Hyperpigmented rash of imatinib

The c-KIT receptor tyrosine kinase is constitutively activated and oncogenic in the majority of gastrointestinal stromal tumors. The identification of selective inhibitors of c-KIT, such as imatinib, has provided a novel therapeutic approach in the treatment of this chemotherapy refractory tumor. However, despite the clinical importance of these findings and the potential it provides as a model system for understanding targeted therapy, this approach has not yielded curative outcomes in most patients, and the biochemical pathways connecting c-KIT inhibition to cell death are not completely understood. Here, we show that inhibition of c-KIT with imatinib in gastrointestinal stromal tumors (GISTs) triggered the up-regulation of the proapoptotic protein BIM via both transcriptional and post-translational mechanisms. The inhibition of c-KIT by imatinib increased levels of the dephosphorylated and deubiquitinated form of BIM as well as triggered the accumulation of the transcription factor FOXO3a on the BIM promoter to activate transcription of BIM mRNA. Furthermore, using RNA interference directed against BIM, we demonstrated that BIM knockdown attenuated the effects of imatinib, suggesting that BIM functionally contributes to imatinib-induced apoptosis in GIST. The identification and characterization of the pathways that mediate imatinib-induced cell death in GIST provide for a better understanding of targeted therapy and may facilitate the development of new therapeutic approaches to further exploit these pathways.

The Effect of Nilotinib in Chronic Myeloid Leukemia Treatment Dose on Spermatogenesis and Folliculogenesis in a Healthy Mouse Model

Identification of Biological and Pharmaceutical Mast Cell‐ and Basophil‐Related Targets

Introduction: Cholangiocarcinomas (CCA) are aggressive tumors with poor prognosis. A large number of CCA patients are already in late stage at diagnosis so are only amenable to systematic therapies. Traditional systematic therapies are often associated with high toxicity and low efficacy. Several advanced therapies, including immune checkpoint inhibitors (ICI) and tyrosine kinase inhibitors (TKI) are under testing against CCA. These efforts are highlighted by the recent FDA approval of pemigatinib, which blocks FGFR2 activation. Combination use of anti-angiogenesis agents with ICI or TKI are also hot research areas. However, data are lacking to demonstrate the real-world value of the above advanced or testing therapies. Here we aim to use a real-world CCA patient set to explore the clinic value and best strategy of combination therapy in CCA. Methods: We retrospectively enrolled 286 CCA patients with a majority (219) of intrahepatic CCA. In total, 73 patients received anti-PD-1/L1 therapies, including mono-use of pembrolizumab (19), camelizumab (12), nivolumab (11), toripalimab (7), and sintilimab (4), and mixed-use (8) or unspecified (12) of the above anti-PD-1/L1 agents. On the other hand, 68 patients received one or more treatment of anlotinib, apatinib, regorafenib, and sorafenib/sorafenib tosylate TKIs. We performed whole-exome sequencing (WES) (all 286 patients) and RNA-seq (200 patients) to analyze the patients' somatic mutation profiles and tumor microenvironment (TME). We also analyzed their survival benefits stratified by TME, treatment, and gene mutation/fusion status. Results: We identified 59 patients with FGFR family gene copy number (CNV) gain or gene fusion (9 in FGFR2). Treatment with the above five mentioned TKIs show good prognosis (2-year survival rate 100% vs. 60% in un-treated, p=0.057). However, lenvatinib, an anti-VEGF angiogenesis inhibitor, showed no survival benefit in the 59 patients (HR 0.879, p=0.837). This conclusion was largely recapitulated in 114 patients who had higher transcription (top quartile) of FGFR family genes. Treatment with the first 5 TKIs (counted together) gave HR 0.395 (treated vs. non-treated, p=0.041), while lenvatinib gave HR 0.586 (p=0.164). For the 184 patients with survival data, the above mentioned anti-PD-1/L1 treatments gave HR 0.667 (treated vs. un-treated, p=0.073). Among these who received anti-PD-1/L1 treatment, 64 also received lenvatinib treatment and they gave HR 0.647 (treated vs. non-treated, p=0.265). Conclusion: Multi-TKIs and ICIs treatment are effective in prolonging patient lives in CCA. The combination use of lenvatinib with other TKIs has limited survival benefit. However, it has a trend of giving some additional benefit when in combination with anti-PD-1/L1 therapies. However, more testings are needed to confirm this. Citation Format: Jun Liu, Junning Cao, Guan Wang, Bingyang Hu, Chun Dai, Shengzhou Wang, Fei Xu, Qiang Xu, Shichun Lu. Analysis of efficacy of receptor tyrosine kinase and immune checkpoint inhibitors and insights to potential combinatorial treatment strategies in cholangiocarcinomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 944.

