Retos y avances del cáncer de pulmón de células no pequeñas metastásico EGFR mutado / Challenges and advances in metastatic non-small cell lung cancer with EGFR mutation

RESUMEN Los inhibidores de la tirosina quinasa han cambiado drásticamente la perspectiva clínica de los pacientes con cáncer de pulmón de células no pequeñas avanzado con mutaciones del receptor del factor de crecimiento epidérmico. Sin embargo, existen aún retos en el manejo de los pacientes con esta mutación en un escenario metastásico, como es la resistencia intrínseca y adquirida a inhibidores de tirosina quinasa. Se discutirán los últimos avances y nuevas estrategias en primera línea de tratamiento, resistencia a osimertinib y tratamiento en mutación, en el exón 20.

ABSTRACT Tyrosine kinase inhibitors have dramatically changed the clinical outcomes for patients with advanced non-small cell lung cancer with epidermal growth factor receptor mutations. However, there are still challenges in the management of patients with this mutation in a metastatic setting, such as intrinsic and acquired resistance to tyrosine kinase inhibitors. We will discuss the latest advances and new strategies in first-line treatment, osimertinib resistance, and exon 20 mutation treatment.

Analysis of mutation characteristics in TKI-resistant chronic myeloid leukemia patients based on next-generation sequencing technology / 白血病·淋巴瘤

Objective:To explore the characteristics and patterns of gene mutations in tyrosine kinase inhibitor (TKI)-resistant chronic myeloid leukemia (CML) patients and their relationship with TKI-resistant CML.Methods:A retrospective case series study was performed. Clinical data and next-generation sequencing results from TKI-resistant CML patients in Nanfang Hospital of Southern Medical University and Yuebei People's Hospital of Shantou University Medical College from August 2018 to November 2022 were retrospectively analyzed, and the gene mutations of the patients in general and at different disease stages were analyzed.Results:Sixty patients were enrolled, with the age [ M ( Q1, Q3)] of 41.5 years old (32 years old, 53 years old); 38 cases (63.33%) were male and 22 cases (36.67%) were female; 43 cases were in the chronic stage, and 17 cases were in the progression stage (3 cases were in the accelerated stage and 14 cases were in the blast stage). non-ABL1 mutations were detected in 30 patients (50.00%) including 45 times of 15 non-ABL1 genes. The number of non-ABL1 mutation gene was 1 (0, 2) in 60 patients. Of the 60 patients, 21 (35.00%) had ASXL1 mutations, 5 (8.33%) had DNMT3A mutations, 5 (8.33%) had RUNX1 mutations, and 3 (5.00%) had SETBP1 mutations; the proportions of patients with 1 and ≥2 non-ABL1 mutations were 33.33% (20/60) and 16.67% (10/60), respectively. The total detection rates of non-ABL1 mutations were 52.94% (9/17) and 48.84% (21/43), and the detection rates of ≥2 non-ABL1 mutations were 23.53% (4/17) and 13.95% (6/43) in patients with progression and patients with chronic disease, and the differences were not statistically significant ( χ2 = 0.08, P = 0.774; χ2 = 0.80, P = 0.370). Seventeen of 60 patients (28.33%) had mutations in the ABL1 kinase region, of which 14 (82.35%) had non-ABL1 mutations; of these 17 cases, 6 patients with progressive disease all had non-ABL1 mutations, in 11 patients with chronic disease, 8 patients had non-ABL1 mutations, and the difference was not statistically significant ( P = 0.452). Conclusions:Patients with TKI-resistant CML have high frequencies of non-ABL1 mutations, and there is a trend for higher mutation rates in patients with progressive disease than in patients with chronic disease, and these may be related to the abnormal activation of ABL1 kinase by BCR-ABL1 fusion gene in patients with drug-resistant CML, which leads to the genome-level and epigenome-level mutations, and driving disease progression from chronic phase to accelerated or blast phase.

