non-Hodgkin Lymphoma Cases Research Articles

IBCL-462 Racial-Ethnicity Gap in Survival among Non-Hodgkin Lymphoma Survivors

Non-Hodgkin lymphoma (NHL) is one of the most common cancers in the United States. It is one of the leading causes of cancer-specific morbidity and mortality. An explanation for the significant racial/ethnicity disparity in survival among NHL survivors has been attributed to disparity in access to treatment modalities. We determined if patients' race/ethnicity is an independent predictor of survival following a diagnosis of NHL. We utilized the SEER Registry to identify patients with a primary diagnosis of NHL from 2007 to 2015. Our primary outcome of interest was the patients' survival following a diagnosis of NHL. We determined cancer-specific survival at 1, 3, and 5 years stratified by patients' race/ethnicity. We used Cox regression to determine if the race/ethnicity disparity continues after controlling for disease stage, age, sex, and treatment modalities. There were 171,778 primary cases of NHL in the study period. The majority of the patients were Non-Hispanic Whites (NHW), 72.1%, Non-Hispanic Blacks (NHB), 7.8%, Hispanics, 12.0%, Non-Hispanic Asians, or Pacific Islanders (NHAPI), and 0.5% Non-Hispanic American Indians/Alaska Natives (NHAIAN). There were 54.9% males vs. 45.1% females. The mean age of the study population was 64.7± 16.6 years. Survival at 1, 3 and 5 years by patients' race/ethnicity was, NHW (90.3%, 84.0%, 81.2%), NHB (86.6%, 79.6%, 76.1%), Hispanics (87.4%, 81.5%, 78. 6%). NHB had the worst overall survival (OR=1.53; 95% CI 1.47-1.60), Hispanics (OR=1.23; 95% CI 1.19-1.28), NHAIP (1.26; 95% CI 1.20-1.32) and NHAIAN (OR=1.23; 95%CI 1.04-1.46). There is significant racial disparity in survival outcomes following NHL diagnosis. This disparity persisted even after controlling for patients' insurance type, disease stage, and treatment modalities. Further research is needed to unravel the role of genetics in the racial gap seen in outcomes among NHL survivors.

S2063 Mantle Cell Lymphoma Presenting as Multiple Lymphomatous Polyposis of the Colon

Introduction: Mantle Cell Lymphoma (MCL), a type of non-Hodgkin lymphoma (NHL) is an aggressive neoplasm affecting the lymphatic system. Its incidence is 1–2 cases/105 people/year and accounts for only 5-6% of all cases of NHL. Multiple lymphomatous polyposis (MLP) is a rare presentation seen in MCL consisting of diffuse nodules or polyps covering multiple sites of the gastrointestinal tract. Case Description/Methods: A 68-year-old female with a past medical history of hypertension presented to the clinic with a one-year history of mild diffuse abdominal pain, change in bowel habits including loose stools, and significant involuntary weight loss. A review of systems, physical examination, and routine blood work was non-remarkable. The upper endoscopy was normal but a colonoscopy revealed numerous 1-10 mm submucosal nodules in the entire colon. Biopsies obtained from the nodules of the colon revealed colonic mucosa infiltrated with monotonous, small to medium-sized lymphocytes with irregular nuclear contour, and scant cytoplasm. Immunohistochemistry and immunophenotypic analysis were positive for CD20, CD5, Cyclin D1, BCL6, BCL 2, SOX 11, and negative for CD 10, and P 53. FISH testing revealed 11,14 translocations, consistent with Mantle Cell Lymphoma. CT scan of the abdomen showed pre-carinal, right hilar, extensive para-aortic, and mesenteric lymphadenopathy consistent with stage 4 Mantle Cell Lymphoma. She was subsequently started on Bendamustine and Rituximab combination therapy followed by Rituximab for maintenance. There was a significant improvement in her clinical status with progressive weight recovery. Follow-up upper and lower endoscopic examinations after 6 cycles revealed complete remission with the absence of all polypoid lesions in the GI tract (Figure 1). Discussion: The initial presentation of MCL can widely vary from being asymptomatic to having systemic symptoms of fever and weight loss to marked lymphadenopathy on physical examination. Although 15-30% of individuals with Mantle cell lymphoma (MCL) are reported with involvement in the gastrointestinal (GI) tract, MLP is seen only in less than 10%. It is important for clinicians to not only incorporate MCL as a differential in their workup when they come across diffuse polyps in the GI tract but also to differentiate it from other similar disease processes that present with multiple polyps in the colon. A definitive diagnosis of MLP requires biopsy and histological examination of the tissue with immunophenotypic and immunohistochemistry analysis.Figure 1.: Multiple sessile polypoid lesions of different sizes throughout the colon.

