Bone Marrow Transplantation, (1998) 22, 989–994  1998 Stockton Press All rights reserved 0268–3369/98 $12.00 http://www.stockton-press.co.uk/bmt Ovarian function after autologous bone marrow transplantation in childhood: high-dose busulfan is a major cause of ovarian failure

C Teinturier1, O Hartmann2, D Valteau-Couanet2, E Benhamou3 and PF Bougneres1

1Department of Pediatric Endocrinology, Hopital Saint-Vincent de Paul, Paris; 2Department of Pediatric Oncology; 3Department of Biostatistics, Institut Gustave Roussy, Villejuif, France

Summary: ovarian function in long-term survivors following mye- loablative chemotherapy and bone marrow transplantation. We studied pubertal status and ovarian function in 21 girls aged 11–21 years who had earlier received 1.2– 13 years (median 7 years) high-dose chemotherapy and Patients and methods autologous BMT without TBI for malignant tumors. Ten of them were given busulfan (600 mg/m2) and mel- We screened all long-term female survivors older than 11 phalan (140 mg/m2) with or without cyclophosphamide years who had received high-dose chemotherapy and auto- (3.6 g/m2). Eleven others did not receive busulfan. logous bone marrow transplantation without abdominal or Twelve girls (57%) had clinical and hormonal evidence pelvic radiation for malignant tumors at Institut Gustave of ovarian failure. Among nine others who had com- Roussy. Twenty-one girls fulfilled these criteria. pleted normal puberty, six had normal gonadotropin At time of transplantation, they were aged 2–17 years levels, one had elevated gonadotropin levels and two had (median 9 years). Pubertal development was evaluated gonadotropin levels at the upper limit of normal. The clinically according to Tanner.10 Fourteen girls were prepu- 10 girls who received busulfan all developed severe and bertal (stage 1), two were undergoing puberty (stage 3) and persistent ovarian failure. High-dose busulfan is there- five had regular menses (stage 5). No hormonal evaluation fore a major cause of ovarian failure even when given was carried out before chemotherapy, but pubertal stages in the prepubertal period. These findings emphasize the of all the patients were appropriate for their age. need for long-term endocrine follow-up of these patients The study took place 1.2–13 years (median 7 years) after in order to initiate estrogen replacement therapy. bone marrow transplantation and discontinuation of chemo- Keywords: ovarian function; high-dose chemotherapy; therapy. At time of study, girls were aged 11.5–21 years bone marrow transplantation; busulfan; childhood (median 14.5 years). Serum concentrations of 17␤estradiol, follicle stimulat- ing hormone (FSH) and luteinizing hormone (LH) were measured. Samples from menstruating girls were obtained Increasing numbers of children who receive hematopoietic during the follicular phase of cycle. In six girls, hormones stem cell transplants (HSCT) for malignancies now survive. were measured before and 20, 40, 60 and 90 min after an It is therefore important to evaluate ovarian toxicity second- intravenous injection (100 ␮g/m2) of gonadotropin releas- ary to the therapeutic regimens. New chemotherapy proto- ing hormone (Stimu-LH; Roussel, Paris, France). Serum cols will have to aim towards effecting long-term survival FSH and LH concentrations were measured using commer- with minimal late morbidity. Chemotherapy is used alone cial immunoradiometric (IRMA) kits. or in combination with total body irradiation. Total body irradiation, used in the preparative regimens for hematol- ogic malignancies, is deleterious to gonadal function.1,2 Chemotherapy regimens Myeloablative therapy consisting of cyclophosphamide, Patients had all received different conventional chemo- busulfan or melphalan, has been used as an alternative to therapies before entering the consolidation phase. Twelve avoid the side-effects of irradiation on endocrine functions girls were treated for metastatic neuroblastoma, four for 1,3,4 and growth. Cytotoxics are known to induce ovarian Ewing’s sarcoma, three for lymphoma (Hodgkin’s disease toxicity in adults, dependent upon type of agent, dosage, in one), one for a metastatic rhabdomyosarcoma and 5–7 administration schedule and patient age. Much less is another for a malignant ovarian germinal tumor. The cumu- known about the effects of high-dose chemotherapy on lative doses of alkylating agents used before transplantation 2,8,9 ovarian function in children. We report an analysis of are detailed in Table 1, as well as clinical characteristics of the 21 girls. Nineteen girls received cyclophosphamide (median cumulative doses 7.3 g/m2, range 2–16.7), seven received ifosfamide (median cumulative doses 18 g/m2, Correspondence: Dr C Teinturier, Service d’Endocrinologie Pediatrique, Hopital Saint-Vincent de Paul, 82, Avenue Denfert-Rochereau, 75014 range 11.5–45) and two received other alkylating agents Paris, France (procarbazine, lomustine). Received 18 February 1998; accepted 8 July 1998 Ten girls were prepared for the transplant with busulfan Ovarian function after BMT in childhood C Teinturier et al 990 Table 1 Clinical characteristics of the 21 girls and cumulative doses of alkylating agents administered during conventional chemotherapy

