Lymphoproliferative Disorders In Patients Research Articles

The Clinical Role of CXCR4-Targeted PET on Lymphoproliferative Disorders: A Systematic Review.

Background/Objectives: We conducted a comprehensive investigation to explore the pathological expression of the CXCR4 receptor in lymphoproliferative disorders (LPDs) using [68Ga]Ga-Pentixafor PET/CT or PET/MRI technology. The PICO question was as follows: What is the diagnostic role (outcome) of [68Ga]Ga-Pentixafor PET (intervention) in patients with LPDs (problem/population)? Methods: The study was written based on the reporting items for systematic reviews and meta-analyses (PRISMA) 2020 guidelines, and it was registered on the prospective register of systematic reviews (PROSPERO) website (CRD42024506866). A comprehensive computer literature search of Scopus, MEDLINE, Scholar, and Embase databases was conducted, including articles indexed up to February 2024. To the methodological evaluation of the studies used the quality assessment of diagnosis accuracy studies-2 (QUADAS-2) tool. Results: Of the 8380 records discovered, 23 were suitable for systematic review. Fifteen studies (on 571 LPD patients) focused on diagnosis and staging, and eight trials (194 LPD patients) assessed treatment response. Conclusions: The main conclusions that can be inferred from the published studies are as follows: (a) [68Ga]Ga-Pentixafor PET may have excellent diagnostic performance in the study of several LPDs; (b) [68Ga]Ga-Pentixafor PET may be superior to [18F]FDG or complementary in some LPDs variants and settings; (c) multiple myeloma seems to have a high uptake of [68Ga]Ga-Pentixafor. Overall, this technique is probably suitable for imaging, staging, and follow-up on patients with LPD. Due to limited data, further studies are warranted to confirm the promising role of [68Ga]Ga-Pantixafor in this context.

Classifications of cutaneous lymphomas and lymphoproliferative disorders: An update from the EORTC cutaneous lymphoma histopathology group.

The classification of primary cutaneous lymphomas and lymphoproliferative disorders (LPD) is continuously evolving by integrating novel clinical, pathological and molecular data. Recently two new classifications for haematological malignancies including entities of cutaneous lymphomas were proposed: the 5th edition of the WHO classification of haematolymphoid tumours and the International Consensus Classification (ICC) of mature lymphoid neoplasms. This article provides an overview of the changes introduced in these two classifications compared to the previous WHO classification. The main changes shared by both classifications include the downgrading of CD8+ acral T-cell lymphoma to CD8+ acral T-cell LPD, and the recognition of entities that were previously categorized as provisional and have now been designated as definite types including primary cutaneous small or medium CD4+ T-cell LPD, primary cutaneous gamma/delta T-cell lymphoma, primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma, Epstein-Barr virus-positive mucocutaneous ulcer. Both classifications consider primary cutaneous marginal zone B-cell clonal neoplasm as an indolent disease but use a different terminology: primary cutaneous marginal zone lymphoma (WHO) and primary cutaneous marginal zone LPD (ICC). The 5th WHO classification further introduces and provides essential and desirable diagnostic criteria for each disease type and includes chapters on reactive B- or T-cell rich lymphoid proliferations formerly referred as cutaneous pseudolymphomas, as well as histiocyte and CD8 T-cell rich LPD in patients with inborn error of immunity. As already emphasized in previous lymphoma classifications, the importance of integrating clinical, histological, phenotypic and molecular features remains the crucial conceptual base for defining cutaneous (and extracutaneous) lymphomas.

Prevalence of IgG antibodies against Malawi polyomavirus in patients with autoimmune diseases and lymphoproliferative disorders subjected to bone marrow transplantation.