ALL-436 Association Between ABO and Rh Blood Groups and Pediatric Hematological Malignances in Armenia

Despite the higher incidence of hematological malignances, their etiology is not clearly understood. In some reports, the risk of these diseases and survival are associated with ABO blood groups and rhesus. According to World Population Review, Armenia belongs to the ten countries with the highest prevalence of type A+ blood. The investigation of the association between pediatric hematological malignances and both ABO and Rh blood groups in Armenia. Retrospective analysis of ABO blood groups and Rh factor in children with cancer aged 0-18 years between 1995 and 2021 were performed. All the statistical information was taken from clinical records available in Hematology Center after Prof. R.H. Yeolyan. The number of children diagnosed with hematological malignances was 798. Male/female ratio was 1.5. Among 577 children with acute lymphoblastic leukemia (ALL), A+ blood group was the most common (43.67% [252]), followed by O+ (25.48% [147]), B+ (10.92% [63]), AB+ (6.93% [40]), A- (5.89 % [34]), O- (4.33% [25]) and B- (2.08% [12]), AB- (0.69% [4]). A+ was also the highest (46.42% [39]) in 84 children with acute myeloid leukemia (AML) in comparison to the other groups: O+ (20.2% [17]), B+ (14.2% [12]), AB+ (2.38% [2]), A- (5.95% [5]), O- (8.3% [7]), B- (2.38% [2]). Unlike the patients with ALL and AML, the increase of AB+ portion was discovered among 81 cases of Hodgkin lymphoma (HL): A+ (38.2% [31]), O+ (23.5% [19]), B+ (11.1% [9]), AB+ (13.58% [11]), A- (7.4% [6]), O- (3.7% [3]), B- (1.23% [1]), AB-(1.23% [1]). The blood group of 16 patients with chronic myeloid leukemia (CML) included O+ (37.5% [6]); A+ (31.25% [5]), B+ (6.25% [1]), AB+ (6.25% [1]), A- (18.75% [3]). ABO blood group distribution in 40 cases of non-Hodgkin lymphoma (NHL) was O+ (37.5% [15]), A+ (32.5% [13]), B+ (17.5% [7]), A- (5% [2]), O-(2.5% [1]), AB+ (2.5% [1]), AB- (2.5% [1]). The analysis showed that children with A+ blood type in Armenia are most affected by hematological malignances in comparison with the ones who inherited the rest of blood groups. In order to evaluate the risk of developing hematological malignances depending on blood types, further investigations are needed.

Low Incidence of Central Nervous System (CNS) Relapse of Diffuse Large B-Cell Lymphoma despite Limited Use of Intrathecal Prophylaxis

Diffuse large B cell lymphoma (DLBCL) is the commonest sub type of non-Hodgkin's lymphoma (NHL) accounting for 30–50 % of NHL cases. Around 2% to 10% of patients with diffuse large B-cell lymphoma (DLBCL) experience central nervous system (CNS) relapse after initial therapy which is associated with a poor prognosis and most often a fatal outcome. The incidence of CNS relapse can vary from <1% in younger, good-risk patients, to around 30% in patients with multiple risk factors, however, the relapse risk was reported to be lower in the rituximab era in some studies. Moreover, optimal modality of CNS prophylaxis remains to be defined, with both systemic and intrathecal (IT) chemotherapy being widely used. As the incidence of CNS relapse and type of prophylaxis used varies in different reports, it is important to study this risk in different populations to implement optimal prophylaxis strategies. The Objectives of this study was to evaluate the incidence of CNS relapse in DLBCL patients at our institution and to study risk factors and the type and role of CNS prophylaxis. We retrospectively analyzed patients diagnosed with DLBCL at King Khalid University Hospital, Riyadh, from January 2011 to June 2019. Data were collected from computerized hospital information system and from the files of the patients. Variables studied included age at diagnosis, stage at diagnosis, international prognostic index (IPI) and CNS-IPI score, site(s) of extra-nodal involvement, type of chemotherapy received, CNS prophylaxis and CNS relapse. CNS prophylaxis was administered on the basis of presence of high-risk features like presence of ≥2 extranodal sites, involvement of bone marrow, bone, testes, nasopharynx and paranasal sinuses. Patients with presence of CNS involvement at diagnosis and primary CNS lymphoma were excluded. A total of 101 patients were diagnosed with DLBCL during the study period. There were 58 males and 43 females with a median age of 56 (range: 16-87) years. Ann Arbor stage of I-IV was assigned in 9, 21, 17 and 50 patients, respectively. The lung was the most common extranodal site involved in 27 (26.7%) patients, and liver and bone marrow involved in 20 (19.8%) patients each. Gastrointestinal tract was involved in 9 (8.9%) patients, kidneys in 5 (4.95%), breast in 4 (4%), and testis and adrenal in 2 (2%) patients each. Twenty-five (24.75%) patients had high risk CNS-IPI score, 44 (43.5%) had intermediate risk score and 32 (31.7%) had low risk score. Ninety-four (93%) patients received R-CHOP chemotherapy while rest of the patients received other types of chemotherapy, mostly a milder regimen (R-CVP), because of comorbidities and poor performance status. Sixteen patients received CNS prophylaxis, which was IT methotrexate (MTX) ± cytarabine/hydrocortisone in all patients. Nine of 25 (36%) patients with high-risk CNS-IPI score did not receive CNS prophylaxis. After a median follow up of 36 months (range 4-114), 2 (2%) patients developed CNS relapse and died shortly after this diagnosis. Both the patients with CNS relapse had high risk CNS-IPI score and did not receive CNS prophylaxis. CNS relapse of DLBCL was uncommon in this patient population despite limited use of IT CNS prophylaxis in high-risk patients. Low incidence of CNS relapse in many high-risk patients despite limited use of IT prophylaxis may be related to rituximab use and/or other factors. Our data indicate that IT CNS prophylaxis may be adequate for DLBCL patients at high risk of CNS relapse.

