scholarly journals Anti-Spike (S) Antibody Production Post Covid-19 Vaccination after B Cell Depleting Therapy (BCDT) for Non-Hodgkin Lymphoma (NHL)

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2486-2486
Author(s):  
Josselyn Glamyr Molina
Keyword(s):  
B Cell ◽  
Solid Tumors ◽  
Antibody Production ◽  
Conflicts Of Interest ◽  
Hematologic Malignancies ◽  
Cytotoxic Chemotherapy ◽  
Spike Protein ◽  
Low Grade ◽  
Patients With Cancer ◽  
Almost All

Abstract Introduction: Patients with NHL have a longer duration of illness and higher mortality rate after infection with Covid-19 1-3. Vaccination is strongly recommended to mitigate these problems in the general population, however, patients with cancer were not eligible to enter the pivotal vaccine trials. Furthermore, patients with NHL as well as other hematologic malignancies are frequently treated with B cell depleting therapies (BCDT) such as Rituximab and other anti-CD20 antibodies which in theory affect antibody production after vaccination. There are no data in the literature regarding patients with NHL and scarce data on other tumors concerning the antibody response against the S protein of Sars-Cov-2. To investigate the production of antibodies against the spike protein following vaccination against Sars-Cov-2, we studied 180 patients with cancer. We also aimed to determine if factors such as timing of BCDT in relation to number of days elapsed between such treatment and vaccination, as well as other features such as peripheral blood absolute B cell count correlate with antibody production. Materials and Methods: Anti-spike protein antibody production was evaluated in 104 patients with NHL and 76 with other malignancies. Eligible participants were aged 21 years or older. Study inclusion criteria included diagnosis of lymphoma or other hematological malignancy as well as solid tumors. The Dimension Exel 200 method for qualitative detection of total antibodies was used to determine antibody production. The antibody test was performed > 14 days after the second Moderna or Pfizer vaccine dose or after the Johnson & Johnson single dose. We prospectively evaluated antibody production following administration of BCDT as well as cytotoxic chemotherapy in 104 patients with NHL, 27 hematologic malignancies and in 49 solid tumors. In addition, we explored the timing of such treatments in relation to the vaccination date as well as the type of vaccine administered. Results: Median age was 61 and 59% were females. Of 180 entered, 104 had NHL. Of these, 95 (91.3%) were treated with BCDT, including rituximab (89), obinutuzumab (5) or anti-CD19 CAR-T cell therapy (1). BCDT was usually given together with induction chemotherapy and followed by maintenance. Histologic types of NHL treated with these therapies were: aggressive NHLs (N=35), follicular low grade (N=33), marginal zone NHL (14) and others (N=13). There were 49 patients with solid tumors. We also included 10 patients with other hematologic tumors who received BCDT and were analyzed together with the 95 NHLs to determine if this treatment interfered with anti-spike antibody production. Conclusions: These results imply a deleterious effect of BCDT on the humoral immune response to the SARS-Cov-2 vaccine. The correlation between the administration of BCDT and poor production of anti-spike antibodies is very robust, particularly in those cases who were vaccinated 9 months or less after BCDT. However, administration of cytotoxic chemotherapy without BCDT was not associated with reduced production of antibodies. In fact, almost all patients (94%) who received cytotoxic chemotherapy without BCDT, produced antibodies against spike protein (table 2). However, when chemotherapy was combined with BCDT there was a significant reduction of antibody production. These results strongly suggest that the major problem with poor antibody production following vaccination against Sars-Cov-2 relates to the use of BCDT and not so much to cytotoxic chemotherapy. The same findings apply to the 104 cases of NHL where half of patients treated with BCDT did not produce antibodies while 88% who did not receive BCDT produced antibodies (table 2). Almost all patients with solid tumors in our study (95.9%) were able to produce antibodies, irrespective of whether they received chemotherapy or not. These data raise the question whether vaccinated patients treated with BCDT who failed to make antibodies against the spike protein, could also benefit from a third dose. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Pathological Confirmation Of Apparent Metastatic Disease Is Essential: Incidentally Diagnosed Low Grade B Cell Lymphomas In Patients With Solid Tumors

