Humoral and Cellular Immune Responses to SARS-CoV-2 Infection and Vaccination in Autoimmune Disease Patients With B Cell Depletion.

OBJECTIVE: B cell depletion is an established therapeutic principle in a wide range of autoimmune diseases. However, B cells are also critical for inducing protective immunity after infection and vaccination. We undertook this study to assess humoral and cellular immune responses after infection with or vaccination against SARS-CoV-2 in patients with B cell depletion and controls who are B cell-competent. METHODS: Antibody responses (tested using enzyme-linked immunosorbent assay) and T cell responses (tested using interferon-γ enzyme-linked immunospot assay) against the SARS-CoV-2 spike S1 and nucleocapsid proteins were assessed in a limited number of previously infected (n = 6) and vaccinated (n = 8) autoimmune disease patients with B cell depletion, as well as previously infected (n = 30) and vaccinated (n = 30) healthy controls. RESULTS: As expected, B cell and T cell responses to the nucleocapsid protein were observed only after infection, while respective responses to SARS-CoV-2 spike S1 were found after both infection and vaccination. A SARS-CoV-2 antibody response was observed in all vaccinated controls (30 of 30 [100%]) but in none of the vaccinated patients with B cell depletion (0 of 8). In contrast, after SARS-CoV-2 infection, both the patients with B cell depletion (spike S1, 5 of 6 [83%]; nucleocapsid, 3 of 6 [50%]) and healthy controls (spike S1, 28 of 30 [93%]; nucleocapsid, 28 of 30 [93%]) developed antibodies. T cell responses against the spike S1 and nucleocapsid proteins were found in both infected and vaccinated patients with B cell depletion and in the controls. CONCLUSION: These data show that B cell depletion completely blocks humoral but not T cell SARS-CoV-2 vaccination response. Furthermore, limited humoral immune responses are found after SARS-CoV-2 infection in patients with B cell depletion.

CMV Infection and CMV-Specific Immune Reconstitution Following Haploidentical Stem Cell Transplantation: An Update.

Haploidentical stem cell transplantation (haploSCT) has advanced to a common procedure for treating patients with hematological malignancies and immunodeficiency diseases. However, cure is seriously hampered by cytomegalovirus (CMV) infections and delayed immune reconstitution for the majority of haploidentical transplant recipients compared to HLA-matched stem cell transplantation. Three major approaches, including in vivo T-cell depletion (TCD) using antithymocyte globulin for haploSCT (in vivo TCD-haploSCT), ex vivo TCD using CD34 + positive selection for haploSCT (ex vivo TCD-haploSCT), and T-cell replete haploSCT using posttransplant cyclophosphamide (PTCy-haploSCT), are currently used worldwide. We provide an update on CMV infection and CMV-specific immune recovery in this fast-evolving field. The progress made in cellular immunotherapy of CMV infection after haploSCT is also addressed. Groundwork has been prepared for the creation of personalized avenues to enhance immune reconstitution and decrease the incidence of CMV infection after haploSCT.

Emerging New Approaches in Desensitization: Targeted Therapies for HLA Sensitization.

There is an urgent need for therapeutic interventions for desensitization and antibody-mediated rejection (AMR) in sensitized patients with preformed or de novo donor-specific HLA antibodies (DSA). The risk of AMR and allograft loss in sensitized patients is increased due to preformed DSA detected at time of transplant or the reactivation of HLA memory after transplantation, causing acute and chronic AMR. Alternatively, de novo DSA that develops post-transplant due to inadequate immunosuppression and again may lead to acute and chronic AMR or even allograft loss. Circulating antibody, the final product of the humoral immune response, has been the primary target of desensitization and AMR treatment. However, in many cases these protocols fail to achieve efficient removal of all DSA and long-term outcomes of patients with persistent DSA are far worse when compared to non-sensitized patients. We believe that targeting multiple components of humoral immunity will lead to improved outcomes for such patients. In this review, we will briefly discuss conventional desensitization methods targeting antibody or B cell removal and then present a mechanistically designed desensitization regimen targeting plasma cells and the humoral response.

Randomized phase II trial of lymphodepletion plus adoptive cell transfer of tumor-infiltrating lymphocytes, with or without dendritic cell vaccination, in patients with metastatic melanoma.

