scholarly journals Monitoring the safety of nilotinib in patients with chronic myeloid leukemia

2019 ◽  
Vol 65 (2) ◽  
pp. 67-72
Author(s):  
Marija Pendovska ◽  
Zorica Naumovska ◽  
Irina Panovska ◽  
Marica Pavkovic ◽  
Goce Kalcev ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Adverse Reactions ◽  
Kinase Inhibitors ◽  
Chronic Phase ◽  
Age Group ◽  
Duration Of Treatment ◽  
Men And Women ◽  
The Mean ◽  
Future Evaluation

The aim of the study was to evaluate the safety profile of nilotinib administered to chronic myeloid leukemia (CML) at patients. The study was conducted from March 2018 to May 2019 and it included 20 patients with CML in chronic phase. Of these 20 patients, 17 had previously been treated with imatinib and 3 with hydroxyurea. The mean duration of treatment with Nilotinib was 6.75 months. In nine patients treated with nilotinib (400 mg), 55% complained of fatigue, 33% of headache and 22.2% of pruritus. In five patients treated with Nilotinib (600 mg), 20% complained of headache, 40% of fatigue and 20% of pruritus. In addition, in six patients treated with nilotinib (800 mg), 50% complained of headache and fatigue, 17% with pruritus and visual disorder was observed in 20% of cases. In the study, the adverse reactions were observed between the age of 20 and 40 and it was 7.1%, in contrast to the group of patients between the age of 40 and 60 where the incidence of adverse reactions was 21.42%. The incidence of adverse reactions in patients in the age group over 60 years it was 57.1%. In terms of gender, the incidence of adverse reactions was equal to 50% for both men and women. In conclusion, this study showed that treatment with nilotinib was well tolerated, with adverse reactions of an easy degree. Future evaluation is necessary in order to understanding the adverse reaction of nilotinib in comparison with other tyrosine kinase inhibitors. Keywords: nilotinib, pharmacovigilance, safety, chronic myeloid leukemia

Bosutinib in patients with chronic phase chronic myeloid leukemia intolerant to prior tyrosine kinase inhibitors: Analyses from the BYOND study.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 7551-7551
Author(s):  
Susanne Saussele ◽  
Carlo Gambacorti-Passerini ◽  
Valentin García Gutierrez ◽  
Camille N. Abboud ◽  
Simon Purcell ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Dose Intensity ◽  
Duration Of Treatment

7551 Background: Bosutinib (BOS) is approved for patients (pts) with Philadelphia chromosome (Ph)+ chronic myeloid leukemia (CML) resistant/intolerant to prior therapy and in newly diagnosed pts in chronic phase (CP). Methods: The ongoing phase 4 BYOND study is further evaluating efficacy and safety of BOS (starting dose 500 mg/d) for CML resistant/intolerant to prior tyrosine kinase inhibitors (TKIs). We report findings in pts intolerant to all prior TKIs. Data are reported ≥1 y after the last enrolled pt (~85% TKI-intolerant pts had ≥2 y follow-up). Results: Of 163 pts who received BOS, 156 had Ph+ CP CML. 73 pts entered the study due to intolerance; 29, 26 and 18 had 1 (CP2L), 2 (CP3L) and 3 (CP4L) prior TKIs, respectively. After a median follow-up of 30.4 mo, median treatment duration across all 3 cohorts (CP2L, CP3L, CP4L, respectively) was 25.3 mo (29.2, 24.6, 17.6) and median dose intensity was 292.0 mg/d (304.5, 284.8, 272.1). Across CP CML cohorts (CP2L, CP3L, CP4L, respectively), 84.9% of patients (82.8%, 88.5%, 83.3%) had ≥1 dose reduction and 83.6% (79.3%, 84.6%, 88.9%) had ≥1 dose interruption due to adverse events (AEs). At the data cutoff, 53.4% (CP2L 65.5%, CP3L 42.3%, CP4L 50.0%) were still receiving BOS. The most common reason for discontinuation was AEs (28.8%). The most common ( > 40%) treatment-emergent AEs (TEAEs) were diarrhea (87.7%) and nausea (43.8%). Grade 3/4 TEAEs in > 10% of pts were diarrhea (16.4%), increased alanine aminotransferase (19.2%) and increased lipase (12.3%). Most pts with a valid baseline assessment achieved major molecular responses (MMR) across therapy lines (Table). Deaths occurred in 4 pts (CP2L 1, CP3L 3, CP4L 0); none were related to BOS or CML. Overall survival rate (95% CI) at 2 y in TKI-intolerant pts was 97.2% (89.2–99.3); rates were 96.4% (77.2–99.5), 96.0% (74.8–99.4) and 100% (100–100) in CP2L, CP3L and CP4L pts, respectively. Conclusions: A long duration of treatment and high response rate were observed in TKI-intolerant pts treated with BOS. Despite being intolerant to all prior therapies, ≥50% of pts in the overall intolerant cohort remained on BOS treatment at the data cutoff and > 80% achieved/maintained MMR. These results further support BOS use in pts with Ph+ CP CML and intolerance to all prior TKIs. Clinical trial information: NCT02228382 . [Table: see text]

scholarly journals Retrospective Analysis to Correlate Impact of Symptom Burden and Quality of Life to Treatment Outcome with Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia Chronic Phase

