Rituximab Desensitization Research Articles

Impact of Fc-gamma receptor IIIA polymorphism on late-onset neutropenia and clinical outcomes in kidney transplant recipients following rituximab induction therapy.

This study aimed to investigate the association between the Fc-gamma receptor IIIA (FCGR3A) 158 polymorphism and clinical outcomes in kidney transplantation (KTx) patients. Specifically, we focused on late-onset neutropenia (LON) in ABO-incompatible (ABOi) or HLA-incompatible (HLAi) KTx recipients who underwent rituximab (RTx) desensitization therapy. FCGR3A 158F/V polymorphisms were identified in 85 ABOi or HLAi KTx recipients who underwent RTx desensitization at our institution between April 2008 and October 2021. We analyzed these polymorphism groups in relation to their preoperative background and incidence of LON, infection, and rejection. In addition, we examined the risk factors for LON development. The following FCGR3A 158F/V polymorphisms were identified: FF genotype (n = 45); FV genotype (n = 36), and VV genotype (n = 4). LON occurred in 25 out of 85 recipients within 1year after KTx, significantly more frequently in patients with the FCGR3A FV + VV genotype (17/40) than in those with the FF genotype (8/45) (p = 0.01). A multivariate analysis identified the V-allele as an independent risk factor for LON (OR, 4.03; 95% CI, 1.38-11.73, p = 0.01). However, there were no significant differences in the incidence rates of post-transplant infection and rejection between the FF and FV + VV genotypes. Recipients with the FCGR3A 158V-allele were identified as having a higher risk of developing LON following KTx with RTx desensitization therapy. However, the presence of this V-allele did not affect the safety or efficacy of RTx desensitization before KTx.

Protracted anaphylaxis and cytokine release syndrome 6 days after rituximab desensitization

Protracted anaphylaxis and cytokine release syndrome 6 days after rituximab desensitization

Anti-complement 5 antibody ameliorates antibody-mediated rejection after liver transplantation in rats.

Antibody-mediated rejection (AMR) remains a refractory rejection after donor-specific antibody (DSA)-positive or blood-type incompatible liver transplantation (LT), even in the era of pre-transplant rituximab desensitization. This is due to the lack of not only effective post-transplant treatments but also robust animal models to develop/validate new interventions. Orthotopic LT from male Dark Agouti (DA) to male Lewis (LEW) rats was used to develop a rat LT-AMR model. LEW were pre-sensitized by a preceding skin transplantation from DA 4-6 weeks before LT (Group-PS), while sham procedure was performed in non-sensitized controls (Group-NS). Tacrolimus was daily administered until post-transplant day (PTD)-7 or sacrifice to suppress cellular rejections. Using this model, we validated the efficacy of anti-C5 antibody (Anti-C5) for LT-AMR. Group-PS+Anti-C5 received Anti-C5 intravenously on PTD-0 and -3. Group-PS showed increased anti-donor (DA) antibody-titers (P <0.001) and more C4d deposition in transplanted livers than in Group-NS (P <0.001). Alanine aminotransferase (ALT), alkaline phosphatase (ALP), total bile acid (TBA), and total bilirubin (T-Bil) were all significantly higher in Group-PS than in Group-NS (all P <0.01). Thrombocytopenia (P <0.01), coagulopathies (PT-INR, P =0.04), and histopathological deterioration (C4d+h-score, P <0.001) were also confirmed in Group-PS. Anti-C5 administration significantly lowered anti-DA IgG (P <0.05), resulting in decreased ALP, TBA, and T-Bil on PTD-7 than in Group-PS (all P <0.01). Histopathological improvement was also confirmed on PTD-1, -3, and -7 (all P <0.001). Of the 9,543 genes analyzed by RNA sequencing, 575 genes were upregulated in LT-AMR (Group-PS vs. Group-NS). Of these, 6 were directly associated with the complement cascades. In particular, Ptx3, Tfpi2, and C1qtnf6 were specific to the classical pathway. Volcano plot analysis identified 22 genes that were downregulated by Anti-C5 treatment (Group-PS+Anti-C5 vs. Group-PS). Of these, Anti-C5 significantly down-regulated Nfkb2, Ripk2, Birc3, and Map3k1, the key genes that were amplified in LT-AMR. Notably, just two doses of Anti-C5 only on PTD-0 and -3 significantly improved biliary injury and liver fibrosis up to PTD-100, leading to better long-term animal survival (P =0.02). We newly developed a rat model of LT-AMR that meets all the Banff diagnostic criteria and demonstrated the efficacy of Anti-C5 antibody for LT-AMR.

