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LON_RTX_QJM_2012
- 1. Characteristics of late onset neutropenia in rheumatologic patients treated with rituximab: a case review analysis from a single center E. BESADA1 , W. KOLDINGSNES1 and J. NOSSENT2 From the 1 Department of Rheumatology, University Hospital North Norway, Tromsø, Norway and the 2 Institute of Clinical Medicine, Rheumatology, University of Tromsø, Tromsø, Norway. Address correspondence to: E. Besada, Department of Rheumatology, University Hospital North Norway, postboks 14, Tromsø, 9038, Norway. email: emilio.besada@unn.no Received 14 September 2011 and in revised form 5 January 2012 Summary Background: Late onset neutropenia (LON) second- ary to rituximab has been reported as an adverse event in the treatment of hematological malignan- cies but reports on autoimmune diseases are scarce. Aim: To review the characteristics of LON in rheu- matologic patients from a single center. Design: Retrospective case record study. Methods: Clinical and laboratory data since the introduction of rituximab in our clinic in 2006 were collected and analyzed retrospectively. LON was defined as an absolute neutrophil count <1.0 Â 109 /l occurring 4 weeks after the last rituxi- mab infusion. Results: LON was identified in eight patients (6% of all patients receiving rituximab). All patients had complicated and refractory disease and had been treated with a median of 4.5 different immunosuppressive drugs prior to rituximab. LON appeared after a median interval of 23 weeks with recovery of LON after a median of 6.5 days. Four patients had concomitant infection at the onset of neutropenia, when six patients had both low immunoglobulin M and immunoglobulin G. Six patients were rechallenged with rituximab without recurrence of LON. Conclusion: The characteristics of LON after rituxi- mab treatment in patients with autoimmune disease are comparable with experiences from hematologic- al malignancies. LON seems to precede B-cell recovery implying a perturbation of the granulocyte homeostasis. LON with its rapid recovery does not seem to increase the risk for serious infection in con- trast to the sustained hypogammaglobulinemia that may follow rituximab. The risk of LON recurrence after rechallenge is low. Introduction Rituximab is a chimeric human–mouse monoclonal antibody that reacts specifically with the CD20 antigen present on most B-cells and is used in the treatment of hematological malignancies and auto- immune diseases. Rituximab gives rapid sustained depletion of premature and mature B-cells that return to pre-treatment level generally within 12 months.1 Rituximab can lead to a state of immunosuppression through B-cell depletion, but also through the development of late onset neutropenia (LON) and hypogammaglobulinemia.1 The reported incidence of LON secondary to rituximab in the treatment of hematological malig- nancies is between 3 and 27% and resulting infec- tions are neither frequent nor severe.2 Reports of LON in the treatment of autoimmune diseases are scarce.3,4 Herein, we review eight cases of LON secondary to rituximab from a single center and we aim to identify both patients’ and LON charac- teristics in a rheumatologic setting. ! The Author 2012. Published by Oxford University Press on behalf of the Association of Physicians. All rights reserved. For Permissions, please email: journals.permissions@oup.com Q J Med 2012; 105:545–550 doi:10.1093/qjmed/hcs015 Advance Access Publication 1 February 2012 atUniversityLibraryofTromsøonJune13,2013http://qjmed.oxfordjournals.org/Downloadedfrom