BACKGROUND: The adoptive transfer of tumor-infiltrating lymphocytes (TIL) has demonstrated robust efficacy in metastatic melanoma patients. Tumor antigen-loaded dendritic cells (DCs) are believed to optimally activate antigen-specific T lymphocytes. We hypothesized that the combined transfer of TIL, containing a melanoma antigen recognized by T cells 1 (MART-1) specific population, with MART-1-pulsed DC will result in enhanced proliferation and prolonged survival of transferred MART-1 specific T cells in vivo ultimately leading to improved clinical responses. DESIGN: We tested the combination of TIL and DC in a phase II clinical trial of patients with advanced stage IV melanoma. HLA-A0201 patients whose early TIL cultures demonstrated reactivity to MART-1 peptide were randomly assigned to receive TIL alone or TIL +DC pulsed with MART-1 peptide. The primary endpoint was to evaluate the persistence of MART-1 TIL in the two arms. Secondary endpoints were to evaluate clinical response and survival. RESULTS: Ten patients were given TIL alone while eight patients received TIL+DC vaccine. Infused MART-1 reactive CD8+ TIL were tracked in the blood over time by flow cytometry and results show good persistence in both arms, with no difference in the persistence of MART-1 between the two arms. The objective response rate was 30% (3/10) in the TIL arm and 50% (4/8) in the TIL+DC arm. All treatments were well tolerated. CONCLUSIONS: The combination of TIL +DC showed no difference in the persistence of MART-1 TIL compared with TIL therapy alone. Although more patients showed a clinical response to TIL+DC therapy, this study was not powered to resolve differences between groups. TRIAL REGISTRATION NUMBER: NCT00338377.

Comparison of non-myeloablative lymphodepleting preconditioning regimens in patients undergoing adoptive T cell therapy.

BACKGROUND: Adoptive cell therapy with T cells genetically engineered to express a chimeric antigen receptor (CAR-T) or tumor-infiltrating T lymphocytes (TIL) demonstrates impressive clinical results in patients with cancer. Lymphodepleting preconditioning prior to cell infusion is an integral part of all adoptive T cell therapies. However, to date, there is no standardization and no data comparing different non-myeloablative (NMA) regimens. METHODS: In this study, we compared NMA therapies with different doses of cyclophosphamide or total body irradiation (TBI) in combination with fludarabine and evaluated bone marrow suppression and recovery, cytokine serum levels, clinical response and adverse events. RESULTS: We demonstrate that a cumulative dose of 120 mg/kg cyclophosphamide and 125 mg/m2 fludarabine (120Cy/125Flu) and 60Cy/125Flu preconditioning were equally efficient in achieving deep lymphopenia and neutropenia in patients with metastatic melanoma, whereas absolute lymphocyte counts (ALCs) and absolute neutrophil counts were significantly higher following 200 cGyTBI/75Flu-induced NMA. Thrombocytopenia was most profound in 120Cy/125Flu patients. 30Cy/75Flu-induced preconditioning in patients with acute lymphoblastic leukemia resulted in a minor ALC decrease, had no impact on platelet counts and did not yield deep neutropenia. Following cell infusion, 120Cy/125Flu patients with objective tumor response had significantly higher ALC and significant lower inflammatory indexes, such as neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR). Receiver-operating characteristics curve analysis 7 days after cell infusion was performed to determine the cut-offs, which distinguish between responding and non-responding patients in the 120Cy/125Flu cohort. NLR≤1.79 and PLR≤32.7 were associated with clinical response and overall survival. Cytokine serum levels did not associate with clinical response in patients with TIL. Patients in the 120Cy/125Flu cohort developed significantly more acute NMA-related adverse events, including thrombocytopenia, febrile neutropenia and cardiotoxicity, and stayed significantly longer in hospital compared with the 60Cy/125Flu and TBI/75Flu cohorts. CONCLUSIONS: Bone marrow depletion and recovery were equally affected by 120Cy/125Flu and 60Cy/125Flu preconditioning; however, toxicity and consequently duration of hospitalization were significantly lower in the 60Cy/125Flu cohort. Patients in the 30Cy/75Flu and TBI/75Flu groups rarely developed NMA-induced adverse events; however, both regimens were not efficient in achieving deep bone marrow suppression. Among the regimens, 60Cy/125Flu preconditioning seems to achieve maximum effect with minimum toxicity.

