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Prognosis and Therapy of Chronic Myeloid Leukemia

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A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Hematology".

Deadline for manuscript submissions: closed (31 July 2021) | Viewed by 42118

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Prof. Dr. Domenico Russo

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Unit of Blood Diseases and Bone Marrow Transplantation, DPT of Clinical and Experimental Sciences, University of Brescia, Viale Europa 11, 25121 Brescia, Italy
Interests: prognosis and therapy of chronic myeloid leukemia; therapy of acute leukemias, lymphomas and myeloma; multidrug resistance (MDR); stem cell transplantation
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Dr. Valentín García Gutiérrez

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Servicio de Hematología, Hospital Universitario Ramón y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain

Dr. Simona Soverini

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Department of Experimental, Diagnostic and Specialty Medicine, Hematology/Oncology "L. e A. Seragnoli", University of Bologna, Via Massarenti 9, 40138 Bologna, Italy
Interests: hematology; leukemias; next-generation sequencing; mutation analysis
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Michele Baccarani

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Professor of Hematology, University of Bologna, Via Massarenti 9, 40138 Bologna, Italy
Interests: clinical hematology (chronic myeloid leukemia, acute leukemias, myelodysplastic syndrome, multiple myeloma, lymphomas); stem cell transplantation (allogeneic and autologous); experimental hematology (stem cells, chemotherapy, multidrug resistance, cell kinetics)

Special Issue Information

Dear Colleagues,

The treatment, prognosis, and management of chronic myeloid leukemia (CML) changed significantly during the last two decades. At the beginning of 2000, the introduction of TKIs allowed the disease’s blastic transformation to be prevented and for the survival to be significantly prolonged in 90% of patients. Moreover, many improvements have been made in hot topics such as cell biology, prognosis, drug development, and therapy driven by molecular response. Nevertheless, the scientific community is still focused on several criticisms concerning: the eradication of Ph+ leukemic stem cell, the detection and monitoring of minimal residual disease by RT-qPCR, digital-PCR, NGS or more advanced techniques, the adherence and resistance to TKIs therapy, the optimization of therapy by drug, risk- and age-adapted strategies aiming to treatment-free remission (TFR) or quality of life.

In this Special Issue, improvements, criticisms, and perspective on CML prognosis and therapy will be discussed.

Prof. Dr. Domenico Russo
Dr. Valentín García Gutiérrez
Dr. Simona Soverini
Prof. Dr. Michele Baccarani
Guest Editors

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Keywords

Ph+ cell biology
CML modelling
CML prognosis
BCR-ABL1 detection and quantitation
BCR-ABL1 minimal residual disease
target drugs
therapy discontinuation
TFR
de-escalation treatment
pregnancy in CML
quality of life

Published Papers (11 papers)

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Editorial

Jump to: Research, Review

9 pages, 259 KiB

Open AccessEditorial

Chronic Myeloid Leukemia Prognosis and Therapy: Criticisms and Perspectives

by Domenico Russo, José Valentín Garcia-Gutierrez, Simona Soverini and Michele Baccarani

J. Clin. Med. 2020, 9(6), 1709; https://doi.org/10.3390/jcm9061709 - 02 Jun 2020

Cited by 19 | Viewed by 3885

Abstract

Ph+ chronic myeloid leukemia (CML) is a clonal myeloproliferative disease whose clinical course is characterized by progression disease from the early chronic phase (CP) to the fatal blastic phase (BP). This programmed course is closely related to the translocation t(9;22)(q22;q11) and the resulting BCR-ABL1 fusion protein (p210) that drives the leukemic transformation of hematopoietic stem cells. Therefore, the cure of CML can only pass through the abrogation of the Ph+ clone. Allogeneic stem cell transplantation (allo-SCT) and interferon-alpha (IFNα) have been proven to reduce the Ph+ clone in a limited proportion of CML population and this translated in a lower rate of progression to BP and in a significant prolongation of survival. Tyrosine-kinase inhibitors (TKIs), lastly introduced in 2000, by preventing the disease blastic transformation and significantly prolonging the survival in up to 90% of the patient population, radically changed the fate of CML. The current therapy with TKIs induces a chronicization of the disease but several criticisms still persist, and the most relevant one is the sustainability of long-term therapy with TKIs in terms of compliance, toxicity and costs. The perspectives concern the optimization of therapy according to the age, the risk of disease, the potency and the safety profiles of the TKIs. The prolongation of survival is the most important end point which should be guaranteed to all patients. The treatment free remission (TFR) is the new goal that we would like to give to an increasing number of patients. The cure remains the main objective of CML therapy. Full article

