Specific Lymphoma Subtypes Research Articles

Lymphoma Treatment Alterations in the Context of Autoimmune Disease

Background: Autoimmune disease (AD) confers an increased risk for lymphoma. Several studies have shown that pre-existing AD portends a worse prognosis for lymphoma patients, but the reasons for this are unknown. 1,2,3 We hypothesize that one reason may be poor treatment tolerance in AD patients due to concurrent risk for cytopenias, infections, and immune-related adverse events. Methods: We conducted a retrospective cohort study to understand whether AD is associated with higher risk for treatment alterations, hospitalizations, and transfusions among lymphoma patients. The study population consisted of adult patients (aged 18-74 at lymphoma diagnosis) who underwent lymphoma treatment at one tertiary care center from 2017-2022. Patients who developed AD after or within the 12 months before lymphoma diagnosis were excluded to avoid including patients whose AD was paraneoplastic or a treatment side effect. Subjects were found by using cohort builder in electronic medical record then reviewing records for eligibility. The primary exposure of interest was pre-existing diagnosis of AD and the primary outcome was treatment alteration, such as dose reduction, delay, or discontinuation. The secondary outcomes were hospitalization, and transfusion. Outcomes were compared between groups with non-parametric tests. Logistic regression was used to estimate the association of AD with any treatment alteration. Results: We reviewed 357 records, with 30 eligible for inclusion in AD cohort and 65 eligible for non-AD cohort. There were 17 different lymphoma types with diffuse large B cell lymphoma as the most common (10 in AD cohort, 20 in non-AD). In the AD cohort, there were 12 distinct autoimmune diagnoses and rheumatoid arthritis was the most common (n=11). Baseline patient characteristics did not differ between the AD and non-AD cohorts in age, sex, diagnosis, stage, renal function, hemoglobin or type of treatment received. However, patients in the AD cohort were more likely to be Black or Asian compared to the non-AD cohort (Table 1). There were no differences in frequency of treatment alterations, unplanned hospitalizations, or incidence of transfusion between the AD and non-AD groups. Logistic regression showed no association of study group with incidence of any treatment alteration, even after controlling for baseline characteristics. Discussion: This study examines whether autoimmune disease impacts treatment tolerance among lymphoma patients. In a Swedish retrospective study of lymphoma, worse outcomes were seen among patients with AD due to increased non-lymphoma risk of death, suggesting that AD patients may have more frequent serious and life-threatening complications from lymphoma therapy. 1 In our study, there were no differences in treatment tolerance between the AD and non-AD groups. However, sample size is a limitation, and chart review is ongoing. Notably, treatment alterations were common in both groups, and no increase in unplanned hospitalizations was seen in the AD group. Clinical decisions to dose reduce, delay or discontinue therapy may mitigate against hospitalization from serious treatment related complications even in lymphoma patients with concurrent AD. Future directions include examining interactions between treatment alterations, autoimmune disease, and prognosis in specific lymphoma subtypes. 1. Simard JF, Baecklund F, Chang ET, Baecklund E, Hjalgrim H, et al. Lifestyle factors, autoimmune disease and family history in prognosis of non-hodgkin lymphoma overall and subtypes. Int J Cancer. 2013 Jun 1;132(11):2659-66. doi: 10.1002/ijc.27944. Epub 2012 Dec 3. PMID: 23160780. 2. Jachiet V, Mekinian A, Carrat F, Grignano E, Retbi A, Boffa JJ, et al. Autoimmune manifestations associated with lymphoma: Characteristics and outcome in a multicenter retrospective cohort study. Leuk. Lymphoma. 2018;59:1399-1405 3. Kleinstern G, Averbuch M, Abu Seir R, Perlman R, Ben Yehuda D, Paltiel O. Presence of autoimmune disease affects not only risk but also survival in patients with B-cell non-Hodgkin lymphoma. Hematol. Oncol. 2018;36:457-462.

Real-World Impact of Differences in the World Health Organization (WHO) Classification and International Consensus Classification (ICC) Systems on the Diagnosis of Non-Hodgkin Lymphoma: An Analysis from the LEO Cohort Study