Prolonged and severe SARS-CoV-2 infection in patients under B-cell-depleting drug successfully treated: A tailored approach.

Prolonged B-cell depletion due to anti-CD20 monoclonal antibody (mAbs) therapy impairs the adaptive immune response, causing severe manifestations during COronaVIrus Disease-2019 (COVID-19). The cases of two patients under anti-CD20 therapy who experienced prolonged and severe COVID-19 successfully treated with mAbs against Severe Acute Respiratory Syndrome-CoV-2 spike proteins are reported.

Ex vivo T-cell depletion vs post-transplant cyclophosphamide, sirolimus, and mycophenolate mofetil as graft-vs-host disease prophylaxis for allogeneic hematopoietic stem cell transplantation.

OBJECTIVE: To compare the efficacy and safety of CD34+ selected ex vivo T-cell depletion (TCD) vs post-transplant cyclophosphamide, sirolimus, and mycophenolate mofetil (PTCy-Sir-MMF) as graft-vs-host disease (GVHD) prophylaxis. METHODS: We retrospectively included patients who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) with either TCD (n = 38) or PTCy-Sir-MMF (n = 91). RESULTS: Cumulative incidence of neutrophil and platelet recovery was 92% vs 99% (P = .06) and 89% vs 97% (P = .3) in TCD and PTCy-Sir-MMF, respectively. Cumulative incidences of aGHVD grade II-IV, III-IV, and moderate to severe cGVHD were 11% vs 19% (P = .2), 3% vs 2% (P = .9), and 3% vs 36% (P < .001) in TCD and PTCy-Sir-MMF, respectively. The 2-year non-relapse mortality, relapse, disease-free and overall survival were 25% vs 8% (P = .01), 20% vs 16% (P = .2), 55% vs 76% (P = .004), 57% vs 83% (P = .004) for TCD and PTCy-Sir-MMF, respectively. Cumulative incidence of cytomegalovirus and Epstein-Barr infection requiring therapy was 76% vs 40% (P < .001) and 32% vs 0% (P < .001) in TCD and PTCy-Sir-MMF, respectively. PTCy-Sir-MMF platform showed faster T-cell reconstitution. CONCLUSIONS: PTCy-Sir-MMF provides better survival outcomes but is associated with higher risk of cGVHD compared to TCD.

Long-term effects of intensive B cell depletion therapy in severe cases of IgG4-related disease with renal involvement.

IgG4-related disease (IgG4-RD) is an immune-mediated disorder often showing elevated serum IgG4 concentrations, dense T and B lymphocyte infiltration, and IgG4-positive plasma cells and storiform fibrosis. We prospectively evaluated for 4 years 5 patients with histologically proven IgG4-RD of whom 3 had tubulointerstitial nephritis (TIN) and 2 had retroperitoneal fibrosis (RPF). They received an intensive B depletion therapy with rituximab. The estimated glomerular filtration rate of TIN patients after 1 year increased from 9 to 24 ml/min per 1.73 m2. IgG/IgG4 dropped from 3236/665 to 706/51 mg/dl, C3/C4 went up from 49/6 to 99/27 mg/dl, and the IgG4-RD responder index fell from 10 to 1. CD20+ B cells decreased from 8.7 to 0.5%. A striking drop in interstitial plasma cell infiltrate as well as normalization of IgG4/IgG-positive plasma cells was observed at repeat biopsy. Both clinical and immunological improvement persisted over a 4-year follow-up. Treating these patients who were affected by aggressive IgG4-RD with renal involvement in an effort to induce a prolonged B cells depletion with IgG4 and cytokine production decrease resulted in a considerable rise in eGFR, with IgG4-RD RI normalization and a noteworthy improvement in clinical and histological features. Furthermore, the TIN subgroup was shown not to need for any maintenance therapy.

Evolution of the role of haploidentical stem cell transplantation: past, present, and future.

