Lymphoproliferative Malignancies Research Articles

Abstract B41: Modeling marginal zone lymphomagenesis

Abstract Introduction: Indolent B-cell non-Hodgkin’s lymphomas (NHL) represent a heterogeneous group of lymphoproliferative malignancies that remain largely incurable. Marginal zone lymphomas (MZL) are the second most common subtype of indolent NHL and lack a unique cytogenetic identifying abnormality. The B-cell receptor signaling pathway is activated in B-cell malignancy and mediates its activity mainly through the phosphoinositide 3-kinase (PI3K) pathway. Furthermore, novel PI3K inhibitors, such as copanlisib and parsaclisib, have shown impressive clinical activity in several indolent lymphomas, including MZL. This further supports the important role of the PI3K pathway in the pathogenesis of this tumor. Therefore, we hypothesized that the PI3K-mTOR pathway is sufficient for driving the pathogenesis of MZL. Methods: In order to test our hypothesis, we generated a genetically engineered mouse model carrying heterozygous global knockout alleles of both the tumor suppressor genes Phosphatase and Tensin Homolog (PTEN) and Liver Kinase B1 (LKB1). This led to overactivation of the PI3K-mTOR pathway in all mouse tissues. We closely monitored these mice for tumor formation via weekly physical examinations for several months. Upon tumor detection, the mouse was sacrificed and tumors were sectioned for histologic characterization. In order to generate a more specific model of B cells, and more accurately mimic the underlying human disease, we used the Cre-LoxP system to create the CD19-Cre-PTENfl/fl-LKB1fl/fl. Results: Thirty mice of global KO PTEN+/- LKB1 +/- died or were sacrificed due to disease progression, defined as either lymph node enlargement and/or splenomegaly. All mice showed either abnormal lymphadenopathy or splenomegaly. By Kaplan-Meier analysis, we saw a steady decrease in both tumor-free and overall survival after 3 months of age. Utilizing the product limit method, the median survival time was 6 months (95% CI: 6, 8). A total of 51 lymph nodes were sent for immunohistochemistry and pathologic characterization. Of the 51 nodes, 61.5% (N=32) showed indolent non-Hodgkin’s lymphoma, 25% (N=13) were atypical, and 11.5% (N=6) were reactive. All lymph nodes with indolent NHL were of MZL subtype. Compared to wild-type (n=3), the new CD19-Cre-PTENfl/fl-LKB1fl/fl (n=3) showed an overall increase in spleen mass (120 vs. 196 mg, p=0.0564), % B1 cells (4% vs. 59%, p= 0.0075), % MZ cells (5% vs. 30%, p=0.0547), % plasma cells (1% vs. 12%, p=0.0729), and a decrease in % FO cells (80% vs. 12%, p=0.0003) by flow cytometry. Further characterization of the new model is currently under way. Conclusion: Marginal zone lymphoma remains an incurable lymphoma that lacks reliable preclinical models. Our data provide, for the first time, a proof of concept on the role of the PI3K-mTOR pathway in the pathogenesis of marginal zone lymphoma and pave the way for future studies understanding the biology of this disease and developing rational therapies for this incurable malignancy. Citation Format: Victor Yazbeck, Ian McConnell, Emily Harris, Joseph Lownick, Ariel Sindel, Roy Sabo, Alden Chesney, Guanhua Lai, Adolfo Mauro, Chad Cain, Fadi Salloum, Steven Grant, Jamal Zweit, Jolene Windle, Steven Grossman. Modeling marginal zone lymphomagenesis [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr B41.

Acquired Haemophilia Associated with Urticarial Vasculitis.

Acquired haemophilia (AHA) is a rare autoimmune disorder caused by circulating autoantibodies that inhibit the activity of factor VIII (FVIII). Acquired inhibitors against FVIII are rarely seen, with a reported incidence of approximately 1 case per million/year. Clinical conditions and contexts associated with AHA include autoimmune diseases, lymphoproliferative malignancies, drug treatment, pregnancy and infections. An association with urticarial vasculitis is even more rare. Here, we report a case of a 59-year-old woman presenting with cutaneous and muscle haematomas secondary to AHA in association with urticarial vasculitis, who was successfully treated with factor eight inhibitor bypassing activity (FEIBA) and prednisolone.LEARNING POINTSAcquired haemophilia (AHA) is a rare autoimmune disease.AHA predisposes to severe, potentially life-threatening haemorrhage.An association with urticarial vasculitis is even more rare.

