Registry Data Indicate a Meaningful Chance for Successful Pregnancies after Allogeneic Stem Cell Transplantation: Results from the German Stem Cell Transplant Registry (DRST)

Background Long-term survival following allogeneic hematopoietic cell transplantation (alloHCT) has improved significantly over the last decades. Beyond curation, return to a normal social life, including family planning, represents an important goal especially for young adult cancer survivors.

However, alloHCT recipients are at high risk for infertility due to precedent chemotherapy, total body irradiation, transplant-related morbidity and long-term immunosuppressive medication. Nevertheless, spontaneous pregnancies following alloHCT were reported occasionally. Systematic studies on fertility preservation and pregnancies after alloHCT are very rare and do not cover the most recent era of transplantation. To fill this gap, we conducted a national multicenter study to investigate the pregnancy rate after alloHCT and their outcomes and to analyze potential risk factors in female transplant recipients.

Methods Retrospectively, we evaluated data on disease and transplant characteristics from all women of childbearing age (18-40 years), who received an alloHCT in Germany between 2003 and 2018. Data were retrieved from the German Registry for Stem Cell Transplantation (DRST). Follow-up data were introduced into a competing risk model in order to calculate rates of pregnancies and first live birth per person-year after alloHCT. "First live birth” and "death w/o prior live birth” were considered as competing risks. Cumulative hazards were estimated with the Nelson-Aalen estimator. To perform a risk factor analysis for the expected incidence rate we used multivariable Poisson regression. In addition, we performed structured guideline interviews with those women who consented in providing detailed information about conception, course of pregnancy, and children's health.

Results In total, 2,654 women met the eligibility criteria and 74 pregnancies were reported in 50 women. Pregnancies were reported at a median of 4.7 years (0.7-14.7 years) following alloHCT. Women who conceived pregnancy had a median age of 24 years (range 18 to 34) at alloHCT. Underlying diseases were AML/MDS in 19 patients, bone marrow failure syndromes in 17 patients, Lymphoma/ALL in 8 patients, and CML in 6 patients. Most patients underwent non-myeloablative or RIC (NMA/RIC) conditioning (76%). Total body irradiation (TBI) was part of the conditioning regimen in 12 patients (24%) of whom 4 patients received a cumulative TBI dose ≥8 Gray. Notably, acute GVHD grade II-IV had been reported in 11 women and chronic GvHD in 14 women.

Factors associated with a better chance of pregnancy were younger age at alloHCT (p<0.001), TBI with <8 Gray (p<0.020), NMA/RIC conditioning (p= 0.032) and non-malignant transplant indications such as hemoglobinopathy/bone marrow failure syndrome (p=0.006). Fifty-three of 74 pregnancies resulted in live births. Based on competing risk analyses this translated into an annual rate of 0.45% (95% CI: 0.31 to 0.59 %) first-livebirths after alloHCT. This rate is 6 times lower than the corresponding first-birth rate of 3% for german women between 18 and 40 years of age.

Detailed informations on conception and outcomes were obtained for 52 pregnancies. Forty out of 52 (77%) pregnancies occurred spontaneously, while assisted reproductive technologies (ART) were used in the remaining women. Techniques that resulted in successful pregnancies were: IVF (n=2), ICSI (n=2), ovarian tissue cryopreservation (n=2), oocyte donation (n=6). Preterm deliveries (29%) and low birth weight (21%) were higher as compared to reference data for the general population.

Conclusions Our data strongly indicate that female alloHCT survivors should be educated about the realistic possibility to become pregnant after HCT. Lower age at alloHCT (<35 years), non-myeloablative or reduced-intensity conditioning, cumulative doses of TBI <8 Gray and non-malignant transplant indications increase the chances to preserve fertility.

Interdisciplinary fertility counseling before alloHCT is essential to inform about the possibilities of assisted reproductive technologies. Nevertheless, the chances for spontaneous pregnancies should not be underestimated, and patients should be aware of this to avoid unexpected or unwanted pregnancies. Further research is needed to better understand and tailor procedural choices for conditioning regimens with respect to fertility preservation.

Sockel:Active Biotech: Research Funding; Gilead: Honoraria; SOBI: Honoraria; BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Middeke:Abbvie: Membership on an entity's Board of Directors or advisory committees. Kröger:Takeda: Consultancy, Honoraria; Sanofi: Honoraria; Kite: Honoraria; Neovii: Honoraria, Research Funding; Riemser: Research Funding; DKMS: Research Funding; Amgen: Honoraria; BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Jazz: Honoraria. Ayuk:Medac: Honoraria; Takeda: Honoraria; Mallinckrodt/Therakos: Honoraria, Research Funding; Janssen: Honoraria; Gilead: Honoraria; Celgene/BMS: Honoraria; Miltenyi Biomedicine: Honoraria; Novartis: Honoraria. Finke:Riemser Pharma: Research Funding. Platzbecker:Jazz: Honoraria; Takeda: Honoraria; Silence Therapeutics: Honoraria; Janssen: Honoraria; BMS/Celgene: Honoraria; Abbvie: Honoraria; Novartis: Honoraria; Geron: Honoraria. Schmid:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite: Research Funding; Abbvie: Research Funding. Teipel:Amgen, BMS/Celgene, Janssen, GSK, Karyopharm, Oncopeptides, Pfizer, Sanofi, Takeda: Honoraria; Janssen; Travel Expenses: Janssen, Amgen: Research Funding. Bug:Gilead: Consultancy, Honoraria; Celgene /BMS: Consultancy, Honoraria; Jazz: Honoraria; Pfizer: Consultancy; Novartis: Consultancy. Wolff:Incyte Corporation: Honoraria; Sanofi: Honoraria; Behring: Honoraria; Novartis: Honoraria, Research Funding. Luft:JAZZ Pharmaceuticals: Honoraria. Scheid:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Holtick:CLS Behring: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Novartis: Honoraria, Research Funding; Miltenyi Biotech: Honoraria; BMS/Celgene: Honoraria; Kite/Gilead: Honoraria. Burchert:Incyte: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; AOP Health: Honoraria, Research Funding.