Iatrogenic Immunodeficiency-associated Lymphoproliferative Disorders Research Articles

A case of methotrexate-related lymphoproliferative disease showing multiple liver lesions in a patient with rheumatoid arthritis.

A 66-year-old woman with rheumatoid arthritis (RA) who had been receiving methotrexate (MTX) for 2years presented with tarry stools. Contrast-enhanced computed tomography (CT) of the abdomen revealed irregular wall thickening in the ileocecal region and multiple low-contrast masses in both lobes of the liver. Lower gastrointestinal endoscopy revealed a type 2 tumor in the ileocecal region with a semi-peripheral ulcer. Histological examination of liver and colon biopsies showed other iatrogenic immunodeficiency-associated lymphoproliferative disorder (Oi-LPD), diffuse large B-cell lymphoma type, with positivity for Epstein-Barr virus DNA. After withdrawal of MTX, the LPD lesions disappeared and the patient achieved remission. We considered this to be a sporadic case of Oi-LPD, diffuse large B-cell lymphoma type, in the liver and colon due to treatment with MTX. There has been no previous report of this condition with simultaneous hepatic and colonic lesions, and the present case is thought to be highly informative in relation to the pathogenesis.

The incidence and prognosis of other iatrogenic immunodeficiency-associated lymphoproliferative disorders of the lung related to methotrexate: A retrospective study

Background and objectiveOther iatrogenic immunodeficiency-associated lymphoproliferative disorders (OIIA-LPD) are rare but well-known diseases that manifest during or after methotrexate (MTX) administration. Limited information is available on the clinical characteristics of OIIA-LPD of the lung because only a few cases have been reported. Thus, we aimed to assess the incidence and prognosis of patients with OIIA-LPD of the lung. MethodsPatients with OIIA-LPD of the lung treated at our institution between January 2008 and July 2020 were retrospectively analysed. ResultsAmong the 51 patients with OIIA-LPD, 16 (31.3%, 7 men, 9 women) had OIIA-LPD of the lung (median age, 69 [range, 63–82] years). Peripheral lesions were observed in 10 (62.5%), central lesions in two (12.5%), and both lesions in four (25.0%) patients. Nine of the 16 patients underwent bronchoscopic biopsy, seven were diagnosed (diagnostic yield, 77.8%) and, re-biopsy was performed in 2 patients. Eight (50.0%) patients had LPD and six (37.5%) had diffuse large B-cell lymphoma. In the 14 patients with confirmed treatment efficacy, the overall response rate to MTX withdrawal was 71.4%. However, chemotherapy was required in case of larger lesions (three patients). Death related to OIIA-LPD occurred in only one patient, and 11 of the 14 patients were alive during the study period (median follow-up time, 53.7 [range, 4.3–84.2] months). ConclusionThe incidence of OIIA-LPD of the lung is 31.3% and higher than that reported previously. The treatment effect of MTX withdrawal seems to be sufficient; however, in some cases, chemotherapy may be required from the beginning.

Lymphoproliferative disorder during temozolomide therapy; a representative case of a formidable complication and management challenges

BackgroundLymphoproliferative disorder represents a heterogeneous clinicopathological spectrum characterized by uncontrolled proliferation of lymphocytes. Immunodeficiency is a major trigger of its development. While induction of immunodeficiency is a well-known adverse effect of temozolomide therapy, development of lymphoproliferative disorder following temozolomide therapy has not previously been described.Case presentationA patient with brainstem glioma developed constitutional symptoms, pancytopenia, splenomegaly and generalized lymphadenopathy during the 2nd cycle of maintenance therapy following induction therapy with temozolomide. Epstein-Barr virus-infected lymphocytes were observed histopathologically and “other iatrogenic immunodeficiency-associated lymphoproliferative disorder” (OIIA-LPD) was diagnosed. Although discontinuation of temozolomide led to rapid remission, relapse was observed 4 months later. CHOP chemotherapy was induced, resulting in secondary remission. Vigilant follow-up for another 14 months showed radiologically stable brainstem glioma and no further recurrence of OIIA-LPD.ConclusionsThis is the first report documenting OIIA-LPD during temozolomide administration. Timely diagnosis of the disease and discontinuation of the causative agent were considered to be the management of choice. Close monitoring for relapse should be continued. Finding a balance between glioma management and controlling the remission of OIIA-LPD remains to be clarified.