Measurement of the concentration of serum soluble interleukin-2 receptor alpha chain in dogs with lymphoma

Soluble interleukin-2 receptor (sIL-2r) is released directly from the surface of lymphocytes expressing interleukin-2 receptor alpha chain (CD25), and its serum concentration has been found to reflect the prognosis of human lymphoproliferative malignancies. In this study, we demonstrated the presence of sIL-2r in canine serum and developed a specific sandwich enzyme-linked immunosorbent assay (ELISA) to quantify the concentration of canine serum sIL-2r. In the immunoprecipitation (IP) assay, CD25 protein weighing approximately 45 kDa was detected in canine serum, smaller than the membrane-bound CD25 (approximately 55 kDa). To measure the concentration of serum sIL-2r in dogs, an ELISA system was developed. Serum sIL-2r levels were significantly higher in dogs with multicentric high-grade B-cell lymphoma before therapy than that in healthy dogs. Serum sIL-2r concentration was also found to be elevated in a proportion of dogs with other types of lymphoma. Changes in serum sIL-2r levels generally paralleled the changes in mass and lymph node size in dogs with high-grade B-cell lymphoma. This study demonstrated that serum sIL-2r level would be a marker to monitor tumour growth and regression in canine lymphoma.

BCMA-targeting Bispecific Antibody That Simultaneously Stimulates NKG2D-enhanced Efficacy Against Multiple Myeloma.

B-cell maturation antigen (BCMA) is a highly plasma cell-selective protein expressed on malignant plasma cells of patients with multiple myeloma (MM), and it is a defined therapeutic target. Major histocompatibility complex class I-related chain A (MICA) is frequently expressed in lymphoproliferative malignancies including MM. MICA activates natural killer (NK) cells and costimulates T cells by interaction with its immunoreceptor NK cell receptor G2D (NKG2D). Nonetheless, during full-blown MM, tumor cells promote efficient MICA shedding, which evokes NKG2D internalization and immune suppression. To enhance the directional killing efficacy of immune cells against myeloma cells, we constructed a novel bispecific antibody 2A9-MICA and explored its potential antimyeloma activity against MM. 2A9-MICA consists of human MICA extracellular region and a single-chain antibody fragment (scFv) that targets BCMA generated by phage display technology. In vitro, 2A9-MICA activated NK cell-mediated cytotoxicity and induced NK cells to kill BCMA-positive human myeloma cells. Moreover, in BCMA-positive, MM-bearing nude mice, 2A9-MICA specifically targeted tumor tissue, where it effectively recruited immune cells and inhibited tumor tissue growth showed superior antitumor activity. Taken together, bispecific antibody 2A9-MICA provides a new approach for MM-targeting immunotherapy and has attractive potential for clinical applications.

Identification of Familial Hodgkin Lymphoma Predisposing Genes Using Whole Genome Sequencing.

Hodgkin lymphoma (HL) is a lymphoproliferative malignancy of B-cell origin that accounts for 10% of all lymphomas. Despite evidence suggesting strong familial clustering of HL, there is no clear understanding of the contribution of genes predisposing to HL. In this study, whole genome sequencing (WGS) was performed on 7 affected and 9 unaffected family members from three HL-prone families and variants were prioritized using our Familial Cancer Variant Prioritization Pipeline (FCVPPv2). WGS identified a total of 98,564, 170,550, and 113,654 variants which were reduced by pedigree-based filtering to 18,158, 465, and 26,465 in families I, II, and III, respectively. In addition to variants affecting amino acid sequences, variants in promoters, enhancers, transcription factors binding sites, and microRNA seed sequences were identified from upstream, downstream, 5′ and 3′ untranslated regions. A panel of 565 cancer predisposing and other cancer-related genes and of 2,383 potential candidate HL genes were also screened in these families to aid further prioritization. Pathway analysis of segregating genes with Combined Annotation Dependent Depletion Tool (CADD) scores >20 was performed using Ingenuity Pathway Analysis software which implicated several candidate genes in pathways involved in B-cell activation and proliferation and in the network of “Cancer, Hematological disease and Immunological Disease.” We used the FCVPPv2 for further in silico analyses and prioritized 45 coding and 79 non-coding variants from the three families. Further literature-based analysis allowed us to constrict this list to one rare germline variant each in families I and II and two in family III. Functional studies were conducted on the candidate from family I in a previous study, resulting in the identification and functional validation of a novel heterozygous missense variant in the tumor suppressor gene DICER1 as potential HL predisposition factor. We aim to identify the individual genes responsible for predisposition in the remaining two families and will functionally validate these in further studies.

