Genetic Analysis of B-Cell Lymphomas Associated with Hemophagocytic Lymphohistiocytosis (HLH)

Abstract Introduction: HLH is an aggressive and life-threatening syndrome of excessive immune activation. HLH can be familial or secondary. Secondary HLH is usually associated with malignancy, infections or rheumatologic disorders. 27% of the secondary HLH are related to malignancy, the vast majority of which are hematologic malignancies (HM), and are associated with a mortality rate of 80%. Chemotherapy may not salvage these patients due to end-organ dysfunction at presentation (Johnson 2016). We sought to further describe the genetic landscape of HM associated HLH to identify potential targets for clinical trials. Methods: We queried the National Cancer Institute's Mitelman Database of Chromosome Aberrations and Gene Fusions in Cancer to identify patients (pts) with HM associated HLH. All identified references were reviewed and pt data was extracted regarding clinical and pathologic details as well as therapy and outcomes. Frequencies of gene rearrangements in HLH associated lymphomas were contrasted to non-HLH associated lymphomas within the Mitelman database. Data was analyzed using Microsoft Excel and GraphPad Prism. All p-values are two- sided and results ≤0.05 were considered significant. Results: 16 pts with HLH associated B-cell lymphomas were identified. 8 pts had DLBCL associated HLH, 5 had EBV associated B-cell lymphomas and 3 had B-cell lymphomas NOS. The 8 pts without DLBCL were considered as a single group for further analysis. Pts with DLBCL-HLH were significantly older (mean 64.9 years, range 41-82) than the others (8.9, 0.3-33, t-test <0.0001) (Figure 1). 75% (6/8) of DLBCL-HLH pts were male vs 63% (5/8) of others. Median LDH, median ferritin, and median IL-2R were 1,117 (U/L), 1,073 (ng/mL), and 13,323 (pg/mL) respectively in the DLBCL-HLH pts and these were not reported in the others. 88% (7/8) pts with DLBCL-HLH received CHOP while 100% (8/8) of the others received etoposide and corticosteroids with or without other agents. DLBCL-HLH were more likely to harbor unbalanced rearrangements (75% v 13%, RR=3.9, 95%CI 1.1 - 13.6, p=0.04) and rearrangements in immune related loci (9p24 - PDL1/2 (2), 19q13 - IFN lambda 1,2,3 (2), and 12p11 - DDX11 (1)) versus none in the others (63% v 0%, RR=3.7, 95%CI 1.4 - 9.6, p=0.03). One pt each with DLBCL-HLH harbored rearrangements of MYC (1/8) and BCL2 (1/8) while none of the others had rearrangements in MYC or BCL2. No patient in either group had a rearrangement of BCL6. Median overall survival was 12.5m in DLBCL-HLH versus 4.5m in the others (log rank p=0.23) (Figure 2). Compared to non-HLH associated cases of DLBCL within Mitelman the incidence of rearrangements and additions in the immune related loci 9p24 (25% (2/8) v 3% (37/1413) (p=0.02)), 19q13 (25% (2/8) v 4% (61/1413) (p<0.05)) and 12p11 (13% (1/8) v <1% (6/1413) (p=0.04)) were significantly higher in DLBCL-HLH. Conclusion: DLBCL-HLH is a distinct entity with dismal outcomes with standard chemotherapy and frequent rearrangements of immune related genes. Novel treatment strategies are needed and may include immune modulatory agents such as PD-1 inhibitors. Figure 1 Age distribution of HLH associated lymphomas. Figure 1. Age distribution of HLH associated lymphomas. Figure 2 Overall survival for both groups. Figure 2. Overall survival for both groups. Disclosures No relevant conflicts of interest to declare.

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Co-Expression of MYC, BCL2 and PD-L1 in Primary Central Nervous System Diffuse Large B Cell Lymphomas ( PCNSL)

Blood ◽

10.1182/blood.v128.22.5311.5311 ◽

2016 ◽

Vol 128 (22) ◽

pp. 5311-5311 ◽

Cited By ~ 1

Author(s):

Nibal Saad ◽

Ankit Anand ◽

Rana Naous ◽

Vajpayee Neerja ◽

Shengle Zhang ◽

...

