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A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (31 October 2020) | Viewed by 32695

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Special Issue Editor

Dr. Francesco Buccisano

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Haematology and Stem Cell Transplant Unit, Department of Biomedicine and Prevention, University of Rome ‘Tor Vergata’, 00133 Rome, Italy
Interests: clinical hematology; acute leukemias; acute myeloid leukemia; immunophenotyping of hematological malignancies; allogeneic transplantation; measurable residual disease by flow cytometry and molecular techniques
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Special Issue Information

Dear Colleagues,

Up until recently, we used to begin our manuscripts by conceding that despite the increasing knowledge of the genetic/cytogenetic landscape of acute myeloid leukemia (AML), the capacity to renew our treatment approach for the majority of patients was minimal and that their eventual outcome inevitably remained poor. However, since 2017, the treatment scenario has substantially changed. A relevant number of new drugs have been licensed for AML, targeting mutated genes (e.g., FLT3, IDH1/2) or growth/apoptosis regulators (e.g., hedgehog, BCL2), whose safety and efficacy have not only been proven in monotherapy but also challenged in combination with conventional chemotherapy. With the availability of a larger set of drugs with a more tolerable safety profile, the validation of more appropriate criteria to determine fitness for intensive or attenuated protocols has allowed clinicians to extend cure-aimed treatments to a much larger population of patients, including older ones or those with comorbidities. In addition to the advances in drug development, biomarkers such as measurable residual disease (MRD) are increasingly being used to prospectively allocate AML patients to a different intensity of post-remission treatment (e.g., allogeneic transplant vs. autologous transplant or chemotherapeutic consolidation). For high-risk disease, the availability of new targeted well-tolerated small molecules has renewed the possibility to administer long-term maintenance treatments to preemptively avoid or delay relapse, even after transplant. Finally, several immunotherapeutic weapons, ranging from antibodies (BiTE, DART, toxin-immunoconjugates, etc.) to monospecific/bispecific CAR-T cells have also been challenged in the AML field.

In the present Special Issue, we will review how all these approaches may be combined in a modern treatment algorithm allowing physicians to tailor AML therapy on each specific category of patients, balancing the intensity of treatment between the biological aggressiveness of disease and the opportunity to give to each patient a reliable improvement of length and quality of life.

Dr. Francesco Buccisano
Guest Editor

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Keywords

new drugs
combination therapies
minimal residual disease
leukemic stem cells
new pathogenetic pathways
targeted therapies
stem-cell transplantation
immunotherapy
cellular therapies
fitness
quality of life

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Published Papers (8 papers)

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Research

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12 pages, 1491 KiB

Open AccessArticle

Use of Measurable Residual Disease to Evolve Transplant Policy in Acute Myeloid Leukemia: A 20-Year Monocentric Observation

by Francesco Buccisano, Raffaele Palmieri, Alfonso Piciocchi, Luca Maurillo, Maria Ilaria Del Principe, Giovangiacinto Paterno, Stefano Soddu, Raffaella Cerretti, Gottardo De Angelis, Benedetta Mariotti, Maria Antonietta Irno Consalvo, Consuelo Conti, Daniela Fraboni, Mariadomenica Divona, Tiziana Ottone, Serena Lavorgna, Paola Panetta, Maria Teresa Voso, William Arcese and Adriano Venditti