A112 ANGIOEDEMA,A RARE YET AN IMPORTANT CAUSE OF ABDOMINAL PAIN. A CASE STUDY AND LITERATURE REVIEW

Abstract Background Abdominal pain is a common gastroenterological symptom with an extensive deferential diagnoses. Angioedema is an important cause to remember after the more common causes have been excluded.It is caused by a deficiency in the inhibitor of the first component of classical complement pathway and is divided into hereditary or acquired.Acquired angioedema is associated with autoimmune or lymphoproliferative neoplasms.The clinical features of both include recurrent,self-limiting and circumscribed edema affecting the subcutaneous tissue of the upper respiratory airways and gastrointestinal tract. Aims We describe an interesting case of acquired angioedema presenting with recurrent abdominal pain. We also systematically review the current literature on this rare entity. Methods A search of electronic databases was performed inclusive to September 2019, for all studies and reviews of patients with acquired angioedema manifested as recurrent attacks of abdominal pain. Results: Case Report: 65 year old lady ho has an at least 2 year long history of abdominal pain and bloating associated on some occasions with nausea and vomiting.She presented to our emergency department in August,2018 with a day history of severe generalized abdominal pain and was found to have circumferential thickening,edema with mucosal hyperenhancement involving the distal segment of the small bowel.Splenomegaly was noted on that study.A double balloon enteroscopy was planned,but ultimately cancelled as her ileitis had resolved.The patient was discharged home as her pain resolved with conservative management which included intravenous fluid, pain medications and antiemetics.She then represented to the hospital on September 16, 2019 severe abdominal pain and throat tightness associated with shortness of breath. Again,noted was an extremely short segment of ileum with mucosal edema and hyperenhancement which resolved on a repeat CT scan done during that admission on September 18th, 2019.In light of the patient’s symptoms,CT scan findings,progressive anemia, thrombocytopenia and splenomegaly. It was thought that her abdominal pain is related to secondary to angioedema driven by a lymphoproliferative process as evident by the splenomegaly and worsening cytopenia. A bone marrow was done which revealed clonal B, so the diagnosis of lymphoma was made. The patient’s C1 esterase was 0.2 with reduced functional activity.CH50 less 10 perecent. A diagnosis of acquired angioedema was made and the patient was started on BERINERT 3000 IU SQ every three days with 1500 IU for break through with significant improvement in the frequency and severity of abdominal pain episodes. Conclusions Acquired angioedema is to be considered as a cause of recurrent abdominal pain in a patient with a lymphoproliferative malignancy after common causes and etiologies have been ruled out. Funding Agencies None

Tumor lysis syndrome in childhood malignancies.

BackgroundTumor lysis syndrome (TLS) is the most common life-threatening oncological emergency encountered by physicians treating children with lymphoproliferative malignancies. Healthcare providers should be aware of the condition in order to prevent occurrence and prompt timely management to avoid severe consequences.ObjectiveTo provide an update on the current understanding, evaluation, and management of tumor lysis syndrome in childhood malignancies.MethodsA PubMed search was performed in Clinical Queries using the keywords ‘tumor lysis syndrome’ and ‘malignancies’ with Category limited to clinical trials and reviews for ages from birth to 18 years.ResultsThere were 22 clinical trials and 37 reviews under the search criteria. TLS is characterized by acute electrolyte and metabolic disturbances resulting from massive and abrupt release of cellular contents into the circulation due to breakdown of tumor cells. If left untreated, it can lead to multiorgan compromise and eventually death. Apart from close monitoring and medical therapies, early recognition of risk factors for development of TLS is also necessary for successful management.ConclusionsProphylactic measures to patients at risk of TLS include aggressive fluid management and judicious use of diuretics and hypouricemic agents. Both allopurinol and urate oxidase are effective in reducing serum uric acid. Allopurinol should be used as prophylaxis in low-risk cases while urate oxidase should be used as treatment in intermediate to high-risk cases. There is no evidence on better drug of choice among different urate oxidases. The routine use of diuretics and urine alkalinization are not recommended. Correction of electrolytes and use of renal replacement therapy may also be required during treatment of TLS.

Ichthyosiform Mycosis Fungoides: An Atypical Variant Of Cutaneous T-Cell Lymphoma : About A Case And Literature Review

Acquired ichthyosis is a known paraneoplastic sign of lymphoproliferative malignancies, with histopathologic findings that are nonspecific, revealing no insinuation of the underlying neoplasm. Mycosis fungoides (MF) is a skin malignancy of T helper lymphocytes with a wide clinical spectrum. Among the atypical variants of MF, there is an ichthyosis- like presentation. However, to date, rare cases of ichthyosiform MF has been reported. We report here the clinical and histopathological features of patient with IMF.

