Patterns of development of immune complications in patients with lymphoproliferative diseases receiving rituximab therapy

   Rituximab is a synthetic (genetically engineered) chimeric monoclonal antibody that has occupied its niche of application not only in relation to lymphoproliferative diseases (non-Hodgkin lymphomas and chronic lymphocytic leukemia), but also in relation to a number of other diseases. However, when using this drug, a number of complications occur, including immune ones. A certain pattern of development of immune complications has been revealed depending on the stage of therapy. During rituximab therapy, cases of transient decrease in B-lymphocytes or immunoglobulin levels are often reported, which are leveled 6-12 months after the end of treatment with this drug. It also describes the development of prolonged and persistent neutropenia, which develops delayed in relation to the end of therapy. There are risk factors associated with immunological complications: male gender, Caucasian race, age over 50 years, immunocompromised conditions (immunosuppressive therapy, primary and secondary immunodeficiency). The most effective methods of prevention include: detection of severe infectious complications in the last 6 months of patient follow-up, detection of a critical decrease in the level of class G immunoglobulins (less than 4 g /l) and its correction by immunosuppression therapy; determination of the content of mature B lymphocytes in peripheral blood and preventive sanitation of foci of chronic infection.

1. Nasonov E.L. Prospects of using rituximab in human autoimmune diseases. Russian Medical Journal. 2007. 26.1958

2. Sarah Stabler, Jonathan Giovannelli, David Launay, et al. Serious infectious events and immunoglobulin replacement therapy in patients with autoimmune diseases receiving rituximab. a retrospective cohort study. Clinical Infectious Diseases. 2020. ciaa127.

3. Dunleavy K., Tay K., Wilson WH. Rituximabassotiated neutropenia. SeminHematol. 2010.47.180–86

4. Marco H., Smith R.M., Jones R.B. et al. The effect of rituximab therapy on immunoglobulin levels in patients with multisystem autoimmune disease. BMC. 2014. doi: 10.1186/1471-2474-15-178

5. Irie E., Shirota Y., Suzuki C., et al. Severe hypogammaglobulinemia persisting for 6 years after treatment with rituximab combined chemotherapy due to arrest of B lymphocyte differentiation together with alteration of T lymphocyte homeostasis. Int J Hematol. 2010. 501-508. doi: 10.1007.s12185.010.0528.6. PubMed PMID. 20217285

6. Athni TS., Barmettler S. Hypogammaglobulinemia, late-onset neutropenia, and infections following rituximab. Ann Allergy Asthma Immunol. 2023 Jun.130(6).699.712. Epub 2023 Jan 24. PMID. 36706910. PMCID. PMC10247428.

7. Barmettler S., Ong MS., Farmer JR., et al. Association of Immunoglobulin Levels, Infectious Risk, and Mortality With Rituximab and Hypogammaglobulinemia. JAMA Netw Open. 2018 Nov 2.1(7).e184169. doi: 10.1001/jamanetworkopen.2018.4169. PMID. 30646343. PMCID. PMC6324375.

8. Martín Moro F., Marquet J., Piris M. et al. Survival study of hospitalised patients with concurrent COVID 19 and haema tological malignancies. Br. J. Haematol 2020.190(1).e16.20. DOI: 10.1111/bjh.16801.

9. Lopez C.A., Chitty D., Chi J. et al. Outcomes in patients with hematological malignancies receiving anti CD20 therapy in the setting of COVID 19 infection. Blood 2020.136.8.9. DOI: 10.1182/blood-2020143124.

10. Regalado Artamendi I., Jiménez Ubieto A., Hernández Rivas J.Á. et al. Risk factors and mortality of COVID 19 in patients with lymphoma: a multicenter study. Hemasphere 2021.5(3).e538. DOI: 10.1097/HS9.0000000000000538.

11. Lamure S., Dulery R., Delord M. et al. High incidence of persistent COVID 19 among patients with lymphoma treated with B cell depleting immunotherapy. Clin Cancer Res 2021.27(6).S09.2. DOI: 10.1158/15573265.COVID1921S0902.

