Myeloid Leukemia Receiving Tyrosine Kinase Research Articles

A predictive model for therapy failure in patients with chronic myeloid leukemia receiving tyrosine kinase inhibitor therapy

AbstractAlthough tyrosine kinase inhibitor (TKI) therapy has markedly improved the survival of people with chronic-phase chronic myeloid leukemia (CML), 20% to 30% of people still experienced therapy failure. Data from 1955 consecutive patients with chronic-phase CML diagnosed by the European LeukemiaNet recommendations from 1 center receiving initial imatinib or a second-generation (2G) TKI therapy were interrogated to develop a clinical prediction model for TKI-therapy failure. This model was subsequently validated in 3454 patients from 76 other centers. Using the predictive clinical covariates associated with TKI-therapy failure, we developed a model that stratified patients into low-, intermediate- and high-risk subgroups with significantly different cumulative incidences of therapy failure (P < .001). There was good discrimination and calibration in the external validation data set, and the performance was consistent with that of the training data set. Our model had the better prediction discrimination than the Sokal and European Treatment and Outcome Study long-term survival scores, with the greater time-dependent area under the receiver-operator characteristic curve values and a better ability to redefine the risk of therapy failure. Our model could help physicians estimate the likelihood of initial imatinib or 2G TKI–therapy failure in people with chronic-phase CML.

High sensitivity c-reactive protein and circulating biomarkers of endothelial dysfunction in patients with chronic myeloid leukemia receiving tyrosine kinase inhibitors

Tyrosine kinase inhibitors (TKIs) have revolutionized the management of patients with chronic myelogenous leukemia (CML); however, they may cause cardiovascular (CV) toxicities. In this cross-sectional study, we explored whether high-sensitivity C-reactive protein (hsCRP) and novel markers of vascular dysfunction were associated with exposure to specific TKIs, in 262 CML patients. Hs-CRP level was not associated with CML disease activity or treatment with a specific TKI. Body mass index (OR: 1.15, 95% CI: 1.108–1.246; p < 0.001) and CML duration (OR: 1.004, 95% CI: 1.001–1.008; p = 0.024) were independently associated with higher hs-CRP. In exploratory analyses, novel endothelial-centric markers (e.g. ET-1 and VCAM-1) were differential across the various TKIs, particularly amongst nilotinib- and ponatinib-treated patients. While Levels of hs-CRP do not appear to be correlated with specific TKIs, circulating markers of vascular dysfunction were altered in patients treated with specific TKIs and should be explored as potential markers of TKI-associated CV risk.

Health-Related Quality of Life and Financial Burden of Ethiopian Patients with Chronic Myeloid Leukemia Receiving Tyrosine Kinase Inhibitors

