Rituximab Induced Serum Sickness Or Immune Complex Deposition Disease: Case Report and Desensitisation Protocol

HEMATOCASE 75

Rituximab induced serum sickness or immune complex deposition disease: case report and desensitisation protocol

N. Granacher, MD, T. Eyckmans, MD

SUMMARY The chimeric monoclonal IgG1 antibody directed to CD20 Rituximab is used to treat various haematological malignancies and auto-immune diseases. Serum sickness is a type III hypersensitivity reaction leading to the formation and tissue deposition of immune antibody-antigen complexes. It has been described as a very rare complication of Rituximab treatment, mainly seen in patients treated for auto-immune diseases. We report the case of a patient with Waldenström’s macroglobulinaemia whose Rituximab treatment was com- plicated by documented immune complex deposition or serum sickness. We successfully applied a Rituximab desensitisation protocol, which allowed us to complete treatment. (BELG J HEMATOL 2020;11(2):75-8)

INTRODUCTION to 22.9 g/l. Two weeks later, he experienced mild general Serum sickness is an immune complex-mediated hyper- malaise and arthralgias. These symptoms were self-limiting sensitivity disease or type III allergic reaction to a certain and patient therefore did not consult his treating haemato- antigen in which auto-antibodies bind a foreign antigen and logist. Four weeks after the first treatment cycle he received form immune complexes. Although very rare, it has been a second cycle of Rituximab-Bendamustine. Blood exami- reported in patients treated with Rituximab. nation at start showed normal haematopoiesis and an IgM level of 27 g/l (monoclonal protein concentration 16 g/l). CASE REPORT Previously he had been diagnosed with atrial flutter treated A 73-year old man was diagnosed in 2000 with an IgM with apixaban and bisoprolol. A day after the administration monoclonal gammopathy of undetermined significance of Rituximab the patient experienced intense shivering (IgM MGUS, monoclonal protein of 11.8 g/l). He had no and fever of up to 38,5 degrees Celsius. He was admitted at other comorbidities nor was he taking any medication. Eigh- our ward of haematology for observation. The day after his teen years later, he progressed to a symptomatic MYD88 platelet count significantly dropped (23 x 10^9/l, ref range positive Waldenström’s macroglobulinaemia with signs of 140 - 340 x 10^9/l), LDH levels increased (1400 U/l, ref hyperviscosity (polyneuropathy, dyspnoea and visual dis- range 313 - 618 U/l) and his inflammatory markers were turbances). IgM levels at that time were 42.8 g/l (ref 0.4-2.3 elevated (leucocytosis/neutrophilia and CRP up to 90 mg/l g/l) with monoclonal protein concentration of 36.3 g/l. (ref range <10 mg/l). He complained of general fatigue and Haemoglobin levels and thrombocytes/leukocytes count were arthralgia in the shoulders and hips. Two days later his com- normal. He was immediately treated with plasmapheresis plaints gradually decreased thanks to systemic analgesia after which immuno-chemotherapy (Rituximab 375 mg/m² and the thrombocytopenia slowly recovered (on discharge on day 1 and bendamustine 70 mg/m² on day 1 and 2) was thrombocyte count was 49 x 10^9/l, ref range 140 - 340 x initiated. On discharge (day 3) his IgM levels had dropped 10^9/l). Additional blood examination was able to confirm

Department of Haematology, ZNA Stuivenberg, Antwerp, Belgium. Please send all correspondence to: N. Granacher, MD, Haematology, ZNA Stuivenberg (Ziekenhuis Netwerk Antwerp), Lange Beeldeken- straat 267, 2060 Antwerp, Belgium, tel: +32 3 217 72 57, email: [email protected]. Conflict of interest: The authors have nothing to disclose and indicate no potential conflict of interest. Keywords: desensitisation, immune complex deposition disease, rituximab, serum sickness, Waldenström’s macroglobulinaemia.

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TABLE 1. Rituximab induced serum sickness in haematological malignancies.

Reference Patient Diagnosis Dosing Cycle number Time of onset Treatment

Demonaco F, 47yr Follicular 375 mg/m² 4th administration Day 7 Steroids (not further et al ³ lymphoma specified)

Disperati F, 52yr Follicular 180 mg/m² 5th administration Day 2 Methylprednisolone et al 4 lymphoma Diphenhydramine Meperidine

Todd M, 68yr Mantle cell 375 mg/m² 1st administration Day 13 Methylprednisolone et al 5 lymphoma

Portlock M, 70yr Follicular 375 mg/m² 1st administration Day 5 Prednisone et al 6 lymphoma

Portlock F, 51yr Follicular 375 mg/m² 2nd administration Day 7 Prednisone et al 6 lymphoma

Fajt F, 37yr Gastric MALT 375 mg/m² 2nd administration Day 3 Methylprednisolone et al 7 lymphoma Diphenhydramine