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5059-5059
Author(s):  
Sameh Gaballa ◽  
Cherif Abdelmalek ◽  
Onder Alpdogan ◽  
Rita S. Axelrod ◽  
Barbara Campling ◽  
...  
Keyword(s):  
Lymph Nodes ◽  
B Cell ◽  
Solid Tumors ◽  
Conflicts Of Interest ◽  
Cell Cancer ◽  
Stage Iv ◽  
Bone Lesions ◽  
Low Grade ◽  
Advanced Stage ◽  
B Cell Lymphomas

Abstract Background The detection of skeletal metastasis, enlarged lymph nodes or parenchymal lesions in patients (pts) with established solid tumors most commonly denotes advanced stage disease. If not confirmed histologically, a subset of pts might be over staged and mismanaged palliatively. Methods We report 7 cases of low-grade B cell lymphomas diagnosed in a bone, lymph node or lung biopsy during staging workup in patients with suspected metastatic solid tumors. Results All pts were men aged 41 to 80 yo diagnosed with: non-small cell lung (NSCL), prostate, lip squamous cell, bladder, renal cell cancer (CA) and nasal adenoid cystic carcinoma. Imaging studies done during initial workup or follow up after resection of the primary tumor revealed bone metastasis, lymphadenopathy or lung nodules suggesting advanced stage of the primary CA. Invasive workup of the lesions in question revealed incidental low-grade B cell lymphomas (2 low grade lymphomas of bone, 2 CLL/SLL, 1 BALT, 1 marginal zone and 1 nodular lymphocyte predominant Hodgkin lymphoma). In all cases, this led to down staging and changed the management of the solid CA. Surgical resection of the tumor was done after it was down staged from non-resectable to resectable in 2 pts with head/neck CA; 1 pt with NSCL was down staged from stage IV to IIIA and received chemo/radiotherapy; 1 pt with prostate CA was down staged from stage IV to I; 3 pts were down staged from stage IV and were in remission from previously resected solid tumors. Only 2 pts required therapy for the newly diagnosed lymphoma. Avidity of the lesions revealed SUV ranging from 1.28 to 14.11 in the bone and from 2.17 to 6.98 in the lymph nodes. Conclusions Accurate staging of pts with solid tumors is critical in defining optimal goals of therapy. The growing use of PET/CT scans results in a higher rate of incidentally detected bone lesions or lymphadenopathy. Whereas a number of solid tumors readily spread to bone and lymph nodes, a spectrum of indolent lymphoid disorders may coexist in pts with established solid tumors. These lymphomas may remain asymptomatic for years. This might be misinterpreted as advanced stage solid tumor unless confirmed histologically. Disclosures: No relevant conflicts of interest to declare.

Occurence of Malignancies in Patients with Primary Immunodeficiencies: An Analysis of the French Primary Immunodeficency Registry

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1057-1057
Author(s):  
Felipe Suarez ◽  
Hugo Chapdelaine ◽  
Laetitia Compain ◽  
Nizar Mahlaoui ◽  
Chantal Andriamanga ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
Solid Tumors ◽  
Conflicts Of Interest ◽  
Primary Immunodeficiencies ◽  
Age At Diagnosis ◽  
Low Grade ◽  
Lymphoid Malignancies ◽  
Younger Age ◽  
Increased Risk

