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

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. 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.

SUBMITTER: Clark RE

PROVIDER: S-EPMC6934633 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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

Clark Richard E RE

Current hematologic malignancy reports 20191201 6

<h4>Purpose</h4>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).<h4>Recent findings</h4>Most TFR studies have focussed on abrupt cessation in patients with long-standing deep remissions, b ...[more]

PMID: 31701369

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Project description:IntroductionIn the earliest cases of COVID-19, a higher percentage of severe and fatal cases was observed in patients with cancer, including those with haematological malignancies. However, patients with chronic myeloid leukaemia (CML) had better prognoses, suggesting that tyrosine kinase inhibitors (TKIs) may have a therapeutic effect against SARS-CoV-2. This study describes the clinical and epidemiological characteristics of patients with CML receiving the TKIs tested for SARS-CoV-2 in Tegucigalpa, Honduras.MethodologyAn Analytical cross-sectional study was conducted. The sample included patients with Philadelphia chromosome-positive (Ph+) CML, who had been tested at least once for COVID-19 at the Emma Romero de Callejas Cancer Centre (CCERC). Sociodemographic and clinical variables were both analysed. Epi Info 7.2.4.0 and Stata/MP 16.0 were used to collect and analyse data. The COVID-19 positivity percentage and the association between severity and the TKI used were determined using Fisher's exact test and odds ratio (OR). Data were gathered from clinical records with approval of CCERC institutional management.ResultsOne hundred and forty-nine patients with Ph+ CML were included; 20.1% were COVID-19-positive; 56% were male; mean age was 46 years; 81% were receiving imatinib, with a mean treatment duration of 6 years; 55% achieved a BCR -ABL molecular response ≤ 0.1% (IS). Twenty-one percent had comorbidities. COVID-19 was asymptomatic in 38.7% of patients, mild in 35.5% and severe in 9.7%. One patient died, a fatality rate of 3.2%. No statistical association was found between disease severity and treatment with imatinib versus second-line TKI (OR: 0.833, p: 0.8493, 95% CI: 0.098-10.998).ConclusionDespite high COVID-19 positivity in CML when compared with the literature, this study found a lower fatality rate. The type of TKI used or molecular response at the time of infection was not associated with case severity. Determining the effectiveness of imatinib or other TKIs as a COVID-19 treatment requires randomised clinical trials.

Project description:BackgroundTyrosine-kinase inhibitors improve overall survival in patients with chronic myeloid leukaemia in chronic phase (CML-CP). Survival compared with the general population by age, response, and type of tyrosine-kinase inhibitor is not known. With use of data from trials of tyrosine kinase inhibitors, we compared overall survival in patients with newly diagnosed CML-CP to that of general population.MethodsIn this cohort analysis, we included data from patients with CML-CP enrolled in six consecutive or parallel prospective clinical trials of tyrosine-kinase inhibitors at a single institution from July 30, 2000, to Sept 17, 2012. We analysed data for response and survival with the Kaplan-Meier method. For estimated overall survival in the general population, we obtained data from national vital statistics reports and matched to patients with CML-CP by age, sex, ethnicity, and year at diagnosis. We assessed numbers and causes of death within 1 year of beginning treatment by age group and by response to therapy. We then did univariate analysis and multivariate analysis to investigate factors associated with survival probability.FindingsOur analysis included 483 patients, 271 received imatinib, 105 received nilotinib, and 107 received dasatinib. Most patients were younger than 65 years, and no patients were older than 85 years. Median follow-up was 99·4 months (IQR 44·9-121·6), by which time 53 (11%) patients had died. The most common causes of death were progression to advanced disease stage, including complications of stem-cell transplantation (17 [4%] patients), secondary malignancies (nine [2%] patients), and cardiovascular causes (nine [2%] patients). 5-year overall survival in patients with CML-CP decreased in older age categories. For the whole population of patients with CML-CP, 5-year survival was only slightly lower than that of the matched general population (relative survival 94·7% [95% 92·1-97·4]). Individuals of all ages with a report of complete cytogenetic response to treatment or deeper within 1 year had a 5-year survival similar to that of the general population.InterpretationIn the era of treatment with tyrosine-kinase inhibitors, patients diagnosed with CML-CP can expect a 5-year survival that is only slightly lower than that of the general population. With access to tyrosine-kinase inhibitors, most patients with chronic myeloid leukaemia could enjoy a near normal life expectancy.FundingMD Anderson Cancer Center, National Cancer Institute.

Project description:Background: Long-term treatment-free remission (TFR) represents a new goal for chronic myeloid leukemia (CML). Optimizing dose of tyrosine kinase inhibitors (TKIs) in the CML treatment maybe a new challenge to maintain effective and improving patients' quality of life. We hypothesized that administration of low-dose TKIs does not compromise major molecular response (MMR) in patients with CML who have a deep molecular response (DMR). Methods: We did an open-label, randomized trial at eight hospitals in China. Eligible CML-CP patients (aged 18-70 years) had shown continuous response to TKI more than 5 years and maintained MR4.5 (BCR-ABLIS ≤ 0.0032%) in recent 18 months. Patients were randomly assigned (1:1) to the TKI de-escalation group or the discontinuation group. Randomization was done with permuted blocks (block size four) and implemented through an interactive web-based randomization system. Recurrence was defined as the single sample with real time Quantitative PCR (RT-qPCR) measurement greater than 0.1% (MMR). The primary endpoint was 12-month MMR rate in patients who received de-escalation or discontinuation of TKIs. This study was registered at ClinicalTrials.gov (NCT04143087). Results: Around 125 patients were enrolled between October 23, 2019 and October 31, 2020, 62 patients received dose de-escalation of TKIs, while 63 patients in the discontinuation group. In the de-escalation group, molecular recurrence-free survival at 12 months was 88.32% (95% CI 79%-98%), whereas molecular recurrence-free survival in the discontinuation group at 12 months was 59.98% (95% CI 47-73). No progressions occurred at the data cut-off date. All 29 recurrence cases restart TKI treatment returned to MMR. Cytolytic NK cells as a proportion of lymphocyte cells were significantly increased from baseline after 6 months whether in the de-escalation or TKIs cessation group (P = 0.048, 0.001, respectively); compared with the relapsing patients, Tregs proportion was decreased (P = 0.003), and higher proportion of NK cells were found in non-relapsing patients whether in TKI de-escalation or discontinuation group (P = 0.011, 0.007, respectively). We also found that the de-escalation group showed better disease-specific HRQOL in regards to its impact on emotional functioning, fatigue, pain, and financial difficulties. Conclusion: With 88.32% MMR in 12-months follow-up after de-escalation TKIs' treatment, dose-halving could become a new treatment paradigm for CML patients who with DMR under continuing maintenance therapy with TKIs.

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

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

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