Iatrogenic immunodeficiency-associated lymphoproliferative disorders of the central nervous system: a treatment paradox.

Primary central nervous system lymphomas (PCNSLs) have historically had dismal survival rates until the advent of high-dose methotrexate (HD-MTX) based chemotherapy regimens. With increasing prevalence of autoimmune disease and development of new immunosuppressants, a genetically distinct entity known as iatrogenic immunodeficiency-associated lymphoproliferative disorder (LPD) has emerged. Many of these cases arise following methotrexate use, challenging feasibility of standard HD-MTX regimens. The aim of this study was to further characterize this disorder and determine the optimal management strategy. We describe a case of a 76-year-old female with iatrogenic immunodeficiency-associated PCNSL successfully treated with surgical resection followed by an antiviral and rituximab based regimen. We then performed a systematic literature review and identified 58 cases of non-transplant iatrogenic immunodeficiency-associated LPD involving the CNS. We used a linear probability statistical model to determine correlations with outcome. Natalizumab was associated with EBV negative tumors (P=.023), and EBV positive tumors were associated with improved outcomes (P=.016). Surgical resection was associated with improved outcomes (P=.032), although limited by potential confounding effect. Antiviral treatment (P=.095), rituximab (P=.111), and stem cell transplant (SCT) (P=.198) showed a trend toward improved outcomes. The remaining treatments including methotrexate showed no improvement. We propose that surgical resection, rituximab, and antiviral treatment may be considered as an alternative to standard HD-MTX based regimens when managing iatrogenic immunodeficiency-associated LPD of the CNS. Further study through prospective cohort studies or randomized clinical trials is warranted.

MO12-4 Clinical management of other iatrogenic immunodeficiency-associated lymphoproliferative disorders

Other iatrogenic immunodeficiency-associated lymphoproliferative disorder (OIIA-LPD) is known to develop during the use of immunosuppressive drugs (ISDs). Since lesions may regress spontaneously after discontinuation of ISDs, four-week follow-up is recommended after cessation of ISDs. However, it was not clear whether chemotherapy should be given promptly to patients who did not resolve spontaneously within 4 weeks.

Intracerebral manifestation of iatrogenic, immunodeficiency-associated polymorphic B-LPD with morphology mimicking Hodgkin lymphoma: a case report and literature review

Iatrogenic immunodeficiency-associated lymphoproliferative disorders (IA-LPD) may arise in patients treated with immunosuppressive drugs for autoimmune disease or other conditions. Polymorphic EBV-positive B-lymphoproliferations often have features mimicking Hodgkin lymphoma and typically a self-limited, indolent course. We present an unusual case with isolated, intracerebral manifestation of polymorphic B-LPD with features of classic Hodgkin-lymphoma in an immunosuppressed patient treated with methotrexate and infliximab, including clinical-radiological features and a detailed description of morphological findings, together with a literature review on reported cases of primary CNS manifestation of cHL and IA-LPD with Hodgkin-like morphology. The patient achieved complete remission following neurosurgery with gross total tumor resection and drug withdrawal without any additional treatment. Post-operative staging revealed no evidence for focal relapse or systemic disease during the 18 months follow-up period. Among the previously reported 24 cases of primary, isolated Hodgkin lymphoma in the central nervous system, three similar cases of iatrogenic, IA-LPDs were identified and are discussed here. Polymorphic B-LPD are destructive lesions with a range of morphologic features and disease manifestations. It is clinically important to recognize the spectrum of proliferations with features of classic Hodgkin lymphoma in immunodeficiency, iatrogenic settings, because they are likely to impact the choice of treatment strategies.

