Extranodal Diffuse Large B-cell Lymphoma Research Articles

Coexpression of MYC and BCL2 oncoproteins in primary nodal versus primary extranodal diffuse large B-cell lymphoma

Objectives: Diffuse large B-cell lymphoma (DLBCL) is a morphologically and molecularly diversified disease with aggressive biological behavior. The double expression of MYC/BCL2 proteins portends a poorer prognosis. This study aims to evaluate the frequency, describe the clinicopathological features of the double-expressor phenotype of DLBCL in primary nodal (PN) versus primary extranodal (PEN) sites, and investigate their associations. Materials and Methods: A total of 48 patients with the double-expressor phenotype of lymphoma (DEPL) in a tertiary care hospital were included over three years. Clinicopathological parameters and associations were investigated based on the primary site. Statistical Analysis: Data were documented and analyzed using appropriate statistical tests. Results: The incidence of DEPL in our study was 28.7%. The median age of all DEPL patients was 56 years, with a predominance of men (69%). DEPL cases were further subcategorized as PN-DEPL (n = 33) and PEN-DEPL (n=15). Males were affected almost equally in both groups. More PN-DEPL patients exhibited B symptoms (82%), elevated lactate dehydrogenase (LDH) levels (73%), III/IV stage disease (71%), and maximum revised international prognostic index (R-IPI) score (64%) compared to PEN-DEPL patients. On the other hand, bone marrow (BM) involvement (87%), activated B-cell-type phenotype (80%), pathologic stage I/II (67%), and Ki67 index >90% (93%) were more common in PEN-DEPL patients. Conclusions: Significant differences were observed between PN-DEPL and PEN-DEPL in terms of B symptoms, LDH levels, stage at presentation, BM involvement, pathological subtype, Ki67 index, and R-IPI score. This study provides an estimate of the burden of this aggressive entity and encourages further prognostic studies and therapeutic trials.

Primary Extranodal Diffuse Large B-Cell Lymphoma in the Rituximab Era: a Single-Center Retrospective Analysis

To investigate the clinical features and prognostic factors of patients with primary extranodal diffuse large B-cell lymphoma (DLBCL) in the rituximab era. The continuous data of newly diagnosed DLBCL patients with complete case data and first-line treated with rituximab, cyclophosphamide, epirubicin, vincristine, prednisone (R-CHOP) or R-CHOP treatment admitted to the Affiliated Hospital of Inner Mongolia Medical University from January 2013 to November 2023 were retrospectively analyzed. The clinical and molecular immunological features and prognosis of extranodal DLBCL were analyzed, Logistics regression model was used to analyzed the influencing factors of patients prognosis. A total of 237 patients were enrolled, of which 54.4% (129 cases) were primary extranodal sources of DLBCL, and the most common extranodal sites were as follows: stomach (19.4%), colon (14.7%), tonsils (12.4%), skin/muscle (9.3%), central (7.7%), nasal/nasopharynx (6.2%), bone marrow (5.4%), testes (4.7%). The 3-year PFS and OS of DLBCL patients with extranodal involvement of bone marrow, central, liver, gastrointestinal or pulmonary origin were significantly lower than those of other patients with extranodal DLBCL of non-special site origin, and the difference was statistically significant (PFS: 65.2% vs 76.7%, P =0.008; OS: 82.6% vs 88.3%, P =0.04). Multivariate analysis showed that the prognostic factors affecting OS included NCCN-IPI score >3 (OR : 0.142, 95%CI : 0.041-0.495, P =0.002), non-germinal center source (OR : 2.675，95%CI :1.069-6.694，P =0.036), and DEL patients (OR : 0.327, 95%CI : 0.129-0.830, P =0.019). An NCCN-IPI score >3 was the only independent adverse prognostic factor for PFS (OR : 0.235, 95%CI : 0.116-0.474, P < 0.001). Patients with primary extranodal source DLBCL are more common in gastrointestinal involvement, and the overall prognosis is worse than that of patients with lymph node origin. NCCN-IPI score is an important independent adverse prognostic factor for predicting overall survival and progression-free survival in patients with primary extranodal diffuse large B-cell lymphoma.

Cystatin SN (CST1) Is a Poor Independent Prognostic Biomarker for Gastrointestinal Diffuse Large B-Cell Lymphoma.

BACKGROUND Gastrointestinal diffuse large B-cell lymphoma (GI-DLBCL) is the most common histological subtype of extra-nodal DLBCL, but the risk factors, prognostic biomarkers, histopathological classifications, and treatment strategies have not had significant progress. Emerging evidence shows that cystatin SN (CST1) is involved in tumor progression in several cancer types, but its role in GI-DLBCL has not been revealed. MATERIAL AND METHODS We established a cohort consisting of 84 patients with GI-DLBCL who underwent surgical resection. The expression of CST1 in the cohort was investigated by immunohistochemistry, which divided the patients into subgroups with low or high expression of CST1. Moreover, the CST1 expression in GI-DLBCL tissues or adjacent GI tissues were compared with RT-qPCR. The correlation between CST1 expression and clinicopathological factors was analyzed with the chi-square test. The prognostic significance of CST1 was estimated by univariate and multivariate analysis, and statistical significance was analyzed with the log-rank test. RESULTS CST1 was aberrantly upregulated in GI-DLBCL tissues compared with in non-tumor GI tissues. High expression of CST1 indicated poor prognosis of GI-DLBCL (P=0.012), and CST1 can be regarded as an independent prognostic biomarker of GI-DLBCL (hazard ratio=3.07). In our study, serum lactate dehydrogenase (P=0.002), performance status (P=0.003), Lugano stage (P=0.002), and International Prognostic Index (P=0.001) were also prognostic factors of GI-DLBCL. CONCLUSIONS CST1 is an independent prognostic biomarker of GI-DLBCL, indicating unfavorable prognosis. Our results suggested that CST1 detection can be a promising method to stratify high-risk patients and guide individual treatment.

