First-line Tyrosine Kinase Inhibitors Research Articles

CLINICAL FACTORS PREDECTING T790M MUTATION IN NON-SMALL CELL LUNG CANCER PROGRESSED AFTER FIRST- AND SECOND-GENERATION TKI TREATMENT

Objective: We aimed to identify the T790M mutation rate and clinical factors predicting the occurrence of acquired T790M mutations in advanced non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations after first- and second-generation tyrosine kinase inhibitor (TKI) treatment. Method: The EGFR-mutant NSCLC patients who experienced progression after first- and second-generation TKI treatment and underwent testing for EGFR using plasma samples between January 2021 and April 2023 were enrolled. The T90M mutation rate and related clinical factors were evaluated. We utilized the Chi-square test or Fisher’s exact test for univariate analysis and multivariable logistic binary regression for multivariate analysis. Results: A total of 247 patients were eligible for the study. Patients harbored the exon 19 deletion mutation (Del19), exon 21 L858R point mutation, and uncommon mutations in 63.2%, 34.4%, and 2.4% of cases, respectively. The overall T790M mutation rate was 33.6%. In multivariate analyses, the Del19 mutation versus L858R mutation, duration of first-line TKI exceeding 12 months versus below 12 months, and solitary lesion progression versus multiple lesion progression were identified as favorable prognostic factors for the occurrence of T790M mutation. Conclusion: Patients with EGFR exon 19 deletion, a prolonged treatment duration of first-line EGFR-TKI, and solitary lesion progression pattern are more likely to acquire the T790M mutation, as detected by the PCR method in plasma samples.

Expectations and outcomes of varying treatment strategies for CML presenting during pregnancy.

Diagnosing chronic myeloid leukaemia (CML) during pregnancy is rare. Tyrosine kinase inhibitors (TKIs) have traditionally been contraindicated owing to their teratogenicity. Management decisions should consider the risks to mother and foetus of uncontrolled disease and teratogenic medications. Further cases are required to build upon the paucity of current literature. We report 22 cases of CML diagnosed during pregnancy from 2002 to date. Twenty-one pregnancies resulted in healthy babies and one patient miscarried. Some patients remained untreated throughout pregnancy but the majority received one or both of interferon-α and leucapheresis. One patient was started on imatinib at Week 26, and one on hydroxycarbamide in the third trimester. We report haematological parameters during pregnancy to provide clinicians with realistic expectations of management. There were no fetal abnormalities related to treatment during pregnancy. Seventeen patients achieved at least major molecular response on first-line TKI. A diagnosis of CML during pregnancy can be managed without significant consequences for mother or child. Leucapheresis and interferon-α are generally safe throughout pregnancy. Despite having been avoided previously, there is growing evidence that certain TKIs may be used in particular circumstances during the later stages of pregnancy. Future work should aim to further elucidate this safety profile.

A Radiomics-clinical Nomogram based on CT Radiomics to Predict Acquired T790M Mutation Status in Non-small Cell Lung Cancer Patients.

To develop and validate a radiomics-clinical nomogram for the detection of the acquired T790M mutation in patients with advanced non-small cell lung cancer (NSCLC) with resistance after the duration of first-line epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) treatment. Thoracic CT was collected from 120 advanced NSCLC patients who suffered progression on first- or second-generation TKIs. Radiomics signatures were retrieved from the entire tumor. Pearson correlation and the least absolute shrinkage and selection operator (LASSO) regression method were adopted to choose the most suitable radiomics features. Clinical and radiological factors were assessed using univariate and multivariate analysis. Three Machine Learning (ML) models were constructed according to three classifiers, including Logistic Regression (LR), Support Vector Machine (SVM), and RandomForest (RF), combining clinical and radiomic features. A nomogram combining clinical features and the rad score signature was built. The predictive ability of the nomogram was assessed by the ROC curve, calibration curve, and decision curve analysis (DCA). Multivariate regression analysis showed that two clinicopathological characteristics and two radiological features were highly correlated with the acquired T790M mutation, including the progression-free survival (PFS) of first-line EGFR TKIs (P = 0.029), the initial EGFR profile (P = 0.01), vascular convergence (P = 0.043), and air bronchogram (P = 0.030). The AUCs of clinical, radiomics, and combined models using RF classifiers for T790M mutation detection were 0.951 (95% confidence interval [CI] 0.911,0.991), 0.917 (95%CI 0.856,0.978), and 0.961 (95%CI 0.927,0.995) in the training cohort, respectively, higher than those of other classifier models.The calibration curve and Hosmer-Lemeshow Test showed good calibration power, and the DCA demonstrated a significant net benefit. A radiomics-clinical nomogram based on CT radiomics proved valuable in non-invasively and efficiently predicting the acquired T790M mutation in patients who suffered progression on first-line TKIs.