Reed Sternberg-Like Cells in Non-Hodgkin Lymphoma: A Diagnostic Challenge.

Reed-Sternberg cells are distinguishing features of classical Hodgkin lymphoma. However, they are seen infrequently, in both B and T cells Non-Hodgkin lymphomas with a comparable morphology and immunophenotype. These cells are known as Reed-Sternberg-like cells. The characteristic background milieu of classical Hodgkin lymphoma is typically not present in Non-Hodgkin lymphomas, and Reed-Sternberg-like cells are typically present as dispersed cells or in tiny clusters. They are positive for CD30, show variable expression of B cell lineage markers and are negative for CD45/LCA in Non-Hodgkin lymphomas. Reed-Sternberg-like cells have phenotypes that are remarkably similar to those of conventional Reed-Sternberg cells. In this interesting case report, we discuss a case of disseminated B-cell Non-Hodgkin lymphoma with Reed-Sternberg-like cells that presented as a diagnostic challenge. It is essential to distinguish between classical Hodgkin lymphoma and Non-Hodgkin lymphomas due to distinct therapy protocols and prognosis. The presence of large CD30 positive Reed-Sternberg like cells may mimic Hodgkin's Lymphoma. However, monomorphic background population with CD20 positivity should always raise the suspicious of B-cell Non-Hodgkin lymphoma. Immunohistochemical detection of a panel of targets should always be applied to correctly diagnose these rare cases of B-cell Non-Hodgkin lymphoma with Reed-Sternberg like cells.

Primary diffuse large B-cell lymphoma of orbit: A population-based analysis.

ObjectivePrimary orbital lymphoma (POL) accounts for an essential part of adult orbital malignancies. Nevertheless, it remains a relatively rare lymphoid malignancy, accounting for <1% of all non-Hodgkin's lymphoma (NHL) cases. Orbital diffuse large B-cell lymphoma (DLBCL) is one of the most prevalent subtypes of POL that confers the worst outcomes. The prognostic determinants of orbital DLBCL remain unknown. Therefore, a retrospective analysis was conducted by investigating the Surveillance, Epidemiology, and End Results (SEER) database for independent predictive factors for the prognosis of orbital DLBCL.Materials and methodsUsing the SEER program, we acquired patient data including demographics, clinical characteristics, and treatment strategies. Our cohort included cases of primary orbital DLBCL diagnosed from 2000 to 2017. We conducted Kaplan-Meier analyses to visualize the overall survival (OS) and cause-specific survival (CSS). The Cox proportional hazard regression models were applied to assess the effects of these prognostic factors on OS and CSS.ResultsThe present cohort included 332 patients with orbital DLBCL. Age was the most impacted variable by orbital DLBCL. Three independent prognostic variables of orbital DLBCL were identified on diagnosis: advanced age, no radiation treatment, and late-stage (Stage IV). Moreover, patients who underwent chemotherapy demonstrated a greater OS when compared with those who did not. In orbital DLBCL, being unmarried was also a poor prognostic factor.ConclusionThe current study is the largest population-based case series of orbital DLBCL. The age at the time of diagnosis, marital status, absence of chemotherapy or radiotherapy, and tumor stage were all found to be correlated with worse prognosis.

The Korea Cohort Consortium: The Future of Pooling Cohort Studies.

ObjectivesWe introduced the cohort studies included in the Korean Cohort Consortium (KCC), focusing on large-scale cohort studies established in Korea with a prolonged follow-up period. Moreover, we also provided projections of the follow-up and estimates of the sample size that would be necessary for big-data analyses based on pooling established cohort studies, including population-based genomic studies.MethodsWe mainly focused on the characteristics of individual cohort studies from the KCC. We developed “PROFAN”, a Shiny application for projecting the follow-up period to achieve a certain number of cases when pooling established cohort studies. As examples, we projected the follow-up periods for 5000 cases of gastric cancer, 2500 cases of prostate and breast cancer, and 500 cases of non-Hodgkin lymphoma. The sample sizes for sequencing-based analyses based on a 1:1 case-control study were also calculated.ResultsThe KCC consisted of 8 individual cohort studies, of which 3 were community-based and 5 were health screening-based cohorts. The population-based cohort studies were mainly organized by Korean government agencies and research institutes. The projected follow-up period was at least 10 years to achieve 5000 cases based on a cohort of 0.5 million participants. The mean of the minimum to maximum sample sizes for performing sequencing analyses was 5917–72 102.ConclusionsWe propose an approach to establish a large-scale consortium based on the standardization and harmonization of existing cohort studies to obtain adequate statistical power with a sufficient sample size to analyze high-risk groups or rare cancer subtypes.