Efficacy and prognosis comparison of first-line treatment with EGFR-TKI versus chemotherapy for non-small cell lung cancer patients harboring EGFR rare mutation / 肿瘤研究与临床

Objective:To investigate the therapeutic effect difference between first-line treatment with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) and chemotherapy in non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) rare mutation.Methods:A retrospective case-control study was performed. Data of NSCLC patients with rare EGFR mutation who were treated in Shanxi Province Cancer Hospital from January 2013 to October 2019 were retrospectively analyzed. EGFR mutations in living tissues or blood were detected by using amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) before first-line treatment. According to first-line treatment methods,they were divided into EGFR-TKI treatment group and chemotherapy group. Objective remission rate (ORR) and disease control rate (DCR) of both groups were compared. Kaplan-Meier method was used to draw progression-free survival (PFS) and the overall survival (OS) curves. Log-rank test was used for comparison among groups. Single-factor and multi-factor Cox proportional risk models were used to analyze the influencing factors of PFS and OS.Results:A total of 169 patients with EGFR rare mutations were included, and the age [ M (IQR)] was 63 years (12 years); there were 96 cases (56.8%) < 65 years and 73 cases (43.2%) ≥65 years; 70 (41.4%)males and 99 (58.6%) females; 55 cases (32.5%) had EGFR G719X mutation,45 cases (26.6%) had L861Q mutation, 17 cases (10.1%) had S768I mutation, and 52 cases (30.8%) had complex mutation; 55 cases (32.5%) received the first-line chemotherapy and 114 cases (67.5%) received the first-line EGFR-TKI treatment. In the chemotherapy group, ORR was 36.4% (20/55) and DCR was 85.5% (47/55); in EGFR-TKI treatment group, ORR was 72.8% (83/114) and DCR was 90.4% (103/114). The ORR of EGFR-TKI treatment group was higher than that of chemotherapy group ( χ2 = 20.70, P = 0.001), and there was no statistically significant difference in DCR between two groups ( χ2 = 1.76, P = 0.184). Subgroup analysis showed that ORR in EGFR-TKI treatment group with G719X, L861Q and complex mutations was higher than that of the corresponding mutations in chemotherapy group, and the differences were statistically significant (all P < 0.05), while there were no significant differences in DCR among subgroups (all P > 0.05). The median PFS time was 9.7 months (95% CI: 6.0-13.4 months) and 3.8 months (95% CI: 3.1-7.1 months), respectively in EGFR-TKI treatment group and chemotherapy group, and there was a statistically significant difference in PFS between the two groups ( P < 0.001). The median OS time was 25.6 months (95% CI: 18.0-37.9 months) and 31.7 months (95% CI: 18.0-42.8 months), respectively in EGFR-TKI treatment group and chemotherapy group, and there was no statistically significant difference in OS between the two groups ( P = 0.231). Multivariate Cox regression analysis showed that brain metastasis [with vs. without: HR = 2.306, 95% CI: 1.452-3.661, P < 0.001] and the first-line treatment methods (EGFR-TKI vs. chemotherapy: HR = 0.457, 95% CI:0.317-0.658, P < 0.001) were independent influencing factors for PFS of NSCLC patients with EGFR rare mutation; brain metastasis (with vs. without: HR = 2.087, 95% CI: 1.102-3.953, P = 0.024; unknown vs. without: HR = 2.118,95% CI: 1.274-3.520, P = 0.004) were independent influencing factors for OS of NSCLC patients with EGFR rare mutation. Conclusions:Compared with the first-line chemotherapy, EGFR-TKI first-line treatment could improve objective remission and PFS of NSCLC patients with EGFR rare mutation, while no OS benefit is observed.

Application and clinical progress of pyrotinib in breast cancer / 肿瘤研究与临床

Pyrotinib is a new irreversible epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) dual tyrosine kinase inhibitor, and it has shown excellent clinical efficacy in treatment of HER2-positive breast cancer patients. The combination of pyrotinib and capecitabine in the treatment of advanced breast cancer has been recognized at home and abroad. Further exploration of whether there are other antitumor agents that work well in combination with pyrotinib, and whether pyrotinib can enhance clinical benefit in patients with early-stage or middle-stage breast cancer, could develop additional potential of pyrotinib. This article reviews the progress related to pyrotinib in recent years.

