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Blood, Vol. 93 No. 9 (May 1), 1999:
pp. 3154-3154
CORRESPONDENCE
Hormonal Therapy After Stem Cell Transplantation and the Risk of
Veno-occlusive Disease
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LETTER |
To the Editor:
The elegant report from Hagglund et al1 recently published
in Blood raises a very important ethical issue in clinical
hematology practice: primum non nocere. The authors describe
the impact of norethisterone treatment, routinely used in the
prevention of menstrual bleeding in women submitted to allogeneic bone
marrow transplantation, on veno-occlusive disease, which is one of most dreadful complications of an otherwise successfull stem cell
transplantation (SCT). This is an example of how we can interfere
dramatically on the outcome of transplantation by simply adding an
unsafe drug to the corollary of what we call "supportive
treatment." Neverthless, the management of menstrual bleeding during
the phase of thrombocytopenia in premenopausal women may still be
troublesome and requires specific treatment, particularly when
concomitant gynecological disorders are present (ie, uterine
fibromyomata or dysfunctionl bleeding), and the use of
estroprogestinics should be clearly avoided. Estroprogestinics may
induce liver toxicity, primarily intrahepatic cholestasis and
transaminitis,2 and they also interfere with hemostasis through a reduction in the natural anticoagulant protein S and an
increase in factor II levels inducing a thrombophilic state, which may
be further amplified by genetically determined prothrombotic defects
that occur fairly commonly in the general population. These defects
include activated protein C resistance related to factor V Leiden,
factor II G20210 A mutation, or antithrombin III
deficiency.3-5
Therefore, in 1993 we started using a luteinizing hormone-releasing
hormone analogue (LHRH) in a pilot study for the prevention of uterine
bleeding in premenopausal women undergoing SCT.6 LHRH
analogues induce a profound amenorrhea through the suppression of the
pituitary-gonadal axis, do not interfere with the hemostatic balance,7 and do not cause liver toxicity. With leuprorelin acetate we have currently treated 47 consecutive premenopausal women
submitted to SCT with no episodes of amenorrhea lasting more than 6 months and sexual hormone levels in the nonmenopausal range. Informed
consent was obtained from all patients or guardians after discussion
with the consultant gynecologist. The median age was 33 (range, 17 to
52) years. Diagnoses were acute myeloid leukemia (15), acute
lymphoblastic leukemia Ph+ (3), non-Hodgkin's lymphoma
(11), Hodgkin's disease (11), multiple myeloma (2), chronic myeloid
leukemia (4), and RAEB-T (1). Thirty-one patients were submitted to
allogeneic SCT from HLA-identical donors while the remaining 16 patients were submitted to autologous SCT. Conditioning regimen
consisted of busulfan 4 mg/kg on 4 consecutive days and
cyclophosphamide 60 mg/kg for 2 days in 33 patients, busulfan 4 mg/kg
on 4 consecutive days and melphalan 90 mg/kg for 1 day in 5 patients,
and BEAM in 9 patients. Graft-versus-host disease prophylaxis in the
allogeneic SCT group was cyclosporine A and methrotrexate. Leuprorelin
depot was administered at the dose of 3.75 mg as a subcutaneous
injection at least 30 days before the conditioning regimen, and a
second injection was administered 28 days after the first dose.
Veno-occlusive disease was not observed in these patients despite the
fact that busulfan-containing conditioning regimen was predominantly
used. Only 2 of 47 patients (4.2%) developed mild uterine bleeding
during thrombocytopenia. Thus, a profound amenorrhea was obtained in
the majority of patients without additional toxicity. Therefore, we
strongly agree with the recommendations of Hagglund at al for concern
in the use of norethisterone or analogues in women undergoing SCT, but
we do recommend the use of LHRH analogues for the management and
prophylaxis of uterine bleeding, which should not be ignored after SCT.
Simona Sica
Prassede Salutari
Patrizia Chiusolo
Silvia Cicconi
Federica Sorá
Luca Laurenti
Nicola Piccirillo
Paola Scirpa
Giuseppe Leone
Division of Hematology
Istituto di Semeiotica Medica and
Istituto di Ostetricia e Ginecologia
Universitá Cattolica Sacro
Cuore
Rome, Italy
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REFERENCES |
1.
Hagglund H, Remberger M, Klaesson S, Lonnqvist B, Ljungman P, Ringden O:
Norethisterone treatment, a major risk-factor for veno-occlusive disease of the liver after allogeneic bone marrow transplantation.
Blood
92:4568, 1998[Abstract/Free Full Text]
2.
Lindgren A, Olsson R:
Liver damage from low-dose oral contraceptives.
J Intern Med
234:287, 1993[Medline]
[Order article via Infotrieve]
3.
Samsioe G:
Coagulation and anticoagulation effects of contraceptives steroids.
Am J Obstet Gynecol
70:1523, 1994
4.
Poort SR, Rosendaal FR, Retsma PH, Bertina RM:
A common genetic variation in the 3'-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and increase in venous thromboses.
Blood
88:3698, 1996[Abstract/Free Full Text]
5.
Dahlback B, Carlsson M, Svensson PJ:
Familial thrombophilia due to a previous unrecognized mechanism characterized by poor anticoagulant response to protein C: Prediction of a cofactor to activated protein C.
Proc Natl Acad Sci USA
90:1004, 1993[Abstract/Free Full Text]
6.
Chiusolo P, Salutari P, Sica S, Scirpa P, Laurenti L, Piccirilo N, Leone G:
Luteinizing hormone-releasing hormone analogue: Leuprorelin acetate for the prevention of menstrual bleeding in premenopausal women undergoing stem cell transplantation.
Bone Marrow Transplant
21:821, 1998[Medline]
[Order article via Infotrieve]
7.
Winkler U, Buhler K, Koslowsky S, Oberhoff C, Schindler AE:
Plasmatic hemostasis in gonadotropin releasing hormone analogue therapy: Effect of leuprorelin acetate depot on coagulation and fibrinolytic activities.
Clin Ther
14:114, 1992 (suppl A)
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