scholarly journals Chronic Myeloid Leukemia Prognosis and Therapy: Criticisms and Perspectives

2020 ◽  
Vol 9 (6) ◽  
pp. 1709
Author(s):  
Domenico Russo ◽  
José Valentín Garcia-Gutierrez ◽  
Simona Soverini ◽  
Michele Baccarani
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Chronic Phase ◽  
Current Therapy ◽  
Term Therapy ◽  
Myeloproliferative Disease ◽  
Hematopoietic Stem ◽  
Significant Prolongation ◽  
Number Of Patients

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.

scholarly journals The chronic myeloid leukemia stem cell: stemming the tide of persistence

Blood ◽  
2017 ◽  
Vol 129 (12) ◽  
pp. 1595-1606 ◽  
Author(s):  
Tessa L. Holyoake ◽  
David Vetrie
Keyword(s):  
Stem Cell ◽  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Chronic Phase ◽  
Hemopoietic Stem Cell ◽  
Term Therapy ◽  
Myeloproliferative Disease ◽  
Cell Transforming

Abstract Chronic myeloid leukemia (CML) is caused by the acquisition of the tyrosine kinase BCR-ABL1 in a hemopoietic stem cell, transforming it into a leukemic stem cell (LSC) that self-renews, proliferates, and differentiates to give rise to a myeloproliferative disease. Although tyrosine kinase inhibitors (TKIs) that target the kinase activity of BCR-ABL1 have transformed CML from a once-fatal disease to a manageable one for the vast majority of patients, only ∼10% of those who present in chronic phase (CP) can discontinue TKI treatment and maintain a therapy-free remission. Strong evidence now shows that CML LSCs are resistant to the effects of TKIs and persist in all patients on long-term therapy, where they may promote acquired TKI resistance, drive relapse or disease progression, and inevitably represent a bottleneck to cure. Since their discovery in patients almost 2 decades ago, CML LSCs have become a well-recognized exemplar of the cancer stem cell and have been characterized extensively, with the aim of developing new curative therapeutic approaches based on LSC eradication. This review summarizes our current understanding of many of the pathways and mechanisms that promote the survival of the CP CML LSCs and how they can be a source of new gene coding mutations that impact in the clinic. We also review recent preclinical approaches that show promise to eradicate the LSC, and future challenges on the path to cure.

scholarly journals Allografting for Bosutinib, Imatinib, Nilotinib, Dasatinib, and Interferon Resistant Chronic Myeloid Leukemia without ABL Kinase Mutation

2011 ◽  
Vol 2011 ◽  
pp. 1-4
Author(s):  
B. Uz ◽  
O. Bektas ◽  
E. Eliacik ◽  
H. Goker ◽  
Y. Erbilgin ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Chronic Phase ◽  
Kinase Domain ◽  
Current Treatment ◽  
Hematopoietic Stem ◽  
Abl Kinase ◽  
Kinase Domain Mutation ◽  
Kinase Mutation

The current treatment of chronic phase chronic myeloid leukemia (CML) consists of oral tyrosine kinase inhibitors (TKIs). However, high-risk CML may present with an aggressive course which may result in blastic crisis or a “difficult-to-manage” state with available treatments. The aim of this paper is to report a patient with complicated CML resistant to treatment and progressed despite the administration of bosutinib, imatinib mesylate, nilotinib, dasatinib, interferon alpha 2a, cytotoxic chemotherapy, and allogeneic hematopoietic stem cell transplantation. The striking point of this case story is that no Abl kinase domain mutation against TKIs has been detected during this very complicated disease course of CML. Meanwhile, challenging cases will always be present despite the hope and progress in CML in the TKI era.

scholarly journals A Retrospective Analysis about Frequency of Monitoring in Italian Chronic Myeloid Leukemia Patients after Discontinuation

