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• This ESMO Clinical Practice Guideline update provides key recommendations for managing acute lymphoblastic leukaemia. • The update covers recent developments in the use of targeted therapies. • Algorithms for the management of newly diagnosed and relapsed or refractory disease are provided. • The author group encompasses a multidisciplinary group of experts from different institutions in Europe. • Recommendations are based on available scientific data and the authors' collective expert opinion. [ABSTRACT FROM AUTHOR]

The incidence of thyroid cancer is increasing worldwide with the disease burden in Europe second only to that in Asia. In the last several decades, molecular pathways central to the pathogenesis of thyroid cancer have revealed a spectrum of targetable kinases/kinase receptors and oncogenic drivers characteristic of each histologic subtype, such as differentiated thyroid cancer, including papillary, follicular, and medullary thyroid cancer. Oncogenic alterations identified include B-Raf proto-oncogene (BRAF) fusions and mutations, neurotrophic tyrosine receptor kinase (NTRK) gene fusions, and rearranged during transfection (RET) receptor tyrosine kinase fusion and mutations. Multikinase inhibitors (MKIs) targeting RET in addition to multiple other kinases, such as sorafenib, lenvatinib and cabozantinib, have shown favourable activity in advanced radioiodine-refractory differentiated thyroid cancer or RET-altered medullary thyroid cancer; however, the clinical utility of MKI RET inhibition is limited by offtarget toxicity resulting in high rates of dose reduction and drug discontinuation. Newer and selective RET inhibitors, selpercatinib and pralsetinib, have demonstrated potent efficacy and favourable toxicity profiles in clinical trials in the treatment of RET-driven advanced thyroid cancer and are now a therapeutic option in some clinical settings. Importantly, the optimal benefits of available specific targeted treatments for advanced RET-driven thyroid cancer require genetic testing. Prior to the initiation of systemic therapy, and in treatment-naïve patients, RET inhibitors may be offered as first-line therapy if a RET alteration is found, supported by a multidisciplinary team approach. [ABSTRACT FROM AUTHOR]

Advanced Systemic Mastocytosis (Adv‐SM) is rare and has a poor prognosis. Midostaurin (Rydapt®) is one of the few treatments for Adv‐SM in Europe. The study aims were to describe the characteristics of patients treated with midostaurin, their treatment modalities, outcomes, and serious events requiring hospitalization. This retrospective observational study was conducted using the French National Healthcare Database (SNDS) and included adult Adv‐SM patients treated with midostaurin between 01‐01‐2012 and 09‐30‐2018. Kaplan‐Meier method was used to assess survival and treatment duration. Eighty‐one patients were included: 37 with Aggressive Systemic Mastocytosis (SM) (46%), 31 with SM with an Associated Hematological Neoplasm (38%), and 4 with Mast Cell Leukemia (5%). The SM subtype was undetermined in 9 patients (11%). The median age was 67 years; 64% of patients were male. Over the mean follow‐up of 11.4 months, median midostaurin treatment duration was 8.4 months and 28 patients (35%) were still under treatment at the end of the study. One‐year and 5‐year overall survival rates estimated since the time of diagnosis were 83% and 56%, respectively. Twelve serious events (among those frequently reported during clinical trials and compassionate use) requiring hospitalization were identified; a causal association with Adv‐SM treatment could neither be excluded nor established. In this first real‐life study on patients treated with midostaurin for Adv‐SM, the patients' characteristics, their management, treatment discontinuation, and survival were in line with previous results (compassionate use and clinical trials). [ABSTRACT FROM AUTHOR]