441 An Atypical Case of Marantic Endocarditis in Undiagnosed Antiphospholipid Syndrome

Marantic endocarditis (ME) is difficult to differentiate from infective endocarditis (IE) [[1]Bussani R. F DE-G Pesel G. Zandona L. Sinagra G. Grassi S. et al.Overview and Comparison of Infectious Endocarditis and Non-infectious Endocarditis: A Review of 814 Autoptic Cases.In vivo (Athens, Greece). 2019; 33: 1565-1572PubMed Google Scholar]. We demonstrate an atypical case of ME presenting as an independently-mobile mass and severe MR. A 57-year-old man presented with a right parietal stroke secondary to mitral valve(MV) endocarditis. Past history was significant for a provoked pulmonary embolus. Family history was insignificant. Transthoracic (TTE) and transoesophageal echocardiogram revealed a 1.1x0.6cm independently-mobile MV vegetation with severe mitral regurgitation (MR) and normal left atrium size. He was clinically euvolaemic. Empiric antibiotics were commenced. Inflammatory markers were normal and blood cultures negative. He was considered for MV surgery. Preoperative coagulation studies revealed an incidental elevated activated partial thromboplastin time (APTT) (77s) which did not correct with mixing studies. Thrombophilia screen demonstrated high anti-cardiolipin >2024 and beta-2-glycoprotein-1 antibodies >6100. A diagnosis of ME due to presumed antiphospholipid syndrome (APLS) was established. Multidisciplinary decision was made to trial anticoagulation with warfarin over surgery. TTE at 4 months demonstrated resolution of the vegetation with mild mitral incompetence. While rare(prevalence 0.9-1.6%), ME is associated with high morbidity and mortality [[2]Gundersen H. Moynihan B. An Uncommon Cause of Stroke: Non-bacterial Thrombotic Endocarditis.Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association. 2016; 25: e163-e164Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar]. Causes of ME can be inflammatory, autoimmune or malignant [[3]Ahmed S. Jani P. Yamani M.H. Ailawadhi S. Alegria V.R. Ailawadhi M. Marantic Endocarditis Associated With T-Cell Large Granular Lymphocytic Leukemia: First Report of Its Occurrence With a Lymphoproliferative Malignancy in Adults.Journal of oncology practice. 2018; 14: 625-627Crossref PubMed Scopus (2) Google Scholar]. ME commonly affects the MV [[4]Murtaza G. Iskandar J. Humphrey T. Adhikari S. Kuruvilla A. Lupus-Negative Libman-Sacks Endocarditis Complicated by Catastrophic Antiphospholipid Syndrome.Cardiology research. 2017; 8: 57-62Crossref PubMed Google Scholar] and presents with embolic phenomena [[5]Deppisch L.M. Fayemi A.O. Non-bacterial thrombotic endocarditis: clinicopathologic correlations.American heart journal. 1976; 92: 723-729Crossref PubMed Scopus (122) Google Scholar]. ME vegetations typically attach firmly to valve leaflets and move with them compared to independently-mobile infective vegetations [[6]Bouma W. Klinkenberg T.J. van der Horst I.C. Wijdh-den Hamer I.J. Erasmus M.E. Bijl M. et al.Mitral valve surgery for mitral regurgitation caused by Libman-Sacks endocarditis: a report of four cases and a systematic review of the literature.Journal of cardiothoracic surgery. 2010; 5: 13Crossref PubMed Scopus (59) Google Scholar]. Significant valvular regurgitation is rare. Surgical treatment in ME is seldom required with the mainstay treatment being therapeutic anticoagulation [[6]Bouma W. Klinkenberg T.J. van der Horst I.C. Wijdh-den Hamer I.J. Erasmus M.E. Bijl M. et al.Mitral valve surgery for mitral regurgitation caused by Libman-Sacks endocarditis: a report of four cases and a systematic review of the literature.Journal of cardiothoracic surgery. 2010; 5: 13Crossref PubMed Scopus (59) Google Scholar]. Our case highlights the value of a multidisciplinary approach to endocarditis and importance of a thorough history and scrutiny of investigations.

Complexity of chromosomal aberrations and gene expression changes in human blood lymphocytes after exposure to alpha particle radiation

Background: Targeted alpha therapy (TAT) is emerging as an effective treatment modality of cancer especially for micrometastasis, lymphoproliferative malignancies, and palliative approaches of bone cancer. Human blood lymphocytes may encounter alpha (a) exposure while traversal of targeted a particle emitting radio isotopes to the tumor site, due to their nonspecificity and release of radio isotopes from the legends used for targeting. Such radiation effects to lymphocytes may be implicated in short and long term health effects during TAT. Aims and Objectives: To see the effects of a-particle in blood lymphocytes and to compare their complexity of aberration with both and X-rays. Materials and Methods: Chromosomal aberrations such as dicentric chromosome, micronuclei, nucleoplasmic bridge (NPB) in the peripheral blood lymphocytes were scored for both a alpha particle and X rays. Then, the chromosome aberrations (CA) frequency was correlated with the gene expression (FDXR, CDKN1A and GADD45A) to both the type of radiations. Results: CA induced by a radiation was complex and highly dispersed when compared to low LET radiation. Moreover, magnitude of NPB was significantly higher in case of a radiation than radiation. A dose dependent increase in gene expression (FDXR, CDKN1A and GADD45) was observed after a radiation, which however, was higher in case of a radiation than X rays. Conclusion: These results provide better understanding about effects of a radiation on human lymphocytes, which may be significant implications in developing better TAT strategies for cancer.

