Prolonged Lymphocytepenia after Bendamustine with or without Rituximab Treatment in Patients with Relapsed or Refractory Indolent B-Cell and Mantle Cell Lymphoma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3066-3066 ◽  
Author(s):  
Hideaki Saito ◽  
Dai Maruyama ◽  
Akiko Miyagi Maeshima ◽  
Shin-ichi Makita ◽  
Hideaki Kitahara ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
Research Funding ◽  
Marginal Zone ◽  
Cell Lymphoma ◽  
Median Number ◽  
Marginal Zone Lymphoma ◽  
Cell Counts ◽  
Mantle Cell

Abstract Introduction: Although bendamustine with or without rituximab has demonstrated remarkable efficacy in patients with relapsed or refractory indolent B-cell lymphoma (B-NHL) and mantle cell lymphoma (MCL), previous reports showed that the incidence of lymphocytopenia was higher in patients receiving bendamustine with or without rituximab than in those receiving other conventional cytotoxic chemotherapies such as R-CHOP regimen. However, the length of time until recovery of the decreased lymphocytes and CD4-positive T cells to the baseline upon bendamustine treatment is still unclear. Patients and Methods: We retrospectively analyzed 56 consecutive patients with relapsed or refractory B-NHL and MCL who received bendamustine with or without rituximab at our institution between 2011 and 2014. We analyzed their peripheral blood lymphocytes and CD4-positive T-cell counts at baseline, during, and after bendamustine treatment, the details of infectious events, and their correlations. Results: Thirty-one (55%) patients were male and 25 (45%) female, with a median age of 63 years (range: 36-86). Twenty (35%) patients had follicular lymphoma, 14 (25%) MCL, nine (16%) transformed lymphoma, five (9%) extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue, four (7%) small lymphocytic lymphoma, two (4%) nodal marginal zone lymphoma, and one (2%) each had lymphoplasmacytic lymphoma and low-grade B-NHL, unclassifiable. The median number of prior regimens administered was two (range: 1-9). Twenty-three (41%) of the 56 patients received rituximab in combination with bendamustine. The median number of bendamustine cycles was four (range: 1-6). The median follow-up period was nine months (range: 0-33 months). At baseline, median lymphocyte and CD4-positive T-cell counts were 1,025/µL (range: 270-3,420/µL) and 282/µL (range: 83-645/µL), respectively. After the first cycle, they immediately decreased to 545/µL (range: 60-2,900/µL) and 190/µL (range: 116-635/µL), respectively. The median lymphocyte and CD4-positive T-cell count nadirs during observation were 365/µL (range: 20-1,310/µL) and 93/µL (range: 7-178/µL), respectively. Significantly decreased lymphocyte counts (median: 260 vs. 410/µL) were detected in the patients who received bendamustine with rituximab compared with those who received bendamustine alone (p=0.03). Recovery of lymphocyte and CD4-positive T-cell counts to those at baseline was observed at 7-9 months after the completion of bendamustine with or without rituximab, and median lymphocyte and CD4-positive T-cell counts were 1,045/µL (range: 170-2,580/µL) and 223/µL (range: 47-709/µL), respectively (Figures A, B). The numbers of patients who received prophylaxis against pneumocystis pneumonia (PCP), varicella zoster virus (VZV), and fungal infection were 44 (78%), 37 (66%), and four (7%), respectively, at the physician's discretion. Infectious events were observed in 32 (57%) patients during follow-up. Cytomegalovirus antigenemia was detected in 15 (27%) patients, VZV infection in two (3%), cytomegalovirus colitis in one (2%), and other infectious complications such as sepsis or febrile neutropenia in 20 (35%) patients. Interestingly, all infectious events occurred within nine months after the completion of bendamustine with or without rituximab in patients who received no treatment after bendamustine during follow-up. Conclusion: The results of this analysis revealed that the majority of relapsed or refractory patients with indolent B-NHL and MCL showed prolonged lymphocytopenia and low CD4-positive T-cell counts, for at least 7-9 months, after the completion of bendamustine with or without rituximab. Because lymphocytopenia, especially low CD4-positive T-cell counts, may increase the risk of opportunistic infections, the prophylaxis against PCP and VZV deserves consideration for at least 7-9 months after bendamustine treatment. Further investigations, especially a prospective study, are needed to confirm our results. Figure A: Figure A:. Figure B: Figure B:. Box plots of lymphocyte counts (Figure A) and CD4-positive T-cell counts (Figure B) among patients who were treated with bendamustine with or without rituximab. Disclosures Maruyama: Eisai Co., Ltd: Honoraria. Kobayashi:Boehringer Ingelheim GmbH: Research Funding; ARIAD Pharmaceuticals, Inc.: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Research Funding. Tobinai:Eisai Co., Ltd.: Research Funding; SymBio Pharmaceuticals Ltd.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding; Zenyaku Kogyo Co., Ltd.: Research Funding.