The case study of other iatrogenic immunodeficiency-associated lymphoproliferative disorders among the patients during the course of rheumatoid arthritis

The case study of other iatrogenic immunodeficiency-associated lymphoproliferative disorders among the patients during the course of rheumatoid arthritis

A Case of Other Iatrogenic Immunodeficiency-associated Lymphoproliferative Disorders Induced by Methotrexate with Extensive Tracheobronchial Involvement

A Case of Other Iatrogenic Immunodeficiency-associated Lymphoproliferative Disorders Induced by Methotrexate with Extensive Tracheobronchial Involvement

Rheumatoid arthritis relapse in patients with other iatrogenic immunodeficiency-associated lymphoproliferative disorders and its treatment

Objectives Rheumatoid arthritis (RA) in patients undergoing immunosuppressive therapy (IS) is sometimes involved with other iatrogenic immunodeficiency-associated lymphoproliferative disorders (LPD). We aimed to clarify the effects of LPD treatment on RA and the current status of RA treatment options after LPD onset and subsequent IS withdrawal. Methods We retrospectively analyzed data of patients who had RA with LPD and examined the relationship between LPD course and RA treatment as well as that between RA relapse and LPD treatment. Results LPD patients were categorized into two groups: patients who regressed spontaneously (n = 19) and those who needed chemotherapy (n = 12). The chemotherapy group had significantly less RA relapse than the spontaneous regression group (p = .041). RA almost relapsed early in the spontaneous regression group and needed treatment for RA. Chemotherapy with rituximab prevented long-term RA relapse, and RA did not relapse for long even after rituximab monotherapy. The total dose of rituximab in monotherapy correlated with the time to RA relapse. Six patients with RA relapse received biologics and had no LPD relapse for more than 1 year. Conclusions Rituximab in chemotherapy for LPD may help prevent RA relapse with LPD. Large-scale studies are required in the future for verification.

Retrospective analyses of other iatrogenic immunodeficiency-associated lymphoproliferative disorders in patients with rheumatic diseases.

SummaryOther iatrogenic immunodeficiency‐associated lymphoproliferative disorders (OIIA‐LPDs) occur in patients receiving immunosuppressive drugs for autoimmune diseases; however, their clinicopathological and genetic features remain unknown. In the present study, we analysed 67 patients with OIIA‐LPDs, including 36 with diffuse large B‐cell lymphoma (DLBCL)‐type and 19 with Hodgkin lymphoma (HL)‐type. After discontinuation of immunosuppressive drugs, regression without relapse was achieved in 22 of 58 patients. Spontaneous regression was associated with Epstein–Barr virus positivity in DLBCL‐type (P = 0·013). The 2‐year overall survival and progression‐free survival (PFS) at a median follow‐up of 32·4 months were 92·7% and 72·1% respectively. Furthermore, a significant difference in the 2‐year PFS was seen between patients with DLBCL‐type and HL‐type OIIA‐LPDs (81·0% vs. 40·9% respectively, P = 0·021). In targeted sequencing of 47 genes in tumour‐derived DNA from 20 DLBCL‐type OIIA‐LPD samples, histone‐lysine N‐methyltransferase 2D (KMT2D; eight, 40%) and tumour necrosis factor receptor superfamily member 14 (TNFRSF14; six, 30%) were the most frequently mutated genes. TNF alpha‐induced protein 3 (TNFAIP3) mutations were present in four patients (20%) with DLBCL‐type OIIA‐LPD. Cases with DLBCL‐type OIIA‐LPD harbouring TNFAIP3 mutations had shorter PFS and required early initiation of first chemotherapy. There were no significant factors for spontaneous regression or response rates according to the presence of mutations. Overall, OIIA‐LPDs, especially DLBCL‐types, showed favourable prognoses.

