non-Hodgkin Lymphoma Histologic Subtypes Research Articles

Epidemiological and histopathological aspects of lymphomas at Zinder National Hospital, Niger

Introduction: Lymphoma is a malignant lymphocytic hemopathy characterized by diffuse lymph node or extranodal infiltration. It occurs at all ages and poses a problem for us in terms of positive diagnosis and management. The objective of this study is to determine the epidemiological and histological aspects of lymphomas at the National Hospital Zinder. Methodology: This was a retrospective cross-sectional study of patient records collected for histopathological examination between November 2019 and December 2023. Included were patients of any age and of both sexes with their histopathological findings available. Results: Lymphomas accounted for 3.47% of all malignancies. The 40 to 60 age group was the most affected with 40.90% (n=9) of cases. The mean age was 45±20.05. The sex ratio was 1.75. Lymph node localization accounted for 68.18% (n=15) of cases. Histological examination confirmed the type of non-Hodgkin lymphoma in 77.27% (n=17) of cases. Phenotype B lymphoma predominates in 86.36% of cases (n=19). Our study showed that indolent lymphoma was the most common histological subtype of non-Hodgkin lymphoma in 31.82% (n=7) of cases. Hodgkin's lymphocytic depleted lymphoma was found in 13.63% (n=3) of cases. Conclusion: The analysis of these results allowed us to appreciate the extent of lymphomas and their multiple implications in our society by highlighting a high frequency of non-Hodgkin's lymphomas in the region.

Primary appendiceal diffuse large B-cell lymphoma initially presenting as acute appendicitis: A case report.

IntroductionDiffuse large B-cell lymphoma (DLBCL) is the most common histologic subtype of non-Hodgkin lymphoma (NHL), accounting for approximately 25% of all NHL cases. Primary appendiceal lymphomas (PAL) presenting as acute appendicitis are very rare, occurring in only 0.015% of all cases of gastrointestinal lymphoma.Case presentationA 57-year-old man who was initially presented as acute appendicitis and subsequently underwent interval laparoscopic appendectomy. Pathological examination revealed diffuse large B cell lymphoma with cut end involvement. Whole-body positron emission tomography (PET) scan revealed enlarged right palatine tonsil and raised a suspicion of lymphoma involvement in two right cervical lymph nodes (level II and III); biopsy, however, showed that the lymph nodes were benign, with non-specific cellular changes. Bone marrow biopsy of the iliac crest also did not show lymphoma involvement. Subsequently, a diagnosis of primary appendiceal diffuse large B cell lymphoma (Ann Arbor Stage II) was established. After six courses of definite chemotherapy with cyclophosphamide, doxorubicin HCl, vincristine, and rituximab (R-CHOP), PET/CT showed complete remission of the prior FDG-avid malignancy of appendiceal DLBCL. The patient continued to be stable with no recurrence for fifteen months of regular outpatient department follow-ups.ConclusionsPAL is rare, and it clinically manifests the signs and symptoms of acute appendicitis. Specific characteristics of lymphoma in CT scans may lead to a more confirmative diagnosis. PET/CT is important for staging the lymphoma. Patients with PAL should be managed with surgical resection followed by R-CHOP-21 for 6 cycles regardless of whether they have localized disease or disseminated disease.

FDG PET/CT versus Bone Marrow Biopsy for Diagnosis of Bone Marrow Involvement in Non-Hodgkin Lymphoma: A Systematic Review

The management of non-Hodgkin lymphoma (NHL) patients requires the identification of bone marrow involvement (BMI) using a bone marrow biopsy (BMB), as recommended by international guidelines. Multiple studies have shown that [18F]FDG positron emission tomography, combined with computed tomography (PET/CT), may provide important information and may detect BMI, but there is still an ongoing debate as to whether it is sensitive enough for NHL patients in order to replace or be used as a complimentary method to BMB. The objective of this article is to systematically review published studies on the performance of [18F]FDG PET/CT in detecting BMI compared to the BMB for NHL patients. A population, intervention, comparison, and outcome (PICO) search in PubMed and Scopus databases (until 1 November 2021) was performed. A total of 41 studies, comprising 6147 NHL patients, were found to be eligible and were included in the analysis conducted in this systematic review. The sensitivity and specificity for identifying BMI in NHL patients were 73% and 90% for [18F]FDG PET/CT and 56% and 100% for BMB. For aggressive NHL, the sensitivity and specificity to assess the BMI for the [18F]FDG PET/CT was 77% and 94%, while for the BMB it was 58% and 100%. However, sensitivity and specificity to assess the BMI for indolent NHL for the [18F]FDG PET/CT was 59% and 85%, while for the BMB it was superior, and equal to 94% and 100%. With regard to NHL, a [18F]FDG PET/CT scan can only replace BMB if it is found to be positive and if patients can be categorized as having advanced staged NHL with high certainty. [18F]FDG PET/CT might recover tumors missed by BMB, and is recommended for use as a complimentary method, even in indolent histologic subtypes of NHL.

