NHL Cases Research Articles

EMERGING ACTIVITY OF CELLULAR IMMUNOTHERAPY FOR TREATMENT OF CANCER IN BRAZIL

Chimeric antigen receptor T-cells (CAR T cells) are genetically modified cellular immunotherapies approved for standard of care treatment of patients with lymphoma and leukemia worldwide. Here we report the initial activity in Brazilian centers through the collaboration between the Brazilian Cellular Therapy and Bone Marrow Transplant Society (SBTMO) and Center for International Blood and Marrow Transplant Research (CIBMTR). A total of 38 patients who received CAR T cells between 2020 and 2023. The median age was 47 years (range 4-77). Indications include Non-Hodgkin Lymphoma (NHL; 26 cases; 68%), Acute Lymphoblastic Leukemia (ALL; 9 cases; 24%), and Multiple Myeloma (MM; 3 cases; 8%). 84% (75% - 24 NHL cases and 25% - 8 ALL cases) were commercial. This report demonstrates the initial implementation of CAR T cells in Brazil among centers that report to the SBTMO/CIBMTR. This infrastructure will assist in further capturing the activity, assessing the outcomes, and complying with regulatory requirements.

Abstract 3165: Targeting angiogenesis for improved survival in mantle cell lymphoma

Abstract Mantle cell lymphoma (MCL) is a subtype comprising 6% of all NHL cases and is characterized by overexpression of cyclin D1 due to chromosomal translocation t(11;14) in the nodal MCL subtype. One of the best discriminatory genes between these conventional and indolent MCL tumors is SOX11; in addition, SOX11 has been shown to promote angiogenesis in MCL. Further SOX11 protein expression in MCL patients correlated with increased microvascular density and poor outcomes. Bulk transcriptomics analysis was performed on MCL patients (n=24) and CD19-purified B cells from healthy donors (HD,n=3). To understand the role of the angiogenic process in MCL, we queried 141 genes related to angiogenesis (GO:0001525). Our analysis showed that many genes involved in angiogenesis were predominantly overexpressed in MCL compared to HD, including FLT1 and KDR (p-value;0.05; FC>2). SOX11 has been shown to regulate PDGFA in MCL cell lines. Consistent with this observation, we also see upregulated PDGFA levels in MCL patients. However, PDGFA upregulation was not statistically significant in our analysis. Further expression of VEGFR2 is overexpressed in MCL Patients (n=122) compared to naïve or activated-B cells from HD. We validated that VEGFR2 protein levels were higher in MCL primary patients than in healthy donor PBMC. Further, in two independent cohorts, high VEGFR2 expression shows significant adverse effects on 5-year overall survival (OS). To explore the potential of targeting VEGFR, we utilized lucitanib, which potently and selectively inhibits VEGFRs. Treatment with lucitanib resulted in a dose-dependent decrease in cell viability and cellular death as determined by Annexin PI staining; further, MCL cells treated with lucitanib showed inhibition of autophosphorylation of VEGFR2 and demonstrated PARP cleavage associated with cytotoxicity in-vitro. To assess the role of VEGFR2 inhibitor lucitanib as a single agent in MCL growth in-vivo, we utilized two different murine models of MCLs. First, we used cell-line-derived xenograft (CDX) models of MCL where Jeko-1 and HS5 cells were injected together, followed by treatment (lucitanib;15mg/kg QOD; IP) and measured tumor volume until the ERC of any experimental mice was reached. Kaplan-Meier survival graphs were plotted, demonstrating that lucitanib treatment prolongs survival in-vivo. Further, to confirm if the lucitanib can provide an overall survival benefit in the systemic PDX MCL model, we injected the PDX cells via the tail vein in NSG mice and followed human-B2M levels for disease progression, and overall survival was the endpoint. Lucitanib treatment significantly prolonged median overall survival significantly in the systemic MCL model. Our data demonstrates that targeting angiogenesis in MCL can provide therapeutic benefits, as demonstrated in preclinical MCL models. Citation Format: Satishkumar Singh, Anuvrat sircar, Audrey Odier, Narendranath Epperla, Natarajan Muthusamy, Samir Parekh, Lalit Sehgal. Targeting angiogenesis for improved survival in mantle cell lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3165.

Clinicopathological Profile of Primary Extra Nodal Lymphoma from a Tertiary Care Center in South India.

