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Chronic Myeloid Leukemia: Clinical Diagnosis and Treatment
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Chronic Myeloid Leukemia: Clinical Diagnosis and Treatment

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

Deadline for manuscript submissions: closed (25 May 2023) | Viewed by 9088

Special Issue Editors

Dr. Sílvia Marcé

E-Mail Website
Guest Editor
Myeloid Neoplasms Group, Hematology Department, ICO Badalona-Hospital Germans Trias i Pujol, Josep Carreras Leukaemia Research Institute (IJC), 08916 Badalona, Spain
Interests: TKI treatment; p210 transcripts; molecular response; DMR; discontinuation; TFR
Dr. Blanca Xicoy Cirici

E-Mail Website
Guest Editor
Myeloid Neoplasms Group, Hematology Department, ICO Badalona-Hospital Germans Trias i Pujol, Josep Carreras Leukaemia Research Institute (IJC), 08916 Badalona, Spain
Interests: TKI treatment; resistance; intolerance; progression; discontinuation; TFR

Special Issue Information

Dear Colleagues,

Following the development of tyrosine kinase inhibitors (TKI), the survival of patients with chronic myeloid leukemia (CML) drastically improved. Taking into consideration the side effects, toxicity, and high cost, discontinuing TKI became a goal for patients with chronic phase CML. In all, 40–60% of patients who achieved deep molecular response (DMR) and discontinued TKI remained in treatment-free remission (TFR), with relapses occurring mainly within the first six months. In this Special Issue, we welcome authors to submit papers on the possible prognostic factors of relapse after discontinuation, dPCR as a monitoring method, and strategies targeting leukemic stem cells through the inhibition of signal pathways or favoring immune responses, among others, to improve and better understand the TFR.

Dr. Silvia Marcé
Dr. Blanca Xicoy Cirici
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Journal of Clinical Medicine is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • TKI discontinuation
  • TFR prognostic factors
  • leukemic stem cell
  • TKI resistance
  • immune system

Published Papers (5 papers)