Non Hodgkin lymphoma in Lebanon: a retrospective epidemiological study between 1984 and 2019

BackgroundLymphomas are ranked as the fifth most common cancer in Lebanon. There is concern about the need of information regarding the prevalence of lymphoid neoplasm particularly Non-Hodgkin lymphoma (NHL) subtypes in the Lebanese population. This study intended to establish a descriptive status of NHL histological subtypes distribution in Lebanon thus identifying the most common types, knowing that the literature is poor regarding the distribution of lymphoid malignancies particularly NHLs in Lebanon.MethodsA bicenter retrospective descriptive study was performed. Patients aged above 18, diagnosed with NHL between January 1984 and March 2019 and registered in two Lebanese Medical centers were included in this study; 699 medical files were reviewed and the baseline characteristics of the disease were collected. Histological classification was based on the Working Formulation (WF) and World Health Organization (WHO) classification systems, whereas staging was based on the Ann Arbor system. Disease status was monitored with imaging studies.ResultsThe mean age at diagnosis was 53.52 ± 17.46 years in the studied population, with 380 (54.4%) males and 319 (45.6%) females. B-cell lymphoma (BCL) accounted for 86.3% while T-cell neoplasms accounted for 13.7%. The most common subtype was diffuse large B-cell lymphoma (DLBCL) (54%) followed by follicular lymphoma (FL) (17.2%). Mantle cell lymphoma (MCL) represented 3% of all BCL and small lymphocytic lymphoma (SLL) comprised less than 2%. Mucosa-associated lymphoid tissue (MALT) and Burkitt’s lymphomas represented 3 and 1.7% respectively. 36.5% of the patients had extranodal disease at diagnosis. High-grade tumor represented 80.1% with 33.1% stage IV disease.ConclusionThese observations indicate that the epidemiological patterns of NHLs in Lebanon were comparable to Western countries. Aggressive lymphomas account for the majority of NHLs in Lebanon.

Pediatric Anaplastic Large Cell Lymphoma with Concomitant Involvement of Spine and Central Nervous System: A Case Report and Review of Literature

Anaplastic large cell lymphoma (ALCL) is a histological subtype of non-Hodgkin lymphoma, largely characterized by anaplastic lymphoma kinase (ALK) positivity, resulting from the chromosomal translocation t(2;5). We report a pediatric case of ALK-positive ALCL with primary concomitant involvement of bone and central nervous system (CNS); thereafter, a literature review about pediatric primary bone and primary CNS ALCL was conducted. According to the analyzed data, our case is unique because it is characterized by the contemporary involvement of the spine and CNS. During and after chemotherapy, our patient was monitored by detecting minimal residual disease (MRD) through the analysis of fusion transcript nucleophosmin-ALK. MRD assessment, not only in bone marrow but also in peripheral blood, seems to be a very powerful tool for predicting the prognosis of pediatric ALCL patients, as already described in the literature. Moreover, as shown in our case, it could be used during the follow-up for early recognition of relapse.

Economic Impact and Healthcare Utilization in Patients with Diffuse Large B-Cell Lymphoma (DLBCL) in Routine Clinical Care in the United States (US) - a Claims Database Study

Background: DLBCL is the most common histologic subtype of non-Hodgkin lymphoma, accounting for about 33% of all NHL cases. However, the healthcare burden associated with DLBCL has not been extensively studied in a US population. We evaluated the costs of care and healthcare utilization (HCU) of DLBCL patients treated during routine care in the US.Methods: The Optum claims database was used to identify adult patients (≥18 years old) with newly diagnosed DLBCL between 01/01/08 and 10/31/15. DLBCL diagnosis was based on ≥1 inpatient claim or ≥2 outpatient claims with DLBCL diagnosis codes, with the index date being the first DLBCL claim. Patients were followed from index date until end of continuous enrollment, death, or end of study period (12/31/15) for the assessment of HCU and costs. DLBCL-related and non-DLBCL-related HCU and costs incurred during follow-up were evaluated. DLBCL-related HCU and costs were medical claims with a primary diagnosis of DLBCL or DLBCL-related treatments (chemotherapy, radiation, stem cell transplant (SCT), supportive care) and pharmacy claims for DLBCL treatment. Proportions of patients with HCU were reported. Costs were calculated as per-patient-per-month (PPPM) costs and reported as mean and standard deviation (SD). Patients with a capitated payment plan were excluded from the cost analysis.Results: 1,267 treated DLBCL patients were identified. Median follow-up from index diagnosis date was 19.5 months (interquartile range: 8.8, 37.3). Over the follow-up period, 66.0% of patients had ≥1 inpatient admission, with more patients having a non-DLBCL-related than DLBCL-related admissions (Table 1). 60.0% of patients had ≥1 emergency room visit over the follow-up period; visits were predominately for non-DLBCL-related. Nearly all patients had ≥1 physician office visits (92.4%) and other outpatient visits (99.6%). The mean PPPM costs incurred during the follow-up period was $11,890 (SD: $11,515) (Table 1), and costs were higher in Year 1 ($14,402, SD: $10,951) than in Year 2 ($4,190, SD: $8,076). About 55% of costs overall were related to DLBCL-medical services ($6,532 PPPM, SD: $6,457). DLBCL-related medical PPPM costs decreased substantially from Year 1 ($8,327, SD: $5,925) to Year 2 ($1,443, SD: $4,349). This decrease was driven by the decreases in chemotherapy and supportive care medical services from Year 1 to Year 2. Non-DLBCL-related medical costs accounted for about 42% of the overall PPPM costs ($4,955, SD: $7,210); and a decrease was observed from Year 1 ($5,640, SD: $7,468) to Year 2 ($2,447, SD: $5,456). Inpatient admission was the main component of non-DLBCL-related costs, and associated costs decreased from Year 1 to 2.Conclusions: The economic burden associated with the treated DLBCL population is high, with the majority of costs incurred during the first year of diagnosis. Between the first and second year of diagnosis, costs decrease mainly because of the decrease in the DLBCL-related treatment costs. In addition, HCU for DLBCL-related services decreased in Year 1 vs Year 2. [Display omitted] DisclosuresGalaznik:Takeda Pharmaceuticals: Employment, Equity Ownership. Bell:Takeda Pharmaceuticals: Employment, Equity Ownership. Hamilton:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Consultancy; Xcenda: Employment. Ogbonnaya:Xcenda: Employment; Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Consultancy. Hennenfent:Xcenda: Employment; Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Consultancy. Eaddy:Xcenda: Employment; Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Consultancy. Shou:Takeda Pharmaceuticals: Employment, Equity Ownership.