Primary extranodal lymphoma (pENL) is a malignant lymphoid neoplasm that presents with the main bulk of disease at an extranodal site. The incidence of primary pENL has risen sharply in recent years due to the advent of better diagnostic modalities. Diagnosing pENL can be challenging due to its morphological overlap with other tumors native to the site of origin. This study aims to establish the anatomic distribution, clinical presentations, possible etiologic correlations, and histological subtypes of pENL in a tertiary care center located in South India. This is a retrospective study of 109 patients with pENL (69 males, 40 females, M: F = 1.7:1) over 5 years (October 2012 to September 2017). The tumors were reclassified according to WHO classification of Haematolymphoid tumors, 5th edition, 2022. pENL constituted 109/481 cases (22.6%) of all NHL cases, with the highest incidence in 7th decade. The gastrointestinal tract (39%) was the predominant site involved, followed by head and neck (26%). Diffuse large B cell lymphoma (DLBCL) was the most common histomorphological variant followed by Follicular lymphoma (FL). The majority of the patients were immunocompetent (89%) and presented with stage IV disease (31.1%) at diagnosis. This study presents an overview of the diverse distribution patterns of both common and rare pENL within a tertiary care center. The accurate diagnosis of pENL necessitates the elimination of secondary extranodal involvement. It is important to note that the accurate diagnosis of pENL requires careful evaluation and exclusion of other possible causes.

A Retrospective Analysis of the Trends in Mantle Cell Lymphomas in the United States

Introduction: Mantle Cell Lymphoma (MCL) refers to the malignant B lymphocytes arising from the outer (mantle) zone of the lymphoid follicle. This rare and aggressive subtype of Non-Hodgkin Lymphoma, which accounts for ~5 percent of all NHL cases. It is associated with t(11:14) that leads to over-expression of cyclin D1, resulting in tumor cell proliferation via cell cycle dys-regulation, chromosomal instability, and epigenetic regulation. The aim of this study is to understand the epidemiology and survival predictors of MCL. Methods: The data was collected from Surveillance, Epidemiology and End Result database Research Plus Data, 17 Registries, Nov 2022 Sub (2000-2020). We extracted Mantle Cell Lymphoma cases diagnosed after 20 years of age, with Lymphoid neoplasm recode 2(a)2.1.3. The analysis was stratified based on age, sex, racial incidence rates, & survival curves based were compared, using the Log-rank test (GraphPad Prism). Results: A total of 14166 cases of MCL were found between 2000 to 2020. Out of these, ~70.73% cases were males, and ~29.27% were females. The median age at the time of diagnosis was 69 years. Of the affected population, ~80.60% were Caucasians, ~3.92% were African-Americans, ~4.10% were Asians/Pacific Islanders, only ~0.50% were American Indians/Alaskan Natives, and ~10.32% were Hispanics. The incidence per 1,000,000, as of 2020, was 10.83 for the general population, 13.00 for Caucasians, 5.01 for African-Americans, 13.71 for American Indians/Alaskan Natives, 3.28 for Asians/Pacific Islanders, and 9.43 for Hispanics. Survival curves were not significant when compared based on the race of the patients. However, survival curves showed statistical significance when compared based on gender, with median of survival (mOS) for males was 50 months, and for females mOS was 56 months (p-value 0.0.008, Hazard Ratio 1.084 [Confidence Interval 1.035 to 1.136], using Log-rank test. Conclusions: Mantle Cell Lymphoma has a strong predilection for males. It is more commonly diagnosed in the late 60s, median age being 69. Unequal racial distribution was noted, with caucasians (~80%) comprising most of the patient population, and the least commonly encountered were American Indians/Alaskan Natives(~0.50%). However, when incidence rates were calculated per 1,000,000 population in 2020, it was found that the incidence in American Indians/Alaskan Natives (13.71), is drastically higher than the general population(10.83) vs. incidence in Asians/Pacific Islanders(3.28) is significantly lower than the other races. Although race played no role in prognosis, females had better survival rates than males. This retrospective study was done to aid in better understanding of this curable malignancy, despite its rarity, aggressivity and the complexity in treatment.

Mature B-cell lymphomas in adolescents and young adults.

Pediatric non-Hodgkin lymphoma includes over 30 histologies (many with subtypes), with approximately 800 cases per year in the US, compared to>60,000 cases of adult NHL annually. Improvements in survival in pediatric and adolescent mature B cell NHL over the past 5 decades align with the overall success of the cooperative trial model with dramatic improvements in outcomes through dose escalation of chemotherapy and, more recently, targeted therapy with rituximab. Pediatric dose-intense strategies carry risks of long-term consequences, but treatment failure is nearly universally fatal. By comparison, adult mature B cell lymphoma is typically less aggressive and treated with less intense chemotherapy. Optimizing therapy for adolescents and young adults remains a major challenge that requires creative solutions, including engineering study groups to combine biologically comparable adult and pediatric populations and developing effective salvage strategies that will ultimately be required for investigations of front-line dose reduction. In this review, we discuss challenges and opportunities for improving outcomes for adolescents and young adults with high-grade mature B cell lymphomas, diffuse large B cell lymphoma, and primary mediastinal B cell lymphoma.