2020 ◽  
Vol 9 (11) ◽  
pp. 3692
Author(s):  
Matteo Dragani ◽  
Giovanna Rege Cambrin ◽  
Paola Berchialla ◽  
Irene Dogliotti ◽  
Gianantonio Rosti ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Chronic Phase ◽  
Molecular Response ◽  
Molecular Monitoring ◽  
Delay In Diagnosis ◽  
Number Of Patients

Successful discontinuation of tyrosine kinase inhibitors has been achieved in patients with chronic-phase chronic myeloid leukemia (CML). Careful molecular monitoring after discontinuation warrants safe and prompt resumption of therapy. We retrospectively evaluated how molecular monitoring has been conducted in Italy in a cohort of patients who discontinued tyrosine kinase inhibitor (TKI) treatment per clinical practice. The outcome of these patients has recently been reported—281 chronic-phase CML patients were included in this subanalysis. Median follow-up since discontinuation was 2 years. Overall, 2203 analyses were performed, 17.9% in the first three months and 38.4% in the first six months. Eighty-six patients lost major molecular response (MMR) in a mean time of 5.7 months—65 pts (75.6%) during the first six months. We evaluated the number of patients who would experience a delay in diagnosis of MMR loss if a three-month monitoring schedule was adopted. In the first 6 months, 19 pts (29.2%) would have a one-month delay, 26 (40%) a 2-month delay. Very few patients would experience a delay in the following months. A less intense frequency of monitoring, particularly after the first 6 months off treatment, would not have affected the success of treatment-free remission (TFR) nor put patients at risk of progression.

Treosulfan, Fludarabine, and Antithymocyte Globulin - A Low Toxicity Conditioning Regimen for Unrelated Donor - Hematopoietic Stem Cell Transplantation in Chronic Myeloid Leukemia.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2948-2948
Author(s):  
Jerzy Holowiecki ◽  
Sebastian Giebel ◽  
Jerzy Wojnar ◽  
Miroslaw Markiewicz ◽  
Aleksandra Holowiecka-Goral ◽  
...  
Keyword(s):  
Stem Cell ◽  
Chronic Myeloid Leukemia ◽  
Hematopoietic Stem Cell Transplantation ◽  
Myeloid Leukemia ◽  
Acute Gvhd ◽  
Kinase Inhibitors ◽  
Chronic Phase ◽  
Unrelated Donor ◽  
Hematopoietic Stem ◽  
Grade 3

Abstract Unrelated donor - hematopoietic stem cell transplantation (URD-HSCT) is the treatment of proved long-term efficacy for chronic myeloid leukemia (CML) patients not having an HLA-identical sibling. However, high procedure-related toxicity observed after oral busulfan- or TBI-based conditioning limits its applicability and deteriorates outcome [Radich, Blood2003, 102, 31–5]. This is of increasing importance in the presence of challanging options offered by tyrosine kinase inhibitors. Between 2003–2006 we introduced a new preparetive regimen consisting of Treosulfan (a soluble alkylyting agent) 14 g/m2/d on days -6, -5, -4, Fludarabine 30 mg/m2/d on days -6, -5, -4, -3, -2, and, anti-thymocyte globulin (ATG) at a total dose of 6 mg/kg. Thirty patients (age 32, range 16–48 years) with CML in the 1st chronic phase (n=29) or in 2nd chronic phase (n=1) were included in the study. Median interval from diagnosis to alloHSCT equaled 1.0 (0.5–12.0) years. 63% of patients had previously been treated with Imatinib. The donors were selected based on high resolution typing for both HLA class I and II. 43% of donors were mismatched for a single HLA-C (n=9), HLA-DQB1 (n=3) or HLA-B locus (n=1). Bone marrow was used a source of stem cells in 19 patients, peripheral blood - in 11 cases. GVHD prophylaxis consisted of Cyclosporin A and short-course Methotrexate. All patients engrafted with the median time to neutrophil recovery >0.5 G/L and PLT >50 G/L of 19 (10–30) days and 18 (12–29) days, respectively. Complete donor chimerism was achieved until day +100 in all but one patient. Grade 3–4 neutropenic infections occurred in 13% of patients. Grade 3–4 mucositis as well as hepatic toxicity including VOD were not observed. The incidence of grade II acute GVHD was 23%, whereas grade III-IV acute GVHD was not observed. The incidence of extensive chronic GVHD was 10%. At 3 years the probability of the overall survival and hematological relapse-free survival equaled 82% (+/−7%). The cumulative incidence of non-relapse moratlity was 18% (+/−7%) (fungal infection n=3, bacterial infection n=1, EBV-LPD n=1). Four patients required donor lymphocyte infusion or additional interferon or imatinib treatment because of incomplete donor chimerism or molecular/cytogenetic relapse after initial response. We conclude that treosulfan + fludarabine + ATG conditioning is associated with low organ toxicity, low incidence of severe GVHD and NRM. The regimen is feasible option for CML patients referred for URD-HSCT in tyrosine kinase inhibitors era.

