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Impact of the Inhibitors of Tyrosine Kinase on the Male Fertility

18 Years
60 Years
Not Enrolling
Chronic Myeloid Leukemia, Gastrointestinal Stromal Tumors

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Trial Information

Impact of the Inhibitors of Tyrosine Kinase on the Male Fertility

Antityrosine - kinases, such as imatinib are presently the gold standard therapy of chronic
myeloid leukaemia (CML), with complete cytogenetic responses being achieved in 70-90% of
patients receiving the drug as first -line monotherapy. Imatinib selectively inhibits the
hybrid oncogen BCR/ABL involved in the genesis of CML and other tyrosine kinases, such as
c-kit and platelet derived growth factor receptor (PGDF-R), involved in malignant gastro
intestinal stromal tumours (GIST) . Despite its good tolerance, in vivo animal studies
have proved that imatinib induces teratogenesis and dose-related effect on spermatogenesis.
In humans, few pregnancies involving male CML patients have been reported with one
spontaneous abortion, one case of gut malrotation and 15 healthy children. However, in the
absence of detailed and definite evidence of the lack of deleterious effect of imatinib on
spermatogenesis and sperm nuclear integrity in humans, specific studies are warranted. Male
patients (38) will be included in this study if they are 18 to 60 years old, presenting with
chronic myeloid leukaemia or malignant GIST and receiving for the first time a treatment by
imatinib, a tyrosin-kinase inhibitor, preceded or not by hydroxyurea therapy for less than
one month. These patients should have signed the informed consent and be covered by the
French social security system. In this open prospective study, each patient will be his own
control. The effect of imatinib on the spermatogenesis will be evaluated by the
concentration of spermatozoa before the beginning of the treatment and after 6 months of
imatinib, representing 2 cycles of spermatogenesis. Patients will be recruited by the
onco-haematologists (5 corresponding centres) and referred to the CECOS Tenon. A medical
investigator will collect the informed consent and fill the study file. A classical sperm
analysis, according to OMS, will be performed. A sample of the ejaculate will be fixed for
further analysis of the percentage of sperm nuclei with fragmented DNA (TUNEL procedure).
The rest of the semen will be frozen, packaged in straws and stored in liquid nitrogen to be
used, if necessary, by the patient if an ART is mandatory to conceive a child.Another sperm
recovery will be performed after a period of 6 months under the anti tyrosine-kinase (ATK)
therapy and the same sperm analysis will be carried out and the results compared to the
first evaluation, before ATK. The plasmatic concentration of imatinib will be determined,
for each patient, the day of the second sperm recovery to check the efficiency of ATK

Inclusion Criteria:

- Men from 18 to 60 years old

- Patients recently diagnosed CML or GIST

- Patients for whom a treatment by an inhibitor of tyrosine kinase in monotherapy is

- Patients having signed the informed consent

- Patients with social security

Exclusion Criteria:

- Patients already subjected to a treatment potentially sterilizing

- Patients under supervision or guardianship

Type of Study:


Study Design:

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Average difference of the concentration of spermatozoa in the ejaculate measured before treatment and after 6 months of treatment.

Outcome Time Frame:

At the inclusion and M6 visits

Safety Issue:


Principal Investigator

Jacqueline Mandelbaum, Dr

Investigator Role:

Principal Investigator

Investigator Affiliation:

Assistance Publique - Hôpitaux de Paris


France: Ministry of Health

Study ID:




Start Date:

October 2008

Completion Date:

May 2009

Related Keywords:

  • Chronic Myeloid Leukemia
  • Gastrointestinal Stromal Tumors
  • Spermatogenesis
  • Inhibitors of tyrosine kinase
  • Fragmentation of the spermatic DNA
  • Leukemia
  • Leukemia, Myeloid
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive
  • Gastrointestinal Stromal Tumors