Successful pregnancies involving men with chronic myeloidleukaemia on imatinib therapy

Imatinib mesylate (STI 571, Glivec, Gleevec; Novartis, Basel,

Switzerland) is used for the first line management of chronic

myeloid leukaemia in chronic and accelerated phase (Druker

et al, 2006). Although developed to inhibit selectively the bcr-

abl tyrosine kinase, Imatinib has been subsequently discovered

to inhibit potently other tyrosine kinases, such as c-abl, c-kit

and platelet-derived growth factor receptor (PDGFR). Murine

studies have demonstrated imatinib-induced teratogenesis and

its effects on spermatogenesis appear to be dose-related (http://

www.pharma.us.novartis.com/product/pi/pdf/gleevec_tabs.pdf).

Male rats exposed to 75% of the maximum human equivalent

dose of 800 mg/d for about 70 d prior to mating had lower

epididymal and testicular weight along with reduction in the

number of motile sperm. Summary product characteristics

recommend strict avoidance in pregnant women. Although

there are reports of successful pregnancies on imatinib therapy,

there have also been reports of spontaneous abortion and

meningocoele in the literature, highlighting potential risks of

conception whilst undergoing imatinib therapy (Ault et al,

2006). To date, there are limited data available on the outcome

of pregnancies that occur while the male partner is receiving

imatinib. We report here on five healthy pregnancies conceived

from four male patients on long-term imatinib therapy.

In our four patients, median duration of imatinib exposure

prior to conception was 18 months (range: 4–48 months) and

their median age was 45 years (range: 41–46 years). Three

patients were on an imatinib dose of 600 mg/d or greater at the

time of conception. Cumulative imatinib dose prior to concep-

tion ranged from 48 to 852 g (median 216 g). All the patients

were compliant and tolerated imatinib therapy, achieving a

significant response (Table I). Sperm counts and levels of

androgens were not performed, as patients had no symptoms

suggestive of impotence. Partners of all four men had an

uneventful full-term delivery by normal vaginal delivery except

for one, which was by caesarean section. Birth weights and

lengths were between 25th and 75th centiles, and duration of stay

in hospital was comparable with that of normal deliveries.

Ault et al (2006) reported on the outcome of pregnancies

involving eight men (median age 35 years; range: 26–38 years)

at a median dose of imatinib 700 mg/d and exposure period of

20 months. Of the eight reported pregnancies, there was one

case of spontaneous abortion and of the seven successful

pregnancies there was one baby born with gut malrotation

needing surgical intervention (Ault et al, 2006). Hensley and

Ford (2003) reported four normal pregnancies: two therapeu-

tic abortions, one spontaneous abortion and one death in utero

at 13 weeks in eight of 13 completed pregnancies involving

male patients on imatinib therapeutic trials. Oligospermia has

been reported in one patient on imatinib at a dose of 800 mg/d

for at least 6 months for chronic eosinophilic leukaemia

(Seshadri et al, 2006). Gynaecomastia has also been noted in

seven patients, median age 60 years (39–84 years) on imatinib

therapy at a dose of 600–800 mg/d (Gambacorti-Passerini

et al, 2003). In these patients, testosterone levels were low and

progesterone levels were high and median onset of gynaeco-

mastia was at 12 (5–13) months of therapy. Inhibition of C-kit

and PDGFR expression in testicular tissue by Imatinib has

been speculated to be causative in testosterone reduction.

We report on five uneventful pregnancies in partners of

patients who were on prolonged high-dose imatinib therapy

Table I. Patient characteristics and parturition information.

Sex/age

(years)

Imatinib

dose (mg)/disease

status at time of

conception

Cumulative

Imatinib dose prior

to conception (g)

Duration of Imatinib

therapy prior to conception

(months)

Duration of

pregnancy/mode

of delivery

Weight of

neonate (kg)

Length

(cm)/sex Complications

M/45* 400/MCyR 48 4 Term/NVD 3.7 59/M Nil

M/45* 600/CCyR 315 19 Term/NVD 3.6 59/F Nil

M/46 400/PCyR 216 18 Term/CS 3.0 52/F Nil

M/41 800/CCyR 852 48 Term/NVD 2.7 51/F Nil

M/41 800/MCyR 186 13 Term/NVD 2.9 52.4/M Nil

*Indicates the details of the patient that fathered two children.

NVD, normal vaginal delivery; CS, caesarean section; MCyR, major cytogenetic remission; CCyR, complete cytogenetic remission; PCyR, partial

cytogenetic remission.

correspondence

First published online 4 April 2007 ª 2007 The Authorsdoi:10.1111/j.1365-2141.2007.06542.x Journal Compilation ª 2007 Blackwell Publishing Ltd, British Journal of Haematology, 137, 374–383

for CML. In spite of the successful conception in these four

patients, existing data suggest that use of imatinib can be

deleterious to spermatogenesis. Appropriate pharmacovigi-

lance must be exercised and patients should be advised to take

appropriate contraceptive precautions while on imatinib.

Studies into the dose–effect relationship of imatinib and male

fertility are warranted.