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4548-4548
Author(s):  
Binsah George ◽  
Williams Lori ◽  
Quiling Shi ◽  
Talha Badar ◽  
Susan O'Brien ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Skin Rash ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Memory Loss ◽  
Chronic Phase ◽  
Symptom Burden ◽  
The Mean ◽  
Over Time

Abstract Retrospective analysis to correlate Impact of Symptom Burden and Quality of life to treatment outcome with Tyrosine kinase inhibitors in chronic myeloid Leukemia chronic phase Binsah George, Lori Williams, Quiling Shi, Talha Badar, Susan O'Brien, Elias Jabbour, Guillermo Garcia-Manero, Nitin Jain, Farhad Ravandi, Gautam Borthakur, William Wierda, Charles Cleeland, Hagop Kantarjian and Jorge Cortes Department of Leukemia, MD Anderson Cancer Center, Houston, Texas; Department of Symptom Research, MD Anderson Cancer Center Background: With the advent of Tyrosine kinase inhibitors (TKI) in the treatment of Chronic Myeloid Leukemia chronic phase (CML-CP), patients (pts) live longer emphasizing the importance of symptom burden control to improve quality of life for these patients. The objectiveof this study isto analyze the symptom burden with different TKIs used as initial therapy for CML-CP and their impact on outcome Methods: We analyzed a total of 200 patients with CP-CML enrolled in prospective clinical trials with frontline TKI therapy; ponatinib [PONA]=33, dasatinib [DASA]=85, nilotinib [NILO]=82 between the years of 2005-2013. At time points including baseline, 3months, 6 months, 12months, 18months, 24 months pts symptom burden was assessed by the MD Andersron Symptom Inventory for CML (MDASI-CML) (Blood 2013; 122: 641). Results: The overall median age was 48 years (range, 22-76) and the median follow up was 24 months (range, 11-31months). The entire cohort of 200 patients reached a complete cytogenetic response (CCyR) at 3 months, all with reverse-transcriptase (RT)-polymerase chain reaction (PCR) for the BCR-ABL fusion transcript of <10 percent (%) by international Scale (IS). At 6 months 184/200 pts (92%), 12 months 160/189 (84%), 18 months 129/181 (71%), and 24 months 125/173 (72%) had reached PCR BCR-ABL of <1%, <0.1%, <0.01%, and <0.0035%, respectively. The mean worst symptom over 24 months of treatment with NILO and DASA was fatigue while for ponatinib was skin rash. The mean top 5 worst symptoms for DASA were (figure 1) fatigue (p=0.001 compared to baseline), drowsiness, memory loss, skin rash and sleep disturbance; for NILO (figure 2) top 5 were fatigue, sleep disturbance, memory loss, drowsiness, and skin rash; for patients treated with PONA (figure 3) top 5 symptoms were skin rash, fatigue, drowsiness, generalized muscle soreness, dry mouth. Mean overall symptom scores were 1.45 for DASA, 1.63 for NILO and 2.83 for PONA. Work was the aspect of daily life most interfered with by symptoms for the whole cohort at baseline and over the 24 month treatment period (mean DASA=1.11, NILO=1.95 and PONA=2.43). By individual TKI, the top mean aspects of daily life (after work) interfered with in order of severity were, for PONA, activities (2.12), mood (2.11) and ability to enjoy life (2.09); for DASA, ability to enjoy life (1.07), activities (0.99) and mood (0.98); and for NILO, mood (1.05), ability to enjoy life (0.99), and activities (0.93). The mean overall impact of function scores were 1.74 for DAS, 1.29 for NILO and 2.18 for PONA. In the DASA and NILO cohort who completed the MDASI-CML at 24 months, 6 of 19 (31%) did not reach MR4.5 (%BCR-ABL <0.0032%) while 13 (68%) achieved this response at 24 months (PONA cohort not included as most patients had not reached a 24 month treatment follow up at the time of this report). The top 5 significant symptom mean scores in the cohort who did not reach MR4.5 were fatigue (1.67), pain (1.33), memory loss (1.33), and drowsiness (1.17) and swelling of hands and legs (1.17) while for patients who reached MR4.5, fatigue (2.38), drowsiness (1.62), swelling of hands and legs (1.46), memory loss (1.46), and generalized pain (1.33) were the top mean symptoms. Patients that reached MR4.5 in this cohort had a higher mean symptom burden (1.65) in comparison to those not reaching MR4.5 (1.33) Conclusions: Symptom burden is affected in different ways by different TKI used as initial therapy for CML. The NILO and DASA cohort that had MR4.5 at 24 months had a worse symptomatology mean in comparison to the cohort that did not reach MR4.5. Figure: (1) Top 5 symptoms with Dastinib treatment over time Figure: (1). Top 5 symptoms with Dastinib treatment over time Figure: (2) Top 5 symptom with Nilotinib treatment over time Figure: (2). Top 5 symptom with Nilotinib treatment over time Figure: (3) Top 5 symptoms with ponatinib time over time Figure: (3). Top 5 symptoms with ponatinib time over time Disclosures Cortes: Ariad, BMS, Novartis, Pfizer, Teva: Consultancy, Research Funding.

