EHA Library - The official digital education library of European Hematology Association (EHA)

Abstract
Discussion Forum (0)
Presentation during EHA2022: All (e)Poster presentations will be made available as of Friday, June 10, 2022 (09:00 CEST) and will be accessible for on-demand viewing until Monday, August 15, 2022 on the Congress platform.

Abstract: P388

Type: Poster presentation

Session title: Acute myeloid leukemia - Biology & Translational Research

Background

Acute myeloid leukemia (AML) is an aggressive hematological malignancy with poor prognosis characterized by a high rate of relapse after conventional combination chemotherapy, highlighting the need for improved therapeutic interventions. Genes involved in pre-mRNA splicing, namely SF3B1, U2AF1 and SRSF2, are frequently mutated in AML.Recent studies suggest that pharmacological targeting of the splicing machinery results in preferential lethality of splicing mutant AML cells, potentially providing a novel strategy for treatment of this disease. Existing anti- cancer sulfonamides have been shown to interfere with splicing and induce preferential killing of splicing mutant AML cell lines. A particular sulfonamide drug, indisulam, was previously studied in cancer clinical trials where it was found to be safe but demonstrated limited efficacy, most likely because neither the mechanism of action nor potential biomarkers of response were known.

Aims

We investigated, in this study, the efficacy of indisulam, either alone or in combination with ABT-199 (venetoclax) and azacitidine, in cultured primary human AML cells.

Methods

Bone marrow cells were collected from adults newly diagnosed with AML, non-treated. Cells were cultured and incubated for 48 and 72 hours with indisulam at a range of nanomolar concentrations. Additionally, cells were incubated with ABT-199 (10nM) and azacitidine (1μM), alone or in combination with indisulam. Cell viability and cell death were measured. For mutation profiling, a targeted myeloid gene panel was used.

Results

We found that treatment with indisulam resulted in lethality of primary AML cells harboring mutations in SF3B1, but had minor or no effect on AML cells with other mutations including mutations in splicing factors U2AF1 and SRSF2. In SF3B1-mutated cells, a clear synergistic effect was further observed when indisulam was combined with ABT-199 and azacitidine. The correlation between efficacy of indisulam and synergy with ABT-199 and azacitidine in AML cells with different mutations will be shown and discussed.

Conclusion

Our results indicate that indisulam is preferentially active and synergistic with venetoclax and azacitidine in SF3B1-mutated cells from newly diagnosed, non-treated AML patients.

Keyword(s): Acute myeloid leukemia, Mutation status, Therapy

Presentation during EHA2022: All (e)Poster presentations will be made available as of Friday, June 10, 2022 (09:00 CEST) and will be accessible for on-demand viewing until Monday, August 15, 2022 on the Congress platform.

Abstract: P388

Type: Poster presentation

Session title: Acute myeloid leukemia - Biology & Translational Research

Background

Acute myeloid leukemia (AML) is an aggressive hematological malignancy with poor prognosis characterized by a high rate of relapse after conventional combination chemotherapy, highlighting the need for improved therapeutic interventions. Genes involved in pre-mRNA splicing, namely SF3B1, U2AF1 and SRSF2, are frequently mutated in AML.Recent studies suggest that pharmacological targeting of the splicing machinery results in preferential lethality of splicing mutant AML cells, potentially providing a novel strategy for treatment of this disease. Existing anti- cancer sulfonamides have been shown to interfere with splicing and induce preferential killing of splicing mutant AML cell lines. A particular sulfonamide drug, indisulam, was previously studied in cancer clinical trials where it was found to be safe but demonstrated limited efficacy, most likely because neither the mechanism of action nor potential biomarkers of response were known.

Aims

We investigated, in this study, the efficacy of indisulam, either alone or in combination with ABT-199 (venetoclax) and azacitidine, in cultured primary human AML cells.

Methods

Bone marrow cells were collected from adults newly diagnosed with AML, non-treated. Cells were cultured and incubated for 48 and 72 hours with indisulam at a range of nanomolar concentrations. Additionally, cells were incubated with ABT-199 (10nM) and azacitidine (1μM), alone or in combination with indisulam. Cell viability and cell death were measured. For mutation profiling, a targeted myeloid gene panel was used.

Results

We found that treatment with indisulam resulted in lethality of primary AML cells harboring mutations in SF3B1, but had minor or no effect on AML cells with other mutations including mutations in splicing factors U2AF1 and SRSF2. In SF3B1-mutated cells, a clear synergistic effect was further observed when indisulam was combined with ABT-199 and azacitidine. The correlation between efficacy of indisulam and synergy with ABT-199 and azacitidine in AML cells with different mutations will be shown and discussed.

