Phase I Study of Decitabine Alone or in Combination With Valproic Acid in Acute Myeloid Leukemia

Purpose To determine an optimal biologic dose (OBD) of decitabine as a single agent and then the maximum-tolerated dose (MTD) of valproic acid (VA) combined with decitabine in acute myeloid leukemia (AML). Patients and Methods Twenty-five patients (median age, 70 years) were enrolled; 12 were untreated and 13 had relapsed AML. To determine an OBD (based on a gene re-expression end point), 14 patients received decitabine alone for 10 days. To determine the MTD, 11 patients received decitabine (at OBD, days 1 through 10) plus dose-escalating VA (days 5 through 21). Results The OBD of decitabine was 20 mg/m2/d intravenously, with limited nonhematologic toxicity. In patients treated with decitabine plus VA, dose-limiting encephalopathy occurred in two of two patients at VA 25 mg/kg/d and one of six patients at VA 20 mg/kg/d. Drug-induced re-expression of estrogen receptor (ER) was associated with clinical response (P ≤ .05). ER promoter demethylation, global DNA hypomethylation, depletion of DNA methyltransferase enzyme, and histone hyperacetylation were also observed. In an intent-to-treat analysis, the response rate was 44% (11 of 25). Of 21 assessable patients, 11 (52%) responded: four with morphologic and cytogenetic complete remission (CR; each had complex karyotype), four with incomplete CR, and three with partial remission. In untreated AML, four of nine assessable patients achieved CR. Clinical responses appeared similar for decitabine alone or with VA. Conclusion Low-dose decitabine was safe and showed encouraging clinical and biologic activity in AML, but the addition of VA led to encephalopathy at relatively low doses. On the basis of these results, additional studies of decitabine (20 mg/m2/d for 10 days) alone or with an alternative deacetylating agent are warranted.

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Hotspot DNMT3A mutations in Clonal Hematopoiesis and Acute Myeloid Leukemia sensitize cells to Azacytidine via viral mimicry response

10.21203/rs.3.pex-1436/v1 ◽

2021 ◽

Author(s):

Marina Scheller ◽

Anne Kathrin Ludwig ◽

Stefanie Göllner ◽

Christian Rohde ◽

Stephen Krämer ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Dna Methyltransferase ◽

Predictive Marker ◽

Protein Translation ◽

Dna Hypomethylation ◽

Hematopoietic Stem ◽

Clonal Hematopoiesis ◽

Viral Mimicry ◽

Acute Myeloid

Abstract Somatic mutations in DNA Methyltransferase 3A (DNMT3A) are among the most frequent alterations in clonal hematopoiesis (CH) and Acute Myeloid Leukemia (AML), with a hotspot in exon 23 at arginine 882 (DNMT3A-R882). Here we demonstrate that DNMT3A-R882H-dependent CH- and AML cells are specifically susceptible to the hypomethylating agent azacytidine (AZA). Addition of AZA to chemotherapy prolonged AML survival solely in patients with DNMT3A-R882 mutation, suggesting its potential as a novel predictive marker for AZA response. AML and CH mouse models confirmed AZA susceptibility specifically in DNMT3A-R882H-expressing cells. Hematopoietic stem and progenitor cells expressing DNMT3A-R882H exhibited cell-autonomous viral mimicry response as a result of focal DNA hypomethylation at retrotransposon sequences. Administration of AZA boosted hypomethylation of retrotransposons specifically in DNMT3A-R882H expressing cells and maintained elevated levels of canonical interferon-stimulated genes (ISGs), thus leading to suppressed protein translation and increased apoptosis.

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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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FLT3 mutated acute myeloid leukemia: 2021 treatment algorithm

Blood Cancer Journal ◽

10.1038/s41408-021-00495-3 ◽

2021 ◽

Vol 11 (5) ◽

Author(s):

Naval Daver ◽

Sangeetha Venugopal ◽

Farhad Ravandi

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Single Agent ◽

Prognostic Significance ◽

Treatment Algorithm ◽

Molecular Testing ◽

Prognostic Impact ◽

Cell Transplant ◽

Newly Diagnosed ◽

Acute Myeloid

AbstractApproximately 30% of patients with newly diagnosed acute myeloid leukemia (AML) harbor mutations in the fms-like tyrosine kinase 3 (FLT3) gene. While the adverse prognostic impact of FLT3-ITDmut in AML has been clearly proven, the prognostic significance of FLT3-TKDmut remains speculative. Current guidelines recommend rapid molecular testing for FLT3mut at diagnosis and earlier incorporation of targeted agents to achieve deeper remissions and early consideration for allogeneic stem cell transplant (ASCT). Mounting evidence suggests that FLT3mut can emerge at any timepoint in the disease spectrum emphasizing the need for repetitive mutational testing not only at diagnosis but also at each relapse. The approval of multi-kinase FLT3 inhibitor (FLT3i) midostaurin with induction therapy for newly diagnosed FLT3mut AML, and a more specific, potent FLT3i, gilteritinib as monotherapy for relapsed/refractory (R/R) FLT3mut AML have improved outcomes in patients with FLT3mut AML. Nevertheless, the short duration of remission with single-agent FLT3i’s in R/R FLT3mut AML in the absence of ASCT, limited options in patients refractory to gilteritinib therapy, and diverse primary and secondary mechanisms of resistance to different FLT3i’s remain ongoing challenges that compel the development and rapid implementation of multi-agent combinatorial or sequential therapies for FLT3mut AML.