Challenges Encountered and Pattern-Based Analysis of Bone Marrow Biopsy in Lymphomas: An Institutional Experience.

Objective The evaluation of bone marrow (BM) status is an integral part of the initial workup of patients diagnosed with lymphoma as it plays an important role in staging and predicting prognosis in these patients. This article determines the incidence and pattern of BM involvement in lymphoma cases and distinguishes benign from malignant lymphoid aggregates in BM biopsies. Materials and Methods The study group included 121 cases of Hodgkin and non-Hodgkin lymphomas for which BM biopsies were performed, fixed in acetic acid-zinc formalin solution, decalcified using 10% formic acid, and subjected to hematoxylin and eosin and immunohistochemistry. Results The overall incidence of BM biopsy involvement in our study was 31.4% (37/118), including 34.7% (35/101) in cases of B cell lymphomas, 25% (2/8) in cases of T cell lymphomas, and no involvement in Hodgkin lymphoma. The predominant histological pattern of BM involvement was diffused (14/37; 37.8%), followed by interstitial (10/37; 27.1%). Five cases revealed benign nonparatrabecular lymphoid aggregates which could be confused with lymphomatous involvement, especially in low grade lymphomas. Conclusion A careful examination of the BM biopsies along with clinical history, peripheral blood examination, flow cytometry, and immunohistochemistry will help in arriving at the correct diagnosis.

NON-HODGKIN LYMPHOMA IN THE MANDIBULAR BRANCH: A CASE REPORT

Lymphomas are neoplasms caused by aberrant transformations of lymphoid cells that are predominant in lymphoid tissues. Non-Hodgkin lymphoma (NHL) can reach several organs, including the oral cavity. The aim of this study is to relate a case of oral NHL. A 48-year-old male patient, with a history of treatment between 2014 and 2019 for NHL, was admitted for diagnostic investigation of discomfort in the lower limbs, significant anemia, hepatosplenomegaly and generalized pain in the mandible, dental mobility, and purulent secretion. A facial computed tomography exam showed a lytic area in the left posterior region of the mandible, with ill-defined limits and an infiltrating aspect. Due to the history of NHL and possibility of dissemination, tooth extraction and biopsy of the adjacent tissue were performed, resulting in a diagnosis of infiltration by NHL. The patient was referred for hematopoietic stem cell transplantation and is under follow-up. Lymphomas are neoplasms caused by aberrant transformations of lymphoid cells that are predominant in lymphoid tissues. Non-Hodgkin lymphoma (NHL) can reach several organs, including the oral cavity. The aim of this study is to relate a case of oral NHL. A 48-year-old male patient, with a history of treatment between 2014 and 2019 for NHL, was admitted for diagnostic investigation of discomfort in the lower limbs, significant anemia, hepatosplenomegaly and generalized pain in the mandible, dental mobility, and purulent secretion. A facial computed tomography exam showed a lytic area in the left posterior region of the mandible, with ill-defined limits and an infiltrating aspect. Due to the history of NHL and possibility of dissemination, tooth extraction and biopsy of the adjacent tissue were performed, resulting in a diagnosis of infiltration by NHL. The patient was referred for hematopoietic stem cell transplantation and is under follow-up.

Risk of Cancer in Connective Tissue Diseases in Northeastern Italy over 15 Years.

Objective: To evaluate cancer risk among individuals with connective tissue disease (CTD) in Friuli Venezia Giulia, northern Italy. Methods: A population-based cohort study was conducted based on data from health records available in the regional healthcare database. Demographic characteristics, hospital discharges, exemption from medical charges, drug prescriptions, were individually matched with data from the population-based cancer registry. Cancer risk was assessed in people diagnosed with the following diseases: systemic lupus erythematosus (SLE), Sjögren’s syndrome (SS), systemic sclerosis (SSc), polymyositis (PM), and dermatomyositis (DM). Results: In all, 2504 patients were followed for a total of 18,006 person-years (median follow-up: 6.8 years). After 5 and 10 years of follow-up, the cumulative cancer incidence was 2.6% and 8.5%, respectively. The most common cancers were breast (n = 34), lung (n = 24), colon–rectum–anus (n = 20), and non-Hodgkin lymphomas (NHL) (n = 20). Overall, no excess cancer risk was noted (SIR = 0.87), whereas the number of observed NHL cases was more than two-fold significantly higher than expected (SIR = 2.52). The subgroup analysis showed a higher risk of NHL among SS patients (SIR = 3.84) and SLE patients (SIR = 2.69). Conversely, the study population showed a decreased risk for breast cancers (SIR = 0.61) and corpus uteri (SIR = 0.21). Conclusions: The incidence of NHL was higher among patients with SS and SLE. Careful surveillance for hematological malignancies in these patients is recommended.

