Use of the IgG degrader imlifidase for a poorly desensitized patient undergoing haematopoietic stem cell transplantation with donor‐specific antibodies

Donor-specific antibodies (DSA) pose a barrier to allogeneic stem cell transplantation and desensitization strategies used for kidney transplant may be inadequate in patients with a high level of DSA. The streptococcal endopeptidase, imlifidase rapidly cleaves immunoglobulin G (IgG) within 6 h and has received conditional approval in Europe for heavily sensitized patients undergoing deceased donor kidney transplant but has not been tested in allogeneic transplant patients with high levels of DSA. We report the use of imlifidase in a patient with myelodysplasia and a high DSA that only partially responded to rituximab, daratumumab and therapeutic plasma exchange. A 67-year old Hispanic woman with a 3-year history of transfusion-dependent myelodysplasia was referred for allogeneic haematopoietic stem cell transplantation (HSCT). An 8/8 unrelated donor was identified but was mismatched at DPA1*01:03/DPB1*04:01 and DQA1*05:05/DQB1*03:01 with median fluorescent antibody levels (MFI) of 18 475 and 19 045 respectively. Desensitization included four weekly doses of rituximab followed by seven weekly doses of daratumumab and then several rounds of plasmapheresis, but the MFI of the DSA against the DP antigen remained above 5000 (Figure 1). Given the patient's age and advanced comorbidities preceding transplant, she received a non-myeloablative condition regimen that included 3 days of fludarabine and a single dose of 3 Gy TBI.1 Six hours before transplant with 3.73 × 10E6 CD34 cells/kg, she received compassionate use imlifidase 0.25 mg/kg administered intravenously over 15 min. MFI of the DSA prior to the administration of imlifidase was 6900 but 6 h later, prior to stem cell infusion, was no longer measurable (Figure 1A). To delay potential rebound, she received a second dose of imlifidase 3 days later (day +3). For GVHD prophylaxis, she received half-dose (25 mg/kg) post-transplant cyclophosphamide (PTCy) on days +3 and +4 as well as tacrolimus, mycophenolate mofetil and weekly abatacept × 3, beginning on day +5.2 Due to delayed engraftment despite 100% donor chimerism on day +30, she received a CD34-selected boost after which she achieved neutrophil and platelet engraftment. Transplant was complicated by endocarditis causing severe heart failure and eventual death on day +163. DSA remained negative until death; however, third party anti-HLA antibodies showed evidence of rebound (Figure 1B–D) before eventually dropping again. A recent analysis showed that the presence of DSA is associated with a sevenfold risk of primary graft failure or poor graft function in patients who primarily had haploidentical (HI) and umbilical cord blood transplants.3 DSA tend to be of higher titre in recipients of HI transplant because of an increased representation of women with very high DSA formed during pregnancy to paternal antigens of their HI donor children. In the present case, the resistant DSA against DPB1 was probably secondary to exposure during pregnancy as our patient's daughter carried this antigen. The management of DSA in patients undergoing allogeneic transplant has been modelled after that of solid organ transplant (SOT) and typically includes intravenous immunoglobulin (IVIG), plasma exchange, bortezomib and rituximab.4 As in SOT, these desensitization strategies may be ineffective in eliminating the high-level DSA in some sensitized patients. Although a prohibitive level of DSA has not been established, we would probably have not proceeded to transplant the patient described above, given that the MFI remained above 5000.5 As noted in recent French Consensus Guidelines, imlifidase could represent a major breakthrough in kidney transplantation because it could allow for transplantation of patients thus far considered 'untransplantable'.6 The issue of antibody rebound after kidney transplant remains challenging as nearly 40% of patients who received imlifidase had evidence of antibody-mediated rejection that required further treatment.7 In contrast, the present HSCT patient described above remained free of DSA beginning hours after the first dose of imlifidase. There are several factors that probably contributed to the lack of rebound. First, desensitization therapies which contain lymphodepleting agents like rituximab contribute to reducing rebound.8 Similarly, conditioning therapy and PTCy, unique to HSCT, should further inhibit rebound because of lymphoid and plasma cell cytotoxicity with a recent study showing that myeloablative regimens greatly reduce the negative effect of DSA on engraftment.9 Indeed, a lack of clinically significant rebound is consistent with the mostly positive studies of HSCT in patients with DSA who have been treated with desensitization therapy.4, 10, 11 Third, it seems likely that donor mononuclear cells may play a role in neutralizing DSA produced by surviving host plasma cells. This hypothesis is supported by the success of other strategies that can absorb DSA such as the intentional use of mismatched platelets (for class I DSA) and donor buffy coat cells (for class I and II DSA) immediately before transplant.12, 13 The rebound of third-party anti-HLA antibodies but not DSA in our patient may be due to an anti-DSA-specific neutralizing effect of donor cells (Figure 1B). Finally, also unique to HSCT, donor plasma cells should eventually replace host plasma cell-producing DSA, likely accounting for the late decrease in third-party anti-HLA antibodies (Figure 1C,D). Because most HSCT patients with DSA treated with desensitization do not reject their graft, we cannot conclude that imlifidase was the sole explanation for successful engraftment. However, following imlifidase administration, DSA became unmeasurable, there was complete donor engraftment and DSA did not reappear despite a high MFI (>5 K) just before transplant. Imlifidase is the only known treatment to immediately degrade DSA and by resetting the DSA level to zero may facilitate studies targeting prevention of DSA rebound including the use of agents that decrease recycling of IgG such as efgartigimod. The latter agent is approved for patients with myasthenia gravis and chronic inflammatory polyneuropathy and is being tested in patients with antibody-mediated renal graft rejection.14 As the number of patients with DSA undergoing mismatched donor HSCT increases, further investigation of mitigating strategies is required. Imlifidase may be considered for patients who continue to have prohibitive levels of DSA after standard desensitization or who need to proceed to transplant quickly and thus are unable to undergo aggressive desensitization. D.L.C., J.A.V., T.K. and M.P. wrote the paper and analysed the data. All the authors cared for the patient and edited/reviewed the manuscript. M.K.: Research Funding: AbbVie, Allogene, AstraZeneca, Genentech, Gilead, ImmunoGen, MEI Pharma, Precision, Rafael, Sanofi, Stemline, Advisory/Consulting: AbbVie, AstraZeneca, Auxenion, Bakx, Boehringer, Dark Blue Therapeutics, F. Hoffman La-Roche, Genentech, Gilead, Janssen, Legend, MEI Pharma, Redona, Sanofi, Sellas, Stemline, Vincerx, Stock options/Royalties: Reata Pharmaceutical (IP), Patent: Novartis, Eli Lilly, Reata Pharmaceutica, A.S.: Received research funding from Kymera Therapeutics, advisory board fees from Gilead Sciences, Rigel Pharmaceuticals and Kymera Therapeutics, consultancy fees from Janssen Pharmaceuticals and honoraria from National Association of Continuing Education & PeerView, A.V.: Received research funding from Prelude, BMS, GSK, Incyte, Medpacto, Curis and Eli Lilly and is a scientific advisor for Stelexis, Novartis, Acceleron and Celgene and receives honoraria from Stelexis and Janssen and holds equity in Stelexis and Throws Exception. All other authors have no disclosures. This was a single patient emergency use IND; IRB # 2023-15290. Signed permission obtained from patient's daughter to publish case report. All data available in submitted figure.