scholarly journals TKI discontinuation in CML: how do we make more patients eligible? How do we increase the chances of a successful treatment-free remission?

Hematology ◽  
2021 ◽  
Vol 2021 (1) ◽  
pp. 106-112
Author(s):  
Andreas Hochhaus ◽  
Thomas Ernst
Keyword(s):  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Immune Surveillance ◽  
Decision Making Process ◽  
Molecular Response ◽  
Depth Of Response ◽  
Speed Of Response ◽  
Deep Molecular Response ◽  
Treatment Free Remission ◽  
Tki Discontinuation

Abstract Treatment-free remission (TFR) is a new and significant goal of chronic myeloid leukemia management. TFR should be considered for patients in stable deep molecular response (DMR) after careful discussion in the shared decision-making process. Second-generation tyrosine kinase inhibitors (TKIs) improve the speed of response and the incidence of DMR. Treatment may be changed to a more active TKI to improve the depth of response in selected patients who have not reached DMR. Stem cell persistence is associated with active immune surveillance and activation of BCR-ABL1-independent pathways, eg, STAT3, JAK1/2, and BCL2. Ongoing studies aim to prove the efficacy of maintenance therapies targeting these pathways after TKI discontinuation.

scholarly journals Treatment-free remission in CML: who, how, and why?

Hematology ◽  
2017 ◽  
Vol 2017 (1) ◽  
pp. 102-109 ◽  
Author(s):  
Francois-Xavier Mahon
Keyword(s):  
Clinical Trials ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Chronic Phase ◽  
Healthy Population ◽  
Molecular Response ◽  
Treatment Free Remission ◽  
Tki Discontinuation

Abstract Chronic myeloid leukemia (CML) is the best example of successful targeted therapy. Today, the overall survival of patients with CML treated by using tyrosine kinase inhibitors (TKIs) is very close to that of the healthy population. The current question is: how can we further ameliorate the clinical outcome of patients with CML? Clinical trials have shown that some patients with CML in the chronic phase who achieve sustained deep molecular responses on TKI therapy can safely suspend therapy with no evidence of relapse. The long follow-up studies and the number of eligible patients have now validated the concept of treatment-free remission (ie, the ability to maintain a molecular response after stopping therapy). It should be considered as the future criterion to evaluate the success of clinical trials, especially if we want to take into account the quality of life of patients in addition to the economic aspect. Because post-TKI discontinuation follow-ups have been increasing over time with no evidence of relapse in some patients, the next step for the coming decade will be to address the topic of CML cure.

scholarly journals Why is it critical to achieve a deep molecular response in chronic myeloid leukemia?

Haematologica ◽  
2020 ◽  
Vol 105 (12) ◽  
pp. 2730-2737
Author(s):  
Susan Branford
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Kinase Inhibitor ◽  
Outcome Measurement ◽  
Quantitative Polymerase Chain Reaction ◽  
Response To Therapy ◽  
Molecular Response ◽  
Deep Molecular Response ◽  
Treatment Free Remission ◽  
Tki Discontinuation

The primary goal of tyrosine kinase inhibitor (TKI) therapy for patients with chronic myeloid leukemia is survival, which is achieved by the vast majority of patients. The initial response to therapy provides a sensitive measure of future clinical outcome. Measurement of BCR-ABL1 transcript levels using real-time quantitative polymerase chain reaction standardized to the international reporting scale is now the principal recommended monitoring strategy. The method is used to assess early milestone responses and provides a guide for therapeutic intervention. When patients successfully traverse the critical first 12 months of TKI therapy, most will head towards another milestone response, deep molecular response (DMR, BCR-ABL1 ≤0.01%). DMR is essential for patients aiming to achieve treatment-free remission and a prerequisite for a trial of TKI discontinuation. The success of discontinuation trials has led to new treatment strategies in order for more patients to reach this milestone response. DMR has been incorporated into endpoints of clinical trials and is considered by some expert groups as the optimal treatment response. But is DMR a stable response and does it provide the ultimate protection against TKI resistance and death? Do we need to increase the sensitivity of detection of BCR-ABL1 to better identify the patients who would likely remain in treatment-free remission after TKI discontinuation? Is it necessary to switch current TKI therapy to a more potent inhibitor if the goal is to achieve DMR? These are issues that I will explore in this review.

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 Treatment-free remission in CML: who, how, and why?