Keyword(s):

Cell Growth ◽

B Cell ◽

Conflicts Of Interest ◽

Immune Surveillance ◽

Hematologic Malignancies ◽

Immune Checkpoints ◽

B Cell Lymphomas ◽

Number Of Patients ◽

Clinical Responses ◽

Large B Cell

Abstract Background Increased protein expression and gene translocations of MYC and BCL2/BCL6promote increased cell growth and inhibit apoptosis. They are associated with inferior prognosis in systemic diffuse large B cell lymphomas (DLBCLs). Their role in primary PCNSLs however is less clear. The immune checkpoint molecules, programmed death 1 (PD1) and its ligand PD-L1 are involved in inhibitory pathways to maintain immune tolerance and it is now clear that tumor cells interfere with these pathways to promote escape from immune surveillance. Antibody blockade of these immune checkpoints has been shown to enhance antitumor immunity and is emerging as an important target for cancer immunotherapy. We examined the co expression of these proteins on tumor samples from patients with PCNSL . Methods Immunohistochemistry (IHC) for MYC, BCL2 and PDL-1 and florescence in situ hybridization ( FISH) for MYC (8q24), BCL2 ( 18q21) and BCL6 (3q27) were performed on tumor samples from 14 patients with PCNSL. Results Eleven patients were positive for PDL-1 (79%) by IHC. Of these eleven patients, six (55%) were also positive for both MYC and BCL2 by IHC and negative by FISH. Eight patients (57%) were positive for MYC and BCL2 by IHC but negative for PD-L1. One patient was positive by FISH for MYC, BCL2, and BCL6 but negative for PDL-1. Conclusions Our results, although in a small number of patients, demonstrate that a large percentage of patients with PCNSL who express MYC and BCL2 also express PD-L1.It has been suggested that the frequent over expression of MYC, BCL2, and BCL6 noted in PCNSL may underlie the inferior prognosis as compared to systemic DLBCL. We suggest that the co-expression of MYC/ BCL2 with PD-L1 may contribute to this poor prognosis by engaging the complimentary mechanisms of increasing cell growth, inhibiting apoptosis and evading immune surveillance. The use of PD-L1 inhibitors in hematologic malignancies is limited but has demonstrated clinical responses in relapsed/refractory disease following multiple lines of therapy and warrants further investigation in PCNSLs. Table Table. Disclosures No relevant conflicts of interest to declare.

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CD180 Expression in B-Cell Lymphomas: A Multicenter Geil Study

Blood ◽

10.1182/blood.v124.21.1628.1628 ◽

2014 ◽

Vol 124 (21) ◽

pp. 1628-1628

Author(s):

Caroline Mayeur-Rousse ◽

Julien Guy ◽

Laurent Miguet ◽

Sabrina Bouyer ◽

Franck Genevieve ◽

...

Keyword(s):

