Current Challenges in the Assessment of Related Donors for Hematopoietic Stem Cell Transplantation
Authors: Lamas Rodriguez Brais , Santiago Marta , Asensi Pedro , Balaguer Rosello Aitana , Chorao Pedro , Gálvez Ana Belén , Liquori Alessandro , Lloret Pilar , Montoro Juan , Sopeña Pell-Ilderton Clara , Such Esperanza , Villalba Marta , Fernández Jose M. , Sanz Guillermo , Cervera José , Solves Pilar , Sanz Jaime , de la Rubia Javier , Gómez Seguí Inés 
Published: December 2024

INTRODUCTION:
Related donors (RDs) for hematopoietic stem cell transplantation (HSCT) are increasingly older and comorbid. Meanwhile, germline predisposition has emerged as a new relevant issue in bone marrow failure conditions and myeloid neoplasms. The impact of those factors on donor and recipient safety constitutes a field of intensive clinical research.
OBJECTIVE:
The aim of this study is to describe our experience in evaluating RDs and to explore the potential apparition of donor-derived conditions in HSCT recipients from RDs.
METHODS:
We retrospectively analyzed the family history, hematological abnormalities, and autoimmune diseases of RDs evaluated for HSCT between January 2014 and December 2023, as well as the long-term outcomes of both donors and recipients.
RESULTS:
A total of 515 RDs were included, of whom 309 were HLA-identical donors (60%) and 206 were haploidentical donors (40%). Median donor age at the time of HSCT was 41 years (range 3-74), 70 (14%) RDs were 60 years or older, and 263 (51%) RDs were male. Myeloid malignancies were the most frequent HSCT indication (n=299, 58%). The median follow-up for the recipients was 45 months (range, 7-124).
Seventy-eight RDs (15%) had oncological first-degree family history (FDFH) at evaluation. Additionally, 23 RDs (5%) had hematological FDFH at evaluation. Specifically, 8 (2%) were donors to a family member with myeloid neoplasia and had at least one other myeloid FDFH.
Eighty-four (16%) RDs presented a hematological abnormality at initial evaluation or during follow-up: anemia (n=23, 4%), erythrocytosis (n=16, 3%), thrombocytopenia (n=6, 1%), thrombocytosis (n=6, 1%), macrocytosis (n=6, 1%), neutrophilia (n=5, 1%), eosinophilia (n=5, 1%), beta-thalassemia minor (n=4, 0.8%), monocytosis (n=3, 0.6%), monoclonal gammopathy of undetermined significance (n=3, 0.6%), and neutropenia (n=1, 0.2%). Nineteen (5%) had a mild autoimmune disease (mainly hypothyroidism or psoriasis).
No recipient developed the oncological condition of their FDFH. One donor with a hematological FDFH at evaluation, carrying a pathogenic variant in DDX41, transmitted this alteration to the recipient, who developed donor cell leukemia. Another donor with mild monocytosis (0.8x109/L) at donation was later diagnosed with chronic myelomonocytic leukemia, which also developed in the recipient with identical molecular alterations. Donors with beta-thalassemia minor transmitted this condition to their recipients.
A donor with hematological FDFH and macrocytosis at evaluation developed a newly onset, moderate thrombocytopenia after G-CSF administration. This patient was mobilizing poorly as compared with healthy donors and required two days of apheresis. No germline alteration was demonstrated in this family and the recipient has exhibited normal hematopoiesis. Another donor with similar alterations (macrocytosis and mild thrombocytopenia) mobilized poorly as well. In this case, hematopoiesis was also normal in the recipient, and the donor was eventually diagnosed with systemic sclerosis during follow-up.
The analysis identified 7 patients carrying a cancer predisposition syndrome. In 3 donors, the pathogenic variant (in BRCA1, CHEK2, and ATM) was also proven and transmitted with the donation. In the other 4 cases, the donor was not studied. The CHEK2+ carrier relapsed after 5 months. The other recipients have not developed related abnormalities to date with a median follow-up of 50 months (range, 20-75).
Finally, clonal hematopoiesis of indeterminate potential (CHIP) was transmitted from a 62-year-old healthy donor to a recipient. The recipient presented an extramedullary relapsed 6 years later without medullar involvement (where the CHIP was detected). The donor is currently under follow-up after developing a clonal cytopenia (anemia) of undetermined significance.
CONCLUSION:
Older donors and newly recognized germline predisposition neoplasms are significant challenges in the assessment of RDs today. Donors with more than one first-degree relative with myeloid disease should be evaluated cautiously within a multidisciplinary context. As recipient survival increases, genetic predisposition may become a more apparent clinical concern. It remains to be defined which donors and which genes should initially be studied, how to approach these findings, and the ethical dilemmas that this entails.