Cancers 2021, 13(5), 1083; https://doi.org/10.3390/cancers13051083 - 3 Mar 2021

Cited by 4 | Viewed by 2155

Abstract

Measurable residual disease (MRD) is increasingly employed as a biomarker of quality of complete remission (CR) in intensively treated acute myeloid leukemia (AML) patients. We evaluated if a MRD-driven transplant policy improved outcome as compared to a policy solely relying on a familiar donor availability. High-risk patients (adverse karyotype, FLT3-ITD) received allogeneic hematopoietic cell transplant (alloHCT) whereas for intermediate and low risk ones (CBF-AML and NPM1-mutated), alloHCT or autologous SCT was delivered depending on the post-consolidation measurable residual disease (MRD) status, as assessed by flow cytometry. For comparison, we analyzed a matched historical cohort of patients in whom alloHCT was delivered based on the sole availability of a matched sibling donor. Ten-years overall and disease-free survival were longer in the MRD-driven cohort as compared to the historical cohort (47.7% vs. 28.7%, p = 0.012 and 42.0% vs. 19.5%, p = 0.0003). The favorable impact of this MRD-driven strategy was evident for the intermediate-risk category, particularly for MRD positive patients. In the low-risk category, the significantly lower CIR of the MRD-driven cohort did not translate into a survival advantage. In conclusion, a MRD-driven transplant allocation may play a better role than the one based on the simple donor availability. This approach determines a superior outcome of intermediate-risk patients whereat in low-risk ones a careful evaluation is needed for transplant allocation. Full article

(This article belongs to the Special Issue Updates in Acute Myeloid Leukemia)

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14 pages, 1937 KiB

Open AccessArticle

CD123 Is Consistently Expressed on NPM1-Mutated AML Cells

by Vincenzo Maria Perriello, Ilaria Gionfriddo, Roberta Rossi, Francesca Milano, Federica Mezzasoma, Andrea Marra, Orietta Spinelli, Alessandro Rambaldi, Ombretta Annibali, Giuseppe Avvisati, Francesco Di Raimondo, Stefano Ascani, Brunangelo Falini, Maria Paola Martelli and Lorenzo Brunetti

Cancers 2021, 13(3), 496; https://doi.org/10.3390/cancers13030496 - 28 Jan 2021

Cited by 24 | Viewed by 5691

Abstract

NPM1-mutated (NPM1mut) acute myeloid leukemia (AML) comprises about 30% of newly diagnosed AML in adults. Despite notable advances in the treatment of this frequent AML subtype, about 50% of NPM1mut AML patients treated with conventional treatment die due to disease progression. CD123 has been identified as potential target for immunotherapy in AML, and several anti-CD123 therapeutic approaches have been developed for AML resistant to conventional therapies. As this antigen has been previously reported to be expressed by NPM1mut cells, we performed a deep flow cytometry analysis of CD123 expression in a large cohort of NPM1mut and wild-type samples, examining the whole blastic population, as well as CD34⁺CD38⁻ leukemic cells. We demonstrate that CD123 is highly expressed on NPM1mut cells, with particularly high expression levels showed by CD34⁺CD38⁻ leukemic cells. Additionally, CD123 expression was further enhanced by FLT3 mutations, which frequently co-occur with NPM1 mutations. Our results identify NPM1-mutated and particularly NPM1/FLT3 double-mutated AML as disease subsets that may benefit from anti-CD123 targeted therapies. Full article

(This article belongs to the Special Issue Updates in Acute Myeloid Leukemia)

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13 pages, 1029 KiB

Open AccessArticle

Fludarabine, High-Dose Cytarabine and Idarubicin-Based Induction May Overcome the Negative Prognostic Impact of FLT3-ITD in NPM1 Mutated AML, Irrespectively of FLT3-ITD Allelic Burden

by Paola Minetto, Anna Candoni, Fabio Guolo, Marino Clavio, Maria Elena Zannier, Maurizio Miglino, Maria Vittoria Dubbini, Enrico Carminati, Anna Sicuranza, Sara Ciofini, Nicoletta Colombo, Girolamo Pugliese, Riccardo Marcolin, Adele Santoni, Filippo Ballerini, Luca Lanino, Michele Cea, Marco Gobbi, Monica Bocchia, Renato Fanin and Roberto Massimo Lemoli Show full author list Hide full author list