Clinicopathological differences in MYC and BCL2 protein expression between primary extranodal and nodal diffuse large B-cell lymphoma

Diffuse large B-cell lymphoma (DLBCL) exhibits clinical, genetic, and immunohistochemical heterogeneity. However, the differences between primary extranodal or nodal DLBCL and double-expressor lymphoma (DEL), which is characterized by high MYC and BCL2 expression, remain unclear. This study aimed to elucidate the clinicopathological features, response to therapy, and clinical outcomes of primary extranodal (n=61) and nodal (n=128) DLBCL. Patients with primary nodal DLBCL had higher BCL2 expression than those with extranodal DLBCL (p=0.048), with high MYC expression and DEL as poor prognostic factors. Conversely, in patients with primary extranodal DLBCL, high BCL2 expression, low BCL6 expression, non-germinal center B-cell-like type, and DEL indicated poor prognosis. DEL was significantly associated with progression free survival and overall survival in patients with primary extranodal DLBCL (p=0.014 and p=0.021, respectively) but not in patients with primary nodal DLBCL (p=0.37 and p=0.084, respectively). Our findings highlight primary extranodal DEL as a strong adverse prognostic factor in DLBCL.

Primary gastric diffuse large B-cell lymphoma: A multicentre retrospective study.

Primary gastric diffuse large B-cell lymphoma (PG-DLBCL) accounts for the majority of extra-nodal DLBCL. Even so, literature is lacking on early, localised presentations. We studied a cohort of patients with stage I disease, diagnosed between 2006 and 2018, from six centres between Australia, Canada and Denmark. Our goal was to characterise outcomes, review treatmentand investigate the role of interim positron emission tomography (iPET). Thirty-seven eligible patients were identified. The median duration of follow-up was 42.2 months. All received chemoimmunotherapy with 91.9% (n = 34) given rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP). 35.1% (n = 13) underwent consolidative radiotherapy. Eighteen patients were H. pylori positive and 11 had the documentation of H. pylori eradication therapy. The 4-year progression-free survival and overall survival of R-CHOP was 88% (95% CI: 71-95) and 91% (95% CI: 75-97) respectively. All patients who achieved a partial metabolic response or complete metabolic response on iPET went on to achieve complete response at the end of treatment. R-CHOP-based therapy with iPET assessment appears to offer favourable outcomes, with radiotherapy and H. pylori eradication therapy implemented on a case-by-case basis.

A case report of extranodal diffuse large B-cell lymphoma involving upper limb soft tissue in a patient with rheumatoid arthritis on immunosuppressive therapy

An 80-year-old woman affected by rheumatoid arthritis on immunosuppressive therapy was evaluated for an 11-month history of swelling of her left upper limb. The patient did not report systemic symptoms. Ultrasonographic examination showed hypoechoic masses in the upper limb soft tissue, brachial vein thrombosis, and suspected malignant axillary lymphadenopathy. The patient underwent an excisional biopsy of the lymphadenopathy for histologic examination; a diagnosis of diffuse large B-cell lymphoma was made. The patient started anticoagulation therapy and chemotherapy, with a follow-up at a hematology clinic. At a 3-month follow-up visit in our clinic, the swelling of her left upper limb decreased, and an ultrasonographic control demonstrated a reduction in the size and number of the soft tissue masses and resolution of vein thrombosis.

Primary Skeletal Muscle Diffuse Large B Cell Lymphoma in Lumbar Region – A Rare Occurrence

Diffuse large B cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma worldwide. Patients most often present with a rapidly growing tumour mass in single or multiple, nodal, or extranodal sites. Extranodal involvement is seen in up to 40% cases. Initial presentation as soft tissue lesion is rare. We report a case of extranodal DLBCL in an elderly male, presenting as a soft tissue mass in the left lumbar region, clinically suggestive of lipoma. The patient had no palpable lymphadenopathy. Complete blood counts were within normal limits. Initial ultrasonography was suggestive of abscess, possibly of tubercular origin. On fine needle aspiration cytology, features were of a malignant neoplasm; a lymphomatous process. Subsequent histopathological evaluation followed by IHC confirmed the diagnosis of DLBCL. Primary extranodal DLBCL involving the soft tissue is rare. Owing to its non- specific and unusual clinical presentation, accurate diagnosis may be delayed. Besides, imaging modalities are also diagnostically challenging due to a wide range of differentials, thereby emphasising the need for tissue diagnosis. Histopathological examination and immunohistochemistry are paramount in accurate diagnosis and tailoring treatment options.International Journal of Human and Health Sciences Vol. 08 No. 01 Jan’24 Page: 95-98

Development of Diffuse Large B-Cell Lymphoma and Sarcoidosis In The Course Of Multiple Myeloma: A Case Report with Literature Review

Despite significant survival increment due to treatment improvement, multiple myeloma (MM) remains an incurable disease. We herein describe a unique patient that is not only a MM long survivor despite adverse features, such as the occurrence of extramedullary disease at relapse, but also developed, sixteen years after MM diagnosis, an extranodal diffuse large B-cell lymphoma (DLBCL) of the small intestine. The patient eventually achieved cure but developed sarcoidosis two years later that regressed with corticosteroids. Today, after 26 years of follow-up the patient is in remission and in good clinical condition.