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Research

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15 pages, 1409 KiB  
Article
Association between Germline Single-Nucleotide Variants in ADME Genes and Major Molecular Response to Imatinib in Chronic Myeloid Leukemia Patients
by Natalia Estrada, Lurdes Zamora, Francisca Ferrer-Marín, Laura Palomo, Olga García, Patricia Vélez, Iris De la Fuente, Miguel Sagüés, Marta Cabezón, Montserrat Cortés, Rolando Omar Vallansot, María Alicia Senín-Magán, Concepción Boqué and Blanca Xicoy
J. Clin. Med. 2022, 11(20), 6217; https://doi.org/10.3390/jcm11206217 - 21 Oct 2022
Cited by 1 | Viewed by 1554
Abstract
Imatinib is the most common first-line tyrosine kinase inhibitor (TKI) used to treat chronic-phase chronic myeloid leukemia (CP-CML). However, only a proportion of patients achieve major molecular response (MMR), so there is a need to find biological factors that aid the selection of [...] Read more.
Imatinib is the most common first-line tyrosine kinase inhibitor (TKI) used to treat chronic-phase chronic myeloid leukemia (CP-CML). However, only a proportion of patients achieve major molecular response (MMR), so there is a need to find biological factors that aid the selection of the optimal therapeutic strategy (imatinib vs. more potent second-generation TKIs). The aim of this retrospective study was to understand the contribution of germline single-nucleotide variants (gSNVs) in the achievement of MMR with imatinib. In particular, a discovery cohort including 45 CP-CML patients was analyzed through the DMET array, which interrogates 1936 variants in 231 genes related to the absorption, distribution, metabolism and excretion (ADME) process. Variants statistically significant in the discovery cohort were then tested in an extended and independent cohort of 137 CP-CML patients. Finally, a total of 7 gSNVs (ABCG1-rs492338, ABCB11-rs496550, ABCB11-rs497692, CYP2D6-rs1135840, CYP11B1-rs7003319, MAT1A-rs4934027 and SLC22A1-rs628031) and one haplotype in the ABCB11 gene were significantly associated with the achievement of MMR with first-line imatinibtreatment. In conclusion, we identified a genetic signature of response to imatinib in CP-CML patients that could be useful in selecting those patients that may benefit from starting imatinib as first-line therapy, therefore avoiding the toxicity related to second-generation TKIs. Full article
(This article belongs to the Special Issue Chronic Myeloid Leukemia: Clinical Diagnosis and Treatment)
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11 pages, 2745 KiB  
Article
Immunomodulatory Effects of IFNα on T and NK Cells in Chronic Myeloid Leukemia Patients in Deep Molecular Response Preparing for Treatment Discontinuation
by Maria Cristina Puzzolo, Massimo Breccia, Paola Mariglia, Gioia Colafigli, Sara Pepe, Emilia Scalzulli, Elena Mariggiò, Roberto Latagliata, Anna Guarini and Robin Foà
J. Clin. Med. 2022, 11(19), 5594; https://doi.org/10.3390/jcm11195594 - 23 Sep 2022
Cited by 5 | Viewed by 1429
Abstract
A deep and stable molecular response (DMR) is a prerequisite for a successful treatment-free remission (TFR) in chronic myeloid leukemia (CML). In order to better identify and analyze potential candidates of successful TFR, we examined the phenotypic and functional host immune compartment in [...] Read more.
A deep and stable molecular response (DMR) is a prerequisite for a successful treatment-free remission (TFR) in chronic myeloid leukemia (CML). In order to better identify and analyze potential candidates of successful TFR, we examined the phenotypic and functional host immune compartment in DMR patients who had received TKI treatment only (TKI-only) or had been previously treated with interferon-alpha (IFNα + TKI) or had received IFNα treatment only (IFNα-only). The T/NK-cell subset distribution, NK- and T-cell cytokine production, activation and maturation markers were measured in 44 patients in DMR treated with IFNα only (9), with IFNα + TKI (11) and with TKI-only (24). IFNα + TKI and TKI-only groups were eligible to TKI discontinuation according to the NCCN and ESMO guidelines (stable MR4 for more than two years). In IFNα-treated patients, we documented an increased number of lymphocytes capable of producing IFNγ and TNFα compared to the TKI-only group. In INFα + TKI patients, the percentage of NKG2C expression and its mean fluorescence intensity were significantly higher compared to the TKI-only group and to the INFα-only group in the CD56dim/CD16+ NK cell subsets (INFα + TKI vs. TKI-only p = 0.041, p = 0.037; INFα + TKI vs. INFα-only p = 0.03, p = 0.033, respectively). Furthermore, in INFα-only treated patients, we observed an increase of NKp46 MFI in the CD56bright/CD16- NK cell subset that becomes significant compared to the INFα + TKI group (p = 0.008). Our data indicate that a previous exposure to IFNα substantially and persistently modified the immune system of CML patients in memory T lymphocytes, differentiated NKG2C+ “long-lived” NK cells responses, even years after the last IFNα contact. Full article
(This article belongs to the Special Issue Chronic Myeloid Leukemia: Clinical Diagnosis and Treatment)
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15 pages, 2016 KiB  
Article
