Toxicity Of Tyrosine Kinase Inhibitors Research Articles

Marrow fibrosis is an independent predictor of hematological toxicity of tyrosine kinase inhibitors for the treatment of chronic myeloid leukemia

Hematological toxicity is a common adverse effect of tyrosine kinase inhibitors (TKIs) for the treatment of chronic myeloid leukemia (CML). We retrospectively investigated the incidence of hematological toxicity after TKI administration in 143 CML patients and parameters associated with hematological toxicity. Severe hematological toxicity (grade 3–4) existed in 26 (18.2%) patients. Marrow fibrosis (MF), age, Sokal score, and spleen enlargement were associated with severe hematological toxicity. Further multivariate analysis showed that only MF was an independent predictor. Complete cytogenetic response(CCyR) rates and major molecular response (MMR) rates with grade 3–4 hematological toxicity were 42.3% and 26.9%, respectively, significantly lower than patients with grade 1–2 and without hematological toxicity (p = .032 for CCyR and p = .044 for MMR). Similar results were observed regarding progression-free survival (PFS) and overall survival (OS) (p = .011 for PFS and p = .037 for OS). This study indicated that MF was an independent predictor of severe hematological toxicity of TKIs.

Blinatumomab in Combination with Tyrosine Kinase Inhibitors Safely and Effectively Induces Rapid, Deep, and Durable Molecular Responses in Relapsed and Refractory Philadelphia Positive Acute Leukemias

Background The addition of tyrosine kinase inhibitors (TKIs) to chemotherapy improves the prognosis of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). Single agent blinatumomab, a bi-specific T-cell engaging CD3-CD19 antibody construct, is more effective than multi-agent chemotherapy in relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL) and successfully achieves minimal residual disease (MRD) negativity in MRD positive patients. Limited data is available on the safety and efficacy of these agents in combination and uncertainties remain regarding the optimal use of blinatumomab +TKIs. Dual therapy with blinatumomab and TKIs may offer a safe and effective treatment option for relapsed and refractory patients without the incorporation of chemotherapy. Patients and Methods We report our retrospective experience in 18 patients who received blinatumomab +TKI for relapsed/refractory (R/R) Ph+ ALL (n=14), MRD+ Ph+ ALL (n=2) and chronic myeloid leukemia in lymphoid blast crisis (CML-LBC) (n=2). Ten patients received ponatinib; 8 patients received second generation TKIs (dasatinib, n=5; nilotinib, n=2; bosutinib, n=1). Blinatumomab was administered according to the package insert and TKI was initiated on day 1. Median follow up was 15 months and median number of blinatumomab +TKI cycles was 2 (range, 1-5). The median age was 47 years (range, 22-77). The median number of prior therapies was 2 (range, 1-8) and the median number of prior TKIs was 2 (range 1-4). Preexisting T315I mutations were present in one third of patients and 5 patients had relapsed following allogeneic stem cell transplant (alloHSCT). Results Transient grade 2-3 transaminase elevation was observed in 3 patients (ponatinib=2, dasatinib=1). Cytokine Release syndrome was observed in 2 patients. Transient neurotoxicity was observed in 3 patients (1patient with grade 3). All grade 2 and 3 toxicities were observed during the first cycle and all patients were successfully able to complete induction with blinatumomab +TKI. One patient on dasatinib experienced a PICC-associated DVT. There were no other vascular events observed. For patients with r/r disease the CR rate was 88% (14/16) with most of these remissions being MRD negative by flow and PCR (12/14). Both of the patients treated for MRD positivity achieved an MRD negative response. Among T315I mutated patients, 5/6 achieved a CR and 4/5 were MRD negative. The median time to remission was 35 days. The 1 year survival was 80% and the median overall survival following blinatumomab therapy was 45 months. Among 16 pts who achieved an initial response to blinatumomab +TKI, six have expired at the time of this analysis. At the time of relapse on combination therapy, 3/8 pts exhibited new T315I mutations. Of note, all of these were treated with blinatumomab in combination with a second generation TKI. All patients maintained their CD19 positivity at the time of relapse. Both pts with CML-LBC were able to move to a transplant following therapy with blinatumomab +TKI and both attained MRD negative status as measured by Bcr/Abl PCR values. In total, 10 patients treated with blinatumomab +TKI proceeded to alloHSCT, 7 of these are still alive. Median duration of response (DOR) was 5.1 months with maximum DOR of 23.3 months. Discussion While limited due to its retrospective nature and relatively small sample size, this data set begins to answer important regarding the safety and efficacy of blinatumomab +TKI. Combination therapy was effective at achieving rapid and deep responses in this refractory patient population. The toxicities observed with blinatumomab +TKI were in keeping with those seen with blinatumomab alone. However, care should be taken in regard to potential overlapping toxicities of TKIs and blinatumomab, such as hepatotoxicity. The study also suggests a role for blinatumomab treatment in patients with CML-LBC, a rare and difficult disease state to treat. The identification of T315I mutation at relapse in 40% of patients on blinatumomab +second generation TKIs supports further prospective studies with ponatinib and blinatumomab in combination. Finally, loss of C19, which has relevance with regards to the potential benefit of subsequent CD19-directed therapies such as chimeric antigen receptor T-cell therapy was not seen in patients treated with blinatumomab +TKI. Disclosures McCloskey: Jazz: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Takeda: Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Abbvie: Speakers Bureau; Novartis: Speakers Bureau. Gagnon:Amgen: Speakers Bureau. Goldberg:Cancer Outcomes Tracking and Analysis (COTA) Inc.: Equity Ownership; Bristol-Myers Squibb: Consultancy; COTA: Equity Ownership. Koprivnikar:Amgen: Speakers Bureau; Pfizer: Honoraria; Novartis: Speakers Bureau; Abbvie: Speakers Bureau.