JAK2 as Predictor of Therapeutic Response in Patients with Chronic Myeloid Leukemia Treated with Imatinib.

Chronic myeloid leukemia (CML) or chronic granulocytic leukemia is a myeloproliferative neoplasm indicated by the presence of the Philadelphia (Ph+) chromosome. First-line tyrosine kinase inhibitor, imatinib, is the gold standard for treatment. However, there has been known unresponsiveness to treatment, especially due to the involvement of other genes, such as the Janus kinase 2 (JAK2) gene. This study aimed to evaluate the relationships between JAK2 levels and complete hematological response (CHR), as well as early molecular response (EMR) after 3 months of imatinib treatment in patients with chronic phase CML. Patients with Ph+ CML in the chronic phase (n = 40; mean age, 40 ± 11 years) were recruited to complete assessments consisting of clinical examination and blood test, including evaluation of complete blood counts and the JAK2 levels, at baseline and following 3 months of therapy with imatinib (at an oral dose of 400 mg per day). Subjects were divided into two groups according to the presence of CHR and EMR. JAK2 gene levels, phosphorylated, and total JAK2 proteins at baseline were significantly lower in the group with the presence of CHR and EMR. In addition, baseline JAK2 levels, including JAK2 gene expression, phosphorylated, and total JAK2 proteins, were negatively correlated with the presence of CHR and EMR. Based on these findings, JAK2 levels may be a potential indicator for evaluating treatment response on imatinib due to its role in the pathophysiology of CML.

Outcome benefits of upfront cytoreductive nephrectomy for patients with metastatic renal cell carcinoma: An analysis of the TriNetX database.

The role of upfront cytoreductive nephrectomy remains debatable in the present era of tyrosine kinase inhibitors and immune checkpoint inhibitors. Here, we aimed to evaluate the outcomes of metastatic renal cell carcinoma patients treated with upfront CN and modern systemic therapies. Using the TriNetX network database, we identified patients, in the period from 2008 to 2022, who were diagnosed with metastatic renal cell carcinoma, receiving first-line systemic therapies with tyrosine kinase inhibitors or immune checkpoint inhibitors. Their overall survivals were evaluated using the Kaplan-Meier method as well as multivariable regressions. We identified 11,094 patients with metastatic renal cell carcinoma. Of them, 2,914 (43%) patients in the tyrosine kinase inhibitor cohort (n = 6,779), and 1,884 (43.7%) in the immune checkpoint inhibitors cohort (n = 4315) underwent upfront cytoreductive nephrectomy. Those receiving upfront cytoreductive nephrectomy showed survival advantages with either tyrosine kinase inhibitor (Hazard ratio 0.722, 95% Confidence interval 0.67-0.73, p<0.001) or immune checkpoint inhibitors (Hazard ratio 65.1, 95% Confidence interval 0.59-0.71, p<0.001). In multivariable analysis, upfront cytoreductive nephrectomy was a factor for improved OS in both cohorts: tyrosine kinase inhibitors (Hazard ratio 0.623, 95% Confidence interval 0.56-0.694, p<0.001) and immune checkpoint inhibitors cohort (Hazard ratio 0.688, 95% Confidence interval 0.607-0.779, p<0.001). Upfront cytoreductive nephrectomy was associated with an improved overall survival for patients with metastatic renal cell carcinoma receiving either first-line tyrosine kinase inhibitors or immune checkpoint inhibitors. Our results support a clinical role of upfront cytoreductive nephrectomy in the modern era.