(This article belongs to the Special Issue Prognosis and Therapy of Chronic Myeloid Leukemia)

Research

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13 pages, 430 KiB

Open AccessArticle

Chronic Myeloid Leukemia and Pregnancy: When Dreams Meet Reality. State of the Art, Management and Outcome of 41 Cases, Nilotinib Placental Transfer

by Elisabetta Abruzzese, Stefano Aureli, Francesco Bondanini, Mariavita Ciccarone, Elisabetta Cortis, Antonello Di Paolo, Cristina Fabiani, Sara Galimberti, Michele Malagola, Alessandra Malato, Bruno Martino, Malgorzata Monika Trawinska, Domenico Russo and Paolo de Fabritiis

J. Clin. Med. 2022, 11(7), 1801; https://doi.org/10.3390/jcm11071801 - 24 Mar 2022

Cited by 10 | Viewed by 3429

Abstract

The overwhelming success of tyrosine kinase inhibitor (TKI) therapy in chronic myeloid leukemia (CML) patients has opened a discussion among medical practitioners and the lay public on the real possibility of pregnancy and conception in females and males with CML. In the past 10 years this subject has acquired growing interest in the scientific community and specific knowledge has been obtained “from bench to bedside”. Embryological, pharmacological, and pathophysiological studies have merged with worldwide patient databases to provide a roadmap to a successful pregnancy and birth in CML patients. Male conception does not seem to be affected by TKI therapy, since this class of drugs is neither genotoxic nor mutagenic, however, caution should be used specially with newer drugs for which little or no data are available. In contrast, female patients should avoid TKI therapy specifically during the embryonic stage of organogenesis (5–12 weeks) because TKIs can be teratogenic. In the last 15 years, 41 pregnancies have been followed in our center. A total of 11 male conceptions and 30 female pregnancies are described. TKI treatment was generally terminated as soon as the pregnancy was discovered (3–5 weeks), to avoid exposure during embryonic period and to reduce the risk of needing treatment in the first trimester. Eleven pregnancies were treated with interferon, imatinib or nilotinib during gestation. Nilotinib plasma levels in cord blood and maternal blood at delivery were studied in 2 patients and reduced or absent placental crossing of nilotinib was observed. All of the patients were managed by a multidisciplinary team of physicians with obligatory hematological and obgyn consultations. This work provides an update on the state of the art and detailed description of pregnancy management and outcomes in CML patients. Full article

(This article belongs to the Special Issue Prognosis and Therapy of Chronic Myeloid Leukemia)

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15 pages, 2403 KiB

Open AccessArticle

Combined Inhibition of Bcl2 and Bcr-Abl1 Exercises Anti-Leukemia Activity but Does Not Eradicate the Primitive Leukemic Cells

by Michele Massimino, Paolo Vigneri, Stefania Stella, Elena Tirrò, Maria Stella Pennisi, Laura Nunziatina Parrinello, Calogero Vetro, Livia Manzella, Fabio Stagno and Francesco Di Raimondo

J. Clin. Med. 2021, 10(23), 5606; https://doi.org/10.3390/jcm10235606 - 29 Nov 2021

Cited by 7 | Viewed by 1939

Abstract

Background: The management of Philadelphia Chromosome-positive (Ph+) hematological malignancies is strictly correlated to the use of BCR-ABL1 tyrosine kinase inhibitors (TKIs). However, these drugs do not induce leukemic stem cells death and their persistence may generate a disease relapse. Published reports indicated that Venetoclax, a selective BCL2 inhibitor, could be effective in Ph+ diseases, as BCL2 anti-apoptotic activity is modulated by BCR-ABL1 kinase. We, therefore, investigated if BCL2 inhibition, alone or combined with Nilotinib, a BCR-ABL1 inhibitor, affects the primitive and committed Ph+ cells survival. Methods: We used Ph+ cells isolated from leukemic patients at diagnosis. To estimate the therapeutic efficacy of BCL2 and BCR-ABL1 inhibition we employed long-term culture, proliferation and apoptosis assay. Immunoblot was used to evaluate the ability of treatment to interfere with the down-stream targets of BCR-ABL1. Results: Blocking BCL2, we observed reduced proliferation and clonogenic potential of CML CD34-positive cells and this cytotoxicity was improved by combination with BCR-ABL1 inhibitor. However, BCL2 inhibition, alone or in combination regiment with BCR-ABL1 inhibitor, did not reduce the self-renewal of primitive leukemic cells, while strongly induced cell death on primary Ph+ Acute Lymphoblastic Leukemia (ALL). Conclusion: Our results suggest that primitive CML leukemic cells are not dependent on BCL2 for their persistence and support that committed CML and Ph + ALL cells are dependent by BCL2 and BCR-ABL1 cooperation for their survival. The antileukemic activity of BCL2 and BCR-ABL1 dual targeting may be a useful therapeutic strategy for Ph+ ALL patients. Full article