Human polyomaviruses (HPyVs) cause persistent/latent infections in a large fraction of the population. HPyV infections may cause severe diseases in immunocompromised patients. Malawi polyomavirus (MWPyV) is the 10th discovered human polyomavirus (HPyV 10). MWPyV was found in stool samples of healthy children. So far, the few investigations carried out on HPyV 10 did not find an association with human disease. In this study, to verify the putative association between MWPyV and human diseases, MWPyV seroprevalence was investigated in patients affected by i) lymphoproliferative disorders (LPDs) and ii) immune system disorders, i.e., autoimmune diseases (ADs), and in iii) healthy subjects. An indirect ELISA, employing virus-like particles (VLPs) to detect serum IgG antibodies against MWPyV/HPyV 10, was carried out. The study also revealed the prevalence of another polyomavirus, Merkel cell polyomavirus (MCPyV). Sera from patients with distinct autoimmune diseases (n = 44; mean age 20 years) had a prevalence of MWPyV antibodies of 68%, while in patients with lymphoproliferative disorders (n = 15; mean age 14 years), subjected to bone marrow transplantation, the prevalence was 47%. In healthy subjects (n = 66; mean age 13 years), the prevalence of MWPyV antibodies was 67%. Our immunological investigation indicates that MWPyV/HPyV 10 seroconversion occurs early in life and MWPyV/HPyV 10 appears to be another polyomavirus ubiquitous in the human population. A significantly lower MWPyV antibody reactivity together with a lower immunological profile was detected in the sera of LPD patients compared with HS2 (*p < 0.05) (Fisher's exact test). LPD and AD patients have a similar MCPyV seroprevalence compared with healthy subjects. MWPyV seroprevalence indicates that this HPyV is not associated with lymphoproliferative and autoimmune diseases. However, the ability to produce high levels of antibodies against MWPyV appears to be impaired in patients with lymphoproliferative disorders. Immunological investigations indicate that MWPyV seroconversion occurs early in life. MCPyV appears to be a ubiquitous polyomavirus, like other HPyVs, in the human population.

Evaluation of the frequency of benign reactive lymphocytosis and lymphoproliferative disorders by flow cytometry in patients with persistent lymphocytosis in peripheral blood

Introduction: Lymphocytosis is characterized by an elevation in the absolute lymphocyte count (ALC) to over 4000 lymphocytes per microliter among adults. In lymphocytosis, the important matter is whether lymphocytosis is a benign reactive condition or a neoplastic lymphoproliferative disorder (LPD), which can be determined by immunophenotyping methods by flow cytometry. Objectives: Due to the need to use flow cytometry to confirm the diagnosis of patients with lymphocytosis, the purpose of this study was to compare the frequency of benign reactive lymphocytosis and LPDs in patients with persistent lymphocytosis using flow cytometry in the peripheral blood and report the results based on the patient’s demographic characteristics. Materials and Methods: This study was a cross-sectional study and the study population was all peripheral blood samples referred to Seyed Al-Shohada hospital in Isfahan to study the cause of absolute and persistent lymphocytosis by immunophenotyping analysis through flow cytometry between 2015 and 2020. Inclusion criteria were patients over 18 years of age with absolute lymphocytosis in complete blood count (CBC) or peripheral blood smear (PBS) who were examined by flow cytometry. Results: This study involved 222 samples, 139 (62.6%) of the cases were male. The mean age was 60.41 (15.91) years. All samples had absolute lymphocytosis and were divided into two groups: benign, with 62 (27.9%), and malignant, with 160 (72.1%). Conclusion: The relationship between gender and malignancy showed that the male gender was associated with an increased risk of malignancy. The mean age between the two groups of malignant and benign was determined by independent t test, and it was shown that the mean (±standard deviation) age of malignant cases is higher than the mean age of benign cases. It is recommended that cases of suspected lymphoproliferative cases and cases with cell counts below the lymphocytosis threshold be investigated in separate studies.

Analysis of Notch1 protein expression in methotrexate-associated lymphoproliferative disorders.