Case Age at Pubertal Diagnosis Alkylating agents No. of cycles No. transplantation stage (g/m2) (years) (Tanner)10

1 4 1 Neuroblastoma CY 9 8 2 2 1 Neuroblastoma CY 8.5 6 3 8 1 Neuroblastoma CY 8.5 5 4 2 1 Neuroblastoma CY 9 6 5 5.8 1 Neuroblastoma CY 3 4 6 4.7 1 Rhabdomyosarcoma IFO 45 10 7 3.8 1 Neuroblastoma CY 9.8 7 8 14.8 3 Hodgkin’s disease CY 3.5 9 IFO 12.5 PCZ 9.4 9 12.7 1 Ovarian germinal tumor CY 4 5 IFO 11.5 10 7.5 1 Neuroblastoma CY 8 8 11 14.2 5 Neuroblastoma CY 9 9 12 4.7 1 Neuroblastoma CY 4.5 6 13 7.8 1 Neuroblastoma CY 3 6 14 5.7 1 Neuroblastoma IFO 18 6 15 9.2 1 Ewing’s sarcoma CY 10 10 16 13.2 5 Ewing’s sarcoma CY 5.3 8 IFO 18.4 17 12.2 1 Lymphoma CY 7 10 Lomustine 0.7 18 13.5 5 Ewing’s sarcoma CY 5 8 IFO 18 19 14.5 5 Neuroblastoma CY 16.7 8 20 17.3 5 Ewing’s sarcoma CY 2 8 IFO 19 21 14.5 3 Lymphoma CY 7.3 7

CY = cyclophosphamide; IFO = ifosfamide; PCZ = procarbazine; lomustine = 1-(2-chloroethyl)-3cyclohexyl-1-nitrosourea.