Background Assessment of health-related quality of life (HRQoL) of patients with chronic myeloid leukemia (CML) treated with modern tyrosine kinase inhibitors (TKIs) is critical to support informed decision-making. However, HRQoL data currently available mainly stems from patients enrolled in high-income countries. Little is known about HRQoL of patients with CML living in low-income African countries and on the potential impact of financial difficulties experienced by these patients. Purpose The main objective of this study was to examine prevalence of clinically relevant problems and symptoms of Ethiopian patients with CML. A secondary objective was to investigate the impact of financial burden on HRQoL profile of these patients. Methods This was an observational cross-sectional study conducted at Tikur Anbessa Hospital (Addis Ababa), which is the only Ethiopian center providing TKI therapy to CML patients from all over the country. Adult patients (at least 18 years old) with a confirmed diagnosis of CML were eligible for this study. At study entry, HRQoL was assessed with the EORTC QLQ-C30 and the QLQ-CML24 questionnaires. Prevalence of clinically important problems and symptoms, at the patient level, was examined using established criteria for the use of the EORTC QLQ-C30 in routine clinical practice. This prevalence reflects the number of patients indicating limitations of everyday life, worrying, or need for help or care related to a specific symptom or functional impairment (Giesinger JM. J Clin Epidemiol. 2020;118:1-8). For descriptive purposes, EORTC QLQ-CML24 scores of Ethiopian patients were compared to that of patients included in the validation study of this questionnaire, who were mainly enrolled from high-income countries (Efficace F, et al Leuk Lymphoma. 2021;62:669-678). Multivariable linear regression analysis was performed to examine the association between financial difficulty (EORTC QLQ-C30) on "impact on daily life" scale (EORTC QLQ-CML24) while controlling for key potential observed confounding factors. The study was approved from ethical committee of the institution and all patients provided informed consent. Results Between February 2021 and June 2021, 395 patients were consecutively enrolled. Median age of patients was 39 years (range 18-82) and there were 62.8%, and 37.2% of males and females' patients respectively. Median time since diagnosis was 3.9 years (range 0.2-16) and 94% were diagnosed in chronic phase (CP) of the disease. The majority of patients (92.7%) were in treatment with imatinib and, overall, 82.3% were in complete hematologic response but unknown molecular remission status. The majority of patients (82.8%) were not able to afford follow-up BCR-ABL tests to monitor molecular response. The top three most prevalent clinically important problems were found for physical functioning (60%), emotional functioning (40%) and social functioning (38%). Pain was the most prevalent clinically important symptom reported by 43% of patients. Notably, 89% of patients reported relevant financial difficulties. Mean EORTC QLQ-C30 global health status/QoL score of patients with higher financial difficulties was 14 points lower (worse) than those with lower financial difficulties (P<0.001). Gender specific descriptive comparison of Ethiopian patients with CML patients mainly from high-income countries, revealed worse mean scores in key domains of the EORTC QLQ-CML24. For example, male Ethiopian patients reported a higher (worse) mean score (+25.2 points) than male patients from high-income countries (Table 1). In the multivariable analysis, higher financial difficulty, was associated (P<.001) with a greater impact on daily life (EORTC QLQ-CML24) and this was independent of other key variables including: age, sex, time since diagnosis, comorbidity, distance to hospital as well as fatigue and symptom burden. Conclusions Financial burden is a major problem affecting a large proportion of Ethiopian patients with CML receiving TKIs. Our findings also suggest that financial difficulties of these patients are also associated with worse HRQoL outcomes. Future studies are needed to assess whether efforts to reduce financial burden in these patients could improve HRQoL and facilitate adherence to therapy, thereby maximizing TKIs efficacy. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Chronic disease management practices and factors associated with health-related quality-of-life for persons with chronic myeloid leukemia receiving tyrosine kinase inhibitor therapy.

The main objective of this study was to explore health-related quality of life (HRQoL) profiles, chronic disease management practices and key factors associated with HRQoL in 540 patients with chronic myeloid leukemia in chronic phase (CML-CP) administered tyrosine kinase inhibitors (TKIs). Adult CML-CP patients treated with TKIs in Henan Cancer Hospital from March 2015 to October 2019 were assessed via questionnaires, including demographic characteristics, TKI medications, participation in CML disease management, and HRQoL, in a cross-sectional investigation. Respondents were anonymous. Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu) was used to measure HRQoL. A multivariate linear regression model with stepwise entry was used to investigate variables independently associated with HRQoL domain and total scores. Totally, 540 respondents were included; 302 (55.93%) were male. Mean participant age was 42.90±13.00 years; 169 (31.3%), 178 (32.9%) and 193 (35.7%) individuals had a low, moderate or high disease management level, respectively. Except for insignificant event-free survival information, participants with higher disease management levels also had significantly higher rates of completing re-examination, drug withdrawal, cytogenetic response (CcyR) and/or major molecular response (MMR) (all P<0.01). Moreover, higher disease management level was accompanied by eight significantly higher HRQoL domains (all P<0.01). In multivariate linear regression analysis, variables significantly associated with a higher HRQoL included: (I) high disease management level (B=3.68, P=0.046); (II) transportation convenience (B=6.67, P<0.001); (III) family annual income >10,000 CNY (B=5.97, P<0.001); (IV) completed re-examination (B=4.58, P=0.036); (V) MMR (B=3.75, P=0.021) and CcyR (B=5.15, P=0.035). Female sex (B=-3.53, P=0.010), single status or divorce (B=-1.89 and -2.94, P=0.005 and 0.011), and low education level (B=-1.44, P=0.019) were significantly associated with lower HRQoL. Higher disease management level was significantly associated with higher elevated treatment efficacy and HRQoL in Chinese individuals with CML-CP administered TKIs. These data indicate the importance of chronic disease management on people's HRQoL and clinical outcome.