P13-8 A retrospective analysis on the prognosis of other iatrogenic immunodeficiency-associated lymphoproliferative disorders

P13-8 A retrospective analysis on the prognosis of other iatrogenic immunodeficiency-associated lymphoproliferative disorders

Clinicopathological Study of Methotrexate-Associated Lymphoproliferative Disorders in Rheumatoid Arthritis Patients: Histological Classification and Predictive Factors for Disease Progression

Introduction: Rheumatoid arthritis (RA) patients treated with methotrexate (MTX) may develop lymphoproliferative disorders (LPD), and MTX-associated LPD (MTX-LPD) are recognized as iatrogenic immunodeficiency-associated LPDs. However, the clinicopathological features of MTX-LPD have not been well documented, and distinct diagnostic criteria have not been established. This study analyzed clinicopathological features of MTX-LPD to clarify its characteristics.Methods: Between 2004 and 2015, 193 patients with RA were diagnosed with MTX-LPD at Kurume University. Lesions were classified into the following 4 diagnostic categories: (1) reactive hyperplasia (RH) - lesions with lymphoid proliferation characterized by retention of architecture; (2) polymorphic LPD (Poly-LPD) - diffuse and destructive lesions composed of plasma cells, immunoblasts, and variably-sized lymphocytes, with lesions not fulfilling criteria for lymphoid neoplasms in immunocompetent hosts; (3) diffuse, large B-cell lymphoma (DLBCL) type - fulfilling criteria for immunocompetent hosts; (4) classic Hodgkin lymphoma (CHL) type - fulfilling morphologic and immunophenotypic criteria of CHL. Low grade B-cell lymphoma and peripheral T-cell lymphoma were excluded from this study.Results: All 193 patients received low-dose MTX; and the patients were classified as having RH (n=28), Poly-LPD (n=33), DLBCL type (n=107), and CHL type (n=25) lesions. The clinical features of patients with RH, Poly-LPD, DLBCL-type, and CHL-type lesions were as follows: median age, 62 (range, 26-81 years), 68 (42-83 years), 69 (39-88 years), and 66 (46-85 years); extra-nodal involvement, 11% (3/28), 36% (12/33), 70% (73/105), and 16% (4/25); multiple involved sites, 46% (12/26), 48% (16/33), 62% (64/104), and 48% (12/25), respectively. Of the patients who discontinued MTX without concurrent chemotherapy or surgery at the time of diagnosis, 100% (14/14), 73% (22/30), 49% (34/70), and 11% (2/19) of patients with RH, Poly-LPD, DLBCL-type, and CHL-type lesions had spontaneous regression. Among those who received chemotherapy, 78% (7/9), 72% (48/67), and 70% (14/20) of patients with Poly-LPD, DLBCL-type, and CHL-type lesions had complete remission. One, 17, and 2 patients with Poly-LPD, DLBCL-type, and CHL-type lesions had disease- or treatment-related death during the follow-up period (median, 25 months; range, 1-143 months).Respective histological features of RH, Poly-LPD, DLBCL-type, and CHL-type lesions were as follows: necrosis - 0% (0/27), 48% (16/33), 34% (36/107), 16% (4/25); angioinvasion - 0% (0/27), 9% (3/33), 14% (15/106), 4% (1/25); epithelioid clusters - 0% (0/27), 9% (3/32), 0% (0/105), 24% (6/25). Hodgkin/Reed-Sternberg-like cells were observed in 15% (4/27), 48% (14/29), and 25% (25/100) of patients with RH, Poly-LPD, and DLBCL-type lesions, respectively. Epstein-Barr virus-encoded RNA (EBER)-positive lymphocytes/neoplastic cells were observed in 64% (18/28), 75% (24/32), 54% (56/104), and 84% (21/25) of patients with RH, Poly-LPD, DLBCL-type, and CHL-type lesions, respectively. On immunohistochemical analysis, neoplastic cells, detected in patients with DLBCL-type and CHL-type lesions, were positive for each antibody as follows: CD20 - 98% (104/106), 0% (0/25); CD30 - 43% (40/93), 100% (25/25); CD15 - 6% (4/63), 48% (12/25); LMP-1 - 59% (43/73), 72% (18/25); EBNA-2 - 23% (15/65), 0% (0/22), respectively.Among patients who discontinued MTX without concurrent chemotherapy at diagnosis, RH and Poly-LPD patients had significant favorable chemotherapy-free survival (CFS) (p<0.0001, p=0.0120), while CHL patients had unfavorable CFS (p=0.0344) compared to DLBCL patients (Figure 1). Moreover, EBER-positive DLBCL patients had significantly favorable CFS compared to negative DLBCL patients (p=0.0046), although there were no significant differences in other categorized groups. Overall survival was not significantly different between any categorized groups; however, DLBCL patients with high risk according to the international prognostic index had unfavorable prognoses (p<0.0001).Conclusions: MTX-LPD patients of histological type RH and Poly-LPD lesions had favorable clinical outcomes, while CHL patients had significantly unfavorable clinical outcomes, compared to patients with DLBCL. Histological classification may help predict disease progression in patients with MTX-LPD. [Display omitted] DisclosuresTamaru:Takeda Pharmaceutical Co., Ltd.: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; Nichirei Biosciences Inc.: Research Funding. Tokuhira:Ezai: Honoraria.