Primary Extranodal Diffuse Large B-cell Lymphoma Presenting in the Lips: A Case Report and Literature Review.

Approximately 30-40% of malignant lymphomas are classified as diffuse large B-cell lymphoma (DLBCL), with 30% of DLBCL cases manifesting as extranodal lymphomas. Among these extranodal DLBCLs, primary DLBCL in oral lesions, particularly in the lips, is rare. While the treatment methods, chemotherapy assessment, and prognosis for nodal and extranodal DLBCLs are generally similar, diagnostic challenges can lead to delayed therapeutic intervention. We herein present a recent case of primary extranodal DLBCL in the lips that was swiftly diagnosed and managed using rituximab-containing chemotherapies. Our experience underscores the important role that hematologists play in identifying the possibility of oral hematological tumors, thereby allowing for a rapid diagnosis and timely intervention.

Первичная экстранодальная диффузная крупноклеточная В-клеточная лимфома: молекулярный ландшафт, противоопухолевое лечение и прогноз

Диффузная крупноклеточная В-клеточная лимфома (ДВКЛ) представляет собой крайне гетерогенное опухолевое заболевание лимфоидной природы и является наиболее распространенным иммуноморфологическим вариантом из группы агрессивных неходжкинских лимфом (НХЛ). Треть ДВКЛ характеризуется первичной экстранодальной локализацией и вариабельным прогнозом в зависимости от зоны поражения. Следует отметить, что именно молекулярные характеристики играют ключевую роль в различиях клинических проявлений, прогнозе опухолевого заболевания и совершенствовании терапевтического подхода с включением новых противоопухолевых агентов. Экстранодальная ДВКЛ молочной железы, кожи, матки, иммунопривелигированных зон, таких как центральная нервная система (ЦНС), и яичка, обладает фенотипом В-клеток постгерминального уровня (non-GCB) и высокой частотой мутаций MYD88/CD79B. В свою очередь для экстранодальной ДВКЛ желудка и щитовидной железы характерно благоприятное течение заболевания с низкой частотой выявляемости non-GCB-фенотипа. Ритуксимаб-содержащая иммунохимиотерапия (ИХТ) служит стандартом не только для нодальных форм заболевания, но и при первичной экстранодальной локализации. В настоящее время оптимизация стратегии терапии в соответствии с клинико-иммуноморфологическими характеристиками и молекулярной гетерогенностью является крайне актуальной проблемой. В данном обзоре рассматриваются ключевые сигнальные пути и новые подходы к противоопухолевой терапии первичной экстранодальной ДВКЛ. Diffuse large B-cell lymphoma (DLBCL) is an extremely heterogeneous tumour disease of lymphoid nature and is the most common immunomorphological variant from the group of aggressive non-Hodgkin’s lymphomas (NHL). One third of DLBCL is characterised by primary extranodal localization and a variable prognosis depending on the area of the lesion. It should be noted that it is molecular characteristics that play a key role in the differences in clinical manifestations, prognosis of tumour disease and improvement of the therapeutic approach with the inclusion of new antitumour agents. Extranodal DLBCL of the breast, skin, uterus, immunoprivileged areas such as the central nervous system (CNS) and testis have a postgerminal B-cell (non-GCB) phenotype and a high frequency of MYD88/CD79B mutations. In turn, extranodal gastric and thyroid DLBCL is characterised by a favourable disease course with a low incidence of the non-GCB phenotype. Rituximab- containing immunochemotherapy (ICT) is the standard not only for nodal forms of the disease, but also for primary extranodal localisation. Currently, optimizing the therapy strategy according to clinical and immunomorphological characteristics and molecular heterogeneity is a highly relevant problem. In this review, key signalling pathways and new approaches to antitumour therapy of primary extranodal DLBCL are discussed.

CNSC-36. INDOLENT INTRAVASCULAR LARGE B-CELL LYMPHOMA (IVLBCL) ORIGINALLY PRESENTING AS A STROKE MIMIC

Abstract BACKGROUND IVBCL is a rare subtype of extranodal diffuse large B-cell lymphoma, characterized by the growth of neoplastic cells in blood vessels with no other apparent extravascular mass, making diagnosis a challenge. It usually has an aggressive and fast-paced course; however, there is limited data regarding incidence due to its rarity. CASE A 73 year-old woman presented with progressive gait worsening a year prior to presentation to our institution. Her symptoms then developed to include left-sided hemiparesis with associated headaches, warranting a local emergency department visit. Brain magnetic resonance imaging (MRI) without contrast showed a Flair hyperintense lesion in the right MCA territory with restricted diffusion, assumed to be an ischemic stroke, and she was started on stroke prevention measures. The patient continued to decline, becoming wheelchair-bound and developing short-term memory loss, chronic headaches, and pseudobulbar affect. Repeat brain MRI without contrast five months later showed progression of the Flair hyperintensity to the left hemisphere with restricted diffusion. Brain MRI with contrast followed, revealing subtle enhancement. Vessel imaging was unremarkable, and cerebrospinal fluid (CSF) analysis was normal with negative cytology and flow cytometry, yet elevated beta-2-microglobulin at 3.25 mcg/mL. A year after symptoms onset, the patient presented to our Neuro-Oncology clinic. Repeat Brain MRI with contrast and spectroscopy showed progression on the left-sided lesion with persistent restriction diffusion and enhancement, prompting a biopsy. Pathology confirmed large B cell lymphoma. PET-CT body scan showed no evidence of systematic disease. The patient was treated with Rituximab, Methotrexate, Vincristine, and Procarbazine (RMVP) with complete response demonstrated by complete resolution of the diffusion restriction and symptoms improvement. CONCLUSIONS Although IVLBCL is known for being a fast progressive disease, we present a case of indolent course delaying diagnosis. Unexplained progressive neurological symptoms with restricted diffusion on MRI should prompt consideration for this diagnosis.

