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Takeshi Tokuhisa - One of the best experts on this subject based on the ideXlab platform.
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a role for BCL6 in sequential class switch recombination to ige in b cells stimulated with il 4 and il 21
Molecular Immunology, 2008Co-Authors: Daisuke Kitayama, Akemi Sakamoto, Masafumi Arima, Masahiko Hatano, Masaru Miyazaki, Takeshi TokuhisaAbstract:Abstract IgE plays an important role in the pathogenesis of allergic diseases and high-affinity IgE memory B cells are differentiated from IgG1 B cells developed in germinal centers. BCL6, a sequence specific transcriptional repressor, is highly expressed in germinal center B cells and suppresses expression of Cɛ germline transcript. However, a role for BCL6 in inhibition of the sequential class switching from IgG1 to IgE in germinal center B cells is not known. When splenic B cells from BCL6-deficient (BCL6-KO) and BCL6-transgenic (BCL6-TG) mice were stimulated with anti-IgM Ab and anti-CD40 Ab plus IL-4, IgG1+IgE+ B cells were detected in BCL6-KO B cell culture but not in BCL6-TG B cell culture. Cγ1 and Cɛ germline transcript in BCL6-KO B cells were induced earlier than those in wild-type (BCL6-WT) B cells after stimulation. When activated B cells were simultaneously stimulated with IL-21, expression of Cγ1 germline transcript in BCL6-WT and BCL6-KO B cells was enhanced by IL-21 stimulation, indicating that IL-21 is an enhancer of Cγ1 expression induced by IL-4. The amount of Cγ1 germline transcript in the BCL6-KO B cells was more than that in the BCL6-WT B cells. Conversely, IL-21 stimulation suppressed Cɛ expression in the BCL6-WT B cells. However, the suppression was not observed in the BCL6-KO B cells, suggesting that the IL-21-mediated suppression of Cɛ expression is due to BCL6. Thus, BCL6 controls the Cγ1 and Cɛ expression and stabilizes class switching to IgG1 in activated B cells simultaneously stimulated with IL-4 and IL-21.
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A role for BCL6 in sequential class switch recombination to IgE in B cells stimulated with IL-4 and IL-21.
Molecular immunology, 2007Co-Authors: Daisuke Kitayama, Akemi Sakamoto, Masafumi Arima, Masahiko Hatano, Masaru Miyazaki, Takeshi TokuhisaAbstract:IgE plays an important role in the pathogenesis of allergic diseases and high-affinity IgE memory B cells are differentiated from IgG1 B cells developed in germinal centers. BCL6, a sequence specific transcriptional repressor, is highly expressed in germinal center B cells and suppresses expression of Cvarepsilon germline transcript. However, a role for BCL6 in inhibition of the sequential class switching from IgG1 to IgE in germinal center B cells is not known. When splenic B cells from BCL6-deficient (BCL6-KO) and BCL6-transgenic (BCL6-TG) mice were stimulated with anti-IgM Ab and anti-CD40 Ab plus IL-4, IgG1(+)IgE(+) B cells were detected in BCL6-KO B cell culture but not in BCL6-TG B cell culture. Cgamma1 and Cvarepsilon germline transcript in BCL6-KO B cells were induced earlier than those in wild-type (BCL6-WT) B cells after stimulation. When activated B cells were simultaneously stimulated with IL-21, expression of Cgamma1 germline transcript in BCL6-WT and BCL6-KO B cells was enhanced by IL-21 stimulation, indicating that IL-21 is an enhancer of Cgamma1 expression induced by IL-4. The amount of Cgamma1 germline transcript in the BCL6-KO B cells was more than that in the BCL6-WT B cells. Conversely, IL-21 stimulation suppressed Cvarepsilon expression in the BCL6-WT B cells. However, the suppression was not observed in the BCL6-KO B cells, suggesting that the IL-21-mediated suppression of Cvarepsilon expression is due to BCL6. Thus, BCL6 controls the Cgamma1 and Cvarepsilon expression and stabilizes class switching to IgG1 in activated B cells simultaneously stimulated with IL-4 and IL-21.