Methotrexate (MTX)-associated lymphoproliferative disorder (MTX-LPD) is a lymphoproliferative disorder in patients treated with MTX. The mechanism of pathogenesis is still elusive, but it is thought to be a complex interplay of factors, such as underlying autoimmune disease activity, MTX use, Epstein-Barr virus infection, and aging. The NOTCH genes encode receptors for a signaling pathway that regulates various fundamental cellular processes, such as proliferation and differentiation during embryonic development. Mutations of NOTCH1 have been reported in B-cell tumors, including chronic lymphocytic leukemia/lymphoma, mantle cell lymphoma, and diffuse large B-cell lymphoma (DLBCL). Recently, it has also been reported that NOTCH1 mutations are found in post-transplant lymphoproliferative disorders, and in CD20-positive cells in angioimmunoblastic T-cell lymphoma, which might be associated with lymphomagenesis in immunodeficiency. In this study, to investigate the association of NOTCH1 in the pathogenesis of MTX-LPD, we evaluated protein expression of Notch1 in nuclei immunohistochemically in MTX-LPD cases [histologically DLBCL-type (n = 24) and classical Hodgkin lymphoma (CHL)-type (n = 24)] and de novo lymphoma cases [DLBCL (n = 19) and CHL (n = 15)]. The results showed that among MTX-LPD cases, the expression of Notch1 protein was significantly higher in the DLBCL type than in the CHL type (P < 0.001). In addition, among DLBCL morphology cases, expression of Notch1 tended to be higher in MTX-LPD than in the de novo group; however this difference was not significant (P = 0.0605). The results showed that NOTCH1 may be involved in the proliferation and tumorigenesis of B cells under the use of MTX. Further research, including genetic studies, is necessary.

Arterial structure and function in patients with hemoblastoses before and after high-dose chemotherapy and autologous hematopoietic stem cell transplantation

Background: High dose chemotherapy (HDCT) preceding autologous hematopoietic stem cell transplantation (autoSCT) can be toxic for cardiovascular system, which can be mediated with the development of endothelial dysfunction. No studies on the assessment of arterial stiffness and endothelial function after HDCT and autoSCT have been performed before.&#x0D; Aim: To evaluate endothelial function and arterial rigidity parameters by photoplethysmography in patient candidates for HDCT with autoSCT, to identify associated factors and to analyze changes of these parameters over time after HDCT and autoSCT.&#x0D; Materials and methods: In this cohort prospective observational study in 71 patients with verified hemoblastosis (mean age 43.8 ± 12.6 years) we assessed endothelial function and stiffness by photoplethysmography (AngioScan-01, Russia) before and after HDCT with autoSCT. Thirty two (32, 45%) patients had multiple myeloma (ММ), 39 (55%), lymphoproliferative disorders (LPD). We measured the stiffness index (SI), reflection index (RI), augmentation index normalized by heart rate of 75 beats per minute (AIp75) and performed the occlusion test with measurement of occlusion index (ОI) and phase shift (PS).&#x0D; Results: Mean RI in the total study group before HDCT with autoSCT was increased to RI 34.9% [24.5; 50.6], OI decreased to OI 1.5 [1.25; 1.80], and PS module decreased to PS 6.7 ms [3.9; 8.9]. After HDCT with autoSCT the PS module increased to 8.4 ms [5.0; 12.4] (p = 0.001) and OI increased to 1.7 [1.3; 2.2] (p = 0,007), which indicates an improvement in endothelial function.&#x0D; Changes in other parameters of arterial function were non-significant. We also analyzed a selected group of the patients with MM who had higher cardiovascular risk, compared to the LPD patients: they were older (53 vs 36.1 years; p 0.001), had higher rates of arterial hypertension (p 0.001) and diabetes mellitus (p = 0.048). Compared to the LPD patients, the MM patients had higher baseline values of SI (7.5 m/s [7.3; 7.9]), RI (42.9% [32.1; 53.6]), and AIp75 (6.3% [-1.65; 13.8]), indicating higher vascular stiffness. They also had lower PS module values (5.0 ms [2.1; 8.5]). The LPD patients had been more frequently treated with anthracyclines (p 0.001) and radiation (p = 0.002). After HDCT with autoSCT, they had a higher increment of OI, namely, from 1.4 [1.3; 1.8] to 1.7 [1.4; 2.1] (p = 0.003).&#x0D; Conclusion: This study was the first to show a high rate of endothelial dysfunction and vascular stiffness abnormalities in patients with hemoblastoses who were candidates for HDCT with autoSCT. After HDCT with autoSCT, changes of endothelial function and stiffness were multidirectional. Despite a significant improvement, endothelial function parameters were not normalized. We were unable to find any predictors of the abnormalities. Thus, the identified baseline abnormalities in stiffness and endothelial function cannot be a contraindication to HDCT with autoSCT.

