Intravascular Large B-cell Lymphoma Patients Research Articles

Plasma circulating tumour DNA is a better source for diagnosis and mutational analysis of IVLBCL than tissue DNA.

Diagnosis of intravascular large B-cell lymphoma (IVLBCL) is a challenge due to its heterogeneous clinical presentation and lack of specific markers. This retrospective study investigated the utility of circulating tumour DNA (ctDNA) sequencing for diagnosing IVLBCL and analysing its mutation landscape. A cohort of 34 IVLBCL patients enrolled and underwent plasma ctDNA targeted sequencing. The median plasma ctDNA concentration was 135.0 ng/mL, significantly higher than that in diffuse large B-cell lymphoma (DLBCL) controls. Correlations were found between ctDNA concentration and disease severity indicators, LDH and SF. Mutation analysis revealed frequent mutations in B-cell receptor and NF-κB signalling pathways, including MYD88 (56%), CD79B (44%), TNFAIP3 (38%) and IRF4 (29%). CNS involvement was significantly related with BCL6 and CD58 mutation. Patients with complicated hemophagocytic lymphohistiocytosis had significantly higher mutation rates in B2M. Comparison with DLBCL subtypes showed distinctive mutation profiles in IVLBCL. Moreover, plasma ctDNA detected more mutations with higher variant allele fraction than tissue DNA, suggesting its superiority in sensitivity and accessibility. Dynamic monitoring of ctDNA during treatment correlated with therapeutic responses. This study revealed the role of ctDNA in IVLBCL diagnosis, mutation analysis, and treatment monitoring, offering a promising avenue for improving patient diagnosis in this rare lymphoma subtype.

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 > 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 > 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.

FIVE‐YEAR RESULTS OF A PHASE 2 STUDY OF CNS‐ORIENTED THERAPY WITH R‐CHOP FOR UNTREATED INTRAVASCULAR LARGE B‐CELL LYMPHOMA: FINAL ANALYSIS OF THE PRIMEUR‐IVL STUDY

Introduction: Intravascular large B-cell lymphoma (IVLBCL) is a rare disease entity of extranodal large B-cell lymphoma characterized by selective growth of lymphoma cells in the lumina of small vessels. The prognosis of IVLBCL is typically poor without timely diagnosis. Based on the promising efficacy of rituximab-containing chemotherapy and a high incidence of secondary central nervous system (CNS) involvement after rituximab-chemotherapy, we conducted the PRIMEUR-IVL study to explore the efficacy of CNS-oriented therapy with rituximab-chemotherapy whose primary analysis demonstrated 2-year progression-free survival (PFS) of 76% and 2-year overall survival (OS) of 92% with a low incidence of secondary CNS involvement of 3%. Patients and Methods: The PRIMEUR-IVL study is a multicenter, single-arm, phase 2 trial at 22 hospitals in Japan for untreated histologically confirmed IVLBCL patients without apparent CNS involvement at diagnosis. The treatment regimen includes three cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) followed by two cycles of rituximab with high-dose methotrexate and additional three cycles of R-CHOP. Intrathecal chemotherapy including methotrexate, cytarabine, and prednisolone was administered four times during the R-CHOP phase. We present a preplanned final analysis of the PRIMEUR-IVL study including 5-year PFS, OS and secondary CNS involvement. Results: A total of 38 patients were enrolled, of whom 37 patients were eligible. One patient with a history of testicular lymphoma was excluded. As of July 2021, with a median follow-up of 7.1 years (interquartile range 5.6–8.7), 5-year PFS in all eligible patients was 68% (95% confidence interval [CI] 50%–80%) and OS was 78% (95% CI 61%–89%). Median PFS and OS were not reached. No additional secondary CNS involvement was observed after primary analysis with 3% of cumulative incidence. Severe adverse events after the primary analysis were grade 4 neutropenia (n = 1) and grade 4 myelodysplastic syndrome that did not require specific treatment (n = 1). During the observation period after enrollment, there were a total of eight deaths due to following reasons: primary disease (n = 6), sepsis (n = 1), and unknown sudden death (n = 1). Conclusions: In this 5-year, long-term follow-up analysis of the PRIMEUR-IVL study, frontline treatment of CNS-oriented therapy with standard R-CHOP for untreated IVLBCL patients without apparent CNS involvement provided durable response and clinically meaningful results for PFS, OS, and low incidence of secondary CNS involvement with manageable toxicity. Our result provides one of active treatment for untreated IVLBCL patients. The research was funded by: The Practical Research for Innovative Cancer Control, the Japan Agency for Medical Research and Development (AMED), Japan, JP19ck0106511 and the National Cancer Center Research and Development Fund, 23-A-17 and 26-A-4. The research was supported by the Center for Supporting Hematology-Oncology Trials (C-SHOT). Keyword: chemotherapy Conflicts of interests pertinent to the abstract K. Shimada Honoraria: AstraZeneca, Chugai, Eisai, Kyowa Kirin, Symbio M. Yamaguchi Honoraria: AbbVie, Bristol Myers Squibb, Chugai, Janssen, Kyowa Kirin, Meiji Seika, MSD, Nippon Shinyaku, SymBio, Takeda Research funding: AstraZeneca, Chugai Pharma, Genmab, Incyte, Eisai, Takeda, Nippon Shinyaku, Otsuka, Asahi Kasei, Kyowa Kirin, Chugai H. Nagai Honoraria: Kyowa Kirin, Takeda, Chugai, Bristol Myers Squibb, Eisai, Novartis, Janssen, Mundi Pharma, Lilly, AstraZeneca, Ono, Meiji, AbbVie, Nippon Shinyaku, GSK, Sumitomo Pharma, Genmab, CSL Behring Research funding: Kyowa Kirin, Takeda, Chugai, Bristol Myers Squibb, Janssen, AstraZeneca, Ono, AbbVie, Nippon Shinyaku, Daiichi-Sankyo, Zenyaku Kogyo, Solasia J. Takizawa Honoraria: Chugai, Kyowa Kirin N. Fukuhara Honoraria: Chugai, Genmab, AbbVie, Takeda, Eli Lilly, AstraZeneca, Meiji Seika, Ono, Janssen, Bristol-Myers Squibb, Eisai, Kyowa Kirin, Symbio, Novartis Research funding: Chugai, Genmab, AbbVie, Takeda, Eli Lilly, Incyte, Chordia Therapeu D. Ennishi Honoraria: Eisai, Kyowa Kirin, Chugai Research funding: Nippon Shinyaku, Chugai Y. Minami Consultant or advisory role: Takeda, Novartis Honoraria: Bristol-Myers Squibb, Novartis, Pfizer, Daiichi Sankyo, Astellas Research funding: CMIC, Bristol-Myers Squibb, Novartis, Takeda, Chugai, Ono Y. Atsuta Consultant or advisory role: Meiji Seika, JCR Pharmaceuticals, Kyowa Kirin Honoraria: Novartis, AbbVie H. Kiyoi Honoraria: Novartis, Astellas, AbbVie, Chugai Research funding: Zenyaku Kogyo, Nippon Shinyaku, Chugai, Astellas, Kyowa Kirin, Takeda, Sumitomo Pharma, Sanofi, Eisai, Ono, FUJIFILM, Kyowa Kirin, Otsuka, Perseus Proteomics, Daiichi Sankyo, CURED, Bristol-Myers Squibb, AbbVie