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Testicular germ cell apoptosis in BCL6-deficient mice.
Development (Cambridge England), 2001Co-Authors: Satoko Kojima, Masahiko Hatano, Tetsuya Fukuda, Seiji Okada, Yoshiro Toyama, Shigeki Yuasa, Haruo Ito, Takeshi TokuhisaAbstract:BCL6 protein has been detected in testicular germ cells, mainly spermatocytes, of normal mice, but its physiological role is largely unknown. The number of spermatozoa in the cauda epididymis of adult BCL6-deficient (BCL6-/-) mice is lower than that of BCL6+/+ mice. We have found numerous apoptotic spermatocytes at the metaphase I stage with induction of Bax protein in adult BCL6-/- testes. Developmentally, the incidence of germ cell apoptosis of BCL6-/- mice was similar to that of BCL6+/+ mice until six weeks of age and increased after eight weeks of age. The incidence of apoptosis in heterozygous BCL6+/- mice was also higher than that of BCL6+/+ mice. Since the activated form of p38 MAP kinase was detected in spermatocytes of adult BCL6-/- mice, the germ cell apoptosis may be induced by stressors. Treatment of testes of adult BCL6+/+ mice with a mild hyperthermia resulted in germ cell apoptosis predominantly in metaphase I spermatocytes with induction of Bax protein and activation of p38 MAP kinase and this apoptosis mimics that in adult BCL6-/- mice. Thus, BCL6 may play a role as a stabilizer in protecting spermatocytes from apoptosis induced by stressors.
Samir Parekh - One of the best experts on this subject based on the ideXlab platform.
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dose adjusted epoch r etoposide prednisone vincristine cyclophosphamide doxorubicin and rituximab in untreated aggressive diffuse large b cell lymphoma with myc rearrangement a prospective multicentre single arm phase 2 study
The Lancet Haematology, 2018Co-Authors: Kieron Dunleavy, Stefania Pittaluga, Jeremy S Abramson, Michelle A Fanale, Paolo Caimi, Samir Parekh, Ann S Lacasce, John Hayslip, Deepa Jagadeesh, Sunil NagpalAbstract:Summary Background MYC gene rearrangement is present in approximately 10% of aggressive B-cell lymphomas, with half also harbouring a BCL2 gene rearrangement. Multiple retrospective studies of R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone or prednisolone) have shown a worse outcome in patients with MYC rearrangement (alone or with rearrangement of BCL2 or BCL6, or both) than in patients without MYC rearrangement, and suggest improved outcomes after more intensive treatment. We aimed to determine the outcome of dose-adjusted EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab; DA-EPOCH-R), an intensive infusional treatment regimen, in untreated aggressive B-cell lymphoma with MYC rearrangement. Methods We present the final analysis of a prospective, multicentre, single-arm, phase 2 study of DA-EPOCH-R in patients with untreated aggressive B-cell lymphoma with MYC rearrangement. DA-EPOCH-R was scheduled to be administered with CNS prophylaxis for six cycles. Primary endpoints included event-free and overall survival. This study is registered with ClinicalTrials.gov ( NCT01092182 ). Findings 53 patients were enrolled, with median age of 61 years (range 29–80; IQR 50–70); 43 (81%) patients had stage III–IV disease and 26 (49%) had high-intermediate or high international prognostic index (IPI) scores. 19 patients had confirmed MYC rearrangement alone (single-hit) and 24 also had rearrangement of BCL2, BCL6, or both (double-hit), with similar characteristics between these two groups. After a median follow-up of 55·6 months (IQR 50·5–61·1), 48-month event-free survival was 71·0% (95% CI 56·5–81·4) and 48-month overall survival was 76·7% (95% CI 62·6–86·1) for all patients. Toxicity included grade 4 neutropenia in 160 (53%) of 301 cycles, grade 4 thrombocytopenia in 40 (13%) cycles, and any grade of fever with neutropenia in 56 (19%) cycles. There were three treatment-related deaths (all infections). Interpretation In this study, DA-EPOCH-R produced durable remission in patients with MYC-rearranged aggressive B-cell lymphomas and should be considered for the treatment of these diseases. Funding Cancer Trials Support Unit and Center for Cancer Research of the National Cancer Institute and Genentech.