Comparison of Ki67 Proliferation Index in Gastrointestinal Non-Hodgkin Large B-Cell Lymphomas: The Conventional Method of Evaluation or AI Evaluation?

The most common NHL subtype in SEEU is DLBCL (39%), and it manifests with a variety of cellular morphologies and a high proliferation index. Also, the GI tract is the most common site of extranodal NHLs, and most NHLs involving the GI tract are of B-cell lineage, of which diffuse large B-cell lymphoma is the most common subtype, irrespective of location. The last few years have seen digital pathology as a vital technology that has a positive impact on diagnostics, but studies on the use of DP for lymphoma identification, however, are still restricted to only determining whether a tumor is present or absent. Using the example of cases of malignant NHL, we aim to investigate the diagnostic utility of DP using QuPath software in evaluating the proliferation index and the prognostic significance and to show that improved visualization and analysis contribute to the convergence of these complementary diagnostic modalities for lymphomas. The average proliferation index (Ki67) was 58.33% with values between 10% and 85%. After the stratification of the cases, an increased proliferation index was observed in the majority of cases (53.33%), and this aspect was associated with the advanced age of the patients (p = 0.045). Visual assessment provides lower Ki67 values than automated digital image analysis. However, the agreement coefficient between the conventional method and the AI method indicates an excellent level of reliability (ICC1-0.970, ICC2-0.990). The multivariate analysis revealed that in the cases where the proliferation index Ki67 is high (˃70%), the IPI score represents an important risk factor predicting mortality (HR = 10.597, p = 0.033).

Revisiting the Utility of Granulocyte Colony-Stimulating Factor Post-Autologous Hematopoietic Stem Cell Transplantation for Outpatient-Based Transplantations

The use of granulocyte colony-stimulating factor (G-CSF) after autologous stem cell transplantation (ASCT) has been shown to reduce the time to neutrophil engraftment, as well as the duration of hospitalization post-transplantation. However, prior studies have focused on inpatient-based ASCT, where patients are routinely admitted for conditioning and frequently remain hospitalized until signs of neutrophil recovery. Given improvements in post-transplantation care, an increasing number of patients, particularly those receiving ASCT for multiple myeloma, are now undergoing transplantation in an outpatient setting. We hypothesized that the routine use of G-CSF for outpatient-based ASCT might not result in the same benefit with respect to a reduced duration of hospitalization and thus should be reconsidered in this setting. We performed a retrospective cohort study of 633 consecutive patients with multiple myeloma (MM; n=484) or non-Hodgkin lymphoma (NHL; n=149) who underwent ASCT between September 2018 and February 2023. Outpatient ASCT comprised 258 (53%) of combined MM and NHL cases. Starting in September 2021, post-transplantation G-CSF was incorporated into the supportive care regimen for all ASCTs. A total of 410 patients (309 with MM, 101 with NHL) underwent ASCT during the pre-G-CSF policy period and 223 (175 with MM, 48 with NHL) did so in the post-G-CSF policy period. The primary outcome focused on the duration of hospitalization within the first 30 days following graft infusion. As expected, after implementation of the G-CSF policy, the time to neutrophil engraftment was reduced in the patients with MM (mean, -2.8 days; P < .0001) and patients with NHL (mean, -2.9 days; P < .0001). However, among the patients with MM, roughly one-half of whom underwent outpatient-based ASCT, the inpatient duration during the first 30 days was not reduced after G-CSF implementation (P=.40). Comparatively, the inpatient duration (mean, -1.8 days; P=.030) was reduced among patients with NHL, all of whom were electively admitted for ASCT. For patients with MM at an outpatient-based transplant center, incorporation of G-CSF post-ASCT resulted in reduced time to neutrophil engraftment but did not significantly reduce the time spent in the inpatient setting through day +30.

Non-Hodgkin Lymphoma - Nodal and Extranodal: 20-Year Comparative Mortality, Survival & Biologic Behavior Analysis by Age, Sex, Race, Stage, Cell Morphology/Histology, Cohort Entry Time-Period and Disease Duration: A Systematic Review of 384,651 Total NHL Cases Including 261,144 Nodal and 123,507 Extranodal Cases for Diagnosis Years 1975-2016: (SEER*Stat 8.3.6).

