Secondary Malignancies in Mantle Cell Lymphoma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5596-5596
Author(s):  
Sandhya Talakokkla ◽  
Renuka Mahatara ◽  
Christine A Welch ◽  
Arun Nagarajan
Keyword(s):  
Pancreatic Cancer ◽  
B Cell ◽  
Mantle Cell Lymphoma ◽  
Conflicts Of Interest ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Secondary Malignancies ◽  
Increased Risk ◽  
Mantle Cell ◽  
Second Primaries

Abstract Background: Mantle cell lymphoma is a B cell lymphoma (CD5 +) which represents 5-10 % of Non-Hodgkin's lymphoma. Most patients have advanced disease at presentation and thus carry a poor prognosis. This type of uncommon malignant lymphoma has a distinct and recurring cytogenetic abnormality involving t(11, 14) q(13, 32). Although extra nodal involvement is common, not many cases of MCL having concomitant other malignancies are reported. We hypothesized that patients with MCL have chronic immunosuppression, comparable to chronic lymphocytic leukemia patients, and therefore are at risk for developing secondary malignancies similar to CLL patients. The aim of our study is to report the retrospective analysis of patients diagnosed with MCL and the associated secondary malignancies before or after the diagnosis of MCL. Patients and methods: The records of 41 patients who presented with MCL to "The David Lee Cancer Center" at CAMC, WVU with MCL from 2000 - 2015 were retrospectively reviewed. The number of other malignancies presenting before or after the diagnosis of MCL were analyzed. Results: The population with MCL was represented by 41, all Caucasian patients, which were 75.6% male (n = 31) and had an average age of 68.6 ± 11.3 years. Mean follow up for all patients was 23.9 ± 32.43 months. A total of 14.6% (n=6), 83.3% males, experienced a second primary. Within the second primaries 50.0% were GI cancers which included pancreatic cancer and cholangiocarcinoma while 16.7% were prostate cancer, diffuse large B-cell lymphoma or adenocarcinoma of lungs. The time to second primaries varied with 50% of the cases being diagnosed simultaneously with MCL, while 33.3% were diagnosed prior to MCL at an average time of 34.5 months, and 16.7% were diagnosed post MCL diagnosis at an average time of 18 months. Conclusion: Patients with MCL are typically CD5 positive, CD10 negative, and CD23 negative which make it different from other lymphomas like small cell lymphoma, B-cell CLL that are CD 23 positive. Rare cases of MCL may be CD5 negative or CD23 Positive. We hypothesized that MCL patients have an increased risk for developing secondary cancers due to their disease biology and from underlying chronic immunosuppression. Patients with MCL have twice the risk of developing secondary malignancies and an increased frequency of certain types of cancers such as cholangiocarcinoma & pancreatic cancer. Disclosures No relevant conflicts of interest to declare.

Analysis of Mantle Cell Lymphoma Patients Reveals Novel Regulatory Circuits Involving MicroRNAs and Their Targets

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4624-4624
Author(s):  
Vojtech Kulvait ◽  
Vit Pospisil ◽  
Karin Vargova ◽  
Marek Trneny ◽  
Pavel Klener ◽  
...  
Keyword(s):  
B Cell ◽  
Mantle Cell Lymphoma ◽  
Target Gene ◽  
Zinc Finger Protein ◽  
Conflicts Of Interest ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Differentially Expressed ◽  
Regulatory Pathways ◽  
Mantle Cell