INTRODUCTION: The accessibility to haplo-donors has led to an increase in the number of haplo-HSCT worldwide. A systematic search of the PubMed database between 2000 to present was performed. AREAS COVERED: In this review, the authors discussed the most used approaches to perform haplo-HSCT and its results: T-cell depletion (TCD, including Perugia platform and its modifications) and T-cell repleted haplo (TCR, including the high-dose post-transplant cyclophosphamide strategy (Baltimore protocol) and the Beijing protocol). The improvements and modifications made to the different strategies have increased the indications of haplo-HSCT, including both malignant and nonmalignant disorders. Focusing on the Baltimore protocol, the authors review the results of the retrospective studies that have compared it to other donor transplants. The limitations of this strategy in terms of toxicity, graft complications, and GVHD are also discussed in detail. Finally, possible approaches to improve the outcomes of TCR haplo-HSCT are presented. EXPERT OPINION: The recent advances in the field of haplo-HSCT have allowed a large number of patients with incurable diseases to benefit from this procedure despite not having a matched donor. With all available strategies, virtually no patient who needs an allogeneic transplant should be excluded by the absence of a donor.

Mogamulizumab in Combination with Durvalumab or Tremelimumab in Patients with Advanced Solid Tumors: A Phase I Study.

PURPOSE: The study goal was to determine safety, antitumor activity, and pharmacodynamic profile of mogamulizumab, an anti-C-C chemokine receptor 4 (anti-CCR4) mAb targeting effector regulatory T cells (eTreg), in combination with mAb checkpoint inhibitors durvalumab or tremelimumab. PATIENTS AND METHODS: This was a multicenter, phase I, dose escalation study, followed by disease-specific cohort expansion (NCT02301130). Mogamulizumab dose escalation proceeded with concurrent dose escalation of durvalumab or tremelimumab in patients with advanced solid tumors. Cohort expansion occurred with mogamulizumab 1 mg/kg plus durvalumab 10 mg/kg or tremelimumab 10 mg/kg in patients with advanced pancreatic cancer. RESULTS: Forty patients were enrolled during dose escalation, followed by 24 patients during dose expansion. No dose-limiting toxicities occurred during dose escalation. No new or unexpected toxicities were seen. Tolerability, the primary endpoint, was acceptable utilizing mogamulizumab 1 mg/kg plus durvalumab or tremelimumab 10 mg/kg in the combined dose escalation and dose expansion cohorts (each n = 19). At these doses, the objective response rate was 5.3% (95% confidence interval, 0.1%-26.0%; one partial response) with each combination treatment. At all doses, mogamulizumab treatment led to almost complete depletion of peripheral eTregs, as well as reduction of intratumoral Tregs in the majority of patients. There was no clear correlation of clinical response with peripheral or intratumoral reduction in CCR4+ eTregs or with baseline degree of CCR4+ expression. CONCLUSIONS: Mogamulizumab in combination with durvalumab or tremelimumab did not result in potent antitumor efficacy in patients with advanced solid tumors. Tolerability of mogamulizumab 1 mg/kg combined with durvalumab or tremelimumab 10 mg/kg was acceptable.

Histiocyte predominant myocarditis resulting from the addition of interferon gamma to cyclophosphamide-based lymphodepletion for adoptive cellular therapy.

BACKGROUND: Adoptive cellular therapy (ACT) is a promising treatment for synovial sarcoma (SS) with reported response rates of over 50%. However, more work is needed to obtain deeper and more durable responses. SS has a 'cold' tumor immune microenvironment with low levels of major histocompatibility complex (MHC) expression and few T-cell infiltrates, which could represent a barrier toward successful treatment with ACT. We previously demonstrated that both MHC expression and T-cell infiltration can be increased using systemic interferon gamma (IFN-γ), which could improve the efficacy of ACT for SS. CASE PRESENTATION: We launched a phase I trial incorporating four weekly doses of IFN-γ in an ACT regimen of high-dose cyclophosphamide (HD Cy), NY-ESO-1-specific T cells, and postinfusion low-dose interleukin (IL)-2. Two patients were treated. While one patient had significant tumor regression and resultant clinical benefit, the other patient suffered a fatal histiocytic myocarditis. Therefore, this cohort was terminated for safety concerns. CONCLUSION: We describe a new and serious toxicity of immunotherapy from IFN-γ combined with HD Cy-based lymphodepletion and low-dose IL-2. While IFN-γ should not be used concurrently with HD Cy or with low dose IL-2, IFN-γ may still be important in sensitizing SS for ACT. Future studies should avoid using IFN-γ during the immediate period before/after cell infusion. TRIAL REGISTRATION NUMBERS: NCT04177021, NCT01957709, and NCT03063632.