Abstract 5521: Racial and ethnic disparities for intravascular large B-cell lymphoma: A Surveillance, Epidemiology, and End Results (SEER) database analysis with emphasis on Hispanics

Abstract Background: Intravascular large b-cell lymphoma (IVLBCL) is a rare but highly aggressive subtype of non-Hodgkin lymphoma (NHL). IVLBCL is a clonal proliferation with selective growth within the blood vessel. It has been primarily described in Asian and European populations, and a median age presentation is in the sixth to seventh decades without a sex predilection. The US incidence is 0.95 in 1 million, but is thought to be higher, as the diagnosis is mainly done postmortem. Meanwhile, the incidence rate of IVBCL in Hispanics (HI) remained unknown. This study looks at demographics, treatment patterns, and outcomes of patients with IVLBCL in the US, examining disparities by HI vs Non-Hispanic (NH). Methods: Data were analyzed on IVLBCL patients reported to the SEER 18 database between 2000 and 2018. SEER 18 contains the most comprehensive population-based cancer information in the US, covering approximately 27% of the US population and 36% of HI alone. The racial groups analyzed were NH whites, HI whites, blacks, and Asians/PIs (Pacific Islanders). Patient characteristics, age-adjusted incidence rate, and survival rate were compared across ethnic groups. Kaplan-Meier and Cox regression analyses compared overall survival (OS) between HI and NH. Multivariate analysis and propensity score matching were performed, with adjustment for age, stage and B-symptoms. Results: We identified 164 patients with IVLBCL, of which 10% were HI. 41% of HI were male vs 44% of NH. HI were diagnosed at an older age, 72. vs 69 y.o., compared to NHI (p=0.907). Most of NH and HI were diagnosed between 60-80 y.o. (p=0.322), 53.1% and 47.1%, respectively. Regarding race, HI and NH were mainly identified as whites (88% vs 78%), followed by Asians (6% vs 17%) (p=0.013). For HI, 53% presented B symptoms compared to 16% of NH (p=<0.001). On survival analysis, the survival probability at 2, 5 and 10 years of HI vs NH was (0.540 vs 0.505), (0.432 vs 0.425), and (0.443 vs 0.237), respectively. The median survival time was 0.8 years for HI and 1.9 years for NH. The 10 year OS probability was not significantly different for HI vs NH (p=0.66).On multivariate analysis, when adjusted for age, those patients who were 60 to 80 y.o. had worse OS compared to those younger than 60 y.o., with HR 1.4 (95% CI: 0.7 - 2.1). Conclusion: In our study, despite a lower percentage of patients identified as Asian in our HI population, there is a significant difference in the presence of B-symptoms between HI and NH, going against the traditional description of an Asian variant with increased systemic symptoms. Despite this finding, it demonstrated similar outcomes in the 10 years survival analysis for HI and NH. Standardized treatment may explain why no variation was reported in OS. Our analysis shows that ethnic variations do not seem to affect oncological outcomes in IVLBCL for HI in the US. Citation Format: Daniela Urueta Portillo, Daniel Rosas, Joel E. Michalek, Qianqian Liu, Adolfo E. Diaz Duque. Racial and ethnic disparities for intravascular large B-cell lymphoma: A Surveillance, Epidemiology, and End Results (SEER) database analysis with emphasis on Hispanics. [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 5521.

Intravascular Large B-Cell Lymphoma: A Review with a Focus on the Prognostic Value of Skin Involvement.

Intravascular large B-cell lymphoma (IVLBCL) is an aggressive Non-Hodgkin lymphoma (NHL) characterised by the presence of neoplastic lymphoid cells within small- and medium-sized blood vessels. According to the clinical presentation, the current WHO classification distinguishes the ‘classic’ (formerly ‘Western’) from a hemophagocytic syndrome-associated (formerly ‘Asian’) variant. A third ‘cutaneous’ variant has been proposed, characterised by a good prognosis and unique clinical features. While laboratory findings can hint at diagnosis, symptoms are rather nonspecific, and deep skin biopsy supported by further measures such as bone marrow aspiration and positron emission tomography-computed tomography scanning is needed to make a definite diagnosis. Treatment is comprised of anthracycline-based chemotherapy supplemented with rituximab and central nervous system prophylaxis. While there are various prognostic models for NHL, only one is specific to IVLBCL, which does not sufficiently represent some patient groups, especially regarding the lack of differentiation within the patient collective with skin involvement. This underlines the necessity for the establishment of further prognostic models in particular for IVLBCL patients with cutaneous manifestations.

Immunohistochemistry of the oncofetal protein IMP3 is helpful in the diagnosis of intravascular large B-cell lymphoma using skin biopsy.