The PIG-A Gene Is Hypermutable in Lymphoid Neoplasms.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2395-2395
Author(s):  
Kimberly DiTata ◽  
David J. Araten
Keyword(s):  
T Cell ◽  
Cell Survival ◽  
Genomic Instability ◽  
Mutation Rate ◽  
Marginal Zone ◽  
Cell Lymphoma ◽  
Marginal Zone Lymphoma ◽  
Cell Divisions ◽  
Flow Cytometric ◽  
Mantle Cell

Abstract In neoplasms, the presence of chromosomal abnormalities and point mutations is suggestive of genomic instability, but could also be a consequence of selection. While genomic instability may increase the chances that a malignant population acquires adaptive mutations, extremely high mutation rates may not be compatible with cell survival. To investigate the role of genomic instability in lymphoid neoplasms, we have applied a new method for the quantification of the human mutation rate, using the PIG-A gene as a sentinel. PIG-A is essential for the biosynthesis of glycosylphosphatidylinositol (GPI) and is mutated in blood cells of patients with Paroxysmal Nocturnal Hemoglobinuria. A broad range of mutations can produce the GPI (−) phenotype, and because PIG-A is on the X-chromosome, the effect of a single mutation is detectable. Since a host of proteins require GPI for attachment to the cell surface, rare mutants are readily detected by flow cytometry. We have previously shown that PIG-A mutations arise spontaneously in normal donors, and we determined that the mutation rate in normal B cell lines ranges from 2 to 29 per 107 cell divisions. Here we analyzed cell lines derived from: a transformed low grade lymphoma harboring a t(14;18) translocation; a mantle cell lymphoma harboring a t(11;14) translocation; a marginal zone lymphoma; and T cell ALL. Cells were first stained with an antibody specific for CD59 (a representative GPI-linked protein) and pre-existing GPI (−) cells were eliminated from the population by flow cytometric sorting, by gating on the upper 50th percentile of the distribution curve. The collected GPI (+) cells were then returned to culture and the number of cell divisions (d) determined by cell counts. After 3–4 weeks, the frequency (f) of new mutants arising in culture was determined by flow cytometric analysis of a large number of cells (median 2.3 x 106). Cells were stained simultaneously with antibodies specific for at least 3 GPI-linked proteins (e.g. CD48, CD52, CD55, and CD59) as well as a transmembrane protein (e.g. HLA-DR or CD45) to identify live cells. FLAER and proaerolysin-- which bind to GPI-- were used to confirm the phenotype. The frequency of mutants was determined by the number of GPI(−) cells divided by the number of GPI(+) cells analyzed, and the mutation rate (μ) was calculated with the formula μ = f ÷ d. We demonstrated a high mutation rate in 3 out of the 4 cells lines: 1750 x 10−7 (transformed lymphoma), 335 x 10−7 (mantle cell lymphoma), 112 x 10−7 (T cell ALL). Of note, the mutation rate was normal (4 x 10−7) in the marginal zone lymphoma—consistent with this being an indolent neoplasm. These data support the hypothesis that an elevated mutation rate is part and parcel of aggressive neoplasms and demonstrate that a 2-log elevation in this parameter is compatible with cell survival. With this model, it may be possible to predict the development of mutations that confer chemotherapy drug resistance.

scholarly journals A clinical analysis of two indolent lymphoma entities: mantle cell lymphoma and marginal zone lymphoma (including the mucosa-associated lymphoid tissue and monocytoid B-cell subcategories): a Southwest Oncology Group study

Blood ◽  
1995 ◽  
Vol 85 (4) ◽  
pp. 1075-1082 ◽  
Author(s):  
RI Fisher ◽  
S Dahlberg ◽  
BN Nathwani ◽  
PM Banks ◽  
TP Miller ◽  
...  
Keyword(s):  
Overall Survival ◽  
B Cell ◽  
Marginal Zone ◽  
Cell Lymphoma ◽  
Marginal Zone Lymphoma ◽  
Indolent Lymphoma ◽  
Free Survival ◽  
Mantle Cell ◽  
Monocytoid B Cell ◽  
Working Formulation