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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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Effect of histone deacetylase inhibitor valproic acid on progenitor cells of acute myeloid leukemia

Haematologica ◽

10.3324/haematol.10758 ◽

2007 ◽

Vol 92 (4) ◽

pp. 542-545 ◽

Cited By ~ 35

Author(s):

G. Bug ◽

K. Schwarz ◽

C. Schoch ◽

M. Kampfmann ◽

R. Henschler ◽

...

Keyword(s):

Valproic Acid ◽

Acute Myeloid Leukemia ◽

Progenitor Cells ◽

Histone Deacetylase ◽

Histone Deacetylase Inhibitor ◽

Myeloid Leukemia ◽

Deacetylase Inhibitor ◽

Acute Myeloid

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Single-agent and combination biologics in acute myeloid leukemia

Hematology ◽

10.1182/hematology.2019000059 ◽

2019 ◽

Vol 2019 (1) ◽

pp. 548-556 ◽

Cited By ~ 4

Author(s):

Guillaume Richard-Carpentier ◽

Courtney D. DiNardo

Keyword(s):

Acute Myeloid Leukemia ◽

Older Patients ◽

Myeloid Leukemia ◽

Single Agent ◽

Gemtuzumab Ozogamicin ◽

Targeted Agents ◽

Newly Diagnosed ◽

Rational Drug ◽

Genomic Characterization ◽

Acute Myeloid

Abstract Acute myeloid leukemia (AML) is a heterogeneous malignancy characterized by recurrent genetic, epigenetic, and metabolic abnormalities. As a result of our increasing knowledge of the underlying biology of AML leading to rational drug development, several new targeted agents have been recently added to our therapeutic arsenal. The BCL2 inhibitor venetoclax in combination with low-dose cytarabine (LDAC) or hypomethylating agents (HMAs) is safe and effective in older patients with newly diagnosed AML ineligible for intensive chemotherapy. Glasdegib, a hedgehog pathway inhibitor, may be used in combination with LDAC for the same indication and improves survival compared with LDAC alone. In newly diagnosed, fit, older patients with therapy-related AML or AML with myelodysplasia-related changes, the liposome-encapsulated combination of daunorubicin and cytarabine (CPX-351) has shown superiority over the 7 + 3 regimen. The presence of an IDH1 or IDH2 mutation can be effectively targeted by ivosidenib or enasidenib, respectively. Gemtuzumab ozogamicin improves event-free survival in CD33+ patients with favorable or intermediate-risk cytogenetics. With new targeted agents available, comprehensive genomic characterization of AML at diagnosis and relapse is increasingly necessary to select optimal treatment. Herein, we review the new single-agent and combination biologics (omitting FLT3 inhibitors, which are discussed separately) and provide recommendations on how to best use and manage patients on these regimens in clinical practice.

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Resistance to Drug-Induced Cytotoxicity in Acute Myeloid Leukemia is Significantly Correlated Between Inhibitors of Topoisomerases I and II and Nucleoside Analogues

Haematology and Blood Transfusion Hämatologie und Bluttransfusion - Acute Leukemias IX ◽

10.1007/978-3-642-59358-1_46 ◽

2003 ◽

pp. 287-290

Author(s):

I. Zimmermann ◽

M. Fiegl ◽

P. Schneiderat ◽

C. Schoch ◽

W. Kern ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Nucleoside Analogues ◽

Drug Induced ◽

Acute Myeloid

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Quizartinib in the treatment of FLT3-internal-tandem duplication-positive acute myeloid leukemia

Future Oncology ◽

10.2217/fon-2019-0353 ◽

2019 ◽

Vol 15 (34) ◽

pp. 3885-3894 ◽

Cited By ~ 1

Author(s):

Shilpa Paul ◽

Adam J DiPippo ◽

Farhad Ravandi ◽

Tapan M Kadia

Keyword(s):

Acute Myeloid Leukemia ◽

Tyrosine Kinase ◽

Myeloid Leukemia ◽

Tandem Duplication ◽

Kinase Inhibitors ◽

Single Agent ◽

Tyrosine Kinase Domain ◽

Missense Mutations ◽

Internal Tandem Duplication ◽

Acute Myeloid

FLT3 mutations, characterized by an internal-tandem duplication or missense mutations in the tyrosine kinase domain, are observed in a third of patients with newly diagnosed acute myeloid leukemia. FLT3-ITD mutations are associated with high relapse rates and short overall survival with conventional chemotherapy. Several tyrosine kinase inhibitors targeting FLT3 have been developed in an effort to improve survival and therapeutic options. This review focuses on quizartinib, a second-generation FLT3 inhibitor that has demonstrated efficacy and safety as a single agent and in combination with chemotherapy. We discuss its clinical development as well as its place in the treatment of FLT3-mutated acute myeloid leukemia among the other FLT3 inhibtors currently available and its mechanisms of resistance.

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