The oncofetal protein insulin-like growth factor 2 mRNA binding protein-3 (IMP3) is expressed in various cancers. In this study, we examined the diagnostic utility of IMP3 immunohistochemistry in the context of intravascular large B-cell lymphoma (IVL). We obtained 25 skin biopsy (SB) specimens diagnosed as IVL and nine IVL-negative SB specimens from 27 IVL patients. Additionally, 27 negative SB specimens from 26 non-IVL patients were obtained from our pathology archives. We performed IMP3 immunohistochemistry on these 61 SB specimens, considering IMP3 expression in any mononuclear cell as positive. In selected cases, triple immunostaining for IMP3, PAX5, and CD34 was performed to analyze the origin and location of IMP3-positive cells. IMP3 was expressed in most intravascular lymphoma cells in all the 25 SB specimens diagnosed as IVL. Furthermore, our evaluation revealed the presence of intravascular IMP3-positive B-cells in five of the nine negative SB specimens from IVL patients; however, this was not observed in the 27 SB specimens from non-IVL patients. IMP3 was expressed in most IVL cells, and IMP3 immunohistochemistry could serve as a sensitive diagnostic aid for detecting IVL cells in SB.

Imaging Features and Prognostic Value of FDG PET/CT in Patients with Intravascular Large B-Cell Lymphoma.

PurposeThe clinical value of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) in intravascular large B-cell lymphoma (IVLBCL) is unknown. This study investigated the association between PET/CT features and prognosis in IVLBCL patients.Patients and MethodsSubjects were 30 newly diagnosed Asian variant IVLBCL patients at a single institution. Baseline PET/CT was analyzed for the distribution and intensity of FDG lesions, and PET/CT pattern groups were compared for the outcome.ResultsEight patients had hypermetabolic lymph node (LN) lesions (Nodal group). The remaining 22 patients with extranodal (EN) involvement were categorized into Deauville score 3–4 (EN/DS3-4; n = 14) and DS5 groups (EN/DS5; n = 8). First-line therapy resulted in a complete or partial response in 75.0%, 64.3%, and 100% of the respective groups. Treatment-related deaths occurred in one nodal group and three EN/DS3-4 group cases, but none among the EN/DS5 group. During 56 months of follow-up, disease progression or relapse occurred in five, four, and one case of respective groups. Cancer-related death occurred more frequently in the Nodal (n = 6) and EN/DS3-4 groups (n = 7) than the EN/DS5 group (n = 1; P = 0.041). Nodal and EN/DS3-4 groups had worse 5-year event-free survival (EFS; 25.0% and 49.0%, respectively, P = 0.010 and 0.076) and overall survival (OS; 33.3% and 48.2%, P = 0.010 and 0.068) compared to the EN/DS5 group (87.5% EFS and 87.5% OS).ConclusionIn patients with Asian variant IVLBCL, the distribution and intensity of FDG uptake lesions on PET/CT can be useful for predicting treatment outcomes and survival.

Detection of Recurrent Genetic Mutations in Intravascular Large B-Cell Lymphoma By Comprehensive Genetic Analyses Using Peripheral Blood Circulating Cell-Free DNA

Abstract Background: Intravascular large B-cell lymphoma (IVLBCL) is a subtype of diffuse large B-cell lymphoma (DLBCL) characterized by the selective growth of tumor cells in the lumina of small vessels. The characteristics of the disease, such as the lack of remarkable lymphadenopathy and the presence of non-specific clinical symptoms, including documented fever of unknown origin, make precise diagnosis difficult; random organ biopsies from bone marrow, skin, and lung are still performed to detect tumor cells. Recently, many recurrent genetic mutations have been detected, especially in DLBCL, but the genetic background in IVLBCL has not been fully elucidated because of the difficulty in obtaining sufficient live tumor cells from diagnostic specimens for subsequent genetic analyses. Previously, we demonstrated that peripheral blood circulating cell-free DNA (cfDNA) in DLBCL is an alternative tumor DNA (tDNA) source for comprehensive genetic analyses (Suzuki Y, et al. ASH 2014 #1658). In this report, we demonstrate that the concentration of cfDNA is significantly higher in IVLBCL than in DLBCL, and that efficiently accumulating the tDNA in peripheral blood is useful for comprehensive genetic analyses to detect recurrent genetic mutations in IVLBCL. Aims: Confirmation of recurrent genetic mutations in IVLBCL using plasma cfDNA. Methods: The study population included 54 B-cell lymphoma patients (IVLBCL, N=21; DLBCL, N=21; follicular lymphoma, N=12) and healthy volunteer donors (N=14). In IVLBCL patients, primary bone marrow (BM) cells containing tumor cells were transplanted into NOD/Shi- scid IL2Rγnull mice to generate a xenograft model (Shimada K, et al. Leukemia 2016), and the tumor cells from tumors formed in the spleen of the mouse model were purified using anti-CD19 antibody-conjugated magnetic beads to obtain tDNA. For genetic analyses using cfDNA and DNAs from purified tumor cells, whole-exome sequencing (WES) using the HiSeq 2000 (Illumina) and Sanger sequencing for reconfirmation of those mutations were performed. Results: The cfDNA concentrations were significantly higher in DLBCL and IVLBCL than in normal donors (p=0.037 and 0.036, respectively), and the concentration was significantly higher in IVLBCL than in DLBCL (p Discussion: The concentration of cfDNA is significantly higher in IVLBCL than in DLBCL, and it appeared to be sufficient to carry out comprehensive genetic analyses to accumulate tDNA. Moreover, the WES analysis using cfDNA could detect genetic mutations more efficiently than that using corresponding BM-DNA. The profiling of recurrent genetic mutations in IVLBCL is partly similar to that in activated B-cell type DLBCL with mutations in NF-κB pathway-related factors, and, intriguingly, they resemble those in B-cell lymphomas that infiltrate into immunologically sanctuary organs, e.g., primary CNS, testis, and breast lymphomas. The present data suggest that genetic analysis using cfDNA in addition to random organ biopsies may become a powerful, safer, and painless strategy to predict the presence of IVLBCL in the clinical setting. Disclosures Shimada: Kyowa Hakko Kirin Co., Ltd.: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; Eisai Co., Ltd.: Honoraria; Janssen Pharmaceutical K.K.: Honoraria. Kusumoto: Chugai: Honoraria, Other: GALLIUM and GOYA are sponsored by F. Hoffmann-La Roche Ltd. Third-party medical writing support, under the direction of Shigeru Kusumoto, was provided by Cheryl Wright of Gardiner-Caldwell Communications, and was funded by F. Hoffmann-La Roche Ltd, Research Funding. Masaki: MSD: Research Funding; Eisai: Research Funding; Astellas Pharma: Research Funding; Kyowa Hakko Kirin: Research Funding; Daiichi Sankyo: Research Funding; Taisho Toyama Pharmaceuticals: Research Funding; Taiho Pharmaceutical: Research Funding; Takeda Pharmaceuticals: Research Funding; Mitsubishi Tanabe Pharmaceutical: Research Funding; Chugai Pharmaceutical: Research Funding; Teijin Pharmaceutical: Research Funding; Japan Blood Products Organization: Research Funding; Pfizer: Research Funding; Asahi Kasei Pharmaceutical: Research Funding; Ono Pharmaceutical: Research Funding; Shinogi Pharmaceutical: Research Funding; Meiji Seika Pharma: Research Funding; Mochida Pharmaceutical: Research Funding. Kiyoi: Meiji Seika Pharma Co.,Ltd.: Research Funding; Phizer Japan Inc.: Honoraria, Research Funding; FUJIFILM Corporation: Patents & Royalties, Research Funding; MSD K.K.: Research Funding; JCR Pharmaceuticals Co.,Ltd.: Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Kyowa Hakko Kirin Co., Ltd.: Research Funding; Takeda Pharmaceutical Co., Ltd.: Research Funding; ONO Pharmaceutical Co., Ltd.: Research Funding; Eisai Co., Ltd.: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Nippon Boehringer Ingelheim Co., Ltd.: Research Funding; Astellas Pharma Inc.: Consultancy, Research Funding; Nippon Shinyaku Co., Ltd.: Research Funding; Zenyaku Kogyo Co., Ltd.: Research Funding; Celgene Corporation: Consultancy, Research Funding; Novartis Pharma K.K.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding.