The objectives of this study were (1) to determine the clinical presentation and natural history associated with two newly recognized pathologic entities termed mantle cell lymphoma (MCL) and marginal zone lymphoma (MZL), including the mucosa-associated lymphoid tissue (MALT) and monocytoid B-cell subcategories, and (2) to determine whether these entities differ clinically from the other relatively indolent non- Hodgkin's lymphomas with which they have been previously classified. We reviewed the conventional pathology and clinical course of 376 patients who had no prior therapy; had stage III/IV disease; were classified as Working Formulation categories A, B, C, D, or E; and received cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) on Southwest Oncology Group (SWOG) studies no. 7204, 7426, or 7713. All slides were reviewed by the three pathologists who reached a consensus diagnosis. Age, sex, performance status, bone marrow and/or gastrointestinal involvement, failure-free survival, and overall survival were compared among all the categories. We found that (1) MCL and MZL each represent approximately 10% of stage III or IV patients previously classified as Working Formulation categories A through E and treated with CHOP on SWOG clinical trials; (2) the failure-free survival and overall survival of patients with MZL is the same as that of patients with Working Formulation categories A through E, but the failure-free survival and overall survival of the monocytoid B-cell patients were higher than that of the MALT lymphoma patients (P = .009 and .007, respectively); and (3) the failure-free survival and overall survival of patients with MCL is significantly worse than that of patients with Working Formulation categories A through E (P = .0002 and .0001, respectively). In conclusion, patients with advanced stage MALT lymphomas may have a more aggressive course than previously recognized. Patients with MCL do not have an indolent lymphoma and are candidates for innovative therapy.

SELDI-TOF Identifies Specific Protein Patterns in Small Lymphocytic Lymphoma, Marginal Zone Lymphoma and Mantle Cell Lymphoma.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 988-988
Author(s):  
Delphine Rolland ◽  
Ali Bouamrami ◽  
Benoit Ballester ◽  
Samuel Grangeaud ◽  
Marie Arlotto ◽  
...  
Keyword(s):  
Lymph Nodes ◽  
B Cell ◽  
Mantle Cell Lymphoma ◽  
Marginal Zone ◽  
Cell Lymphoma ◽  
Recursive Partitioning ◽  
Marginal Zone Lymphoma ◽  
Small Lymphocytic Lymphoma ◽  
Protein Patterns ◽  
Mantle Cell

Abstract Non-germinal centre small B-cell lymphomas represent a heterogeneous group of non-hodgkin lymphomas which most frequent histologic subtypes are small lymphocytic lymphoma (SLL), marginal zone lymphoma (MZL) and mantle cell lymphoma (MCL). These three lymphoma entities have very different clinical outcomes but may be difficult to distinguish either histologically or clinically. We previously identified transcriptomic signatures specific of these 3 lymphoma subtypes. We further analyzed these lymphomas using Surface-Enhanced Laser Desorption/Ionisation Time of Flight (SELDI-TOF). A total of 58 tumors, including 20 SLL (all lymph nodes), 20 MZL (1 lymph node and 19 spleens) and 18 MCL (19 lymph nodes and 1 spleen) were analyzed. In addition, we included 7 controls obtained from traumatic normal spleens. The spectra were generated on weak cation exchange (CM10), strong anion exchange (Q10) and reversed-phase (H50) ProteinChip arrays. Protein patterns of all samples were comparatively analysed using two distinct strategies. We first used a binary recursive partitioning method with the Biomarker Pattern software (Ciphergen®), and second a hierarchical clustering method to visualized patterns of protein peaks completed with a supervised method (discriminating score) to point out individual peaks distinguishing the three histological subtypes (SLL, MZL and MCL). Spectra analyses revealed a very homogeneous protein patterns among all lymphoma samples. However specific SLL, MZL and MCL signatures based on 34 protein peaks with differential expression could be identified and allowed to classify 95% of the samples in their respective entity. SLL signature included 9 peaks, MZL signature 16 peaks and MCL signature 9 peaks. The binary recursive partitioning analysis was concordant but identified only the five most discriminant peaks. Further identification of the discriminating peaks is currently realized using SELDI-assisted purification. We are focusing on peaks at 9942 Da for SLL and at 11324 Da for MCL. Functional genomic studies can distinguish non-germinal small B-cell lymphomas at the transcriptomic level (our previous study) and at the proteomic level. This will provide new markers for diagnosis and potentially new therapeutic targets.

Non Hodgkin Lymphoma (NHL) Distribution and Clinical Characteristics in a Mexican Registry with High Frequency of T Cell NHL: A Descriptive Study on Behalf of Mexican Hematology Study Group (MHSG).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4407-4407
Author(s):  
Gregorio Ignacio ◽  
Francisco Tripp ◽  
Petty Rodríguez ◽  
Mario Martínez ◽  
Concepción Martínez ◽  
...  
Keyword(s):  
T Cell ◽  
High Risk ◽  
B Cell ◽  
Marginal Zone ◽  
Cell Lymphoma ◽  
Prognostic Index ◽  
B Cell Lymphoma ◽  
Risk Groups ◽  
T Cell Lymphomas ◽  
Mantle Cell