Systemic Lupus Erythematosus mimicking lymphoproliferative malignancy in a child

Systemic Lupus Erythematosus (SLE) is a chromic autoimmune disease with multisystemic involvement. The estimated prevalence of SLE among children is 1-6/100000. Here we report a child who presented with generalized lymphadeopathy as the first manifestation of SLE. A 13 year old previously healthy girl presented with cervical lymphadenopathy and low grade remitting fever for 1 month duration. On examination she was found to have generalized lymphadenopathy and unremarkable rest of the clinical examination. Her basic haematological and biochemical parameters were normal. ESR was 110mm/hr and CRP was 6mg/dL. Ultrasound scan and Contrast CT of the abdomen and pelvis revealed extensive mediastinal, mesenteric, para-aortic, splenic hilar, bilateral axillary and inguinal lymphadenopathy suggestive of lymphoproliferative malignancy. However, her bone marrow and lymph node biopsies revealed reactive pattern. Meantime she developed a malar rash, oral ulcers and 2 episodes of generalized tonic-clonic convulsions. Her urinalysis revealed microscopic haematuria and sub nephrotic range proteinuria. Her ANA and dsDNA levels were positive. Her subsequent full blood count revealed severe bicytopenia, predominetly lymphopenia.The diagnosis of SLE was made and she was started on Hydroxychloroquine, high dose prednisolone and cyclophosphamide pulse therapy. The most common presenting symptoms of SLE in children include, constituitional symptoms, joint symptoms and haematological abnormalities. It is estimated 23-34% children with SLE are having lymphadenopathy. Though, generalized lymphadenopathy as the presenting symptom of SLE is uncommon, it should not be forgotten in order to avoid diagnostic delay.

Myeloproliferative and lymphoproliferative malignancies occurring in the same patient: a nationwide discovery cohort.

Myeloid and lymphoid malignancies are postulated to have distinct pathogenic mechanisms. The recent observation that patients with a myeloproliferative neoplasm have an increased risk of developing lymphoproliferative malignancies has challenged this assumption. We collected a nationwide cohort of patients with both malignancies. Patients diagnosed between 1990 and 2015 were identified through the national Danish Pathology Registry. We identified 599 patients with a myeloproliferative neoplasm and a concomitant or subsequent diagnosis of lymphoma. Histopathological review of the diagnostic samples from each patient led to a final cohort of 97 individuals with confirmed dual diagnoses of myeloproliferative neoplasm and lymphoma. The age range at diagnosis of these individuals was 19-94 years (median: 71 years). To avoid the inclusion of cases of therapy-induced myeloproliferative neoplasm occurring in patients previously treated for lymphoma, only patients with myeloproliferative neoplasm diagnosed unequivocally before the development of lymphoma were included. The average time interval between the diagnoses of the two malignancies was 1.5 years. In the majority of patients (90%) both diagnoses were established within 5 years of each other. Among the lymphoma entities, the frequency of peripheral T-cell lymphomas was markedly increased. Interestingly, all but one of the T-cell lymphomas were of angioimmunoblastic type. These findings suggest that a myeloproliferative neoplasm and lymphoproliferative malignancy developing in the same patient may have common pathogenic events, possibly already at the progenitor level. We believe that the molecular characterization of the newly developed biorepository will help to highlight the mechanisms driving the genesis and clonal evolution of these hematopoietic malignancies.

