perspective, imatinib should be discontinued due to the potential risk of serious developmental abnormalities; from the maternal perspective, this may not be appropriate [9]. So in these cases considerations should include the wishes of the parents, disease status of father or mother, the availability of suitable alternative therapies and the ability to reinduce responses to imatinib after a prolonged period of discontinuation of imatinib. In the present study, we compared our data of 22 pregnancies among 166 CML individuals with the other reported study [9, 18–21]. Ault et al. were the first [19] to analyze data on the effects of imatinib on pregnancy. They reported 19 pregnancies in which either male or female patient was getting treatment. There were 3 spontaneous abortions (15.7 %, 1
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planned), 1 planned termination (5.2 %), but the other 16 were uneventful. One of the bigger series was reported [9], who analyzed data on 180 women being exposed to imatinib during pregnancy. Out of the 125 patients, a total of 63 pregnancies resulted in the birth of normal live infants. Among them 28 % underwent elective termination and 14.4 % underwent spontaneous termination. These studies [9, 11, 17, 19, 20, 22] reported the high incidence of the abortion in case of CML patients on imatinib therapy. Our present data also shows moderately high incidence (3 out of 22 or 13.6 %) of spontaneous abortion and 4 elective abortions (18 %) due to clinical abnormalities of fetus. In our data, spontaneous abortion rate is higher in female patients than in the male patients who were on imatinib therapy. The high rate of termination is understandable, considering many of the pregnancies were unplanned. Therefore, the CML patients under tyrosine kinase inhibitor therapy are advised to practice adequate contraception. Still the marriageable patients wish to conceive and they must be monitored for their disease status before conception. Planned pregnancies may be encouraged which include those patients remaining in CHR, CCR and at least MMR for 2 years. But in some cases, accidental pregnancies are also occurred. For planned/accidental pregnancies, weighing the risk or benefit ratio and carrying out individual counseling are probably the appropriate options. Also, though this was not one of our end points, the discontinuation of imatinib and the effect of restarting it have to be kept in mind with the limited data available. In unplanned cases, there is the risk of spontaneous abortion and or teratogenic anomalies of the fetus due to the effect of imatinib. According to references, half-life of imatinib and its major active metabolite, the N-desmethyl derivative, were approximately 18 and 40 h (NCBI database). The effect of imatinib on fertility, pregnancy outcome and lactation are known mostly from animal studies (Gleevec, product label; Novertis, Basel, Switzerland). Imatinib was teratogenic in rats when administered during organogenesis at doses more than 100 mg./kg, which is equivalent to 800 mg/day of human dose. Female rats, where it had been given as greater than 45 mg/kg (approximately equivalent to a human dose of 400 mg/day based on body surface area) experienced significant postimplantation loss with increased fetal resorption, still births, nomiable pups and early pup mortality [9]. Earlier studies reported various fetal abnormalities like meningoecoele, scoliosis, hydrocephalus, cerebellar hypoplasia, hypospadia, hypoplastic lungs, etc. Pye et al. reported 9.6 % fetal abnormality where as another study [19] showed 12.5 % of minor birth defects.