Clinico-Haematological Profile Of Chronic Lymphoproliferative Disorders In Patients Presenting With Lymphocytosis.

To assess the spectrum and clinico-haematological profile of chronic lymphoproliferative disorders in patients presenting with lymphocytosis. The cross-sectional, retrospective study was conducted at the Aga Khan University Hospital, Karachi, and comprised data related to cases of bone marrow aspirate and trephine from January to November 2020. Patients for whom the bone marrow was done for lymphocytosis were studied for the presence of lymphoproliferative disorders, sub-types and patients'characteristics. The diagnosis and classification were based on the World Health Organisation criteria for tumours of haematopoietic and lymphoid tissues. Data was analysed using SPSS 21. Of the 3,334 bone marrow specimenstested, 103(3%) were related to lymphocytosis. Of these, 84(82%) were diagnosed with lymphoproliferative disorders, while diagnosisremained undetermined in 19(18%) cases. Male:female ratio was 3.6:1 and median age was 60 years (range: 21-85 years). Constitutional symptoms were found in 61(73%) patients. Median absolute lymphocyte count was 45x109/L (range: 5.3-480). All 84(100%) patients were classified as B-cell lymphoproliferative disorder. Chronic lymphocytic leukaemia wasthe most common form, 61(73%), and 31(51%) of them presented with advanced stage disease. A huge majority of patients presenting with lymphocytosis had underlying lymphoproliferative disorders of which B-cell chronic lymphocytic leukaemia was found to be the most common.

The Risk of Lymphoproliferative Disorders and Skin Cancers in Patients with Psoriasis and Inflammatory Bowel Disease Administered Biologics

Few large population-based studies have investigated the effects of biologic agents on the risks of lymphoproliferative disorders (LPDs) and skin cancers in patients with psoriasis and inflammatory bowel disease (IBD). The objective of this study is to determine the effects of biologic agents on the risk of LPDs and skin cancers in South Korean patients with psoriasis and IBD. The Korean Health Insurance Review and Assessment Service database was reviewed, and patients newly diagnosed with psoriasis or IBD between 2008 and 2019 were included. The effects of exposure to biologics on the risk of cancer were assessed using multivariable Cox regression models. The study included 191,678 patients with psoriasis, 23,640 with Crohn’s disease (CD), and 66,730 with ulcerative colitis (UC). The tumor necrosis factor (TNF)-α inhibitor was associated with increased risks of overall lymphoma (adjusted hazard ratio (aHR), 2.93; 95% confidence interval (CI), 1.01–8.50), non-Hodgkin lymphoma (NHL) (aHR, 2.98; 95% CI, 1.02–8.69), and cutaneous lymphoma (aHR, 3.46; 95% CI, 1.07–11.21) in patients with psoriasis. TNF-α inhibitor exposure was associated with increased risks of overall lymphoma (aHR, 3.70; 95% CI, 1.81–7.55) and NHL (aHR, 3.72; 95% CI, 1.81–7.62) in patients with CD, whereas it did not increase the risks of cancer in patients with UC. In conclusion, treatment with TNF-α inhibitors can increase the risks of LPDs in patients with psoriasis or CD.

Waldenström macroglobulinemia with secondary pure red cell aplasia in a patient with metastatic castrate resistant prostate cancer receiving an immune checkpoint inhibitor: a case report

BackgroundHypoproliferative anemia is a frequently encountered adverse event in cancer patients receiving immune checkpoint inhibitors (ICI). Secondary pure red cell aplasia (PRCA) is a rare but recognized immune related adverse event. With the burgeoning use of ICIs, the association of secondary PRCA with an underlying lymphoproliferative disorder is often overlooked.Case presentationWe report a case of a 67-year-old non-Hispanic Caucasian male with metastatic castrate resistant prostate cancer, who developed severe transfusion dependent anemia with reticulocytopenia while receiving treatment with olaparib and pembrolizumab. His bone marrow findings demonstrated erythroid hypoplasia, in addition to a CD5-negative, CD10-negative monotypic B-cell population and a somatic MYD88L265P mutation. With a presence of an IgM-paraprotein, he was diagnosed with Waldenström macroglobulinemia (WM) with secondary PRCA and treated with 6 cycles of bendamustine and rituximab. He achieved a complete response with this regimen and was transfusion independent.ConclusionIn this case, underlying WM was uncovered through systematic investigation of anemia caused by ICI therapy. This report highlights the possibility of a lymphoproliferative disorder in patients with concerns for PRCA with prior ICI exposure. If identified, treating the underlying lymphoproliferative disorder is highly efficacious in the management of the secondary PRCA.

