Pretransplant desensitization of donor-specific anti-HLA antibodies with plasmapheresis and immunoglobulin produces equivalent outcomes to patients with no donor specific antibodies in haploidentical hematopoietic cell transplant.

Haploidentical hematopoietic cell transplants (haplo-HCT) with donor-specific anti-HLA antibodies (DSAs) are associated with high rates of primary graft failure and poor overall survival (OS). Limited data exists regarding the effect of desensitization. Our institution began routine desensitization for patients with DSAs in 2014. Adult patients undergoing haplo-HCT at Washington University from 2009-2021 were identified and divided into three cohorts: no DSA, untreated DSA (2009-2014) or treated DSA (2014-2021). Desensitization therapy using plasmapheresis and IVIg was performed. Retrospectively, 304 patients were identified. 14 of 30 patients with DSAs underwent desensitization. By day +2, 57% of patients cleared all DSAs. After multivariable analysis, OS was similar between treated DSA and no DSA (HR: 0.69, p = 0.37). Untreated DSA had significantly lower OS compared to no DSA group (HR 1.80, p = 0.046). Desensitization with a backbone of plasmapheresis and IVIg before haplo-HCT may produce similar outcomes to patients without DSAs.

Pretransplant Desensitization of Donor-Specific Anti-HLA Antibodies with Plasmapheresis and Immunoglobulin Produces Equivalent Outcomes to Patients with No Donor Specific Antibodies in Haploidentical Hematopoietic Cell Transplant.

In patients requiring haploidentical hematopoietic cell transplant (haplo-HCT), the presence of donor specific anti-HLA antibodies (DSAs) is associated with high rates of primary graft failure and poor overall survival (OS). There is limited data regarding the effect of desensitization. Adult patients undergoing haplo-HCT at Washington University School of Medicine from 2009-2021 were identified. Patients were divided into three cohorts: no DSA, untreated DSA or treated DSA. DSA testing was performed. Desensitization therapy using plasmapheresis and IVIg (immunoglobulin) was performed. We retrospectively identified 304 patients for study inclusion. 14 of 30 patients with DSAs underwent desensitization. By day +2, 57% of patients cleared all DSAs. OS was expectedly worse in patients with untreated DSAs. There were similar results between treated DSA and patients without DSA (OS median: control: 352 days vs. treated: 1331 days vs. untreated: 137 days, p = 0.02). RFS was also significantly different between the groups however with similar RFS in treated DSA and control groups (RFS median: control: 248 vs. treated: 322 v. untreated: 119, p = 0.03). Desensitization before haplo-HCT produces similar outcomes to patients without DSAs. While the optimal desensitization protocol has not been established, all patients received a backbone of plasmapheresis and immunoglobulin.

Impact of donor age and relationship on outcomes of peripheral blood haploidentical hematopoietic cell transplantation.

Here we describe a retrospective analysis of outcomes in 299 patients who underwent peripheral blood haplo-HCT with PTCy from July 2009 through May 2021 and their association with donor characteristics. Patients had mostly acute leukemias and high or very high DRI. Multivariate analyses were conducted examining OS, NRM, relapse, cytokine release syndrome, acute and chronic GVHD. Donor characteristics included age, sex, relationship, ABO status, CMV status, and HLA match grade. Our analysis revealed increasing donor age was associated with higher NRM (compared to age <30; age 30-44 HR, 1.65; P = 0.110, age >44 HR, 1.80; P = 0.056) but lower relapse risk (compared to age <30; age 30-44 HR, 0.61; P = 0.034, age > 44 HR, 0.71; P = 0.132). There were no differences in CRS, aGVHD or cGVHD. We found no difference in outcomes based on the donor-recipient relationship. No differences were found based on HLA match grade or DRB1 match status. Increasing donor age was associated with lower relapse risk but higher NRM, resulting in no difference in OS based on donor age. Other donor factors including relationship (parent/sibling/child/ maternal), CMV status, donor sex, HLA match grade, and DRB1 status were not associated with outcomes.

CDC-42 Orients Cell Migration during Epithelial Intercalation in the Caenorhabditis elegans Epidermis.

Cell intercalation is a highly directed cell rearrangement that is essential for animal morphogenesis. As such, intercalation requires orchestration of cell polarity across the plane of the tissue. CDC-42 is a Rho family GTPase with key functions in cell polarity, yet its role during epithelial intercalation has not been established because its roles early in embryogenesis have historically made it difficult to study. To circumvent these early requirements, in this paper we use tissue-specific and conditional loss-of-function approaches to identify a role for CDC-42 during intercalation of the Caenorhabditis elegans dorsal embryonic epidermis. CDC-42 activity is enriched in the medial tips of intercalating cells, which extend as cells migrate past one another. Moreover, CDC-42 is involved in both the efficient formation and orientation of cell tips during cell rearrangement. Using conditional loss-of-function we also show that the PAR complex functions in tip formation and orientation. Additionally, we find that the sole C. elegans Eph receptor, VAB-1, functions during this process in an Ephrin-independent manner. Using epistasis analysis, we find that vab-1 lies in the same genetic pathway as cdc-42 and is responsible for polarizing CDC-42 activity to the medial tip. Together, these data establish a previously uncharacterized role for polarized CDC-42, in conjunction with PAR-6, PAR-3 and an Eph receptor, during epithelial intercalation.