Conclusion

Our results indicate that indisulam is preferentially active and synergistic with venetoclax and azacitidine in SF3B1-mutated cells from newly diagnosed, non-treated AML patients.

Keyword(s): Acute myeloid leukemia, Mutation status, Therapy

PREFERENTIAL SYNERGISTIC EFFECT OF INDISULAM IN COMBINATION WITH VENETOCLAX AND AZACYTIDINE IN AML CELLS WITH SF3B1 MUTATIONS.
Paulo Bernardo
Paulo Bernardo
Author(s): Paulo Bernardo,  
Paulo Bernardo
Affiliations:
Instituto Medicina Molecular João Lobo Antunes,Faculdade de Medicina, Universidade de Lisboa,Lisbon,Portugal;Instituto Medicina Molecular João Lobo Antunes,Faculdade de Medicina, Universidade de Lisboa,Lisbon,Portugal;Instituto Medicina Molecular João Lobo Antunes,Faculdade de Medicina, Universidade de Lisboa,Lisbon,Portogallo;Instituto Medicina Molecular João Lobo Antunes,Faculdade de Medicina, U
Michelle Pereira,  
Michelle Pereira
Affiliations:
Instituto Medicina Molecular João Lobo Antunes,Faculdade de Medicina, Universidade de Lisboa,Lisbon,Portugal;Instituto Medicina Molecular João Lobo Antunes,Faculdade de Medicina, Universidade de Lisboa,Lisbon,Portugal;Instituto Medicina Molecular João Lobo Antunes,Faculdade de Medicina, Universidade de Lisboa,Lisbon,Portogallo;Instituto Medicina Molecular João Lobo Antunes,Faculdade de Medicina, U
Beatriz Galvão,  
Beatriz Galvão
Affiliations:
Instituto Medicina Molecular João Lobo Antunes,Faculdade de Medicina, Universidade de Lisboa,Lisbon,Portugal;Instituto Medicina Molecular João Lobo Antunes,Faculdade de Medicina, Universidade de Lisboa,Lisbon,Portugal;Instituto Medicina Molecular João Lobo Antunes,Faculdade de Medicina, Universidade de Lisboa,Lisbon,Portogallo;Instituto Medicina Molecular João Lobo Antunes,Faculdade de Medicina, U
Joana Desterro,  
Joana Desterro
Affiliations:
Instituto Medicina Molecular João Lobo Antunes,Faculdade de Medicina, Universidade de Lisboa,Lisbon,Portugal;Instituto Medicina Molecular João Lobo Antunes,Faculdade de Medicina, Universidade de Lisboa,Lisbon,Portugal;Instituto Medicina Molecular João Lobo Antunes,Faculdade de Medicina, Universidade de Lisboa,Lisbon,Portogallo;Instituto Medicina Molecular João Lobo Antunes,Faculdade de Medicina, U
Albertina Nunes,  
Albertina Nunes
Affiliations:
Serviço de Hematologia Clínica,Instituto Português de Oncologia de Lisboa Francisco Gentil,Lisbon,Portugal;Serviço de Hematologia Clínica,Instituto Português de Oncologia de Lisboa Francisco Gentil,Lisbon,Portugal;Serviço de Hematologia Clínica,Instituto Português de Oncologia de Lisboa Francisco Gentil,Lisbon,Portogallo;Serviço de Hematologia Clínica,Instituto Português de Oncologia de Lisboa Fra
Maria de Jesus Frade,  
Maria de Jesus Frade
Affiliations:
Serviço de Hematologia Clínica,Instituto Português de Oncologia de Lisboa Francisco Gentil,Lisbon,Portugal;Serviço de Hematologia Clínica,Instituto Português de Oncologia de Lisboa Francisco Gentil,Lisbon,Portugal;Serviço de Hematologia Clínica,Instituto Português de Oncologia de Lisboa Francisco Gentil,Lisbon,Portogallo;Serviço de Hematologia Clínica,Instituto Português de Oncologia de Lisboa Fra
Joana Lobato,  
Joana Lobato
Affiliations:
Serviço de Hematologia Clínica,Instituto Português de Oncologia de Lisboa Francisco Gentil,Lisbon,Portugal;Serviço de Hematologia Clínica,Instituto Português de Oncologia de Lisboa Francisco Gentil,Lisbon,Portugal;Serviço de Hematologia Clínica,Instituto Português de Oncologia de Lisboa Francisco Gentil,Lisbon,Portogallo;Serviço de Hematologia Clínica,Instituto Português de Oncologia de Lisboa Fra
