article about pregnancy during gleevec

November 25, 2005

here is a case story of 1 indian patient. it only strengthen the caution that

should be exercised if a woman wants to become pregnant on gleevec

shalom

gior

ls of Oncology letter to the editor

Pregnancy on imatinib: fatal

outcome with meningocele

We read with interest a recent letter by Prabhash et al. [1]

showing a successful outcome of pregnancy in two patients on

imatinib. There have also been a few other recent reports where

no adverse effects have been reported [2–4]. However, we

would suggest extreme caution, based on our experience in

a patient who conceived while on imatinib with an adverse

outcome.

A 25-year-old female was diagnosed as having chronic

myeloid leukemia in chronic phase in July 2004. She had no

significant past medical history and was nulliparous.

Examination revealed spleen palpable 10 cm below costal

margin. Hematological parameters (hemoglobin 7.8 g/dl, white

blood cell count 23.4 · 109/l and platelet count 383 · 109/l) and

RT–PCR revealed positive BCR-ABL translocation. Her

biochemical parameters, including liver, renal functions and

uric acid, were within normal limits. Therapy was started with

imatinib (Glivec; Novartis, Basel, Switzerland) 400 mg/day as

part of a research project where the drug was provided free. She

was counseled to avoid pregnancy. Complete hematological

remission was achieved at the end of 1 month and molecular

remission after 3 months. Imatinib was continued at the same

dosage. The patient reported to the clinic with history of

amenorrhea of one and half months’ duration in January 2005

and a pregnancy test was positive. After counseling, she

declined termination of pregnancy, but imatinib was stopped.

No drug was administered until completion of the first

trimester. As the patient could not afford interferon,

hydroxyurea was administered to control the blood counts and

symptoms. At 30 weeks, ultrasound abdomen revealed the

presence of a meningocele. She delivered a dead fetus with the

meningocele at the 34th week of pregnancy. She was restarted

on imatinib with further advice for strict contraception and to

stop the drug before any planned pregnancy.

The limited published literature suggests that imatinib is

safe in pregnancy [1–4]. However, animal experiments suggest

it is unsafe. Imatinib, an inhibitor of abl-tyrosine kinase, is

teratogenic in mouse and rats when administered during

organogenesis at doses of >100 mg/kg, causing exencephaly or

encephalocele, and absent or reduced frontal and absent

parietal bones [5]. The most critical period for teratogenicity is

the first trimester as this period correlates with active

organogenesis. Our patient had been exposed to imatinib

during conception and for 6 weeks thereafter with development

of a meningocele and a fatal outcome. The few reports of

delivery of a normal fetus, even with intake of imitanib during

pregnancy, should not suggest that the drug is safe. Our case

clearly highlights that the drug is potentially teratogenic. To the

best of our knowledge this is the first such complication

reported in humans. We strongly recommend effective

contraception for all patients who are on imatinib.

D. R. Choudhary, P. Mishra, R. Kumar*, M. Mahapatra &

V. P. Choudhry

All India Institute of Medical Sciences, Department of Hematology,

AIIMS, 110029 New Delhi, India

(*E-mail: rajatkr@... or rajat1954@...)

references

1. Prabhash K, Sastry PS, Biswas G et al. Pregnancy outcome of two patients

treated with imatinib. Ann Oncol 2005; doi:10.1093/annonc/mdi398.

2. Ali R, Ozkalemkas F, Ozcelik T et al. Pregnancy under treatment of imatinib

and successful labor in a patient with chronic myelogenous leukemia (CML).

Outcome of discontinuation of imatinib therapy after achieving a molecular

remission. Leuk Res 2005; 29: 971–973.

3. AlKindi S, Dennison D, Pathare A. Imatinib in pregnancy. Eur J Haematol 2005;

74: 535–537.

4. Heartin E, Walkinshaw S, RE. Successful outcome of pregnancy in

chronic myeloid leukaemia treated with imatinib. Leuk Lymphoma 2004; 45:

1307–1308.

5. Hensley ML, Ford JM. Imatinib treatment: specific issues related to safety,

fertility,

and pregnancy. Semin Hematol 2003; 40: 21–25.

doi:10.1093/annonc/mdj065

letter to

the editor

ª 2005 European Society for Medical Oncology

ls of Oncology Advance Access published November 15, 2005

a

November 26, 2005

Shalom Giora,

And here is what Talpaz and Giles had to say in response to a question

on this subject.

Trevor from Houston:

My wife, 28 years old, is taking 800 milligrams of Gleevec and has

responded very well. What are the odds of her being able to get pregnant

and have a baby while on Gleevec and, subsequently, if that's not

possible, going off the drug and coming back in about a year or so?

Dr. Talpaz:

You may have two answers, and they may not be the same because it's an

issue that is not a settled issue. First of all, the general notion is

we would not like to see pregnancy on Gleevec, and the reason is

Gleevec, theoretically, is teratogenic, which means because it can

destabilize the DNA, it can cause embryonic defects. There are animal

models which suggest teratogenesis. However, whether it happens in

reality or not, we don't know, but we absolutely do not recommend

pregnancy on Gleevec.

The other issue is, can we interrupt Gleevec and allow pregnancy to go

on? There is very limited experience with patients that achieve complete

molecular remission and interrupt the treatment with Gleevec. It has

been done in a handful of patients. Regretfully, in the majority of

them, there was molecular and cytogenetic relapse to suggest that a

small amount of the disease is still present, even at the time of

complete molecular remission, and the disease may come back while on

therapy. So, at this point, I cannot recommend this approach. What I may

recommend is, of course, to interrupt treatment for a month or two and

collect eggs and eventually plan something around that. But, at this

point, I would not recommend pregnancy with the involvement of Gleevec

or interruption.

Dr. Giles:

And just to emphasize, we have absolutely no knowledge that could allow

a physician to responsibly tell somebody it is okay to keep taking this

drug deliberately while you go ahead and have a child. Just to review

the data that is available, the fact is that as Gleevec has offered a

normal lifespan potentially, people want to get on and have their

family, and this database is growing. There are three situations. One is

where people have become pregnant by accident and, of course, you never

know what the denominator is. Nature may take care of any really bad

teratogenicity. But, certainly, there are examples where people have

gone to full term and had a perfectly normal, healthy child. The

literature also contains examples of where people have deliberately

stopped in order to go ahead and have a child, and the data is split

roughly 50-50. About half of the patients are able to have a normal

pregnancy. They have no evident progression of their disease, and they

take up their drug where they left off. The other half have at least

evidence, if not of clinical disease, that by the cytogenetics or the

molecular markers, the disease is coming back. Thankfully, in almost

all, if not all of those cases, they have not lost sensitivity to

Gleevec, so they're able to recapture their response.

I think the only responsible advice we could give somebody is that if

you're intent on doing this, you should at least try and get a major

molecular remission first, at least try and get to the minimum disease

tumor load you're entitled to during the years that you're fertile. Get

there, discuss it, and then if you're going to do it, take a deliberate

break, monitor closely and reintroduce the drug if needed.

Zavie

[ ] article about pregnancy during gleevec

here is a case story of 1 indian patient. it only strengthen the caution

that should be exercised if a woman wants to become pregnant on gleevec