Baseline 18f-Fluorodeoxyglucose PET/CT Radiomics Predicts Outcome in Newly Diagnosed Intravascular Large B-Cell Lymphoma

[Introduction] Treatment outcomes of intravascular large B-cell lymphoma (IVLBCL), a rare subtype of extra-nodal diffuse large B-cell lymphoma (DLBCL), have dramatically improved in recent years. However, prognostic factors for IVLBCL are largely unknown. Several studies have explored the potential of the baseline 18F-fluorodeoxyglucose (FDG) PET/CT radiomics features to identify patients with poor prognosis. For example, metabolic tumor volume (MTV) reflects the FDG-avid tumor burden, and the maximum distance between the largest lesion and any other lesion quantifies the dissemination of the tumor, and both factors are inversely related to overall survival (OS) and progression-survival (PFS) in DLBCL. In this study, we explored prognostic impact of FDG PET/CT radiomics features in newly diagnosed IVLBCL. [Methods] We retrospectively evaluated patients with histopathologically proven newly diagnosed IVLBCL according to the 2008 World Health Organization criteria between January 2010 through February 2022 from hospitals participating in the North Japan Hematology Study Group (NJHSG). Quantitative analysis of all FDG PET/CT was performed using Metavol (Hokkaido University, Sapporo, Japan), with exclusion of physiological accumulation. MTV was defined as the volume of lymphoma lesions visualized on PET/CT scans with standardized uptake value (SUV) peaks greater than or equal to hepatic SUV peak. To quantify the dissemination of the tumor, we calculated the number of the body areas (head-neck, chest, abdomen, upper-extremities, lower-extremities) having BM lesions with a higher SUV peak than liver SUV peak. Patients with BM lesions spread across 4-5 areas were defined as cases having widely disseminated lesions (WDL). Progression-free survival (PFS) was defined as the time from the start of treatment to the first of progression, relapse, or death from any cause. Patients undergoing upfront autologous stem-cell transplantation (auto-SCT) were censored at the time of transplantation. [Results] We identified fifty-two IVLBCL patients (age 30-89 years, median 65 years; 57.7% male) who performed FDG PET/CT at diagnosis. Twenty-eight patients (54.9%) had poor performance status (ECOG PS ≥2), and 49 patients (94.2%) showed stage III-IV. Forty-nine patients (94.2%) had 2 or more extranodal involvement. Elevated serum LDH level was observed in 49 cases (94.2%) (median, 623.5 IU/L; range, 147-4907 IU/L). The median serum levels of soluble IL-2 receptor (sIL-2R), ferritin, and C-reactive protein (CRP) were 4496.5 IU/mL (range, 321-19900 IU/mL), 655.15 ng/mL (range, 50-6657 ng/mL), and 6.905 mg/dL (range, 0.11-25.86 mg/dL), respectively. The median MTV was 415.527 cm 3 (range, 0-3000 cm 3). ROC analysis revealed that the cutoff value of the MTV &amp;gt; 388 cm 3 could predict progression events within 2 years. Area under curve was 0.71 (95% CI: 0.564-0.857). Twenty-nine patients (55.8%) were classified as having MTV &amp;gt; 388 cm 3 (high MTV). Twenty-three patients (44.2%) had WDL. Fifty-one (98.1%) patients received chemotherapy, all of which was rituximab-containing regimen. Three patients (5.8%) received upfront auto-SCT. Median follow-up duration was 48.8 months (range, 5.8-140.5 months) in survivors. Age, LDH level, number of extranodal lesions, clinical stage, and PS did not affect OS and PFS. Although the high MTV and WDL did not significantly affect OS ( P = 0.095, P = 0.173, respectively; Log-rank), these findings did correlate significantly with poor PFS ( P = 0.011, P = 0.042, respectively; Log-rank). Thus, we defined a high MTV or a WDL as poor PET findings. Thirty-two patients had poor PET findings. Importantly, patients with poor PET findings showed significantly poor OS and PFS compared to patients without (2-year OS: 71.2% vs. 93.3%, P = 0.015, 2-year PFS: 45.5% vs. 93.8%, P = 0.001; Log-rank, Fig. 1, 2). [Conclusion] This is the largest study to assess prognostic impact of FDG PET/CT radiomics features on newly diagnosed IVLBCL. Poor PET findings were significantly correlated with worse OS and PFS.

