2023

Jump to: 2022, 2021

16 pages, 7412 KiB

Open AccessArticle

High-Dimensional Mass Cytometry Analysis of Embryonic Antigens and Their Signaling Pathways in Myeloid Cells from Bone Marrow Aspirates in AML Patients at Diagnosis

by Carmen-Mariana Aanei, Estelle Devêvre, Adrian Șerban, Emmanuelle Tavernier-Tardy, Denis Guyotat and Lydia Campos Catafal

Cancers 2023, 15(19), 4707; https://doi.org/10.3390/cancers15194707 - 25 Sep 2023

Viewed by 928

Abstract

Background: Embryonic antigens (EA) regulate pluripotency, self-renewal, and differentiation in embryonic stem (ES) cells during their development. In adult somatic cells, EA expression is normally inhibited; however, EAs can be re-expressed by cancer cells and are involved in the deregulation of different signaling [...] Read more.

Background: Embryonic antigens (EA) regulate pluripotency, self-renewal, and differentiation in embryonic stem (ES) cells during their development. In adult somatic cells, EA expression is normally inhibited; however, EAs can be re-expressed by cancer cells and are involved in the deregulation of different signaling pathways (SPs). In the context of AML, data concerning the expression of EAs are scarce and contradictory. Methods: We used mass cytometry to explore the expression of EAs and three SPs in myeloid cells from AML patients and normal bone marrow (NBM). Imaging flow cytometry was used for morphological assessment of cells in association with their OCT3/4 expression status (positive vs. negative). Results: An overall reduction in or absence of EA expression was observed in immature myeloid cells from AML patients compared to their normal counterparts. Stage-specific embryonic antigen-3 (SSEA-3) was consistently expressed at low levels in immature myeloid cells, whereas SSEA-1 was overexpressed in hematopoietic stem cells (HSCs) and myeloblasts from AML with monocytic differentiation (AML M4/M5). Therefore, these markers are valuable for distinguishing between normal and abnormal myeloid cells. These preliminary results show that the exploration of myeloid cell intracellular SPs in the setting of AML is very informative. Deregulation of three important leukemogenic SPs was also observed in myeloid cells from AML. Conclusions: Exploring EAs and SPs in myeloid cells from AML patients by mass cytometry may help identify characteristic phenotypes and facilitate AML follow-up. Full article

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11 pages, 2501 KiB

Open AccessArticle

The Application of GHRH Antagonist as a Treatment for Resistant APL

by Ravinder S. Chale, Stephanie M. Almeida, Mario Rodriguez, Ivan Jozic, Simonetta I. Gaumond, Andrew V. Schally and Joaquin J. Jimenez

Cancers 2023, 15(12), 3104; https://doi.org/10.3390/cancers15123104 - 08 Jun 2023

Cited by 1 | Viewed by 1188

Abstract

GHRH is a hypothalamic peptide shown to stimulate the proliferation of malignant cells in humans. We have previously shown that the use of GHRH antagonist MIA-602 successfully suppressed the growth of many human cancer cell lines, spanning more than 20 types of cancers. [...] Read more.

GHRH is a hypothalamic peptide shown to stimulate the proliferation of malignant cells in humans. We have previously shown that the use of GHRH antagonist MIA-602 successfully suppressed the growth of many human cancer cell lines, spanning more than 20 types of cancers. In this study, we demonstrate the presence of GHRH-R in the NB4, NB4-RAA, and K-562 model cell lines. Furthermore, we demonstrate the inhibited proliferation of all three cell lines in vitro after incubation with MIA-602. The treatment of xenografts of human APL cell lines with MIA-602 led to a significant reduction in tumor growth. Additionally, combination therapy with both doxorubicin (DOX) and MIA-602 showed a marked synergistic effect in reducing the proliferation of the K-562 AML cell line. These findings suggest that MIA-602 could be utilized to address resistance to all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) therapies, as well as in augmenting anthracycline-based regimens. Full article

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23 pages, 1288 KiB

Open AccessArticle

Incidence and Risk Factors for Development of Cardiac Toxicity in Adult Patients with Newly Diagnosed Acute Myeloid Leukemia

by Blanca Boluda, Antonio Solana-Altabella, Isabel Cano, David Martínez-Cuadrón, Evelyn Acuña-Cruz, Laura Torres-Miñana, Rebeca Rodríguez-Veiga, Irene Navarro-Vicente, David Martínez-Campuzano, Raquel García-Ruiz, Pilar Lloret, Pedro Asensi, Ana Osa-Sáez, Jaume Aguero, María Rodríguez-Serrano, Francisco Buendía-Fuentes, Juan Eduardo Megías-Vericat, Beatriz Martín-Herreros, Eva Barragán, Claudia Sargas, Maribel Salas, Margaret Wooddell, Charles Dharmani, Miguel A. Sanz, Javier De la Rubia and Pau Montesinos Show full author list Hide full author list

Cancers 2023, 15(8), 2267; https://doi.org/10.3390/cancers15082267 - 12 Apr 2023

Cited by 1 | Viewed by 1953

Abstract

The incidence of cardiac morbimortality in acute myeloid leukemia (AML) is not well known. We aim to estimate the cumulative incidence (CI) of cardiac events in AML patients and to identify risk factors for their occurrence. Among 571 newly diagnosed AML patients, 26 [...] Read more.

The incidence of cardiac morbimortality in acute myeloid leukemia (AML) is not well known. We aim to estimate the cumulative incidence (CI) of cardiac events in AML patients and to identify risk factors for their occurrence. Among 571 newly diagnosed AML patients, 26 (4.6%) developed fatal cardiac events, and among 525 treated patients, 19 (3.6%) experienced fatal cardiac events (CI: 2% at 6 months; 6.7% at 9 years). Prior heart disease was associated with the development of fatal cardiac events (hazard ratio (HR) = 6.9). The CI of non-fatal cardiac events was 43.7% at 6 months and 56.9% at 9 years. Age ≥ 65 (HR = 2.2), relevant cardiac antecedents (HR = 1.4), and non-intensive chemotherapy (HR = 1.8) were associated with non-fatal cardiac events. The 9-year CI of grade 1–2 QTcF prolongation was 11.2%, grade 3 was 2.7%, and no patient had grade 4–5 events. The 9-year CI of grade 1–2 cardiac failure was 1.3%, grade 3–4 was 15%, and grade 5 was 2.1%; of grade 1–2, arrhythmia was 1.9%, grade 3–4 was 9.1%, and grade 5 was 1%. Among 285 intensive therapy patients, median overall survival decreased in those experiencing grade 3–4 cardiac events (p < 0.001). We observed a high incidence of cardiac toxicity associated with significant mortality in AML. Full article

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21 pages, 2821 KiB

Open AccessArticle

by Lisa Pleyer, Sonja Heibl, Christoph Tinchon, Sonia Vallet, Martin Schreder, Thomas Melchardt, Norbert Stute, Kim Tamara Föhrenbach Quiroz, Michael Leisch, Alexander Egle, Lukas Scagnetti, Dominik Wolf, Richard Beswick, Manuel Drost, Julian Larcher-Senn, Thomas Grochtdreis, Marc Vaisband, Jan Hasenauer, Nadja Zaborsky, Richard Greil and Reinhard Stauder Show full author list Hide full author list

Cancers 2023, 15(5), 1388; https://doi.org/10.3390/cancers15051388 - 22 Feb 2023

Cited by 3 | Viewed by 1983

Abstract

In this prospective study (NCT01595295), 272 patients treated with azacitidine completed 1456 EuroQol 5-Dimension (EQ-5D) questionnaires. Linear mixed-effect modelling was used to incorporate longitudinal data. When compared with a matched reference population, myeloid patients reported more pronounced restrictions in usual activities (+28%, p [...] Read more.

In this prospective study (NCT01595295), 272 patients treated with azacitidine completed 1456 EuroQol 5-Dimension (EQ-5D) questionnaires. Linear mixed-effect modelling was used to incorporate longitudinal data. When compared with a matched reference population, myeloid patients reported more pronounced restrictions in usual activities (+28%, p < 0.0001), anxiety/depression (+21%, p < 0.0001), selfcare (+18%, p < 0.0001) and mobility (+15%, p < 0.0001), as well as lower mean EQ-5D-5L indices (0.81 vs. 0.88, p < 0.0001), and lower self-rated health on the EuroQol Visual Analogue Scale (EQ-VAS) (64 vs. 72%, p < 0.0001). After multivariate-adjustment, (i) the EQ-5D-5L index assessed at azacitidine start the predicted time with clinical benefit (TCB) (9.6 vs. 6.6 months; p = 0.0258; HR = 1.43), time to next treatment (TTNT) (12.8 vs. 9.8 months; p = 0.0332; HR = 1.42) and overall survival (OS) (17.9 vs. 12.9 months; p = 0.0143; HR = 1.52); (ii) Level Sum Score (LSS) predicted azacitidine response (p = 0.0160; OR = 0.451) and the EQ-5D-5L index showed a trend (p = 0.0627; OR = 0.522); (iii) up to 1432 longitudinally assessed EQ-5D-5L response/clinical parameter pairs revealed significant associations of EQ-5D-5L response parameters with haemoglobin level, transfusion dependence and hematologic improvement. Significant increases of the likelihood ratios were observed after addition of LSS, EQ-VAS or EQ-5D-5L-index to the International Prognostic Scoring System (IPSS) or the revised IPSS (R-IPSS), indicating that they provide added value to these scores. Full article

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14 pages, 972 KiB

Open AccessReview

NPM 1 Mutations in AML—The Landscape in 2023

by Naman Sharma and Jane L. Liesveld

Cancers 2023, 15(4), 1177; https://doi.org/10.3390/cancers15041177 - 12 Feb 2023

Cited by 5 | Viewed by 4863

Abstract

Acute myeloid leukemia (AML) represents 80% of acute leukemia in adults and is characterized by clonal expansion of hematopoietic stem cells secondary to genomic mutations, rendering a selective growth advantage to the mutant clones. NPM1mut is found in around 30% of AML [...] Read more.