Red blood cell membrane trans fatty acid levels and risk of non-Hodgkin lymphoma: a prospective nested case–control study

Trans fatty acid (TFA) intake persists in much of the world, posing ongoing threats to public health that warrant further elucidation. Published evidence suggests a positive association of self-reported TFA intake with non-Hodgkin lymphoma (NHL) risk. To confirm those reports, we conducted a prospective study of prediagnosis RBC membrane TFA levels and risk of NHL and common NHL histologic subtypes. We conducted a nested case-control study in Nurses' Health Study and Health Professionals Follow-Up Study participants with archived RBC specimens and no history of cancer at blood draw (1989-1090 and 1994-1995, respectively). We confirmed 583 incident NHL cases (332 women and 251 men) and individually matched 583 controls on cohort (sex), age, race, and blood draw date/time. We analyzed RBC membrane TFA using GLC (in 2013-2014) and expressed individual TFA levels as a percentage of total fatty acids. We used unconditional logistic regression adjusted for the matching factors to estimate ORs and 95% CIs for overall NHL risk per 1 SD increase in TFA level and assessed histologic subtype-specific associations with multivariable polytomous logistic regression. Total and individual TFA levels were not associated with risk of all NHL or most subtypes. We observed a positive association of total TFA levels with diffuse large B cell lymphoma (DLBCL) risk [n=98 cases; OR (95% CI) per 1 SD increase: 1.30 (1.05, 1.61); P=0.015], driven by trans 18:1n-9(ω-9)/elaidic acid [OR (95% CI): 1.34 (1.08, 1.66); P=0.007], trans 18:1n-7/vaccenic acid [OR (95% CI): 1.28 (1.04, 1.58); P=0.023], and trans 18:2n-6t,t [OR (95% CI): 1.26 (1.01, 1.57); P=0.037]. Our findings extended evidence for TFA intake and DLBCL risk but not for other NHL subtypes. Reduced TFA consumption through dietary choices or health policy measures may support prevention of DLBCL, an aggressive NHL subtype.

ABCL-119: Epidemiology and Subtype Distribution of Non-Hodgkin Lymphoma Neoplasms from Two Institutions in Lebanon Between 1984 and 2019

Context: Patients diagnosed with Non-Hodgkin Lymphoma (NHL) have been the subject of many epidemiologic studies done at the time that aimed to explain the distribution of different subtypes among different countries. Because there is unpublished data and only a small percentage of all newly Lebanese cancer cases are diagnosed in tertiary hospitals, there is constant need of studies to supplement the literature. Objective: To establish a descriptive status of NHL histological subtypes distribution in Lebanon, thus identifying the most common types, knowing that the literature is poor regarding the distribution of lymphoid malignancies, particularly NHLs in Lebanon. Design: Multicenter retrospective cohort data analysis. Setting: Two Lebanese medical centers. Patients or other participants: Patients aged above 18 years, diagnosed with NHL between January 1984 and March 2019 inclusive, were included in the study. Interventions: 699 medical files were extracted from the hospital archives and reviewed. The baseline characteristics of the patients and the disease at presentation were collected. Histological classification was based on the Working Formulation (WF) and the World Health Organization (WHO) classification systems for patients diagnosed before and after 2001, respectively, whereas staging was based on the Ann Arbor system. Disease status and response to chemotherapy regimens were monitored with imaging studies. Results: The mean age at diagnosis was 53.52 ± 17.46 years in the studied population, with 380 (54.4%) males and 319 (45.6%) females. The mean age for males was 53.56 ± 17.95 years, and for female 53.48 ± 16.87 years (p=0.954). B-cell lymphoma (BCL) accounted for 86.3% while T-cell neoplasms accounted for 13.7%. The most common subtype was diffuse large B-cell lymphoma (54%) followed by follicular lymphoma (17.2%). Mantle cell lymphoma represents 3% of all BCL and small lymphocytic lymphoma comprised less than 2%. MALT and Burkitt lymphomas represented 3% and 1.7%, respectively. 36.5% of the patients had extranodal disease at diagnosis. High-grade tumor represented 80.1% with 33.1% stage IV disease. Conclusions: These observations indicate that the epidemiological patterns of NHLs in Lebanon were slightly comparable to Western countries. Aggressive lymphomas account for the majority of NHLs in Lebanon.

Posterior reversible encephalopathy syndrome presenting as acute blindness

Introduction: Diffuse large B-cell lymphoma (DLBCL) is the most common histologic subtype of non-Hodgkin lymphoma (NHL) accounting for approximately 25–30% of NHL cases. The treatment is based upon stage and extent of disease. In most cases, NHL is treated with systemic chemotherapy and sometimes also radiation. As it is well known, there are numerous side effects to chemotherapy that includes rituximab. We are here to present one rare side effect of treatment called posterior reversible encephalopathy syndrome (PRES).