Clinical Case of a Patient with Extranodal Diffuse Large B-Cell Lymphoma and Surgical Complications

Summary Diffuse large B-cell lymphoma (DLBCL) is one of the most common types of non-Hodgkin lymphoma in adults. In most of the cases a complete remission is possible to obtain by applying conventional immunochemotherapy (rituximab in combination with cyclophosphamide, doxorubicin, vincristine, methylprednisolone or R-CHOP). Its effect depends on some risk factors, cellular origin of the lymphoma and to some extend – the localization when extranodal involvement is confirmed. We present the case of a patient with DLBCL of small intestine and non-specific clinical manifestation. Following treatment with standard therapy R-CHOP patient fail to achieve disease response and gastrointestinal track (GIT) complications were registered.

Clinical features and prognosis of double primary malignant neoplasms in patients with non-hodgkin lymphoma

To investigate the clinical features, survival, and prognostic factors of patients with double primary malignant neoplasms (DPMNs) comprising non-Hodgkin lymphoma (NHL) and malignant solid tumors. Of the 2352 patients diagnosed with NHL, 105 (4.46%) patients were diagnosed with DPMNs, 42 (40.0%) had NHL first (the NHL-first group) and 63 (60.0%) had solid tumor first (the ST-first group). Females were more frequent in the ST-first group, and the interval time between the two tumors was longer. More NHLs in early stages and originating from extranodal sites were observed in the NHL-first group. Male, age ≥ 55 years at diagnosis of the first tumor, interval time <60 months, NHL diagnosed first, NHL arising from an extranodal site, DPMNs without breast cancer, and no surgery for the first primary tumor were associated with poorer overall survival (OS). Interval time <60 months and NHL diagnosed first were independent risk factors that affected the prognosis of patients with DPMNs. Therefore, careful monitoring and follow-up are especially important for these patients. 50.5% (53/105) of patients with DPMNs did not receive chemotherapy or radiotherapy prior to the diagnosis of the second tumor. We further compared the baseline characteristics of diffuse large B-cell lymphoma(DLBCL) patients with and without solid tumors, the former had a higher proportion of extranodal DLBCL, suggesting that extranodal DLBCL is more likely to develop solid tumors than nodal DLBCL.

Ocular Involvement in a Patient with Intravascular Large B-Cell Lymphoma: A Diagnostic Challenge. Clinical Case Report and Literature Review

ABSTRACT Purpose To describe the ophthalmic findings and diagnosis of a case of intravascular large B-cell lymphoma. Methods Clinical case observational report. Clinical case A Spanish 51-year-old man referred to our hospital with a diagnosis of panuveitis. The patient presented with blurred vision, photophobia, fever, and weight loss. Ocular examination revealed anterior uveitis, vitritis, and multiple round and oval creamy spots on the posterior pole. Fluorescein angiography, optical coherence tomography (OCT), and angio-OCT were used for the ocular examination. The diagnosis of lymphoma was formulated on the basis of a random normal skin biopsy, which showed significant CD20 cellularity within the vessels and extensive CD3 expression. Conclusions Intravascular lymphoma is a rare form of extranodal diffuse large B-cell lymphoma, often with delayed diagnosis because of the nonspecific symptoms. Hence, random skin biopsy could be useful in the diagnosis.

Clinicopathological Characteristics and Prognosis of Diffuse Large B-Cell Lymphoma in Relation to CA-125 and CA 19-9 Expression.

Background: Some epithelial tumors express the carbohydrate antigen 125 (Cancer antigen-125, CA-125) and CA 19-9, especially ovarian and pancreatic tumors. Patients with non-Hodgkin lymphoma (NHL) were reported to have a close association between serum CA-125 levels and adverse prognostic factors with worse survival. We aimed to investigate CA-125 and 19-9 expression in nodal diffuse large B-cell lymphoma, not otherwise specified (DLBCL NOS) tissues using immunohistochemistry (IHC) and their relations to clinicopathological manifestations and patients' survival. Methods: 65 cases of DLBCL NOS were examined. A modified mechanical pencil tip was used to construct Manual Tissue Micro-array (TMA) blocks. Immunohistochemical staining for CA-125 and CA 19-9 was performed and scored semi-quantitatively. All relations were analyzed using established statistical methodologies. Results: Aberrant expression of CA 19-9 was detected in 12% of cases without any expression of CA-125. Moreover, 75% of the CA 19-9 positive cases were statistically significantly associated with anemia and performance status 1. Also, 75% of the CA 19-9 positive cases were females. Conclusions: CA 19-9 was aberrantly expressed in 12% of nodal DLBCL NOS cases and significantly related to anaemia and performance status but not to survival. In cases of DLBCL NOS, CA 19-9 expression cannot be considered an independent prognostic factor. CA-125 was not expressed in nodal DLBCL NOS tissues, necessitating re-evaluation studies. Therefore, it is advised to conduct more research to clarify the potential correlation between serum and tissue CA 19-9 levels and other clinic-pathological characteristics of nodal and extranodal DLBCL NOS patients.

