TY - JOUR
T1 - Phase 1b trial of tagraxofusp in combination with azacitidine with or without venetoclax in acute myeloid leukemia
AU - Lane, Andrew A.
AU - Garcia, Jacqueline S.
AU - Raulston, Evangeline G.
AU - Garzon, Jada L.
AU - Galinsky, Ilene
AU - Baxter, Emilie W.
AU - Leonard, Rebecca
AU - DeAngelo, Daniel J.
AU - Luskin, Marlise R.
AU - Reilly, Christopher R.
AU - Stahl, Maximilian
AU - Stone, Richard M.
AU - Vedula, Rahul S.
AU - Wadleigh, Martha M.
AU - Winer, Eric S.
AU - Mughal, Tariq
AU - Brooks, Christopher
AU - Gupta, Ira V.
AU - Stevenson, Kristen E.
AU - Neuberg, Donna S.
AU - Ren, Siyang
AU - Keating, Julia
AU - Konopleva, Marina
AU - Stein, Anthony
AU - Pemmaraju, Naveen
N1 - Publisher Copyright:
© 2024 by The American Society of Hematology.
PY - 2024/2/13
Y1 - 2024/2/13
N2 - CD123, a subunit of the interleukin-3 receptor, is expressed on ~80% of acute myeloid leukemias (AMLs). Tagraxofusp (TAG), recombinant interleukin-3 fused to a truncated diphtheria toxin payload, is a first-in-class drug targeting CD123 approved for treatment of blastic plasmacytoid dendritic cell neoplasm. We previously found that AMLs with acquired resistance to TAG were re-sensitized by the DNA hypomethylating agent azacitidine (AZA) and that TAG-exposed cells became more dependent on the antiapoptotic molecule BCL-2. Here, we report a phase 1b study in 56 adults with CD123-positive AML or high-risk myelodysplastic syndrome (MDS), first combining TAG with AZA in AML/MDS, and subsequently TAG, AZA, and the BCL-2 inhibitor venetoclax (VEN) in AML. Adverse events with 3-day TAG dosing were as expected, without indication of increased toxicity of TAG or AZA+/−VEN in combination. The recommended phase 2 dose of TAG was 12 μg/kg/day for 3 days, with 7-day AZA +/− 21-day VEN. In an expansion cohort of 26 patients (median age 71) with previously untreated European LeukemiaNet adverse-risk AML (50% TP53 mutated), triplet TAG-AZA-VEN induced response in 69% (n=18/26; 39% complete remission [CR], 19% complete remission with incomplete count recovery [CRi], 12% morphologic leukemia-free state [MLFS]). Among 13 patients with TP53 mutations, 7/13 (54%) achieved CR/CRi/MLFS (CR = 4, CRi = 2, MLFS = 1). Twelve of 17 (71%) tested responders had no flow measurable residual disease. Median overall survival and progression-free survival were 14 months (95% CI, 9.5-NA) and 8.5 months (95% CI, 5.1-NA), respectively. In summary, TAG-AZA-VEN shows encouraging safety and activity in high-risk AML, including TP53-mutated disease, supporting further clinical development of TAG combinations. The study was registered on ClinicalTrials.gov as #NCT03113643.
AB - CD123, a subunit of the interleukin-3 receptor, is expressed on ~80% of acute myeloid leukemias (AMLs). Tagraxofusp (TAG), recombinant interleukin-3 fused to a truncated diphtheria toxin payload, is a first-in-class drug targeting CD123 approved for treatment of blastic plasmacytoid dendritic cell neoplasm. We previously found that AMLs with acquired resistance to TAG were re-sensitized by the DNA hypomethylating agent azacitidine (AZA) and that TAG-exposed cells became more dependent on the antiapoptotic molecule BCL-2. Here, we report a phase 1b study in 56 adults with CD123-positive AML or high-risk myelodysplastic syndrome (MDS), first combining TAG with AZA in AML/MDS, and subsequently TAG, AZA, and the BCL-2 inhibitor venetoclax (VEN) in AML. Adverse events with 3-day TAG dosing were as expected, without indication of increased toxicity of TAG or AZA+/−VEN in combination. The recommended phase 2 dose of TAG was 12 μg/kg/day for 3 days, with 7-day AZA +/− 21-day VEN. In an expansion cohort of 26 patients (median age 71) with previously untreated European LeukemiaNet adverse-risk AML (50% TP53 mutated), triplet TAG-AZA-VEN induced response in 69% (n=18/26; 39% complete remission [CR], 19% complete remission with incomplete count recovery [CRi], 12% morphologic leukemia-free state [MLFS]). Among 13 patients with TP53 mutations, 7/13 (54%) achieved CR/CRi/MLFS (CR = 4, CRi = 2, MLFS = 1). Twelve of 17 (71%) tested responders had no flow measurable residual disease. Median overall survival and progression-free survival were 14 months (95% CI, 9.5-NA) and 8.5 months (95% CI, 5.1-NA), respectively. In summary, TAG-AZA-VEN shows encouraging safety and activity in high-risk AML, including TP53-mutated disease, supporting further clinical development of TAG combinations. The study was registered on ClinicalTrials.gov as #NCT03113643.
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U2 - 10.1182/bloodadvances.2023011721
DO - 10.1182/bloodadvances.2023011721
M3 - Article
C2 - 38052038
AN - SCOPUS:85185567418
SN - 2473-9529
VL - 8
SP - 591
EP - 602
JO - Blood Advances
JF - Blood Advances
IS - 3
ER -