Flow Cytometry ◽

B Cell ◽

Conflicts Of Interest ◽

Lymphocytic Leukemia ◽

University Hospital ◽

Routine Practice ◽

Similar Data ◽

B Cell Lymphomas ◽

Whitney Test ◽

Mann Whitney Test

Abstract CD180 is a Toll-Like Receptor homolog strongly expressed on normal human B-cells and involved in innate immune responses. Previous proteomic analyses on microparticles derived from mature B-cell neoplasms allowed us to identify CD180 as a marker of marginal zone lymphomas (MZL)(Miguet, Leukemia, 2013). Using flow cytometry on blood samples we showed that this protein is lost or underexpressed at the plasma membrane for almost all B-cell lymphomas except MZL. In order to confirm its clinical relevance, we conducted a prospective multicenter flow cytometry study in 5 French University Hospital laboratories, on behalf of the GEIL. Blood or bone marrow samples from 236 patients were studied (20 normal controls ; 74 chronic lymphocytic leukemia (CLL); 21 mantle cell lymphoma (MCL); 42 lymphoplasmacytic lymphoma (LPL); 13 follicular lymphoma (FL) ; 58 MZL, 14 of which with numerous villous lymphocytes; 8 hairy cell leukemia (HCL)). Analyses were performed either on FACSCanto II (BD Biosciences, 3 centers) or on Navios (Beckman Coulter, 2 centers) instruments. Harmonization process was performed using Rainbow beads (Spherotech). For the CLL group, CD180 Median fluorescence (MdFI) in each center was not significantly different (Anova test, p>0.05). Instruments’ harmonization was therefore effective enough to obtain similar data from all centres. In the whole cohort, CD180 was significantly less expressed in the group of lymphomas -including CLL, MCL, LPL and FL- than in controls (Mann-Whitney test, p<0.05). Conversely, in the group of MZL and HCL, CD180 MdFI was not different from those of controls (Mann-Whitney test, p>0.05) but significantly higher than in CLL, MCL, LPL and FL (Mann-Whitney test, p<0.0001). Distinction between MZL and lymphomas with numerous villous lymphocytes was possible (Mann-Whitney test, p=0.0012) but not between MZL and HCL. ROC curve analysis determined a CD180 MdFI threshold of 1800 which allow the positive diagnosis of MZL with a sensitivity of 77% and specificity of 92%. These results underline the efficiency of CD180 as a single positive and robust marker for MZL diagnosis, and confirm that between centers and between instruments harmonization is largely feasible in routine practice as published recently (Solly F et al. Cytomery part A, 2013). It should be emphasized that among the group of lymphomas with intense expression of CD180, all interestingly originating from the spleen, those with numerous villous lymphocytes display the highest expression. We described for the first time in this study the strong positivity of CD180 in HCL. Anti-CD180 antibody may be included in diagnosis combination markers in order to improve the diagnosis of chronic B-cell malignancies Disclosures No relevant conflicts of interest to declare.

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Translocations Involving 8q24 in Burkitt Lymphoma and Other Malignant Lymphomas: A Historical Review of Cytogenetics in the Light of Todays Knowledge

Blood ◽

10.1182/blood.v112.11.2814.2814 ◽

2008 ◽

Vol 112 (11) ◽

pp. 2814-2814

Author(s):

Evert-Jan Boerma ◽

Reiner Siebert ◽

Michael Baudis ◽

Philip Kluin

Keyword(s):