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dose adjusted epoch r etoposide prednisone vincristine cyclophosphamide doxorubicin and rituximab in untreated aggressive diffuse large b cell lymphoma with myc rearrangement a prospective multicentre single arm phase 2 study
The Lancet Haematology, 2018Co-Authors: Kieron Dunleavy, Stefania Pittaluga, Jeremy S Abramson, Michelle A Fanale, Paolo Caimi, Samir Parekh, Ann S Lacasce, John Hayslip, Ariela Noy, Deepa JagadeeshAbstract:Summary Background MYC gene rearrangement is present in approximately 10% of aggressive B-cell lymphomas, with half also harbouring a BCL2 gene rearrangement. Multiple retrospective studies of R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone or prednisolone) have shown a worse outcome in patients with MYC rearrangement (alone or with rearrangement of BCL2 or BCL6, or both) than in patients without MYC rearrangement, and suggest improved outcomes after more intensive treatment. We aimed to determine the outcome of dose-adjusted EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab; DA-EPOCH-R), an intensive infusional treatment regimen, in untreated aggressive B-cell lymphoma with MYC rearrangement. Methods We present the final analysis of a prospective, multicentre, single-arm, phase 2 study of DA-EPOCH-R in patients with untreated aggressive B-cell lymphoma with MYC rearrangement. DA-EPOCH-R was scheduled to be administered with CNS prophylaxis for six cycles. Primary endpoints included event-free and overall survival. This study is registered with ClinicalTrials.gov ( NCT01092182 ). Findings 53 patients were enrolled, with median age of 61 years (range 29–80; IQR 50–70); 43 (81%) patients had stage III–IV disease and 26 (49%) had high-intermediate or high international prognostic index (IPI) scores. 19 patients had confirmed MYC rearrangement alone (single-hit) and 24 also had rearrangement of BCL2, BCL6, or both (double-hit), with similar characteristics between these two groups. After a median follow-up of 55·6 months (IQR 50·5–61·1), 48-month event-free survival was 71·0% (95% CI 56·5–81·4) and 48-month overall survival was 76·7% (95% CI 62·6–86·1) for all patients. Toxicity included grade 4 neutropenia in 160 (53%) of 301 cycles, grade 4 thrombocytopenia in 40 (13%) cycles, and any grade of fever with neutropenia in 56 (19%) cycles. There were three treatment-related deaths (all infections). Interpretation In this study, DA-EPOCH-R produced durable remission in patients with MYC-rearranged aggressive B-cell lymphomas and should be considered for the treatment of these diseases. Funding Cancer Trials Support Unit and Center for Cancer Research of the National Cancer Institute and Genentech.
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Therapeutic targeting of the BCL6 oncogene for diffuse large B-cell lymphomas.
Leukemia & lymphoma, 2008Co-Authors: Samir Parekh, Gilbert G. Privé, Ari MelnickAbstract:BCL6 is a transcriptional repressor often expressed constitutively in diffuse large B-cell lymphomas (DLBCL) due to mutations of its genomic locus. BCL6 mediates aberrant survival, proliferation, genomic instability and differentiation blockade in DLBCL cells. The biochemical study of BCL6 mediated gene repression has provided the basis for design of agents that inhibit BCL6 and kill lymphoma cells. The repressor activity of the BCL6 BTB domain is particularly well defined from the structural standpoint. Design of inhibitors targeting BCL6 BTB domain protein interaction surfaces appears to be an effective approach, which reactivates important BCL6 target genes and readily kills DLBCL cells. Targeting other domains of BCL6 or using histone deacetylase inhibitors to overcome BCL6 mediated repression may also be useful. Recent studies in DLBCL transcriptional signatures have revealed a subset of DLBCLs that are particularly dependent on BCL6 to maintain their survival and these patients could be candidates for clinical trials of BCL6 inhibitors.
Deepa Jagadeesh - One of the best experts on this subject based on the ideXlab platform.
