Leuprorelin Acetate for the Prevention of Menstrual Bleeding in Premenopausal Women Undergoing Stem Cell Transplantation

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Luteinizing hormone-releasing hormone analogue: leuprorelin acetate for the prevention of menstrual bleeding in premenopausal women undergoing stem cell transplantation

P Chiusolo1, P Salutari1, S Sica1, P Scirpa2, L Laurenti1, N Piccirillo1 and G Leone1 ` 1Division of Hematology, Istituto de Semeiotica Medica, and 2Istituto di Ostetricia e Ginecologia, Universita Cattolica Sacro Cuore, Rome, Italy

Summary: need to be administered by mouth and can influence hemo- stasis1 and hepatic function in patients already prone to sys- Prevention of uterine bleeding after stem cell transplan- temic problems.2 We investigated the role of leuprorelin, a tation was attempted in 30 consecutive premenopausal LHRH analogue, in preventing uterine bleeding in pre- women affected by hematological malignancies. This menopausal women undergoing high-dose chemotherapy was with luteinizing hormone-releasing hormone and stem cell transplantation. The effect on gonadal (LHRH) leuprorelin acetate depot 3.75 mg administered function after transplantation was also assessed during subcutaneously at least 30 days before the conditioning follow-up. regimen and then 28 days after the first dose. Complete prevention resulted in all but one patient (96.5%) during the phase of profound thrombocytopenia. No side- Patients and methods effects related to leuprorelin were observed. All patients developed amenorrhea after transplantation. Gonadal Premenopausal women eligible for stem cell transplantation function was periodically assessed by means of luteiniz- were entered into the trial with leuprorelin. Inclusion cri- ing hormone (LH), follicular stimulating hormone teria were: presence of a hematological malignancy, age (FSH) and estradiol serum levels. Hormone levels were Ͻ50 years, anticipated nadir platelet count Ͻ50 × 109/l, no consistent with menopause in all patients. After trans- episodes of amenorrhea lasting Ͼ6 months, hormone levels plantation, patients required hormone replacement with in the non-menopausal range. Informed consent was estroprogestinics or estrogens alone when indicated. obtained from all patients or guardians after discussion with Leuprorelin is highly effective in preventing uterine the consultant gynecologist. Gonadal function was assessed bleeding in premenopausal women undergoing stem cell in all patients pretransplant and during follow-up, by pelvis transplantation and has an excellent toxicity profile and ultrasound and serum levels of LH, FSH and estradiol. virtually no interface with hemostatic balance and Thirty patients were entered on the protocol. Median age hepatic function. The role of leuprorelin in gonadal was 32 years (range 17–45). Eleven patients had acute mye- protection is currently unclear and deserves further logenous leukemia, seven had Hodgkin’s disease, seven had investigations. non-Hodgkin’s lymphoma, one had chronic myelogenous Keywords: LHRH analogue; leuprorelin; menstrual leukemia, three had acute lymphoblastic leukemia and one bleeding; stem cell transplantation had multiple myeloma. Patient characteristics are listed in Table 1. Nine patients underwent allogeneic bone marrow transplantation, 15 underwent autologous peripheral blood pro- High-dose chemotherapy followed by stem cell transplan- genitor cell transplantation and six underwent autologous tation is widely used for treating hematological malig- bone marrow transplantation. Conditioning therapy was nancies and solid tumors. Supportive therapy is crucial for busulphan 4 mg/kg p.o. in divided doses daily for 4 days success and for reducing procedure-related toxicity. Uterine and cyclophosphamide 60 mg/kg once daily for 2 consecu- bleeding in premenopausal women undergoing