Late-Onset Neutropenia More Common Than Expected in Patients on Rituximab

Steve Cimino

September 22, 2020

A new study has found that late-onset neutropenia is a notably common and occasionally serious occurrence in rituximab-treated patients with autoimmune diseases.

Dr. Reza Zonozi

"The literature on late-onset neutropenia – or LON – has, to date, been limited in size and scope," first author Reza Zonozi, MD, of Massachusetts General Hospital in Boston, said in an interview. "At the Vasculitis and Glomerulonephritis Center at Mass General, we've seen a number of cases of LON. Even though most are incidental and can be self-limiting, some can be severe and associated with sepsis. As such, we've come to appreciate it as one of the more concerning side effects of rituximab.

"Our hope was to offer a practical analysis of LON, how often it happens, and what it looks like," he added, "as well as to share our approach to its management." Their findings were published in Arthritis & Rheumatology.

To investigate the incidence, clinical features and outcomes of LON, the researchers launched a study of 738 adult patients with autoimmune diseases who were being treated with rituximab-induced continuous B-cell depletion. For the purposes of this study, LON was defined as an unexplained absolute neutrophil count of less than 1,000 cells/mcL during the period of B-cell depletion. Regarding disease type, 529 of the patients had antineutrophil cytoplasmic antibody–associated vasculitis (AAV), 73 had membranous nephropathy (MN), 59 had minimal change disease or focal segmental glomerulosclerosis (MCD/FSGS), 24 had lupus nephritis, and 53 had another autoimmune disease. Their average age was 58, and 53% were female.

All patients received a median of eight doses of rituximab – most commonly administered as one 1,000-mg IV dose every 4-6 months – and were in a state of B-cell depletion for a median of 2.5 years. Two months of low-dose daily oral cyclophosphamide was also used concurrently in 70% (n = 515) of patients. Glucocorticoids were used in 95% (n = 698) of patients.

During follow-up, 107 episodes of LON occurred in 71 patients. At 1, 2, and 5 years of continuous B-cell depletion, the incidence of LON was 6.6% (95% confidence interval, 5.0%-8.7%), 7.9% (95% CI, 6.1%-10.2%), and 13.5% (95% CI, 10.4%-17.4%), respectively. The first year following treatment initiation saw a much higher incidence rate of 7.2 per 100 person-years (95% CI, 5.4-9.6), compared with the rate thereafter of 1.5 per 100 person-years (95% CI, 1.0-2.3). LON occurred at a median of 4.1 months (interquartile range, 1.6-23.1) after the first rituximab infusion. The most common treatment for a LON episode was filgrastim.

Of the 107 episodes, 63 (59%) were asymptomatic. No infections were identified in asymptomatic episodes, while infections were identified in all symptomatic episodes. The most common symptom was a fever, and all 30 patients with LON and fever were hospitalized for management of febrile neutropenia. Four of the episodes included gingival soreness, and eight were complicated by sepsis. All the sepsis cases were resolved with standard therapy. One patient died with multiple relapsing LON.

Of the 71 patients with LON, 9 were not rechallenged with rituximab. A total of four of those patients had second LON episodes. Of the 62 patients who were rechallenged, 13 had second LON episodes over a median follow-up period of 2.4 years. The cumulative incidence of recurrent LON at 1, 2, and 5 years after rechallenge was 11.5% (95% CI, 5.6%-22.6%), 23.4% (95% CI, 13.8%-38.2%), and 30.4% (95% CI, 16.9%-50.9%), respectively.

Percentagewise, LON occurred significantly more often in patients with lupus nephritis (25%) than in patients with AAV (10.4%), MN (8.2%), or other diseases (7.6%) (P = .03). LON did not occur in any of the patients with MCD/FSGS. After multivariable analysis, lupus nephritis was associated with higher odds of developing LON (adjusted hazard ratio, 2.96; 95% CI, 1.10-8.01). A multivariable model also found that patients treated with cyclophosphamide and rituximab had higher odds of developing LON, compared with patients who did not receive cyclophosphamide (aHR, 1.98; 95% CI, 1.06-3.71).

Still More to Learn About What Leads to LON

"In large part, these findings quantify what our experience has been with LON in clinical practice," Dr. Zonozi said. "It is indeed common, it's often incidental, and most cases are reversible and respond well to treatment. But it can be associated with severe infections, including sepsis, and warrants close monitoring."

Dr. Md Yuzaiful Md Yusof

In an interview, Md Yuzaiful Md Yusof, MBChB, PhD, observed that this incidence rate was notably higher than what he'd seen previously. Dr. Md Yusof presented at EULAR Congress 2015 on rituximab and LON, finding that 23 patients (2.5%) from a cohort of 912 developed rituximab-associated neutropenia.

"Most of our cases were in patients with rheumatoid arthritis," he added, "so it may just be a difference in cohorts."

Regardless, he applauded additional research in this area, noting that "the etiology of rituximab-associated LON is still unclear. The reasons behind this occurrence need investigating, particularly in regard to severe neutropenia cases. If we can find the predictors of those, it will be extremely helpful for the future of treatment."

Dr. Zonozi agreed that "more investigation is needed to accurately define the mechanism of LON, which remains unknown. This will likely lead to more targeted strategies to both prevent and treat it."

The authors acknowledged their study's limitations, including being a single-center study that relied on retrospective data collection. They also acknowledged that, because the center is a nephrology-based practice, there was a low number of certain diseases like RA, opening up the possibility that "rates of LON are different" in those patients.

Two authors' work on the study was funded by grants from the National Institutes of Health. The authors disclosed no potential conflicts of interest.

SOURCE: Zonozi R et al. Arthritis Rheumatol. 2020 Sep 6. doi: 10.1002/art.41501.

This article originally appeared on, part of the Medscape Professional Network.


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