Ascites does not accompany pleural effusion developing under dasatinib therapy in patients with CML-CP.

Pleural effusion (PE) is the most frequent pulmonary complication of dasatinib, a tyrosine kinase inhibitor (TKI). Concurrent pericardial effusions have been reported in about one-third of the cases. In this study, we aimed to investigate ascites generation in chronic-phase chronic myeloid leukemia (CML-CP) patients developing PE under dasatinib. We conducted a cross-sectional study to evaluate whether pericardial effusion and ascites accompany PE inCML-CP patients treated with dasatinib. For this purpose, consecutive patients with CML-CP who developed PE underdasatinib therapy have been evaluated with chest X-ray, transthoracic echocardiography, and abdominal ultrasonography. There were seven patients, and the median age was50 years (range, 31-73 years). Most of patients were male(n=5). All patients received imatinib as first-line TKI. Sixpatients received dasatinib following imatinib failure in second line. The median duration from dasatinib initiation to PE generation was 58months (range, 8-135months). Consequently, four patients had grade 1 pericardial effusion, and no patient had ascites. In our small study, dasatinib-related PE was associated with low-grade pericardial effusion but no ascites. There are hypothetical explanations of this phenomenon including the simultaneous activation/inhibition of kinases; however, more research needs to be performed on this topic.

Utility of T315I mutation in Egyptian patients with chronic myeloid leukemia

ABSTRACT Chronic myeloid leukemia(CML) is a myeloproliferative neoplasm (MPN) characterized by the presence of the Philadelphia chromosome (BCR:ABL), and there is a higher risk in untreated CML to be transformed to blast crisis phase. The development of tyrosine kinase inhibitor (TKI) imatinib was a remarkable step in CML treatment. However, patients showed resistance due to some mutations including T315I which still be the most challenging mutation in CML. Therefore, the aim of our study is to screen T315I in our Egyptian CML patients to predict and determine the frequency of T315I in patients with TKIs resistance. AS-PCR performed on 50 CML patients resistant to the first-line TKIs and 50 CML patients respond to the first-line TKIs. Positive-T315I was found in 15 (30%) of TKIs resistant cases. T315I was significantly associated with higher WBC, platelet count, cellularity of BM aspiration and biopsy when compared to those with negative-T315I. Resistant positive-T315I was significantly associated with lower cumulative OS 55.9% and shorter mean OS 93.4 months when compared to resistant negative-T315I. We conclude that T315I can exist at the diagnosis before starting treatment. Therefore, screening test for T315I can be performed at the time of diagnosis to help in choosing the suitable treatment protocol.

Taurohyocholic acid acts as a potential predictor of the efficacy of tyrosine kinase inhibitors combined with programmed cell death-1 inhibitors in hepatocellular carcinoma.

Background and aims: Tyrosine kinase inhibitors (TKIs) combined with programmed cell death protein-1 (PD-1) have significantly improved survival in patients with unresectable hepatocellular carcinoma (uHCC), but effective biomarkers to predict treatment efficacy are lacking. Peripheral blood bile acids (BAs) are associated with tumor response to therapy, but their roles in HCC remain unclear. Methods: This retrospective study included HCC patients who received first-line TKIs combined with PD-1 inhibitors treatment (combination therapy) in our clinical center from November 2020 to June 2022. The aim of this study was to analyze the changes in plasma BA profiles before and after treatment in both the responding group (Res group) and the non-responding group (Non-Res group). We aimed to explore the potential role of BAs in predicting the response to combination therapy in HCC patients. Results: Fifty-six patients with HCC who underwent combination therapy were included in this study, with 28 designated as responders (Res group) and 28 as non-responders (Non-Res group). There were differences in plasma BA concentrations between the two groups before systemic therapy. Plasma taurohyocholic acid (THCA) levels in the Res group were significantly lower than those in the Non-Res group. Patients with low levels of THCA exhibited superior median progression-free survival (7.6 vs. 4.9months, p = 0.027) and median overall survival (23.7 vs. 11.6months, p = 0.006) compared to those of patients with high levels of THCA. Conclusion: Peripheral blood BA metabolism is significantly correlated with combination therapy response and survival in patients with HCC. Our findings emphasize the potential of plasma BAs as biomarkers for predicting combination therapy outcomes and offering novel therapeutic targets for modulating responses to systemic cancer therapy.