Over the last 20 years, treatment of patients with human epidermal growth factor receptor 2-positive (HER2+) early breast cancer has considerably improved. The development and addition of (neo)adjuvant trastuzumab to chemotherapy in patients with early HER2+ breast cancer (EHBC) has been shown to provide improvements in both disease-free survival (DFS) and overall survival, with some patients having a good prognosis being candidates for chemotherapy de-escalation strategies. However, despite such promising clinical outcomes, a significant proportion of patients still recur calling for the development of new preventive approaches. To this aim, the use of (neo)adjuvant trastuzumab for longer than one year or followed by lapatinib were tested without additional clinical improvement. Based on more recent advances, therapeutic strategies for patients with HER2+ tumours are now incorporating the use of newer (neo)adjuvant treatments, such as pertuzumab and trastuzumab emtansine, which have shown to further improve the invasive DFS (iDFS) benefit gained with trastuzumab. In this context, the tyrosine kinase inhibitor neratinib is approved in Europe for the extended adjuvant treatment of adult patients with early-stage hormone receptor-positive HER2+ breast cancer who completed adjuvant trastuzumab-based therapy less than one year ago. Clinical data have demonstrated that neratinib significantly improves iDFS when used for the total recommended duration of 12 months. This review paper provides an overview of the treatment of patients with EHBC, with a focus on the post-trastuzumab use of neratinib. [ABSTRACT FROM AUTHOR]

Five tyrosine kinase inhibitors (TKIs) are currently approved in the European Union for treatment of chronic myeloid leukemia (CML) and all have considerable overlap in their indications. While disease-specific factors such as CML phase, mutational status, and line of treatment are key to TKI selection, other important features must be considered, such as patient-specific comorbidities and TKI safety profiles. Ponatinib, the TKI most recently approved, has demonstrated efficacy in patients with refractory CML, but is associated with an increased risk of arterial hypertension, sometimes severe, and serious arterial occlusive and venous thromboembolic events. A panel of European experts convened to discuss their clinical experience in managing patients with CML. Based on the panel discussions, scenarios in which a CML patient may be an appropriate candidate for ponatinib therapy are described, including presence of the T315I mutation, resistance to other TKIs without the T315I mutation, and intolerance to other TKIs. [ABSTRACT FROM AUTHOR]

Purpose The approval history, pharmacology, pharmacokinetics, clinical trials, efficacy, dosing recommendations, drug interactions, safety, place in therapy, and economic considerations of gefitinib are reviewed. Summary Lung cancer is one of the most commonly diagnosed cancers and is the leading cause of cancer death. Platinum-based chemotherapy and tyrosine kinase inhibitors, such as erlotinib and afatinib, are recommended therapies for nonsmall cell lung cancer. The European Medicines Association based their approval of gefitinib on the randomized, multicenter Iressa Pan-Asia Study (IPASS, NCT00322452) and a single-arm study showing effectiveness in Caucasians (IFUM, NCT01203917). Both studies were recently referenced by the United States Food & Drug Administration to reapprove gefitinib for the first-line treatment of advanced nonsmall cell lung cancer with epidermal growth factor receptor exon 19 deletions or exon 21 substitution. Diarrhea, acneiform rash, and interstitial lung disease are known side effects of gefitinib. Conclusion Use of gefitinib for the first-line therapy of metastatic nonsmall cell lung cancer with epidermal growth factor receptor exon 19 deletions (residues 747–750) or exon 21 substitution mutation (L858R) is well-documented and supported. [ABSTRACT FROM AUTHOR]

