scholarly journals Ponatinib Facilitates Treatment-Free Remission By Inducing Deep Molecular Responses

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5460-5460 ◽  
Author(s):  
Brendan Wisniowski ◽  
Sally Mapp ◽  
Louise Knop ◽  
James Morton ◽  
Paul Eliadis ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Molecular Response ◽  
Vascular Events ◽  
Deep Molecular Response ◽  
Multiple Trials ◽  
T315i Mutation ◽  
Artery Disease ◽  
Grade 3 ◽  
Treatment Free Remission ◽  
The One

Abstract Multiple trials now demonstrate the potential for treatment-free remission (TFR) in patients with sustained deep molecular response to tyrosine kinase inhibitors (TKIs). We describe two patients who remain in treatment-free remission after achieving undetectable BCR-ABL with ponatinib on the phase II PACE trial, despite being multiply resistant/intolerant to other agents or carrying the T315I mutation. Patient 1 previously had a suboptimal response to imatinib (BCRABL >10% at 15mo) and then was intolerant of nilotinib and dasatinib due to grade 3 liver enzyme abnormalities. He achieved undetectable BCR-ABL (Molecular MD laboratories) by six months on ponatinib. His ponatinib dose was gradually reduced from 45mg/d to 15mg/d due to vascular events (myocardial infarction requiring stenting, carotid stenosis requiring endarterectomy, recurrent ischaemic colitis). At the time of his last episode of colitis, his BCR-ABL had been undetectable for 47 months and hence a decision to attempt TFR was made. He remains in TFR 11 months post-cessation. Patient 2 progressed on imatinib and was found to carry the T315I mutation. He achieved undetectable BCR-ABL by nine months on ponatinib. His ponatinib dose was also gradually reduced from 45mg/d to 15mg/d due to vascular events (popliteal stenosis requiring stenting, embolic stroke, coronary artery disease requiring stenting). At the time of his last event, his BCR-ABL had been undetectable for 30 months and hence a decision to attempt TFR was made. He remains in TFR 17 months post-cessation. This series adds to the one prior case report of ponatinib facilitating treatment-free remission (Engel NW et al. J Oncol Pract 2016. 12(6);592-4) and these remissions are notable because they occur in patients not considered for other TFR studies because of refractoriness to other agents or known T315I mutations. This is an alternative avenue to dose reduction to reduce the risk of vascular events in ponatinib-treated patients. Disclosures Mills: Ariad: Other: This clinical study funded by Ariad.

scholarly journals Moving treatment-free remission into mainstream clinical practice in CML

Blood ◽  
2016 ◽  
Vol 128 (1) ◽  
pp. 17-23 ◽  
Author(s):  
Timothy P. Hughes ◽  
David M. Ross
Keyword(s):  
Clinical Practice ◽  
Kinase Inhibitors ◽  
Financial Burden ◽  
Molecular Response ◽  
Best Interest ◽  
Deep Molecular Response ◽  
Potential Risks ◽  
Treatment Free Remission ◽  
The Many

Abstract The dramatic success of tyrosine kinase inhibitors (TKIs) has led to the widespread perception that chronic myeloid leukemia (CML) has become another chronic disease, where lifelong commitment to pharmacologic control is the paradigm. Recent trials demonstrate that some CML patients who have achieved stable deep molecular response can safely cease their therapy without relapsing (treatment free remission [TFR]). Furthermore, those who are unsuccessful in their cessation attempt can safely re-establish remission after restarting their TKI therapy. Based on the accumulated data on TFR, we propose that it is now time to change our approach for the many CML patients who have achieved a stable deep molecular response on long-term TKI therapy. Perhaps half of these patients could successfully achieve TFR if offered the opportunity. For many of these patients ongoing therapy is impairing quality of life and imposing a heavy financial burden while arguably achieving nothing. This recommendation is based on the evident safety of cessation attempts and TFR in the clinical trial setting. We acknowledge that there are potential risks associated with cessation attempts in wider clinical practice, but this should not deter us. Instead we need to establish criteria for safe and appropriate TKI cessation. Clinical trials will enable us to define the best strategies to achieve TFR, but clinicians need guidance today about how to approach this issue with their patients. We outline circumstances in which it would be in the patient's best interest to continue TKI, as well as criteria for a safe TFR attempt.

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 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 The Relationship between Molecular Response of BCR-ABL1 Transcripts within 6 Months and Deep Molecular Response at 18 Months to Dasatinib Treatment for Newly Diagnosed Patients with CML-CP

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2928-2928
Author(s):  
Daigo Michimata ◽  
Kazunori Murai ◽  
Yasuro Miyairi ◽  
Yoshiaki Okano ◽  
Yuuzou Suzuki ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Second Generation ◽  
Hematological Toxicity ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Transcript Levels ◽  
Deep Molecular Response ◽  
Grade 3 ◽  
Treatment Free Remission ◽  
Dasatinib Treatment