In our present study, two babies (13 %) were born with defect, one with hypospadia and one with mild hydrocephalus. But both cases were happened in case of unplanned female pregnancies where imatinib was continued unknowingly during first trimester of pregnancy. They reported the concentration of imatinib in placenta, umbilical cord blood and breast milk as 2,452, 0–157 and 596 ng/ml, respectively. In maternal perspective, in our present study, 13 patients who had all been in CHR, CCR and MMR for a period of at least 2 years, 3 (23.3 %) patients developed molecular relapse after withholding imatinib therapy, but the remaining 10 continued to have undetectable BCR-ABL transcripts at a median of 18 months’ follow-up. Of those who relapsed, most again achieved a CCR and MMR within a relatively short period following reintroduction of imatinib dose of 600–800 mg/day according to clinical presentation. In paternal perspective, very limited data are available about the effect of imatinib on spermatogenesis. According to study in leukaemic mouse model by Beate Schulthei et al. [22] imatinib mesylate as therapeutic doses has no impact on folliculogenesis or spermatogenesis. While in other rodent study, the effects of imatinib on the reproductive system were noticed. Oligospermia in a patient receiving imatinib therapy was noticed for the hypereosinophilic syndrome [23]. Other studies reported the deleterious effect of imatinib on differentiation of sperms but no effect of imatinib on the sperm count [24]. However, in present study, in case of planned pregnancies, we have suggested the male patients to stop imatinib for 1 month prior to conception and perform the sperm analysis. But no significant change was detected in their sperm analysis. Though we have no data of sperm analysis in cases of unplanned pregnancies. However, some previous data and our present data suggest that imatinib intake in CML patients can be a barrier of conception. Our data also suggest that if pregnancy is planned when the patient is in hematological, cytogenetic and molecular remission, then withholding imatinib may not interfere with ultimate outcome. All of the planned patients with CHR, CCR and MMR get back to previous levels within 18 months of restarting imatinib. But in unplanned pregnancy where the patient is in accelerated phase, withholding imatinib is a risky process and ultimate disease outcome is not that satisfactory. Another point of view is that if imatinib is withholding from the period of conception to organogenesis it may not cause major birth defect. Two of our children (one hypospadi and one mild hydrocephalus) resulted from unplanned pregnancies and imatinib exposure during the first trimester of organogenesis.
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There was another small study by Kuwabara et al., in which 7 patients interrupted treatment by imatinib at the advent of pregnancy. They concluded that adequate response after discontinuation of therapy due to pregnancy is seen only in those who had an optimal response (MMR) before discontinuation [25]. Therefore, we can suggest that planned pregnancy during imatinib therapy may be encouraged but imatinib therapy in unplanned pregnancy can cause spontaneous abortion or congenital anomaly. Hence, women of child bearing potential should use adequate contraception while using imatinib. Willing parents who are in CHR, CCR and MMR for at least 2 years may be advised to plan for pregnancy under strict medical supervision and imatinib must be withheld at least 1 month prior to conception to 3 months post conception (organogenesis period). Lactating mothers on imatinib therapy should avoid breast feeding for the benefit of the babies. The present data are the first report of pregnancy in CML patients on imatinib therapy from India so it is significant but the number of subjects is too small to strongly conclude about the positive or negative teratogenic effect of imatinib, while more data are required. In respect to the total number of CML patients treated in our institute, the present data show very low frequency of CML patients becoming pregnant on imatinib therapy. Because all the patients are advised to use contraceptive measures. Still, in the ethical as well as medical ground, the data are significant in case of willing CML parents. Acknowledgment We owe our sincere acknowledgement to Max Foundation, USA and Novartis, India with thanks for providing the patients with imatinib free of cost. We also acknowledge all of our patients and other fellows of Pathology and Molecular Biology department for their constant help and support. We are also grateful to West Bengal University of Health Sciences under which our Institute is affiliated. Conflict of interest
None.