Variables Associated with Patient-Reported Symptoms in Patients with Chronic Myeloid Leukemia Receiving Tyrosine Kinase Inhibitors

ObjectivesExplore the prevalence and severity of patient-reported symptoms in patients with chronic myeloid leukemia (CML) receiving tyrosine kinase inhibitors (TKIs), and identify associated demographics and clinical variables.MethodsA cross-sectional questionnaire, including questions assessing demographics [sex,age, household registration, marital status, education level and co-morbidity(ies)], TKI used (imatinib versus nilotinib versus dasatinib; branded drugs versus Chinese generics versus foreign generics), interval from diagnosis to starting TKI, TKI-therapy duration, therapy response [complete molecular response (CMR) versus complete cytogenetic response (CCyR) but no CMR versus no CCyR] and common patient-reported symptoms, was distributed to patients with CML in the chronic phase (CP) across China and anonymously answered. Symptoms were reported as (1) not at all; (2) mild; (3) moderate and (4) severe. Patients with CML in the CP >18 years and receiving a TKI for ≥3 months were eligible. Multivariate logistic regression model was built to identify variables associated with each symptom.ResultsData of 1142 respondents were analyzed. 724 (63%) were male. 558 (49%) had ≥bachelor degree. Median age was 42 years (range 18-88 years). 859 (75%) were receiving imatinib, 183 (16%), nilotinib; 100 (9%), dasatinib; 761 (66%), branded drugs; 225 (20%), Chinese generics; 156 (14%), foreign generics, when they answered the questionnaire. Median TKI-therapy duration was 30 months (range, 3-192 months). 472 (41%) had achieved a CMR. The top 10 common patient-reported symptoms were fatigue (77%), periorbital and lower limb edema (72%), chest distress/shortness of breath (61%), memory deterioration (54%), skin color change (44%), alopecia (44%), muscle cramp (42%), weight gain (42%), musculoskeletal pain (42%) (Figure). In multivariate analyses, female (OR 1.5-2.7, p=<0.001-0.007), urban registration (OR 1.4-1.6, p=0.004-0.023), co-morbidity(ies) (OR 1.4-2.3, p=<0.001-0.049), interval from diagnosis to starting TKI ≥6 months (OR 1.6-1.9, p=0.013-0.016), foreign generics (OR 1.5-4.0, p=<0.001-0.027), longer therapy duration (OR 1.5-4.5, p=<0.001-0.048) were factors associated with more common and severer symptoms. Unmarried person (OR 0.2-0.7, p=<0.001-0.051), nilotinib (OR 0.1-0.7, p=<0.001-0.046), achieving a CCyR but no CMR (OR 0.5-0.8, p=<0.001-0.052) were factors associated with fewer and milder symptoms. Different ages were associated with different prevalence and severity of the symptoms. Education level ≥bachelor (OR 1.4-2.1, p=0.004-0.024) was associated with more common and severer symptoms of skin color change and hypermenorrhea (in female ≤50 years), however, fewer and milder symptom of weight gain (OR 0.76, p=0.031).Conclusions This survey showed that demographics, current TKI used, therapy response and duration were associated with the prevalence and severity of patient-reported symptoms in patients with CML receiving TKIs. These results will contribute to making treatment decisions and improving quality of care and patients' quality of life. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Variables associated with self-reported anxiety and depression symptoms in patients with chronic myeloid leukemia receiving tyrosine kinase inhibitor therapy

