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.

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 Clinical and Psychological Factors to Consider in Achieving Treatment-Free Remission in Patients With Chronic Myeloid Leukemia

2021 ◽  
Vol 11 ◽  
Author(s):  
Massimo Breccia ◽  
Elisabetta Abruzzese ◽  
Mario Annunziata ◽  
Luigia Luciano ◽  
Simona Sica
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Clinical Aspects ◽  
Molecular Response ◽  
Multiple Points ◽  
Psychological Issues ◽  
Therapeutic Goals ◽  
Treatment Free Remission

Treatment of chronic myeloid leukemia (CML) has evolved dramatically in recent years. In this regard, the introduction of second-generation tyrosine kinase inhibitors (TKI) has revolutionized therapeutic goals, and it is now desirable to obtain treatment-free remission (TFR), i.e. when a patient who has stopped TKI therapy maintains a major molecular response and does not need to restart treatment. This report summarizes the main findings from a group of expert hematologists in Italy who met to discuss treatment and management of patients with CML with focus on broad-ranging aspects of TFR. A survey was used to obtain information about the clinicians’ experience with TFR and to better understand the clinical and psychological issues that patients and physicians face when considering TFR. The overall goal was to explore the possibility of discontinuing treatment from multiple points of view, considering both clinical aspects of TFR as well as psychological management of patients. Practical information is provided on aspects associated with initiating TFR, clinical data supporting it, the role of monitoring, and management of discontinuation-related adverse events. This publication outlines many of the shortcomings and highlights proposed solutions for routine clinical practice, and provides an overview of the literature relative to TFR.

scholarly journals Treatment free remission in patients with chronic myeloid leukemia: recommendations of LALNET expert panel

2021 ◽  
Author(s):  
Carolina Pavlovsky ◽  
Virginia Abello Polo ◽  
Katia Borgia Barbosa Pagnano ◽  
Ana I Varela ◽  
Claudia Agudelo Lopez ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Daily Practice ◽  
Response Monitoring ◽  
Molecular Response ◽  
Molecular Monitoring ◽  
Glucose Levels ◽  
Treatment Free Remission ◽  
Tki Treatment

Tyrosine kinase inhibitors (TKI) have dramatically changed the survival of chronic myeloid leukemia (CML) patients and treatment-free remission (TFR) has recently merged as a new goal of CML treatment. The aim of this work was to develop recommendations for TKI discontinuation in Latin America (LA), outside clinical trials. A working group of CML experts from LA discussed 22 questions regarding TFR and reached a consensus for TFR recommendations in the region. TFR is indicated in patients in first CP, with typical BCR-ABL transcripts, under TKI treatment for a minimum of 5 years, in sustained deep molecular response (DMR: MR4.5) for 2 years. Sustained DMR must be demonstrated on at least 4 IS qPCR tests, separated by at least 3 months, in the immediate prior 2 years. After 2nd line therapy, TFR is indicated in previously intolerant patients, not resistant. Molecular monitoring is recommended monthly the first 6 months, every 2-3 months from months 7 to 12, and every 3 months during the second year, indefinitely. Treatment should be reintroduced if loss of major molecular response. Monitoring of withdrawal syndrome, glucose levels, and lipid profile are recommended after discontinuation. After TKI reintroduction, molecular monitoring is indicated every 2-3 months until MR4.0 achievement, later every 3-6 months. For TFR attempt, is mandatory to have standardized, and reliable BCR-ABL PCR tests. These recommendations will be useful for safe discontinuation in the daily practice and will benefit patients who wish to stop treatment in emergent regions, in particular, with TKI related chronic adverse events.

scholarly journals How I treat chronic myeloid leukemia in children and adolescents

Blood ◽  
2019 ◽  
Vol 133 (22) ◽  
pp. 2374-2384 ◽  
Author(s):  
Nobuko Hijiya ◽  
Meinolf Suttorp
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Children And Adolescents ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Clinical Investigation ◽  
Limited Experience ◽  
Poor Treatment ◽  
Third Line ◽  
Treatment Free Remission ◽  
Leukemia In Children

AbstractEvidence-based recommendations have been established for treatment of chronic myeloid leukemia (CML) in adults treated with tyrosine kinase inhibitors (TKIs), but the rarity of this leukemia in children and adolescents makes it challenging to develop similar recommendations in pediatrics. In addition to imatinib, which was approved for pediatric CML in 2003, the second-generation TKIs dasatinib and nilotinib were recently approved for use in children, expanding the therapeutic options and pushing allogeneic stem cell transplantation to a third-line treatment of most pediatric cases. Yet, without sufficient data on efficacy and safety specific to pediatric patients, the selection of a TKI continues to rely on clinical experience in adults. Here, we present 4 case scenarios highlighting common yet challenging issues encountered in the treatment of pediatric CML (suboptimal response, poor treatment adherence, growth retardation, and presentation in advanced phases). Limited experience with very young children, the transition of teenagers to adult medicine, and the goal of achieving treatment-free remission for this rare leukemia are additional significant obstacles that require further clinical investigation through international collaboration.