Elevated FDG Uptake in the Lung Is a Characteristic Finding of Intravascular Large B-Cell Lymphoma

[Introduction] Intravascular large B-cell lymphoma (IVBCL) is a rare subtype of extra-nodal diffuse large B-cell lymphoma (DLBCL), characterized by preferential growth of lymphoma cells within the lumina of small vessels. Clinical presentation of IVBCL is highly variable, and it often includes organ dysfunction related to obstruction of blood vessels. Up to 80% of IVBCL cases experienced hypoxemia at initial presentation, suggesting a high rate of respiratory involvement. In recent years, some IVBCL cases with diffuse pulmonary uptake on 18F-fluorodeoxyglucose (FDG) PET/CT have been reported from Asia and Western countries. It may also reflect the pulmonary infiltration of IVBCL; however, there are no reports of detailed studies with a large number of IVBCL cases. [Methods] We retrospectively evaluated patients with histopathologically proven newly diagnosed IVBCL according to the 2008 World Health Organization criteria between January 2010 through February 2022 from hospitals participating in the North Japan Hematology Study Group (NJHSG). PET/CT images were reviewed by an experienced nuclear medicine physician (S.W.). In addition to the general PET/CT evaluation, the ratio of the lung to mediastinum standardized uptake value (SUV) peaks (L/M ratio) was calculated to assess the degree of FDG accumulation in the lungs objectively. Lung SUV peaks were measured uniformly about 1 cm medial to the right lower lobe pleura, and mediastinum SUV peaks were measured in the left atrium. The L/M ratio of 226 advanced stage DLBCL cases diagnosed within the same periods was also calculated and compared with IVBCL cases. [Results] We identified fifty-one IVBCL patients (age 30-89 years, median 65 years; 56.9% male) who performed PET/CT at diagnosis, and 29 of whom also underwent after chemotherapy. IVBCL was diagnosed via skin biopsy in 31 (60.8%) cases, bone marrow biopsy in 15 (29.4%) cases, and lung biopsy in 8 (15.7%) cases. Hypoxemia were observed in 25 (49.0%) patients. Twenty-eight (54.9%) patients had poor performance status (ECOG score ≥2). Elevated LDH level was observed in 48 (94.1%) cases (median, 631 IU/L; range, 147-4907 IU/L). Diffusely elevated FDG uptake was seen at the lung in 28 (54.9%) patients, bone marrow in 40 (78.4%), and spleen in 32 (62.7%). Chest CT evaluation revealed that ground-glass opacity lesion corresponding to the areas of FDG accumulation on PET was observed in 14 of 28 patients. At diagnosis, the median L/M ratio was significantly higher in IVBCL patients than in DLBCL patients (IVBCL: median, 0.903; range, 0.22-2.583 vs. DLBCL: median, 0.421; range, 0.177-0.639, P < 0.0001, Fig.). ROC analysis revealed that the cutoff value of the L/M ratio of 0.649 predict IVBCL diagnosis. Area under curve was 0.916 (95% CI: 0.859-0.974). Thus, we classified patients with a threshold of 0.649 for the definition of "high” or "low” levels of the L/M ratio. At the time of diagnosis, 38 of 51 (74.5%) IVBCL cases were classified as having a high L/M ratio. The L/M ratio decreased to low levels in all patients who underwent FDG PET/CT after chemotherapy (median, 0.471; range, 0.269-0.647, Fig.). The high L/M ratio was significantly correlated with diffuse FDG uptake in the lung (P < 0.0001), bone marrow (P = 0.0507) and spleen (P < 0.001) and the presence of hypoxemia (P < 0.01). Surprisingly, 14 of 26 (53.8%) patients who did not present with hypoxemia showed high L/M ratio. Fifty (98%) patients received rituximab-containing chemotherapy. Of the patients treated, 13 (26%) patients experienced a relapse, and 9 (18%) patients eventually died. The 2-year overall survival (OS) was 84.6 % (range, 70.3-92.4 months). Median follow-up duration was 48.8 months (range, 4.7-140.5 months) in survivors. The L/M ratio did not stratify the prognosis significantly (L/M high: 2-year OS, 82.3%; 95% CI, 64.6-91.6 vs L/M low: 2-year OS, 90.9%; 95% CI, 64.6-91.6, P = 0.7). [Conclusion] To our knowledge, this is the largest study to assess pulmonary PET/CT findings in newly diagnosed IVBCL cases. A high L/M ratio was found in about 75% of patients with IVBCL while not in advanced stage DLBCL. Given that the L/M ratio decreased after treatment, the high L/M ratio reflects pulmonary infiltration of lymphoma cells. In cases of suspected IVBCL, FDG-PET can be a good indicator of whether to perform a lung biopsy, even in patients without hypoxemia. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Orelabrutinib in Combination with Rituximab and Chemotherapy for Newly Diagnosed Aggressive B-Cell Lymphoma: A Multicenter, Single-Arm, Prospective Study