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6. Fey MF, Surbek D (2008) Leukaemia and pregnancy. Recent Results Cancer Res 178:87–110 7. Hensley ML, Ford JM (2003) Imatinib treatment: specific issues related to safety, fertility and pregnancy. Semin Hematol 40(2 Suppl 2):21–25 8. Cole S, Kantarjian H, Ault P, Cortes JE (2009) Successful completion of pregnancy in a patient with chronic myeloid leukemia without active intervention: a case report and review of literature. Clin Lymphoma Myeloma 9(4):324–327 9. Pye SM, Cortes J, Ault P et al (2008) The effects of imatinib on pregnancy outcome. Blood 111(12):5505–5508 10. Faderal S, Talpaz Estrov E (1999) The biology of chronic myeloid leukemia. N Engl J Med 341(3):164–172 11. Ali R, Ozkalemkas F, Ozkocaman V et al (2004) Successful pregnancy and delivery in a patient with chronic myelogenous leukemia (CML), and management of CML with Leukapheresis during pregnancy: a case report and review of the literature. J Clin Oncol 34(4):215–217 12. Mukhopadhyay A, Dasgupta S, Mukhopadhyay S et al (2012) Imatinib mesylate therapy in patients of chronic myeloid leukemia with Philadelphia chromosome positive: an experience from eastern India. Indian J Haematol Blood Transfus 28:82–88 13. Kantarjian HM, Cortes JE, O’Brien S (2003) Imatinib mesylate therapy in newly diagnosed patients with Philadelphia chromosome-positive chronic myelogenous leukemia: high incidence of early complete and major cytogenetic responses. Blood 101(1):97–100 14. Jacob LA, Bapsy PP, BabuK Govind et al (2007) Lokanatha imatinib mesylate in newly diagnosed patients of chronic myeloid leukemia. Indian J Med Paediatr Oncol 28:1 15. Deshmukh C, Saikia T, Bakshi A et al (2005) Imatinib mesylate in chronic myeloid leukemia: a prospective, single arm, nonrandomized study. J Assoc Phy India 53:291–295 16. Guoqing W, Shamudheen R, Delong L (2010) First line treatment for chronic myeloid leukemia: dasatinib, nilotinib or imatinib. J Hematol Oncol 3(47):3–10 17. Russell MA, Carpenter MW, Akhtar MS et al (2007) Imatinib mesylate and metabolite concentrations in maternal blood, umbilical cord blood, placenta and breast milk. J Perinatol 27:241–243 18. Ali R, Ozkalemkas F, Ozcelik T et al (2006) Imatinib and pregnancy. J Clin Oncol 24(23):3812–3813 19. Ault P, Cortes J (2010) Planned pregnancy for a patient with chronic myeloid leukemia. Inter J Oncol 7(2):1528–8331 20. Risch HA, Weiss NS, Clarke EA et al (1988) Miller AB. Risk factors for spontaneous abortion and its recurrence. Am J Epidemiol 128:420–430 21. Ault P, Kantarjian H, O’Brien S et al (2006) Pregnancy among patients with chronic myeloid leukemia treated with imatinib. J Clin Oncol 24:1204–1208 22. Schultheis Beate, Nijmeijer BA, Yin H et al (2012) Imatinib mesylate at therapeutic doses has no impact on folliculogenesis or spermatogenesis in a leukaemic mouse model. Leuk Res 36(3):271–274 23. Seshadri T, Seymour JF, McArthur GA (2004) Oligospermia in a patient receiving imatinib therapy for the hypereosinophilic syndrome. N Engl J Med 351:2134–2135 24. Heim C, Minniear K, Dann CT (2011) Imatinib has deleterious effects on differentiating spermatogonia while sparing spermatogonial stem cell self renewal. Reprod Toxicol 31(4):454–463 25. Kuwabara A, Babb A, Ibrahim A et al (2010) Poor outcome after reintroduction of imatinib in patients with chronic myeloid leukemia who interrupt therapy on account of pregnancy without having achieved an optimal response. Blood 116:1014–1016
ORIGINAL ARTICLE
Pregnancy outcome in chronic myeloid leukemia patients on imatinib therapy A. Mukhopadhyay • S. Dasgupta • U. Kanti Ray F. Gharami • C. K. Bose • S. Mukhopadhyay
•
Received: 22 February 2013 / Accepted: 8 February 2014 Ó Royal Academy of Medicine in Ireland 2014
Abstract Introduction Imatinib is a first-line therapy to treat chronic myeloid leukemia (CML) patients. Materials and methods We selected 22 CML cases of pregnancies and reported 9 accidental and 13 planned pregnancies that were on imatinib therapy. Willing female patients remaining in complete hematological, cytogenetic and major molecular responses for at least 2 years planned for pregnancy and were advised to stop imatinib for 1 month prior to conception and 3 months after conception (first trimester). Willing male patients stopped therapy 1 month prior to conception of their wives. In unplanned cases, all patients were in exposure to imatinib during conception. Twenty-two pregnancies resulted in seven male children and eight female children. There were three spontaneous abortions and four elective abortions along