Mechanism and strategies of hypoxia-inducible factor-mediated resistance to tyrosine kinase inhibitors in hepato-cellular carcinoma / 中国药房

The use of tyrosine kinase inhibitors （TKI） has been an important advance in the systemic treatment of hepatocellular carcinoma， but their sustained anti-angiogenic therapy leads to increased tumor hypoxia， accelerates the development of a hypoxic microenvironment and promotes the expressions of hypoxia-inducible factors （HIF）， thereby inducing drug resistance of tumor patients to TKI. This paper summarizes the mechanism of action of HIF mediating TKI resistance in hepatocellular carcinoma in aspects of metabolic reprogramming， abnormal expressions of cancer and cancer-associated genes， and ferroptosis， and sorts resistance response strategies to provide reference for clinical solutions to TKI resistance issues. As results show， HIF/ glycolysis axis inhibitors （isoflavonoid genistein， simvastatin， etc.） can improve TKI resistance based on metabolic reprogramming mechanism； oncogene-targeted inhibitors combined with TKI （the combination of capsaicin and sorafenib） can improve TKI resistance based on abnormal expression of cancer and cancer-related genes； fatty acid synthase inhibitor （orlistat） can improve TKI resistance based on ferroptosis mechanism.

Clinical comprehensive evaluation of three oral Janus kinase inhibitors for atopic dermatitis / 中国药房

OBJECTIVE To comprehensively evaluate the three oral Janus kinase inhibitors （JAKi） such as upadacitinib， abrocitinib and baricitinib in the treatment of atopic dermatitis. METHODS The six dimensions of safety， efficacy， economy， appropriateness， accessibility and innovativeness were used for evaluation. Meta-analysis was conducted to evaluate the safety and efficacy of three oral JAKi； pharmacoeconomic studies were searched， and the treatment costs were calculated to evaluate the economy of each JAKi. Appropriateness was described based on literature review and drug labels. Accessibility of three oral JAKi was assessed by using a questionnaire survey. The innovation of JAKi was elucidated from the perspective of its mechanism of action. RESULTS In terms of safety， the incidence of upper respiratory tract infection （OR＝1.47， 95%CI of 1.04-2.08， P＝0.03） and nasopharyngitis （OR＝1.44， 95%CI of 1.06-1.95， P＝0.02） in the upadacitinib 30 mg group was significantly higher than that in the placebo group； the incidence of nasopharyngitis in baricitinib 4 mg group was significantly higher than that in the placebo group （OR＝2.24， 95%CI of 1.39-3.61， P＝0.000 8） and baricitinib 2 mg group （OR＝0.48， 95%CI of 0.31-0.74，P＝0.001）. In terms of efficacy， regardless of the dosage， all three JAKi groups were superior to the placebo group， and the high-dose groups of upadacitinib and abrocitinib were superior to the low-dose groups （P＜0.000 1）. In terms of economy， the annual treatment cost of baricitinib was the lowest （13 870.0 yuan）， but it has not been approved for atopic dermatitis indication in China； next was upadacitinib （27 192.5 yuan）. In terms of appropriateness， the overall appropriateness of the three JAKis was good， but none of them was suitable for patients with severe liver injury. In terms of accessibility， baricitinib had the highest availability rate （59.4%）， but the affordability of upadacitinib was relatively good under China’s medical insurance system. In terms of innovation， among the three types of JAKi， upadacitinib and abrocitinib had better innovation. CONCLUSIONS Three oral JAKi treatments for atopic dermatitis have controllable safety and good efficacy. Considering the issue of medical insurance reimbursement， it is recommended that Chinese patients use upadacitinib.