Other iatrogenic immunodeficiency-associated lymphoproliferative disorders in the oral cavity: a clinicopathologic study of 4 cases and literature review

Other iatrogenic immunodeficiency-associated lymphoproliferative disorders (OI-LPD) have been reported as one of the adverse effects of immunosuppressive therapy. The aim of this study was to describe the clinicopathologic and immunohistochemical features of OI-LPD in the oral cavity. Immunohistochemistry was performed to describe the immunohistochemical features in our 4 cases. The results were analyzed along with 62 cases of oral OI-LPD in the English and Japanese literature to define clinical and pathologic characteristic features. In our immunohistochemical analysis, Epstein-Barr virus (EBV)-positive OI-LPD showed a higher percentage of mouse double minute 2-positive cells than EBV-negative samples. A literature survey revealed that OI-LPD (including the present cases) arises primarily in the gingiva, followed by the tongue, and usually occurs with a male-to-female ratio of 1:1.9. The rate of EBV positivity was 93.8%. Further, 31 of 66 patients had osteonecrosis of the jaw and 24 of 31 patients had taken multiple immunosuppressive drugs in combination. We can therefore conclude that the overexpression of mouse double minute 2 in OI-LPD is associated with EBV infection, and the combination of multiple immunosuppressive drugs may be a risk factor for osteonecrosis of the jaw.

Increased MYC expression without MYC gene translocation in patients with the diffuse large B-cell-lymphoma subtype of iatrogenic immunodeficiency-associated lymphoproliferative disorders.

Post-transplant lymphoproliferative disorder (PTLD) and other iatrogenic immunodeficiency-associated lymphoproliferative disorders (OIIA-LPD) are iatrogenic lymphoproliferative disorders (LPD) that develop in association with immunosuppressive treatment in the setting of organ transplantation and autoimmune disease, respectively. Each has a spectrum of pathologies ranging from lymphoid hyperplasia to lymphoma. To clarify the characteristics of the diffuse large B-cell lymphoma (DLBCL) subtype in a cohort of 25 patients with PTLD or OIIA-LPD from our institute, we selected 13 with a histological subtype of DLBCL, including 2 cases of PTLD and 11 of OIIA-LPD. The median patient age at diagnosis was 70 years, with a female predominance. Both PTLD cases developed after kidney transplant. Of the patients with OIIA-LPD, 10 had rheumatoid arthritis, 1 had mixed connective tissue disease, and 8 were treated using methotrexate. Both of the PTLD patients and 6 of the OIIA-LPD patients had extranodal manifestations. All patients except for one were classified as having the non-germinal center B-cell (non-GCB) subtype according to the Hans algorithm. Tissue samples from 8 patients were positive for CD30 and 8 were positive for Epstein–Barr virus (EBV)-encoded small RNA. Seven patients had MYC-positive tissue samples, but none had MYC translocation. Our study suggests that extranodal manifestations and the non-GCB subtype are common, that EBV is associated with the DLBCL subtype of PTLD and OIIA-LPD, and that anti-CD30 therapy is applicable. In addition, our patients with the DLBCL subtype of PTLD and OIIA-LPD exhibited MYC overexpression without MYC translocation, suggesting an alternative mechanism of MYC upregulation.