(600 mg/m2) given orally for 4 consecutive days, combined ovarian failure in the six girls tested, as already shown by with melphalan (140 mg/m2) with or without cyclophos- their high basal FSH values. phamide (3.6 g/m2) given intravenously on 2 consecutive days or other drugs depending on the tumor type (Table 2). Ovarian function following busulfan The other 11 girls received no busulfan, but melphalan (140–180 mg/m2) combined with other drugs depending on The 10 girls who had received busulfan (case Nos 12–21), tumor type (Table 2). all had evidence of ovarian failure based on lack of pubertal development and raised basal serum gonadotropin concen- trations. Pubertal development had not progressed since Results bone marrow transplantation (no sexual development has occurred in five, no progression in puberty in one) and the The pubertal stage and biological features of the patients four girls who had menses before transplantation remained at time of study are presented in Table 3. Nine girls had amenorrheic with a follow-up of 3–5 years after transplan- normal pubertal development including six with menses. tation. Basal LH values ranged from 9.7 to 36 IU/l (mean However, 12 other girls had clinical evidence of ovarian 23.1, normal range Ͻ8) and FSH from 26 to more than failure, with no pubertal development in six, arrested devel- 70 IU/l (normal range Ͻ12). Basal oestradiol values were opment of puberty in two others and secondary amenorrhea low (Ͻ100 pm/l) in all these patients. in the last four girls (Table 3). Serum gonadotropin and estradiol levels were in the menopausal range in all these Ovarian function after administration of conditioning cases: basal FSH values were above 20 IU/l (normal range regimens without busulfan Ͻ12), and estradiol values remained below 100 pm/l. Hor- monal status of the other nine girls was normal, except for Eleven patients had not received busulfan, but other combi- one (case No. 11) who had elevated plasma concentrations nations including melphalan in 10 girls. Only three had evi- of LH and FSH despite persistence of menses (Table 3). dence of ovarian failure (case Nos 1, 8, 11) (Table 2). One These results were confirmed by three hormonal evalu- (case No. 8) was treated for Hodgkin’s disease during ations over the last 4 years. In two other girls (case Nos 3 puberty and received high cumulative doses of alkylating and 4), FSH levels were at the upper limit of normal values. agents (procarbazine 9.4 g/m2, cyclophosphamide 3.5 g/m2, The gonadotropin releasing hormone test confirmed ifosfamide 12.5 g/m2 and carmustine 300 mg/m2). Another Ovarian function after BMT in childhood C Teinturier et al 991 Table 2 Details of preparative regimens and ovarian function in 21 Table 3 Pubertal development according to Tanner.10 Plasma gonado- girls tropin concentrations and serum basal estradiol in 21 girls after bone mar- row transplantation Case No. Preparative No. of grafts Ovarian regimens failure Case Age Pubertal Estradiol LH FSH No. (years) stage (pm/l) (IU/l) (IU/l) 1TM1ϩ 2 CTM 1 Ϫ 1 12.5 1 100 2.5 21.8 3 CaM 1 Ϫ 2 11.5 5 MϩϽ36 2.5 4 CTM 2 Ϫ 3 11.5 1 Ͻ36 1.7 13 5 CTM 2 Ϫ 4 13.8 5 Mϩ 210 4.8 12.2 6 VCM 2 Ϫ 5 12.8 2 Ͻ0.5 7 7 CTM 2 Ϫ 6 12.5 4 215 1.6 4.6 8 BEAM 1 ϩ 7125Mϩ 315 2.3 2 9 Cy-E-Cis 1 Ϫ 8 16.8 3 Ͻ36 11 41.7 10 M 1 Ϫ 9 19.7 5 Mϩ 48 4.5 8.5 11 CTM 2 ? 10 20 5 Mϩ 362 3.5 2.7 12 BuMCy 1 ϩ 11 21 5 Mϩ 95 9.3 27 13 BuMCy 1 ϩ 12 12 1 40 32 Ͼ70 14 BuMCy 1 ϩ 13 12.3 1 Ͻ36 11 39 15 BuM 1 ϩ 14 14 1 Ͻ36 28 Ͼ70 16 BuM 1 ϩ 15 15.2 1 58 28 42 17 BuM 1 ϩ 16 14.5 5 MϪϽ36 22 Ͼ70 18 BuMCy 1 ϩ 17 14.6 1 44 31 Ͼ70 19 BuM 1 ϩ 18 15.5 5 MϪ 70 17.5 56 20 BuM 1 ϩ 19 16.7 5 MϪϽ36 36 Ͼ70 21 BAM 1 ϩ 20 18.8 5 MϪ 48 16.1 56 21 15 3 106 9.7 26 TM = teniposide 1 g/m2, melphalan 180 mg/m2; CTM = carmustine 300 mg/m2, teniposide 1 g/m2, melphalan 180 mg/m2; CaM = carboplatin LH = luteinising hormone: Normal values Ͻ8 IU/l in follicular phase. 