Abstract Abstract 1057 Background: Primary immunodeficiencies (PID) are rare congenital disorders involving defects of the immune system. Aside from infectious complications, patients are at increased risk of malignant complications, which represent a leading cause of mortality in this context. The pathophysiology underlying malignant complications, especially lymphoid malignancies, in PID is not fully understood. The molecular mechansims of PID, that often involve lymphoid developent pathways, may also play a role in oncogenesis. A better understanding of the epidemiology of malignancies in PID may provide important insights in oncogenesis, particularly in lympomagenesis. Material and methods: French National Reference Center for Primary Immune Deficiencies (CEREDIH) has registered 4632 patients with PID as of July 2012. T-cell immunoficiencies and B-cell immodificencies reprensent 35.8% and 46.1% respectively. Patients with Ataxia-Telangiectasia and Severe Congenital Neutropenia were excluded frome the present analysis as they represent a more homogeneous group in terms of molecular pathophysiology and have been described elsewhere. T-cell immunodeficiencies comprise Severe combined immudoficiencies, Combined immunodeficiencies, other well defined T-cell immunoficiencies (including Wiskott-Aldrich Syndrome), and diseases of immune regulation (including X-linked lymphoproliferative disease and Autoimmune lymphoproliferative syndrome). B-cell immunodeficiencies include Agammaglobulinemia, Common Variable Immunodeficiency, Unspecified primary hypogammaglobulinemia, Selective IgA deficiency, Hyper-IgM symdrome and IgG subclass deficiency. Diagnostic class of PID, Age at diagnosis of PID, age at diagnosis of neoplastic complication, type of neoplasia, and survival were retrospectively colloected from the medical files. Non-melanomatous skin cancers and lymphoproliferative disorders occuring after allogeneic stem cell tranplantation were excluded from the analysis. Results: 4632 patients with PID were analyzed. Two hundred and sixty seven patients developed 276 cancers (incidence 5.8%). One hundred and fifty seven patients developed lymphoid malignancies and 78 patients developed solid tumors (56.4% vs. 28.3% respectively). Compared to patients with B-cell PID, patients with T-cell PID had lower age at diagnosis of PID (5.5 [0–12.4] vs. 1.3–78]). Lymphoid malignancies, mainly high grade lymphomas were more prevalent in T-cell PID and PID diagnosed at a younger age (median age at diagnosis of PID for patients with lymphoid malignancies vs. solid tumors, 5.2 yr [0–85] and 37.5 [0–80] respectively, p<0,001). More than 75% of solid tumors occured in patients with B-cell PID with a median age of 45 yr. at diagnosis of cancer (p<0,001 compared to lymphoid malignancies for the entire cohort). Occurence of lymphoid malignancies had a major impact on mortality in patients with PID, with an overall survival (OS) of 24.7 yr [0.2–86] vs. 58.3 yr [0.2–90.8] for patients with solid tumors (p<0,001). The difference in OS between PID patients developing solid tumors was not statistically different than the whole cohort of PID patients. Both high and low-grade lymphomas were observed in patients with PID developing lymphoid malginancies. The majority of low grade-malignancies were oberserved in patients with B-cell PID. Discussion: PID bear a high risk of malignancies (5.8%). Solid tumors are observed mainly in B-cell PID and are diagnosed at an older age. Lymphoid malignancies are observed mainly in T-cell PID and B-cell PID diagnosed at a younger age, underlying a possible pathophysiological link between T-cell PID and a subset of B-cell PID. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Predicting Responses to Checkpoint Inhibitors in Lymphoma: Are We Up to the Standards of Solid Tumors?

2020 ◽  
Vol 14 ◽  
pp. 117955492097636
Author(s):  
Ah-Reum Jeong ◽  
Edward D Ball ◽  
Aaron Michael Goodman
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
B Cell ◽  
Solid Tumors ◽  
Cell Lymphoma ◽  
Checkpoint Inhibitors ◽  
B Cell Lymphoma ◽  
Hematologic Malignancies ◽  
Checkpoint Blockade ◽  
Programmed Cell Death 1

Treatment of cancer has transformed with the introduction of checkpoint inhibitors. However, the majority of solid tumor patients do not respond to checkpoint blockade. In contrast, the response rate to programmed cell death 1 (PD-1) blockade in relapsed/refractory classical Hodgkin lymphoma (cHL) is 65% to 84% which is the highest among all cancers. Currently, checkpoint inhibitors are only approved for cHL and primary mediastinal B-cell lymphoma as the responses to single-agent checkpoint blockade in other hematologic malignancies is disappointingly low. Various established biomarkers such as programmed cell death 1 ligand 1 (PD-L1) protein surface expression, mismatch repair (MMR) status, and tumor mutational burden (TMB) are routinely used in clinical decision-making in solid tumors. In this review, we will explore these biomarkers in the context of hematologic malignancies. We review characteristic 9p24.1 structural alteration in cHL and primary mediastinal B-cell lymphoma (PMBCL) as a basis for response to PD-1 inhibition, as well as the role of antigen presentation pathways. We also explore the reported frequencies of MMR deficiency in various hematologic malignancies and investigate TMB as a predictive marker.

scholarly journals Anlotinib Shows Potent Antileukemia Effects in B-Cell Acute Lymphocytic Leukemia through the Blockage of Angiogenic Related Pathways

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 49-49
Author(s):  
Qiuling Chen ◽  
Yuelong Jiang ◽  
Qinwei Chen ◽  
Long Liu ◽  
Bing Xu
Keyword(s):  
B Cell ◽  
Solid Tumors ◽  
Molecular Mechanisms ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Unmet Need ◽  
Lymphocytic Leukemia ◽  
Advanced Lung Cancer ◽  
Antitumor Effects

