The DOT1L inhibitor pinometostat reduces H3K79 methylation and has modest clinical activity in adult acute leukemia

Publication Date:
2018-06-15
Publisher:
American Society of Hematology (ASH)
Print ISSN:
0006-4971
Electronic ISSN:
1528-0020
Topics:
Biology
Medicine
Keywords:
Myeloid Neoplasia, Clinical Trials and Observations
Published by:
http://www.hematology.org/
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autor Stein, E. M., Garcia-Manero, G., Rizzieri, D. A., Tibes, R., Berdeja, J. G., Savona, M. R., Jongen-Lavrenic, M., Altman, J. K., Thomson, B., Blakemore, S. J., Daigle, S. R., Waters, N. J., Suttle, A. B., Clawson, A., Pollock, R., Krivtsov, A., Armstrong, S. A., Di; Martino, J., Hedrick, E., Löwenberg, B., Tallman, M. S.
beschreibung Pinometostat (EPZ-5676) is a first-in-class small-molecule inhibitor of the histone methyltransferase disrupter of telomeric silencing 1-like (DOT1L). In this phase 1 study, pinometostat was evaluated for safety and efficacy in adult patients with advanced acute leukemias, particularly those involving mixed lineage leukemia ( MLL ) gene rearrangements ( MLL-r ) resulting from 11q23 translocations. Fifty-one patients were enrolled into 6 dose-escalation cohorts (n = 26) and 2 expansion cohorts (n = 25) at pinometostat doses of 54 and 90 mg/m 2 per day by continuous intravenous infusion in 28-day cycles. Because a maximum tolerated dose was not established in the dose-escalation phase, the expansion doses were selected based on safety and clinical response data combined with pharmacodynamic evidence of reduction in H3K79 methylation during dose escalation. Across all dose levels, plasma pinometostat concentrations increased in an approximately dose-proportional fashion, reaching an apparent steady-state by 4-8 hours after infusion, and rapidly decreased following treatment cessation. The most common adverse events, of any cause, were fatigue (39%), nausea (39%), constipation (35%), and febrile neutropenia (35%). Overall, 2 patients, both with t(11;19), experienced complete remission at 54 mg/m 2 per day by continuous intravenous infusion, demonstrating proof of concept for delivering clinically meaningful responses through targeting DOT1L using the single agent pinometostat in MLL-r leukemia patients. Administration of pinometostat was generally safe, with the maximum tolerated dose not being reached, although efficacy as a single agent was modest. This study demonstrates the therapeutic potential for targeting DOT1L in MLL-r leukemia and lays the groundwork for future combination approaches in this patient population. This clinical trial is registered at www.clinicaltrials.gov as NCT01684150.
citation_standardnr 6283208
datenlieferant ipn_articles
feed_id 310
feed_publisher American Society of Hematology (ASH)
feed_publisher_url http://www.hematology.org/
insertion_date 2018-06-15
journaleissn 1528-0020
journalissn 0006-4971
publikationsjahr_anzeige 2018
publikationsjahr_facette 2018
publikationsjahr_intervall 7984:2015-2019
publikationsjahr_sort 2018
publisher American Society of Hematology (ASH)
quelle Blood
relation http://www.bloodjournal.org/cgi/content/short/131/24/2661?rss=1
schlagwort Myeloid Neoplasia, Clinical Trials and Observations
search_space articles
shingle_author_1 Stein, E. M., Garcia-Manero, G., Rizzieri, D. A., Tibes, R., Berdeja, J. G., Savona, M. R., Jongen-Lavrenic, M., Altman, J. K., Thomson, B., Blakemore, S. J., Daigle, S. R., Waters, N. J., Suttle, A. B., Clawson, A., Pollock, R., Krivtsov, A., Armstrong, S. A., Di; Martino, J., Hedrick, E., Löwenberg, B., Tallman, M. S.