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.

scholarly journals Significance of deeper molecular responses in patients with chronic myeloid leukemia in early chronic phase treated with tyrosine kinase inhibitors

2013 ◽  
Vol 88 (12) ◽  
pp. 1024-1029 ◽  
Author(s):  
Lorenzo Falchi ◽  
Hagop M. Kantarjian ◽  
Xuemei Wang ◽  
Dushyant Verma ◽  
Alfonso Quintás-Cardama ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Chronic Phase ◽  
Molecular Responses

scholarly journals Metabolomic Analysis of Patients with Chronic Myeloid Leukemia and Cardiovascular Adverse Events after Treatment with Tyrosine Kinase Inhibitors

2020 ◽  
Vol 9 (4) ◽  
pp. 1180 ◽  
Author(s):  
Giovanni Caocci ◽  
Martino Deidda ◽  
Antonio Noto ◽  
Marianna Greco ◽  
Maria Pina Simula ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Adverse Events ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Chronic Phase ◽  
Endothelial Damage ◽  
Gas Chromatography Mass Spectrometry ◽  
Metabolomic Analysis

Background: Cardiovascular adverse events (CV-AEs) are considered critical complications in chronic myeloid leukemia (CML) patients treated with second- and third-generation tyrosine kinase inhibitors (TKIs). The aim of our study was to assess the correlation between metabolic profiles and CV-AEs in CML patients treated with TKIs. Methods: We investigated 39 adult CML patients in chronic-phase (mean age 49 years, range 24–70 years), with no comorbidities evidenced at baseline, who were consecutively identified with CML and treated with imatinib, nilotinib, dasatinib, and ponatinib. All patients performed Gas-Chromatography-Mass-Spectrometry-based metabolomic analysis and were divided into two groups (with and without CV-AEs). Results: Ten CV-AEs were documented. Seven CV-AEs were rated as 3 according to the Common Toxicity Criteria, and one patient died of a dissecting aneurysm of the aorta. The patients’ samples were clearly separated into two groups after analysis and the main discriminant metabolites were tyrosine, lysine, glutamic acid, ornithine, 2-piperdinecarboxylic acid, citric acid, proline, phenylalanine, threonine, mannitol, leucine, serine, creatine, alanine, and 4-hydroxyproline, which were more abundant in the CV-AE group. Conversely, myristic acid, oxalic acid, arabitol, 4-deoxy rithronic acid, ribose, and elaidic acid were less represented in the CV-AE group. Conclusions: CML patients with CV-AEs show a different metabolic profile, suggesting probable mechanisms of endothelial damage.

scholarly journals Metabolomics Profile of Patients with Chronic Myeloid Leukemia and Cardiovascular Adverse Events after Treatment with Tyrosine Kinase Inhibitors

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4144-4144
Author(s):  
Giovanni Caocci ◽  
Martino Deidda ◽  
Antonio Noto ◽  
Christian Cadeddu ◽  
Marianna Greco ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Adverse Events ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Dissecting Aneurysm ◽  
Metabolomic Profile ◽  
The Mean