B Cell ◽

Burkitt Lymphoma ◽

Age Distribution ◽

Classification Systems ◽

Proliferation Index ◽

Molecular Profile ◽

Steady Increase ◽

B Cell Lymphomas ◽

The Core ◽

Core Subset

Abstract Burkitt lymphoma (BL) has a characteristic clinical presentation, morphology, immunophenotype and primary chromosomal aberration, i.e. the translocation t(8;14) (q24;q32) or its variants. However, diagnostic dilemmas may arise in daily practice due to overlap of BL with subsets of other aggressive, mature B cell lymphomas such as a small subset of diffuse large B cell lymphomas (DLBCL). Recently, two gene expression studies have described a distinct molecular profile for BL, but also showed the persistence of some cases intermediate between BL and DLBCL. An alternative approach to define BL is to consider (cyto)genetic data, in particular chromosomal abnormalities other than the t(8;14) or its variants. In this study the “Mitelman Database of Chromosome Aberrations in Cancer”, harboring the majority of all published neoplasia related karyotypes, was explored to define a cytogenetic profile of “true” BL. To that end a core subset of BL was defined by a histologic diagnosis of BL, the presence of a t(8;14), t(2;8) or t(8;22) indicating a MYC/IG breakpoint, and the absence of a 3q27/BCL6, 18q21/BCL2 or 11q13/CCND1 breakpoint additional to the 8q24/MYC breakpoint. These core BL (N=481) showed a very low complexity of chromosomal changes, with 40% of the cases having the IG-MYC fusion as the sole abnormality; in the remaining cases additional recurrent and partially exclusive abnormalities included gains at chromosomes 1q, 7 and 12, and losses of 6q, 13q32-34 and 17p. No differences were found between pediatric (N=205) and adult patients (N=215). Moreover, no differences were found between such core BL cases published before (N= 280) and after 1994 (N=201) indicating that historical changes in classification systems had no major impact on this profile. The genetic profiles and age distribution of the core subset were significantly different from BL with an 8q24 breakpoint not affecting one of the three IG loci (N=13), lymphomas that were diagnosed as BL but had a translocation involving 18q21/BCL2, 3q27/BCL6 or 11q13/BCL1 additional to a breakpoint at 8q24/MYC (“double hit BL”; N=44), and from other morphological types of lymphomas with an 8q24/MYC breakpoint (N=327; 256/327 cases had an IG-MYC breakpoint). These groups showed an other age distribution and a higher cytogenetic complexity than the core subset of BL. BL without a detectable 8q24/MYC breakpoint (N=108) might have been heterogeneous and deserves further studies. We suggest that, concordant with the WHO classification to be published in 2008, the diagnosis of BL should be restricted to cases with expression of CD10 and BCL6, absence or very weak expression of BCL2 protein, a homogeneously very high proliferation index, and a proven IG-MYC translocation without evidence of a chromosomal translocation typical for other lymphoma entities. Additionally, a high number of non-specific cytogenetic abnormalities should suggest need for a critical review of the diagnosis of BL. Finally, the steady increase in age of lymphomas that mimic BL strongly emphasizes that there is no distinct age at which a pathologist can safely make a diagnosis of BL without any ancillary cytogenetic or molecular studies.

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Outcome of Adults with Acute Lymphoblastic Leukemia Treated with a Pediatric-Inspired Therapy: A Single Institution Experience

Blood ◽

10.1182/blood.v116.21.4337.4337 ◽

2010 ◽

Vol 116 (21) ◽

pp. 4337-4337

Author(s):

Guillermo J. Ruiz-Delgado ◽

Julio Macias-Gallardo ◽

Julia Lutz-Presno ◽

Maryel Montes-Montiel ◽

Guillermo J. Ruiz-Arg\)elles

Keyword(s):

Overall Survival ◽

B Cell ◽

Conflicts Of Interest ◽

Lymphoblastic Leukemia ◽

Single Institution ◽

B Cell Malignancies ◽

Secondary Diabetes ◽

Free Survival ◽

Results Of Treatment ◽

Better Than

Abstract Abstract 4337 The results of treatment of adults with ALL remain unsatisfactory. Pediatric-inspired treatments seem to be related with better outcomes. Eighty adult ALL patients were prospectively treated in a single institution in a 16-year period with a schedule based on the St. Jude's TOTAL XI pediatric protocol employing vincristine, prednisone, asparaginase, daunorubicin, etoposide, cytarabine, methotrexate, mercaptopurine and triple intratecal therapy. Median age was 31 years (range 18 – 86); 92% were B-cell malignancies and 14% were Ph1 (+). Ten patients did not complete the first course of chemotherapy and 4 exited early. 44 of 66 patents (67%) achieved a complete remission; relapses presented in 57%. The median probability of overall survival (OS) was 28 months, whereas the 144-month OS was 27%. The median probability of leukemia-free survival (LFS) was 28 months, and the 144-month LFS 35%. Ph1 (+) patients did worse than Ph1-negative and T-cell leukemias did better than B-cell ones. Concerning toxicity, eight patients had toxic deaths (12%), two developed acute pancreatitis and one secondary diabetes. This pediatric-inspired therapy rendered better results than those obtained in similar socioeconomic circumstances using adult-oriented treatments; tolerance was acceptable and costs were low since it employs affordable drugs and can be delivered as outpatients. Disclosures: No relevant conflicts of interest to declare.

