The TKI Era in Chronic Leukemias

Novellis, Danilo De; Cacace, Fabiana; Caprioli, Valeria; Wierda, William G.; Mahadeo, Kris Michael; Tambaro, Francesco Paolo

doi:10.3390/pharmaceutics13122201

Cited by 14 publications

(9 citation statements)

References 131 publications

(137 reference statements)

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“…As previously reported, GNF-7 functions as a BCR-ABL inhibitor that can overcome the "gatekeeper" BCR-ABL/T315I mutation that resistant to tyrosine kinase inhibitors (TKIs) [16]. Indeed, GNF-7 potently inhibited the proliferation of BCR-ABL/T315I expressing BaF3 cells that resistant to the BCR-ABL inhibitors imatinib and dasatinib (Figure S1A-C) [17]. Interestingly, we found that GNF-7 showed potent anti-proliferation on Ba/F3 cells stably express FLT3-ITD, whereas TKIs such as imatinib and dasatinib exhibited no signi cant proliferation inhibition (Figure S2).…”

Section: Gnf-7 Selectively Inhibits the Proliferation Of Flt3-itd Aml...supporting

confidence: 64%

GNF-7, a novel FLT3 inhibitor, overcomes drug resistance for the treatment of FLT3‑ITD acute myeloid leukemia

Xiao

Wang

Zhang

et al. 2023

Preprint

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Background Acute myeloid leukemia (AML) with FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) mutation accounts for a large proportion of AML patients and diagnosed with dismay prognosis. Although the prognosis of FLT3-ITD AML has been greatly improved, the drug resistance frequently occurred in the treatment of FLT3 target drugs. GNF-7, a multitargeted kinase inhibitor, which provided a novel therapeutic strategy for overriding leukemia. In this study, we explored the antitumor activity of GNF-7 against FLT3-ITD and clinically-relevant drug resistance in FLT3 mutant AML. Methods Growth inhibitory assays were performed in AML cell lines and Ba/F3 cells expressing various FLT3 mutants to evaluate the antitumor activity of GNF-7 in vitro. Western blotting was used to examine the activity of FLT3 and its downstream pathways. Molecular docking was performed to predict the binding sites of FLT3 to GNF-7. The survival benefit of GNF-7 in vivo was assessed in mouse models of transformed Ba/F3 cells harboring FLT3-ITD and FLT3-ITD/F691L mutation. Primary patient samples and a patient-derived xenograft (PDX) model were also used to determine the efficacy of GNF-7. Results GNF-7 inhibited the cell proliferation of Ba/F3 cells expressing FLT3-ITD and exhibited potently anti-leukemia activity on primary FLT3-ITD AML samples. Moreover, GNF-7 could bind to FLT3 protein and inhibit the phosphorylation of downstream effectors in the FLT3 signaling pathways. In vitro and in vivo studies showed that GNF-7 exhibited a potent inhibitory activity against FLT3-ITD/F691L that confers resistant to quizartinib (AC220) or gilteritinib. Importantly, GNF-7 showed potent cytotoxic effect on leukemic stem cells, significantly extend the survival of PDX model and exhibited similar therapy effect compared with gilteritinib. Conclusions Our results show that GNF-7 is a potent FLT3-ITD inhibitor and may become a promising lead compound applied for treating some of the clinically drug resistant patients.

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Section: Gnf-7 Selectively Inhibits the Proliferation Of Flt3-itd Aml...supporting

confidence: 64%

GNF-7, a novel FLT3 inhibitor, overcomes drug resistance for the treatment of FLT3‑ITD acute myeloid leukemia

Xiao

Wang

Zhang

et al. 2023

Preprint

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“…Furthermore, high-cytogenetic-risk diseases are much more effectively treated with tyrosine kinase inhibitors. Several trials with patients with CML have already shown that in predetermined conditions (CMR for at least 2 years after ≥3 years of TKI treatment), the production of BCR::ABL1 inhibitor can be discontinued and rechallenged in the case of molecular relapse [ 15 ].…”

