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54 active trials for Chronic Myeloid Leukemia

Effect of Pharmacogenetics on Imatinib Plasma Level and Response

Imatinib, the tyrosine kinase inhibitor, is used for treatment of Philadelphia positive chronic myeloid leukemia. Despite its efficacy and favorable pharmacokinetic profile, there is a large inter-individual variability in imatinib plasma concentrations, which may lead to treatment failure and disease progression. Polymorphisms in genes related to absorption, distribution, metabolism and excretion of imatinib may affect the bioavailability and consequently the response to the drug. The study aims to investigate the possible effect of genetic polymorphisms in certain metabolizing enzymes [CYP3A5*3 (rs776746), CYP2C8*3 (rs11572080 and rs10509681)] and membrane transporters [ABCB1 2677G>T/A (rs2032582) and SLC22A1 1222A > G (rs628031)] by PCR on the plasma level (by HPLC-UV) and molecular response (MMR) of imatinib in patients with CML. The study also aims to provide CML patients with a personalized treatment option, thereby probably improving the response and reducing the side effects.

Start: October 2017

TyrosIne Kinase Inhibitors in Chronic Myeloid Leukemia: Efficacy and Tolerability. The TIKlet Study

Rationale The pharmacokinetics of imatinib and nilotinib, two BCR/Abl tyrosine-kinase inhibitors (TKI), is variable among patients suffering from chronic myeloid leukemia (CML). Transmembrane transporters may play a pivotal role in interindividual variability in TKI disposition. Furthermore, minimum plasma concentrations (Cmin) higher than 1 mg/L could be associated with a higher likelihood of molecular and cytogenetic responses. The TIKlet study is aimed at evaluating correlations among the pharmacogenetics, pharmacokinetics and treatment efficacy/tolerability of imatinib and nilotinib in CML patients. 1. PATIENTS AND METHODS 1.1. Patients Patients affected by CML will be enrolled after the informed consent will be signed, according to the following inclusion criteria: patients of both sexes, age between 18 and 80 years, treated with imatinib or nilotinib, included in follow-up activities at the participating Hematology Divisions, able to give informed consent, with a proved compliance with the scheduled treatment. The administration of other drugs will be allowed, being known the dose and duration of treatment, as well as smoking and herbal products. Alterations in organ functions or physicochemical exams, body mass index >28 do not represent exclusion criteria. 1.2. Enrollment and follow-up visits During enrollment visit: patients will be informed about the study, their signed informed consent form will be collected and an individual alphanumeric code will be assigned. Patients' data will be recorded within the individual case report form (CRF) and a blood sample will be obtained. At follow-up visits, a blood sample will be collected for therapeutic drug monitoring (TDM) and patients' CRF will be updated. 1.3. Blood samples After centrifugation, the resulting plasma will be collected for TDM. During the enrollment visit, an aliquot of whole blood will be collected for molecular analyses. 1.4 Laboratory analyses TDM will be performed by high-performance liquid chromatography systems, then results will be evaluated by a population pharmacokinetic analysis. Single nucleotide polymorphisms will be investigated in the following genes: ABCB1, ABCG2, hOCT1, OCTN1, OATP1A2. Finally, response to drugs, in terms of Major Molecular Response (MMR) and Complete Cytogenetic Response (CCyR), and tolerability will be evaluated. Any possible correlation among drug disposition, pharmacogenetics and treatment effects will be analyzed.

Start: May 2013

2nd or 3rd TKI-stop After 2 Years Nilotinib Pre-treatment in Patients With First or Second Unsuccessful Treatment Discontinuation in CML

The main goal of the study is the assessment of duration of major molecular response (MMR) or better at 12 and 36 months after stopping tyrosine kinase inhibitors (TKI) therapy a second or third time in patients with at least three years prior TKI treatment comprising at least two years of nilotinib treatment within this trial and maintained stable MR4 (BCR-ABL ratio <0,01% on international Scale (IS) for at least one year and MR4.5 (BCR-ABL ratio <0,0032% on IS) for at least 6 months: who failed a first stop in the EURO-SKI study (standardized criteria) who failed a first or second stop outside the EURO-SKI study but would have had fulfilled same eligible criteria and were stopped according to EURO-SKI rules who failed a first or second stop outside the EURO-SKI study without fulfilling EURO-SKI rules