-To update trends in incidence and prevalence in the United States of non-Hodgkin lymphoma, examine, compare and contrast short and long-term patterns of survival and mortality, and consider the outcome impacts of anatomic location of NHL nodal and extranodal subdivisions, utilizing selected ICD-O-3 histologic oncotypes stratified by age, sex, race/ethnicity, stage, cell behavioral morphology and histologic typology, cohort entry time-period and disease duration, employing the statistical database of the National Cancer Institute SEER*Stat 8.3.6 program for diagnosis years 1975-2016.4 Methods.- A retrospective, population-based cohort study using nationally representative data from the National Cancer Institute's (NCI) Surveillance, Epidemiology, and End Results (SEER) program to evaluate 384,651 NHL cases for diagnosis years 1975-2016 comparing multiple variables of age, sex, race, stage, cell behavioral morphology, cohort entry time-period, disease duration and histologic oncotype. Relative survival statistics were analyzed in two cohorts: 1975-1995 and 1996-2016. Survival statistics were derived from SEER*Stat Database: Incidence - SEER 9 Regs Research Data, November 2018 Submission (1975-2016) <Katrina/Rita Population Adjustment> released April 2019, based on the November 2018 submission. - Incidence rates, relative frequency distributions, survival and mortality by age, sex, stage and cell behavioral morphology, of adult nodal (N) and extranodal (EN) NHL in 2 entrant time-periods as recorded in the SEER Program of the National Cancer Institute for diagnosis years 1975-2016 (SEER Stat 8.3.6) are summarized. Shifts in trends over time are identified, and the findings are correlated with prognosis, including short and long-term observed (actual), expected and relative survival, median observed and relative survival, mortality rates and excess death rates per 1000 people. - Trends in SEER incidence, prevalence, survival and mortality by age, sex, race, stage, cell behavioral morphology, cohort entry time-period, relative frequency and percent distribution, were examined to provide a current epidemiologic and medical-actuarial risk assessment framework for nodal (N) and extranodal (EN) non-Hodgkin's lymphoma in the 1975-2016 timeframe.

Extranodal NK/T-Cell lymphoma with Behcet’s syndrome: A case report

Extranodal natural killer cell (NK) T cell lymphoma (ENKL) is a rare type of non Hodgkins lymphoma, accounting for 5% 10% of total NHL cases.

Hypercalcemia of malignancy with simultaneous production of parathyroid hormone-related peptide and 1,25-Dihydroxyvitamin D by non-Hodgkin lymphoma: Case report &amp; brief review

We report the case of a 63-year-old man with severe hypercalcemia, acute kidney injury, and concomitant diagnosis of germinal center diffuse large B-cell lymphoma (nHL). Hypercalcemia is a common finding in patients with cancer. Multiple mechanisms can lead to hypercalcemia of malignancy, and different malignancies are often associated with a specific mechanism of hypercalcemia. Parathyroid hormone-related protein (PTHrP) and excessive production of 1,25-dihydroxyvitamin D can independently (and rarely, concomitantly) lead to development of hypercalcemia in patients with a variety of malignancies. Literature review of hypercalcemia related with PTHrP and 1,25-dihydroxyvitamin D co-secretion shows that most reported cases are associated with solid tumors and responded to tumor directed therapy. Our case of nHL was associated with increased PTHrP and 1,25-dihydroxyvitamin D making this an unusual presentation.

Clinical and Histopathological Features of Non-Hodgkin Lymphoma in Gastrointestinal System at RSUP Dr. Hasan Sadikin Bandung 2018-2020

BackgroundNon-Hodgkin's lymphoma (NHL) is an abnormal growth of lymphocytes that manifests as tumor or enlargement of lymph nodes (lymphadenopathy). New NHL cases in Indonesia in 2020 reached 16.125 cases (4.1%) with 9.024 deaths (3.6%). The WHO classification categorizes NHL into two, B cells and T/NK cells.2 NHL is also divided into low-grade and high-grade based on its progression. The gastrointestinal tract is the most frequently involved extranodal site in NHL. The clinical manifestations of NHL can be non-specific and vary depending on anatomic location. This study aims to determine the clinical and histopathological features in patients with gastrointestinal NHL.MethodsThis research is a descriptive study using medical record data of inpatients at RSUP Dr. Hasan Sadikin Bandung period 2018-2020 diagnosed with gastrointestinal NHL.ResultsPatient characteristics were dominated by patients aged 40 years and male (65.2%), with the most clinical manifestations being enlarged lymph nodes. NHL most often attacks the liver (26.1%) and most patients present at stage IV (34.8%). The most histopathological features were B cells (52.5%) and high-grade (43.5%).ConclusionThe risk of gastrointestinal LNH increases with age and the majority is in men. Clinical manifestations vary and can show local or constitutional symptoms. Most patients are found to be in the late stages and among all gastrointestinal system, most NHL attacks the liver. Many patients were not subjected to further immunohistochemical examination, but the most common histopathological features were B cells and high grade NHL.