Introduction: The use of standardized, evidence-based classification systems is crucial for the accurate diagnosis and treatment of diseases. Moreover, standardized classification facilitates research and epidemiologic studies and promotes consistency in communication among healthcare professionals. Since 2016, the revised 4 th edition of the World Health Organization classification (WHO-HAEM4R) has been the global standard for diagnosis of lymphoid malignancies. With the emergence of new data, 2 new classification systems were developed and published in 2022: the 5 th edition of the WHO Classification (WHO-HAEM5) and the International Consensus Classification (ICC). Both WHO-HAEM5 and ICC maintain a shared fundamental concept of disease classification that integrates clinical, pathologic, and molecular data. However, they differ on nomenclature, establishment of new entities, and/or diagnostic criteria for some disease categories. To evaluate the impact of these differences on real-world diagnosis of non-Hodgkin lymphoma (NHL), we examined the diagnostic classification of NHL in the Lymphoma Epidemiology of Outcomes (LEO) Cohort Study (NCT02736357). Methods: Initiated in 2015, LEO is an ongoing prospective observational study of patients aged ≥18 years with newly diagnosed NHL. Patients are enrolled at 8 major U.S. medical centers. Clinical, epidemiologic, pathologic, and treatment data are abstracted at baseline and active follow-up is conducted for all patients. Lymphoma subtype is coded for each case based on expert hematopathology re-review of the diagnostic pathology slides, the pathology report, biomarker data, and clinical data. Of note, NHL subtype distribution is similar to SEER data. We studied all patients enrolled in LEO between 7/1/2016 (the date LEO pathology review started using WHO-HAEM4R diagnostic codes) and 5/31/2020. WHO-HAEM4R diagnoses and additional clinicopathologic data, when relevant, were used to map cases into the corresponding WHO-HAEM5 and ICC diagnoses. Differences between WHO-HAEM5 and ICC were annotated for each case as: None - same disease entity; Minor - difference in nomenclature with similar diagnostic criteria; Major - difference in disease category and/or diagnostic criteria; or Unevaluable - insufficient data to assign WHO-HAEM5 and/or ICC diagnosis. Results: LEO enrolled 6143 patients during the study period. Of these, comparison between WHO-HAEM5 and ICC was evaluable in 5730 (93.3%). Unevaluable cases included those without a specific WHO-HAEM4R diagnosis at enrollment (N=384; e.g., patients with a low-grade B-cell lymphoma that could not be definitively sub-classified) and those with a specific WHO-HAEM4R diagnosis, but with insufficient clinicopathologic data to assign a specific WHO-HAEM5 and/or ICC diagnosis (N=29). Of the 5730 evaluable cases, 5376 (93.8%) showed no difference between WHO-HAEM5 and/or ICC diagnosis, 311 (5.4%) showed minor differences (nomenclature only), and 43 (0.8%) showed major differences (Table 1). The 43 major differences all involved B-cell NHLs; 20 (46.5%) were attributable to different approaches to classifying double-hit lymphomas, 21 (48.9%) to classification of splenic/leukemic B-cell lymphomas, and 2 (4.6%) to classification of B-cell lymphomas occurring at specific anatomic sites (Table 2). Conclusion: In a large, prospective lymphoma cohort reflecting real-world clinical practice at 8 major U.S. medical centers, major diagnostic differences in the classification of NHL using WHO-HAEM5 or ICC classification criteria were seen in 0.8%, whereas the remaining 99.2% of diagnoses were either the same or showed differences in nomenclature only. The existence of 2 concurrent classification systems presents potential for discrepancies in pathologic diagnosis, clinical practice, clinical trials, and other lymphoma research. Furthermore, some of the differences between WHO-HAEM5 and ICC are clinically and potentially therapeutically significant, and their resolution requires further study. Nevertheless, our findings argue that the proportion of patients affected would be small in real-world practice settings. This appears largely related to incidence rates of specific lymphoma subtypes, with major differences between the 2 classifications predominantly affecting rare entities, while there is general concordance on the most common forms of NHL.

A phase 1/2 study of STP938, a first-in-class inhibitor of CTP synthase 1, in patients with relapsed/refractory B or T cell lymphoma.

TPS7591 Background: The rate limiting step in de novo pyrimidine synthesis is catalyzed by two homologous enzymes, CTPS1 and CTPS2. CTPS1 is essential for lymphocyte proliferation, whereas CTPS2 is sufficient in non-haemopoietic cells. STP938 is a first in class oral CTPS1 inhibitor showing > 1,300-fold selectivity over CTPS2. In preclinical studies, STP938 induced death of cancer cells by apoptosis at nanomolar concentrations, and inhibited tumor growth in in vivo models of hematological malignancies. Methods: The study employs a seamless dose escalation, dose expansion design. The phase 1 dose escalation follows a standard 3+3 approach. Intra-patient dose escalation will be permitted. The recommended phase 2 dose (RP2D) will be nominated based on safety, target engagement and early signs of efficacy. An additional six patients will be treated at the RP2D with a preliminary assessment of food effect. Key phase 1 endpoints are safety and tolerability. Key phase 2 endpoints are objective response rate and duration of response. The study is open to adult patients following at least 2 prior lines of therapy who have no treatment options known to provide clinical benefit. The phase 1 study is recruiting patients with B or T cell lymphoma; the phase 2 study will be limited to cohorts of patients with specific lymphoma subtypes, which may include T cell lymphoma (peripheral or cutaneous), mantle cell lymphoma, indolent B cell lymphoma and diffuse large B cell lymphoma. Standard exclusion criteria apply; patients with ECOG performance score > 2 or known CNS involvement by lymphoma are not eligible. The phase 2 study will follow a Simon two-stage design with an interim analysis for futility based on predefined, lymphoma subtype specific response rates. In the case of STP938 showing promising efficacy, provision is included in the protocol to expand a cohort using an adaptive approach based on early efficacy signals (Mehta and Pocock, 2011). Target engagement is assessed by measuring cytokine release (TNFα, IFNγ, IL2, IL8) from ex vivo stimulated patient T cells. Exploratory studies include pre- and on-treatment lymphoma biopsies to assess biomarkers of response and mechanism of action. Tumor genomics will be assessed by sequencing of circulating tumor DNA prior to treatment and at disease progression using a bespoke genomic assay designed to elucidate biomarkers of response and understand mechanisms of resistance. The phase 1 study (NCT05463263) opened to enrolment in the US and UK in September 2022. No dose limiting toxicities were observed in the first cohort of 3 patients. The phase 2 study will include additional centers in France. Clinical trial information: NCT05463263 .