Start: September 2016

European Stop Tyrosine Kinase Inhibitor Study

The EURO-SKI is a multicenter open label, uncontrolled trial estimating the persistence of molecular remission in Chronic Myeloid Leukemia (CML) patients after stopping Tyrosine Kinase Inhibitor (TKI). Main goal is the assessment of the duration of major molecular response (MMR) or better after stopping TKI therapy. Secondary goals include: Identification of clinical and biological factors affecting the persistence of complete molecular remission after stopping TKI (e.g. level of Complete molecular remission (CMR), risk score, duration of TKI treatment, type of TKI pretreatment) Evaluation of quality of life (QoL) in patients stopping TKI Evaluation of medico-economic impact of stopping TKI Estimating the number of patients in CMR who are eligible for stopping TKI therapy by setting up a screening log Time to recovery of CMR There will be no randomised comparison. Based on the experience of the STIM trial (Mahon et al., Lancet Onc 2010) we expect an overall six-month molecular-relapse-free survival probability of at least 40%. An interim analysis will be performed after a pilot phase where 200 patients have been observed for at least six months. Formally, it is planned to test the null hypothesis H0: Six-month molecular relapse-free survival probability P ≤ 40% against the alternative hypothesis H1: Six-month molecular-relapse-free survival probability P > 40%. Eligible are adult CML patients in chronic phase on TKI treatment in CMR for at least one year (> 4 log reduction of BCR-ABL transcripts on IS, TKI treatment for at least 3 years, confirmed by a PCR within a standardized CMR laboratory). Clinical and biological monitoring will be performed during 3 years: Associated scientific projects are performed. Recruitment period: 2 years; follow up: 3 years. Planned patient recruitment in main phase: n=500

Start: May 2012

Targeting Leukemic Stem Cell Expressing the IL-1RAP Protein in Chronic Myelogenous Leukemia (CML)

The tyrosine kinase inhibitor therapy (iTKs) is the first-line treatment of chronic myelogenous leukemia (CML). Its effectiveness in controlling the progression of the disease is such that it is possible today to consider stopping treatment in patients with deep molecular response (> RM4.0). Only in about 50% of cases, patients relapse. It has been shown in these patients that hematopoietic stem cells (HSCs) are persistant, quiescent and insensitive to iTKs. These cells are probably at the origin of relapse. It is therefore necessary to develop complementary therapies to cure the disease and consider discontinuation iTKs The development of anti-tumor immunotherapy approach using genetically modified T cells to express a chimeric antigen receptor (CAR) and specifically targeting CML CSH + could address this issue. The membrane expression of the IL-1-RAP protein could be an interesting target.

Start: October 2015

A Study of Dasatinib Management Among CP-CML (Chronic Phase, Chronic Myeloid Leukemia) Participants Initiating Dasatinib in a Real Life Setting

This is a prospective, non-interventional study conducted in CP-CML patients receiving dasatinib who are enrolled by a sample of hematologists in France.

Start: April 2016

Treatment-free Remission Accomplished With Dasatinib in Patients With CML

The purpose of this study is to find out how to increase the potential for achieving an "operational cure" from chronic myeloid leukemia. An "operational cure" is a state in which a person does not require further treatment, although there may be some remaining cancer cells. Patients would normally remain on a TK inhibitor indefinitely within a standard of care setting for chronic myeloid leukemia. Within this clinical trial, patients will discontinue their TK inhibitor prematurely. If any signs of progression are identified, dasatinib will be introduced. This research is being done because dasatinib has been shown to achieve a greater response in a much higher proportion of patients as compared to imatinib. Dasatinib is approximately 300 times more potent than imatinib, and it is possible that a greater response can be achieved by dasatinib than by imatinib.

Start: October 2014

Muscle Dysfunction in Patients With Hematological Diseases Referred to Stem Cell Transplant

PURPOSE: To investigate the effect of the disease and HSCT on muscle dysfunction and to investigate the prognostic role of muscle dysfunction at critical decision points in patients with hematological diseases referred to hematopoietic stem cell transplant (HSCT). HSCT: Patients diagnosed with malignant hematological diseases who are referred to myeloablative HSCT, to a myeloablative "reduced toxicity conditioning" regime with Fludarabine and Treosulfane (FluTreo) or to non-myeloablative HSCT.