Structure-based development of potent and selective type-II kinase inhibitors of RIPK1

Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) functions as a key regulator in inflammation and cell death and is involved in mediating a variety of inflammatory or degenerative diseases. A number of allosteric RIPK1 inhibitors (RIPK1i) have been developed, and some of them have already advanced into clinical evaluation. Recently, selective RIPK1i that interact with both the allosteric pocket and the ATP-binding site of RIPK1 have started to emerge. Here, we report the rational development of a new series of type-II RIPK1i based on the rediscovery of a reported but mechanistically atypical RIPK3i. We also describe the structure-guided lead optimization of a potent, selective, and orally bioavailable RIPK1i, 62, which exhibits extraordinary efficacies in mouse models of acute or chronic inflammatory diseases. Collectively, 62 provides a useful tool for evaluating RIPK1 in animal disease models and a promising lead for further drug development.

Design, synthesis and structure-activity relationship of a series of novel BCR-ABL inhibitors / 中国药科大学学报

@#Abstract: In this study, molecular skeleton I N-phenylindoline-5-formamide was obtained by optimizing the structure of the existing allosteric BCR-ABL inhibitor asciminib. Based on this molecular skeleton, compounds 1-12 were designed and synthesized assisted by molecular docking. After characterizing their structures using ESI-MS and NMR, the anti-BCR-ABL1-dependent Luc-Ba/F3 cell proliferation activity of the target compounds in vitro was determined by CCK-8 assay. Finally, highly active lead compound 1 was screened out. For high clearance rate and short half-life period exposed in subsequent druggability evaluation, its druggability was optimized by introducing hydrophilic groups. Afterwards, compounds 13-22 were designed and synthesized. Compound 17 presented high cell inhibitory activity, low clearance rate and long half-life, and is expected to be used as a clinical candidate for further evaluation of biological activity and druggability.

Pediatric and adolescent chronic myeloid leukemia: A follow-up study in Western India

Background: Chronic myeloid leukemia (CML) is relatively rare in pediatric and adolescent age groups. The purpose of this study was to evaluate the clinical, hematopathological, and biochemical parameters of CML in pediatric and adolescent age groups, along with an assessment of the treatment response with first-line tyrosine kinase inhibitors (TKI) and its correlation with the prognostic scoring systems of adults. Materials and Methods: A retrospective study of 44 Breakpoint Cluster Region-Abelson leukemia virus (BCR-ABL1)-positive pediatric and adolescent CML cases registered at our hospital was done. The clinical and laboratory parameters were evaluated using hospital software. The treatment response was monitored and scoring was performed using mathematical calculations. Results: The mean age was 11.6 (±4.7) years. The median hemoglobin was 8.4 g/dL and 63.6% of the cases showed white blood cell (WBC) counts >250,000/?L. The average follow-up was 21 months. A total of 97.7 and 78.1% cases achieved complete hematological response (CHR) and molecular response, respectively, during the treatment course. The maximum number of patients had low Sokal and European treatment and Outcomes Study (EUTOS) scores. Seventy-five per cent of the cases achieved CHR at 3 months, while 73.6 and 78.6% CML-Chronic phase (CP) cases with low Sokal and EUTOS scores achieved CHR at 3 months, respectively. Conclusion: This study revealed that the CML cases in pediatric and adolescent age groups are normally present with higher WBC counts at the time of diagnosis. The association of the prognostic scoring system with treatment response was statistically insignificant. However, a larger cohort study is needed to determine the treatment response of TKI in children and adolescent CML and its correlation with the prognostic scoring systems.

Netarsudil monotherapy as the initial treatment for open-angle glaucoma and ocular hypertension in Indian patients: A real-world evaluation of efficacy and safety