A. Mukhopadhyay (&) Department of Haemato-Oncology, Netaji Subhas Chandra Bose Cancer Research Institute, 16 A Park Lane, Kolkata 700016, India e-mail: [email protected] S. Dasgupta S. Mukhopadhyay Department of Molecular Biology, Netaji Subhas Chandra Bose Cancer Research Institute, Kolkata, India U. Kanti Ray Department of Pathology and Immunology, Netaji Subhas Chandra Bose Cancer Research Institute, Kolkata, India F. Gharami Department of Clinical Research, Netaji Subhas Chandra Bose Cancer Research Institute, Kolkata, India C. K. Bose Department of Gynaecological Oncology, Netaji Subhas Chandra Bose Cancer Research Institute, Kolkata, India
with one case of hypospadia and another one of mild hydrocephalus. Conclusion We may suggest that planned pregnancy during therapy may be encouraged but imatinib therapy in unplanned pregnancy can cause spontaneous abortion or congenital anomaly. Keywords Unplanned pregnancy Planned pregnancy CML Imatinib Teratogenic effects
Introduction Imatinib inhibits constitutively active BCR-ABL tyrosine kinase in chronic myeloid leukemia (CML). CML is a myeloproliferative disorder that carries the Philadelphia chromosome which results from a reciprocal translocation between the long arms of chromosome 9 and 22, t(9; 22) (q34; q11). The molecular consequence of this translocation is a novel fusion gene, BCR-ABL which encodes a constitutively active protein, tyrosine kinase. The effects of ABL kinase activity have been found to be successfully reversed by a novel molecule STI571 or imatinib mesylate which specifically binds to the ATPbinding site of the BCR-ABL kinase and inhibits it [1, 2]. In chronic phase, a Complete Cytogenetic Response (CCR) has been achieved in 40–90 % of patients treated with imatinib after the failure with interferon alfa [3–8] and also in 75–90 % of patients treated with imatinib as a firstline therapy [8–11]. Overall, imatinib is well tolerated although adverse events may be observed in up to 50 % of patients, which are usually mild and manageable [12–15]. Only 2–5 % of patients have adverse events that require permanent discontinuation of the first-line therapy and need to start the second-line therapy [16].
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The only 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. Most information regarding the reproductive effect of imatinib is derived from pre-clinical animal studies. In a rat model, high doses of imatinib increased embryonic loss and malformations (exencephaly, encephalocele and chemical bone hypoplasia) [17]. At the present time, in view of the lack of sufficient information while receiving imatinib and the therapy is discontinued if the patient becomes pregnant. So this is an unexplored area to focus on the teratogenic effect of imatinib mesylate on the pregnancies of CML patients who are on imatinib therapy. In the present study, female patients were treated with imatinib and conceived children or the wives became pregnant while their husbands were receiving imatinib. In Indian perspective, this is the first report of pregnancy of CML patients on imatinib therapy.
Materials and methods From November 2002 to May 2010, among 800 enrolled CML patients, 22 individuals reported the pregnancies while they (male and female patients) were on imatinib therapy. 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 [12]. Here, we reported the information of 22 pregnancies involving 22 patients (12 females and 10 males) who or their wives conceived while receiving imatinib for the treatment of CML. All patients were in chronic phase except one patient remaining in accelerated phase. In ‘‘planned pregnancy’’ both males and females who were willing to conceive, were instructed to stop the therapy for 1 month when they had planned for pregnancy. Once they or their wives conceived, male patients were advised to start imatinib immediately while female patients were instructed to discontinue the therapy for 1st. trimester (organogenesis period of embryo) and then restart it. In ‘‘unplanned pregnancy’’ the patients who or their wives became pregnant unknowingly, on imatinib therapy, whenever they reported their conception, imatinib was stopped in female patients for rest of the first trimester period then advised to restart it and continue it throughout the pregnancy and male patients were advised to continue it as earlier. So, in unplanned pregnancies, male patients did not withdraw the therapy and their wives conceived when their
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husbands were on imatinib therapy and the female patients discontinued the therapy for 4–9 weeks post conception. But in planned pregnancies male patients discontinued the therapy only for 1 month prior to conception of their wives and the female patients discontinued the treatment for 4 months (1 month before conception and 3 months after conception). Moreover, in planned pregnancies, both male and female patients had been monitored before planning for complete hematological, cytogenetic and major molecular response which could not be possible in unplanned cases.