Variables associated with self-reported anxiety and depression symptoms were explored in 1169 adults with chronic myeloid leukemia (CML) receiving tyrosine kinase inhibitor (TKI)-therapy. The Self-Rating Anxiety Scale and Self-Rating Depression Scale questionnaires were used to measure anxiety and depression symptoms. Two hundred and fifty-one (22.4%) and 415 (37.1%) respondents reported anxiety and depression, respectively. In multivariate analyses, female sex, lower education level, comorbidities, advanced-line TKI-therapy, and longer TKI-therapy duration were significantly associated with more severe anxiety and/or depression. It is concluded that socio-demographics, comorbidities, advanced-line TKI-therapy, and longer TKI-therapy duration were significantly associated with anxiety and/or depression symptoms in CML patients receiving TKI-therapy.

Outcome of COVID-19 in patients with chronic myeloid leukemia receiving tyrosine kinase inhibitors.

IntroductionIn this study, we aim to report the outcome of COVID-19 in chronic myeloid leukemia (CML) patients receiving tyrosine kinase inhibitor (TKI).MethodThe data of 16 laboratory-confirmed COVID-19 patients with CML receiving TKI and age, gender, and comorbid disease matched COVID-19 patients without cancer at a 3/1 ratio (n = 48), diagnosed between March 11, 2020 and May 22, 2020 and included in the Republic of Turkey, Ministry of Health database, were analyzed retrospectively.ResultsThe rates of intensive care unit (ICU) admission, and mechanical ventilation (MV) support were lower in CML patients compared to the control group, however, these differences did not achieve statistical significance (p = 0.1, and p = 0.2, respectively). The length of hospital stay was shorter in CML patients compared with the control group; however, it was not statistically significant (p = 0.8). The case fatality rate (CFR) in COVID-19 patients with CML was 6.3%, and it was 12.8% in the control group. Although the CFR in CML patients with COVID-19 was lower compared to the control group, this difference did not achieve statistical significance (p = 0.5). When CML patients were divided into 3 groups according to the TKI, no significant difference was observed regarding the rate of ICU admission, MV support, CFR, the length of stay in both hospital and ICU (all p > 0.05).ConclusionThis study highlights that large scale prospective and randomized studies should be conducted in order to investigate the role of TKIs in the treatment of COVID-19.

Flow cytometry and targeted immune transcriptomics identify distinct profiles in patients with chronic myeloid leukemia receiving tyrosine kinase inhibitors with or without interferon-\u03b1

BackgroundTumor cells have evolved complex strategies to escape immune surveillance, a process which involves NK cells and T lymphocytes, and various immunological factors. Indeed, tumor cells recruit immunosuppressive cells [including regulatory T-cells (Treg), myeloid-derived suppressor cells (MDSC)] and express factors such as PD-L1. Molecularly targeted therapies, such as imatinib, have off-target effects that may influence immune function. Imatinib has been shown to modulate multiple cell types involved in anti-cancer immune surveillance, with potentially detrimental or favorable outcomes. Imatinib and other tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML) have dramatically changed disease course. Our study aimed to characterize the different populations of the immune system in patients with CML affected by their treatment.MethodsForty-one patients with CML [33 treated with TKIs and 8 with TKIs plus interferon (IFN)-α] and 20 controls were enrolled in the present study. Peripheral blood populations of the immune system [referred to as the overview of immune system (OVIS) panel, Treg cells and MDSCs] and PD-1 expression were evaluated by flow cytometry. The immunological profile was assessed using the mRNA Pan-Cancer Immune Profiling Panel and a NanoString nCounter FLEX platform.ResultsPatients receiving combination therapy (TKIs + IFN-α) had lower numbers of lymphocytes, particularly T cells [838/µL (95% CI 594–1182)] compared with healthy controls [1500/µL (95% CI 1207 – 1865), p = 0.017]. These patients also had a higher percentage of Treg (9.1%) and CD4+PD-1+ cells (1.65%) compared with controls [Treg (6.1%) and CD4+/PD-1+(0.8%); p ≤ 0.05]. Moreover, patients treated with TKIs had more Mo-MDSCs (12.7%) whereas those treated with TKIs + IFN-α had more Gr-MDSC (21.3%) compared to controls [Mo-MDSC (11.4%) and Gr-MDSC (8.48%); p ≤ 0.05]. CD56bright NK cells, a cell subset endowed with immune-regulatory properties, were increased in patients receiving TKIs plus IFN-α compared with those treated with TKIs alone. Interestingly, serum IL-21 was significantly lower in the TKIs plus IFN-α cohort. Within the group of patients treated with TKI monotherapy, we observed that individuals receiving 2nd generation TKIs had lower percentages of CD4+ Treg (3.63%) and Gr-MDSC (4.2%) compared to patients under imatinib treatment (CD4+ Treg 6.18% and Gr-MDSC 8.2%), but higher levels of PD-1-co-expressing CD4+ cells (1.92%).ConclusionsOur results suggest that TKIs in combination with IFN-α may promote an enhanced immune suppressive state.