Comorbidities and outcomes of patients with chronic myeloid leukemia treated with tyrosine kinase inhibitors: a real-world, nationwide, retrospective study from Hungary.

Purpose: This study aimed to provide real-world evidence on the characteristics, treatment patterns, and outcomes of patients with chronic myeloid leukemia (CML) receiving tyrosine kinase inhibitor (TKI) treatment in Hungary between 2011 and 2019. Patients and methods: This nationwide, retrospective study included patients who were newly diagnosed with CML in Hungarian clinical practice between January 2011 and December 2019. The analysis was based on the reimbursed prescription claims for imatinib, bosutinib, dasatinib, nilotinib, or ponatinib with the ICD-10 code C9210 in a public pharmacy between January 2009 and December 2019 using data from the National Health Insurance Fund (NHIF) of Hungary. CML incidence and prevalence, TKI treatment patterns, comorbidities, and overall survival (OS) were examined. Results: Between 2011 and 2019, altogether 1,407 patients were diagnosed with CML, with an annual average of 156 patients. The number of patients newly initiating first-line TKI therapy for CML significantly increased between 2011 and 2019 (2011: n = 136 vs. 2019: n = 191; p = 0.0043). Nilotinib was typically prescribed for younger patients (≤64years), while older patients (≥65years) mostly received imatinib. The most common comorbidity of CML patients was hypertension, and the proportion of patients with other malignancies was relatively high in all treatment groups. 5-year OS was 77.1% during the whole study period. Patients initiating first-line TKI treatment for CML in 2015 had significantly better 4-year OS compared to those starting treatment in 2011 (82.4% vs. 73.5%, respectively, (HR 0.53 (95%CI 0.32-0.87) p = 0.0118). Conclusion: This study is the first to provide insights into the characteristics, treatment patterns, and outcomes of CML patients treated with TKIs in Hungarian clinical practice between 2011 and 2019. We found slightly lower OS rates compared to other European countries, however, there was a statistically significant improvement in 4-year OS during the study period. The management of CML was in line with international guidelines and recommendations.

Male Fertility and Fatherhood in Chronic Myeloid Leukemia: Current Understanding and Future Perspectives.

Chronic myeloid leukemia (CML), while traditionally a disease of the elderly, has recently risen in incidence among younger patients. Hence, fertility concerns have emerged considering the disease process and treatments, especially with the current scarce and conflicting recommendations. This review explores the impact of CML treatments including the first-line tyrosine kinase inhibitors (TKIs) and other treatments on male fertility in chronic myeloid leukemia (CML) patients. The aim of this review was to compile the available evidence on male fertility to ultimately tailor treatment plans for male CML patients for whom fertility and future chances for conception pose a concern. The data available on the conventional and newer TKIs to address fertility concerns were reviewed, particularly the potential long- and short-term effects. Also, the possible side effects on subsequent generations were a crucial focus point of this review to reach a more comprehensive CML management approach. We found and compared the evidence on TKIs approved to treat CML. We also reported the effects of hydroxyurea, interferon, and transplantation, which are considered second-line treatments. Our findings suggest that these drugs might have an undiscovered effect on fertility. More research with larger sample sizes and longer follow-up periods is essential to solidify our understanding of these effects.

