A Novel Daratumumab-Based Regimen for Desensitization in Highly HLA-Presensitized Patients Awaiting Kidney Transplantation

the most ef ﬁ cacious desensitization strategy is to

A phase 2 therapy was initiated to maintain the antibody reduction achieved in phase 1 while the patient waited for an HLA-suitable donor.The patient received 400 mg daratumumab monthly and one session of PP/IVIG during the first 12 weeks.Intensive therapy with PP/IVIG plus daratumumab weekly was given to reverse the mild antibody rebound for the following 4 weeks.Daratumumab (400 mg) was administered once during the last 2 weeks (Figure 1A).Desensitization was thus maintained and improved during the 18 weeks after phase 1 (Figure 1B).The total cPRA further decreased from 65.3% to 35.7% and class II cPRA remained at 0 (MFI cutoff: 5,000, Figure 1C, D).
At the end of phase 2, an ABO-compatible kidney obtained from a 52-year-old man after brain death was allocated to the patient via the Chinese organ transplant responding system.The donor-recipient HLA mismatch grade was 4 (Figure 1E).There were low levels of anti-DRB1 0901 (MFI: 2,253) and anti-B2704 (MFI: 1,673) donor-specific antibodies (DSAs) in the patient's pre-transplant serum, whereas their MFI values before desensitization had been 15,684 and 6,513, respectively (Figure 1F).The complement-dependent cytotoxicity test result was negative.
The allocated kidney was transplanted.The patient received induction therapy of 200 mg rituximab on day −1, 500 mg methylprednisolone daily on days 0-2 and 25 mg thymoglobulin daily on days 0-5 plus maintenance therapy with oral tacrolimus (trough level 7-10 ng/mL), mycophenolate mofetil (750 mg/12 h) and prednisone (10 mg/d).In addition, 20 g/d IVIG on days 1-5 and 15 g/d on days 6-13 were given to prevent DSA rebound.The patient showed good post-operative recovery without any episodes of rejection.DSAs disappeared 2 weeks posttransplantation (Figure 1F).The patient was discharged 30 days after transplantation with a serum creatinine level of 162 μmol/L.Oral compound sulfamethoxazole and valganciclovir were given every 3 days for 3 months to prevent opportunistic infection.
The patient was followed up for 1 year during which graft function remained stable.A 3-month protocol biopsy showed no signs of antibody or T cell-mediated rejections.One-year protocol biopsy results were similar but showed mild peritubular capillary C4d deposition (Figure 1G).DSA levels kept negative, while almost all non-DSAs with high levels before transplantation also declined during the 1-year follow-up period and none of those with low levels rebounded after transplantation.
The patient developed some flu-like symptoms, including nasal discharge, dry cough, and fatigue, after the initial daratumumab administration and was given intravenous infusion of 5 mg dexamethasone in advance of subsequent treatments which suppressed the symptoms.The patient developed myelosuppression during the later stages of intensive desensitization therapy.Myelosuppression was relieved during maintenance treatment, possibly due to the reduced frequency of daratumumab treatment.In addition, no significant toxicity to vision, peripheral nerves or liver was observed and no incidents of infection occurred.
High levels of preformed circulatory antibodies generally take a long time to gradually decay without assistance and the expectation was that the antibody-lowering effect of daratumumab monotherapy might be difficult to show in the short term.However, PP directly removed some of the circulating antibodies and IVIG reduced endogenous antibody rebound after PP-mediated depletion.Therefore, the regime was designed to elicit a synergistic action of daratumumab and PP/IVIG in reducing antibodies and improving desensitization.When a significant response to the intensive desensitization therapy had been achieved, phase 2 treatment with daratumumab monotherapy was initiated to maintain the antibody reduction while waiting for an HLA-matched donor.
In conclusion, the present case provides a novel desensitization strategy for kidney transplantation in highly presensitized patients.Further clinical studies are required for validation of this approach.