Isatuximab Monotherapy for Desensitization in Highly Sensitized Patients Awaiting Kidney Transplant

Abstract

Background Patients with calculated panel reactive antibody (cPRA) ≥80.00%, particularly those with cPRA ≥99.90%, are considered highly sensitized and underserved by the Kidney Allocation System. Desensitization removes circulating reactive antibodies and/or suppresses antibody production to increase chances of a negative crossmatch. CD38 is expressed highly on plasma cells, thus is a potential target for desensitization. Methods This was an open-label single-arm Phase 1/2 study investigating the safety, pharmacokinetics, and preliminary efficacy of isatuximab in patients awaiting kidney transplantation. There were two cohorts, Cohorts A and B, which enrolled cPRA ≥99.90% and 80.00%–<99.90%, respectively. Results 23 patients (12 Cohort A, 11 Cohort B) received isatuximab 10 mg/kg weekly for 4 weeks then every 2 weeks for 8 weeks. Isatuximab was well tolerated with pharmacokinetic and pharmacodynamic profiles that indicated similar exposure to multiple myeloma trials. It resulted in decreases in CD38+ plasmablasts, plasma cells, and NK cells; and significant reductions in HLA-specific IgG-producing memory B cells. Overall response rate, based on a pre-defined composite desensitization end-point, was 83.3% and 81.8% in Cohorts A and B. Most responders had decreases in anti-HLA antibodies that were maintained for 26 weeks after the last dose. Overall cPRA values were minimally impacted, however, with only 9/23 patients (39%) having cPRA decreases to target levels. By study cut-off (median follow-up 68 weeks), 6 patients received transplant offers, of which 4 were accepted. Conclusions In this open-label trial, isatuximab was well tolerated and resulted in a durable decrease in anti-HLA antibodies with partial desensitization activity.

Clinical relevance of HLA-DQ eplet mismatch and maintenance immunosuppression with risk of allosensitization after kidney transplant failure

“…Applying a fixed cPRA threshold to define clinically significant sensitization will also fail to capture the profound clinical impact of a minor increase in cPRA in patients that are already highly sensitized at baseline (i.e., moving from 99.90% to 99.99%). In this study, we defined a meaningful cPRA change as one that would reduce the compatible donor pool by 50%, a criterion that was recently used as one of the key outcome measures in an international desensitization trial ( Vincenti et al, 2023 ). Using this method, we were able to interpret the cPRA change of each patient on the same scale independent of their baseline cPRA.…”

“…To account for this effect, we defined the outcome of a meaningful cPRA (mcPRA) increase in this study as the increase in cPRA that resulted in a 50% reduction in the size of the compatible donor pool between the baseline measure (prior to or within 1 month of the date of transplant failure) and the last follow-up sample. This metric has recently been utilized in other studies to quantify secular changes in cPRA ( Vincenti et al, 2023 ).…”

Clinicopathological and Molecular Characteristics of Plasma Cell Rich Rejection in Renal Transplant Biopsies

“…If these plasma cells are indeed causally related to graft failure, treatment with the new line of immunosuppressants targeting CD38 can be beneficial (Daratumumab, Felzartamab, Isatuximab). [41][42][43] Alternatively, the influx of plasma cells in the graft could be a bystander effect reflective of prior damage without causal involvement in the pathogenesis leading to graft failure or, due to its morphological overlap with BKPyVAN, a presentation of a yet to discover viral infection.…”

Successful Desensitization with Imlifidase and Daratumumab in a Highly Immunized, Crossmatch Positive, Blood Group-Incompatible Living-Donor Re-Transplant Recipient with Systemic Lupus Erythematosus and Antiphospholipid Syndrome

“…Three years after transplantation, highly sensitized patients with imlifidase graft survival is 84%, but the rate of antibody-mediated rejection (ABMR) is 38%, indicating the need for better rejection prophylaxis [2]. Recently, anti-CD38 monotherapy with isatuximab was used to deplete plasma cells for desensitization in highly sensitized patients awaiting kidney transplants [5]. Here we report a case where we used combined therapy of imlifidase and anti-CD38 therapy to successfully transplant a patient with high levels of allo-and autoantibodies.…”