(This article belongs to the Special Issue Prognosis and Therapy of Chronic Myeloid Leukemia)

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12 pages, 1164 KiB

Open AccessArticle

Impact of BCR-ABL1 Transcript Type on Response, Treatment-Free Remission Rate and Survival in Chronic Myeloid Leukemia Patients Treated with Imatinib

by Sílvia Marcé, Blanca Xicoy, Olga García, Marta Cabezón, Natalia Estrada, Patricia Vélez, Concepción Boqué, Miguel Sagüés, Anna Angona, Raúl Teruel-Montoya, Francisca Ferrer-Marín, Paula Amat, Juan Carlos Hernández-Boluda, Mariana M. Ibarra, Eduardo Anguita, Montserrat Cortés, Andrés Fernández-Ruiz, Sandra Fontanals, Lurdes Zamora and on behalf of the Grupo Español de Leucemia Mieloide Crónica (GELMC)

J. Clin. Med. 2021, 10(14), 3146; https://doi.org/10.3390/jcm10143146 - 16 Jul 2021

Cited by 10 | Viewed by 3399

Abstract

The most frequent BCR-ABL1-p210 transcripts in chronic myeloid leukemia (CML) are e14a2 and e13a2. Imatinib (IM) is the most common first-line tyrosine–kinase inhibitor (TKI) used to treat CML. Some studies suggest that BCR-ABL1 transcript types confer different responses to IM. The objective of this study was to correlate the expression of e14a2 or e13a2 to clinical characteristics, cumulative cytogenetic and molecular responses to IM, acquisition of deep molecular response (DMR) and its duration (sDMR), progression rate (CIP), overall survival (OS), and treatment-free remission (TFR) rate. We studied 202 CML patients, 76 expressing the e13a2 and 126 the e14a2, and correlated the differential transcript expression with the above-mentioned parameters. There were no differences in the cumulative incidence of cytogenetic responses nor in the acquisition of DMR and sDMR between the two groups, but the e14a2 transcript had a positive impact on molecular response during the first 6 months, whereas the e13a2 was associated with improved long-term OS. No correlation was observed between the transcript type and TFR rate. Full article

(This article belongs to the Special Issue Prognosis and Therapy of Chronic Myeloid Leukemia)

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21 pages, 1946 KiB

Open AccessArticle

Identification of Immunological Parameters as Predictive Biomarkers of Relapse in Patients with Chronic Myeloid Leukemia on Treatment-Free Remission

by Lorena Vigón, Alejandro Luna, Miguel Galán, Sara Rodríguez-Mora, Daniel Fuertes, Elena Mateos, Miguel Piris-Villaespesa, Guiomar Bautista, Esther San José, José Rivera-Torres, Juan Luis Steegmann, Fernando de Ory, Mayte Pérez-Olmeda, José Alcamí, Vicente Planelles, María Rosa López-Huertas, Valentín García-Gutiérrez and Mayte Coiras

J. Clin. Med. 2021, 10(1), 42; https://doi.org/10.3390/jcm10010042 - 25 Dec 2020

Cited by 13 | Viewed by 4466

Abstract

BCR-ABL is an aberrant tyrosine kinase responsible for chronic myeloid leukemia (CML). Tyrosine kinase inhibitors (TKIs) induce a potent antileukemic response mostly based on the inhibition of BCR-ABL, but they also increase the activity of Natural Killer (NK) and CD8+ T cells. After several years, patients may interrupt treatment due to sustained, deep molecular response. By unknown reasons, half of the patients relapse during treatment interruption, whereas others maintain a potent control of the residual leukemic cells for several years. In this study, several immunological parameters related to sustained antileukemic control were analyzed. According to our results, the features more related to poor antileukemic control were as follows: low levels of cytotoxic cells such as NK, (Natural Killer T) NKT and CD8±TCRγβ+ T cells; low expression of activating receptors on the surface of NK and NKT cells; impaired synthesis of proinflammatory cytokines or proteases from NK cells; and HLA-E*0103 homozygosis and KIR haplotype BX. A Random Forest algorithm predicted 90% of the accuracy for the classification of CML patients in groups of relapse or non-relapse according to these parameters. Consequently, these features may be useful as biomarkers predictive of CML relapse in patients that are candidates to initiate treatment discontinuation. Full article

(This article belongs to the Special Issue Prognosis and Therapy of Chronic Myeloid Leukemia)