Variables associated with patient-reported symptoms in persons with chronic phase chronic myeloid leukemia receiving tyrosine kinase inhibitor therapy.

The aim of this study was to evaluate the variables associated with patient-reported symptoms and the impact of symptoms on health-related quality-of-life (HRQoL) in patients with chronic myeloid leukemia (CML) receiving tyrosine kinase inhibitors (TKIs). Anonymous Chinese-language questionnaires were distributed to adults with chronic-phase CML (CML-CP) receiving TKIs therapy >3 months regarding symptoms' incidence, severity, and HRQoL. The multivariate cumulative logistic regression model was built to identify variables associated with the symptoms. General Linear Model was used to model the relationship between symptoms and HRQoL using stepwise-forward algorithm. A total of 1142 respondents were included in this study. The top 10 common TKI-related symptoms were fatigue, periorbital and lower limb edema, chest distress and shortness of breath, memory deterioration, skin color change, alopecia, muscle cramp, weight gain and musculoskeletal pain, and itchy skin. One hundred forty-one (50%) females ≤50 years reported menstrual disorders. Female, married, therapy duration 1 to 3 years, and foreign generic TKIs were associated with increased symptoms' frequency and severity. In contrast, receiving nilotinib or dasatinib, and achieving a complete cytogenetic response but not complete molecular response were associated with fewer and milder symptoms. Chest distress and shortness of breath and loss of appetite were associated with both lower physical component summary (PCS) and mental component summary (MCS) scores; fatigue, musculoskeletal pain, dizziness and abdominal pain, were associated with lower PCS score; anxiety-depression, was associated with lower MCS score in multivariate analyses. Demographic and social variables, type of TKI-therapy, therapy duration, and depth of response were associated with patient-reported symptoms in persons with chronic phase CML. Certain symptoms have adverse impact on HRQoL.

Planned Pregnancy in Female Patients with Chronic Myeloid Leukemia Receiving Tyrosine Kinase Inhibitor Therapy.