Three decades of transplantation for chronic myeloid leukemia: what have we learned?

Blood ◽  
2011 ◽  
Vol 117 (3) ◽  
pp. 755-763 ◽  
Author(s):  
Jiří Pavlů ◽  
Richard M. Szydlo ◽  
John M. Goldman ◽  
Jane F. Apperley
Keyword(s):  
Stem Cell ◽  
Chronic Myeloid Leukemia ◽  
Stem Cell Transplantation ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Cell Transplantation ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Chronic Phase ◽  
Hematopoietic Stem

Abstract Last year marked 30 years of hematopoietic stem cell transplantation as a curative treatment of chronic myeloid leukemia (CML). Initially studies used stem cells from identical twins but techniques rapidly developed to use cells first from HLA-identical siblings and later unrelated donors. During the 1990s CML became the most frequent indication for allogeneic transplantation worldwide. This, together with the relative biologic homogeneity of CML in chronic phase, its responsiveness to graft-versus-leukemia effect and the ability to monitor low level residual disease placed CML at the forefront of research into different strategies of stem cell transplantation. The introduction of BCR-ABL1 tyrosine kinase inhibitors during the last decade resulted in long-term disease control in the majority of patients with CML. In those who fail to respond and/or develop intolerance to these agents, transplantation remains an effective therapeutic solution. The combination of tyrosine kinase inhibitors with transplantation is an exciting new strategy and it provides inspiration for similar approaches in other malignancies.

scholarly journals The HIGH BCR-ABL1 GENE PERCENTAGE AT TIME OF PRESENTATION: A TOOL TO PREDICT FAILURE IN ACHIEVING EARLY MOLECULAR RESPONSE IN CHRONIC MYELOID LEUKEMIA (CML): A TERTIARY CARE CENTER EXPERIENCE

2021 ◽  
Vol 71 (Suppl-1) ◽  
pp. S71-75
Author(s):  
Amjad Khan ◽  
Riaz Ahmed ◽  
Sarah Fatimah ◽  
Muhammad Nadeem ◽  
Shama Iqbal ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Chronic Phase ◽  
Imatinib Therapy ◽  
Military Hospital ◽  
Molecular Response ◽  
Number Of Patients

Objective: To determine the relationship of baseline quantitative BCR ABL1 gene percentage and therapeutic response i.e. Early Molecular Response (EMR) at 3 months with first generation Tyrosine kinase inhibitors (Imatinib) in patients with Chronic Myeloid Leukemia (CML) in chronic phase (CP). Study Design: Prospective observational study. Place and Duration of Study: Combined Military Hospital, Rawalpindi, Pakistan, and Armed Forces Institute of Pathology Rawalpindi, Pakistan from Oct 2017 to Oct 2019. Methodology: One hundred and seventy patients, 18 years of age or older with newly diagnosed Chronic Myeloid Leukemia (CML) in chronic phase (CP) with quantitative baseline BCR-ABL (IS) transcript were included in the study. All enrolled patients were placed on Imatinib therapy (400 mg/day) and Reverse transcription polymerase chain reaction (RT-PCR) for BCR ABL transcript was repeated at 3 months to document EMR (BCR-ABL (IS) <10%). Patients who were in accelerated/blast phase, or already taking any Tyrosine Kinase Inhibitors (TKI) or chemotherapy were excluded from the study. Results: In our study 101 (59.4%) patients achieved early molecular response. Out of these 80 (70.8%) patients with BCR-ABL<50% at baseline value showed early molecular response. However, only 21 (36.8%) with BCRABL >50% at baseline achieved early molecular response (p-value <0.001). Conclusion: A significant number of patients achieved early molecular response with Imatinib therapy that had BCR ABL below 50%, however those with baseline BCR ABL >50%, the rate of EMR was comparatively lower.

