Impact of measurable residual disease by decentralized flow cytometry: a PETHEMA real-world study in 1076 patients with acute myeloid leukemia

Paiva, Bruno; Vidriales, María‐Belén; Sempere, Amparo; Tarín, Fabián; Colado, Enrique; Benavente, Celina; Cedena, María-Teresa; Sánchez, Joaquín; Velázquez, T; Cordón, Lourdes; Garcés, Juan-José; Simoes, Catia; Martínez‐Cuadrón, David; Bernal, Teresa; Botella, C.; Grille, Sofía; Serrano, Josefina; Rodríguez-Medina, Carlos; Algarra, Lorenzo; Alonso-Domínguez, Juan-Manuel; Amigo, María‐Luz; Barrios, Manuel; García‐Boyero, Raimundo; Colorado, Mercedes; Pérez-Oteyza, J; Pérez‐Encinas, Manuel; Costilla-Barriga, Lisette; Sayas, María-José; Pérez, Olga; González‐Díaz, Marcos; Pérez-Simón, Josè Antonio; Martínez‐López, Joaquín; Sossa, Claudia; Órfão, Alberto; Miguel, Jesús F. San; Sanz, Miguel Á.; Montesinos, Pau

doi:10.1038/s41375-021-01126-3

Cited by 36 publications

(30 citation statements)

References 47 publications

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“…Our strategy extends further by allowing the identification of LAIPs even if they are expressed only in a small part of the leukemic population, which are otherwise impossible to detect by conventional methods. Thus, our findings confirm previous observations evidencing that conventional strategies could be significantly improved [ 4 , 20 , 21 , 22 ]. One of the greatest challenges for MFC-MRD assessment is the presence of cell populations expressing the identified LAIPs in healthy or regenerating bone marrow samples [ 8 , 23 ].…”

Section: Discussionsupporting

confidence: 92%

Identification of Leukemia-Associated Immunophenotypes by Databaseguided Flow Cytometry Provides a Highly Sensitive and Reproducible Strategy for the Study of Measurable Residual Disease in Acute Myeloblastic Leukemia

Piñero¹,

Morilla

Gutiérrez

et al. 2022

Cancers

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Background: Multiparametric Flow Cytometry (MFC) is an essential tool to study the involved cell lineages, the aberrant differentiation/maturation patterns and the expression of aberrant antigens in acute myeloid leukemia (AML). The characterization of leukemia-associated immunophenotypes (LAIPs) at the moment of diagnosis is critical to establish reproducible strategies for the study of measurable residual disease using MFC (MFC-MRD). Methods: In this study, we identify and characterize LAIPs by comparing the leukemic populations of 145 AML patients, using the EuroFlow AML/ MDS MFC panel, with six databases of normal myeloid progenitors (MPCs). Principal component analysis was used to identify and characterize the LAIPs, which were then used to generate individual profiles for MFC-MRD monitoring. Furthermore, we investigated the relationship between the expression patterns of LAIPs and the different subtypes of AML. The MFC-MRD study was performed by identifying residual AML populations that matched with the LAIPs at diagnosis. To further validate this approach, the presence of MRD was also assessed by qPCR (qPCR-MRD). Finally, we studied the association between MFC-MRD and progression-free survival (PFS). Results: The strategy used in this study allowed us to describe more than 300 different LAIPs and facilitated the association of specific phenotypes with certain subtypes of AML. The MFC-MRD monitoring based on LAIPs with good/strong specificity was applicable to virtually all patients and showed a good correlation with qPCR-MRD and PFS. Conclusions: The described methodology provides an objective method to identify and characterize LAIPs. Furthermore, it provides a theoretical basis to develop highly sensitive MFC-MRD strategies.

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Section: Discussionsupporting

confidence: 92%

Identification of Leukemia-Associated Immunophenotypes by Databaseguided Flow Cytometry Provides a Highly Sensitive and Reproducible Strategy for the Study of Measurable Residual Disease in Acute Myeloblastic Leukemia

Piñero¹,

Morilla

Gutiérrez

et al. 2022

Cancers

Self Cite

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show abstract

“…Our strategy goes further allowing the identification of LAIPs even if they are expressed only in a small part of the leukemic population, which are otherwise impossible to detect by conventional methods. Thus, our findings confirm previous observations evidencing that conventional strategies could be significantly improved [4,[20][21][22] One of the greatest challenges for MFC-MRD assessment is the presence of cell populations expressing the identified LAIPs in healthy or regenerating bone marrow samples [8,23]. Our results confirm these observations even using individual monitoring profiles and database guided analysis for the exclusion of phenotypically normal cells.…”

Section: Discussionsupporting

confidence: 89%

Identification of leukemia-associated immunophenotypes by database-guided flow cytometry provides a highly sensitive and reproducible strategy for the study of measurable residual disease in acute myeloblastic leukemia