Start: January 2020

Leukemic Stem Cell Detection for Chronic Myeloid Leukemia Patients With Major Molecular Response

Multi-Center, national, non-drug, prospective cohort study Target patient number is 100 The amount of CD45+/CD34+/CD38-/CD26+ levels of chronic myeloid leukemia (CML) stem cells in CML patients with and without BCR-ABL hematopoiesis will be compared. There will be 2 arms; Patients with BCR-ABL-positive hematopoiesis CML patients with BCR-ABL activity inhibition under tyrosine kinase inhibitor (TKI) therapy

Start: August 2019

Consolidation Treatment With Ponatinib 15 mg on Treatment Free-Remission Rate in Patients With Chronic Myeloid Leukemia

Ponatinib has shown to induce deeper molecular responses compared with imatinib. Therefore, ponatinib treatment could increase the proportion of patients who could discontinue treatment successfully. This strategy that includes treatment change to a more powerful treatment before treatment discontinuation has not been evaluated in any of the previous clinical trials, and will be explored in the current study. In this framework, the purpose is to determine the rate of successful treatment-free remission (TFR) within the first 48 weeks following cessation of treatment in patients who achieved Molecular Response 4 (MR4) on imatinib and maintained MR4 on ponatinib after a switch from imatinib. Eligible patients have been previously treated with imatinib as unique tyrosine kinase inhibitor (at least 4 years) and have documented MR4 (at least 12 months) at the time of switch to ponatinib to study entry.

Start: April 2019

Safety and Feasibility of the Use of Natural Killer Cells in Patients With Chronic Myeloid Leukemia

The purpose of this study is to evaluate safety, feasibility and maximum tolerated dose of NK cells cultured in vitro as adjuvant treatment of patients with chronic myeloid leukemia candidates to allogenic bone marrow transplantation or refractory to conventional treatment.

Start: March 2019

The Hong Kong CML Registry

Chronic myeloid leukaemia (CML) is a malignant disorder of the haematopoietic system. It is characterized by the chromosomal translocation between chromosomes 9 and 22, resulting in the formation of the Philadelphia chromosome which contains the BCRABL1 fusion gene. The projected prevalence of CML is rising steadily, due to the significantly improved survival of CML patients and that the incidence rate increases with age. The efficacious yet costly tyrosine kinase inhibitors pose a significant financial burden to both patients and the health care system, while they carry their own side effects and long-term risks. This study aims to set up a local disease registry of CML to improve the knowledge concerning this disease, including epidemiology,characteristics and treatment outcome of CML in Hong Kong,as well as long-term safety and toxicities of therapeutic agents.

Start: April 2018

Regional Central Database Recording of Chronic Myeloid Leukemia

It will be a centralized database , multicentre (6 centers) , regional, chronic myelogenous leukemia cases of registration (CML) prospectively and retrospectively.

Start: January 2014

Vitro Study of Tigecycline to Treat Chronic Myeloid Leukemia

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm companies with the BCR-ABL fusion gene encoded by the Philadelphia (Ph) chromosome. The BCR-ABL fusion protein(the formation of the chimeric gene BCR/ABL on chromosome 22 and a reciprocal ABL/BCR on chromosome 9,it has no expanded name) plays key role on CML leukemogenesis by activating its downstream signaling pathway of survival and proliferation. Imatinib, a targeted competitive inhibitor of a BCR-ABL tyrosine kinase, changed the clinical treatment and prognosis of CML. As its optimized generation, other tyrosine kinase inhibitors (TKIs), dasatinib and nilotinib have more potent anti-leukemic activity and less side-effect. However, acquired resistance to TKIs is one of the main obstacles to effective CML treatment and is involved in gene amplication of ABL tyrosine kinase point mutations. The outcomes of patients with these ABL tyrosine kinase point mutations have linked to worse prognosis and higher mortality generally. Metabolic adaptations are common in cancer cells, and cancer cells become more dependent on mitochondrial biogenesis. Tigecycline, as a broad-spectrum antibiotics, inhibits mitochondrial biogenesis as its an interesting "side-effect".In recent study,researchers indicated that tigecycline can eradicate cancer stem cells by targeting mitochondrial.Here, the investigators test tigecycline's anti-leukemic activity to chronic myeloid leukemia in vitro.

Start: September 2016