scholarly journals Interruption or Discontinuation of Tyrosine Kinase Inhibitor Treatment in Chronic Myeloid Leukaemia: A Retrospective Cohort Study (SPARKLE) in Belgium

2019 ◽  
Vol 142 (4) ◽  
pp. 197-207 ◽  
Author(s):  
Timothy Devos ◽  
Gregor Verhoef ◽  
Eva Steel ◽  
Dominiek Mazure ◽  
Philippe Lewalle ◽  
...  
Keyword(s):  
Side Effects ◽  
Chronic Myeloid Leukaemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Myeloid Leukaemia ◽  
Kinase Inhibitor ◽  
Chronic Phase ◽  
Molecular Response ◽  
Treatment Free Remission ◽  
Tki Treatment

Objectives: To assess interruptions/discontinuations of tyrosine kinase inhibitor (TKI) treatment in Belgian patients with chronic myeloid leukaemia (CML). Methods: This retrospective study included patients with TKI interruptions/discontinuations of ≥4 continuous weeks (no clinical trial context) between May 2013 and May 2016. Data collection took place between October 2016 and February 2017. Results: All 60 participants (69 interruptions/discontinuations) had chronic-phase CML and 75% had at least a major molecular response (≥MMR) at interruption/discontinuation. Most interruptions/discontinuations occurred while on imatinib (36/69; 49%) and dasatinib (20/69; 29%). Most interruptions/discontinuations occurred due to side effects/intolerance (46/69; 67%); other reasons included a wish to conceive (6/69; 9%) and attempts to achieve treatment-free remission (TFR) (6/69; 9%). Interruptions due to side effects occurred later for imatinib- or dasatinib-treated patients than for those on nilotinib or ponatinib. Treatment was re-initiated in 62% (43/69) of cases. Most interruptions caused by side effects/intolerance were followed by treatment changes. All 4 patients with ≥MR 4.5 at interruption/discontinuation and ≥11-month follow-up who had not restarted treatment maintained the response. Conclusion: Although TKIs are used for long-term CML treatment, physicians sometimes recommend interruptions/discontinuations. In this study, interruptions/discontinuations were mainly caused by side effects or intolerance, rather than TFR attempts.

scholarly journals Tyrosine Kinase Inhibitor Therapy Discontinuation for Patients with Chronic Myeloid Leukaemia in Clinical Practice

2019 ◽  
Vol 14 (6) ◽  
pp. 507-514 ◽  
Author(s):  
Richard E. Clark
Keyword(s):  
Chronic Myeloid Leukaemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Myeloid Leukaemia ◽  
Kinase Inhibitor ◽  
Molecular Response ◽  
Therapy Discontinuation ◽  
Tyrosine Kinase Inhibitor Therapy ◽  
Treatment Free Remission ◽  
Inhibitor Treatment

Abstract Purpose In chronic myeloid leukaemia, tyrosine kinase inhibitor treatment is traditionally given continuously for life. However, these drugs produce excellent responses for many patients, and this is accompanied by survival that is close to normal. This has prompted studies of whether it is possible to stop treatment, thus achieving a treatment-free remission (TFR). Recent Findings Most TFR studies have focussed on abrupt cessation in patients with long-standing deep remissions, but recent data suggest that more gradual treatment de-escalation may improve TFR success, and that it may be possible to extend TFR attempts to patients who are in stable major molecular response but not necessarily MR4. Summary Further data are badly needed on TFR for patients whose remission is less than stable MR4 and on the importance of prior interferon-alpha treatment. Funding TFR trials in a disease with such an excellent outlook is an increasing challenge.

scholarly journals PF-114: A 4th Generation Tyrosine Kinase-Inhibitor for Chronic Phase Chronic Myeloid Leukaemia Including BCRABL1T315I

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1638-1638 ◽  
Author(s):  
Anna G. Turkina ◽  
Olga Vinogradova ◽  
Elza Lomaia ◽  
Evgeniya Shatokhina ◽  
Oleg A. Shukhov ◽  
...  
Keyword(s):  
Adverse Events ◽  
Chronic Myeloid Leukaemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Myeloid Leukaemia ◽  
Research Funding ◽  
Kinase Inhibitor ◽  
Molecular Response ◽  
Travel Grant ◽  
Grade 3