Acute lymphoblastic leukemia (ALL) derives from the malignant transformation of lymphoid progenitor cells with ~85% being originated from B-cell progenitors (B-ALL). Despite fairly good prognoses for most pediatric B-ALL patients, the outcome is fatal in over 50% of adult patients who have a recurrent or progressive disease and lack of effective therapeutic approaches. Therefore, novel treatment strategies with high efficacy and low toxicity are an unmet need for B-ALL patients, especially those with relapsed or refractory status. Angiogenesis is a process of new vessel formation that requires the participation of multiple proangiogenic factors (e.g., VEGF, PDGF, and FGF) and their corresponding receptors (e.g., VEGFR, PDGFR, and FGFR). Angiogenesis, a well-established feature of solid tumors, also contributes to leukemia progression and correlates with the involvement of specific sanctuary sites in ALL, highlighting that the perturbation of angiogenesis would be an attractive approach for ALL treatment. Anlotinib is an oral tyrosine kinase (TKI) inhibitor with a broad range of antitumor effects via the suppression of VEGFR, PDGFR and FGFR. Of importance, anlotinib has been approved for the treatment of advanced lung cancer in China. Here, we evaluated the antileukemia activity of anlotinib in preclinical B-ALL models and its underlying molecular mechanisms. In this study, we observed that anlotinib significantly blunted the capability of cell proliferation and arrested cell cycle at G2 phase in B-ALL cell lines. Subsequently, we found that anlotinib resulted in remarkably enhanced apoptosis in B-ALL in vitro. To assess the in vivo antileukemia potential, we established a B-ALL patient-derived xenograft (PDX) mouse model and then treated the B-ALL PDX model with anlotinib. As a result, oral administration of anlotinib pronouncedly delayed in vivo B-ALL cell growth and reduced leukemia burden with acceptable safety profiles in this model. As for the mechanism of action, the antileukemia effect of anlotinib was associated with the disruption of the role of VEGFR2, PDGFRb, and FGFR3. Moreover, we revealed that this drug blocked the PI3K/AKT/mTOR/ signaling, a pathway that is linked with angiogenesis and its proangiogenic regulators, including VEGFR2, PDGFRb, and FGFR3. In aggregate, these results indicate that anlotinib is a potent antitumor agent for the treatment of B-ALL via the inhibition of angiogenic relevant pathways, which provide a novel potential treatment intervention for patients with B-ALL who have little effective therapy options. Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: Anlotinib originally designed by China is a novel orally active multitarget inhibitor that is evaluating in clinical trials against multiple solid tumors.

Increased Risk for Thromboembolism Associated with High Coagulation Factor VIII (F VIII) Levels in Patients with Malignant Lymphoma.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1380-1380
Author(s):  
Martin Mohren ◽  
Ilka Markmann ◽  
Astrid Franke ◽  
Kathleen Jentsch-Ullrich ◽  
Michael Koenigsmann ◽  
...  
Keyword(s):  
Factor Viii ◽  
Malignant Lymphoma ◽  
Solid Tumors ◽  
Protein C ◽  
Factor V Leiden ◽  
Coagulation Factor ◽  
Hematologic Malignancies ◽  
Low Grade ◽  
Factor V Leiden Mutation ◽  
Increased Risk