Assessment of Cell-Free DNA (cfDNA) in 221 Patients with Lymphoproliferative Malignancies at Diagnosis and during Follow-up

Background:The isolation of cell-free DNA (cfDNA) evolved the concept of liquid biopsy. Several works have analyzed the presence of cfDNA in lymphomas, especially in diffuse large B-cell lymphoma (DLBCL) and Hodgkin lymphoma (HL), however there is limited information regarding the detection of cfDNA in other types of lymphomas or the role of cfDNA detection to monitor disease outcome. Objectives:1.- To analyze the presence of cfDNA at diagnosis of patients with lymphoproliferative malignancies. 2.- To evaluate the change in concentration of cfDNA ([cfDNA]) after treatment in DLBCL patients. Material and Methods:A retrospective study in a single center was performed including 221 adult patients since January 2015 to February 2019 with: DLBCL, HL, marginal zone lymphoma (MZL), follicular lymphoma (FL), chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), lymphoplasmacytic lymphoma (LPL) and peripheral T-cell lymphomas (TCL). All patients had plasma samples collected at diagnosis that were stored in the institutional biobank (MarBiobank). The cfDNA were obtained from 1 mL of -80°C frozen stored plasma using the MagMax Cell Free DNA isolation kit (Thermo Fisher Scientific). The cfDNA quantification was performed using the Qubit system with the dsDNA high sensitivitykit (Thermo Fisher) and is expressed as ng/mL of plasma. In addition, patients with DLBCL who were treated with rituximab-CHOP/CHOP-like regimens were evaluated for [cfDNA] analysis, pre and post-treatment, and results were compared with PET-CT scan findings. Results: Stored plasma samples at diagnosis were available in 221 patients: DLBCL 82, HL 22, CLL/LPL 13, FL 36, MZL 37, MCL: 11, TCL 10 and others 10 (B-cell lymphoma unclassified, hairy cell leukemia, Burkitt lymphoma). Successful identification of cfDNA was obtained in 95.9% (212/221) of samples. DLBCL patients showed higher [cfDNA] globally and, DLBCL, HL and FL patients showed a higher concentration than MZL who exhibited the lower concentration of all groups (p=0.009; p=0.013 and p=0.002); see table 1. 50 DLBCL patients with a median follow-up since diagnosis of 25.5 (5-51) months were analyzed. Median age was 67 (19-79) years, males 56% (28). IPI distribution: low-risk 28% (14), low-intermediate 26% (13), high-intermediate 24% (12) and high risk 22% (11) cases. Detection of cfDNA was successful in 100% at diagnosis and in 98% (49) cases post-therapy. The mean [cfDNA] at diagnosis was 2.21 (standard deviation- SD: 1.60) ng/mL with a correlation with LDH concentration (p<0.001) and with high-risk IPI category (p=0.02). The mean [cfDNA] in the post-therapy sample was 4.39 (SD 16.46) ng/mL. After therapy 86% (43) of patients achieved at least PR (41 complete response), and the mean [cfDNA] for these patients was 1.58 (SD 1.96); patients who showed no response or progressive disease after therapy exhibited higher [cfDNA] 21.25 ng/mL (SD 41.91)(p<0.001). In order to evaluate the clinical relevance of the changes of [cfDNA] after treatment, we considered a variation of +/-25% of [cfDNA at diagnosis] regarding [cfDNA after therapy] to classify the results. Therefore, 13 patients had an increase of [cfDNA after therapy], 6 patients had no change, and 31 patients had a decrease. Patients with a decrease in [cfDNA] at the end of therapy were less likely to relapse (p<0.01) During follow-up, two patients relapsed after 24 and 8 months. The patient who relapsed after 24 months showed an increase in [cfDNA], from 0.966 ng/mL to 20.80ng/mL three months before the histological confirmation of relapse. Conclusions:Isolation of cfDNA was feasible in >95% of lymphoma patients independently of histology or disease stage. Patients with DLBCL exhibited the higher cfDNA concentration which were also correlated with LDH concentrations and high-risk IPI. Kinetics of [cfDNA] is related to response to therapy in DLBCL and also might detect relapse. Even though additional studies are necessary, monitoring of cfDNA may help in management of patients with DLBCL. Disclosures Salar: Roche: Research Funding, Speakers Bureau; Janssen Pharmaceuticals: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Celgene: Consultancy. Sanchez-Gonzalez:Takeda: Consultancy, Speakers Bureau; Alexion: Speakers Bureau; Gilead: Speakers Bureau; Shire: Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau. Gimeno:JANSSEN: Consultancy, Speakers Bureau; Abbvie: Speakers Bureau. Bellosillo:Qiagen: Consultancy, Speakers Bureau; TermoFisher Scientific: Consultancy, Speakers Bureau.

