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Late-onset neutropenia during long-term rituximab therapy in neuromyelitis optica
Multiple Sclerosis and Related Disorders, 2, 3, pages 269 - 272
Late-onset neutropenia (LON) has been described as a side effect of rituximab (RX) therapy in patients with rheumatological and/or haematooncological diseases but not neuromyelitis optica (NMO). We describe a 71-year old female patient, who had NMO for 22 years, had been treated with RX monotherapy five times (cumulative dosage: 11 g; duration of treatment: 3 years) before she developed severe neutropenia (IV) 3 months after the last RX infusion. 1 1 This case report was written with the consent of the patient.
After exclusion of other causes, the diagnosis of LON was made. No complications occurred and neutropenia resolved without therapy. RX therapy was continued with intensive monitoring without any further LON and/or complications. In conclusion LON is a possible side effect during RX therapy and may also occur in NMO patients.
Keywords: Neuromyelitis optica (NMO), Rituximab, Late-onset neutropenia (LON), Haematological disease, B-cell depletion, Leukopenia.
Rituximab (RX), a monoclonal anti-CD20 antibody, has become an established therapy and is widely used in patients with NMO since it has shown clinical disease stabilisation in several retrospective studies and case series ( Pellkofer et al., 2011 ).
A known side effect of RX is late-onset neutropenia (LON). Most investigators define LON as grade III–IV neutropenia (according to the Common Terminology Criteria for Adverse Events of the National Cancer Institute) following 3–4 weeks after last RX treatment without any other causes of aetiology ( Wolach et al., 2010 ). The same group detected a median onset of 38–191 days of LON based on several studies two years later ( Wolach et al., 2012 ). So far it has been described in patients with rheumatological as well as haematological diseases but not in NMO. Neutropenia is divided into different grades according to the absolute neutrophil count (ANC, grade 1: ≥1.5 and <2.0×109/l; grade 2: ≥1.0 and <1.5×109/l; grade 3: ≥0.5 and <1.0×109/l; grade 4: <0.5×109/l). The incidence of LON in patients with a monotherapy of RX is around 5%, while additional therapy with e.g., mitoxantrone (MTX) does not seem to influence the incidence in rheumatological patients ( Tesfa et al., 2011 ) LON has a higher incidence (26.9%) among patients with B-cell lymphoma who have received different schemes of chemotherapies including rituximab. The same cohort had an incidence of up to 7.5% with severe LON (grade III and IV) in 160 patients ( Rozman et al., 2012 ). Here we report on an NMO patient who developed recurrent neutropenia 96 and 156 days after the 5th RX treatment.
2. Case description
This 71-year-old female Caucasian patient 1 had been diagnosed with NMO in 1990 due to recurrent longitudinally extensive myelitis (LEM) and optic neuritis (ON). In 2005 she tested positive for aquaporin-4 antibodies (AQP-4 abs). She had been treated with azathioprine from 1999 until 2008 but still showed clinical disease activity and was therefore switched to RX therapy in 2008. The first RX application was given in 12/2008 with 2×1000 mg two weeks apart between infusions. RX led to complete B-cell depletion and stabilisation of disease activity. The patient received further cycles of RX therapy in 6/2009, 2/2010, 8/2010 and 3/2011 before she developed neutropenia (12%; 410 granulocytes/µl; 2.3 G/l Leucocytes) in 6/2011 (see Fig. 1 ). During RX therapy, serum immunoglobulin levels remained stable at a lower level (IgG 4.8–5.4 g/l; IgM: 0.3–0.4 g/l) than the reference value (IgG 7–16 g/l, IgM 0.4–2.3 g/l). Before neutropenia occurred, no other side effects of RX therapy were observed and differential blood cell count (BCC) was always unremarkable apart from B-cell depletion. Neutropenia was detected during a routine BCC control without any clinical symptoms. 3 days and 35 days later BCC showed normal levels of neutrophils (58%: no detailed ANC available and 54%: 1890 granulocytes/µl). Neutropenia (8%: 340 granulocytes/µl; 2.0 G/l leucocytes) recurred again 4 weeks later without any symptoms and resolved a few days later (52%: 2580 granulocytes/µl). No other diseases occurred before or during neutropenia and no new medications that might possibly account for neutropenia were given. The IgG level of the patient was low prior to RX therapy (4.4 g/l; reference value 7–16 g/l). During RX therapy, serum immunoglobulin levels remained stable at a low level (IgG 4.8–5.4 g/l). The IgM level was normal prior to RX therapy but turned out to be lower after the first appearance of LON and stayed at a lower level (0.2–0.3 g/l; reference value 0.4–2.3 g/l). The IgA level has always been within the normal range. The diagnosis of LON was made. Since LON was short and self-limiting, RX therapy was continued with no further episodes of LON so far during follow-up.