Result Twenty-two patients (10 men and 12 women) conceived while on therapy with imatinib, resulting in 22 pregnancies. Data are listed in Tables 1 and 2. Female patients Among 12 female patients who became pregnant, 7 patients planned for pregnancy. The time when pregnancy was detected, all seven patients were in Complete Hematological Response (CHR), Complete Cytogenetic Response (CCR) and Major Molecular Response (MMR). Pregnancy of other five female patients were unplanned, among them three had CHR. Out of these three patients, one was in CCR, none was in MMR. Data are listed in Table 2. In ‘‘planned pregnancy’’ imatinib was stopped for 1 month before their planning and restarted after 12 weeks of report of conception and in unplanned pregnancy imatinib was immediately discontinued, on detection of the pregnancy. In case of unplanned pregnancies of female patients the median estimated time of exposure to imatinib from conception to treatment discontinuation was 8 weeks on average (range 6–9 weeks). Immediately after the information of conception, the unplanned pregnant women were advised to stop the imatinib for rest of the first trimester period. During pregnancy, two unplanned patients who were not in CHR had an increase in WBC and/or platelets. At the time of delivery, another two (17 %) patients did not meet criteria for CHR, two (1 unplanned and 1 planned) patients were not fulfilling the criteria for CCR (Table 2). Thus, six patients had an increase of Philadelphia chromosome-positive metaphases during pregnancy. Two patients (1 planned and 1 unplanned) had a spontaneous abortion shortly after discontinuation of imatinib. There were no other known medical conditions, personal or family history, or other factors that were considered to increase the risk of abortion. Three other patients (2 unplanned, 1 planned) were elected to have a therapeutic abortion shortly after the pregnancy was identified due to
Ir J Med Sci Table 1 Individual data of 22 CML patients and their pregnancy outcome ID no.
Age
Sex
Types of pregnancy
Parental data (total interruption of imatinib therapy due to pregnancy)
Interval between exposure and conception
1 st trimester exposure
Pregnancy outcome
CML-436/07
27
F
Planned
18 weeks
6 weeks
Imatinib was stopped
Healthy male child
CML-478/07
25
F
Planned
17 weeks
5 weeks
Imatinib was stopped
Healthy female child
CML-507/08
26
F
Planned
16 weeks
4 weeks
Imatinib was stopped
Spontaneous abortion
CML 554/08
31
F
Planned
16 weeks
4 weeks
Imatinib was stopped
Healthy female child
CML 603/09
33
F
Planned
19 weeks
7 weeks
Imatinib was stopped
Healthy male child
CML-678/10
28
F
Planned
18 weeks
6 weeks
Imatinib was stopped
Healthy female child
CML-764/10
26
F
Planned
17 weeks
5 weeks
Imatinib was stopped
Elective abortion
CML-103/03
26
F
Unplanned
4 weeks
Imatinib was continued at the time of conception
9 weeks
Imatinib was continued at the time of conception Imatinib was continued at the time of his wife’s conception
7 weeks
Spontaneous abortion
5 weeks
Healthy female child
Male child with hypospandium
CML-301/05
31
F
Unplanned
6 weeks
CML-448/07
29
F
Unplanned
9 weeks
CML-517/08
24
F
Unplanned
6 weeks
Continued treatment at the time of conception
7 weeks
Elective abortion
CML-616/09
23
F
Unplanned
5 weeks
Continued treatment at the time of conception
8 weeks
Elective abortion
CML-452/07
29
M
Planned
5 weeks
5 weeks
NA
Healthy male child
CML-566/08
34
M
Planned
6 weeks
6 weeks
NA
Spontaneous abortion
CML-596/08
35
M
Planned
4 weeks
4 weeks
NA
Healthy female child
CML-612/09
33
M
Planned
5 weeks
5 weeks
NA
Healthy male child
CML-653/09
34
M
Planned
5 weeks
5 weeks
NA
Healthy male child
CML-732/10
33
M
Planned
6 weeks
5 weeks
NA
Healthy female child
CML-42/02
24
M
Unplanned
No interruption
Imatinib was continued at the time of his wife’s conception
NA
Elective abortion
CML-210/04
32
M
Unplanned
No interruption
Imatinib was continued at the time of his wife’s conception
NA
Healthy female child
CML-399/06
27
M
Unplanned
No interruption
Imatinib was continued at the time of his wife’s conception
NA
Male child with
Imatinib was continued at the time of his wife’s conception
NA
CML-412/06
27
M
Unplanned
No interruption
mild hydrocephalus Healthy female child
NA Not applicable
abnormal clinical findings of the fetus (Table 1). Five patients who had gone abortions, restarted the treatment with imatinib 2 weeks after their abortions. Seven other pregnancies were carried to term, resulting in the birth of seven babies. There was a hypospadia in one unplanned pregnancy case (Table 1). Other six babies were healthy with average weight of 2.5–3.4 kg (Table 1). Among them, in case of one unplanned pregnancy, the healthy child was born (Table 1). After a median follow-up time of 18 months of restart of imatinib all patients archived CHR with major cytogenetic response.
