Rezlidhia (olutasidenib)

CHT regimens usually mimic those used in osteosarcoma, including methotrexate-doxorubicin-cisplatin (MAP), doxorubicin-ifosfamide (AI), or doxorubicin-cisplatin (AP) - albeit with lower pathological response rates and substantial haematological toxicity. Emerging systemic treatment strategies were also described. Prospective data on the inhibition of mutant IDH1 indicate that olutasidenib (NCT03684811) can control the disease, but its activity in DCS is limited (median progression-free survival (PFS) of 1.5 months, 95% confidence interval (CI) 0.2-not reached (NR)).

P4, N=16, Recruiting, Rigel Pharmaceuticals

P2, N=25, Not yet recruiting, Timothy Pardee

While not confirmatory, these findings may be clinically relevant in the context of this difficult-to-treat R/R IDH1m AML population.

Currently, most leukemias are effectively treated with immunotherapies (highly effective monoclonal antibodies targeting CD19 [blinatumomab], or CD22 [inotuzumab ozogamicin]), BCR::ABL1 tyrosine kinase inhibitors (TKIs; e.g., dasatinib, ponatinib), Bruton TKIs (e.g., ibrutinib, acalabrutinib), BCL-2 inhibitors (venetoclax), IDH1/2 inhibitors (ivosidenib, olutasidenib, and enasidenib), FLT3 inhibitors (e.g., midostaurin, quizartinib, and gilteritinib), menin inhibitors (revumenib, ziftomenib), and chimeric antigen receptor T-cell therapies. Herein, we provide a high-level overview of prominent clinical developments across all leukemias. In contemporary times, harnessing the benefits of novel targeted therapies and the evolving treatment landscape bolster the optimistic view that most, if not all, leukemias are curable.

While differentiation therapy revolutionized acute promyelocytic leukemia (APL) with all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), its extension into non-APL AML has been limited until recent targeted agents...IDH1/2 inhibitors (ivosidenib, enasidenib, olutasidenib) yield overall response rates (ORRs) of 30-94% in AML with DS in 10-19%. Menin inhibitors (revumenib, ziftomenib, enzomenib, bleximenib) achieve ORRs of 33-88% in KMT2A-rearranged or NPM1-mutated AML, with DS in 10-25% and QT prolongation as key toxicities. FLT3 inhibitors (gilteritinib, quizartinib) improve survival in FLT3-mutated AML with DS in 1-5%...Improved recognition of DS and rational combination approaches will be essential to maximize the therapeutic benefit. Future research should address mechanisms of resistance and biomarkers to achieve cures beyond APL.

P1, N=20, Not yet recruiting, M.D. Anderson Cancer Center

Inhibitors of mutated IDH1 and IDH2, vorasidenib, ivosidenib, olutasidenib, and enasidenib, respectively, were recently approved by the FDA for relapsed/refractory AML. In this review, we mainly focus on IDH inhibitors in leukemia therapy, including the discovery, structure optimization, activity of IDH inhibitors, and applications, which provided the reference for the discovery of new anticancer agents.

P1, N=15, Recruiting, Virginia Commonwealth University | Not yet recruiting --> Recruiting | Trial completion date: Oct 2029 --> Oct 2030 | Trial primary completion date: Oct 2027 --> Oct 2028

Olutasidenib was well tolerated and conferred disease control in cCS. Study limitations include open-label design and low patient sample due to rarity of cCS.

P2, N=28, Recruiting, University of California, Davis | Not yet recruiting --> Recruiting

Olutasidenib-based therapy demonstrated 100% response rates in previously untreated IDH1-mutated AML and MDS and modest efficacy in heavily pretreated R/R AML and MDS. Durable remissions occurred in select responders and with stem cell transplant. Further evaluation of olutasidenib as frontline therapy in IDH1-mutated AML or MDS and as a bridge to transplant is warranted.