case report

Acute Leukemia Relapse after Ovarian Cortex Autograft: A Case Report

Sophie Frontczak1,2*, Tristan Zver1,2, Jean Baptiste Pretalli1,3, Francine  Garnache-Ottou2,4, Francine Arbez-Gindre5, Berceanu Ana6, Deconinck Eric6, Clotilde Amiot2, Christophe Roux1-3

1Service de Biologie et Médecine de la Reproduction, Cryobiologie, CECOS Bourgogne Franche-Comté, CHU de Besançon, F-25000 Besançon, France.

2INSERM, EFS BFC, UMR1098 RIGHT Interaction Hôte-Greffon-Tumeur/ Ingénierie Cellulaire et génique, Université de FrancheComté, F-25000 Besançon, France.

3INSERM CIC 1431, CHU Besançon, F-25000 Besançon, France.

4Etablissement Français du Sang Bourgogne Franche-Comté, Laboratoire d’hématologie, F-25000 Besançon, France

5In memoriam.

6Service d’hématologie, CHU de Besançon, F-25000 Besançon, France.

*Corresponding author: Sophie Frontczak, Service de Biologie et Médecine de la Reproduction, Cryobiologie, CECOS Bourgogne Franche Comté, CHU de Besançon, F-25000 Besançon, France

Received Date: 17 April 2023

Accepted Date: 22 April 2023

Published Date: 25 April 2023

Citation: Frontczak S, Zver T, Pretalli JB, Garnache-Ottou F, Arbez-Gindre F, et al. (2023) Acute Leukemia Relapse after Ovarian Cortex Autograft: A Case Report. Ann Case Report 8: 1274. DOI:


The management of young adults with cancer must now include the preservation of fertility. In some situations, the only option is ovarian tissue cryopreservation (OTC). Reuse by autograft offers good results, but is not always possible, or may induce a risk of relapse for pathologies with high risk of ovarian localization. Thanks to the various techniques currently available to investigate residual disease in ovarian tissue, the risk of reintroduction of malignant cells is considered low. We report here a case of acute leukemia relapse after ovarian tissue autograft. This was a patient with a diagnosis of pro B acute lymphoblastic leukemia (ALL). Before a highly gonadotoxic treatment, cryopreservation of ovarian tissue was performed. Following these cancer treatments, the patient was in persistent complete molecular remission. The carcinological and functional qualification of the ovarian cortex were favorable. After multidisciplinary agreement and as part of the DATOR protocol, ovarian cortex autograft was performed. Fourteen months after ovarian tissue autotransplantation, a relapse of ALL was diagnosed. The assessments performed are in favor of a late relapse of the patient’s cells, but whose origin cannot be confirmed. The management of patients with high-risk pathologies is complex. For some of these patients, OTC and subsequent autograft is the sole treatment available. This case highlights the importance of ensuring the carcinological safety of the grafts before ovarian tissue transplantation by developing and improving residual disease investigation techniques, but also by developing alternative reuse techniques, such as folliculogenesis in vitro or models for ovary reconstruction.

Keywords: Case Report; Fertility Preservation; Ovarian Tissue Cryopreservation; Auto transplantation; Leukemia


Anti-cancer therapy is often a cause of premature ovarian insufficiency and infertility; since the ovarian follicle reserve is extremely sensitive to the effects of chemotherapy and radiotherapy [1]. Ovarian tissue cryopreservation (OTC) and transplantation have emerged as a strategy for fertility preservation, especially for prepubertal girls, adolescents and women in whom cancer treatment cannot be delayed, and OTC is no longer considered experimental [2-5]. In terms of efficacy and success rates, according to some publications reporting cumulative data from several centers, around 30% of auto transplanted patients conceive and deliver with the aid of OTC [6-8].

Myeloblastic (AML) and lymphoblastic (ALL) acute leukemia are a group of life-threatening malignant disorders of the blood and bone marrow. In the adolescent and young adult (AYA) population, acute leukemias are the most prevalent cancer [9]. Overall 5-year survival among AYAs has increased since the 1970s [10].

In cases of leukemia, since standard chemotherapy protocols are devoid of alkylating agents, significant ovarian damage is unlikely. Only patients who subsequently need additional highdose chemotherapy (for example, before allograft myeloablative therapy) are referred for OTC harvesting due to the high risk of sterilization [11].

However, in cases of cancer with a high risk of ovarian metastasis, such as leukemia, an important concern is the risk of relapse via the graft. Although the risk of reintroducing malignant cells is very low [7], it is essential to ensure the carcinological safety of the autograft, especially through the detection of minimal residual disease (MRD) in the ovarian cortex. This can be done using multicolor flow cytometry (MFC), molecular techniques and next generation sequencing, or xenografting in immunodeficient mice [11-14]. Making the decision of performing or not the graft depends on the results of carcinological and functional characterization.