shingle_author_2 Stein, E. M., Garcia-Manero, G., Rizzieri, D. A., Tibes, R., Berdeja, J. G., Savona, M. R., Jongen-Lavrenic, M., Altman, J. K., Thomson, B., Blakemore, S. J., Daigle, S. R., Waters, N. J., Suttle, A. B., Clawson, A., Pollock, R., Krivtsov, A., Armstrong, S. A., Di; Martino, J., Hedrick, E., Löwenberg, B., Tallman, M. S.
shingle_author_3 Stein, E. M., Garcia-Manero, G., Rizzieri, D. A., Tibes, R., Berdeja, J. G., Savona, M. R., Jongen-Lavrenic, M., Altman, J. K., Thomson, B., Blakemore, S. J., Daigle, S. R., Waters, N. J., Suttle, A. B., Clawson, A., Pollock, R., Krivtsov, A., Armstrong, S. A., Di; Martino, J., Hedrick, E., Löwenberg, B., Tallman, M. S.
shingle_author_4 Stein, E. M., Garcia-Manero, G., Rizzieri, D. A., Tibes, R., Berdeja, J. G., Savona, M. R., Jongen-Lavrenic, M., Altman, J. K., Thomson, B., Blakemore, S. J., Daigle, S. R., Waters, N. J., Suttle, A. B., Clawson, A., Pollock, R., Krivtsov, A., Armstrong, S. A., Di; Martino, J., Hedrick, E., Löwenberg, B., Tallman, M. S.
shingle_catch_all_1 The DOT1L inhibitor pinometostat reduces H3K79 methylation and has modest clinical activity in adult acute leukemia
Myeloid Neoplasia, Clinical Trials and Observations
Pinometostat (EPZ-5676) is a first-in-class small-molecule inhibitor of the histone methyltransferase disrupter of telomeric silencing 1-like (DOT1L). In this phase 1 study, pinometostat was evaluated for safety and efficacy in adult patients with advanced acute leukemias, particularly those involving mixed lineage leukemia ( MLL ) gene rearrangements ( MLL-r ) resulting from 11q23 translocations. Fifty-one patients were enrolled into 6 dose-escalation cohorts (n = 26) and 2 expansion cohorts (n = 25) at pinometostat doses of 54 and 90 mg/m 2 per day by continuous intravenous infusion in 28-day cycles. Because a maximum tolerated dose was not established in the dose-escalation phase, the expansion doses were selected based on safety and clinical response data combined with pharmacodynamic evidence of reduction in H3K79 methylation during dose escalation. Across all dose levels, plasma pinometostat concentrations increased in an approximately dose-proportional fashion, reaching an apparent steady-state by 4-8 hours after infusion, and rapidly decreased following treatment cessation. The most common adverse events, of any cause, were fatigue (39%), nausea (39%), constipation (35%), and febrile neutropenia (35%). Overall, 2 patients, both with t(11;19), experienced complete remission at 54 mg/m 2 per day by continuous intravenous infusion, demonstrating proof of concept for delivering clinically meaningful responses through targeting DOT1L using the single agent pinometostat in MLL-r leukemia patients. Administration of pinometostat was generally safe, with the maximum tolerated dose not being reached, although efficacy as a single agent was modest. This study demonstrates the therapeutic potential for targeting DOT1L in MLL-r leukemia and lays the groundwork for future combination approaches in this patient population. This clinical trial is registered at www.clinicaltrials.gov as NCT01684150.
Stein, E. M., Garcia-Manero, G., Rizzieri, D. A., Tibes, R., Berdeja, J. G., Savona, M. R., Jongen-Lavrenic, M., Altman, J. K., Thomson, B., Blakemore, S. J., Daigle, S. R., Waters, N. J., Suttle, A. B., Clawson, A., Pollock, R., Krivtsov, A., Armstrong, S. A., Di; Martino, J., Hedrick, E., Löwenberg, B., Tallman, M. S.