Purpose: Glaucoma is the second leading cause of blindness worldwide, affecting more than 64 million people aged 40–80. The best way to manage primary open?angle glaucoma (POAG) is by lowering the intraocular pressure (IOP). Netarsudil is a Rho kinase inhibitor, the only class of antiglaucoma medications that reorganizes the extracellular matrix to improve the aqueous outflow through the trabecular pathway. Methods: An open?label, real?world, multicentric, observation?based 3?month study was performed for assessing the safety and ocular hypotensive efficacy of netarsudil ophthalmic solution (0.02% w/v) in patients with elevated IOP. Patients were given netarsudil ophthalmic solution (0.02% w/v) as a first?line therapy. Diurnal IOP measurements, best?corrected visual acuity, and adverse event assessments were recorded at each of the five visits (Day?1: screening day and first dosing day; subsequent observations were taken at 2 weeks, 4 weeks, 6 weeks, and 3 months). Results: Four hundred and sixty?nine patients from 39 centers throughout India completed the study. The mean IOP at baseline of the affected eyes was 24.84 ± 6.39 mmHg (mean ± standard deviation). After the first dose, the IOP was measured after 2, 4, and 6 weeks, with the final measurement taken at 3 months. The percentage reduction in IOP in glaucoma patients after 3 months of once?daily netarsudil 0.02% w/v solution use was 33.34%. The adverse effects experienced by patients were not severe in the majority of cases. Some adverse effects observed were redness, irritation, itching, and others, but only a small number of patients experienced severe reactions, as reported in a decreasing order: redness > irritation > watering > itching > stinging > blurring. Conclusion: We found that netarsudil 0.02% w/v solution monotherapy when used as the first?line treatment in primary open?angle glaucoma and ocular hypertension was both safe and effective.

Inhibidores de JAK en pacientes con dermatitis atópica: revisión sistemática sobre el uso de Abrocitinib

Introducción: La dermatitis atópica es una enfermedad cutánea inflamatoria, crónica y pruriginosa. De etiología multifactorial que se produce con mayor frecuencia durante la lactancia y en la infancia temprana. Objetivos: Describir la evidencia científica sobre el efecto de los inhibidores de janus quinasa sobre la mejoría clínica y la remisión de la dermatitis atópica. Métodos: Se realizará una revisión sistemática y metaanálisis. Esta revisión sistemática se regirá de acuerdo con las directrices PRISMA. Se realizó una búsqueda en PubMed, Scopus, Web of Science. Resultados: Se incluyeron 14 artículos en la revisión. Conclusiones: El tratamiento con inhibidores del janus cinasas, como el abrocitinib, está siendo investigado como una opción potencial para el tratamiento de la dermatitis atópica y los artículos incluidos en esta revisión han demostrado resultados prometedores. El abrocitinib mostró una mejora sostenible de los síntomas de la dermatitis atópica, ha demostrado ser bien tolerado en los ensayos clínicos, con menor cantidad e intensidad de efectos secundarios, respeto a otros fármacos como cremas o corticoides sistémicos, y hasta el momento sugieren que los inhibidores de la janus cinasas son bien tolerados por la mayoría de los pacientes. Es importante destacar que el abrocitinib aún es una terapia relativamente nueva y su uso a largo plazo en el tratamiento de la dermatitis atópica requieren más investigaciones.

Introduction: Atopic dermatitis is an inflammatory, chronic, pruritic skin disease. It has a multifactorial etiology and occurs most frequently during infancy and early childhood. Aims: To describe the scientific evidence on the effect of janus kinase inhibitors on clinical improvement and remission of atopic dermatitis. Methods: A systematic review and meta-analysis will be performed. This systematic review will be conducted according to PRISMA guidelines. A search will be performed in Pubmed, Scopus, Web of Science. Results: 14 articles were included in the review. Conclusions: Treatment with janus kinase inhibitors, such as abrocitinib, is being investigated as a potential option for the treatment of atopic dermatitis and the articles included in this review have shown promising results. abrocitinib showed a sustainable improvement of atopic dermatitis symptoms, has been shown to be well tolerated in clinical trials, with fewer and less intense side effects compared to other drugs such as creams or systemic corticosteroids, and so far suggest that janus kinase inhibitors are well tolerated by most patients. Importantly, abrocitinib is still a relatively new therapy and its long-term use in the treatment of atopic dermatitis requires further investigations.

