Hematological malignancies

Fertility preservation for patients diagnosed with leukemia is a challenge for a number of reasons, including (i) the prepubertal status, (ii) the systemic presentation of the diseases, and (ii) the need of an immediate start of chemotherapeutic treatments in the majority of cases, which greatly limit fertility preservation options. 

In postpubertal patients, controlled ovarian stimulation followed by oocyte retrieval (oocyte cryopreservation) can be considered at least 6 months after chemotherapy (compatibly with the time needed to wash out each and every chemotherapeutic drug with teratogenic effects on oocytes), with high risk of no or poor response to ovarian stimulation (1-4). 

Ovarian tissue cryopreservation Ovarian tissue cryopreservation can be offered to young patients with leukemia however since leukemic cells are blood borne and can be found in the ovary, risk of re-implantation of the leukemic cells following transplantation would be high. This risk can be reduced following consolidation therapy when there is no evidence of disease on a bone marrow biopsy where the ovarian tissue can be removed and cryopreserved prior to initiating high dose chemotherapy and bone marrow transplantation. Ex vivo immature oocyte retrieval can be performed in combination irrespective of pubertal status and phase of the cycle, but preserving oocytes is not advisable if chemotherapy has already started. 

Ovarian tissue transplantation upon patient healing and pregnancy wish is usually avoided in most cases due to an estimated high risk of reintroducing occult malignant cells with the ovarian tissue (5-7). 

Indeed, there is evidence of leukemic cells in ovarian biopsies in more than 50% of cases using molecular biology techniques, especially in the presence of acute leukemia (7). The neoplastic potential of these occult lesions is difficult to predict, since the presence of malignant cells does not necessarily translate into disease recurrence after transplantation (8). Recent studies showed that is possible to decrease the risk of recurrence up to be potentially negligible by harvesting ovarian cortex for cryopreservation after some chemotherapy and upon patient complete remission (9).  

Before transplantation, the ovarian cortex is searched extensively for evidence of residual disease, namely with sensitive molecular methods and immunolabeling techniques targeting leukemia-specific markers and long-term xenotransplantation to combined immunodeficient mice. Few case reports of ovarian tissue transplantation in survivors of adult acute leukemia (10-13) and one in childhood leukemia (14) have been reported, describing this approach to minimize disease recurrence.

References:

1. Meirow D, Epstein M, Lewis H, Nugent D, Gosden RG. Administration of cyclophosphamide at different stages of follicular maturation in mice: effects on reproductive performance and fetal malformations. Hum Reprod. 2001 Apr;16(4):632-7.
2. Arnon J, Meirow D, Lewis-Roness H, Ornoy A. Genetic and teratogenic effects of cancer treatments on gametes and embryos. Hum Reprod Update. 2001 Jul-Aug;7(4):394-403.
3. Maman E, Prokopis K, Levron J, Carmely A, Dor J, Meirow D. Does controlled ovarian stimulation prior to chemotherapy increase primordial follicle loss and diminish ovarian reserve? An animal study. Hum Reprod. 2009 Jan;24(1):206-10.
4. Diaz-Garcia C, Domingo J, Garcia-Velasco JA, Herraiz S, Mirabet V, Iniesta I, et al. Oocyte vitrification versus ovarian cortex transplantation in fertility preservation for adult women undergoing gonadotoxic treatments: a prospective cohort study. Fertil Steril. 2018 Mar;109(3):478-485.e2. 
5. Meirow D, Hardan I, Dor J, Fridman E, Elizur S, Ra’anani H, et al. Searching for evidence of disease and malignant cell contamination in ovarian tissue stored from hematologic cancer patients. Hum Reprod. 2008 May;23(5):1007-13. 
6. Rosendahl M, Andersen MT, Ralfkiær E, Kjeldsen L, Andersen MK, Andersen CY. Evidence of residual disease in cryopreserved ovarian cortex from female patients with leukemia. Fertil Steril. 2010 Nov;94(6):2186-90.
7. Dolmans MM, Marinescu C, Saussoy P, Van Langendonckt A, Amorim C, Donnez J. Reimplantation of cryopreserved ovarian tissue from patients with acute lymphoblastic leukemia is potentially unsafe. Blood. 2010 Oct 21;116(16):2908-14.
8. Manavella DD, Herraiz S, Soares M, Buigues A, Pellicer A, Donnez J, et al. Disease-inducing potential of two leukemic cell lines in a xenografting model. J Assist Reprod Genet. 2021 Jun;38(6):1589-1600.
9. Greve T, Clasen-Linde E, Andersen MT, Andersen MK, Sorensen SD, Rosendahl M, et al. Cryopreserved ovarian cortex from patients with leukemia in complete remission contains no apparent viable malignant cells. Blood 2012, 120(22):4311-4316.
10. Shapira M, Raanani H, Barshack I, Amariglio N, Derech-Haim S, Marciano Mn et al. First delivery in a leukemia survivor after transplantation of cryopreserved ovarian tissue, evaluated for leukemia cells contamination. Fertil Steril 2018, 109(1):48-53.
11. Silber SJ, DeRosa M, Goldsmith S, Fan Y, Castleman L, Melnick J. Cryopreservation and transplantation of ovarian tissue: results from one center in the USA. J Assist Reprod Genet. 2018;35(12):2205-2213. 
12. Poirot C, Fortin A, Dhédin N, Brice P, Socié G, Lacorte JM, et al. Post-transplant outcome of ovarian tissue cryopreserved after chemotherapy in hematologic malignancies. Haematologica. 2019 Aug;104(8):e360-e363. 
13. Sonmezer M, Ozkavukcu S, Sukur YE, Kankaya D, Arslan O. First pregnancy and live birth in Turkey following frozen-thawed ovarian tissue transplantation in a patient with acute lymphoblastic leukemia who underwent cord blood transplantation. J Assist Reprod Genet. 2020;37(8):2033-2043. 
14. Rodriguez-Wallberg KA, Milenkovic M, Papaikonomou K, Keros V, Gustafsson B, Sergouniotis F, et al. Successful pregnancies after transplantation of ovarian tissue retrieved and cryopreserved at time of childhood acute lymphoblastic leukemia – A case report. Haematologica. 2021 Oct 1;106(10):2783-2787.