American Society of Hematology (ASH)
0006-4971
00064971
1528-0020
15280020
shingle_catch_all_2 The DOT1L inhibitor pinometostat reduces H3K79 methylation and has modest clinical activity in adult acute leukemia
Myeloid Neoplasia, Clinical Trials and Observations
Pinometostat (EPZ-5676) is a first-in-class small-molecule inhibitor of the histone methyltransferase disrupter of telomeric silencing 1-like (DOT1L). In this phase 1 study, pinometostat was evaluated for safety and efficacy in adult patients with advanced acute leukemias, particularly those involving mixed lineage leukemia ( MLL ) gene rearrangements ( MLL-r ) resulting from 11q23 translocations. Fifty-one patients were enrolled into 6 dose-escalation cohorts (n = 26) and 2 expansion cohorts (n = 25) at pinometostat doses of 54 and 90 mg/m 2 per day by continuous intravenous infusion in 28-day cycles. Because a maximum tolerated dose was not established in the dose-escalation phase, the expansion doses were selected based on safety and clinical response data combined with pharmacodynamic evidence of reduction in H3K79 methylation during dose escalation. Across all dose levels, plasma pinometostat concentrations increased in an approximately dose-proportional fashion, reaching an apparent steady-state by 4-8 hours after infusion, and rapidly decreased following treatment cessation. The most common adverse events, of any cause, were fatigue (39%), nausea (39%), constipation (35%), and febrile neutropenia (35%). Overall, 2 patients, both with t(11;19), experienced complete remission at 54 mg/m 2 per day by continuous intravenous infusion, demonstrating proof of concept for delivering clinically meaningful responses through targeting DOT1L using the single agent pinometostat in MLL-r leukemia patients. Administration of pinometostat was generally safe, with the maximum tolerated dose not being reached, although efficacy as a single agent was modest. This study demonstrates the therapeutic potential for targeting DOT1L in MLL-r leukemia and lays the groundwork for future combination approaches in this patient population. This clinical trial is registered at www.clinicaltrials.gov as NCT01684150.
Stein, E. M., Garcia-Manero, G., Rizzieri, D. A., Tibes, R., Berdeja, J. G., Savona, M. R., Jongen-Lavrenic, M., Altman, J. K., Thomson, B., Blakemore, S. J., Daigle, S. R., Waters, N. J., Suttle, A. B., Clawson, A., Pollock, R., Krivtsov, A., Armstrong, S. A., Di; Martino, J., Hedrick, E., Löwenberg, B., Tallman, M. S.
American Society of Hematology (ASH)
0006-4971
00064971
1528-0020
15280020
shingle_catch_all_3 The DOT1L inhibitor pinometostat reduces H3K79 methylation and has modest clinical activity in adult acute leukemia
Myeloid Neoplasia, Clinical Trials and Observations
Pinometostat (EPZ-5676) is a first-in-class small-molecule inhibitor of the histone methyltransferase disrupter of telomeric silencing 1-like (DOT1L). In this phase 1 study, pinometostat was evaluated for safety and efficacy in adult patients with advanced acute leukemias, particularly those involving mixed lineage leukemia ( MLL ) gene rearrangements ( MLL-r ) resulting from 11q23 translocations. Fifty-one patients were enrolled into 6 dose-escalation cohorts (n = 26) and 2 expansion cohorts (n = 25) at pinometostat doses of 54 and 90 mg/m 2 per day by continuous intravenous infusion in 28-day cycles. Because a maximum tolerated dose was not established in the dose-escalation phase, the expansion doses were selected based on safety and clinical response data combined with pharmacodynamic evidence of reduction in H3K79 methylation during dose escalation. Across all dose levels, plasma pinometostat concentrations increased in an approximately dose-proportional fashion, reaching an apparent steady-state by 4-8 hours after infusion, and rapidly decreased following treatment cessation. The most common adverse events, of any cause, were fatigue (39%), nausea (39%), constipation (35%), and febrile neutropenia (35%). Overall, 2 patients, both with t(11;19), experienced complete remission at 54 mg/m 2 per day by continuous intravenous infusion, demonstrating proof of concept for delivering clinically meaningful responses through targeting DOT1L using the single agent pinometostat in MLL-r leukemia patients. Administration of pinometostat was generally safe, with the maximum tolerated dose not being reached, although efficacy as a single agent was modest. This study demonstrates the therapeutic potential for targeting DOT1L in MLL-r leukemia and lays the groundwork for future combination approaches in this patient population. This clinical trial is registered at www.clinicaltrials.gov as NCT01684150.