Male patients Among 10 male patients whose wives conceived while they were on imatinib treatment, 6 pregnancies were planned in which cases male patients were advised to interrupt treatment for 1 month and they restarted imatinib immediately after conception of their wives. All six planned pregnancies were in CHR, CCR and MMR (Tables 1 and 2). Other four patients were on treatment while their wives became pregnant accidentally. In unplanned pregnancy imatinib continued uninterruptedly. In unplanned pregnancy
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Ir J Med Sci Table 2 Dose of imatinib therapy and status of disease of 22 CML patients before pregnancy and after their child birth lD no.
Sex
Age
Types of pregnancy
At the time of conception
At the time of termination of pregnancy
Imatinib dose (mg/d)
CHR
CCR
MMR
CHR
CCR
MMR Yes
CML-436/07
F
27
Planned
400
Yes
Yes
Yes
Yes
Yes
CML-478/07
F
25
Planned
300
Yes
Yes
Yes
Yes
Yes
Yes
CML-507/08
F
26
Planned
400
Yes
Yes
Yes
No
No
No
CML 554/08
F
31
Planned
400
Yes
Yes
Yes
Yes
Yes
Yes
CML 603/09
F
33
Planned
400
Yes
Yes
Yes
Yes
Yes
No
CML-678/10
F
28
Planned
400
Yes
Yes
Yes
Yes
Yes
Yes
CML-764/10 CML-103/03
F F
26 26
Planned Unplanned
400 400
Yes Yes
Yes Yes
Yes No
Yes No
Yes No
Yes No
CML-301/05
F
31
Unplanned
400
Yes
No
No
Yes
No
No
CML-448/07
F
29
Unplanned
400
Yes
No
No
No
No
No
CML-517/08
F
24
Unplanned
600
No
No
No
No
No
No
CML-616/09
F
23
Unplanned
600
No
No
No
No
No
No
CML-452/07
M
29
Planned
400
Yes
Yes
Yes
NA
NA
NA
CML-566/08
M
34
Planned
400
Yes
Yes
Yes
NA
NA
NA
CML-596/08
M
35
Planned
400
Yes
Yes
Yes
NA
NA
NA
CML-612/09
M
33
Planned
400
Yes
Yes
Yes
NA
NA
NA
CML-653/09
M
34
Planned
400
Yes
Yes
Yes
NA
NA
NA
CML-732/10
M
33
Planned
400
Yes
Yes
Yes
NA
NA
NA
CML-42/02
M
24
Unplanned
800
No
No
No
NA
NA
NA
CML-210/04
M
32
Unplanned
600
Yes
No
No
NA
NA
NA
CML-399/06
M
27
Unplanned
600
No
No
No
NA
NA
NA
CML-412/06
M
27
Unplanned
400
Yes
Yes
No
NA
NA
NA
CHR Complete hematological response CCR Complete cytogenetic response MMR Major molecular response NA Not applicable
incidentally two patients were in complete hematological response and among them one was in complete cytogenetic response. One patient was in accelerated phase. There was one spontaneous abortion (planned pregnancy) and one elective abortion (unplanned pregnancy) (Table 1). The conceptions resulted in the birth of eight babies (four female and four male babies of average weight of 2.5–3.5 kg). Among them, one baby (unplanned pregnancy) was born with mild hydrocephalus (Table 1). There was no other identifiable congenital anomaly or adverse medical condition at the time of birth (Table 1).
