Flow cytometric significance of cellular alkaline phosphatase activity in acute myeloid leukemia

In this prospective hospital-based cohort study that included 43 newly diagnosed patients with acute myeloid leukemia, flow cytometric cellular alkaline phosphatase (ALP) activity within primitive leukemic cells allowed us to identify two groups of patients at diagnosis according to the numbers of leukemic blasts expressing ≥ 12% of ALP+ cells (27 patients, Group A) and less than 12% of ALP+ cells (16 patients, Group B). Differences in outcome for complete response, relapse or treatment resistance, and exitus were statistically analyzed and were significant, when comparing the two groups. The overall survival (OS) and event-free survival (EFS) differences between Group A and B were statistically significant. The survival of Group A patients was significantly shorter than those for Group B. No significant relationship was detected in outcome when comparing ELN prognostic-risk group based on cytogenetic and molecular profile (patients in the favorable, intermediate, and adverse risk groups). Flow cytometric cellular ALP activity at diagnosis may be used to estimate relapses and disease persistence more accurately. The limitations of our study include the small number of patients enrolled and a short follow-up, due to its prospective nature

Unmasking the expression of PD-L1 in Myeloid Derived Suppressor Cells : a case study in lung cancer to discover new drugs with specific on-target efficacy

Altres ajuts: We thank CERCA Programme/Generalitat de Catalunya and The Josep Carreras Foundation for institutional support. The authors are also very grateful for their advice and technical support to Sergio Ramón, Víctor Querol, Clara Streiff, Paola Paglia, and Lluís Sainz from Thermo Fisher for all his comments and discussions on earlier work in this research field. Jordi Petriz also acknowledges the financial support from The Obra Social La Caixa and Thermo Fisher Scientific

Unique clinico-biological, genetic and prognostic features of adult early T-cell precursor acute lymphoblastic leukemia

Altres ajuts: this project was supported by the Asociación Española Contra el Cáncer (project ref: GC16173697BIGA), [...], and Obra Social "La Caixa"

Flow cytometric significance of cellular alkaline phosphatase activity in acute myeloid leukemia

In this prospective hospital-based cohort study that included 43 newly diagnosed patients with acute myeloid leukemia, flow cytometric cellular alkaline phosphatase (ALP) activity within primitive leukemic cells allowed us to identify two groups of patients at diagnosis according to the numbers of leukemic blasts expressing ≥ 12% of ALP+ cells (27 patients, Group A) and less than 12% of ALP+ cells (16 patients, Group B). Differences in outcome for complete response, relapse or treatment resistance, and exitus were statistically analyzed and were significant, when comparing the two groups. The overall survival (OS) and event-free survival (EFS) differences between Group A and B were statistically significant. The survival of Group A patients was significantly shorter than those for Group B. No significant relationship was detected in outcome when comparing ELN prognostic-risk group based on cytogenetic and molecular profile (patients in the favorable, intermediate, and adverse risk groups). Flow cytometric cellular ALP activity at diagnosis may be used to estimate relapses and disease persistence more accurately. The limitations of our study include the small number of patients enrolled and a short follow-up, due to its prospective nature

41BB-based and CD28-based CD123-redirected T-cells ablate human normal hematopoiesis in vivo.

Background Acute myeloid leukemia (AML) is a hematopoietic malignancy which is biologically, phenotypically and genetically very heterogeneous. Outcome of patients with AML remains dismal, highlighting the need for improved, less toxic therapies. Chimeric antigen receptor T-cell (CART) immunotherapies for patients with refractory or relapse (R/R) AML are challenging because of the absence of a universal pan-AML target antigen and the shared expression of target antigens with normal hematopoietic stem/progenitor cells (HSPCs), which may lead to life-threating on-target/off-tumor cytotoxicity. CD33-redirected and CD123-redirected CARTs for AML are in advanced preclinical and clinical development, and they exhibit robust antileukemic activity. However, preclinical and clinical controversy exists on whether such CARTs are myeloablative. Methods We set out to comparatively characterize in vitro and in vivo the efficacy and safety of 41BB-based and CD28-based CARCD123. We analyzed 97 diagnostic and relapse AML primary samples to investigate whether CD123 is a suitable immunotherapeutic target, and we used several xenograft models and in vitro assays to assess the myeloablative potential of our second-generation CD123 CARTs. Results Here, we show that CD123 represents a bona fide target for AML and show that both 41BB-based and CD28-based CD123 CARTs are very efficient in eliminating both AML cell lines and primary cells in vitro and in vivo. However, both 41BB-based and CD28-based CD123 CARTs ablate normal human hematopoiesis and prevent the establishment of de novo hematopoietic reconstitution by targeting both immature and myeloid HSPCs. Conclusions This study calls for caution when clinically implementing CD123 CARTs, encouraging its preferential use as a bridge to allo-HSCT in patients with R/R AML

41BB-based and CD28-based CD123-redirected T-cells ablate human normal hematopoiesis in vivo

Altres ajuts: We thank CERCA/Generalitat de Catalunya and Fundació Josep Carreras-Obra Social la Caixa for their institutional support. PM acknowledges financial support from theSpanish Cancer Research Association (AECC-Semilla19), the Fundación Uno entre Cienmil, the Obra Social La Caixa (LCF/PR/HR19/52160011), the Leo Messi Foundation, the Banco Santander Foundation and the "Heroes hasta la médula" initiative.BACKGROUND: Acute myeloid leukemia (AML) is a hematopoietic malignancy which is biologically, phenotypically and genetically very heterogeneous. Outcome of patients with AML remains dismal, highlighting the need for improved, less toxic therapies. Chimeric antigen receptor T-cell (CART) immunotherapies for patients with refractory or relapse (R/R) AML are challenging because of the absence of a universal pan-AML target antigen and the shared expression of target antigens with normal hematopoietic stem/progenitor cells (HSPCs), which may lead to life-threating on-target/off-tumor cytotoxicity. CD33-redirected and CD123-redirected CARTs for AML are in advanced preclinical and clinical development, and they exhibit robust antileukemic activity. However, preclinical and clinical controversy exists on whether such CARTs are myeloablative. METHODS: We set out to comparatively characterize in vitro and in vivo the efficacy and safety of 41BB-based and CD28-based CARCD123. We analyzed 97 diagnostic and relapse AML primary samples to investigate whether CD123 is a suitable immunotherapeutic target, and we used several xenograft models and in vitro assays to assess the myeloablative potential of our second-generation CD123 CARTs. RESULTS: Here, we show that CD123 represents a bona fide target for AML and show that both 41BB-based and CD28-based CD123 CARTs are very efficient in eliminating both AML cell lines and primary cells in vitro and in vivo. However, both 41BB-based and CD28-based CD123 CARTs ablate normal human hematopoiesis and prevent the establishment of de novo hematopoietic reconstitution by targeting both immature and myeloid HSPCs. CONCLUSIONS: This study calls for caution when clinically implementing CD123 CARTs, encouraging its preferential use as a bridge to allo-HSCT in patients with R/R AML