Evaluation of Diagnostic Usefulness of CD200 Expression in B-cell Chronic Lymphoproliferative Disorders.

Immunophenotyping by flow cytometry (FCM) is a useful diagnostic tool for the evaluation of mature B-cell neoplasms (MBN). Here, CD200 expression may play a significant role and improve the distinction between various MBNs, but any potential as a prognostic marker is yet to be established. The present prospective study was conducted on all the suspected cases of MBNs. Immunophenotyping was done using a BD FACS Canto FCM using a panel of 4 to 6 color combinations of monoclonal antibodies; CD45, CD34, CD5, CD19, CD20, CD22, CD23, CD79b, FMC7, CD10, CD38, ZAP70, CD200, IgG, IgM, CD25, CD103, CD2, CD3, CD11c as well as κ and λ light chains. CD200 expression was compared in different subgroups. Of the total of 130 cases included in the study, CD200 was positive in 118 cases (90%). CD200 was expressed in 100% of the cases of CLL(86 cases), atypical CLL(06 cases), HCL(14 cases), FL(02 cases), SMZL(04 cases), LPL (01 case), and low-grade NHL (05 cases), with the highest intensity of fluorescence in HCL followed by CLL. All the cases of MCL and PLL were exclusively negative for CD200. In conclusion, the results of the present study support inclusion of this marker in the flow cytometric panels for the differential diagnosis of MBNs.

Low Back Pain: An Unusual Presentation of Non-Hodgkin Lymphoma

Abstract Non-Hodgkin lymphoma (NHL) is a lymphoid tissue neoplasm originating from B- and T-cells and usually presents with fever, lymphadenopathy, and hepatosplenomegaly. Here is a case of NHL who presented to us with low backache. We describe a patient 63 year old female who had a known history of systemic hypertension, presented with spasmodic low back pain. On examination, she had a single right lymph node 1 cm × 2 cm palpable with spinal tenderness. Her blood reports were all within normal limits with slightly elevated inflammatory markers. Magnetic resonance imaging of the spine revealed multiple enlarged lymph nodes in the abdomen, which were compressing the celiac plexus. After a lymph node biopsy, it was revealed that she had follicular NHL. On the initiation of steroids and chemotherapy, her pain subsided. NHL has a variety of presentations. It is not necessary always fever should be a part of the presentation. Physicians should have a suspicion of lymphoma also in patients presenting with low backache.

Updates in the treatment of mantle cell lymphoma: A Canadian expert framework

Mantle cell lymphoma (MCL) is a B cell Non-Hodgkin Lymphoma that develops in the mantle zone of the lymph node. It is more common in men and is usually diagnosed at an advanced stage with involvement of lymph nodes, bone marrow, and potentially the gastrointestinal tract. MCL accounts for 5–10% of all new NHL cases per year in Canada, which is estimated at 11,400 for 2022. While most patients respond to initial treatment, relapses occur early and MCL generally shows a variable response to subsequent treatments, often with limited duration of benefit. Two main subtypes of MCL can be distinguished that arise from in situ MCL lesions. The most common subtype, classic MCL, arises from these cells with limited or no immunoglobulin heavy chain variable region (IGHV) mutations. Cells from this subtype express SOX11, are genetically unstable, and have naïve B cell-like characteristics. Classic MCL is more often nodal and extranodal and may eventually progress to aggressive blastoid or pleomorphic MCL. The other subtype, leukemic non-nodal MCL, arises from cells that have undergone IGHV somatic hypermutations, do not express SOX11, and exhibit characteristics of memory B cells. This subtype can have an indolent clinical behavior for a long time, often several years, but frequently acquires TP53 and other mutations and progresses to a more aggressive subtype. Treatment options have expanded significantly over the past decades, with improvements in both overall survival (OS) and progression-free survival (PFS) compared to earlier treatment eras. This Canadian expert framework aims to discuss the management considerations for patients with MCL, and will present both front-line treatment options as well as those for relapsed and refractory disease.