Abstract An increased annual incidence of thromboembolic events (TE) of up to 11% has been observed in patients with solid tumors, whereas there exists little data on TE in hematologic malignancies. A previous study found a 6,6% incidence of TE in patients with high grade Non Hodgkin’s lymphoma (HG-NHL) mostly occuring during the first three months of therapy. Little is known about pathogenesis and risk factors in this patient group. We retrospectively evaluated the medical records of all patients with malignant lymphoma treated at our institution between 1991 and 2004. In a seperate effort laboratory analysis for detection of acquired and hereditary thrombophilia was performed at diagnosis and during treatment in 44 patients with various hematologic malignancies: HG-NHL (n = 22), Low grade- NHL (LG-NHL) (n = 7), Hodgkin’s disease (HD) (n = 6), CNS-lymphoma (n = 1) and acute myeloid leukemia (AML) (n = 8). A total of 96 TE occurred in 80 of 1048 patients (7,6%) with malignant lymphoma: DVT (n = 51), pulmonary embolism (n = 19), central venous catheter thrombosis (n = 11), upper extremity thrombosis due to tumor compression (n = 9), central nervous system thrombosis (n = 3), arterial thrombosis (n = 2) and portal vein thrombosis (n = 1). 69 TE (72%) occurred during treatment, whereas 27 (28%) were diagnosed prior to (n = 16) (17%) or after completion of therapy (n = 11) (11%). 9 patients (9%) had comorbid solid tumors. In 12 patients (15%) results of thrombophilia screening were available and FVIII levels were high (&gt; 150%) in 7 (58%). In the prospectively analyzed patient cohort 30 (68%) had high FVIII levels, 22 (50%) showing very high levels (&gt; 180%). High FVIII was associated with high von Willebrand factor (vWF) and increased collagen binding activity, but not with elevated IL 6 or TNF-a. 4 patients (9%) had heterozygous factor V Leiden mutation, one had the G20210A mutation of the prothrombin gene. Fibrinolysis was normal in all patients as were protein C, S and AT-III. No anticardiolipin antibodies or lupus anticoagulants were detected. However only 2 patients (4,4%) in this cohort developed TE, one of whom also had heterozygous protein C resistance. Patients with malignant lymphoma are at substantial risk for TE, especially during treatment, thus prophylactic anticoagulation seems warranted. Our study shows sustained strikingly high factor VIII levels in patients with malignant lymphoma even months or years after a TE as well as in a prospectively analyzed, yet mostly asymptomatic cohort with lymphoma and acute leukemia. Infection as a cause of secondary F VIII elevation in these patients was ruled out by absence of fever and normal IL 6 and TNF-a. Increased FVIII activity (&gt; 150%) has been recognized as an independent risk factor for TE, however the pathogenesis is unclear so far and high FVIII and vWF levels have previously also been found in Multiple Myeloma patients. Ongoing investigations will focus on the implication of these findings in the pathophysiology of hematologic disease.

Absence of Mutations of the Histone Methyltransferase Gene EZH2 In Splenic B-Cell Marginal Zone Lymphoma

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 5086-5086
Author(s):  
Luz Martínez-Avilés ◽  
Marta Salido ◽  
Beatriz Bellosillo ◽  
Vera Adema ◽  
Ana Ferrer ◽  
...  
Keyword(s):  
B Cell ◽  
Marginal Zone ◽  
Mutational Analysis ◽  
Conflicts Of Interest ◽  
Direct Sequencing ◽  
Normal Karyotype ◽  
Marginal Zone Lymphoma ◽  
Low Grade ◽  
Splenic Marginal Zone Lymphoma ◽  
7Q Deletion

Abstract Abstract 5086 Background Splenic marginal zone lymphoma (SMZL) is a rare low-grade B-cell lymphoproliferative disorder with characteristic clinical, cytological, histological and immunophenotypical features. The most common cytogenetic abnormality, present in 30–40% of the patients is the 7q deletion, that extends from 7q21 to 7q36. This aberration may represent a primary pathogenic event in SMZL. Recently, mutations in the EZH2 gene, located at 7q36.1, have been described in different hematological malignancies including B-cell lymphomas. However, the role of the EZH2 gene in SMZL has to be elucidated. Aim To determine the prevalence of EZH2 mutations in a cohort of SMZL patients. Patients and Methods Twenty-nine patients with SMZL were screened for mutations in the EZH2 gene. From the whole cohort, 11 patients presented 7q deletion (three of them as a single anomaly), 11 had a normal karyotype and 7 had other cytogenetic aberrations. The mutational analysis of the EZH2 gene was performed by direct sequencing using primers covering the whole exome of the gene. DNA was extracted from CD19 isolated B-cells from peripheral blood or from total lymphocytes if the percentage of pathologic B-cell was higher than 50%. Results From the whole cohort of 29 SMZL patients, no pathogenic mutations (frameshift or nonsense mutations) were detected in the EZH2 gene in any of the patients analyzed. Five patients harboured the missense mutation D185H in exon 6, that has been previously described as a single nucleotide polymorphism (SNP). Conclusions In conclusion, the EZH2 gene is not mutated in our series of SMZL patients suggesting that this gene is not involved in the pathogeny of this entity. Acknowledgments: Fellowship FI2008 (AGAUR) to LMA, This work was supported (in part) by grants from Instituto de Salud Carlos III FEDER; Red Temática de Investigación Cooperativa en Cáncer (RTICC, FEDER): RD06/0020/0031 and RD07/0020/2004; Ministerio de Sanidad y Consumo (Spain): PI07/0586. Disclosures: No relevant conflicts of interest to declare.

