Oxidative Stress and Chronic Myeloid Leukemia: A Balance between ROS-Mediated Pro- and Anti-Apoptotic Effects of Tyrosine Kinase Inhibitors.

The balanced reciprocal translocation t (9; 22) (q34; q11) and the BCR-ABL fusion gene, which produce p210 bcr-abl protein production with high tyrosine kinase activity, are characteristics of chronic myeloid leukemia, a myeloproliferative neoplasm. This aberrant protein affects several signaling pathways connected to both apoptosis and cell proliferation. It has been demonstrated that tyrosine kinase inhibitor treatment in chronic myeloid leukemia acts by inducing oxidative stress and, depending on its level, can activate signaling pathways responsible for either apoptosis or survival in leukemic cells.

The Italian Multicentric Randomized OPTkIMA Trial on Fixed vs Progressive Intermittent TKI Therapy in CML Elderly Patients: 3-Years of Molecular Response and Quality of Life Monitoring After Completing the Treatment Plan.

Background: Intermittent treatment with tyrosine kinase inhibitors (TKIs) is an option for elderly chronic myeloid leukemia (CML) patients who are often candidates for life-long treatment.

Materials And Methods: The Italian phase III multicentric randomized Optimize TKIs Multiple Approaches (OPTkIMA) study aimed to evaluate if a progressive de-escalation of TKIs is able to maintain the molecular remission (MR) and to improve Health-Related Quality of Life (HRQoL) in CML elderly patients.

Results: A total of 215 patients in stable MR/MR were randomized to receive an intermittent TKI schedule 1 month ON-1 month OFF for 3 years (FIXED arm; n = 111) vs.

Determinants of frontline tyrosine kinase inhibitor choice for patients with chronic-phase chronic myeloid leukemia: A study from the Registro Italiano LMC and Campus CML.

Background: Imatinib, dasatinib, and nilotinib are tyrosine kinase inhibitors (TKIs) approved in Italy for frontline treatment of chronic-phase chronic myeloid leukemia (CP-CML). The choice of TKI is based on a combined evaluation of the patient's and the disease characteristics. The aim of this study was to analyze the use of frontline TKI therapy in an unselected cohort of Italian patients with CP-CML to correlate the choice with the patient's features.

Treatment-Free Remission in Chronic Myeloid Leukemia Patients Treated With Low-Dose TKIs: A Feasible Option Also in the Real-Life. A Campus CML Study.

Treatment-free remission (TFR) has become a primary therapeutic goal in CML and is also considered feasible by international guidelines. TKIs dose reduction is often used in real-life practice to reduce adverse events, although its impact on TFR is still a matter of debate. This study aimed to explore the attitude of Italian hematologists towards prescribing TKIs at reduced doses and its impact on TFR.

COVID-19 infection in chronic myeloid leukaemia after one year of the pandemic in Italy. A Campus CML report.

Limited information is available on the impact of the COVID-19 pandemic on the management of chronic myeloid leukaemia (CML). The Campus CML network collected retrospective information on 8 665 CML patients followed at 46 centres throughout Italy during the pandemic between February 2020 and January 2021. Within this cohort, we recorded 217 SARS-CoV-2-positive patients (2·5%).

Targeting Chronic Myeloid Leukemia Stem/Progenitor Cells Using Venetoclax-Loaded Immunoliposome.

CML is a hematopoietic stem-cell disorder emanating from breakpoint cluster region/Abelson murine leukemia 1 (BCR/ABL) translocation. Introduction of different TKIs revolutionized treatment outcome in CML patients, but CML LSCs seem insensitive to TKIs and are detectable in newly diagnosed and resistant CML patients and in patients who discontinued therapy. It has been reported that CML LSCs aberrantly express some CD markers such as CD26 that can be used for the diagnosis and for targeting.

Molecular response and quality of life in chronic myeloid leukemia patients treated with intermittent TKIs: First interim analysis of OPTkIMA study.