The aim of this study was to explore outcomes of planned pregnancy in female patients with chronic myeloid leukemia (CML) on tyrosine kinase inhibitors (TKIs). Data of female patients proceeding with a planned pregnancy were retrospectively reviewed. A total of 17 patients with CML who achieved at least a major molecular response (MMR) during imatinib (n = 13) or nilotinib (n = 4) therapy prior to a planned pregnancy were enrolled. At the time of TKI interruption, six were in MMR, two in molecular response 4 (MR4), and nine in molecular response 4.5 (MR4.5). TKI therapy was discontinued 6 weeks (range, 2-15 weeks) before conception in 4 patients and at gestational age of 4 weeks (range, 2-5 weeks) after determination of pregnancy in 13 patients. Apart from 1 patient who suffered a spontaneous abortion, 16 patients delivered uneventfully. A total of 10 patients lost MMR after stopping TKIs; 8 lost molecular response 2, and 3 lost complete hematological response. Log-rank analyses showed achieving MR4 (p = .030) or MR4.5 (p = .031), complete cytogenetic response duration ≥3.5 years (p = .049), and MMR duration ≥3.5 years (p = .040) were significantly associated with longer MMR-failure-free survival during TKI interruption. Planned pregnancy might be pragmatic in female patients with CML on TKIs. Achieving deep molecular response and, importantly, MMR duration ≥3.5 years were significantly associated with maintaining MMR during pregnancy. Female patients with chronic myeloid leukemia on tyrosine kinase inhibitors (TKIs) wishing to conceive are currently advised to discontinue TKIs before conception. However, the ideal degree and duration of response before stopping TKI, in addition to whether there will be any adverse effect caused by a short exposure of TKI, is unknown. Data of 17 female patients, who achieved at least a major molecular response (MMR) before TKI interruption, was revised, and it was found that achieving deep molecular response and MMR duration ≥3.5 years was significantly associated with maintaining MMR during pregnancy. This provides direct evidence for a planned pregnancy strategy, and stopping TKI immediately after determination of pregnancy in female patients might be pragmatic.

Enhanced perforin expression associated with dasatinib therapy in natural killer cells

We investigated the effects of dasatinib on natural killer (NK) cell-induced signaling protein and perforin expression as well as plasma cytokine levels by analyzing blood samples from patients with well-controlled chronic myeloid leukemia receiving tyrosine kinase inhibitor (TKI) therapy. Perforin expression and phosphorylation of signal transducer and activator of transcription (STAT) 1, STAT3, Janus kinase (JAK) 1, and JAK2 in NK cells were evaluated by flow cytometry, and the levels of plasma cytokines, including interferon (IFN)-γ and interleukin (IL)-2, were determined by enzyme-linked immunosorbent assays in 40 patients (dasatinib, n = 23; imatinib, n = 11; and nilotinib, n = 6). Perforin levels in NK cells were higher in dasatinib-treated patients before TKI treatment; phospho (p)-STAT1 levels were closely correlated with pJAK1 and perforin levels, and pSTAT3 levels were correlated with pJAK2 and perforin levels. The correlation between pJAK1 and pSTAT1 was apparent in dasatinib-treated patients but not in other TKI-treated patients, and the correlation between pJAK2 and pSTAT3 was apparent in patients treated with other TKIs. Constitutive expression of IFN-γ was higher in patients treated with dasatinib or with other TKIs than in those who were in treatment-free remission (TFR). In contrast, constitutive expression of IL-2 was lower in patients treated with other TKIs than in those treated with dasatinib or in those who were in TFR. These results provided insights into the effects of dasatinib on JAK/STAT signaling in NK cells in vivo and the mechanisms underlying NK cell activation induced by dasatinib therapy.

Second Generation Tyrosisne Kinase Inhibitors As Upfront Therapy in the Era of Sleeve Gastrectomy Does It Work

