Durable Remissions with Ivosidenib in<i>IDH1</i>-Mutated Relapsed or Refractory AML

DiNardo, Courtney D.; Stein, Eytan M.; Botton, Stéphane de; Roboz, Gail J.; Altman, Jessica K.; Mims, Alice S.; Swords, Ronan; Collins, Robert H.; Mannis, Gabriel N.; Pollyea, Daniel A.; Donnellan, William B.; Fathi, Amir T.; Pigneux, Arnaud; Erba, Harry P.; Prince, Gabrielle T.; Stein, Anthony S.; Uy, Geoffrey L.; Foran, James M.; Traer, Elie; Stuart, Robert K.; Arellano, Martha; Slack, James L.; Sekeres, Mikkael A.; Willekens, Christophe; Choe, Sung; Wang, Haina; Zhang, V.; Yen, Katharine; Kapsalis, Stephanie M.; Yang, Hua; Dai, David L.; Fan, Bin; Goldwasser, Meredith A.; Liu, H.; Agresta, Samuel V.; Wu, Bin; Attar, Eyal C.; Tallman, Martin S.; Stone, Richard; Kantarjian, Hagop M.

doi:10.1056/nejmoa1716984

Cited by 1,127 publications

(1,055 citation statements)

References 21 publications

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“…Specific driver genetic mutations occur in different subtypes of AML, and therapies targeting mutations in AML have emerged: midostaurin (Stone et al , ) in combination with induction chemotherapy for upfront treatment and gilteritinib monotherapy (Perl et al , ) for relapsed or refractory disease in AML with FMS‐like tyrosine kinase 3 ( FLT3 ) mutations; and ivosidenib (DiNardo et al , ) and enasidenib (Stein et al , ) for relapsed or refractory AML with isocitrate dehydrogenase 1 and 2 ( IDH1 and IDH2 ) mutations. Strategies targeting other genetic mutations and their activated cellular pathways are urgently needed (Lam et al , ).…”

Section: Introductionmentioning

confidence: 99%

Follistatin is a novel therapeutic target and biomarker in FLT 3/ ITD acute myeloid leukemia

Yang

Man

et al. 2020

EMBO Mol Med

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Internal tandem duplication of Fms‐like tyrosine kinase 3 (FLT3/ITD) occurs in about 30% of acute myeloid leukemia (AML) and is associated with poor response to conventional treatment and adverse outcome. Here, we reported that human FLT3/ITD expression led to axis duplication and dorsalization in about 50% of zebrafish embryos. The morphologic phenotype was accompanied by ectopic expression of a morphogen follistatin (fst) during early embryonic development. Increase in fst expression also occurred in adult FLT3/ITD‐transgenic zebrafish, Flt3/ITD knock‐in mice, and human FLT3/ITD AML cells. Overexpression of human FST317 and FST344 isoforms enhanced clonogenicity and leukemia engraftment in xenotransplantation model via RET, IL2RA, and CCL5 upregulation. Specific targeting of FST by shRNA, CRISPR/Cas9, or antisense oligo inhibited leukemic growth in vitro and in vivo. Importantly, serum FST positively correlated with leukemia engraftment in FLT3/ITD AML patient‐derived xenograft mice and leukemia blast percentage in primary AML patients. In FLT3/ITD AML patients treated with FLT3 inhibitor quizartinib, serum FST levels correlated with clinical response. These observations supported FST as a novel therapeutic target and biomarker in FLT3/ITD AML.

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Section: Introductionmentioning

confidence: 99%

Follistatin is a novel therapeutic target and biomarker in FLT 3/ ITD acute myeloid leukemia

Yang

Man

et al. 2020

EMBO Mol Med

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“…163,164 Enasidenib was approved in August 2017 for the treatment of IDH2mutated, refractory-relapsed AML. Enasidenib, an IDH2 inhibitor, and ivosidenib, an IDH1 inhibitor, were developed as targeted therapies for these subgroups.…”