Targeting AXL induces tumor-intrinsic immunogenic response in tyrosine kinase inhibitor-resistant liver cancer

Hepatocellular carcinoma (HCC) is an aggressive malignancy without effective therapeutic approaches. Here, we evaluate the tumor-intrinsic mechanisms that attenuate the efficacy of immune checkpoint inhibitor (ICI) that is observed in patients with advanced HCC who progress on first-line tyrosine kinase inhibitor (TKI) therapy. Upregulation of AXL observed in sorafenib- and lenvatinib-resistant HCCs is correlated with poor response towards TKI and ICI treatments. AXL upregulation protects sorafenib-resistant HCC cells from oxidative stress, mitochondrial damage, and accompanying immunogenic cell death through suppressed tumor necrosis factor-α (TNF-α) and STING-type I interferon pathways. Pharmacological inhibition of AXL abrogates the protective effect and re-sensitizes TKI-resistant HCC tumors to anti-PD-1 treatment. We suggest that targeting AXL in combination with anti-PD-1 may provide an alternative treatment scheme for HCC patients who progress on TKI treatment.

Overcoming Central β-Sheet #6 (Cβ6) ALK Mutation (L1256F), TP53 Mutations and Short Forms of EML4-ALK v3/b and v5a/b Splice Variants are the Unmet Need That a Re-Imagined 5th-Generation (5G) ALK TKI Must Deliver.

Despite the development and approval of seven anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) spanning over three "generations" since the discovery of ALK fusion positive (ALK+) non-small cell lung cancer (NSCLC), there remains intrinsic and acquired resistances to these approved TKIs. Currently, a fourth-generation (4G) ALK TKI, NVL-655, is being developed to attack some of the unmet needs such as compound resistance mutations in cis. However, EML4-ALK variant 3 and TP53 mutations are intrinsic genomic alterations that negatively modulate efficacy of ALK TKIs. Potentially, in the shifting landscape where lorlatinib should be the first-line ALK TKI of choice based on the CROWN trial, the central β-sheet #6 (Cβ6) mutation ALK L1256F will be the potential acquired resistance mutation to lorlatinib which may be resistant to current ALK TKIs. Here we opine on what additional capacities a putative fifth-generation (5G) ALK TKI will need to possess if it can be achieved in one single molecule. We propose randomized trial schemas targeting some of the intrinsic resistance mechanisms that will lead to approval of a prototypic fifth-generation (5G) ALK TKI and actually be beneficial to ALK+ NSCLC patients rather than just design a positive pivotal superiority trial for the sole purpose of drug approval.

Advances in the Treatment of Chronic Myeloid Leukemia

Background: The treatment of chronic myeloid leukemia has progressed in recent decades, becoming a model for a disease whose pathogenesis is primarily based on a genetic mutation and has led to survivals comparable to those of the general population. Objective: This review aims to present recent therapeutic advances in this area. Methods: A mini-review was achieved using the articles published in Web of Science and Pub- Med between January 2021 - May 2022, and new patents were made in this field. Results: The three generations of tyrosine kinase inhibitors have transformed chronic myeloid leukemia into a manageable disorder and greatly improved the treatment results of the chronic phase, the prognosis, survival, and quality of life of patients. The therapeutic goals today include achieving a deep and lasting molecular response as soon as possible, successful treatment-free remission, and discovering and applying new therapeutic strategies to act on impaired immune modulation and dormant leukemic stem cells. The allosteric inhibitor asciminib targets the ABL myristoyl pocket, reduces Abl kinase activity, and is effective against most cells that have mutations in the ABL1 kinase domain. Progress and recommendations for achieving long-term treatment- free remission are set out. Nearly 50% of the patients who received first-line tyrosine kinase inhibitors required a change of treatment by 10 years due to intolerance or resistance to treatment. Their main side effects are presented. Conclusion: Obtaining a deep and persistent molecular response contributes to achieving longterm treatment-free remission.

