PATHOLOGY OF THE REPRODUCTIVE SYSTEM AFTER ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION IN CHILDREN: A SINGLE CENTER EXPERIENCE

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) nowadays allows cure malignant and nonmalignant diseases considered to be fatal previously. The number of cancer survivors’ children progressively increases over years. Unfortunately, numerous late effects of allo-HSCT become both a serious problem and a cause of the morbidity and mortality. Among them the reproductive pathology seems to be frequent, and fertility problems influence the quality of life of patients significantly.
Material and methods. We present the results of the evaluation of reproductive system in 294 children after allo-HSCT. Reproductive problems were revealed in 43 children and adolescents (15% of all patients and 46% of the patients with endocrine pathology). Hypergonadotropic hypogonadism was the dominating problem (33 patients, 77% of all reproductive dysfunctions).
Results. Risk factors of its development included: busulfan-containing conditioning regimen (р < 0.001, risk ratio (RR) of hypogonadism was 26.7% compared to 5.2% in other regimens), diagnosis of the malignant disease (р = 0.002, RR 26.6% in malignant and only 8.1% in nonmalignant pathology), central nervous system irradiation prior to HSCT (p = 0.002, RR 32.6% with cranial irradiation compared to 15.6% without it), female gender (р = 0.003, RR increases up to 3 times – 26.9% in girls against 9.3% in boys). We also describe cases of the fertility restoration and birthgiving. The algorithm of diagnostic and follow-up of gonadal pathology in children after allo-HSCT is shown.

1. Smith M.A., Seibel N.L., Altekruse S.F., Ries L.A., Melbert D.L., O’Leary M., et al. Outcomes for children and adolescents with cancer: challenges for the twenty-first century. J. Clin. Oncol. 2010; 28(15): 2625–34. doi:10.1200/JCO.2009.27.0421.

2. Hudson M.M. Survivors of childhood cancer: coming of age. Hematol. Oncol. Clin. North Am. 2008; 22(2): 211–31, v-vi. doi: 10.1016/j. hoc.2008.01.011.

3. Landier W., Bhatia S., Eshelman D.A., Forte K.J., Sweeney T., Hester A.L., et al. Development of risk-based guidelines for pediatric cancer survivors: the Children’s Oncology Group Long-Term Follow-Up Guidelines from the Children’s Oncology Group Late Effects Committee and Nursing Discipline. J. Clin. Oncol. 2004; 22(24): 4979–90.

4. Hudson M.M. Reproductive outcomes for survivors of childhood cancer. Obstet. Gynecol. 2010; 116(5): 1171–83. doi: 10.1097/ AOG.0b013e3181f87c4b.

5. Majhail N.S., Rizzo J.D., Lee S.J., Aljurf M., Atsuta Y., Bonfim C., et al. Recommended screening and preventive practices for long-term survivors after hematopoietic cell transplantation; Center for International Blood and Marrow Transplant Research (CIBMTR); American Society for Blood and Marrow Transplantation (ASBMT); European Group for Blood and Marrow Transplantation (EBMT); Asia-Pacific Blood and Marrow Transplantation Group (APBMT); Bone Marrow Transplant Society of Australia and New Zealand (BMTSANZ); East Mediterranean Blood and Marrow Transplantation Group (EMBMT); Sociedade Brasileira de Transplante de Medula Ossea (SBTMO). Hematol. Oncol. Stem Cell Ther. 2012; 5(1): 1–30. doi: 10.5144/1658-3876.2012.1.

6. Müller J. Impact of cancer therapy on the reproductive axis. Horm. Res. 2003; 59(Suppl. 1): 12–20.

7. Thomson A.B., Critchley H.O., Kelnar C.J., Wallace W.H. Late reproductive sequelae following treatment of childhood cancer and options for fertility preservation. Best Pract. Res. Clin. Endocrinol. Metab. 2002; 16(2): 311–34.

8. Dvorak C.C., Gracia C.R., Sanders J.E., Cheng E.Y., Baker K.S., Pulsipher M.A., Petryk A. NCI, NHLBI/PBMTC first international conference on late effects after pediatric hematopoietic cell transplantation: endocrine challenges-thyroid dysfunction, growth impairment, bone health, and reproductive risks. Biol. Blood Marrow Transplant. 2011; 17(12): 1725–38. doi: 10.1016/j.bbmt.2011.10.006.

9. Bath L.E., Wallace W.H., Critchley H.O. Late effects of the treatment of childhood cancer on the female reproductive system and the potential for fertility preservation. BJOG. 2002; 109(2): 107–14.

10. Johnston R.J., Wallace W.H. Normal ovarian function and assessment of ovarian reserve in the survivor of childhood cancer. Pediatr. Blood Cancer. 2009; 53(2): 296–302. doi: 10.1002/pbc.22012.

