Allogeneic hematopoietic SCT (HSCT) is an established method of treating patients with high-risk hematological malignancies. However, intensified conditioning regimen before transplantation results in serious complications for long-term survivors such as growth deceleration, hypogonadism, thyroid dysfunctions, cardiovascular or lung complications and secondary cancers.1 More than 80% of long-term female survivors demonstrate ovarian failure.2, 3 Practices such as TBI with ovarian shielding, and collection of mature oocytes before gonadotoxic therapy4, 5 have been used to preserve ovarian function.
The high rate of infertility causes great anxiety for young women, and the estrogen deficiency promotes severe osteoporosis. A previous report demonstrated that TBI and BU are highly associated with ovarian dysfunction. Ovarian recovery occurs in 10% of the women who undergo a TBI 12 Gy regimen, and only 1% of those receiving a BU–CY regimen.6
Reduced intensity conditioning (RIC) has been developed for patients who are not eligible for conventional myeloablative transplantation because of older age, organ dysfunction or severe infection. Recently RIC has been applied more widely because of its reduced toxicity. Since 2001, we have used RIC for the treatment of children and adolescents, because we had previously encountered severe growth failure, hormonal deficiency and gonadal dysfunction after myeloablative conditioning (MAC) followed by HSCT. In that context, we present encouraging results showing recovery of ovarian function after RIC in this report.
We retrospectively analyzed female patients who underwent allogeneic HSCT in our institute between November 1991 and March 2010. The inclusion criterion was patients who were post menarcheal at HSCT. The exclusion criteria applied to patients who had undergone HSCT two or more times and those who died or relapsed within 2 years. There were 15 eligible patients in the MAC group and 11 in the RIC group. MAC was basically TBI 12 Gy (n=11) or BU 16 mg/m2 (n=4) combined with at least one other alkylator; representative regimens were TBI 12 Gy+CY 120 mg/kg+/−other agents (n=6), TBI 12 Gy+melphalan 210 mg/m2 (n=3), BU+CY 200 mg/kg (n=3). RIC was Flu 120 mg/m2 or 180 mg/m2+melphalan 140 mg/m2 (n=11). We defined recovery of ovarian function as the recovery of spontaneous menstruation after HSCT, and amenorrhea as absence of menstruation for >12 months.
The patient characteristics are shown in Table 1. Patients undergoing RIC were older than those undergoing MAC. Ovarian function was recovered in 7% (1/15) of patients in the MAC group, and 82% (9/11) of patients in the RIC group (P<0.001). All patients who did not recover from amenorrhea showed high levels of lutenising hormone and follicle-stimulating hormone, and low E2.
In the MAC group, the patient who recovered ovarian function had AML and was given TBI 12 Gy, CY and CA conditioning regimen at 13 years old (MAC-1). Although she had shown amenorrhea after HSCT and received sex hormone replacement therapy, she became pregnant 8 years after HSCT.
Two patients receiving RIC (RIC-1 and 2) demonstrated sustained amenorrhea. Patients ages were 18 and 38 years at HSCT. One of them (RIC-1) showed malnutrition due to extensive chronic GvHD (G1 tract: severe diarrhea with weight loss; skin: sclerotic features). Patients showed ovarian recovery at a median of 7 months (range 1–44 months) after HSCT.
A previous report suggested that treatment with chemotherapeutic agents alone might have a gonadotoxic effect.7 Although there was a major difference among the diagnose of the patients between the two groups (the ratio of acute leukemia was 60% (9/15) in the MAC group and 18% (2/11) in the RIC group), the ratios of patients previously treated combined chemotherapy were similar between the two groups (80% in MAC and 91% in RIC group).
EBV-associated T/natural killer cell lymphoproliferative disease is categorized in T/natural killer cell neoplasm in the most recent World Health Organization classification 2008.8 Patients with EBV-associated T/natural killer cell lymphoproliferative disease who are not treated with HSCT without preceding chemotherapy appear to be at higher risk of rejection.9 Regarding the interval until ovarian recovery after HSCT, there was no apparent association with age at transplantation, diagnosis or conditioning regimen.
Flu/BU is sometimes preferred for RIC in the treatment of aged patients. However, the ovarian function recovery rate is reported to be very low. Thus, BU does not seem to be a suitable agent for RIC in adolescents and young adults.
In conclusion, RIC consisting of Flu/L-PAM showed an advantage in recovery of ovarian function in adolescent and young adult patients.
Bresters D, van Gils IC, Kollen WJ, Ball LM, Oostdijk W, van der Bom JG et al. High burden of late effects after haematopoietic stem cell transplantation in childhood: a single-centre study. Bone Marrow Transplant 2010; 45: 79–85.
Socié G, Salooja N, Cohen A, Rovelli A, Carreras E, Locasciulli A et al. Nonmalignant late effects after allogeneic stem cell transplantation. Blood 2003; 101: 3373–3385.
Tauchmanovà L, Selleri C, De Rosa G, Esposito M, Orio Jr F, Palomba S et al. Gonadal status in reproductive age women after haematopoietic stem cell transplantation for haematological malignancies. Hum Reprod 2003; 18: 1410–1416.
Brougham MF, Wallace WH . Subfertility in children and young people treated for solid and haematological malignancies. Br J Haematol 2005; 131: 143–155.
Nakagawa K, Kanda Y, Yamashita H, Nagakawa S, Sasano N, Ohtomo K et al. Ovarian shielding allows ovarian recovery and normal birth in female hematopoietic SCT recipients undergoing TBI. Bone Marrow Transplant 2008; 42: 697–699.
Sanders JE, Hawley J, Levy W, Gooley T, Buckner CD, Deeg HJ et al. Pregnancies following high-dose cyclophosphamide with or without high-dose busulfan or total-body irradiation and bone marrow transplantation. Blood 1996; 87: 3045–3052.
Marquis A, Kuehni CE, Strippoli MP, Kühne T, Brazzola P . Sperm analysis of patients after successful treatment of childhood acute lymphoblastic leukemia with chemotherapy. Pediatr Blood Cancer 2010; 55: 208–210.
Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H et al. WHO Classification of Tumor of Haematopoietic and Lymphoid Tissues, 4th edn. IARC Press: Lyon, France, 2008.
Kawa K, Sawada A, Sato M, Okamura T, Sakata N, Kondo O et al. Excellent outcome of allogeneic hematopoietic SCT with reduced-intensity conditioning for the treatment of chronic active EBV infection. Bone Marrow Transplant 2010; 46: 77–83.
The authors declare no conflict of interest.
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