Abstract 5233: Germline CHEK2 variants and risk of lymphoma

Abstract Lymphoma is the sixth most commonly diagnosed cancer in the US. Genome-wide association studies have identified common variants associated with risk of specific lymphoma subtypes, but less is known about the contribution of rare inherited variants in the genetic architecture of lymphoma risk. CHEK2 is important to DNA repair and 2 small studies have found evidence of an association between CHEK2 variants and risk of lymphoma. Here, we investigated loss of function (LoF) variants in CHEK2 with risk of lymphoma (overall and subtypes). The study population included newly diagnosed lymphoma cases from Mayo who were enrolled in the Lymphoma SPORE Molecular Epidemiology Resource (MER). Controls were from the Mayo Clinic Biobank, from which we excluded a prior hematologic malignancy. Whole exome sequencing was performed by Regeneron on an Illumina NovaSeq panel (mean coverage of 48X). Variants were called using GATK v4 and variant annotation was performed using BioR. All LoF variants (nonsense, frameshift and consensus splice sites) in CHEK2 with a minor allele frequency < 0.5% were included in the analyses. Logistic regression was used to estimate odds ratio (OR) and 95% confidence intervals (CI) for the association between CHEK2mutation status and risk of lymphoma overall, and by lymphoma subtypes that had more than 5 mutation carriers, which included diffuse large B-cell (DLBCL), follicular (FL), and T-cell lymphoma (TCL). All analyses were adjusted for age (at diagnosis for cases and at enrollment for controls) and sex. A total of 4,852 lymphoma cases and 49,724 controls were included in this analysis. Median age for both cases and controls was 62 years (range 18-99 years). Males accounted for 57.5% (n=2,789) of the cases and 40.6% (n=20,186) of the controls. The DLBCL (23.6% of cases) and FL (23.3% of cases) subtypes were the most common; 7.6% of cases had TCL. A total of 407 (0.7%) individuals had a LoF variant. The frequency of LoF variants was 1.2% in lymphoma cases and 0.7% in controls. LoF variants were associated with increased risk of lymphoma overall (OR=1.77; 95%CI: 1.32-2.33), DLBCL (OR=2.07; 95%CI: 1.20-3.13), and TCL (OR=2.78; 95%CI: 1.178-5.50), but not FL (OR=1.31; 95%CI: 0.65-2.34). CHEK2 c.1100delC was the most frequently mutated variant in this population, accounting for 76% of all LoF variants. Individuals with a c.1100delC variant had an increased risk of lymphoma overall (OR=1.90; 95%CI: 1.37-2.58), DLBCL (OR=2.06; 95%CI: 1.09-3.54), and TCL (OR=3.17; 95%CI:1.24-6.58), but not FL (OR=1.05; 95%CI: 0.41-2.15). When restricted to cases, there was no significant difference in age at diagnosis (P=0.62) or sex (P=0.53) between LoF variant carriers and non-carriers. In this large lymphoma case-control study, CHEK2 LoF variants were associated with increased risk of lymphoma, demonstrating that rare inherited variants may play an important role in the etiology of lymphoma. Additional work is needed to investigate missense variants in CHEK2 and risk of lymphoma. Citation Format: Nicholas J. Boddicker, Raphael Mwangi, Dennis P. Robinson, Allison C. Rosenthal, Thomas M. Habermann, Andrew L. Feldman, Lisa M. Rimsza, Rebecca L. King, Melissa C. Larson, Brianna J. Gysbers, Stephen M. Ansell, Jithma P. Abeykoon, Grzegorz S. Nowakowski, Thomas E. Witzig, Anne J. Novak, Susan L. Slager, James R. Cerhan. Germline CHEK2 variants and risk of lymphoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5233.

Classification of B-Cell Lymphomas and Immunodeficiency-Related Lymphoproliferations: What’s New?

New insights from genomic studies have had an impact on the definition and the diagnosis of several lymphoid tumors including follicular B-cell lymphomas, aggressive diffuse large B-cell lymphomas, and lymphoproliferations associated with acquired and posttransplant immunodeficiencies. Follicular lymphoma (FL) includes tumors whose behavior varies widely from indolent/early lesions to aggressive/transformed lymphomas. Although some large B-cell lymphomas can be subclassified as specific entities, the majority lack the characteristics necessary for subclassification and, thus, are termed diffuse large B-cell lymphoma, NOS. There have been, however, some changes in the classification of specific subtypes of large B-cell lymphoma as well as the addition of new entities, a few of which are highlighted in this article. The immunodeficiency-related lymphoproliferative disorders are currently divided into four major categories based on the clinical setting in which they arose: primary immune deficiency, post-transplant, HIV infection, and iatrogenic immunosuppression. In the two upcoming classifications systems for hematolymphoid neoplasms, International Consensus Classification (ICC) and WHO-HAEM-5, there is a divergence in the approach to categorize these lesions. Furthermore, whereas the WHO-HAEM-5 confirms the ability to classify a spectrum of EBV+ lesions as EBV+ DLBCL, NOS, the ICC has separated out lesions that are composed of a heterogenous cellular infiltrate into a new separate category, “EBV-positive polymorphic B cell lymphoproliferative disorder, NOS”. Both WHO-HAEM-5 and ICC recognize a number of KSHV/HHV8-associated lymphoid lesions and acknowledge that there is significant overlap among the different lesions. In the future, translation of these innovations in general practice requires further validation.

Hepatitis B and C infections among lymphoma patients: a national study in the Republic of Moldova

Hepatitis B virus (HBV) and hepatitis C virus (HCV) represent common infections that are presumably associated with various types of lymphoma and specific clinical features. However, conclusive data are lacking and results from different regional studies are conflicting. Hence, a national study was performed in order to investigate potential associations between hepatitis infections and lymphoma in the Republic of Moldova. Data were collected from newly diagnosed adult lymphoma patients from January 2020 to January 2022. Patients who were not tested for HBsAg and anti-HCV and those with an undetermined lymphoma subtype diagnosis were excluded from the study. Subjects with and without viral hepatitis were then evaluated on the basis of clinical and pathological characteristics. One hundred and twenty-nine lymphoma patients were included in the study; 15 (11.6%) patients were diagnosed with hepatitis B, 21 (16.3%) patients with hepatitis C, and 1 (0.78%) patient was positive for both. The majority of hepatitis patients were over 60 years old (62.2%), presented with stage III or IV (81%), had normal lactate dehydrogenase (58.3%) and 0 or 1 extranodal sites (78.4%). The most common lymphoma subtypes were diffuse large B-cell lymphoma (64.9%) and marginal zone lymphoma (8.1%). We did not find any statistically significant differences between infected and uninfected lymphoma patients in regards to clinical features, specific lymphoma subtypes, and presence and location of extranodal involvement. Presence of hepatitis B or C virus infections is not associated with specific clinical and pathological features in Moldovan lymphoma patients.

