Outcome of patients with IDH1/2-mutated post-myeloproliferative neoplasm AML in the era of IDH inhibitors

Abstract

1. IDH1/2-inhibitor–based combinations conferred significant clinical responses in patients with IDH1/2-mutated post–MPN AML.

2. Complete remission was achieved in 3/7 patients (1 attaining MRD–) with new IDH1/2-mutated post–MPN AML treated with IDH1/2-i combinations.

Graphical abstract

Figure 1.

Timelines and treatments (IDH1/2-inhibitor–based regimens and others) during MPN in chronic- or accelerated-phase (MPN-CP/AP), post-MPN acute leukemia (for patients 8 through 12), and IDH1/2-mutated post-MPN AML for the patients in this study (N = 12). (A) Type of antecedent MPN, duration of disease, and treatment(s) are depicted for each patient; horizontal bar colors are coded according to the type of MPN (left panel). Acute leukemia that evolved from MPN (AML in patients 8-11 and ALL in patient 12), duration, and treatment of disease at other institutions (right panel). (B) Continued timelines from (A) for patients 1 through 12 with IDH1/2-mutated post–MPN AML, treated with IDH1/2 inhibitors as monotherapies or combinations, at the MD Anderson Cancer Center. Patients 1 through 7 had newly diagnosed post–MPN AML (depicted with green horizontal bars), and patients 8 through 12 had R/R post–MPN AML (depicted with blue horizontal bars); horizontal bar length indicates the duration of each treatment. Treatments based on IDH1/2 inhibitors are shown on the green and blue horizontal bars. IDH1/2 inhibitors were named according to their clinical use: enasidenib for the IDH2 inhibitor AG-221 if it was used off clinical study, and AG-221 if it was used in a clinical study; and ivosidenib for the IDH1 inhibitor AG-120 if it was used off clinical study, and AG-120 if it was used in a clinical study. FT-2102 and IDH-305 are IDH1 inhibitors (IDH-305 is no longer in clinical development). ACE-011, LCL161, inhibitor of bromodomain containing protein 4 (BRD4i), and HM43239 are investigational agents. IDH1/2 clearance is defined as undetectable VAF by NGS. AL, acute leukemia; ALL, acute lymphoblastic leukemia; Ara-C, cytarabine; AZA, azacitidine; [7+3], 7-day continuous infusion of cytarabine on days 1 to 7 and idarubicin on days 1 to 3; BIDFA, combination chemotherapy comprising fludarabine and idarubicin twice daily; BLINA, blinatumomab; CLIA, combination chemotherapy with cladribine, high-dose cytarabine, and idarubicin; CLOF, clofarabine; DAC, decitabine; EWALL, regimen comprising dasatinib in combination with chemotherapy, used in the European Working Group on Adult Acute Lymphoblastic Leukemia study for treatment of patients with ALL; FLAG-IDA, combination chemotherapy regimen comprising fludarabine, cytarabine, idarubicin and granulocyte colony-stimulating factor (G-CSF); GO, gemtuzumab ozogamicin (Mylotarg); HU, hydroxyurea; Inv IDH1-i, investigational IDH1 inhibitor; IDH2-i Rx, IDH2-inhibitor–based treatment; IVO, ivosidenib; LEN, lenalidomide; MF-AP, myelofibrosis in accelerated phase (≥10%-19% blasts in the bone marrow or peripheral blood); MRD, measurable residual disease; ND, newly diagnosed; Pt, patient; R/R, relapsed/refractory; RUX, ruxolitinib; SOR, sorafenib; VEN, venetoclax.