Oncogene Amplification as an Incidental Finding in FISH Testing for Gene Rearrangements in Lymphoid Hematopoietic Neoplasms

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2505-2505
Author(s):  
Guoxian Sun ◽  
Lya Montella
Keyword(s):  
B Cell ◽  
Gene Amplification ◽  
Conflicts Of Interest ◽  
Cell Lymphoma ◽  
Lymphoblastic Leukemia ◽  
B Cell Lymphoma ◽  
Low Grade ◽  
Oncogene Amplification ◽  
Lymphoid Neoplasms ◽  
Myc Gene

Abstract Abstract 2505 Oncogene amplification resulting in overexpression, although common in solid tumors, is rare in hematopoietic neoplasms. This is particularly true in lymphoid neoplasms compared to AML where MYC, MLL or RUNX1 (AML1) amplification has been mostly seen, and to CML where BCR/ABL fusion gene amplification has been also reported. Typically, lymphoid neoplasms are tested at diagnosis by FISH for specific reciprocal chromosome translocations that lead to overexpression of deregulated oncogenes such as BCL1, BCL2, BCL6 and MYC in B-cell lymphoma and myeloma or BCR/ABL gene fusion in ALL. Nevertheless, we have unexpectedly seen oncogene amplification from time to time in our FISH lab. To study the incidence of gene amplification and its diagnostic and clinical implications, we retrospectively analyzed FISH results routinely performed on paraffin embedded lymphoma tissues, lymph nodes, bone marrow aspirates and peripheral bloods in the past three and half years using translocation probes for BCL2/IGH, BCL1/IGH, MYC/IGH and BCR/ABL and break apart probes for BCL6 and MYC. The highest amplification rate seen was in BCL2/IGH testing: 11 of the 1,710 cases were positive (0.643%). In 2 cases with follicular lymphoma (FL), BCL2 amplification presented as homogenously staining regions (hsr), one case with diffuse large B-cell lymphoma (DLBCL) showed double minutes (dmin), and two cases with FL had a pattern of combined hsr and dmin. Five cases with low grade FL intriguingly showed a similar pattern of BCL2/IGH translocation and concomitant amplification of the rearranged BCL2 as a small hsr. The remaining case diagnosed as Burkitt lymphoma (BL) was positive for MYC/IGH translocation and for BCL2 amplification present as large hsr. BCL6 amplification was observed in 4 of 1,537 cases tested (0.26%). In all these cases, amplification presented as hsr. One case diagnosed as EBV+ DLBLC was positive for MYC/IGH translocation and 3' BCL6 high level amplification. Another case with FL showed BCL6 rearrangement and 5' BCL6 amplification. BCL1 amplification with translocation was seen as hsr in 1 case with mantle cell lymphoma out of 2,898 tested. BCL1 amplification was observed in another case with plasma cell myeloma as hsr out of 3,413 tests performed. MYC gene amplification was positive in 3 of 2,186 (0.137%). One case with BL showed MYC rearrangement with a concomitant 3' deletion and 5' amplification. The second case diagnosed as B-cell lymphoma with features intermediate between DLBCL and BL showed highly amplified MYC gene as hsr. The third case was DLBCL with 15–50 copies of MYC gene per cell as dmin. Among 530 BCR/ABL tests ordered for acute leukemia or ALL, 2 (0.377%) cases with T cell lymphoblastic leukemia/lymphoma (T-ALL/LBL) showed ABL amplification as episomes (4–8 copies in one case; 6–30 in another). Both were abnormal by cytogenetics analysis, but negative for t(9;22)(q34;q11.2) and without dmin or hsr identified. Although detection rates of oncogene amplification seem to be very low with limited specific translocation probes applied to lymphoid neoplasms, they may well be higher when FISH signal patterns are analyzed more carefully. In our study, 5 of the 11 FL cases tested for IGH/BCL2 showed a peculiar pattern positive for the t(14;18)-IGH/BCL2 and a concomitant red signal amplification of BCL2, the size of which is usually small and may be overlooked under microscope. All these 5 cases had low grade FL, suggesting that oncogene amplification can be an early genomic event in lymphomagenesis. MYC gene amplification is generally considered a late stage genomic alteration. When MYC is rearranged, amplification of BCL2, BCL6 or BCL1 may need to be taken into consideration for disease stratification, or vice versa. For instance, so called “double-hit” or “triple-hit” lymphomas currently require two or three concurrent translocations for diagnosis. Oncogene amplification, equally important for deregulation/overexpression as a translocation, should be considered as a second or a third hit in diagnosis and differential diagnosis of B-cell lymphoma unclassifiable with features intermediate between DLBCL and BL. FISH is a very useful tool to identify episomal oncogene amplification. Episomes, unlike cytogenetically evident dmin and hrs, are invisible by chromosome analysis, but their detection is important as reported for integration of targeted tyrosine kinase inhibitors into chemotherapeutic regimens. Disclosures: No relevant conflicts of interest to declare.