Patient Reported Outcomes (PROs) Show Superior Quality of Life (QOL) of Patients with Chronic Myeloid Leukemia (CML) Treated with First Compared to Newer Generations of Tyrosine Kinase Inhibitors (TKIs)

Background: Tyrosine kinase inhibitors (TKIs) prolong the survival of patients with chronic myeloid leukemia (CML). Nowadays, the life expectancy of these patients is approaching that of an age-matched population. Since imatinib, was first introduced 20 years ago, several newer more potent TKIs, have been approved for CML. While these drugs are effective, they come with the trade-off of adverse effects, some are common to all and some are drug-specific. Most patients will receive prolonged treatment, therefore quality of life (QOL) is becoming a major concern. QOL under these drugs has not been directly compared. Herein, we compared the QOL of patients with CML treated with imatinib, dasatinib and nilotinib using patient reported outcomes (PROs) questionnaire. Methods: This nationwide study was a joint initiative of the Israeli CML patients' organization and the division of hematology at Rabin Medical Center, Israel. Patients completed computerized questionnaires that were provided to us by the European Organization for Research and Treatment of Cancer (EORTC). The questionnaires included 30 items core questionnaire (QLQ-C30), 24 items of CML-specific questionnaire (QLQ-CML24) and additional items that were added by the researchers. Questioners are composed of functional, symptom and global health/QOL scales/items. All scales and single-item measures were standardized and the score ranges from 0 to 100. High score for functional and QOL items/scales represents better function and QOL. High score in symptoms items represents worse symptomatology. We used the Mann-Whitney test to compare medians and χ2 to compare categorical variables. Results: Overall, 195 patients completed the questionnaire. The median age was 58 years (range: 23 to 89) and of those 102 patients (59%) were males. Time from diagnosis ranged between less than a year and 46 years (median: 7 years). In the primary analysis we included 139 patients (71%) who received either imatinib (n = 70, 36%), dastainib (n = 45, 23%) or nilotinib (n = 24, 12%). We did not include the few patients who received bosutinib (n = 8, 4%), ponatinib (n = 2, 1%) or patients who discontinued treatment (n = 22, 11%). Patients on imatinib were older (median age 67 years, range : 32 to 89) compared with patients on either nilotinib (median age 50 years, range 26 to 85 ) or dasatinib (median age 47 years, range: 26 to 85) (P<0.0001), but had similar demographics and disease characteristics. The EORTC questionnaires included 34 items related to symptoms experienced by patients within the last week. These items were grouped into 13 symptom scales. Overall, the symptomatic profile was more severe in patients who received either dasatinib or nilotinib compared with imatinib. For example, compared with patients who received dasitinib or nilotinib, patients on imatinib experienced lesser limitation on daily activities (38 and 47 vs. 25 respectively, P = 0.02), less fatigue (53 and 57 vs. 37 respectively, P = 0.001) and lesser degree of impaired body image (38 and 46 vs. 26 respectively, P = 0.022). Likewise, symptom burden score was 41 in patients on nilotinib, higher than in patients receiving dasatinib (27, P = 0.005) or imatinib (30, P = 0.018). In addition, patients on imatinib had less painful episodes compared with patients on nilotinib (28 vs. 47. P = 0.014). The questionnaire included also 18 items that were grouped into 8 scales which estimated their functional status. Compared with nilotinib, patients on imatinib had better emotional functioning (77 vs. 61, P = 0.009); patients were less worried, stressed depressed or nervous. Patients were also more satisfied of the knowledge and treatment they received by their caregivers (41 vs. 19 24, P = 0.01). Finally, although patients on imatinib were older, they reported better home and work function (67) compared with either nilotinib (50) or dasatinib (50) (P < 0.001). Conclusions: Compared with nilotinib and dasatinib, patients who received imatinib reported lower levels of symptomatology. They reported less fatigue, limitation of daily activities, impaired body image and pain. They were also more satisfied by their caregiver, had better emotional functioning and were less worried, depressed or nervous. Since patients on 2nd generation TKIs were almost 2 decades younger, these differences reflect not only the TKI toxicity profile but also the generation-gap and the primary significance "Generation Y" gives to QOL issues. Disclosures Shacham: novartis: Consultancy. Sharf:Janssen: Other: Advocacy grants funding; Novartis: Honoraria, Other: Advocacy Advisory Board, Research Funding; Abbvie: Other: Advocacy grants funding; Takeda: Other: Advocacy grants funding; Incyte: Honoraria, Other: Advocacy Advisory Board, Research Funding; Pfizer: Honoraria, Other: Advocacy Advisory Board, Research Funding; BMS: Other: Advocacy grants funding, Research Funding; Roche: Other: Advocacy grants funding.