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dose adjusted epoch r etoposide prednisone vincristine cyclophosphamide doxorubicin and rituximab in untreated aggressive diffuse large b cell lymphoma with myc rearrangement a prospective multicentre single arm phase 2 study
The Lancet Haematology, 2018Co-Authors: Kieron Dunleavy, Stefania Pittaluga, Jeremy S Abramson, Michelle A Fanale, Paolo Caimi, Samir Parekh, Ann S Lacasce, John Hayslip, Deepa Jagadeesh, Sunil NagpalAbstract:Summary Background MYC gene rearrangement is present in approximately 10% of aggressive B-cell lymphomas, with half also harbouring a BCL2 gene rearrangement. Multiple retrospective studies of R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone or prednisolone) have shown a worse outcome in patients with MYC rearrangement (alone or with rearrangement of BCL2 or BCL6, or both) than in patients without MYC rearrangement, and suggest improved outcomes after more intensive treatment. We aimed to determine the outcome of dose-adjusted EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab; DA-EPOCH-R), an intensive infusional treatment regimen, in untreated aggressive B-cell lymphoma with MYC rearrangement. Methods We present the final analysis of a prospective, multicentre, single-arm, phase 2 study of DA-EPOCH-R in patients with untreated aggressive B-cell lymphoma with MYC rearrangement. DA-EPOCH-R was scheduled to be administered with CNS prophylaxis for six cycles. Primary endpoints included event-free and overall survival. This study is registered with ClinicalTrials.gov ( NCT01092182 ). Findings 53 patients were enrolled, with median age of 61 years (range 29–80; IQR 50–70); 43 (81%) patients had stage III–IV disease and 26 (49%) had high-intermediate or high international prognostic index (IPI) scores. 19 patients had confirmed MYC rearrangement alone (single-hit) and 24 also had rearrangement of BCL2, BCL6, or both (double-hit), with similar characteristics between these two groups. After a median follow-up of 55·6 months (IQR 50·5–61·1), 48-month event-free survival was 71·0% (95% CI 56·5–81·4) and 48-month overall survival was 76·7% (95% CI 62·6–86·1) for all patients. Toxicity included grade 4 neutropenia in 160 (53%) of 301 cycles, grade 4 thrombocytopenia in 40 (13%) cycles, and any grade of fever with neutropenia in 56 (19%) cycles. There were three treatment-related deaths (all infections). Interpretation In this study, DA-EPOCH-R produced durable remission in patients with MYC-rearranged aggressive B-cell lymphomas and should be considered for the treatment of these diseases. Funding Cancer Trials Support Unit and Center for Cancer Research of the National Cancer Institute and Genentech.
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dose adjusted epoch r etoposide prednisone vincristine cyclophosphamide doxorubicin and rituximab in untreated aggressive diffuse large b cell lymphoma with myc rearrangement a prospective multicentre single arm phase 2 study
The Lancet Haematology, 2018Co-Authors: Kieron Dunleavy, Stefania Pittaluga, Jeremy S Abramson, Michelle A Fanale, Paolo Caimi, Samir Parekh, Ann S Lacasce, John Hayslip, Ariela Noy, Deepa JagadeeshAbstract:Summary Background MYC gene rearrangement is present in approximately 10% of aggressive B-cell lymphomas, with half also harbouring a BCL2 gene rearrangement. Multiple retrospective studies of R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone or prednisolone) have shown a worse outcome in patients with MYC rearrangement (alone or with rearrangement of BCL2 or BCL6, or both) than in patients without MYC rearrangement, and suggest improved outcomes after more intensive treatment. We aimed to determine the outcome of dose-adjusted EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab; DA-EPOCH-R), an intensive infusional treatment regimen, in untreated aggressive B-cell lymphoma with MYC rearrangement. Methods We present the final analysis of a prospective, multicentre, single-arm, phase 2 study of DA-EPOCH-R in patients with untreated aggressive B-cell lymphoma with MYC rearrangement. DA-EPOCH-R was scheduled to be administered with CNS prophylaxis for six cycles. Primary endpoints included event-free and overall survival. This study is registered with ClinicalTrials.gov ( NCT01092182 ). Findings 53 patients were enrolled, with median age of 61 years (range 29–80; IQR 50–70); 43 (81%) patients had stage III–IV disease and 26 (49%) had high-intermediate or high international prognostic index (IPI) scores. 19 patients had confirmed MYC rearrangement alone (single-hit) and 24 also had rearrangement of BCL2, BCL6, or both (double-hit), with similar characteristics between these two groups. After a median follow-up of 55·6 months (IQR 50·5–61·1), 48-month event-free survival was 71·0% (95% CI 56·5–81·4) and 48-month overall survival was 76·7% (95% CI 62·6–86·1) for all patients. Toxicity included grade 4 neutropenia in 160 (53%) of 301 cycles, grade 4 thrombocytopenia in 40 (13%) cycles, and any grade of fever with neutropenia in 56 (19%) cycles. There were three treatment-related deaths (all infections). Interpretation In this study, DA-EPOCH-R produced durable remission in patients with MYC-rearranged aggressive B-cell lymphomas and should be considered for the treatment of these diseases. Funding Cancer Trials Support Unit and Center for Cancer Research of the National Cancer Institute and Genentech.