Current Therapies for Chronic Myeloid Leukemia

2008 ◽  
Vol 21 (2) ◽  
pp. 116-125
Author(s):  
Laureen K. Kenealy ◽  
Courtney B. Christenson ◽  
Casey B. Williams
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Management Strategies ◽  
Treatment Strategies ◽  
Chronic Phase ◽  
Initial Therapy ◽  
Molecular Monitoring ◽  
Hematopoietic Stem ◽  
Current Therapies

Management strategies for patients with chronic-phase chronic myeloid leukemia (CML) have changed dramatically since the introduction of imatinib into clinical trials in 1998. Imatinib is generally accepted, at present, to be the most appropriate initial therapy for newly diagnosed chronic-phase CML; however, a proportion of patients will not respond adequately. Many of these patients may benefit from alternative treatment strategies, including second- and third-generation BCR-ABL kinase inhibitors and allogeneic hematopoietic stem cell transplantation (HSCT). Additionally, with continued improvements in molecular monitoring, it is much more clinically routine to measure ongoing treatment efficacy or characterize pending disease relapse via molecular analysis. The challenge is to now combine molecular monitoring information with timely treatment decisions to achieve the best possible outcomes. Additionally, unanswered questions about HSCT remain, and include (1) What is the role of allogeneic HSCT in CML? (2) What type of transplant, reduced-intensity or myeloablative, should be performed? The goal of this article is to provide an overview of where we stand in the treatment of CML in 2008.

BMS-214662 potently induces apoptosis of chronic myeloid leukemia stem and progenitor cells and synergizes with tyrosine kinase inhibitors

Blood ◽  
2008 ◽  
Vol 111 (5) ◽  
pp. 2843-2853 ◽  
Author(s):  
Mhairi Copland ◽  
Francesca Pellicano ◽  
Linda Richmond ◽  
Elaine K. Allan ◽  
Ashley Hamilton ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Progenitor Cells ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Blast Crisis ◽  
Chronic Phase ◽  
Hematopoietic Stem

Chronic myeloid leukemia (CML), a hematopoietic stem-cell disorder, cannot be eradicated by conventional chemotherapy or the tyrosine kinase inhibitor imatinib mesylate (IM). To target CML stem/progenitor cells, we investigated BMS-214662, a cytotoxic farnesyltransferase inhibitor, previously reported to kill nonproliferating tumor cells. IM or dasatinib alone reversibly arrested proliferation of CML stem/progenitor cells without inducing apoptosis. In contrast, BMS-214662, alone or in combination with IM or dasatinib, potently induced apoptosis of both proliferating and quiescent CML stem/progenitor cells with less than 1% recovery of Philadelphia-positive long-term culture-initiating cells. Normal stem/progenitor cells were relatively spared by BMS-214662, suggesting selectivity for leukemic stem/progenitor cells. The ability to induce selective apoptosis of leukemic stem/progenitor cells was unique to BMS-214662 and not seen with a structurally similar agent BMS-225975. BMS-214662 was cytotoxic against CML blast crisis stem/progenitor cells, particularly in combination with a tyrosine kinase inhibitor and equally effective in cell lines harboring wild-type vs mutant BCR-ABL, including the T315I mutation. This is the first report of an agent with activity in resistant and blast crisis CML that selectively kills CML stem/progenitor cells through apoptosis and offers potential for eradication of chronic phase CML.