Abstract Sleeve gastrectomy is a restrictive procedure. It greatly reduces the size of the stomach and limits the amount of food that can be eaten at one time. About 75% of the stomach is removed leaving a narrow gastric “tube” or “sleeve”. The effects of this kind of surgery in patients with chronic myeloid leukemia receiving tyrosine kinase inhibitors is not known Here we described the effects of sleeve gastrectomy in two patients underwent sleeve gastrectomy one underwent sleeve while on Dasatinib and the other started Nilotinib after sleeve gastrectomy both patients received TKI as upfront therapy. Case 1: A 34-year-old, morbidly obese woman was diagnosed with chronic myeloid leukemia. She had a low-risk Sokal score and was treated with Dasatinib 100 mg once daily as upfront therapy. The patient tolerated Dasatinib well, and she achieved a complete molecular response. 3 years later, the patient underwent a sleeve gastrectomy while receiving Dasatinib treatment ,weight decreased from 140 to 65 kg.She continued Dasatinib 100mg after sleeve but she lost her hematological response Testing for mutation analysis tends to be negative switched to Imatinib 400 mg with which she reachieved Hematologial remission and currently being followed as per ELN recommendations 2013 Case 2: A30 year old morbidly obese male underwent Gastric sleeve gastrectomy weight decreased from 120 kg to 52 kg two years later diagnosed with chronic myeloid leukemia with low risk Sokal Score started on Nilotinib 300 mg BID as upfront therapy .The patient tolerated Nilotinib well and he achieved complete hematological response but failed cytogentic and molecular response mutation analysis tends to be negative. Shifted to Imatinib where he achieved hematological, cytogentics and molecular response as per ELN recommendations 2013. Conclusion: overall it seems 2nd generations TKIs are not suitable as upfront therapy for patients with CML after sleeve gastrectomy Imatinib works better however further studies are needed to confirm these observations Disclosures No relevant conflicts of interest to declare.

Peripheral Artery Occlusive Disease Among Patients With Chronic Myeloid Leukemia Receiving Tyrosine Kinase Inhibitors: A Cross-Sectional Case-Control Study.

Background:There were some reports of peripheral artery occlusive disease (PAOD) associated with nilotinib usage in chronic myeloid leukemia (CML). These complications in other tyrosine kinase inhibitors are revealed as unknown.Materials and methods:We determined the prevalence of PAOD in patients with CML as compared with matched-control population by cross-sectional case-control study. Peripheral artery occlusive disease was screened by ankle-brachial index (ABI).Results:In total, 78 CML and 156 matched-control patients were included. The median age was 55 years. In all, 61 (78.2%) were on imatinib and 13 (16.7%) were on nilotinib, whereas 4 patients (5.2%) were on dasatinib. Prevalence of low ABI (<0.9) was 9.0%, and nilotinib users had the highest prevalence of low ABI of 30.7%. All cases with low ABI were not shown to be clinically overt of PAOD. There were well-balanced characteristics between cases of CML and matched control except in higher levels of hypercholesterolemia in the control. Interestingly, CML had more amounts of pathologic ABI than the control (odds ratio: 2.09, 95% confidence interval: 0.71-6.21), and diagnosis of diabetes found it to be independent of the risk of PAOD.Conclusions:Peripheral artery occlusive disease was higher among patients with CML than the control, especially in patients who had diabetes.

High Prevalence of Platelet Dysfunction Among Patients with Chronic Myeloid Leukemia Receiving Tyrosine Kinase Inhibitors