Acute myeloid leukemia (AML) represents 80% of acute leukemia in adults and is characterized by clonal expansion of hematopoietic stem cells secondary to genomic mutations, rendering a selective growth advantage to the mutant clones. NPM1mut is found in around 30% of AML and clinically presents with leukocytosis, high blast percentage and extramedullary involvement. Considered as a “gate-keeper” mutation, NPM1mut appears to be a “first hit” in the process of leukemogenesis and development of overt leukemia. Commonly associated with other mutations (e.g., FLT 3, DNMT3A, TET2, SF3B1), NPM1 mutation in AML has an important role in diagnosis, prognosis, treatment and post-treatment monitoring. Several novel therapies targeting NPM1 are being developed in various clinical phases with demonstration of efficacy. In this review, we summarize the pathophysiology of the NPM1 gene mutation in AML, clinical implications and the novel targeted therapies to date. Full article

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Graphical abstract

20 pages, 3005 KiB

Open AccessArticle

The Class IIA Histone Deacetylase (HDAC) Inhibitor TMP269 Downregulates Ribosomal Proteins and Has Anti-Proliferative and Pro-Apoptotic Effects on AML Cells

by Laura Urwanisch, Michael Stefan Unger, Helene Sieberer, Hieu-Hoa Dang, Theresa Neuper, Christof Regl, Julia Vetter, Susanne Schaller, Stephan M. Winkler, Emanuela Kerschbamer, Christian X. Weichenberger, Peter W. Krenn, Michela Luciano, Lisa Pleyer, Richard Greil, Christian G. Huber, Fritz Aberger and Jutta Horejs-Hoeck

Cancers 2023, 15(4), 1039; https://doi.org/10.3390/cancers15041039 - 07 Feb 2023

Cited by 2 | Viewed by 3197

Abstract

Acute myeloid leukemia (AML) is a hematopoietic malignancy characterized by altered myeloid progenitor cell proliferation and differentiation. As in many other cancers, epigenetic transcriptional repressors such as histone deacetylases (HDACs) are dysregulated in AML. Here, we investigated (1) HDAC gene expression in AML [...] Read more.

Acute myeloid leukemia (AML) is a hematopoietic malignancy characterized by altered myeloid progenitor cell proliferation and differentiation. As in many other cancers, epigenetic transcriptional repressors such as histone deacetylases (HDACs) are dysregulated in AML. Here, we investigated (1) HDAC gene expression in AML patients and in different AML cell lines and (2) the effect of treating AML cells with the specific class IIA HDAC inhibitor TMP269, by applying proteomic and comparative bioinformatic analyses. We also analyzed cell proliferation, apoptosis, and the cell-killing capacities of TMP269 in combination with venetoclax compared to azacitidine plus venetoclax, by flow cytometry. Our results demonstrate significantly overexpressed class I and class II HDAC genes in AML patients, a phenotype which is conserved in AML cell lines. In AML MOLM-13 cells, TMP269 treatment downregulated a set of ribosomal proteins which are overexpressed in AML patients at the transcriptional level. TMP269 showed anti-proliferative effects and induced additive apoptotic effects in combination with venetoclax. We conclude that TMP269 exerts anti-leukemic activity when combined with venetoclax and has potential as a therapeutic drug in AML. Full article

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21 pages, 3121 KiB

Open AccessArticle

Molecular Landscape and Validation of New Genomic Classification in 2668 Adult AML Patients: Real Life Data from the PETHEMA Registry

by Claudia Sargas, Rosa Ayala, María José Larráyoz, María Carmen Chillón, Estrella Carrillo-Cruz, Cristina Bilbao-Sieyro, Esther Prados de la Torre, David Martínez-Cuadrón, Rebeca Rodríguez-Veiga, Blanca Boluda, Cristina Gil, Teresa Bernal, Juan Miguel Bergua, Lorenzo Algarra, Mar Tormo, Pilar Martínez-Sánchez, Elena Soria, Josefina Serrano, Juan Manuel Alonso-Domínguez, Raimundo García-Boyero, María Luz Amigo, Pilar Herrera-Puente, María José Sayas, Esperanza Lavilla-Rubira, Joaquín Martínez-López, María José Calasanz, Ramón García-Sanz, José Antonio Pérez-Simón, María Teresa Gómez-Casares, Joaquín Sánchez-García, Eva Barragán, Pau Montesinos and on behalf of PETHEMA group Show full author list Hide full author list

Cancers 2023, 15(2), 438; https://doi.org/10.3390/cancers15020438 - 10 Jan 2023

Cited by 8 | Viewed by 3306

Abstract

Next–Generation Sequencing (NGS) implementation to perform accurate diagnosis in acute myeloid leukemia (AML) represents a major challenge for molecular laboratories in terms of specialization, standardization, costs and logistical support. In this context, the PETHEMA cooperative group has established the first nationwide diagnostic network [...] Read more.

Next–Generation Sequencing (NGS) implementation to perform accurate diagnosis in acute myeloid leukemia (AML) represents a major challenge for molecular laboratories in terms of specialization, standardization, costs and logistical support. In this context, the PETHEMA cooperative group has established the first nationwide diagnostic network of seven reference laboratories to provide standardized NGS studies for AML patients. Cross–validation (CV) rounds are regularly performed to ensure the quality of NGS studies and to keep updated clinically relevant genes recommended for NGS study. The molecular characterization of 2856 samples (1631 derived from the NGS–AML project; NCT03311815) with standardized NGS of consensus genes (ABL1, ASXL1, BRAF, CALR, CBL, CEBPA, CSF3R, DNMT3A, ETV6, EZH2, FLT3, GATA2, HRAS, IDH1, IDH2, JAK2, KIT, KRAS, MPL, NPM1, NRAS, PTPN11, RUNX1, SETBP1, SF3B1, SRSF2, TET2, TP53, U2AF1 and WT1) showed 97% of patients having at least one mutation. The mutational profile was highly variable according to moment of disease, age and sex, and several co–occurring and exclusion relations were detected. Molecular testing based on NGS allowed accurate diagnosis and reliable prognosis stratification of 954 AML patients according to new genomic classification proposed by Tazi et al. Novel molecular subgroups, such as mutated WT1 and mutations in at least two myelodysplasia–related genes, have been associated with an adverse prognosis in our cohort. In this way, the PETHEMA cooperative group efficiently provides an extensive molecular characterization for AML diagnosis and risk stratification, ensuring technical quality and equity in access to NGS studies. Full article

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14 pages, 1772 KiB

Open AccessArticle

Association between Prior Cytotoxic Therapy, Antecedent Hematologic Disorder, and Outcome after Allogeneic Hematopoietic Cell Transplantation in Adult Acute Myeloid Leukemia

by Corentin Orvain, Eduardo Rodríguez-Arbolí, Megan Othus, Brenda M. Sandmaier, H. Joachim Deeg, Frederick R. Appelbaum and Roland B. Walter

Cancers 2023, 15(2), 352; https://doi.org/10.3390/cancers15020352 - 05 Jan 2023

Cited by 4 | Viewed by 1736

Abstract

(1) Background: Secondary acute myeloid leukemia (AML), i.e., AML arising from prior therapy (therapy-related) and/or an antecedent hematologic disorder (AHD) is generally associated with worse outcomes compared to de novo AML. However, recognizing the prognostic importance of genetic characteristics rather than clinical history, [...] Read more.

(1) Background: Secondary acute myeloid leukemia (AML), i.e., AML arising from prior therapy (therapy-related) and/or an antecedent hematologic disorder (AHD) is generally associated with worse outcomes compared to de novo AML. However, recognizing the prognostic importance of genetic characteristics rather than clinical history, secondary AML is now considered a diagnostic qualifier rather than a separate disease entity. (2) Methods: To assess the association between clinical history and AML outcomes in the context of allogeneic hematopoietic cell transplantation (HCT), we retrospectively analyzed 759 patients with de novo AML, 115 with AHD AML, and 105 with therapy-related AML who received first allografts while in first or second remission. (3) Results: At the time of HCT, these three cohorts differed significantly regarding many patient and disease-specific characteristics, including age (p < 0.001), gender (p < 0.001), disease risk (p = 0.005), HCT-CI score (p < 0.001), blood count recovery (p = 0.003), first vs. second remission (p < 0.001), remission duration (p < 0.001), measurable residual disease (MRD; p < 0.001), and conditioning intensity (p < 0.001). Relative to patients with de novo AML, relapse rates were similar for patients with AHD (hazard ratio [HR] = 1.07, p = 0.7) and therapy-related AML (HR = 0.86, p = 0.4) after multivariable adjustment, as were relapse-free survival (HR = 1.20, p = 0.2, and HR = 0.89, p = 0.5) and overall survival (HR = 1.19, p = 0.2, and HR = 0.93, p = 0.6). Non-relapse mortality was higher for AHD AML (HR = 1.59, p = 0.047). (4) Conclusions: These data suggest that the clinical history by itself contains limited prognostic value for adults with AML undergoing allografting, supporting the most recent approach to use this information as a diagnostic qualifier rather than a disease entity. Full article

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2022

Jump to: 2023, 2021

11 pages, 1066 KiB

Open AccessArticle

The Impact of Mutation of Myelodysplasia-Related Genes in De Novo Acute Myeloid Leukemia Carrying NPM1 Mutation

by Yi Wang, Andres E. Quesada, Zhuang Zuo, L. Jeffrey Medeiros, C. Cameron Yin, Shaoying Li, Jie Xu, Gautam Borthakur, Yisheng Li, Chao Yang, Yasmin Abaza, Juehua Gao, Xinyan Lu, M. James You, Yizhuo Zhang and Pei Lin

Cancers 2023, 15(1), 198; https://doi.org/10.3390/cancers15010198 - 29 Dec 2022

Cited by 4 | Viewed by 1799

Abstract

Background: The impact of gene mutations typically associated with myelodysplastic syndrome (MDS) in acute myeloid leukemia (AML) with NPM1 mutation is unclear. Methods: Using a cohort of 107 patients with NPM1-mutated AML treated with risk-adapted therapy, we compared survival outcomes of patients [...] Read more.