Background: Intermittent treatment with TKIs is an option for the great majority (70%-80%) of CML patients who do not achieve a stable deep molecular response and are not eligible for treatment discontinuation. For these patients, the only alternative is to assume TKI continuously, lifelong.

Methods: The Italian phase III multicentric randomized OPTkIMA study started in 2015, with the aim to evaluate if a progressive de-escalation of TKIs (imatinib, nilotinib, and dasatinib) is able to maintain the molecular response (MR ) and to improve Health Related Quality of Life (HRQoL).

Next-generation sequencing improves BCR-ABL1 mutation detection in Philadelphia chromosome-positive acute lymphoblastic leukaemia.

BCR-ABL1 kinase domain mutation testing in tyrosine kinase inhibitor (TKI)-resistant Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukaemia (ALL) patients is routinely performed by Sanger sequencing (SS). Recently, next-generation sequencing (NGS)-based approaches have been developed that afford greater sensitivity and straightforward discrimination between compound and polyclonal mutations. We performed a study to compare the results of SS and NGS in a consecutive cohort of 171 Ph+ ALL patients.

Successful Management of a Pregnant Patient With Chronic Myeloid Leukemia Receiving Standard Dose Imatinib.

Background/aim: As approximately 10% of individuals developing chronic myeloid leukemia (CML) are females aged 20-44 years, a considerable number will consider a planned pregnancy if disease is well controlled by pharmacological treatment. The management of these young patients during pregnancy represents a therapeutic dilemma due to the potential teratogen effects of several tyrosine kinase inhibitors (TKIs) and is a matter of continuous debate. Indeed, despite the existence of several studies, there is currently no consensus on how to manage different pregnancy situations in subjects with CML.

Outcome of very elderly chronic myeloid leukaemia patients treated with imatinib frontline.

Very elderly (> 75 years) chronic myeloid leukaemia (CML) patients at diagnosis are sometimes treated with different doses of imatinib (IM) based on concomitant diseases and physicians' judgement. However, data on long-term follow-up of these patients are still lacking. To investigate treatment response and outcome, we retrospectively revised an Italian database of 263 very elderly CML patients receiving IM from the time of diagnosis.

Clinical Implications of Discordant Early Molecular Responses in CML Patients Treated with Imatinib.

A reduction in transcript levels to <10% after 3 months or <1% after 6 months of tyrosine kinase inhibitor therapy are associated with superior clinical outcomes in chronic myeloid leukemia (CML) patients. In this study, we investigated the reliability of multiple thresholds in predicting treatment outcomes for 184 subjects diagnosed with CML and treated with standard-dose imatinib mesylate (IM). With a median follow-up of 61 months, patients with concordant transcripts below the defined thresholds (10% at 3 months and 1% at 6 months) displayed significantly superior rates of event-free survival (86.

Flow Cytometry Assessment of CD26 Leukemic Stem Cells in Peripheral Blood: A Simple and Rapid New Diagnostic Tool for Chronic Myeloid Leukemia.

Background: Recent investigations in chronic myeloid leukemia (CML) have focused on the identification and characterization of leukemic stem cells (LSCs). These cells reside within the CD34 /CD38 /Lin fraction and score positive for CD26 (dipeptidylpeptidase IV) a marker, expressed in both bone marrow (BM) and peripheral blood (PB) samples, that discriminates CML cells from normal hematopoietic stem cells (HSCs) or from LSCs of other myeloid neoplasms. CD26 evaluation could be a useful tool to improve the identification of CML LCSs by using flow-cytometry assay.

Anticancer Activity of Curcumin and Its Analogues: Preclinical and Clinical Studies.

Curcumin has been shown to have a wide variety of therapeutic effects, ranging from anti-inflammatory, chemopreventive, anti-proliferative, and anti-metastatic. This review provides an overview of the recent research conducted to overcome the problems with the bioavailability of curcumin, and of the preclinical and clinical studies that have reported success in combinatorial strategies coupling curcumin with other treatments. Research on the signaling pathways that curcumin treatment targets shows that it potently acts on major intracellular components involved in key processes such as genomic modulations, cell invasion and cell death pathways.