Section: Discussionmentioning

confidence: 99%

A Real-World Evidence-Based Study of Long-Term Tyrosine Kinase Inhibitors Dose Reduction or Discontinuation in Patients with Chronic Myeloid Leukaemia

et al. 2023

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The therapeutic approach to chronic myeloid leukaemia (CML) has changed in recent years. As a result, a high percentage of current patients in the chronic phase of the disease almost have an average life expectancy. Treatment also aims to achieve a stable deep molecular response (DMR) that might allow dose reduction or even treatment discontinuation. These strategies are often used in authentic practices to reduce adverse events, yet their impact on treatment-free remission (TFR) is a controversial debate. In some studies, it has been observed that as many as half of patients can achieve TFR after the discontinuation of TKI treatment. If TFR was more widespread and globally achievable, the perspective on toxicity could be changed. We retrospectively analysed 80 CML patients treated with tyrosine kinase inhibitor (TKI) at a tertiary hospital between 2002 and 2022. From them, 71 patients were treated with low doses of TKI, and 25 were eventually discontinued, 9 of them being discontinued without a previous dose reduction. Regarding patients treated with low doses, only 11 of them had molecular recurrence (15.4%), and the average molecular recurrence free survival (MRFS) was 24.6 months. The MRFS outcome was not affected by any of the variables examined, including gender, Sokal risk scores, prior treatment with interferon or hydroxycarbamide, age at the time of CML diagnosis, the initiation of low-dose therapy and the mean duration of TKI therapy. After TKI discontinuation, all but four patients maintained MMR, with a median follow-up of 29.2 months. In our study, TFR was estimated at 38.9 months (95% CI 4.1–73.9). This study indicates that low-dose treatment and/or TKI discontinuation is a salient, safe alternative to be considered for patients who may suffer adverse events (AEs), which hinder the adherence of TKI and/or deteriorate their life quality. Together with the published literature, it shows that it appears safe to administer reduced doses to patients with CML in the chronic phase. The discontinuation of TKI therapy once a DMR has been reached is one of the goals for these patients. The patient should be assessed globally, and the most appropriate strategy for management should be considered. Future studies are needed to ensure that this approach is included in clinical practice because of the benefits for certain patients and the increased efficiency for the healthcare system.

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“…The course of the disease in adults is usually milder compared to children and adolescents [ 25 ]. The long-term treatment of CML for pediatric patients is analogous to therapy for adults, and it involves tyrosine kinases inhibitors (TKI): first-generation TKI: Imatinib, second-generation: Dasatinib, Nilotinib and third-generation such asBosutinib [ 26 ]. However, all clinical evidence indicates that a continued search for unique therapy guidelines adapted for children is required.…”

Section: Chronic Myeloid Leukemia (Cml)mentioning

confidence: 99%

“…Classic Hodgkin Lymphoma is divided into four subtypes: lymphocyte-rich CHL, lymphocyte-depleted CHL, mixed cellularity CHL, and nodular sclerosis CHL. HL is the most commonly diagnosed cancer in adolescents (aged 15–19 years) [ 26 ]. For children aged 0–14 years, HL represents 4% of all children's cancers.…”

Section: Hodgkin’s Lymphoma (Hd)mentioning

confidence: 99%

Modern treatment strategies in pediatric oncology and hematology

Adamczewska-Wawrzynowicz,

Wiącek,

Kozłowska

et al. 2023

Discov Onc

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Every year, approximately 400 00 children worldwide are diagnosed with cancer. Although treatment results in most types of childhood neoplasms are excellent with survival more than 80%, there are some with poor prognosis. Also recurrent and resistant to treatment childhood cancer remain a therapeutic challenge. Besides chemotherapy, which has been the basis of cancer therapy for years, molecular methods and precisely targeted therapies have recently found their usage. As a result of that, survival has improved and has positively impacted the rate of toxicities associated with chemotherapy (Butler et al. in CA Cancer J Clin 71:315–332, 2021). These achievements have contributed to better quality of patients' lives. Current methods of treatment and ongoing trials give hope for patients with relapses and resistance to conventional chemotherapy. This review focuses on the most recent progress in pediatric oncology treatments and discusses specific therapy methods for particular cancers types of cancer. Targeted therapies and molecular approaches have become more beneficial but research need to be continued in this field. Despite significant breakthroughs in pediatric oncology in the last few years, there is still a need to find new and more specific methods of treatment to increase the survival of children with cancer.

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The TKI Era in Chronic Leukemias

Cited by 14 publications

References 131 publications

GNF-7, a novel FLT3 inhibitor, overcomes drug resistance for the treatment of FLT3‑ITD acute myeloid leukemia

GNF-7, a novel FLT3 inhibitor, overcomes drug resistance for the treatment of FLT3‑ITD acute myeloid leukemia

A Real-World Evidence-Based Study of Long-Term Tyrosine Kinase Inhibitors Dose Reduction or Discontinuation in Patients with Chronic Myeloid Leukaemia

Modern treatment strategies in pediatric oncology and hematology

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