Impact of Metastatic Site in Favorable-Risk Renal Cell Carcinoma Receiving Sunitinib or Pazopanib

BackgroundAlthough in metastatic renal cell carcinoma (mRCC) patients with intermediate and poor risk the benefit of combination strategies versus tyrosine kinase inhibitor (TKI) has been ascertained, in those with favorable risk data are ambiguous. Herein, we investigated the impact of number and type of metastatic site in patients with favorable risk to contribute to the best therapeutic choice. Material and MethodsMulticenter data regarding patients with favorable risk mRCC carcinoma receiving first-line TKIs, sunitinib or pazopanib, were retrospectively collected. We divided our population into 2 groups based on the number of metastatic sites and analyzed its impact on tumor response and efficacy outcome. The Kaplan-Meier method was used to estimate efficacy outcomes and the log-rank test to examine differences between subgroups. ResultsA total of 107 patients with a median age of 69 years were included in the final analysis. Patients with 1 metastatic site, compared with patients with > 1 site, had a significantly longer overall survival (OS) (not reached vs. 66 months) and a trend, although not statistically significant, of better progression-free survival (PFS) (31 vs. 17 months). In patients with 1 metastatic site, liver involvement was correlated with worse PFS and OS at the univariate analysis (P = .01) and was confirmed as independent poor prognostic factor for PFS at multivariate analysis. ConclusionIn conclusion, we reported a longer OS in favorable risk mRCC patients receiving TKI with only 1 metastatic site. Nevertheless, in patients with a single metastatic site, hepatic involvement correlated with worse PFS compared to other metastatic sites.

Phase III randomized controlled trial of gefitinib versus chemotherapy in EGFR-positive treatment-naïve metastatic lung cancer: Long-term outcome after eight years

Background: This was the first Phase III randomized study comparing an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), gefitinib, to standard-of-care chemotherapy (pemetrexed + carboplatin followed by pemetrexed maintenance) in advanced EGFR-mutated lung cancer. The initial interim analysis showed the superiority of gefitinib over chemotherapy in terms of progression-free survival (PFS), objective response rate (ORR), and safety. Objectives: We aimed to evaluate the long-term outcomes. Our primary endpoint was to evaluate the overall survival (OS) and the secondary endpoints were progression-free survival 2 (PFS2) and duration of response (DOR). Materials and Methods: This was a Phase III open-label, randomized, parallel-group study conducted in the Department of Medical Oncology, Tata Memorial Hospital, Mumbai, India, in patients with EGFR mutation-positive treatment-naïve Stage IIIB or IV lung adenocarcinoma. Patients were randomized to gefitinib (250 mg orally daily) or carboplatin (area under the curve 5) and pemetrexed (500 mg/m2) chemotherapy, followed by maintenance pemetrexed (500 mg/m2). Results: Between February 2012 and April 2016, 290 patients were randomized:145 to each arm. At a median follow-up of 104 months, all 290 (100%) patients had progressed, and 287 (99%) deaths had occurred. The median OS in the gefitinib arm was 19.5 months (95% confidence interval [CI], 16.7-24.8) compared to 22.6 months (95% CI, 19.2-25.2) in the chemotherapy arm; hazard ratio [HR], 1.11; 95% CI, 0.87-1.39; P, 0.423. The median PFS2 in the gefitinib arm was 15.5 months (95% CI, 13.5-18.1) compared to 12.5 months (95% CI, 11.1-14.5) in the chemotherapy arm; HR, 0.86 (95% CI, 0.66-1.13); P, 0.270. The median DOR was improved in the gefitinib arm (7.6 months; 95% CI, 5.45-9.88) compared to 3.9 months (95% CI, 3.49-6.35) in the chemotherapy arm; HR, 0.59; 95% CI, 0.42-0.82; P, 0.002. The 5-year survival was 4.1% in the gefitinib arm versus 6.8% in the chemotherapy arm. Conclusions: This study establishes the advantages of first-line EGFR TKI therapy over chemotherapy in terms of a durable response and numerically superior PFS2. Due to crossover post-progression, there was is no significant difference in OS (Clinical Trials Registry of India number: CTRI/2015/08/006113).