12. Passamonti F., Cattaneo C., Arcaini L. et al. Clinical characteristics and risk factors associated with COVID 19 severity in patients with haematological malignancies in Italy: a retrospective, multicentre, cohort study. Lancet Haematol 2020.7(10). e737.45. DOI: 10.1016/S23523026(20)30251 9.

13. Avouac J., Drumez E., Hachulla E. et al. COVID 19 outcomes in patients with inflammatory rheumatic and musculoskeletal diseases treated with rituximab: a cohort study. Lancet Rheumatol2021.3(6).e419.26. DOI: 10.1016/S26659913(21)00059 X.

14. Quartuccio L., Treppo E., Binutti M. et al. Timing of rituximab and immunoglobulin level influence the risk of death for COVID 19 in ANCA associated vasculitis. Rheumatology (Oxford) 2021.60(7).3476.7. DOI: 10.1093/rheumatology/keab175.

15. Beketova T.V., Babak V.V., Suprun M.D. Course and outcomes of COVID19 in patients with ANCA-associated systemic vasculitis treated with genetically engineered biological drugs (rituximab, mepolizumab): the results of the first 8 months of the pandemic. Scientific and practical rheumatology 2021.59(1).37.46. DOI: 10.47360/1995448420213746.

16. Hoffmann M.S., Ganguly S. Delayed COVID 19 respiratory failure in patients with lymphoma on rituximab based chemoimmunotherapy. Clin Lymphoma Myeloma Leuk 2021.21(6).e548.50. DOI: 10.1016/j.clml.2021.02.009.

17. Gelinck L.B., Teng Y.K., Rimmelzwaan G.F. et al. Poor serological responses upon influenza vaccination in patients with rheumatoid arthritis treated with rituximab. Ann Rheum Dis 2007.66(10).1402.3. DOI: 10.1136/ard.2007.071878.

18. Bedognetti D., Zoppoli G., Massucco C. et al. Impaired response to influenza vaccine associated with persistent memory B cell depletion in non Hodgkin’s lymphoma patients treated with rituximab containing regimens. J. Immunol 2011.186(10).6044.55. DOI: 10.4049/jimmunol.1004095.

19. Van Assen S., Holvast A., Benne C.A. et al. Humoral responses after influenza vaccination are severely reduced in patients with rheumatoid arthritis treated with rituximab. Arthritis Rheum 2010.62(1).75.81. DOI: 10.1002/art.25033.

20. Devauchelle Pensec V., Morvan J., Rat A.C. et al. Effects of rituximab therapy on quality of life in patients with primary Sjögren’s syndrome. Clin Exp Rheumatol 2011.29(1).6.12.

21. Dunleavy K., Hakim F., Kim H.K. et al. B cell recovery following rituximab based therapy is associated with perturbations in stromal derived factor 1 and granulocyte homeostasis. Blood 2005.106(3).795.802. DOI: 10.1182/blood2004083198.

22. Nakou M., Katsikas G., Sidiropoulos P. et al. Rituximab therapy reduces activated B cells in both the peripheral blood and bone marrow of patients with rheumatoid arthritis: depletion of memory B cells correlates with clinical response. Arthritis Res Ther 2009.11(4).R131. DOI: 10.1186/ar2798.

23. Re D., Barrière J., Chamorey E. et al. Low rate of seroconversion after mRNA anti SARS CoV 2 vaccination in patients with hematological malignancies. Leuk Lymphoma 2021.62(13).3308.10. DOI: 10.1080/10428194.2021.1957877.

24. Chilimuri S., Mantri N., Zahid M., Sun H. COVID 19 vaccine failure in a patient on rituximab therapy. Rheumatol Adv Pract 2021.5(2).rkab038. DOI: 10.1093/rap/rkab038.

25. Teh B.W., Tam C.S. Between a rock and a hard place: COVID 19 vaccination and patients on rituximab therapy. Leuk Lymphoma 2021.62(12).2820.2. DOI: 10.1080/10428194.2021.1957879.