Global patterns of non-Hodgkin lymphoma in 2020.

We evaluated the global patterns of non-Hodgkin lymphoma (NHL) in 2020 using the estimates of NHL incidence and mortality in 185 countries that are part of the GLOBOCAN 2020 database, developed by the International Agency for Research on Cancer (IARC). As well as new cases and deaths of NHL, corresponding age-standardized (world) rates (ASR) of incidence and mortality per 100 000 person-years were derived by country and world region. In 2020, an estimated 544 000 new cases of NHL were diagnosed worldwide, and approximately 260 000 people died from the disease. Eastern Asia accounted for a quarter (24.9%) of all cases, followed by Northern America (15.1%) and South-Central Asia (9.7%). Incidence rates were higher in men than in women, with similar geographical patterns. While the incidence rates were highest in Australia and New Zealand, Northern America, Northern Europe and Western Europe (>10/100 000 for both sexes combined), the highest mortality rates (>3/100 000) were found in regions in Africa, Western Asia and Oceania. The large variations and the disproportionately higher mortality in low- and middle-income countries can be related to the underlying prevalence and distribution of risk factors, and to the level of access to diagnostic and treatment facilities.

Chimeric antigen receptor T-cell therapy for relapsed and refractory large B-cell lymphoma

Comprising approximately 40% of diagnoses, lymphoma is the most common hematological malignancy in Canada, and 80% of lymphoma cases are non-Hodgkin lymphoma (NHL). Diffuse large B-cell lymphoma (DLBCL) accounts for approximately 30% of new NHL cases in Canada. First-line treatment with standard of care chemoimmunotherapy consisting of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) results in a cure in approximately 60–70% of patients. Nevertheless, 30–40% of patients will experience relapse of their disease or are refractory to first-line therapy.&#x0D; Among those patients with relapsed or refractory DLBCL (R/R DLBCL), about 10–15% will exhibit primary refractory disease with either stable or progressive disease despite first-line therapy, while 20–25% will experience relapse after an initial response to treatment. Most relapses will occur within 2–3 years following initial treatment. For these patients, the standard approach is salvage chemotherapy followed by high-dose chemotherapy and autologous stem cell transplantation (ASCT) for those who meet the eligibility criteria and have chemosensitive disease.

Unveiling the journey of diagnosing cutaneous lymphomas- A case series

Cutaneous manifestation of Non-Hodgkin lymphoma can histologically and clinically manifest as Mycosis fungoides or Vasculitis. Histopathologic features of cutaneous lymphoma show dense tumor with a “bottom heavy” configuration. Tumor comprises either large lymphoid cells or sheets of monotonous small lymphoid cells with plasmacytoid configuration. A detailed work up is mandatory to conclude the diagnosis and provide definitive treatment in cutaneous lymphomas. In our case series, we present and describe 5 cases of Non-Hodgkin lymphoma with cutaneous manifestations. Two cases of Angioimmunoblastic T Cell Lymphoma with clinical and histological presentation as vasculitis, 2 cases of Mycosis fungoides concluded as Human T-cell Lymphotrophic Virus (HTLV) positive Adult T Cell Lymphomas on evaluation, 1 case which was lost to follow up are discussed. Thus, this case series emphasizes on the need to do complete work up of cutaneous lymphomas.

Abstract 3720: TACH101, a first-in-class inhibitor of KDM4 histone lysine demethylase for the treatment of diffuse large B-cell lymphoma

