Blinatumomab as the first-line induction for ANCA-associated rapidly progressive glomerulonephritis

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a leading cause of rapidly progressive glomerulonephritis (RPGN; defined as an estimated glomerular filtration rate (eGFR) decline ≥50% within 3 months), which is associated with significant morbidity and mortality.¹ Induction with cyclophosphamide (CyC) or rituximab (RTX) is the current standard of care for controlling systemic inflammation in AAV,² yet reversal of renal function impairment in RPGN is frequently limited, often making permanent nephron loss inevitable. For example, a report focusing on AAV-RPGN using CyC/RTX-based induction (with or without the addition of avacopan, a C5aR inhibitor), renal functional improvements are generally limited to approximately 20 mL/min/1.73 m².³ Thus, based on the concept of profound B-cell depletion and immune reset, and inspired by previous case reports demonstrating that CD19 CAR-T therapy and T-cell engagers (TCEs) can induce remission in patients with non-renal refractory AAV,^4–7 we here report two cases of AAV-RPGN treated with blinatumomab as first-line B-cell depleting induction therapy, with a maximum follow-up of 52 weeks.

To establish a reference benchmark, we analysed a retrospective cohort of 57 patients with active AAV-RPGN treated at our centre since 2010 (baseline eGFR 0–30 mL/min/1.73 m²; mean 15.4±12.3; relapsing AAV 8.8%; microscopic polyangiitis (MPA) 93%; median follow-up 20 months; online supplemental table 1). Induction therapy with CyC or anti-CD20 monoclonal antibodies significantly reduced disease activity as measured by the Birmingham Vasculitis Activity Score (figure 1C, online supplemental figures 1A,B). However, renal functional recovery remained suboptimal, with a mean eGFR increase of 15.0 ± 11.1 mL/min/1.73 m² at 6 months postinduction and 13.9 ± 16.2 mL/min/1.73 m² at the last follow-up (figure 1C). Event-free survival for the composite endpoint of death or end-stage kidney disease was 80.5% (95% CI 66.5% to 89.1%) at 1 year and 49.6% (95% CI 20.6% to 73.3%) at 5 years, with a median event-free survival of 60 months. eGFR trajectories were broadly similar across induction regimens (CyC vs RTX/obinutuzumab; online supplemental figure 1A). To minimise confounding factors, we further generated a matched control group characterised by newly diagnosed MPA, baseline eGFR 15–30 mL/min/1.73 m², dialysis-independence at onset, and biopsy-confirmed non-sclerotic pathology (online supplemental table 1). In this group, eGFR increased by only 13.8±14.3 mL/min/1.73 m² (95% CI 8.1 to 17.5) at 6 months post-induction, with no subsequent improvement during follow-up (online supplemental figure 1B). Collectively, these findings underscore a persistent unmet need for novel therapies capable of promoting meaningful renal recovery in AAV-RPGN.

Figure 1. Treatment schedule, safety, laboratory parameters and immunological dynamics in patients with antineutrophil cytoplasmic autoantibody-associated RPGN treated with blinatumomab. (A) Treatment schema of blinatumomab administration. *MMF was initiated at week 12 for maintenance therapy. ^#A third cycle of blinatumomab was administered at month 6 in Patient 1. (B) Safety profile during follow-up. ^&Febrile neutropenia is indicated. (C) Longitudinal changes in renal and systemic disease parameters. eGFR change, 24-hour proteinuria, BVAS and ANCA titres are shown over time in the overall AAV-RPGN cohort (grey) and in patients treated with blinatumomab (coloured lines). Cohort data are presented as means with 95% CIs. ANCA titres quantified using a commercial MPO/PR3-ELISA kit, positive cut-off ≥1 AU. (D) Immunophenotypic dynamics of circulating B cells. (1) UMAP representation of peripheral CD19⁺ B cells at baseline and 3 months after blinatumomab treatment. (2) Distribution of B-cell subsets within residual peripheral CD19⁺ B cells over time. (E) Temporal dynamics of circulating lymphocytes. Absolute counts of (1) CD19⁺ B cells and (2) CD3⁺ T cells during treatment and follow-up. AAV, ANCA-associated vasculitis; ANCA, antineutrophil cytoplasmic antibody; BLINA, blinatumomab; BVAS, Birmingham Vasculitis Activity Score; CRS, cytokine release syndrome; eGFR, estimated glomerular filtration rate; ICANS, immune effector cell-associated neurotoxicity syndrome; MMF, mycophenolate mofetil; MPO, myeloperoxidase; PR3, proteinase-3; RPGN, rapidly progressive glomerulonephritis; UMAP, uniform manifold approximation and projection.