Monoclonal Gammopathy with Secondary Atypical Hemolytic-Uremic Syndrome

Monoclonal gammopathy is a clonal plasma cell disorder associated with an increased risk of progression to lymphoproliferative malignancy. In children, monoclonal and oligoclonal gammopathies are rare, and their clinical relevance unrecognized. Atypical hemolytic uremic syndrome (aHUS) is a rare endotheliopathy associated with dysregulated activation of complement, microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. We present a case of aHUS that we hypothesize was triggered by monoclonal gammopathy in a child several years after cardiac transplantation. An 11 year old African-American girl with sickle trait was transferred to our cardiac center with a two week history of epigastic pain, emesis, microcytic anemia, hypergammaglobulinemia, and development of renal failure requiring dialysis. She had undergone cardiac transplantation at 7 months of age for dilated cardiomyopathy of unknown etiology and had recovered from acute cardiac rejection requiring ECMO at age 5 years. She had previously experienced at least two episodes of acute kidney injury requiring dialysis with full recovery of function reported. Renal biopsy revealed a severe collapsing glomerulopathy and a thrombotic microangiopathy. Upon transfer to our institution, her labs were notable for microcytic anemia, normal platelet count, haptoglobin, and LDH. A week later, she developed aHUS diagnosed by hemoglobin 9.5 gm/dL, haptoglobin < 30 mg/dL, LDH 314 U/L, platelets 100,000, and a predominance of schistocytes on peripheral blood smear in the setting of acute renal failure. Serum protein electrophoresis (SPEP) revealed a monoclonal spike (1g/dL), identified as IgG kappa by immunoabsorption. A second, smaller monoclonal spike was identified as IgA lambda. aHUS evaluation revealed low C3, normal C4, and 50% CD46 expression by flow cytometry. Bone marrow biopsy with flow cytometry excluded lymphoproliferative disorders. EBV did not amplify with quantitative PCR of peripheral blood, and computed tomography imaging of the body did not detect abnormal mass or lymph nodes. A trial of plasmapheresis did not improve biochemical and hematologic features of aHUS. A trial of eculizumab resulted led to normalization of platelet count and C3, increased haptoglobin, reduced need for red cell transfusion, and less frequent dialysis. Monoclonal gammopathy of unknown significance (MGUS) is rare in children, but may be more common in transplant recipients, especially after cardiac transplants in infants when thymectomy is performed. MGUS associated with secondary aHUS has been rarely reported in adults. The mechanism for aHUS was demonstrated in one case to result from affinity of the paraprotein to a binding site on complement factor H, with subsequent loss of factor H cofactor activity to inhibit alternative complement activation. We hypothesize that immune dysregulation from fluctuating levels of paraproteins during inflammation in our patient with monoclonal gammopathy resulted in recurrent, intermittent episodes of aHUS. We speculate that this was responsible for the patient's collapsing glomerulopathy and dialysis-dependent chronic renal failure. This case highlights the importance of considering monoclonal gammopathy in pediatric patients who develop recurrent kidney failure or atypical hemolytic uremic syndrome in the setting of immune dysregulation. The merit of treating the monoclonal gammopathy with Bortezumib and Rituximab is currently under consideration. Disclosures No relevant conflicts of interest to declare.

NCMP-16. IMMUNO-ONCOTHERAPY (IO) PROVOKED ENCEPHALITIS AND METASTATIC MIMICRY: PATIENT WITH HISTORY OF RENAL CELL CARCINOMA ON IO PRESENTS WITH SEIZURE, FIELD CUT, AND BRAIN MASS

Abstract With the success of immuno-oncotherapy (IO) to treat systemic cancers came the risk for multi-organ autoimmune inflammation (esophagitis, colitis, hypophysitis, pneumonitis, etc.). Immune-mediated encephalitis, however, has been only rarely described in patients treated on IO. Here we present the first case of a 70-year-old male with history of clear cell renal cell carcinoma (CCRCC, Fuhrman grade 4, April 2017) post-nephrectomy with early progressive pulmonary metastases treated with pazopanib before switching to single-agent nivolumab (February 2018) with demonstrated early response. Further progression (March 2019) added body irradiation and continued systemic nivolumab with questionable medication-induced dermatitis. Patient presented to ED in May 2019 with new-onset generalized tonic-clonic seizure, left visual field cut, and 4.6cm heterogeneous enhancing right occipital mass with vasogenic edema on brain MRI, presumed metastasis. However, unknown to the patient was a remote area of right occipital encephalomalacia (found on skull-based portion of staging PET, July 2018) presumed silent stroke or TBI endorsed 20-years-ago. Patient started anti-epileptic therapy and underwent negative CSF evaluation before neurosurgical resection. Tissue pathology concerning for lymphoproliferative malignancy versus reactive lymphocytic infiltrate with perivascular distribution of monomorphic CD4+ T-cell predominance (97%) and positive T-cell receptor (gamma, beta) gene rearrangement. While clonal T-cell populations are highly suggestive of T-cell malignancies, reactive conditions can also rarely show clonal T-cell populations. Patient underwent a negative systemic staging for lymphoma and IO was discontinued without immediate initiation of steroids. Follow up clinical evaluation reveal patient improved off IO therapy. Patient was determined to have reactive immune-mediated encephalitis secondary to IO therapy causing seizure mimicking brain metastasis of primary CCRCC. Interestingly, the prior area of encephalomalacia allowed for a cellular bed to collect, resembling brain mass. Upfront staging brain MRI prior to starting IO might have revealed susceptible area and could be considered in these patients

Juvenile idiopathic arthritis and risk of cancer before and after the introduction of biological therapies

BackgroundThe risk of cancer, including any secular trends in risk, in patients with juvenile idiopathic arthritis (JIA) is incompletely understood.MethodsWe performed a register-based cohort study of patients with JIA from...