A Phase 2 Study of MT-3724 to Evaluate Safety, Pharmacodynamics and Efficacy of MT-3724 for the Treatment of Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma

Introduction: Diffuse large B-cell lymphoma (DLBCL) is the most common histologic subtype of non-Hodgkin Lymphoma (NHL) accounting for approximately 30-40% of NHL cases. Approximately 40% of all newly diagnosed DLBCL patients are either refractory or relapsed following initial response to therapy and represent a population with high unmet need for new therapeutic strategies to achieve or regain disease remission. Because of the near ubiquity and persistence of CD20 expression in B-cell malignancies, there is strong rationale to develop compounds with novel mechanisms of action targeting CD20. However, CD20's non-internalizing nature has, to date, leveraged only cytotoxic mechanisms such as antibody-dependent cellular cytotoxicity to which resistance can arise and has impeded the development of agents that internalize a cytotoxic payload. MT-3724 is a novel engineered toxin body designed to overcome this limitation by combining the specific target selectivity of a single chain variable fragment with the lethality of a genetically fused Shiga-like toxin A subunit that facilitates both internalization and cell killing by inactivating ribosomal protein synthesis. MT-3724 has been shown to specifically bind and kill CD20+ malignant human B-cells in vitro (IC50 <1 nM) and in CB17 SCID and PDX mice (Rajagopalan 2016; Huang 2018). As a direct-kill immunotoxin against CD20, MT-3724 has achieved clinical response in subjects with relapsed NHL regardless of acquired resistance to other treatments. Thus, MT-3724 could be a valuable addition to the armamentarium of treating DLBCL. Study Design and Methods: MT-3724 is being evaluated in this Phase 2 study as monotherapy (NCT02361346) in adult subjects with histologically confirmed, relapsed or refractory DLBCL. The primary objective is to determine the efficacy of MT-3724 as monotherapy based on the overall response rate (ORR) by the revised Lugano Classification for Lymphoma adjusted according to immunomodulatory therapy criteria (LYRIC), hereinafter referred to as "revised Lugano Criteria" (Cheson 2014, 2016). Overall response rate is defined as the proportion of subjects with either a complete response or a partial response as determined by independent, blinded central review. Secondary objectives include safety, progression‐free survival, investigator‐assessed ORR, duration of response, and overall survival as well as pharmacokinetics and pharmacodynamics, immunogenicity, and quality of life. To be eligible, patients must have histologically confirmed, relapsed or refractory DLBCL, have received at least 2 standard of care systemic NHL treatment regimens, and have measurable disease according to the revised Lugano criteria. Since rituximab and MT-3724 compete for the same CD20 domain, subjects must have serum rituximab levels < 500 ng/mL before the start of treatment to allow adequate binding of MT-3724. This single arm phase 2 study is being conducted in three stages, where the first two stages will follow the Simon two-stage optimal design [Simon 1989]. Subjects will be enrolled in successive cohorts with each cohort evaluated for efficacy before opening the subsequent cohort, toward a total sample size of 100 subjects. Subjects will receive MT-3724 as an IV infusion over 1 hour on Days 1, 3, 5, 8, 10 and 12 of a 21-day treatment cycle. All subjects will be treated with a 50 µg/kg/dose of MT-3724, which was the recommended Phase 2 dose, as determined in the Phase 1/1b portion of the trial. Sites are open and recruiting in the US, Canada, and Europe. Disclosures Persky: Sandoz: Consultancy; Debiopharm: Other: Member, Independent Data Monitoring Committee; Bayer: Consultancy; Morphosys: Other: Member, Independent Data Monitoring Committee. Musteata:Arensia EM: Other: Principal Investigator; Institute of Oncology: Employment. Strack:Molecular Templates, Inc.: Employment. Burnett:Molecular Templates, Inc.: Employment. Wilson:Molecular Templates, Inc.: Employment. Baetz:Bristol Meyers Squibb: Other: Advisory board; Merck: Other: Advisory board; Gilead: Other: Advisory board; Roche: Other: Advisory board.

A Phase 2a Open-Label Study to Investigate Safety and Tolerability (including the MTD), Efficacy, Pharmacokinetics, Pharmacodynamics and Immunogenicity of MT-3724 in Combination with Lenalidomide in Subjects with Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma

Introduction: Diffuse large B cell lymphoma (DLBCL) is the most common histologic subtype of Non-Hodgkin Lymphoma (NHL) accounting for approximately 30-40% of NHL cases. Approximately 40% of all newly diagnosed DLBCL patients are either refractory or relapsed following initial response to therapy and represent a population with high unmet need for new therapeutic strategies to achieve or regain disease remission. Because of the near ubiquity and persistence of CD20 expression in B-cell malignancies, there is strong rationale to develop compounds with novel mechanisms of action targeting CD20. However, CD20's non-internalizing nature has, to date, leveraged only cytotoxic mechanisms such as antibody-dependent cellular cytotoxicity to which resistance can arise, and has impeded the development of agents that internalize a cytotoxic payload. MT-3724 is a novel engineered toxin body designed to overcome this limitation by combining the specific target selectivity of a single chain variable fragment with the lethality of a genetically fused Shiga-like toxin A subunit that facilitates both internalization and cell killing by inactivating ribosomal protein synthesis. MT-3724 has been shown to specifically bind and kill CD20+ malignant human B-cells in vitro (IC50 <1 nM) and in CB17 SCID and PDX mice (Rajagopalan 2016; Huang 2018). Given MT-3724's unique ability to kill CD20+ cells by ribosomal inhibition, combining MT-3724 with standard cytotoxic chemotherapy and/or immune modulatory agents may provide enhanced benefit in NHL treatment algorithms. To evaluate this possibility, MT-3724 was tested in combination with Lenalidomide (LEN) to assess additive, synergistic or antagonistic effects in CD20-positive Daudi cell lines. This combination significantly (Ki = 0.40) potentiated cytotoxicity. Based on these results and the known safety profile of MT-3724, LEN was chosen as a combination agent to maximize anti-tumor effects in patients with B-cell NHL while minimizing overlapping toxicity risks. Study Design and Methods: MT-3724 is being evaluated in this Phase 2a study (NCT03645395) in combination with LEN in adult patients with histologically confirmed, relapsed or refractory NHL. The primary objective of this study is to determine the safety and tolerability, including the maximum tolerated dose (MTD), of MT-3724 + LEN. Secondary objectives include pharmacokinetics (PK), pharmacodynamics (PD), immunogenicity and tumor response in subjects treated with MT-3724 + LEN. The study will be conducted in two parts. Part 1 will include MT-3724 dose escalation according to the modified 3+3 design to identify the MTD of MT-3724 in combination with standard doses of LEN and will include up to 24 subjects with histologically confirmed NHL. Part 2 is designed to confirm the safety and tolerability of MT-3724 + LEN in the MTD Expansion Cohort, where the dose declared as MTD of MT-3724 in Part 1 would be given in combination with LEN in up to 40 subjects with CD20+ DLBCL. In addition, the PK, PD, immunogenicity and tumor response of MT-3724 + LEN will be evaluated in Part 2. Eligible subjects will have histologically confirmed, relapsed or refractory CD20+ B-cell NHL that, in the investigator's opinion, could benefit from MT-3724 + LEN therapy. Patients must have received all approved therapies for NHL that are applicable for the patient in the opinion of the treating physician and must have measurable disease by Lugano Classification for NHL. Subjects that are refractory to treatment are eligible, as well as patients who have progressed following CAR T-cell therapy, autologous- or allogeneic stem cell transplant. Serum rituximab level must be negative (<500 ng/mL) at screening. Subjects will receive MT-3724 IV infusions over 1 hour on Days 1, 3, 5, 8, 10 and 12 and will receive LEN on days 1-21 of each 28-day treatment cycle during cycles 1 and 2. Thereafter, MT-3724 will be administered weekly on Days 1, 8, 15, and 22 of each cycle with continued LEN dosing on Days 1-21 for cycles 3 to 6. The study is currently ongoing. Eligible subjects will be identified and treated through competitive enrollment at multiple study centers in North America. Disclosures Burnett: Molecular Templates, Inc.: Employment. Gordon:Abbott: Equity Ownership; Abbvie: Equity Ownership. Strack:Molecular Templates, Inc.: Employment. Lehner:Molecular Templates, Inc.: Employment. Higgins:Molecular Templates, Inc.: Employment, Equity Ownership.

Prognostic Validation of Diffuse Large B Cell Lymphoma International Prognostic Index for High Grade B Cell Lymphoma with and without MYC and BCL2 or BCL6 Rearrangements: An Institutional Review

Background: Diffuse large B cell lymphoma (DLBCL) NOS is the most common histologic subtype of non-Hodgkin lymphoma (NHL). Double hit lymphoma is re-classified as high-grade B cell lymphoma, with and without MYC and BCL2 or BCL6 rearrangements (HGBCL) in 2016. The International Prognostic Index (IPI) is the main prognostic tool for DLBCL NOS. We aimed to identify if IPI index scores can accurately predict the prognosis in patients with HGBCL. Methods: We observed the outcome of a cohort of patients (pts) with DLBCL NOS and HGBCL diagnosed and treated from 2008-2019 at SUNY Upstate Medical University. Fisher's exact test was used for the 2X2 comparison analysis. Results: 24 pts (82.8%) had DLBCL NOS and 5 (17.2%) pts had HGBCL. The median age was 58 yrs (13-81 yrs). 65.5% were males and 79.3% were caucasians. 8 pts had bone marrow involvement, 1 pt had brain metastasis and 12 pts had bulky disease. 15 DLBCL NOS pts (68.2%) and 4 HGBCL pts (80%) had low-intermediate IPI (</=3). 7 DLBCL NOS pts (31.8%) and 1 HGBCL pt (20%) had high IPI (>/=4). 2 DLBCL NOS pts (13.33%) vs 1 HGBCL pt (25%) died in the low-intermediate IPI group. None of the DLBCL NOS pts (0%) vs 1 HGBCL pt (100%) died in the high risk group. Conclusion: Our study sample size is very small to identify prognostic relation of IPI score to predict the outcome for HGBCL. Our observation raises the hypothesis that patient with HGBCL might have a worse prognosis despite low IPI score which needs to be validated in a larger study population. Disclosures No relevant conflicts of interest to declare.

Single Cell Phenotypic Profiling of 27 DLBCL Cases Reveals Marked Intertumoral and Intratumoral Heterogeneity.