Background: PF-114 is a 4th-generation oral tyrosine kinase-inhibitor (TKI) active against wild-type and mutated BCR-ABL1 isoforms including BCR-ABL1T315I. We present data from a phase-1 study in patients with chronic or accelerated phase chronic myeloid leukaemia (CML) failing ≥2 TKIs or with BCR-ABL1T315I (NCT02885766) with ≥6 months therapy. Methods: 3+3 dose-escalation study to determine maximum tolerated dose (MTD) and dose-limiting toxicity (DLT). Secondary objectives included safety and efficacy based on haematological, cytogenetic, and molecular criteria. Adverse events (AEs) were graded using NCI-CTCAE v4.03. Results: 51 patients were enrolled. Daily doses were 50 mg (n=3), 100 mg (n=3), 200 mg (n=9), 300 mg (n=11), 400 mg (n=12), 500 mg (n=3), 600 mg (n=6), 750 mg (n=4) given continuously. Median age was 50 years (range, 29-82 years). Median CML duration pre-study was 10 years (range, 0.3-23 years). All patients had baseline ECOG performance scores 0-1. Twelve patients had BCR-ABL1T315I. Patients were heavily pre-treated: 25 received ≥3 prior TKIs; 5 patients with BCR-ABL1T315I received 1 prior TKI. Interim analysis was conducted at follow-up of ≥6 months (cut-off date January 16th 2019). Therapy was ongoing in 17 patients at doses 200 mg (n=4), 300 mg (n=9), 400 mg (n=3) and 600 mg (n=1) with median duration of exposure of 7,4 (range, 4,6-26), 9,2 (range, 7,4-26), 9,2 (range, 8,3-9,2) and 9,2 months. Other patients discontinued because of progression (n=18), adverse events (n=6), consent withdrawal (n=4), participation in another study (n=3) or other reasons (n=3). The MTD was 600 mg with the grade-3 psoriasis-like skin lesions the DLT, which occurred during the first 28 days of treatment. Reversible grade-3 skin toxicity occurred in 11 patients at doses ≥400 mg. There were no other drug-related non-hematologic grade-3 toxicities except 1 grade-3 toxic hepatitis at 400 mg and there were no detectable effects on ankle-brachial index or vascular occlusive events. The best safety/efficacy dose was 300 mg/d with 6 of 11 patients achieving a major cytogenetic response (MCyR) and 4 of them - a major molecular response (MMR). Higher doses were less effective probably because of toxicity-related therapy interruptions and discontinuations. Five of 12 patients with BCR-ABL1T315I responded, 3 of which achieved a complete hematologic response and 4 achieved MCyR. Conclusion: PF-114 was safe and effective in patients with CML failing ≥2 TKIs or with BCR-ABL1T315I. The most effective dose was 300 mg/d. Five of 12 patients with BCR-ABL1T315I responded. A pivotal study is beginning. Disclosures Turkina: Novartis: Consultancy, Speakers Bureau; Pfizer: Consultancy; Bristol Myers Squibb: Consultancy; fusion pharma: Consultancy; Novartis: Consultancy, Speakers Bureau. Vinogradova:Novartis: Consultancy; Fusion Pharma: Consultancy. Lomaia:Novartis: Other: Travel Grant;Lecture fee; Pfizer: Other: Travel Grant. Shukhov:Pfizer: Consultancy; Novartis: Consultancy. Chelysheva:Novartis: Consultancy, Honoraria; Fusion Pharma: Consultancy. Shikhbabaeva:Novartis: Consultancy; Fusion Pharma: Consultancy. Shuvaev:Fusion Pharma: Consultancy; Novartis: Consultancy; Pfize: Honoraria; BMS: Consultancy. Cortes:Pfizer: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Biopath Holdings: Consultancy, Honoraria; Immunogen: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; BiolineRx: Consultancy; Sun Pharma: Research Funding; Merus: Consultancy, Honoraria, Research Funding; Forma Therapeutics: Consultancy, Honoraria, Research Funding. Baccarani:Novartis: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Takeda: Consultancy. Ottmann:Roche: Honoraria; Pfizer: Honoraria; Fusion Pharma: Honoraria; Takeda: Honoraria; Novartis: Honoraria; Celgene: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; Amgen: Honoraria, Research Funding. Mikhailov:Fusion Pharma: Employment. Novikov:Fusion Pharma: Employment. Shulgina:Fusion Pharma: Employment. Chilov:Fusion Pharma: Consultancy.