Abstract Background: Among the NHL, B Cells NHL are more frequent than T Cells NHL (6%) as described in USA & European reports. The highest frequencies of T Cell NHL have been reported in Japan with 9% and India with 12%. In a Mexican retrospective study we found a T Cell NHL frequency of 13%. Objective: To corroborate the patterns and frequency of B and T cell lymphomas in Mexico. Methods: The registry of lymphoid neoplasms was created based on the WHO classification. The Lymphoma subtype analysis was prepared in two periods: retrospectively from 2002 to December 2005 and prospectively from January to December 2006. The data recorded were: age, sex, cell type (B o T), NHL frequency, primary site, stage and prognostic index (IPI and FLIPI). Results: In the first group 2375 Lymphomas were included: 2122 B Cell NHL (89.34%) and 253 T-cell lymphomas 253 (10.6%). B-cell NHL: gender 55.17% male and 44.66 female, median age of 55.21 years Age >60 years 45.7%; 62% III–IV stage. After applying the FLIPI index, the patients were divided into three risk groups: low (8.4% of cases), intermediate (81%), and high (10.6%). The distribution of patients in IPI risk groups was 15.7%, 76%, and 8.3% of cases classified as low, intermediate, and high risk The frequencies of B cell lymphoma were: 49% DLBCL, 15% Follicular Lymphoma, 5.35% CLL/SLL, 1.6% Mantle cell Lymphoma, 0.9% Follicular Center Lymphoma, 1.6% Marginal Zone B Lymphoma, 6.1% MALT, 1.6% Burkitt Lymphoma. T cell lymphomas were distributed in: Peripheral T Cell 253 (46.36%), Cutaneous Anaplastic 42 (16.09%), T/NKcell 35 (13.40%), Lymphoblastic 28 (6.16%), T non classifiable 10 (3.83%). The second group included 344 lymphomas; 309 (89.82%) B Cell NHL and 31 (10.01%) T cell Lymphomas. Gender 51.7 male and 48.3 female, medium age 57.79 years (SD 16.09); . >60 years 44%. After applying the FLIPI index the distribution of patients was 24.5% with intermedium risk and 9.5.8% high risk. Patients were divided into three IPI risk groups: Low 69.2% Intermediate 23% and high risk 7.8%. The frequencies of B cell lymphomas subtype were: DLBCL 168 (52.3%), Follicular 58(18.4%), CLL/SLL 19 (6.14%), Mantle Cell 10 (3.2%), Follicle Center Lymphoma (0.9%), Marginal Zone B 4 (1.2%), MALT 14 (4.5%), Burkitt’s Lymphoma 5 (1.6%). The T Cell Lymphoma subgroup frequencies were: T Cell Peripheral 7 (22.5%), Cutaneous Anaplastic 5 (16.1%), N/K cell 4 (12.9), Lymphoblastic 3 (9.6%), T lymphoma non classifiable 6 (19%). Conclusions: We confirmed a high incidence of T cell NHL in consecutive registries in Mexico. In the B cell subgroup it seems to be a difference where the DLBCL has a higher frequency and the CLL/SLL subgroup the lowest compared with other series. These differences in frequency might be explained by ethnic characteristics, however we need more epidemiological and viral studies, looking for Epstein Barr virus.

scholarly journals Outcomes, Causes of Discontinuation and Mutation Profile of Patients with Mantle Cell Lymphoma Who Progressed on Acalabrutinib

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4151-4151 ◽  
Author(s):  
Preetesh Jain ◽  
Rashmi Kanagal-Shamanna ◽  
Shaojun Zhang ◽  
Chi Young Ok ◽  
Makhdum Ahmed ◽  
...  
Keyword(s):  
Disease Progression ◽  
Board Of Directors ◽  
Copy Number ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Median Number ◽  
Copy Number Alterations ◽  
Advisory Committees ◽  
Mantle Cell

