[转载]TKI与怀孕生育（译）
在5月10日，我转载了一篇费希翻译的《TKI和生育》。这篇博文中的表格也译自《Tyrosine
Kinase Inhibitors and Pregnancy》，未尽之处大家可以参考费希翻译的表格。
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原文作者对TKI动物实验结果、现有的慢粒人怀孕生育研究报告进行了回顾和总结，并对慢粒人怀孕生育提出了自己的见解。
该文章再次肯定了伊马替尼男和尼罗替尼男生育的安全性，并提出慢粒女也可以在各科专家的指导下顺利怀孕并进行母乳喂养。
文章主要内容翻译如下：
（一）慢粒男
1.研究表明，服用伊马替尼或者尼罗替尼对慢粒男的生育能力不会造成特定的危害，他们配偶的怀孕生育情况已经证实了这一点。
2.服用达沙替尼的慢粒男，在生育方面要谨慎一些，因为关于服用达沙替尼的男性的生育情况的数据非常有限。服用博舒替尼和普纳替尼的慢粒男的生育情况的研究报告还是空白（文章提到，服用博舒替尼和普纳替尼的慢粒男的研究报告，也就是REPORTS还是零。但是作者也提到他所在的医院中，有一位参与博舒替尼临床试验的男性病人，在服用博舒替尼之前冷冻了精子，后来通过人工授精的方式，有了一个健康的女儿。他女儿现在已经三岁了，一直都发育良好）。这些病人，可以在治疗之初就考虑冷冻精子。
（二）慢粒女
1.处于生育年龄的慢粒女，在确诊时，医生就应该告诉她们要进行有效地避孕。在获得稳定的MMR（或者获得更好的治疗效果，例如大于MR4.5)至少18-24个月后，再尝试有计划的怀孕（小沐洱注：也就是，planned
conception，和意外怀孕相对）。强烈建议慢粒女在怀孕前，去妇产科进行孕前检查（有时候也要对配偶的精子质量进行评估）、超声检查，并且要有计划地怀孕。
2.在怀孕紧跟前或者怀孕后要立刻停止治疗。在胎儿器官形成（organogenesis）的过程中（上次月经后的31-71日内，孕5-13周之间），所有的药物都要停止。
每个月或者每两个月进行一次Q-PCR监测，以确定转录本的情况。
只有在细胞遗传学或血液学复发的情况下，才考虑在孕期进行治疗。根据病人复发的速度、CML临床治疗史，最重要的是怀孕的阶段（怀孕的周数），来具体问题具体分析从而确定病人的治疗方案。
整个孕期，使用干扰素都是安全的。胎儿器官形成后，可以用羟基脲来减少白细胞的数量。
需要的话，可以在胎盘形成之后和器官发育完成后，使用伊马替尼和尼罗替尼这样的TKI进行治疗。但在动物实验中，我们发现使用尼罗替尼的话，胎儿肝脏中的尼罗替尼含量很高。
达沙替尼似乎能够穿过胎盘，因此不能在孕期服用达沙替尼。
3.所有的慢粒女都可以在产后2-5天内进行母乳喂养，给新生儿提供初乳。新生儿的消化系统尚不完善，初乳虽然量很少，却可以给新生儿提供浓缩的营养。而且初乳还有诸多好处，例如……(小沐洱注：这里省去初乳的诸多好处，初乳的好处大家可以百度一下)
在产后2-5天再开始恢复治疗，其实也没拖上几天，对产妇来说不会有什么大事，但是，让新生儿吃上初乳，对新生儿来说，却是件大事。
如果分子学转录本情况（molecular
transcript）良好，根据血液学专家的判断，在产后，可以适当地将开始恢复吃药的时间往后拖，从而使母乳时间最大化。
4.有很多慢粒女在怀孕期间慢粒控制良好，也有很多慢粒女怀孕前服用某种TKI治疗效果良好在怀孕后停药，恢复治疗后3-6月内又重新实现了MMR，所有这些病人的治疗效果都证明，我们是可以让慢粒女平安顺利地怀孕的。
5.有一点非常重要，那就是，我们要对每一个病人进行具体问题具体分析，因为病人慢粒情况的生物学特征、慢粒的治疗效果、怀孕期间的情况，以及病人自己的意愿这些因素都可能对最终的结果起着至关重要的作用，因此，所有这些因素都需要考虑在内。
原文链接：
原文题目：Tyrosine Kinase Inhibitors
and Pregnancy
作者：Elisabetta Abruzzese, Malgorzata Monika Trawinska, Alessio Pio
Perrotti and Paolo De Fabritiis
Hematology, S. Eugenio Hospital, Tor
Vergata University.
