Tumour Lysis Syndrome in Solid Tumours Associated with Tyrosine Kinase Inhibitors – A Case Illustrated Review

There are a variety of tyrosine kinase inhibitors (TKIs) that are used in oncology for the treatment of malignancies now and consequently there have been increased observations of tumour lysis syndrome (TLS) associated with these drugs. As per the Cairo-Bishop criteria, laboratory and clinical TLS is typically diagnosed within 3 days before and 7 days after cytotoxic chemotherapy is started. In this report, we describe a case of TLS in a patient with gastrointestinal stromal tumour (GIST) that occurred 15 days after commencement of imatinib. In addition, in a review of the literature, we have found that TLS in solid tumours is observed on average 10 days (95% confidence interval [CI] 7.8–13.7) and up to 3 weeks after initiating TKIs. By comparison, TLS in patients with solid organ tumours treated with cytotoxic chemotherapy occurs within 3 days (95% CI 2.9–4.4). Given the high rate of mortality and the morbidity inherent to TLS, clinicians should be aware that in solid tumour, TKIs may be associated with a delayed onset of TLS.

Download Full-text

Safety and efficacy of addition of VEGFR and EGFR-family small-molecule tyrosine kinase inhibitors to cytotoxic chemotherapy in solid cancers: A meta-analysis.

Journal of Clinical Oncology ◽

10.1200/jco.2014.32.4_suppl.415 ◽

2014 ◽

Vol 32 (4_suppl) ◽

pp. 415-415

Author(s):

Tomohiro Funakoshi ◽

Asma Latif ◽

Matt D. Galsky

Keyword(s):

Adverse Events ◽

Tyrosine Kinase ◽

Tyrosine Kinase Inhibitors ◽

Small Molecule ◽

Randomized Trials ◽

Kinase Inhibitors ◽

Meta Analysis ◽

Cytotoxic Chemotherapy ◽

Safety And Efficacy ◽

Egfr Family

415 Background: The approach of combining cytotoxic chemotherapy with small molecule tyrosine kinase inhibitors (TKIs) has been explored in a large number of randomized trials, in a diverse range of tumor. We performed a systematic review and meta-analysis to evaluate the safety and efficacy of this therapeutic approach. Methods: PubMed and the ASCO databases were searched up to March 2013. Eligible studies included randomized trials in which the FDA approved TKI in combination with chemotherapy was compared with chemotherapy alone in patients with any type of solid cancer. The endpoints included safety [fatal adverse events (FAEs), treatment discontinuation, any severe (grade 3 or 4) adverse events (AEs), and individual severe AEs] and efficacy [progression-free survival (PFS), and overall survival (OS)]. The pooled relative risk (RR) or hazard ratio (HR), with corresponding 95% confidence intervals (CI) were calculated. Results: A total of 16,011 patients from 43 trials were included. Among the 43 trials, ten met their primary efficacy endpoints. Among the 21 phase III trials, two led to Food and Drug Administration approval for the combination. Compared with chemotherapy alone, the addition of a TKI significantly increased the risk of FAEs (RR, 1.63; 95% CI, 1.32-2.01), treatment discontinuation (RR, 1.80; 95% CI, 1.58-2.06), and any severe AE (RR, 1.25; 95% CI, 1.16-1.36). Compared with chemotherapy alone, the addition of a TKI was associated with a significant improvement in PFS (HR, 0.82; 95% CI, 0.76-0.89), but not OS (HR, 0.99; 95% CI, 0.95-1.03). Chemotherapy plus TKI was also associated with a significant higher risk of seven of the 11 evaluated individual AEs: neutropenia (RR, 1.18; P =.004), thrombocytopenia (RR, 1.70; P <.001), febrile neutropenia (RR, 1.48; P <.001), hypertension (RR, 3.01; P <.001), skin toxicities (RR, 6.38; P <.001), diarrhea (RR, 2.57; P =.002) and fatigue (RR, 1.35; P <.001). Conclusions: The addition of a VEGFR or EGFR-family TKI to chemotherapy in solid cancers increases the risk of severe toxicities and treatment discontinuations. These findings might explain the general lack of a survival benefit with these regimens.

Download Full-text

MicroRNAs as Mediators of Resistance Mechanisms to Small-Molecule Tyrosine Kinase Inhibitors in Solid Tumours

Targeted Oncology ◽

10.1007/s11523-018-0580-3 ◽

2018 ◽

Vol 13 (4) ◽

pp. 423-436 ◽

Cited By ~ 2

Author(s):

Michele Ghidini ◽

Jens C. Hahne ◽

Melissa Frizziero ◽

Gianluca Tomasello ◽

Francesco Trevisani ◽

...

