Late-onset Neutropenia after Rituximab Treatment for MPO-ANCA-associated Vasculitis

Abstract

An underestimated side effect of rituximab is late-onset neutropenia (R-LON), which often resolves spontaneously and rarely results in a severe infection. We herein report a case of febrile neutropenia due to R-LON in a 91-year-old woman with renal failure who was treated with rituximab to induce remission of myeloperoxidase antineutrophil cytoplasmic antibodies-associated vasculitis. Fifty-four days after the last rituximab administration, the patient was hospitalized for febrile neutropenia due to R-LON, which improved with granulocyte colony-stimulating factor and antibiotics. Although R-LON may resolve spontaneously and remain unnoticed, it can cause severe infections in the elderly and patients with renal failure.

Introduction

Rituximab, an anti-CD20 monoclonal antibody, has become a treatment strategy for many autoimmune diseases and is increasingly frequently used to induce remission and maintain antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis. An underestimated side effect of rituximab is late-onset neutropenia (R-LON), in which the neutrophil count often improves without treatment. However, febrile neutropenia and sepsis may occur (1), and the risk is particularly high in the elderly and patients with renal failure (2).

We herein report a patient with myeloperoxidase antineutrophil cytoplasmic antibodies (MPO-ANCA)-associated vasculitis who developed R-LON and febrile neutropenia after rituximab treatment.

Case Report

The patient was a 91-year-old woman with type 2 diabetes mellitus but no other comorbidities, such as malignancy. In October 2022, the patient's serum creatinine was 0.62 mg/dL. In January 2023, the patient presented with a fever, dyspnea, and edema. Blood tests showed serum creatinine 6.0 mg/dL, C-reactive protein 18.7 mg/dL, MPO-ANCA 246 U/mL, and she was diagnosed with MPO-ANCA-associated vasculitis.

Methylprednisolone 250 mg/day was administered intravenously for three days, followed by oral prednisolone 30 mg/day. After the treatment was started, her renal function deteriorated to serum creatinine (Cr) 8.3 mg/dL with an estimated glomerular filtration rate (eGFR) of 3.8 mL/min/1.73 m², and she required hemodialysis. We decided to start with only one dose of rituximab and reduce the steroid dose as soon as possible, considering the possibility that the patient might not be able to be weaned off of hemodialysis even with immunosuppressive therapy and the risk of complications from infection caused by rituximab once a weekly for four weeks. Rituximab 480 mg (375 mg/m²) was administered as the first dose. Twenty-seven days after the first dose of rituximab, the patient was weaned off of hemodialysis with a Cr level of 6.3 mg/dL and eGFR of 5.2 mL/min/1.73 m². The following day, a second dose of rituximab was administered.

Forty-six days after the last dose of rituximab, there was no significant change in the neutrophil count (2,516 /μL). Eight days later, however, the neutrophil count markedly decreased to 165 /μL. She was taking prednisolone, furosemide, trichlormethiazide, tolvaptan, roxadustat, lansoprazole, linagliptin, repaglinide, febuxostat, sulfamethoxazole-trimethoprim, alendronic acid, sodium zirconium cyclosilicate hydrate, clonazepam, and trazodone hydrochloride. As no new medications had been started in the last month, we diagnosed her with R-LON and continued these medications. She also had a fever and was hospitalized with a diagnosis of febrile neutropenia.

The time course from the induction of remission of MPO-ANCA-associated vasculitis to the onset of neutropenia is shown in Fig. 1. On admission, the patient was alert and had a temperature of 39.0°C, blood pressure of 112/49 mmHg, pulse rate of 90/min, oxygen saturation of 98% on 2 L/min supplemental oxygen via nasal cannula. Chest auscultation revealed coarse crackles in both lung fields. Edema of the lower legs was observed. Blood test results on admission were as follows: white blood cell count 1,500 /μL, neutrophil count 165 /μL, red blood cell count 3,890,000 /μL, platelet count 104,000 /μL, blood urea nitrogen 84 mg/dL, serum creatinine 6.0 mg/dL, C-reactive protein 1.76 mg/dL, IgG 1,248 mg, MPO-ANCA 82.4 U/L, β-D-glucan 9.4 pg/mL, and cytomegalovirus antigenemia negative. Blood culture results were negative. Chest radiography showed an infiltrative shadow in the right lung field (Fig. 2a). Chest computed tomography (CT) revealed pneumonia and pleural effusion (Fig. 2b-e). CT of the chest/abdominal/pelvis showed no malignant tumors.

Figure 1.

Time course from induction of remission of MPO-ANCA-associated vasculitis to the onset of neutropenia. HD: hemodialysis, mPSL: methylprednisolone, PSL: prednisolone, RTX: rituximab

Figure 2.

a: Chest radiographs showed an infiltrative shadow in the right lung field. b-e: Chest computed tomography images showed pneumonia and pleural effusion.

The time course of hospitalization for treatment of febrile neutropenia is shown in Fig. 3. Meropenem 0.5 g was initiated for pneumonia and febrile neutropenia. Granulocyte colony-stimulating factor (G-CSF; 200 μg) was administered only on the day of admission. The fever resolved promptly after treatment initiation, and meropenem administration was terminated after 14 days. The neutrophil count remained above 2,000 cells/μL. This infection elicited a decline in the renal function and eventually led to end-stage renal failure. The patient was discharged from the hospital after peritoneal dialysis was introduced. There was no decrease in the neutrophil count after discharge from the hospital.