myelo- tive days (BuCy2) in 21 patients, BuCY2 + ATG in one ablative therapy can be an uncomfortable and troublesome patient, BEAM in five patients and busulphan 4 mg/kg p.o. complication. It also increases requirements for blood pro- in divided doses daily for 4 days and melphalan 90 mg/m2 ducts and the attendant risks of immunization and infec- (BuMel) in three patients. tious complications. Management may be difficult in Patients received leuprorelin acetate depot 3.75 mg as a patients with uterine leyomiomata and severe bleeding, subcutaneous injection at least 30 days (range 30–45 days) excluding them from an effective anticancer treatment. The before conditioning regimen. A second injection was classical approach includes use of estroprogestinics which administered 28 days after the first one. No other hormone treatment was permitted within the first 100 days of trans- ` Correspondence: Dr P Salutari, Division of Hematology, Universita Catto- plantation. The following endpoints were considered: inci- lica Sacro Cuore, Largo Agostino Gemelli, 8, 00168 Rome, Italy dence and duration of vaginal bleeding during the first 100 Received 13 August 1997; accepted 13 November 1997 days after transplantation, incidence of amenorrhea after Prevention of menstrual bleeding with leuprorelin after SCT P Chiusolo et al 822 Table 1 Characteristics of patients bocytopenia with no evidence of disseminated intravascu- lar coagulopathy. UPN Follow- Age Dx CR Tx Vaginal No patient developed vaginal spotting during thrombocy- up bleeding topenia after transplantation. No side-effects were encoun- (months) tered which could be related to leuprorelin administration. + There were two early deaths related to GVHD and multi- 55 57 17 HD BuCy2 ABMT no + 59 29 33 NHL BuCy2 PBPCT no organ failure, respectively, at day 114 and 109. Twenty- 60 55+ 21 ALL BuCy2 AlloBMT no eight patients were observed during follow-up for a median 64 51+ 24 HD BuCy2 PBPCT no of 17 months (range 3–51) and all developed amenorrhea. 65 20 35 HD BuCy2 PBPCT no Hormonal status, assessed regularly at 3, 6 and 12 months 68 47+ 30 NHL BuCy2 PBPCT no 75 7 34 NHL BuCy2 PBPCT no after transplantation, was consistent with menopause, with 77 43+ 17 AML BuCy2 ABMT no median levels of LH of 40 mIU/ml (range 30–60) FSH 78 11 45 AML BuCy2 ABMT no 35 mIU/ml (range 30–80), estradiol 15 pg/ml (range 10– 83 38+ 35 NHL BuCy2 PBPCT no 25). Only one patient had normal estradiol levels which + 86 39 34 AML BuCy2 AlloBMT no could be attributed to adrenal production, or to residual 93 5 35 NHL BuCy2 PBPCT no 97 31+ 37 HD BuMel PBPCT no ovarian function since she was the youngest patient 100 30+ 27 AML BuCy2 ABMT no undergoing stem cell transplantation. Nine patients are 105 9 35 AML BuCy2 ABMT no already receiving hormone replacement therapy with cyclic 109 27+ 34 MM BuMel PBPCT no estroprogestinics or transdermic estrogen, seven patients 111 26+ 19 AML BuCy2 ABMT no 115 23+ 20 HD BEAM PBPCT no did not start treatment because of disease recurrence and 121 20+ 34 HD BEAM PBPCT no death at a median of 10 months (range 4–20) after trans- 124 3 41 AML BuCy2 AlloBMT no plantation. Three patients are not receiving hormone 127 17+ 37 AML BuCy2 AlloBMT no replacement due to concurrent hepatic chronic GVHD. Two + 129 14 26 AML BuCy2 AlloBMT no patients are lost to follow-up. Eight patients are under 133 8 26 ALL BuCy2 AlloBMT no 136 13+ 28 CML Bu-ATG Cy AlloBMT yes evaluation for hormone replacement therapy. 137 13+ 27 NHL BuMel PBPCT no One patient developed deep venous thrombosis during 145 10+ 31 HD BEAM PBPCT no treatment with estroprogesterones as hormone replacement, 148 9 33 HD BEAM PBPCT no 1 year after transplantation. This patient was discovered to 151 3 28 AML BuCy2 AlloBMT no 3 157 6+ 31 NHL BuCy2 PBPCT no be an heterozygote for factor II G20210A mutation by 160 4+ 49 AML BuCy2 AlloBMT no PCR analysis.

