Epstein-Barr Virus-Negative, CD5-Positive Diffuse Large B-Cell Lymphoma Developing after Treatment with Oral Tacrolimus for Mixed Connective Tissue Disease : A Case Report and Review of the Literature

Abstract

A 69-year-old woman, who had been diagnosed as having Sjögren's syndrome at 37 years old and mixed connective tissue disease at 42 years old, was under treatment with oral prednisolone. In 2009, she was diagnosed as having active systemic lupus erythematosus, and started on treatment with tacrolimus at 3 mg/day. In 2010, para-aortic lymphadenopathy and superficial multiple lymphadenopathy were detected. Tacrolimus was discontinued. Axillary lymph node biopsy revealed Epstein-Barr (EB) virus-negative CD5-positive diffuse large B-cell lymphoma (DLBCL). The patient was classified into clinical stage IIIA and as being at high risk according to the international prognostic index. After the discontinuation of tacrolimus, the lymph nodes reduced temporarily in size. In January 2011, the lymphadenopathy increased again, and the patient received a total of 8 courses of therapy with rituximab, pirarubicin, vincristine, cyclophosphamide and prednisolone, followed by intrathecal injection to prevent central nervous system infiltration, which was followed by complete remission. In February 2012, fluorodeoxyglucose positron emission tomography showed relapse in multiple lymph nodes and central nervous system infiltration. The patient was considered to have iatrogenic lymphoproliferative disorder classified as "other iatrogenic immunodeficiency-associated lymphoproliferative disorders" by the WHO, and this is the first reported case of CD5-positive DLBCL and central nervous system infiltration following administration of the drug. The patient was considered to have a poor prognosis as EB virus was negative, discontinuation of tacrolimus was ineffective and there was evidence of central nervous system infiltration. 〔J Clin Exp Hematopathol 52(3) : 211-218, 2012〕

Incidence of Malignancy and the Risk of Lymphoma in Japanese Patients with Rheumatoid Arthritis Compared to the General Population

“…In addition to MTX, the use of tacrolimus was significantly associated with the development of lymphoma in our multivariate analysis. Our results are supported by a report of a small number of Japanese patients with autoimmune diseases who were thought to have developed tacrolimus-induced lymphoma 45 . However, the risk of lymphoma development associated with oral tacrolimus in patients with autoimmune diseases has not been evaluated because this drug is approved for RA in only a few countries worldwide and insufficient data exist.…”

Case of immune‐mediated necrotizing myopathy associated with anti‐signal recognition particle antibodies: Dramatic improvement after rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone therapy for intravascular large B‐cell lymphoma

“…However, a previous cohort study showed that in contrast to other immune‐mediated necrotizing myopathies, anti‐SRP myopathy is not commonly associated with neoplasms . Furthermore, tacrolimus has been shown to cause iatrogenic immunodeficiency‐associated lymphoproliferative disorders, even after just a few months of treatment . Therefore, we suspect that the addition of tacrolimus to the patient's regimen caused IVLBCL.…”

Other immunomodulatory agent-related lymphoproliferative diseases: a single-center series of 72 biopsy-confirmed cases

“…The increased risk for lymphoproliferative disorders in the post-transplant population [1,[41][42][43][44][45] and case reports with a clear relation in time between therapy initiation and the development of lymphoproliferative disorders [46,47] support the existence of a causative role between immunosuppressive/immunomodulatory therapy and lymphoproliferative disorders. This causative role of immunomodulatory/suppressive therapy in immunosuppressive/immunomodulatory agent-related lymphoproliferative disorders has been repeatedly suggested by case reports of lymphoproliferative disorders regression following discontinuation of methotrexate [48][49][50][51][52], anti-TNFα therapy [53][54][55][56] thiopurines [55], tacrolimus [57], and others [56]. A limitation in studying the effect of these drugs on lymphoproliferative disorder incidence is the still open question how long after cessation of therapy the immunosuppressive/immunomodulatory effects of these drugs linger.…”