- 2. Method LON was defined as grade III–IV neutropenia (abso- lute neutrophil count under 1.0  109 /l) according to the National Cancer Institute Common Toxicity Criteria occurring 4 weeks after the last rituximab administration.2,5,6 Using this case definition, we identified eight patients since 2006 in our center with LON secondary to rituximab. They rep- resent 5.8% of the total number of patients receiving rituximab. Two additional patients experienced early neutropenia occurring 2 weeks after the first rituximab administration and were not included. All patients were initially treated according to the rheumatoid arthritis (RA) protocol with two rituximab infusions of 1000 mg each, 2 weeks apart. Patients then received maintenance therapy either every 6 months (1000 mg) or every 9–12 months (1000 mg  2, 2 weeks apart). Rituximab was either added to previous immunosuppressive treatment or given in combination with methotrexate. Patient records were reviewed retrospectively and data on comorbidities, previous immunosuppressive treatments, infections, disease duration prior to rituximab administration, the cumulative rituximab dose, the time interval between the last rituximab infusion and LON and the duration of neutropenia were extracted. Immunological parameters, such as immunoglobulin (Ig) subclass levels, CD4 count (ratio CD4/CD8) and autoantibody titers prior to, during and following LON development were also recorded. B-cells recovery was defined as an absolute B-cells count 50.01  109 /l when complete B-cells deple- tion was lost. Results Patients’ characteristics The underlying disease was granulomatosis with polyangiitis (GPA earlier called Wegener’s granulo- matosis) in five patients; the others patients had type 1 cryoglobulinemia, juvenile idiopathic arthritis and anti-citrullinated peptide antibody positive RA (Table 1). The male to female ratio was 1; but all men had GPA. Rituximab was administered because patients were considered to have complicated dis- ease that was refractory to our standard immunosup- pressive treatment protocols. Three GPA patients received renal transplants, two patients prior to and one after the initiation of rituximab therapy. Two patients had hematological malignancies: one patient was diagnosed with non-Hodgkin’s lymph- oma prior to rituximab and one with smoldering myeloma 6 months after rituximab therapy. The median duration of the disease prior to rituximab treatment was 156 months (75–408 months). The daily median dose of prednisolone was 3.75 mg (0–15 mg daily) and the median number of immunosuppressive drugs used prior to rituximab was 4.5 (2–7). The median cumulative cyclophosphamide dose in GPA patients was 23.7 g (2.4–250 g). Five patients had previous epi- sodes of leucopenia prior to rituximab and during the use of cyclosporin A, cyclophosphamide, sulfa- salazine and azathioprine for two patients. LON characteristics LON appeared after a median interval of 23 weeks (7–48 weeks) following rituximab administration (Table 2). The median absolute neutrophil count was 0.2  109 /l and neutrophils were undetectable in three patients. Neutropenia recovered after a median of 6.5 days (3–270 days). B-cells recovery came shortly after the onset of neutropenia in two patients 1 and 2 months, respectively (B-cells counts 0.05 and 0.3  109 /l, respectively). Four patients were symptomatic during LON: fever, diarrhea and oral ulcers were the most common symptoms. Candida albicans from an oral swab and Clostridium difficile from feces were identified in one patient each. A third patient was hospitalized for severe Staphylococcus aureus pneumonia in the in- tensive therapy unit complicated afterwards with C. albicans and Stenotrophomonas maltophilia, sec- ondary to an obstructed bronchial stent due to GPA damage. Four patients received intravenous antibiot- ics, but none were treated with the granulocyte col- ony-stimulating factor during LON. Immunological abnormalities 1. The relation between LON and immunological abnormalities is shown in Table 3. Significant reduc- tion in all Ig subclasses was seen at LON. Seven patients had some immunological abnormality prior to rituximab: four patients had Ig class deficiency, five patients had low CD4. At the onset of neutropenia, six patients had both lower IgM level (one patient had undetectable level) and lower IgG—three patients also had deficiency in IgA. After the onset of neutropenia, six patients had low IgM levels, two patients had un- detectable IgM levels. Both IgM and IgG levels were equivalent at the time of LON and at last visit despite discontinuation of rituximab in seven patients. 2. Three of five GPA patients had positive anti-neutrophil cytoplasmic antibody (ANCA) at rituximab initiation; ANCA disappeared in two patients although one still had ANCA positive (although with decreasing titer) by the time of LON. The two ANCA-negative patients also responded to rituximab and are in remission with negative ANCA. 546 E. Besada et al. atUniversityLibraryofTromsøonJune13,2013http://qjmed.oxfordjournals.org/Downloadedfrom