Correspondence to: Elisabetta
Abruzzese, MD, PhD. Hematology, S. Eugenio Hospital, Tor Vergata
University. Piazzale dell’Umanesimo 10, 00144 Rome, Italy. Tel +39
06-, Fax +39 . E-mail:
Published: 2014
Received: January 15, 2014
Accepted: March 10, 2014
Meditterr J Hematol Infect Dis ): e2014028, DOI
This article is available on PDF format at:
This is an Open Access article
distributed under the terms of the Creative Commons Attribution
License (),
which permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited
The management of patients with
chronic myeloid leukemia (CML) during pregnancy has become recently
a matter of continuous debate. The introduction of the Tyrosine
Kinase Inhibitors (TKIs) in clinical practice has dramatically
changed the prognosis of CML in fact, patients diagnosed
in chronic phase can reasonably expect many years of excellent
disease control and good quality of life, as well as a normal life
expectancy, including the necessity to address issues relating to
fertility and pregnancy. Physicians are frequently being asked for
advice regarding the need for, and/or the appropriateness of,
stopping treatment in order to conceive. In this report, we will
review the data published in terms of fertility, conception,
pregnancy, pregnancy outcome and illness control for TKI treated
CML patients, as well as how to manage a planned and/or unplanned
pregnancy.&
IntroductionThe
hybrid BCR-ABL gene and its tyrosine kinase constitutionally active
recombinant fusion protein (p210 BCR-ABL) deriving from the
reciprocal translocation between chromosomes 9 and 22 is associated
with the clinical development of chronic myeloid leukemia
(CML).[] This
fusion results in the expression of two forms of protein-tyrosine
kinases: p190 (BCR-ABL) and p210 (BCR-ABL) with subsequent
dysregulation of intracellular signaling that drive cells to
enhanced proliferative capability and resistance to
apoptosis.
The presence of this well defined pathogenetic defect at the
molecular level led to the development of Imatinib, a tyrosin
kinase inhibitor able to block the BCR-ABL aberrant molecule, thus
shutting down the leukemia phenotype.[]
Imatinib (Glivec, Novartis), is the first of a series of tyrosin
kinase inhibitors (TKIs), a group of drugs used to manage patients
with chronic myeloid leukemia (CML) through the competitive ATP
inhibition at the catalytic binding site of the bcr-abl
protein.[] The
second and third generation TKIs include Nilotinib (Tasigna,
Novartis), Dasatinib (Sprycel, Bristol Myers Squibb), Bosutinib
(Bosulif, Pfizer), and the recently approved Ponatinib (Iclusig,
Ariad Pharma).
The introduction of TKIs in clinical practice has dramatically
changed the prognosis of CML patients. Data derived from first line
therapy (IRIS Study) at 7 years follow up, confirmed one year
later, reports cumulative best rates of complete cytogenetic
remission (CCR) of 82%, and an estimated overall survival of
Patients diagnosed in chronic phase can reasonably expect many
years of excellent disease control and good quality of life (QoL);
furthermore, patients in an optimal response can reach a life
expectancy similar to the non-leukemic, same age,
population.[]
Even if a higher median age at diagnosis (55-60 y.o.) were
reported, the GIMEMA registry of CML has reported that
approximately 50% of patients at diagnosis are in reproductive age
(Figure 1). This has addressed issues relating fertility and
pregnancy and physicians are frequently asked for advice regarding
the need and/or the appropriateness of stopping treatment in order
to conceive.