26. Kant S., Kronbichler A., Salas A. et al. Timing of COVID 19 vaccine in the setting of anti CD20 therapy: a primer for nephrologists. Kidney Int. Rep. 2021.6(5).1197.9. DOI: 10.1016/j.ekir.2021.03.876.

27. Bonelli M.M., Mrak D., Perkmann T. et al. SARS CoV 2 vaccination in rituximab treated patients: evidence for impaired humoral but inducible cellular immune response. Ann Rheum Dis 2021.80(10).1355.6. DOI: 10.1136/annrheumdis2021220408.

28. Tieu J., Smith RM., Gopaluni S., et al. Rituximab Associated Hypogammaglobulinemia in Autoimmune Disease. Front Immunol. 2021 May 12.12.671503. doi: 10.3389/fimmu.2021.671503. PMID: 34054846; PMCID: PMC8149951.

29. Moskalets O.V. Selective immunoglobulin A deficiency in the long-term period after rituximab therapy. 2022.21(6). 63.66. DOI: 10.31550/1727-2378-2022-21-6-63-66

30. Pecoraro A., Crescenzi L., Galdiero M.R. et al. Immunosuppressive therapy with rituximab in common variable immunodeficiency. ClinMol Allergy 17. 9 (2019). doi: 10.1186/s12948-019-0113-3

31. Lukina G.V., Sigidin Ya.A., Nasonov E.L. Interim results of the Russian registry of monoclonal antibodies to B lymphocytes (rituximab) in rheumatoid arthritis. Russian Medical Journal. 2008.24.1596.

32. Dunleavy K., Tay K., Wilson WH. Rituximab-associated neutropenia. SeminHematol.2010.Apr.47(2)180-6. doi: 10.1053/j.seminhematol.2010.01.009. PMID: 20350665. PMCID: PMC7304500.

33. Grant C., Wilson WH., Dunleavy K. Neutropenia associated with rituximab therapy. CurrOpinHematol.2011.Jan.18(1).49-54. doi: 10.1097/MOH.0b013e3283414edf. PMID: 21102324

34. Wolach O., Bairey O., Lahav M. Late-onset neutropenia after rituximab treatment: case series and comprehensive review of the literature. Medicine (Baltimore).2010.Sep.89(5).308.318. doi: 10.1097/MD.0b013e3181f2caef. PMID: 20827108

35. Mears V., Jakubecz C., Seeco C., et al. Predictors of hypogammaglobulinemia and serious infections among patients receiving ocrelizumab or rituximab for treatment of MS and NMOSD. J.Neuroimmunol.2023Apr.15.377.578066. doi: 10.1016/j.jneuroim.2023.578066. Epub. 2023. Mar. 8. PMID: 36917920.

36. Kridin K., Ahmed AR. Post-rituximab immunoglobulin M (IgM) hypogammaglobulinemia. AutoimmunRev. 2020 Mar.19(3).102466. doi: 10.1016/j.autrev.2020.102466. Epub. 2020. Jan 7. PMID: 31917267.

37. Minard-Colin V., Aupérin A., Pillon M., et al. European Intergroup for Childhood Non-Hodgkin Lymphoma. Children’s Oncology Group. Rituximab for High-Risk, Mature B-Cell Non-Hodgkin's Lymphoma in Children. N Engl J Med. 2020. Jun 4.382(23).2207.2219. doi: 10.1056/NEJMoa1915315. PMID: 32492302. PMCID: PMC7720281

38. Andreescu M. Risk of Severe Infections Secondary to the Use of Targeted Therapies in Hematological Malignancies. Cureus. 2024. Jan 10.16(1).e52050. doi: 10.7759/cureus.52050. PMID:38344573. PMCID: PMC10857843.

39. Labrosse R., Barmettler S., Derfalvi B., et al. Rituximab-induced hypogammaglobulinemia and infection risk in pediatric patients. J. Allergy ClinImmunol.2021.Aug.148(2).523.532.e8. doi: 10.1016/j.jaci.2021.03.041. Epub. 2021. Apr 20. PMID: 33862010.