Background: The impact of gene mutations typically associated with myelodysplastic syndrome (MDS) in acute myeloid leukemia (AML) with NPM1 mutation is unclear. Methods: Using a cohort of 107 patients with NPM1-mutated AML treated with risk-adapted therapy, we compared survival outcomes of patients without MDS-related gene mutations (group A) with those carrying concurrent FLT3-ITD (group B) or with MDS-related gene mutations (group C). Minimal measurable disease (MMD) status assessed by multiparameter flow cytometry (MFC), polymerase chain reaction (PCR), and/or next-generation sequencing (NGS) were reviewed. Results: Among the 69 patients treated intensively, group C showed significantly inferior progression-free survival (PFS, p < 0.0001) but not overall survival (OS, p = 0.055) compared to group A. Though groups A and C had a similar MMD rate, group C patients had a higher relapse rate (p = 0.016). Relapse correlated with MMD status at the end of cycle 2 induction (p = 0.023). Survival of group C patients was similar to that of group B. Conclusion: MDS-related gene mutations are associated with an inferior survival in NPM1-mutated AML. Full article

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17 pages, 1769 KiB

Open AccessArticle

Impact of FLT3–ITD Mutation Status and Its Ratio in a Cohort of 2901 Patients Undergoing Upfront Intensive Chemotherapy: A PETHEMA Registry Study

by Rosa Ayala, Gonzalo Carreño-Tarragona, Eva Barragán, Blanca Boluda, María J. Larráyoz, María Carmen Chillón, Estrella Carrillo-Cruz, Cristina Bilbao, Joaquín Sánchez-García, Teresa Bernal, David Martinez-Cuadron, Cristina Gil, Josefina Serrano, Carlos Rodriguez-Medina, Juan Bergua, José A. Pérez-Simón, María Calbacho, Juan M. Alonso-Domínguez, Jorge Labrador, Mar Tormo, Maria Luz Amigo, Pilar Herrera-Puente, Inmaculada Rapado, Claudia Sargas, Iria Vazquez, María J. Calasanz, Teresa Gomez-Casares, Ramón García-Sanz, Miguel A. Sanz, Joaquín Martínez-López and Pau Montesinos Show full author list Hide full author list

Cancers 2022, 14(23), 5799; https://doi.org/10.3390/cancers14235799 - 24 Nov 2022

Cited by 4 | Viewed by 1821

Abstract

FLT3–ITD results in a poor prognosis in terms of overall survival (OS) and relapse-free survival (RFS) in acute myeloid leukemia (AML). However, the prognostic usefulness of the allelic ratio (AR) to select post-remission therapy remains controversial. Our study focuses on the prognostic impact [...] Read more.

FLT3–ITD results in a poor prognosis in terms of overall survival (OS) and relapse-free survival (RFS) in acute myeloid leukemia (AML). However, the prognostic usefulness of the allelic ratio (AR) to select post-remission therapy remains controversial. Our study focuses on the prognostic impact of FLT3–ITD and its ratio in a series of 2901 adult patients treated intensively in the pre-FLT3 inhibitor era and reported in the PETHEMA registry. A total of 579 of these patients (20%) harbored FLT3–ITD mutations. In multivariate analyses, patients with an FLT3–ITD allele ratio (AR) of >0.5 showed a lower complete remission (CR rate) and OS (HR 1.47, p = 0.009), while AR > 0.8 was associated with poorer RFS (HR 2.1; p < 0.001). Among NPM1/FLT3–ITD-mutated patients, median OS gradually decreased according to FLT3–ITD status and ratio (34.3 months FLT3–ITD-negative, 25.3 months up to 0.25, 14.5 months up to 0.5, and 10 months ≥ 0.5, p < 0.001). Post-remission allogeneic transplant (allo-HSCT) resulted in better OS and RFS as compared to auto-HSCT in NPM1/FLT3–ITD-mutated AML regardless of pre-established AR cutoff (≤0.5 vs. >0.5). Using the maximally selected log-rank statistics, we established an optimal cutoff of FLT3–ITD AR of 0.44 for OS, and 0.8 for RFS. We analyzed the OS and RFS according to FLT3–ITD status in all patients, and we found that the group of FLT3–ITD-positive patients with AR < 0.44 had similar 5-year OS after allo-HSCT or auto-HSCT (52% and 41%, respectively, p = 0.86), but worse RFS after auto-HSCT (p = 0.01). Among patients with FLT3–ITD AR > 0.44, allo-HSCT was superior to auto-HSCT in terms of OS and RFS. This study provides more evidence for a better characterization of patients with AML harboring FLT3–ITD mutations. Full article

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15 pages, 1218 KiB

Open AccessArticle

Identification of Predictive Factors for Overall Survival and Response during Hypomethylating Treatment in Very Elderly (≥75 Years) Acute Myeloid Leukemia Patients: A Multicenter Real-Life Experience

by Matteo Molica, Carla Mazzone, Pasquale Niscola, Ida Carmosino, Ambra Di Veroli, Cinzia De Gregoris, Fabrizio Bonanni, Salvatore Perrone, Natalia Cenfra, Luana Fianchi, Anna Lina Piccioni, Antonio Spadea, Giovanni Luzi, Andrea Mengarelli, Laura Cudillo, Luca Maurillo, Livio Pagano, Massimo Breccia, Luigi Rigacci and Paolo De Fabritiis

Cancers 2022, 14(19), 4897; https://doi.org/10.3390/cancers14194897 - 06 Oct 2022

Cited by 5 | Viewed by 1981

Abstract

Elderly patients represent the most challenging and hard-to-treat patient population due to dismal characteristics of the disease, such as secondary-acute myeloid leukemia (AML), enrichment of unfavorable molecular genes (TP53) and comorbidities. We conducted a multicentric retrospective study to evaluate activity and [...] Read more.

Elderly patients represent the most challenging and hard-to-treat patient population due to dismal characteristics of the disease, such as secondary-acute myeloid leukemia (AML), enrichment of unfavorable molecular genes (TP53) and comorbidities. We conducted a multicentric retrospective study to evaluate activity and safety in a real-life setting of hypomethylating drugs (HMAs) in patients older than 75 years with AML. Between September 2010 and December 2021, 220 patients were treated, 164 (74.5%) received AZAcitidine and 56 DECitabine; most patients (57.8%), received more than four cycles of HMAs. The best response obtained was CR in 51 patients (23.2%), PR in 23 (10.5%) and SD in 45 (20.5%); overall transfusion independence was obtained in 47 patients (34%), after a median of 3.5 months. The median OS (mOs) was 8 months (95% CI 5.9–10.2), with 1- and 2-years OS of 39.4% (95% CI 32.7–46) and 17.4% (95% CI 11.7–23.1), respectively; similar mOS was observed according to HMA treatment (AZA 8.3 vs. DEC 7.8 months, p = 0.810). A subset of 57 long survivors (44 in AZA group and 13 in DEC group) received at least 12 cycles of HMAs, their mOS was 24.3 months. In multivariate analysis, age (≥80), Charlson comorbidity index (≥3), creatinine clearance and the type of best response (≥PR) during treatment maintained independent significance in predicting survival. Infectious complications, most frequently pneumonia (35) and septic shock (12), were lethal in 49 patients (22.2%). Our data show that HMAs have similar efficacy compared to pivotal trials and are well tolerated in a setting of very elderly patients with several co-comorbidities. Full article

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12 pages, 303 KiB

Open AccessReview

How I Treat TP53-Mutated Acute Myeloid Leukemia and Myelodysplastic Syndromes

by Michael Loschi, Pierre Fenaux and Thomas Cluzeau

Cancers 2022, 14(18), 4519; https://doi.org/10.3390/cancers14184519 - 18 Sep 2022

Cited by 9 | Viewed by 4377

Abstract

TP53-mutated acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) are among the myeloid malignancies with the poorest prognosis. In this review, we analyze the prognosis of these two diseases, focussing particularly on the extent of the mono or biallelic mutation status of [...] Read more.

TP53-mutated acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) are among the myeloid malignancies with the poorest prognosis. In this review, we analyze the prognosis of these two diseases, focussing particularly on the extent of the mono or biallelic mutation status of TP53 mutation, which is largely correlated with cytogenetic complexity. We discuss the possible/potential improvement in outcome based on recent results obtained with new drugs (especially eprenetapopt and magrolimab). We also focus on the impact of allogeneic hematopoietic stem cell transplantation (aHSCT) including post aHSCT treatment. Full article

27 pages, 2730 KiB

Open AccessReview

Overcoming Resistance: FLT3 Inhibitors Past, Present, Future and the Challenge of Cure

by Debora Capelli, Diego Menotti, Alessandro Fiorentini, Francesco Saraceni and Attilio Olivieri

Cancers 2022, 14(17), 4315; https://doi.org/10.3390/cancers14174315 - 02 Sep 2022

Cited by 8 | Viewed by 4364

Abstract

FLT3 ITD and TKD mutations occur in 20% and 10% of Acute Myeloid Leukemia (AML), respectively, and they represent the target of the first approved anti-leukemic therapies in the 2000s. Type I and type II FLT3 inhibitors (FLT3i) are active against FLT3 TKD/ITD [...] Read more.

FLT3 ITD and TKD mutations occur in 20% and 10% of Acute Myeloid Leukemia (AML), respectively, and they represent the target of the first approved anti-leukemic therapies in the 2000s. Type I and type II FLT3 inhibitors (FLT3i) are active against FLT3 TKD/ITD and FLT3 ITD mutations alone respectively, but they still fail remissions in 30–40% of patients due to primary and secondary mechanisms of resistance, with variable relapse rate of 30–50%, influenced by NPM status and FLT3 allelic ratio. Mechanisms of resistance to FLT3i have recently been analyzed through NGS and single cell assays that have identified and elucidated the polyclonal nature of relapse in clinical and preclinical studies, summarized here. Knowledge of tumor escape pathways has helped in the identification of new targeted drugs to overcome resistance. Immunotherapy and combination or sequential use of BCL2 inhibitors and experimental drugs including aurora kinases, menin and JAK2 inhibitors will be the goal of present and future clinical trials, especially in patients with FLT3-mutated (FLT3mut) AML who are not eligible for allogeneic transplantation. Full article

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20 pages, 813 KiB

Open AccessReview

A Focus on Intermediate-Risk Acute Myeloid Leukemia: Sub-Classification Updates and Therapeutic Challenges

by Hassan Awada, Moaath K. Mustafa Ali, Bicky Thapa, Hussein Awada, Leroy Seymour, Louisa Liu, Carmelo Gurnari, Ashwin Kishtagari, Eunice Wang and Maria R. Baer

Cancers 2022, 14(17), 4166; https://doi.org/10.3390/cancers14174166 - 28 Aug 2022

Cited by 3 | Viewed by 2683

Abstract

Acute myeloid leukemia (AML) represents a heterogeneous group of hematopoietic neoplasms deriving from the abnormal proliferation of myeloid progenitors in the bone marrow. Patients with AML may have highly variable outcomes, which are generally dictated by individual clinical and genomic characteristics. As such, [...] Read more.

Acute myeloid leukemia (AML) represents a heterogeneous group of hematopoietic neoplasms deriving from the abnormal proliferation of myeloid progenitors in the bone marrow. Patients with AML may have highly variable outcomes, which are generally dictated by individual clinical and genomic characteristics. As such, the European LeukemiaNet 2017 and 2022 guidelines categorize newly diagnosed AML into favorable-, intermediate-, and adverse-risk groups, based on their molecular and cytogenetic profiles. Nevertheless, the intermediate-risk category remains poorly defined, as many patients fall into this group as a result of their exclusion from the other two. Moreover, further genomic data with potential prognostic and therapeutic influences continue to emerge, though they are yet to be integrated into the diagnostic and prognostic models of AML. This review highlights the latest therapeutic advances and challenges that warrant refining the prognostic classification of intermediate-risk AML. Full article

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15 pages, 6293 KiB

Open AccessArticle

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

by Paula Piñero, Marina Morillas, Natalia Gutierrez, Eva Barragán, Esperanza Such, Joaquin Breña, María C. García-Hernández, Cristina Gil, Carmen Botella, José M. González-Navajas, Pedro Zapater, Pau Montesinos, Amparo Sempere and Fabian Tarín

Cancers 2022, 14(16), 4010; https://doi.org/10.3390/cancers14164010 - 19 Aug 2022

Cited by 5 | Viewed by 2375

Abstract

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 [...] Read more.