Immunogenicity of immunomodulatory, antibody-based, oncology therapeutics.

The increasing use of multiple immunomodulatory (IMD) agents for cancer therapies (e.g. antibodies targeting immune checkpoints, bispecific antibodies, and chimeric antigen receptor [CAR]-T cells), is raising questions on their potential immunogenicity and effects on treatment. In this review, we outline the mechanisms of action (MOA) of approved, antibody-based IMD agents, potentially related to their immunogenicity, and discuss the reported incidence of anti-drug antibodies (ADA) as well as their clinical relevance in patients with cancer. In addition, we discuss the impact of the administration route and potential strategies to reduce the incidence of ADA and manage treated patients. Analysis of published reports indicated that the risk of immunogenicity did not appear to correlate with the MOA of anti-programmed death 1 (PD-1)/PD-ligand 1 monoclonal antibodies nor to substantially affect treatment with most of these agents in the majority of patients evaluated to date. Treatment with B-cell depleting agents appears associated with a low risk of immunogenicity. No significant difference in ADA incidence was found between the intravenous and subcutaneous administration routes for a panel of non-oncology IMD antibodies. Additionally, while the data suggest a higher likelihood of immunogenicity for antibodies with T-cell or antigen-presenting cell (APC) targets versus B-cell targets, it is possible to have targets expressed on APCs or T cells and still have a low incidence of immunogenicity.

Long-term survival of pig-to-rhesus macaque renal xenografts is dependent on CD4 T cell depletion.

The shortage of available organs remains the greatest barrier to expanding access to transplant. Despite advances in genetic editing and immunosuppression, survival in experimental models of kidney xenotransplant has generally been limited to <100 days. We found that pretransplant selection of recipients with low titers of anti-pig antibodies significantly improved survival in a pig-to-rhesus macaque kidney transplant model (6 days vs median survival time 235 days). Immunosuppression included transient pan-T cell depletion and an anti-CD154-based maintenance regimen. Selective depletion of CD4+ T cells but not CD8+ T cells resulted in long-term survival (median survival time >400 days vs 6 days). These studies suggested that CD4+ T cells may have a more prominent role in xenograft rejection compared with CD8+ T cells. Although animals that received selective depletion of CD8+ T cells showed signs of early cellular rejection (marked CD4+ infiltrates), animals receiving selective CD4+ depletion exhibited normal biopsy results until late, when signs of chronic antibody rejection were present. In vitro study results suggested that rhesus CD4+ T cells required the presence of SLA class II to mount an effective proliferative response. The combination of low pretransplant anti-pig antibody and CD4 depletion resulted in consistent, long-term xenograft survival.

Phase I Trial of Inducible Caspase 9 T Cells in Adult Stem Cell Transplant Demonstrates Massive Clonotypic Proliferative Potential and Long-term Persistence of Transgenic T Cells.

PURPOSE: Inducible caspase 9 (iCasp9) is a cellular safety switch that can make T-cell therapy safer. The purpose of this phase I trial was to investigate the use of iCasp9-transduced T-cell addback in adult patients undergoing haploidentical stem cell transplantation for high-risk hematologic malignancies. PATIENTS AND METHODS: Patients undergoing myeloablative, CD34-selected haploidentical stem cell transplantation were treated with 0.5-1.0 × 106/kg donor-derived iCasp9-transduced T cells on day +25 or 26 post-transplant, with additional doses allowed for disease relapse, infection, or mixed chimerism. RESULTS: Three patients were enrolled. iCasp9-transduced T cells were readily detectable by 4 weeks post-infusion in all patients and remained at high level (114 cells/µL, 11% of T cells) in 1 patient alive at 3.6 years. One patient developed donor-derived Epstein-Barr virus-associated post-transplant lymphoproliferative disease (EBV-PTLD), which was followed by a marked expansion of iCasp9 T cells and cytokine release syndrome (CRS). These iCasp9-transduced T cells infiltrated the affected lymph nodes and secreted IFNγ and IL-10. They peaked at 1,848 cells/µL and were found to be monoclonal by T-cell receptor (TCR) clonotype and oligoclonal by viral integrant analysis, representing a 6-log in vivo expansion of the dominant T-cell clone. These T cells were not autonomous and contracted with the resolution of EBV-PTLD, which did not recur. CONCLUSIONS: iCasp9-transduced T cells could persist long-term. They retained very high in vivo clonotypic proliferative capacity and function, and could cause CRS in response to de novo lymphoma development.