Dx = diagnosis; CR = conditioning regimen; Tx = type of transplantation; HD = Hodgkin’s disease; NHL = non-Hodgkin’s lymphoma; AML = acute Discussion myeloid leukemia; ALL = acute lymphoblastic leukemia; MM = multiple myeloma. BuCy2, busulphan 16 mg/kg and cytoxan 60 mg/kg; BEAM, BCNU Complications after high-dose chemotherapy and/or radio- 300 mg/m2, VP16, 200 mg/m2, Ara-c, 200 mg/m2, Melphalan, 140 mg/m2; therapy relate to profound pancytopenia, mucosal damage BuMel, busulphan 16 mg/kg, Melphalan 100 mg/m2; ATG, antithymocyte and immunosuppressive treatment. Menstrual bleeding is a globulin; ABMT, autologous bone marrow transplantation; AlloBMT, common complication in premenopausal women during the allogeneic bone marrow transplantation; PBPCT, peripheral blood pro- profound and long-lasting thrombocytopenia. Before the genitor cell transplant. introduction of LHRH agonists, treatment of uterine bleeding invariably included the use of oral contraceptives. Estroprogestinics, although capable of inducing amenor- transplantation and induction of menopausal status after rhea, require oral administration. There may be poor com- treatment. Side-effects were reported if encountered. pliance after chemotherapy and erratic absorption in patients with mucositis and diarrhea.4 Estroprogestinics may also induce liver toxicity (primarily intrahepatic chol- Results estasis and transaminitis) and they may also interfere with hemostasis1 through a reduction in the natural anticoagu- All patients received at least two doses of leuprorelin before lant, protein S, and an increase in factor II levels. These transplantation. Ten patients reported menstrual bleeding modifications induce a thrombophilic state which may be after the first dose of leuprorelin. further amplified by genetically determined prothrombotic All patients were evaluable for the incidence of men- defects which occur fairly commonly in the general popu- strual bleeding within the first 100 days after stem cell lation and include activated protein C resistance related to infusion. factor V Leiden, or antithrombin III deficiency.5 Median duration of severe thrombocytopenia (platelets Thus, the use of estroprogestinics after stem cell trans- Ͻ20 × 109/l) was 28 days (range 0–Ͼ100). plantation may increase the risks of toxicity in patients Only one patient developed menstrual bleeding (96.5% already prone to metabolic complications and they may were free of bleeding) during the period of thrombocyto- play a role in the development of veno-occlusive disease penia after transplantation. This was a 28-year-old patient after transplantation. with chronic myelogenous leukemia who developed Conversely, LHRH analogues which induce amenorrhea hemorrhagic complications at multiple sites during throm- secondary to suppression of the pituitary–gonadal axis6 do Prevention of menstrual bleeding with leuprorelin after SCT P Chiusolo et al 823 not interfere with the hemostatic system7 and do not cause treatment for younger patients unless clinically contraindi- hepatic damage. Side-effects after prolonged treatment are cated. A detailed coagulation screen encompassing the mild and related to a profound and transient hypoestrogen- recently recognized inherited or acquired thrombophilic emia. In a review by Fogelman8 a decrease in bone mineral parameters should be mandatory in these patients before density is well documented in females receiving LHRH; long-term hormone replacement is instituted in order to within 3 months of eliminating the protective effect of avoid thromboembolic complications. estrogen on the skeleton, there is a rise in serum parameters, reflecting an increase in bone resorption and bone forma- tion. As demonstrated by other authors and by us in pre- References vious studies, LHRH analogues are effective and safe for prevention of menstrual bleeding in women with hemato- 1 Samsioe G. Coagulation and anticoagulation effects of contra- logical malignancies at the onset of their disease or after ceptives steroids. Am J Obstet Gynecol 1994; 70: 1523–1530. stem cell transplantation.9–12 The mechanism of action of 2 Lindgren S, Olsson R. Liver damage from low-dose oral con- LHRH analogues is characterized by two phases: first, they traceptives. 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