Clinical considerations for the use of FLT3 inhibitors in acute myeloid leukemia

Weis, Taylor M; Marini, Bernard L.; Bixby, Dale

doi:10.1016/j.critrevonc.2019.06.011

Cited by 37 publications

(27 citation statements)

References 90 publications

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“…The high risk of relapse in patients with FLT3-ITD AML after allo-HSCT provides a strong rationale for continuD 3 1 1 X Xing therapy with FLT3 inhibitors after consolidation HSCT in patients with first CR or in patients with R/R disease [7,8]. Data from retrospective analyses and prospective data from the SORMAIN trial demonstrated that post-HSCT continuation therapy with the FLT3 inhibitor sorafenib was associated with longer diseasefree survival or OS in patients with FLT3-ITD AML in D 3 1 2 X Xfirst CR [13,[25][26][27]. In QuANTUM-R, the median OS was 27.1 months (95% CI, 18.2 months to NA) in patients with a last recorded response of CRc D 3 1 3 X Xbefore allo-HSCT who continued quizartinib after transplantation.…”

Section: Discussionmentioning

confidence: 99%

Clinical Outcomes in Patients with FLT3-ITD-Mutated Relapsed/Refractory Acute Myelogenous Leukemia Undergoing Hematopoietic Stem Cell Transplantation after Quizartinib or Salvage Chemotherapy in the QuANTUM-R Trial

Ganguly

Cortés

Krämer

et al. 2021

Transplantation and Cellular Therapy

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Despite the substantial clinical activity of fms-related tyrosine kinase 3 (FLT3) inhibitors in relapsed or refractory (R/R) FLT3-ITD-positive acute myelogenous leukemia (AML), durable remissions and prolonged survival in this population require allogeneic hematopoietic stem cell transplantation (allo-HSCT). Quizartinib, a once-daily oral, highly potent, and selective FLT3 inhibitor, significantly prolonged overall survival (OS) and improved clinical benefit compared with salvage chemotherapy (median OS, 6.2 months versus 4.7 months; hazard ratio [HR], .76; 95% confidence interval [CI], .58 to .98; P = .018; composite complete remission [CRc] rate, 48% versus 27%; median duration of CRc, 2.8 months versus 1.2 months; mortality rate, .8% versus 14% by day 30, 7% versus 24% by day 60) in patients with R/R FLT3-ITD AML in the phase 3 QuANTUM-R trial. In this post hoc analysis, we described the characteristics of and clinical outcomes in patients who underwent on-study HSCT in QuANTUM-R at the investigator's discretion and institutional practices. Of 367 randomized patients, 78 (32%) in the quizartinib arm and 14 (11%) in the salvage chemotherapy arm underwent on-study allo-HSCT without any intervening therapy for AML after quizartinib or study-specified salvage chemotherapy. Pooled data of patients from both treatment arms showed a longer median overall survival (OS) in transplant recipients versus those treated without HSCT (12.2 months versus 4.4 months; HR, .315; 95% CI, .233 to .427). Pooled data also showed a longer median OS in patients with a last recorded response of CRc before allo-HSCT versus patients without a CRc (20.1 months versus 8.8 months; HR, .506; 95% CI, .296 to .864). By treatment arm, the median OS was 25.1 months with quizartinib and 20.1 months with salvage chemotherapy in patients with a last recorded response of CRc before allo-HSCT. Fortyeight patients in the quizartinib arm continued quizartinib treatment after allo-HSCT. In the 31 patients with a last recorded response of CRc before allo-HSCT who continued quizartinib after allo-HSCT, the median OS was 27.1 months. Continuation of quizartinib after allo-HSCT was tolerable, and no new safety signals were identified. These results suggest that post-transplantation survival following salvage chemotherapy and quizartinib treatment are similar. However, quizartinib response occurs more frequently than with salvage chemotherapy, potentially allowing more patients to undergo transplantation and achieve durable clinical benefit. In addition,

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Section: Discussionmentioning

confidence: 99%

Clinical Outcomes in Patients with FLT3-ITD-Mutated Relapsed/Refractory Acute Myelogenous Leukemia Undergoing Hematopoietic Stem Cell Transplantation after Quizartinib or Salvage Chemotherapy in the QuANTUM-R Trial

