scholarly journals Frequency of aberrant promoter methylation of p15INK4b and O6-methylguanine-DNA methyltransferase genes in b-cell non-Hodgkin lymphoma: A pilot study

2010 ◽  
Vol 62 (2) ◽  
pp. 211-221 ◽  
Author(s):  
Nada Kraguljac-Kurtovic ◽  
Milena Krajnovic ◽  
B. Dimitrijevic ◽  
Biljana Mihaljevic ◽  
Mirjana Gotic ◽  
...  
Keyword(s):  
B Cell ◽  
Hodgkin Lymphoma ◽  
Dna Methyltransferase ◽  
De Novo ◽  
Clinical Stage ◽  
Methylation Status ◽  
Mgmt Gene ◽  
Methylguanine Dna Methyltransferase ◽  
Non Hodgkin Lymphoma ◽  
P15 Gene

The methylation status of the target promoter sequences of p15INK4B (p15) and O6-methylguanine-DNA methyltransferase (MGMT) genes was studied by methylation-specific PCR in 10 adult patients with de novo B-cell non- Hodgkin lymphoma (B-NHL). The aberrant hypermethylation of the p15 gene was more frequent (50%) compared to the hypermethylation of the MGMT gene (30%), and was detected in different types of B-NHL in both genes. Hypermethylation of the MGMT gene occurred exclusively in association with the hypermethylation of the p15 gene. All lymphoma patients with hypermethylation of the p15 and/or MGMT genes had a higher clinical stage of the disease (IV - V). We show the association of anemia and/or thrombocytopenia with the hypermethylation of the p15 gene, ascribing the p15 gene as a potential prognostic marker in B-NHL. Comethylation of MGMT with the p15 gene represents a novel finding and presents both genes as candidates for future studies of the hypermethylation profiles of B-NHL.

scholarly journals Radioimmunotherapy with iodine 131I tositumomab for relapsed or refractory B-cell non-Hodgkin lymphoma: updated results and long-term follow-up of the University of Michigan experience

Blood ◽  
2000 ◽  
Vol 96 (4) ◽  
pp. 1259-1266 ◽  
Author(s):  
Mark S. Kaminski ◽  
Judith Estes ◽  
Kenneth R. Zasadny ◽  
Isaac R. Francis ◽  
Charles W. Ross ◽  
...  
Keyword(s):  
B Cell ◽  
Hodgkin Lymphoma ◽  
De Novo ◽  
Hematologic Toxicity ◽  
Low Grade ◽  
Cell Transplant ◽  
Non Hodgkin Lymphoma ◽  
Therapeutic Doses ◽  
131I Tositumomab

Abstract CD20-targeted radioimmunotherapy is a promising new treatment for B-cell non-Hodgkin lymphoma (NHL). We now provide updated and long-term data on 59 chemotherapy-relapsed/refractory patients treated with iodine 131I tositumomab in a phase I/II single-center study. Fifty-three patients received individualized therapeutic doses, delivering a specified total-body radiation dose (TBD) based on the clearance rate of a preceding dosimetric dose. Six patients received dosimetric doses only. Dose-escalations of TBD were conducted separately in patients who had or had not undergone a prior autologous stem cell transplant (ASCT) until a nonmyeloablative maximally tolerated TBD was established (non-ASCT = 75 cGy, post-ASCT = 45 cGy). Fourteen additional non-ASCT patients were treated with 75 cGy. Unlabeled antibody was given prior to labeled dosimetric and therapeutic doses to improve biodistribution. Forty-two (71%) of 59 patients responded; 20 (34%) had complete responses (CR). Thirty-five (83%) of 42 with low-grade or transformed NHL responded versus 7 (41%) of 17 with de novo intermediate-grade NHL (P = .005). For all 42 responders, the median progression-free survival was 12 months, 20.3 for those with CR. Seven patients remain in CR 3 to 5.7 years. Sixteen patients were re-treated after progression; 9 responded and 5 had a CR. Reversible hematologic toxicity was dose limiting. Only 10 patients (17%) had human anti-mouse antibodies detected. Long-term, 5 patients developed elevated thyroid-stimulating hormone levels, 5 were diagnosed with myelodysplasia and 3 with solid tumors. A single, well-tolerated treatment with iodine 131I tositumomab can, therefore, produce frequent and durable responses in NHL, especially low-grade or transformed NHL.

