Pure Red Cell Aplasia after ABO-Mismatched Allogeneic Stem Cell Transplantation Treated with Therapeutic Plasma Exchange and Rituximab
Authors: Karp Rebecca , Arnason Jon E. , Rosenblatt Jacalyn , Avigan David , Joyce Robin , Nahas Myrna Rita , Uhlmann Erik , Hamdan Ayad 
Published: October 2019

Abstract
Introduction
Pure red cell aplasia (PRCA) is a severe consequence of major and bi-directional ABO-mismatched allogeneic stem cell transplantation (allo-SCT), likely the result of persistent isoagglutinin-producing host plasma cells that have escaped pre-transplant conditioning or graft vs. plasma cell effect (Aung et. al. 2013). PRCA, defined as anemia with reduced reticuloytosis and absence of red cell precursors in the bone marrow at 60 days after transplantation, complicates about 10-20% of all ABO-mismatched allo-SCTs; however, optimal treatment remains unknown. We report 5 cases from our institution of ABO mismatched allo-SCT complicated by PRCA treated with therapeutic plasma exchange (PEX) with or without the anti-CD20 monoclonal antibody rituximab.
Report
Patient characteristics are shown in Table 1. Indications for transplantation included refractory multiple myeloma, acute myeloid leukemia, and myelodysplastic syndrome (table 1); four of five patients underwent myeloablative conditioning, and the fifth received a reduced-intensity regimen due to age and co-morbidities. Prophylaxis for graft-versus-host disease consisted of cyclosporine alone, cyclosporine and prednisone, or tacrolimus and prednisone. ABO mismatching was major in four patients and bi-directional in one patient; all donors and recipients were Rh(D) positive. In all five patients, neutrophil engraftment occurred between days 11-15 after transplantation, with failure of red cell engraftment by day 60.
Response
Intervention included PEX in all patients, performed every-other-day (table 1). Three patients also received adjuvant rituximab in addition to PEX. Resolution of PRCA, which we defined as transfusion independence, presence of erythroid precursors on bone marrow biopsy, and Òmixed fieldÓ on blood type crossing, occurred in four out of five patients (mean 95 days). In two patients (patients 3 and 5) PEX and rituximab led to transfusion independence in less than 30 days after initiation of PEX. In one patient (patient 2), red cell engraftment occurred 87 days after initiation of PEX; another patient (patient 4) required 10 sessions of PEX and 2 cycles of rituximab (4 weekly doses separated by 6 months) to achieve transfusion independence 253 days after initiation of PEX. One patient (patient 1) had persistent PRCA despite 10 sessions of PEX and died of disease relapse 398 days after transplantation. In one patient (patient 2), tapering of immunosuppression was attempted in conjunction with PEX and led to resolution of PRCA; in the other four, withdrawal of immunosuppression was either not clinically indicated or unsuccessful in resolving PRCA.
Conclusion
We report five cases of PRCA after ABO-mismatched allo-SCT in the setting of major or bi-directional ABO incompatibility treated with PEX with or without rituximab, with four out of five patients responding to this intervention. This case series demonstrates the potential efficacy of PEX and rituximab for the treatment of PRCA. However, the optimal number of sessions of PEX, timing of this intervention, dosing and schedule of rituximab, and appropriate patient selection still remain unknown. A prospective study is planned.
Table 1. Patient characteristics and treatment outcomes Patient Age Disease Graft Conditioning Recipient/Donor ANC>500 Treatment Outcome/TTE 1 48M IgG MM PB MURD MyeloablativeBu/Cy O+/A+ F D+15 PEX 10 sessions PRCA unresolved Died 398 days after transplant of recurrent disease 2 56 M MDS PB MURD MyeloablativeFlu/Bu/ATG O+/B+ M D+11 PEX 10 sessions Withdrawal of immunosuppression Resolution of PRCA 87 days 3 58 M AML PB MRD MyeloablativeFlu/Bu O+/A+ M D+13 PEX 10 sessions Rituximab 2 doses Resolution of PRCA 13 days 4 49 M AML PB MRD MyeloablativeBu/Cy B+/A+ F D+11 PEX 10 sessions Rituximab 8 doses (2 cycles of 4 weekly doses separated by 6 months) Resolution of PRCA 253 days 5 70 M MDS PB MRD RIC Flu/Bu O+/A+ M D+15 PEX 7 sessions Rituximab 4 doses Resolution of PRCA 15 days
M: male; MM: multiple myeloma; MDS: myelodysplastic syndrome; AML: acute myelogenous leukemia PB: peripheral blood; MRD: matched related donor; MURD: matched unrelated donor; Bu: busulfan; Cy: cyclophosphamide; Flu: fludarabine; RIC: reduced intensity conditioning regimen; F: female; ANC: absolute neutrophil count; PEX: plasma exchange; TTE: time to red cell engraftment after PEX.

Disclosures
No relevant conflicts of interest to declare.