Liquid Biopsy for the Identification of Intravascular Large B-Cell Lymphoma

[Backgrounds] Intravascular large B cell lymphoma (IVLBCL) is a rare subtype of extranodal diffuse large B-cell lymphoma (DLBCL) that features lymphoma cells lodged in lumina of small vessels. Because of the lack of mass formation, diagnosis by tumor biopsy is often difficult, and thus, cell-free DNA (cfDNA) analysis might be useful for assisting diagnosis of IVLBCL. In this study, we first aimed at investigating the prevalence of mutations in genes involved in the B-cell receptor, Toll-like receptor/interleukin-1 receptor, and nuclear factor kappa B pathways. We then evaluated the liquid biopsies for detection of hot-spot mutations by droplet digital polymerase chain reaction (ddPCR).[Patients and Methods] Twenty-seven IVLBCL patients whose archived samples were available were included in this study. The patients were diagnosed as IVLBCL from January 2005 to May 2017 in University of Tsukuba Hospital, JA Toride Medical Center, and Kameda Medical Center. The study was approved by the review board in each institution, and conducted according to the Declaration of Helsinki. Tissue-derived DNA (tdDNA) was extracted from formalin-fixed paraffin-embedded specimens and/or cryo-preserved bone marrow samples, in which the lymphoma cell infiltration had been pathologically confirmed. cfDNA was extracted from 1 ml of serum or plasma obtained prior to chemotherapy. We performed targeted sequence for 8 genes (B2M, BTG2, CARD11, CD79B, MYD88, PIM1, PRDM1, and TNFAIP3) in paired tdDNA and cfDNA from 9 IVLBCL subjects by Ion Torrent Personal Genome Machine (Thermo Fisher Scientific). MYD88 L265P (c.794T>C) mutational analysis was performed by ddPCR assays (BioRad) for 46 samples in total collected from 27 subjects. Statistical analysis was performed with EZR version 1.3.2. Paired t-test was used to compare variant allele frequencies (VAFs) in paired samples.[Results] All cases were categorized as the non-GCB by Hans classification. Random skin biopsies (RSB) and bone marrow biopsies (BMB) were performed in 21 and 27 patients. The diagnostic yield of RSB was 81.0% (17 of 21). Initial BMB detected lymphoma cells in 48.1% (13/27) patients, but repeated BMB increased successful detection up to 66.7% (18/27). tdDNA was available in 26 out of 27 subjects, and in 9 of which paired cfDNA was also available (Figure 1). In one subject, only cfDNA but not tdDNA was available. Targeted sequencing for 8 genes demonstrated at least one mutation in CD79B, MYD88, PIM1, or PRDM1 in both tdDNA and cfDNA, or only in cfDNA, in 8 of 9 subjects (Figure 2). We identified 3 missense CD79B mutations in 6 (66.7%; Y196C in 2, Y196H in 3, and L199P in 1). All MYD88 mutations were L265P, which were found in 5 of 9 (55.6%). Together, either Y196 CD79B or L265P MYD88 mutation was found in 7 of 9 (77.8%). PIM1 mutations and PRDM1 mutations were seen each in 3 (33.3%). VAFs were higher in cfDNA than in tdDNA (mean, 45.6% vs. 3.7%; P=0.0006, Figure 3). Four mutations in 3 patients were detected only in cfDNA. On the other hand, all variants detected in tdDNA were confirmed in cfDNA. ddPCR assay for the L265P MYD88 mutation with all 46 samples including tdDNA and cfDNA revealed the L265P MYD88 mutation in 24/46 (52.2%) samples from 16/27 (59.3%) IVLBCL patients. Furthermore, sequential analysis of cfDNA was performed in one of the MYD88 -mutated patients. The L265P MYD88 mutation was detected (VAF=30%) in cfDNA collected 17 weeks before the diagnosis of IVLBCL, whereas the mutation was not detected in DNA derived from the bone marrow sample that was collected at the same timing and resulted in the negative pathological finding.[Conclusion] Mutations in MYD88 and CD79B are frequent in IVLBCL . Targeted sequencing suggested that tumor cell-derived DNA is abundant in serum/plasma. Liquid biopsy to detect L265P MYD88 and Y196 CD79B may provide a powerful tool for approaching diagnosis of IVLBCL. [Display omitted] DisclosuresChiba:Nippon Shinyaku: Honoraria, Research Funding.