scholarly journals Evaluation of MGMT gene methylation in neuroendocrine neoplasms

2021 ◽  
Author(s):  
Rosa Della Monica ◽  
Mariella Cuomo ◽  
Roberta Visconti ◽  
Annabella di Mauro ◽  
Michela Buonaiuto ◽  
...  
Keyword(s):  
Dna Methyltransferase ◽  
Alkylating Agents ◽  
Methylation Status ◽  
Neuroendocrine Neoplasms ◽  
Mgmt Methylation ◽  
Gene Methylation ◽  
Mgmt Gene ◽  
Methylguanine Dna Methyltransferase ◽  
Specific Pcr ◽  
Well Differentiated

Unresectable neuroendocrine neoplasms (NENs) often poorly respond to standard therapeutic approaches. Alkylating agents, in particular temozolomide, commonly used to treat high-grade brain tumors including glioblastomas, have recently been tested in advanced or metastatic NENs, where they showed promising response rates. In glioblastomas, prediction of response to temozolomide is based on the assessment of the methylation status of the MGMT gene, as its product, O-6-methylguanine-DNA methyltransferase, may counteract the damaging effects of the alkylating agent. However, in NENs, such a biomarker has not been validated yet. Thus, we have investigated MGMT methylation in 42 NENs of different grades and from various sites of origin by two different approaches: in contrast to methylation-specific PCR (MSP), which is commonly used in glioblastoma management, amplicon bisulfite sequencing (ABS) is based on high resolution next-generation sequencing and interrogates several additional CpG sites compared to those covered by MSP. Overall, we found MGMT methylation in 74% (31/42) of the NENs investigated. A higher methylation degree was observed in well-differentiated tumors and in tumors originating in the gastrointestinal tract. Comparing MSP and ABS results, we demonstrate that the region analyzed by the MSP test is sufficiently informative of the MGMT methylation status in NENs, suggesting that this predictive parameter could routinely be interrogated also in NENs

Hypermethylation of O6-Methylguanine-DNA Methyltransferase (MGMT) Predicts Response to Laromustine (Cloretazine®) in Patients with Acute Myelogenous Leukemia (AML) or High-Risk Myelodysplastic Syndrome (MDS)

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4463-4463
Author(s):  
Ilan Bernstein ◽  
Francis Giles ◽  
Susan O’Brien ◽  
Elizabeth Sullivan ◽  
Norbert Vey ◽  
...  
Keyword(s):  
Dna Methylation ◽  
High Risk ◽  
Dna Methyltransferase ◽  
Methylation Status ◽  
Single Agent ◽  
Epigenetic Silencing ◽  
Dna Hypermethylation ◽  
Mgmt Gene ◽  
Methylguanine Dna Methyltransferase ◽  
Encoding Gene

