Summary
The effectiveness of tyrosine kinase inhibitors (TKIs) has made it possible to consider treatment discontinuation in chronic myeloid leukaemia (CML) patients that achieve an excellent ...response. However, a few of the patients included in the Europe Stop Tyrosine Kinase Inhibitors (EURO‐SKI) trial reported musculoskeletal pain shortly after stopping TKIs, considered as a withdrawal syndrome (WS). To identify factors that may predispose to TKI WS, we analysed the pharmacovigilance declarations for the 6 months after stopping TKIs in a large cohort of CML (n = 427) that combined the French patients included in the STop IMatinib 2 (STIM2; n = 224) and EURO‐SKI (n = 203) trials. Among these patients, 23% (99/427) developed TKI WS after stopping imatinib (77/373; 20·4%), nilotinib (12/29; 41·4%) or dasatinib (10/25; 40%). WS concerned mainly the upper body joints, and required multiple symptomatic treatments in 30% of patients. Univariate and multivariate analyses identified two risk factors: duration of TKI treatment risk ratio (RR) = 1·68 (1·02–2·74) with a 93‐month cut‐off time, and history of osteoarticular symptoms RR = 1·84 (1·04–3·28). These findings confirm that WS is a TKI class effect. CML patients should be carefully screened before treatment initiation to identify pre‐existent osteoarticular symptoms. Moreover, before TKI discontinuation, patients should be informed of the possibility of WS, particularly after a long treatment period.
Background
MDS‐RS patients are characterized by chronic anemia and a low risk of Acute Myeloid Leukemia (AML) progression and they generally become Red Blood Cell (RBC) transfusion dependent (TD).
...Study design and methods
We performed a retrospective “real‐life” observational study of 6 months in 100 MDS‐RS TD patients, recruited in 12 French centers, to describe transfusion characteristics, and evaluate the frequency and causes of hospitalizations, health costs, and morbidity, associated with transfusion dependency, in a French population of RBC transfusion‐dependent MDS‐RS patients.
Results
79% of the patients had high transfusion burden (HTB) and 21% low transfusion burden (LTB). HTB patients had a longer disease duration (6 vs. 3.7 years, p = 0.0078), more frequent iron chelation (82% vs. 50%, p = 0.0052) and higher serum ferritin (p = 0.03). During the 6‐month study period, 22% of the patients required inpatient hospitalization, 36% of them for symptomatic anemia requiring emergency RBC transfusion. The 6‐month median transfusion costs, including the cost of the day care facility, transportation to and from the hospital, iron chelation, and lab tests, was 16,188€/patient.
Discussion
MDS‐RS represents the archetypal type of chronically transfused lower‐risk MDS. Most of those patients have a high transfusion burden and thus frequently need visits to the hospital's day care facility, and frequent hospitalizations, with an overall high median treatment cost. Those costs should be compared with costs of new treatments potentially able to avoid RBC transfusion dependence and to reduce the complications of chronic anemia in MDS‐RS patients.
Summary
Superior rates of deep molecular response (DMR) have been reported with the combination of tyrosine kinase inhibitors and pegylated‐interferon‐alpha (Peg‐IFN) in patients with newly diagnosed ...chronic phase‐chronic myeloid leukaemia (CP‐CML). In this setting, this study investigated the efficacy and safety of dasatinib combined to Peg‐IFN‐α2b (Dasa‐PegIFN, NCT01872442). A total of 79 patients (age ≤65 years) started dasatinib; 61 were eligible for Peg‐IFNα‐2b add‐on therapy at month 3 for a maximum 21‐months duration. Dasatinib was continued thereafter. The primary endpoint was the cumulative rate of molecular response 4.5 log (MR4.5) by 12 months. The results are reported for the 5‐year duration of the study. Grade 3 neutropenia was frequent with the combination but did not induce severe infection (one of grade 3). Other adverse events were generally low grade (4% of grade 3–4) and expected. Seventy‐nine per cent and 61% of patients continued the Peg‐IFN until months 12 and 24, respectively. Overall, at these time points, MR4.5 rates were 25% and 38%, respectively. Thereafter, 32% and 46% of patients achieved a sustained (≥2 years) MR4.5 or MR4, respectively. This work established the feasibility and high rates of achievement of early and sustained DMR (a prerequisite for treatment‐free‐remission) with dasatinib and Peg‐IFNα‐2b combination as initial therapy.
