Phase 1b trial of tagraxofusp in combination with azacitidine with or without venetoclax in acute myeloid leukemia DOI Creative Commons
Andrew A. Lane, Jacqueline S. Garcia,

Evangeline G. Raulston

et al.

Blood Advances, Journal Year: 2023, Volume and Issue: 8(3), P. 591 - 602

Published: Dec. 5, 2023

CD123, a subunit of the interleukin-3 receptor, is expressed on ∼80% acute myeloid leukemias (AMLs). Tagraxofusp (TAG), recombinant fused to truncated diphtheria toxin payload, first-in-class drug targeting CD123 approved for treatment blastic plasmacytoid dendritic cell neoplasm. We previously found that AMLs with acquired resistance TAG were re-sensitized by DNA hypomethylating agent azacitidine (AZA) and TAG-exposed cells became more dependent antiapoptotic molecule BCL-2. Here, we report phase 1b study in 56 adults CD123-positive AML or high-risk myelodysplastic syndrome (MDS), first combining AZA AML/MDS, subsequently TAG, AZA, BCL-2 inhibitor venetoclax (VEN) AML. Adverse events 3-day dosing as expected, without indication increased toxicity AZA+/-VEN combination. The recommended 2 dose was 12 μg/kg/day 3 days, 7-day +/- 21-day VEN. In an expansion cohort 26 patients (median age 71) untreated European LeukemiaNet adverse-risk (50% TP53 mutated), triplet TAG-AZA-VEN induced response 69% (n=18/26; 39% complete remission [CR], 19% incomplete count recovery [CRi], 12% morphologic leukemia-free state [MLFS]). Among 13 mutations, 7/13 (54%) achieved CR/CRi/MLFS (CR = 4, CRi 2, MLFS 1). Twelve 17 (71%) tested responders had no flow measurable residual disease. Median overall survival progression-free 14 months (95% CI, 9.5-NA) 8.5 5.1-NA), respectively. summary, shows encouraging safety activity AML, including TP53-mutated disease, supporting further clinical development combinations. registered ClinicalTrials.gov #NCT03113643.

Language: Английский

IL-3 in the development and function of basophils DOI
Gilda Varricchi, Remo Poto, Gianni Marone

et al.

Seminars in Immunology, Journal Year: 2021, Volume and Issue: 54, P. 101510 - 101510

Published: April 1, 2021

Language: Английский

Citations

42
North American Blastic Plasmacytoid Dendritic Cell Neoplasm Consortium: position on standards of care and areas of need DOI Open Access
Naveen Pemmaraju, Hagop M. Kantarjian, Kendra Sweet

et al.

Blood, Journal Year: 2022, Volume and Issue: 141(6), P. 567 - 578

Published: Nov. 18, 2022

Language: Английский

Citations

31
Characteristics and outcomes of patients with blastic plasmacytoid dendritic cell neoplasm treated with frontline HCVAD DOI Creative Commons
Naveen Pemmaraju, Nathaniel R. Wilson, Guillermo Garcia‐Manero

et al.

Blood Advances, Journal Year: 2022, Volume and Issue: 6(10), P. 3027 - 3035

Published: Jan. 21, 2022

Abstract Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a clinically aggressive blood cancer, often involving the skin, bone marrow, lymph nodes, and central nervous system (CNS) in 20% to 30% of patients. Despite significant progress CD123- BCL-2–targeted therapy, most patients are not cured without hematopoietic stem transplant (HSCT), CNS relapses occur quite frequently. Combination approaches with targeted chemotherapy agents plus incorporation prophylactic CNS-directed therapy urgently needed. In this setting, we sought analyze outcomes using cytotoxic backbone regimen hyperfractionated cyclophosphamide, vincristine, adriamycin, dexamethasone (HCVAD). We conducted retrospective analysis BPDCN (n = 100), evaluating complete remission (CR) median overall survival (OS) among 3 groups: those who received frontline HCVAD-based 35), SL-401 37), or other regimens 28). yielded higher CR (80% vs 59% 43%; P .01). There was no difference OS (28.3 13.7 22.8 months; .41) duration probability treatment groups (38.6 reached 10.2 .24). HSCT performed 51% 49% 38%, respectively (P .455). These results suggest continued important role for BPDCN, even modern targeted-therapy era, high rates setting. Further studies must establish clinical activity, feasibility, safety doublet/triplet combinations therapies addition prophylaxis, ultimate goal durable long-term BPDCN.