Risk factors for antibody-mediated rejection in ABO blood-type incompatible and donor-specific antibody-positive liver transplantation.

Antibody-mediated rejection (AMR) is a refractory rejection after ABO blood-type incompatible (ABOi) or donor-specific antibody (DSA)-positive liver transplantation (LT). Pretransplant rituximab desensitization dramatically reduced posttransplant AMR development; however, risk factors for AMR in the rituximab era remain unclear in both ABOi living-donor LT (ABOi-LDLT) and preformed DSA-positive LT (pDSA-LT). Of our 596 adult LDLTs (≥18y) after rituximab introduction (2004-2019), 136 were ABOi-LDLT (22.8%). After excluding retransplants (9), acute liver failure (7), and protocol deviations (16), 104 ABOi-LDLTs were finally enrolled. Of these, 19 recipients developed AMR, 18 of which occurred within 2 weeks after transplantation (95%). ABOi-AMR significantly worsened graft and recipient survival than those without ( p =0.02 and 0.04, respectively). Model for End-stage Liver Disease (MELD) ≤13 (OR: 5.15 [1.63-16.3], p =0.005) and pre-rituximab anti-ABO IgM-titer ≥128 (OR: 3.25 [1.05-10.0], p =0.03) were identified as independent risk factors for ABOi-AMR development. Recipients fulfilling both factors showed significantly worse survival rates than those who did not ( p =0.003). Of 352 adult LTs, after introducing the LABScreen Single Ag method (2009-2019), pDSA with mean fluorescence intensity (MFI) ≥500 was detected in 50 cases (14.2%). After excluding 10 ABOi-LDLTs, 40 pDSA-LTs were finally analyzed, of which 5 developed AMR. The combination of high-titer (sum-MFI ≥10,000) and multi-loci pDSAs was a significant risk factor for pDSA-AMR development ( p <0.001); however, it did not affect the 5-year recipient survival compared with those without ( p =0.56). In conclusion, preoperative MELD ≤13 and pre-rituximab anti-ABO IgM-titer ≥128 for ABOi-LDLT, and the combination of sum-MFI ≥10,000 and multi-loci pDSAs for pDSA-LT, are risk factors for AMR in the era of rituximab desensitization. Characteristically, ABOi-AMR significantly deteriorated graft and recipient survival, whereas pDSA-AMR did not.

Rituximab and infliximab desensitization with anti-IgE mAb omalizumab as adjuvant therapy: a case series

Rituximab and infliximab are mAbs used in hematologic and autoimmune disease. Their use can be associated with hypersensitivity reactions (HSRs). Drug desensitization (DD) represents a therapeutic strategy to overcome HSRs.1 Although most DDs are completed successfully and safely, some can be complicated by breakthrough reactions, preventing further drug administration. We describe four patients who were treated with anti-IgE mAb omalizumab as part of DD in addition to premedication with montelukast (10 mg), famotidine (40 mg), chlorphenamine (10 mg), paracetamol (1,000 mg), and 6-methylprednisolone (40 mg), after we received approval from our ethical committee.

ABO-incompatible living donor liver transplantation with high preoperative antibody titer: A case report.

