scholarly journals Treatment-Free Remission in Chronic Myeloid Leukemia and New Approaches by Targeting Leukemia Stem Cells

2021 ◽  
Vol 11 ◽  
Author(s):  
Yilin Chen ◽  
Jing Zou ◽  
Fanjun Cheng ◽  
Weiming Li
Keyword(s):  
Stem Cells ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Monitoring Methods ◽  
Therapeutic Landscape ◽  
Key Factor ◽  
Treatment Free Remission ◽  
First And Second Generation ◽  
Tki Discontinuation

The therapeutic landscape for chronic myeloid leukemia (CML) has improved significantly with the approval of tyrosine kinase inhibitors (TKIs) for therapeutic use. Most patients with optimal responses to TKIs can have a normal life expectancy. Treatment-free remission (TFR) after discontinuing TKI has increasingly become a new goal for CML treatment. However, TKI only “control“ CML, and relapse after discontinuation has become a key factor hindering patient access to attempt TFR. In this study, we reviewed studies on TKI discontinuation, including both first and second-generation TKI. We also reviewed predictors of relapse, new monitoring methods, and strategies targeting leukemic stem cells.

scholarly journals DYRK2 controls a key regulatory network in chronic myeloid leukemia stem cells

2020 ◽  
Vol 52 (10) ◽  
pp. 1663-1672
Author(s):  
Chun Shik Park ◽  
H. Daniel Lacorazza
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Stem Cell Population ◽  
Leukemia Stem Cells ◽  
Treatment Free Remission

Abstract Chronic myeloid leukemia is a hematological cancer driven by the oncoprotein BCR-ABL1, and lifelong treatment with tyrosine kinase inhibitors extends patient survival to nearly the life expectancy of the general population. Despite advances in the development of more potent tyrosine kinase inhibitors to induce a durable deep molecular response, more than half of patients relapse upon treatment discontinuation. This clinical finding supports the paradigm that leukemia stem cells feed the neoplasm, resist tyrosine kinase inhibition, and reactivate upon drug withdrawal depending on the fitness of the patient’s immune surveillance. This concept lends support to the idea that treatment-free remission is not achieved solely with tyrosine kinase inhibitors and that new molecular targets independent of BCR-ABL1 signaling are needed in order to develop adjuvant therapy to more efficiently eradicate the leukemia stem cell population responsible for chemoresistance and relapse. Future efforts must focus on the identification of new targets to support the discovery of potent and safe small molecules able to specifically eradicate the leukemic stem cell population. In this review, we briefly discuss molecular maintenance in leukemia stem cells in chronic myeloid leukemia and provide a more in-depth discussion of the dual-specificity kinase DYRK2, which has been identified as a novel actionable checkpoint in a critical leukemic network. DYRK2 controls the activation of p53 and proteasomal degradation of c-MYC, leading to impaired survival and self-renewal of leukemia stem cells; thus, pharmacological activation of DYRK2 as an adjuvant to standard therapy has the potential to induce treatment-free remission.

scholarly journals Shedding Light on Targeting Chronic Myeloid Leukemia Stem Cells

2021 ◽  
Vol 10 (24) ◽  
pp. 5805
Author(s):  
Mohammad Houshmand ◽  
Alireza Kazemi ◽  
Ali Anjam Najmedini ◽  
Muhammad Shahzad Ali ◽  
Valentina Gaidano ◽  
...  
Keyword(s):  
Stem Cells ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Term Treatment ◽  
Leukemia Stem Cells ◽  
Hematopoietic Stem ◽  
Long Term Treatment ◽  
Treatment Free Remission

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.

scholarly journals Combination Therapies in Chronic Myeloid Leukemia for Potential Treatment-Free Remission: Focus on Leukemia Stem Cells and Immune Modulation

2021 ◽  
Vol 11 ◽  
Author(s):  
Hui Mu ◽  
Xiaojian Zhu ◽  
Hui Jia ◽  
Lu Zhou ◽  
Hong Liu
Keyword(s):  
Stem Cells ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Immune Modulation ◽  
Kinase Inhibitors ◽  
Treatment Strategies ◽  
Current Therapy ◽  
Molecular Response ◽  
Deep Molecular Response ◽  
Treatment Free Remission

Although tyrosine Kinase Inhibitors (TKI) has revolutionized the treatment of chronic myeloid leukemia (CML), patients are not cured with the current therapy modalities. Also, the more recent goal of CML treatment is to induce successful treatment-free remission (TFR) among patients achieving durable deep molecular response (DMR). Together, it is necessary to develop novel, curative treatment strategies. With advancements in understanding the biology of CML, such as dormant Leukemic Stem Cells (LSCs) and impaired immune modulation, a number of agents are now under investigation. This review updates such agents that target LSCs, and together with TKIs, have the potential to eradicate CML. Moreover, we describe the developing immunotherapy for controlling CML.

scholarly journals Interferon-α may help prevent molecular relapse of chronic myeloid leukemia after the discontinuation of tyrosine kinase inhibitors

2021 ◽  
Vol 12 ◽  
pp. 204062072098664
Author(s):  
Kong Jun ◽  
Qin Ya-zhen ◽  
Zhao Xiao-su ◽  
Shi Hong-Xia ◽  
Lai Yue-Yun ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Chinese Patients ◽  
Interferon Α ◽  
Molecular Response ◽  
Treatment Free Remission ◽  
Tki Discontinuation