Abstract Background: Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma (NHL) in the US accounting for about 22% of newly diagnosed cases of B-cell NHL. It is considered to be more aggressive and to have worse prognosis due to low response to existing treatments. KDM4 is a family of histone demethylases that can drive tumor growth by regulating transcription, cell cycle, and DNA replication/repair. Overexpression of KDM4 alters post-translational histone modification and is associated with many types of cancer, including DLBCL. TACH101 is a novel, potent small molecule inhibitor of KDM4 that is being developed for treatment of advanced cancers, including DLBCL. Methods: TACH101 was evaluated in vitro and in vivo using cancer cell lines and patient-derived organoid (PDO) and xenograft (PDX) models of DLBCL. Results: TACH101 is a reversible, α-ketoglutarate competitive, selective and potent inhibitor of KDM4 isoforms A-D with IC50 values &amp;lt; 0.100 μM for all four isoforms. An initial screen using a 301-cell line panel showed that DLBCL cell lines are sensitive to TACH101 (IC50 &amp;lt; 10 nM). In an additional panel of DLBCL cell lines, TACH101 inhibited proliferation in a dose-dependent manner in all DLBCL cell lines, independent of molecular subtype, with mean IC50’s of 0.03 ± 0.01 μM in ABC DLBCL cell lines (n=6); 0.02 ± 0.01 μM in GCB DLBCL cell lines (n=7) and 0.02 ± 0.01 μM in PMBL DLBCL cell lines (n=2). In OCI-LY19 DLBCL xenografts in vivo, TACH101 was well tolerated and inhibited tumor growth by 55% to 100%, depending on dosing regimen (either QD or BID following a 3 days on/4 days off schedule). In PK studies, TACH101 exhibited low clearance, moderate volume of distribution, and good oral bioavailability in mouse, rat, and dog. Moreover, treatment with TACH101 resulted in little or no inhibitory effects on CYP enzymes. Toxicity studies in rats and dogs identified potential target tissues and provided safety guidance for the use of TACH101 in human studies. Conclusions: The KDM4 inhibitor, TACH101, had compelling activity in preclinical DLBCL models, suggesting that TACH101 could be an effective therapy for DLBCL. Preparations to advance the drug into clinical trials are underway. Citation Format: Frank Perabo, Chandtip Chandhasin, Sanghee Yoo, Joselyn Del Rosario, Young K. Chen, Ellen Filvaroff, Jeffrey A. Stafford, Stephen Quake, Michael F. Clarke. TACH101, a first-in-class inhibitor of KDM4 histone lysine demethylase for the treatment of diffuse large B-cell lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3720.

Abstract 5432: Targeted alpha therapy with 212Pb-NNV003 in treatment of NHL

Abstract Introduction: CD37 has shown promise as a new therapeutic target for B-cell malignancies. CD37 is highly and selectively expressed on the surface of mature B lymphocytes and B-cell malignancies. Alpha-emitting radionuclides have demonstrated potential for cancer targeted therapies because of efficient energy deposition along the short alpha track (50-100 µm) causing localized and irreparable DNA damage while sparing surrounding healthy tissues. We have developed a targeted alpha therapy (TAT) where the CD37-specific antibody NNV003 is coupled to the alpha-particle-generating radioisotope 212Pb for the treatment of non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL). Approximately 90,000 cases of CLL and NHL are expected annually in the US. Standard of care includes chemotherapy combined with anti-CD20 antibodies (obinutuzumab and rituximab) and Bruton’s tyrosine kinase inhibitor ibrutinib. While these therapies are initially effective, most patients inevitably relapse. Materials and methods: The efficacy and tolerability of a single dose 212Pb-NNV003 treatment were evaluated in disseminated models using CD37-expressing human CLL (MEC-2) and Burkitt’s lymphoma (Daudi) cells. Comparison to therapeutic doses of ibrutinib was investigated in the MEC-2 model. R2G2 or CB17-SCID mice were injected intravenously with 2.5×106 MEC-2 or 10×106 Daudi cells on day 0, followed by intravenous injection of 212Pb-NNV003 (2.5, 5 or 7.5 µCi in Daudi model and 5, 10, 15 or 20 µCi in MEC-2 model) or daily oral administration of ibrutinib (12.5 or 25 mg/kg) starting on day 2 (n=10-12 per group). 212Pb-cetuximab (unspecific isotype control), unlabelled NNV003 and NaCl were used as controls. Results: In vitro testing of the antibody showed that MEC-2 cells were 5 times more resistant to ibrutinib than Daudi cells. Treatment of mice injected intravenously with Daudi cells with 2.5 μCi 212Pb-NNV003 resulted in survival of 100% of the mice 100 days after start of treatment, while 100 days after start of treatment with 100 μg obinutuzumab only 40% of the mice were still alive. Control mice had a median survival of 7-8 weeks. Treatment of mice injected intravenously with MEC-2 cells with 15 μCi 212Pb-NNV003 resulted in survival of 90-100% for more than 25 weeks in two independent experiments. Ibrutinib treated mice with intravenous MEC-2 cells presented a median survival of only 4.3-4.4 weeks, comparable to the unlabelled NNV003 and saline groups (4.1 and 4.4 weeks). Mice receiving non-specific 212Pb-cetuximab presented a median survival of 7-9 weeks. Conclusion: The study shows that a single injection 212Pb-NNV003 is safe and effective for the treatment of CD37 positive CLL and NHL in preclinical models, with promising efficacy in both ibrutinib-resistant and sensitive CLL models. Treatment with 212Pb-NNV003 was superior to both ibrutinib and obinutuzumab. Further clinical testing is warranted. Citation Format: Jostein Dahle, Amal Saidi, Tania Stallons, Helen Heyerdahl, Ada Repetto-Llamazares, Julien Torgue. Targeted alpha therapy with 212Pb-NNV003 in treatment of NHL [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5432.