Introduction and importanceABO-incompatible living donor liver transplantation (ABOi-LDLT) is essential for expanding the donor pool. ABOi-LDLT prognosis has improved since desensitization treatment with rituximab; however, patients with high antibody titers are considered to be at high risk of antibody mediated rejection (AMR). Nevertheless, the preoperative antibody titer cutoff levels that preclude ABOi-LDLT have not yet been determined. In this study, the highest preoperative antibody titer was 1:4096, and the recipient had good outcomes. There has been only one report of good outcomes with a preoperative antibody titer of more than 1:4096. We hypothesized that high preoperative antibody titers in ABOi-LDLT may not be associated with AMR in protocols involving rituximab.Case presentationThe recipient was a 22-year-old man with biliary atresia and underwent ABOi-LDLT (B to O). We administered 500 mg of rituximab 14 days prior and then 300 mg of rituximab one day prior to ABOi-LDLT. The recipients preoperative IgG antibody titer was 1:4096. Postoperative immunosuppressive protocol involved steroids, tacrolimus, and mycophenolate mofetil. The patient had satisfactory graft function three years following ABOi-LDLT.Clinical discussionThe antibody that is responsible for posttransplant AMR should be newly synthesized after transplantation as a result of sensitization by antigens on the vascular endothelial cells of the graft. In ABOi-LDLT, natural antibodies may not cause AMR.ConclusionsThe most important factor for preventing AMR in recipients undergoing ABOi-LDLT is the suppression of de novo antibodies. High preoperative antibody titers may not necessarily preclude ABOi-LDLT, provided that rituximab is used in desensitization.

Rituximab Desensitization in Liver Transplant Recipients With Preformed Donor-specific HLA Antibodies: A Japanese Nationwide Survey.

Background.The significance of preformed donor-specific anti-HLA antibodies (DSAs) in liver transplant recipients is controversial. Moreover, there has been no established desensitization protocol for DSA-positive recipients.Methods.A Japanese nationwide survey was performed to investigate the clinical practice among preformed DSA-positive patients with special reference to rituximab desensitization.Results.There was a total of 47 cases, including 2 pediatric cases, in which rituximab (287 ± 159 mg [319 (50–916)/m2]) was administered to desensitize preformed DSA. The decision for the indication of rituximab desensitization was based on a single-antigen assay in the majority of cases (83%, 39/47), and the most frequent protocol was rituximab monotherapy (n = 12) followed by quadruple treatment with rituximab tacrolimus, mycophenolate mofetil, and plasmapheresis (n = 11). The overall 1-, 3-, and 5-y graft and patient survival rates among adult patients were 85%, 83%, 83%, and 81%, 77%, 74%, respectively, while neither graft loss nor death was observed in the 2 pediatric cases. The 1-, 3-, and 12-mo cumulative incidence of antibody-mediated rejection (AMR) was 11%, 13%, and 13%, respectively. The incidence of AMR was significantly higher in the lower rituximab dose group than in the higher rituximab dose group (cutoff 300 mg/m2, 4% versus 24%, P = 0.041). The rate of infusion-related adverse drug reactions (ADRs) was 4.4%, and all ADRs were mild and self-limiting. A total of 99 ADRs among 27 patients were reported, none of which were severe adverse events associated with rituximab.Conclusions.The rituximab induction was well tolerated among DSA-positive liver transplant recipients with a satisfactory outcome. A rituximab dose >300 mg/m2 was observed to achieve less incidence of the development of AMR.

No diffuse intrahepatic biliary stricture after ABO-incompatible adult living donor liver transplantation using tailored rituximab-based desensitization protocol.

BackgroundRituximab (RTx) desensitization protocol offered good outcome in ABO-incompatible (ABOi) living donor liver transplantation (LDLT). However, diffuse intrahepatic biliary stricture (DIHBS) is still inevitable hurdle. We selectively added postoperative high dose intravenous immunoglobulin (IVIG) and/or simultaneous splenectomy if ABO isoagglutinin titer just before liver transplantation after plasma exchange (PE) was higher than 1/16. Herein, we reported the excellent outcome of ABOi LDLT without DIHBS using tailored desensitization protocol and compared it with that of ABO-compatible (ABOc) LDLT.MethodsSixty-five cases (14.8%) of ABOi LDLTs were performed among 438 primary adult LDLTs in our center between March 2012 and June 2017. We performed 1-to-2 propensity score matching (PSM) to extract 60 cases of ABOi LDLTs and 120 cases of ABOc LDLTs.ResultsThere were no significant differences in clinical characteristics between ABOi and ABOc recipients. There were no significant differences in complications and rejection. There was no DIHBS in both groups. The 1-, 3-, and 5-year overall survival rates were 98.3%, 86.7%, and 82.9% in ABOi group and 96.7%, 86.7%, and 85.4% in ABOc group, respectively (P=0.88). Most common cause of deaths of both groups was hepatocellular recurrence. The 1-, 3-, and 5-year biliary complication (anastomosis leakage or stricture) free survival rates were 81.4%, 69.5%, and 67.5% in ABOi group and 83.0%, 81.3%, and 80.0% in ABOc group, with no significant differences (P=0.11).ConclusionsRTx-based tailored (optional IVIG + splenectomy) desensitization protocol for ABOi LDLT was feasible and acceptable.