TKIs in Animal Model
Imatinib: Studies on either males or females rats and
mice have shown that Imatinib administered to fertile animals has a
teratogenic but not gonadotoxic activity.
However, when male rats were given Imatinib at dosages between 20
and 60mg/kg (corresponding to the human dose of 200-600mg/d) lower
testicular weight and reduction of sperm mobility were observed at
higher dosage. If similar dosages were given to immature rats,
interference with the normal process of testis maturation was
noticed, while, at sexual maturity, a normal number of sperm
counts, motility, maturation and development and higher levels of
FSH and LH were registered.[]
Effects of Imatnib on ovary were unremarkable, so that the
fertility of male and female rats was not affected.
The effects on gestation differed by the dosage utilized:
teratogenic effects of skull and bone formation (exencephaly,
encephalocele, absent or reduced frontal bones and absent parietal
bones) were seen when Imatinib was administered during
organogenesis at 100mg/kg (corresponding to 1000 mg in humans),
while, at higher dosages, total fetal loss was seen in all animals.
Fetal loss was not observed at dosages &=30 mg (Novartis:
Imatinib investigator brochure).
Nilotinib: As reported with Imatinib, genotoxicity
studies in bacterial in vitro and in vivo mammalian systems did not
reveal evidences for a mutagenic potential of Nilotinib.
In pharmacokinetic distribution studies in rats at dosages up to
180mg/kg per day, Nilotinib showed minimal brain and testis
penetration. A significant decrease in total epididymal weight was
observed at the maximum dose level, while all other male
reproductive parameters, including sperm count and sperm motility,
were unaffected.
Reproductive and developmental studies have been completed in rats
and rabbit. No effects on fertility were noticed in males or
females rats, while at doses &20mg/kg/d the embryos died.
Compared to Imatinib, no evidence of teratogenicity in rabbits or
rats was seen, while the drug was embryo- and fetotoxic in rats and
rabbits at dosage producing maternal toxicity. The oral
administration of Nilotinib in female rats from d6 gestation to d21
post-partum resulted in only maternal effects, as observed after
longer gestational period, reduced food consumption and lower body
weight gain at 60mg/kg. The maternal dose of 60mg was also
associated with decreased pup body weight and changes in some minor
physical, developmental parameters (earlier tooth eruptions and eye
Following a single dose of 20 mg/kg oral dose of C14 Nilotinib in
pregnant rats, the higher tissue concentration compared to blood
were observed in the maternal liver, kidney, uterus heart and
amnion. In the fetus, the tissue concentration was lower than that
observed in the maternal organs, except for the liver, which had
1.6 fold higher levels. After oral daily dosing between 30 and 100
mg/kg, Nilotinib concentration was below the limit of
quantification in rabbit’s fetuses, while in the group treated with
300mg/ fetus concentration was only 8% of the maternal serum,
indicating a low absorption of Nilotinib in the fetus. The transfer
of drug and metabolites to milk was observed following an oral dose
of C14 Nilotinb to lactating rats. It is estimated that, in 1L of
human milk, the infant can be exposed to 0.26% of a 400mg adult
dose. (Novartis: Nilotinib investigator brochure)
Dasatinib: Dasatinib did not appear to affect
fertility in male rats at dosage &10 mg/kg/day and was not toxic
to the offspring at these doses, while effects included reduced
size and secretion of seminal vesicles and testis and an immature
In female rats, Dasatinib was observed to be teratogenic,
extensively distributed in maternal tissues, and secreted into
At plasma concentrations below those observed in humans receiving
therapeutic dosage of Dasatinib, embryo-fetal toxicities were
observed in pregnant rabbit and rats. Fetal deaths were observed in
rats. In both rats and rabbits, the lowest doses of Dasatinib
tested resulted in embryo-fetal toxicities. These doses produced
maternal AUCs 0.3 fold the human AUC in females at dose of 70 mg
twice daily, and 0.1 fold the human AUC in rats and rabbits.
