Clinical outcomes in patients with relapsed/refractory FLT3-mutated acute myeloid leukemia treated with gilteritinib who received prior midostaurin or sorafenib

Perl, Alexander E.; Hosono, Naoko; Montesinos, Pau; Podoltsev, Nikolai A.; Martinelli, Giovanni; Panoskaltsis, Nicki; Récher, Christian; Smith, Catherine C.; Levis, Mark J.; Strickland, Stephen A.; Röllig, Christoph; Gross-Langenhoff, Marco; Chou, Wen‐Chien; Lee, Je Hwan; Yokoyama, Hisayuki; Hasabou, Nahla; Lu, Qiaoyang; Tiu, Ramon V.; Altman, Jessica K.

doi:10.1038/s41408-022-00677-7

Cited by 30 publications

(25 citation statements)

References 37 publications

(71 reference statements)

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“…Therefore, dual Axl and FLT3-ITD inhibitors have an advantage in targeting FLT3-ITD selective inhibitor-resistant AML cells. In support of this, there is a report showing that sorafenib-resistant FLT3-ITD patients respond to gilteritinib [ 49 ]. However, gilteritinib still exhibits transient effects in FLT3-ITD AML patients.…”

Section: Discussionmentioning

confidence: 80%

The GSK3β/Mcl-1 axis is regulated by both FLT3-ITD and Axl and determines the apoptosis induction abilities of FLT3-ITD inhibitors

et al. 2023

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Acute myeloid leukemia (AML) patients with FLT3-ITD mutations are associated with poor prognosis. FLT3-ITD inhibitors are developed and result in transient disease remission, but generally resistance develops. We propose that resistance occurs due to apoptosis evasion. We compared the abilities of five clinically used FLT3-ITD inhibitors, namely, midostaurin, crenolanib, gilteritinib, quizartinib, and sorafenib, to induce apoptosis. These drugs inhibit FLT3-ITD and induce apoptosis. Apoptosis induction is associated with GSK3β activation, Mcl-1 downregulation, and Bim upregulation. Sorafenib-resistant MOLM-13/sor cells have the secondary D835Y mutation and increased Axl signaling pathway with cross-resistance to quizartinib. Gilteritinib and crenolanib inhibit both FLT3-ITD and Axl and induce apoptosis in MOLM-13/sor cells, in which they activate GSK3β and downregulate Mcl-1. Inactivation of GSK3β through phosphorylation and inhibitors blocks apoptosis and Mcl-1 reduction. The Axl/GSK3β/Mcl-1 axis works as a feedback mechanism to attenuate apoptosis of FLT3-ITD inhibition. Homoharringtonine decreases the protein levels of Mcl-1, FLT3-ITD, and Axl. Moreover, it synergistically induces apoptosis with gilteritinib in vitro and prolongs survival of MOLM-13/sor xenografts. The GSK3β/Mcl-1 axis works as the hub of FLT3-ITD inhibitors and plays a critical role in resistance against FLT3-ITD AML-targeted therapy.

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Section: Discussionmentioning

confidence: 80%

The GSK3β/Mcl-1 axis is regulated by both FLT3-ITD and Axl and determines the apoptosis induction abilities of FLT3-ITD inhibitors

et al. 2023

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“…Although SHP2 inhibitors are only in early phase trials, the FLT3 inhibitor Gilteritinib is used clinically for the treatment of FLT3-ITD + AML (50, 51). MOLM13 and MV4-11 express FLT3-ITD, and our results indicate that INPPL1, MAP4K5, and LZTR1 act downstream of this fusion-RTK receptor.…”

Section: Resultsmentioning

confidence: 99%

Genome-wide CRISPR/Cas9 Screens Reveal Shared and Bespoke Mechanisms of Resistance to SHP2 inhibition