Assessment of Confirmed Clinical Hypersensitivity to Rituximab in Patients Affected with B-Cell Neoplasia.

Rituximab hypersensitivity reactions are rare but are one of the main causes of rituximab elimination from antilymphoma immunochemotherapy treatments. While the clinical picture may be indistinguishable from other infusion-related reactions, hypersensitivity reactions (HSR) do not disappear and instead become more intense with subsequent administrations. Objective. To describe the use of the 12-step protocol for desensitization to intravenous rituximab in clinical practice and the complementary study of a possible IgE-mediated HSR in the context of B-cell lymphoma treatment. Methods. A 12-step rituximab desensitization protocol was performed prospectively within clinical practice in 10 patients with a history of severe infusion reactions or in patients who had a repeated reaction at subsequent doses despite taking more intense preventive measures. Skin prick tests were performed at the time of reaction and at a later time to eliminate false negatives due to possible drug interference. Results. Overall, with the desensitization protocol, 70% of patients were able to complete the scheduled immunochemotherapy. Two patients had to discontinue the therapy due to clinical persistence and the third due to lymphoma progression. Intradermal tests with 0.1% rituximab were positive in only 20% of cases, demonstrating a mechanism of hypersensitivity. Conclusions. The 12-step desensitization protocol is very effective and assumable within healthcare practice. There is a need to determine the mechanism underlying the infusion reaction in a large proportion of cases due to the risk of future drug exposure.

Comparison of one-bag and multibag desensitization protocols for the prevention of rituximab hypersensitivity

Purpose: Rituximab is prone to infusion-related reactions, which commonly requires desensitization to maintain its administration. Conventional desensitization protocols are using multistep infusion by diluting solutions. However, the process of diluting drugs and stepwise delivery needs additional time and effort. The objective of this study was to investigate the safety and efficacy of a nondiluting, one-bag protocol of rituximab desensitization. Methods: A retrospective study was performed by reviewing the medical records of patients who underwent rituximab desensitiza tion between 2009 and 2018. The completion rate, occurrence and severity of breakthrough reactions (BTR), and time required to complete the therapy were compared between one-bag protocol and multibag protocol. Results were analyzed by generalized es timation equation method, and odds ratios (ORs) of completion rate and BTR incidence were estimated. Results: Total 190 cases of desensitization therapy were performed in 49 patients; the incidence of BTR was 16.84% and the overall completion rate was 96.32%. No significant difference in completion rate was found (OR, 3.58; 95% confidence interval [CI], 0.79-16.38) and there was no significant difference in BTR incidence (OR, 0.81; 95% CI, 0.23-2.82) in one-bag protocol. BTR in the one-bag protocol tended to occur even through entire steps, whereas most of the BTR in the multibag protocol occurred at later steps of the process. The average time spent in the desensitization was 60 minutes shorter in the one-bag than the multibag protocol (258.15 minutes vs. 329.81 minutes, P<0.001). Conclusion: One-bag desensitization protocol showed no significant difference in safety and efficiency compared to the conven tional multibag protocol, with shortening the time required for completion. (Allergy Asthma Respir Dis 2020;8:135-141)

Rituximab for Desensitization during HLA-Mismatched Stem Cell Transplantation in Patients with a Positive Donor Specific Anti-HLA Antibody: A Prospective Study