Embryo-fetal toxicities included skeletal malformations at multiple
sites (scapula and all long bones, including ribs), reduced
ossification, generalized oedema and microhepatia. (Dasatinib
Investigator B Sprycel� (Dasatinib) tablets, Summary of
Product Characteristics)
It is not known whether Dasatinib is excreted in human milk.
Other TKIs: Little is known concerning the recently
approved Bosutinib (Bosulif, Pfizer) and Ponatinib (Iclusig, Aria
Pharma), although for both of them preclinical studies of
mutagenesis seem to be negative, and teratogenity is similar to the
other described TKIs with effects on osteogenesis and
vasculogenesis.
TKIs in Pregnancies and Conception
Imatinib in man: Since the first reports of unplanned
conception in male taking Imatinib at standard and higher dosages,
no increased risk of congenital malformations or increased abortion
have been reported.[]
In a series of female and male patients treated with Imatinib, Ault
described 8 male patients who conceived, with an exposure of 18
months (range 4-48 months) to Imatinib. Taking into consideration
the 72 days for male gonads to come to maturation, the majority of
those patients have been fully exposed to the drug at conception.
In those 8 patients, conception resulted in the birth of 8 babies
(1 spontaneous abortion and one twin pregnancy). One of those
babies was born with a mild malrotation of the small intestine,
surgically fixed. No problems were observed after the birth in
terms of growth and development in 38 months follow up.
More than 150 cases have been described so far and except for the
malrotation of the intestine reported earlier and one stillbirth
with malformations in the previous series, the other
pregnancies/deliveries resulted uneventfully.
Imatinib in women: Completely different is the
outcome when the woman is taking Imatinib, and the embryo-fetus is
exposed to the drug.
Different reports have been published in the past years reporting
patients treated with Imatinib who conceived and or became pregnant
during therapy. In the series of Ault et al., together with the 8
male patients, 10 female were presented (1 in CCR, 1 in accelerated
phase and 8 in an advanced phase of the disease) who received
Imatinib at standard dose (9 patients) or 800mg (1 patient) until
pregnancy was identified, with exposure between 4 and 9 weeks. Two
patients had a spontaneous abortion after discontinuation of
Imatinib, while one patient had a therapeutic abortion. The
remaining seven pregnancies were carried to term resulting in the
birth of 8 babies (twin girls). One baby had a hypospadias that was
surgically corrected, while the remaining 7 were healthy and
presented with a normal growth and development after 53 month
follow up.
The first systematic review of pregnancies was reported by Pye et
collected information from different Institutions, describing 180
women exposed to Imatinib during pregnancy. Of these pregnancies,
outcome data are available for only 125 (69%). Women were exposed
to Imatinib during all pregnancy (38 patients), during
1st trimester (103 patients), during both 1st
and 2nd trimester (4 patients) or after the
1st trimester (4 patients). Of those with known
outcomes, 50% delivered normal infants and 28% underwent elective
terminations, 3 following the identification of abnormalities. Of
12 infants with abnormalities identified in carried pregnancies, 8
were live births, 1 stillbirth, and 3 terminations. A total of 10
of the 12 infants with abnormalities have been exposed to Imatinib
during the first trimester (information unavailable for the
remaining 2 infants). Because of both tyrosine kinases and bcr-abl
inhibition by Imatinib, it is conceivable that the congenital
abnormalities result from inhibition of members of this extensive
family. Furthermore, the abnormalities evidenced were similar to
those observed in preclinical studies (exencephaly,
encephalopathies and abnormalities of the skull bones observed in
the rodent studies).