RISK FACTORS FOR ACUTE KIDNEY INJURY IN OUTPATIENT ADMINISTRATION OF HIGH-DOSE METHOTREXATE IN ADULTS WITHOUT DRUG MONITORING

Methotrexate is an antifolate that has been an essential part of chemotherapy regimens for acute lymphoblastic leukemia (ALL) and specific subtypes of non-Hodgkin lymphoma (NHL), when it is used in high-dose (HD, ≥ 1 g/m2) to overcome the blood-brain barrier. Nephrotoxicity is the major toxicity of HDMTX, possibly inducing critical organ damage and death if not early treated. Although some factors for drug-induced acute kidney injury (AKI) have been pointed out, the reality is that in resource-poor settings, HDMTX is usually administered in an outpatient clinic and without drug monitoring. The exact incidence of AKI after MTX in these conditions was not reported in adults yet. In this study, we intend to summarize our toxicity data after outpatient administration of HDMTX without drug monitoring. We aim to find risk factors and describe their outcomes in a real-life setting. This is a retrospective nested case-control study conducted at a large academic medical center in Sao Paulo, Brazil. Patients from 16 years old and above with ALL and NHL who received at least one outpatient infusion of HDMTX without drug level monitoring between Jan/2010 and Jun/2020 were included. Cases were those patients who developed AKI by KDIGO definition or with delayed MTX clearance (serum MTX level > 0.1 mM after 72h from drug infusion), when clinically suspected. A nested cohort of controls was composed of patients who did not develop the complication, sampling from a larger cohort of patients who received HDMTX. Cases and controls were randomly matched 1:2 for the employed protocol only. Conditional logistic regression was used to find baseline risk factors. A total of 404 patients received at least one HDMTX, with 102 not fulfilling the inclusion criteria. Among 302 patients included, 840 infusions were performed (median 2 infusions/patient, range 1-10). Most patients had a diffuse large B-cell lymphoma (DLBCL) (37%), Burkitt lymphoma (BL) (19.5%), or ALL (18%) diagnosis. Most subjects received HDMTX within a course of Hyper-CVAD (HCVAD) or monotherapy (61%). Hospitalization occurred in 8.6% of infusions during the MTX nadir, with 4.6% needing intensive care, being febrile neutropenia the most common complication (63%). Twenty-five patients presented AKI after HDMTX administration, corresponding to 3% (95% CI 2-4.4) of MTX infusions and 8.3% (95% CI 5.5-12.1) of patients. Univariate analysis for finding pre-treatment factors related to AKI after HDMTX were age>44 y (OR 3.2 [95% CI 1 - 9.7], p = 0.045), body surface≥1.76 m2 (OR 3.4 [95% CI 1.2-9.9], p = 0.039), BMI≥23.8 kg/m2 (OR 3.5 [95% CI 1.2-9.9], p = 0.02), baseline creatinine clearance (OR 0.96 [95% CI 0.93-0.99], p = 0.012), thrombocytopenia (<150x109/L) (OR 4.7 [95% CI 1.7-13.1], p = 0.002). Multivariate analysis for adjusting such factors found that only BMI is independently related to AKI after HDMTX in our setting (OR 3.8 [95% CI 1.2-11.8], p = 0.06). Among these cases, 9/25 had their MTX serum level measured at the AKI, with delayed MTX clearance in 7/9. HIV-associated BL was more frequent in cases (18 vs. 6.8%, p = 0.03). 22/25 needed hospitalization, with infection diagnosed in 23/25 e need for dialysis in 5/25 cases. Death after AKI occurred in 56% (14/25). Our data showed a similar rate of AKI after HDMTX to that reported in the literature, even without drug monitoring. However, patients who developed AKI in our cohort fare worse than expected, with more hospitalizations and death. Higher BMI was associated with MTX-induced AKI in our cohort, suggesting a differential drug clearance and the need for specific guidelines for obese patients.

Primary Brainstem Lymphoma: A Population-Based Study.

BackgroundPrimary brainstem lymphoma (PBSL) is rare and malignant. An understanding of this disease is lacking. We aimed to characterize clinical features, estimate survival, and explore survival-related factors of PBSL.MethodsPatients with a histological diagnosis of primary lymphoma in the brainstem (C71.7) from 1975 to 2016 were retrieved from the Surveillance, Epidemiology, and End Results (SEER) program. Log-rank tests and univariate and multivariate Cox proportional hazard analyses were used to identify survival-related factors.ResultsPBSL constituted 2.7% of brainstem malignancies. The median age of the PBSL patients was 59.5 years. Diffuse large B cell lymphoma (n = 49, 84.5%) was the most prevalent histology among the 58 cases with reported specific lymphoma subtype. The majority of PBSLs were localized (n = 46, 52.3%), at low Ann Arbor Stage (I/II, n = 63, 70.5%), and presented as a single primary (n = 71, 80.7%). Chemotherapy was applied in 50 (56.8%) cases. Three-year overall survival (OS) and disease-specific survival (DSS) rates were 42.7% and 53.5%, respectively. Multivariate analyses showed that independent predictive/prognostic factors for OS were age (P = 0.004), tumor number (P = 0.029), and chemotherapy (P = 0.001); DSS-related factors only included age (P = 0.014) and chemotherapy (P = 0.008).ConclusionsWe estimated survival rates for PBSL patients. Factors associated with OS and DSS were also identified. Our findings addressed the importance of chemotherapy in treating PBSL patients.

P1270: IMMUNE REGULATORY CELLS IN B-CELL LYMPHOMAS: SIGNIFICANT HETEROGENEITY ACROSS HISTOLOGIC TYPES.