Abstract Laromustine (Cloretazine®) (1,2-bis(methylsulfonyl)-1-(2-chloroethyl)-2-[(methylamino)carbonyl] hydrazine), a sulfonylhydrazine prodrug producing chlorethylating and carbamoylating subspecies, has demonstrated clinical activity in patients with hematologic disorders (Giles et al., J Clin Oncol, 2007). The effect of laromustine is modulated primarily through the formation of hard chloroethylating electrophiles with preferential alkylating activity for the O6 position of guanine, ultimately resulting in the formation of interstrand cross-links which prevent DNA replication and transcription, leading to cell death. The DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) plays a major role in repairing O6-chloroethylguanine alkylations, critical to the formation of interstrand crosslinks. Epigenetic silencing of the MGMT encoding gene related to DNA hypermethylation has been shown to participate in the pathogenesis of neoplastic disease (Hegi et al., NEJM 2005). Since the alkylating properties of laromustine target DNA sites normally repaired by MGMT, the absence of the enzyme may represent a unique cellular environment for specific susceptibility to laromustine (Ishiguro et al., Mol Cancer Ther, 2005). In vitro findings have supported the hypothesis that cellular content of MGMT may predict response. In vivo correlation between clinical response in patients treated with laromustine and the cellular evidence of epigenetic silencing of the encoding MGMT gene has yet to be demonstrated (Giles et al., Clin Cacner Res, 2004). Our research aimed to determine the DNA methylation status of MGMT isolated from the peripheral blood or bone marrow of patients with AML or high-risk MDS enrolled to a phase II, single-agent study of laromustine (600 mg/m2 IV over 30 minutes) (Giles et al. J Clin Oncol, 2007). We also aimed to establish a correlation between hypermethylation of MGMT and clinical response to laromustine. Combined bisulfite restriction analysis (COBRA) was used to determine the MGMT gene methylation status of patients treated with laromustine. Bone marrow or peripheral blood leukocyte samples from 76 patients enrolled in a phase II, single agent study of laromustine were coded and blinded to investigators. DNA from each sample was extracted and bisulfite treated. PCR was used to amplify the MGMT CpG Island promoter region (REF/NT_008818.15/Hs10_8975) from 58 patients, prior to methylation specific restriction enzyme digestion. Results were correlated with clinical data of response to laromustine. The DNA methylation status of MGMT was determined in 58 of the enrolled patients. DNA hypermethylation was found in 3 of the 58 patients (5%). Two of these 3 patients achieved a complete response (CR) (66%), compared to 11 of the 55 patients who achieved a CR, CR with platelet recovery < 100,000/mm3 (CRp) or a partial response (PR) and did not exhibit MGMT hypermethylation (20%). Hypermethylation of the MGMT gene promoter is a rare event in AML (5%), however, epigenetic inactivation of MGMT may predict a subgroup of patients with a higher likelihood of response to laromustine (Odds Ratio=8). Clinical investigation of laromustine in patients with AML, high-risk MDS and other cancers, specifically those with a higher methylation frequency of the MGMT encoding gene is warranted.

Expression of BLyS and its receptors in B-cell non-Hodgkin lymphoma: correlation with disease activity and patient outcome

Blood ◽  
2004 ◽  
Vol 104 (8) ◽  
pp. 2247-2253 ◽  
Author(s):  
Anne J. Novak ◽  
Deanna M. Grote ◽  
Mary Stenson ◽  
Steven C. Ziesmer ◽  
Thomas E. Witzig ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Hodgkin Lymphoma ◽  
De Novo ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Lactic Dehydrogenase ◽  
Response To Therapy ◽  
Non Hodgkin Lymphoma ◽  
Important Therapeutic Target

Abstract BLyS, recently shown to be critical for survival of normal B cells, has been found to be elevated in a number of immune disease models. A role for BLyS in the survival of malignant B cells has also been revealed and we therefore sought to identify a role for BLyS and its receptors in non-Hodgkin lymphoma (NHL). We found that tumor cells from all NHL histologic subtypes expressed one or more of 3 known receptors (BCMA, TACI, and BAFF-R) for BLyS; however, the pattern of expression was variable. We provide evidence that BLyS is expressed in tumors from patients with NHL and that BLyS levels increase as tumors transform to a more aggressive phenotype. Additionally, we provide evidence that serum BLyS levels are elevated in a subgroup of patients with NHL. In patients with de novo large B-cell lymphoma, a high BLyS level correlated with a poorer median overall survival, the presence of constitutional symptoms, and elevated values of lactic dehydrogenase. When BLyS levels were correlated with response to therapy in all patients, responding patients had a significantly lower BLyS level than those with progressive disease. In summary, we found that BLyS and its receptors represent a potentially important therapeutic target in B-cell lymphoma.

scholarly journals Results of a Phase 3 Randomised Multicenter Study Comparing Pixantrone + Rituximab with Gemcitabine + Rituximab in Patients with Relapsed Aggressive B-Cell Non-Hodgkin Lymphoma Not Eligible for Stem Cell Transplantation