Keyword(s):

Tyrosine Kinase ◽

Tyrosine Kinase Inhibitors ◽

Small Molecule ◽

Kinase Inhibitors ◽

Resistance Mechanisms ◽

Solid Tumours

Download Full-text

A New Monoclonal Antibody that Blocks KIT Dimerisation and Inhibits Gastrointestinal Stromal Tumour Growth

10.21203/rs.3.rs-48780/v1 ◽

2020 ◽

Author(s):

Chen Guang Bai ◽

Yi Xu ◽

Cen Qiu

Keyword(s):

Monoclonal Antibody ◽

Cell Growth ◽

Tyrosine Kinase ◽

Tyrosine Kinase Inhibitors ◽

Kinase Inhibitors ◽

Gastrointestinal Stromal Tumour ◽

Signalling Pathway ◽

Stromal Tumour ◽

Growth Responses ◽

Kit Mutation

Abstract Gastrointestinal stromal tumour (GIST) is the most common sarcoma of the gastrointestinal tract, and arises owing to oncogenic mutations in c-kit that result in constitutive auto-phosphorylation of KIT in the absence of ligand binding. Small-molecule tyrosine kinase inhibitors have shown good clinical activity by inhibiting ATP binding to the receptor. Unfortunately, majority of patients eventually develop drug resistance, which limits the long-term benefits of the tyrosine kinase inhibitors and poses a significant challenge in the clinical management of GIST. Here, we demonstrate c-kit mutation-driven KIT auto-dimerisation prior to tyrosine kinase phosphorylation as same as the procedure in ligand-dependent signalling pathway and describe a monoclonal antibody, KITMAb, with strong affinity to the dimerisation domain of KIT that blocks the important step in both the KIT signalling pathways. Treatment of KIT-dimer-expressing cells with the KITMAb slowed down cell growth. Furthermore, KITMAb reduced the proportion of cells in the proliferative phase (S+G2-M). Finally, we also demonstrate that KITMAb treatment accelerated cell apoptosis. These results indicate that KITMAb strongly inhibits KIT receptor dimerisation-mediated signalling pathway and cell growth responses in vitro. Further, the results suggest that treatment with KITMAb may be potentially therapeutic in imatinib-resistant GIST.

Download Full-text

Tyrosine Kinase Inhibitors and Solid Tumours: Case Report and Review of the Literature

Pharmacology ◽

10.1159/000225970 ◽

2009 ◽

Vol 84 (1) ◽

pp. 38-41 ◽

Cited By ~ 6

Author(s):

F. Roszkiewicz ◽

R. Garidi ◽

I. Vaida ◽

B. Royer ◽

A. Parcelier ◽

...

Keyword(s):

Case Report ◽

Tyrosine Kinase ◽

Tyrosine Kinase Inhibitors ◽

Kinase Inhibitors ◽

Solid Tumours ◽

Review Of The Literature

Download Full-text

The Risk of Herpes Zoster in Patients with Non-small Cell Lung Cancer according to Chemotherapy Regimens: Tyrosine Kinase Inhibitors versus Cytotoxic Chemotherapy

Cancer Research and Treatment ◽

10.4143/crt.2017.491 ◽

2019 ◽

Vol 51 (1) ◽

pp. 169-177 ◽

Cited By ~ 2

Author(s):

Ji Young Choi ◽

Miso Kim ◽

Bhumsuk Keam ◽

Tae Min Kim ◽

Dong-Wan Kim ◽

...

Keyword(s):

Lung Cancer ◽

Herpes Zoster ◽

Tyrosine Kinase ◽

Small Cell Lung Cancer ◽

Tyrosine Kinase Inhibitors ◽

Cell Lung Cancer ◽

Kinase Inhibitors ◽

Cytotoxic Chemotherapy ◽

Small Cell ◽

Small Cell Lung

Download Full-text

Tyrosine kinase inhibitors significantly improved survival outcomes in patients with metastatic gastrointestinal stromal tumour: a multi-institutional cohort study

Current Oncology ◽

10.3747/co.27.5869 ◽

2020 ◽

Vol 27 (3) ◽

Author(s):

A. Deruchie ◽

K. Willemsma ◽

A. MacNeill ◽

K. DeVries ◽

A. Srikanthan ◽

...

Keyword(s):

British Columbia ◽

Clinical Practice ◽

Tyrosine Kinase ◽

Tyrosine Kinase Inhibitors ◽

Real World ◽

Kinase Inhibitors ◽

Gastrointestinal Stromal Tumour ◽

Survival Outcomes ◽

The Real ◽

Metastatic Gist

Background The real-world impact of tyrosine kinase inhibitors (tkis) in clinical practice for gastrointestinal stromal tumour (gist) has not been extensively reported. We sought to assess how outcomes have changed over the eras and to evaluate the effect of access to imatinib and sunitinib on survival in patients with unresectable or metastatic gist in British Columbia. Methods Patients with metastatic or unresectable gist were allocated to one of three eras: pre-2002, 2002–2007, and post-2007 based on treatment availability (pre-imatinib, post-imatinib, and post-sunitinib). Overall survival (os) and progression-free survival (pfs) were compared between eras. Univariate and multivariate analyses were performed to determine the effects of tumour, patient, and treatment characteristics on survival outcomes. Results Of 657 patients diagnosed with gist throughout British Columbia during 1996–2016, 196 had metastatic disease: 23 in the pre-imatinib era, 67 in the post-imatinib era, and 106 in the post-sunitinib era. A significant increase in os, by 53.6 months (p = 0.0007), and pfs, by 29.1 months (p = 0.044), was observed after the introduction of imatinib. The introduction of sunitinib did not significantly affect os or pfs. Conclusions Implementation of tkis has drastically improved survival outcomes for patients with metastatic gist by up to 4.55 years in the real-world setting. Our study demonstrates that implementation of tkis in clinical practice has outperformed their benefit predicted in clinical trials.

Download Full-text