Hepatic Hodgkin Lymphoma Presenting as Solitary Hepatic Mass Following Other Iatrogenic Immunodeficiency-Associated Lymphoproliferative Disorder in a Patient With Rheumatoid Arthritis

Lymphoproliferative disorders (LPDs) occur frequently in patients with rheumatoid arthritis (RA) under methotrexate treatment. Some LPDs spontaneously regressed after methotrexate discontinuation, but classic Hodgkin lymphoma (CHL)-type LPDs frequently relapse, and chemotherapy is usually required for the treatment. CHL usually spreads in contiguous lymph nodes and then infiltrates in organs at an advanced stage. Thus, hepatic Hodgkin lymphoma (HHL) without lymphadenopathy is extremely rare at diagnosis. We present a case of methotrexate-associated LPDs associated with systemic lymphadenopathy and hepatosplenic mass in a 71-year-old woman with RA under methotrexate treatment over 10 years. Although spontaneous remission occurred after methotrexate discontinuation, she developed HHL presenting as a solitary hepatic mass without lymphadenopathy 3 years after spontaneous regression. She received brentuximab vedotin (BV) combination chemotherapy without bleomycin to avoid pulmonary toxicity. Complete metabolic response was achieved after four courses of BV combination chemotherapy, and the activity of RA was kept to be in remission. Our case suggested that the recurrence lesions of LPDs may present at unexpected site, which is not coincide with the primary site, and BV combination chemotherapy is a promising regimen for limited-stage CHL-type LPDs in patients with RA owing to its anti-lymphoma effect on CHL-type LPDs and a possible targeted therapy for RA. J Med Cases. 2021;12(2):79-83 doi: https://doi.org/10.14740/jmc3636

S3534 A Rare Presentation of Other Iatrogenic Immunodeficiency-Associated Lymphoproliferative Disorder, Classic Hodgkin’s Lymphoma-Type, With Hepatic Impairment Treated With Salvage Chemotherapy of Gemcitabine

S3534 A Rare Presentation of Other Iatrogenic Immunodeficiency-Associated Lymphoproliferative Disorder, Classic Hodgkin’s Lymphoma-Type, With Hepatic Impairment Treated With Salvage Chemotherapy of Gemcitabine

Lymphopenia at diagnosis predicts survival of patients with immunodeficiency-associated lymphoproliferative disorders.