Daisuke Kitayama - One of the best experts on this subject based on the ideXlab platform.
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a role for BCL6 in sequential class switch recombination to ige in b cells stimulated with il 4 and il 21
Molecular Immunology, 2008Co-Authors: Daisuke Kitayama, Akemi Sakamoto, Masafumi Arima, Masahiko Hatano, Masaru Miyazaki, Takeshi TokuhisaAbstract:Abstract IgE plays an important role in the pathogenesis of allergic diseases and high-affinity IgE memory B cells are differentiated from IgG1 B cells developed in germinal centers. BCL6, a sequence specific transcriptional repressor, is highly expressed in germinal center B cells and suppresses expression of Cɛ germline transcript. However, a role for BCL6 in inhibition of the sequential class switching from IgG1 to IgE in germinal center B cells is not known. When splenic B cells from BCL6-deficient (BCL6-KO) and BCL6-transgenic (BCL6-TG) mice were stimulated with anti-IgM Ab and anti-CD40 Ab plus IL-4, IgG1+IgE+ B cells were detected in BCL6-KO B cell culture but not in BCL6-TG B cell culture. Cγ1 and Cɛ germline transcript in BCL6-KO B cells were induced earlier than those in wild-type (BCL6-WT) B cells after stimulation. When activated B cells were simultaneously stimulated with IL-21, expression of Cγ1 germline transcript in BCL6-WT and BCL6-KO B cells was enhanced by IL-21 stimulation, indicating that IL-21 is an enhancer of Cγ1 expression induced by IL-4. The amount of Cγ1 germline transcript in the BCL6-KO B cells was more than that in the BCL6-WT B cells. Conversely, IL-21 stimulation suppressed Cɛ expression in the BCL6-WT B cells. However, the suppression was not observed in the BCL6-KO B cells, suggesting that the IL-21-mediated suppression of Cɛ expression is due to BCL6. Thus, BCL6 controls the Cγ1 and Cɛ expression and stabilizes class switching to IgG1 in activated B cells simultaneously stimulated with IL-4 and IL-21.
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A role for BCL6 in sequential class switch recombination to IgE in B cells stimulated with IL-4 and IL-21.