Background: Immune regulatory cell populations play a fundamental role in tumor development and tumor immune evasion. Myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) considered as dominant suppressor cells which are significantly enriched in blood, bone marrow (BM), or tumor sites of patients with hematologic malignancies and often associate with high tumor burden, adverse clinical features, and outcome. Studies in lymphoma patients however, have generated conflicting results, regarding the function and phenotype of MDSC and Tregs mainly due to large heterogeneity of the disease as well as due to the lack of a unanimous nomenclature of these cell subsets in human samples. Furthermore, the molecular mechanisms via which MDSCs and Tregs contribute to clinical outcomes of disease and how they interfere with response to therapy remain elusive. Aims: To investigate the prevalence of immune suppressive population in B-cell lymphomas according to histologic, subtype providing the basis for further analysis of their biologic properties and association with clinical features and outcome of specific lymphoma subtypes. Methods: Peripheral blood (PB) and BM samples were collected from healthy individuals (n= 22) and lymphoma patients (n=50). Specifically, lymphoma subtypes were as follows:Marginal Zone (MZL, N=19), Diffuse Large B-cell Lymphoma (DLBCL, N=18) and Follicular Lymphoma (FL, N=13). Peripheral blood mononuclear cells (PBMCs) were isolated with ficoll gradient and subjected to flow cytometry analysis. MDSC characterization was based on HLADR-/lowCD11b+CD33- expression with CD14+CD15- for M-MDSCs and CD14-CD15+ for PMN-MDSCs. In addition, Treg cells were denoted as CD4+CD25highCD127-Foxp3+. Expression of PDL1 and PD1 on MDSCs and Tregs respectively, was also determined by flow cytometry. M-MDSCs and PMN-MDSCs were sorted from BM samples, RNA was extracted in order to subjected to transcriptomic analysis (RNAseq). Informed consent was obtained. Results: Frequencies of MDSCs were significantly increased in PB of all lymphoma patients compared to healthy individuals, with MZL subtype exhibiting the most prominent increase of MDSCs (p<.0001). Notably numbers of M-MDSCs were increased in FL and MZL patients and to a lesser extend in DLBCL patients while PMN-MDSCs were elevated in all subtypes with MZL displaying the higher frequencies. Regarding the Treg cells, although all lymphoma patients exhibited increased absolute numbers of CD4+CD25highCD127- Treg cells, Foxp3-expressing Tregs were significantly increased in the PB of DLBCL and MZL patients, but not in FL patients. Of interest, CD4+ and CD8+ T cells in the PB of DLBCL patients exhibited increase expression of PD1 compared to respective cell subsets from healthy individuals. Summary/Conclusion: Our findings comprehensively demonstrate enhanced numbers of MDSC and Treg immune suppressive cells in the PB of B-cell lymphoma patients while an increased heterogeneity was observed among the different histological lymphoma types. Functional characterization of MDSCs and Tregs by transcriptomic (RNAseq) and proteomic analysis are ongoing.

The Diagnostic Value of Ultrasound-Guided Cervical Core Needle Biopsy in Diagnosis of Lymphoma in Suspected Patients.

Background: Core needle biopsy (CNB) guided by imaging modalities seems to be an acceptable modality for diagnosis of lymphoma due to its safety, good applicability, availability as well as diagnostic accuracy, however; Studies have not reached a consensus on its diagnostic accuracy and factors affecting its performance. The present study aimed to assess the value of ultrasound-guided cervical CNB in the diagnosis of lymphoma in suspected patients. Materials and Methods: This cross-sectional study was performed on 46 consecutive patients (20 to 82 years) with cervical mass or lymphadenopathy suspected of lymphoma and were candidates for diagnostic evaluation. Ultrasound-guided core needle biopsies (UGCNB) were done by a single radiologist under guided ultrasonography. The diagnostic value of UGCNB in the diagnosis and determination of specific lymphoma subtypes was assessed. Results: Using UGCNB led to the diagnosis of lymphoma in 34.8% and non-lymphoma lesions in 43.5%, while the diagnosis remained unclear in other 21.7% with a total UGCNB-based identification rate of 78.3%. No patient with lymphoma was missed. All patients were followed up over a 6-month period. In none of the cases, clinical diagnosis and treatment response were found contrary to the initial pathologic diagnosis. No significant complication such as hematoma or infection was reported. Conclusion: UGCNB has a high diagnostic value for determining the nature of the cervical lesions suspected of lymphoma.

A Phase 1 Study of HMPL-689, a Small Molecule, Highly Selective, and Potent Inhibitor of Phosphoinositide 3 Kinase-Delta, in Patients with Relapsed or Refractory Lymphoma

Background: The B-cell receptor (BCR) signaling pathway plays a critical role in the pathogenesis of lymphomas, particularly in non-Hodgkin lymphomas (NHL). Despite availability of therapeutic agents targeting BCR pathway, there is an unmet medical need for more effective and well-tolerated therapeutic agents for patients with advanced relapsed, refractory, or resistant NHL. HMPL-689 is a novel, orally available, highly selective, and potent small molecule inhibitor of phosphosinositide 3 kinase-delta (PI3Kδ), a crucial signaling transduction molecule in the BCR signaling pathway. A global clinical study of HMPL-689 is currently ongoing in the USA and the EU countries of France, Italy, Poland, and Spain. Preliminary results from dose escalation and expansion stages of this study are expected soon. Herein is the description of an ongoing phase 1, open-label, multi-center, single-arm study of HMPL-689 in patients with advanced relapsed, refractory, or resistant (R/R) NHL (NCT03786926). Study Population: Target patient population is adult patients with histologically confirmed advanced relapsed, refractory, or resistant NHL. To be eligible for enrollment, patients must have exhausted all approved therapeutic options available. Patients are ineligible for the study if they have primary central nervous system lymphoma. Objectives and Endpoints: The primary objective is to determine the maximum-tolerated dose (MTD)/recommended phase 2 dose (RP2D) of HMPL-689. The primary endpoints are the incidence of dose-limiting toxicity (DLT) and safety parameters, including treatment-emergent adverse events and laboratory abnormalities The secondary objective is to evaluate the pharmacokinetic (PK) parameters and preliminary efficacy. The secondary endpoints include concentration-time profiles, PK parameters, and efficacy parameters, including objective response rate, time to response, duration of response, and progression-free survival. Study Design: Study consists of a dose escalation and dose expansion stages. The dose-escalation stage utilizes a mTPI-2 design, with anticipated enrollment of approximately 24 patients until MTD is reached, and RP2D is determined. The proposed doses for escalation cohorts are 10, 15, 20, 25, 30, 35, 40, 45, and 50 mg, QD, PO in a 28-day cycle. Patients will be treated until disease progression, intolerable toxicity, no further benefit, withdrawal, end of study, or death. The expansion stage will be dosed at the MTD. Approximately 10 patients will be enrolled in each of the following cohorts: Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL),Mantle cell lymphoma (MCL),Follicular lymphoma (FL)Marginal zone lymphoma (MZL)Peripheral T-cell lymphoma (PTCL)Cutaneous B-cell lymphomaWaldenström's macroglobulinemia / lymphoplasmacytic lymphoma (WM) Statistical Methods: The maximum sample size in the dose-escalation stage will be determined based on the accumulated safety data and the mTPI-2 design. The maximum sample size under the mTPI-2 method is k × (d + 1), where k denotes the cohort size and d denotes the number of doses. The minimum cohort size in this study is 3 patients per cohort. To ensure that the highest dose (if needed) is reached, it is estimated that approximately 33-39 patients will be needed in this study. For dose expansion, approximately 70 patients (10 in each cohort) will provide robust safety data in the patient populations studied. For a given AE with a true rate of 10%, 5%, or 1%, the probability of observing at least one such AE in 70 patients is 99.9%, 97.2%, and 50.5%, respectively. For preliminary assessment of anti-tumor activity based on ORR, if at least 8 patients in a specific lymphoma subtype are evaluable for tumor response, the chance of observing at least one response is 94.2%, if the true ORR is 30%. Data will be summarized by dose level, subtype of malignancy, and overall as appropriate. Continuous assessments will be summarized by number of patients (n), mean, standard deviation, median, minimum and maximum. Significance: This study is the first global clinical study of HMPL-689, a novel inhibitor of the BCR signaling pathway, which is currently enrolling patients with advanced relapsed, refractory, or resistant NHL who have exhausted all approved therapeutics options available. Disclosures Lawrence: Hutchison MediPharma International, Inc:Current Employment, Current equity holder in publicly-traded company.Hahka-Kemppinen:Hutchison MediPharma International, Inc:Current Employment, Current equity holder in publicly-traded company.Cohen:Janssen, Adicet, Astra Zeneca, Genentech, Aptitude Health, Cellectar, Kite/Gilead, Loxo:Consultancy;Genentech, BMS, Novartis, LAM, BioInvent, LRF, ASH, Astra Zeneca, Seattle Genetics:Research Funding.Kania:Hutchison MediPharma International, Inc:Current Employment, Current equity holder in publicly-traded company.

