High Deliverability of a Midostaurin Triplet Regimen Incorporating Venetoclax and Low Dose Cytarabine in Non-Adverse Cytogenetic Risk Acute Myeloid Leukaemia: A Sub-Analysis of the Australasian Leukaemia Lymphoma Group (ALLG) Intervene Study

Chua, Chong Chyn; Anstee, Natasha S.; Enjeti, Anoop K; Hiwase, Devendra; Marlton, Paula; Bajel, Ashish; Tan, Shuh Ying; Morris, Edward S.; Ma, Chun-Kei-Kris; Grove, Carolyn; Cooney, Julian; Beligaswatte, Ashanka; Koldej, Rachel; Ting, Stephen B.; Perera, Travis; Johnston, A.; Reynolds, John; Ritchie, David; Wei, Andrew H.

doi:10.1182/blood-2022-163084

Cited by 5 publications

(3 citation statements)

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“…The regimen was well tolerated, as evidenced by inter-cycle times of 28–35 days. A randomized phase 2 trial comparing LDAC/venetoclax/midostaurin to LDAC/venetoclax, is currently ongoing [ 34 ].…”

Section: Flt3 Inhibitors In the Front-line Settingmentioning

confidence: 99%

Targeting FLT3 Mutation in Acute Myeloid Leukemia: Current Strategies and Future Directions

Fedorov

Maiti

Konopleva

2023

Cancers

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FLT3 mutations are present in 30% of newly diagnosed patients with acute myeloid leukemia. Two broad categories of FLT3 mutations are ITD and TKD, with the former having substantial clinical significance. Patients with FLT3-ITD mutation present with a higher disease burden and have inferior overall survival, due to high relapse rates after achieving remission. The development of targeted therapies with FLT3 inhibitors over the past decade has substantially improved clinical outcomes. Currently, two FLT3 inhibitors are approved for use in patients with acute myeloid leukemia: midostaurin in the frontline setting, in combination with intensive chemotherapy; and gilteritinib as monotherapy in the relapsed refractory setting. The addition of FLT3 inhibitors to hypomethylating agents and venetoclax offers superior responses in several completed and ongoing studies, with encouraging preliminary data. However, responses to FLT3 inhibitors are of limited duration due to the emergence of resistance. A protective environment within the bone marrow makes eradication of FLT3mut leukemic cells difficult, while prior exposure to FLT3 inhibitors leads to the development of alternative FLT3 mutations as well as activating mutations in downstream signaling, promoting resistance to currently available therapies. Multiple novel therapeutic strategies are under investigation, including BCL-2, menin, and MERTK inhibitors, as well as FLT3-directed BiTEs and CAR-T therapy.

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Section: Flt3 Inhibitors In the Front-line Settingmentioning

confidence: 99%

Targeting FLT3 Mutation in Acute Myeloid Leukemia: Current Strategies and Future Directions

Fedorov

Maiti

Konopleva

2023

Cancers

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“…Data comparing LDAC + VEN + MIDO to LDAC + VEN regimens will be presented from an ongoing phase 2 clinical trial (ACTRN12619001655134) [129].…”

Section: Bcl-2 and Flt3 Inhibitorsmentioning

confidence: 99%

AML under the Scope: Current Strategies and Treatment Involving FLT3 Inhibitors and Venetoclax-Based Regimens

Milnerowicz,

Maszewska,

Skowera

et al. 2023

IJMS

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Acute myeloid leukemia (AML) is a disease that mainly affects elderly patients who are more often unfit for intensive chemotherapy (median age of diagnosis is 68). The regimens, including venetoclax, a highly specific BCL-2 (B-cell lymphoma-2) inhibitor, are a common alternative because of their safer profile and fewer side effects. However, the resistance phenomenon of leukemic cells necessitates the search for drugs that would help to overcome the resistance and improve treatment outcomes. One of the resistance mechanisms takes place through the upregulation of MCL-1 and BCL-XL, preventing BAX/BAK-driven MOMP (mitochondrial outer membrane permeabilization), thus stopping the apoptosis process. Possible partners for BCL-2 inhibitors may include inhibitors from the FLT3i (FMS-like tyrosine kinase-3 inhibitor) group. They resensitize cancer cells through the downregulation of MCL-1 expression in the FLT3 mutated cells, resulting in the stronger efficacy of BCL-2 inhibitors. Also, they provide an additional pathway for targeting the clonal cell. Both preclinical and clinical data suggest that the combination might show a synergistic effect and improve patients’ outcomes. The aim of this review is to determine whether the combination of venetoclax and FLT3 inhibitors can impact the therapeutic approaches and what other agents they can be combined with.

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“…The ALLG tested a sequential triplet regimen of low-dose cytarabine/ Ven with midostaurin in patients with non-adverse risk AML. Results were encouraging, but only 1/18 patients enrolled had FLT3-ITDmut AML [22]. A randomized phase 2 trial comparing LDAC/Ven/ midostaurin to LDAC/Ven, is currently ongoing.…”

Section: Fms-like Tyrosine Kinase 3 Inhibitors In Front-line Treatmen...mentioning

confidence: 99%

Fms-like tyrosine kinase 3 positive acute myeloid leukemia

Isidori,

Visani,

Ferrara

2023

Current Opinion in Oncology

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Purpose of review Fms-like tyrosine kinase 3 (FLT3) mutations are common in newly diagnosed patients with acute myeloid leukemia (AML). They are associated with a high risk of relapse. The identification of FLT3 mutations has important implications for the management of AML. FLT3 inhibitors have shown improved outcomes in FLT3-positive AML when used as a single agent in the salvage setting. However, the combination of inhibitors and chemotherapy in the first-line setting is the real game changer in FLT3mutant AML. The introduction of these drugs has improved the prognosis of FLT3-mutant AML, but the development of resistance is common. There are still many unanswered questions about FLT3-mutant AML. Recent findings This article will analyze recent advances for FLT3-mutant AML, focusing on front-line therapy and post-transplant maintenance. Summary Novel drug combinations and strategies against FLT3 mutated AML are currently under investigation and will be the focus of future studies. The development of more selective and potent FLT3 inhibitors may further improve outcomes for patients with FLT3-positive AML. Monitoring minimal residual disease and overcoming resistance are key issues for the future.

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High Deliverability of a Midostaurin Triplet Regimen Incorporating Venetoclax and Low Dose Cytarabine in Non-Adverse Cytogenetic Risk Acute Myeloid Leukaemia: A Sub-Analysis of the Australasian Leukaemia Lymphoma Group (ALLG) Intervene Study

Cited by 5 publications

References 0 publications

Targeting FLT3 Mutation in Acute Myeloid Leukemia: Current Strategies and Future Directions

Targeting FLT3 Mutation in Acute Myeloid Leukemia: Current Strategies and Future Directions

AML under the Scope: Current Strategies and Treatment Involving FLT3 Inhibitors and Venetoclax-Based Regimens

Fms-like tyrosine kinase 3 positive acute myeloid leukemia

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