BACKGROUND: The overall survival of patients with newly diagnosed chronic myeloid leukemia (CML) has improved significantly since the introduction of tyrosine kinase inhibitors (TKIs), and recently, some patients with CML who achieve stable deep molecular response (DMR) to TKI therapy could safely suspend treatment. In addition to European LeukemiaNet criteria (ELN), the European Society for Medical Oncology (ESMO) proposed that less than 0.01% of BCR-ABL1 transcript (MR4.0) on the International Scale (IS) after 18 months is optimal for patients to achieve treatment-free remission. Branford et al. indicated that major molecular response (MMR; less than or equal to 0.1% of BCR-ABL1 IS ; MR3.0) at three months predicts stable undetectable BCR-ABL1 transcript levels during imatinib treatment. However, second-generation TKIs induce more rapid and deeper responses at early time points compared to imatinib; however, whether early molecular response predicts MR4.0 by 18 months to second-generation TKI therapy, remains unclear. AIMS: We retrospectively analyzed BCR-ABL1 transcript levels in patients with CML in chronic phase (CML-CP) at 3, 6, 12, and 18 months after initiating dasatinib treatment to identify molecular milestones that would predict MR4.0 by 18 months. METHODS: Fifty-nine newly diagnosed patients with CML-CP were included in this study. The median age was 61 years (18-81 years), 72% of whom were males, and patients older than 65 years comprised 31% of the overall enrollment. Eighty-six percent of them had low and intermediate Sokal scores. Patients received 100 mg of dasatinib once daily. Dose interruption or reduction was allowed if drug-related grade 3 non-hematological toxicity or grade 3 or worse hematological toxicity occurred.BCR-ABL1/ ABL ratio IS (BCR-ABL1 IS) was performed at approximately 3-month intervals. To assess the kinetics of response, we calculated halving time (HT) of BCR-ABL1 IS. HT-BCR-ABL1 was calculated as described by Branford et al. We used a receiver-operating characteristic (ROC) curve to identify the cut-offs in transcript levels at three and six months. Mann-Whitney test was used to determine statistical significance. Categorical variables were compared using Fisher's exact test. Factors were subjected to multivariate analysis using Cox regression; differences with p<0.05 were considered statistically significant. RESULTS: The median BCR-ABL1 IS level before therapy was 82.1% (range 13.5-157.9 %). The estimated MMR by 12 months and MR4.0 by 18 months were 86.4% and 50.8%, respectively. We analyzed each into a cohort that achieved MR4.0 by 18 months (MR4.0 cohort) and a cohort that did not achieve MR4.0 (non-MR4.0 cohort). The BCR-ABL1 IS level in each cohort is indicated in the Table. Median HT-BCR-ABL1 IS 0-3 months was 10.8 days (6.5-71.3 days) in MR4.0 cohort, and 13.0 days (8.5- 169.6 days, p<0.05) in non-MR4.0 cohort, whereas that of 3-6 months was 24.4 days (6.5-228.9 days) in MR4.0 cohort and 47.3 days (18.0- 154.9 days, p<0.01) in non-MR4.0 cohort. The shape of BCR-ABL1 IS descent was biphasic in MR4.0 cohort. The cut-off values of BCR-ABL1 IS at 3 months and 6 months for prediction of MR4.0 by 18 months were 0.122% (specificity 0.964, sensitivity 0.586, AUC 0.784) and 0.048% (0.852, 0.833, 0.909), respectively. We determined the optimal threshold for predicting MR4.0 by 18 months using these parameters. Some of them (BCR-ABL1 IS 3 months ≤0.122%,BCR-ABL1 IS 6 months ≤ 0.048%, BCR-ABL1 IS 6 months ≤1%: ELN optimal criteria) were identified as predictive cut-off values for MR4.0 by 18 months in univariate analysis (BCR-ABL1 IS 3 months ≤0.122%; 94.4% vs. 30.7%, p<0.01, BCR-ABL1 IS 6 months ≤ 0.048%; 85.7% VS. 20.7%, p<0.01 and BCR-ABL1 IS 6 months <1.0%; 58.8% vs. 0%, p<0.01). However, BCR-ABL1 IS 3 months ≤ 10% (ELN optimal criteria at three months) was not identified as predictive cut-off value for MR4.0 (54.7% vs. 20%, N.S.). Multivariate analysis indicated that BCR-ABL1 IS 6 months ≤ 0.048% was a significant independent factor for achievement of MR4.0 by 18 months (hazard ratio 0.05, p<0.01). CONCLUSION: Even though dasatinib is highly-priced, dasatinib treatment results in higher rates of molecular responses in newly diagnosed patients with CML-CP. Assessment of molecular reduction within six months has become an important landmark to predict MR4.0 by 18 months during dasatinib treatment for patients with the aim to achieve treatment-free remission. Disclosures Oyake: Astellas: Speakers Bureau; Celgene: Honoraria; Chugai: Honoraria; Kyowa-Hakko Kirin: Honoraria. Ito:Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Ono: Honoraria.

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 Silent NK/T cell reactions to dasatinib during sustained deep molecular response before cessation are associated with longer treatment‐free remission

2020 ◽  
Vol 111 (8) ◽  
pp. 2923-2934
Author(s):  
Takashi Kumagai ◽  
Chiaki Nakaseko ◽  
Kaichi Nishiwaki ◽  
Chikashi Yoshida ◽  
Kazuteru Ohashi ◽  
...  
Keyword(s):  
T Cell ◽  
Molecular Response ◽  
Deep Molecular Response ◽  
Nk T Cell ◽  
Treatment Free Remission

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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