Keywords: Orelabrutinib, B-cell lymphoma, overall response rate Introduction Dysregulated B-cell receptor (BCR) signaling has been identified as an important feature of B-cell lymphomas. Inhibition of Bruton's tyrosine kinase (BTK), downstream of BCR, has demonstrated promising efficacy profiles in B-cell malignancies. Orelabrutinib is a newly developed BTK inhibitor with high selectivity for B-cell malignancies. This study was conducted to evaluate the preliminary efficacy and safety of orelabrutinib in combination with rituximab and chemotherapy for newly diagnosed aggressive B-cell lymphoma. Methods This was a single-arm, multicenter, prospective study in patients with clinical and histopathological confirmed aggressive B-cell lymphoma. The primary endpoints were investigator-assessed overall response rate (ORR) and complete response (CR) rate. Adverse events (AEs) were assessed in accordance with NCI CTCAE v4.03. Results A total of 42 patients with newly diagnosed aggressive B-cell lymphoma were enrolled from October 2020 to May 2022, including 28 diffuse large B-cell lymphoma (DLBCL), 12 primary central nervous system lymphoma (PCNSL), and 2 patients with high-grade B-cell lymphoma. The median age was 66.5 years (range, 35-86 years), and 23 (54.7%) were male. 66.7% of enrolled patients had stage III-IV disease. The median follow-up was 8.0 months (2.0-20.0 months). All the patients received orelabrutinib combined with rituximab and chemotherapy regimens. At data cutoff, 28 patients completed 6 cycles of treatment and were evaluated for therapeutic efficacy. Next-generation sequencing was performed and the genetic mutations included MYD88, BCL6, BCL2, CD79b, KMT2D, etc. All 42 patients were evaluable for toxicity. The toxic reactions were relatively mild, including grade 3 febrile neutropenia in 2 cases (4.8%), grade 3 neutropenia (2.4%), grade 3 thrombocytopenia (2.4%), and grade 3 leukopenia (2.4%). No other grade 3-4 non-hematologic AEs were reported. There was no dose modification due to AEs. The therapeutic responses were assessed. Among the 30 patients with DLBCL or high-grade B-cell lymphoma, 21 patients completed 6 cycles of treatment at data cutoff, with an ORR of 100%, and 15 (71.4%) patients achieved CR. The estimated 1-year overall survival (OS) and 1-year progression-free survival (PFS) rates were 100% and 94.1%, respectively. In addition, subgroup analyses were performed. Seventeen patients were non-GCB subtype, with a CR rate of 84.5%. Among the included DLBCL patients, 13 patients had MYC/BCL2 protein dual expression (DE), and the ORR and CR rate were 100% and 90.9%, respectively. Twenty-two patients were extra-nodal DLBCL, with a CR rate of 86.7%. The estimated 1-year PFS rate was 93.8%. Among them, 13 patients were non-GCB subtype, and 11 of them received 6 courses of treatment, with a CR rate of 81.8%. We further analyzed the treatment response of PCNSL patients. A total of 12 patients with newly diagnosed PCNSL were included in this study, with a median age of 57 years (range, 35-75 years) and 7 (58.2%) patients were male. Ten (83.3%) patients were non-GCB subtype. Seven patients completed 6 courses of treatment, with an ORR of 100%, and 4 patients achieved CR. Conclusions The preliminary results of this study suggested that orelabrutinib in combination with rituximab and chemotherapy may be a well-tolerated and effective regimen in newly diagnosed aggressive B-cell lymphoma patients. A larger sample size and longer follow-up time are needed in the future to validate this conclusion. Next-generation sequencing results are expected to provide additional explanations for differential treatment responses. Disclosure: No relevant conflicts of interest to declare.

Mivavotinib, a Syk Inhibitor, in Relapsed/Refractory (R/R) Non-GCB Diffuse Large B-Cell Lymphoma (DLBCL) with or without MYD88 and/or CD79 Mutations: A Phase 2 Study

Background: Spleen tyrosine kinase (Syk) is a key signaling protein that activates survival pathways in B-cell lymphomas. The non-germinal center B-cell like (non-GCB) or activated B-cell like (ABC) cell-of-origin subtype of DLBCL has greater reliance on the B-cell receptor pathway and Syk signaling for survival, compared with the GCB subtype. Multiple signaling pathways are activated by Syk in ABC DLBCL (NF-κB and phosphoinositide 3-kinase [PI3K]), whereas only the PI3K pathway is activated by Syk in GCB DLBCL. MYD88 and/or CD79b mutations are strongly enriched within ABC DLBCL and are associated with poor prognosis. Syk hyperactivation has been observed in ABC DLBCL cell lines harboring MYD88/CD79 mutations, with activation of NF-κB via Syk-mediated signaling through both the BCR and the toll-like-receptor (TLR)-MYD88 pathways. Mivavotinib is an orally dosed, potent, and selective Syk inhibitor, which showed potent single agent activity in preclinical studies in ABC and GCB DLBCL cell lines, with the strongest activity against those harboring MYD88 and/or CD79b mutations. In the clinical setting, heavily pre-treated all-comer R/R DLBCL patients receiving single agent mivavotinib at the recommended phase 2 dose (100 mg once daily [QD]) showed an overall response rate (ORR) of 33% (16% complete responses [CR]) with durable responses (median duration of response [DoR] not reached [95% CI: 7 months - NE]) and a favorable safety profile. Subgroups by cell-of-origin showed a substantially higher ORR in patients with the non-GCB subtype (53%; 95% CI: 27, 79) than GCB (22%; 95% CI: 0.11, 0.37), and a median DoR of 15.7 months (95% CI: 2.2, NE) in non-GCB responders. CX-659-401 (NCT05319028) is an ongoing study evaluating two dosing regimens of mivavotinib monotherapy in patients with R/R non-GCB DLBCL, in whom circulating tumor DNA-based next generation sequencing (NGS) will be used to determine MYD88/CD79b mutational status. The goals of this strategy are to confirm the activity of mivavotinib previously observed in non-GCB DLBCL, evaluate its activity in DLBCL according to mutational status of MyD88/CD79b, and optimize the dose and schedule in this biomarker-defined patient population. Methods: This multicenter, open-label, phase 2 study will enroll patients with histologically confirmed de novo or transformed DLBCL that is non-GCB by immunohistochemistry (IHC) per Hans algorithm or ABC by gene expression profiling, including primary mediastinal and primary extranodal DLBCL. Patients must have had at least 2 but no more than 5 prior lines of systemic anticancer therapy. Following standard first-line R-CHOP (or equivalent), patients must have received 2nd-line salvage therapy with or without autologous stem cell transplant (ASCT), and/or CAR-T therapy, unless ineligible for 2nd-line salvage, ASCT, or CAR-T. Additional key eligibility criteria include age >18 years, ECOG performance status 0-2, and FDG-PET-avid measurable disease per 2014 Lugano criteria. DLBCL patients with primary brain or secondary central nervous system involvement with active disease will be excluded. Patients will be randomized to 1 of 2 arms (n=25 planned per arm): (1) 100 mg QD; or (2) 120 mg QD for 2 weeks followed by 80 mg QD thereafter; in 28-day cycles until disease progression or unacceptable toxicity. The primary endpoints are ORR (by independent radiology review according to 2014 Lugano Criteria) and safety/tolerability. Secondary endpoints include DoR, progression-free survival (PFS), overall survival (OS), and CR rate. Exploratory endpoints include pharmacokinetic, biomarker assessments, and investigator-assessed ORR, DoR, PFS, and CR rate. Results of this study will help to define the optimal dose and provide confirmatory efficacy and safety data of mivavotinib in patients with non-GCB DLBCL, including MYD88/CD79b-mutated DLBCL to guide further expansion in these biomarker-defined cohorts.