Blinatumomab, a CD19×CD3 bispecific T-cell engager approved for B-cell acute lymphoblastic leukaemia,⁸ induces rapid and profound B-cell depletion and has shown immunomodulatory effects in selected autoimmune conditions.^{7 9–11} Here, we report its use in two patients with newly diagnosed myeloperoxidase (MPO)-AAV presenting with RPGN (online supplemental tables 1,2). Both patients exhibited active systemic vasculitis with renal and pulmonary involvement. Patient 1 presented with fever, myalgia and RPGN (renal biopsy: mixed class), accompanied by multiple pulmonary exudative lesions. Patient 2 presented with fever, RPGN (renal biopsy: crescentic class), and diffuse pulmonary infiltrates on imaging.

Blinatumomab was administered in an inpatient setting following premedication with dexamethasone 20 mg. Patients received a continuous intravenous infusion over 5 days (cumulative dose 38.5 µg), followed by a 2-week interval, and a subsequent 2-day infusion totalling 38.5 µg (19 µg on day 1 and 19.5 µg on day 2). In patient 1, a third cycle of blinatumomab was given at month 6 for elevated MPO-ANCA titres and persistent proteinuria (figure 1A). Flow cytometry was used to quantify peripheral blood lymphocyte subsets during treatment. Antibody panels for B-cell and T-cell immunophenotyping are listed in online supplemental tables 3,4, respectively.

The most common adverse event was grade 1 cytokine release syndrome (CRS), characterised by low-grade fever and transient elevations in C-reactive protein that peaked on days 2–4 and normalised within 3 days. No neurotoxicity was observed during follow-up (figure 1B). Regarding infectious complications, one patient developed herpes zoster. Notably, Patient 2 developed grade 4 febrile neutropenia and profound hypogammaglobulinaemia at 2 months post-treatment, which was complicated by bacterial, Epstein-Barr virus, herpesvirus and fungal pulmonary infections. Bone marrow biopsy revealed granulocytic hypoplasia with maturation arrest. The neutropenia persisted for approximately 2 weeks despite dexamethasone, granulocyte colony-stimulating factor and intravenous immunoglobulin (IVIG) therapy, but eventually resolved with supportive care. No other severe adverse events were recorded during follow-up. Overall, a 50%–60% decline in serum immunoglobulins (IgG, IgA and IgM) was observed (online supplemental figure 1C). Immunophenotyping demonstrated rapid peripheral B-cell depletion following the first cycle, alongside a transient reduction in circulating T cells likely attributable to redistribution (figure 1D,E; online supplemental figure 2). Clinically, both patients exhibited rapid improvement in systemic disease activity (figure 1C). Marked renal recovery was seen in both patients. Within the first 2 months of therapy, eGFR improved by 50 mL/min/1.73 m² in Patient 1 and 65 mL/min/1.73 m² in patient 2. Notably, patient 2 experienced a transient eGFR decline likely driven by infectious injury, followed by sustained renal stabilisation through the 12-month follow-up. This renal recovery was accompanied by the resolution of haematuria by month 2 and a reduction in proteinuria. Pulmonary lesions resolved within 4 weeks (online supplemental figure 1D), and no disease relapse occurred throughout the follow-up period.

As a CD19/CD3 bispecific T-cell engager, blinatumomab exhibits structural advantages of small molecular size and Fc-free configuration, conferring superior tissue penetration relative to conventional monoclonal antibodies,¹² which is speculated to facilitate intrarenal pathogenic B-cell depletion. This proposed mechanism may explain the rapid ANCA clearance and unprecedented renal recovery observed in our two AAV-RPGN cases, outcomes unachievable with standard CyC or RTX therapy. Of note, this mechanistic hypothesis remains presumptive, as direct histological evidence of renal resident B-cell depletion is absent in our study.

This study has limitations. First, temporal updates of eGFR calculation equations introduced minor heterogeneity in retrospective cohort analyses. Second, the absence of post-treatment renal biopsies prevents histological validation of the hypothesised intrarenal B-cell depletion and cannot pathologically differentiate irreversible chronic renal damage from subtle residual inflammation. The observed persistent proteinuria is most likely driven by pre-existing chronic renal lesions and haemodynamic derangements rather than active autoimmune injury, though definitive confirmation is not feasible without follow-up biopsy. Additionally, blinatumomab dosing regimens and maintenance strategies for AAV-RPGN remain unstandardised due to limited clinical experience.

Together, these two cases suggest that T-cell-redirected CD19⁺ B-cell elimination may contribute to robust renal recovery in selected AAV-RPGN patients. Further large-scale clinical trials are warranted to validate the benefits of early TCE intervention before irreversible renal injury and define its optimal clinical application, efficacy and safety profile in AAV-RPGN.

The author is a staff member of the World Health Organization. The author alone is responsible for the views expressed in this publication and they do not necessarily represent the views, decisions or policies of the World Health Organization.