We report here a case of relapse of lymphoblastic leukemia after autograft of ovarian tissue. As far as we know, no similar case has yet been published in the literature.

Case Presentation

This is the case of a 32-year-old Caucasian woman with no notable medical history. Mother of a 10-month-old baby, she carried out a systematic biological assessment in September 2012. The blood count showed neutropenia. A myelogram was performed and found marrow infiltration by 89% of lymphoblasts. The immunophenotype by MFC was CD19+, CD20-, CD34+, CD10-, and CD123+. Bone marrow molecular biology analysis found VH1-JH6 and Vg4-Jg1.3/2.3 as markers. The diagnosis of ALL pro B non-hyper leukocytic was retained. The patient was treated with chemotherapy according to the GRAALL 2005 protocol (prednisone, vincristine, daunorubicin, cyclophosphamide, L asparaginase). Due to the persistence of minimal residual disease, bone marrow allograft was planned. Before a highly gonadotoxic conditioning treatment (total body irradiation and cyclophosphamide), unilateral ovariectomy for fertility preservation by cryopreservation of ovarian tissue was performed in March 2013.

Following these cancer treatments, the patient was in persistent complete molecular remission, without any sign of graft versus host disease or immunosuppressive medication. In September 2015, she expressed her desire for a new pregnancy. In view of her ovarian insufficiency (FSH level at 79 IU/L, amenorrhea and hot flashes, non-measurable antral follicular count), the reuse of cryopreserved ovarian tissue by autograft was proposed.

The carcinological qualification of the ovarian cortex was favorable. Histological analysis did not find neoplastic cells. MRD detection by MFC in cryopreserved ovarian cortex with the diagnosis markers (CD19, CD34, CD10, CD123) was negative (at the maximum threshold of < 1x10-4). Molecular markers (VH1JH6) was also negative (threshold 10-5).

The functional qualification of the ovarian cortex was also favorable. Pathological examination documented the presence of many preantral and primordial follicles (22 follicles per 28 mm2 of the thawed test fragment). The trypan blue viability test found 95% of live follicles after thawing.

After multidisciplinary agreement and as part of the DATOR protocol [6], ovarian cortex autograft was performed in July 2018. After 2 months, recovery of ovarian function was observed with a decrease in FSH level and the appearance of the first antral follicles at endovaginal ultrasound. Her husband’s spermogram, without abnormalities, was compatible with a natural conception. As early as the 3rd month, the ultrasound and hormonal monitoring of the cycle made it possible to obtain a pregnancy 6 months after the ovarian cortex autograft. The outcome of this pregnancy was an early miscarriage.

During a follow-up myelogram in September 2019, a relapse of ALL was diagnosed. MFC found an immunophenotype close to the initial diagnosis (CD19+, CD20-, CD34+, CD10- and CD123+ low). Molecular biology revealed a clonal evolution, with presence of the Vg4-Jg1.3/2.3 marker and disappearance of the VH1-JH6 marker. The bone marrow karyotype initially corresponded to that of the donor (XY) with the presence of trisomy 8 (5 out of 20 mitoses analyzed). This anomaly was no longer highlighted on subsequent karyotypes (absence of trisomy 8 image on 50 mitoses analyzed). A pathological analysis of the grafts was not performed, as removal was deemed unnecessary.

In October 2020, the patient was in remission thanks to chemotherapy treatments inspired from EORTC protocol, with a combination of chemotherapy and blinatumomab. The complete molecular remission was obtained again; we did not performed a new transplantation, and the patient received Blinatumomab for 5 consolidation cycles. Due to her age at the end of chemotherapy, the couple gave up the project of a new child.

Figure 1: Comparison of multicolor flow cytometry at the time of diagnosis on bone marrow (A), at the time of MRD in ovarian tissue (B) and at the time of relapse on bone marrow (C).


Markers in multicolor flow cytometry

Markers by molecular biology

At the time of diagnosis on bone marrow

CD19+ CD20- CD34+ CD10- CD123+

Vg4-Jg1.3/2.3 and VH1-JH6

MRD in ovarian tissue

CD19- CD34 - CD123 negative

VH1 JH6 negative

At the time of relapse on bone marrow

CD19+ CD20- CD34+ CD10- CD123+low


Table 1: Comparison of markers investigated by flow cytometry and molecular biology.