Diffuse large B-cell lymphoma (DLBCL) is the most common histologic subtype of non-Hodgkin lymphoma and is notorious for its clinical heterogeneity. Patient outcomes can be predicted by cell-of-origin (COO) classification, demonstrating that the underlying transcriptional signature of malignant B-cells informs biological behavior in the context of standard combination chemotherapy regimens. In the current study, we used mass cytometry (CyTOF) to examine tumor phenotypes at the protein level with single cell resolution in a collection of 27 diagnostic DLBCL biopsy specimens from treatment naïve patients. We found that malignant B-cells from each patient occupied unique regions in 37-dimensional phenotypic space with no apparent clustering of samples into discrete subtypes. Interestingly, variable MHC class II expression was found to be the greatest contributor to phenotypic diversity. Within individual tumors, a subset of cases showed multiple phenotypic subpopulations, and in one case, we were able to demonstrate direct correspondence between protein-level phenotypic subsets and DNA mutation-defined subclones. In summary, CyTOF analysis can resolve both intertumoral and intratumoral heterogeneity among primary samples and reveals that each case of DLBCL is unique and may be comprised of multiple, genetically distinct subclones. © 2019 International Society for Advancement of Cytometry.

Surveillance imaging in pediatric lymphoma.

Current therapies used in treating children with Hodgkin lymphoma and many histological subtypes of non-Hodgkin lymphoma have resulted in overall survival rates exceeding 90% in many instances. With increasing concerns related to the cost of radiologic imaging, exposure to ionizing radiation, and potential false-positive results, the role of routine off-therapy surveillance imaging has been called into question. Although radiologic imaging plays an important role in diagnosing and assessing treatment response, in these children - the majority of whom have an excellent outcome following completion of therapy - there is an opportunity to dramatically reduce the number of off-therapy imaging evaluations. This review summarizes several recent studies in both Hodgkin and non-Hodgkin lymphoma providing evidence to support these efforts. In addition, we propose a surveillance imaging strategy that uses a novel risk-adapted and response-based approach to determine which children would most benefit from off-therapy imaging surveillance.

A Prospective Analysis of Red Blood Cell Trans Fatty Acid Levels and Risk of Non-Hodgkin Lymphoma

Abstract To confirm previous reports of increased non-Hodgkin lymphoma (NHL) risk with higher intake of dietary trans fatty acids (TFA), we conducted the first prospective study of pre-diagnosis red blood cell (RBC) TFA levels and risk of NHL and common NHL histologic subtypes (diffuse large-B cell lymphoma (DLBCL), follicular lymphoma, chronic lymphocytic lymphoma/small lymphocytic leukemia, other B-cell NHL, T-cell NHL). Methods: We conducted a nested case-control study in Nurses' Health Study (NHS) and Health Professionals Follow-Up Study (HPFS) participants with archived RBC specimens and no history of cancer at sample collection (NHS: 1989–90; HPFS: 1994–5). We confirmed 583 NHL cases (332 women in NHS, 251 men in HPFS) and matched 583 controls by cohort (sex), age, race/ethnicity and blood draw date/time. We analyzed RBC TFAs using gas-liquid chromatography; individual TFA levels were expressed as a percentage of total fatty acids. We used unconditional logistic regression, adjusted for the matching factors, to estimate odds ratios (OR) and 95% confidence intervals (CI) for overall NHL risk per 1 standard deviation (SD) unit increase in TFA level. We fitted multivariate polytomous logistic regression models to assess associations for the specific subtypes listed above. Results: Total and individual RBC TFAs were not associated with overall NHL risk or risk of most histologic subtypes. However, we observed a positive association of total RBC TFA with DLBCL risk (n = 86 cases; OR [95% CI] per 1 SD: 1.29 [1.02, 1.64]), driven primarily by 18:1 TFAs (1.35 [1.07, 1.72]). Among 18:1 TFA isomers, we found a positive association for trans 18:1 n-9 (elaidic acid; 1.33 [1.05, 1.68]) but not for other isomers. Conclusions: We observed significant positive associations for RBC TFA levels with DLBCL risk. These findings are consistent with published studies of self-reported TFA intake; further, previous studies have shown that TFA levels – particularly trans 18:1n-9, which is industrially-derived – are positively correlated with biomarkers of inflammation and immune activation, supporting the biologic plausibility of our findings. Food industry and public health measures to diminish TFA intake may help to reduce risk of NHL, and particularly of DLBCL.

5-Hydroxymethylcytosines of Circulating Cell-Free DNA and Prognosis in Diffuse Large B-Cell Lymphoma

Background: Elevated levels of circulating cell-free DNA (cfDNA) have been associated with poor prognosis and relapse in patients with diffuse large B-cell lymphoma (DLBCL). However, the tumor-specific molecular targets in cfDNA that have prognostic significance remain unclear. We investigated the association between 5-hydroxymethylcytosine (5hmC), a mark of active demethylation and gene activation, in cfDNA from plasma and prognosis in DLBCL.Methods: We used the 5hmC-Seal, a highly sensitive chemical labeling technique integrated with next-generation sequencing (NGS), to profile 5hmC in plasma cfDNA samples from Caucasian patients at the University of Chicago who were newly diagnosed with DLBCL (n=43) or follicular lymphoma (FL, n=28), the two most common histological subtypes of non-Hodgkin lymphoma (NHL), in 2011-13. Baseline clinical, laboratory, and vital status data were abstracted from medical records. Patients were followed through December 31, 2017 and those who relapsed after completion of treatment, lost to follow-up, or died were censored. We profiled 5hmC with 1-2 ng of cfDNA extracted from ~2 ml of plasma for library construction and the NGS. We obtained ~25 million reads per sample, providing a depth of coverage ~600X in terms of gene bodies. We normalized read counts and identified differential 5hmC markers using DESeq2. Cox proportional hazards model were used to estimate the association between 5hmC markers and overall survival.Results: We found that in cfDNA from DLBCL patients, 5hmC markers were enriched within gene bodies and depleted in CpG islands. The cfDNA-based 5hmC profiles at diagnosis differed between DLBCL and FL, and in DLBCL, the 5hmC profiles differed between Ann Arbor stage (stage 1/2 vs stage 3/4), lactate dehydrogenase (LDH) level (normal vs elevated), and cell-of-origin (germinal center B-like and activated B-cell-like DLBCL). In addition, genome-wide 5hmC distribution patterns in cfDNA samples are highly correlated with those found in cfDNA-paired tumor tissues, supporting the tumor relevance of cfDNA in a patient. Next, we evaluated the prognostic significance of cfDNA-based 5hmC in DLBCL using a two-step approach. In the discovery phase (7 DLBCL patients with relapse and 12 age- and sex-matched patients without relapse within two years following treatment), a substantial number of 5hmC markers were associated with relapse (449 gene bodies at 5% false discovery rate [FDR]). These relapse-associated 5hmC signatures showed high sensitivity, specificity, and overall accuracy (area under curve [AUC]=0.91) in predicting relapse in the independent validation set (relapse=5, no relapse=13). Finally, we identified a panel of 128 5hmC markers (fold change >20% and p-value <0.05) that were associated with 4-year overall survival.Conclusion: These findings suggest that 5hmC signatures in cfDNA at the time of DLBCL diagnosis correlate with standard clinical prognostic indices and hold promise as non-invasive markers for prognosis and survival. DisclosuresSmith:BMS: Consultancy; Portola: Honoraria.

