Abstract
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.
Highlights
Many acute myeloid leukemia (AML) patients are not eligible to receive initial or salvage standard cytotoxic chemotherapy due to advanced age, comorbidities or cumulative toxicity from prior therapy
The mechanism by which glycogen synthase kinase-3 (GSK3) inhibition leads to AML cell differentiation is largely unknown, we previously reported that GSK3 inhibition can potentiate the differentiation effects of tretinoin [2, 8, 9]
We describe a novel approach using lithium, a GSK3 inhibitor, in combination with tretinoin for differentiation therapy in relapsed, refractory AML patients
Summary
Many acute myeloid leukemia (AML) patients are not eligible to receive initial or salvage standard cytotoxic chemotherapy due to advanced age, comorbidities or cumulative toxicity from prior therapy. Prior studies have shown that glycogen synthase kinase-3 (GSK3) inhibition induces differentiation and proliferation arrest in non-promyelocytic AML cells in vitro and in pre-clinical animal models [2,3,4,5,6,7]. The “leadin” period prior to cycle 1 was designed to allow for correlative studies to investigate the effects of lithium on leukemic cell GSK3 activity and to ensure achievement of adequate serum lithium concentrations prior to tretinoin exposure. In order to study the separate effects of GSK3 inhibition or tretinoin on AML stem cells, we used previously obtained cryopreserved blood samples from the Eastern Cooperative Oncology Group (ECOG) tumor repository of newly diagnosed and untreated AML patients (independent of this trial) to
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