Response to Tyrosine Kinase Inhibitors in Patients with BCR-ABL1 Positive Chronic Myeloid Leukemia; 13.5 Years’ Experience at Patan Hospital, Nepal

Background:Since the advent of Tyrosine Kinase Inhibitor (TKI), well controlled studies in developed world have shown that the life expectancy of patients with CML is comparable to normal people without the disease. But long-term follow up studies are lacking in resource poor setting. Methods:This is a retrospective follow up study looking at the molecular response and resistance to Tyrosine Kinase Inhibitors (TKI) in patients enrolled in the Max Access Program since February 2003 till March 2017. Patients with twoor more BCR-ABL1 levels by Karyotyping/ fluorescent in situ hybridization (FISH) / reverse transcriptase polymerase chain reaction (RT-PCR) were included. At baseline, complete blood count (CBC), renal function test (RFT), and liver function test (LFT) were evaluated. Bone marrow aspiration and biopsy for morphology, cytogenetic analysis by Karyotyping/FISH and/or molecular analysis by RT-PCR were also done if these tests were not performed earlier. FISH or RT-PCR was done on peripheral blood every 3–12 months as necessary if the patient could afford. Patients with warning response/failure underwent BCR-ABL1 Resistance Mutation Analysis (IRMA).Results:Three hundred and forty six (346) patients had two or more BCR-ABL1 monitoring tests done. Optimal response was seen in 49.42%. Similarly, suboptimal response and failure were seen in 16.5% and 34% respectively. Overall Survival is 89.6% (at 1.8 -165 months, mean 62 months) . If only CML related events is considered survival is 95.9%. Seventy seven (77) patients with a total of 80 BCR-ABL1 domain Imatinib Resistance Mutation Analyses (IRMA) showed 19 different types of mutations with the most common being T315I mutation (8 and 19.5%). About 22.25% of the total patients showed resistance to Glivec out of which 10.98% showed mutations. Nine patients underwent trial for treatment free response (TFR) and 5 of them relapsed between 2-8 months.Conclusions:Despite all the odds of having financial problem, accessibility problem due to distances, transportation, etc. and difficulty monitoring with routine BCR-ABL1 and IRMA, our findings show that the outcome of TKI therapy in our CML patients is comparable to well controlled studies done elsewhere. Overall survival, molecular and cytogenetic responses and mutations in our patients who developed resistance as well as TFR are also similar to other studies. The resistance rate of 22.25% is slightly higher compared to other studies in developed world. This is mainly because of poor monitoring due to unavailability of the test including IRMA in our country and affordability until 2012. It proves that TKI is very effective in CML even in a resource-poor, developing country

Research progress of furmonertinib for EGFR-mutated non-small cell lung cancer / 中国药房

Lung cancer is mainly non-small cell lung cancer （NSCLC）. NSCLC is often associated with epidermal growth factor receptor （EGFR） gene mutations. Currently， epidermal growth factor receptor tyrosine kinase inhibitors （EGFR-TKI） are the preferred first-line treatment option for EGFR-mutated NSCLC. Furmonertinib is the second third-generation EGFR-TKI marketed in China， which is developed independently by China. In this review， it is found that furmonertinib has dual activity， strong tumor suppression， high selectivity， and high safety profile， and is effective in the treatment of EGFR-sensitive mutation， EGFR exon 20 T790M resistance mutation， EGFR exon 20 insertion mutation， and central nervous system metastasis NSCLC， and its relevant clinical trials are only enrolled in Chinese patients， which is more guidance for Chinese NSCLC patients in China.

Factors influencing severe cytopenia in chronic phase chronic myeloid leukemia patients receiving initial second generation tyrosine kinase inhibitors and its impact on treatment responses and outcomes / 中华血液学杂志