Anthropometric Traits and Risk of Non-Hodgkin Lymphoma (NHL) and Major NHL Subtypes: A Pooled Prospective Analysis

Background: Collectively, non-Hodgkin lymphomas (NHL) are expected to account for >95,000 new cancer diagnoses and >24,000 cancer deaths in the United States in 2018. Few NHL risk factors are known other than severe immune compromise, family history of lymphoid malignancies, and some pathogens. Evidence for modifiable risk factors that could inform prevention strategies is limited, especially from prospective studies. An association of anthropometric traits with NHL risk is biologically plausible given the emerging knowledge that obese individuals have heightened inflammation and deregulation of endogenous hormonal pathways that can influence cell cycle control and lymphocyte activation. We undertook the present prospective study to elucidate the associations of young (aged 18-21 years) and usual adult body mass index (BMI), height, weight, and waist circumference with risk of NHL and major histologic subtypes of NHL. The completed analysis will leverage the resources of several large population samples across the United States with prospectively assessed repeated measures of anthropometric traits and high rates of follow-up for disease ascertainment.Methods: We pooled data from large prospective cohort studies with repeated measures of anthropometric traits and follow-up over 23 - 38 years for cancer endpoints, including the Cancer Prevention Study-II (CPS-II) Nutrition Cohort, Health Professionals Follow-up Study (HPFS), Nurses' Health Study (NHS), and NHS II. Incident NHL diagnoses were confirmed by review of medical records or cancer registries, and classified for histologic subtype according to the WHO classification scheme and corresponding InterLymph-recommended analytic groups: chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and T-cell NHL (T-NHL). Weight was ascertained approximately every two years throughout follow-up, all other anthropometric measures were ascertained on a single survey, usually at baseline. We considered cumulative average of BMI (hereafter “usual adult BMI”) by averaging across all completed cohort-specific questionnaires. Current weight was analyzed as time-varying. In cohort- and sex-specific analyses, there was no evidence of statistically significant heterogeneity; thus we pooled directly across cohorts to maximize our sample size for statistical modeling. Cox proportional hazard regression models adjusted for age, cohort, and sex were used to estimate hazard ratios (HR) and 95% confidence intervals (CIs) for each trait's association with NHL or NHL subtype risk.Results: The pooled sample comprised 5,005 confirmed incident cases of NHL, including 1117 CLL/SLL, 918 DLBCL, 709 FL and 277 T-NHLs ascertained over 9.4 million person-years of follow-up. There was a significant, positive association of usual adult BMI with NHL overall (HR: 1.05, 95% CI: 1.01-1.08 per 5 kg/m2; Table 1), which was driven by DLBCL (HR: 1.21, 95% CI: 1.12-1.30 per 5 kg/m2). No association was apparent for FL, CLL/SLL or T-NHL. Similarly, waist circumference was associated with NHL risk overall (HR: 1.04, 95% CI: 1.00-1.09 per 15cm), but driven by the association for DLBCL (HR: 1.16, 95% CI: 1.05-1.27 per 15cm). In contrast, a statistically significant or suggestive association for BMI in young adulthood was observed for all NHL endpoints, but again, most strongly with DLBCL (HR: 1.28, 95% CI: 1.15-1.43 per 5 kg/m2). Height was positively associated with all NHL endpoints except T-NHL. Associations for current and young adult weight were similar to those for the corresponding BMI variables.Conclusions: Preliminary results from this prospective analysis suggest that, unlike BMI later in life, young adult BMI is consistently associated with all major subtypes of NHL. In contrast, usual adult BMI and waist circumference are uniquely associated with DLBCL. In general, the strongest associations with anthropometric factors were observed for DLBCL. Further analyses of these data are ongoing, including efforts to incorporate data from two additional large cohorts. These findings further demonstrate the etiologic heterogeneity of NHL subtypes and underscore the importance of maintaining a healthy body weight throughout life, including at younger ages. [Display omitted] DisclosuresChao:Seattle Genetics: Research Funding.