Targeting Chronic Myeloid Leukemia Stem/Progenitor Cells Using Immunolipsome Loaded Venetoclax

This article reports the case of a paediatric patient who experienced depigmentation of his hair, eyelashes and eyebrows, four-to-six weeks after initiating treatment with Dasatinib (BMS-354825, Sprycel®), a novel dual Bcr-Abl/Src family tyrosine kinase inhibitor for chronic myeloid leukaemia (CML). This case illustrates a previously unreported side-effect of Dasatinib that is most likely due to the drug's inhibition of the c-kit, Src family, and platelet-derived growth factor receptor-beta (PDGFR-beta) tyrosine kinases. Hair depigmentation has been shown to occur with disruption of the interaction between the c-kit ligand stem cell factor (SCF) with its class III receptor tyrosine kinase c-kit, localized on melanocytes’ surface. Further studies on cutaneous depigmentation as a side effect of multi-kinase inhibitors can provide useful informations on hair and melanocyte physiology.

Selective Inhibition of Tyrosine Kinases – a New Therapeutic Principle in Oncology Tyrosine kinases are enzymes that regulate mitosis, differentiation, migration, neovascularization, and apoptosis. Their spectrum and association with specific malignancies offer multiple targets for therapeutic intervention. Chronic myelogenous leukemia (CML) represents an ideal target for a therapy using a selective inhibitor of the BCR-ABL tyrosine kinase. The 2-phenylpyrimidine derivative STI571 was rationally designed to inhibit ABL and BCR-ABL tyrosine kinase activities through competitive ATP-binding pocket interactions. Phase II data demonstrate hematologic and cytogenetic responses in interferon refractory chronic-phase, accelerated-phase and blast crisis patients. However, long-term observation is needed to confirm that response data result in prolongation of survival. STI571 is being studied in other malignancies, including leukemias characterized by expression of alternate molecular forms of BCR-ABL and those expressing protein tyrosine kinases with ATP-binding pockets structurally similar to ABL, e.g. c-kit and PDGF-R. Gastrointestinal stromal tumor (GIST) cells overexpress the stem cell factor receptor CD117, the product of the proto-oncogene c-kit. Inhibition of c-kit in vivo results in an immediate metabolic change of the tumor cells, detectable by positron emission tomography. Since c-kit overexpression is inhibited in small-cell lung cancer cell lines, a study with STI571 as second-line therapy of c-kit-positive small-cell lung cancer is in progress. Clinical studies are ongoing in malignancies associated with an enhanced activity of the PDGF-R, such as highgrade glioma, prostate cancer and leukemias with rearrangements of PDGF-R. The development of selective tyrosine kinase inhibitors is considered a promising approach for the design of new drugs. Clinical responses to STI571 in various malignancies may stimulate greater interest in the clinical use of tyrosine kinase inhibitors.

Discontinuation of Tyrosine Kinase Inhibitor in Children with Chronic Myeloid Leukemia (JPLSG STKI-14 study)

CML Patients Show Sperm Alterations At Diagnosis That Are Not Improved On Tyrosine Kinase Inhibitor Treatment

The discovery of mutations in tyrosine kinases (TKs) involved in the pathogenesis of many diseases, particularly oncological, encouraged the investigation of inhibitors of tyrosine kinases (ITKs) as therapeutic strategies.The aim of this study was to perform a review of the different ITKs available in the national and international markets, their therapeutic indications, and their potential directions in research. It was also a revision of the main ITKs which are currently being evaluated in various stages of clinical trials.We conducted a literature search in the PubMed electronic database using the term “tyrosine kinase inhibitors” and 219 publications were included in the present review, published from August 2011 to July 2012. We also consulted the databases of the Portuguese National Authority of Medicines and Health Products, IP (INFARMED), the European Medicines Agency (EMA) and the United States Food and Drug Administration (FDA).Presently there are 14 ITKs approved by FDA. In Portugal there are 13 ITKs with marketing authorization (MA), and bosutinib currently in the authorization phase. There are ITKs approved for the treatment of chronic myeloid leukemia, acute lymphoblastic leukemia, carcinoma of non-small-cell lung cancer, renal cell carcinoma, hepatocellular carcinoma, breast cancer, gastrointestinal stromal tumor, pancreatic neuroendocrine carcinoma, thyroid carcinoma, myelofibrosis and soft tissue sarcomas. ITKs are under investigation for other potential indications such as autoimmune diseases, namely rheumatoid arthritis and psoriasis, among others.Because there is a wide variety of TKs and not all of them are yet studied, more research is needed so that other potential therapeutic targets can be discovered in the future. The TKs are therefore a promising therapeutic target, which makes the ITKs a pharmacological class with great clinical potential.