Abstract 2255: Alu retroelement copy number alterations and non-Hodgkin lymphoma

Abstract Background: Alu retrotransposons are repetitive DNA elements that make up nearly 10% of the human genome and reflect genomic instability. Genomic instability plays an important role in the pathogenesis of non-Hodgkin lymphoma (NHL). However, the relationship between Alu retrotransposons and future risk of NHL is unclear. Methods: We conducted a nested case-control study of NHL risk and Alu retroelement copy number within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) study, a prospective cohort with prediagnostic blood samples from 29,133 male Finnish smokers. We measured Alu copy number in 107 incident NHL cases and 1:1 matched controls (± 5 years age). DNA samples extracted from blood were assayed in triplicate using a monochrome multiplex quantitative polymerase chain reaction. We used the albumin gene for the single copy gene to control for genome content in samples. The odds ratios (OR) and 95% confidence intervals (CI) for all NHL were estimated using conditional logistic regression models, adjusting for age at randomization, number of cigarettes smoked per day and smoking duration. Polytomous logistic regression models were fit to compute ORs with Alu copy number for NHL subtypes. To determine if the association might be driven in part by elevated Alu copy number among undiagnosed cases at the time of blood sample collection, we excluded cases diagnosed within the first two years of follow-up. Results: Higher Alu copy number (using the median as the cut-point) was associated with an increased risk of NHL, both overall [OR, 95% CI=3.80 (1.76-8.17)] as well as for the diffuse large B-cell lymphoma [OR, 95% CI=4.83 (1.50-15.55)] and chronic lymphocytic leukemia/small lymphocytic lymphoma (SLL) [OR, 95% CI=2.66 (1.10-6.40)] subtypes. These associations were similar after excluding individuals diagnosed with NHL within two years after blood draw. Conclusions: These findings, which require replication, suggest that higher Alu copy number in prediagnostic leukocytes may play a role in the pathogenesis of NHL. Citation Format: Wei Hu. Alu retroelement copy number alterations and non-Hodgkin lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2255.

Malignant lymphoma and occupational exposure to extremely low frequency magnetic fields and electrical shocks: a nested case-control study in a cohort of four Nordic countries

BackgroundExposure to extremely low frequency magnetic fields (ELF-MFs) and electric shocks is a common occupational risk factor in many workplaces. Recent investigations have highlighted a possible association between such exposures...

Clinicopathological Spectrum of Hodgkin's and Non-Hodgkin's Lymphoma: A Tertiary Care Cancer Hospital Study in Pakistan.

IntroductionLymphomas are a heterogeneous group of disorders that arise primarily from lymphoid tissue and are categorized based on histological features and immunophenotypes. The distribution and frequency of different types of lymphoma vary in different parts of the world. This study aimed to document the frequency and clinicopathological characteristics of various types of lymphoma in our population to understand the ever-increasing burden of disease and formulate the optimal management and prevention plans.Materials and methodsThis study was conducted at Nuclear Medicine, Oncology and Radiotherapy Institute (NORI) from August 2015 to March 2022. A total of 300 cases of lymphoma that were diagnosed and treated at NORI were included in the study. We measured the frequency of different lymphomas and patient age, sex, and stage IV presentation at the time of diagnosis. IBM SPSS Statistics for Windows, Version 23.0 (Armonk, NY: IBM Corp.) was used to analyze the data.ResultsThree hundred patients with lymphoma were included in the study. There were more non-Hodgkin’s lymphoma (NHL) cases (n=224; 74.6%) than Hodgkin’s lymphoma (HL) cases (n=76; 25.3%). T-cell NHL was seen in 11 cases (4.8%), while B-cell NHL was found in 214 cases (95%). Diffuse large B-cell lymphoma was the predominant type (n=156; 69.3%). Among T-cell lymphomas, anaplastic T-cell lymphoma was the most common subtype (n=6; 2.6%) followed by angioimmunoblastic T-cell lymphoma (n=2; 0.8%) and T-cell lymphoblastic lymphoma (n=1; 0.4%). For classical HL, mixed cellularity was the predominant type (n=38; 50%) followed by nodular sclerosis (n=31; 40.8%), lymphocyte depleted (n=5; 6.6%), and lymphocyte rich (n=2; 2.6%). Stage IV was present in 21 HL cases (27.6%), and stage IV was seen in 67 NHL cases (29.7%) at the time of diagnosis. Most HL and NHL patients were male. Most HL cases presented in the younger age group (aged 15 to 35 years), while the largest group of NHL patients were aged 56 to 75 years.ConclusionOur population has a broad spectrum of lymphoma and its subtypes. NHL is more common than HL, and the frequency of B-cell NHL is higher than that of T-cell NHL. Approximately one-third of the patients presented in stage IV at the time of diagnosis. An awareness of clinicopathological characteristics of lymphoma in our setup would aid in diagnosis, formulating standard management plans, and prevention strategies for optimal patient outcomes.