LON after RX treatment has so far been reported in patients with haematological diseases such as B-cell lymphomas and rheumatological diseases like rheumatoid arthritis (RA) or lupus erythematosus (LE) with a frequency of 3–27% ( Wolach et al., 2012 ). In one retrospective study, 8 out of 113 patients (7%) with lymphomas developed LON 88 days (median time) after the last RX application ( Tesfa et al., 2008 ). Another investigation reports a median onset of neutropenia 102 days after RX therapy, which is similar to our patient who developed LON 96 days after the last treatment with the 5th RX cycle ( Tesfa et al., 2011 ). The duration of LON in these studies ranged from 5 days up to 120 days. Neutrophil counts in our patient recovered without any intervention 3 days after first appearance of LON. Our patient also showed recurrent (96 and 156 days after RX) short-lasting LON, which has also been reported in one patient who developed neutropenia twice, 112 and 259 days after RX application ( Tesfa et al., 2008 ). The exact time point of the beginning of LON cannot be determined in our patient since BCC examinations were performed only every 3 months during RX therapy and our patient was asymptomatic. Thus we cannot exclude additional undetected short-lasting episodes of neutropenia in our patient. LON is often self-limiting and resolves without therapy in most cases. The infection rate during LON was 16.9% in one analysis with pooled data from several retrospective studies ( Wolach et al., 2010 ). In one cohort of patients with rheumatic diseases (e.g., RA and LE) 11 out of 209 (5%) patients treated with RX developed severe neutropenia. Seven of them had to be hospitalised due to infections, 6 with sepsis ( Tesfa et al., 2011 ). In one lymphoma study a patient with LON died due to cytomegalovirus reactivation and Pneumocystis jirovecii pneumonia ( Cattaneo et al., 2006 ). Another study detected mostly a rapid recovery of LON without any severe infection or interference. There was only one patient who had additional panhypogammaglobulinemia and who suffered from severe pneumonia ( Besada et al., 2012 ). Our patient neither exhibited signs of infection nor showed clinical disease activity of NMO during LON. LON disappeared spontaneously without therapy. Thus we continued RX therapy in our patient and no further LON has been detected so far. The use of granulocyte colony-stimulating factor (GCSF) in LON has been described in single cases but has not been investigated systematically. GCSF showed positive effects on duration and outcome in patients with drug-induced neutropenia ( Andersohn et al., 2007 ).
Several risk factors for the occurrence of LON after RX have been identified. A higher risk for LON was found in lymphoma patients who had received previous chemotherapy or more than four doses of RX before LON ( Cattaneo et al., 2006 ). This is in line with our patient who received azathioprine for several years and 5 cycles of RX therapy before LON. Other risk factors for LON which have been described in the literature are (1) stem cell transplantation (SCT) in the past ( Wolach et al., 2012 ), (2) advanced disease stage with more intensive cytotoxic therapeutic regimens ( Nitta et al., 2007 ) and (3) AIDS-related lymphomas ( Dunleavy et al., 2005 ). There has been a higher risk of infections described in patients with LON and sustained hypoimmunoglobulinemia ( Diwakar et al., 2010 ). Our patient already showed IgG hypoimmunoglobulinemia prior to RX treatment which has remained stable at a low level until the present. IgM decreased after the first appearance of LON and also remained at a low level. It is therefore recommended to monitor patients with low IgG and/or IgM levels even more closely ( Gottenberg et al., 2010 ). IgA deficiency does not seem to have a big impact on a higher infectious rate ( Furst, 2009 ). The exact pathogenesis of LON is not well understood. A variety of mechanisms including an antibody-mediated process ( Voog et al., 2003 ) and lymphocyte subpopulation imbalance ( Papadaki et al., 2002 ) as well as genetic factors with specific polymorphisms have been discussed ( Weng et al., 2010 ). For example, a polymorphism in the immunoglobulin G Fc receptor FCγRIIIa 158 V/F (specifically the FCγRIIIa 158 V allele) has been described more recently as a potential risk factor for LON in patients with B-cell lymphoma ( Keane et al., 2012 ).
It has also been discussed that LON is caused during B-cell recovery mediated by close interactions with the chemokine stromal-derived factor-1 (SDF-1) ( Grant et al., 2011 ). In a study with rheumatological patients LON was detected in 5.8% of the cohort. In two out of 8 patients LON appeared at the time of B-cell recovery ( Besada et al., 2012 ). At the time at which LON occurred in our patient B-cells were still completely depleted both times.
This is, to our knowledge, the first case of LON during RX treatment in a patient with NMO. Since LON may lead to severe infections and RX is now widely used for long-term treatment in NMO patients, one should be aware of this potential side effect. We recommend frequent BCC examinations, especially in patients with several risk factors including low levels of immunoglobulins and past immunosuppressive therapies.
Conflict of interest
Dr. Plate reports nothing to declare.
Dr. Havla received speaker honoraria, travel expenses and personal compensations from Merck-Serono, Teva Pharma, Bayer Healthcare, Novartis Pharma and Biogen-Idec.
Dr. Kümpfel has received travel expenses and personal compensations from Bayer Healthcare, Teva Pharma, Merck-Serono, Novartis Pharma, and Biogen-Idec as well as grant support from Bayer-Schering AG and Novartis Pharma.
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Institute of Clinical Neuroimmunology, Ludwig-Maximilians-University, Munich, Germany
Correspondence to: Institute of Clinical Neuroimmunology, Medical Campus Grosshadern, Ludwig-Maximilians-University, Marchioninistraße 15, D-81377 Munich, Germany. Tel.: +49 89 7095 4435; fax: +49 89 7095 7435.
1 This case report was written with the consent of the patient.
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