Recently, more attention is given to the possibility of a
planned/unplanned pregnancy in CML patients of both sexes. The
majority of the events described, including 2 cases from our
institution (unpublished data), are carefully followed, pregnancies
are possibly planned, and Imatinib interrupted early or right
before conception, so all of the pregnancies resulted in normal
babies. The behavior of both physicians and patients may be
different in other Countries where discontinuation of the drug is
not systematic, and most of the pregnancies were not even reported
to the hematologist when discovered.[] Of
the 28 pregnancies from 21 female patients in remission reported by
the Pakistan group, 27 assumed Imatinib. Of the 27 exposed
pregnancies, 6 were exposed during 1st trimester (wks
6-12), 12 during 1st and 3rd,[] and
9 throughout the pregnancy until delivery. One stillbirth presented
with congenital malformations and one baby died without
malformations after one week after an apparently uneventful
pregnancy. In this series, the authors reported as adverse event 2
babies born prematurely with low birth weight. Finally, three
spontaneous abortion and 3 elective abortions were recorded.
Table 1 summarizes 167 of a total 210 Imatinib female
pregnancies published and/or observed in our Institution with
sufficient data and follow up. Within those 167 pregnancies, 128
were uneventful (77%), while 24 ended in spontaneous abortion
(14%), a percentage slightly higher compared to the normal
population (10-12%).[]
Fifteen/167 (9%) presented with abnormalities, including one
referred to a concomitant drug (warfarin syndrome). All patients in
this group were exposed to Imatinib during organogenesis (&5wk
gestation).
Table 1. Outcome in 265 described pregnancies in CML
Imatinib-treated patients.
Finally, although most pregnancies
exposed to Imatinib may have a successful outcome, a significant
proportion of drug-related serious fetal malformations and a
slightly higher risk of spontaneous abortion remain at risk. For
this reason, pregnancy should not be avoided, but planned.
Nilotinib in men: Little is reported regarding
conception during Nilotinib treatment. One case from our Institute
(unpublished data) regards a 33 years male patient with CML
enrolled in the GIMEMA NILIM trial (alternated Nilotinib/Imatinib),
who wanted to conceive his 2nd child. He discussed the
opportunity to delay therapy but, taking into consideration the 72
days necessary to complete gonads maturation process in male, we
suggested conceiving in the first two months on Nilotinib therapy.
He conceived after 40 days and had a healthy boy born at term. He
is now 5 years old, regularly growing and healthy.
The investigator brochure, ed.8 (June 2012) refers to a total of 36
cases of drug exposure via the father. One of these cases presented
with fetal abnormalities ended in a therapeutic abortion.
Nilotinib in woman: As for men, very little is
reported for women getting pregnant while exposed to Nilotinib. Two
cases were published and indexed, and one more case was reported by
an Italian institution. The firstly published case regards a
30-year-old woman with chronic myeloid leukemia who became pregnant
twice successfully. Philadelphia-positive CML in its chronic phase
was diagnosed at 16 weeks of her first gestation and received no
treatment throughout her pregnancy. At 38 weeks of gestation, a
normal infant was delivered by cesarean section. Two years later,
while, in major molecular response (MMR) on Nilotinib 200 mg bid,
she became pregnant again. The unplanned pregnancy was identified
during her first trimester of gestation after the patient had
experienced 7.4 weeks of amenorrhea. The patient was informed of
the potential fetal toxicities of therapy, but decided to carry on
her pregnancy. Nilotinib was stopped, and no further treatment was
given until delivery. A follow-up with ultrasound scans during the
course of the pregnancy was unremarkable. At gestational week 33,
she delivered via cesarean section a healthy male baby weighing 3.2
kg. He was breast-fed for 2 months and at 5 months post-partum, the
child was healthy and normally developing.[]
The second case was reported by the French intergroup of
regarded a 38 years female who got her 5th pregnancy
while on Nilotinib. Treatment was stopped when pregnancy was
discovered, and replaced by Interpheron-a. Three months ultrasound
showed a big omphalocele ending into the pregnancy
interruption.
The other case, unpublished, was reported in Italy: a 41 years
female resistant to Imatinib, switched to Nilotinib 400 bid,
achieving MMR after 3 months, and complete molecular remission
(CMR) with bcr-abl transcript undetectable at 9 months. After 11
months she became pregnant. Fetus was exposed for 5 weeks before
stopping therapy. The pregnancy was unremarkable. She lost CMR, but
PCR stayed &0.19% IS until delivering a healthy baby girl.