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. Full article

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10 pages, 1606 KiB

Open AccessArticle

FLT3-ITD Expression as a Potential Biomarker for the Assessment of Treatment Response in Patients with Acute Myeloid Leukemia

by Diego Carbonell, María Chicano, Alfonso J. Cardero, Ignacio Gómez-Centurión, Rebeca Bailén, Gillen Oarbeascoa, Diana Martínez-Señarís, Carolina Franco, Paula Muñiz, Javier Anguita, Mi Kwon, José Luis Díez-Martín, Ismael Buño and Carolina Martínez-Laperche

Cancers 2022, 14(16), 4006; https://doi.org/10.3390/cancers14164006 - 19 Aug 2022

Cited by 2 | Viewed by 2081

Abstract

FLT3-internal tandem duplication (ITD) analysis is not typically performed in cDNA samples and is not considered an appropriate marker for monitoring measurable residual disease (MRD). The aims of this study were to compare FLT3-ITD mutation analysis in DNA and cDNA samples [...] Read more.

FLT3-internal tandem duplication (ITD) analysis is not typically performed in cDNA samples and is not considered an appropriate marker for monitoring measurable residual disease (MRD). The aims of this study were to compare FLT3-ITD mutation analysis in DNA and cDNA samples at diagnosis and to demonstrate the usefulness of its expression measurement as an MRD marker after allogeneic stem cell transplantation (allo-HSCT) or FLT3 inhibitor (FLT3i) administration. A total of 46 DNA and cDNA diagnosis samples, 102 DNA and cDNA post-allo-HSCT samples from 34 patients and 37 cDNA samples from 7 patients with refractory/relapse AML treated with FLT3i were assessed for the FLT3-ITD mutation through fragment analysis. In terms of sensitivity, the analysis of cDNA was superior to that of DNA, quantifying higher allelic ratio values in most cases at diagnosis, and thus optimizing the detection of minor clones and prognostic classification. Regarding the last sample before post-HSCT relapse, cDNA analysis anticipated relapse in most cases, unlike DNA analyses. With regard to the post-FLT3i follow-up, FLT3-ITD expression was reduced after the first FLT3i cycle when the treatment was effective, whereas it was not reduced in refractory patients. FLT3-ITD expression could be a useful additional biomarker at diagnosis and for the assessment of MRD after allo-HSCT and FLT3i in AML. Full article

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11 pages, 813 KiB

Open AccessArticle

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

by Shin Yeu Ong, Melinda Tan Si Yun, Nurul Aidah Abdul Halim, Dheepa Christopher, Wei Ying Jen, Christian Gallardo, Angeline Tan Hwee Yim, Yeow Kheong Woon, Heng Joo Ng, Melissa Ooi and Gee Chuan Wong

Cancers 2022, 14(15), 3576; https://doi.org/10.3390/cancers14153576 - 22 Jul 2022

Cited by 5 | Viewed by 2195

Abstract

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 [...] Read more.

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. Full article

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23 pages, 1703 KiB

Open AccessReview

NF-κB: A Druggable Target in Acute Myeloid Leukemia

by Barbara Di Francesco, Daniela Verzella, Daria Capece, Davide Vecchiotti, Mauro Di Vito Nolfi, Irene Flati, Jessica Cornice, Monica Di Padova, Adriano Angelucci, Edoardo Alesse and Francesca Zazzeroni

Cancers 2022, 14(14), 3557; https://doi.org/10.3390/cancers14143557 - 21 Jul 2022

Cited by 14 | Viewed by 3206

Abstract

Acute Myeloid Leukemia (AML) is an aggressive hematological malignancy that relies on highly heterogeneous cytogenetic alterations. Although in the last few years new agents have been developed for AML treatment, the overall survival prospects for AML patients are still gloomy and new therapeutic [...] Read more.

Acute Myeloid Leukemia (AML) is an aggressive hematological malignancy that relies on highly heterogeneous cytogenetic alterations. Although in the last few years new agents have been developed for AML treatment, the overall survival prospects for AML patients are still gloomy and new therapeutic options are still urgently needed. Constitutive NF-κB activation has been reported in around 40% of AML patients, where it sustains AML cell survival and chemoresistance. Given the central role of NF-κB in AML, targeting the NF-κB pathway represents an attractive strategy to treat AML. This review focuses on current knowledge of NF-κB’s roles in AML pathogenesis and summarizes the main therapeutic approaches used to treat NF-κB-driven AML. Full article

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21 pages, 728 KiB

Open AccessReview

Targeting Acute Myeloid Leukemia with Venetoclax; Biomarkers for Sensitivity and Rationale for Venetoclax-Based Combination Therapies

by Mila S. Griffioen, David C. de Leeuw, Jeroen J. W. M. Janssen and Linda Smit

Cancers 2022, 14(14), 3456; https://doi.org/10.3390/cancers14143456 - 15 Jul 2022

Cited by 20 | Viewed by 6574

Abstract

Venetoclax is a BCL-2 inhibitor that effectively improves clinical outcomes in newly diagnosed, relapsed and refractory acute myeloid leukemia (AML) patients, with complete response rates (with and without complete blood count recovery) ranging between 34–90% and 21–33%, respectively. Here, we aim to give [...] Read more.

Venetoclax is a BCL-2 inhibitor that effectively improves clinical outcomes in newly diagnosed, relapsed and refractory acute myeloid leukemia (AML) patients, with complete response rates (with and without complete blood count recovery) ranging between 34–90% and 21–33%, respectively. Here, we aim to give an overview of the efficacy of venetoclax-based therapy for AML patients, as compared to standard chemotherapy, and on factors and mechanisms involved in venetoclax sensitivity and resistance in AML (stem) cells, with the aim to obtain a perspective of response biomarkers and combination therapies that could enhance the sensitivity of AML cells to venetoclax. The presence of molecular aberrancies can predict responses to venetoclax, with a higher response in NPM1-, IDH1/2-, TET2- and relapsed or refractory RUNX1-mutated AML. Decreased sensitivity to venetoclax was observed in patients harboring FLT3-ITD, TP53, K/NRAS or PTPN11 mutations. Moreover, resistance to venetoclax was observed in AML with a monocytic phenotype and patients pre-treated with hypomethylating agents. Resistance to venetoclax can arise due to mutations in BCL-2 or pro-apoptotic proteins, an increased dependency on MCL-1, and usage of additional/alternative sources for energy metabolism, such as glycolysis and fatty acid metabolism. Clinical studies are testing combination therapies that may circumvent resistance, including venetoclax combined with FLT3- and MCL-1 inhibitors, to enhance venetoclax-induced cell death. Other treatments that can potentially synergize with venetoclax, including MEK1/2 and mitochondrial complex inhibitors, need to be evaluated in a clinical setting. Full article

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21 pages, 4191 KiB

Open AccessArticle

Lymphocyte Exhaustion in AML Patients and Impacts of HMA/Venetoclax or Intensive Chemotherapy on Their Biology

by Dmitry Zhigarev, Asya Varshavsky, Alexander W. MacFarlane IV, Prathiba Jayaguru, Laura Barreyro, Marina Khoreva, Essel Dulaimi, Reza Nejati, Christina Drenberg and Kerry S. Campbell

Cancers 2022, 14(14), 3352; https://doi.org/10.3390/cancers14143352 - 10 Jul 2022

Cited by 5 | Viewed by 2883

Abstract

Acute myeloid leukemia (AML) is an aggressive malignancy that requires rapid treatment with chemotherapies to reduce tumor burden. However, these chemotherapies can compromise lymphocyte function, thereby hindering normal anti-tumor immune responses and likely limiting the efficacy of subsequent immunotherapy. To better understand these [...] Read more.

Acute myeloid leukemia (AML) is an aggressive malignancy that requires rapid treatment with chemotherapies to reduce tumor burden. However, these chemotherapies can compromise lymphocyte function, thereby hindering normal anti-tumor immune responses and likely limiting the efficacy of subsequent immunotherapy. To better understand these negative impacts, we assessed the immunological effects of standard-of-care AML therapies on lymphocyte phenotype and function over time. When compared to healthy donors, untreated AML patients showed evidence of lymphocyte activation and exhaustion and had more prevalent CD57⁺NKG2C⁺ adaptive NK cells, which was independent of human cytomegalovirus (HCMV) status. HMA/venetoclax treatment resulted in a greater fraction of T cells with effector memory phenotype, inhibited IFN-γ secretion by CD8⁺ T cells, upregulated perforin expression in NK cells, downregulated PD-1 and 2B4 expression on CD4⁺ T cells, and stimulated Treg proliferation and CTLA-4 expression. Additionally, we showed increased expression of perforin and CD39 and enhanced IFN-γ production by T cells from pre-treatment blood samples of venetoclax-resistant AML patients. Our results provide insight into the lymphocyte status in previously untreated AML patients and the effects of standard-of-care treatments on their biology and functions. We also found novel pre-treatment characteristics of T cells that could potentially predict venetoclax resistance. Full article

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17 pages, 322 KiB

Open AccessReview

CPX-351: An Old Scheme with a New Formulation in the Treatment of High-Risk AML

by Matteo Molica, Salvatore Perrone, Carla Mazzone, Laura Cesini, Martina Canichella and Paolo de Fabritiis

Cancers 2022, 14(12), 2843; https://doi.org/10.3390/cancers14122843 - 08 Jun 2022

Cited by 3 | Viewed by 2936

Abstract

Therapy-related acute myeloid leukemia (t-AML) and acute myeloid leukemia with myelodysplasia-related changes (AML-MRC) represent aggressive diseases characterized by a dismal prognosis if compared with de novo acute myeloid leukemia, especially in older patients. In these AML subsets, standard chemotherapy regimens produce poor response [...] Read more.