BACKGROUND - Tyrosine kinase inhibitors (TKIs) have become a standard of care for chronic myeloid leukemia (CML) with the favorable safety profile. However, there were few reports regarding TKIs induced platelet dysfunction, which might be contributed to bleeding complication. Therefore, we aimed to examine the prevalence and pattern of platelet function abnormalities responding to different agonists among patients with CML receiving TKIs.METHODS - This is a descriptive cross-sectional study. Patients with CML at any phases, either on TKIs or treatment-naïve, were included. Patients with known cause of platelet dysfunction or thrombocytopenia were excluded. We tested platelet aggregation on stimulation by 4 agonists, including 2.5 and 20-mmol/L ADP, 10-mmol/L epinephrine, 2-mg/mL collagen and 1-mmol/L arachidonic acid. Significant platelet dysfunction was defined as less than 60% of platelet aggregation upon stimulation by at least 2 agonists.RESULT- There were 78 patients with CML either treatment naïve (n=5) or receiving imatinib (n= 56), nilotinib (n = 15) or dasatinib (n = 2). Most of patients (n = 69) were in chronic phase while there were 2 and 3 patients were in accelerated and blastic phase, respectively. Majority of patients achieved at least complete cytogenetic response (86.4%). Prevalence of significant platelet dysfunction among patients with CML receiving imatinib, nilotinib, dasatinib and treatment-naïve were 77%, 60%, 50% and 20%, respectively (p < .0001). Impaired platelet aggregation (aggregation < 60%) on stimulation with arachidonic acid, collagen and epinephrine was observed in 80%, 68%, and 52% of patients on imatinib, meanwhile, the corresponding figures for patients on nilotinib were 33%, 53% and 47%, respectively. All TKIs seemed to have the same pattern of impaired platelet aggregation on stimulation by arachidonic acid, collagen and epinephrine; however, the proportion of patients with impaired platelet aggregation responding to arachidonic acid was more prominent in imatinib group (p < .0001). Mean maximal amplitude of platelet aggregation on stimulation by arachidonic acid in treatment-naïve, imatinib, nilotinib and dasatinib were 77.4%, 33.4%, 58.2% and 61.0%, respectively (p < .0001) (Figure 1). While mean maximal amplitude of platelet aggregation responding to collagen in treatment-naïve, imatinib, nilotinib and dasatinib were 78.4%, 39.9%, 46.2% and 66.0%, respectively (p = .001) (Figure 2).CONCLUSION- High prevalence of platelet dysfunction has been demonstrated in CML patients receiving all types of TKIs including imatinib. The cause of platelet dysfunction is likely to be from TKIs more than intrinsic platelet dysfunction from CML itself as majority of treatment-naïve patients had normal platelet function. The risk of bleeding in patients taking TKIs should be concerned in particularly those receiving concomitant antiplatelet medications or undergoing invasive procedures. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Considerations in the Management of Patients With Philadelphia Chromosome–Positive Chronic Myeloid Leukemia Receiving Tyrosine Kinase Inhibitor Therapy

The phenomenal success of therapy with tyrosine kinase inhibitors (TKIs) in Philadelphia chromosome (Ph) –positive chronic myeloid leukemia (CML) has drastically changed the prognosis of this disease. With imatinib mesylate, the estimated 7- to 10-year survival is 80% to 85%, 90% to 93% if only CML-related deaths are considered.1–5 Nilotinib and dasatinib are more potent second generation TKIs with activity in CML after imatinib failure.6–8 In randomized trials of first-line CML therapy, nilotinib and dasatinib, compared with imatinib, demonstrated significantly higher rates of complete cytogenetic response (CCyR) and of major molecular response (MMR) at 12 to 18 months, reductions in the incidence of transformation to accelerated and blastic phases, and, on average, better tolerance.9,10 Both nilotinib (300-mg twice daily) and dasatinib (100-mg once daily) were recently approved for first-line CML therapy. In the accompanying article, Hehlmann et al11 report the results of first-line CML therapy with standard dose imatinib with or without interferon alfa, and with high-dose imatinib. They analyze the incidence of MMR as the study primary end point.11 This emphasis on MMR as a primary end point in CML therapy, and the availability of three TKIs for CML therapy, raise important questions related to the management of chronic phase CML in our daily practice. What are the important early end points of therapy with TKI in CML that predict long-term prognosis (eg, achievement of CCyR, MMR)? How should we monitor response to therapy (cytogenetic, fluorescent in situ hybridization [FISH], molecular studies, mutational analysis)? What are the long-term end points relevant to therapeutic decisions (survival, progression-free survival [PFS], event-free survival [EFS])? Imatinib will become available in generic formulations in the next few years, at a significantly lower cost than second generation TKIs. Oncologists are then faced with important therapeutic questions. Would it be better to use the less expensive TKI, imatinib, as first-line CML therapy and reserve the second generation TKIs for imatinib failure, or should second generation TKIs be used as first-line therapy? What is a clinically relevant definition of poor response to imatinib? If imatinib is selected for first-line therapy, is it better to change to second generation TKIs at the time of suboptimal response to imatinib, or at the time of cytogenetic or hematologic relapse? These questions raise several important issues related to how best to integrate the new generation of TKIs into the management of patients with CML.