Hypomethylating agent and venetoclax with FLT3 inhibitor “triplet” therapy in older/unfit patients with FLT3 mutated AML

Yılmaz, Musa; Kantarjian, Hagop M.; Short, Nicholas J.; Reville, Patrick K.; Konopleva, Marina; Kadia, Tapan M.; DiNardo, Courtney D.; Borthakur, Gautam; Pemmaraju, Naveen; Maiti, Abhishek; Jabbour, Elias; Jain, Nitin; Issa, Ghayas C.; Takahashi, Koichi; Sasaki, Koji; Ohanian, Maro; Pierce, Sherry; Tang, Guilin; Loghavi, Sanam; Patel, Keyur P.; Wang, Sa A.; Andreeff, Michael; Ravandi, Farhad; Daver, Naval

doi:10.1038/s41408-022-00670-0

Cited by 45 publications

(35 citation statements)

References 23 publications

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“…87 A phase I/II study explored the triplet combination based on azacitidine, venetoclax and gilteritinib for FLT3-mutated AML patients with de novo (11 patients) or refractory/relapsing (15 patients) disease. 86 In ND AML patients, 82% of CRs were observed, with 18% of patients proceeding to HSCT; in R/R AML patients, 27% of CRs were observed. 88 New drug combinations involving VEN are under preclinical for the therapy of FLT3-mutated AMLs.…”

Section: Flt3-mutatedmentioning

confidence: 96%

“…After a median follow-up of 24 months, patients receiving the triplet regimen displayed a longer mOS than those treated with the doublet regimen: not reached vs. 9.5 months, respectively. 86 Another recent study explored the triplet drug combination based on quizartinib (a second-generation FLT3 inhibitor), VEN and DEC in newly diagnosed and R/R patients with FLT3-ITD mutated AML. 87 Preclinical studies supported the rationale of the association of VEN with quizartinib.…”

Section: Flt3-mutatedmentioning

confidence: 99%

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The Growing Role of the Bh3 Mimetic Drug Venetoclax in the Therapy of Acute Myeloid Leukemia

Castelli¹,

Testa²

2022

Mediterr J Hematol Infect Dis

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In spite recent progresses, acute myeloid leukemia (AML) remains a disease associated with poor prognosis, particularly in older AML patients unfit to tolerate intensive chemotherapy treatment. The development and introduction in therapy of the drug Venetoclax, a potent BH3 mimetic targeting the antiaopoptotic protein BCL-2, inducing apoptosis of leukemic cells, has shown to be a promising treatment for newly diagnosed, relapsed and refractory AML patients ineligible for induction chemotherapy. Combination treatments using Ventoclax and a hypomethylating agent (azacytidine or decitabine) or low-intensity chemotherapy have shown in newly diagnosed patients variable response rates, with highly responsive patients with NPM1, IDH1-IDH2, TET2 and RUNX1 mutations and with scarcely responsive patients with FLT3, TP53 and ASXL1 mutations, complex karyotypes and secondary AMLs. Patients with refractory/relapsing disease are less responsive to Venetoclax-based regimens. However, in the majority of patients the responses have only a limited duration and development of resistance is frequently observed. Understanding mechanisms of resistance is of crucial importance for the development of new strategies and identification of rational drug combination regimens. In this context, two strategies seem to be promising: (i) triplet therapies based on the combined administration of Venetoclax, a hypomethylating agent (or low-dose chemotherapy) and an agent targeting a specific genetic alteration of leukemic cells (i.e., FLT3 inhibitors in FLT3-mutated AMLs) or an altered signaling pathway; (ii) combination therapies based on the administration of two BH3 mimetics (i.e., BCL-2 +MCL-1 mimetics) and a hypomethylating agent.

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Section: Flt3-mutatedmentioning

confidence: 96%

Section: Flt3-mutatedmentioning

confidence: 99%

The Growing Role of the Bh3 Mimetic Drug Venetoclax in the Therapy of Acute Myeloid Leukemia

Castelli¹,

Testa²

2022

Mediterr J Hematol Infect Dis

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“…The median 2-year OS for newly diagnosed and relapsed or refractory AML patients, when treated with triple therapy, was 80% and 29%, respectively [ 134 ]. In addition, in a retrospective analysis in FLT3-mutated patients, CR/CRi rates improved to 93% with triple therapy (low intensity chemotherapy, FLT3 inhibitor and venetoclax) compared to 70% with double therapy (low intensity chemotherapy and an FLT3 inhibitor) [ 135 ]. Possibly, future treatment options for FLT3-mutated AML patients should include the combination of venetoclax together with an FLT3 inhibitor.…”