Therapy-related acute myeloid leukemia (t-AML) and acute myeloid leukemia with myelodysplasia-related changes (AML-MRC) represent aggressive diseases characterized by a dismal prognosis if compared with de novo acute myeloid leukemia, especially in older patients. In these AML subsets, standard chemotherapy regimens produce poor response rates and unsatisfactory outcomes. Historically, conventional approaches consisted of an anthracycline combined with continuous infusion of cytarabine for 7 days, the “3+7” regimen. Several attempts have been conducted to ameliorate this combination regimen but inconsistent improvements in response rates and no significant changes in overall survival have been observed, until the recent introduction of targeted molecules. A liposomal formulation of traditional chemotherapy agents cytarabine and daunorubicin, termed CPX-351, enhances pharmacodynamics and synergistic effects through the maintenance of the optimal 5:1 molar ratio, which extends the treatment’s half-life and increases the bone marrow tropism of the drug. The use of CPX-351 in newly diagnosed AML-MRC and t-AML patients aged 60–75 years has demonstrated superior remission rates compared to conventional chemotherapy and improvements in event-free and overall survival. Recently, published data from a 5-year follow-up highlighted evidence that CPX-351 has the ability to produce and contribute to long-term remission and survival in older patients with newly diagnosed high-risk/secondary AML. Future perspectives include evaluation of dose intensification with CPX-351 in high-risk settings, combining this agent with targeted therapies, and better understanding the mechanism of improved responses in t-AML and AML-MRC. In this review, we will examine the role of CPX-351 inside the new AML therapeutic scenario and how its employment could potentially modify the treatment algorithm of high-risk and elderly patients with AML Full article

15 pages, 1055 KiB

Open AccessArticle

Characteristics and Outcomes of Adult Patients in the PETHEMA Registry with Relapsed or Refractory FLT3-ITD Mutation-Positive Acute Myeloid Leukemia

by David Martínez-Cuadrón, Josefina Serrano, José Mariz, Cristina Gil, Mar Tormo, Pilar Martínez-Sánchez, Eduardo Rodríguez-Arbolí, Raimundo García-Boyero, Carlos Rodríguez-Medina, Carmen Martínez-Chamorro, Marta Polo, Juan Bergua, Eliana Aguiar, María L. Amigo, Pilar Herrera, Juan M. Alonso-Domínguez, Teresa Bernal, Ana Espadana, María J. Sayas, Lorenzo Algarra, María B. Vidriales, Graça Vasconcelos, Susana Vives, Manuel M. Pérez-Encinas, Aurelio López, Víctor Noriega, María García-Fortes, María C. Chillón, Juan I. Rodríguez-Gutiérrez, María J. Calasanz, Jorge Labrador, Juan A. López, Blanca Boluda, Rebeca Rodríguez-Veiga, Joaquín Martínez-López, Eva Barragán, Miguel A. Sanz, Pau Montesinos and on behalf of the PETHEMA Group Show full author list Hide full author list

Cancers 2022, 14(11), 2817; https://doi.org/10.3390/cancers14112817 - 06 Jun 2022

Cited by 1 | Viewed by 2287

Abstract

This retrospective study investigated outcomes of 404 patients with relapsed/refractory (R/R) FMS-like tyrosine kinase 3 (FLT3)-internal tandem duplication (ITD) acute myeloid leukemia (AML) enrolled in the PETHEMA registry, pre-approval of tyrosine kinase inhibitors. Most patients (63%) had received first-line intensive therapy with 3 [...] Read more.

This retrospective study investigated outcomes of 404 patients with relapsed/refractory (R/R) FMS-like tyrosine kinase 3 (FLT3)-internal tandem duplication (ITD) acute myeloid leukemia (AML) enrolled in the PETHEMA registry, pre-approval of tyrosine kinase inhibitors. Most patients (63%) had received first-line intensive therapy with 3 + 7. Subsequently, patients received salvage with intensive therapy (n = 261), non-intensive therapy (n = 63) or supportive care only (n = 80). Active salvage therapy (i.e., intensive or non-intensive therapy) resulted in a complete remission (CR) or CR without hematological recovery (CRi) rate of 42%. More patients achieved a CR/CRi with intensive (48%) compared with non-intensive (19%) salvage therapy (p < 0.001). In the overall population, median overall survival (OS) was 5.5 months; 1- and 5-year OS rates were 25% and 7%. OS was significantly (p < 0.001) prolonged with intensive or non-intensive salvage therapy compared with supportive therapy, and in those achieving CR/CRi versus no responders. Of 280 evaluable patients, 61 (22%) had an allogeneic stem-cell transplant after they had achieved CR/CRi. In conclusion, in this large cohort study, salvage treatment approaches for patients with FLT3-ITD mutated R/R AML were heterogeneous. Median OS was poor with both non-intensive and intensive salvage therapy, with best long-term outcomes obtained in patients who achieved CR/CRi and subsequently underwent allogeneic stem-cell transplant. Full article

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10 pages, 2049 KiB

Open AccessArticle

Potential Prognostic Markers for Relapsed/Refractory vs. Responsive Acute Myeloid Leukemia

by Aida Vitkevičienė, Giedrė Skliutė, Andrius Žučenka, Veronika Borutinskaitė and Rūta Navakauskienė

Cancers 2022, 14(11), 2752; https://doi.org/10.3390/cancers14112752 - 01 Jun 2022

Cited by 1 | Viewed by 1936

Abstract

Acute myeloid leukemia (AML) is a heterogeneous disease. A significant proportion of AML patients is refractory to clinical treatment or relapses. Our aim is to determine new potential AML clinical treatment prognosis markers. We investigated various cell fate and epigenetic regulation important gene [...] Read more.

Acute myeloid leukemia (AML) is a heterogeneous disease. A significant proportion of AML patients is refractory to clinical treatment or relapses. Our aim is to determine new potential AML clinical treatment prognosis markers. We investigated various cell fate and epigenetic regulation important gene level differences between refractory and responsive AML patient groups at diagnosis stage and after clinical treatment using RT-qPCR. We demonstrated that oncogenic MYC and WT1 and metabolic IDH1 gene expression was significantly higher and cell cycle inhibitor CDKN1A (p21) gene expression was significantly lower in refractory patients’ bone marrow cells compared to treatment responsive patients both at diagnosis and after clinical treatment. Moreover, we determined that, compared to clinical treatment responsive patients, refractory patients possess a significantly higher gene expression of histone deacetylase 2 (HDAC2) and epigenetic DNA modulator TET1 and a significantly lower gene expression of lysine acetyltransferase 6A (KAT6A) and nucleosome remodeling and deacetylase (NuRD) complex component GATAD2A. We suggest that MYC, WT1, IDH1, CDKN1A, HDAC2, TET1, KAT6A and GATAD2A gene expression changes might characterize refractory AML. Thus, they might be useful for AML prognosis. Additionally, we suggest that epigenetic modulation might be beneficial in combination with standard treatment. Full article

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16 pages, 2567 KiB

Open AccessArticle

Azacitidine vs. Decitabine in Unfit Newly Diagnosed Acute Myeloid Leukemia Patients: Results from the PETHEMA Registry

by Jorge Labrador, David Martínez-Cuadrón, Adolfo de la Fuente, Rebeca Rodríguez-Veiga, Josefina Serrano, Mar Tormo, Eduardo Rodriguez-Arboli, Fernando Ramos, Teresa Bernal, María López-Pavía, Fernanda Trigo, María Pilar Martínez-Sánchez, Juan-Ignacio Rodríguez-Gutiérrez, Carlos Rodríguez-Medina, Cristina Gil, Daniel García Belmonte, Susana Vives, María-Ángeles Foncillas, Manuel Pérez-Encinas, Andrés Novo, Isabel Recio, Gabriela Rodríguez-Macías, Juan Miguel Bergua, Víctor Noriega, Esperanza Lavilla, Alicia Roldán-Pérez, Miguel A. Sanz, Pau Montesinos and on behalf of PETHEMA Group Show full author list Hide full author list

Cancers 2022, 14(9), 2342; https://doi.org/10.3390/cancers14092342 - 09 May 2022

Cited by 4 | Viewed by 2721

Abstract

The hypomethylating agents, decitabine (DEC) and azacitidine (AZA), allowed more elderly acute myeloid leukemia (AML) patients to be treated. However, there are little direct comparative data on AZA and DEC. This multicenter retrospective study compared the outcomes of AZA and DEC in terms [...] Read more.

The hypomethylating agents, decitabine (DEC) and azacitidine (AZA), allowed more elderly acute myeloid leukemia (AML) patients to be treated. However, there are little direct comparative data on AZA and DEC. This multicenter retrospective study compared the outcomes of AZA and DEC in terms of response and overall survival (OS). Potential predictors associated with response and OS were also evaluated. A total of 626 AML patients were included (487 treated with AZA and 139 with DEC). Response rates were similar in both groups: CR was 18% with AZA vs. 23% with DEC (p = 0.20), CR/CRi was 20.5% vs. 25% (p = 0.27) and ORR was 32% vs. 39.5% (p = 0.12), respectively. Patients with leukocytes < 10 × 10⁹/L, bone marrow blasts < 50% and ECOG ≥ 2 had higher ORR with DEC than with AZA. OS was similar in both groups: 10.4 months (95% CI: 9.2–11.7) vs. 8.8 months (95% CI: 6.7–11.0, p = 0.455), for AZA and DEC, respectively. Age (≥80 years), leukocytes (≥ 10 × 10⁹/L), platelet count (<20 × 10⁹/L) and eGFR (≥45 mL/min/1.73 m²) were associated with higher OS with AZA compared to DEC. In conclusion, we found no differences in response and OS rates in AML patients treated with AZA or DEC. Full article

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10 pages, 1189 KiB

Open AccessArticle

Healthcare Resource Utilization among Patients between 60–75 Years with Secondary Acute Myeloid Leukemia Receiving Intensive Chemotherapy Induction: A Spanish Retrospective Observational Study

by Antonio Solana-Altabella, Juan Eduardo Megías-Vericat, Octavio Ballesta-López, Blanca Boluda, Isabel Cano, Evelyn Acuña-Cruz, Rebeca Rodríguez-Veiga, Laura Torres-Miñana, Claudia Sargas, Miguel Á. Sanz, Carmela Borrell-García, Eduardo López-Briz, José Luis Poveda-Andrés, Javier De la Rubia, Pau Montesinos and David Martínez-Cuadrón

Cancers 2022, 14(8), 1921; https://doi.org/10.3390/cancers14081921 - 11 Apr 2022

Cited by 2 | Viewed by 1910

Abstract

Background: Information regarding the impact on healthcare systems of secondary acute myeloid leukemia (sAML) is scarce. Methods: A retrospective review of medical charts identified patients aged 60–75 years with sAML between 2010 and 2019. Patient information was collected from diagnosis to death or [...] Read more.