The number of patients who are administered immunosuppressive agents has been increasing. Accordingly, more patients face higher risks for developing immunodeficiency-associated lymphoproliferative disorders (LPD). Although immunodeficiency-associated LPD are distinct from other lymphoid neoplasms in terms of their immunocompromised backgrounds, little is known about the impact of lymphopenia at diagnosis on survival in patients with these LPD. Seventy-one immunodeficiency-associated LPD in Kyoto University Hospital (post-transplant LPD (PTLD), n= 26; other iatrogenic immunodeficiency-associated LPD, n= 45) were reviewed and analyzed. The median age at diagnosis was 63years (range, 3-83). Diffuse large B cell lymphoma was the most common subtype (n= 33), followed by Hodgkin lymphoma (n= 12), B cell monomorphic LPD not specified (n= 11), and polymorphic LPD or early-phase diseases (n= 15). The median follow-up period for survivors was 2.5years and overall survival (OS) and progression-free survival (PFS) at 2.5years were 75% and 67%, respectively. Multivariate analysis showed that lymphopenia (≤ 800/μL) at diagnosis predicted inferior OS (HR, 3.72; P= 0.043) and PFS (HR, 3.82; P= 0.012). Serum albumin values also strongly affected OS (> 3.18g/dL vs. ≤ 3.18g/dL; HR, 0.21; P= 0.010) and PFS (HR, 0.26; P= 0.013). Lymphopenia at diagnosis is suggested to predict inferior OS and PFS in patients with immunodeficiency-associated LPDs. Immunocompromised status might affect disease progression in these distinct lymphoid neoplasms growing under immunocompromised backgrounds.

Clinicopathological Analysis of “Other Iatrogenic Immunodeficiency-Associated Lymphoproliferative Disorders” Reveals a Favorable Outcome Independent of the Effectiveness of Methotrexate Discontinuation in Autoimmune Disease Patients

[Background] Patients treated with immunosuppressive drugs for autoimmune diseases may suffer "other iatrogenic immunodeficiency-associated lymphoproliferative disorders" (OIIA-LPD). Some OIIA-LPDs regress after drug withdrawal but others need cytotoxic chemotherapy. However, the factors associated with a response to drug cessation remain unknown. [Methods] We collected clinical data on OIIA-LPD diagnosed between 2009 and 2018 at the University of Tsukuba Hospital and Toranomon Hospital in Japan. Clinicopathological features were retrospectively analyzed. The probability of overall survival (OS) and progression-free survival (PFS) was calculated using the Kaplan-Meier method. OS was defined as the time between the date of diagnosis of OIIA-LPD and the date of death or last follow-up. PFS was defined as the time from the date of diagnosis of OIIA-LPD to the date of commencing chemotherapy or the date of death or last follow up. [Results] Fifty-four cases of OIIA-LPD were identified, of which 25 were diagnosed at the University of Tsukuba Hospital and 29 at Toranomon Hospital. The male to female ratio was 1:3.5 and the median age at diagnosis was 70 years (range, 35-85). Thirty-four patients (63%) had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Most patients (n=50 [93%]) had rheumatoid arthritis (RA). The remaining 4 patients had systemic lupus erythematosus (SLE), myasthenia gravis (MG), polymyalgia rheumatica (PMR), and polymyositis (PM), respectively. Methotrexate (MTX), tacrolimus, and biological agents were used in 49, 17, and 16 cases, respectively. Histological diagnoses of OIIA-LPD type were diffuse large B-cell lymphoma (DLBCL) (n=24), composite lymphoma of DLBCL and follicular lymphoma (FL) (n=1), Hodgkin lymphoma (HL) (n=18), MALT lymphoma (n=2), peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) (n=2), angioimmunoblastic T-cell lymphoma (AITL) (n=1), B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and classic HL (n=1), extranodal NK/T-cell lymphoma (ENKTL) (n=1), Burkitt lymphoma (n=1), and not specified (n=3). Epstein-Barr virus (EBV) was detected in 61% of cases tested (31/51) by in situ hybridization for EBER. At diagnosis of OIIA-LPD, 44 cases (81%) were under MTX treatment. MTX was discontinued in all of these, after which spontaneous regression was observed in 27 (61%). There was no clinical response in 5 patients (11%) within 2 months of MTX cessation, and 12 patients (27%) received chemotherapy without confirming whether stopping MTX would have been sufficient intervention. In 27 cases with spontaneous regression after cessation of MTX, 18 achieved complete remission without chemotherapy, but 9 needed chemotherapy due to re-initiation of LPD. Regarding the histological diagnosis, spontaneous regression was observed in OIIA-LPD patients with DLBCL in 12 of 24 cases (50%) and those with HL in 8 of 18 (44%). After achieving spontaneous regression, patients with DLBCL (10/12 cases, 83%) did not require any form of chemotherapy more often than those with HL (4/8 cases, 50%). Neither EBV positivity nor histology were associated with spontaneous regression. With a median follow-up of 26.1 months (range, 1-120.7), 2-year OS and PFS was 91.9% and 30.1%, respectively. The 2-year PFS of DLBCL and HL was 33.1% and 17.5%, respectively (p=0.533). Only four patients died due to the progression of OIIA-LPD. [Conclusion] Fifty-four cases of OIIA-LPD were retrospectively analyzed. Spontaneous regression after MTX discontinuation was observed in approximately 60% of these patients. No factors associated with response to drug cessation were associated with histological features or EBV positivity, but patients with DLBCL remained in complete remission more frequently than those with HL. Despite the fact that 2-year PFS is low, our retrospective analyses revealed favorable OS of OIIA-LPD because chemotherapy resulted in a good response regardless of whether MTX discontinuation was effective. Disclosures No relevant conflicts of interest to declare.