A Phase 1 Study of HMPL-523, Highly Selective and Potent a Small Molecule Inhibitor of Spleen Tyrosine Kinase in Patients with Relapsed or Refractory Lymphoma

Background: The B-cell receptor (BCR) signaling pathway plays a critical role in the pathogenesis of lymphomas, particularly in non-Hodgkin lymphomas (NHL). Despite availability of therapeutic agents targeting BCR pathway, there continue to be unmet medical need for more effective and less toxic therapeutic agents for patients with advanced relapsed, refractory or resistant lymphoma. HMPL-523 is a novel, orally available, highly selective, and potent small molecule inhibitor of spleen tyrosine kinase (SYK), a crucial component of BCR signaling pathway. A clinical study is currently ongoing in the USA and in EU countries of France, Italy, Poland, and Spain. Preliminary results from dose escalation and expansion stages of these trials are expected soon. Herein is the description of an ongoing phase 1 open-label, multi-center, single-arm study of HMPL-523 in patients with advanced relapsed, refractory or resistant (R/R) NHL (NCT03779113). Study Population: Targeted patient population is adult patients with histologically confirmed advanced relapsed, R/R NHL. To be eligible for enrollment, patients must have exhausted all approved therapeutic options available. Objectives and Endpoints: The primary objective is to assess safety and tolerability of HMPL-523 and to determine the maximum-tolerated dose (MTD)/recommended phase 2 dose (RP2D). The primary endpoints are the incidence of dose-limiting toxicity (DLT) and safety parameters, including treatment-emergent adverse events and laboratory abnormalities The secondary objectives are to characterize the pharmacokinetic (PK) parameters and to evaluate the safety and preliminary efficacy of HMPL-523. The secondary endpoints are the incidence of treatment-emergent adverse events (TEAE), PK parameters, and efficacy parameters, including objective response rate, duration of response, time to response, and progression-free survival. Study Design: Study consists of a dose escalation stage and an expansion stage. The dose-escalation utilizes a modified 3+3 design, with anticipated enrollment of approximately 24 patients until MTD is reached, and RP2D is determined. The proposed doses of escalation cohorts are 100, 200, 400, 600 and 800 mg, QD, PO in a 28-day cycle. Patients will be treated until disease progression, intolerable toxicity, no further benefit, withdrawal, end of study, or death. The expansion stage will be dosed at the MTD to further evaluate safety, tolerability, PK, drug exposure, target engagement, PD and their correlation with clinical benefit of HMPL-523. Approximately 10 patients will be enrolled in each of the following cohorts: Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL),Mantle cell lymphoma (MCL),Follicular lymphoma (FL)Marginal zone lymphoma (MZL)Peripheral T-cell lymphoma (PTCL)Cutaneous B-cell lymphomaWaldenström's macroglobulinemia / lymphoplasmacytic lymphoma (WM) Statistical Methods: For the escalation stage, the sample size is based on the dose-escalation rules of the 3+3 design. For a given AE with a true rate of 10%, 5%, or 1%, the probability of observing at least one such AE in a given cohort of 6 patients is 46.9%, 26.5%, and 5.8%, respectively. For the dose expansion stage, a total of 70 patients (10 patients per expansion cohort) will provide robust safety data in the study patient populations. For a given AE with a true rate of 10%, 5%, or 1%, the probability of observing at least one such AE in 70 patients is 99.9%, 97.2%, and 50.5%, respectively. For preliminary assessment of anti-tumor activity based on ORR, if at least 8 patients in a specific lymphoma subtype are evaluable for tumor response, the chance of observing at least one response is 94.2%, if the true ORR is 30%. Safety parameters, including DLTs, recorded TEAEs, clinical laboratory parameters, vital signs, 12-lead ECG parameters and physical examination findings, will be summarized by dose level across both dose escalation and dose expansion stages. Efficacy endpoints will be summarized by dose level for each type of malignancy. Significance: This study is the first global clinical study of HMPL-523, a novel inhibitor of the BCR signaling pathway currently enrolling patients with advanced relapsed, refractory or resistant NHL who have exhausted all approved therapeutics options available. Disclosures Lawrence: Hutchison MediPharma International, Inc:Current Employment, Current equity holder in publicly-traded company.Hahka-Kemppinen:Hutchison MediPharma International, Inc:Current Employment, Current equity holder in publicly-traded company.Kania:Hutchison MediPharma International, Inc:Current Employment, Current equity holder in publicly-traded company.