New Evidence of Significant Association between EBV Presence and Lymphoproliferative Disorders Susceptibility in Patients with Rheumatoid Arthritis: A Systematic Review with Meta-Analysis.

Development of lymphoproliferative disorders (LPDs) is one of the well-known life-threatening complications in rheumatoid arthritis (RA) patients. However, there is a lack of definitive conclusions regarding the role of Epstein-Barr virus (EBV) activity in RA initiation and progression, especially in promoting LPDs. A systematic review and meta-analysis of studies that reported an EBV positive result in RA-LPD patients and controls were conducted. Studies published before 27 July 2021 were identified through PubMed, Web of Science, and SCOPUS. A total of 79 articles were included in the systematic review. The prevalence of EBV positive result among RA-LPD patients was 54% (OR = 1.54, 95% CI = 1.45–1.64). There was a statistically significant association between EBV presence and LPD susceptibility in RA patients in comparison with all controls (OR = 1.88, 95% CI = 1.29–2.73) and in comparison with LPD patients only (OR = 1.92, 95% CI = 1.15–3.19). This association was not shown in comparison with patients with autoimmune diseases other than RA who developed LPD (OR = 0.79, 95% CI = 0.30–2.09). This meta-analysis confirmed a high prevalence of EBV in the RA-LPD population. Furthermore, it provides evidence for the association between EBV presence and LPD susceptibility in RA patients, but not in those with other autoimmune diseases who developed LPD.

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.

Iatrogenic Immunodeficiency Associated Lymphoproliferative Disorder in Patients with Acute Lymphoblastic Leukemia:A Case Series.

Iatrogenic Immunodeficiency Associated Lymphoproliferative Disorder in Patients with Acute Lymphoblastic Leukemia:A Case Series.

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.

Managing lymphoproliferative disorders in patients with rheumatoid arthritis

Managing lymphoproliferative disorders in patients with rheumatoid arthritis

Allogeneic Stem Cell Transplantation for the Treatment of Lymphoproliferative Disorders in Patients Affected By Primary Immunodeficiencies: The UK Experience