- 5. Outcome Six patients received maintenance therapy (rechal- lenge) with rituximab after a median of 2 months (1–5 months) after the onset of neutropenia but no recurrence of neutropenia was observed (Table 2). One patient experienced an unexplained recurrent neutropenia 6 weeks after resolution of the first LON episode without being challenged again with rituximab. Two patients were not rechallenged with rituximab because of hypogammaglobulinemia and low CD4 count. One patient is currently receiving intravenous Igs and the other is closely monitored with improving levels of Igs—as well as slow recov- ery of B-cells (B-cells count 0.04 Â 109 /l)—29 months after the last rituximab administration. At last visit—a median of 30.5 months (12–48 months) after rituximab initiation and a median of 16 months (4–44 months) after LON, seven patients have discontinued rituximab. One patient de- veloped severe hypogammaglobulinemia during rituximab maintenance therapy. One patient had no clinical response to rituximab despite hypogam- maglobulinemia. One patient developed colitis attributed to rituximab. One patient had maintained remission following kidney transplantation. One GPA patient died of sepsis without an identifiable cause 24 months after LON and after being diag- nosed with a myelodysplastic syndrome; this patient had sustained low CD4 with a nadir of 0.05, panhy- pogammaglobulinemia and had received a total of 250 g of cyclophosphamide. Discussion This case review showed that LON occurs in 6% of patients with a heterogeneous group of rheumatic diseases, $5 months after rituximab administration. This is comparable with the occurrence of LON in hematological malignancies, where it seems to co- incide with the time of B-cell recovery.2 The associ- ation of LON with B-cells recovery is illustrated by the two patients achieving B-cells recovery 1 and 2 months after LON. It has been hypothesized that LON is caused by perturbation of the granulocyte homeostasis during B-cell recovery as stromal- derived factor-1 level regulates granulocytes egress and is required for B-cells lymphopoiesis.5,6 Rechallenge with rituximab has not led to recurrent LON in our patients; the one patient with LON re- currence 6 weeks after the first episode without rechallenge suggests a subacute break down of the homeostasis with either maturation arrest or hematopoietic stem cell competition.7 The majority of patients in our analysis suffered from GPA that may have led to some important biases. The use of aggressive immunosuppressive therapy including methotrexate, azathioprine and cyclophosphamide in refractory GPA and its com- plications (three patients with renal transplantation and one patient with bronchial stenting) are likely to have contributed to the risk of LON development. This is in agreement with the increased risk of rituximab-induced LON in patients after autologous stem cell transplantation, patients with acquired im- munodeficiency syndrome-related lymphoma, pa- tients treated with purine analogs and patients that received previous cytotoxic treatment.2 Similar to hematological patients,2 LON usually has a rapid recovery without the use of colony-sti- mulating factors and does not seem to increase the risk for serious infection in our patients even though four out of eight patients had concomitant infection with LON. This is in disagreement with the study of Tesfa et al.4 that concludes that LON is a significant adverse event associated with severe infections . Our patients seem to differ as they received a lower daily dose of prednisolone (3.75 vs. 20 mg) and none was treated concomitantly with cyclo- phosphamide (zero vs. four patients). The only pa- tient (Case 5) needing intensive care for severe pneumonia had LON and concomitant sustained panhypogammaglobulinemia