Karthik Ramasamy

Janet Hayden

ZiYi Lim

Ghulam J. Mufti

Aloysius Y. L. Ho

Department of Haematology, Kings College Hospital NHS Foundation

Trust and Kings College London, London, UK

E-mail: aloysius.ho@kch.nhs.uk

References

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Koller, C., Giles, F., Keating, M., Talpaz, M. & Cortes, J.

(2006). Pregnancy among patients with chronic myeloid

leukaemia treated with imatinib. Journal of Clinical Oncology, 24,

1204–1208.

Druker, B.J., Guilhot, F., O’Brien, S.G., Gathmann, I., Kantarjian, H.,

Gattermann, N., Deininger, M.W., Silver, R.T., Goldman, J.M.,

Stone, R.M., Cervantes, F., Hochhaus, A., Powell, B.L., Gabrilove,

J.L., Rousselot, P., Reiffers, J., Cornelissen, J.J., Hughes, T., Agis, H.,

Fischer, T., Verhoef, G., Shepherd, J., Saglio, G., Gratwohl, A.,

Nielsen, J.L., Radich, J.P., Simonsson, B., Taylor, K., Baccarani, M.,

So, C., Letvak, L. & Larson, R.A. (2006) Five-year follow-up of

patients receiving imatinib for chronic myeloid leukaemia. New

England Journal of Medicine, 355, 2408–2417.

Gambacorti-Passerini, C., Tornaghi, L., Cavagnini, F., Rossi, P., Pecori-

Giraldi, F., Mariani, L., Cambiaghi, N., Pogliani, E., Corneo, G. &

Gnessi, L. (2003) Gynaecomastia in men with chronic myeloid

leukaemia after Imatinib (Letter). The Lancet, 363, 1954–1956.

Hensley, M.L. & Ford, J.M. (2003) Imatinib treatment: specific issues

related to safety, fertility, and pregnancy. Seminars in Hematology,

40, 21–25.

Seshadri, T., Seymour, J.F. & McArthur G.A. (2006) Oligospermia in

a patient receiving imatinib therapy for the hypereosinophilic syn-

drome (Letter). New England Journal of Medicine, 351, 2134–2135.

Keywords: chronic myeloid leukaemia, imatinib mesylate,

spermatogenesis.

First published online 4 April 2007

doi:10.1111/j.1365-2141.2007.06542.x

GATA1 mutational analysis in chronic myeloid leukaemia

Chronic myeloid leukaemia (CML) is characterized by the

presence of a reciprocal t(9;22)(q34;q11) translocation. This

leads to production of the bcr-abl oncoprotein with enhanced

tyrosine kinase activity. Thus, aberrant expression of an

enzyme involved in cell signaling (type 1 mutation) leads to

immortalization of a haematopoietic stem cell. Key genetic

changes associated with progression to accelerated phase and

blast crisis are not well understood but would be predicted to

involve mutations in transcription factors or other genes

involved in haematopoietic differentiation (type II mutations).

The haematopoietic transcription factor GATA1 plays an

essential role in the commitment to, and subsequent differen-

tiation within, erythroid, megakaryocyte, eosinophil and mast

cell lineages. The observation of frequent eosinophilia and

thrombocytosis alongside neutrophilia in CML suggests that

GATA1 is expressed in the chronic phase of the disease.

GATA1 mutations have been described in the acute megakar-

yoblastic leukaemia of Down syndrome (Wechsler et al, 2002).

GATA1 mutations are also associated with transient abnormal

myelopoiesis seen in up to 10% of infants with Down

syndrome, this disease can morphologically resemble CML

with basophilia and eosinophilia in addition to circulating

blast cells (Zipursky, 2003).

The expressed sequence tag (EST) and nucleotide database

for Human GATA1 contains five sequences cloned from CML

sources. In four of five cases (BF212679, BF211536, BF210926,

BF183877) these ESTs showed multiple mutations when

compared with the established GATA1 mRNA (NM-002049).

In the fifth case (BC009797) the transcript corresponded to an

alternative splice variant.

Given the plausible association between perturbations in

GATA1 function and the molecular pathogenesis of CML,

along with suggestive EST evidence, we hypothesized that

mutations in GATA1 are involved in progression from chronic

phase to blast crisis in CML.

Following informed consent and ethical approval we

performed GATA1 mutational analysis. Peripheral blood or

bone marrow samples were obtained from 24 patients with

CML at the time of diagnosis of accelerated phase (n ¼ 1),

myeloid blast crisis (n ¼ 15) or lymphoid blast crisis (n ¼ 8).

Leucocytes were isolated following ammonium chloride red

cell lysis and some samples underwent CD34 selection to

enrich for blast populations. Genomic DNA was extracted and

initial screening for mutations used Denaturing High-per-

formance Liquid Chromatographic (DHPLC) profiling

(WAVE; Transgenomics, Omaha, NE, USA). This technique

Correspondence

ª 2007 The AuthorsJournal Compilation ª 2007 Blackwell Publishing Ltd, British Journal of Haematology, 137, 374–383 375