The impact on outcome of the addition of all-trans retinoic acid to intensive chemotherapy in younger patients with nonacute promyelocytic acute myeloid leukemia: overall results and results in genotypic subgroups defined by mutations in NPM1, FLT3, and CEBPA

AbstractWe investigated the benefit of adding all-trans retinoic acid (ATRA) to chemotherapy for younger patients with nonacute promyelocytic acute myeloid leukemia and high-risk myelodysplastic syndrome, and considered interactions between treatment and molecular markers. Overall, 1075 patients less than 60 years of age were randomized to receive or not receive ATRA in addition to daunorubicin/Ara-C/thioguanine chemotherapy with Ara-C at standard or double standard dose. There were data on FLT3 internal tandem duplications and NPM1 mutations (n = 592), CEBPA mutations (n = 423), and MN1 expression (n = 195). The complete remission rate was 68% with complete remission with incomplete count recovery in an additional 16%; 8-year overall survival was 32%. There was no significant treatment effect for any outcome, with no significant interactions between treatment and demographics, or cytarabine randomization. Importantly, there were no interactions by FLT3/internal tandem duplications, NPM1, or CEBPA mutation. There was a suggestion that ATRA reduced relapse in patients with lower MN1 levels, but no significant effect on overall survival. Results were consistent when restricted to patients with normal karyotype. ATRA has no overall effect on treatment outcomes in this group of patients. The study did not identify any subgroup of patients likely to derive a significant survival benefit from the addition of ATRA to chemotherapy. This study is registered at http://www.controlled-trials.com under ISRCTN17833622.

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Proteomic Studies of Primary Acute Myeloid Leukemia Cells Derived from Patients Before and during Disease-Stabilizing Treatment Based on All-Trans Retinoic Acid and Valproic Acid

Cancers ◽

10.3390/cancers13092143 ◽

2021 ◽

Vol 13 (9) ◽

pp. 2143

Author(s):

Maria Hernandez-Valladares ◽

Rebecca Wangen ◽

Elise Aasebø ◽

Håkon Reikvam ◽

Frode S. Berven ◽

...

Keyword(s):

Valproic Acid ◽

Acute Myeloid Leukemia ◽

Retinoic Acid ◽

Protein Kinase ◽

Myeloid Leukemia ◽

Rna Metabolism ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid ◽

Acute Myeloid

All-trans retinoic acid (ATRA) and valproic acid (VP) have been tried in the treatment of non-promyelocytic variants of acute myeloid leukemia (AML). Non-randomized studies suggest that the two drugs can stabilize AML and improve normal peripheral blood cell counts. In this context, we used a proteomic/phosphoproteomic strategy to investigate the in vivo effects of ATRA/VP on human AML cells. Before starting the combined treatment, AML responders showed increased levels of several proteins, especially those involved in neutrophil degranulation/differentiation, M phase regulation and the interconversion of nucleotide di- and triphosphates (i.e., DNA synthesis and binding). Several among the differentially regulated phosphorylation sites reflected differences in the regulation of RNA metabolism and apoptotic events at the same time point. These effects were mainly caused by increased cyclin dependent kinase 1 and 2 (CDK1/2), LIM domain kinase 1 and 2 (LIMK1/2), mitogen-activated protein kinase 7 (MAPK7) and protein kinase C delta (PRKCD) activity in responder cells. An extensive effect of in vivo treatment with ATRA/VP was the altered level and phosphorylation of proteins involved in the regulation of transcription/translation/RNA metabolism, especially in non-responders, but the regulation of cell metabolism, immune system and cytoskeletal functions were also affected. Our analysis of serial samples during the first week of treatment suggest that proteomic and phosphoproteomic profiling can be used for the early identification of responders to ATRA/VP-based treatment.