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9 pages, 941 KiB

Open AccessArticle

by Adi Shacham Abulafia, Sivan Shemesh, Lena Rosenmann, Tamar Berger, Avi Leader, Giora Sharf, Pia Raanani and Uri Rozovski

J. Clin. Med. 2020, 9(11), 3417; https://doi.org/10.3390/jcm9113417 - 25 Oct 2020

Cited by 4 | Viewed by 2178

Abstract

The life expectancy of patients with chronic myeloid leukemia (CML) approaches that of the age-matched population and quality of life (QOL) issues are becoming increasingly important. To describe patients’ characteristics and assess QOL, we delivered a 30-item core questionnaire, a 24-item CML-specific questionnaire, both from the European Organization for Research and Treatment of Cancer (EORTC), and additional health-related items to 350 patients. Among 193 patients who completed the questionnaires, 139 received either imatinib (n = 70, 33%), dasatinib (n = 45, 23%) or nilotinib (n = 24, 12%). Patients’ median age was 58 (range: 23 to 89) years and 86 (63%) were males. Stratifying patients by treatment, we recognized two distinct populations. In comparison to patients on dasatinib and nilotinib, patients on imatinib were two decades older, had a longer duration of disease and current treatment, experienced fewer limitations on daily activities (p = 0.02), less fatigue (p = 0.001), lower degree of impaired body image (p = 0.022) and less painful episodes (p = 0.014). Similarly, they had better emotional functioning, were less worried, stressed, depressed or nervous (p = 0.01) and were more satisfied with their treatment (p = 0.018). Not only does age associate with current treatments, but it also predicts how patients perceive QOL. Young patients express impaired QOL compared with elderly patients. Full article

(This article belongs to the Special Issue Prognosis and Therapy of Chronic Myeloid Leukemia)

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Review

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13 pages, 619 KiB

Open AccessReview

Shedding Light on Targeting Chronic Myeloid Leukemia Stem Cells

by Mohammad Houshmand, Alireza Kazemi, Ali Anjam Najmedini, Muhammad Shahzad Ali, Valentina Gaidano, Alessandro Cignetti, Carmen Fava, Daniela Cilloni, Giuseppe Saglio and Paola Circosta

J. Clin. Med. 2021, 10(24), 5805; https://doi.org/10.3390/jcm10245805 - 11 Dec 2021

Cited by 6 | Viewed by 2647

Abstract

Chronic myeloid leukemia stem cells (CML LSCs) are a rare and quiescent population that are resistant to tyrosine kinase inhibitors (TKI). When TKI therapy is discontinued in CML patients in deep, sustained and apparently stable molecular remission, these cells in approximately half of the cases restart to grow, resuming the leukemic process. The elimination of these TKI resistant leukemic stem cells is therefore an essential step in increasing the percentage of those patients who can reach a successful long-term treatment free remission (TFR). The understanding of the biology of the LSCs and the identification of the differences, phenotypic and/or metabolic, that could eventually allow them to be distinguished from the normal hematopoietic stem cells (HSCs) are therefore important steps in designing strategies to target LSCs in a rather selective way, sparing the normal counterparts. Full article

(This article belongs to the Special Issue Prognosis and Therapy of Chronic Myeloid Leukemia)

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12 pages, 284 KiB

Open AccessReview

Dose Optimization of Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia: A New Therapeutic Challenge

by Alessandra Iurlo, Daniele Cattaneo, Cristina Bucelli and Massimo Breccia

J. Clin. Med. 2021, 10(3), 515; https://doi.org/10.3390/jcm10030515 - 01 Feb 2021

Cited by 23 | Viewed by 3574

Abstract

The chronic myeloid leukemia (CML) therapeutic landscape has dramatically changed with tyrosine kinase inhibitor (TKI) development, which allows a near-normal life expectancy. However, long-term TKI exposure has been associated with persistent adverse events (AEs) which negatively impact on quality of life (QoL) and have the potential to cause significant morbidity and mortality. In clinical practice, TKI dose reduction is usually considered to reduce AEs and improve QoL, but dose optimization could have also another aim, i.e., the achievement and maintenance of cytogenetic and molecular responses. While therapy cessation appeared as a safe option for about half of the patients achieving an optimal response, no systematic assessment of long-term TKI dose de-escalation has been made. The present review is focused on the most recent evidences for TKIs dose modifications in CML clinical studies and in the real-life setting. It will consider TKI dose modifications in newly diagnosed patients, dose reduction for AEs, or in deep molecular response, either as a prelude to treatment-free remission (TFR) or as continuous maintenance therapy in those patients not wishing to attempt TFR. In addition, it will focus on patients not achieving a molecular response deep enough to go to TFR, and for whom dose reduction could be an option to avoid AEs. Full article