Piñero¹,

Morillas²,

Gutiérrez³

et al. 2022

Preprint

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Background: Multiparametric Flow Cytometry (MFC) is an essential tool to study the involved cell lineages, the aberrant differentiation/maturation patterns and the expression of aberrant antigens in acute myeloid leukemia (AML). The characterization of leukemia-associated immunophenotypes (LAIPs) at the moment of diagnosis is critical to establish reproducible strategies for the study of measurable residual disease using MFC (MFC-MRD). Methods: In this study, we identified and characterized LAIPs by comparing the leukemic populations of 145 AML patients, using the EuroFlow AML/ MDS MFC panel, with 6 databases of normal myeloid progenitors (MPCs). Principal component analysis was used to identify and characterize the LAIPs, which were then used to generate individual profiles for MFC-MRD monitoring. Furthermore, we investigated the relationship between the expression patterns of LAIPs and the different subtypes of AML. The MFC-MRD study was performed by identifying residual AML populations that matched with the LAIPs at diagnosis. To further validate this approach, the presence of MRD was also assessed by qPCR (qPCRMRD). Finally, we studied the association between MFC-MRD and progression-free survival (PFS). Results: The strategy used in this study allowed us to describe more than 300 different LAIPs and facilitated the association of specific phenotypes with certain subtypes of AML. The MFC-MRD monitoring based on LAIPs with good/strong specificity was applicable to virtually all patients and showed a good correlation with qPCR-MRD and PFS. Conclusions: The described methodology provides an objective method to identify and characterize LAIPs. Furthermore, it provides a theoretical basis to develop highly sensitive MFC-MRD strategies.

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“…While flow cytometry is highly applicable in more than 90% of AML cases [ 26 ], there is limited harmonization and standardization which may limit sensitivity and specificity in real-world settings [ 11 ]. Assessment of MRD at our centers utilized an eight-color Euroflow platform that incorporates the markers recommended in the recent ELN consensus document for MFC MRD assessment in AML [ 27 , 28 ].…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, a retrospective analysis of older patients treated with azacitidine showed that MRD negativity was not associated with improved OS due to the competing risk of death and infectious complications in a frail patient population [ 10 ]. In addition, MRD assessment in an off-trial setting may suffer methodological heterogeneity with reduced sensitivity and specificity, thus reducing its prognostic significance [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

Real-World Experience of Measurable Residual Disease Response and Prognosis in Acute Myeloid Leukemia Treated with Venetoclax and Azacitidine

Ong

Yun

Halim

et al. 2022

Cancers

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The prognostic value of measurable residual disease (MRD) by flow cytometry in acute myeloid leukemia (AML) patients treated with non-intensive therapy is relatively unexplored. The clinical value of MRD threshold below 0.1% is also unknown after non-intensive therapy. In this study, MRD to a sensitivity of 0.01% was analyzed in sixty-three patients in remission after azacitidine/venetoclax treatment. Multivariable cox regression analysis identified prognostic factors associated with cumulative incidence of relapse (CIR), progression-free survival (PFS) and overall survival (OS). Patients who achieved MRD < 0.1% had a lower relapse rate than those who were MRD ≥ 0.1% at 18 months (13% versus 57%, p = 0.006). Patients who achieved an MRD-negative CR had longer median PFS and OS (not reached and 26.5 months) than those who were MRD-positive (12.6 and 10.3 months, respectively). MRD < 0.1% was an independent predictor for CIR, PFS, and OS, after adjusting for European Leukemia Net (ELN) risk, complex karyotype, and transplant (HR 5.92, 95% CI 1.34-26.09, p = 0.019 for PFS; HR 2.60, 95% CI 1.02-6.63, p = 0.046 for OS). Only an MRD threshold of 0.1%, and not 0.01%, was predictive for OS. Our results validate the recommended ELN MRD cut-off of 0.1% to discriminate between patients with improved CIR, PFS, and OS after azacitidine/venetoclax therapy.

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Impact of measurable residual disease by decentralized flow cytometry: a PETHEMA real-world study in 1076 patients with acute myeloid leukemia

Cited by 36 publications

References 47 publications

Identification of Leukemia-Associated Immunophenotypes by Databaseguided Flow Cytometry Provides a Highly Sensitive and Reproducible Strategy for the Study of Measurable Residual Disease in Acute Myeloblastic Leukemia

Identification of Leukemia-Associated Immunophenotypes by Databaseguided Flow Cytometry Provides a Highly Sensitive and Reproducible Strategy for the Study of Measurable Residual Disease in Acute Myeloblastic Leukemia

Identification of leukemia-associated immunophenotypes by database-guided flow cytometry provides a highly sensitive and reproducible strategy for the study of measurable residual disease in acute myeloblastic leukemia

Real-World Experience of Measurable Residual Disease Response and Prognosis in Acute Myeloid Leukemia Treated with Venetoclax and Azacitidine

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