▪Malignancies represent a significant morbidity for patients (pts) affected by primary immunodeficiency (PID). 4-25% of pts with PID will develop a malignancy during the course of their life, lymphoproliferative disorders being the most common. Dysfunctional T-cell surveillance, particularly against EBV, and impaired DNA repair mechanisms lie at the basis of this susceptibility. Malignancies in PID pts are difficult to treat as these pts often harbor co-morbidities that increase the risk of treatment-related toxicity. Allogeneic stem cell transplantation (SCT) offers a treatment for both PID and LPD. Data on the outcome of pts referred to SCT for LPD in PID are scant, as PID are rare and sometimes under diagnosed.We retrospectively collected data on pts 0-18 years referred to SCT for LPD in PID in the 12 pediatric SCT centres in the UK from 2000 to 2015. Centralized review for histopathology specimens and radiological imaging was performed to confirm the LPD diagnosis and the disease staging/remission status at SCT. Ethical approval was obtained.40 patients affected by 13 different PIDs were identified, X-linked lymphoproliferative disease being the most common (15% of the pts).Median age at LPD diagnosis was 6.1 years (range 0.2-17.2). Pts were diagnosed with a B-cell lymphoma (60%), Hodgkin lymphoma (15%), polymorphic LPD (10%), plasmacytic hyperplasia (7%), T-cell lymphoma (5%) or atypical lymphoid proliferation (3%). 83% of the pts presented with stage III/IV disease, 4% had CNS involvement. LPD proved EBER positive in 66% of the tested samples. Pts received a median of 2 lines of chemo/immunotherapy to treat LPD, which proved resistant to front line treatment in 64% of the pts. 7 pts were referred for SCT but did not receive one due to disease progression (3), donor unavailability (1) or medical decision (3). Among the non-transplanted pts, 1 died from sepsis during chemotherapy, 4 died from disease progression; the OS of this group is 28% at a median follow up of 10 months from LPD diagnosis. For the 33 pts who underwent SCT, median age at SCT was 8.4 yrs (range 0.6-17.7). 58% of the pts had 1 or more comorbidities at SCT (chronic lung disease being most common). Of these, 67% of the pts receiving SCT were in complete remission (CR), 24% in partial remission, and 10% had active disease when starting their conditioning regimen.7 different types of conditioning regime were used, as per participating center local policies. In 94% of the cases a reduced intensity conditioning (RIC) was used. 74% of treated pts received in vivo T cell depletion with Alemtuzumab (71%) or Anti-Thymocyte Globulin (3%). 27% of the pts received the graft from a matched related, 39% matched unrelated and 33% mismatched donor. Bone marrow and peripheral blood were the most common sources of stem cells (46% and 42% of the cases, respectively).All pts achieved neutrophil engraftment and secondary graft loss was experienced by 2 pts (6%). 4 pts (12%) died from SCT related toxicity (3 infections, 1 pulmonary VOD/hemorrhage). Acute GVHD grade I-IV developed in 42% of the pts. LPD recurred in 2 cases (1 after secondary graft loss) and was successfully treated with surgery/chemotherapy. With a median follow up of 48 months, 88.0% patients are alive, in CR post SCT. 76% of the evaluable patients exhibited a full donor engraftment at the latest follow up.Disease stage, histology, underlying PID and remission status at SCT did not impact on the patients´ outcomes. Overall survival was significantly higher in SCT recipients as compared to patients who did not receive SCT (88 vs 28%, p= 0.03). Even among the 3 pts who underwent SCT without achieving LPD remission, OS was 67%, thus underlying that restoring competent immunity might play a role in this context, allowing for LPD control post SCT via the newly grafted T-cells.This cohort of pts is the largest described of its kind. We conclude that SCT with RIC is safe and efficacious for pts affected by LPD in PID. While larger cohorts of pts are required to confirm these data, our study suggests that remission status at SCT plays a partial role in LPD control. As a consequence, limited pre-SCT chemotherapy might be required and SCT indication might be plausible for pts not achieving CR. DisclosuresLucchini:Alexion: Membership on an entity's Board of Directors or advisory committees.

Clinicopathological characteristics of lymphoproliferative disorders in 232 patients with rheumatoid arthritis in Japan: A retrospective, multicenter, descriptive study.

To describe the clinicopathological characteristics of lymphoproliferative disorders (LPDs) in patients with rheumatoid arthritis (RA). In this multicenter case series, we retrospectively reviewed the medical records of RA patients who were newly diagnosed as having LPDs with or without biopsy confirmation between 2000 and 2017 in eight hospitals in Japan. We included 232 patients with LPDs. The median age was 67 years (interquartile range [IQR], 60-73 years), and 77.1% were female. At the time of LPD diagnosis, 94.8% and 62.6% of the patients were methotrexate users and in remission or had low RA disease activity, respectively; lymphadenopathy and extranodal involvement were present in 77.1% and 51.9%, respectively. Major extranodal sites were the lungs and oral/oropharyngeal mucosa. The most common LPD pathological subtype was diffuse large B-cell lymphoma (40.5%), followed by classic Hodgkin lymphoma (10.8%), Epstein-Barr virus-positive mucocutaneous ulcer (7.7%), and reactive lymphoid hyperplasia (6.2%). The clinical and laboratory characteristics varied across the pathological subtypes. LPD occurred mainly in methotrexate users, while RA disease activity did not seem to be associated with LPD development. Although the clinical manifestations vary among pathological subtypes, manifestations of LPD in patients with RA can include lymphadenopathy, extranodal mass, and mucocutaneous ulcer.

Association of methotrexate use and lymphoproliferative disorder in patients with rheumatoid arthritis: Results from a Japanese multi-institutional retrospective study.