Imatinib and polypharmacy in very old patients with chronic myeloid leukemia: effects on response rate, toxicity and outcome.

Background: About 40% of all patients with chronic myeloid leukemia are currently old or very old. They are effectively treated with imatinib, even though underrepresented in clinical studies. Furthermore, as it happens in the general population, they often receive multiple drugs for associated chronic illnesses.

Possible Role of Interleukin-31/33 Axis in Imatinib Mesylate-Associated Skin Toxicity.

Imatinib mesylate is a small-molecule tyrosine kinase inhibitor (TKi) designed to target c-ABL and BCR-ABL, approved for the treatment of chronic myeloid leukemia and gastrointestinal stromal tumors. Adverse cutaneous reactions induced by imatinib are frequent, generally moderate, and dose-dependent. The aim of this work was to investigate the possible contribution of interleukin (IL)-33 and IL-31, cytokines involved in disorders associated with itching, in the pathogenesis of pruritus in a patient undergoing imatinib mesylate treatment.

Vaccination of multiple myeloma: Current strategies and future prospects.

Tumor immunotherapy holds great promise in controlling multiple myeloma (MM) and may provide an alternative treatment modality to conventional chemotherapy for MM patients. For this reason, a major area of investigation is the development of cancer vaccines to generate myeloma-specific immunity. Several antigens that are able to induce specific T-cell responses are involved in different critical mechanisms for cell differentiation, inhibition of apoptosis, demethylation and proliferation.

Age influences initial dose and compliance to imatinib in chronic myeloid leukemia elderly patients but concomitant comorbidities appear to influence overall and event-free survival.

We applied Charlson comorbidity index (CCI) stratification on a large cohort of chronic myeloid leukemia (CML) very elderly patients (>75 years) treated with imatinib, in order to observe the impact of concomitant diseases on both compliance and outcome. One hundred and eighty-one patients were recruited by 21 Italian centers. There were 95 males and 86 females, median age 78.

Effect of therapeutic plasma exchange on plasma levels of oxidative biomarkers in a patient with thrombotic thrombocytopenic purpura.

Background: The role of oxidative stress in the initiation and progression of endothelial damage in thrombotic thrombocytopenic purpura (TTP) syndrome has been the subject of much speculation in the recent past.

Objectives: The aim of this study was to measure the concentration of plasma advanced oxidation protein products (AOPPs), advanced glycation end products (AGEs), and carbonyl groups (CG) as markers of oxidative stress in plasma of a patient with TTP during the course of the disease until recovery and to evaluate the effect of plasmapheresis (PE) on these biomarkers.

Materials And Methods: The study consisted of plasma analysis of the patient, and 23 healthy subjects served as controls.

MiRNome expression is deregulated in the peripheral lymphoid compartment of multiple myeloma.

MicroRNAs (miRNAs) are short non-coding RNAs involved in the regulation of gene expression. Selected groups of miRNAs are differentially expressed in various types of cancers. Alterations in miRNAs gene expression have been shown in cells from the B-cell malignancy, multiple myeloma (MM).

New orally active proteasome inhibitors in multiple myeloma.

Bortezomib is the first proteasome inhibitor approved for the therapy of multiple myeloma (MM). Although Bortezomib has renovated the treatment of MM, a considerable proportion of subjects fail to respond to Bortezomib treatment and almost all patients relapse from this drug either alone or when used in combination therapies. However, the good clinical outcome of Bortezomib treatment in MM patients gave impulsion for the development of second generation proteasome inhibitors with the ambition of improving efficacy of proteasome inhibition, enhancing antitumor activity, and decreasing toxicity, as well as providing flexible dosing schedules and patient convenience.

Long term outcome of Ph+ CML patients achieving complete cytogenetic remission with interferon based therapy moving from interferon to imatinib era.

Interferon α (IFNα) prolongs survival of CML patients achieving CCyR and potentially synergizes with TKIs. We report on the molecular status and long term outcome of 121 patients who were treated in Italy between 1986 and 2000 with IFNα based therapy and who obtained CCyR. After a median follow up of 16.