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Rituximab Hypersensitivity Reactions and Tolerance of Ofatumumab Therapy

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Rituximab Hypersensitivity Reactions and Tolerance of Ofatumumab Therapy BRIEF PAPER Clinical and Experimental Rheumatology 2021; 39: 648-650. Rituximab hypersensitivity ABSTRACT tion in rituximab treatment, significant B-cell depleting agents play a key role in reactions have also been documented reactions and tolerance of a variety of disease entities. Rituximab, (4, 5). These include type I and type ofatumumab therapy a murine-human chimeric anti-CD20 III hypersensitivity reactions (6). Hu- monoclonal antibody, as one of these man anti-chimeric antibodies (HACA) 1,2 1 S.B. Ali , C. Yuson , major agents, has been associated with to rituximab have been implicated in P. Hissaria1,2 hypersensitivity reactions, which not a few of these immunogenic reactions only include the classic hypersensitivity and in some cases, have become con- 1 Department of Clinical Immunology ranging from immediate (type 1) to de- traindications for future rituximab use and Allergy, Royal Adelaide Hospital; layed (type IV), but also infusion-related (5). The newer monoclonal antibod- 2Department of Immunology, reactions (IRRs). Whilst these typical hy- SA Pathology, Adelaide, Australia. ies are humanised or fully human and persensitivity reactions occur in the set- hence will not react with HACA anti- Syed Basharat Ali, MBBS Chino Yuson, MBBS, FRACP ting of prior exposure, IRRs may occur bodies resulting in a better safety pro- Pravin Hissaria, MD, MBBS, FRACP, in first exposure. Factors to consider in- file with similar efficacy. FRCPA clude chimeric composition of agent, for We present three cases initiated on ofa- Please address correspondence to: example, rituximab with murine compo- tumumab therapy with a history of type Pravin Hissaria, nent, which may be responsible for such one or three hypersensitivity reactions Department of Clinical hypersensitivity reactions. In these in- to rituximab therapy. Immunology and Allergy, dividuals, alternate anti-CD20, such as 1 Port Road, oftatumumab, a fully human monoclonal Case 1 Royal Adelaide Hospital, antibody may be used. We report three A 74-year-old female with chronic Adelaide, SA 5000, Australia. E-mail: [email protected] cases of rituximab hypersensitivity in severe myasthenia gravis resulting patients with auto-immune disease, and in multiple hospital admissions, was Received on November 19, 2020; accepted in revised form on February 10, 2021. in whom ofatumumab therapy was given treated with rituximab due to refractory and subsequently tolerated. disease despite mycophenolate, cyclo- © Copyright CLINICAL AND EXPERIMENTAL RHEUMATOLOGY 2021. sporine and intravenous immunoglobu- Rituximab hypersensitivity lin. She had a remarkable response and Key words: monoclonal antibody, reactions and tolerance of was asymptomatic for 9 months when rituximab, hypersensitivity, ofatumumab therapy she relapsed. infusion reaction The clinical applications of anti-CD20 On day five of first rituximab infu- monoclonal antibody therapies (mAbs) sion on second cycle, she developed continue to expand. Initially used for generalised urticaria. Subsequent in- B-cell lymphoproliferative disorders, fusion was postponed for a few days their indications have widened to in- and treated with prednisolone and an- clude conditions which involve autoan- tihistamines. After the second dose, she tibody producing or T cell-activating B developed urticaria again immediately cells (1) and is now used to treat refrac- post–infusion, managed with a short tory rheumatoid arthritis, as well as re- course of prednisolone as well as ongo- lapsing remitting multiple sclerosis. ing cetirizine. She then received a third While rituximab, a murine-human chi- infusion and within minutes she devel- meric anti-CD20 mAb, was the first oped generalised erythema, flushing, agent to have gained widespread use, itchiness and irritation in throat. She alternative agents have been intro- was treated with adrenaline and event duced in recent times These include tryptase was elevated at 24μg/L (ref- humanised agents, such as ocrelizum- erence range <11.9μg/L). Subsequent ab, veltuzumab and obinutuzumab, as HACA titres to rituximab were strongly well as the fully human agent, ofatu- positive and skin prick test (SPT) was mumab (1). Though having the same not pursued. Baseline tryptase was target, i.e. CD20, these next generation 9.5μg, consistent with IgE mediated mAbs are not only suggested to have hypersensitivity. better binding affinity to B cells and Over the next 8 years, her symptoms re- increased complement dependent cy- mained relatively controlled with pred- totoxicity (2), but in some cases also nisolone, methotrexate and hydroxy- to potentially have less immunogenic chloroquine; however, in 2017, she