From a phase 1 study of 258 patients with IDH1-mutant advanced hematologic malignancies, we report results for 34 patients with newly diagnosed acute myeloid leukemia (AML) ineligible for standard therapy who received ivosidenib 500 mg once daily.
IDH1 mutations are closely related to the development and progression of various human cancers, such as glioblastoma, sarcoma, and acute myeloid leukemia.
Advances in the understanding of the complex mechanisms of AML leukemogenesis have led to the development and recent US Food and Drug Administration (FDA) approval of several targeted therapies: midostaurin and gilteritinib targeting activated FLT3, and ivosidenib and enasidenib targeting mutated IDH1/2.
Acute myeloid leukemia with isolated del(5q) is associated with IDH1/IDH2 mutations and better prognosis when compared to acute myeloid leukemia with complex karyotype including del(5q).
Although the first reports have also already emerged describing acquired resistance for these mutant IDH inhibitors, combination treatment might overcome this problem, which could drastically change the treatment landscape of AML over the next few years.
In particular, these results provide an additional rationale supporting the combination of FLT3 and mutant IDH1 inhibitors as a promising clinical treatment of mutant IDH1-positive AML.<i>See related commentary by Horton and Huntly, p. 699</i>.<i>This article is highlighted in the In This Issue feature, p. 681</i>.
For example, the small molecule inhibitor ivosidenib, which targets IDH1 with a mutation at R132, has been approved by the FDA for the clinical treatment of acute myeloid leukemia.
The analysis of these mutations in AML patients is of great importance as a prognostic factor due to their impact on survival and their use as potential therapeutic targets or as targets of inhibitors of IDH1(Ivosidenib, Tibsovo) and IDH2 (Enasidenib, Idhifa).
Indeed, in addition to the IDH1/2-mutated AML model which established the proof-of-concept for specifically targeting metabolic adaptations in AML, several recent reports have expanded the scope of such strategies in these diseases.
Mutations involving <i>IDH1</i> or <i>IDH2</i> (<i>IDH1/2</i>) (<i>P</i> = .007) and <i>FLT3</i> (internal tandem duplication, <i>P</i> < .0001; noninternal tandem duplication, <i>P</i> = .01) were less frequent in <i>NPM1</i><sup>+</sup> MN than in <i>NPM1</i><sup>+</sup> AML.
NPM1, DNMT3A, and IDH2 mutations were more common while biallelic CEBPA and IDH1 mutations were less seen in e-AML patients. s-AML patients carried a higher frequency of KMT2A-AF9.
The aim was to analyze DNA methylation, hydroxymethylation and mRNA expression profiles in AML with mutations in DNMT3A and IDH1/2 (individually and in combinations).
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.
With median follow-up of 8.3 months for 174 adults with IDH1-mutated R/R AML treated with 500 mg ivosidenib daily, the CR + CRh rate was 33% [95% confidence interval (CI), 26-40], median duration of response was 8.2 (95% CI, 5.6-12) months, and conversion from TD to TI occurred in 37% of patients.
Three mutation-specific targeted therapies have recently been approved by the FDA for the treatment of acute myeloid leukemia (AML): midostaurin for FLT3 mutations, enasidenib for relapsed or refractory cases with IDH2 mutations, and ivosidenib for cases with an IDH1 mutation.
Mutations in isocitrate dehydrogenase 1 (IDH1) drive most low-grade gliomas and secondary glioblastomas and many chondrosarcomas and acute myeloid leukemia cases.