(This article belongs to the Special Issue Prognosis and Therapy of Chronic Myeloid Leukemia)

16 pages, 1373 KiB

Open AccessReview

Molecular Testing in CML between Old and New Methods: Are We at a Turning Point?

by Simona Soverini, Simona Bernardi and Sara Galimberti

J. Clin. Med. 2020, 9(12), 3865; https://doi.org/10.3390/jcm9123865 - 27 Nov 2020

Cited by 24 | Viewed by 4584

Abstract

Molecular monitoring of minimal residual disease (MRD) and BCR-ABL1 kinase domain (KD) mutation testing have a well consolidated role in the routine management of chronic myeloid leukemia (CML) patients, as they provide precious information for therapeutic decision-making. Molecular response levels are used to define whether a patient has an “optimal”, “warning”, or “failure” response to tyrosine kinase inhibitor (TKI) therapy. Mutation status may be useful to decide whether TKI therapy should be changed and which alternative TKI (or TKIs) are most likely to be effective. Real-time quantitative polymerase chain reaction (RQ-qPCR) and Sanger sequencing are currently the gold standard for molecular response monitoring and mutation testing, respectively. However, in recent years, novel technologies such as digital PCR (dPCR) and next-generation sequencing (NGS) have been evaluated. Here, we critically describe the main features of these old and novel technologies, provide an overview of the recently published studies assessing the potential clinical value of dPCR and NGS, and discuss how the state of the art might evolve in the next years. Full article

(This article belongs to the Special Issue Prognosis and Therapy of Chronic Myeloid Leukemia)

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15 pages, 883 KiB

Open AccessReview

The New ELN Recommendations for Treating CML

by Rüdiger Hehlmann

J. Clin. Med. 2020, 9(11), 3671; https://doi.org/10.3390/jcm9113671 - 16 Nov 2020

Cited by 25 | Viewed by 6387

Abstract

After normal survival has been achieved in most patients with chronic myeloid leukemia (CML), a new goal for treating CML is survival at good quality of life, with treatment discontinuation in sustained deep molecular response (DMR; MR⁴ or deeper) and treatment-free remission (TFR). Four tyrosine kinase inhibitors (TKIs) have been approved for first-line therapy: imatinib, dasatinib, nilotinib, bosutinib. Unexpectedly, the outcome of long-term randomized trials has shown that faster response as achieved by higher doses of imatinib, imatinib in combination, or second-generation (2G)-TKIs, does not translate into a survival advantage. Serious and frequent, and in part cumulative long-term toxicities, have led to a reevaluation of the role of 2G-TKIs in first-line therapy. Generic imatinib is the current most cost-effective first-line therapy in the chronic phase. A change of treatment is recommended when intolerance cannot be ameliorated or molecular milestones are not reached. Patient comorbidities and contraindications of all TKIs must be considered. Risk profile at diagnosis should be assessed with the EUTOS score for long-term survival (ELTS). Monitoring of response is by polymerase chain reaction (PCR). Cytogenetics is still required in the case of atypical translocations, atypical transcripts, and additional chromosomal aberrations. TKIs are contraindicated during pregnancy. Since the majority of patients are at risk of lifelong exposure to TKIs, amelioration of chronic low-grade side effects is important. Full article

(This article belongs to the Special Issue Prognosis and Therapy of Chronic Myeloid Leukemia)

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14 pages, 2639 KiB

Open AccessReview

Current Treatment Options for Chronic Myeloid Leukemia Patients Failing Second-Generation Tyrosine Kinase Inhibitors

by Valentín García-Gutiérrez and Juan Carlos Carlos Hernández-Boluda

J. Clin. Med. 2020, 9(7), 2251; https://doi.org/10.3390/jcm9072251 - 15 Jul 2020

Cited by 11 | Viewed by 4640

Abstract

Despite the excellent overall survival (OS) of patients with chronic myeloid leukemia (CML), a significant proportion will not achieve optimal response to imatinib or second-generation tyrosine kinase inhibitors (2GTKI). For patients with inadequate response to 2GTKIs, alternative 2GTKIs or ponatinib are widely available treatment options in daily clinical practice. Treatment decisions should be guided by correct identification of the cause of treatment failure and accurate distinction between resistant from intolerant or nonadherence patients. This review aims to provide practical advice on how to select the best treatment option in each clinical scenario. Full article

(This article belongs to the Special Issue Prognosis and Therapy of Chronic Myeloid Leukemia)

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