Benefits and limitations of TKIs in patients with medullary thyroid cancer: a systematic review and meta-analysis

Introduction Tyrosine kinase inhibitors (TKIs) have been used in patients with advanced medullary thyroid carcinoma (MTC); however, data on their effectiveness and safety are limited. The aim of this systematic review and meta-analysis was to document clinical response and toxicities of TKIs in advanced MTC. Methods We systematically searched major databases for articles or abstracts on TKI use in MTC patients until May 2018. Objective response (OR), defined as the sum of complete + partial response, expressed as percentage, was our primary endpoint, while disease stability, disease progression (DP), median progression-free survival (PFS), and drug discontinuation rate due to adverse events (AEs) were secondary endpoints. Pooled percentages, PFS time, and 95% CIs were reported. Results Thirty-three publications were finally included in the analysis: 1 phase IV, 2 phase III trials evaluating vandetanib and cabozantinib, respectively, 20 phase I or II studies, and the remaining 10 studies of retrospective-observational nature. OR was documented in 28.6% (95% CI 25.9-31.9) of patients. Stable disease was recorded in 46.2% (95% CI 43.3-49.1). Overall, DP was observed in 22.9% (95% CI 20.4-27.6). Grade 3 or more AEs occurred in 48.5% (95% CI 45.5-51.5) of patients, and drug discontinuation was reported in 44.7% (95% CI 41.7-47.6). In general, use of TKIs conferred a PFS of 23.3 months (95% CI 21.07-25.5). In particular, vandetanib induced an OR in 33.8% (95% CI 29.6-38.0) of patients and cabozantinib in 27.7% (95% CI 22.05-33.4). DP occurred in 23.7% (95% CI 19.9-27.6) with vandetanib use and in 22.6% (95% CI 17.4-27.9) in cabozantinib-treated patients. Sorafenib, the third most frequently studied drug, showed intermediate efficacy, but higher discontinuation rates. Conclusion Treatment with TKIs in MTC patients with progressive disease is associated with a moderate therapeutic benefit, with achievement of either disease stability or partial response in 73%. The toxicity of these drugs is not negligible, but it is, nonetheless, manageable.

A phosphoproteomic signature in endothelial cells predicts vascular toxicity of tyrosine kinase inhibitors used in CML

Key Points Newer CML kinase inhibitors increase ischemia risk and are toxic to endothelial cells where they produce a proteomic toxicity signature. This phosphoproteomic EC toxicity signature predicts bosutinib to be safe, providing a potential screening tool for safer drug development.

Preventing and Managing Cardiovascular Toxicities of Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia

Preventing and Managing Cardiovascular Toxicities of Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia

Annals for Educators - 3 April 2018.