In the Nilotinib investigator’s brochure, 45 cases have been
reported of drug exposure during pregnancy. There was only one case
with fetal abnormalities (probably the same already described by
the French group). In addition, there was one female exposed
pregnant of twins with one twin experiencing congenital
transposition of great vessels resulting in death, and the other
twin experiencing a non-serious heart murmur.
Dasatinib in men: Cortes et al evaluated the effect
of Dasatinib on pregnant partners of 9 male patients who conceived
children while receiving Dasatinib (22). Normal newborns were
reported in 7 cases, with the outcome of the other cases unknown.
All male patients remained on treatment during and after the
pregnancies. In 1 case, the mother experienced pre-eclampsia but
delivered a healthy newborn at 37 weeks, without birth defects or
neonatal complications.
Dasatinib in woman. Published information regarding
the use of Dasatinib in pregnancy is limited to 17 cases describing
the outcome of female patients with CML, who became pregnant while
receiving Dasatinib. In all but 1 case, Dasatinib was stopped upon
confirmation of pregnancy in patients electing to give birth. Data
from 16 patients with CML enrolled in phase 1 to 3 Dasatinib
clinical trials and 6 voluntarily submitted reports were used to
complete the study described by Cortes et al..[] A
total of 13 pregnant female patients were identified: of these, 1
patient gave birth to a normal newborn, 1 to a premature newborn, 4
had induced abortions, 2 had spontaneous abortions and 5 were
pregnant at last reported follow-up. The normal infant was born to
a 36-year-old female patient with CML in chronic phase (CP).
Pregnancy was identified after 7 weeks of gestation when the
patient was under treatment with 70 mg of Dasatinib twice daily.
The premature infant was born to a 29-year-old female patient with
CML in accelerated phase treated with Dasatinib 70
he was delivered by caesarian section after 7 months' gestation,
was “small for dates” but had no defects.
Kroll et al[]
reported the use of Dasatinib in a 23-year-old female patient with
CP-CML, who became pregnant while undergoing treatment. When
pregnancy was identified after approximately 5 weeks of gestation,
she was being treated with Dasatinib 70 mg once daily and was in
CCR. Treatment was discontinued immediately. While the patient was
closely monitored and off therapy, she developed leukocytosis and a
mild thrombocytosis. Subsequently, she was given hydroxyurea, but
developed progressive leukocytosis and increased levels of lactic
dehydrogenase levels. Cytarabine was administered to reduce the
white blood cells (WBC) count to normal within several days. To
avoid further fetal exposure to chemotherapy and resume more
definitive therapy for the mother’s CML, doctors induced labor at
35 weeks. The patient delivered a healthy female baby without any
developmental delay or structural and functional anomalies. Three
days post delivery, Dasatinib 70 mg daily was restarted
concurrently with a 2-week hydroxyurea tapering. She reached CCR in
the peripheral blood 5 months after re-initiating Dasatinib.
Conchon et al[]
reported the use of Dasatinib in a 25-year-old female patient with
CP-CML, who became pregnant while undergoing treatment with 70 mg
twice daily. Pregnancy was identified during the first trimester,
while she was in hematologic remission and Dasatinib was
discontinued immediately. Hematologic relapse occurred, and the
patient was, therefore, treated with INF-α (although complete
hematologic response was not achieved). The patient delivered a
male baby at 33 weeks with no sequelae or malformations. A few days
following delivery, the patient was treated with hydroxyurea for 4
months, and then restarted TKI.
Berveiller et al[]
reported a 23-year-old woman with CML, who became pregnant after
the switch to Dasatinib following Imatinib failure. When pregnancy
was identified at 9 weeks of gestation, she was treated with
Dasatinib 100 mg once daily for 4 weeks achieving complete
hematologic response. Dasatinib was not discontinued due to the
high-risk characteristics of the patient, and an obstetric
ultrasonography at 16 weeks of gestation revealed a fetal hydrops
with subcutaneous edema, pleural effusion, and ascites. Pregnancy
was terminated due to the poor perinatal prognosis after 17 weeks
of gestation. The patient delivered a eutrophic male fetus with no
organ malformations except for microretrognathia and hypertelorism.
