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Letters to the Editor
Table 1. Outcomes of ovarian tissue transplantation in survivors of adult acute leukemia.
Diagnosis
AML
AML
AML ALL
Age Age OTC OTT
26 37
19 27
19 32 24 39
Chemotherapy MRD prior to OTC bone
marrow at OTC
2 x ADE CR
1 x MAC, 1 x HDAC+ASPA CR
Ara-C+Daunorubicin CR no information CR
Treatment after OTC
Allogeneic HSCT (TBI*)
Allogeneic HSCT
Allogeneic HSCT
no information
Evaluation OTC MRD
Molecular detection of leukemia-specific marker Molecular detection of leukemia-specific v marker Molecular detection of fusion transcript + xenograft
no information
Outcome
Reference
AML 25 28 no information CR no information ALL 19 26 VD+ASPA+MTX CR Allogeneic
HSCT FluCy-TBI
no information ROF 4 Molecular 1 LB 5
detection of fusion transcript + IHC
OTC: ovarian tissue cryopreservation; OTT: ovarian tissue transplantation; MRD: minimal residual disease; AML: acute myeloid leukemia; ALL: acute lymphoblastic leukemia; ROF: re-establishment of ovarian function; ADE: Ara-C (Cytarabine), Daunorubicin, Etoposide; MAC: Myeloablative conditioning Aracytine Mitoxantrone; HDAC+ASPA: Aracytine,L-Asparaginase;VD+ASPA+MTX:Vincristine,Daunorubicin,L-Asparaginase,Methotrexate;CR:complete remission;HSCT:hematopoietic stem cell transplantation, TBI: total body irradiation; FluCy: Fludarabine cyclophosphamide; IHC: immunohistochemistry; LB: live birth. .
only isolated cases of OTT in survivors of hematological malignancies have been described to date.4,8,9 The major- ity of the reported OTT for hematological malignancies concern lymphomas, while only a handful cases of OTT in survivors of adult acute leukemia have been reported (Table 1).3-5,8
Residual disease is often detected when the tissue is investigated with sensitive molecular methods targeting leukemia-specific genetic markers and OTC has been per- formed before the patient has achieved molecular remis- sion.10-12 Also, xenografts of cryopreserved OT from women diagnosed with chronic myeloid leukemia (CML) and ALL into severe combined immunodeficient (SCID) mice could transfer leukemic cells, demonstrating that viable malignant cells may be present in the grafts. However, only the xenografts with detectable leukemic markers, as determined by sensitive molecular methods, showed leukemic cell transfer together with the xenografted OT.10 Importantly, studies have shown that OTC retrieved after the patient has achieved complete remission in the bone marrow in most cases also is neg- ative for leukemia markers in the cryopreserved ovarian tissue8,13,14 and OTC that scored negative for molecular leukemic markers did not transfer leukemia to the recipi- ent mice.13 In a recent study Chevillon and co-workers investigated the presence of minimal residual disease (MRD) in OTC harvested from acute leukemia patients that achieved complete remission and showed significant concordance between bone marrow and OT; however, four of nine discordant patients had undetectable MRD in the bone marrow while positive in the OT.15
Taken together, these studies support that OTC har- vested once the patient has achieved remission in the bone marrow has a very low likelihood to transmit leukemia provided the OTC is negative for the molecular
marker present in the blast cells.
The present case shares several important features
with the published reports of live births following OTT in patients cured from acute leukemia that provide details on treatment preceding the OTC (Table 1). In all cases the OTC was performed after induction and consolida- tion therapy when the patient had achieved complete remission in the bone marrow.3,5 One important common fact regarding previously reported OTT patients and our patient is that they had all received allogeneic HSCT as part of the leukemia treatment and graft-versus-leukemia effect may contribute to eliminate small amounts of leukemic cells potentially introduced with the OTT.3,5 Another important aspect in common is the availability of a fusion transcript unique to the malignant blasts that could be investigated in the OTT with very sensitive methods.3,5
To the best of our knowledge three live births have been reported to date after ovarian tissue transplantation in patients with adult acute leukemia.3-5 The present case is the third reported of a live birth after OTT in a patient with acute leukemia and the first one in pediatric ALL, as well as the first case where spontaneous pregnancy has additionally occurred after ovarian tissue transplantation in a survivor from pediatric ALL that recovered fertility following the transplantation procedures. The patient has been disease-free for 20 years after the diagnosis of ALL, and at the time of this report 43 and 31 months have elapsed from the first and second transplantations, respectively. Our results suggest that OT harvested in remission after several courses of chemotherapy and cry- opreserved may be a reproductive option for young women and girls treated for ALL. However, one should be cautious and carefully inform patients about the limi- tations of the available methods to exclude persistence of
ROF 8
ROF 8
1 LB 3 1 LB 4
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