Phase 1 Study of KT-413, a Targeted Protein Degrader of IRAK4 and IMiD Substrates, in Adult Patients with Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma

Background: Oncogenic mutations in myeloid differentiation primary response 88 (MYD88) occur in approximately 25% of diffuse large B-cell lymphoma (DLBCL) cases, including approximately 30% of activated B-cell DLBCL and up to 70% of primary extranodal DLBCL, and are associated with poor survival following 1st line therapy. Furthermore, based on new genetic classifications, co-mutations in MYD88 and CD79 (C5 and MCD subgroups) are associated with an inferior survival after standard R-CHOP. MYD88 mutations result in activation of the NF-κB pathway which drive a range of pro-tumor activities, including upregulation of proinflammatory cytokines and genes involved in tumor cell proliferation and survival. Activation of this pathway results in upregulation of IRF4 through the transcription factors Ikaros and Aiolos, which in turn further augments NF-kB activation while simultaneously downregulating Type I IFN signaling, thereby preventing oncogene-induced cell death. Constitutive NF-kB pathway activation resulting from MYD88 mutations is dependent on the interleukin-1 receptor associated kinase 4 (IRAK4), a key component of the myddosome complex which normally stimulates NF-kB signaling following TLR or IL-1R engagement and MYD88 activation. KT-413 is a potent and selective heterobifunctional small molecule protein degrader mediating the degradation of both IRAK4 and the IMiD substrates Ikaros and Aiolos via the ubiquitin-proteasome system. The therapeutic hypothesis is that degradation of IRAK4 and IMiD substrates will maximize NF-κB inhibition while simultaneously upregulating the Type I Interferon response, thus restoring the apoptotic response and enabling oncogene-mediated cell death, resulting in robust antitumor response in MYD88-mutant DLBCL. KT-413 induced strong antitumor activity, including complete or partial regressions, in the in-vivo preclinical models of MYD88MT DLBCL and showed strong tumor growth inhibition in MYD88MT patient-derivedxenograft models (Mayo 2021). Methods: KT-413 is being evaluated in an open label, dose escalation (Phase 1a) study in patients with relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (NHL) according to the 2016 World Health Organization (WHO) classification, followed by dose expansion (Phase 1b) in patients with R/R DLBCL with documented tumor MYD88 mutation status. All patients must have at least one bi-dimensionally measurable disease site per Lugano Classification and be relapsed and/or refractory to at least 2 accepted standard systemic regimens and ineligible or refused autologous stem cell transplant (ASCT) or CAR-T therapy; however, prior ASCT or CAR-T therapy are not exclusionary. Patients with known CNS lymphoma or meningeal involvement are excluded as well as those that received prior treatment with an IRAK4 inhibitor, experienced disease progression on IMiD-containing regimen < 6 months, are R/R after ≥ 2 prior IMiD-containing regimens or discontinued a prior IMiD therapy due to IMiD-related toxicity. Patients who underwent a prior allogeneic hematopoietic stem cell transplant are also excluded. The Phase 1a (n=40) utilizes an accelerated titration followed by a 3+3 design in ascending doses of IV administered KT-413 in once every 21-day cycles to identify the maximum tolerated dose (MTD)/recommended Phase 2 dose (RP2D) (primary endpoint). Secondary and exploratory endpoints include pharmacokinetics (PK) and preliminary pharmacodynamic effects (PD) using blood and tumor tissue, respectively. Once a tolerable and pharmacologically optimal dose is determined in 3-6 patients, it will be confirmed by enrolling additional patients with B-cell NHL, for a total of nine patients. In Phase 1b, up to 40 R/R DLBCL patients will be enrolled into one of two cohorts (n=20): MYD88MT or MYD88WT and treated at the RP2D to further characterize safety, tolerability, preliminary efficacy, PK, and PD. Enrollment in the Phase 1a portion of the KT413-DL-101 study is ongoing. NCT05233033.