Background: Information regarding the impact on healthcare systems of secondary acute myeloid leukemia (sAML) is scarce. Methods: A retrospective review of medical charts identified patients aged 60–75 years with sAML between 2010 and 2019. Patient information was collected from diagnosis to death or last follow-up. Outpatient resource use, reimbursement, frequency and duration of hospitalization, and transfusion burden were assessed. Forty-six patients with a median age of 64 years were included. Anthracycline plus cytarabine regimens were the most common induction treatment (39 patients, 85%). The ratio of the total days hospitalized between the total follow-up was 29%, with a sum of 204 hospitalizations (average four/patient; average duration 21 days). The total average reimbursement was EUR 90,008 per patient, with the majority (EUR 77,827) related to hospital admissions (EUR 17,403/hospitalization). Most hospitalizations (163, mean 22 days) occurred in the period before the first allogeneic hematopoietic stem cell transplant (alloHSCT), costing EUR 59,698 per patient and EUR 15,857 per hospitalization. The period after alloHSCT (in only 10 patients) had 41 hospitalizations (mean 21 days), and a mean reimbursement cost of EUR 99,542 per patient and EUR 24,278 per hospitalization. In conclusion, there is a high consumption of economic and healthcare resources in elderly patients with sAML receiving active treatments in Spain. Full article

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12 pages, 564 KiB

Open AccessArticle

Use of Venetoclax in Patients with Relapsed or Refractory Acute Myeloid Leukemia: The PETHEMA Registry Experience

by Jorge Labrador, Miriam Saiz-Rodríguez, Dunia de Miguel, Almudena de Laiglesia, Carlos Rodríguez-Medina, María Belén Vidriales, Manuel Pérez-Encinas, María José Sánchez-Sánchez, Rebeca Cuello, Alicia Roldán-Pérez, Susana Vives, Gonzalo Benzo-Callejo, Mercedes Colorado, María García-Fortes, María José Sayas, Carmen Olivier, Isabel Recio, Diego Conde-Royo, Álvaro Bienert-García, María Vahi, Carmen Muñoz-García, Cristina Seri-Merino, Mar Tormo, Ferran Vall-llovera, María-Ángeles Foncillas, David Martínez-Cuadrón, Miguel Ángel Sanz and Pau Montesinos Show full author list Hide full author list

Cancers 2022, 14(7), 1734; https://doi.org/10.3390/cancers14071734 - 29 Mar 2022

Cited by 12 | Viewed by 3086

Abstract

The effectiveness of venetoclax (VEN) in relapsed or refractory acute myeloid leukemia (RR-AML) has not been well established. This retrospective, multicenter, observational database studied the effectiveness of VEN in a cohort of 51 RR-AML patients and evaluated for predictors of response and overall [...] Read more.

The effectiveness of venetoclax (VEN) in relapsed or refractory acute myeloid leukemia (RR-AML) has not been well established. This retrospective, multicenter, observational database studied the effectiveness of VEN in a cohort of 51 RR-AML patients and evaluated for predictors of response and overall survival (OS). The median age was 68 years, most were at high risk, 61% received ≥2 therapies for AML, 49% had received hypomethylating agents, and ECOG was ≥2 in 52%. Complete remission (CR) rate, including CR with incomplete hematological recovery (CRi), was 12.4%. Additionally, 10.4% experienced partial response (PR). The CR/CRi was higher in combination with azacitidine (AZA; 17.9%) than with decitabine (DEC; 6.7%) and low-dose cytarabine (LDAC; 0%). Mutated NPM1 was associated with increased CR/CRi. Median OS was 104 days (95% CI: 56–151). For the combination with AZA, DEC, and LDAC, median OS was 120 days, 104 days, and 69 days, respectively; p = 0.875. Treatment response and ECOG 0 influenced OS in a multivariate model. A total of 28% of patients required interruption of VEN because of toxicity. Our real-life series describes a marginal probability of CR/CRi and poor OS after VEN-based salvage. Patients included had very poor-risk features and were heavily pretreated. The small percentage of responders did not reach the median OS. Full article

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10 pages, 839 KiB

Open AccessArticle

Blood Count Recovery Following Induction Therapy for Acute Myeloid Leukemia in Children Does Not Predict Survival

by Lauren Pommert, Todd M. Cooper, Robert B. Gerbing, Lisa Brodersen, Michael Loken, Alan Gamis, Richard Aplenc, Todd A. Alonzo and Edward Anders Kolb

Cancers 2022, 14(3), 616; https://doi.org/10.3390/cancers14030616 - 26 Jan 2022

Cited by 4 | Viewed by 3279

Abstract

International Working Group (IWG) and European LeukemiaNet (ELN) response definitions are utilized to evaluate the efficacy of new agents for childhood acute myeloid leukemia (AML) for regulatory purposes. However, these criteria are not consistent with definitions used in pediatric AML trials or with [...] Read more.

International Working Group (IWG) and European LeukemiaNet (ELN) response definitions are utilized to evaluate the efficacy of new agents for childhood acute myeloid leukemia (AML) for regulatory purposes. However, these criteria are not consistent with definitions used in pediatric AML trials or with standard pediatric practice to proceed with subsequent therapy cycles prior to IWG/ELN-defined count recovery. We retrospectively analyzed data from the two most recent Phase 3 pediatric AML clinical trials conducted by the Children’s Oncology Group (COG) to assess the incidence, timing, and prognostic significance of count recovery following induction chemotherapy. Of the patients with fewer than 5% bone marrow blasts at the end of first induction, 21.5% of patients proceeded to a second induction cycle prior to achieving ANC ≥ 500 cells/μL and platelets ≥ 50,000 cells/μL, both well below the IWG/ELN thresholds of ANC > 1000 cells/μL and platelets > 100,000 cells/μL. In these two sequential childhood AML Phase 3 trials, neither ANC nor platelet recovery predicted survival. Intensification of treatment through the initiation of subsequent therapy cycles prior to attainment of IWG/ELN-defined CR is common practice in clinical trials for children with AML, suggesting that updated response definitions are needed for pediatric AML. Full article

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21 pages, 1026 KiB

Open AccessReview

Challenges and Advances in Chimeric Antigen Receptor Therapy for Acute Myeloid Leukemia

by Jennifer Marvin-Peek, Bipin N. Savani, Oluwole O. Olalekan and Bhagirathbhai Dholaria

Cancers 2022, 14(3), 497; https://doi.org/10.3390/cancers14030497 - 19 Jan 2022

Cited by 17 | Viewed by 6746

Abstract

The advent of chimeric antigen receptor (CAR) T-cell therapy has led to dramatic remission rates in multiple relapsed/refractory hematologic malignancies. While CAR T-cell therapy has been particularly successful as a treatment for B-cell malignancies, effectively treating acute myeloid leukemia (AML) with CARs has [...] Read more.

The advent of chimeric antigen receptor (CAR) T-cell therapy has led to dramatic remission rates in multiple relapsed/refractory hematologic malignancies. While CAR T-cell therapy has been particularly successful as a treatment for B-cell malignancies, effectively treating acute myeloid leukemia (AML) with CARs has posed a larger challenge. AML not only creates an immunosuppressive tumor microenvironment that dampens CAR T-cell responses, but it also lacks many unique tumor-associated antigens, making leukemic-specific targeting difficult. One advantage of CAR T-cell therapy compared to alternative treatment options is the ability to provide prolonged antigen-specific immune effector and surveillance functions. Since many AML CAR targets under investigation including CD33, CD117, and CD123 are also expressed on hematopoietic stem cells, CAR T-cell therapy can lead to severe and potentially lethal myeloablation. Novel strategies to combat these issues include creation of bispecific CARs, CAR T-cell “safety switches”, TCR-like CARs, NK CARs, and universal CARs, but all vary in their ability to provide a sustained remission, and consolidation with an allogeneic hematopoietic cell transplantation (allo-HCT) will be necessary in most cases This review highlights the delicate balance between effectively eliminating AML blasts and leukemic stem cells, while preserving the ability for bone marrow to regenerate. The impact of CAR therapy on treatment landscape of AML and changing scope of allo-HCT is discussed. Continued advances in AML CAR therapy would be of great benefit to a disease that still has high morbidity and mortality. Full article

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17 pages, 712 KiB

Open AccessReview

Early Palliative Care in Acute Myeloid Leukemia

by Leonardo Potenza, Eleonora Borelli, Sarah Bigi, Davide Giusti, Giuseppe Longo, Oreofe Odejide, Carlo Adolfo Porro, Camilla Zimmermann, Fabio Efficace, Eduardo Bruera, Mario Luppi and Elena Bandieri

Cancers 2022, 14(3), 478; https://doi.org/10.3390/cancers14030478 - 18 Jan 2022

Cited by 13 | Viewed by 3848

Abstract

Background: Several novel targeted therapies seem to improve the outcome of acute myeloid leukemia (AML) patients. Nonetheless, the 5-year survival rate remains below 40%, and the trajectory of the disease remains physically and emotionally challenging, with little time to make relevant decisions. For [...] Read more.

Background: Several novel targeted therapies seem to improve the outcome of acute myeloid leukemia (AML) patients. Nonetheless, the 5-year survival rate remains below 40%, and the trajectory of the disease remains physically and emotionally challenging, with little time to make relevant decisions. For patients with advanced solid tumors, the integration of early palliative care (EPC) with standard oncologic care a few weeks after diagnosis has demonstrated several benefits. However, this model is underutilized in patients with hematologic malignancies. Methods: In this article, we analyze the palliative care (PC) needs of AML patients, examine the operational aspects of an integrated model, and review the evidence in favor of EPC integration in the AML course. Results: AML patients have a high burden of physical and psychological symptoms and high use of avoidant coping strategies. Emerging studies, including a phase III randomized controlled trial, have reported that EPC is feasible for inpatients and outpatients, improves quality of life (QoL), promotes adaptive coping, reduces psychological symptoms, and enhances the quality of end-of-life care. Conclusions: EPC should become the new standard of care for AML patients. However, this raises issues about the urgent development of adequate programs of education to increase timely access to PC. Full article

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2021

Jump to: 2023, 2022

23 pages, 345 KiB

Open AccessReview

Venetoclax in Relapsed/Refractory Acute Myeloid Leukemia: Are Supporting Evidences Enough?

by Serena Brancati, Lucia Gozzo, Giovanni Luca Romano, Calogero Vetro, Ilaria Dulcamare, Cinzia Maugeri, Marina Parisi, Laura Longo, Daniela Cristina Vitale, Francesco Di Raimondo and Filippo Drago

Cancers 2022, 14(1), 22; https://doi.org/10.3390/cancers14010022 - 21 Dec 2021

Cited by 13 | Viewed by 4247

Abstract

Despite the progress in the development of new therapeutic strategies, relapsed/refractory (R/R) acute myeloid leukemia (AML) still represents a high unmet medical need. Treatment options in this setting include enrollment into clinical trials, allogeneic stem cell transplantation and/or targeted therapy. Nevertheless, it is [...] Read more.