Alteration in the gene expression profiling of mitochondrial Electron Transport Chain genes in lymphoma patients

Background: Many genes are involved in non-Hodgkin lymphoma (NHL)-associated translocations regulate the cell cycle, apoptosis, and lymphocyte development. NHL commonly occurs along with molecular genetic abnormalities. Certain molecular genetic abnormalities in NHL are related to specific lymphoma subtypes, which are associated with prognosis or potential therapeutic targets. Aim: This study aimed to screen for the potential expression of key genes in metabolic pathways in lymphoma patients (NHL) in early diagnosed cases and its clinical relevance. Materials and Methods: The relative expression of RNA profiling in 6 early diagnosed NHL patients and 3 healthy control volunteers were determined by using Affymetrix® HTA 2.0 array technology. Results: The total number of screened genes was 67528 around 44,699 coding genes in humans and 22,829 non-coding genes for evidence which has shown fundamental significance in normal development, differentiation, regulation of growth and in human diseases such as cancer. Only 6395 genes were differentially expressed between NHL patients and control. From these genes, 451 genes are up-regulated, and 655 genes were down-regulated. Compared to the control group; NHL patients displayed a significant 1.2 fold increase in the expression of mitochondrial biogenesis genes (POLMRT, TFAM) and ATPAse gene (ATP5D). Whereas a significant decrease was observed in the expression of NADH dehydrogenase genes (NDUFS1, NDUFV2, NDUFA1, NSDYFAB1) and mitochondrial biogenesis genes (TFB2M, UCP2, SLC25A) by 1.5 fold. Additionally, cytochrome oxidase genes (COX5A and COX6A1) exhibited a significant 1.3 fold decrease. This expression alteration is associated with cytogenetic abnormalities and may lead to hematological malignancies. Conclusion: This study explored the importance of certain mitochondrial related genes which can be used as biomarkers for diagnosis and/or prognosis of the disease.

B-cell neoplasms and Hodgkin lymphoma in the spleen

B-cell lymphoma of spleen may be primary (most commonly splenic diffuse large B-cell lymphoma) or secondary (typically low-grade non-Hodgkin lymphoma). Depending on the specific lymphoma subtype, there may be a predominantly white pulp pattern of involvement, a predominantly red pulp pattern or a focal nodular pattern. Splenectomy is the ideal specimen for a multiparametric integrative diagnosis of splenic lymphoma, as it allows for a combined study of morphology, immunohistology, flow cytometry, cytogenetics, and molecular genetic techniques. This review article describes the clinicopathologic characteristics of all the relevant B-cell neoplasms that may be encountered in a splenic biopsy or a splenectomy specimen.

AG-636 for the Treatment of Adults with Advanced Lymphoma: Initiation of a Phase 1 Clinical Study

AG-636 for the Treatment of Adults with Advanced Lymphoma: Initiation of a Phase 1 Clinical Study

A multivariable approach for risk markers from pooled molecular data with only partial overlap

BackgroundIncreasingly, molecular measurements from multiple studies are pooled to identify risk scores, with only partial overlap of measurements available from different studies. Univariate analyses of such markers have routinely been performed in such settings using meta-analysis techniques in genome-wide association studies for identifying genetic risk scores. In contrast, multivariable techniques such as regularized regression, which might potentially be more powerful, are hampered by only partial overlap of available markers even when the pooling of individual level data is feasible for analysis. This cannot easily be addressed at a preprocessing level, as quality criteria in the different studies may result in differential availability of markers – even after imputation.MethodsMotivated by data from the InterLymph Consortium on risk factors for non-Hodgkin lymphoma, which exhibits these challenges, we adapted a regularized regression approach, componentwise boosting, for dealing with partial overlap in SNPs. This synthesis regression approach is combined with resampling to determine stable sets of single nucleotide polymorphisms, which could feed into a genetic risk score. The proposed approach is contrasted with univariate analyses, an application of the lasso, and with an analysis that discards studies causing the partial overlap. The question of statistical significance is faced with an approach called stability selection.ResultsUsing an excerpt of the data from the InterLymph Consortium on two specific subtypes of non-Hodgkin lymphoma, it is shown that componentwise boosting can take into account all applicable information from different SNPs, irrespective of whether they are covered by all investigated studies and for all individuals in the single studies. The results indicate increased power, even when studies that would be discarded in a complete case analysis only comprise a small proportion of individuals.ConclusionsGiven the observed gains in power, the proposed approach can be recommended more generally whenever there is only partial overlap of molecular measurements obtained from pooled studies and/or missing data in single studies. A corresponding software implementation is available upon request.Trial registrationAll involved studies have provided signed GWAS data submission certifications to the U.S. National Institute of Health and have been retrospectively registered.