Combinatorial PI3K/AKT Pathway Inhibition As a Therapeutic Approach in Diffuse Large B-Cell Lymphoma

Background. Diffuse large B-cell lymphoma (DLBCL) is the most frequent type of non-Hodgkin lymphoma (NHL, ~ 25-30% of NHL cases). Currently, DLBCL treatment is based on non-specific chemotherapy combination (cyclophosphamide, doxorubicin, vincristine, and prednisone) with anti-CD20 monoclonal antibody. Although the DLBCL survival dramatically improved during last decades, approximately 40 % of DLBCL patients could not be cured with the currently used therapeutic approaches. Novel approaches are, therefore, needed to improve DLBCL survival and to decrease treatment related toxicity. Since many DLBCL tumors depend on phosphatidylinositol 3-kinase /protein kinase B (PI3K/AKT) signaling pathway, it represents one of the possible novel therapeutic targets. Despite promising results in various cancers, PI3K/AKT pathway inhibitors show only partial efficacy, low specificity, and resistance development in lymphomas. Since the PI3K/AKT activity is highly regulated, we hypothesize that the PI3K/AKT pathway needs to be inhibited at multiple levels simultaneously to achieve its full and lasting inhibition. Methods. To provide a proof of principle of multilevel vertical PI3K/AKT inhibition, we tested the effect of four inhibitors targeting the PI3K/AKT pathway at four different levels: PI3Kδ inhibitor idelalisib, PDPK1 inhibitor GSK2334470, AKT inhibitor ipatasertib, and mTOR inhibitor rapamycin on a spectrum of commonly used DLBCL model cell lines. Precise measurement of AKT activity in living cells was done using our recently published genetically encoded Förster Resonance Energy Transferred (FRET) based AKT activity reporter including novel methodology for flow cytometry-based FRET measurement (PMID: 34128311) allowing medium throughput and measurement in kinetics setting. Results. First, we measured how single inhibitors affect the AKT activity. The AKT activity IC50 concentrations were in 100 nM range except for rapamycin that had no AKT inhibitory effect. These concentrations were approximately 10 times lower in comparison to IC50 values calculated from net cell growth inhibition assessing the overall inhibitor toxicity. This suggests compensatory mechanisms and/or off target effects of PI3K/AKT inhibitors. Precise measurement of AKT activity allowed us to identify the minimal concentration of each inhibitor at which AKT activity was fully inhibited. Kinetics and short time course experiments showed that maximal AKT inhibition is achieved within hours of inhibitors treatment initiation. Importantly, pharmacological inhibition of one or two members of PI3K/AKT signaling cascade did not lead to lasting AKT activity inhibition. Cellular contra-regulatory mechanisms compensated for the decrease of AKT activity within 24 hours even in the presence of the inhibitors. Moreover, we detected a massive increase in AKT activity following release of the cells from media with PI3K/AKT pathway inhibitors. This further illustrates the powerful cellular contra-regulatory mechanisms and highlights the need for combinatorial approach. Combination of at least three inhibitors was necessary to achieve lasting AKT activity decrease (long time course experiment, Fig. 1A). Cross titration experiments further confirmed synergistic effect between tested PI3K/AKT pathway inhibitors on cell growth inhibition and allowed to determine the concentration ratios of their maximal synergism. Importantly, testing of single inhibitors and two, three, or all four inhibitors in fixed concentration combinations identified a substantial decrease in cell growth/toxicity IC50 concentrations of individual inhibitors (Fig. 1B). Conclusions. Concept of inhibiting more members of PI3K/AKT pathway was suggested before using combinations and/or dual inhibitors of AKT and mTOR, however, our data suggest that more than two inhibitors are needed for lasting PI3K/AKT inhibition. Moreover, we provided a proof of principle for further multilevel PI3K/AKT signaling inhibition testing, including in vivo cell line and/or patient derived xenograft models. Our data suggest that proposed combinations should allow significant decrease of inhibitors concentrations limiting off-target effect. This approach might overcome above mentioned issues of PI3K/AKT pathway inhibition and allow full therapeutical utilization of this pathway inhibition possibly applicable to other lymphoma types. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

ABCL-263 Our Experience in the Management of Patients With Lymphoma During Pregnancy