11. Chemaitilly W., Mertens A.C., Mitby P., Whitton J., Stovall M., Yasui Y., et al. Acute ovarian failure in the childhood cancer survivor study. J. Clin. Endocrinol. Metab. 2006; 91(5): 1723–8.

12. Sklar C.A., Mertens A.C., Mitby P., Whitton J., Stovall M., Kasper C., et al. Premature menopause in survivors of childhood cancer: a report from the childhood cancer survivor study. J. Natl. Cancer Inst. 2006; 98(13): 890–6.

13. Green D.M., Sklar C.A., Boice J.D. Jr., Mulvihill J.J., Whitton J.A., Stovall M., Yasui Y. Ovarian failure and reproductive outcomes after childhood cancer treatment: results from the Childhood Cancer Survivor Study. J. Clin. Oncol. 2009; 27(14): 2374–81. doi: 10.1200/ JCO.2008.21.1839.

14. Sklar C. Maintenance of ovarian function and risk of premature menopause related to cancer treatment. J. Natl. Cancer Inst. Monogr. 2005; (34): 25–7.

15. Letourneau J.M., Ebbel E.E., Katz P.P., Oktay K.H., McCulloch C.E., Ai W.Z., et al. Acute ovarian failure underestimates age-specific reproductive impairment for young women undergoing chemotherapy for cancer. Cancer. 2012; 118(7): 1933–9. doi: 10.1002/cncr.26403.

16. Liu J., Malhotra R., Voltarelli J., Stracieri A.B., Oliveira L., Simoes B.P., Ball E.D., Carrier E. Ovarian recovery after stem cell transplantation. Bone Marrow Transplant. 2008; 41(3): 275–8.

17. Schimmer A.D., Quatermain M., Imrie K., Ali V., McCrae J., Stewart A.K., et al. Ovarian function after autologous bone marrow transplantation. J. Clin. Oncol. 1998; 16(7): 2359–63.

18. Howell S.J., Shalet S.M. Spermatogenesis after cancer treatment: damage and recovery. J. Natl. Cancer Inst. Monogr. 2005; (34): 12–7.

19. Brennan BM, Shalet SM. Endocrine late effects after bone marrow transplant. Br J Haematol. 2002 Jul;118(1):58-66. Review. No abstract available.

20. Ishiguro H., Yasuda Y., Tomita Y., Shinagawa T., Shimizu T., Morimoto T., et al. Gonadal shielding to irradiation is effective in protecting testicular growth and function in long-term survivors of bone marrow transplantation during childhood or adolescence. Bone Marrow Transplant. 2007; 39(8): 483–90.

21. Sanders J.E., Hawley J., Levy W., Gooley T., Buckner C.D., Deeg H.J., et al. Pregnancies following high-dose cyclophosphamide with or without high-dose busulfan or total-body irradiation and bone marrow transplantation. Blood. 1996; 87(7): 3045–52.

22. Bath LE, Anderson RA, Critchley HO, Kelnar CJ, Wallace WH. Hypothalamic-pituitary-ovarian dysfunction after prepubertal chemotherapy and cranial irradiation for acute leukaemia. Hum. Reprod. 2001; 16(9): 1838–44.

23. Orio F., Muscogiuri G., Palomba S., Serio B., Sessa M., Giudice V., et al. Endocrinopathies after allogeneic and autologous transplantation of hematopoietic stem cells. Sci. World J. 2014; 2014: 282147. doi: 10.1155/2014/282147.

24. Frey Tirri B., Hausermann P., Bertz H., Greinix H., Lawitschka A., Schwarze C.P., et al. Clinical guidelines for gynecologic care after hematopoietic SCT. Report from the international consensus project on clinical practice in chronic GVHD. Bone Marrow Transplant. 2015; 50(1): 3–9. doi: 10.1038/bmt.2014.242.

25. Peigne M., Decanter C. Serum AMH level as a marker of acute and long-term effects of chemotherapy on the ovarian follicular content: a systematic review. Reprod. Biol. Endocrinol. 2014; 12: 26. doi: 10.1186/1477-7827-12-26.

26. Tauchmanova L., Selleri C., Rosa G.D., Pagano L., Orio F., Lombardi G., et al. High prevalence of endocrine dysfunction in long-term survivors after allogeneic bone marrow transplantation for hematologic diseases. Cancer. 2002; 95(5): 1076–84.

27. Andersson A.M., Petersen J.H., Jørgensen N., Jensen T.K., Skakkebaek N.E. Serum inhibin B and follicle-stimulating hormone levels as tools in the evaluation of infertile men: significance of adequate reference values from proven fertile men. J. Clin. Endocrinol. Metab. 2004; 89(6): 2873–9.