Abstract Introduction: Acalabrutinib is a Bruton tyrosine kinase (BTK) inhibitor approved for treatment of relapsed patients (pts) with mantle cell lymphoma. We have reported previously that ibrutinib refractory MCL pts have poor survival. However, outcomes, causes of discontinuation, management and the genomic landscape of MCL in pts who discontinued acalabrutinib are rarely reported. Method: We reviewed charts from all MCL pts treated with single agent acalabrutinib (n=28) in the relapsed setting and identified 15 pts who discontinued acalabrutinib and who are described in this analysis. Outcome after discontinuing acalabrutinib is reported. Whole-exome sequencing (WES) with SureSelect Human All Exon V6 was performed on 10 tumor specimens and 5 matched germline samples collected from 9 pts whose MCL progressed on acalabrutinib; among these pts 4 tumors were collected at baseline and 6 were collected after disease progression. One patient had sufficient DNAs available for both time points (baseline and progression). Results: The median duration on treatment with acalabrutinib was 6.5 months (1 to 29 months) and the median number of cycles of acalabrutinib treatment was 6 (range, 1-30). Seven pts had complete remission (CR) as their best response on acalabrutinib, 5 were primary refractory and 3 achieved partial remission. In 12 pts (80%) acalabrutinib was discontinued due to disease progression (2 pts transformed from classic to blastoid and pleomorphic type at progression) and 3 pts were discontinued due to intolerance (one for fatigue and idiopathic encephalopathy, one due to unrelated severe aortic stenosis and another for cytopenias secondary to therapy related myelodysplasia; all three pts were in CR). Nine pts had classic and 3 pts each had blastoid or pleomorphic features before starting acalabrutinib. Overall, median Ki-67 expression was 50% (range, 5-100) and all pts had high a MIPI score. The median number of prior treatments was 1 (range, 1-3); all chemo-immunotherapy (10 pts were previously treated with rituximab-hyper-CVAD) and none with ibrutinib. Two pts who transformed on acalabrutinib received acalabrutinib for a median duration of 12 months (range, 8-16.5). Median follow up after discontinuation was 27 months and the median survival was 25 months (26 months for progression and 1.5 months for intolerance; p <0.001, Figure-1A). Patients who discontinued due to intolerance did not get subsequent treatment for MCL. Among the 12 pts who progressed on acalabrutinib, 11 pts received systemic therapy for MCL [seven received ibrutinib based therapies (2 non responders, 3 achieved CR and 2 were PR and all pts progressed subsequently), 3 got chemo-immunotherapy and progressed and one pt did not receive any treatment and was lost to follow up and died. Six patients received a clinical trial with CAR-T cells (results will be reported separately). Overall, at the time of last follow up, 8 pts were alive and 7 were in CR. Recurrently mutated genes in these tumors included ATM (6/10; 60%), TP53 (4/10; 40%), KMT2C (3/10), MYCN (2/10), NOTCH1 (2/10), NOTCH3 (2/10), and MEF2B (2/10) (Fig. 1B). We did not detect any mutation or copy number alterations in BTK, PLCG2, TRAF2/3 and MYD88 that have been reported previously to be associated with ibrutinib resistance. Compared to tumors at baseline, ATM was mutated at a higher frequency in samples at progression (67% vs. 50%; p=NS). To investigate the mutation evolution on acalabrutinib treatment, mutation profiles, particularly the mutation variant allelic fractions (VAFs), were compared between the baseline and progression samples from pt-1 (Fig. 1C). Mutation of MYCN, MEF2B, ATM, and NOTCH1 were identified in both tumors at similar VAFs, whereas mutation of CARD11 (two mutations), NLRC5 and B2M were detected only at progression. In pt-1, both the NLRC5 and β2M mutations acquired at disease progression were truncating, suggesting loss-of-function alterations. Copy number analysis reveals frequent whole-genome doubling and intensive copy number alterations in all tumors, including recurrent losses of chromosome 9p, 17p, and chromosome 13, indicating chromosomal instability as a driver of disease progression. Conclusion: Patients who progress on acalabrutinib have a poor outcome, and newer therapies are required for their treatment. In this small cohort, we observed non-BTK mutations associated with acalabrutinib resistance and disease progression. Disclosures Nastoupil: Genentech: Honoraria, Research Funding; TG Therappeutics: Research Funding; Spectrum: Honoraria; Gilead: Honoraria; Merck: Honoraria, Research Funding; Janssen: Research Funding; Celgene: Honoraria, Research Funding; Karus: Research Funding; Novartis: Honoraria; Juno: Honoraria. Neelapu:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; Poseida: Research Funding; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta: Research Funding; Karus: Research Funding; Bristol-Myers Squibb: Research Funding; Unum Therapeutics: Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees. Fowler:Janssen: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding. Wang:Acerta Pharma: Honoraria, Research Funding; MoreHealth: Consultancy; AstraZeneca: Consultancy, Research Funding; Kite Pharma: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Dava Oncology: Honoraria; Juno: Research Funding; Pharmacyclics: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding.

scholarly journals Preliminary evidence of imaging of chemokine receptor-4 targeted PET/CT with [68Ga]pentixafor in non-Hodgkin lymphoma: comparison to [18F]FDG

2020 ◽  
Author(s):  
Qingqing Pan ◽  
Yaping Luo ◽  
Yan Zhang ◽  
Long Chang ◽  
Ji Li ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
Marginal Zone ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Marginal Zone Lymphoma ◽  
Lymphoplasmacytic Lymphoma ◽  
Non Hodgkin Lymphoma ◽  
Pet Ct ◽  
18F Fdg

