scholarly journals Rates of peripheral arterial occlusive disease in patients with chronic myeloid leukemia in the chronic phase treated with imatinib, nilotinib, or non-tyrosine kinase therapy: a retrospective cohort analysis

Leukemia ◽  
2013 ◽  
Vol 27 (6) ◽  
pp. 1310-1315 ◽  
Author(s):  
F J Giles ◽  
M J Mauro ◽  
F Hong ◽  
C-E Ortmann ◽  
C McNeill ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Peripheral Arterial Occlusive Disease ◽  
Myeloid Leukemia ◽  
Retrospective Cohort ◽  
Cohort Analysis ◽  
Chronic Phase ◽  
Arterial Occlusive Disease ◽  
Retrospective Cohort Analysis ◽  
Peripheral Arterial

Retrospective Cohort Analysis of Peripheral Arterial Occlusive Disease (PAOD) Events in Patients (pts) with Chronic Myeloid Leukemia in Chronic Phase (CML-CP)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2757-2757 ◽  
Author(s):  
Francis J. Giles ◽  
Michael J. Mauro ◽  
Frank Hong ◽  
Christine-Elke Ortmann ◽  
Richard C. Woodman ◽  
...  
Keyword(s):  
Risk Factors ◽  
Peripheral Arterial Occlusive Disease ◽  
Research Funding ◽  
Retrospective Cohort ◽  
Cohort Analysis ◽  
Arterial Occlusive Disease ◽  
Occlusive Disease ◽  
Arterial Stenosis ◽  
Retrospective Cohort Analysis ◽  
Peripheral Arterial

Abstract Abstract 2757 Background: Recently there have been reports of PAOD events in pts with CML-CP treated with tyrosine kinase inhibitors (TKI). Although asymptomatic PAOD is common, occurring in 12–20% of adults (55–70 years of age), the incidence of PAOD in pts with CML is unknown. Risk factors for PAOD include hypercholesterolemia, hypertension, diabetes, smoking, and vascular disease. It remains to be determined if PAOD may be related to CML and/or TKIs. These considerations are important as atherosclerotic disease has been observed with other pt populations (HIV and hemophilia) with improved survival similar to CML due to effective treatments. To investigate the association of PAOD in CML pts a retrospective cohort analysis was conducted with the objective of comparing TKI treated pts to a comparator arm of no TKI therapy. Methods: This analysis was based on a database of pooled randomized, multi-center, clinical trial data from ENESTnd, TOPS, and IRIS in pts with newly-diagnosed CML-CP. From this database (n = 2393), 3 cohorts of pts were generated: Cohort 1–No TKI exposure (IFN+Ara-C only, n = 533), Cohort 2–Nilotinib only (300 and 400 mg BID, n = 556) and Cohort 3–Imatinib only (400 mg QD or BID, n = 1304). Exclusion criteria for cardiovascular disease varied across cohorts and pts with risk factors for PAOD were not excluded in any cohorts. The case definition for PAOD included atherosclerotic and thrombotic events, excluding the functional (vasoreactive), embolic, or aneurysmal disorders, in the arteries of lower and upper extremities according to ACC/AHA guidelines. Events indicative of PAOD were represented by a group of broad terms including: arterial disorder, arteriosclerosis, peripheral ischaemia, arterial insufficiency, arteriosclerosis obliterans, peripheral vascular disorder, arterial occlusive disease, femoral arterial stenosis, arterial stenosis, femoral artery occlusion, peripheral artery angioplasty, arterial stenosis limb, intermittent claudication, peripheral revascularization, arterial thrombosis limb, peripheral arterial occlusive disease, and poor peripheral circulation. The cumulative incidence of PAOD cases reported represents the crude rate without accounting for duration of exposure; exposure adjusted incidence rate was also provided since the duration of therapy differed substantially among cohorts. Relative risks (RR) with 95% confidence intervals (CI) are presented for Cohorts 2 (nilotinib only) and 3 (imatinib only) compared with Cohort 1 (no TKIs). Results: As shown in the table, when using Cohort 1 (no TKIs) as the control for TKI therapies the RR for Cohort 2 (nilotinib only) was 1.9 (95% CI 0.5, 7.6) and the RR for Cohort 3 (imatinib only) was 0.8 (95% CI 0.2, 3.3). When accounting for exposure using pt-years, the exposure adjusted RR was 1.0 (95% CI 0.2, 4.0) for Cohort 2 (nilotinib only), and 0.2 (95% CI 0.1, 1.0) for Cohort 3 (imatinib only). The CIs for these RRs overlap 1.0 suggesting no significant increased risk. Conclusions: Based on the large cohort of pts in this analysis, the results demonstrate a low incidence of PAOD cases for pts on either nilotinib or imatinib. In comparison with the no-TKI control, the risk and causality of PAOD due to nilotinib or imatinib could not be established with current available data. However, caution should be exercised when interpreting retrospective comparisons and further investigation is required to better understand whether PAOD events are increased in CML pts treated with TKIs. Disclosures: Giles: Novartis: Consultancy, Honoraria, Research Funding. Mauro:Novartis: Research Funding; Bristol Myers Squibb: Research Funding; Ariad: Research Funding. Hong:Novartis: Employment. Ortmann:Novartis: Employment. Woodman:Novartis: Employment, Equity Ownership. LeCoutre:Bristol Myers Squibb: Honoraria; Novartis: Honoraria, Research Funding, Speakers Bureau. Saglio:Bristol Myers Squipp: Consultancy, Speakers Bureau; Novartis Pharmaceutical: Consultancy, Speakers Bureau; Pfizer: Consultancy.