Despite the high efficiency of tyrosine kinase inhibitors (TKI), some patients with chronic myeloid leukemia (CML) will display residual disease that can become resistant to treatment, indicating ...intraclonal heterogeneity in chronic‐phase CML (CP‐CML). To determine the basis of this heterogeneity, we conducted the first exhaustive characterization of the DNA methylation pattern of sorted CP‐CML CD34+CD15− (immature) and CD34−CD15+ (mature) cells at diagnosis (prior to any treatment) and compared it to that of CD34+CD15− and CD34−CD15+ cells isolated from healthy donors (HD). In both cell types, we identified several hundreds of differentially methylated regions (DMRs) showing DNA methylation changes between CP‐CML and HD samples, with only a subset of them in common between CD34+CD15− and CD34−CD15+ cells. This suggested DNA methylation variability within the same CML clone. We also identified 70 genes that could be aberrantly repressed upon hypermethylation and 171 genes that could be aberrantly expressed upon hypomethylation of some of these DMRs in CP‐CML cells, among which 18 and 81, respectively, were in CP‐CML CD34+CD15− cells only. We then validated the DNA methylation and expression defects of selected candidate genes. Specifically, we identified GAS2, a candidate oncogene, as a new example of gene the hypomethylation of which is associated with robust overexpression in CP‐CML cells. Altogether, we demonstrated that DNA methylation abnormalities exist at early stages of CML and can affect the transcriptional landscape of malignant cells. These observations could lead to the development of combination treatments with epigenetic drugs and TKI for CP‐CML.
To understand the molecular basis of the intraclonal heterogeneity observed in the chronic phase of chronic myeloid leukemia (CML), we conducted the first exhaustive analysis of DNA methylation of chronic‐phase CML cell subsets prior to treatment. We found that DNA methylation abnormalities are already present at this early stage of CML, and they contribute to intraclonal heterogeneity and can affect the transcriptional landscape, suggesting that epigenetic drugs could be useful.
In the multinational IRIS study comparing imatinib with interferon plus cytarabine (IFN/Ara-C) in patients with newly diagnosed chronic-phase chronic myelogenous leukemia (CP CML), imatinib ...demonstrated significantly higher rates of complete cytogenetic responses (CCyRs) and improved progression-free survival (PFS). However, because of a high early crossover rate to imatinib, survival benefit was not assessable. Here, we report the result of a study comparing long-term outcome of patients included in 2 prospective randomized trials: 551 patients assigned to imatinib in the IRIS trial from 2000 to 2001 and 325 patients who received the combination IFN/Ara-C in the CML91 trial between 1991 and 1996 before imatinib was available. With a follow-up of 42 months for both groups of patients, estimated CCyR, survival free of transformation, and overall survival were significantly higher with imatinib compared with IFN/Ara-C (P < .001, P = .004, and P < .001, respectively). Improved overall survival was also confirmed within different Sokal prognostic risk groups. Of interest, among all patients who achieved major cytogenetic response or CCyR at 12 months, the survival rate was similar irrespective of their treatment. In conclusion, within the limitation of this historical comparison, there is a survival advantage from first-line therapy with imatinib over IFN/Ara-C.
Summary
The availability of tyrosine kinase inhibitors has extended therapeutic options for chronic myeloid leukaemia (CML) patients. Monitoring recommendations and clinical response goals have ...recently been updated. The objective of this study was to describe the profile of CML patients in chronic phase currently receiving first‐line therapy, including treatment, monitoring and response kinetics. A multicentre, cross‐sectional, epidemiological survey in unselected chronic phase CML patients in France attending consultations during a one‐month period was performed. 438 of 697 (62·8%) reported patients were currently receiving first‐line treatment and were analysed. Imatinib was the most frequently received treatment (72·4% of patients). Retrospective cytogenetic and molecular assessments at 3, 6, 12 or 18 months were available in 88·4% of patients. At the 12‐month assessment, 32·2% were not in major molecular response (MMR). At last assessment, among 355 patients with duration of treatment ≥ 12 months, 91·5% had achieved MMR and 66·5% were in deep molecular response. This study, performed in everyday practice population of CML patients, suggests that monitoring of molecular responses in real‐life practice is aligned with European LeukaemiaNet recommendations. The majority of patients still receiving first‐line treatment are in optimal response, with a few being classified as in the warning area or responding to failure.