Cancers 2021, 13(1), 34; https://doi.org/10.3390/cancers13010034 - 24 Dec 2020

Cited by 17 | Viewed by 3569

Abstract

The mutations of NPM1 and FLT3-ITD represent the most frequent genetic aberration in acute myeloid leukemia. Indeed, the presence of an NPM1 mutation reduces the negative prognostic impact of FLT3-ITD in patients treated with conventional “3+7” induction. However, little information is available on their prognostic role with intensified regimens. Here, we investigated the efficacy of a fludarabine, high-dose cytarabine and idarubicin induction (FLAI) in 149 consecutive fit AML patients (median age 52) carrying the NPM1 and/or FLT3-ITD mutation, treated from 2008 to 2018. One-hundred-and-twenty-nine patients achieved CR (86.6%). After a median follow up of 68 months, 3-year overall survival was 58.6%. Multivariate analysis disclosed that both NPM1mut (p < 0.05) and ELN 2017 risk score (p < 0.05) were significant predictors of survival. NPM1-mutated patients had a favorable outcome, with no significant differences between patients with or without concomitant FLT3-ITD (p = 0.372), irrespective of FLT3-ITD allelic burden. Moreover, in landmark analysis, performing allogeneic transplantation (HSCT) in first CR proved to be beneficial only in ELN 2017 high-risk patients. Our data indicate that FLAI exerts a strong anti-leukemic effect in younger AML patients with NPM1mut and question the role of HSCT in 1st CR in NPM1mut patients with concomitant FLT3-ITD. Full article

(This article belongs to the Special Issue Updates in Acute Myeloid Leukemia)

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15 pages, 994 KiB

Open AccessArticle

Survival Improvement over Time of 960 s-AML Patients Included in 13 EORTC-GIMEMA-HOVON Trials

by Safaa M. Ramadan, Stefan Suciu, Marian J. P. L. Stevens-Kroef, Roelof Willemze, Sergio Amadori, Theo de Witte, Bob Löwenberg, Petra Muus, Boris Labar, Liv Meert, Gaetan de Schaetzen, Giovanna Meloni, Giuseppe Leone, Marco Vignetti, Jean-Pierre Marie, Michael Lübbert and Frédéric Baron

Cancers 2020, 12(11), 3334; https://doi.org/10.3390/cancers12113334 - 11 Nov 2020

Cited by 6 | Viewed by 2696

Abstract

We report the outcomes of secondary acute myeloid leukemia (s-AML) patients included in one of 13 European Organisation for Research and Treatment of Cancer (EORTC) collaborative AML trials using intensive remission-induction chemotherapy. Among 8858 patients treated between May 1986 and January 2008, 960 were identified as having s-AML, either after MDS (cohort A; n = 508), occurring after primary solid tumors or hematologic malignancies other than MDS (cohort B; n = 361), or after non-malignant conditions or with a history of toxic exposure (cohort C; n = 91). Median age was 64 years, 60 years and 61 years in cohort A, B and C, respectively. Among patients ≤60 years and classified in the cohorts A or B (n = 367), the 5-year overall survival (OS) rate was 28%. There was a systematic improvement in the 5-year OS rate over three time periods (p < 0.001): 7.7% (95% CI: 1.3–21.7%) for patients treated before 1990 (period 1: n = 26), 23.3% (95% CI: 17.1–30.0%) for those treated between 1990 and 2000 (period 2: n = 188) and 36.5% (95% CI: 28.7–44.3%) for those treated in 2000 or later (period 3: n = 153). In multivariate analysis, male gender (HR = 1.39; p = 0.01), WBC ≥ 25 × 10⁹/L (HR = 2.00; p < 0.0001), age 46-60 years (HR = 1.65; p < 0.001) and poor-risk cytogenetics (HR = 2.17; p < 0.0001) were independently associated with shorter OS, while being treated during period 2 (HR = 0.50, p = 0.003) or period 3 (HR = 0.43; p = 0.0008). Having received high-dose cytarabine (HD-AraC) (n = 48) in the induction chemotherapy (HR = 0.54, p = 0.012) was associated with a longer OS. In contrast, among patients >60 years of age (n = 502), the OS was dismal, and there was no improvement over time. Full article

