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.

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.

Optimizing patient selection for treatment-free remission

2020 ◽  
Vol 26 (5) ◽  
pp. 1220-1224
Author(s):  
Caitlin R Rausch ◽  
Shilpa Paul
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Chronic Phase ◽  
Heterogeneous Data ◽  
Healthy Population ◽  
Molecular Response ◽  
Treatment Free Remission

The advent of BCR–ABL1 tyrosine kinase inhibitors has revolutionized the treatment and prognosis of chronic myeloid leukemia. Life expectancy for patients with chronic phase chronic myeloid leukemia now nears that of the healthy population; however, optimal outcomes require continuous tyrosine kinase inhibitor administration, which can impact patient quality of life. Consequently, the concept of treatment-free remission has been explored in patients achieving and sustaining a deep molecular response. Heterogeneous data exist with multiple tyrosine kinase inhibitors; however, nilotinib is currently the only therapy that has been approved by the US Food and Drug Administration for treatment-free remission. The decision to pursue treatment-free remission is one that relies heavily on both patient- and disease-related factors. Herein, we will discuss relevant considerations to be made when determining an optimal candidate for treatment-free remission.

scholarly journals Handling challenging questions in the management of chronic myeloid leukemia: when is it safe to stop tyrosine kinase inhibitors?

Hematology ◽  
2020 ◽  
Vol 2020 (1) ◽  
pp. 243-247
Author(s):  
Delphine Rea
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Tyrosine Kinase Inhibitors ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Term Treatment ◽  
Long Term Treatment ◽  
Treatment Free Remission

Abstract The paradigm for managing patients with chronic myeloid leukemia is evolving. In the recent past, restoring a normal life expectancy while patients are receiving never-ending targeted therapy with BCR–ABL1 tyrosine kinase inhibitors through prevention of progression to blast phase and mitigation of iatrogenic risks was considered the best achievable outcome. Now, long-term treatment-free remission with continued response off tyrosine kinase inhibitor therapy is recognized as the most optimal benefit of treatment. Indeed, numerous independent clinical trials provided solid proof that tyrosine kinase inhibitor discontinuation was feasible in patients with deep and sustained molecular responses. This article discusses when tyrosine kinase inhibitors may be safely stopped in clinical practice on the basis of the best and latest available evidence.

scholarly journals Recommendations from a Portuguese Expert Group for Discontinuation of Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia Patients in Clinical Practice

2019 ◽  
Vol 32 (7-8) ◽  
pp. 550
Author(s):  
Antonio Almeida ◽  
Francesca Pierdomenico ◽  
Blanca Polo Guerrero ◽  
Filipa Saraiva ◽  
Ana Montalvão ◽  
...  
Keyword(s):  
Clinical Practice ◽  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Chronic Phase ◽  
Molecular Response ◽  
National Guidelines ◽  
Treatment Free Remission

Until recently, the main goal of chronic myeloid leukemia therapy was disease control with the best overall survival, which required lifelong treatment. However, currently, the treatment-free remission concept is becoming an important goal in clinical practice, and several tyrosine kinase inhibitors discontinuation studies have shown that round 50% of patients with a durable deep molecular response beyond major molecular response successfully interrupt tyrosine kinase inhibitors for at least three years without loss of molecular response. However, and regardless of the existing evidence, the exact conditions for attempting treatment-free remission remain poorly defined. Different authors tried to guide the clinical decision regarding this topic but there are some points that differ, namely with respect to the recommended duration of tyrosine kinase inhibitors therapy and the appropriate molecular response prior to treatment-free remission. The goal of this article is to propose an algorithm to guide clinical practice in Portugal concerning chronic phase-chronic myeloid leukemia patients who wish to attempt treatment-free remission, since there are no national guidelines.

scholarly journals Handling challenging questions in the management of chronic myeloid leukemia: when is it safe to stop tyrosine kinase inhibitors?

2020 ◽  
Vol 4 (21) ◽  
pp. 5589-5594
Author(s):  
Delphine Rea
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Tyrosine Kinase Inhibitors ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Term Treatment ◽  
Long Term Treatment ◽  
Treatment Free Remission

Abstract The paradigm for managing patients with chronic myeloid leukemia is evolving. In the recent past, restoring a normal life expectancy while patients are receiving never-ending targeted therapy with BCR–ABL1 tyrosine kinase inhibitors through prevention of progression to blast phase and mitigation of iatrogenic risks was considered the best achievable outcome. Now, long-term treatment-free remission with continued response off tyrosine kinase inhibitor therapy is recognized as the most optimal benefit of treatment. Indeed, numerous independent clinical trials provided solid proof that tyrosine kinase inhibitor discontinuation was feasible in patients with deep and sustained molecular responses. This article discusses when tyrosine kinase inhibitors may be safely stopped in clinical practice on the basis of the best and latest available evidence.

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