Hodgkin and Non-Hodgkin lymphomas (HL and NHL) associated with childbearing pose extremely difficult questions for the patient and her physician. The aim of the current study was a comprehensive analysis of our experience in the management of patients with HL and NHL during pregnancy in Armenia during the last 10 years. The main data source for this study was clinical data from the Register of Blood Diseases of the Hematology Center after R. Yeolyan. Diagnosis of HL and NHL as well as the definition of the stage were carried out according to the generally accepted international criteria. During this period, we had cases with HL and 4 with NHL associated with pregnancy. The median age for HL was 28.2±0.2 (range 26-30) and for NHL - 23.8±0.3 years (range 23-25). Their first visit to a hematologist for HL and NHL was at the stage of 32-34 and 22-23 weeks of pregnancy respectively. According to the literature data and the results of our study, the frequency of the subtype, stages, and prognosis in patients with HL is the same in both pregnant and non-pregnant cohorts. Among them, there were both patients with the first pregnancy and patients with the second and third pregnancies. They were mostly diagnosed with stage 2 or 3 HL, with nodular sclerosis, involving the cervical, axillary, and mediastinal lymph nodes. Patients with HL were closely monitored by a hematologist-oncologist until delivery, after delivery they began treatment under the BEACOPP program. All patients and their children are currently alive. All cases of NHL were DLBCL, with an aggressive course of the disease. The issue of therapy for patients with NHL was decided individually, depending on the patient's condition, and the stage of the disease. Basically, it was a course of CHOP or R-CHOP, then childbirth, after that few more courses. Three patients and their children are currently alive. We have only one deadly case and one mother after delivery refused treatment. Only well-coordinated teamwork of hematologist-oncologists, obstetrician-gynecologist with an element of the patient's choice can lead to saving the life of the mother and normal delivery.

LOCALIZED LARGE ENDOBRONCHIAL NON-HODGKIN LYMPHOMA PRESENTING WITH FEVER, DYSPNEA, AND HEMOPTYSIS

LOCALIZED LARGE ENDOBRONCHIAL NON-HODGKIN LYMPHOMA PRESENTING WITH FEVER, DYSPNEA, AND HEMOPTYSIS

Gastric DLBCL clonal evolution as function of patient age.

Diffuse large B cell lymphoma (DLBCL) is the most common type of NHL, accounting for about 40% of NHL cases, and is one of the most aggressive lymphomas. DLBCL is widespread in individuals aged more than 50 years old, with a maximum incidence in the seventh decade, but it may also occur in younger patients. DLBCL may occur in any immune system tissue, including those around the gastrointestinal tract, and even in the stomach, though gastric DLBCL has yet to be sufficiently investigated. This study aimed to understand changes in gastric Diffuse Large B cell lymphoma (gastric DLBCL) development with age. Immunoglobulin (Ig) heavy chain variable region genes were amplified from sections of nine preserved biopsies, from patients whose age varied between 25 and 89 years, sequenced and analyzed. We show first that identification of the malignant clone based on the biopsies is much less certain than was previously assumed; and second that, contrary to expectations, the repertoire of gastric B cell clones is more diverse among the elderly DLBCL patients than among the young.

PB2120: HIV AND MALIGNANT HEMOPATHIES

Background: Hematological malignancies remain a major cause of morbidity and mortality in patients living with the HIV virus (PLHIV). Their training would be linked to several factors. Aims: The objective of our study is to describe the main types of blood diseases malignancies and their epidemiological characteristics in PLHIV followed up internal medicine department – ​​clinical hematology of the CHU Ibn Sina in Rabat. Methods: This is a retrospective and descriptive observational study of PLHIV having an associated hematological malignancy. Results: Among the 1035 PLHIV followed, we collected 11 patients with blood disease malignant (1.06%). The average age was 40.6 years (29 – 73 years). The F/M sex ratio was 0.1. 90% of patients were in stage C. Heterosexual transmission was the main mode of contamination (100%). They had as antecedent: chronic smoking 60%; pulmonary tuberculosis 30%; drug addiction 10%. The regimens of ARVs received corresponded to international recommendations: 90% received triple therapy of the TNF+FTC+EFZ type and 10% received DTG+TNF+3TC. HIV infection was discovered incidentally in 73% of PLHIV during the pre-therapeutic assessment of the management of hemopathy. their viral status revealed an average viral load of 6.2 log (4.3 – 6.5 log). the mean CD4 count was estimated at 148 (78 – 243 cells/mm3). 27% of patients had an average follow-up time of 4 months. they had an undetectable viral load and persistently low CD4 count (< 200 /mm3). We identified 9 cases (82%) of NHL: 2 DLBCL (22%), 2 plasmablastic lymphomas (22%), 3 Burkitt’s lymphomas (34%), 1 T-cell lymphoma angioimmunoblastic (11%), 1 T/NK lymphoma (11%), 1 case of classic HL at mixed cellularity (9%), and 1 case of multiple myeloma (9%). The other syndromes lymphoproliferative or myeloproliferative were not found in our series. The advanced Ann Arbor stage (III – IV) was found in 90% of PLHIV. All patients received first-line poly-chemotherapy: 40% of patients received an R-DAEPOCH, 20% CHOEP, 20% R-CHOP, 10% BEACOPP, 10% CTD. 10% of patients required a second line of therapy (R-DHAOX) then a third line (Ciclosporine). The evolution was favorable with remission complete in 30% of patients. A negative viral load was obtained in 80% of PLHIV. We mourn 6 deaths: 5 deaths were related to hematological malignancy, and 1 was related to opportunistic infections complicating HIV after poor adherence to ARVs. Summary/Conclusion: Our series is mainly distinguished by a low frequency of the HIV association – hematological malignancy, but also by the diversity of these hemopathies. The persistence of a low CD4 count in PLHIV on ARVs should encourage look for possible hematological malignancies. Early introduction of ARVs is mandatory before starting any chemotherapy. The prognosis mainly depends type and stage of hemopathies.