Hematology ◽  
2017 ◽  
Vol 2017 (1) ◽  
pp. 102-109 ◽  
Author(s):  
Francois-Xavier Mahon
Keyword(s):  
Clinical Trials ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Chronic Phase ◽  
Healthy Population ◽  
Molecular Response ◽  
Treatment Free Remission ◽  
Tki Discontinuation

Chronic myeloid leukemia (CML) is the best example of successful targeted therapy. Today, the overall survival of patients with CML treated by using tyrosine kinase inhibitors (TKIs) is very close to that of the healthy population. The current question is: how can we further ameliorate the clinical outcome of patients with CML? Clinical trials have shown that some patients with CML in the chronic phase who achieve sustained deep molecular responses on TKI therapy can safely suspend therapy with no evidence of relapse. The long follow-up studies and the number of eligible patients have now validated the concept of treatment-free remission (ie, the ability to maintain a molecular response after stopping therapy). It should be considered as the future criterion to evaluate the success of clinical trials, especially if we want to take into account the quality of life of patients in addition to the economic aspect. Because post-TKI discontinuation follow-ups have been increasing over time with no evidence of relapse in some patients, the next step for the coming decade will be to address the topic of CML cure.

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.

scholarly journals Treatment-Free Remission in Chronic Myeloid Leukaemia: Can We Identify Prognostic Factors?

2021 ◽  
Author(s):  
Hilbeen Hisham Saifullah ◽  
Claire Marie Lucas
Keyword(s):  
Prognostic Factors ◽  
Chronic Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
Kinase Inhibitors ◽  
Chronic Phase ◽  
Molecular Response ◽  
Predicting Success ◽  
Treatment Free Remission ◽  
Almost All ◽  
Tki Discontinuation

Following the development of tyrosine kinase inhibitors (TKI), the survival of patients with chronic myeloid leukaemia (CML) drastically improved. With the introduction of these agents, CML is now considered a chronic disease, for some patients. Taking into consideration the side effects, toxicity, and high cost, discontinuing TKIs became a goal for patients with chronic phase CML. Patients who achieved deep molecular response (DMR) and discontinued TKI, remained in treatment-free remission (TFR). Currently, the data from the published literature demonstrate that 40-60% of patients achieve TFR, with relapses occurring within the first six months. In addition, almost all patients who relapsed regained a molecular response upon re-treatment, indicating TKI discontinuation is safe. However, there is still a gap in the understanding the mechanisms behind TFR, and whether there are prognostic factors that can predict the best candidates who qualify for TKI discontinuation with a view to keeping them in TFR. Furthermore, the information about a second TFR attempt and the role of gradual de-escalation of TKI before complete cessation is limited. This review highlights the factors predicting success or failure of TFR. In addition, it ex-amines the feasibility of a second TFR attempt after the failure of the first one, and the current guidelines concerning TFR in clinical practice.

scholarly journals Incidences of Deep Molecular Responses and Treatment-Free Remission in de Novo CP-CML Patients

Cancers ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 2521
Author(s):  
Gabriel Etienne ◽  
Stéphanie Dulucq ◽  
Fréderic Bauduer ◽  
Didier Adiko ◽  
François Lifermann ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
De Novo ◽  
Chronic Phase ◽  
Risk Scores ◽  
Prolonged Treatment ◽  
Molecular Response ◽  
First Line ◽  
Treatment Free Remission ◽  
Tki Discontinuation

Background: Tyrosine Kinase Inhibitors (TKIs) discontinuation in patients who had achieved a deep molecular response (DMR) offer now the opportunity of prolonged treatment-free remission (TFR). Patients and Methods: Aims of this study were to evaluate the proportion of de novo chronic-phase chronic myeloid leukemia (CP-CML) patients who achieved a sustained DMR and to identify predictive factors of DMR and molecular recurrence-free survival (MRFS) after TKI discontinuation. Results: Over a period of 10 years, 398 CP-CML patients treated with first-line TKIs were included. Median age at diagnosis was 61 years, 291 (73%) and 107 (27%) patients were treated with frontline imatinib (IMA) or second- or third-generation TKIs (2–3G TKI), respectively. With a median follow-up of seven years (range, 0.6 to 13.8 years), 182 (46%) patients achieved a sustained DMR at least 24 months. Gender, BCR-ABL1 transcript type, and Sokal and ELTS risk scores were significantly associated with a higher probability of sustained DMR while TKI first-line (IMA vs. 2–3G TKI) was not. We estimate that 28% of CML-CP would have been an optimal candidate for TKI discontinuation according to recent recommendations. Finally, 95 (24%) patients have entered in a TFR program. MRFS rates at 12 and 48 months were 55.1% (95% CI, 44.3% to 65.9%) and 46.9% (95% CI, 34.9% to 58.9%), respectively. In multivariate analyses, first-line 2–3G TKIs compared to IMA and TKI duration were the most significant factors of MRFS. Conclusions: Our results suggest that frontline TKIs have a significant impact on TFR in patients who fulfill the selection criteria for TKI discontinuation.

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