Clinical Analysis of Immunodeficiency-Associated Lymphoproliferative Disorders in a Single Institution
Authors: Watanabe Mizuki , Kanda Junya , Arai Yasuyuki , Nishikori Momoko , Hishizawa Masakatsu , Kondo Tadakazu , Yamashita Kouhei , Takaori Akifumi Kondo 
Published: October 2019

Abstract
Background
Recent progress in medicine faces more patients to iatrogenic immunosuppressive state, which increases the risk of following immunodeficiency-associated lymphoproliferative disorders (LPD), such as post-transplant lymphoproliferative disorders (PTLD) which arise after solid organ or hematopoietic stem cell transplantation (HSCT), and other lymphoid proliferations or lymphomas which arise in patients treated with immunosuppressive agents for any reasons. Methotrexate for patients with rheumatoid arthritis (RA) has been the most discussed immunosuppressive agent associated with iatrogenic LPD. Nevertheless, the number of patients treated with other immunosuppressive agents such as biological response modifiers for RA and calcineurin inhibitors after HSCT has recently increased and clinical assessment of iatrogenic-LPD under this recent immunosuppressive setting is still limited. Clinical prognostic factors remain controversial due to the heterogeneity of this disease concept, patients' background and treatment.
Methods: A total of 71 patients diagnosed as iatrogenic immunodeficiency-associated lymphoproliferative disorders (PTLD, n=26; other LPD, n=45) over last 20 years in Kyoto University Hospital were reviewed. Cox regression analysis was used to examine the impact of patient characteristics including immunological backgrounds and tumor status on outcomes.
Results: Median age at diagnosis of LPD was 63 (range, 3-83; PTLD, 50; other LPD, 66). Regarding the PTLD patients, 12 were recipients of liver transplantation, 8 were of HSCT, 4 were of lung and 2 were of kidney transplantation. Background diseases of the other LPD were RA in 43, systemic lupus erythematosus in 1 and systemic sclerosis in 1. Median time from the initiation of immunosuppressive agents to LPD diagnosis was 82 months (range, 1.5-348.5; PTLD, 35.4; other LPD, 116.5). The number of immunosuppressive agents given at LPD diagnosis was 0 in 1 patient, 1 in 14, 2 in 42, 3 in 12 and 4 in 1 patient. Twenty-nine percentage of those receiving multiple immunosuppressive agents were administered methotrexate in combination with PSL or biological response modifiers. Ann Arbor stage at diagnosis was I in 8 patients, II in 13, III in 20 and IV in 28 patients. Histologic subtypes of PTLD were monomorphic (n=19), polymorphic (n=4), and non-destructive PTLD (n=3). Pathological diagnosis of other LPD were DLBCL (n=20), polymorphic LPD (n=5), classical Hodgkin lymphoma (n=6), Hodgkin-like lesion (n=3), Burkitt lymphoma (n=1), EBV-positive mucocutaneous ulcer (n=3), and other B-cell lymphomas (n=7). EBER in situ hybridization was positive in 38 (63.3%) and systemic EBV reactivation was detected in 17 (43.6%).First line therapy included reduction of immunosuppressive agents without chemotherapy in 33 patients (PTLD, n=4; other LPD, n=29), RTX-containing chemotherapy in 23 (PTLD, n=14; other LPD, n=9), other chemotherapies in 7 (PTLD, n=4; other LPD, n=3), radiation therapy in 2, and no additional treatment in 2 patients.After the first line therapy, complete remission was achieved in 35 patients, partial response in 13, and stable or progressive disease in 14. A total of 4 patients died during the first line therapy. Five-year survival rate was 49.9% (PTLD, 39.0%; other LPD, 54.0%; P=0.101).Multivariate analysis showed that low number of lymphocyte count (&lt; 890/µl, median lymphocyte count) at diagnosis (HR, 5.55; P=0.013), hypoalbuminemia (serum albumin value &lt;3.2 g/dl) at diagnosis (HR, 6.36; P=0.015) and higher IPI (high-risk group vs others, HR, 2.71; n=0.021) were risk factors for poor prognosis. In subgroup analysis for PTLD, low IgG (&lt;825 mg/dl, lowest limiting value of our center) was also an independent prognostic factor for inferior outcome (HR, 15.5; P=0.011).
Conclusions: Overall survival of immunodeficiency-associated lymphoproliferative disorders under recent immunosuppressive settings, especially PTLD, was still poor. We found that low number of lymphocyte count could be a new risk factor for poor prognosis, along with known factors as IPI and hypoalbuminemia. Low IgG value was also suggested to be a prognostic factor for inferior outcome in PTLD patients.
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Disclosures
Nishikori: Eisai: Research Funding; Ono Pharmaceuticals: Research Funding.