Risk for malignancies of infectious etiology among adult survivors of specific non-Hodgkin lymphoma subtypes

AbstractInfectious agents have been identified in the etiology of certain non-Hodgkin lymphoma (NHL) subtypes and solid tumors. The impact of this shared etiology on risk for second cancers in NHL survivors has not been comprehensively studied. We used US population–based cancer registry data to quantify risk of solid malignancies associated with infectious etiology among 127 044 adult 1-year survivors of the 4 most common NHL subtypes diagnosed during 2000 to 2014 (mean follow-up, 4.5-5.2 years). Compared with the general population, elevated risks for liver, stomach, and anal cancers were observed among diffuse large B-cell lymphoma (DLBCL) survivors (standardized incidence ratio [SIR], 1.85; 95% confidence interval [CI], 1.46-2.31; SIR, 1.51; 95% CI, 1.16-1.94; SIR, 3.71; 95% CI, 2.52-5.27, respectively) and marginal zone lymphoma (MZL; SIR, 1.98; 95% CI, 1.34-2.83; SIR, 2.78; 95% CI, 2.02-3.74; SIR, 2.36; 95% CI, 1.02-4.64, respectively) but not follicular lymphoma or chronic lymphocytic leukemia/small lymphocytic lymphoma. Anal cancer risk was particularly elevated among DLBCL survivors with HIV (SIR, 68.34; 95% CI, 37.36-114.66) vs those without (SIR, 2.09; 95% CI, 1.22-3.34). The observed patterns are consistent with shared associations between these cancers and hepatitis C virus, Helicobacter pylori, and HIV, respectively. In contrast, risks for cervical and oropharyngeal/tonsil cancers were not elevated among survivors of any NHL subtype, possibly because of the lack of NHL association with human papillomavirus or population-wide screening practices (for cervical cancer). In summary, patterns of elevated second cancer risk differed by NHL subtype. Our results suggest shared infectious etiology has implications for subsequent cancer risks among DLBCL and MZL survivors, which may help inform surveillance for these survivors.

Breed-associated risks for developing canine lymphoma differ among countries: an European canine lymphoma network study

BackgroundCanine breeds may be considered good animal models for the study of genetic predisposition to cancer, as they represent genetic clusters. From epidemiologic and case collection studies it emerges that some breeds are more likely to develop lymphoma or specific subtypes of lymphoma but available data are variable and geographically inconsistent. This study was born in the context of the European Canine Lymphoma Network with the aim of investigating the breed prevalence of canine lymphoma in different European countries and of investigating possible breed risk of lymphoma overall and/or different lymphoma subtypes.ResultsA total of 1529 canine nodal lymphoma cases and 55,529 control cases from 8 European countries/institutions were retrospectively collected. Odds ratios for lymphoma varied among different countries but Doberman, Rottweiler, boxer and Bernese mountain dogs showed a significant predisposition to lymphoma. In particular, boxers tended to develop T-cell lymphomas (either high- or low-grade) while Rottweilers had a high prevalence of B-cell lymphomas. Labradors were not predisposed to lymphoma overall but tended to develop mainly high-grade T-cell lymphomas. In contrast with previous studies outside of Europe, the European golden retriever population did not show any possible predisposition to lymphoma overall or to specific subtypes such as T-zone lymphoma.ConclusionFurther prospective studies with more precise and consistent subtype identification are needed to confirm our retrospective results and to create the basis for the investigation of possible genes involved in different predispositions.

Flow Cytometric Characterization of S-phase Fraction and Ploidy in Lymph Node Aspirates from Dogs with Lymphoma

Canine lymphoma is a multifaceted disease encompassing numerous entities with different prognosis. Objective assessment of the proliferation rate is of importance from the pathological and clinical perspectives. Different methods have been described in the literature to assess proliferation rate, including evaluation of Ki67 expression in fresh lymph node (LN) aspirates measured by flow cytometry (FC). This test has a high accuracy in discriminating between low- and high-grade lymphomas, and provides prognostic information among high-grade B-cell lymphomas. DNA content analysis is less expensive and suitable for well-preserved samples. We describe DNA-content analysis using LN aspirates from 112 dogs with lymphoma. S-phase fraction (SPF) accurately discriminated between low- and high-grade lymphomas, with 3.15% being the best discriminating cut-off value. SPF values strongly correlated with Ki67 expression as assessed by FC. Survival analyses were restricted to 33 dogs with high-grade B-cell lymphoma receiving standardized multi-agent chemotherapy, but no significant result was obtained for SPF. We also describe a subset of aneuploid cases and their respective follow-up. We conclude that DNA content analysis may be combined with morphological examination of LN aspirates to improve the objectivity in lymphoma subtype classification in dogs. Further studies are needed to assess the possible prognostic role of SPF and ploidy status within specific lymphoma subtypes in dogs.

Occupational extremely low frequency magnetic fields (ELF-MF) exposure and hematolymphopoietic cancers – Swiss National Cohort analysis and updated meta-analysis

PurposePrevious studies have examined risks of leukaemia and selected lymphoid malignancies in workers exposed to extremely low frequency magnetic fields (ELF-MF). Most studies evaluated hematolymphopoietic malignancies as a combined category, but some analyses suggested that effects may be contained to some specific leukaemia or lymphoma subtypes, with inconsistent results. MethodsWe examined exposure to ELF-MF and mortality 1990–2008 from different types of hematolymphopoietic cancers in the Swiss National Cohort, using a job exposure matrix for occupations recorded at censuses 1990 and 2000. We analysed 3.1 million workers exposed at different levels to ELF-MF: ever-high, only-medium, only-low exposure using Cox proportional hazard models. We evaluated risk of death from acute myeloid leukaemia (AML), chronic myeloid leukaemia, lymphoid leukaemia, diffuse large B-cell lymphomas, follicular lymphoma, Waldenström's macroglobulinemia, multiple myeloma and Hodgkin lymphoma. ResultsMortality from hematolymphopoietic cancers was not associated with exposure to ELF-MF with the exception of an increase in ever-high exposed men of myeloid leukaemias (HR 1.31, 95% CI 1.02–1.67), and AML (HR 1.26, 95%CI 0.93–1.70). If workers had been high exposed during their vocational training and at both censuses, these HR increased to 2.24 (95%CI 0.91–5.53) and 2.75 (95%CI 1.11–6.83), respectively. ConclusionsOur analysis provided no convincing evidence for an increased risk of death from a range of hematolymphopoietic cancers in workers exposed to high or medium levels of ELF magnetic fields. However, we observed an increased risk of acute myeloid leukaemia in workers exposed to high levels for a longer duration. Observed risks are in line with meta-analysed previous reports on ELF-MF exposure and AML risk, with a summary relative risk of 1.21 (95%CI 1.08–1.37).