Megakaryocytic Expansion in Gilteritinib-Treated Acute Myeloid Leukemia Patients Is Associated With AXL Inhibition

Suknuntha, Kran; Jung, Ho Sun; Majumder, Aditi; Shah, Sujal I.; Slukvin, Igor I.; Ranheim, Erik A.

doi:10.3389/fonc.2020.585151

Cited by 3 publications

(3 citation statements)

References 35 publications

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“…Gilteritinib may also directly affect platelet functions and indirectly megakaryocytes [ 18 ]. Twenty-two percent of patients treated with this drug developed thrombocytopenia [ 4 ], and gastrointestinal bleeding has been reported in animal models and in the AZA/gilteritinib trial [ 7 , 19 ].…”

Section: Discussionmentioning

confidence: 99%

Gilteritinib and the risk of intracranial hemorrhage: a case series of a possible, under-reported side effect

Perrone,

Imperatore,

Sucato

et al. 2023

Ann Hematol

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Gilteritinib is currently approved for patients with relapsed/refractory AML with FLT3 mutations, based on the positive results of the pivotal ADMIRAL study. In ADMIRAL trial, no increased risk of bleeding was reported, but in the previous dose finding study, a single event of intracranial hemorrhage (ICH) was registered after exposure to subtherapeutic doses of gilteritinib. Here, we report the first case series on five ICHs diagnosed in patients with FLT3-mutated AML, occurred within the first month of exposure to gilteritinib. Our cohort included 24 patients treated in three Italian centers. Most of these ICH cases were non-severe and self-limiting, while one was fatal. This link with ICHs remains in any case uncertain for the presence of active AML. We further reported that an analysis of the post-marketing surveillance data (EudraVigilance) retrieved other 11 cases of ICHs present in the database after gilteritinib treatment. A causality assessment was performed according to the Dx3 method to evaluate the possibility that ICHs might be an actual side effect of gilteritinib. In conclusion, further research is needed to elucidate the potential role of gilteritinib in the pathogenesis of ICHs.

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Section: Discussionmentioning

confidence: 99%

Gilteritinib and the risk of intracranial hemorrhage: a case series of a possible, under-reported side effect

Perrone,

Imperatore,

Sucato

et al. 2023

Ann Hematol

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“…Altogether, these data indicate that AXL inhibition can positively impact altered erythropoiesis in MPN. Interestingly, pharmacologic blockade of AXL has also been previously described to induce differentiation of megakaryocytes 47 . Nevertheless, subcutaneous models and models in immunocompromised mice have their limitations regarding the study of neoplasms originating in the BM and further studies using more sophisticated models of MPN are warranted in the future 48,49 …”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, pharmacologic blockade of AXL has also been previously described to induce differentiation of megakaryocytes. 47 Nevertheless, subcutaneous models and models in immunocompromised mice have their limitations regarding the study of neoplasms originating in the BM and further studies using more sophisticated models of MPN are warranted in the future. 48,49 These data form the preclinical rationale for clinical trials of bemcentinib in combination with ruxolitinib as first line treatment in MPN.…”

Section: Discussionmentioning

confidence: 99%

AXL Inhibition Represents a Novel Therapeutic Approach in BCR-ABL Negative Myeloproliferative Neoplasms

Beitzen-Heineke

Berenbrok²,

Waizenegger

et al. 2021

HemaSphere

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BCR-ABL negative myeloproliferative neoplasms (MPNs) consist of essential thrombocythemia, polycythemia vera, and myelofibrosis. The majority of patients harbor the JAK2-activating mutation V617F. JAK2 inhibitors were shown to reduce symptom burden and splenomegaly in MPN patients. However, treatment options are limited after failure of JAK2 inhibitors. AXL, a member of the TAM family of receptor tyrosine kinases, mediates survival and therapy resistance of different myeloid cancers including acute myeloid leukemia and chronic myeloid leukemia. We studied the relevance of AXL as a target in MPN using primary patient cells and preclinical disease models. We found that AXL is abundantly activated in MPN cells and that its ligand growth arrest-specific gene 6 is upregulated in MPN patients. Pharmacologic and genetic blockade of AXL impaired viability, decreased proliferation and increased apoptosis of MPN cells. Interestingly, ruxolitinib treatment induced increased phosphorylation of AXL indicating that activation of AXL might mediate resistance to ruxolitinib. Consistently, the AXL inhibitor bemcentinib exerted additive effects with ruxolitinib via impaired STAT3, STAT5, and AKT signaling. Both agents had activity when employed alone and exerted an additive effect on survival and splenomegaly in vivo. Moreover, bemcentinib treatment normalized red blood cell count and hemoglobin levels in vivo. Thus, our data indicate that AXL inhibition represents a novel treatment option in MPN warranting clinical investigation.

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Efficacy and safety of second‑generation FLT3 inhibitors in acute myeloid leukemia: A systematic review and meta‑analysis of randomized controlled trials

Lin,

Chao,

Lin

et al. 2024

Mol Clin Oncol

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Acute myeloid leukemia (AML) is one of the most frequent forms of acute leukemia and the second most common leukemia subtype in adults. In 2020, the incidence of AML in the United States was estimated to be ~4 cases per 100,000 adults. The FMS-like tyrosine kinase 3 ( FLT3 ) internal tandem duplication (ITD) and tyrosine kinase domain (TKD) mutation are major prognostic indicators of AML. They are more frequently observed in younger AML patients (aged <60 years), likely due to their association with de novo . Additionally, these mutations have a stronger negative impact on survival in younger patients. Therefore, quizartinib and gilteritinib are second-generation FLT3 inhibitors that are frequently applied for treating patients with AML. However, to the best of our knowledge, few studies have compared the efficacy of second-generation FLT3 inhibitors for AML treatment. Therefore, the present study conducted a comprehensive search for studies on the efficacy and safety of FLT3 inhibitors across PubMed, Embase, the Cochrane Library and ClinicalTrials.gov . The search criteria were limited to randomized controlled trials (RCTs). Subsequently, a meta-analysis was performed on a total of five randomized controlled trials, involving 1,543 participants in total, using a random-effects model. In each RCT, compared to the salvage chemotherapy used in the control group, the groups that received second-generation FLT3 inhibitors experienced significant improvements in overall survival (hazard ratio, 0.717; 95% CI, 0.604-0.850; P<0.001). In addition, overall survival was found to be consistent across the different types of second-generation FLT3 inhibitors used and different types of AML. The risks associated with a prolonged heart-rate corrected QT interval (QTc) interval were next evaluated. Compared with the salvage chemotherapy used in the control group, the second-generation FLT3 inhibitor group exhibited a significantly higher risk of having a prolonged QTc interval (odds ratio, 6.311; 95% CI, 3.061-13.013; P<0.001). In conclusion, these findings suggest that second-generation FLT3 inhibitors can improve the overall survival of patients with AML. However, QTc prolongation is a potential adverse effect that should be monitored.

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Megakaryocytic Expansion in Gilteritinib-Treated Acute Myeloid Leukemia Patients Is Associated With AXL Inhibition

Cited by 3 publications

References 35 publications

Gilteritinib and the risk of intracranial hemorrhage: a case series of a possible, under-reported side effect

Gilteritinib and the risk of intracranial hemorrhage: a case series of a possible, under-reported side effect

AXL Inhibition Represents a Novel Therapeutic Approach in BCR-ABL Negative Myeloproliferative Neoplasms

Efficacy and safety of second‑generation FLT3 inhibitors in acute myeloid leukemia: A systematic review and meta‑analysis of randomized controlled trials

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