ex- adverse reactions (3). perienced a progressive decline in func- While infusion-related reactions (IRRs) tion due to her disease. In view of excel- Competing interests: none declared. remain the most common adverse reac- lent response to previous B cell deple- 648 Clinical and Experimental Rheumatology 2021 Rituximab hypersensitivity reactions / S.B. Ali et al. Table I. Clinical summaries of patients transitioned to ofatumumab therapy with prior rituximab and relevant histories of reactions. Case Clinical summary Rituximab adverse Rituximab Ofatumumab adverse Ofatumumab Progress reaction infusion number reaction infusion number 1 Myaesthenia gravis Type 1 Hypersensitivity 2 Infusion related reaction but 1 Clinical subsequently tolerated improvement 2 Systemic lupus Type 1 Hypersensitivity 3 Infusion related reaction but 1 Clinical erythematosus subsequently tolerated improvement 3 Overlap mixed Type 3 Immune complex 6 Nil Nil Clinical connective tissue improvement disease tion therapy, ofatumumab was initiated use on compassionate grounds. How- Due to ongoing symptoms, ofatumum- as per neurologist preference. Midway ever, midway through her initial infu- ab was given uneventfully on com- through her first infusion she developed sion, she experienced significant ver- passionate grounds. Overall, she had an erythematous maculopapular rash on tiginous symptoms. The infusion was improvement in both subjective and her abdomen and back. There were no held, and she was given an antihista- objective weakness over the next three other systemic symptoms. The infusion mine. Her symptoms subsided and the months. was stopped immediately and cetirizine ofatumumab was restarted at half the 20mg given. The rash subsided after original rate. She completed treatment Discussion an hour and the infusion was restarted and has since been able to reduce her We present three cases of rituximab at half the original rate. There was no corticosteroid dose while her SLE has intolerance who subsequently toler- event tryptase taken. She was able to remained stable. ated another B cell depleting agent, complete the infusion without further ofatumumab. There were minor IRR incident and subsequently demonstrated Case 3 to ofatumumab in two of these patients clinical improvement. A 64-year-old woman with severe which were easily managed by reduc- overlap mixed connective tissue dis- ing the infusion rate. Case 2 ease with primary Sjogren’s Syndrome, In 2006, Pichler had proposed catego- A 44-year-old female with severe sys- polymyositis and peripheral demyeli- ries to classify adverse reactions to temic lupus erythematosus (SLE) char- nating neuropathy developed worsen- biologic agents, which included reac- acterised by polyarthritis, pancytopenia ing bulbar, proximal upper and lower tions due to overstimulation (cytokine and rash responded to rituximab and limb weakness. Pulse methylpredniso- release syndromes) as well as hyper- corticosteroids after failing hydroxy- lone and intravenous immunoglobulin sensitivity reactions, which includes chloroquine, leflunomide and metho- (IVIG) resulted in clinical improve- IRRs and IgE mediated reactions (7). trexate therapies. She relapsed after 7 ment but she developed tachyphylaxis. In a large proportion (77%) of IRRs years and was re-treated with rituximab Subsequently, she did not tolerate my- with symptoms, such as fever, chills, resulting in sudden onset chest pain, cophenolate and methotrexate and had nausea, dyspnea or headache are re- tachycardia and vomiting during second no clinical response to cyclosporine. ported to occur within the first dose cycle of rituximab in 2013. Subsequent Hydroxychloroquine was started there- (8). Although the mechanism of such cardiology work-up was negative. Her after. Five years later, disease was reactions is not entirely cleared, pos- event tryptase at 14 μg/L was markedly complicated by diagnosis of interstitial sibilities include activation of cells or elevated from her baseline (1μg/L). lung disease and she had a relapse with complement (7), or a cytokine release Given the history of type one hypersen- severe demyelinating neuropathy and syndrome (4). In these cases, the IRRs sitivity rituximab desensitisation was debility. Rituximab therapy was given decrease when the rate is slowed down undertaken. However, she continued to with disease stabilisation and symptoms are treated, with subse- experience chest tightness and nausea One year later, she had disease progres- quent infusions more likely to be toler- during the desensitisation program, and sion and further rituximab was given. ated (9). as such this was ceased. In-vivo testing On the second infusion, she developed Like IRRs, IgE mediated reactions to protocol as previously demonstrated by acute tongue angioedema. There were rituximab can also occur and reported Wong and Long (2017) was undertaken
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