Successful Desensitization of Severe Alloimmune Platelet Refractoriness and Provision of Permissive Platelet Transfusions with a Novel IgG-Targeted Enzyme Therapeutic

AK and JCS contributed equallyBACKGROUND Alloimmune platelet refractoriness (APR), inadequate response to platelet transfusion secondary to alloantibodies targeting Human Leukocyte Antigens (HLA), affects ~25% of acute myeloid leukemia (AML) patients. For profoundly sensitized thrombocytopenic patients, HLA- or crossmatch-compatible platelet units may be unavailable, increasing the risk of thrombocytopenic hemorrhage. Imlifidase cleaves systemic IgG precluding complement fixation/phagocytosis and has been used to desensitize renal allograft recipients.¹ Here we show that desensitization with imlifidase can significantly improve compatible platelet availability in APR and post-hematopoietic stem cell transplant platelet nadir.

PATIENT CASE A 43-year-old woman with AML treated with cytarabine and daunorubicin was referred for matched-unrelated donor allogeneic hematopoietic progenitor cell transplantation. Her induction, at an outside institution, was complicated by bilateral retinal and mucosal hemorrhage secondary to APR and profound thrombocytopenia (platelet count to 0/µL). On presentation, her panel reactive antibody (PRA) showed exquisite sensitization (99.9%, i.e. ~99.9% of all donor platelet units predicted incompatible), precluding identification of HLA-compatible platelet units to support the patient through her anticipated platelet nadir. Desensitization included rituximab 375 mg/m2 (transplant D-13 and -6), therapeutic plasma exchange (TPE, D-2 and -1) and FDA-emergency-use-authorized imlifidase 0.25 mg/kg IV (D-1 and D+1). Following imlifidase administration, the number of unacceptable antigens and PRA decreased significantly (Figure) allowing sufficient compatible platelets to be identified and procured. During admission, the patient received 7 total platelet transfusions and experienced no hemorrhage (Table). She was discharged stable, post-platelet engraftment on D+19.

STUDY DESIGN With IRB approval, the number of predicted clinically significant alloantibodies (antibodies with ≥ 3000 mean fluorescence intensity, MFI) and PRA (LABScreen single antigen and PRA Class I, One Lambda/ThermoFisher, West Hills, California) were compared at baseline, after rituximab/TPE, and after imlifidase administration. Corrected count increment (CCI) to platelet transfusions administered following imlifidase desensitization was calculated. CCI > 5000 was judged a permissive transfusion. Categorical variables were compared with Chi-squared followed by Fisher's Exact. P < .05 was significant.

RESULTS AND CONCLUSION Compared to the baseline, unacceptable antigens (antigens targeted by antibodies at clinically significant levels) decreased significantly after rituximab/TPE (N=53/55 to 44/55 antigens, P = .015) and imlifidase (N = 44/55 to 16/55, P < .0001). PRA did not decrease significantly with rituximab/TPE (99.9 to 99.5%, P = .22) but did following imlifidase (99.5 to 87.2%, P < .0001). Of 7 transfusions given post imlifidase, the median CCI was 6000 (interquartile range: 500-7500), N=5/7 were judged permissive. In summary, the imlifidase-mediated decrease in PRA significantly aided the identification of numerous compatible platelet units for this patient and prevented further thrombocytopenic hemorrhage.

Our limited data suggest a potentially novel application of imlifidase for desensitization of highly platelet allo-refractory patients requiring multiple platelet transfusions over a short period. We will perform western blot analysis of antibodies from in vivo samples collected over the treatment course to compare antibody fragmentation over time, as partially cleaved immunoglobulin detected by our microbead-based assays may not be pathologic.² Additionally, as the patient's initial antibody levels exceeded the range of linearity of the bead-based assay, serial dilution studies of patient serum over the treatment course will more precisely semi-quantitate the true peak antibody levels.

REFERENCES 1. Jordan SC, Legendre C, Desai NM, et al. Imlifidase desensitization in crossmatch-positive, highly sensitized kidney transplant recipients: results of an international phase 2 trial (Highdes). Transplantation. 2021;105(8):1808-1817.

2. Bockermann R, Järnum S, Runström A, et al. Imlifidase-generated single-cleaved IgG: implications for transplantation. Transplantation. 2022;106(7):1485-1496.

Klein:Lilly: Consultancy, Other: Member of Data Safety Monitoring Board; Millennium: Consultancy, Other: Member of Data Safety Monitoring Board; Pfizer: Consultancy, Other: Member of Data Safety Monitoring Board.

Imlifidase is an human IgG-specific endopeptidase which produces rapid cleavage of IgG. In August 2020, imlifidase received global approval in the EU for desensitization treatment of highly sensitized adult kidney transplant patients with positive crossmatch against an available deceased donor. In this abstract, we describe successful off-label use of imlifidase to desensitize and increase platelet availability during bone marrow transplant nadir in a patient with profound alloimmune platelet refractoriness.