Abstract 2215: The role of primary lymph node sites in survival and mortality prediction in DLBCL: A SEER population-based retrospective study

Abstract Background Diffuse large B cell lymphoma (DLBCL) is the most common histological subtype of non-Hodgkin lymphoma (NHL), accounting for 25% of NHL subtypes. Usually associated with classic B-symptoms, such as fever, weight loss and night sweats in about 30% of patients, accompanied with elevated lactate dehydrogenase. Approximately in 25-40% of DLBCL cases, the disease arises from extra-nodal sites, such as stomach/gastrointestinal tract. Differences in clinical outcomes between extra-nodal and nodal site involvement suggest that both types should be considered as different entities. Our study aims to identify the role of primary nodal site as predictive tool for clinical and survival outcomes in patients with DLBCL. Methods Our study was based on data from the Surveillance, Epidemiology, and End Results program database. We used the Kaplan-Meier curve, log-rank test, and Cox proportional hazard regression models to examine predictors affecting the DLBCL survival. We used the multi-variable analysis to get overall survival (OS) as well as the disease-specific survival (DSS). Results From a total of 34,231 DLBCL patients were identified. The mean age was 61.3 years. The majority had multiple regions (M) lymph nodes (LNs) (18,044, 52.7%) followed by head, face and neck (HFN), intra-abdominal, intra-thoracic, axilla or arm (AA), inguinal or leg (IL) then pelvic LNs. Moreover, male, unmarried, black or Asian/Pacific Islander, older patients, advanced stages, and patients did not receive radiation and/or surgery were associated with a worse survival. We found a mean survival time of 61.07 months with OS and DSS of 39.1/54.1% only. The multiple regions, intra-abdominal, intrathoracic LNs were significantly associated with a worse survival. Conclusions DLBCL incidence has increased in the recent years. The multiple regions, intra-abdominal, intrathoracic LNs were significantly associated with a worse survival, suggesting that DLBCL nodal primary site can serve as a simple yet prognostic tool. Hence, we strongly encourage future studies to compare DLBCL patients' survival affected by these aggressive primary sites with other unfavorable predictors in IPI. Moreover, biomarkers, within these aggressive sites, may demonstrate their aggressive behaviors. Furthermore, more studies need to shed the light on the biological theory beyond these aggressive primary sites and to validate its reliability. Citation Format: Mohamed Gomaa Kamel, Fatma A. Abd-Elhay, Sara Morsy, Amr E. El-Qushayri, Khaled M. Elhusseiny, Muhammed K. Elfaituri, Ahmed M. Kamel, Sherief Ghozy, Nourin A. Sherif, Nguyen Tien Huy. The role of primary lymph node sites in survival and mortality prediction in DLBCL: A SEER population-based retrospective study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2215.

Diffuse large B-Cell lymphoma-review

Diffuse large B cell lymphoma (DLBCL) is the most common histologic subtype of non-Hodgkin lymphoma (NHL) accounting for approximately 30 percent of all NHL cases, involving both nodal and extra-nodal sites. Apart from distinct morphological and clinicopathological subtypes, DLBCL can be dived into molecular subtypes, Germimal Centre Subtype (GCB) and Activated B-Cell (ABC) based on gene expression profiling. IPI (International Prognostication Index) and its variants are used to prognosticate the patients. Limited stage DLBCL is primarily treated with combined modality therapy consisting of abbreviated systemic chemotherapy (three cycles), and involved field radiation therapy, whereas advanced stage disease is treated with full course of chemotherapy with recommendation of addition of novel agents ( Bortezomib, Ibrutinib, Lenalidomide) in ABC type DLBCL.

A Rare Case of Primary Hepatic B-cell Lymphoma and Upper Gastrointestinal Hemorrhage

Diffuse large B-cell lymphoma (DLBCL) is the most common histologic subtype of non-Hodgkin lymphoma(NHL) accounting for approximately 25 % of all NHL cases. Extranodal extramedullary involvement occurs in up to 40% of cases. The most common site for extranodal extramedullary lymphoma is the stomach. Primary hepatic lymphoma is rare with a prevalence of 0.4% among extranodal NHL and 0016% among all NHLs. We hereby present a rare case of a 70-year old female with diffuse large B-cell lymphoma of the liver who had a metastasis to stomach resulting in a gastric ulcer. 70-year old female with a history of chronic hepatitis B infection, hypertension, recent admission for deep vein thrombosis (on Lovenox) and recently diagnosed via liver biopsy, of DLBCL of the liver presented to our hospital with episodes of melena and sharp epigastric pain after meals, for 1 week duration. The patient denied having any other complaints. Physical exam was unremarkable except distended abdomen with palpable epigastric abdominal mass and negative rectal exam. Lab results were significant for Hgb 7.1 of gm/dL, LDH of 2200 U/L, mildly elevated AST, ALT and ALP and normal total and direct bilirubin levels. Endoscopy was performed which revealed clean based ulcer of 6 mm x 4 mm in the body of stomach, with heaped margins and surrounding erythema with no signs of active bleeding, moderate size flat clean based duodenal bulb ulcer and sub-mucosal raised nodule of 6 mm x 3 mm in 2nd portion of the duodenum. Biopsy from gastric ulcer was determined to be positive for DLBCL with the similar pattern as seen in a Liver biopsy. Review of literature indicates that there are no reported cases of primary hepatic lymphoma presented with gastric ulceration and secondary gastrointestinal hemorrhage. Moreover, it should be known that the association found in the case presented carries morbidity and should be listed as part of a working differential in a patient with Hepatic B-Cell Lymphoma who are admitted with gastrointestinal hemorrhage.Figure