Other Iatrogenic Immunodeficiency-Associated Lymphoproliferative Disorders with a T- or NK-cell phenotype.

Other iatrogenic immunodeficiency-associated lymphoproliferative disorders (OIIA-LPDs) with a T- or NK-cell phenotype are markedly rare, with only a limited number of cases having been reported thus far. Methotrexate (MTX) is the most common agent used for OIIA-LPD patients, and 43 cases of MTX-associated T-LPDs (MTX T-LPDs) and five cases of MTX-associated NK/T-LPDs (MTX NK-LPDs) have been described. In addition to MTX T-LPDs and MTX NK/T-LPDs, T-LPD and NK/T-LPDs have been reported in patients receiving other immunosuppressive agents such as thiopurines, TNF antagonists, and cyclosporine. Hepatosplenic T-cell lymphoma (HSTL) is specifically associated with iatrogenic immunodeficiency, and 10% of HSTL cases develop in patients receiving thiopurines and/or TNF antagonists for inflammatory bowel disease (IBD). In this review, we focused on MTX T-LPD, MTX NK/T-LPD, and HSTL in patients with IBD. These T- and NK/T-cell associated OIIA-LPDs are the most common in daily medical practice.

Clinical management for other iatrogenic immunodeficiency-associated lymphoproliferative disorders.

Other iatrogenic immunodeficiency-associated lymphoproliferative disorders (OIIA-LPD), a category of immunodeficiency-associated LPD according to the World Health Organization classification, is associated with immunosuppressive drugs (ISDs). Several factors, including autoimmune disease (AID) activity, Epstein-Barr virus (EBV) infection, ISD usage, and aging, influence the development of OIIA-LPD, resulting in complicated clinical courses and outcomes. Most OIIA-LPD develops in patients with rheumatoid arthritis using methotrexate (MTX-LPD). The management of MTX-LPD is based on the clinical course, i.e., with/without regression, with/without relapse/regrowth event (RRE), LPD subtype, and ISDs for AIDs after LPD development. There are three clinical courses after ISD withdrawal: regressive LPD without relapse/regrowth (R-G), regressive LPD with RRE (R/R-G), and persistent LPD (P-G). The majority of EBV+ diffuse large B-cell lymphomas are classified in R-G, whereas classic Hodgkin lymphoma is generally classified in R/R-G. Polymorphic LPD (P-LPD) in MTX-LPD develops with heterogeneous pathological features similar to monomorphic LPD. Chemotherapy for MTX-LPD is selected according to that for de novo LPD, although the strategy for aggressive P-LPD and non-specific LPD is not well established. The absolute lymphocyte count in the peripheral blood has been suggested as a candidate marker for MTX-LPD development and RRE. Several clinical issues, including correct diagnosis among overlapping clinicopathological features in MTX-LPD and clinical management of LPD by ISDs other than MTX, require further investigation.