No detrimental association between antibiotic use and immune checkpoint inhibitor therapy: an observational cohort study comparing patients with ICI-treated and TKI-treated melanoma and NSCLC

BackgroundThe role of antibiotics in malignancies treated with immune checkpoint inhibitors (ICI) remains unclear. Several studies suggested a detrimental impact of antibiotic use on the response to ICI, but were...

Unusual presentation of extramedullary blast crisis in chronic myeloid leukemia: A case report

BACKGROUND Extramedullary blast crisis in chronic myeloid leukemia (CML) is an uncommon occurrence of leukemic blast infiltration in regions other than the bone marrow. Malignant infiltration of the serosal membranes should be considered in cases where CML presents with ascites or pleural effusion. CASE SUMMARY A 23-year-old female with CML presented with progressively worsening ascites and pleural effusion despite first-line tyrosine kinase inhibitor treatment. Her blood work indicated leukocytosis with myelocyte bulge and 2% blasts. Analysis of the patient’s bone marrow confirmed the chronic phase of CML. Abdominal ultrasound revealed hepatosplenomegaly with ascites. The fluid investigation of both ascites and pleural effusion revealed a predominance of neutrophils with exudate. However, no acid-fast bacilli or growth was observed after culturing. Although hydroxyurea reduced cell counts, there was no observed effect on ascites or pleural effusion. Repeat investigation of the ascitic and pleural fluid revealed a polymorphous myeloid cell population consisting of myelocytes, metamyelocytes, band forms, neutrophils and a few myeloblasts. Extramedullary blast crisis was suspected, and mutation analysis was performed. We switched the patient to dasatinib. The patient’s symptoms were relieved, and ascites and pleural effusion diminished. CONCLUSION Serosal membrane involvement in CML is extremely rare. In this case, the patient responded well to dasatinib treatment.

Cardiovascular adverse events in patients with hepatocellular carcinoma receiving vascular endothelial growth factor inhibitors.

Vascular endothelial growth factor inhibitors, including tyrosine kinase inhibitors (TKIs) and anti-angiogenics, are first-line therapies for advanced and metastatic hepatocellular carcinoma. Although TKIs have a greater potential for off-target adverse effects compared with bevacizumab (anti-angiogenics), a direct comparison of the risk of cardiovascular adverse events between these two types of therapies has not been performed. To compare the incidence of and characterize cardiovascular adverse events in patients with hepatocellular carcinoma receiving TKIs versus bevacizumab. This cohort study included adult patients with hepatocellular carcinoma who received first-line TKIs (sorafenib or lenvatinib) or bevacizumab at two academic medical centers and one community cancer center from September 2018 to August 2021. The primary outcome was risk of cardiovascular adverse events. Major secondary outcomes included the incidence of individual types of cardiovascular adverse events and risk factors associated with major adverse cardiovascular events (MACE). The study included 221 patients (159 TKI patients; 62 bevacizumab patients). At a median follow-up of 5 months, the probability of cardiovascular adverse events was not significantly different between the two groups (hazard ratio [HR]: 0.85; 95% confidence interval [95% CI]: 0.58-1.24; p = 0.390). The cumulative incidence of cardiovascular events was highest in patients receiving lenvatinib (sub-distribution hazard ratio [SHR]: 1.53; 95% CI: 1.02-2.30) compared with those receiving sorafenib (reference) or bevacizumab (SHR: 1.05; 95% CI: 0.68-1.64) after adjustment for comorbidities, liver transplant status, and presence of portal vein thrombosis at baseline. Cardiovascular adverse events were observed in 151 (68%) patients, and MACE were observed in 27 (12%) patients. Risk factors associated with MACE were hypertension (SHR: 3.5; 95% CI: 0.9087-15.83; p = 0.086), prior history of MACE (SHR: 2.01; 95% CI: 0.83-4.87; p = 0.124), and tobacco use (SHR: 2.85; 95% CI: 0.90-8.97; p = 0.074). Cardiovascular risk was not significantly different between TKIs and bevacizumab. Lenvatinib appears to have the highest risk of cardiovascular adverse events among these first-line VEGF inhibitors.