Prognostic Value of Concurrent Expression of C-MYC and BCL2 in Intravascular Large B-Cell Lymphoma: A 10-Year Retrospective Study

Background Intravascular large B-cell lymphoma (IVLBCL) is a variant of extranodal diffuse large B-cell lymphoma (DLBCL), characterized by the presence of a B-lymphoma cell in the lumina of small blood vessels or capillaries. Due to its extremely variable clinical manifestations, IVLBCL typically results in a delayed diagnosis and poor disease prognosis. Skin biopsy, particularly random skin biopsy, has shown a potential role in the diagnosis of IVLBCL. However, information of clinicopathological features in patients with IVLBCL diagnosed by skin biopsy is limited. Objectives To study the clinicopathological features in relation to immunohistochemical features and to identify prognostic factors in IVLBCL patients diagnosed by skin biopsy. Materials and Methods Clinical characteristics; laboratory, histological, and immunohistochemical findings; and therapeutic response of all biopsy-confirmed IVLBCL patients during the years 2008-2017 were retrospectively reviewed. Results The mean age was 67.4 (±9.8) years. Fever was the most common presenting symptom, accounting for 64.7%. Cutaneous and bone marrow involvement was found in 23.5% and 35.3% of patients, respectively. Patients receiving R-CHOP showed more favorable therapeutic outcome. C-MYC/BCL2 double expressors showed significantly higher incidence rate to mortality compared with nondouble expressors (p = 0.042). One-year and two-year overall survival rates were 67.2% and 53.8%, respectively. Conclusions Skin biopsy is an effective diagnostic method for IVLBCL. Concurrent expression of C-MYC and BCL2 may be a useful prognostic indicator and should be performed in order to predict the prognosis in IVLBCL patients.

Rituximab, cyclophosphamide, vincristine, and prednisolone with high-dose methotrexate as an effective regimen in a frail patient with intravascular large B-cell lymphoma

Intravascular large B-cell lymphoma (IVLBCL) is a rare non-Hodgkin lymphoma characterized by the presence of lymphoma cells within the lumina of small vessels. Membranous CD20 is universally expressed on IVLBCL cells in immunohistochemical staining. The outcome of IVLBCL was dismal in the prerituximab era; however, rituximab in combination with chemotherapy has been proposed to be an effective treatment for IVLBCL. Herein, we report a 68-year-old female with “Asian variant” IVLBCL diagnosed from a pleural biopsy. We administered rituximab, cyclophosphamide, vincristine, and prednisolone (R-CVP) with high-dose methotrexate as the initial treatment. The patient achieved a complete response after the treatment. Therefore, R-CVP with high-dose methotrexate can be considered as a treatment option for frail IVLBCL patients.

Favorable Outcomes of Newly Diagnosed Intravascular Large B-Cell Lymphoma Patients Treated with R-CHOP Combined with High-Dose Methotrexate Plus Intrathecal Chemotherapy: Results from a Multicenter Phase 2 Trial (PRIMEUR-IVL)

Favorable Outcomes of Newly Diagnosed Intravascular Large B-Cell Lymphoma Patients Treated with R-CHOP Combined with High-Dose Methotrexate Plus Intrathecal Chemotherapy: Results from a Multicenter Phase 2 Trial (PRIMEUR-IVL)

Diagnosis of intravascular large B cell lymphoma: novel insights into clinicopathological features from 42 patients at a single institution over 20 years

SummaryThis study aimed to clarify the comprehensive clinical, laboratory, pathological and imaging features of intravascular large B‐cell lymphoma (IVLBCL) using data on 42 IVLBCL patients diagnosed at our hospital over the past 20 years. The majority of patients were diagnosed via random skin biopsy (29/42, 69·0%) followed by bone marrow biopsy alone (8/42, 19·0%). Characteristic features included persistent fever (41/42, 97·6%), decreased performance status (≥2) (100%), hypoxaemia (32/40, 80·0%), impaired consciousness (19/42, 45·2%), hypoalbuminemia (42/42, 100%) and extreme elevation of lactate dehydrogenase and soluble interleukin 2 receptor levels. Brain magnetic resonance imaging showed abnormal findings in 32/37 patients (86·4%). Hyperintense lesion in the pons was a peculiar finding that was unrelated to the neurological deficits. Positron emission tomography‐computed tomography revealed a high incidence of bone marrow (26/34, 76·5%), spleen (19/34, 55·9%) and adrenal gland (9/34, 26·5%) involvement. Neurolymphomatosis was noted in 6 patients during the course of the disease. About 60% of IVLBCL patients in whom in vivo diagnosis was possible survived more than 5 years with combination chemotherapy. Our observations provide additional insight into the diagnosis of IVLBCL and indicate that early disease recognition via random skin biopsy combined with imaging, enables in vivo diagnosis of the disease and improved survival for many patients.

Clinical characteristics of intravascular large B cell lymphoma: a single-center retrospective study

目的提高对血管内大B细胞淋巴瘤（IVLBCL）的认识。方法回顾性分析北京协和医院自2010年1月至2016年6月收治的12例IVLBCL患者的临床资料。结果①12例患者中，男6例，女6例，中位年龄为58.5（32~76）岁。临床表现：发热最为常见（10/12），其次为呼吸系统症状（咳嗽、呼吸困难、胸腔积液等，6/12）、噬血细胞综合征（6/12）、神经系统症状（1/12）；所有患者均有LDH升高（367~1 700 U/L）、铁蛋白升高（805~1 527 µg/L）、结外器官受累（肺6例，骨髓3例，脑2例，软脑膜、肾上腺、副鼻窦、胆囊、甲状腺各1例）。②组织病理特征：光镜下可见分布于小血管内的单个或小簇状淋巴瘤细胞，毛细血管或血窦结构得以保留，免疫组化显示CD20、CD79a等B淋巴细胞标志阳性。③疗效及预后：11例患者接受CHOP或R-CHOP方案化疗，其总反应率为90.1%，完全缓解率为66.7%。患者平均随访20（1~40）个月，中位生存期及中位无进展生存期尚未达到。单因素Cox回归分析未能发现年龄、分期、IPI等临床参数与预后相关。结论IVLBCL临床罕见，出现肺部受累比例高，肺活检有较高阳性率；R-CHOP方案目前仍是最主要的治疗方案。

Retrospective study of intravascular large B-cell lymphoma cases diagnosed in Quebec: A retrospective study of 29 case reports.