A prospective, clinical trial in non-manipulated haploidentical allografts was initiated to define the efficacy of a single dose of 375 mg/m2 rituximab as a desensitization regimen for donor-specific anti-HLA antibody (DSA)-positive patients with 2,000 ≤ mean fluorescence intensity (MFI) &lt; 10,000. In the clinical cohort, compared to pretransplantation [median, 4791, n=28], the median MFI levels at day 7 [0], 14 [0], 21 [0], 30 [0], and 45 [0] following transplantation were significantly decreased (P&lt;0.0001 for all). The incidence of primary poor graft function (PGF) in the clinical cohort (n=55) was comparable to that in the matched-pair cohort (n=110) negative for the DSA (5% vs. 1%, P=0.076), both of which were significantly lower than that in the historical cohort (n=22) with 2,000 ≤ MFI&lt;10,000 without receiving any treatment to cope with DSA (27%, P&lt;0.001, for all). Rituximab desensitization was associated with a reduced incidence of primary PGF (HR 0.200, P=0.023). The 3-year non-relapse mortality of patients in the clinical cohort and the matched-pair cohort were 23% and 24%, respectively, both of which were lower than that of patients in the historical cohort (37%), although no statistical significance was observed. These results led to a low 3-year overall survival in patients in the historical cohort (58%) compared to those in the clinical cohort (71%) and the matched-pair cohort (73%). These results suggest that a single dose of rituximab could be effectively used to desensitize patients and prevent the onset of primary PGF in patients who receive HLA-mismatched allografts. This study is registered at http://www.chictr.org.cn/ChiCTR-OPC-15006672. Disclosures No relevant conflicts of interest to declare.

Rituximab hypersensitivity and desensitization: a personalized approach to treat cancer and connective tissue diseases

Rituximab hypersensitivity and desensitization: a personalized approach to treat cancer and connective tissue diseases

Outcomes of a tailored rituximab-based desensitization protocol without local infusion therapy for ABO-incompatible adult living donor liver transplantation

Introduction: Rituximab (RTx) desensitization protocol in ABO-incompatible (ABOi) living donor liver transplantation (LDLT) offered new paradigm shift beyond ABO blood barrier to obtain donor pool expanding. The Aim of our study is to evaluate the outcome of ABOi adult LDLT using tailored desensitization protocol and to compare with that of ABO compatible (ABOc) LT in single center experience. Method: Between March 2012 and June 2017, 65 cases (14.8%) of ABOi LDLTs were performed in our center among 438 primary adult LDLTs. In ABOi cases, reduced RTx (300mg/m2) was administered around 3 weeks before LDLT, followed by 3 times of plasmapheresis at one week before LT regardless initial and final isoagglutinin titer. If issoagglutinin titer was higher than x32 after plasmapheresis, simultaneous splenectomy with perioperative high dose intravenous immunoglobulin (5 day s/0.8g/Kg) was selectively added. The immunosuppression was maintained with triple therapy (tacrolimus, steroids and mycophenolate mofetil). We performed propensity score matching and 120 ABOc cases and 60 ABOi cases were selected. Outcomes were then retrospectively compared between two groups. Result: There were no significant differences in recipients’ characteristics including MELD score, with HCC or not, and final graft to recipient weight ratio (GRWR) between two groups. Overall survival rates at 5 years are 89.2% in ABOc cases, and 87.8% in ABOi cases without any significant differences. There were also no significant differences in complication rates such as biliary complication, infection, acute cellular rejection. There were no cases with antibody-mediated rejection in ABOi cases. In cases with HCC (89 cases of ABOc group, and 42 cases of ABOi group), recurrence-free survival at 5 years were 90.4% in ABOc, and 77.5% in ABOi. There was also no significant difference. Conclusion: Our RTx-based tailored desensitization protocol for ABOi LDLT was feasible and the outcome was considered acceptable.

Cytomegalovirus Immunity After Alemtuzumab Induction in Desensitized Kidney Transplant Patients.