Abstract Background: In order to study the CXCR4 expression with [68Ga]pentixafor PET in different types of non-Hodgkin lymphoma, we performed a retrospective study to describe the [68Ga]pentixafor PET/CT imaging in a spectrum of lymphomas and to compare it with [18F]FDG PET/CT. Results: Twenty-seven patients with newly diagnosed non-Hodgkin lymphoma were recruited retrospectively. [68Ga]pentixafor PET showed increased radioactivity in lymphoplasmacytic lymphoma (n = 8), marginal zone lymphoma (n = 4), diffuse large B cell lymphoma (n = 3), follicular lymphoma (n = 2), mantle cell lymphoma (n = 1), unclassified indolent B cell lymphoma (n = 3) and enteropathy associated T cell lymphoma (n = 3). However, peripheral T cell lymphoma, not otherwise specified (n = 1), and NK/T cell lymphoma (n = 2) were not avid for [68Ga]pentixafor. In comparison to [18F]FDG PET, [68Ga]pentixafor PET demonstrated more extensive disease and higher radioactivity in lymphoplasmacytic lymphoma and marginal zone lymphoma. Conclusion: CXCR4 expression varies in different types of non-Hodgkin lymphoma. Overexpression of CXCR4 was detected with [68Ga]pentixafor PET/CT in lymphoplasmacytic lymphoma, marginal zone lymphoma, diffuse large B cell lymphoma, follicular lymphoma, mantle cell lymphoma, unclassified indolent B cell lymphoma, and enteropathy associated T cell lymphoma. The uptake of [68Ga]pentixafor was higher than [18F]FDG in lymphoplasmacytic lymphoma and marginal zone lymphoma.

scholarly journals A Phase I Trial of Alisertib Plus Romidepsin for Relapsed/Refractory Aggressive B- and T-Cell Lymphomas

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1744-1744 ◽  
Author(s):  
Michelle A. Fanale ◽  
Fredrick B. Hagemeister ◽  
Luis Fayad ◽  
Yasuhiro Oki ◽  
Nathan Fowler ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
Research Funding ◽  
Kinase Inhibitor ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Median Number ◽  
Aurora A Kinase ◽  
Aurora A ◽  
T Cell Lymphomas

Abstract Background: The histone deacetylase inhibitor (HDACi) romidepsin, while a clear advance for relapsed peripheral and cutaneous T cell lymphomas (CTCL and PTCL), induces short durations of remission at 9 to 10 months (Piekarz et al., 2011 and Coiffier et al., 2011). Other HDACi have been evaluated in other lymphoma types including Hodgkin lymphoma (HL) with panobinostat having a 27% ORR in patients with post-ASCT relapsed disease (Younes et al., 2012). The aurora A kinase inhibitor alisertib has shown promising results to date including in a phase II sponsored trial (Friedberg et al., 2011) in which the ORR was 32% with responses of 100% in Burkitt lymphoma (BL), 20% in diffuse large B cell lymphoma (DLBCL), and 57% in PTCL. Recent data from a SWOG further showed an ORR of 20% in all TCL and 50% in PTCL (Barr et al., 2014), and a registration trial is ongoing in relapsed PTCL. Preclinical data supports the combination of an aurora A kinase inhibitor plus a HDACi. The pan-aurora kinsase inhibitor MK-0457 in combination with the HDACi vorinostat enhanced lymphoma cell death through repression of C-Myc and C-Myc responsive micro RNAs (Kretzner et al., 2008). Also alisertib plus romidepsin exhibit highly synergistic effects in lymphoma cell lines (O’Connor, 2012). Thus, this collective data supports the rationale for the evaluation of the combination of romidepsin plus alisertib in patients with multiple lymphoma subtypes. Methods: Eligible histologies included Hodgkin lymphoma (HL), Burkitt lymphoma (BL), double-hit lymphoma (DHL), other c-Myc positive B-cell lymphomas, diffuse large-B cell lymphoma (DLBCL), mantle cell lymphoma (MCL), or peripheral T-cell lymphoma (PTCL). Patients were treated with alisertib orally on days 1 to 7 and romidepsin IV on days 1 and 8. There are 5 planned escalation dose levels with respective dosing of alisertib plus romidespin of 20 mg BID and 8 mg/m2, 20 mg BID and 10 mg/m2, 40 mg BID and 10 mg/m2, 40 mg BID and 12 mg/m2, and 40 mg BID and 14 mg/m2. Next cycle is given if ANC ≥ 1000 and platelets ≥ 50,000 and maximum cycles is 8. Restaging is done after every 2 cycles with revised response criteria (Cheson et al., 2007). DLT is defined as: 1) grade 4 neutropenia or thrombocytopenia ≥ 14 days and/or 2) grade 3 or 4 non-hematological toxicity attributed to study drugs that could not be controlled by supportive care. Patients with an ANC < 1000 received growth factor support. A lymph node core biopsy is conducted at baseline and at the end of 1 cycle of therapy, and whole peripheral blood is also collected. Evaluation of intensity of immnohistochemistry (IHC) expression of aurora A kinase will be performed and will be correlated with response, 2. Gene expression profiling (GEP) will be performed and assessments of markers of apoptosis and mitotic catastrophe, 3. GEP of whole peripheral blood will be performed to assess changes beyond those limited to within the tumor that can contribute towards response to therapy. Results: 9 patients were enrolled and 8 are evaluable for response. The median age was 60 years and histologies were 3 PTCL, 3 DHL defined by FISH, 1 DLBCL with c-Myc translocation by FISH, 1 high-grade (HG) DLBCL, and 1 transformed DLBCL. Median number of prior therapies was 4 (2 to 7) and no patients underwent prior transplant given refractory disease. 3 patients have been enrolled to each of the dose levels 1, 2, and 3. Median number of cycles is 1.5 (1 to 8) with median time for retreatment of 28.5 days (22 to 40). Grade 3/4 toxicities were neutropenia, thrombocytopenia, and anemia in respectively 45%, 45%, and 20% of the cycles. Responses to date are CR (PTCL, dose level 1), SD (PTCL, dose level 3), PD (3 DHL, 1 HG DLBCL, 1 DLBCL with c-Myc, 1 PTCL). 4 of the patients with PD have died from continued refractory disease and 1 has been transitioned to hospice. The CR patient received 7 prior lines of treatment and remains in remission at 5 months in follow-up and declined transplant. The SD patient is now 1 month out from a matched unrelated donor transplant. Conclusions: Enrollment continues. Based on preclinical data, clinical data for both agents, and responses thus far we plan to consider a dose expansion PTCL patient cohort at the MTD. Reversible cytopenias are the main toxicity to date. We anticipate the correlative studies will allow us to further define the patients with the higher likelihood of having disease response to this targeted therapeutic combination. Disclosures Fanale: Seattle Genetics: Consultancy, Honoraria, Research Funding; Millennium/Takeda: Honoraria, Research Funding; Celgene: Research Funding; Novartis: Research Funding; Spectrum: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; MedImmune: Research Funding; Roche: Research Funding; Amgen : DMC, DMC Other. Off Label Use: Will discuss off label use of alisertib plus romidepsin in a phase I trial.. Fowler:Gilead Sciences: Research Funding.