Matsui Not MALT 375 mg/m² 1st administration Day 9 Steroids (not further et al 8 specified lymphoma specified)

Matsui Not Waldenström’s 375 mg/m² 1st administration Day 17 Steroids (not further et al 8 specified macroglobuli- specified) naemia

our suspicion of immune complex deposition disease (serum daily and non-steroidal anti-inflammatory drugs (ibuprofen sickness) presumably provoked by Rituximab with documen- 800 mg twice daily) as supporting measures for five days. ted IgG and IgM circulating immune complexes (IgG-CIC Using this protocol Rituximab was successfully administered 29 µg/ml, ref range <25 µg/ml and IgM 33 µg/ml, ref range for the subsequent three cycles (in combination with ben- <11 µg/ml) and hypocomplementemia for C3 and C4 damustin on day 2 and 3). After completion of therapy indicating complement consumption. Ten days later, his patient had a very good partial response with only 5,2 g/l complaints had disappeared and blood results returned to IgM remaining (monoclonal protein concentration 4 g/l). normal. We decided to administer a third cycle of Rituxi- Approximately ten months later, he remains in a very good mab via fractionated subcutaneous injection (two injections partial remission. spread over two administration days) hoping that a slower release of the monoclonal antibody might prevent immune CASE DISCUSSION complex formation. He was also pre-medicated with 100 mg of Serum sickness is an immune complex-mediated hyper- hydrocortisone on day 1. Nevertheless, he developed similar sensitivity disease or type III allergic reaction to a certain complaints of arthralgia and fatigue, albeit postponed and antigen in which auto-antibodies bind a foreign antigen not occurring before day 4. We once again documented the and form immune complexes. The syndrome was initially formation of immune complexes with pronounced LDH rise described in the early 1900’s when it was seen in association (4144 U/l). Thrombocytes dropped to 77 x 10^9/l on day 4. with the use of horse serum containing diphtheria antitoxin. Searching the literature, we found similar cases to ours. We In a normal situation, the antigen-antibody complexes are found a Rituximab desensitisation protocol developed for cleared via phagocytosis however; in serum sickness disease patients with IgE hypersensitivity but successfully used in a this elimination system is either malfunctioning or saturated few patients with documented immune complex deposition by the immune complex load. The remaining immune com- disease. We decided to continue treatment using this desen- plexes deposit in several tissues such as joints and skin. sitisation protocol and added methylprednisolone 32 mg once Clinical features of serum sickness are rash, fever, general

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FIGURE 1. Rituximab desensitisation protocol adapted from Wong et al.1 Total amount of drug was diluted into 250 cc of NaCl 0,9% for the rapid and intermediate protocol and 1000cc of NaCl 0,9% for the high-risk protocol Serial 10-fold dilutions were made for the rapid (1 dilution) and intermediate (2 dilutions) and high risk protocol (3 dilutions).

Rapid protocol Intermediate protocol High-risk protocol

Step Time Concentration Infusion Concentration Infusion Concentration Infusion (mg/cc) rate (cc/h) (mg/cc) rate (cc/h) (mg/cc) rate (cc/h)

1 0:00 0,2 5 0,02 2,5 0,0005 20

2 0:15 0,2 10 0,02 5 0,0005 40

3 0:30 0,2 20 0,02 10 0,0005 80

4 0:45 0,2 49 0,02 20 0,005 20

5 1:00 2,0 10 0,2 5 0,005 40

6 1:15 2,0 20 0,2 10 0,005 80

7 1:30 2,0 40 0,2 20 0,05 20

8 RP 1:45 – 4:40 2,0 80

8 other 1:45 0,2 40 0,05 40

9 2:00 2,0 10 0,05 80

10 2:15 2,0 20 0,5 20

11 2:30 2,0 40 0,5 40

12 2:45 2,0 60 60

13 IP 3:00 – 5:45 2,0 80

13 HRP 3:00 – 15:00 0,5 80

malaise, polyarthralgia or even polyarthritis, fever and pro- chronic immune mediated thrombocytopenia, Sjögren’s teinuria occurring 1-2 weeks after first exposure to the disease or SLE).1 Although even more rare Rituximab indu- responsible antigen or occurring within a few days of secon- ced serum sickness has also been reported in patients with dary antigen exposure. Symptoms are generally self-limiting haematological malignancies (namely lymphoproliferative and resolve within weeks after initial exposure to the culprit diseases) indicating that the underlying pathophysiology antigen. The responsible immune complexes can be docu- might be related to, in general, increased antibody production mented in the peripheral blood and most patients have sig- or hypergammaglobulinemia. Table 1 gives an overview of nificant hypocomplementemia characterised by low CH50, patients diagnosed with Rituximab induced serum sickness, C3 and C4. treated for a haematological malignancy (Table 1). Serum sickness associated with Rituximab is a very rare Of the eight patients reported, only 50% experienced serum treatment complication and has only been described in a sickness after the first administration of Rituximab with few case reports, most of them discussing patients with symptoms arising day 5-17 after initial exposure. Symptoms rheumatoid arthritis or other auto-immune diseases (e.g. seemed to occur more quickly if they presented after subse-

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KEY MESSAGES FOR CLINICAL PRACTICE

1 Immune complex deposition disease or serum sickness is a rare side effect of monoclonal antibody treatment.

2 Cardinal clinical features include rash, fever, general malaise, polyarthralgia/polyarthritis and proteinuria occurring 1-2 weeks after initial exposure or several days after secondary antigen exposure.