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Therapeutic Use of Valproic Acid and All-Trans Retinoic Acid in Acute Myeloid Leukemia—Literature Review and Discussion of Possible Use in Relapse after Allogeneic Stem Cell Transplantation

Pharmaceuticals ◽

10.3390/ph14050423 ◽

2021 ◽

Vol 14 (5) ◽

pp. 423

Author(s):

Øystein Bruserud ◽

Galina Tsykunova ◽

Maria Hernandez-Valladares ◽

Hakon Reikvam ◽

Tor Henrik Anderson Tvedt

Keyword(s):

Valproic Acid ◽

Acute Myeloid Leukemia ◽

Stem Cell ◽

Retinoic Acid ◽

Myeloid Leukemia ◽

Low Intensity ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid ◽

Low Toxicity ◽

Acute Myeloid

Even though allogeneic stem cell transplantation is the most intensive treatment for acute myeloid leukemia (AML), chemo-resistant leukemia relapse is still one of the most common causes of death for these patients, as is transplant-related mortality, i.e., graft versus host disease, infections, and organ damage. These relapse patients are not always candidates for additional intensive therapy or re-transplantation, and many of them have decreased quality of life and shortened expected survival. The efficiency of azacitidine for treatment of posttransplant AML relapse has been documented in several clinical trials. Valproic acid is an antiepileptic fatty acid that exerts antileukemic activity through histone deacetylase inhibition. The combination of valproic acid and all-trans retinoic acid (ATRA) is well tolerated even by unfit or elderly AML patients, and low-toxicity chemotherapy (e.g., azacitidine) can be added to this combination. The triple combination of azacitidine, valproic acid, and ATRA may therefore represent a low-intensity and low-toxicity alternative for these patients. In the present review, we review and discuss the general experience with valproic acid/ATRA in AML therapy and we discuss its possible use in low-intensity/toxicity treatment of post-allotransplant AML relapse. Our discussion is further illustrated by four case reports where combined treatments with sequential azacitidine/hydroxyurea, valproic acid, and ATRA were used.

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Chemotherapy and All-Trans Retinoic Acid in Patients >60 Years with Acute Myeloid Leukemia: First Results of the Multicenter Treatment Trial AML HD98-B

Haematology and Blood Transfusion / Hämatologie und Bluttransfusion - Acute Leukemias VIII ◽

10.1007/978-3-642-18156-6_96 ◽

2001 ◽

pp. 604-608 ◽

Cited By ~ 2

Author(s):

S. FröHling ◽

R. F. Schlenk ◽

F. Del Valle ◽

F. Hartmann ◽

A. Glasmacher ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Retinoic Acid ◽

Myeloid Leukemia ◽

Treatment Trial ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid ◽

First Results ◽

Acute Myeloid

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All-trans retinoic acid enhances, and a pan-RAR antagonist counteracts, the stem cell promoting activity of EVI1 in acute myeloid leukemia

Cell Death and Disease ◽

10.1038/s41419-019-2172-2 ◽

2019 ◽

Vol 10 (12) ◽

Cited By ~ 5

Author(s):

Chi Huu Nguyen ◽

Katharina Bauer ◽

Hubert Hackl ◽

Angela Schlerka ◽

Elisabeth Koller ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Stem Cell ◽

Retinoic Acid ◽

Cell Lines ◽

Myeloid Leukemia ◽

Leukemic Cells ◽

Dependent Manner ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid ◽

Acute Myeloid

AbstractEcotropic virus integration site 1 (EVI1), whose overexpression characterizes a particularly aggressive subtype of acute myeloid leukemia (AML), enhanced anti-leukemic activities of all-trans retinoic acid (atRA) in cell lines and patient samples. However, the drivers of leukemia formation, therapy resistance, and relapse are leukemic stem cells (LSCs), whose properties were hardly reflected in these experimental setups. The present study was designed to address the effects of, and interactions between, EVI1 and retinoids in AML LSCs. We report that Evi1 reduced the maturation of leukemic cells and promoted the abundance, quiescence, and activity of LSCs in an MLL-AF9-driven mouse model of AML. atRA further augmented these effects in an Evi1 dependent manner. EVI1 also strongly enhanced atRA regulated gene transcription in LSC enriched cells. One of their jointly regulated targets, Notch4, was an important mediator of their effects on leukemic stemness. In vitro exposure of leukemic cells to a pan-RAR antagonist caused effects opposite to those of atRA. In vivo antagonist treatment delayed leukemogenesis and reduced LSC abundance, quiescence, and activity in Evi1high AML. Key results were confirmed in human myeloid cell lines retaining some stem cell characteristics as well as in primary human AML samples. In summary, our study is the first to report the importance of EVI1 for key properties of AML LSCs. Furthermore, it shows that atRA enhances, and a pan-RAR antagonist counteracts, the effects of EVI1 on AML stemness, thus raising the possibility of using RAR antagonists in the therapy of EVI1high AML.

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