B-cell depleting immunotherapies: therapeutic opportunities and toxicities.

INTRODUCTION: The last few years have witnessed what can certainly be defined as a 'period of renaissance' for immunotherapy in the field of hematological malignancies. In particular, antibody-mediated and cell-mediated immunotherapy have significantly changed the treatment approach of patients with B-cell lymphoproliferative disorders. These therapies, initially employed in patients with refractory/relapsed disease, are now integrated in the treatment of newly diagnosed patients. Together with the therapeutic success, we have also learnt that these innovative therapies can induce relevant, sometimes life-threatening or even fatal, side effects. Areas covered: In this review article, we analyzed the applicative therapeutic scenario and the peculiar toxicities associated with approaches of immunotherapy, paying particular attention to the new emerging side effects, substantially unknown before the introduction of these therapies. Expert commentary: Both monoclonal antibodies and cell therapy with lymphocytes genetically modified to be redirected against leukemia targets through the transduction with chimeric antigen receptors (CARs) have obtained unprecedented success in rescuing patients with resistant B-cell malignancies. Complications, such as neurotoxicity, cytokine release syndrome or persistent B-cell lymphopenia, must always be taken into consideration and diagnosed in a timely manner in patients with B-cell neoplasms to guarantee optimal management, thus avoiding they blunting the efficacy of immunotherapy.

Lymphocyte depletion and risk of acute rejection in renal transplant recipients at increased risk for delayed graft function.

Delayed graft function (DGF) is a risk factor for acute rejection (AR) in renal transplant recipients, and KDIGO guidelines suggest use of lymphocyte-depletion induction when DGF is anticipated. We analyzed the United Network for Organ Sharing/Organ Procurement and Transplantation Network (UNOS/OPTN) database to assess the impact of induction immunosuppression on the risk of AR in deceased kidney recipients based on pretransplant risk of DGF using a validated model. Recipients were categorized into 4 groups based upon the induction immunosuppression: (1) Rabbit anti-thymocyte globulin (rATG); (2) Alemtuzumab (C1H); (3) IL2-receptor antagonists (IL2-RA; basiliximab or daclizumab), and (4) No antibody induction. The primary endpoint for analysis was a composite endpoint of treated AR or graft failure by 1-year posttransplantation. Compared to no antibody induction, rATG and C1H had consistently lower adjusted odds of the composite endpoint across all risk strata for DGF risk, whereas IL2-Ra was associated with increased adjusted odds of the composite endpoint with increasing DGF risk. When the induction agents were compared, rATG and C1H were associated with decreasing adjusted odds for the composite endpoint with increasing risk of DGF, especially at the higher risk spectrum of DGF. Consideration must be given to use of lymphocyte-depletion induction when the anticipated risk of DGF is increased.

Long-term outcomes after early treatment with rituximab for Japanese children with cyclosporine- and steroid-resistant nephrotic syndrome.

BACKGROUND: Although rituximab (RTX) may be effective treatment in children with nephrotic syndrome who are resistant to cyclosporine A and steroid (CsA-SRNS), long-term outcomes after B cell depleting therapy remain unclear. CASE-DIAGNOSIS/TREATMENT: We retrospectively reviewed the clinical courses (median follow-up, 5.1 years) of six CsA-SRNS children (three boys; median age at RTX, 4.2 years) unresponsive to oral cyclosporine combined with ≥ 2 courses of intravenous methylprednisolone pulses, who received RTX within 6 months after disease onset (median 11 weeks). After initial RTX treatment (median two doses of 375 mg/m2) followed by retreatment with intravenous methylprednisolone pulses and/or high-dose prednisolone, all patients achieved complete remission at a median of 158 days. Although 17 relapses occurred in five patients during follow-up, all but one patient became steroid sensitive. Severe neutropenia and hypogammaglobulinemia developed in two and four patients, respectively. However, no life-threatening infections were identified in the cohort. At last visit (median age, 11.3 years), all patients maintained complete remission without renal insufficiency. CONCLUSIONS: Although late-onset adverse events should be considered, particularly for young patients, early RTX treatment may have positive outcomes in children with CsA-SRNS in the long term.