M229 ACTIVATED PHOSPHOINOSITIDE 3-KINASE DELTA SYNDROME: A CASE SERIES

Advances in genetics with whole exome sequencing have identified mutations linked with immunodeficiencies that were previously unknown. One of the more recent is a mutation in PI3Kδ causing activated phosphatidylinositol-3-OH kinase δ syndrome (APDS). This rare primary immunodeficiency has a highly variable clinical presentation from recurrent infections and persistent lymphadenopathy to life-threatening lymphoproliferative disease and malignancy.

A Review of Viral-Related Malignancies and the Associated Imaging Findings.

OBJECTIVE. Imaging plays an important role in the diagnosis and staging of malignancies. Many common lymphoproliferative and other solid tumor malignancies can be viral-related. CONCLUSION. This review discusses the imaging findings that can be associated with common viral-induced malignancies. Knowledge of these imaging presentations can help narrow the differential diagnosis to reach a specific diagnosis through a precise workup and proper management.

Clinical Profile and Treatment Outcomes of Lymphoma Patients: A Real World Experience

Abstract Within the spectrum of lymphoproliferative malignancies, Hodgkin and Non-Hodgkin Lymphomas (NHL) are amongst the most common lymphoid cancers. The objective of this study is to describe the clinical profile and treatment outcomes of patients with lymphoma seen at a tertiary institution. A total of 135 lymphoma patients were included in the analysis. Total of 23 (17.04%) subjects had a diagnosis of HL, while 112 (82.96%) subjects had NHL. The median age at diagnosis was 59 years (18-86 years). There were a total of 51 males and 67 females (ratio 0.76:1). Among patients with HL, the most frequent stage at diagnosis was stage IV (35%), same incidence was obtained with NHL (44%) at Stage IV at diagnosis. The most common first-line chemotherapy used for HL was ABVD (96%), while for NHL was CHOP (34%). Both for HL and NHL, 48% achieved complete response after first-line chemotherapy. The most frequent second-line treatment given in HL were BV, COPP and ICE (all 9%), while that for NHL was R-COP (4%). The PFS for HL is 87% and for NHL is 67.9%, while the OS achieved for HL is 91.3% and for NHL is 90.2%. The results of the analysis showed that the outcome of patients receiving chemotherapy in a developing country has similar outcome as developed countries.

ABC of viral infections in hematology: focus on herpesviruses

AbstractViruses are a form of life that possess genes but do not have a cellular structure. Viruses do not have their own metabolism, and they require a host cell to make new products; therefore, they cannot naturally reproduce outside a host cell. The objective of this paper is to present the basic practical clinical roles of viruses in patients with hematological diseases including malignancies and non-malignan- cies, as well as those undergoing hematopoietic cell transplantation (HCT), with the focus on herpesviruses causing latent infections in severely immunocompromised patients. From the hematologist point of view, viruses can play a major role in four conditions: causing infections; causing lymphoproliferations and/or malignancies; causing (pan)cytopenia; and used as vectors in treatment (e.g., gene therapy, CAR-T cells). Taking into account the role of viruses in hematology, infection is the most frequent condition. Among DNA viruses, the highest morbidity potential for human is expressed by Herpesviridiae (herpesviruses), Adenoviridae (adenovirus; ADV), Polyomavirus (BKV, JCV), and Bocavirus. RNA viruses can play a role in pathogenesis of different clinical conditions and diseases: lymphoproliferative disorders and malignancy, possibly causing NHL, AML, MDS, and others (HCV, HIV, and others); pancytopenia and aplastic anemia (HIV, HCV, Dengue virus); respiratory infections (community-acquired respiratory virus infections; CARV) caused by Orthomyxoviruses (e.g. influenza A/B), Paramyxoviruses (e.g. human parainfluenza virus PIV-1, -2, -3, and -4; respiratory syncytial virus RSV-A and -B), picornaviruses (e.g., human rhinovirus), coronaviruses (e.g., human coronavirus), Pneumoviridiae (e.g., human metapneumovirus), and potentially other viruses.