Phase I Trial of Lithium and Tretinoin for Treatment of Relapsed and Refractory Non-promyelocytic Acute Myeloid Leukemia
Glycogen synthase kinase-3 (GSK3) inhibitors induce differentiation and growth inhibition of acute myeloid leukemia (AML) cells. Our pre-clinical studies showed GSK3 inhibition leads to sensitization of AML cells to tretinoin-mediated differentiation. We conducted a phase I trial of lithium, a GSK3...
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Frontiers Media S.A.
2020-03-01
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Series: | Frontiers in Oncology |
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Online Access: | https://www.frontiersin.org/article/10.3389/fonc.2020.00327/full |
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Article |
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DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Masumi Ueda Masumi Ueda Tammy Stefan Lindsay Stetson James J. Ignatz-Hoover Benjamin Tomlinson Benjamin Tomlinson Richard J. Creger Richard J. Creger Brenda Cooper Brenda Cooper Hillard M. Lazarus Hillard M. Lazarus Marcos de Lima Marcos de Lima David N. Wald David N. Wald Paolo F. Caimi Paolo F. Caimi |
spellingShingle |
Masumi Ueda Masumi Ueda Tammy Stefan Lindsay Stetson James J. Ignatz-Hoover Benjamin Tomlinson Benjamin Tomlinson Richard J. Creger Richard J. Creger Brenda Cooper Brenda Cooper Hillard M. Lazarus Hillard M. Lazarus Marcos de Lima Marcos de Lima David N. Wald David N. Wald Paolo F. Caimi Paolo F. Caimi Phase I Trial of Lithium and Tretinoin for Treatment of Relapsed and Refractory Non-promyelocytic Acute Myeloid Leukemia Frontiers in Oncology AML differentiation stem cells lithium tretinoin |
author_facet |
Masumi Ueda Masumi Ueda Tammy Stefan Lindsay Stetson James J. Ignatz-Hoover Benjamin Tomlinson Benjamin Tomlinson Richard J. Creger Richard J. Creger Brenda Cooper Brenda Cooper Hillard M. Lazarus Hillard M. Lazarus Marcos de Lima Marcos de Lima David N. Wald David N. Wald Paolo F. Caimi Paolo F. Caimi |
author_sort |
Masumi Ueda |
title |
Phase I Trial of Lithium and Tretinoin for Treatment of Relapsed and Refractory Non-promyelocytic Acute Myeloid Leukemia |
title_short |
Phase I Trial of Lithium and Tretinoin for Treatment of Relapsed and Refractory Non-promyelocytic Acute Myeloid Leukemia |
title_full |
Phase I Trial of Lithium and Tretinoin for Treatment of Relapsed and Refractory Non-promyelocytic Acute Myeloid Leukemia |
title_fullStr |
Phase I Trial of Lithium and Tretinoin for Treatment of Relapsed and Refractory Non-promyelocytic Acute Myeloid Leukemia |
title_full_unstemmed |
Phase I Trial of Lithium and Tretinoin for Treatment of Relapsed and Refractory Non-promyelocytic Acute Myeloid Leukemia |
title_sort |
phase i trial of lithium and tretinoin for treatment of relapsed and refractory non-promyelocytic acute myeloid leukemia |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Oncology |
issn |
2234-943X |
publishDate |
2020-03-01 |
description |
Glycogen synthase kinase-3 (GSK3) inhibitors induce differentiation and growth inhibition of acute myeloid leukemia (AML) cells. Our pre-clinical studies showed GSK3 inhibition leads to sensitization of AML cells to tretinoin-mediated differentiation. We conducted a phase I trial of lithium, a GSK3 inhibitor, plus tretinoin for relapsed, refractory non-promyelocytic AML. Nine patients with median (range) age 65 (42–82) years were enrolled. All subjects had relapsed leukemia after prior therapy, with a median (range) of 3 (1–3) prior therapies. Oral lithium carbonate 300 mg was given 2–3 times daily and adjusted to meet target serum concentration (0.6 to 1.0 mmol/L); tretinoin 22.5 or 45 mg/m2/day (two equally divided doses) was administered orally on days 1–7 and 15–21 of a 28-day cycle. Four patients attained disease stability with no increase in circulating blasts for ≥4 weeks. Median (range) survival was 106 days (60–502). Target serum lithium concentration was achieved in all patients and correlated with GSK3 inhibition in leukemic cells. Immunophenotypic changes associated with myeloid differentiation were observed in five patients. The combination treatment led to a reduction in the CD34+ CD38– AML stem cell population both in vivo and in vitro. The combination of lithium and tretinoin is well-tolerated, induces differentiation of leukemic cells, and may target AML stem cells, but has limited clinical activity in the absence of other antileukemic agents. The results of this clinical trial suggest GSK3 inhibition can result in AML cell differentiation and may be a novel therapeutic strategy in this disease, particularly in combination with other antileukemic agents. Lithium is a weak GSK3 inhibitor and future strategies in AML treatment will probably require more potent agents targeting this pathway or combinations with other antileukemic agents. This trial is registered at ClinicalTrials.gov NCT01820624. |