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4189-4189
Author(s):  
Gilles Andre Salles ◽  
Wojciech Jurczak ◽  
David J. Andorsky ◽  
Donald P. Quick ◽  
Jack W. Singer ◽  
...  
Keyword(s):  
Stem Cell ◽  
B Cell ◽  
Hodgkin Lymphoma ◽  
Stock Options ◽  
Research Funding ◽  
De Novo ◽  
Phase 3 ◽  
Non Hodgkin Lymphoma ◽  
Grade 3 ◽  
To Receive

Abstract Introduction: There are limited treatment options for patients with relapsed aggressive B-cell non-Hodgkin lymphoma (NHL) who are not candidates for high-dose therapy and stem-cell transplant (SCT). Reasons for ineligibility for intensive treatment include advanced age and overall condition, comorbidities, failure to respond to standard salvage treatment regimens, progressive disease following previous SCT, and presence of other adverse risk factors. The PIX306 study evaluated the efficacy of pixantrone + rituximab (PIX+R) compared with gemcitabine + rituximab (GEM+R) in patients with relapsed aggressive B-cell NHL in this particular clinical setting. We present the primary results of the core analysis of the PIX306 trial. Methods: PIX306 was a phase 3, multicentre, open-label, randomized trial in patients aged ≥18 years diagnosed with de novo diffuse large B-cell lymphoma (DLBCL), DLBCL transformed from indolent lymphoma, or grade 3 follicular lymphoma (FL) who relapsed after at least one standard rituximab-containing multi-agent regimen. Primary refractory de novo DLBCL and grade 3 FL, defined as progression within 12 weeks of the last cycle of the first-line treatment regimen, was an exclusion criterion. Patients were randomly allocated 1:1 to receive PIX 50 mg/m2 or GEM 1000 mg/m2 on days 1, 8 and 15 of a 28-day cycle, each in combination with R 375 mg/m2 on day 1, for up to 6 cycles, with follow-up for progression up to 96 weeks. The primary endpoint was progression-free survival (PFS) as determined by the Independent Radiology Committee (IRC). Disease response was assessed according to the Modified IWG 2007 Revised Response Criteria. The current analysis is based on 197 PFS events (IRC). Overall survival (OS), complete response (CR), overall response rate (ORR), and safety were secondary endpoints. Results: The ITT population included 312 patients; 155 and 157 patients were randomly allocated to receive PIX+R and GEM+R, respectively. Groups were well balanced; no statistically significant differences in baseline demographics were shown (Table). Median age was 73 years (range: 26-91 years). Overall, 193 (61.9%) patients had received only one line of prior chemotherapy. Most patients (n=242; 77.6%) had de novo DLBCL, 43 (13.8%) had DLBCL transformed from indolent NHL and 27 (8.7%) had grade 3 FL. The majority of patients had Ann Arbor stage III/IV (n=230; 73.7%) disease, 166 (53.2%) patients had an IPI score of ≥3, and in 195 (62.5%) patients extranodal disease was diagnosed at baseline. In total, 116 (37.2%) patients had their first disease relapse within 1 year following the initiation of the front-line therapy for DLBCL or FL. Thirty-three (10.6%) patients had undergone a previous SCT. The study did not meet its primary objective of efficacy, as measured by PFS, of PIX+R vs GEM+R [P= 0.28; HR=0.85 (95% CI: 0.64, 1.14)]. The median PFS (95% CI) in the PIX+R and the GEM+R groups were 7.3 months (5.2; 8.4) and 6.3 months (4.4; 8.1), respectively. Median OS was 13.3 vs 19.6 months [HR=1.13 (95% CI: 0.83, 1.53), P=0.43], CR was observed in 35.5% vs 21.7% of patients, and ORR was 61.9% vs 43.9% in the PIX-R and GEM-R groups, respectively. Both regimens were reasonably tolerated and no new safety signals were reported. Cardiac failure was reported as a serious adverse event in 3 and 2 patients (2.0% and 1.3%) receiving PIX-R and GEM-R, respectively. Conclusions: This is the first study to investigate the efficacy of PIX+R vs GEM+R as second-line or later therapy in patients with relapsed aggressive B-cell NHL who are not eligible for SCT and who have few therapeutic options. Even though the present study did not meet its primary endpoint, the PFS observed in both the PIX+R and GEM+R groups were longer than the study outcomes previously reported in similar patient populations. Disclosures Salles: Merck: Honoraria; Servier: Honoraria; Pfizer: Honoraria; Gilead: Honoraria; Acerta: Honoraria; AbbVie: Honoraria; Celgene: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Takeda: Honoraria; Janssen: Honoraria; Amgen: Honoraria; Epizyme: Honoraria; Morphosys: Honoraria. Jurczak:Epizyme: Research Funding; Celgene: Research Funding; Beigene: Research Funding; Bayer: Research Funding; Afimed: Research Funding; Gilead: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Sandoz-Novartis: Consultancy; Acerta: Consultancy, Research Funding; AstraZeneca: Consultancy; European Medicines Agency: Consultancy; Servier: Consultancy, Honoraria, Research Funding; Nordic Nanovector: Research Funding; Merck: Research Funding; Morphosys: Research Funding; Pharmacyclics: Research Funding; Roche: Research Funding; TG therapeutics: Research Funding. Andorsky:AstraZeneca: Consultancy; CTI BioPharma: Consultancy, Research Funding; Celgene: Research Funding; Genentech: Consultancy. Quick:CTI BioPharma: Research Funding. Singer:CTI BioPharma: Employment, Other: Stock options. Bedi Singh:CTI BioPharma: Employment, Other: Stock options. Wang:CTI BioPharma: Employment, Equity Ownership. Egorov:Servier: Employment. Gabarroca:Servier: Employment. Pettengell:CTI: Honoraria; Pfizer: Honoraria; Roche: Honoraria; Servier: Honoraria; Takeda: Honoraria.