Introduction:Intravascular large B-cell lymphoma (IVL) is an extremely rare malignancy, mainly studied through European and Asian series. Due to the low incidence of this condition, our understanding of the clinical presentation as well as the management of IVL relies on a limited number of patients.We report the largest North American study to date on IVL with 29 cases from Quebec hospital diagnosed between 1990 and 2016. The aim of our study is to describe the clinical presentations, diagnostic and staging procedures, therapeutic management and clinical outcomes of IVL patients in our population and compare the disease phenotype to European and Asian series reported.In our cohort, all patients had stage IV IVL at diagnosis, with a median age of 66.7 years (range 47.2–90.8). Clinical presentation was characterized by constitutional symptoms (100%), poor ECOG-PS (100% ≥ 2), cytopenias (93% anemia), and elevated lactate dehydrogenase (97%) and C-reactive protein (96%). Our cohort presented with mainly cutaneous and neurological symptoms. However, neurological involvement (75.9%) was predominant and no “cutaneous variant” was observed; this differs from European literature, where “classical” IVL is reported with mainly cutaneous involvement. Two of our Caucasian patients presented “Asian variant” IVL; this observation is not unusual, as cases of “classical” IVL have been reported in Asians and “Asian variant” IVL has been reported in Europeans. All patients were classified according to their immunophenotypic features in 3 different subgroups (CD5+ or CD5−CD10+, CD5−CD10−, CD5+CD10−) with no difference in outcome. Finally, 62% of our cohort received anthracycline-based chemotherapy and 53% of them achieved a complete response. After a median follow-up of 328 days, OS at 3 years was 42.7% for the entire cohort and 47.4% for the cases with in vivo diagnosis.Conclusion:Unlike European studies on “classical” IVL, our study showed that the French Canadian presentation of this subtype of IVL is more frequently observed with neurological rather than cutaneous involvement. Finally, an early diagnosis is of primary importance since almost a quarter of patients receive a post-mortem diagnosis. A prompt diagnosis allows the introduction of an early treatment, associated with a CR in 53% of patients.

Intravascular Large B Cell Lymphoma in the United States (US): A Population- Based Study Using Surveillance, Epidemiology, and End Results Program and National Cancer Data Base

Background: Intravascular large B cell lymphoma (IVLBCL) is a rare and aggressive non-Hodgkin lymphoma lacking any prior US based population studies. We aimed to conduct a population based study of IVLBCL in the US and compare characteristics and survival to diffuse large B cell lymphoma, not otherwise specified (DLBCL, NOS).Methods: We used Surveillance, Epidemiology, and End Results (SEER) registries from 2000 to 2013 to calculate incidence rates (case/1,000,000) and age-adjusted to the US 2000 standard population. We collected patient level data from the NCDB Participant User Files using ICD-O-3 histology code 9680 with ICD-O-3 primary site modifier C499 and analyzed for demographic and clinical characteristics as well as overall survival (2004-2013). Chi-Square test was used to compare the characteristics of patients with IVLBCL to that of DLBCL, NOS. Overall survival analysis was performed using Kaplan- Meier method and compared by log rank. Overall survival (OS) of IVLBCL was compared to propensity-matched cohort of DLBCL, NOS. Multivariate analysis was conducted using weighted Cox Proportional Hazard regression model.Results: In the years 2000-2013, the overall crude incidence rate of IVLBCL was 0.093 (case/1,000,000) and age-adjusted incidence rate of IVLBCL was 0.095 (case/1,000,000). A total of 388 IVLBCL patients were identified in NCDB database. Patients with IVLBCL (n=388), compared to DLBCL, NOS (n=155,436), were more likely to be of age ≥ 65 (64.2% vs 56.9%, p=0.0039), female (51.8% vs 46.5, p=0.036), diagnosed at advanced stage (stage IV, 51.5% vs 33.4%, p<0.0001) and less likely to receive chemotherapy (70.4% vs 78.9%, p = 0.0001).The median 1, 3 and 5-year OS rates for IVLBCL were 66.2%, 51.8% and 46.3% respectively. After propensity matching, the 5-year overall survival of IVLBCL was comparable to DLBCL, NOS (46.6% vs 45.4%, p=0.61). On multivariate analysis, advanced age (HR 1.03, 95% CI 1.032-1.034; p<0.0001), advanced stage (Stage III: HR 1.34, 95% CI 1.31-1.38; <0.0001, Stage IV: HR 1.81, 95% CI 1.77-1.85; p<0.0001), having Medicaid (HR 1.72, 95% CI 1.66-1.79; p<0.001) or Medicare (HR 1.24, 95% CI 1.20-1.26; p<0.0001) predicted worse OS, whereas female gender (HR 0.86, 95% CI 0.85-0.88; p<0.0001) and use of radiation therapy (HR 0.76, 95% CI 0.75-0.78; p<0.0001) predicted better OS.Conclusions: This is the largest series of IVLBCL reported to date. Our study provides characteristics and OS of a large cohort of this rare entity, which can be used for patient education and may provide background information for future research. In the Rituximab era, the OS of patients with IVLBCL is comparable to DLBCL, NOS. In addition, our study also reports predictors of OS in patients with IVLBCL. [Display omitted] [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Development and Analysis of Novel Intravascular Large B-Cell Lymphoma NOD/Shi-Scid IL2Rγnull Mouse Xenograft Model