Stein, E. M., Garcia-Manero, G., Rizzieri, D. A., Tibes, R., Berdeja, J. G., Savona, M. R., Jongen-Lavrenic, M., Altman, J. K., Thomson, B., Blakemore, S. J., Daigle, S. R., Waters, N. J., Suttle, A. B., Clawson, A., Pollock, R., Krivtsov, A., Armstrong, S. A., Di; Martino, J., Hedrick, E., Löwenberg, B., Tallman, M. S.
American Society of Hematology (ASH)
0006-4971
00064971
1528-0020
15280020
shingle_catch_all_4 The DOT1L inhibitor pinometostat reduces H3K79 methylation and has modest clinical activity in adult acute leukemia
Myeloid Neoplasia, Clinical Trials and Observations
Pinometostat (EPZ-5676) is a first-in-class small-molecule inhibitor of the histone methyltransferase disrupter of telomeric silencing 1-like (DOT1L). In this phase 1 study, pinometostat was evaluated for safety and efficacy in adult patients with advanced acute leukemias, particularly those involving mixed lineage leukemia ( MLL ) gene rearrangements ( MLL-r ) resulting from 11q23 translocations. Fifty-one patients were enrolled into 6 dose-escalation cohorts (n = 26) and 2 expansion cohorts (n = 25) at pinometostat doses of 54 and 90 mg/m 2 per day by continuous intravenous infusion in 28-day cycles. Because a maximum tolerated dose was not established in the dose-escalation phase, the expansion doses were selected based on safety and clinical response data combined with pharmacodynamic evidence of reduction in H3K79 methylation during dose escalation. Across all dose levels, plasma pinometostat concentrations increased in an approximately dose-proportional fashion, reaching an apparent steady-state by 4-8 hours after infusion, and rapidly decreased following treatment cessation. The most common adverse events, of any cause, were fatigue (39%), nausea (39%), constipation (35%), and febrile neutropenia (35%). Overall, 2 patients, both with t(11;19), experienced complete remission at 54 mg/m 2 per day by continuous intravenous infusion, demonstrating proof of concept for delivering clinically meaningful responses through targeting DOT1L using the single agent pinometostat in MLL-r leukemia patients. Administration of pinometostat was generally safe, with the maximum tolerated dose not being reached, although efficacy as a single agent was modest. This study demonstrates the therapeutic potential for targeting DOT1L in MLL-r leukemia and lays the groundwork for future combination approaches in this patient population. This clinical trial is registered at www.clinicaltrials.gov as NCT01684150.
Stein, E. M., Garcia-Manero, G., Rizzieri, D. A., Tibes, R., Berdeja, J. G., Savona, M. R., Jongen-Lavrenic, M., Altman, J. K., Thomson, B., Blakemore, S. J., Daigle, S. R., Waters, N. J., Suttle, A. B., Clawson, A., Pollock, R., Krivtsov, A., Armstrong, S. A., Di; Martino, J., Hedrick, E., Löwenberg, B., Tallman, M. S.
American Society of Hematology (ASH)
0006-4971
00064971
1528-0020
15280020
shingle_title_1 The DOT1L inhibitor pinometostat reduces H3K79 methylation and has modest clinical activity in adult acute leukemia
shingle_title_2 The DOT1L inhibitor pinometostat reduces H3K79 methylation and has modest clinical activity in adult acute leukemia
shingle_title_3 The DOT1L inhibitor pinometostat reduces H3K79 methylation and has modest clinical activity in adult acute leukemia
shingle_title_4 The DOT1L inhibitor pinometostat reduces H3K79 methylation and has modest clinical activity in adult acute leukemia
timestamp 2025-06-30T23:35:33.410Z
titel The DOT1L inhibitor pinometostat reduces H3K79 methylation and has modest clinical activity in adult acute leukemia
titel_suche The DOT1L inhibitor pinometostat reduces H3K79 methylation and has modest clinical activity in adult acute leukemia
topic W
WW-YZ
uid ipn_articles_6283208