scholarly journals Radioimmunotherapy with iodine 131I tositumomab for relapsed or refractory B-cell non-Hodgkin lymphoma: updated results and long-term follow-up of the University of Michigan experience

Blood ◽  
2000 ◽  
Vol 96 (4) ◽  
pp. 1259-1266 ◽  
Author(s):  
Mark S. Kaminski ◽  
Judith Estes ◽  
Kenneth R. Zasadny ◽  
Isaac R. Francis ◽  
Charles W. Ross ◽  
...  
Keyword(s):  
B Cell ◽  
Hodgkin Lymphoma ◽  
De Novo ◽  
Hematologic Toxicity ◽  
Low Grade ◽  
Cell Transplant ◽  
Non Hodgkin Lymphoma ◽  
Therapeutic Doses ◽  
131I Tositumomab

CD20-targeted radioimmunotherapy is a promising new treatment for B-cell non-Hodgkin lymphoma (NHL). We now provide updated and long-term data on 59 chemotherapy-relapsed/refractory patients treated with iodine 131I tositumomab in a phase I/II single-center study. Fifty-three patients received individualized therapeutic doses, delivering a specified total-body radiation dose (TBD) based on the clearance rate of a preceding dosimetric dose. Six patients received dosimetric doses only. Dose-escalations of TBD were conducted separately in patients who had or had not undergone a prior autologous stem cell transplant (ASCT) until a nonmyeloablative maximally tolerated TBD was established (non-ASCT = 75 cGy, post-ASCT = 45 cGy). Fourteen additional non-ASCT patients were treated with 75 cGy. Unlabeled antibody was given prior to labeled dosimetric and therapeutic doses to improve biodistribution. Forty-two (71%) of 59 patients responded; 20 (34%) had complete responses (CR). Thirty-five (83%) of 42 with low-grade or transformed NHL responded versus 7 (41%) of 17 with de novo intermediate-grade NHL (P = .005). For all 42 responders, the median progression-free survival was 12 months, 20.3 for those with CR. Seven patients remain in CR 3 to 5.7 years. Sixteen patients were re-treated after progression; 9 responded and 5 had a CR. Reversible hematologic toxicity was dose limiting. Only 10 patients (17%) had human anti-mouse antibodies detected. Long-term, 5 patients developed elevated thyroid-stimulating hormone levels, 5 were diagnosed with myelodysplasia and 3 with solid tumors. A single, well-tolerated treatment with iodine 131I tositumomab can, therefore, produce frequent and durable responses in NHL, especially low-grade or transformed NHL.

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