including undetect- able level of IgM. Sustained cellular and humoral immunodeficiency due to myelodysplasia contribu- ted to sepsis and death in another patient (Case 8) 24 months after LON. It has recently been suggested that rituximab- induced LON is a good prognostic indicator in lym- phoproliferative disorders.8 Likewise, our patients Table 3 Medians levels of IgG, IgA and IgM before rituximab, at the time of LON and at last visit in our patients Before RTX At LON At last visit IgG, median (g/l) Normal range (6–15.3 g/l) 9.4 (range 5.8–12.7) 4.9 (range 3.5–11.3) 5.1 (range 3.3–12.8) IgA, median (g/l) Normal range (0.8–4.6 g/l) 1.32 (range 0.59–3.34) 0.87 (range 0.41–3.35) 1.35 (range 0.41–2.89) IgM, median (g/l) Normal range (0.5–2.5 g/l) 0.56 (range 0.14–2.54) 0.19 (range <0.05–1.91) 0.21 (range <0.05–1.11) RTX, rituximab. Characteristics of LON 549 atUniversityLibraryofTromsøonJune13,2013http://qjmed.oxfordjournals.org/Downloadedfrom
- 6. developing LON had a good clinical response to rituximab treatment (except for Case 1), but in the majority of LON patients rituximab was discontin- ued because of side effects. While new-onset hypo- gammaglobulinemia affects <10% of RA patients after the first course of rituximab;9 iterative rituximab treatment has led to a continuous decrease of Igs levels in most of our LON patients resulting in sus- tained hypogammaglobulinemia and contributing to the discontinuation of rituximab in at least four patients. Tesfa et al.4 found that LON patients had longer lasting and more severe B-cells depletion compared with controls, which would increase the risk for developing a sustained hypogammaglobuli- nemia. Thus, a sustained hypogammaglobulinemia either induced or aggravated by rituximab (as renal failure, organ transplantation, use of prednisolone can also induce hypogammaglobulinemia) seems to heighten the risk of infections in LON patients.10,11 These data reflect the continuing chal- lenge in treating rheumatologic patients without overtreating them; while LON does not seem to pose a substantial risk in itself, the question remains which lower limits of Ig levels are safe for our patients following rituximab treatment.11 Conflict of Interest: None declared. References 1. Kelesidis T, Daikos G, Boumpas D, Tsiodras S. Does ritux- imab increase the incidence of infectious complications? A narrative review. Int J Infect Dis 2011; 15:e2–16. 2. Wolach O, Bairey O, Lahaw M. Late-onset neutropenia after rituximab treatment. Case series and comprehensive review of the literature. Medicine 2010; 89:308–18. 3. Rios-Fernandez R, Gutierrez-Salmeron MT, Callejas- Rubio JL, Fernandez-Pugnaire M, Ortego-Centeno N. Late-onset neutropenia following rituximab treatment in patients with autoimmune diseases. Br J Dermatol 2007; 157:1271–3. 4. Tesfa D, Ajeganova S, Ha¨gglund H, Sander B, Fadeel B, Hafstro¨m I, et al. Late-onset neutropenia following rituximab in rheumatic diseases: association with B lympho- cytes depletion and infections. Arthritis Rheum 2011; 63:2209–14. 5. Dunleavy K, Tay K, Wilson WH. Rituximab-associated neu- tropenia. Semin Hematol 2010; 47:180–6. 6. Grant C, Wilson WH, Dunleavy K. Neutropenia associated with rituximab therapy. Curr Opin Hematol 2010; 18:49–54. 7. Cooper N, Arnold DM. The effect of Rituximab on humoral and cell mediated immunity and infection in the treatment of autoimmune diseases. Br J Haematol 2010; 149:3–13. 8. Hincks I, Woodcock BE, Thachil J. Is Rituximab –induced late-onset neutropenia a good prognostic indicator in lymphoproliferative disorders? Br J Haematol 2011; 153:411–3. 9. Samson M, Audia S, Lakomy D, Bonnotte B, Tavernier C, Ornetti P. Diagnostic strategy for patients with hypogamma- globulinemia in rheumatology. Joint Bone Spine 2011; 78:241–5. 10. Diwakar L, Gorrie S, Richter A, Chapman O, Dhillon P, Al-Ghanmi F, et al. Does Rituximab aggravate pre- existing hypogammaglobulinaemia? J Clin Pathol 2010; 63:275–7. 11. Furst DE. Serum immunoglobulins and risk of infection: How low can you go? Semin Arthritis Rheum 2008; 39:18–29. 550 E. Besada et al. atUniversityLibraryofTromsøonJune13,2013http://qjmed.oxfordjournals.org/Downloadedfrom