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 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 Late molecular recurrences in patients with chronic myeloid leukemia experiencing treatment-free remission

2020 ◽  
Vol 4 (13) ◽  
pp. 3034-3040 ◽  
Author(s):  
Philippe Rousselot ◽  
Clémence Loiseau ◽  
Marc Delord ◽  
Jean Michel Cayuela ◽  
Marc Spentchian
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Residual Disease ◽  
Molecular Response ◽  
Residual Rate ◽  
Treatment Free Remission

Abstract Treatment-free remission (TFR) is an opportunity for patients with chronic myeloid leukemia (CML). Reported cumulative incidence curves of molecular recurrence (MRec) arbor a 2-phase shape with mainly early events, but also some late events (late MRec [LMRec]). Having discontinued our first patient in 2004, we have access to a prolonged follow-up, enabling us to characterize these late events. Over 15 years, 128 patients from our institution were registered in the Stop Imatinib (STIM; A Study for Tyrosine Kinase Inhibitors Discontinuation [A-STIM]) trial. MRec was defined by the loss of major molecular response (BCR-ABL1IS >0.1%). At the first TFR attempt, patients had been taking a tyrosine kinase inhibitor for a median of 7.1 years and in BCR-ABL1IS ≤0.01% (MR4) for a median of 4 years. The median follow-up of patients in TFR was 6.5 years. The TFR rate was estimated to be 45.6% after 7 years. For 9/65 (14%) patients experiencing MRec, recurrence occurred after 2 years in TFR (median, 3.6 years). The residual rate of MRec after 2 years was estimated to be 18%. The probability of remaining in TFR was 65.4% for patients having experienced fluctuations of their minimal residual disease (MRD) (at least 2 consecutive measurements BCR-ABL1IS >0.0032% or loss of MR4), whereas it was 100% for those with stable MRD (P = .003). After 2 years in TFR, we observed an 18% residual rate of LMRec. These late events represent 14% of all MRec and occur in patients with fluctuating MRD measurements. A long-term molecular follow-up therefore remains mandatory for CML patients in TFR. The A-STIM study was registered at www.clinicaltrials.gov as #NCT02897245.

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 Cost effectiveness of treatment-free remission in chronic myeloid leukemia patients: A report from a developing country.

2019 ◽  
Vol 5 (suppl) ◽  
pp. 131-131
Author(s):  
Wasim Sattar
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Financial Burden ◽  
Chronic Phase ◽  
Small Subset ◽  
Molecular Response ◽  
The Government ◽  
Treatment Free Remission ◽  
The Cost

131 Background: Current recommendations for first line therapy in chronic phase chronic myeloid leukemia (CP-CML) is life-time use of tyrosine kinase inhibitors (TKI's). Unfortunately, the financial burden of continuous TKI therapy is unsustainable especially in developing countries. In Pakistan, an access-program for Imatinib (IM) and Nilotinib is available; the cost of therapy is subsidized with the Government paying for 3 months and Novartis for 9 months. Updated results from several trials support continued long term durability of treatment free remission (TFR). We attempted TFR in our patients in an attempt to reduce financial burden and improve quality of life for the patients. We aimed to evaluate the economic impact of discontinuing imatinib versus continuous use of imatinib in patients taking IM 400mg. Methods: 57 patients of CP-CML taking Imatinib 400 mg for the last 10 years who were negative by FISH for at least 3 years or in MR 4.5 at least once in 12 months were evaluated. Of these 30 were screening failures, 4 patients refused consent prior to screening and 25 were eligible for the trial. Two consecutive RQ-PCR were performed 3 months apart prior to enrollment. Patients were eligible if they achieved MR 4.5 for at least 3 months prior to entering the study. Molecular response was assessed by Quantitative BCR-ABL RQ-PCR every 4 weeks after discontinuation for year 1 and 8 weeks at year 2. Cost of Imatinib 400 mg per month was calculated as well as the cost of BCR-ABL RQ-PCR by gene expert for the trial. Results: Of the enrolled 25 patients, 10 lost their deep molecular response and were restarted on therapy, 5 withdrew consent after screening.10 patients are currently on trial at varying time intervals (10-14 months) of cessation of imatinib. The cost of one month of imatinib is US $ 800 and the cost of RT PCR is $ 67. TFR translated into approximately US 1.2 million saved. Conclusions: The discontinuation of TKI in this small subset of patients has resulted in remarkably large savings with significant impact on the meager health budget in our resource limited setting.

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