CD37 Is a Potential Therapeutic Target for B-Cell Non-Hodgkin Lymphoma

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3098-3098 ◽  
Author(s):  
Xiaoxian Zhao ◽  
Suzanne Ybarra ◽  
Lisa Durkin ◽  
Mien Sho ◽  
Neeraj Kumar ◽  
...  
Keyword(s):  
Cell Death ◽  
B Cell ◽  
Cell Lines ◽  
Marginal Zone ◽  
Cell Lymphoma ◽  
Annexin V ◽  
B Cell Lymphoma ◽  
Marginal Zone Lymphoma ◽  
Caspase Activity ◽  
Mantle Cell

Abstract Abstract 3098 Background: The Non-Hodgkin Lymphomas (NHLs) are a heterogeneous group of malignancies with approximately 85% of NHL belonging to the B-cell lineage. The use of monoclonal antibodies (mAb), including the anti-CD20 therapy rituximab, has become a standard of care for the treatment of many forms of NHL. However, only a subset of patients respond to rituximab and the majority of those eventually relapse after treatment. Additional therapeutic options are necessary for these patients. Here we report the expression of CD37, a lineage-specific B-cell antigen, in different subtypes of B-cell NHL tissues and evaluate the functional activity of an anti-CD37 scFv-Fc fusion protein, known as a SMIP ™ protein (CD37-SMIP) against NHL cells. Methods: Fresh NHL tissues or peripheral blood from leukemia-stage lymphoma patients were used for flow cytometric assay of CD37 expression. Monotypic kappa or lambda IgG light chain positive malignant B-cells were gated for this assay. Immunohistochemical (IHC) staining of formalin fixed paraffin-embedded (FFPE) NHL tissues was performed for CD37 expression. Fresh primary NHL cells were isolated and used as targets in assays to measure antibody dependent cellular cytotoxicity (ADCC) activity as well as direct cell death mediated by CD37-SMIP. The effects of CD37-SMIP on multiple B-cell NHL lines was also determined by measuring cell proliferation, Annexin V staining, caspase3/7 release and changes in mitochondria membrane potentials using JC-1 staining. Results: Eighteen cases of NHL (follicular lymphoma (2), chronic lymphocytic leukemia/small lymphocytic lymphoma (3), mantle cell lymphoma (5), persistent marginal zone lymphoma (1), diffuse large B-cell lymphoma (1) and other types (6)) were analyzed by flow cytometry. Six of the eighteen cases had a history of rituximab treatment. Flow data showed malignant B-cells from these NHL specimens were strongly positive for CD37, while other cell populations had minimal to low levels of CD37 expression. IHC results on FFPE samples (n=170) indicated 89% (151 of 170 cases) of stained lymphoma tissues were positive for CD37, including follicular lymphoma (80/88), mantle cell lymphoma (39/44), DLBCL (32/38), and marginal zone lymphoma (5/5). Twenty seven B-cell lymphoma cell lines representing MCL, DLBCL, FL, and Burkitt's lymphoma subtypes were evaluated for CD37 expression and functional response to CD37-SMIP. CD37-SMIP mediated cell death in a wide range of NHL cell lines. The response to CD37-SMIP correlated with the levels of CD37 surface expression in NHL cell lines (Pearson analysis, r=0.78) The CD37-SMIP mediated response was rapid, with Annexin V staining and mitochondria depolarization observed in 3 hours; however, no caspase activity was observed at this time point. Two of ten NHL cell lines had modest caspase 3/7 activity at 24 h post treatment. However, caspase inhibitors did not suppress the CD37-SMIP mediated response. ADCC and direct killing activities elicited by SMIP-CD37 on freshly isolated primary NHL cells are under evaluation. Conclusion: CD37 is highly expressed on majority of B-cell NHL tissues, including those from patients treated with rituximab. CD37-SMIP mediated rapid cell death in NHL cell lines with mitochondria dysfunction but appears to be independent of caspase activity. The expression pattern of CD37 and functional effects of CD37-SMIP supports the targeting of CD37 in B-cell NHL. TRU-016, a humanized SMIP protein specific for CD37, is currently being evaluated in relapsed CLL and NHL patients in a phase 1 trial. Disclosures: No relevant conflicts of interest to declare.