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Mitotic Spindle Assembly Inhibition Through Aurora A (MLN8237) Plus Vincristine Is Synthetic Lethal and Synergizes with Rituximab As a Curative Therapy in Aggressive B-Cell Non-Hodgkin Lymphoma

Blood ◽

10.1182/blood.v118.21.2721.2721 ◽

2011 ◽

Vol 118 (21) ◽

pp. 2721-2721

Author(s):

Daruka Mahadevan ◽

Laurence Cooke ◽

Amy Stejskal ◽

Ann Manziello ◽

Carla Morales ◽

...

Keyword(s):

Gene Expression ◽

Overall Survival ◽

B Cell ◽

Conflicts Of Interest ◽

Tumor Regression ◽

Single Agent ◽

Cyclin B1 ◽

Aurora B ◽

Synthetic Lethal ◽

Over Expression

Abstract Abstract 2721 Most aggressive B-cell non-Hodgkin lymphomas (B-NHL) are not curable with current chemo-immunotherapy combinations. Synthetic lethal interactions with novel agents may yield effective combination therapies with minimal toxicity for aggressive B-NHL. Auroras (A and B) are a family of mitotic oncogenic serine/threonine kinases intimately involved in high fidelity regulation of cell division. Aberrant over-expression of Auroras leads to genetic instability, polyploidy, tumor initiation and progression. Over-expression of Auroras in aggressive B-NHL promotes resistance to microtubule targeted agents (MTA, taxanes and vinca alkaloids). Si-RNA knockdown or pharmacologic inhibition of Aurora with MLN8237 [M], an ATP-site small molecule inhibitor, leads to enhanced sensitivity of B-NHL cells to MTAs. We hypothesized that promotion of microtubule de-polymerization with vincristine [V] would be more effective in synergizing with M than a microtubule polymerizing agent docetaxel [D]. We demonstrated that M plus V is synergistic while M plus D is additive in B-NHL cell culture models. Further, the addition of rituximab [R] enhanced apoptosis of B-NHL cells treated with MV or MD therapy. Mouse xenograft models of mantle cell lymphoma show modest single agent activity for M, R, D and V with tumor growth inhibition (TGI) of ∼10–15% (p=0.01). Of the doublets, MV caused tumor regression while MD and MR caused TGI (∼55–60%) and (∼20–25% (p=0.001) respectively. Although MV caused tumor regression, mice relapsed after 2 weeks of stopping therapy. In contrast, MVR had no relapses 120 days after stopping therapy, while MDR led to TGI of ∼85% (p=0.001). Kaplan-Meier analysis of overall survival showed that the mice treated with MV and MVR had a statistically significant improvement in overall survival when compared with the control (p<0.0001) or MR (p=0.0043). Gene expression profiling (human HG-U133A) and confirmatory Western blotting of harvested tumors at the end of treatment (3 weeks) confirmed reactivation of cell cycle regulatory genes including PCNA, Aurora B, cyclin B1 and cyclin D1, in MV versus MVR. Moreover, MVR therapy continues to inhibit Aurora B by repressing genes regulating mitotic sister chromatid segregation by repressed gene expression analyzed by Gene Ontology. Thus, addition of R to MV represents a novel therapeutic strategy that warrants clinical trial evaluation in aggressive B-NHL [Funded by the Lymphoma SPORE 1 P50 CA 130805 01A1]. Disclosures: No relevant conflicts of interest to declare.

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Targeting Mir-548m-HDAC6 Axis Circumvents Stroma- Mediated Drug Resistance (CAM-DR) and Clonogenicity in Non-Hodgkin B-Cell Lymphomas

Blood ◽

10.1182/blood.v120.21.5094.5094 ◽

2012 ◽

Vol 120 (21) ◽

pp. 5094-5094

Author(s):

Tint Lwin ◽

Xiaohong Zhao ◽

Fengdong Cheng ◽

Xinwei Zhang ◽

Yizhuo Zhang ◽

...