Benzene exposure increases the risk of non-Hodgkin's lymphoma: a systematic review and meta-analysis of observational studies.

BackgroundAlthough there is sufficient evidence that benzene exposure increases the risk of leukemia, whether benzene exposure increases the risk of non-Hodgkin’s lymphoma (NHL) remains controversial. The method of meta-analysis can reduce the uncertainty in evidence-based medicine (EBM) evidence decision-making caused by the bias between studies by systematically searching, evaluating, and combining all relevant literatures.MethodsPubMed, Embase, ScienceDirect and other databases were searched according to the population exposure comparison outcome principles: whether the general population exposed to benzene has a higher risk of developing NHL than the population without benzene exposure. Two independent researchers extracted the main endpoint indicators from the included literature, including the odds ratio (OR) or relative risk (RR) of benzene exposure to the risk of NHL. Risk of bias was assessed for each study using the Newcastle-Ottawa scale (NOS). Heterogeneity between studies was evaluated using the Cochrane Q test and I2 statistics, and combined risk estimates were calculated with the random-effects and fixed-effect models. Meanwhile, source of heterogeneity was evaluated by subgroup analysis. Publication bias was evaluated by funnel plot and Egger’s test, and the stability of results was evaluated by sensitivity analysis. All results with P<0.05 were considered statistically significant.ResultsA total of 14 articles were included in this study for meta-analysis, including 9 cohort studies and 5 case-control studies with NOS scores between 5 and 9. Four of the articles were at low risk of bias, and 10 were at moderate risk of bias. Of 492,719 people with benzene exposure, there were 1,994 cases of NHL. The OR of NHL in the benzene-exposed population compared with nonexposed population was 1.23 (P=0.03), with moderate heterogeneity (I2=63.47%). People with high exposure to benzene showed a higher risk of NHL (OR =1.81) and there was a low degree of heterogeneity (I2=27.56%). The risk of benzene exposure in China (OR =2.48) was higher than that in Europe (OR =1.19), the United Kingdom (OR =1.07), and the United States (OR =1.24).ConclusionsBenzene exposure was positively correlated with the incidence of NHL.

CD20 and CD19 expression loss in relapsed or refractory b-cell non-Hodgkin lymphoma: A retrospective cohort.

e19537 Background: CD20-targeted therapies such as rituximab are widely used in the management of B-cell non-Hodgkin lymphoma (NHL). Re-treatment with anti-CD20 agents is common, however previous research has demonstrated loss of CD20 expression at time of relapse or refractory disease in a subset of patients. There is also amplified interest in alternative targets, specifically CD19, in the relapsed or refractory setting. Incidence of CD19 loss has been explored in post-CAR T cell therapy patients but not described elsewhere. We hypothesized that CD marker loss may be higher than previous reports due to expanded use of CD20- and CD19-targeted therapy. Methods: The present study is a retrospective cohort analysis of 229 patients with B-cell NHL from Harbor-UCLA Medical Center in Los Angeles, CA from 2006 to 2022. Charts were retrospectively reviewed for cases of B-cell NHL, and data was collected about demographics, diagnosis, treatment, and relapses. CD20 and CD19 expression analysis was performed by immunohistochemistry and / or flow cytometry at diagnosis and at each relapse whenever possible. The primary endpoint of the study was the rate of CD marker expression loss at time of relapse. Results: The cohort of 229 patients was composed of 54.1% diffuse large B-cell lymphoma (DLBCL), 14.4% follicular lymphoma (FL), 8.3% high-grade B-cell lymphoma (HGBCL), 7.0% marginal zone lymphoma (MZL), 4.8% mantle cell lymphoma (MCL), and 11.2% other. Overall, 28.8% (66/229) patients had relapsed or refractory disease. The rate of CD20 expression loss was 7.9% (5/63) across all relapses with two patients converting at first relapse (1 FL relapsing as HGBCL, 1 MZL), two patients at 2nd relapse (1 FL relapsing as DLBCL, 1 MZL relapsing as DLBCL), and one patient at 5th relapse (1 MZL). All five patients with CD20 phenotypic conversion received rituximab, and three patients received two or more rounds of anti-CD20 therapy. The median OS after CD20 expression loss was 4 months (95% CI 3.3 – 4.7 months). All patients (14/14) who had CD19 testing performed at relapse maintained CD19 positivity. Conclusions: This retrospective study demonstrates a rate of CD20 expression loss at relapse of 7.9%, which is less than previously reported rates ranging between 11-60%. CD20 expression loss seems to be associated with transformation to high-grade lymphoma, poor overall survival, and marginal zone histology. The conservation of CD19 expression across relapses supports the use of novel anti-CD19 targeted therapy in the relapsed or refractory setting. Whenever possible, repeat biopsy should be done at time of relapse prior to treatment with CD-targeted therapy. This study is of notable clinical relevance with expanded use of anti-CD20 agents and novel CD19-targeted therapies in the management of B-cell NHL.