Molecular immunology, 2007Co-Authors: Daisuke Kitayama, Akemi Sakamoto, Masafumi Arima, Masahiko Hatano, Masaru Miyazaki, Takeshi TokuhisaAbstract:IgE plays an important role in the pathogenesis of allergic diseases and high-affinity IgE memory B cells are differentiated from IgG1 B cells developed in germinal centers. BCL6, a sequence specific transcriptional repressor, is highly expressed in germinal center B cells and suppresses expression of Cvarepsilon germline transcript. However, a role for BCL6 in inhibition of the sequential class switching from IgG1 to IgE in germinal center B cells is not known. When splenic B cells from BCL6-deficient (BCL6-KO) and BCL6-transgenic (BCL6-TG) mice were stimulated with anti-IgM Ab and anti-CD40 Ab plus IL-4, IgG1(+)IgE(+) B cells were detected in BCL6-KO B cell culture but not in BCL6-TG B cell culture. Cgamma1 and Cvarepsilon germline transcript in BCL6-KO B cells were induced earlier than those in wild-type (BCL6-WT) B cells after stimulation. When activated B cells were simultaneously stimulated with IL-21, expression of Cgamma1 germline transcript in BCL6-WT and BCL6-KO B cells was enhanced by IL-21 stimulation, indicating that IL-21 is an enhancer of Cgamma1 expression induced by IL-4. The amount of Cgamma1 germline transcript in the BCL6-KO B cells was more than that in the BCL6-WT B cells. Conversely, IL-21 stimulation suppressed Cvarepsilon expression in the BCL6-WT B cells. However, the suppression was not observed in the BCL6-KO B cells, suggesting that the IL-21-mediated suppression of Cvarepsilon expression is due to BCL6. Thus, BCL6 controls the Cgamma1 and Cvarepsilon expression and stabilizes class switching to IgG1 in activated B cells simultaneously stimulated with IL-4 and IL-21.
Michelle A Fanale - One of the best experts on this subject based on the ideXlab platform.
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dose adjusted epoch r etoposide prednisone vincristine cyclophosphamide doxorubicin and rituximab in untreated aggressive diffuse large b cell lymphoma with myc rearrangement a prospective multicentre single arm phase 2 study
The Lancet Haematology, 2018Co-Authors: Kieron Dunleavy, Stefania Pittaluga, Jeremy S Abramson, Michelle A Fanale, Paolo Caimi, Samir Parekh, Ann S Lacasce, John Hayslip, Deepa Jagadeesh, Sunil NagpalAbstract:Summary Background MYC gene rearrangement is present in approximately 10% of aggressive B-cell lymphomas, with half also harbouring a BCL2 gene rearrangement. Multiple retrospective studies of R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone or prednisolone) have shown a worse outcome in patients with MYC rearrangement (alone or with rearrangement of BCL2 or BCL6, or both) than in patients without MYC rearrangement, and suggest improved outcomes after more intensive treatment. We aimed to determine the outcome of dose-adjusted EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab; DA-EPOCH-R), an intensive infusional treatment regimen, in untreated aggressive B-cell lymphoma with MYC rearrangement. Methods We present the final analysis of a prospective, multicentre, single-arm, phase 2 study of DA-EPOCH-R in patients with untreated aggressive B-cell lymphoma with MYC rearrangement. DA-EPOCH-R was scheduled to be administered with CNS prophylaxis for six cycles. Primary endpoints included event-free and overall survival. This study is registered with ClinicalTrials.gov ( NCT01092182 ). Findings 53 patients were enrolled, with median age of 61 years (range 29–80; IQR 50–70); 43 (81%) patients had stage III–IV disease and 26 (49%) had high-intermediate or high international prognostic index (IPI) scores. 19 patients had confirmed MYC rearrangement alone (single-hit) and 24 also had rearrangement of BCL2, BCL6, or both (double-hit), with similar characteristics between these two groups. After a median follow-up of 55·6 months (IQR 50·5–61·1), 48-month event-free survival was 71·0% (95% CI 56·5–81·4) and 48-month overall survival was 76·7% (95% CI 62·6–86·1) for all patients. Toxicity included grade 4 neutropenia in 160 (53%) of 301 cycles, grade 4 thrombocytopenia in 40 (13%) cycles, and any grade of fever with neutropenia in 56 (19%) cycles. There were three treatment-related deaths (all infections). Interpretation In this study, DA-EPOCH-R produced durable remission in patients with MYC-rearranged aggressive B-cell lymphomas and should be considered for the treatment of these diseases. Funding Cancer Trials Support Unit and Center for Cancer Research of the National Cancer Institute and Genentech.