Figure 3.

Time course of hospitalization for febrile neutropenia. G-CSF: granulocyte colony-stimulating factor, MEPM: meropenem, PD: peritoneal dialysis, PSL: prednisolone

Discussion

LON is an underestimated side effect of rituximab because it often resolves spontaneously and rarely causes severe infection. Older age, concomitant use of immunosuppressive drugs, and renal failure are considered to be risk factors (2,3). We encountered a 91-year-old patient with renal failure and MPO-ANCA-associated vasculitis who developed LON after rituximab treatment, resulting in febrile neutropenia.

Elderly patients and those with renal failure are at an increased risk of side effects of rituximab in ANCA-associated vasculitis (2). Rituximab is an anti-human monoclonal antibody (IgG1-κ), a chimeric antibody consisting of a mouse-derived variable region and a human-derived constant region. Rituximab binds specifically to CD20, which is expressed on the surface of B cell-derived tumors and mature B cells and exerts its effect by disrupting these cells.

R-LON is an underestimated side effect of rituximab and is defined as an absolute neutrophil count of ＜1,000 /μL more than 4 weeks after the last rituximab infusion, followed by spontaneous recovery without apparent causes of severe neutropenia (4). Its incidence ranges from 1.3% to 27% (1,5). Pendergraft et al. reported that 17 (10%) of 172 patients with ANCA-associated vasculitis developed R-LON. Four patients had an associated fever and were hospitalized for intravenous antibiotics. Therefore, the incidence of R-LON in ANCA-associated vasculitis is approximately 10%, but the number of cases that developed febrile neutropenia was small (2.3%) (6). Risk factors included advanced cancer (7), post-chemotherapy (8), IgG Fcγ IIIa receptor mutation (158V/V or 158V/F) (9), post-stem cell transplantation (10), concomitant use of immunosuppressive drugs (3), and older age (7). ANCA-associated vasculitis has a 9-fold risk of rituximab side effects in chronic kidney disease patients with ＜30 mL/min/1.73 m² compared with those with an eGFR ＞30 mL/min/1.73 m² (2). In this case, the risk factors were advanced age and severe renal failure.

R-LON may require administration of G-CSF and antibiotics. The onset of R-LON is 38-175 days after the last rituximab administration (5). In the present case, the patient's neutrophil count decreased markedly to 165 /μL on day 54 after the last rituximab administration. Since no new medications had been started in the last month, and the neutrophil count was maintained at 2,516 /μL eight days before the onset of febrile neutropenia, we diagnosed her with R-LON. She had pneumonia and febrile neutropenia and was treated with meropenem and G-CSF. In general, R-LON is asymptomatic and often resolves spontaneously; however, if sepsis or febrile neutropenia develops, G-CSF and antibiotics may be administered (5,9,11). Of note, it has been reported that G-CSF administration does not affect mortality, although it may shorten the duration of LON (11).

In a report by Zonozi et al., 62 (87%) of 71 patients who developed R-LON were retreated with rituximab for autoimmune disease, and 13 (21%) of them redeveloped R-LON (11). In the present case, the patient was able to maintain remission with prednisolone 5 mg/day, and rituximab was not reintroduced, considering her advanced age, end-stage renal failure, and the high risk of rituximab side effects.

However, the pathogenesis of R-LON remains unknown. Several hypotheses exist regarding its mechanism, including the production of anti-neutrophil antibodies after rituximab, disrupted production, delayed neutrophil maturation due to abnormal B-cell reconstitution, and amplification of T-large granular lymphocyte populations, which may cause granulocyte apoptosis (12,13). Recently, LON has been reported for the treatment of B cell depletion with other anti-CD20 monoclonal antibodies and anti-CD19 chimeric antigen receptor T cells (14,15), suggesting the involvement of B cell depletion and neutropenia. Zhang et al. hypothesized that the loss of B cells leads to a change in hematopoietic growth factors: an increase in serum B-cell activating factor (BAFF) levels during B-cell depletion and a change in stromal-derived factor (SDF-1) concentration can regulate B-cell development and regulate the outflow of neutrophils from the bone marrow (16).

SDF-1 is a chemokine required for B-cell division and excretion of neutrophils from the bone marrow. Rapidly growing B-cell depletion may disturb the SDF-1 gradient in bone marrow. This disruption of the SDF-1 gradient may have reduced neutrophil efflux from the bone marrow, resulting in LON (17). BAFF is essential for promoting B cell proliferation and serves as a survival factor for the development of transitional and mature B cells (18). Terrier et al. hypothesized that competition in the bone marrow that promoted B-cell lymphangiogenesis over granulocyte production caused LON (13). In LON, when BAFF levels peak during B-cell division, dysplasia of granulocytes occurs in the bone marrow, eventually leading to disrupted granulopoiesis and delayed neutrophil maturation (19).

In the present case, CD-19- and CD-20-positive B-cell counts, serum BAFF levels, and bone marrow examinations were not performed, so their involvement remains unknown.

Conclusion

We encountered an elderly patient with renal failure who developed LON after rituximab treatment for MPO-ANCA-associated vasculitis, resulting in febrile neutropenia. Although R-LON may resolve spontaneously and remain unnoticed, it should be recognized that it can cause severe infections in the elderly and patients with renal failure.

The authors state that they have no Conflict of Interest (COI).