Hematologic cancers are the most common indication for fertility preservation, because chemotherapy, radiotherapy, surgery or a combination thereof, can induce premature ovarian insufficiency [8]. Although the risk of reintroducing malignant cells is very low [8], carcinological qualification of the ovarian cortex is essential to assess the risk of reintroducing the initial disease. To this end, several technologies can be used, including MFC [15]. Our team has demonstrated the effectiveness of MFC for the detection of MRD in ovarian cortical tissue [16,17]. However, current MRD techniques have some limitations, including the MFC detection threshold for viable leukemic cells in the ovary. Currently, the level of MRD that can induce relapse after ovarian cortical transplantation remains unknown [12]. To the best of our knowledge, this is the first reported case of a relapse of acute lymphoblastic leukemia occurring after ovarian cortex transplantation. In our case, there is the question of the origin of the relapse of the patient’s ALL, namely whether it was due to relapse from the leukemic cells from the patient, leukemic transformation of the donor cells, the influence of pregnancy or possible dissemination from the fragment of ovarian cortex.

Although leukemia itself represents a common indication for OTC, transplantations are generally avoided in most fertility preservation centers, owing to the potentially high risk for disease recurrence [18]. Most often, as in our patient, OTC is performed after receiving initial chemotherapy. Recent exposure to chemotherapy (< 3 months) does not alter the chances of recovering ovarian function and becoming pregnant [19]. In addition, the literature reports cases of live births after transplantation of frozenthawed ovarian tissue in a patients with leukemia [11,20,21]. The majority of relapses occur within 2 years of allogeneic stem cell transplantation. The patient expressed her wish to perform an autotransplant 2 years after the end of the treatment. Thus, the multidisciplinary medical team decided to postpone this treatment in order to gain some distance from the initial pathology. Most often, leukemia is discovered during pregnancy. The influence of the pregnancy itself on the occurrence of the disease is possible, probably via the immunotolerance it induces. In addition, the patient’s relapse occurred at a distance from pregnancy.

Chimerism analysis on the blood revealed a mixed hematopoietic chimera, with 75% of the CD34 cell fraction coming from the recipient. MFC revealed an immunophenotyping of relapsed ALL-B (close to that of the initial disease with some modulated markers). Molecular biology analysis was positive for Vg4-Jg1.3/2.3 (same marker as at initial diagnosis) but no VH1JH6, indicating a clonal evolution quite frequent in late relapses. In conclusion, the assessments performed are in favor of a late relapse of the patient’s cells, but whose origin cannot be confirmed.

The management of patients with high-risk pathologies is complex. For some of these patients, OTC and subsequent autograft is the sole treatment available. This case highlights the importance of ensuring the carcinological safety of the grafts before ovarian tissue transplantation. Carcinological qualification techniques must be developed and optimized. Alternative techniques for the reuse of self-preserved ovarian tissue are under study, and may mitigate the carcinological risk. One such technique is in vitro folliculogenesis. Although the proof-of-concept has been provided in humans and oocytes at the metaphase II stage have been produced [22], their nuclear and cytoplasmic quality does not enable the use of ART techniques to produce embryos for a parental project. The other, more promising technique is the artificial ovary. This involves reconstructing an ovary from ovarian follicles isolated from the surrounding tissue and incorporating them into a biomaterial matrix, which is then transplanted into the patient.