Background: Currently, the goal of chronic myeloid leukemia (CML) treatment is normal survival and good quality of life without life-long treatment, namely, “treatment-free remission” (TFR). At present, approximately only 50% of patients with CML with a deep molecular response are able to discontinue tyrosine kinase inhibitor (TKI) without experiencing molecular relapse [MR; loss of major molecular response (MMR)]. In addition, prior interferon (IFN) treatment is associated with a higher rate of TFR. Methods: We aimed to evaluate the feasibility of TKI discontinuation in Chinese patients with CML and determine whether IFN could prevent MR when used after TKI discontinuation in patients with 0.0032% < BCR-ABLIS ⩽0.1%. Therefore, we retrospectively analyzed the data of patients with CML who discontinued TKI treatment at our center. Results: Forty-nine patients who discontinued TKI therapy after achieving MR 4.5 were included in this study, and the median follow-up time from TKI discontinuation was 27 (7, 75) months. Nineteen patients eventually lost MMR, and the TFR rate of the 49 patients was 67% (95% confidence interval 53.6%, 80.3%) at 12 months. The duration of MR 4.5 ⩾54 months and duration of imatinib ⩾85 months were significantly associated with a higher TFR rate. Of the 22 patients with 0.0032% < BCR-ABLIS ⩽0.1%, 12 received IFN-α treatment. The median IFN-α therapy duration was nine (2, 18) months, and three patients eventually lost MMR. Three patients discontinued IFN-α after 2, 2.5, and 10 months, and maintained MMR for 9, 8, and 11 months after IFN discontinuation, respectively. Of the 10 patients not receiving IFN-α treatment, eight eventually lost MMR. The MR-free survival rate was significantly different between the patients treated with and those treated without IFN-α over 24 months (70.7% versus 15.0%, p = 0.002). Conclusion: These results indicate that after TKI discontinuation, IFN-α can be administered to patients with 0.0032% < BCR-ABLIS ⩽0.1%, which may help prevent MR.

scholarly journals Chronic Myeloid Leukemia in Children and Adolescents: The Achilles Heel of Oncogenesis and Tyrosine Kinase Inhibitors

2021 ◽  
Vol 22 (15) ◽  
pp. 7806
Author(s):  
Maria Moschovi ◽  
Charikleia Kelaidi
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Children And Adolescents ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Hematopoietic Cell Transplantation ◽  
Adult Life ◽  
Normal Growth ◽  
Molecular Response ◽  
Treatment Paradigm ◽  
Treatment Free Remission

Chronic myeloid leukemia (CML) is a rare disease in children and adolescents. The goal of therapy in children and adolescents is normal life expectancy, without compromising normal growth and development and potential for achievement of milestones in adult life. The perspective of cure is also reflected in the goal of treatment-free remission, with its surrogate markers, such as deep molecular response, also becoming the new endpoints of therapy efficacy in children and adolescents. Chronic myeloid leukemia was a fatal disease to children and adolescents in the past. Following the treatment paradigm of imatinib, it became a chronic disease with the potential of complete remission and even cure without the long-term hazards of allogeneic hematopoietic cell transplantation. The diagnosis and treatment of CML affect a child’s trajectory through life and important physiological events like development and procreation.

Chronic Myeloid Leukemia: What Every Practitioner Needs to Know in 2017

2017 ◽  
pp. 468-479
Author(s):  
Hanna Jean Khoury ◽  
Loretta A. Williams ◽  
Ehab Atallah ◽  
Rüdiger Hehlmann
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Quantitative Polymerase Chain Reaction ◽  
Chronic Phase ◽  
Safety Net ◽  
Patient Reported Outcome ◽  
Patient Reported ◽  
Treatment Free Remission ◽  
Pro Tools

The prognosis of chronic phase chronic myeloid leukemia (CML) has improved so that life expectancy for patients responding to tyrosine kinase inhibitors (TKIs) is now equivalent to age-matched controls. Attention should be paid to comorbidities that impact survival. The success of TKI therapy can be easily and reliably assessed at well-accepted time points using quantitative polymerase chain reaction (PCR) standardized to the international scale. Patient-reported outcome (PRO) tools are readily available for use in the clinic and provide complementary information on the tolerance of TKIs. Effectively managing adverse events of TKIs can improve compliance and quality of life. Discontinuation of TKIs is the next frontier in CML. In select patients with sustained deep molecular remission, a discontinuation of TKI is associated with a durable treatment-free remission in approximately 50%. Patient engagement in their discontinuation can be achieved through a provider multi-team coaching, is complementary to the available guidelines, and may provide an additional safety net so that these discontinuations remain safe when applied in general practices.

scholarly journals Tyrosine kinase inhibitors and pregnancy in chronic myeloid leukemia: opinion, evidence, and recommendations

2020 ◽  
Vol 11 ◽  
pp. 204062072096612
Author(s):  
Elisabetta Abruzzese ◽  
Michael Mauro ◽  
Jane Apperley ◽  
Ekaterina Chelysheva
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Myeloid Leukemia ◽  
Disease Burden ◽  
Kinase Inhibitors ◽  
Position Paper ◽  
Therapeutic Interventions ◽  
Therapy Discontinuation ◽  
Treatment Free Remission

With survival expectation that of age-matched controls and given excellent response and worldwide access to tyrosine kinase inhibitors (TKI), family planning is increasingly important for a considerable fraction of patients with chronic myeloid leukemia (CML). The potential for therapy discontinuation (“treatment free remission”) can afford the opportunity for a CML patient in deep response to plan and carry a pregnancy to full term without any therapeutic interventions. However, the reality of pregnancy desired or occurring when patients are not eligible for treatment-free remission raises the discussion of therapy choices during pregnancy. To date there are no official guidelines available to assist patients and clinicians with these decisions. This first position paper aims to analyze information published and presented surrounding this challenging area, with focus on different scenarios of disease burden and time from CML diagnosis, including CML discovered during pregnancy and pregnancy during CML treatment. An updated review, supported by data and presented together with authors’ joint recommendations, is aimed to counsel the practical management of CML patients and pregnancy.

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