Fetal karyotype was also normal. Fetopathologic examination
revealed a subcutaneous edema in the nuchal and dorsal regions.
Transplacental transfer of Dasatinib was observed with drug
concentrations of 4 ng/mL in maternal plasma, 3 ng/mL in fetal
plasma, and 2 ng/mL in amniotic fluid.
Bayraktar et al[]
reported a normal pregnancy outcome of a 25-year-old patient with
CML, who was treated with Dasatinib 100 mg once daily for the first
6 weeks of gestation. Once the pregnancy was confirmed, Dasatinib
was stopped, and the patient was managed conservatively with close
observation of her disease. During her pregnancy, hematologic
relapse occurred with mild leukocytosis and thrombocytosis that did
not require treatment. The infant was delivered at 37 weeks without
any documented birth defects. The patient was restarted on
Dasatinib 100 mg daily shortly after her delivery and did not
breastfeed. At 2 years’ follow-up post delivery, the patient had
molecular remission and her daughter met all developmental
milestones.
Other TKIs: As far as we know, no
conception/pregnancies were described while taking Bosutinib or
Ponatinib. In our Institution, we followed a male patient diagnosed
with CML and enrolled in a Bosutinib trial that cryopreserved his
sperm before starting therapy and conceived with an intra-uterine
insemination (IUI) a healthy baby girl who is now 3 years old and
normally developing.
Discussion
Imatinib and the subsequent second and third generation TKIs has
represented and represents, a major advance leading to a successful
targeted therapy with substantial improvement of survival and
quality of life in CML patients.
Considering the significant proportion of female/male patients
diagnosed with CML in reproductive age, and the substantial normal
lifespan of those patients when treated and responding, it became
mandatory to address issues relating to fertility and pregnancy.
The management of fertility begins at diagnosis. In fact, the
patient in reproductive age should be informed about the risk of
unplanned pregnancies in terms of fetal problems and/or the risk of
uncontrolled disease in the case of stopping therapy, but also on
the possibility that a controlled pregnancy can be carried out when
the treatment has being started, and the response is optimal.
There are no consensus/guidelines regarding the best behaviour in
case of pregnancy.
While it seems that there are no problems in terms of fertility,
conception and delivery of female partners of male patients (even
if for newer TKIs not enough data are available), female patients
should not be exposed to TKIs during pregnancy.
Based on the published data, 10-20% of maternal exposure during the
1st trimester to TKIs ends in fetal problems or spontaneous
abortion. The problems consist mainly in skeletal malformations,
soft tissue abnormalities (especially involving the vessels and
organs formation) and small for date babies, and are similar to the
one described in animal studies.[]
An independent algorithm by Kumar et al. for the management of CML
during pregnancy recommended discontinuation of TKIs. If patients
are in the first or second trimester, interferon alpha (IFN-α) can
leukapheresis can regulate white blood cell (WBC) counts
as required and hydroxyurea considered for patients not responding
to IFN-α. Patients in their third trimester and not responding to
IFN-α or hydroxyurea can be treated with Imatinib, and if still not
responding, with second generation TKIs.[]
Shapira et al suggested an algorithm in which pregnancies
discovered at diagnosis should be considered for Imatinib treatment
only if& unresponsive to IFN-α and, possibly,
after 1st trimester.[]
Imatinib is a compound that highly binds to plasma proteins and has
a high molecular weight that should limit placental transfer. Two
studies addressed the possibility to administer Imatinib later in
the course of pregnancy, evaluating the concentration of this drug
and its active metabolites in the different maternal/fetus
compartments. In two cases presented by Russell at al, Imatinib
appears to cross the human placenta poorly. In two pregnancies
taking Imatinib during the 3rd trimester, concentration
of drug and his metabolite CGP74588 was measured at delivery in
maternal blood, placenta, and cord blood. Little or no drug was
found in the cord blood, while it was present at high concentration
in maternal blood and placental tissue, confirming this
hypothesis.[] In a
different pregnancy with exposure from 21st to
39th week of gestation, Imatinib was present at 338ng/mL
in the cord blood and 478 ng/mL in the peripheral blood infant (1/3
range) vs 1562 ng/mL in maternal blood.[]
In contrast, an high concentration of drug was found in breast milk
in both studies, as confirmed in other works and described in
animal models.[]
These reports suggest that in a male patient taking Imatinib or
Nilotinib, no particula conception or
pregnancy have been evidenced. Caution should be used when patient
is taking Dasatinib, due to the very few data available. No reports
are available for patients taking Bosutinib or Ponatinib. For those
patients, the possibility to cryopreserve sperm before starting
therapy should be discussed.