Annals for Educators - 3 April 2018.

Bosutinib in chronic myeloid leukemia: patient selection and perspectives

During recent years, the therapeutic landscape in chronic myeloid leukemia (CML) has changed significantly. Since the clinical introduction of tyrosine kinase inhibitors (TKIs) approximately 15 years ago, patients’ concerns have shifted from reduced life expectancy toward long-term toxicities of TKI, depth of remission, and the probability of successful treatment discontinuation. Patients with newly diagnosed CML in chronic phase (at least with a Sokal score not exceeding intermediate) may now expect an almost normal life expectancy. However, even if almost 30% of all newly diagnosed chronic-phase patients might eventually be facing the prospect of a life without CML-specific treatment, based on current knowledge, most, if not all, patients would have to undergo an expected minimum of 5–8 years of TKI treatment and the majority would face a life-long exposure to the side-effects of TKIs. At present, 5 different TKIs are licensed for the treatment of CML, that is, imatinib, which is a first-generation TKI (including its generic derivatives); nilotinib, dasatinib, and bosutinib, which are second-generation TKIs; as well as ponatinib, which is a so-called third-generation TKI and is supposed to be used for patients harboring the T315I-mutation. One of the important, yet unanswered questions is the choice of the best possible TKI upfront for each individual patient. Bosutinib is currently licensed for patients with CML after failure or intolerance of at least 2 other TKIs. It can also be prescribed according to label if after failure of the first TKI therapy, another option does not seem feasible. This review focuses on the existing data on clinical efficacy, tolerability, and side effects of bosutinib treatment in CML patients with the aim to identify patient characteristics and treatment scenarios most suitable for treatment with bosutinib.

Cardiovascular Toxicity of Tyrosine Kinase Inhibitors in Patients with Chronic Myeloid Leukemia

In the present review the cardiovascular complications in patients with chronic myeloid leukemia (CML) receiving tyrosine kinase inhibitors (TKI) are discussed. It covers current views on pathogenesis of TKI cardiovascular toxicity. The pathophysiology of cardiovascular diseases (CVD) is considered as a part of the so-called pathophysiological continuum, i.e. a complex of processes developing at the molecular and cellular levels before clinical symptoms of the above diseases occur. Cardiovascular toxicity of certain TKIs can contribute to progression of pathophysiological processes in CML patients. The study of mechanisms underlying cardiovascular complications of TKI-based therapy is essential for evaluating the risks of their development in each patient. Identification of CVD predictors during TKI-based therapy can allow to elaborate a scheme for cardiovascular monitoring and safe patient management under consideration of individual risks and to avoid severe life-threatening complications.

Skin-Related Toxicity of Tyrosine Kinase Inhibitor in Thyroid Cancer

Skin-Related Toxicity of Tyrosine Kinase Inhibitor in Thyroid Cancer

The evaluation of the efficacy and toxicity of targeted treatment in non-small cell lung cancer patients – single centre experience

Introduction: Tyrosine kinase inhibitors (TKI) are the standard of treatment in patients with advanced non-small cell lung cancer (NSCLC) with EGFR (endothelial growth factor receptor) gene activating mutation. Objective: The evaluation of the efficacy and toxicity of TKI drugs in NSCLC patients treated in single centre. Material and methods: NSCLC patients treated with TKI (gefitinib, erlotynib, afatinib) between 2012– 2016 were retrospectively analysed. We evaluated: overall response rate (ORR) which is the sum of complete responses (CR) and partial remissions (PR), progression free survival (PFS), overall survival (OS) and adverse events (AE) according to CTCAE (Common Terminology Criteria for Adverse Events) scale. Results: The study group were 16 patients ORR was 50% (CR: 1, PR: 7). Median PFS and OS was 8,7 and 22,9 months respectively. Adverse events observed mainly in stage 1 and 2 were related to hyponatraemia, hyperbilirubinemia, skin toxicity and mucositis. There was one death reported due to infectious complications. Conclusion: The efficacy and toxicity of TKI in study group were found to be similar to those described in the literature.

First-line tyrosine kinase inhibitors in metastatic renal cell carcinoma: A regional cancer center experience.