28. Molassiotis A., van den Akker O.B., Milligan D.W., Boughton B.J. Gonadal function and psychosexual adjustment in male long-term survivors of bone marrow transplantation. Bone Marrow Transplant. 1995; 16(2): 253–9.

29. Gharwan H., Neary N.M., Link M., Hsieh M.M., Fitzhugh C.D., Sherins R.J., Tisdale J.F. Successful fertility restoration after allogeneic hematopoietic stem cell transplantation. Endocr. Pract. 2014; 20(9): e157–61. doi: 10.4158/EP13474.CR.

30. Letourneau J.M., Ebbel E.E., Katz P.P., Katz A., Ai W.Z., Chien A.J., et al. Pretreatment fertility counseling and fertility preservation improve quality of life in reproductive age women with cancer. Cancer. 2012; 118(6): 1710–7. doi: 10.1002/cncr.26459.

31. Decanter C., Gligorov J. Oocyte/embryo cryopreservation before chemotherapy for breast cancer. Gynecol. Obstet. Fertil. 2011; 39(9): 501–3. doi: 10.1016/j.gyobfe.2011.07.011.

32. Revel A., Laufer N., Ben Meir A., Lebovich M., Mitrani E. Micro-organ ovarian transplantation enables pregnancy: a case report. Hum. Reprod. 2011; 26(5): 1097–103. doi: 10.1093/humrep/der063.

33. Lambertini M., Del Mastro L., Pescio M.C., Andersen C.Y., Azim H.A. Jr., Peccatori F.A., et al. Cancer and fertility preservation: international recommendations from an expert meeting. BMC Med. 2016; 14: 1. doi: 10.1186/s12916-015-0545-7.

34. Lee S.J., Schover L.R., Partridge A.H., Patrizio P., Wallace W.H., Hagerty K., et al. American Society of Clinical Oncology recommendations on fertility preservation in cancer patients. American Society of Clinical Oncology. J. Clin. Oncol. 2006; 24(18): 2917–31.

35. Loren A.W., Mangu P.B., Beck L.N., Brennan L., Magdalinski A.J., Partridge A.H., et al. Fertility preservation for patients with cancer: American Society of Clinical Oncology clinical practice guideline update. American Society of Clinical Oncology. J. Clin. Oncol. 2013; 31(19): 2500–10. doi: 10.1200/JCO.2013.49.2678.

36. Kucuk M., Bolaman A.Z., Yavasoglu I., Kadıkoylu G. Fertility-preserving treatment options in patients with malignant hematological diseases. Turk. J. Haematol. 2012; 29(3): 207–16. doi: 10.5505/tjh.2012.72681.

37. Vantyghem M.C., Cornillon J., Decanter C., Defrance F., Karrouz W., Leroy C., et al.; Societe Francaise de Therapie Cellulaire. Management of endocrinometabolic dysfunctions after allogeneic hematopoietic stem cell transplantation. Orphanet. J. Rare Dis. 2014; 9: 162. doi: 10.1186/s13023-014-0162-0.

38. Chatterjee R., Kottaridis P.D. Treatment of gonadal damage in recipients of allogeneic or autologous transplantation for haematological malignancies. Bone Marrow Transplant. 2002; 30(10): 629–35.

39. Blumenfeld Z., Patel B., Leiba R., Zuckerman T. Gonadotropin-releasing hormone agonist may minimize premature ovarian failure in young women undergoing autologous stem cell transplantation. Fertil. Steril. 2012; 98(5): 1266–70. e1. doi: 10.1016/j.fertnstert.2012.07.1144.

40. Cheng Y.C., Takagi M., Milbourne A., Champlin R.E., Ueno N.T. Phase II study of gonadotropin-releasing hormone analog for ovarian function preservation in hematopoietic stem cell transplantation patients. Oncologist. 2012; 17(2): 233–8. doi: 10.1634/theoncologist.2011-0205.

41. Cornillon J., Decanter C., Couturier M.A., de Berranger E., François S., Hermet E., et al. Management of endocrine dysfunctions after allogeneic hematopoietic stem cell transplantation: a report of the SFGM-TC on gonadal failure and fertility. SFGM-TC. Pathol. Biol. (Paris). 2013; 61(4): 164–7. doi: 10.1016/j.patbio.2013.07.008.

42. Tichelli A., Rovo A. Fertility issues following hematopoietic stem cell transplantation. Expert Rev. Hematol. 2013; 6(4): 375–88. 10.1586/17474086.2013.816507.