Maria Gomes da Silva,  
Maria Gomes da Silva
Affiliations:
Serviço de Hematologia Clínica,Instituto Português de Oncologia de Lisboa Francisco Gentil,Lisbon,Portugal;Serviço de Hematologia Clínica,Instituto Português de Oncologia de Lisboa Francisco Gentil,Lisbon,Portugal;Serviço de Hematologia Clínica,Instituto Português de Oncologia de Lisboa Francisco Gentil,Lisbon,Portogallo;Serviço de Hematologia Clínica,Instituto Português de Oncologia de Lisboa Fra
Marcos Lemos,  
Marcos Lemos
Affiliations:
Serviço de Hematologia Clínica,Centro Hospitalar Lisboa Central - Hospital de St. António dos Capuchos,Lisbon,Portugal;Serviço de Hematologia Clínica,Centro Hospitalar Lisboa Central - Hospital de St. António dos Capuchos,Lisbon,Portugal;Serviço de Hematologia Clínica,Centro Hospitalar Lisboa Central - Hospital de St. António dos Capuchos,Lisbon,Portogallo;Serviço de Hematologia Clínica,Centro Hos
Madalena Silva,  
Madalena Silva
Affiliations:
Serviço de Hematologia Clínica,Centro Hospitalar Lisboa Central - Hospital de St. António dos Capuchos,Lisbon,Portugal;Serviço de Hematologia Clínica,Centro Hospitalar Lisboa Central - Hospital de St. António dos Capuchos,Lisbon,Portugal;Serviço de Hematologia Clínica,Centro Hospitalar Lisboa Central - Hospital de St. António dos Capuchos,Lisbon,Portogallo;Serviço de Hematologia Clínica,Centro Hos
Patricia Ribeiro,  
Patricia Ribeiro
Affiliations:
Serviço de Hematologia Clínica,Centro Hospitalar Lisboa Central - Hospital de St. António dos Capuchos,Lisbon,Portugal;Serviço de Hematologia Clínica,Centro Hospitalar Lisboa Central - Hospital de St. António dos Capuchos,Lisbon,Portugal;Serviço de Hematologia Clínica,Centro Hospitalar Lisboa Central - Hospital de St. António dos Capuchos,Lisbon,Portogallo;Serviço de Hematologia Clínica,Centro Hos
Sónia Matos,  
Sónia Matos
Affiliations:
GenoMed - Diagnósticos de Medicina Molecular SA,Lisbon,Portugal;GenoMed - Diagnósticos de Medicina Molecular SA,Lisbon,Portugal;GenoMed - Diagnósticos de Medicina Molecular SA,Lisbon,Portogallo;GenoMed - Diagnósticos de Medicina Molecular SA,Lisbon,Portugal;GenoMed - Diagnósticos de Medicina Molecular SA,Lisbon,Portugal;GenoMed - Diagnósticos de Medicina Molecular SA,Lisbon,Portugal;GenoMed - Diag
Noélia Custódio,  
Noélia Custódio
Affiliations:
Instituto Medicina Molecular João Lobo Antunes,Faculdade de Medicina, Universidade de Lisboa,Lisbon,Portugal;Instituto Medicina Molecular João Lobo Antunes,Faculdade de Medicina, Universidade de Lisboa,Lisbon,Portugal;Instituto Medicina Molecular João Lobo Antunes,Faculdade de Medicina, Universidade de Lisboa,Lisbon,Portogallo;Instituto Medicina Molecular João Lobo Antunes,Faculdade de Medicina, U
Maria Carmo-Fonseca
Maria Carmo-Fonseca
Affiliations:
Instituto Medicina Molecular João Lobo Antunes,Faculdade de Medicina, Universidade de Lisboa,Lisbon,Portugal;Instituto Medicina Molecular João Lobo Antunes,Faculdade de Medicina, Universidade de Lisboa,Lisbon,Portugal;Instituto Medicina Molecular João Lobo Antunes,Faculdade de Medicina, Universidade de Lisboa,Lisbon,Portogallo;Instituto Medicina Molecular João Lobo Antunes,Faculdade de Medicina, U
(Abstract release date: 05/12/22) EHA Library. Bernardo P. 06/10/2022; 357251; P388
Abstract
Discussion Forum (0)
Presentation during EHA2022: All (e)Poster presentations will be made available as of Friday, June 10, 2022 (09:00 CEST) and will be accessible for on-demand viewing until Monday, August 15, 2022 on the Congress platform.