Abstract 741: Evaluation of etiologic heterogeneity for risk of diffuse large B-cell lymphoma (DLBCL) subtype defined by cell-of-origin

Abstract Background: DLBCL is the most common non-Hodgkin lymphoma subtype in western countries and is clinically heterogeneous. Gene expression profiling has identified two major biologically distinctive DLBCL subtypes defined by their cell-of-origin (COO): germinal center B-cell (GCB) - characterized by BCL2 rearrangement and C-REL amplification, and activated B-cell (ABC) - characterized by constitutive activation of the NF-kB pathway. We evaluated putative DLBCL risk factors for etiologic heterogeneity as defined by COO. Methods: We used a clinic-based study of newly diagnosed NHL cases and frequency matched controls, enrolled from 2002-2014, with a total of 687 DLBCL cases and 2253 controls for this analysis. Using formalin-fixed, paraffin-embedded tumor tissue, we determined COO by either digital expression profiling (NanoString; classified as GCB, ABC, undetermined) or clinically using the Hans algorithm (immunohistochemical markers; classified as GCB, non-GCB, undetermined). Integrating these two sources of COO data, there were 271 GCB, 170 non-GCB, and 246 undetermined/missing (mainly due to lack of tissue) cases. Risk factor data were collected from self-administered questionnaires and included family history of hematologic malignancy; history of atopy, allergy, asthma, eczema, or autoimmune disease; blood transfusion; vaccination history; regular low-dose aspirin use; body mass index (BMI) 2 years prior diagnosis/enrollment; smoking history; alcohol consumption (never/current/former); leisure-time physical activity; and recreational sun exposure. Polytomous logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals for COO subtypes, adjusted for age, sex and residence. Results: The median age of cases was 64 years with 55% male; the median age of controls was 64 years and 53% male. The association with BMI (30+ vs. 18.5-24.9 kg/m2) was stronger for non-GCB (OR=2.21; 1.40-3.49) than for GCB (OR=1.70; 1.21-2.40) DLBCL (P-heterogeneity 0.02), while a family history of hematologic malignancy was associated with non-GCB (OR=2.27; 1.47-3.50) but not GCB (OR=1.30; 0.86-1.96) DLBCL, although the P-heterogeneity was not significant (P=0.13). For GCB, there was an inverse association with former (vs. never) alcohol use for GCB (OR=0.57; 0.39-0.83) but not for non-GCB (OR=0.98; 0.61-1.57) DLBCL (P-heterogeneity 0.007), and an inverse association with regular use of low-dose aspirin for GCB (OR=0.64; 0.47-0.87) but not for non-GCB (OR=0.88; 0.61-1.25) DLBCL (P-heterogeneity 0.05). No other risk factors evaluated showed important heterogeneity by COO. Conclusions: These initial results suggest most DLBCL risk factors do not show etiologic heterogeneity by DLBCL COO, although associations with BMI and family history with non-GCB DLBCL and alcohol and low-dose aspirin use with GCB DLBCL warrant follow-up. Citation Format: Geffen Kleinstern, Dennis P. Robinson, Lisa M. Rimsza, Melissa C. Larson, Rebecca L. King, Grzegorz S. Nowakowski, Carrie A. Thompson, Stephen M. Ansell, Matthew J. Maurer, Andrew L. Feldman, Susan L. Slager, Anne J. Novak, Thomas M. Habermann, James R. Cerhan. Evaluation of etiologic heterogeneity for risk of diffuse large B-cell lymphoma (DLBCL) subtype defined by cell-of-origin [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 741.