Peripheral Arterial Occlusive Disease (PAOD) In Chronic Phase Chronic Myeloid Leukemia Patients Treated With Nilotinib

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4018-4018 ◽  
Author(s):  
Young-Woo Jeon ◽  
Sung-Eun Lee ◽  
Soo-Young Choi ◽  
Soo-Hyun Kim ◽  
Jin-Eok Park ◽  
...  
Keyword(s):  
Heart Disease ◽  
Chronic Myeloid Leukemia ◽  
Ischemic Heart Disease ◽  
Peripheral Arterial Occlusive Disease ◽  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Arterial Occlusive Disease ◽  
Ischemic Heart ◽  
Second Line ◽  
Peripheral Arterial

Abstract Introduction ENESTnd trial, nilotinib showed superior efficacy and good tolerability compared with standard dose of imatinib in chronic phase chronic myeloid leukemia (CP CML). However, serious vascular adverse events such as ischemic heart disease (IHD) and peripheral arterial occlusive disease (PAOD) have been reported. Therefore, we have prospectively evaluated for emergence of PAOD in all (CML patients treated with nilotinib. Materials and methods Between May 2005 and April 2013, a total of 98 CP CML patients on nilotinib treatment were tested with laboratory studies, electrocardiography and ankle brachial index (ABI) + pulse wave velocity (PWV). Abnormal ABI index was defined with below 1.0 and abnormal PWV as over 1200∼2000 cm/sec adjusted by age. and patients who had abnormal ABI or PWV were performed with computed tomography angiography. Results So far, 88 of total 98 patients (57 male) were evaluated with screening test. 17 patients of 88 showed abnormal ABI or PWV. Finally, 3 patients (3.4%) of 17 were diagnosed with overt PAOD by CT angiography (2 upper extremity, 1 lower extremity). The median age was 46 year old (range, 19∼72). The median duration of disease was 49 months (range,1.2 ∼ 65) and 51.3 months (range,36 ∼ 115) in the patients treated with first-line and second-line nilotinib, respectively. The median mean daily dosage of nilotinib was 710mg (range, 656∼800mg) and 737 mg (range, 500∼800mg) in each group. The duration of nilotinib treatment was 46.3 months (range, 0.7∼64.2) and 25.0 months (range, 2.8∼55.8) in each group. Comparing first and second-line nilotinib treated patients, an abnormal ABI or PWV (1 versus 16 patients) and overt PAOD (0 versus 3 patients) was more frequent in patients with second-line nilotinib (p=0.042, p< 0.001, p<0.001). Conclusion Our preliminary data suggest an importance of PAOD evaluation in patients with long-term nilotinib treatment (p=0.042) and a routine assessment of PAOD including ischemic heart disease (IHD) is strongly recommended on regular basis. Disclosures: No relevant conflicts of interest to declare.

Progressive Peripheral Arterial Occlusive Disease and Other Vascular Events During Nilotinib Therapy in Chronic Myeloid Leukemia

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1679-1679 ◽  
Author(s):  
Luciano Levato ◽  
Renato Cantaffa ◽  
Mariagrazia Kropp ◽  
Domenico Magro ◽  
Eugenio Piro ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Chronic Myeloid Leukemia ◽  
Peripheral Arterial Occlusive Disease ◽  
Myeloid Leukemia ◽  
Second Generation ◽  
Arterial Occlusive Disease ◽  
Occlusive Disease ◽  
Line Treatment ◽  
Second Line ◽  
Peripheral Arterial