Background. Cardiovascular adverse events (CV-AE) are emerging complications in chronic myeloid leukemia (CML) patients treated with second and third generation tyrosine kinase inhibitors (TKIs). Despite the importance of CV risk factors,predictive CV-AE biomarkers are still lacking. Further understanding of the molecular pathways underlying CV-AE may promote novel strategies to prevent its initiation prior to clinical disease. In this scenario, the use of a novel tool such as metabolomics may be useful for the identification of new metabolic pathways related to CV-AE. Metabolites are the output of cellular metabolism, accounting for expression and activity of genes, transcripts, and proteins, and offering unique insights into small molecule regulation. For the first time we evaluated the correlation between CV-AE and metabolomic profile in CML patients treated with TKIs. Methods. We considered 39 adult CP-CML patients (mean age 49, range 24-70), without comorbidity at baseline, consecutively diagnosed and treated with imatinib, dasatinib nilotinib and ponatinib, at the Haematology Unit of "Businco Hospital", Cagliari, Italy. All patients underwent a metabolomic profile detection, after CV-AE or during follow-up, and were stratified in 2 groups (with or without CV-AE). Plasma samples were collected and acquired chromatogram was analysed by means of the free software AMDIS (Automated Mass Spectral Deconvolution and Identification System; http://chemdata.nist.gov/mass-spc/amdis) that identified each peak by comparison of the relative mass spectra and the retention times with those stored in an in-house made library comprising 255 metabolites. Data were investigated by applying the supervised multivariate statistical approach OPLS-DA (Orthogonal partial least square discriminant analysis) (SIMCA, version 13.0, Umetrics, Umea, Sweden). Results. The mean follow-up since CML diagnosis was 3.7 years (range 0.9-5); 22 (56.4%) patients were treated frontline, while 17 (43.5%) underwent second or subsequent TKI lines of treatments. The reason for switching was inefficacy in 15.3% and intolerance in 28.2%. At CV-AE or last follow-up 16 (41%) patients were treated with imatinib, 8 (20.5%) with dasatinib, 14 (35.8%) with nilotinib and 1 patient with ponatinib (2.7%). Overall, 17 CV-AE were recorded: 7 cases of hypercholesterolemia, 5 pleural or pericardial effusions, one episode of hypertension and 4 cardiac events (atrial fibrillation,ST-segment elevation myocardial infarction, reduction of cardiac ejection fraction and dissecting aneurysm of the aorta); 7 CV-AE were graded as 3 according to the common toxicity criteria and one patient died from dissecting aneurysm of the aorta). The 60-month cumulative CV-AE incidence was 54.4±9.1%. The mean time between the start of the treatment and the occurrence of a CV-AE was 44.4 months (range 19-60). OPLS-DA showed that patient's samples were clearly separated into 2 groups indicating that CV-AE patients (blue dots) presented a markedly distinct metabolic profile compared with patients without CV-AE (green dots); (figure 1). The parameters of the model were R2Y = 0.76 and Q2 = 0.44. To validate the OPLS-DA model, a permutation was performed resulting statistically significant (p=0,002). The main discriminant metabolites were tyrosine, lysine, ornithine, glutamic acid, 2-piperdincarboxylic acid, proline, citric acid, phenylalanine, mannitol, threonine, leucine, creatine, serine, 4-hydroxyproline, and alanine (more represented in CV-AE group); while unknown 204, myristic acid, arabitol, oxalic acid, 4-deoxyrithronic acid, elaidic acid and ribose resulted less expressed in CV-AE group. Conclusions. This exploratory study showed different metabolomic profile of CML patients with CV-AE underwent TKI treatment, suggesting possible mechanisms of endothelial damage mediated by the accumulation of metabolites. Tyrosine, highly expressed in the CV-AE CML group, is a reliable marker of oxidative stress in various acute and chronic diseases.Metabolomics research has considerable potential for translating the metabolic fingerprint into personalized therapeutic strategies. These preliminary data should be confirmed in prospective clinical trials. Figure 1 Disclosures No relevant conflicts of interest to declare.

scholarly journals Allografting for Bosutinib, Imatinib, Nilotinib, Dasatinib, and Interferon Resistant Chronic Myeloid Leukemia without ABL Kinase Mutation

2011 ◽  
Vol 2011 ◽  
pp. 1-4
Author(s):  
B. Uz ◽  
O. Bektas ◽  
E. Eliacik ◽  
H. Goker ◽  
Y. Erbilgin ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Chronic Phase ◽  
Kinase Domain ◽  
Current Treatment ◽  
Hematopoietic Stem ◽  
Abl Kinase ◽  
Kinase Domain Mutation ◽  
Kinase Mutation

The current treatment of chronic phase chronic myeloid leukemia (CML) consists of oral tyrosine kinase inhibitors (TKIs). However, high-risk CML may present with an aggressive course which may result in blastic crisis or a “difficult-to-manage” state with available treatments. The aim of this paper is to report a patient with complicated CML resistant to treatment and progressed despite the administration of bosutinib, imatinib mesylate, nilotinib, dasatinib, interferon alpha 2a, cytotoxic chemotherapy, and allogeneic hematopoietic stem cell transplantation. The striking point of this case story is that no Abl kinase domain mutation against TKIs has been detected during this very complicated disease course of CML. Meanwhile, challenging cases will always be present despite the hope and progress in CML in the TKI era.

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