Renal cell carcinoma (RCC) is highly resistant to systemic chemotherapy, and historically a poor prognosis for metastatic disease has been reported, with a 5-year survival rate of <10%. Significant advances have been made in the last decade since the introduction of different tyrosine kinase inhibitors (TKIs) such as sunitinib, pazopanib, and sorafenib. Unfortunately, even though the TKIs have been used for a long time, there are very few published data regarding the experience of TKI therapy in metastatic RCC (mRCC) from India. This is a single institutional review of mRCC patients treated between January 2012 and July 2017. Patients who received at least 1 month of first-line TKIs were included for analysis of response rates, toxicity, survival outcomes, and prognostic factors. Of the 40 mRCC patients, 31 (77.5%) were males. Median age at diagnosis was 58 years (range: 38-80 years). The most common site of metastasis was lungs (n = 24) followed by bone (n = 19) and liver (n = 7). Three patients had favorable risk disease, whereas 25 had intermediate risk and 12 had poor risk disease according to the MSKCC risk criteria. First-line TKI therapy used was sunitinib in 24, pazopanib in 11, and sorafenib in 5 patients. Toxicities of TKIs were Grade 1 or 2 in 13 patients and Grade 3 or 4 in 9 patients; the most common being fatigue, followed by hand-foot syndrome, skin rash, mucositis, and hypertension. Overall, 29 patients (72.5%) had disease control (complete responses in 1, partial responses in 10, and stable disease in 18 patients), whereas 11 had progression of disease at initial evaluation. At a median follow-up of 16 months (range: 2-38 months), median progression-free survival (PFS) was 10.8 months and median overall survival was 19.1 months. Sunitinib and pazopanib are viable first-line options for mRCC and showed a comparable PFS in Indian patients. Careful patient selection, tailoring of TKI doses, and careful toxicity management are essential for optimum therapy.

Differential Toxicities of Tyrosine Kinase Inhibitors in the Management of Metastatic Lung Cancer.

Introduction:Erlotinib and gefitinib are the most commonly used epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) in the treatment of EGFR mutant nonsmall cell lung cancer (NSCLC). Both erlotinib and gefitinib have shown equal efficacy in terms of response rates and overall survival. Hence, their toxicity profile becomes the most important determining factor in choosing these agents when treating EGFR mutant NSCLC. In this study, we compared the toxicity profile of erlotinib and gefitinib among an Indian subset of lung cancer patients.Materials and Methods:In this prospective nonrandomized study, 85 patients of South Indian origin with NSCLC were tested for EGFR mutation status, and EGFR mutant patients were started on either erlotinib or gefitinib. They were periodically monitored for drug toxicities.Results:Out of the 85 patients tested, 34 patients were positive for EGFR mutation. Eleven of them were started on erlotinib and 23 were started on gefitinib. The most common side effect of TKIs was skin rash. Nine out of the 11 patients started on erlotinib and 7 of the 23 patients started on gefitinib had skin rash. Grade 3 and 4 skin rash was significantly more among patients treated with erlotinib which resulted in treatment delays. Other side effects of TKIs such as diarrhea and deranged liver functions were similar among the both subsets of patients.Conclusion:Skin toxicity is the major and serious side effect with erlotinib among Indian patients with EGFR mutant lung cancer. This resulted in significant treatment delay, which might adversely affect the overall survival of patients. Gefitinib was better tolerated and had a safer toxicity profile compared to erlotinib in Indian patients.

P2.03b-084 Profiling of Eph Signaling in Malignant Pleural Effusions- Identification of Therapy Approaches and Associated Biomarkers: Topic: Biomarkers