Discussion Imatinib, used primarily for CML, has demonstrated that tyrosine kinase inhibitors can have a wide therapeutic window and herald the era of targeted cancer and noncancer disease therapy [18]. Imatinib mesylate has become a standard first-line therapy in Chronic Myeloid Leukemia, both in chronic phase and also in accelerated phase, though the response is of shorter duration in the latter.
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There does not seem to be any long-term consequences of its use, even though evidences are not available for more than 5 years (median value). But there is very limited data as far as the effects on pregnancy are concerned. It is very difficult for the patients who become pregnant, while on treatment, to balance the risk to the fetus of continuing imatinib versus the risk to the mother of interrupting treatment. From the fetal perspective, imatinib should be discontinued due to the potential risk of serious developmental abnormalities; from the maternal perspective, this may not be appropriate [9]. So in these cases considerations should include the wishes of the parents, disease status of father or mother, the availability of suitable alternative therapies and the ability to reinduce responses to imatinib after a prolonged period of discontinuation of imatinib. In the present study, we compared our data of 22 pregnancies among 166 CML individuals with the other reported study [9, 18–21]. Ault et al. were the first [19] to analyze data on the effects of imatinib on pregnancy. They reported 19 pregnancies in which either male or female patient was getting treatment. There were 3 spontaneous abortions (15.7 %, 1
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planned), 1 planned termination (5.2 %), but the other 16 were uneventful. One of the bigger series was reported [9], who analyzed data on 180 women being exposed to imatinib during pregnancy. Out of the 125 patients, a total of 63 pregnancies resulted in the birth of normal live infants. Among them 28 % underwent elective termination and 14.4 % underwent spontaneous termination. These studies [9, 11, 17, 19, 20, 22] reported the high incidence of the abortion in case of CML patients on imatinib therapy. Our present data also shows moderately high incidence (3 out of 22 or 13.6 %) of spontaneous abortion and 4 elective abortions (18 %) due to clinical abnormalities of fetus. In our data, spontaneous abortion rate is higher in female patients than in the male patients who were on imatinib therapy. The high rate of termination is understandable, considering many of the pregnancies were unplanned. Therefore, the CML patients under tyrosine kinase inhibitor therapy are advised to practice adequate contraception. Still the marriageable patients wish to conceive and they must be monitored for their disease status before conception. Planned pregnancies may be encouraged which include those patients remaining in CHR, CCR and at least MMR for 2 years. But in some cases, accidental pregnancies are also occurred. For planned/accidental pregnancies, weighing the risk or benefit ratio and carrying out individual counseling are probably the appropriate options. Also, though this was not one of our end points, the discontinuation of imatinib and the effect of restarting it have to be kept in mind with the limited data available. In unplanned cases, there is the risk of spontaneous abortion and or teratogenic anomalies of the fetus due to the effect of imatinib. According to references, half-life of imatinib and its major active metabolite, the N-desmethyl derivative, were approximately 18 and 40 h (NCBI database). The effect of imatinib on fertility, pregnancy outcome and lactation are known mostly from animal studies (Gleevec, product label; Novertis, Basel, Switzerland). Imatinib was teratogenic in rats when administered during organogenesis at doses more than 100 mg./kg, which is equivalent to 800 mg/day of human dose. Female rats, where it had been given as greater than 45 mg/kg (approximately equivalent to a human dose of 400 mg/day based on body surface area) experienced significant postimplantation loss with increased fetal resorption, still births, nomiable pups and early pup mortality [9]. Earlier studies reported various fetal abnormalities like meningoecoele, scoliosis, hydrocephalus, cerebellar hypoplasia, hypospadia, hypoplastic lungs, etc. Pye et al. reported 9.6 % fetal abnormality where as another study [19] showed 12.5 % of minor birth defects.