Despite the progress in the development of new therapeutic strategies, relapsed/refractory (R/R) acute myeloid leukemia (AML) still represents a high unmet medical need. Treatment options in this setting include enrollment into clinical trials, allogeneic stem cell transplantation and/or targeted therapy. Nevertheless, it is associated with poor outcomes. Thus, the development of new treatments, which could ameliorate the prognosis of these patients with a good safety profile are highly demanded. Recently, venetoclax (VEN) has been approved for naïve AML patients unfit for intensive chemotherapy. In this regard, regimens including VEN could represent a valuable treatment option even in those with R/R disease and several studies have been conducted to demonstrate its role in this clinical setting. This review aims to summarize the current evidence on the use of VEN regimens in the treatment of R/R AML. Full article

16 pages, 2901 KiB

Open AccessFeature PaperArticle

Clinically Relevant Oxygraphic Assay to Assess Mitochondrial Energy Metabolism in Acute Myeloid Leukemia Patients

by Quentin Fovez, William Laine, Laure Goursaud, Celine Berthon, Nicolas Germain, Claire Degand, Jean-Emmanuel Sarry, Bruno Quesnel, Philippe Marchetti and Jerome Kluza

Cancers 2021, 13(24), 6353; https://doi.org/10.3390/cancers13246353 - 17 Dec 2021

Cited by 3 | Viewed by 3064

Abstract

Resistant acute myeloid leukemia (AML) exhibits mitochondrial energy metabolism changes compared to newly diagnosed AML. This phenotype is often observed by evaluating the mitochondrial oxygen consumption of blasts, but most of the oximetry protocols were established from leukemia cell lines without validation on [...] Read more.

Resistant acute myeloid leukemia (AML) exhibits mitochondrial energy metabolism changes compared to newly diagnosed AML. This phenotype is often observed by evaluating the mitochondrial oxygen consumption of blasts, but most of the oximetry protocols were established from leukemia cell lines without validation on primary leukemia cells. Moreover, the cultures and storage conditions of blasts freshly extracted from patient blood or bone marrow cause stress, which must be evaluated before determining oxidative phosphorylation (OXPHOS). Herein, we evaluated different conditions to measure the oxygen consumption of blasts using extracellular flow analyzers. We first determined the minimum number of blasts required to measure OXPHOS. Next, we compared the OXPHOS of blasts cultured for 3 h and 18 h after collection and found that to maintain metabolic organization for 18 h, cytokine supplementation is necessary. Cytokines are also needed when measuring OXPHOS in cryopreserved, thawed and recultured blasts. Next, the concentrations of respiratory chain inhibitors and uncoupler FCCP were established. We found that the FCCP concentration required to reach the maximal respiration of blasts varied depending on the patient sample analyzed. These protocols provided can be used in future clinical studies to evaluate OXPHOS as a biomarker and assess the efficacy of treatments targeting mitochondria. Full article

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21 pages, 4235 KiB

Open AccessReview

Immunotherapy as a Turning Point in the Treatment of Acute Myeloid Leukemia

by Anna Aureli, Beatrice Marziani, Tommaso Sconocchia, Maria Ilaria Del Principe, Elisa Buzzatti, Gianmario Pasqualone, Adriano Venditti and Giuseppe Sconocchia

Cancers 2021, 13(24), 6246; https://doi.org/10.3390/cancers13246246 - 13 Dec 2021

Cited by 8 | Viewed by 4687

Abstract

Acute myeloid leukemia (AML) is a malignant disease of hematopoietic precursors at the earliest stage of maturation, resulting in a clonalproliferation of myoblasts replacing normal hematopoiesis. AML represents one of the most common types of leukemia, mostly affecting elderly patients. To date, standard [...] Read more.

Acute myeloid leukemia (AML) is a malignant disease of hematopoietic precursors at the earliest stage of maturation, resulting in a clonalproliferation of myoblasts replacing normal hematopoiesis. AML represents one of the most common types of leukemia, mostly affecting elderly patients. To date, standard chemotherapy protocols are only effective in patients at low risk of relapse and therapy-related mortality. The average 5-year overall survival (OS) is approximately 28%. Allogeneic hematopoietic stem cell transplantation (HSCT) improves prognosis but is limited by donor availability, a relatively young age of patients, and absence of significant comorbidities. Moreover, it is associated with significant morbidity and mortality. However, increasing understanding of AML immunobiology is leading to the development of innovative therapeutic strategies. Immunotherapy is considered an attractive strategy for controlling and eliminating the disease. It can be a real breakthrough in the treatment of leukemia, especially in patients who are not eligible forintensive chemotherapy. In this review, we focused on the progress of immunotherapy in the field of AML by discussing monoclonal antibodies (mAbs), immune checkpoint inhibitors, chimeric antigen receptor T cells (CAR-T cells), and vaccine therapeutic choices. Full article

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13 pages, 1781 KiB

Open AccessArticle

Risk Stratification, Measurable Residual Disease, and Outcomes of AML Patients with a Trisomy 8 Undergoing Allogeneic Hematopoietic Stem Cell Transplantation

by Donata Backhaus, Madlen Jentzsch, Lara Bischof, Dominic Brauer, Christina Wilhelm, Julia Schulz, Georg-Nikolaus Franke, Wolfram Pönisch, Vladan Vucinic, Uwe Platzbecker and Sebastian Schwind

Cancers 2021, 13(22), 5679; https://doi.org/10.3390/cancers13225679 - 13 Nov 2021

Viewed by 2341

Abstract

Background: For most patients with acute myeloid leukemia (AML) harboring a trisomy 8 an allogeneic hematopoietic stem cell transplantation (HSCT) is a suitable and recommended consolidation therapy. However, comparative outcome analyses between patients with and without trisomy 8 undergoing allogeneic HSCT have not [...] Read more.

Background: For most patients with acute myeloid leukemia (AML) harboring a trisomy 8 an allogeneic hematopoietic stem cell transplantation (HSCT) is a suitable and recommended consolidation therapy. However, comparative outcome analyses between patients with and without trisomy 8 undergoing allogeneic HSCT have not been performed so far. Methods: We retrospectively analyzed clinical features, outcomes, and measurable residual disease (MRD) of 659 AML (12%, n = 81, with a trisomy 8) patients subjected to allogeneic HSCT as a consolidation therapy. Results: The presence of a trisomy 8 associated with a trend for higher age at diagnosis, AML of secondary origin, lower white blood cell counts at diagnosis, worse ELN2017 genetic risk, wild-type NPM1, and mutated IDH1/2 and JAK2. Outcomes after allogeneic HSCT in the entire cohort did not differ between patients with a sole trisomy 8, trisomy 8 with additional cytogenetic aberrations or without a trisomy 8. A trisomy 8 did not affect outcomes within the three ELN2017 risk groups. In accordance with findings in unselected patient cohorts, persistent MRD at allogeneic HSCT in patients with a trisomy 8 identified individuals with a higher risk of relapse following allogeneic HSCT. Conclusions: Outcomes of trisomy 8 patients after allogeneic HSCT did not compare unfavorably to that of other AML patients following allogeneic HSCT. Rather than the presence or absence of a trisomy 8, additional genetic aberrations and MRD at HSCT define outcome differences and aid in informed treatment decisions. Full article

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17 pages, 1333 KiB

Open AccessSystematic Review

Use of Azacitidine or Decitabine for the Up-Front Setting in Acute Myeloid Leukaemia: A Systematic Review and Meta-Analysis

by Miriam Saiz-Rodríguez, Jorge Labrador, Beatriz Cuevas, David Martínez-Cuadrón, Verónica Campuzano, Raquel Alcaraz, Isabel Cano, Miguel A. Sanz and Pau Montesinos

Cancers 2021, 13(22), 5677; https://doi.org/10.3390/cancers13225677 - 12 Nov 2021

Cited by 8 | Viewed by 2326

Abstract

Irruption of decitabine and azacitidine has led to profound changes in the upfront management of older acute myeloid leukaemia (AML). However, they have not been directly compared in a randomised clinical trial. In addition, there are no studies comparing the optimal treatment schedule [...] Read more.

Irruption of decitabine and azacitidine has led to profound changes in the upfront management of older acute myeloid leukaemia (AML). However, they have not been directly compared in a randomised clinical trial. In addition, there are no studies comparing the optimal treatment schedule of each drug in AML. A systematic review and meta-analysis on the efficacy of decitabine and azacitidine monotherapy in newly diagnosed AML was conducted. Randomised controlled trials and retrospective studies were included. A total of 2743 patients from 23 cohorts were analysed (10 cohorts of azacitidine and 13 of decitabine). Similar response rates were observed for azacitidine (38%, 95% CI: 30–47%) compared to decitabine (40%, 95% CI: 32–48%) (p = 0.825). Overall survival (OS) between azacitidine (10.04 months, 95% CI: 8.36–11.72) and decitabine (8.79 months, 95% CI: 7.62–9.96) was also similar (p = 0.386). Patients treated with azacitidine showed a lower median OS when azacitidine was administered for 5 days (6.28 months, 95% CI: 4.23–8.32) compared to the standard 7-day schedule (10.83 months, 95% CI: 9.07–12.59, p = 0.002). Among patients treated with decitabine, response rates and OS were not significantly different between 5-day and 10-day decitabine regimens. Despite heterogeneity between studies, we found no differences in response rates and OS in AML patients treated with azacitidine or decitabine. Full article

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15 pages, 3089 KiB

Open AccessArticle

CBFB Break-Apart FISH Testing: An Analysis of 1629 AML Cases with a Focus on Atypical Findings and Their Implications in Clinical Diagnosis and Management

by Richard K. Yang, Gokce A. Toruner, Wei Wang, Hong Fang, Ghayas C. Issa, Lulu Wang, Andrés E. Quesada, Beenu Thakral, Keyur P. Patel, Guang Peng, Shujuan Liu, C. Cameron Yin, Gautam Borthakur, Zhenya Tang, Sa A. Wang, Roberto N. Miranda, Joseph D. Khoury, L. Jeffrey Medeiros and Guilin Tang

Cancers 2021, 13(21), 5354; https://doi.org/10.3390/cancers13215354 - 26 Oct 2021

Cited by 4 | Viewed by 2893

Abstract

Fluorescence in situ hybridization (FISH) is a confirmatory test to establish a diagnosis of inv(16)/t(16;16) AML. However, incidental findings and their clinical diagnostic implication have not been systemically studied. We studied 1629 CBFB FISH cases performed in our institution, 262 (16.1%), 1234 (75.7%), [...] Read more.

