Lower Relapse Incidence and Relapse Mortality in Patients Transplanted from a Younger Sibling in HLA-Identical Stem Cell Transplantation: Does Microchimerism Matter?
Authors: Dobbelstein Christiane , Kamal Haytham , Dammann Elke , Mischak-Weissinger Eva , Stadler Michael , Krauter Juergen , Ganser Arnold , Eder Matthias 
Published: April 2020

Abstract
Background: There is some evidence that microchimerism plays a role in outcome of HLA-identical stem cell transplantation (SCT). Evaluation of primacy of birth revealed a superior outcome for firstborn patients (Bucher et al. 2007). The underlying mechanism may include pre-existing microchimerism due to fetomaternal and transmaternal sibling cell trafficking. In addition, persistent fetal microchimerism in women may be associated with specific HLA-alleles.
Aims: To analyze the impact of relative donor/recipient birth order on outcome of HLA-identical sibling SCT.
Methods: We retrospectively analyzed HLA-identical sibling SCT for all consecutive patients with hematological malignancies from 1995 to 2007 at our center. 215 patients were assigned to one of two groups: 102 (47%) and 113 (53%) recipients had an older (D&gt;R) and younger (R&gt;D) donor, respectively. Transplantation related data for age, sex, disease, conditioning regimen, stem cell source, T-cell depletion (TCD), incidence and severity of acute GvHD, relapse incidence (RI), relapse (RM) and non-relapse mortality (NRM) were analyzed.
Results: Hematologic malignancies at time of SCT in the D&gt;R and R&gt;D group were acute lymphoblastic leukemia (ALL; 19% and 9%), acute myeloid leukemia (AML; 49% and 51%), myelodysplastic syndrome (MDS; both 3%), chronic myeloid leukemia (CML; 13% and 14%), other myeloproliferative syndrome (MPS; 2% and 3%), and Non-Hodgkinlymphoma (NHL; 14% and 20%), respectively. For all evaluable patients (n=215), RI was 37% in the D&gt;R group and 27% in the R&gt;D group (p=0.09). In unmanipulated SCT without TCD (n=157) RI was significantly reduced with 38% as compared to 23% in the D&gt;R and R&gt;D group (p=0.04). Of 91 patients transplanted with unmanipulated grafts after myeloablative conditioning 42 (46%) and 49 (54%) patients belong to R&gt;D and D&gt;R. In this subgroup RI was 33% and 12%, respectively (p=0.02). In addition, RM also compared favorably for the R&gt;D group: 9% versus 24% (p=0.05) with no difference in NRM in the two groups (37% in D&gt;R versus 33% for the R&gt;D (p=0.73). Patients in the R&gt;D group seemed to experience less aGvHD ≥II°: 21% versus 35%, (p=0.16). RI in patients receiving a SCT with myeloablative conditioning without TCD for myeloid malignancies (AML, MDS, CML, n=65) corresponded to that of the whole cohort with 13% for R&gt;D and 33% for D&gt;R, respectively (p=0.04). Similarly, RM and incidence of aGvHD in the R&gt;D and the D&gt;R group were similar for myeloid malignancies as for the whole cohort of patients transplanted with unmanipulated grafts after myeloablative conditioning.
Conclusions: In this retrospective analysis patients with hematological malignancies transplanted from a younger HLA-identical sibling donor have a superior outcome in HLA-identical SCT in terms of relapse incidence and relapse mortality. Multi-center studies for specific diseases are required to establish the impact of donor and recipients birth order on outcome of HLA-identical sibling transplantation.