scholarly journals Treatment Free Remission for Chronic Phase Chronic Myelogenous Leukemia Patients Who Stopped Tyrosine Kinase Inhibitor Therapy Due to Intolerance

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5919-5919
Author(s):  
Daulath Singh ◽  
Sucha Nand ◽  
Hanh Mai
Keyword(s):  
Side Effects ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Chronic Myelogenous Leukemia ◽  
Kinase Inhibitor ◽  
Chronic Phase ◽  
Myelogenous Leukemia ◽  
Median Treatment ◽  
The Past ◽  
Treatment Free Remission

Introduction: Chronic Myelogenous Leukemia (CML) is a myeloproliferative neoplasm that is often diagnosed in adults between the ages of 25-60. The outcome of the chronic phase CML has dramatically changed due to Tyrosine Kinase Inhibitor (TKI) therapy. There are well established guidelines from NCCN and ESMO on stopping TKI for patients achieving prolonged remissions with TKIs. We report clinical outcomes from a single tertiary care center in patients who stopped TKI therapy for reasons other than prolonged remission status. Methods: We retrospectively reviewed all the CML patients who were treated at our institution in the past 10 years (January 1st,2009 - December 31st,2018). We excluded patients who had accelerated or blast phase CML, atypical CML, patients on non-TKI therapy, and patients who received an allogeneic stem cell transplant. Results: A total of 117 patients were diagnosed with chronic phase CML at our institution in the past 10 years. Among the 117 patients, 12 of these discontinued TKI therapy. Six patients stopped TKI after achieving prolonged remission with TKI therapy and the remaining patients discontinued due to intolerance to treatment, fear of side effects, and loss of insurance. The median age of the whole cohort is 66 years (range 42-85). Six patients were male and 6 were females. Six patients were diagnosed with CML prior to year 2009 and rest after 2009. Prior to stopping, six patients received only 1 kind of TKI, 2 patients were treated with 2 types of TKIs, 2 patients received 3 types of TKIs, and 2 patients had 4 lines of TKIs (See Table). Cohort 1: 6 patients who stopped due to prolonged remission, median major molecular remission - MMR4 (BCR-ABL <0.01% IS by RT-PCR testing) prior to stopping TKI is 6 years (range 3-13 years). Of the six, only 1 relapsed (within 1 month of stopping) and was initiated back on the same TKI (imatinib). The relapsed patient has not achieved MMR4 level remission to date. Median treatment free remission for this cohort is 13 months (range 1-24 months). Cohort 2: Of those 6 patients who stopped TKI for other reasons: 4 stopped due to side effects/intolerance, 1 stopped due to fear of side effects after FDA label was updated, and 1 patient discontinued due to a loss of insurance. Median duration of MMR4 prior to stopping is 4 years (range 1-11 years). 5 of these 6 patients relapsed in the median time of 6 months (range 3-16 months). Of these 5, 4 were started back on the TKI therapy (three on the same TKI and one on a different TKI). Median treatment free remission for this cohort is 4 months (range 2-16 months). Conclusion: In this small cohort from a single institution's experience, CML patients who discontinued TKI therapy after achieving MMR4 for reasons other than prolonged remission have experienced poor outcomes including a higher rate of relapse and a shorter treatment free remission. We need studies with larger samples sizes and longer follow up to assess outcomes in patients stopping TKI therapy for various reasons. Disclosures No relevant conflicts of interest to declare.

Cognitive dysfunction after withdrawal of tyrosine kinase inhibitor therapy in chronic myeloid leukaemia

2016 ◽  
Vol 91 (11) ◽  
pp. E480-E481 ◽  
Author(s):  
Simone Claudiani ◽  
Jane F. Apperley ◽  
Simona Deplano ◽  
Jamshid Khorashad ◽  
Letizia Foroni ◽  
...  
Keyword(s):  
Chronic Myeloid Leukaemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Myeloid Leukaemia ◽  
Cognitive Dysfunction ◽  
Kinase Inhibitor ◽  
Inhibitor Therapy ◽  
Tyrosine Kinase Inhibitor Therapy

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.

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