43. Donnez J., Dolmans M.M., Pellicer A., Diaz-Garcia C., Ernst E., Macklon K.T, Andersen C.Y. Fertility preservation for age-related fertility decline. Lancet. 2015; 385(9967): 506–7. doi: 10.1016/S0140-6736(15)60198-2.

44. Macklon K.T., Jensen A.K., Loft A., Ernst E., Andersen C.Y. Treatment history and outcome of 24 deliveries worldwide after autotransplantation of cryopreserved ovarian tissue, including two new Danish deliveries years after autotransplantation. J. Assist. Reprod. Genet. 2014; 31(11): 1557–64. doi: 10.1007/s10815-014-0331-z.

45. Dittrich R., Hackl J., Lotz L., Hoffmann I., Beckmann M.W. Pregnancies and live births after 20 transplantations of cryopreserved ovarian tissue in a single center. Fertil. Steril. 2015; 103(2): 462–8. doi: 10.1016/j.fertnstert.2014.10.045.

46. Silber S., Pineda J., Lenahan K., DeRosa M., Melnick J. Fresh and cryopreserved ovary transplantation and resting follicle recruitment. Reprod. Biomed. Online. 2015; 30(6): 643–50. doi: 10.1016/j.rbmo.2015.02.010.

47. Salooja N., Szydlo R.M., Socie G., Rio B., Chatterjee R., Ljungman P., et al. Pregnancy outcomes after peripheral blood or bone marrow transplantation: a retrospective survey. Late Effects Working Party of the European Group for Blood and Marrow Transplantation. Lancet. 2001; 358(9278): 271–6.

48. Cho W.K., Lee J.W., Chung N.G., Jung M.H., Cho B., Suh B.K., Kim H.K. Primary ovarian dysfunction after hematopoietic stem cell transplantation during childhood: busulfan-based conditioning is a major concern. J. Pediatr. Endocrinol. Metab. 2011; 24(11–12): 1031–5.

49. Byrne J., Rasmussen S.A., Steinhorn S.C., Connelly R.R., Myers M.H., Lynch C.F., et al. Genetic disease in offspring of long-term survivors of childhood and adolescent cancer. Am. J. Hum. Genet. 1998; 62(1): 45–52.

50. Winther J.F., Boice J.D. Jr., Mulvihill J.J., Stovall M., Frederiksen K., Tawn E.J., Olsen J.H. Chromosomal abnormalities among offspring of childhood-cancer survivors in Denmark: a population-based study. Am. J. Hum. Genet. 2004; 74(6): 1282–5.

51. Strahm B., Malkin D. Hereditary cancer predisposition in children: genetic basis and clinical implications. Int. J. Cancer. 2006; 119(9): 2001-6.

52. Nakayama K., Liu P., Detry M., Schover L.R., Milbourne A., Neumann J., et al. Receiving information on fertility- and menopause-related treatment effects among women who undergo hematopoietic stem cell transplantation: changes in perceived importance over time. Biol. Blood Marrow Transplant. 2009; 15(11): 1465–74. doi: 10.1016/j.bbmt.2009.07.019.

53. Papusha L.I., Balashov D.N., Tyul’pakov A.N., Skorobogatova E.V., Kurnikova E.E., Skvortsova Yu.V., Maschan A.A. Sexual development and gonadal function in children and adolescents after allogeneic hematopoietic stem cell transplantation with the use of different conditioning regimens. Oncohematology. Russian Journal (Onkogematologiya). 2009; 2: 61–9. (in Russian)

54. De Vet A., Laven F.H., Themmen A.P., Fauser B.C. Antimullerian hormone serum levels: a putative marker for ovarian aging. Fertil. Steril. 2002; 77(2): 357–62.

55. Laporte S., Couto-Silva A.C., Trabado S., Lemaire P., Brailly-Tabard S., Esperou H., et al. Inhibin B and anti-Müllerian hormone as markers of gonadal function after hematopoietic cell transplantation during childhood. BMC Pediatr. 2011; 11: 20. doi: 10.1186/1471-2431-11-20.

56. Nabhan S.K., Bitencourt M.A., Duval M., Abecasis M., Dufour C., Boudjedir K., et al. Fertility recovery and pregnancy after allogeneic hematopoietic stem cell transplantation in Fanconi anemia patients. Aplastic Anaemia Working Party, EBMT. Haematologica. 2010; 95(10): 1783–7. doi: 10.3324/haematol.2010.023929.

57. Balashov D.N., Papusha L.I., Nazarenko T.A., Trakhtman P.E., Revishvili N.A., Maschan A.A., et al. Recovery of ovarian function and pregnancy in a patient with AML after myeloablative busulphan-based conditioning regimen. J. Pediatr. Hematol. Oncol. 2011; 33(4): e154–5. doi: 10.1097/MPH.0b013e3181faf7b5.