Background
Data on Chronic Myeloid Leukemia (CML) prevalence are scarce. Here we provide an estimation of the prevalence of CML in France for the year 2014 using French national health insurance ...data.
Methods
We selected patients claiming reimbursement for tyrosine kinase inhibitors (TKI) or with hospital discharge diagnoses for CML, BCR/ABL‐positive or with full reimbursement of health care expenses for myeloid leukemia. We built an algorithm which we validated on a random sample of 100 potential CML patients by comparing the results obtained using the algorithm and the opinion of two hematologists who reviewed the patient demographics and sequence of care ed from claims data (internal validity). For external validity, we compared the number of incident CML patients identified using the algorithm with those recorded in French population‐based cancer registries in departments covered by such a registry.
Results
We identified 10 789 prevalent CML patients in 2014, corresponding to a crude prevalence rate of 16.3 per 100 000 inhabitants 95% confidence interval (CI) 16.0‐16.6: 18.5 in men 18.0‐19.0 and 14.2 in women 13.8‐14.6. The crude CML prevalence was less than 1.6 per 100 000 1.2‐2.0 under age 20, increasing to a maximum of 48.2 45.4‐51.2) at ages 75‐79. It varied from 10.2 to 23.8 per 100 000 across French departments. The algorithm showed high internal and external validity. Concordance rate between the algorithm and the hematologists was 96%, and the numbers of incident CML patients identified using the algorithm and the registries were 162 and 150, respectively.
Conclusion
We built and validated an algorithm to identify CML patients in administrative healthcare databases. In addition to prevalence estimation, the algorithm could be used for future economic evaluations or pharmaco‐epidemiological studies in this population.
We built and validated an algorithm to identify CML patients in healthcare administrative databases and estimated the crude CML prevalence in France at 16.3 per 100 000 inhabitants in 2014. Prevalence of CML increased with age, with a peak at 75‐79 years and varied from 10.2 to 23.8 per 100 000 inhabitants across French Departments.
Guidelines for tyrosine kinase inhibitor (TKI)-treated chronic phase-chronic myeloid leukemia (CML) management are essentially based on data from clinical research trials; however, real-world data ...should be valuable for optimizing such recommendations. Here, we analyzed the data collected in the French CML Observatory database, a multicenter real-world cohort (
n
= 646), using a first-line “intention-to-treat” analysis strategy. This cohort included patients treated with first-line imatinib (
n
= 484), nilotinib (
n
= 103), dasatinib (
n
= 17), imatinib and interferon (
n
= 9), or second-generation (2G)-TKIs and interferon (
n
= 29). The cumulative incidence of major molecular response (MMR), MR4, MR4.5 and MR5 confirmed the faster response kinetics with 2G-TKIs. Multivariate analysis identified being a woman and residual disease at month 6 as the main predictive factors of deep molecular response (DMR). Moreover, 30% of patients met the criteria for treatment discontinuation (5 years of treatment and ≥ 2 years of DMR), but only 38% of them stopped treatment. Among the 92 patients who actually discontinued treatment due to optimal response, 31.5% relapsed (48% of them after > 6 months of TKI discontinuation). Multivariate analysis identified age and TKI duration as factors positively correlated with treatment-free remission maintenance. Late (> 6 months) relapses were more frequent in patients with the e14a2 BCR::ABL transcript. Relapse rate was higher in patients who stopped TKI before than after 5 years of treatment (52.6% vs 26%;
p
= 0.040). These results advocate caution concerning early treatment withdrawal, including in patients receiving 2G-TKIs. This still recruiting database is a valuable source of information for the real-world follow-up of patients with CML.
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