Purpose: European Organisation for Research and Treatment of Cancer (EORTC) 90101 (CREATE) was a prospective, multicentric, non-randomised, open-label phase II basket trial to assess the efficacy and safety of crizotinib in patients with different types of cancers, including advanced inflammatory myofibroblastic tumour (IMT) with or without anaplastic lymphoma kinase (ALK) rearrangements. Here, we report updated results with long-term follow-up., Patients/methods: After central reference pathology, eligible ALK-positive and ALK-negative patients with advanced/metastatic IMT deemed incurable with surgery, radiotherapy or systemic therapy received oral crizotinib 250 mg twice daily. The ALK status was assessed centrally using immunohistochemistry and fluorescence in situ hybridisation. The primary end-point was the proportion of patients who achieved an objective response (i.e. complete or partial response). If ≥6 ALK-positive patients achieved a confirmed response, the trial would be deemed successful., Results: At data cut-off on 28th January 2021, we performed the final analysis of this trial. Of the 20 eligible and treated patients (19 of whom were evaluable for efficacy), with a median follow-up of 50 months, five were still on crizotinib treatment (4/12 ALK-positive and 1/8 ALK-negative patients). The updated objective response rate (ORR) was 66.7% (95% confidence interval [CI] 34.9-90.1%) in ALK-positive patients and 14.3% (95% CI 0.0-57.9%) in ALK-negative patients. In the ALK-positive and ALK-negative patients, the median progression-free survival was 18.0 months (95% CI 4.0-NE) and 14.3 months (95% CI 1.2-31.1), respectively; 3-year overall survival rates were 83.3% (95% CI 48.2-95.6) and 34.3% (95% CI 4.8-68.5). Safety results were consistent with previously reported data., Conclusion: These updated results confirm previous findings that crizotinib is effective, with durable responses, in patients with locally advanced or metastatic ALK-positive IMT. With further follow-up after the original primary analysis, the ORR increased, as patients derived long-term benefit and some responses converted from stable disease to partial responses., Clinical Trial Number: EORTC 90101, NCT01524926., Competing Interests: Conflict of interest statement P.S. reports no competing interest related to crizotinib, Pfizer or EORTC, received research support to the institution outside of the scope of this study and reports an advisory or consulting role outside of the scope of this study. M.K., T.S. and A.W. report no competing interest. J-Y.B. reports research support and honoraria from Pfizer outside the scope of this study. S.J.S. received honoraria from Lilly for educational activities. Si.S. reports no competing interest, research support, honoraria and advisory or consulting role outside the scope of this study. P.R. received honoraria from Pfizer outside the scope of this study. V.B., M.G.L., A.I., N.I., M.D-R., R.S., F.S., Ax.N. and An.N. report no competing interest. B.K. reports no competing interest related to crizotinib, Pfizer or EORTC, received research support to the institution outside of the scope of this study and reports an advisory or consulting role outside of the scope of this study., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Our study aims to highlight the critical role of the introduction of second generation tyrosine kinase inhibitors (2nd TKIs) on the prognosis of patients with chronic myeloid leukemia (CML) in chronic phase (CML-CP), as determined by European Treatment and Outcome Study (EUTOS) system. Patients who were diagnosed with CML-CP before March 2009 were classified into the imatinib group, and those diagnosed after April 2009 were classified into the 2nd TKI group. EUTOS high-risk patients exhibited significantly worse outcomes in terms of event-free survival (EFS), progression-free survival (PFS), and CML-associated death than those considered to be low-risk. Risk stratification by EUTOS score was predictive of risk-associated clinical outcomes in patients classified into the imatinib group; however, the EUTOS score failed to predict the outcomes of patients classified into the 2nd TKI group. Our data suggest that the introduction of 2nd TKIs might have improved treatment outcomes, particularly in EUTOS high-risk patients.

Background: Gastrointestinal stromal tumours (GISTs) are the most common gastrointestinal sarcomas. This global, prospective registry followed patients with advanced or localised GIST (2007-2011)., Methods: Current and evolving diagnostics, treatments and outcome measures in patients with GIST were assessed. Eligible patients were diagnosed with advanced or localised GIST within 15months of registry entry. No treatment plan was prescribed, and no visit schedule was mandated. Treating physicians recorded patient information, including tumour response, diagnostic methods, medications, surgeries performed, mutation status and adverse events leading to dose/medication changes. Survival outcomes were estimated using the Kaplan-Meier method. Other data were analysed using descriptive statistics., Results: The registry included 1663 patients (advanced GIST, n=1095; localised GIST, n=537). Medications (e.g. tyrosine kinase inhibitor use and dosing), disease progression or recurrence and physician assessment of response to treatment in registry patients were consistent with controlled trials and prevailing clinical recommendations. In advanced GIST, estimated 30-month progression-free survival (PFS) (59.8%) and overall survival (OS) (82.7%) were higher than results from previously reported trials (≈40% and ≈70%, respectively). Consistent with treatment guidelines, the most common initial treatments were imatinib for advanced GIST, and complete surgical resection for localised GIST. Computed tomography scans were the most common imaging technique used at diagnosis and follow-up. Mutation analysis was performed at diagnosis in only 15.3% and 14.5% of patients with advanced and localised GIST, respectively., Conclusions: In this real-world GIST registry, patients with advanced GIST were treated with imatinib and patients with localised GIST received surgical resection, in accordance with prevailing clinical recommendations., (Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.)