Abstract Abstract 1679 Recent data suggest that second-generation tyrosine-kinase inhibitor (TKI) dasatinib and nilotinib can be responsible for increased non-hematologic adverse events in comparison to imatinib. In particular, there are a few reports of severe peripheral arterial occlusive disease (PAOD) and other vascular occlusive events (infarction) in patients receiving nilotinib. With this in mind we retrospectively evaluated incidence of PAOD or other vascular occlusive events in our cohort including 82 consecutive chronic myeloid leukemia (CML) patients treated at our institution with imatinib alone (n=55) or nilotinib as first-line (n=17) or second-line treatment after imatinib failure (n=10). After a median time of exposition to nilotinib of 24 months (range, 7–34 months) 4 (14.8%) out of 27 patients developed an episode of severe and previously unrecognized PAOD or other vascular occlusive events (2 PAOD, 1 myocardial infarction, 1 ictus). All 4 patients were more than 60 years old and 3 out of 4 were male while obesity was never observed. A history of nicotine abuse could be found in 2 out of 4 patients. The same applied when we looking for the presence of arterial hypertension (2/4) or dyslipidemia (2/4). When 55 patients treated with imatinib were analyzed for PAOD or other vascular occlusive event incidence we detected only one patient who experienced myocardial infarction after 135 months of therapy. We then evaluated the likelihood of developing PAOD in the subset of patients treated only with imatinib and in those who received nilotinib, respectively. The projected 10-year actuarial probability of remaining PAOD-free was 100% in the imatinib group and 67% in the nilotinib group (HR, 14.6; P=0.0008). Interestingly, the two patient cohorts were alike with respect to age (P=0.76), gender (P=0.80), number cardiovascular risk factors (P=0.62) and body mass index (P=0.59). The only difference we observed was a significantly longer exposition to drug among patients treated only with imatinib in comparison to those who received nilotinib (P<0.001). In conclusion this study although hampered by the relatively small patient number suggests that in CML front-line and second-line treatment should be adapted to the individual situation in each patient. Parameters related to risk of developing TKI-associated adverse PAOD events should be considered before choosing a second-generation TKI. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Meta-Analysis of Gastrointestinal Adverse Events from Tyrosine Kinase Inhibitors for Chronic Myeloid Leukemia

Cancers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1643
Author(s):  
Prahathishree Mohanavelu ◽  
Mira Mutnick ◽  
Nidhi Mehra ◽  
Brandon White ◽  
Sparsh Kudrimoti ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Adverse Events ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Meta Analysis ◽  
Chronic Phase ◽  
Molecular Response ◽  
Gastrointestinal Adverse Events

Tyrosine kinase inhibitors (TKIs) are the frontline therapy for BCR-ABL (Ph+) chronic myeloid leukemia (CML). A systematic meta-analysis of 43 peer-reviewed studies with 10,769 CML patients compared the incidence of gastrointestinal adverse events (GI AEs) in a large heterogeneous CML population as a function of TKI type. Incidence and severity of nausea, vomiting, and diarrhea were assessed for imatinib, dasatinib, bosutinib, and nilotinib. Examination of combined TKI average GI AE incidence found diarrhea most prevalent (22.5%), followed by nausea (20.6%), and vomiting (12.9%). Other TKI GI AEs included constipation (9.2%), abdominal pain (7.6%), gastrointestinal hemorrhage (3.5%), and pancreatitis (2.2%). Mean GI AE incidence was significantly different between TKIs (p < 0.001): bosutinib (52.9%), imatinib (24.2%), dasatinib (20.4%), and nilotinib (9.1%). Diarrhea was the most prevalent GI AE with bosutinib (79.2%) and dasatinib (28.1%), whereas nausea was most prevalent with imatinib (33.0%) and nilotinib (13.2%). Incidence of grade 3 or 4 severe GI AEs was ≤3% except severe diarrhea with bosutinib (9.5%). Unsupervised clustering revealed treatment efficacy measured by the complete cytogenetic response, major molecular response, and overall survival is driven most by disease severity, not TKI type. For patients with chronic phase CML without resistance, optimal TKI selection should consider TKI AE profile, comorbidities, and lifestyle.

BCR-ABL kinase domain mutation analysis in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors: recommendations from an expert panel on behalf of European LeukemiaNet

Blood ◽  
2011 ◽  
Vol 118 (5) ◽  
pp. 1208-1215 ◽  
Author(s):  
Simona Soverini ◽  
Andreas Hochhaus ◽  
Franck E. Nicolini ◽  
Franz Gruber ◽  
Thoralf Lange ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Mutation Analysis ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Direct Sequencing ◽  
Chronic Phase ◽  
Kinase Domain ◽  
Abl Kinase

AbstractMutations in the Bcr-Abl kinase domain may cause, or contribute to, resistance to tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia patients. Recommendations aimed to rationalize the use of BCR-ABL mutation testing in chronic myeloid leukemia have been compiled by a panel of experts appointed by the European LeukemiaNet (ELN) and European Treatment and Outcome Study and are here reported. Based on a critical review of the literature and, whenever necessary, on panelists' experience, key issues were identified and discussed concerning: (1) when to perform mutation analysis, (2) how to perform it, and (3) how to translate results into clinical practice. In chronic phase patients receiving imatinib first-line, mutation analysis is recommended only in case of failure or suboptimal response according to the ELN criteria. In imatinib-resistant patients receiving an alternative TKI, mutation analysis is recommended in case of hematologic or cytogenetic failure as provisionally defined by the ELN. The recommended methodology is direct sequencing, although it may be preceded by screening with other techniques, such as denaturing-high performance liquid chromatography. In all the cases outlined within this abstract, a positive result is an indication for therapeutic change. Some specific mutations weigh on TKI selection.

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