Objective: To explore the influencing covariates of severe neutrophils and/or thrombocytopenia and their effect on treatment response and outcome in patients with chronic-phase chronic myeloid leukemia (CP-CML) receiving initial second-generation tyrosine kinase inhibitors (2G-TKI) . Methods: Data from consecutive patients aged ≥18 years with newly diagnosed CP-CML who received initial 2G-TKI at Peking University People's Hospital from September 2008 to November 2021 were interrogated. Binary logistic regression models and Fine-Gray and Cox regression models were applied. Results: Data from 267 patients who received initial 2G-TKI, including nilotinib (n=239, 89.5% ) and dasatinib (n=28, 10.5% ) , were interrogated. The median age was 36 (range, 18-73) years, and 156 (58.4% ) patients were male. At a median treatment period of 1.0 (0.1-3.0) month, 43 (16.1% ) patients developed grade ≥3 neutrophils and/or thrombocytopenia and recovered within 1.0 (0.1-24.6) month. Male (OR=2.9, 95% CI 1.2-6.8; P=0.018) , age of ≥36 years (OR=3.2, 95% CI 1.4-7.2, P=0.005) , a spleen below a costal margin of ≥7 cm (OR=2.8, 95% CI 1.2-6.6, P=0.020) , and a hemoglobin (HGB) level of <100 g/L (OR=2.9, 95% CI 1.3-6.8, P=0.012) at diagnosis were significantly associated with grade ≥ 3 neutrophils and/or thrombocytopenia. Based on their regression coefficients, male, age of ≥36 years, a spleen below a costal margin of ≥7 cm, and an HGB level of <100 g/L were given 1 point to form a predictive system. All patients were divided into three risk subgroups, and the incidence of severe cytopenia significantly differed among the three groups (P < 0.001) . Grade ≥3 neutrophils and/or thrombocytopenia for >2 weeks was significantly associated with lower cumulative incidences of complete cytogenetic response (CCyR, HR=0.5, 95% CI 0.3-0.7, P<0.001) and major molecular response (MMR, HR=0.4, 95% CI 0.3-0.8, P=0.004) and was not significantly associated with failure, progression, and survival. Conclusion: Male, advanced age, a large spleen, and a low HGB level were significantly associated with severe cytopenia. The four covariates were used to establish a prediction model, in which the incidence of severe cytopenia among different risk groups was significantly different. Severe cytopenia for >2 weeks was a negative factor for responses but not for outcomes.

Chronic myeloid leukemia: the latest progress and future directions / 白血病·淋巴瘤

Chronic myeloid leukemia (CML) is a malignant hematological disease driven by BCR-ABL fusion protein. The emergence of tyrosine kinase inhibitor (TKI) targeting BCR-ABL has completely changed the treatment pattern of CML. From the approval of the first generation TKI imatinib in 2001 to the emergence of the fourth generation TKI drugs, CML patients have benefited a lot from it. But even so, many CML patients suffer treatment failure due to drug resistance, relapse after drug withdrawal or disease progression, some patients therefore are difficult to obtain long-term remission and still need multi-line TKI treatment. The research and development of new drugs covering more mutation lineages, more optimized treatment strategies and drug withdrawal-related research are still the focus of CML treatment. This article introduces the research progress of CML reported on the 64th American Society of Hematology annual meeting.

Immunotherapy for EGFR-mutant non-small cell lung cancer after EGFR-TKI acquired resistance / 国际肿瘤学杂志

Epidermal growth factor receptor (EGFR) -mutant advanced non-small cell lung cancer (NSCLC) was previously regarded as a cold tumor according to tumor immune microenvironment (TIME) . However, recent studies have found that EGFR-tyrosine kinase inhibitors (EGFR-TKIs) treatment can transform the host immunity from immunosuppressive to immunosupportive state, bringing new hope for immunotherapy. There are four main therapeutic strategies for patients after EGFR-TKIs acquired resistance: immunotherapy alone (Im) , immunotherapy plus chemotherapy (Im+C) , immunotherapy plus antiangiogenic drugs (Im+A) , and immunotherapy combined with antiangiogenic drugs and chemotherapy (Im+A+C) . Among them, the efficacy of Im is extremely limited, being significantly lower than that of chemotherapy alone, while there is still scarce evidence for the efficacy of Im+A with few clinical studies. The combination of Im+C and Im+A+C shows better efficacy than chemotherapy alone. Im+A+C has a superior clinical outcome to Im+C. Additionally, the EGFR L858R mutation subgroup benefits more from Im+C than the EGFR 19 del mutation subgroup. The T790M-negative subgroup has a greater benefit from Im+A+C than the T790M-positive subgroup. In general, the strategy of combining immunotherapy with chemotherapy and/or an antiangiogenic drug represents a novel and promising method for treating EGFR-mutant NSCLC after EGFR-TKI failure.