Investigation of the Effect of Imatinib and Hydroxyurea Combination Therapy on Hematological Parameters and Gene Expression in Chronic Myeloid Leukemia (CML) Patients
by Esraa K. Al-Amleh, Ola M. Al-Sanabra, Khalid M. Alqaisi, Moath Alqaraleh, Jumana Al-Nahal, Lama Hamadneh, Mohammed Imad Malki and Jehad F. Alhmoud
J. Clin. Med. 2022, 11(17), 4954; https://doi.org/10.3390/jcm11174954 - 24 Aug 2022
Cited by 3 | Viewed by 2388
Abstract
(1) Background: Chronic myeloid leukemia is defined as the neoplastic development of mostly myeloid cells in the bone marrow. Several treatments, including chemotherapy, radiation, hormone treatment, and immunological therapy, can be used to control this condition. The therapeutic impact on leukemic individuals varies, [...] Read more.
(1) Background: Chronic myeloid leukemia is defined as the neoplastic development of mostly myeloid cells in the bone marrow. Several treatments, including chemotherapy, radiation, hormone treatment, and immunological therapy, can be used to control this condition. The therapeutic impact on leukemic individuals varies, and the response to therapy varies between patients due to disease heterogeneity. The primary goal of this study is to compare the effects of single and Imatinib (IM) and Hydroxyurea (HU) combined treatment on hematological parameters and gene expression in CML patients. (2) Methods: This study was conducted on 51 patients, with chronic myeloid leukemia, who were admitted to Al-Basher hospital in Amman, Jordan, for follow-up. Their hematological parameters were checked and gene expression was measured for (BCL2, PP2A, CIP2A, and WT1). (3) Results: The BCL2 gene was found to be less expressed in both IM and (HU + IM) treatments as compared to the HU group alone, while PP2A gene expression was raised. Such a thing indicates that the outcome of the combined therapy method is not ideal, since PP2A activation causes CML cells to move toward the blast crisis stage. Furthermore, CIP2A gene expression revealed that IM and (HU + IM) had the same therapeutic effect and were more successful in CML patients than HU alone. With regards to the treatment effect on hematological parameters, notably in CML patients in later stages, the combination therapy (HU + IM) raised lymphocyte count, indicating a greater response to the treatment. When compared to single medicines, the combination treatment reduced the proportion of neutrophils to normal reference ranges. Platelet counts, on the other hand, dramatically decreased in both IM and (HU + IM). (4) Conclusion: Because the studied genes (BCL2, PP2A, CIP2A, and WT1) are participating in cell proliferation and death, the findings show that the examined genes are significant to understand the efficacy of various therapies. Furthermore, it was found that there was a clear effect of the clinic-based strategic treatment on hematological indicators such as WBCs, lymphocytes, neutrophils, and platelet counts. Full article
(This article belongs to the Special Issue Chronic Myeloid Leukemia: Clinical Diagnosis and Treatment)
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12 pages, 1205 KiB  
Article
Real-World Analysis of the Therapeutic Management and Disease Burden in Chronic Myeloid Leukemia Patients with Later Lines in Italy
by Massimo Breccia, Francesca Chiodi, Aurelio Pio Nardozza, Diletta Valsecchi, Valentina Perrone, Diego Sangiorgi, Elisa Giacomini, Maria Chiara Rendace, Paola Coco, Eleonora Premoli and Luca Degli Esposti
J. Clin. Med. 2022, 11(13), 3597; https://doi.org/10.3390/jcm11133597 - 22 Jun 2022
Cited by 9 | Viewed by 1590
Abstract
Real world data are becoming a crucial tool to understand how cancer is treated in routine daily practice. This real-world analysis aims to describe the characteristics of patients with CML in 2nd or ≥3rd tyrosine kinase inhibitors (TKI) lines of therapy, to evaluate [...] Read more.
Real world data are becoming a crucial tool to understand how cancer is treated in routine daily practice. This real-world analysis aims to describe the characteristics of patients with CML in 2nd or ≥3rd tyrosine kinase inhibitors (TKI) lines of therapy, to evaluate their treatment sequence and utilization in settings of Italian clinical practice in Italy. A retrospective analysis was performed using an administrative databases covering around 15.3 million cases. All adult patients prescribed with TKI as 2nd or ≥3rd lines (L) of therapy for CML during January 2015–December 2018 were included. A total of 491 patients in 2nd and 144 in ≥3rd L was included. In both cohorts, hypertension was the most reported comorbidity, followed by metabolic and blood count alterations. In each calendar inclusion year, an increment of 97.6% was observed in the number of patients treated in ≥3rd L. In the 2nd L cohort, 18.7% had a switch to 3rd L, while 26.4% of ≥3rd L patients switched to a subsequent line. Around 40% in both lines discontinued their treatment after a median time of 5.5 (2nd L) and 4.3 (≥3rd L) years. The results provided insights into CML management clinical practice, indicating a heavy disease burden for patients in later lines that showed an increasing complex management, and suggest that a need for novel treatment strategies might exists. Full article
(This article belongs to the Special Issue Chronic Myeloid Leukemia: Clinical Diagnosis and Treatment)
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Review