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dose adjusted epoch r etoposide prednisone vincristine cyclophosphamide doxorubicin and rituximab in untreated aggressive diffuse large b cell lymphoma with myc rearrangement a prospective multicentre single arm phase 2 study
The Lancet Haematology, 2018Co-Authors: Kieron Dunleavy, Stefania Pittaluga, Jeremy S Abramson, Michelle A Fanale, Paolo Caimi, Samir Parekh, Ann S Lacasce, John Hayslip, Ariela Noy, Deepa JagadeeshAbstract:Summary Background MYC gene rearrangement is present in approximately 10% of aggressive B-cell lymphomas, with half also harbouring a BCL2 gene rearrangement. Multiple retrospective studies of R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone or prednisolone) have shown a worse outcome in patients with MYC rearrangement (alone or with rearrangement of BCL2 or BCL6, or both) than in patients without MYC rearrangement, and suggest improved outcomes after more intensive treatment. We aimed to determine the outcome of dose-adjusted EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab; DA-EPOCH-R), an intensive infusional treatment regimen, in untreated aggressive B-cell lymphoma with MYC rearrangement. Methods We present the final analysis of a prospective, multicentre, single-arm, phase 2 study of DA-EPOCH-R in patients with untreated aggressive B-cell lymphoma with MYC rearrangement. DA-EPOCH-R was scheduled to be administered with CNS prophylaxis for six cycles. Primary endpoints included event-free and overall survival. This study is registered with ClinicalTrials.gov ( NCT01092182 ). Findings 53 patients were enrolled, with median age of 61 years (range 29–80; IQR 50–70); 43 (81%) patients had stage III–IV disease and 26 (49%) had high-intermediate or high international prognostic index (IPI) scores. 19 patients had confirmed MYC rearrangement alone (single-hit) and 24 also had rearrangement of BCL2, BCL6, or both (double-hit), with similar characteristics between these two groups. After a median follow-up of 55·6 months (IQR 50·5–61·1), 48-month event-free survival was 71·0% (95% CI 56·5–81·4) and 48-month overall survival was 76·7% (95% CI 62·6–86·1) for all patients. Toxicity included grade 4 neutropenia in 160 (53%) of 301 cycles, grade 4 thrombocytopenia in 40 (13%) cycles, and any grade of fever with neutropenia in 56 (19%) cycles. There were three treatment-related deaths (all infections). Interpretation In this study, DA-EPOCH-R produced durable remission in patients with MYC-rearranged aggressive B-cell lymphomas and should be considered for the treatment of these diseases. Funding Cancer Trials Support Unit and Center for Cancer Research of the National Cancer Institute and Genentech.
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double hit lymphoma the md anderson cancer center clinical experience
British Journal of Haematology, 2014Co-Authors: Mansoor Noorani, Michelle A Fanale, Richard Eric Davis, Sattva S Neelapu, Mohamed Amin Ahmed, Maria A Rodriguez, Fredrick B Hagemeister, Nathan Fowler, Michael Wang, Loretta J NastoupilAbstract:Summary We report our experience with 129 cases of double hit lymphoma (DHL), defined as B-cell lymphoma with translocations and/or extra signals involving MYC plus BCL2 and/or BCL6. All cases were reviewed for histopathological classification. Median age was 62 years (range, 18–85), 84% of patients had advanced-stage disease, and 87% had an International Prognostic Index score ≥2. Fourteen patients (11%) had a history of low-grade follicular lymphoma. MYC translocation was present in 81%, and extra signals of MYC in 25% of patients. IGH-BCL2 translocation was present in 84% and extra signals of BCL2 in 12% of patients. Two-year event-free survival (EFS) rates in all patients and patients who received R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), R-EPOCH (rituximab, etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin), and R-HyperCVAD/MA (rituximab, hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, alternating with cytarabine plus methotrexate) were 33%, 25%, 67% and 32%, respectively. In patients achieving complete response with initial therapy (n = 71), 2-year EFS rates in patients who did (n = 23) or did not (n = 48) receive frontline stem cell transplantation were 68% and 53%, respectively (P = 0·155). The cumulative incidence of central nervous system involvement was 13% at 3 years. Multivariate analysis identified performance status ≥2 and bone marrow involvement as independent adverse prognostic factors for EFS and OS. Further research is needed to identify predictive and/or targetable biological markers and novel therapeutic approaches for DHL patients.