Wei

Geer

Guo

et al. 2022

Preprint

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SHP2 (PTPN11) acts upstream of SOS1/2 to enable RAS activation. Allosteric inhibitors (SHP2is) stabilize SHP2 auto-inhibition, preventing activation by upstream stimuli. SHP2is block proliferation of RTK- or cycling RAS mutant-driven cancers and overcome adaptive resistance to other RAS-ERK pathway drugs. Several SHP2is are in clinical trials. To identify potential SHP2i resistance mechanisms, we performed genome-wide CRISPR/Cas9 knockout screens on two SHP2i-sensitive AML cell lines and recovered genes expected to cause resistance, including tumor suppressor (NF1, PTEN, CDKN1B) and 'RASopathy' (LZTR1, RASA2) genes, and several novel targets (INPPL1, MAP4K5, epigenetic modifiers). We then screened 14 cancer lines with a focused CRISPR library targeting common 'hits' from the genome-wide screens. LZTR1 deletion conferred resistance in 12/14 lines, followed by MAP4K5 (8/14), SPRED2 (6/14), STK40 (6/14), and INPPL1 (5/14). INPPL1, MAP4K5, or LZTR1 deletion reactivated ERK signaling. INPPL1-mediated sensitization to SHP2i required its NPXY motif but not its lipid phosphatase domain. MAP4K5 acted upstream of MEK via a kinase-dependent target(s), whereas LZTR1 showed cell-dependent effects on RIT and RAS stability. INPPLI, MAP4K5, or LZTR1 deletion also conferred SHP2i resistance in mice. Our results reveal multiple SHP2i resistance genes, emphasizing the need for detailed understanding of the resistance landscape to arrive at effective combinations.

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“…Previous studies have suggested that prior exposure to FLT3 inhibitors may increase the clone transformation and induce resistance [48][49][50]. Alvarado et al found that secondary FLT3-TKD mutations emerged after treatment with FLT3 inhibitors in FLT3-ITD mut AML and may be associated with resistance and poor prognosis [50].…”

Section: Discussionmentioning

confidence: 99%

Sorafenib plus triplet therapy with venetoclax, azacitidine and homoharringtonine for refractory/relapsed acute myeloid leukemia with FLT3‐ITD: A multicenter phase 2 study

Yu,

Zhang,

et al. 2023

J Intern Med

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BackgroundPatients with relapsed or refractory acute myeloid leukemia (R/R AML) and FLT3‐internal tandem duplication (FLT3‐ITD) respond infrequently to salvage chemotherapy.ObjectiveTo investigate the efficacy of sorafenib plus triplet therapy with venetoclax, azacitidine, and homoharringtonine (VAH) as a salvage therapy in this population.MethodsThis multicenter, single‐arm, phase 2 study was conducted at 12 hospitals across China. Eligible patients had R/R AML with FLT3‐ITD (aged 18–65 years) who were treated with VAH. The primary endpoint was composite complete remission (CRc) after two cycles. Secondary outcomes included the overall response rate (ORR), safety, and survival.ResultsBetween July 9, 2020, and March 19, 2022, 58 patients were assessed for eligibility, 51 of whom were enrolled. The median patient age was 47 years (interquartile range [IQR] 31–57). CRc was 76.5% with ORR of 82.4%. At a median follow‐up of 17.7 months (IQR, 8.7–24.7), the median duration of CRc was not reached (NR), overall survival was 18.1 months (95% confidence interval [CI], 11.8‐NR) and event‐free survival was 11.4 months (95% CI, 5.6‐NR). Grade 3 or 4 adverse events occurring in ≥10% of patients included neutropenia in 47 (92.2%), thrombocytopenia in 41 (80.4%), anemia in 35 (68.6%), febrile neutropenia in 29 (56.9%), pneumonia in 13 (25.5%), and sepsis in 6 (11.8%) patients. Treatment‐related death occurred in two (3.9%) patients.ConclusionsThe sorafenib plus VAH regimen was well tolerated and highly active against R/R AML with FLT3‐ITD. This regimen may be a suitable therapeutic option for this population, but larger population trials are needed to be explored.Trial registrationClinical Trials Registry: NCT04424147

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Clinical outcomes in patients with relapsed/refractory FLT3-mutated acute myeloid leukemia treated with gilteritinib who received prior midostaurin or sorafenib

Cited by 30 publications

References 37 publications

The GSK3β/Mcl-1 axis is regulated by both FLT3-ITD and Axl and determines the apoptosis induction abilities of FLT3-ITD inhibitors

The GSK3β/Mcl-1 axis is regulated by both FLT3-ITD and Axl and determines the apoptosis induction abilities of FLT3-ITD inhibitors

Genome-wide CRISPR/Cas9 Screens Reveal Shared and Bespoke Mechanisms of Resistance to SHP2 inhibition

Sorafenib plus triplet therapy with venetoclax, azacitidine and homoharringtonine for refractory/relapsed acute myeloid leukemia with FLT3‐ITD: A multicenter phase 2 study

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