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24 pages, 2258 KiB  
Review
Priapism at Diagnosis of Pediatric Chronic Myeloid Leukemia: Data Derived from a Large Cohort of Children and Teenagers and a Narrative Review on Priapism Management
by Meinolf Suttorp, Stephanie Sembill, Krzysztof Kalwak, Markus Metzler and Frederic Millot
J. Clin. Med. 2023, 12(14), 4776; https://doi.org/10.3390/jcm12144776 - 19 Jul 2023
Viewed by 1482
Abstract
Pediatric chronic myeloid leukemia (CML) is a very rare malignancy (age-related incidence 0.1/100,000) typically presenting with leucocyte counts >100,000/µL. However, clinical signs of leukostasis are observed at diagnosis in only approximately 10% of all cases and among these, priapism is infrequent. Here, we [...] Read more.
Pediatric chronic myeloid leukemia (CML) is a very rare malignancy (age-related incidence 0.1/100,000) typically presenting with leucocyte counts >100,000/µL. However, clinical signs of leukostasis are observed at diagnosis in only approximately 10% of all cases and among these, priapism is infrequent. Here, we analyze data from pediatric CML registries on the occurrence of priapism heralding diagnosis of CML in 16/491 (3.2%) boys (median age 13.5 years, range 4–18) with pediatric CML. In the cohort investigated, duration of priapism resulting in a diagnosis of CML was not reported in 5 patients, and in the remaining 11 patients, occurred as stuttering priapism over 3 months (n = 1), over 6 weeks (n = 1), over 1–2 weeks (n = 2), over several days (n = 2), or 24 h (n = 1), while the remaining 4 boys reported continuous erection lasting over 11–12 h. All patients exhibited splenomegaly and massive leukocytosis (median WBC 470,000/µL, range 236,700–899,000). Interventions to treat priapism were unknown in 5 patients, and in the remaining cohort, comprised intravenous fluids ± heparin (n = 2), penile puncture (n = 5) ± injection of sympathomimetics (n = 4) ± intracavernous shunt operation (n = 1) paralleled by leukocyte-reductive measures. Management without penile puncture by leukapheresis or exchange transfusion was performed in 3 boys. In total, 7 out 15 (47%) long-term survivors (median age 20 years, range 19–25) responded to a questionnaire. All had maintained full erectile function; however, 5/7 had presented with stuttering priapism while in the remaining 2 patients priapism had lasted <12 h until intervention. At its extreme, low-flow priapism lasting for longer than 24 h may result in partial or total impotence by erectile dysfunction. This physical disability can exert a large psychological impact on patients’ lives. In a narrative review fashion, we analyzed the literature on priapism in boys with CML which is by categorization stuttering or persisting as mostly painful, ischemic (low-flow) priapism. Details on the pathophysiology are discussed on the background of the different blood rheology of hyperleukocytosis in acute and chronic leukemias. In addition to the data collected, instructive case vignettes demonstrate the diagnostic and treatment approaches and the outcome of boys presenting with priapism. An algorithm for management of priapism in a stepwise fashion is presented. All approaches must be performed in parallel with cytoreductive treatment of leukostasis in CML which comprises leukapheresis and exchange transfusions ± cytotoxic chemotherapy. Full article
(This article belongs to the Special Issue Chronic Myeloid Leukemia: Clinical Diagnosis and Treatment)
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