Keyword(s):

Drug Resistance ◽

Lymph Node ◽

B Cell ◽

Conflicts Of Interest ◽

Ex Vivo ◽

Lymphoma Cell ◽

Histone Deacetylase 6 ◽

B Cell Lymphomas ◽

Non Hodgkin Lymphoma

Abstract Abstract 5094 A dynamic interaction occurs between the lymphoma cell and its microenvironment, with each profoundly influencing the behavior of the other. Here, we demonstrate that adhesion of mantle cell lymphoma (MCL) and other non-Hodgkin lymphoma cells to lymph node stromal cells, follicular dendritic cells (FDCs), confers drug resistance, enhances lymphoma cell clonogenicity, and is associated with induction of histone deacetylase 6 (HDAC6). Furthermore, stroma down-regulated miR-548m contributes to HDAC6 up-regulation, and HDAC6 is a key determinant for FDC-mediated lymphoma cell survival and colony formation. We further showed that stroma-mediated drug resistance and clonogenic growth are reversed by enforced expression of miR-548m and inhibition of HDAC6. The HDAC6-selective inhibitor tubastatin significantly enhances cell death, abolishes cell adhesion-mediated drug resistance, and suppresses clonogenicity and lymphoma growth suppression ex vivo and in vivo. Together, these data suggest that the lymphoma–stroma interaction in lymph node microenvironment directly impacts the biology of lymphoma through epigenetic regulation of miRNA and HDAC, with HDAC6 as a potential therapeutic target to overcome drug resistance in MCL and other B-cell lymphomas. Disclosures: No relevant conflicts of interest to declare.

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

Blood ◽

10.1182/blood.v120.21.4833.4833 ◽

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.

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Clinical Monoclonal B Lymphocytosis (cMBL), Chronic Lymphocytic Leukemia (CLL) and Small Lymphocytic Lymphoma (SLL): Diagnostic Criteria, Features At Diagnosis and Natural History

Blood ◽

10.1182/blood.v122.21.5273.5273 ◽

2013 ◽

Vol 122 (21) ◽

pp. 5273-5273

Author(s):

Rodrigo Santacruz ◽

Julio Delgado ◽

Tycho Baumann ◽

Maria Rozman ◽

Martha Aymerich ◽

...

Keyword(s):