Application of PET/CT in the treatment of epidermal growth factor receptor tyrosine kinase inhibitor in patients with advanced non-small cell lung cancer / 中华核医学与分子影像杂志

The morbidity and mortality of lung cancer rank first in the world. Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) can significantly prolong survival of patients with advanced non-small cell lung cancer (NSCLC). 18F-FDG PET/CT can evaluate EGFR mutation status and EGFR-TKI efficacy. This article reviews the role of 18F-FDG PET/CT in predicting EFGR mutation, the efficacy and survival prognosis evaluation of EGFR-TKI therapy, as well as the development of latest EGFR-TKI PET imaging agents.

Study of 68Ga-NODAGA-RGD PET/CT in predicting short-term efficacy of tyrosine kinase inhibitor in the treatment of distant metastatic differentiated thyroid cancer / 中华核医学与分子影像杂志

Objective:To investigate the clinical application of 68Ga-cyclo( L-arginylglycyl- L-α-aspartyl- D-tyrosyl-N6-(((4, 7-bis(carboxymethyl)-1, 4, 7-triazonan-1-yl)acetyl))- L-lysyl) (NODAGA-RGD) PET/CT to evaluate short-term efficacy of tyrosine kinase inhibitor (TKI) in distant metastatic differentiated thyroid cancer (dmDTC). Methods:From October 2019 to March 2023, 13 dmDTC patients (5 males, 8 females; age: 68(65, 69) years) from Nanjing First Hospital were retrospectively enrolled, of which 9 were clinically confirmed as radioactive iodine-refractory differentiated thyroid cancer (RAIR-DTC) and 4 were dmDTC without radioactive iodine treatment. All patients underwent 68Ga-NODAGA-RGD PET/CT to assess neovascularization of the target lesions (TL), and the SUV max and target background ratio (T/B) were recorded. After 3 months of TKI treatment (anrotinib ( n=9) or apatinib ( n=4)), change rates of the maximum diameter of TL and thyroglobulin (Tg) were measured. The correlation of SUV max, T/B and the change rate of the maximum diameter of TL were analyzed by Spearman rank correlation analysis. ROC curve analysis was performed for the effectiveness of the T/B and TKI therapy, and the difference of the remission rate of lesions was analyzed by Fisher exact test. Results:In 13 patients, 36 TL were measured by 68Ga-NODAGA-RGD PET/CT with SUV max of 5.44(3.43, 7.56) and T/B of 5.25(4.50, 7.23). The change rate of the maximum diameter of TL was -30%(-39%, -21%) and the change rate of Tg was -68%(-96%, -52%). T/B was negatively correlated with the change rate of the maximum diameter of TL after TKI therapy ( rs=-0.46, P=0.005), while SUV max was not correlated with the change rate of the maximum diameter of TL ( rs=0.03, P=0.883). ROC curve analysis showed that the optimal cut-off value for T/B was 4.95, with the AUC of 0.698, the sensitivity of 87.5%, and the specificity of 60.0%. Compared to lesions with T/B<4.95, those with T/B≥4.95 showed higher remission rate (2/14 vs 63.6%(14/22); P=0.006). After 3 months of TKI treatment, the disease control rate was 12/13. Conclusion:68Ga-NODAGA-RGD PET/CT can effectively reflect tumor neovascularization, predict efficacy of TKI therapy, and provide powerful imaging evidence for TKI therapy in dmDTC.

Thoughts on the timing of targeted therapy initiation for thyroid cancer / 中华核医学与分子影像杂志

The treatment of persistent/recurrent and metastatic thyroid cancer and medullary thyroid cancer has made significant progress through the use of molecule-targeted therapy. While this approach has shown promise in improving patient outcomes and clinical symptoms, it also carries potential risks. The primary focus and challenge of targeted therapy is to optimize benefits while managing risks within predetermined thresholds. This review examines current targeted treatment practices in thyroid cancer and investigates the correlation between the timing of targeted therapy initiation and the patient benefits, aiming to lay the groundwork for subsequent research.