  1. Spears N, Lopes F, Stefansdottir A, Rossi V, De Felici M, et al. (2019) Ovarian damage from chemotherapy and current approaches to its Hum Reprod Update 25: 673‑93.
  2. ESHRE Guideline Group on Female Fertility Preservation, Anderson RA, Amant F, Braat D, D’Angelo A, et al. (2020) ESHRE guideline: female fertility preservation. Hum Reprod Open 2020: hoaa052.
  3. Donnez J, Manavella DD, Dolmans MM (2018) Techniques for ovarian tissue transplantation and results. Minerva Ginecol. août 70: 424‑431.
  4. Practice Committee of the American Society for Reproductive Medicine (2019) Fertility preservation in patients undergoing gonadotoxic therapy or gonadectomy: a committee opinion. Fertil Steril 112: 1022
  5. Rives N, Courbière B, Almont T, Kassab D, Berger C, et al. (2022) What should be done in terms of fertility preservation for patients with cancer? The French 2021 guidelines. Eur J Cancer 173: 146‑166.
  6. Pretalli JB, Frontczak Franck S, Pazart L, Roux C, Amiot C, et al., (2019) Development of Ovarian Tissue Autograft to Restore Ovarian Function: Protocol for a French Multicenter Cohort Study. JMIR Res Protoc 8: e12944.
  7. Shapira M, Dolmans MM, Silber S, Meirow D (2020) Evaluation of ovarian tissue transplantation: results from three clinical centers. Fertil août 114: 388‑397.
  8. Dolmans MM, von Wolff M, Poirot C, Diaz‑Garcia C, Cacciottola L, et (2021) Transplantation of cryopreserved ovarian tissue in a series of 285 women: a review of five leading European centers. Fertil Steril.mai 115: 1102‑1115.
  1. Juliusson G, Hough R (2016) Leukemia. Prog Tumor Res 43: 87‑100.
  2. Miller KD, Fidler‑Benaoudia M, Keegan TH, Hipp HS, Jemal A, et al. (2020) Cancer statistics for adolescents and young adults, 2020. CA Cancer J Clin 70: 443‑459.
  3. Shapira M, Raanani H, Barshack I, Amariglio N, Derech‑Haim S, et (2018) First delivery in a leukemia survivor after transplantation of cryopreserved ovarian tissue, evaluated for leukemia cells contamination. Fertil Steril 109: 48‑53.
  4. Zver T, Frontczak S, Poirot C, Rives‑Feraille A, Leroy‑Martin B, et al. (2022) Minimal residual disease detection by multicolor flow cytometry in cryopreserved ovarian tissue from leukemia patients. J Ovarian Res 15: 9.
  5. Meirow D, Hardan I, Dor J, Fridman E, Elizur S, et al. (2008) Searching for evidence of disease and malignant cell contamination in ovarian tissue stored from hematologic cancer patients. Hum Reprod Oxf Engl 23: 1007‑1013.
  6. Dolmans MM, Marinescu C, Saussoy P, Van Langendonckt A, Amorim C, et al. (2010) Reimplantation of cryopreserved ovarian tissue from patients with acute lymphoblastic leukemia is potentially unsafe. Blood 116: 2908‑2914.
  7. Amiot C, Angelot‑Delettre F, Zver T, Alvergnas‑Vieille M, Saas P, et al. (2013) Minimal residual disease detection of leukemic cells in ovarian cortex by eight-color flow cytometry. Hum Reprod 28: 2157-2167.
  8. Zver T, Alvergnas‑Vieille M, Garnache‑Ottou F, Ferrand C, Roux C, et al. (2014) Minimal residual disease detection in cryopreserved ovarian tissue by multicolor flow cytometry in acute myeloid leukemia. Haematologica 99: e249‑252.
  9. Zver T, Alvergnas‑Vieille M, Garnache‑Ottou F, Roux C, Amiot C (2015) A new method for evaluating the risk of transferring leukemic cells with transplanted cryopreserved ovarian tissue. J Assist Reprod Genet 32: 1263‑1266.
  10. Wingard JR, Majhail NS, Brazauskas R, Wang Z, Sobocinski AK, et al. (2011) Long‑term survival and late deaths after allogeneic hematopoietic cell transplantation. J Clin Oncol 29: 2230‑2239.
  11. Poirot, C, Brugieres, L, Yakouben, K, Prades‑ Borio M, Marzouk F, et al. (2019) Ovarian tissue cryopreservation for fertility preservation in 418 girls and adolescents up to 15 years of age facing highly gonadotoxic treatment. Twenty years of experience at a single center. Acta Obstet Gynecol Scand 98: 630‑ 637.
  12. Sonmezer M, Ozkavukcu S, Sukur YE, Kankaya D, Arslan O (2020) 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 37: 2033‑2043.
  13. Yu J, Ge X, Luo Y, Shi J, Tan Y, et al. (2020) Incidence, risk factors and outcome of extramedullary relapse after allogeneic hematopoietic stem cell transplantation in patients with adult acute lymphoblastic Ann Hematol 99: 2639‑2648.
  14. McLaughlin M, Albertini DF, Wallace WHB, Anderson RA, Telfer EE (2018) Metaphase II oocytes from human unilaminar follicles grown in a multi‑step culture system. Mol Hum Reprod 24: 135‑142.

© by the Authors & Gavin Publishers. This is an Open Access Journal Article Published Under Attribution-Share Alike CC BY-SA: Creative Commons Attribution-Share Alike 4.0 International License. With this license, readers can share, distribute, download, even commercially, as long as the original source is properly cited. Read More.

Annals of Case Reports

slot gacor mudah maxwinagen judi bola resmimahjong ways pola jitu maxwinpola gacor starlight princessslot server kambojarahasia scatter hitam mahjong waysturbo spin slot mahjongrtp slot candy villagepola gacor mahjong wins terbaruslot server luar terbarurtp slot olympusslot mahjong waysrtp sweet bonanzaagen sbobet euro 2024judi bola parlay sbobetslot gates of olympus jepe maxwinrtp slot gacorslot starlight christmas pragmaticslot server filipinaslot deposit danaslot mahjong wins banjir scatterpola gacor mahjong maxwinjackpot naga hitam slot mahjong winsrumus slot mahjongrahasia scatter hitam slot mahjongdemo mahjong mudah menangrtp pg softrumus sbobet mix parlay