Ganguly

Cortés

Krämer

et al. 2021

Transplantation and Cellular Therapy

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“…The identification of Flt3-ITD as a common driver mutation in AML led to the development of Flt3 kinase inhibitors as an approach to precision therapy. Flt3 inhibitors have had some success in clinical trials although low response rates and acquired resistance remain as vexing problems [11], even for the recently FDA-approved Flt3 inhibitor midostaurin [12,13]. Most patients develop resistance to Flt3 inhibitors through mutations in the kinase domain that affect inhibitor binding but not kinase activity [14,15].…”

Section: Introductionmentioning

confidence: 99%

Expression of myeloid Src-family kinases is associated with poor prognosis in AML and influences Flt3-ITD kinase inhibitor acquired resistance

et al. 2019

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Unregulated protein-tyrosine kinase signaling is a common feature of AML, often involving mutations in Flt3 and overexpression of myeloid Src-family kinases (Hck, Fgr, Lyn). Here we show that high-level expression of these Src kinases predicts poor survival in a large cohort of AML patients. To test the therapeutic benefit of Flt3 and Src-family kinase inhibition, we used the pyrrolopyrimidine kinase inhibitor A-419259. This compound potently inhibits Hck, Fgr, and Lyn as well as Flt3 bearing an activating internal tandem duplication (ITD). Flt3-ITD expression sensitized human TF-1 myeloid cells to growth arrest by A-419259, supporting direct action on the Flt3-ITD kinase domain. Cells transformed with the Flt3-ITD mutants D835Y and F691L were resistant to A-419259, while co-expression of Hck or Fgr restored inhibitor sensitivity to Flt3-ITD D835Y. Conversely, Hck and Fgr mutants with engineered A-419259 resistance mutations decreased sensitivity of TF-1/Flt3-ITD cells. To investigate de novo resistance mechanisms, A-419259-resistant Flt3-ITD+ AML cell populations were derived via long-term dose escalation. Whole exome sequencing identified a distinct Flt3-ITD kinase domain mutation (N676S/T) among all A-419259 target kinases in each of six independent resistant cell populations. These studies show that Hck and Fgr expression influences inhibitor sensitivity and the pathway to acquired resistance in Flt3-ITD+ AML.

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“…Patients who were resistant to gilteritinib and other FLT3 inhibitors were also being included in some studies of crenolanib [53,54]. It is forseeable that more FLT3 inhibitors may become available for clinical applications [55][56][57][58]. It will be possible to choose among the approved agents according to a unique property for a particular patient in the near future.…”

Section: Future Perspectivesmentioning

confidence: 99%

Gilteritinib: a novel FLT3 inhibitor for acute myeloid leukemia

2019

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FMS-like tyrosine kinase 3- internal tandem duplication (FLT3-ITD) remains as one of the most frequently mutated genes in acute myeloid leukemia (AML), especially in those with normal cytogenetics. The FLT3-ITD and FLT3-TKD (tyrosine kinase domain) mutations are biomarkers for high risk AML and are associated with drug resistance and high risk of relapse. Multiple FLT3 inhibitors are in clinical development, including lestaurtinib, tandutinib, quizartinib, midostaurin, gilteritinib, and crenolanib. Midostaurin and gilteritinib have been approved by FDA for Flt3 mutated AML. Gilteritinib (ASP2215, Xospata) is a small molecule dual inhibitor of FLT3/AXL. The ADMIRAL study showed that longer overall survival and higher response rate are associated with gilteritinib in comparison with salvage chemotherapy for relapse /refractory (R/R) AML. These data from the ADMIRAL study may lead to the therapy paradigm shift and establish gilteritinib as the new standard therapy for R/R FLT3-mutated AML. Currently, multiple clinical trials are ongoing to evaluate the combination of gilteritinib with other agents and regimens. This study summarized clinical trials of gilteritinib for AML.

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Clinical considerations for the use of FLT3 inhibitors in acute myeloid leukemia

Cited by 37 publications

References 90 publications

Clinical Outcomes in Patients with FLT3-ITD-Mutated Relapsed/Refractory Acute Myelogenous Leukemia Undergoing Hematopoietic Stem Cell Transplantation after Quizartinib or Salvage Chemotherapy in the QuANTUM-R Trial

Clinical Outcomes in Patients with FLT3-ITD-Mutated Relapsed/Refractory Acute Myelogenous Leukemia Undergoing Hematopoietic Stem Cell Transplantation after Quizartinib or Salvage Chemotherapy in the QuANTUM-R Trial

Expression of myeloid Src-family kinases is associated with poor prognosis in AML and influences Flt3-ITD kinase inhibitor acquired resistance

Gilteritinib: a novel FLT3 inhibitor for acute myeloid leukemia

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