Section: Prediction Of Active Venetoclax-based Combination Therapies ...mentioning

confidence: 99%

Targeting Acute Myeloid Leukemia with Venetoclax; Biomarkers for Sensitivity and Rationale for Venetoclax-Based Combination Therapies

Griffioen

Leeuw

Janssen

et al. 2022

Cancers

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Venetoclax is a BCL-2 inhibitor that effectively improves clinical outcomes in newly diagnosed, relapsed and refractory acute myeloid leukemia (AML) patients, with complete response rates (with and without complete blood count recovery) ranging between 34–90% and 21–33%, respectively. Here, we aim to give an overview of the efficacy of venetoclax-based therapy for AML patients, as compared to standard chemotherapy, and on factors and mechanisms involved in venetoclax sensitivity and resistance in AML (stem) cells, with the aim to obtain a perspective of response biomarkers and combination therapies that could enhance the sensitivity of AML cells to venetoclax. The presence of molecular aberrancies can predict responses to venetoclax, with a higher response in NPM1-, IDH1/2-, TET2- and relapsed or refractory RUNX1-mutated AML. Decreased sensitivity to venetoclax was observed in patients harboring FLT3-ITD, TP53, K/NRAS or PTPN11 mutations. Moreover, resistance to venetoclax was observed in AML with a monocytic phenotype and patients pre-treated with hypomethylating agents. Resistance to venetoclax can arise due to mutations in BCL-2 or pro-apoptotic proteins, an increased dependency on MCL-1, and usage of additional/alternative sources for energy metabolism, such as glycolysis and fatty acid metabolism. Clinical studies are testing combination therapies that may circumvent resistance, including venetoclax combined with FLT3- and MCL-1 inhibitors, to enhance venetoclax-induced cell death. Other treatments that can potentially synergize with venetoclax, including MEK1/2 and mitochondrial complex inhibitors, need to be evaluated in a clinical setting.

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“…The composite complete remission (CRc) rates in patients with newly diagnosed AML achieve 92% and 62% in R/R patients ( 64 ). Moreover, a retrospective analysis of their team demonstrated that older and unfit adult patients with newly diagnosed FLT3 mutated AML receiving a triplet regimen (lower intensity chemotherapy + FLT3 inhibitor + venetoclax) had a significantly higher CR/CRi rate (93% vs. 70%, P = 0.02) and longer median overall survival (NR vs. 9.5 months, P < 0.01) compared with doublet (lower intensity chemotherapy + FLT3 inhibitor) regimens ( 65 ). Overall, the combination of venetoclax and FLT3 inhibitors may be an effective frontline regimen for FLT3 mutated AML, which should be further validated prospectively.…”

Section: Flt3 Inhibitors For Aml Therapymentioning

confidence: 99%

Developments and challenges of FLT3 inhibitors in acute myeloid leukemia

Liu

Xue

2022

Front. Oncol.

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FLT3 mutations are one of the most common genetic alterations in acute myeloid leukemia (AML) and are identified in approximately one-third of newly diagnosed patients. Aberrant FLT3 receptor signaling has important implications for the biology and clinical management of AML. In recent years, targeting FLT3 has been a part of every course of treatment in FLT3-ITD/TKD-mutated AML and contributes to substantially prolonged survival. At the same time, wide application of next-generation sequencing (NGS) technology has revealed a series of non-canonical FLT3 mutations, including point mutations and small insertions/deletions. Some of these mutations may be able to influence downstream phosphorylation and sensitivity to FLT3 inhibitors, while the correlation with clinical outcomes remains unclear. Exploration of FLT3-targeted therapy has made substantial progress, but resistance to FLT3 inhibitors has become a pressing issue. The mechanisms underlying FLT3 inhibitor tolerance can be roughly divided into primary resistance and secondary resistance. Primary resistance is related to abnormalities in signaling factors, such as FL, CXCL12, and FGF2, and secondary resistance mainly involves on-target mutations and off-target aberrations. To overcome this problem, novel agents such as FF-10101 have shown promising potential. Multitarget strategies directed at FLT3 and anomalous signaling factors simultaneously are in active clinical development and show promising results.

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Hypomethylating agent and venetoclax with FLT3 inhibitor “triplet” therapy in older/unfit patients with FLT3 mutated AML

Cited by 45 publications

References 23 publications

The Growing Role of the Bh3 Mimetic Drug Venetoclax in the Therapy of Acute Myeloid Leukemia

The Growing Role of the Bh3 Mimetic Drug Venetoclax in the Therapy of Acute Myeloid Leukemia

Targeting Acute Myeloid Leukemia with Venetoclax; Biomarkers for Sensitivity and Rationale for Venetoclax-Based Combination Therapies

Developments and challenges of FLT3 inhibitors in acute myeloid leukemia

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