For late stage lung cancer (LC) patients few treatment options are at hand and the survival time is very limited, hence novel therapies and associated biomarkers are urgently needed. Erythropoietin-Producing Hepatocellular carcinoma receptor (Eph) tyrosine kinase family and their ligands, Ephrins, drive multiple hallmarks of cancer e.g. proliferation/invasion. The Eph signaling pathways are attractive drug targets due to their dual role in oncogenesis and tumor progression. We analyzed Ephs/Ephrins signaling in LC cells from pleural effusions (PE) to reveal altered kinase pathways and putative BMs. We also assessed cytotoxicity and kinome alterations in PE tumor cells exposed to targeted agents and chemotherapy in vitro. Tumor cells purified from PE, assessed for histology, mutation and translocation status (EGFR, KRAS, BRAF and Alk), were grown in vitro. Toxicity of tyrosine kinase inhibitors (TKIs (e.g. erlotinib, crizotinib, AG1024, AZD9291, dasatinib), EGFR blocker (cetuximab) and/or chemotherapy (e.g. cisplatin, gemcitabine, etoposide) were analyzed after 72 h with the Tox8 assay. Ephs/Ephrins signaling components were studied using western blot, immunoprecipitation and by proximity ligation assay. Mutations and signaling heterogeneity were visualized using padlock probe method. For kinome profiling PathScan RTK signalling antibody array was used. PE isolated tumor cells were identified as adenocarcinoma, squamous cell carcinoma and SCLC and their EGFR, KRAS, BRAF and Alk mutational status determined. High levels of Ephrin B3 and phosphorylated EphA2 ser897, previously shown to be instrumental in driving NSCLC proliferation and invasion in vitro, were confirmed and also shown to directly interact, indicating the importance of this signaling event. The G391R mutation in EphA2, which is reported to cause a constitutive activation of EphA2 and to be linked to metastasis, but also mutations in EGFR (G719A, G719S, T790M and L858R) were detected. The PE derived tumor cells were hetereogenous in their survival response to TKIs and chemotherapy. However, cells with ALK translocation were sensitive to crizotinib and EGFR mutated cells showed response to erlotinib, cetuximab, AG1024, AZD9291 and dasatinib. Kinome analysis revealed selective signaling pathways that could also be targeted in combinational drug treatment. Screening of PE samples from LC patients for targeted agents alongside aberrant Ephs and kinome signaling, can be used to identify novel drug candidates. Together with frontline kinome profiling of NSCLC clinical specimens upon treatment it provides an opportunity to explore/identify new therapeutics for LC.

Impact of Long-Term Tyrosine Kinase Inhibitor Exposure on Spermatogenesis in Juvenile Rats

Background: Pediatric patients with chronic myeloid leukemia (CML) are exposed to off-target side effects from long-term treatment with tyrosine kinase inhibitors (TKIs) which have been observed with increasing watchfulness in the last years (Hijiya N, et al. BLOOD 127:392, 2016). TKIs inhibit c-kit and platelet-derived growth factor receptors (PDGF-R alpha/beta) which are known to regulate spermatogenesis (Zhang M, et al. SCI REP 4:5936, 2014). The influence of TKIs on spermatogenesis in pediatric patients with CML is not fully understood yet (Samis J, et al. PEDIATR BLOOD CANCER 63:1332, 2016). Therefore, we studied testicular tissue in juvenile rats following exposure to TKIs imatinib (IMA) and dasatinib (DASA) in a time and dose-dependent manner.Methods: Using an established model (Tauer JT, et al. PLOS ONE 10:e0131192, 2015) of juvenile still growing Wistar rats, animals (age: 4 weeks [w]) were exposed to IMA or DASA at different dosages for 10 w (low dose [LD], high dose [HD], intermittently high dose [ID]; total number of rats: 20 to 32 animals, 5 - 8 rats per cohort). At defined developmental stages, that is at prepubertal age (6 w), pubertal age (8 w), and postpubertal age (14 w), testis weight as well as cellularity (spermatogonia, spermatocytes, spermatids, Ki-67 positive cells) were evaluated histopathologically in seminiferous tubule microscopic cross sections after continuous IMA treatment. Expression of genes involved in spermatogenesis comprising SCF and PDGF-alpha/beta as well as their corresponding receptors c-kit and PDGFR-alpha/beta (Nurmio M, et al. REPRODUC TOXICOL 25:442, 2008) was studied after continuous DASA exposure.Results: Testis weight remained unchanged compared to non-exposed controls by exposure to any TKI. However, spermatogenic cell counts decreased significantly by 10% after IMA HD-exposure. In spermatogenesis cell cycle, the stage of the dominant cell proportion (stage VII according to Perey B, et al. AM J ANAT 108:47, 1961) was shifted to more immature stages (stage II/III) as well. LD- and ID-exposure with IMA attenuated these findings. Cell proliferation as investigated by Ki-67+ expression was significantly lowered by 10% - 20% at all applied IMA doses. Long-term DASA treatment at LD, HD and ID resulted in significantly reduced gene expression of SCF, c-kit and PDGF-R alpha/beta. Gene expression of PDGF-alpha was significantly decreased in HD and ID but not LD, whereas PDGF-beta showed no significant reduction postpubertally.Conclusion: Long-term TKI toxicity in still growing organisms can easily be modelled in juvenile rats and emulates well the so-far clinical experience with regard to osseous side effects of TKIs (Millot F, et al. EUR J CANCER, 50:3206, 2014). Assessment of gonadal toxicity by isolated determination of testis weight represents a rather unspecific approach and will neglect subtle histopathological changes. With regard to spermatogenesis long-term TKI exposure resulted in reduced progenitor cell proliferation and downregulation of involved genes in a cumulative dose-dependent fashion. Thus, at least in juvenile, still growing Wistar rats a long-lasting negative effect of long-term TKI exposure on spermatogenesis has to be taken into account. Improved preclinical testing in well-established leukemia models should help to prioritize TKI agents in the clinical studies pipeline for pediatric patients with CML. Long-term follow-up of pediatric and adolescent patients who are given new targeted agents is mandatory and will prospectively explore potential late effects, and hopefully also provide corrective or preventive measures. DisclosuresGlauche:Bristol Meyer Squib: Research Funding. Suttorp:Novartis, Bristol Meyer Squib, Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