In Pursuit of Surrogate Markers for Treatment-Free Remission in Patients with Chronic Myeloid Leukemia from Argentina Stop Trial

Incidence rates of chronic myeloid leukemia (CML) and Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) are lower but more aggressive in children than in adults due to different biological and host factors. After the clinical application of tyrosine kinase inhibitor (TKI) blocking BCR/ABL kinase activity, the prognosis of children with CML and Ph+ ALL has improved dramatically. Yet, off-target effects and drug tolerance will occur during the TKI treatments, contributing to treatment failure. In addition, compared to adults, children may need a longer course of TKIs therapy, causing detrimental effects on growth and development. In recent years, accumulating evidence indicates that drug resistance and side effects during TKI treatment may result from the cellular metabolism alterations. In this review, we provide a detailed summary of the current knowledge on alterations in metabolic pathways including glucose metabolism, lipid metabolism, amino acid metabolism, and other metabolic processes. In order to obtain better TKI treatment outcomes and avoid side effects, it is essential to understand how the TKIs affect cellular metabolism. Hence, we also discuss the relevance of cellular metabolism in TKIs therapy to provide ideas for better use of TKIs in clinical practice.

Deep Molecular Response Achieved By Second-Generation Tyrosine Kinase Inhibitors (TKIs) Can Lead to Stopping TKIs

In the last decades, the chronic myeloid leukemia (CML) therapeutic landscape has changed dramatically with the introduction of tyrosine kinase inhibitors (TKIs), with 10-year survival rates improving to up to 80%. Long-lasting TKI treatment, in particular with second-generation TKIs, has enabled clinicians to manage the onset of several side effects and other co-morbidities, such as atrial fibrillation or venous thromboembolism (VTE). We retrospectively evaluated nine CML patients treated with TKIs between 2017 and 2020 who experienced atrial fibrillation or VTE and received concomitant administration of TKIs and direct oral anticoagulants (DOACs) outside clinical trials, to evaluate the efficacy and safety of this combination. Median age was 66 years at CML diagnosis (range 52-73 years) and 69 years at the time of starting DOACs. A female predominance was observed. The median follow-up of concomitant DOAC and TKI administration was 8.5 months; edoxaban was administered in six patients and apixaban in two patients, and one patient received rivaroxaban. Regarding CML treatment, four patients received imatinib, two patients bosutinib, and three nilotinib. In eight patients DOACs were started for atrial fibrillation and in one patient for VTE. In none of the patients treated with the combination were additional symptomatic thrombotic adverse events or major bleedings reported. In this small case series, the use of DOACs in CML patients seemed feasible. Additional data on long-term outcomes including a larger cohort of CML patients treated with DOACs are, however, needed.

6602 Background: Management of CML has been transformed by targeted therapies like TKI. It has been described in clinical trial that an increased OS of pts giving hope but also opportunity to observe late effects of TKI treatment (Tt) as an increased occur of K. Our objective was to evaluate in a real life cohort of CML pts the impact of TKI on OS and to report new diagnosed K occurring during Tt. Methods: We conducted a retrospective, observational study from the CML database including all consecutive pts with CML into a French regional network. Included criteria were cytogenetic (Cg) or molecular (MB) proved CML. Clinical and biological data, Tt response and outcome including other K were collected and statistically analyzed. Results: We identified 176 pts with CML diagnosed since 1978, SR 1.2, median age 59 (22-84), regional incidence 1.08 vs 1 in France. At diagnosis, pts were in CML-CP 92% (n = 162), CML-AP 5.7% (n = 10), CML-BC 0.6% (n = 1), missing (ND) 1.7% (n = 3). Sokal < 0.8 for 61% (n = 108), 0.8-1.2 for 24% (n = 42), > 1.2 for 11% (n = 19), ND for 4% (n = 7). t(9,22) or Bcr-Abl expressing in MB was 100% with another Cg abnormality in 8%.Tt was non TKI 28% (n = 49), TKIs for 72% (127/176) with 54% (n = 68) in first line, 20% (n = 26) second line and 26% (n = 33) third line or more. In TKI cohort: RCC at 6, 12 and 24 months (m) were respectively 57%, 66%, 83% and MMR/CMR at 6, 12 and 24 m were 14%, 23%, 37%. K occurred during TKI in 12 pts (9.6%), SR 1.4, median age 76 (59-86), median follow up of CML 40.5 m (28-137), median duration TKI: 37 m (26-77). Histologic type of K : 3 prostate, 2 colon, 1 breast, 1 pancreas, 1 lung, 1 parotid, 1 melanoma, 1 renal and 1 bladder. 92% (n = 11) were treated for K, 75% (n = 9) still alive with TKI. Median OS of pts never receiving TKI: 4 y, receiving TKI in second line or more: 18 y, TKI in first line: not reached (p < 0.0001). Conclusions: In real life,TKI Tt with monitored response according to the guidelineshad improved median OS of pts non included in clinical trial, even if they already received several lines of Tt. The occurence of K diagnosed during TKI in our study was 9.6% vs. 4.07% reported in another study (Verma ASH 2008). The older median age in our series (76 y vs. 67 y) may explain the higher rate of K. No significant financial relationships to disclose.