To investigate the risk factors and clinical characteristics of lymphoproliferative disorder (LPD) in Japanese patients with rheumatoid arthritis (RA). We enrolled patients with RA aged ≥20 years who visited the participating hospitals between April 2011 and July 2011. We investigated the risk factors for LPD using a Cox proportional hazard model and described pathological features and vital prognosis of LPD in patients with RA. We enrolled 9815 patients with the following characteristics at baseline: female 79.4%, median age 63 years; median disease duration 7 years; median DAS28-CRP (3) 3.1; prevalence of MTX use 60.0%. Sixty-eight patients (0.69%) developed LPD in 3-year observation period. Multivariable analysis showed that age by decade (hazard ratio [95% confidence interval], 1.47 [1.18-1.85]) and MTX use at baseline (2.35 [1.25-4.42] for ≤8 mg/week, 4.39 [2.07-9.32] for >8 mg/week versus non-use) were significant risk factors of LPD. Of 55 patients with pathological diagnosis, diffuse large B cell lymphoma was the most frequent (54%). The 5-year mortality of LPD was 24%. The major cause of death was lymphoma (81%). This nationwide study revealed risk factors, clinical characteristics, and prognosis of LPD in the largest number of Japanese patients with RA.

Involvement of Epstein-Barr virus in the development and spontaneous regression of methotrexate-associated lymphoproliferative disorder in patients with rheumatoid arthritis.

Conventionally, some patients with methotrexate-associated lymphoproliferative disorder (MTX-LPD) undergo spontaneous tumour regression after cessation of MTX. Although the involvement of Epstein-Barr virus (EBV) in the development and spontaneous regression has been suggested, the underlying mechanism remains unknown. In this study, we analysed patients who had developed MTX-LPD to evaluate the association between the development and spontaneous regression of MTX-LPD with EBV. We analysed the age, stage, disease activity, MTX dose, lymphocyte count, EBV real-time polymerase chain reaction (PCR) test value, and EBV-encoded small RNA (EBER) positivity rate in patients with MTX-LPD at our hospital. Moreover, we investigated the factors related to spontaneous regression, which is a characteristic of MTX-LPD. Thirty-four patients were enrolled in this study. The MTX dose at LPD onset was 8.3±2.0 mg/week, and the total dose of MTX was 1,530.3±779.2 mg. The EBV load in the peripheral blood was 270.4±431.8 copy/μL, and the pathological tissues of 17 of 34 (50%) patients tested positive for EBER. Twenty-one patients had spontaneous regression after discontinuation of MTX. The factors related to spontaneous regression were examined using a univariate analysis, and the EBV real-time PCR test value in the peripheral blood, EBER in pathological tissues, and improvement rate of lymphocyte count were considered significant factors. The EBV real-time PCR test value in the peripheral blood was defined as an independent factor of spontaneous regression using a multivariate analysis of related factors. EBV may be involved in the development of MTX-LPD and its spontaneous regression.

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

Treatment of rheumatoid arthritis after regression of lymphoproliferative disorders in patients treated with methotrexate: a retrospective, multi-center descriptive study.

To identify the optimal treatment for rheumatoid arthritis (RA) after the regression of lymphoproliferative disorders (LPDs). The subjects were 232 patients with RA who developed LPD between 2000 and 2017 at seven hospitals participating in the LPD-WG study. Kaplan-Meier and Cox proportional regression analyses were performed to determine the factors associated with the rate of LPD relapse and the retention of biological disease-modifying antirheumatic drugs (bDMARDs). Treatment for RA was resumed in 138 patients after spontaneous regression of LPD after the discontinuation of methotrexate and in 52 patients after chemotherapy for LPD (persistent-LPD). LPD relapses occurred in 23 patients. Not DMARDs use but Hodgkin's lymphoma was identified as a risk factor for LPD relapse. In 88 RA patients treated with bDMARDs [tocilizumab, 39 patients; abatacept 20 patients; tumor necrosis factor inhibitor, 29 patients], the one-year retention rate was 67.8%. The risk factors for discontinuation of bDMARDs were persistent-LPD, non-diffuse large B-cell lymphomas (non-DLBCL), and a high clinical disease activity index (CDAI). Tocilizumab showed the highest retention rate among bDMARDs, particularly in DLBCL. Although any bDMARD could be used in patients after LPD regression, effectiveness and risk for relapse should be carefully assessed for each LPD subtype.