In a female patient, in reproductive age, effective contraception
should be suggested at diagnosis. A pregnancy should be planned
only after the milestone of a stable MMR (or better, e.g.
&MR4.5) reached more than 18-24 months earlier. Ob-gyn visit for
pre-conception tests (including in some cases male sperm
evaluation), ultrasound and planned conception is highly
recommended.
Therapy should be stopped immediately before or soon after
conception. All drugs must be avoided during the organogenesis
(post menstrual days 31-71, weeks 5-13), Q-PCR must be monitored
each month/2 months to follow the transcript. Therapy should be
considered only if a cytogenetic or hematologic relapse
occurs.[] Each
single patient should be individually evaluated taking into account
the rapidity of the relapse, the clinical CML history, and most of
all, the pregnancy status (weeks of gestation).
Interferon can be considered safe throughout pregnancy[] and
hydroxyurea can be used to control leucocytosis after
organogenesis.[] When
necessary, TKIs therapy with Imatinib or Nilotinib could be
considered after placenta has been formed and organogenesis
completed,[]
although high Nilotinib concentration has been found in fetal
liver, in animal models. Dasatinib, on the contrary, seems to pass
the barrier and should be avoided.
All patients can breast feed the first 2-5 days postpartum to give
the baby the colostrum. Newborns have very immature digestive
systems, and colostrum delivers its nutrients in a very
concentrated low-volume form. It has a mild laxative effect,
encouraging the passing of the baby' that helps to
clear excess bilirubin, contains immune cells and many antibodies,
immune substances and a series of cytokines and growth
Considering the few days of delay to resume treatment, it could be
important for the newborn to access this.
After delivery and providing a good molecular transcript, therapy
can be postponed to consent full breast feeding, according to the
haematologist judgement.
All cases with good control of the illness at conception and a good
response to a specific TKI stopped during pregnancy and resumed
after delivery, have re-reached MMR within 3-6 months, confirming
the possibility of a safe therapy manipulation during
pregnancy.[]
In conclusion, we can resume all those informations updating a
table earlier presented by Apperly (Table 2). It is
important to take into consideration that each case should be
considered as a single case in which many factors may play a
crucial role: the biology of the illness, the response to
treatment, the outcome during the pregnancy, and the willing of the
patient should be clearly considered and discussed.[]
Table 2.& Management of a female patient with
CML planning a pregnancy.
In our Institution, we have a team
composed by haematologists, urologists, ob-gyn and neonatologists,
that work together during the planning, the conception, the
pregnancy, the delivery and the immediate post-delivery, to assure
the best care to mother and child. We have followed 3 CML female
conception/pregnancies and 6 male conceptions, all with normal
children (1 female patient pregnancy is ongoing) plus many
pregnancies of patients affected by lymphomas or acute leukemia.
The preservation of fertility is part of our routine when a
female/male patient is diagnosed as having a hematologic problem
needing therapy.
Through the GIMEMA CML working party, there is an ongoing
observational retrospective and prospective multicenter study to
register all female pregnancies/male conception in TKIs era and a
similar registry is in preparation through the European Leukemia
Network of CML Working Party, coordinated by Italy and Russia. We
hope that an extensive report of such events will help in managing
the possibility to conceive in CML patients in order to give our
patients not only a normal lifespan, but also a normal life.
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