Gilteritinib or Chemotherapy for Relapsed or Refractory <i>FLT3</i>-Mutated AML

Perl, Alexander E.; Martinelli, Giovanni; Cortes, Jorge; Neubauer, Andreas; Berman, Ellin; Paolini, Stefania; Montesinos, Pau; Baer, Maria R.; Larson, Richard A.; Üstün, Celalettin; Fanfani, Francesco; Erba, Harry P.; Stasi, Antonio Di; Stuart, Robert K.; Olin, Rebecca L.; Kasner, Margaret; Ciceri, Fabio; Chou, Wen‐Chien; Podoltsev, Nikolai A.; Récher, Christian; Yokoyama, Hisayuki; Hosono, Naoko; Yoon, Sung Soo; Lee, Je Hwan; Pardee, Timothy S.; Fathi, Amir T.; Liu, Chaofeng; Hasabou, Nahla; Li, Xuan; Bahceci, Erkut; Levis, Mark J.

doi:10.1056/nejmoa1902688

Cited by 957 publications

(900 citation statements)

References 34 publications

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“…In the ADMIRAL study, 19% of patients with FLT3 TKD mutations only achieved complete remission compared with 20.5% in patients with FLT3 ITD mutations only, though the number of patients with TKD only mutations remained small. 21 Clinical response data from CHYRSALIS (or ADMIRAL) patients with NC FLT3 mutations other than ITD and D835 substitutions have not been previously reported.…”

Section: Discussionmentioning

confidence: 99%

“…19 A randomized phase 3 study of gilteritinib (ADMIRAL) compared with salvage chemotherapy (NCT02421939) in AML demonstrated a significant overall survival benefit in the gilteritinib arm (9.3 months) compared with chemotherapy (5.6 months). 21 Event-free survival in the gilteritinib arm was also superior. 21 Based on findings from this study, the US Food and Drug Administration (FDA) approved gilteritinib as the first FLT3 inhibitor indicated for use as monotherapy in FLT3-mutated R/R AML.…”

Section: Introductionmentioning

confidence: 98%

“…21 Event-free survival in the gilteritinib arm was also superior. 21 Based on findings from this study, the US Food and Drug Administration (FDA) approved gilteritinib as the first FLT3 inhibitor indicated for use as monotherapy in FLT3-mutated R/R AML.…”

Section: Introductionmentioning

confidence: 98%

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Gilteritinib is a clinically active FLT3 inhibitor with broad activity against FLT3 kinase domain mutations

et al. 2020

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Key Points• Gilteritinib is active against a wide range of clinically relevant activating FLT3 mutations.• Resistance-conferring FLT3 kinase domain mutations are responsible for a minority of clinical resistance to gilteritinib.Gilteritinib is the first FMS-like tyrosine kinase 3 (FLT3) tyrosine kinase inhibitor (TKI) approved as monotherapy in acute myeloid leukemia with FLT3 internal tandem duplication and D835/I836 tyrosine kinase domain (TKD) mutations. Sequencing studies in patients have uncovered less common, noncanonical (NC) mutations in FLT3 and have implicated secondary TKD mutations in FLT3 TKI resistance. We report that gilteritinib is active against FLT3 NC and TKI resistance-causing mutations in vitro. A mutagenesis screen identified FLT3 F691L, Y693C/N, and G697S as mutations that confer moderate resistance to gilteritinib in vitro. Analysis of patients treated with gilteritinib revealed that 2/9 patients with preexisting NC FLT3 mutations responded and that secondary TKD mutations are acquired in a minority (5/31) of patients treated with gilteritinib. Four of 5 patients developed F691L mutations (all treated at ,200 mg). These studies suggest that gilteritinib has broad activity against FLT3 mutations and limited vulnerability to resistance-causing FLT3 TKD mutations, particularly when used at higher doses.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