Language: Английский

Citations

30
CAR-T cells dual-target CD123 and NKG2DLs to eradicate AML cells and selectively target immunosuppressive cells DOI Creative Commons
Xin Jin, Danni Xie, Rui Sun

et al.

OncoImmunology, Journal Year: 2023, Volume and Issue: 12(1)

Published: Aug. 26, 2023

Chimeric antigen receptor (CAR)-T cells have not made significant progress in the treatment of acute myeloid leukemia (AML) earlyclinical studies. This lack could be attributed part to immunosuppressive microenvironment AML, such as monocyte-like myeloid-derived suppressor (M-MDSCs) and alternatively activated macrophages (M2 cells), which can inhibit antitumor activity CAR-T cells. Furthermore, AML are usually heterogeneous, single-target may able eliminate all cells, leading disease relapse. CD123 NKG2D ligands (NKG2DLs) commonly used targets for therapy M-MDSCs M2 express both antigens. We developed dual-targeted (123NL CAR-T) targeting NKG2DL by various structural optimization screens. Our study reveals that 123NL eradicate selectively target A highly compact marker/suicide gene, RQR8, binds epitopes CD34 CD20 antigens, was also incorporated front CAR structure. The binding Rituximab RQR8 leads elimination cessation their cytotoxicity. In conclusion, we successfully dual effects against tumor avoid escape resist microenvironment.

Language: Английский

Citations

22
Phase 1b trial of tagraxofusp in combination with azacitidine with or without venetoclax in acute myeloid leukemia DOI Creative Commons
Andrew A. Lane, Jacqueline S. Garcia,

Evangeline G. Raulston

et al.

Blood Advances, Journal Year: 2023, Volume and Issue: 8(3), P. 591 - 602

Published: Dec. 5, 2023

CD123, a subunit of the interleukin-3 receptor, is expressed on ∼80% acute myeloid leukemias (AMLs). Tagraxofusp (TAG), recombinant fused to truncated diphtheria toxin payload, first-in-class drug targeting CD123 approved for treatment blastic plasmacytoid dendritic cell neoplasm. We previously found that AMLs with acquired resistance TAG were re-sensitized by DNA hypomethylating agent azacitidine (AZA) and TAG-exposed cells became more dependent antiapoptotic molecule BCL-2. Here, we report phase 1b study in 56 adults CD123-positive AML or high-risk myelodysplastic syndrome (MDS), first combining AZA AML/MDS, subsequently TAG, AZA, BCL-2 inhibitor venetoclax (VEN) AML. Adverse events 3-day dosing as expected, without indication increased toxicity AZA+/-VEN combination. The recommended 2 dose was 12 μg/kg/day 3 days, 7-day +/- 21-day VEN. In an expansion cohort 26 patients (median age 71) untreated European LeukemiaNet adverse-risk (50% TP53 mutated), triplet TAG-AZA-VEN induced response 69% (n=18/26; 39% complete remission [CR], 19% incomplete count recovery [CRi], 12% morphologic leukemia-free state [MLFS]). Among 13 mutations, 7/13 (54%) achieved CR/CRi/MLFS (CR = 4, CRi 2, MLFS 1). Twelve 17 (71%) tested responders had no flow measurable residual disease. Median overall survival progression-free 14 months (95% CI, 9.5-NA) 8.5 5.1-NA), respectively. summary, shows encouraging safety activity AML, including TP53-mutated disease, supporting further clinical development combinations. registered ClinicalTrials.gov #NCT03113643.

Language: Английский

Citations

18