Overall Survival ◽

Multivariate Analysis ◽

B Cells ◽

B Cell ◽

Cell Count ◽

Diagnostic Criteria ◽

Conflicts Of Interest ◽

Consistent Difference ◽

Transformation Rate ◽

Mutational Status

Abstract Introduction CLL, SLL and cMBL are considered to be part of the same spectrum of clonal expansions of CD5+ B cells. Clinically, the transition from one to another of these forms over time is a well recognized event. Diagnostic criteria to separate these disorders have been proposed (IWCLL, 2008; WHO, 2008). Aim To compare presenting and evolving features of three groups of patients with cMBL, Rai 0 CLL or SLL and to ascertain the usefulness of current diagnostic criteria for these disorders. Patients and Methods Retrospective study of clinical, biologic and evolving characteristics of patients diagnosed with cMBL, Rai 0 CLL or SLL according to current criteria (CLL: ≥5x109 clonal B cells/L in peripheral blood; SLL <5x109/L clonal B cells with lymphadenopathy, organomegaly, cytopenia or disease-related symptoms; cMBL <5x109 clonal B cells with no signs or symptoms). Results Baseline characteristics of the patients are shown in the Table. Median age was 68 years (range, 24-94) and 57% of patients were males. Out of 1,093 patients, 79 had cMBL (7.2%), 522 Rai 0 CLL (48%) and 94 SLL (8.6%). Overall, adverse biomarkers such as high LDH (p<0.001), high B2M (p<0.001), increased ZAP70 (p<0.001), high CD38 (p<0.001), unmutated IGHV status (p=0.002), +12 (p=0.02) and 11q- (p=0.01) were significantly more frequent in SLL. In subgroup analyses, the only difference between cMBL and Rai 0 CLL was a higher proportion of cases with mutated IGHV in cMBL (p=0.008). Furthermore, when SLL was compared to Rai I to IV CLL no differences were observed (data not shown). The actuarial risk for transformation from cMBL or SLL to CLL was 4.2% and 4.4 % per year (p=0.5), respectively. Median TTFT was significantly shorter in the SLL group (12 m.) than in Rai 0 CLL (174 m.) or cMBL (244 m.) (p<0.001). Median overall survival was also significantly shorter for SLL (94 m.) compared with Rai 0 CLL and cMBL (153 and 157 m., respectively) (p=0.028). Multivariate analysis of 695 patients (cMBL/Rai 0-CLL/SLL) revealed four variables independently correlated with shorter TTFT: diagnosis of SLL vs. Rai 0 CLL vs. cMBL (HR 2.28; p=0.008), high ZAP70 (HR 4.08; p<0.001), high CD38 (HR 4.68; p=0.001) and increased serum B2M levels (HR 1.54; p = 0.031). Importantly, however, when the multivariate analysis was restricted to patients with cMBL and Rai 0 CLL, variables correlated with TTFT were the clonal B-cell count (HR 3.76; p=0.01), ZAP70 (HR 3.31; p<0.001), and CD38 (HR 4.61; p=0.02). FISH cytogenetics, IGHV mutational status,NOTCH1 or SF3B1 mutations were not included in the analysis because of missing data. Conclusions Disparities in biologic and clinical features of cMBL, CLL and SLL mainly reflect the different tumor burden in this spectrum of CD5+ monoclonal B cell disorders. In this study, the transformation rate from either cMBL or SLL to CLL was around 4% per year. As a result of differences in tumor mass, the need for therapy was shorter in SLL than in Rai 0 CLL and cMBL, and the overall survival poorer. Biologically, the only consistent difference between cMBL and Rai O CLL was a higher proportion of mutated IGHV in cMBL. Clinically, however, no differences in median survival were observed. Moreover, the clonal B cell count was the most reliable predictor of disease outcome in both cMBL and Rai 0 CLL. Therefore, the distinction between cMBL and Rai 0 CLL seems hardly justified. Disclosures: No relevant conflicts of interest to declare.

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Spontaneous Mutations of Bcor and Jak1/2 genes Lead to an Aggressive Leukemia of B-1 Progenitor B Cells

Blood ◽

10.1182/blood.v124.21.3573.3573 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3573-3573

Author(s):

Sheryl M Gough ◽

Liat Goldberg ◽

Marbin Pineda ◽

Robert L Walker ◽

Yuelin J Zhu ◽

...

Keyword(s):