1.8 g/m2, melphalan 180 mg/m2; VCM = vincristine 6.5 mg/m2, carmus- FSH = follicle stimulating hormone. Normal values Ͻ12 IU/l in follicu- tine 200 mg/m2, melphalan 180 mg/m2; BEAM = carmustine 300 mg/m2, lar phase. etoposide 800 mg/m2, aracytine 800 mg/m2, melphalan 140 mg/m2; Mϩ = with menses; MϪ = amenorrhea. CyECis = cyclophosphamide 6.4 g/m2, etoposide 1750 mg/m2, cisplatin 200 mg/m2;M= melphalan 180 mg/m2; BuMCy = busulfan 600 mg/m2, melphalan 140 mg/m2, cyclophosphamide 3.6 g/m2; BuM = busulfan 600 mg/m2, melphalan 140 mg/m2; BAM = busulfan 600 mg/m2, aracytine Discussion 1.8 g/m2, melphalan 140 mg/m2. Ovarian failure during childhood results in no pubertal development and ultimately sterility. The relative contri- (case No. 11) had evidence of partial ovarian failure with bution of high-dose chemotherapy to ovarian failure is dif- persistence of menses but elevated serum FSH. She was ficult to establish, since the majority of patients treated for treated after puberty for a neuroblastoma with cumulative malignant disease received conventional chemotherapy doses of cyclophosphamide of 9 g/m2 and two courses of before bone marrow transplantation, and often alkylating high-dose chemotherapy (carmustine 600 mg/m2). Her agents known to induce ovarian toxicity in adult women. treatment was similar to that administered to patients 4 and The manifestations of ovarian failure in these women are 7. However, unlike the previous child, these two girls were amenorrhea, high serum gonadotropin levels and histologic treated before 4 years of age. Puberty developed normally features similar to those observed after radiation therapy, and hormonal evaluations showed normal serum FSH at ie reduction in numbers of ova and primordial follicles ages 12 and 13.8 years. The third patient (case No. 1) has together with stromal fibrohyalinization.7,11 The incidence no sexual development at the age of 12.5 years, elevated of amenorrhea depends on chemotherapeutic agent and serum FSH (Table 3) and cardiac failure. She was treated dose, and patient’s age at time of treatment, younger at 4 years of age for a neuroblastoma. women being less likely to develop premature ovarian failure.5–7 Severe impairment of gonadal function is relatively rare Comparison between the two groups with and without busulfan after conventional chemotherapy for acute leukemia. The spinal component of craniospinal irradiation seems to be The group treated with busulfan had a significantly higher the major risk factor, but cyclophosphamide may also be incidence of ovarian failure (100 vs 27%, P Ͻ 0.002) contributory.12–15 Ten percent of girls have sustained (Yates test). Other statistical calculations were not viable asymptomatic ovarian damage after conventional chemo- because the number of patients in each group was too small. therapy for acute lymphoblastic leukemia (ALL) and are Girls treated with busulfan were aged 4.6–17 years (median likely to develop premature menopause.12 In long-term sur- 12.7) at time of transplantation vs 2–14.8 years (median vivors of childhood ALL, irradiation of the ovarian zone 5.8) in the others. Among the 11 girls who did not receive was found to be the main gonadotoxic treatment.13 How- busulfan, eight were prepubertal compared to five out of 10 ever, a high prevalence of primary gonadal damage fol- in the busulfan-treated group. Conventional chemotherapy lowed high doses of cyclophosphamide, cytosine-arabino- regimens were different in the two groups (Tables 1 and 2). side and lomustine.14 Ovarian function after BMT in childhood C Teinturier et al 992 Table 4 Studies of ovarian function after chemotherapy with busulfan in childhood