3 Symptoms are most often self-limiting although drug re-exposure can lead to worsening of symptoms. Symptomatic treatment consists of analgesia, anti-inflammatory drugs and corticosteroids.

4 In the absence of valid treatment alternatives, a desensitisation protocol in monitored circumstances can be applied.

quent administration cycles (interval day 2-7). Patients were resulted in a very good partial remission lasting until now generally treated with corticosteroids in varying regimens (ten months after last treatment cycle). with and without tapering. Re-exposure to the drug is known to lead to worsening of symptoms and is as such CONCLUSION dissuaded.9 However in exceptional circumstances the indi- To our knowledge, this is the second case report of Rituxi- cation for additional Rituximab treatment demands special mab induced serum sickness in a patient with Walden- measures. ström’s macroglobulinaemia. We successfully applied the As such Wong et al. developed a Rituximab desensitisation Rituximab desensitisation protocol as developed by Wong protocol used to treat IgE mediated allergic reactions to et al. Clinicians need to be aware of this potential side effect Rituximab (Figure 1).2 According to this protocol patients of Rituximab and, in selected cases, need to consider the receive a fixed dose of Rituximab (500 mg) in gradually possibility of drug re-exposure using the above mentioned rising concentrations. The ascending rate is determined by desensitisation protocols. the previous severity of the hypersensitivity reaction. Using this protocol, they successfully treated two patients REFERENCES with serum sickness. A similar desensitisation protocol was 1. Karmacharya P, Poudel DR, Pathak R, et al. Rituximab-induced serum applied by Fajt et al. in a patient with serum sickness.7 In sickness: A systematic review. Semin Arthritis Rheum. 2015;45(3):334-40. addition they treated the patient with corticosteroids before 2. Wong JT, Long A. Rituximab Hypersensitivity: Evaluation, Desensitisation, and after desensitisation, a measure that is generally not and Potential Mechanisms. J Allergy Clin Immunol Pract. 2017;5(6):1564-71. recommended in desensitisation procedures for IgE mediated 3. DeMonaco NA, Jacobs SA. Serum sickness in a patient with follicular lym- drug allergy. Subsequent to the first report ofFajt et al. this phoma after rituximab and radioimmunotherapy with ibritumomab tiuxetan. latter desensitisation protocol has been used 25 times in Clinical nuclear medicine. 2007;32(12):933-4. patients with serum sickness without adverse events reports.7 4. Disperati P, Hicks LK, Buckstein R. Rituximab-induced serum sickness in a As Rituximab is an important keystone in the treatment of patient with follicular lymphoma. Leukemia & lymphoma. 2007;48(8):1633-5. Waldenström’s macroglobulinaemia and given our patients 5. Todd DJ, Helfgott SM. Serum sickness following treatment with rituximab. suboptimal response after three cycles of chemo-immuno- The Journal of rheumatology. 2007;34(2):430-3. therapy we discussed with him the option of continuing 6. Portlock CS, O'Connor OA, Straus DJ, et al. Pegylated interferon plus Rituximab treatment according to the earlier suggested rituximab in advanced stage, indolent lymphoma: is there CD20 antigen desensitisation protocols. We decided to use the intermediate upregulation? Leukemia & lymphoma. 2006;47(7):1260-4. protocol by Wong et al. with the addition of systemic corti- 7. Fajt ML, Petrov AA. Desensitisation protocol for rituximab-induced serum coids (methylprednisolone orally 32 mg once daily) and anti- sickness. Curr Drug Saf. 2014;9(3):240-2. inflammatory drugs (ibuprofen 800 mg orally twice daily) 8. Matsui T, Hidaka M, Kawakita T, et al. [Serum sickness induced by rituximab for five days (Figure 1). Our patient successfully completed infusion; report of two cases with hematological malignancies]. Rinsho three additional cycles of Rituximab without any signs or Ketsueki. 2009;50(4):304-8. symptoms of serum sickness and with disappearance of 9. Kumar A, Khamkar K, Gopal H. Serum sickness and severe angioedema the circulating immune complexes. Continuing treatment following rituximab therapy in RA. Int J Rheum Dis. 2012;15(1):e6-7.

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