High Risk ◽

B Cell ◽

Progenitor Cell ◽

Conflicts Of Interest ◽

Fusion Gene ◽

Hot Spot ◽

Lymphoblastic Leukemia ◽

Hematologic Malignancies ◽

Janus Kinase ◽

Hematopoietic Stem

Abstract NUP98 gene fusions, generated by non-random chromosomal translocations, are associated with a wide spectrum of high risk hematologic malignancies and have been shown to alter normal hematopoietic stem and progenitor cell (HSPC) gene expression programs. A recurrent t(11;17)(p15;p13) translocation in patients with AML leads to the production of a NUP98–PHF23 (NP23) fusion gene. The consequent NP23 fusion protein retains the PHD domain, known to bind H3K4me3, and is thought to have aberrant chromatin regulation properties. We have generated a transgenic mouse model of the NUP98-PHF23 gene fusion which develops a range of hematologic malignancies, most commonly pre-T LBL and AML. However, approximately 10% of NP23 mice develop an aggressive B-1 progenitor acute lymphoblastic leukemia (pro B-1 ALL). B-1 and B-2 lymphocytes have distinct developmental pathways and are thought to represent arms of the innate and adaptive immune systems, respectively. Mature B-2 lymphocytes predominate in the peripheral circulation, and are characterized by expression of B220; whereas B-1 lymphocytes are more prevalent in the pleural and peritoneal cavities, and do not express B220. Murine B cell malignancies typically stain positive for B220, and represent transformed B-2 cells. In the present study, NP23 progenitor ALLs displayed an immunophenotype (Lin-B220- CD19+ AA4.1+) that was identical to that of the recently described B-1 progenitor cell. All B-1 progenitor ALLs exhibited clonal rearrangements of the IgH gene locus. Specifically, these rearrangements involve favored usage of 3’ VH regions, similar to observations with fetal B-1 progenitor cells, further supporting the notion that these are leukemias of B-1 progenitors. Using whole exome sequencing, we found acquired mutations in the BCL6 interacting corepressor (Bcor) gene in 5 out of 7 B-1 progenitor leukemias. The mutations were all frame shift or nonsense mutations, and were located within a 9 bp “hot spot” in Bcor exon 8. In addition, 4 of 7 cases had somatic mutations of Janus kinase 1 (Jak1) or 2 (Jak2), and 7/7 cases showed hyperphosphorylation of Stat3 or Stat5, consistent with the contention that the Jak1/2 mutations are activating mutations, and leading to a hypothesis that the NP23 pro B-1 ALLs which do not harbor Jak1/2 mutations may have acquired an unidentified mutation in the Jak-Stat pathway. Of note, Jak1/2 mutations have previously been identified in a subset of high-risk pediatric B-cell precursor ALL patients. The striking correlation between Bcor and Jak1/2 mutations, occurring specifically in a subset of NP23 leukemias, implies that these three mutations (NP23, Bcor, and Jak1/2) collaborate and provide the oncogenic setting for B-1 progenitor transformation. Disclosures No relevant conflicts of interest to declare.

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Clinicopathologic Characteristics and Outcome of Diffuse Large B-Cell Lymphomas Presenting With an Associated Low-Grade Component at Diagnosis

Journal of Clinical Oncology ◽

10.1200/jco.2006.07.5671 ◽

2006 ◽

Vol 24 (33) ◽

pp. 5234-5241 ◽

Cited By ~ 45

Author(s):

Hervé Ghesquières ◽

Françoise Berger ◽

Pascale Felman ◽

Evelyne Callet-Bauchu ◽

Paul-André Bryon ◽

...

Keyword(s):

Overall Survival ◽

B Cell ◽

De Novo ◽

Complete Response ◽

Progression Rate ◽

Low Grade ◽

Control Analysis ◽

B Cell Lymphomas ◽

Response To Chemotherapy ◽

Large B Cell

Purpose Some diffuse large B-cell lymphomas (DLBCL) present at diagnosis with associated morphologic features of small B-cell non-Hodgkin's lymphoma (NHL) and may arise from the transformation of a previously unknown indolent low-grade lymphoma. The characteristics and prognosis of these particular DLBCL are not well known. Patients and Methods The strict morphologic review of consecutive DLBCL patients diagnosed over 12 years in our department (Hematology Department, Centre Hospitalier Lyon-Sud, Lyon, France) allowed to retrieve 60 DLBCL that could be have occurred from the transformation of marginal zone B-cell NHL (32 patients), follicular NHL (22 patients), and small lymphocytic NHL (6 patients). We compared them to 180 matched patients of de novo DLBCL. Results Patients median age was 55 years and presented the following clinical characteristics: poor performance status in 33%, disseminated disease in 97%, more than one extranodal site in 50%, and increased lactate dehydrogenase level in 55%. Complete remission with multidrug chemotherapy regimens was achieved in 60% of the patients, but 48% relapsed: 28% with aggressive and 20% with indolent histology, respectively. Overall survival (OS) and freedom-from-progression rates at 5 years were 57% and 33%, respectively. The matched-control analysis showed that patients with transformed NHL at diagnosis had lower complete response to chemotherapy (P = .004) and higher progression rate (P = .03), whereas no difference was observed in OS (P = .21). Conclusion Compared to de novo DLBCL, transformed NHL at diagnosis have similar overall survival but lower complete response to initial treatment and higher risk of indolent relapses.

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