topic |
AML differentiation stem cells lithium tretinoin |
url |
https://www.frontiersin.org/article/10.3389/fonc.2020.00327/full |
work_keys_str_mv |
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doaj-7a3b5042e3c04c95a7f9e16640dfa4ff2020-11-25T02:07:55ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2020-03-011010.3389/fonc.2020.00327500553Phase I Trial of Lithium and Tretinoin for Treatment of Relapsed and Refractory Non-promyelocytic Acute Myeloid LeukemiaMasumi Ueda0Masumi Ueda1Tammy Stefan2Lindsay Stetson3James J. Ignatz-Hoover4Benjamin Tomlinson5Benjamin Tomlinson6Richard J. Creger7Richard J. Creger8Brenda Cooper9Brenda Cooper10Hillard M. Lazarus11Hillard M. Lazarus12Marcos de Lima13Marcos de Lima14David N. Wald15David N. Wald16Paolo F. Caimi17Paolo F. Caimi18Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United StatesDepartment of Medicine, Division of Medical Oncology, University of Washington, Seattle, WA, United StatesDepartment of Pathology, Case Western Reserve University, Cleveland, OH, United StatesDepartment of Pathology, Case Western Reserve University, Cleveland, OH, United StatesDepartment of Pathology, Case Western Reserve University, Cleveland, OH, United StatesStem Cell Transplant and Hematologic Malignancies Program, University Hospitals Seidman Cancer Center, Cleveland, OH, United StatesCase Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, United StatesStem Cell Transplant and Hematologic Malignancies Program, University Hospitals Seidman Cancer Center, Cleveland, OH, United StatesCase Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, United StatesStem Cell Transplant and Hematologic Malignancies Program, University Hospitals Seidman Cancer Center, Cleveland, OH, United StatesCase Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, United StatesStem Cell Transplant and Hematologic Malignancies Program, University Hospitals Seidman Cancer Center, Cleveland, OH, United StatesCase Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, United StatesStem Cell Transplant and Hematologic Malignancies Program, University Hospitals Seidman Cancer Center, Cleveland, OH, United StatesCase Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, United StatesDepartment of Pathology, Case Western Reserve University, Cleveland, OH, United StatesCase Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, United StatesStem Cell Transplant and Hematologic Malignancies Program, University Hospitals Seidman Cancer Center, Cleveland, OH, United StatesCase Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, United StatesGlycogen synthase kinase-3 (GSK3) inhibitors induce differentiation and growth inhibition of acute myeloid leukemia (AML) cells. Our pre-clinical studies showed GSK3 inhibition leads to sensitization of AML cells to tretinoin-mediated differentiation. We conducted a phase I trial of lithium, a GSK3 inhibitor, plus tretinoin for relapsed, refractory non-promyelocytic AML. Nine patients with median (range) age 65 (42–82) years were enrolled. All subjects had relapsed leukemia after prior therapy, with a median (range) of 3 (1–3) prior therapies. Oral lithium carbonate 300 mg was given 2–3 times daily and adjusted to meet target serum concentration (0.6 to 1.0 mmol/L); tretinoin 22.5 or 45 mg/m2/day (two equally divided doses) was administered orally on days 1–7 and 15–21 of a 28-day cycle. Four patients attained disease stability with no increase in circulating blasts for ≥4 weeks. Median (range) survival was 106 days (60–502). Target serum lithium concentration was achieved in all patients and correlated with GSK3 inhibition in leukemic cells. Immunophenotypic changes associated with myeloid differentiation were observed in five patients. The combination treatment led to a reduction in the CD34+ CD38– AML stem cell population both in vivo and in vitro. The combination of lithium and tretinoin is well-tolerated, induces differentiation of leukemic cells, and may target AML stem cells, but has limited clinical activity in the absence of other antileukemic agents. The results of this clinical trial suggest GSK3 inhibition can result in AML cell differentiation and may be a novel therapeutic strategy in this disease, particularly in combination with other antileukemic agents. Lithium is a weak GSK3 inhibitor and future strategies in AML treatment will probably require more potent agents targeting this pathway or combinations with other antileukemic agents. This trial is registered at ClinicalTrials.gov NCT01820624.https://www.frontiersin.org/article/10.3389/fonc.2020.00327/fullAMLdifferentiationstem cellslithiumtretinoin |