Abstract: P388

Type: Poster presentation

Session title: Acute myeloid leukemia - Biology & Translational Research

Background

Acute myeloid leukemia (AML) is an aggressive hematological malignancy with poor prognosis characterized by a high rate of relapse after conventional combination chemotherapy, highlighting the need for improved therapeutic interventions. Genes involved in pre-mRNA splicing, namely SF3B1, U2AF1 and SRSF2, are frequently mutated in AML.Recent studies suggest that pharmacological targeting of the splicing machinery results in preferential lethality of splicing mutant AML cells, potentially providing a novel strategy for treatment of this disease. Existing anti- cancer sulfonamides have been shown to interfere with splicing and induce preferential killing of splicing mutant AML cell lines. A particular sulfonamide drug, indisulam, was previously studied in cancer clinical trials where it was found to be safe but demonstrated limited efficacy, most likely because neither the mechanism of action nor potential biomarkers of response were known.

Aims

We investigated, in this study, the efficacy of indisulam, either alone or in combination with ABT-199 (venetoclax) and azacitidine, in cultured primary human AML cells.

Methods

Bone marrow cells were collected from adults newly diagnosed with AML, non-treated. Cells were cultured and incubated for 48 and 72 hours with indisulam at a range of nanomolar concentrations. Additionally, cells were incubated with ABT-199 (10nM) and azacitidine (1μM), alone or in combination with indisulam. Cell viability and cell death were measured. For mutation profiling, a targeted myeloid gene panel was used.

Results

We found that treatment with indisulam resulted in lethality of primary AML cells harboring mutations in SF3B1, but had minor or no effect on AML cells with other mutations including mutations in splicing factors U2AF1 and SRSF2. In SF3B1-mutated cells, a clear synergistic effect was further observed when indisulam was combined with ABT-199 and azacitidine. The correlation between efficacy of indisulam and synergy with ABT-199 and azacitidine in AML cells with different mutations will be shown and discussed.

Conclusion

Our results indicate that indisulam is preferentially active and synergistic with venetoclax and azacitidine in SF3B1-mutated cells from newly diagnosed, non-treated AML patients.

Keyword(s): Acute myeloid leukemia, Mutation status, Therapy

Presentation during EHA2022: All (e)Poster presentations will be made available as of Friday, June 10, 2022 (09:00 CEST) and will be accessible for on-demand viewing until Monday, August 15, 2022 on the Congress platform.

Abstract: P388

Type: Poster presentation

Session title: Acute myeloid leukemia - Biology & Translational Research

Background

Acute myeloid leukemia (AML) is an aggressive hematological malignancy with poor prognosis characterized by a high rate of relapse after conventional combination chemotherapy, highlighting the need for improved therapeutic interventions. Genes involved in pre-mRNA splicing, namely SF3B1, U2AF1 and SRSF2, are frequently mutated in AML.Recent studies suggest that pharmacological targeting of the splicing machinery results in preferential lethality of splicing mutant AML cells, potentially providing a novel strategy for treatment of this disease. Existing anti- cancer sulfonamides have been shown to interfere with splicing and induce preferential killing of splicing mutant AML cell lines. A particular sulfonamide drug, indisulam, was previously studied in cancer clinical trials where it was found to be safe but demonstrated limited efficacy, most likely because neither the mechanism of action nor potential biomarkers of response were known.

Aims

We investigated, in this study, the efficacy of indisulam, either alone or in combination with ABT-199 (venetoclax) and azacitidine, in cultured primary human AML cells.

Methods

Bone marrow cells were collected from adults newly diagnosed with AML, non-treated. Cells were cultured and incubated for 48 and 72 hours with indisulam at a range of nanomolar concentrations. Additionally, cells were incubated with ABT-199 (10nM) and azacitidine (1μM), alone or in combination with indisulam. Cell viability and cell death were measured. For mutation profiling, a targeted myeloid gene panel was used.

Results

We found that treatment with indisulam resulted in lethality of primary AML cells harboring mutations in SF3B1, but had minor or no effect on AML cells with other mutations including mutations in splicing factors U2AF1 and SRSF2. In SF3B1-mutated cells, a clear synergistic effect was further observed when indisulam was combined with ABT-199 and azacitidine. The correlation between efficacy of indisulam and synergy with ABT-199 and azacitidine in AML cells with different mutations will be shown and discussed.

Conclusion

Our results indicate that indisulam is preferentially active and synergistic with venetoclax and azacitidine in SF3B1-mutated cells from newly diagnosed, non-treated AML patients.

Keyword(s): Acute myeloid leukemia, Mutation status, Therapy

By clicking “Accept Terms & all Cookies” or by continuing to browse, you agree to the storing of third-party cookies on your device to enhance your user experience and agree to the user terms and conditions of this learning management system (LMS).

Cookie Settings
Accept Terms & all Cookies