(This article belongs to the Special Issue Updates in Acute Myeloid Leukemia)

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15 pages, 2155 KiB

Open AccessArticle

Multilineage Dysplasia as Assessed by Immunophenotype in Acute Myeloid Leukemia: A Prognostic Tool in a Genetically Undefined Category

by Francesco Mannelli, Sara Bencini, Matteo Piccini, Giacomo Gianfaldoni, Maria Ida Bonetti, Benedetta Peruzzi, Roberto Caporale, Barbara Scappini, Fabiana Pancani, Vanessa Ponziani, Leonardo Signori, Michela Zizza, Francesco Annunziato and Alberto Bosi

Cancers 2020, 12(11), 3196; https://doi.org/10.3390/cancers12113196 - 30 Oct 2020

Cited by 5 | Viewed by 2381

Abstract

Acute myeloid leukemia (AML) “with myelodysplasia-related changes (MRC)” is considered a separate entity by the World Health Organization (WHO) classification of myeloid neoplasms. While anamnestic and cytogenetic criteria provide objective attribution to this subset, with clear unfavorable prognostic significance, the actual role of multi-lineage dysplasia (MLD) as assessed by morphology is debated. The aim of our work was to study MLD by a technique alternative to morphology, which is multiparameter flow cytometry (MFC), in a large series of 302 AML patients intensively treated at our Center. The correlation with morphology we observed in the unselected analysis reiterated the capability of the MFC-based approach at highlighting dysplasia. MLD data, estimated through an immune-phenotypic score (IPS), provided no insight into prognosis when considered overall nor within well-defined genetic categories. Of interest, IPS-related dysplasia conveyed significant prognostic information when we focused on genetically undefined patients, triple-negative for NPM1, FLT3 and CEBPA (TN-AML). In this context, the lack of dysplastic features (IPS_0) correlated with a significantly higher CR rate and longer survival compared to patients showing dysplasia in one or both (neutrophil and erythroid) cell lineages. The impact of IPS category maintained its validity after censoring at allogeneic HSCT and in a multivariate analysis including baseline and treatment-related covariates. In a subgroup featured by the lack of genetic determinants, our data could help address the relative unmet needs in terms of risk assessment and treatment strategy, and provide insight into prediction of response in the rapidly evolving therapeutic scenario of AML. Full article

(This article belongs to the Special Issue Updates in Acute Myeloid Leukemia)

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18 pages, 999 KiB

Open AccessArticle

Conditioning Intensity, Pre-Transplant Flow Cytometric Measurable Residual Disease, and Outcome in Adults with Acute Myeloid Leukemia Undergoing Allogeneic Hematopoietic Cell Transplantation

by Linde M. Morsink, Brenda M. Sandmaier, Megan Othus, Raffaele Palmieri, Noa Granot, Evandro D. Bezerra, Brent L. Wood, Marco Mielcarek, Gary Schoch, Chris Davis, Mary E. D. Flowers, H. Joachim Deeg, Frederick R. Appelbaum, Rainer Storb and Roland B. Walter

Cancers 2020, 12(9), 2339; https://doi.org/10.3390/cancers12092339 - 19 Aug 2020

Cited by 33 | Viewed by 3085

Abstract

How conditioning intensity is related to outcomes of AML patients undergoing allografting in morphologic remission is an area of great ongoing interest. We studied 743 patients in morphologic remission and known pre-transplant measurable residual disease (MRD) status determined by multiparameter flow cytometry (MFC) who received a first allograft after myeloablative, reduced intensity, or nonmyeloablative conditioning (MAC, RIC, and NMA). Overall, relapse-free survival (RFS) and overall survival (OS) were longer after MAC than RIC or NMA conditioning, whereas relapse risks were not different. Among MRD^pos patients, 3-year estimates of relapse risks and survival were similar across conditioning intensities. In contrast, among MRD^neg patients, 3-year RFS and OS were longer for MAC (69% and 71%) than RIC (47% and 55%) and NMA conditioning (47% and 52%). Three-year relapse risks were lowest after MAC (18%) and highest after NMA conditioning (30%). Our data indicate an interaction between conditioning intensity, MFC-based pre-transplant MRD status, and outcome, with benefit of intensive conditioning primarily for patients transplanted in MRD^neg remission. Differing from recent findings from other studies that indicated MAC is primarily beneficial for some or all patients with MRD^pos pre-HCT status, our data suggest MAC should still be considered for MRD^neg AML patients if tolerated. Full article