In our present study, two babies (13 %) were born with defect, one with hypospadia and one with mild hydrocephalus. But both cases were happened in case of unplanned female pregnancies where imatinib was continued unknowingly during first trimester of pregnancy. They reported the concentration of imatinib in placenta, umbilical cord blood and breast milk as 2,452, 0–157 and 596 ng/ml, respectively. In maternal perspective, in our present study, 13 patients who had all been in CHR, CCR and MMR for a period of at least 2 years, 3 (23.3 %) patients developed molecular relapse after withholding imatinib therapy, but the remaining 10 continued to have undetectable BCR-ABL transcripts at a median of 18 months’ follow-up. Of those who relapsed, most again achieved a CCR and MMR within a relatively short period following reintroduction of imatinib dose of 600–800 mg/day according to clinical presentation. In paternal perspective, very limited data are available about the effect of imatinib on spermatogenesis. According to study in leukaemic mouse model by Beate Schulthei et al. [22] imatinib mesylate as therapeutic doses has no impact on folliculogenesis or spermatogenesis. While in other rodent study, the effects of imatinib on the reproductive system were noticed. Oligospermia in a patient receiving imatinib therapy was noticed for the hypereosinophilic syndrome [23]. Other studies reported the deleterious effect of imatinib on differentiation of sperms but no effect of imatinib on the sperm count [24]. However, in present study, in case of planned pregnancies, we have suggested the male patients to stop imatinib for 1 month prior to conception and perform the sperm analysis. But no significant change was detected in their sperm analysis. Though we have no data of sperm analysis in cases of unplanned pregnancies. However, some previous data and our present data suggest that imatinib intake in CML patients can be a barrier of conception. Our data also suggest that if pregnancy is planned when the patient is in hematological, cytogenetic and molecular remission, then withholding imatinib may not interfere with ultimate outcome. All of the planned patients with CHR, CCR and MMR get back to previous levels within 18 months of restarting imatinib. But in unplanned pregnancy where the patient is in accelerated phase, withholding imatinib is a risky process and ultimate disease outcome is not that satisfactory. Another point of view is that if imatinib is withholding from the period of conception to organogenesis it may not cause major birth defect. Two of our children (one hypospadi and one mild hydrocephalus) resulted from unplanned pregnancies and imatinib exposure during the first trimester of organogenesis.
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There was another small study by Kuwabara et al., in which 7 patients interrupted treatment by imatinib at the advent of pregnancy. They concluded that adequate response after discontinuation of therapy due to pregnancy is seen only in those who had an optimal response (MMR) before discontinuation [25]. Therefore, we can suggest that planned pregnancy during imatinib therapy may be encouraged but imatinib therapy in unplanned pregnancy can cause spontaneous abortion or congenital anomaly. Hence, women of child bearing potential should use adequate contraception while using imatinib. Willing parents who are in CHR, CCR and MMR for at least 2 years may be advised to plan for pregnancy under strict medical supervision and imatinib must be withheld at least 1 month prior to conception to 3 months post conception (organogenesis period). Lactating mothers on imatinib therapy should avoid breast feeding for the benefit of the babies. The present data are the first report of pregnancy in CML patients on imatinib therapy from India so it is significant but the number of subjects is too small to strongly conclude about the positive or negative teratogenic effect of imatinib, while more data are required. In respect to the total number of CML patients treated in our institute, the present data show very low frequency of CML patients becoming pregnant on imatinib therapy. Because all the patients are advised to use contraceptive measures. Still, in the ethical as well as medical ground, the data are significant in case of willing CML parents. Acknowledgment We owe our sincere acknowledgement to Max Foundation, USA and Novartis, India with thanks for providing the patients with imatinib free of cost. We also acknowledge all of our patients and other fellows of Pathology and Molecular Biology department for their constant help and support. We are also grateful to West Bengal University of Health Sciences under which our Institute is affiliated. Conflict of interest
None.
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