Abstract Abstract 4624 Mantle cell lymphoma (MCL) represents B-cell lymphoma derived from the mantle zone that surrounds normal germinal center follicles. Pathophysiology of this hardly curable disease involves t(11,14)(q13,q32) translocation which leads to upregulation of Cyclin D1(CCND1). Recently, microRNAs were demonstrated to significantly modify MCL pathogenesis (Jian-Jun Zhao et al. 2010) and therapy responsiveness (Jiang et al. 2010). In order to broaden our knowledge of regulatory pathways in MCL we searched for differentially expressed microRNAs and their differentially expressed mRNA targets between MCL samples and control samples. Samples consist of magnetically separated B cells derived from peripheral blood. We used 1) Microarray mRNA hybridization [Affymetrix Human Genome U133 Plus 2.0 Array, N(MCL)=5, N(control)=5] and 2) microRNA profiling [TaqMan® Array Human MicroRNA Card A v2.0 technology, N(MCL)=5, N(control)=5] followed by statistical analysis [limma (Smyth 2005)]. Differentially regulated targets of the deregulated microRNAs were selected from the databases involving both predicted (Betel et al. 2007) or confirmed (Hsu et al. 2010) target mRNAs. Among the most significant upregulated microRNAs (exceeding 10 fold) are miR-9, miR-124 and miR-183. We have found that upregulated miR-9 has confirmed downregulated target gene PRDM1 (PR domain zinc finger protein 1) which plays a role in B cell maturation (Turner et al. 1994) and may act as a tumor suppressor (Pasqualucci et al. 2006). Upregulation of miR-9 and downregulation of its targets was recently demonstrated in Burkitt lymphoma (Onnis A et al. 2010) and Hodgkin lymphoma (Nie K et al. 2008). Two additional upregulated microRNAs, miR-124 and miR-183, yet not associated with lymphomas, have downregulated target gene Integrin beta-1 (CD29) which regulates survival (Fukumori et al. 2003). Among most significant downregulated microRNAs is miR-101 (FC=-7). Downregulated microRNA miR-101 has known oncogene N-Myc (MYCN) as upregulated confirmed target and DNA (cytosine-5)-methyltransferase 3A (DNMT3A) as upregulated target. Overexpression of a well known hematopoietic oncogene MYCN and epigenetic repressor DNMT3A may represent additional pathogenesis-related factors in MCL. Our data support importance of the candidate mechanisms involving microRNAs and their target programs in pathogenesis of MCL. They are currently extended on a larger patient cohort by analyzing expression and functional significance of the candidate microRNAs. (Grants: NT10310-3/2009, MPO FR-TI2/509, NPVII 2B06077, MSM 0021620806, LC 06044, SVV-2011-262507). Disclosures: No relevant conflicts of interest to declare.

Mantle Cell Lymphoma

1999 ◽  
Vol 123 (12) ◽  
pp. 1182-1188 ◽  
Author(s):  
Rebecca C. Hankin ◽  
Susan V. Hunter
Keyword(s):  
Polymerase Chain Reaction ◽  
B Cell ◽  
Mantle Cell Lymphoma ◽  
Diagnostic Tests ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Molecular Diagnostic ◽  
Chain Reaction ◽  
Mantle Cell ◽  
Polymerase Chain

Abstract Objective.—This article summarizes the most useful ancillary immunohistochemical and molecular assays for use in the diagnosis of mantle cell lymphoma. Data Sources.—The English language literature was surveyed, with an emphasis on recent publications, for articles presenting key advances in the molecular characterization of mantle cell lymphomas and for series of cases testing the utility of molecular diagnostic tests. The authors' series of 26 small B-cell lymphomas, analyzed for the cyclin D1 protein by paraffin immunohistochemistry and for t(11;14) by polymerase chain reaction, is included. Conclusions.—Mantle cell lymphoma, a B-cell lymphoma now recognized in the 1994 Revised European-American Classification of Lymphoid Neoplasms (REAL) classification, is a relatively aggressive lymphoma with a poor prognosis. Its characteristic t(11;14)(q13;q32) translocation has a role in oncogenesis and has been exploited for molecular diagnostic tests, but these tests vary in sensitivity, specificity, and ease of use. Improved immunohistochemical tests are sufficient to confirm the diagnosis in most cases. Conventional cytogenetics and molecular diagnostic tests for t(11;14)—Southern blot and polymerase chain reaction analysis—may be helpful in selected cases, but are laborious or of limited sensitivity. Other methods, such as fluorescence in situ hybridization, need further development to provide faster, more sensitive diagnosis.

scholarly journals Retreatment with bendamustine in patients with relapsed/refractory indolent B-cell lymphoma and mantle cell lymphoma

2016 ◽  
Vol 27 ◽  
pp. vii86
Author(s):  
Toshiki Yamada ◽  
Yuhei Shibata ◽  
Nobuhiko Nakamura ◽  
Jun-ichi Kitagawa ◽  
Senji Kasahara ◽  
...  
Keyword(s):  
B Cell ◽  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Mantle Cell

scholarly journals The anaphase-promoting complex/cyclosome: a new promising target in diffuse large B-cell lymphoma and mantle cell lymphoma

2019 ◽  
Vol 120 (12) ◽  
pp. 1137-1146 ◽  
Author(s):  
Anke Maes ◽  
Ken Maes ◽  
Hendrik De Raeve ◽  
Eva De Smedt ◽  
Philip Vlummens ◽  
...  
Keyword(s):  
B Cell ◽  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Anaphase Promoting Complex ◽  
Large B Cell Lymphoma ◽  
Promising Target ◽  
Mantle Cell ◽  
Large B Cell

SOX11 is useful in differentiating cyclin D1-positive diffuse large B-cell lymphoma from mantle cell lymphoma