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Gilteritinib is a clinically active FLT3 inhibitor with broad activity against FLT3 kinase domain mutations

et al. 2020

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“…Most notably, the CR rate in gilteritinib‐treated patients was significantly higher in those who had undergone a prior allo‐SCT as compared to those who had not (35.4% vs 17.6%, P = .01). As with the aforementioned sorafenib results, this suggests alloimmunity potentiates the activity of FLT3 inhibitors . The FLT3 inhibitors being studied for post‐transplant maintenance therapy in FLT3‐ITD + AML include crenolanib in a phase II trial (NCT02400255) and midostaurin in a phase II trial (NCT01883362).…”

Section: Other Therapies With Immunomodulatory Activitymentioning

confidence: 71%

Harnessing the immune system after allogeneic stem cell transplant in acute myeloid leukemia

Sterling

Webster

2020

American J Hematol

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Allogeneic stem cell transplantation (allo-SCT) is the most successful and widely used immunotherapy for the treatment of acute myeloid leukemia (AML), as a result of its anti-leukemic properties driven by T cells and natural killer (NK) cells, leading to a graft-vs-leukemia (GVL) effect. Despite its essential role in AML treatment, relapse after allo-SCT is common and associated with a poor prognosis. There is longstanding interest in developing immunologic strategies to augment the GVL effect posttransplant to prevent relapse and improve outcomes. In addition to prophylactic maintenance strategies, the GVL effect can also be used in relapsed patients to reinduce remission. While immune checkpoint inhibitors and other novel immune-targeted agents have been successfully used in the post-transplant setting to augment the GVL effect and induce remission in small clinical trials of relapsed patients, exacerbations of graft-vs-host disease (GVHD) have limited their broader use. Here we review advances in three areas of immunotherapy that have been studied in post-transplant AML: donor lymphocyte infusion (DLI), immune checkpoint inhibitors, and other monoclonal antibodies (mAbs), including antibody-drug conjugates (ADCs) and ligand receptor antagonists. We also discuss additional therapies with proposed immunologic mechanisms, such as hypomethylating agents, histone deacetylase inhibitors, and the FLT3 inhibitor sorafenib.

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“…Due to promising results from a Phase I/II trial on giltertinib in adults with r/r AML harboring both wild-type and FLT3 mutations [89], a randomized Phase III trial was conducted comparing gilteritinib monotherapy versus salvage chemotherapy in adults with r/r, FLT3-mutated AML. Patients who received gilteritinib demonstrated a significantly higher CR/Cri rate (34% vs. 15%), longer median OS (9.3 months vs. 5.6 months), and longer post-transplant survival (16.2 months vs. 8.4 months) as compared to those who received salvage chemotherapy, resulting in FDA approval for adults with r/r, FLT3-mutated AML [90]. Gilteritinib is planned to be investigated in the upcoming COG AML trial for children with newly diagnosed AML (AAML1831).…”

Section: Flt3 Inhibitorsmentioning

confidence: 99%

New and Emerging Targeted Therapies for Pediatric Acute Myeloid Leukemia (AML)

Chen

Glasser

2020

Children

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The relapse rate for children with acute myeloid leukemia (AML) remains high despite advancements in risk classification, multi-agent chemotherapy intensification, stem cell transplantation, and supportive care guidelines. Prognosis for this subgroup of children with relapsed/refractory AML remains poor. It is well known that the ceiling of chemotherapy intensification has been reached, limited by acute and chronic toxicity, necessitating alternative treatment approaches. In the last several years, our improved understanding of disease biology and critical molecular pathways in AML has yielded a variety of new drugs to target these specific pathways. This review provides a summary of antibody drug conjugates (ADCs), small molecule inhibitors, and tyrosine kinase inhibitors with an emphasis on those that are currently under clinical evaluation or soon to open in early phase trials for children with relapsed/refractory AML.

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Gilteritinib or Chemotherapy for Relapsed or Refractory FLT3-Mutated AML

Cited by 957 publications

References 34 publications

Gilteritinib is a clinically active FLT3 inhibitor with broad activity against FLT3 kinase domain mutations

Gilteritinib is a clinically active FLT3 inhibitor with broad activity against FLT3 kinase domain mutations

Harnessing the immune system after allogeneic stem cell transplant in acute myeloid leukemia

New and Emerging Targeted Therapies for Pediatric Acute Myeloid Leukemia (AML)

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