The Tyrosine Kinase Inhibitor Sunitinib Affects Ovulation but Not Ovarian Reserve in Mouse: A Preclinical Study.

The aim of the study was to evaluate ovarian toxicity of tyrosine kinase inhibitor (TKI) sunitinib, since only scarce data are available on gonadal function after this treatment. Six-week-old female mice received orally, once daily, vehicle or sunitinib (50 mg/kg/d) during 5 weeks. Fertility parameters were analyzed from ovulation to litter assessment. Sunitinib exposure significantly reduced (i) corpora lutea number per ovary (1.1 ± 0.38 in sunitinib group versus 4 ± 0.79 in control group, p<0.01) and (ii) serum Anti Müllerian hormone (AMH) levels in sunitinib treated mice (12.01 ± 1.16) compared to control mice (14.33 ± 0.87 ng/ml, p< 0.05). However, primordial and growing follicles numbers per ovary were not different in both groups. After treatment withdrawal, female mice in both groups were able to obtain litters. These data could be helpful to counsel clinicians and patients, when fertility preservation methods are discussed, before TKI treatment in girls and young women.

Toxicity of tyrosine kinase inhibitors in the treatment of thyroid cancer - a 10-year experience resume

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Therapy of endocrine disease: response and toxicity of small-molecule tyrosine kinase inhibitors in patients with thyroid carcinoma: a systematic review and meta-analysis.

Many tyrosine kinase inhibitors (TKIs) have been studied in patients with thyroid carcinoma (TC). However, the effect and toxicity of various TKIs in differentiated TC (DTC) and medullary TC (MTC) patients have not been directly compared. The aim of the present systematic review and meta-analysis was to systematically summarize response and toxicity of TKIs in TC patients. All major databases were systematically searched for publications on TKIs in TC. Primary endpoint was objective response; secondary endpoints were clinical benefit, percentage TKI dose reduction/discontinuation, hand-foot syndrome, diarrhea, and nausea/vomiting. Meta-analysis was performed using an exact likelihood approach and a logistic regression. Pooled percentages and 95% CIs were reported. In total, 22 publications were included. For DTC patients, gefitinib induced no objective responses. Pooled percentage was highest for pazopanib, 49 (95% CI 33-64)%, and was 17 (95% CI 12-24)% for sorafenib. For MTC, gefitinib and imatinib induced no objective responses, whereas sunitinib induced objective response in 43 (95% CI 14-77)%. For vandetanib and cabozantinib, these numbers were 40 (95% CI 34-46)% and 27 (95% CI 22-32)% respectively. Clinical benefit was found in 53 (95% CI 48-59)% of DTC patients on sorafenib, and in 84 (95% CI 79-88)% and 55 (95% CI 49-61)% of MTC patients on vandetanib and cabozantinib respectively. All TKIs were associated with considerable toxicity. The currently studied TKIs show a modest response, while side effects are not negligible. Therefore, we suggest to solely consider TKIs in TC patients with rapid progressive disease, for whom the benefits of treatment outweigh toxicity.

Improvement in lung cancer outcomes with targeted therapies: an update for family physicians.