Desensitization with IVIG + rituximab combined with alemtuzumab induction gives HLA-sensitized patients an opportunity for successful kidney transplantation. However, it may be associated with a high risk for viral infections due to combined T cell and B cell depletion. Anti-cytomegalovirus (CMV) activity was assessed in 280 pretransplant and posttransplant blood samples from 33 desensitized patients who received alemtuzumab induction. CMV-specific CD8+ (CMV-Tc), CD4+ (CMV-Th) T cell activity, and natural killer (NK) cell number were measured by flow cytometry. Anti-CMV IgG was measured by enzyme-linked immunosorbent assay, and CMV DNA by polymerase chain reaction. All 30 CMV sero (+) patients were (+) for CMV-Tc and/or Th predesensitization, while 3 sero (-) patients showed no CMV-T cell activity. CMV-Tc and/or Th became (-) in 50% to 70% of these sero (+) patients at 1 month post-alemtuzumab. However, 75% showed CMV-T cell (+) by 2 months and 95% did so by 3 months post-alemtuzumab. More than 50% of pretranslpant NK cell levels were detected post-alemtuzumab. Anti-CMV IgG levels did not decrease posttransplant in sero (+) patients. Four patients developed CMV viremia with clearance by 1.2 months, which correlated with an increase or appearance of CMV-T cells, even in the sero (-) patient. CMV-T cell activity, anti-CMV IgG, and NK cell-mediated antibody-dependent cell cytotoxicity were present in aleumtuzumab-treated CMV sero (+) patients. One sero (-) patient developed CMV-T cell responses post-CMV viremia. These results suggest that the IVIG + rituximab desensitization combined with alemtuzmab induction with triple immunosuppression maintenance does not result in prolonged suppression of anti-CMV immunity or increased risk for CMV infection.

Rituximab and hepatitis B reactivation in HBsAg-negative/anti-HBc-positive kidney transplant recipients.

Background Hepatitis B virus (HBV) reactivation is a well-known complication of immunosuppressive therapy. Although rituximab is increasingly used for desensitization of ABO-incompatible or positive crossmatch kidney transplantation, the risk of HBV reactivation in hepatitis B surface antigen (HBsAg)-negative/hepatitis B core antibody (anti-HBc)-positive kidney transplant patients receiving rituximab desensitization remains undetermined. Methods We analysed 172 resolved HBV patients who underwent living donor kidney transplantation between 2008 and 2014. Patients were divided into rituximab ( n = 49) or control ( n = 123) groups. All patients were observed for HBV reactivation, which was defined as the reappearance of hepatitis B surface antigen or HBV DNA. Results During the follow-up period (median, 58 months; range, 4-95 months), five patients (10.2%) in the rituximab group and two patients (1.6%) in the control group experienced HBV reactivation (P = 0.003). In the rituximab group, two patients experienced HBV-related severe hepatitis, and one patient died due to hepatic failure. The median time from rituximab desensitization to HBV reactivation was 11 months (range, 5-22 months). By contrast, no patients in the control group experienced severe hepatitis. The status of hepatitis B surface antibody was similar between groups. Rituximab desensitization [hazard ratio (HR), 9.18; 95% confidence interval (CI), 1.74-48.86; P = 0.009] and hepatitis B surface antibody status (HR, 4.74; 95% CI, 1.05-21.23, P = 0.04) were significant risk factors for HBV reactivation. Conclusions Rituximab desensitization for incompatible kidney transplantation significantly increased the risk of HBV reactivation in HBsAg-negative/anti-HBc-positive patients. Therefore, close monitoring of HBV DNA is required in these patients.

Rituximab and hepatitis B reactivation in HBsAg-negative/ anti-HBc-positive kidney transplant recipients.