Author/Ref. n Diagnosis Conventional Preparative regimens Ovarian chemotherapy failure (n)

De Sanctis28 15 thalassaemia no Bu 14 mg/kg 12 Cy 200 mg/m2 Sanders29 3 hematologic malignancies yes Bu 16 mg/kg 3 Cy 200 mg/m2 Liesner3 1 acute myeloid leukemia yes Bu 16 mg/kg 1 Cy 200 mg/m2 Lopez-Ibor32 1 chronic myelogenous leukemia Bu (1.5 mg/d) 1 Michel33 2 acute myeloid leukemia yes Bu 16 mg/kg 2 Cy 120–200 mg/kg Thibaud34 5 miscellaneous tumors yes Bua 5 Cya Melphalan 140 mg/m2 Giorgiani30 2 acute myeloid leukemia yes Bua 2 Melphalana Cya

aDoses not specified. Bu = busulfan; Cy = cyclophosphamide.

A high incidence of ovarian failure with MOPP and puberty at the time of chemotherapy. Every girl who MVVP regimens for Hodgkin’s disease,5–7 but not with the received busulfan also received melphalan, but 7/10 girls ABVD regimen has been reported.16,17 Amenorrhea is often who received only melphalan had normal ovarian function. transient in young patients and persistent in older patients Busulfan has been reported to influence gonadal function after chemotherapy for Hodgkin’s disease.5 Young women in children and adults.3,28–31 Among 73 women aged 14– treated for Hodgkin’s disease may be at risk of premature 57 years at transplant who received busulfan (16 mg/kg) menopause.7,18 Byrne et al18 report a significantly increased and cyclophosphamide (200 mg/kg), only one recovered relative risk of early menopause in cancer survivors treated normal ovarian function.31 In the literature, we identified with either radiotherapy or alkylating agents alone. Accord- 29 girls who received busulfan in the prepubertal or puber- ing to these authors, 42% of women treated with alkylating tal period; 26 had signs of ovarian failure3,28–30,32–34 (Table agents and subdiaphragmatic radiotherapy were meno- 4). In a study of 15 girls aged 9–17 years treated for thalas- pausal by the age of 31. semia with allogenic bone marrow transplantation, De The prevalence of ovarian dysfunction is high after treat- Sanctis et al28 demonstrated ovarian failure in 12 girls after ment of brain tumors, as a direct effect of radiation to the a busulfan–cyclophosphamide conditioning regimen, with- spinal field19 or chemotherapy with nitrosourea.20,21 out conventional chemotherapy. Thalassemic patients often The majority of women surviving bone marrow trans- sustain impaired gonadal function, but in this series ovarian plantation are amenorrhoeic and infertile following a com- failure is likely the result of the toxic effects of busulfan bination of chemotherapy and TBI.2,15,22–26 Even in chil- itself. dren, it is unclear whether ovarian failure is caused mainly The role of cyclophosphamide in ovarian failure at the by high-dose chemotherapy, TBI, conventional chemo- doses used in BMT (120–200 mg/kg) is not clear since therapy before myeloablative treatment, or the combination some children who receive cyclophosphamide alone as of all three.26 Graft-versus-host disease can also play a toxic transplant preparation for aplastic anemia or a malignant role after allogeneic transplantation.27 disease can have normal puberty and normal serum gonado- Little is known about ovarian damage due to high-dose tropin levels, as well as ovarian failure and impaired puber- chemotherapy alone in children. For this reason, our study tal development.2,23,34 assessed ovarian function in young girls who received high- It is unlikely that ovarian damage, 1.2–13 years (median dose chemotherapy and bone marrow transplantation with- 7) after high-dose chemotherapy in our series is reversible. out TBI or abdominal or pelvic radiotherapy. Grafts were Prolonged follow-up after transplantation, however is autologous so graft-versus-host disease was not implicated necessary, since young adults below the age of 30 years in ovarian damage. Because long-term survival resulted in rarely recover menstruation and fertility 3–7 years after these children, we were able to document late ovarian tox- transplantation.2,29,31,34–36 icity following chemotherapy administered in early infancy. As dividing cells are more sensitive to the cytotoxic It was difficult to estimate the precise contribution of each effects of alkylating agents than are quiescent cells, agent in causing ovarian damage since drug combinations inhibiting the pituitary–gonadal axis could render the ger- and cumulative doses of alkylating agents differed in each minal epithelium less vulnerable to the cytotoxic effects of case. Nevertheless, all the girls who received busulfan chemotherapy. Gn-RH agonists inhibit chemotherapy- developed severe and persistent ovarian damage whatever induced ovarian follicular depletion in the rat and in Rhesus age they were and whether or not they were undergoing monkeys.37,38 In women treated for Hodgkin’s and non- Ovarian function after BMT in childhood C Teinturier et al 993 Hodgkin’s lymphoma, over 93% of surviving patients in 14 Quigley C, Cowell C, Jimenez M et al. Normal or early devel- the Gn-RH-a group resumed ovulation and menses spon- opment of puberty despite gonadal damage in children treated taneously, whereas less than 40% resumed normal ovarian for acute lymphoblastic leukemia. New Engl J Med 1989; 321: cyclic activity in the group without Gn-RH-a.39 This sug- 143–151. gests that cotreatment with Gn-RH-a protects against 15 Keilholz U, Korbling M, Fehrentz D et al. Long-term endo- crine toxicity of myeloablative treatment followed by autolog- ovarian failure during chemotherapy and may explain why ous bone marrow/blood derived stem cell transplantation in ovarian failure is far more frequent when chemotherapy is patients with malignant lymphohematopoietic disorders. Can- administered after the onset of puberty. cer 1989; 64: 641–645. In conclusion, high-dose busulfan is a major cause of 16 Viviani S, Santoro A, Ragni G et al. 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