A Study of the Expression of the LMP1 Oncoprotein in Low-Grade B Cell Lymphomas and Correlation with the Levels of Oxidative Stress

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4833-4833
Author(s):  
Panagiotis Theodorou Diamantopoulos ◽  
Vasiliki Papadopoulou ◽  
Aikaterini Polonyfi ◽  
Athanasios G. Galanopoulos ◽  
Fani Kalala ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
B Cell ◽  
Conflicts Of Interest ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Low Grade ◽  
B Cell Lymphomas ◽  
Ebv Infection ◽  
Lmp1 Expression ◽  
Apoptotic Pathways

Abstract Abstract 4833 Introduction. The Epstein-Barr virus has been implicated in the pathogenesis of certain human B-cell neoplasms, such as Burkitt's lymphoma, Hodgkin's disease and post-transplant lympho-proliferative disorders. Persistent latent EBV infection is, however, frequent and therefore its role is of interest in all types of B cell malignancies. In low-grade B cell lymphomas there are few reports for its potential role in higher grade transformation and its association with stereotypic BCRs in CLL. The mechanisms of EBV-associated B cell transformation are probably associated with its proteins expressed during latency; one of the most studied is the LMP1 oncoprotein, which is considered as an anti-apoptotic factor (activator of NF-êB). Recent studies, however, show evidence of coexisting apoptotic properties of LMP1. The level of oxidative stress reflects activation of caspase-mediated apoptotic pathways. Aims and methods. We measured the levels of oxidative stress in low-grade B cell lymphoma patient samples and correlated them with the expression of the LMP1 oncoprotein in order to study apoptotic functions of LMP1. Whole blood samples from 48 patients aged 51–87 (median age 74 years, 25 males, 23 females) without treatment in the previous six months were examined (chronic lymphocytic leukemia: 27, marginal zone lymphoma: 12, mantle cell lymphoma: 4, hairy cell leukemia: 2, follicular lymphoma: 2, lymphoplasmacytic lymphoma: 1). Latent EBV infection was detected with RT-PCR for the viral BXLF1 gene. LMP1 expression was quantitated with Real-Time PCR in EBV-positive patients. The levels of oxidative stress were quantitated in the sera of all patients with the use of a peroxide measuring kit (PerOx TOS/TOC kit by Immundiagnostik) and compared between the LMP1-positive (13) and LMP1-negative (35) group of patients with the use of 2-tailed Mann-Whitney test. Results. Of the fourty-eight (48) patients tested, nineteen (19) were EBV-positive. Thirteen (13) of the nineteen (19) EBV-positive ones expressed LMP1. Oxidative stress was found to be significantly higher in LMP1-negative vs LMP1-positive patients (372.3 vs 261.4 micromol/L, p=0.014). Discussion. The role of LMP1 expression is under investigation in the non EBV-related low grade B cell lymphomas. In the present study we examined a potential effect of LMP1 expression on oxidative stress and found that levels of oxidative stress were lower in LMP1-positive vs LMP1-negative patients with low-grade B cell lymphomas, reflecting an anti-apoptotic function of LMP1. In accordance with this result, LMP1 has been shown to upregulate BCL-2 using the NF-êB pathway. BCL-2 is a major inhibitor of the initiation of caspase-related apoptotic pathways and BCL-2 upregulation inhibits apoptosis resulting in lower levels of oxidative stress. However, in a study of sixty-four patients with low grade B cell lymphomas, we recently showed that LMP1 expression increases the levels of the apoptotic marker survivin, confirming that LMP1 may also possess an apoptotic function, as has been shown by another recent study on cell lines. Conclusion. The lower oxidative stress in the LMP1-expressing low grade B cell lymphoma samples shows evidence of an apoptotic function of the oncoprotein in this group of diseases. Disclosures: No relevant conflicts of interest to declare.