Hepatitis B virus (HBV) reactivation is a well-known complication of immunosuppressive therapy. Although rituximab is increasingly used for desensitization of ABO-incompatible or positive crossmatch kidney transplantation, the risk of HBV reactivation in hepatitis B surface antigen (HBsAg)-negative/hepatitis B core antibody (anti-HBc)-positive kidney transplant patients receiving rituximab desensitization remains undetermined. We analysed 172 resolved HBV patients who underwent living donor kidney transplantation between 2008 and 2014. Patients were divided into rituximab ( n = 49) or control ( n = 123) groups. All patients were observed for HBV reactivation, which was defined as the reappearance of hepatitis B surface antigen or HBV DNA. During the follow-up period (median, 58 months; range, 4-95 months), five patients (10.2%) in the rituximab group and two patients (1.6%) in the control group experienced HBV reactivation (P = 0.003). In the rituximab group, two patients experienced HBV-related severe hepatitis, and one patient died due to hepatic failure. The median time from rituximab desensitization to HBV reactivation was 11 months (range, 5-22 months). By contrast, no patients in the control group experienced severe hepatitis. The status of hepatitis B surface antibody was similar between groups. Rituximab desensitization [hazard ratio (HR), 9.18; 95% confidence interval (CI), 1.74-48.86; P = 0.009] and hepatitis B surface antibody status (HR, 4.74; 95% CI, 1.05-21.23, P = 0.04) were significant risk factors for HBV reactivation. Rituximab desensitization for incompatible kidney transplantation significantly increased the risk of HBV reactivation in HBsAg-negative/anti-HBc-positive patients. Therefore, close monitoring of HBV DNA is required in these patients.

Rituximab Desensitization in Pediatric Patients: Results of a Case Series.

Rituximab is a monoclonal antibody (mAb) primarily used to treat oncologic and autoinflammatory conditions. Although hypersensitivity reactions (HSRs) and desensitization protocols to mAbs have been well described in adults, the experience in the pediatric population is very limited. We sought to determine the safety and efficacy of desensitization to rituximab in the pediatric population at our institution. We retrospectively reviewed the experience with HSRs and desensitization to rituximab during a 5-year period in our tertiary care pediatric center, including reaction evaluation, premedication regimens, and desensitization procedures and protocols. A total of 17 desensitizations to rituximab were performed in three patients. A 14-year-old patient underwent successful desensitization to rituximab using a published adult protocol without incident. Two younger patients (ages 7 years and 23 months) experienced significant reactions during initial desensitization attempts. Therefore, we designed a modified desensitization protocol to rituximab, with particular attention to the rate of infusion as mg/kg/h. This new patient weight-based protocol was successfully used in a total of 13 desensitizations in these two patients. Desensitization to rituximab was a safe and effective procedure in our pediatric population. We present a new patient weight-based desensitization protocol for pediatric patients who develop HSRs to rituximab, with particular usefulness for younger pediatric patients and potential utility in pediatric patients with HSRs to other mAbs.

JC polyomavirus viremia and progressive multifocal leukoencephalopathy in human leukocyte antigen-sensitized kidney transplant recipients desensitized with intravenous immunoglobulin and rituximab.

Desensitization (DES) with intravenous immunoglobulin (IVIG)+rituximab is effective, safe, and increases the transplantation rate in human leukocyte antigen-sensitized patients. However, reports of progressive multifocal leukoencephalopathy (PML) caused by JC polyomavirus (JCPyV) in autoimmune patients treated with rituximab is concerning. Here, we report on the JCPyV viremia and PML status in kidney transplant patients with/without DES (non-DES). In total 1195 and 699 DNA samples from plasma in 117 DES (78% lymphocyte-depleting [LyD] induction) and 100 non-DES patients (45% LyD), respectively, were submitted for JCPyV-polymerase chain reaction. Results were compared in both groups. No patients in either DES or non-DES developed PML or presented with any neurological symptoms. The JCPyV viremia rate was similar in DES and non-DES patients (3/117 vs. 9/100, P=0.07). The JCPyV levels were low (median peak levels, 1025 copies/mL) and JCPyV viremia was observed only once during the study period in most patients. All 3 DES patients with JCPyV(+) received 1 dose rituximab and no DES patients with >1 dose rituximab showed JCPyV(+). All 3 JCPyV(+) DES patients received LyD induction, while only 2 of 9 JCPyV(+) non-DES patients did so, and the remaining 7 received non-LyD or no induction. JCPyV in leukocyte was mostly negative in DES and non-DES patients. Immunosuppression in patients with or without JCPyV(+) was similar. BK polyomavirus viremia was observed more commonly in patients with JCPyV(+) than in those without (P<0.02). Patients with IVIG+rituximab DES followed by transplantation with LyD induction and additional rituximab rarely show JCPyV viremia and appear at low risk for PML.