▪Background: Intravascular large B-cell lymphoma (IVLBCL) is a distinct disease entity of extranodal large B-cell lymphoma according to the current WHO classification. The peculiar characteristics of the disease of selective growth of tumor cells in the lumina of small vessels make an accurate diagnosis difficult, and the delay of timely diagnosis results in the poor prognosis. Recent retrospective analyses revealed that the prognosis of the disease was improved in the rituximab era (Shimada et al. J Clin. Oncol. 2008 and Lancet Oncol. 2009) and central nervous system recurrence was still important complication (Shimada et al. Cancer Sci. 2010). Meanwhile, the underlying biology of the disease, that is why the tumor cells lodge in the lumina of vessels, remains unknown due to the difficulty of obtaining sufficient patient tumor samples.Purpose: To uncover the underlying mechanisms of the disease, we developed and analyzed the NOD/Shi-scid IL2Rγnull (NOG) mouse xenograft models established from primary IVLBCL patient samples.Material and methods: Patient bone marrow samples were obtained from 4 IVLBCL patients with written informed consent and injected into NOG mice intravenously. The successes of the engraftment and surface antigens of tumor cells were analyzed by the flow cytometry. Pathological specimens of the mouse models were evaluated by hematoxylin-eosin and immunohistochemical stainings. Global gene expression profiling and genomic wide analyses by array comparative genomic hybridization (CGH) were performed and genomic copy number abnormalities were confirmed by RQ-PCR and FISH analyses.Result: Patient tumor cellswere successfully engrafted in all 4 xenograft models.The serial passages of the xenograft tumor cells were also successful. Pathologically, the tumor cells were distributed into systemic organs including liver, bone marrow, spleen, kidney, adrenal gland and lung except for testis. The peculiar characteristics of the growth of tumor cells in the lumina of vessels or the sinusoid in the organs were retained. The surface antigens analyses relevant to the lymphocyte migration revealed the expression of L-selectin (CD62L) was low in all 4 IVLBCL models and the expressions of LFA-1 and VLA-4 were various. The expression of CXCR4 and CXCR5 were observed in all 4 models. The time lapse engraftment analyses revealed that tumor cells initially engrafted in the sinusoid and the lumina of vessels in the liver a week after inoculation and then engrafted in the various organs including bone marrow, lung, spleen and adrenal gland two weeks later after inoculation, which indicated that the sinusoid in the liver might be advantageous for the engraftment of the tumor cells compared to other organs. Intriguingly, tumor cells from bone marrow, spleen and liver in the first transplanted mice distributed into the various organs in the secondary transplanted mice in the serial tumor passage, meanwhile tumor cells from adrenal gland in the first transplanted mice mainly distributed into adrenal gland in the secondary transplanted mice, which indicated that tumor cells might be selected at the engraftment of the specific organ. In terms of the dependency on vascular endothelial cells, the survival of tumor cells were dependent on the human umbilical vein endothelial cells (HUVEC) in in vitro co-culture assay (co-culture vs mono-culture, 84% vs 9%, p=0.0067). Gene expression profiling and array CGH analyses revealed the similar gene expression pattern relevant to the adhesion molecule and the consistent loss of chromosome 6 and 9 in all 4 xenograft models. Genomic copy number analysis targeted the gene located on chromosome 6 and 9 confirmed the loss of copy number in 3 of 4 IVLBCL models. FISH analyses are now under investigation.Discussion and Conclusions: The characteristics of IVLBCL tumor cells from patient bone marrow samples were retained in our xenograft mouse models. Moreover we could expand the tumor cells in the mouse models and then investigate the biological characteristics of this disease entity. Further investigations including global gene mutation analysis to uncover the mechanism of the disease should be required. DisclosuresSugimoto:Otsuka Pharmaceutical Co., Ltd: Employment. Naoe:Otsuka Pharmaceutical Co. LTD: Research Funding; Bristol-Myers Squibb: Research Funding; Novartis Pharma,: Research Funding; Chugai Pharmaceutical Co. LTD: Research Funding; Kyowa Hakko Kirin Co. LTD: Research Funding; Dainippon Sumitomo Pharma: Research Funding; Zenyaku Kogyo: Research Funding; FUJIFILM Corporation: Research Funding. Kiyoi:Bristol-Myers Squibb: Research Funding; Chugai Pharmaceutical Co. LTD: Research Funding; Kyowa Hakko Kirin Co. LTD.: Research Funding; Dainippon Sumitomo Pharma: Research Funding; Zenyaku Kogyo: Research Funding; FUJIFILM Corporation: Research Funding.

Scoring System Using Age, C-Reactive Protein, Hemoglobin, and Albumin (ACHA) For Predicting Outcomes Of Diffuse Large B-Cell Lymphoma In The Rituximab-Era