Section: Acute Myeloid Leukemia (And High-risk Myelodysplastic Syndrome)mentioning

confidence: 99%

“…Among patients with refractory-relapsed AML, both agents produced bone marrow CR rates of 30% to 40% and a median survival of 8 to 9 months. 163,164 Enasidenib was approved in August 2017 for the treatment of IDH2mutated, refractory-relapsed AML. Ivosidenib was approved in July 2018 soon for the treatment of IDH1mutated, refractory-relapsed AML.…”

Section: Acute Myeloid Leukemia (And High-risk Myelodysplastic Syndrome)mentioning

confidence: 99%

Toward the potential cure of leukemias in the next decade

Kantarjian

Keating

Freireich

2018

Cancer

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Historically, progress in leukemia research has been slow, but it has accelerated recently as a result of understanding the pathophysiology of leukemias and implementing more effective and targeted therapies. This review summarizes the progress across leukemia subsets and projects the potential cure of most leukemias in the next decade. Cancer 2018;124:4301-4313.APL constitutes 5% to 10% of AML cases. It is characterized by the translocation between chromosomes 15 and 17-t(15,17)(q22; q12)-and the corresponding promyelocytic leukemia/retinoic acid receptor α (PML-RARα) molecular abnormality. The discovery of daunorubicin and other anthracyclines in the 1970s was the first step toward

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“…Approximately, 35%‐43% of patients have also demonstrated transfusion independence, including those with non‐CR/CRi responses . For responding patients, molecular MRD eradication rates of 35% and 23% for enasidenib (12/35 CR) and ivosidenib (7/31 CR or CR with partial hematologic recovery [CRh]), respectively, have been reported, suggesting the potential for marked suppression of IDH mutant clones in some patients . Response to IDH inhibitors appears greater among patients with fewer concomitant mutations, which may explain the trend for higher response rates when patients are treated at earlier stages of disease.…”

Section: The Challenge Of Relapsed and Refractory (R/r) Amlmentioning

confidence: 99%

“…Both enasidenib (approved August 1, 2017) 108 respectively, have been reported, suggesting the potential for marked suppression of IDH mutant clones in some patients. 48,109 Response to IDH inhibitors appears greater among patients with fewer concomitant mutations, which may explain the trend for higher response rates when patients are treated at earlier stages of disease. Interestingly, late relapses have been reported in association with rising 2-HG and noncatalytic second site mutations located at the homodimer interface.…”

Section: Idh1/2 Inhibitorsmentioning

confidence: 99%

New drugs creating new challenges in acute myeloid leukemia

Tiong

Wei

2019

Genes Chromosomes & Cancer

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The therapeutic landscape is rapidly changing, with eight new drugs approved by the Food and Drug Administration within the last 2 years, including midostaurin and gilteritinib for FLT3 mutant newly diagnosed and relapsed/refractory (R/R) acute myeloid leukemia (AML), respectively; CPX‐351 (liposomal cytarabine and daunorubicin) for therapy‐related AML and AML with myelodysplasia‐related changes; gemtuzumab ozogamicin (anti‐CD33 monoclonal antibody conjugated with calicheamicin) for newly diagnosed and R/R CD33‐positive AML; enasidenib and ivosidenib for IDH2 and IDH1 mutant R/R AML, respectively. Novel therapies have also emerged for newly diagnosed AML in adults who are age 75 years or older, or who have comorbidities that preclude the use of intensive induction chemotherapy. These include venetoclax (BCL‐2 inhibitor) in combination with hypomethylating agents (azacitidine or decitabine) or low‐dose cytarabine (LDAC), and glasdegib (sonic hedgehog pathway inhibitor) in combination with LDAC. This flurry of new drug approvals has markedly altered the treatment landscape in AML and provided new opportunities, as well as new challenges for treating clinicians. This review will focus on how these drugs might shape clinical practice and the hurdles likely to be faced by new therapies seeking entry into this dynamic and rapidly changing therapeutic landscape.

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Durable Remissions with Ivosidenib inIDH1-Mutated Relapsed or Refractory AML

Cited by 1,127 publications

References 21 publications

Follistatin is a novel therapeutic target and biomarker in FLT 3/ ITD acute myeloid leukemia

Follistatin is a novel therapeutic target and biomarker in FLT 3/ ITD acute myeloid leukemia

Toward the potential cure of leukemias in the next decade

New drugs creating new challenges in acute myeloid leukemia

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