A Systematic Review of the Use of Rituximab for Desensitization in Renal Transplantation

Rituximab is a B lymphocyte-depleting agent used to treat lymphoma and autoimmune diseases. Recently, it has been used for desensitization therapy in ABO-incompatible and highly sensitized recipients undergoing renal transplantation. A systematic review was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Four databases and three trial registries were searched for studies comparing rituximab with non-rituximab desensitization protocols. A lack of randomized evidence precluded meta-analysis, and thus a narrative review was conducted. Forty-five records met the inclusion criteria, relating to 21 individual studies (two randomized controlled trials and 19 retrospective cohort studies). Ten studies investigated the use of rituximab in ABO-incompatible patients; most found no significant differences in patient and graft outcomes when compared most frequently to splenectomy-based protocols. Nine studies of limited quality focused on highly sensitized recipients (positive cross-match, donor-specific antibody, and elevated panel reactive antibody) and demonstrated some benefits in graft survival, acute and chronic rejection, and sensitization levels with rituximab. The remaining two studies combined ABO-incompatible and highly sensitized recipients and found no statistically significant increase in infectious complications with rituximab. Evidence of limited quality was identified to support the use of rituximab desensitization in highly sensitized recipients. Among ABO-incompatible recipients, rituximab was found to be equivalent to splenectomy, indicating that this invasive surgical procedure is not necessary. Further randomized controlled trials are required to better define the efficacy, long-term safety, and optimal dosing regimen of rituximab in this setting.

Successful Interim Outcomes of Bortezomib Desensitization on Highly Sensitized Deceased Donor Kidney Transplant Waitlist Patients

Highly sensitized (HS) patients seldom have chance to receive kidney transplant. To increase transplantation rate among those population, previous IV immunoglobulin and rituximab desensitization protocol showed good transplant conversion rate, but also carried moderate rate of antibody mediated rejection. Bortezomib, a proteasome inhibitor can control the production of anti-HLA antibodies through plasma cell apoptosis. A single center waitlist desensitization program was employed to facilitate successful kidney transplantation in HS patients group. We prospectively enrolled 23 patients from Jul 2010 to Dec 2013. Desensitization protocol included two doses of IVIG (2 g/kg), single dose of rituximab (375 mg/m 2 , max 500 mg), and 4 days of bortezomib (1.3 mg/m 2 on days 1,3,7 and 9). Anti-HLA class I and II antibodies were determined by Luminex solid phase bead assay at baseline and M2, M3 and M6. We investigated the difference of transplant conversion rate between desensitized HS patients and non-desensitized HS waitlist patients. Also we analyzed the difference of PRA % values and mean fluorescence intensity (MFI) between pre- and post-desensitization serum. Mean age of treatment group was 48.7±11.2 years old. Male to female ratio was 12:11. O+ blood type patients were 34.8% of patients. Mean duration of previous renal replacement therapy were 153.5±65.5 months. Baseline mean class I and II PRA % values were 86±15.3 and 66±34. Baseline class I and II MFI values were 13,893±6,147 and 12,274±6,891. After desensitization, kidney transplant were successfully performed in 34.8% of patients, compared to 13.8% transplant conversion rate among non-desentized HS controls ( p =0.001 by Log-Rank). Among KT recipients, median duration of waiting after desensitization was 3 months with interquartile range 2-8.1 months. Class I PRA % had showed decreased values until 3 months after desensitization. After 6 months, there were no differences between the class I PRA values between pre-desensitization samples and post-desensitization samples. There were no other differences except class I PRA % values. Desensitization protocol were generally well tolerated, with the completion rate of 92% patients. There were no serious adverse events, but moderate adverse event were in 46%, most commonly fever and diarrhea. Highly sensitized waitlist patients are manageable by desensitization protocol including bortezomib.