2012 ◽  
Vol 61 (4) ◽  
pp. 685-693 ◽  
Author(s):  
Shih-Chuan Hsiao ◽  
Inmaculada Ribera Cortada ◽  
Luis Colomo ◽  
Hongtao Ye ◽  
Hongxiang Liu ◽  
...  
Keyword(s):  
B Cell ◽  
Cyclin D1 ◽  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Large B Cell Lymphoma ◽  
Mantle Cell ◽  
Large B Cell

Rituximab Maintenenance Therapy in CD20+ B-Cell Non-Hodgkin-Lymphoma – Final Results of a Multicenter Prospective Randomised Phase II Study.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1707-1707
Author(s):  
Mathias Witzens-Harig ◽  
Axel Benner ◽  
Michael Rieger ◽  
Fabienne McClanahan ◽  
Manfred Hensel ◽  
...  
Keyword(s):  
Maintenance Therapy ◽  
B Cell ◽  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Large Cell ◽  
Observation Group ◽  
Who Grade ◽  
Rituximab Maintenance ◽  
Mantle Cell

Abstract Abstract 1707 Poster Board I-733 Background Clinical and pharmacokinetic data suggest that the effect of rituximab could be improved by prolonged exposure to the drug. To test for this hypothesis we performed a prospective randomized trial of rituximab maintenance therapy in patients (pts) with CD20+ B-cell Non-Hodgkin-Lymphoma. Methods After completion of standard treatment pts with CD20+ B-cell lymphoma were randomized to either observation or maintenance therapy with rituximab (375 mg/m2) administered every 3 months for 2 years. Both pts after first line therapy and pts after relapse treatment were included in the study. Pts with aggressive lymphoma were enrolled if they had achieved a complete response (CR) after initial treatment. Pts with aggressive lymphoma with residual tumor mass underwent positron emission tomography (PET) and qualified for randomization if this examination showed no signs of tumor activity. Pts with indolent lymphoma were eligible for the study if at least a partial response (PR) was achieved. Primary endpoint of the study was event free survival (EFS), secondary endpoints were relapse rate (RR), relapse free survival (RFS) and overall survival (OS). EFS and OS were analysed using an asymptotic logrank test, RFS using a competing risk model and RR using Fisher's exact test. Results After recruitment of 171 pts the planned final analysis was performed on an intention to treat basis. Complete data sets of 163 pts were evaluable. 91 (62%) pts were male, median age was 58 years, 130 pts (80%) hat one previous therapy, 27 pts (17%) 2 previous therapies, 4 pts (2%) 3 previous therapies and 1 pt (1%) 4 previous therapies. At study entry, 120 pts (74%) were in CR, 2 pts (2%) in unconfirmed CR and 41 pts (25%) in PR. Histological subtypes included diffuse large cell lymphoma (67 pts), follicular lymphoma (35 pts), mantle cell lymphoma (18 pts), primary mediastinal lymphoma (16 pts), marginal zone lymphoma (7 pts), Burkitt's lymphoma (5 pts), and other lymphomas (15 pts). Age, sex, number of previous therapies, remission state and diagnoses were well balanced between the rituximab maintenance and the observation group (p>0.05). After a median follow up of 28 months, EFS (HR 0.50, 95% CI 0.23-1.09, p=0.037,) and RFS (HR 2.52, 95% CI 1.11-5.70 p=0.03) were superior for the maintenance group. In regards to diagnostic subgroups, EFS was in particular prolonged in pts with mantle cell lymphoma (p=0.055, one sided logrank test) and to a lesser extent in pts with follicular lymphoma (p=0.16) and diffuse large cell B cell lymphoma (p=0.18). Relapse occurred more often in the observation group than in the treatment group, however this effect was not significant (relapse rate observation group/treatment group = 2.31, 95% CI 0.86-6.75, p=0.08). There was no difference in OS between the two groups (p=0.74). Maintenance therapy was generally well tolerated: in 5 pts a WHO Grade 3 toxicity event occurred, which were arrhythmia, neuropathy, leucopenia (n=1 each) and infections (n=2). In one pt two WHO Grade 3 toxicities were observed (pain and infection). Conclusion Rituximab maintenance therapy is feasible, safe and well tolerated and improves EFS in patients with CD20+ B-cell lymphoma. In this analysis, the benefit of rituximab maintenance was particularly striking in patients with mantle cell lymphoma. This study has been continued with an amendment including additional pts with mantle cell and diffuse large cell lymphoma. Disclosures No relevant conflicts of interest to declare.