Impaired Precursor B-Cell Maturation/Production In The Bone Marrow: Association With Molecular and Immunophenotypic Markers Of Myeloid Dysplasia In Suspected Low-Grade MDS

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4943-4943
Author(s):  
Charles Repetti ◽  
Hsueh-Hua Chen ◽  
Yongbao Wang ◽  
Vanessa A Jones ◽  
Albert K Ho ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Flow Cytometry ◽  
B Cells ◽  
B Cell ◽  
Somatic Mutation ◽  
Conflicts Of Interest ◽  
Statistical Significance ◽  
Sequence Variant ◽  
Low Grade ◽  
Precursor B Cells

Abstract Rationale Myelodysplastic syndromes (MDS) are clonal stem cell disorders that disrupt orderly maturation of multiple hematopoietic lineages. Several studies have suggested that maturation of precursor B cells (hematogones) is also abnormal in MDS. As a result, the presence of normal numbers or increased precursor B cells in bone marrow (BM) is frequently used as a diagnostic feature arguing against a diagnosis of MDS. We compared the presence of myeloid-associated gene mutations and myeloid maturation abnormalities with qualitative and quantitative precursor B cell findings in BM samples submitted for workup of cytopenias or MDS. Methods Seventeen BM aspirate samples with <5% blasts submitted for cytopenia or MDS evaluation were compared with 10 samples having 5% or more blasts and changes diagnostic of MDS or AML. Mutation analysis was performed on genomic DNA using a targeted exome sequencing assay. This assay employs a TruSeq custom amplicon design on the MiSeq platform (Illumina, San Diego, CA). The assay covers the commonly mutated areas of 19 myeloid-associated genes. Somatic mutation status was assigned based on mutation levels, previous association with myeloid neoplasia, and no prior identification in public or internal databases as a normal sequence variant. Flow cytometry using 6-color (CD19/CD34) and 8-color (CD19/10) formats was used to assess lymphoblasts; CD34/13 was used to assess myeloblasts; and CD11b, CD13, CD16, and CD38 were used to assess abnormalities in myelopoiesis. Results  Among the 17 BM samples submitted for cytopenia or MDS evaluation that had <5% blasts, 7 (41%) had immunophenotypic myeloid maturation abnormalities. Ten (59%) of the 17 cases had at least one myeloid-associated somatic mutation, with TET2 and ASXL1being the most commonly mutated genes. The ratio of myeloblasts to B-lymphoblasts, calculated using either CD10 or CD19, was >10:1 in 10/17 (59%) cases. Nine of the 17 (53%) cases had virtually no precursor B cells detected. Discrete abnormalities in more mature myeloid forms were seen in 7/10 (70%) cases with low numbers of B-lymphoblasts but in none of the 7 cases with significant numbers of B-lymphoblasts. MDS-associated mutations were more common in cases with rare B-lymphoblasts (7/9) than in those with higher percentages of precursor B cells (3/8), but the difference did not reach statistical significance (P = 0.15).  Genes mutated in the group with B-lymphoblasts present included ASXL1 (3 cases), DNMT3A (2), TET2 (1) and TP53 (2). Two of these mutated cases presented with isolated thrombocytopenia. By comparison, myeloblast/lymphoblast ratios were >50:1 in all 10 unequivocal MDS/AML samples (>5% blasts); 8 (80%) of these cases had MDS-associated mutations, and 4 (50%) had mutations in multiple genes. Conclusions Decreases in BM precursor B cells in cases of possible low-grade MDS were usually, but not always, associated with the presence of MDS-associated mutations. However, cases with normal or increased precursor B cell numbers also showed MDS-associated mutations although immunophenotypic evidence of myeloid maturation abnormalities was not seen in this group. The identification of a subgroup of cytopenic patients with likely pathogenic mutations in bone marrow precursors but minimal phenotypic evidence of myeloid dysplasia may indicate clonal abnormalities primarily located outside the granulocyte or common stem precursor populations, e.g. restricted to the megakaryocytic lineage. Therefore, the presence of intact precursor lymphoblast and myeloid maturation by higher-dimensional flow cytometry as a primary criterion to argue against a diagnosis of low-grade MDS needs further evaluation, especially when granulocytopenia is absent. Disclosures: No relevant conflicts of interest to declare.

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