Fluorescence in situ hybridization (FISH) is a confirmatory test to establish a diagnosis of inv(16)/t(16;16) AML. However, incidental findings and their clinical diagnostic implication have not been systemically studied. We studied 1629 CBFB FISH cases performed in our institution, 262 (16.1%), 1234 (75.7%), and 133 (8.2%) were reported as positive, normal, and abnormal, respectively. The last included CBFB copy number changes (n = 120) and atypical findings such as 3′CBFB deletion (n = 11), 5′CBFB deletion (n = 1), and 5′CBFB gain (n = 1). Correlating with CBFB-MYH11 RT-PCR results, totally 271 CBFB rearrangement cases were identified, including five with discrepancies between FISH and RT-PCR due to new partner genes (n = 3), insertion (n = 1), or rare CBFB-MYH11 variant (n = 1) and eight with 3′CBFB deletion. All cases with atypical findings and/or discrepancies presented clinical diagnostic challenges. Correlating FISH signal patterns and karyotypes, additional chromosome 16 aberrations (AC16As) show impacts on the re-definition of a complex karyotype and prognostic prediction. The CBFB rearrangement but not all AC16As will be detected by NGS-based methods. Therefore, FISH testing is currently still needed to provide a quick and straightforward confirmatory inv(16)/t(16;16) AML diagnosis and additional information related to clinical management. Full article

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12 pages, 934 KiB

Open AccessArticle

Risk, Characteristics and Biomarkers of Cytokine Release Syndrome in Patients with Relapsed/Refractory AML or MDS Treated with CD3xCD123 Bispecific Antibody APVO436

by Fatih M. Uckun, Justin Watts, Alice S. Mims, Prapti Patel, Eunice Wang, Paul J. Shami, Elizabeth Cull, Cynthia Lee, Christopher R. Cogle and Tara L. Lin

Cancers 2021, 13(21), 5287; https://doi.org/10.3390/cancers13215287 - 21 Oct 2021

Cited by 5 | Viewed by 4368

Abstract

We evaluate the risk, characteristics and biomarkers of treatment-emergent cytokine release syndrome (CRS) in patients with relapsed/refractory acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) who received APVO436 during the dose-escalation phase of a Phase 1B study (ClinicalTrials.gov, identifier: NCT03647800). Of four patients [...] Read more.

We evaluate the risk, characteristics and biomarkers of treatment-emergent cytokine release syndrome (CRS) in patients with relapsed/refractory acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) who received APVO436 during the dose-escalation phase of a Phase 1B study (ClinicalTrials.gov, identifier: NCT03647800). Of four patients who developed Grade ≥ 3 CRS, two received steroid prophylaxis. The dose level, gender, race, obesity, or baseline hematologic parameters in peripheral blood did not predict the risk of CRS. Patients with a higher leukemia burden as determined by a higher total WBC, higher percentage of blasts in bone marrow, or higher percentage of blasts in peripheral blood (by hematopathology or immunophenotyping) did not have a higher incidence of CRS. There was an age difference between patients who did versus patients who did not develop CRS (72.9 ± 1.6 years (Median 73.5 years) vs. 63.3 ± 2.3 years (Median: 65.0 years), which was borderline significant (p = 0.04). Premedication with steroids did not eliminate the risk of CRS. Cytokine profiling in patients who developed CRS after APVO436 infusion indicates that the predominant cytokine in this inflammatory cytokine response was IL-6. APVO436-associated CRS was generally manageable with tocilizumab with or without dexamethasone. Notably, the development of CRS after APVO436 therapy did not appear to be associated with a response. The prolonged stabilization of disease, partial remissions and complete remissions were achieved in both patients who experienced CRS, as well as patients who did not experience CRS after APVO436 infusions. Full article

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22 pages, 1117 KiB

Open AccessArticle

A Clinical Phase 1B Study of the CD3xCD123 Bispecific Antibody APVO436 in Patients with Relapsed/Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome

by Fatih M. Uckun, Tara L. Lin, Alice S. Mims, Prapti Patel, Cynthia Lee, Anoush Shahidzadeh, Paul J. Shami, Elizabeth Cull, Christopher R. Cogle and Justin Watts

Cancers 2021, 13(16), 4113; https://doi.org/10.3390/cancers13164113 - 15 Aug 2021

Cited by 20 | Viewed by 6073

Abstract

APVO436 is a recombinant T cell-engaging humanized bispecific antibody designed to redirect host T cell cytotoxicity in an MHC-independent manner to CD123-expressing blast cells from patients with hematologic malignancies and has exhibited single-agent anti-leukemia activity in murine xenograft models of acute myeloid leukemia [...] Read more.

APVO436 is a recombinant T cell-engaging humanized bispecific antibody designed to redirect host T cell cytotoxicity in an MHC-independent manner to CD123-expressing blast cells from patients with hematologic malignancies and has exhibited single-agent anti-leukemia activity in murine xenograft models of acute myeloid leukemia (AML). In this first-in-human (FIH) multicenter phase 1B study, we sought to determine the safety and tolerability of APVO436 in R/R AML/myelodysplastic syndrome (MDS) patients and identify a clinically active recommended phase 2 dose (RP2D) level for its further clinical development. A total of 46 R/R AML/MDS patients who had failed 1–8 prior lines of therapy received APVO436 as weekly intravenous (IV) infusions at 10 different dose levels, ranging from a Minimum Anticipated Biological Effect Level (MABEL) of 0.3 mcg to 60 mcg. APVO436 exhibited a favorable safety profile with acceptable tolerability and manageable drug-related adverse events (AEs), and its maximum tolerated dose (MTD) was not reached at a weekly dose of 60 mcg. The most common APVO436-related AEs were infusion-related reactions (IRR) occurring in 13 (28.3%) patients and cytokine release syndrome (CRS) occurring in 10 (21.7%). The single dose RP2D level was identified as 0.2 mcg/kg. Preliminary efficacy signals were observed in both AML and MDS patients: Prolonged stable disease (SD), partial remissions (PR), and complete remissions (CR) were observed in R/R AML patients as best overall responses to APVO436 at the RP2D level. Three of six evaluable MDS patients had marrow CRs. The safety and preliminary evidence of efficacy of APVO436 in R/R AML and MDS patients warrant further investigation of its clinical impact potential. Full article

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10 pages, 2910 KiB

Open AccessCommunication

Novel Polyethylene Glycol-Conjugated Triazole Derivative with High Thyrointegrin αvβ3 Affinity in Acute Myeloid Leukemia Management

by Thangirala Sudha, Kavitha Godugu, Noureldien H. E. Darwish, Tipu Nazeer and Shaker A. Mousa

Cancers 2021, 13(16), 4070; https://doi.org/10.3390/cancers13164070 - 13 Aug 2021

Cited by 4 | Viewed by 2110

Abstract

(1) Background: Acute myeloid leukemia (AML) accounts for up to one-third of more than 60,000 leukemia cases diagnosed annually in the U.S. Primary AML cells express membrane αvβ3 integrin, which is associated with adverse prognosis and resistance to chemotherapies. A novel anticancer compound [...] Read more.

(1) Background: Acute myeloid leukemia (AML) accounts for up to one-third of more than 60,000 leukemia cases diagnosed annually in the U.S. Primary AML cells express membrane αvβ3 integrin, which is associated with adverse prognosis and resistance to chemotherapies. A novel anticancer compound Polyethylene glycol-conjugated bi-TriAzole Tetraiodothyroacetic acid (P-bi-TAT) interacts with high affinity (Ki 0.3 nM) and specificity with the thyrointegrin αvβ3. We evaluated P-bi-TAT activities in two different AML models representing monocytic and myelocytic forms of acute leukemia. (2) Methods and Results: The in vivo AML models were established prior to initiation of treatment protocols by grafting human leukemia cells in immunocompromised mice. IVIS imaging scans revealed that leukemic colonies were extensively established throughout the bone marrow, liver, and lung of the untreated animals. In animals treated with P-bi-TAT at daily doses ranging from 1–10 mg/kg, subcutaneously for 2–3 weeks, IVIS imaging scans revealed 95% reduction in bone marrow colonies and leukemic colonies in liver and lung. Also, the leukemic cells were not detected in bone marrow samples of P-bi-TAT-treated animals. The anti-neoplastic effect of P-bi-TAT administration on leukemic cells was associated with marked inhibition of NF-κB activity. We conclude that experimental P-bi-TAT therapy in vivo appears extraordinarily effective against the two forms of human AML models in mice. Because the P-bi-TAT molecular target, thyrointegrin αvβ3, is consistently expressed in many, if not all, clinical AML samples, P-bi-TAT-based therapy seems to have significant clinical potential in treating most AML sub-types. Hence, P-bi-TAT represents a promising targeted therapeutic agent for AML patients. Full article

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Graphical abstract

20 pages, 674 KiB

Open AccessReview

CD33 Expression and Gentuzumab Ozogamicin in Acute Myeloid Leukemia: Two Sides of the Same Coin

by Matteo Molica, Salvatore Perrone, Carla Mazzone, Pasquale Niscola, Laura Cesini, Elisabetta Abruzzese and Paolo de Fabritiis

Cancers 2021, 13(13), 3214; https://doi.org/10.3390/cancers13133214 - 28 Jun 2021

Cited by 18 | Viewed by 5500

Abstract

Acute myeloid leukemia (AML), the most frequent acute leukemia in adults, has been historically treated with infusional cytarabine (ara-c) + daunorubicin (3 + 7) for at least 40 years. The first “target therapy” to be introduced was the monoclonal anti-CD33 gemtuzumab ozogamicin (GO) [...] Read more.

Acute myeloid leukemia (AML), the most frequent acute leukemia in adults, has been historically treated with infusional cytarabine (ara-c) + daunorubicin (3 + 7) for at least 40 years. The first “target therapy” to be introduced was the monoclonal anti-CD33 gemtuzumab ozogamicin (GO) in 2004. Unfortunately, in 2010 it was voluntarily withdrawn from the market both for safety reasons related to potential liver toxicity and veno-occlusive disease (VOD) and because clinical studies failed to confirm the clinical benefit during induction and maintenance. Seven years later, GO was re-approved based on new data, including insights into its mechanism of action on its target receptor CD33 expressed on myeloid cells. The present review focuses on current biological information and clinical data from several studies investigating GO. Cytogenetic, molecular, and immunophenotypic data are now able to predict the potential positive advantages of GO, with the exception of high-risk AML patients who do not seem to benefit. GO can be considered a ‘repurposed drug’ that could be beneficial for some patients with AML, mostly in combination with new drugs already approved or currently in testing. Full article

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