Combination Anti-CD74 (Milatuzumab) and CD20 (Rituximab) Monoclonal Antibody Therapy Has in Vitro and in Vivo Activity in Mantle Cell Lymphoma

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 886-886 ◽  
Author(s):  
Lapo Alinari ◽  
Erin Hertlein ◽  
David M. Goldenberg ◽  
Rosa Lapalombella ◽  
Fengting Yan ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
B Cell ◽  
Mantle Cell Lymphoma ◽  
Cell Lines ◽  
Combination Treatment ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Preclinical Model ◽  
Mantle Cell

Abstract Mantle cell lymphoma (MCL) is an incurable B-cell malignancy and patients with this disease have limited therapeutic options. Despite the success of Rituximab in treatment of B-cell malignancies, its use as a single agent or in combination with chemotherapy in MCL has demonstrated modest activity; thus, novel strategies are needed. CD74 is an integral membrane protein expressed on malignant B cells and implicated in promoting survival and growth, making it an attractive therapeutic target. The humanized anti-CD74 monoclonal antibody (mAb), Milatuzumab, (Immunomedics) has shown promising preclinical activity against several human B-cell lymphoma cell lines, but has not been studied in MCL. Since Rituximab and Milatuzumab target distinct antigens lacking known association, we explored a combination strategy with these mAbs in MCL cell lines, patient samples, and in a preclinical model of MCL. Flow cytometric analysis shows that the MCL cell lines Mino and JeKo, and MCL patient tumor cells, express abundant surface CD74 compared to the CD74-negative cell line, Jurkat. Incubation of Mino and JeKo cells with immobilized (goat anti-human IgG) Milatuzumab (5 μg/ml) resulted in mitochondrial depolarization and significant induction of apoptosis determined by Annexin V/PI and flow cytometry (apoptosis at 8hr=38.3±0.85% and 25.4±2.6%; 24hr=73.6±3.47% and 36±3.57%; 48hr=84.9±3.91% and 50.4±4.17%, respectively, compared to Trastuzumab (control). Expression of surviving cells from anti-CD74-treated MCL cells consistently demonstrated marked induction of surface CD74 (MFI 762) compared to control (MFI 6.1). Incubation with immobilized Rituximab (10 μg/ml) resulted in 39.5±2.5% and 37.1±8.35% apoptotic events at 8hr, 58.8±3.14%, 41.2±8.27% at 24hr, and 40.1±1.3% and 45.6±3.25% at 48hr, respectively. Combination treatment of Mino and JeKo cells with Milatuzumab and Rituximab led to significant enhancement in cell death, with 77.6±3.95% and 79.6±2.62% apoptosis at 8hr in Jeko and Mino cells (P=0.0008 and P=0.00004 vs. Milatuzumab alone; P=0.00015 and P=0.001 vs. Rituximab alone); 90.4±3.53% and 76.6±4.3% at 24hr, respectively (P=0.0042 and P=0.0002 vs. Milatuzumab, P=0.0003 and P=0.0027 vs. Rituximab alone); 92.8±0.77% and 85.6±2.62% at 48hr, respectively (P= 0.026 and P=0.0002 vs. Milatuzumab alone, P=0.0000005 and P=0.00008 compared to Rituximab alone, respectively). To examine the in vivo activity of Rituximab and Milatuzumab, a preclinical model of human MCL using the SCID (cb17 scid/scid) mouse depleted of NK cells with TMβ1 mAb (anti-murine IL2Rb) was used. In this model, intravenous injection of 40×106 JeKo cells results in disseminated MCL 3–4 weeks after engraftment. The primary end-point was survival, defined as the time to develop cachexia/wasting syndrome or hind limb paralysis. Mice were treated starting at day 17 postengraftment with intraperitoneal Trastuzumab mAb control (300 μg qod), Milatuzumab (300 μg qod), Rituximab (300 μg qod), or a combination of Milatuzumab and Rituximab. The mean survival for the combination-treated group was 55 days (95%CI:41, upper limit not reached as study was terminated at day 70), compared to 33 days for Trastuzumab-treated mice (95% CI:31,34), 35.5 days for the Milatuzumab-treated mice (95% CI:33,37), and 45 days for the Rituximab-treated mice (95%CI:30,46). The combination treatment prolonged survival of this group compared to Trastuzumab control (P=0.001), Milatuzumab (P=0.0006) and Rituximab (P=0.098). No overt toxicity from Milatuzumab or the combination regimen was noted. A confirmatory study with a larger group of mice and detailed mechanistic studies are now underway. These preliminary results provide justification for further evaluation of Milatuzumab and Rituximab in combination in MCL.

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