Decentralized Data Storage to Promote Epidemiological Analysis for Subtypes Non Hodgkin Lymphoma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2386-2386
Author(s):  
Marcelo Bellesso ◽  
Renato Centrone ◽  
Daniela Ferreira Dias ◽  
Rodrigo Santucci
Keyword(s):  
T Cell ◽  
B Cell ◽  
Data Storage ◽  
Marginal Zone ◽  
Advanced Disease ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Marginal Zone Lymphoma ◽  
T Cell Lymphoma ◽  
Electronic Data

Abstract Advanced disease means a poor prognosis factor in patients with non-Hodgkin Lymphoma (NHL). There are few Brazilian data about epidemiologic incidence of NHL, however it was observed that high grade B cell Lymphoma is more frequent than in North America, Argentina and Chile, besides that we have deficient information about Brazilian private service care. Such knowledge is essential to plan economic resources to promote the best treatment and diagnosis. Moreover, is fundamental to elaborate electronic data storage to promote a continuous supply flow of information during clinical practice. We have designed an accessible and automated data collection model built into the electronic medical records for patients with NHL. Here, we show some epidemiological parameters and classic risk factors about NHL in a private care institute stocked by continuous electronic data storage. We evaluated data from patients with NHL during November 2015 to May 2016. Information was obtained by decentralized automated model after each outpatient care. We studied 229 patients with NHL. It was observed 112(48.9%) patients with Diffuse Large B cell Lymphoma not otherwise specified (DLBCL), 65(28.3%) Follicular Lymphoma (FL), 21(9.1%) Mantle Cell Lymphoma (MCL), 12(5.2%) Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue gastric lymphoma (GMALT), 6(2.9%) Extranodal marginal zone lymphoma of nonGastric MALT lymphoma (non-GMALT), 4(1.7%) Splenic B-cell marginal zone lymphoma (SL), 1(0.4%) nodal marginal zone lymphoma (NMZL), 1(0.4%) Sporadic Burkitt Lymphoma (BL), 2(0.8%) peripheral T cell lymphoma not otherwise specified (PTCL), 2(0.8%) anaplastic large T Cell lymphoma, ALK negative (ALTCL), 2(0.8%) Extranodal NK/T-cell lymphoma, basal type and 1(0.4%) mycosis fungoides (MF). It was evidenced advanced disease stage III/IV in DLBCL, FL and MCL: 70(62.5%), 54 (87.1%), 18 (85.7%); Extranodal infiltration sites in DLBCL, FL, MCL: 35/94 (37.2%), 11/50 (22%) and 5/18( 27.7%); Elevated serum LDH in DLBCL, FL, MCL: 31/74( 43.6%), 10/38 (26.3%) and 4/14 (28.5%), Performance status ≥ 2 in DLBCL, FL, MCL: 18/75(24%), 2/28 (4.1) 12/20 (60%), respectively. In this study, we have demonstrated that decentralized electronic data storage was useful and could appear an attractive model for clinical practice; moreover, it was possible observed high incidence of DLCBL and FL with advanced disease. Disclosures No relevant conflicts of interest to declare.

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