IntroductionOverall survival (OS) of B-cell lymphoma patients, including diffuse large B-cell lymphoma (DLBCL), has markedly improved since the development of rituximab. Rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) have been established as the standard initial therapy for DLBCL patients over past 10 years. However, investigation of risk factors for new prediction models for DLBCL patients in the rituximab-era has been limited. Thus, the International Prognostic Index (IPI) has been used over past 20 years for risk stratification of lymphomas, and although it retains some usefulness, the revised IPI model cannot identify the poor prognosis group with 5-year OS of < 40%. This study aimed to verify risk factors for survival and responses to R-CHOP or R-CHOP-like therapy in DLBCL patients, and to construct a new prediction model to supplant the IPI model. MethodsA historical cohort study comprised patients with de novoDLBCL who received R-CHOP or R-CHOP-like therapy as initial therapy at our institutions between January 2002 and July 2013. A retrospective analysis was performed to identify the pre-therapy risk factors for survival and lymphoma progression. Transformed DLBCL and intravascular large B-cell lymphoma patients were excluded. ResultsStudy comprised 254 patients (145 males, 109 females). Median age at diagnosis was 70.0 years (range 20–96 years). Response rates in patients to first regimen of therapy were as follows: 80.7%, CR (n = 205); 9.1%, PR (n = 23); 1.2%, SD (n = 3); and 9.1%, PD (n = 23). Ann Arbor clinical stage was as follows: 42 (16%) patients. stage I; 60 (24%), stage II; 47 (18%), stage III; and 105 (41%), stage IV. B symptom was observed in 40 (16%) patients and a bulky mass in 38 (15%). The revised IPI indicated 23 (9%) very good, 88 (35%) good, and 143 (56%) poor risk cases. In 235 patients, we categorized 80 cases as germinal center B-cell-like (GCB) type and 155 cases as non-GCB type using Hans's algorithm of immunohistochemistry. Autologous peripheral blood stem cell transplantation was performed in 18 patients. Initial therapy that included radiation was performed in 29 patients. 5-year OS was 59.3% and 5-year progression-free survival (PFS) was 48.7%. According to the revised IPI, 5-year OS was stratified as 100%, very good; 69.2%, good; and 46.4%, poor (P< 0.001). Based on univariate analysis using Log-rank tests, significant poor prognostic factors for OS were as follows: B symptom positivity (P = 0.003), hemoglobin< 12.0 g/dL (P< 0.001), albumin < 4.0 g/dL (lower limit of normal; P< 0.001), C-reactive protein (CRP) > 0.6 mg/dL (P< 0.001), soluble IL-2 receptor (sIL-2R) > 2000 U/mL (P< 0.001), and non-GCB type (P = 0.03) along with all IPI factors including age ≥ 61 (P< 0.001), Ann Arbor clinical stage ≥ 3 (P = 0.005), lactate dehydrogenase (LDH) > 220 IU/L (upper limit of normal; P< 0.001), ECOG performance status ≥ 2 (P< 0.001), and number of extranodal disease sites ≥ 2 (P = 0.02). In multivariable analysis for 235 patients using Cox proportional hazards model including 11 previously noted factors, age (P = 0.003), CRP (P = 0.04), hemoglobin (P< 0.001), and albumin (P = 0.02) were significant. Step-down procedure in multivariable analysis also identified these 4 factors, age [hazard ratio (HR) 2.84, P = 0.002], CRP (HR 2.10, P = 0.003), hemoglobin (HR 2.36, P< 0.001), and albumin (HR 2.16, P = 0.008), as significant in 254 patients. These 4 factors were used to define the ACHA (Age-CRP-Hemoglobin-Albumin) score. ACHA scores stratified 5-year OS as 100%, 82.1%, 64.3%, 51.4%, and 22.3%, and 5-year PFS as 93.9%, 71.2%, 51.5%, 37.3%, and 14.6% as 0 (n = 34), 1 (n = 46), 2 (n = 48), 3 (n = 66), and 4 (n = 60) of the ACHA scores, respectively (OS, P< 0.001: PFS, P< 0.001). ConclusionsAlthough predictive power of this scoring system should be validated using another data set, ACHA scoring factors at diagnosis stratified expected survivals. ACHA was constructed without Ann Arbor staging; thus, computed tomography scanning and bone marrow examination were not required for risk stratification. Moreover, this predictive scoring system could extract poor prognosis patients with 5-year OS < 30% and patients highly likely to be resistant to R-CHOP or R-CHOP-like regimen with 5-year PFS < 20%. New therapy regimens that improve OS for such patients with very poor predicted prognosis are required. Disclosures:No relevant conflicts of interest to declare.

LR11 Is a Potential Serum and Histological Biomarker for Intravascular Large B-Cell Lymphoma

Abstract 5104 Introduction:Intravascular large B-cell lymphoma (IVLBCL) is a rare disease entity of malignant lymphoma, characterized by the selective growth of lymphoma cells within the lumina of vessels in various organs. Although recent reports showed that prompt and accurate diagnosis lead to better outcomes, absence of typical clinical manifestations and its aggressive behavior frequently makes it difficult. LR11 (also called SorLA or SORL1) is a type I membrane protein, from which a soluble form (sLR11) is released by proteolytic shedding. sLR11 is originally known to be a biomarker of carotid intima-media thickness. We have recently found that LR11 is expressed on human leukemia cell lines, and sLR11 is released in its culture medium. Serum sLR11 levels are significantly elevated in patient serum samples with acute leukemia and B cell lymphomas, and are associated with tumor burden and bone marrow invasion. Based on these findings, we hypothesized that LR11 may be also expressed and released from IVLBCL cells; therefore we evaluated its clinical importance in IVLBCL. Materials and methods:Serum samples and paraffin embedded tumor specimens were obtained from 6 patients who were histologically diagnosed as IVLBCL from 2009 to 2012. Specimens were subjected to immunostaining using anti-LR11 antibody, and serum sLR11 levels were measured by ELISA method. Patient laboratory and clinical data were collected retrospectively. Also, serum samples from 75 healthy volunteers, and 10 patients with collagen diseases presenting similar clinical manifestations as IVLBCL were analyzed. Results:Tissue samples of IVLBCL were obtained by bone marrow biopsy (N=2), transbronchial lung biopsy (N=2), and random skin biopsy (N=2). Biopsy specimens showed that cytoplasm of IVLBCL cells were specifically immunoreacted against the anti-LR11 antibody (Figure 1). Median serum sLR11 level of IVLBCL patients was 86. 0 ng/ml (mean ± SD: 201. 8 ± 260. 0 ng/ml), which was significantly elevated than those of healthy volunteers (median: 8. 4 ng/ml, mean±SD: 8. 8 ± 1. 8 ng/ml, p<0. 0001) and patients with collagen diseases (median: 14. 4 ng/ml, mean ± SD: 15. 9 ± 5. 9 ng/ml, p<0. 0001). Paired sample analysis showed that elevated sLR11 levels at disease diagnosis were decreased to normal range when disease remission was achieved (median: 13. 3 ng/ml, mean ± SD: 11. 0 ± 3. 3 ng/ml). Conclusions:We have identified LR11 as a novel molecule which was proven to be expressed in IVLBCL cells and circulated in patients' serum. LR11 immunostaining clearly highlights the tumor cells and sLR11 enables to distinguish IVLBCL from other differential diagnosis by serum evaluation. These findings suggest that LR11 is a useful diagnostic tool for IVLBCL, and serum sLR11 is a sensitive biomarker for diagnosis and disease monitoring of this challenging disease. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

A unifying diagnosis for pancytopenia, fever, hypoglycemia, and lactic acidosis

A unifying diagnosis for pancytopenia, fever, hypoglycemia, and lactic acidosis