(This article belongs to the Special Issue Updates in Acute Myeloid Leukemia)

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Review

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21 pages, 3471 KiB

Open AccessReview

Acute Myeloid Leukemia Stem Cells: The Challenges of Phenotypic Heterogeneity

by Marlon Arnone, Martina Konantz, Pauline Hanns, Anna M. Paczulla Stanger, Sarah Bertels, Parimala Sonika Godavarthy, Maximilian Christopeit and Claudia Lengerke

Cancers 2020, 12(12), 3742; https://doi.org/10.3390/cancers12123742 - 12 Dec 2020

Cited by 37 | Viewed by 7756

Abstract

Patients suffering from acute myeloid leukemia (AML) show highly heterogeneous clinical outcomes. Next to variabilities in patient-specific parameters influencing treatment decisions and outcome, this is due to differences in AML biology. In fact, different genetic drivers may transform variable cells of origin and co-exist with additional genetic lesions (e.g., as observed in clonal hematopoiesis) in a variety of leukemic (sub)clones. Moreover, AML cells are hierarchically organized and contain subpopulations of more immature cells called leukemic stem cells (LSC), which on the cellular level constitute the driver of the disease and may evolve during therapy. This genetic and hierarchical complexity results in a pronounced phenotypic variability, which is observed among AML cells of different patients as well as among the leukemic blasts of individual patients, at diagnosis and during the course of the disease. Here, we review the current knowledge on the heterogeneous landscape of AML surface markers with particular focus on those identifying LSC, and discuss why identification and targeting of this important cellular subpopulation in AML remains challenging. Full article

(This article belongs to the Special Issue Updates in Acute Myeloid Leukemia)

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28 pages, 851 KiB

Open AccessReview

Chimeric Antigen Receptor (CAR)-Modified Immune Effector Cell Therapy for Acute Myeloid Leukemia (AML)

by Utkarsh H. Acharya and Roland B. Walter

Cancers 2020, 12(12), 3617; https://doi.org/10.3390/cancers12123617 - 3 Dec 2020

Cited by 11 | Viewed by 4087

Abstract

Despite the availability of an increasing number of targeted therapeutics and wider use of allogeneic hematopoietic stem cell transplantation, many patients with acute myeloid leukemia (AML) ultimately succumb to this disease. Given their remarkable efficacy in B-acute lymphoblastic leukemia and other CD19-expressing B cell malignancies, there is hope adoptive cellular transfer, particularly chimeric antigen receptor (CAR)-modified immune effector cell (IEC) therapies, may afford a novel, potent immune-based approach for the treatment of AML that complements or replaces existing ones and improves cure rates. However, it is unclear how best to translate the success of these therapies from B cell malignancies, where use of highly potent immunotherapies is facilitated by identified target antigens with near ubiquitous expression on malignant cells and non-fatal consequences from “on-target, off-tumor cell” toxicities. Herein, we review the current status of CAR-modified IEC therapies for AML, with considerations regarding suitable, relatively leukemia-restricted target antigens, expected toxicities, and interactions of the engineered cells with a profoundly immunosuppressive tumor microenvironment that restricts their therapeutic efficacy. With these challenges in mind, we will discuss possible strategies to improve the cells’ potency as well as their therapeutic window for optimal clinical use in AML. Full article

(This article belongs to the Special Issue Updates in Acute Myeloid Leukemia)

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