In the past decade the advent of target therapy has led to a silent revolution in the treatment of lung cancer. Thanks to the specificity of their target, new tailored drugs are able to achieve a larger benefit and lower toxicity and provide better quality of life than cytotoxic drugs in a limited number of patients, selected by molecular profile. Nowadays, the epidermal growth factor receptor tyrosine kinase inhibitors erlotinib and gefitinib, and the anaplastic lymphoma kinase inhibitor crizotinib, are targeted agents approved for treatment of non-small-cell lung cancer. Family physicians play an important role in the treatment, detection, and management of common toxicities and in providing emotional support. Therefore this review integrates molecular profile assessment with evidence of the efficacy and toxicity of tyrosine kinase inhibitors to provide an updated overview of the treatment of non-small-cell lung cancer, which radically changed after the advent of targeted therapies. It also aims to promote a more intensive and interactive collaboration between specialists and family physicians in the management of all phases of cancer care.

Treatment Cessation in Chronic Myeloid Leukemia As a Part of Treatment Process: Toxicity Determined and Active Stop of Tyrosine Kinase Inhibitors

Background: Clinical trials demonstrate a safe discontinuation possibility of tyrosine kinase inhibitors (TKI) in patients with deep molecular response (MR). However reasons and indications for TKI cessation as a part of treatment process have not been studied.Aims: To evaluate the eligibility of long term TKI cessation in CML patients with deep and long lasting MR. To describe the reasons of stopping therapy, principles and terms of observation without treatment, preserving and restoring of MR.Methods: We summarized retrospectively and prospectively 25 TKI discontinuation cases in 2 clinics of Russian Federation (Moscow, St.Petersburg, 2008-2014). Inclusion criteria were: 1) Ph+CML 2) MR4 (BCR-ABL<0,01%) for >12 months confirmed by >2 consecutive analyses 3) discontinuation of TKI treatment. Chronic phase (CP)/accelerated phase (AP) at diagnosis was 24/1. Sokal score for CP patients was 15/8/1 for low/intermediate/high risl group. Therapy before discontinuation was the following: imatinib 1st line (n=16), 2nd generation TKI (TKI2) 2nd-3rd line (n=9): 5 dasatinib/ 4 nilotinib. Me TKI duration was 7,2 (range 2,5-13) years, Me MR4 duration was 50 (range 12-97) months. IFN before TKI was received by 13(52%) of 25 patients for Me 18 months (2-60 months).Results: We specify 2 reasons of TKI discontinuation: 1) adverse events (AE) of TKI (Toxicity Group), n=18 2) self decision of patients (Active Group), n=7 (Table 1).Table 1Characteristics of CML patients according to reason of stopping TKI (n=25)Toxicity Group (n=18)Active Group (n=7)Ме of age, years (min-max)55 (27-74)36 (23-58)Ratio male/female (m:f)9m:9f3m:4fМе duration of TKI therapy, years (min-max)5,9 (2,5-13)8,6 (4,4-10,1)Ме duration of МО4 at treatment cessation, months (min-max)41 (12-97)67 (33-79)In Toxicity Group therapy was stopped for 1) AE grade 1-3 in 5 of 18 patients: unstable angina (2), hepatotoxicity (1), acute renal failure (1), menstrual dysfunction and infections (1); 2) AE grade 1-2 in 13 of 18 patients including recurrent or long lasting: fatigue, edema, arthralgia, muscle cramps, diarrhea, recurrent pleural effusion. The key clinical decision was not to restart TKI after AE termination and to continue monitoring of BCR-ABL transcript levels by RQ-PCR. For Active Group self-made discontinuation was in 7 patients with long lasting MR4 due to knowledge of safe discontinuation (4) and for conception (3). In 6 of 7 patients BCR-ABL monitoring was performed, 1 patient refused from monitoring.Treatment was restarted at major molecular response (MMR) loss (BCR-ABL>0,1%) or by decision of physician. In case of severe AE the patients were switched to alternative TKI.Thirteen (52%) of 25 patients were observed without treatment for Me 23 months (6-77 months), in 12 MR4 was maintained, 1 patient being off treatment for 54 months refused from monitoring (Active Group). Therapy was resumed in 10 patients with MMR loss and in 2 without MMR loss, by physician decision. All MMR loss cases occurred within first 6 months, no CML progression observed. Response restoration to MR4 was in 8 of 10 patients in 3-16 months, in other 2 it is early to estimateSummary/Conclusion: Observation without therapy may become an option in CML patients with mostly low/intermediate Sokal risk group, stable MR4 and recurrent/severe TKI toxicity. Self declared decisions of young patients with durable deep MR should be accompanied by regular RQ-PCR especially within first 6 months after TKI discontinuation. Resuming therapy at MMR loss shows to be safe. DisclosuresNo relevant conflicts of interest to declare.