scholarly journals Current perspectives for the treatment of chronic myeloid leukemia

2019 ◽  
Author(s):  
ELİFCAN ALADAĞ KARAKULAK ◽  
İBRAHİM CELALETTİN HAZNEDAROĞLU
Keyword(s):  
Stem Cell ◽  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Hematopoietic Stem Cell ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Chronic Phase ◽  
Hematopoietic Stem

Background: With an annual incidence of 1-2 in a million, Ph*(+) chronic myeloid leukemia (CML) is a clonal hematopoietic stem cell disease that makes myeloid neoplastic cells breed out of control. This BCR-ABL (+) myeloproliferative disease makes up about 15-20% of all leukemia cases in adults. CML is seen more in males than females, with a rate of three to two. However, it does not show difference in prevalence in terms of age. CML consists of three clinical phases. The first one is the chronic phase, defined by rising white blood cell levels and also by myeloid proliferation and bone marrow maturation. While this phase does not exhibit complications, in diagnosis, it composes most of the patients. The second phase is the accelerated phase, which the disease progresses onto if it is not treated or does not respond to treatment. This time usually takes about three years. The third phase is the blastic phase. The chronic phase can still progress onto the next two phases within the first 2 years, with a rate of 10%. In the following years, the possibility increases by a 15-20% each year. Tyrosine kinase inhibitors (TKI) are the revolutionary drugs for the management of disease course in CML. Methods: The aim of this review is to assess current approaches to CML patient’s follow-up and treatment with TKI. The CML and TKI literature search was made in PubMed, Web of Science, Scopus with particular focus on the randomized clinical trials, recommendations, guidelines and expert opinions. Results: In managing CML, various treatment methods have been utilized for many decades. Prior to the development of tyrosine kinase inhibitors (TKI), interferon alpha was the primary tool, which was then complemented by allogeneic hematopoietic stem cell transplantation (HSCT). HSCT was actually successful in slowing the disease down in the long term and curing up to a 50% of the patients. Then the coming of imatinib era opened up different treatment perspectives. For the patients resistant or intolerant to the imatinib, second and third generation TKIs are successfully used in distinct CML disease states. Conclusion: The survival benefits of TKI including imatinib, nilotinib, dasatinib, bosutinib, and ponatinib for the CML patients are outstanding. TKI-related adverse events could impact on the clinical course especially in long-term drug administrations. Current aim for the CML disease management in TKI era is to provide age- and sex-matched normal life duration to the CML patients. Keywords: Chronic, myeloid, leukemia, tyrosine, kinase, inhibitors

scholarly journals Stem Cell Biomarkers in Chronic Myeloid Leukemia

2008 ◽  
Vol 24 (4-5) ◽  
pp. 201-216 ◽  
Author(s):  
Xiaoyan Jiang ◽  
Yun Zhao ◽  
Donna Forrest ◽  
Clayton Smith ◽  
Allen Eaves ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Myeloproliferative Disease ◽  
Cell Compartment ◽  
Hematopoietic Stem ◽  
Stem Cell Compartment ◽  
Treatment Responses

Chronic myeloid leukemia (CML) is a clonal multi-step myeloproliferative disease that is initially produced and ultimately sustained by a rare subpopulation of BCR-ABL+ cells with multi-lineage stem cell properties. These BCR-ABL+ CML stem cells are phenotypically similar to normal hematopoietic stem cells which are also maintained throughout the course of the disease at varying levels in different patients. Defining the unique properties of the leukemic stem cells that produce the chronic phase of CML has therefore had to rely heavily on access to samples from rare patients in which the stem cell compartment is dominated by leukemic elements. Here we review past and ongoing approaches using such samples to identify biologically and clinically relevant biomarkers of BCR-ABL+ stem cells that explain their unusual biology and that may help to design, or at least predict, improved treatment responses in CML patients. These studies are of particular interest in light of recent evidence that chronic phase CML stem cells are not only innately resistant to imatinib mesylate and other drugs that target the BCR-ABL oncoprotein, but are also genetically unstable.

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