Abstract C136: VHL, PBRM1, and BAP1 mutation variants and response to first-line therapies in patients with metastatic clear-cell renal cell carcinoma (mRCC)

Abstract Background VHL, PBRM1, and BAP1 are common mutations in clear-cell renal cell carcinoma (ccRCC). VHL and PBRM1 mutations result in downstream dysregulation of vascular endothelial growth factor receptor (VEGFR) that cause angiogenesis and uncontrolled cell growth. VEGFR tyrosine kinase inhibitors (TKI) are the mainstay of ccRCC treatment. The current first-line (1L) therapies for mRCC include combination anti-VEGFR TKI + anti-PD-1 immune checkpoint inhibitors (CPI), or combination CPI targeting PD-1 and CTLA-4. It is unknown whether VHL and PBRM1 mutations are predictive for response to 1L anti-VEGFR TKI, anti-VEGFR TKI + CPI, or combination CPI immunotherapy. In this retrospective observational study, we evaluated the real-world outcomes of 1L therapies in patients with mRCC with or without VHL, PBRM1, or BAP1 mutations. Methods This study used the nationwide de-identified Flatiron Health-Foundation Medicine RCC clinico-genomic database, originating from approximately 280 cancer clinics (~800 sites of care). Patients with metastatic ccRCC, diagnosed from 8/1996-8/2022, who received 1L therapy with anti-VEGFR TKI, anti-VEGFR TKI + PD-1/PD-L1, or anti-PD-1 + anti-CTLA-4 therapy, and who had comprehensive genomic profiling were included. The primary endpoint was real-world overall survival (rwOS) in mRCC patients with VHL mutations. Secondary endpoints included rwOS and real-world progression-free survival (rwPFS) in patients with BAP1 and PBRM1 mutations, and rwPFS in patients with VHL mutations. The cox proportional hazard model was used to conduct the multivariable analysis adjusting for demographic/clinical factors for rwOS and rwPFS. The Kaplan-Meier method were used to estimate the median survival time. Results149 patients with complete data sets were included, of whom 99 had VHL mutations, 65 had PBRM1 mutations, and 31 had BAP1 mutations. Eight patients (5%) had favorable International Metastatic RCC Database Consortium (IMDC) risk, 110 (74%) had intermediate IMDC risk, and 31 (21%) had poor IMDC risk. The adjusted hazard ratio (HR) for rwOS in patients with VHL mutations compared to those without who received 1L anti-VEGFR TKI, anti-VEGFR TKI + PD-1/PD-L1, or PD-1/PD-L1 + CTLA-4 therapy were 1.53 (95% CI: 0.78-3.00, p=0.221), 0.87 (95% CI: 0.29-2.61, p=0.798), and 1.64 (95% CI: 0.71-3.75,p=0.245), respectively. The median rwOS for patients with PBRM1 mutations who received anti-VEGFR TKI was 50.1 months (95% CI: 34.62-NR) and 30.6 months (95% CI: 19.4-63.2) in patients without PBRM1 mutations (adjusted HR 0.54, 95% CI: 0.29-1.00, p=0.049). The median rwPFS for BAP1 mutations with anti-VEGFR TKI therapy was 5.2 months (95% CI: 3.6-9.1) and 6.4 (95% CI: 4.7-10.8) in patients without BAP1 mutations (adjusted HR 2.45, 95% CI: 1.35-4.44, p=0.003). Conclusion No significant difference was observed in rwOS in mRCC patients with VHL mutations treated with first-line anti-VEGFR TKI, anti-VEGFR TKI + PD-1/PD-L1, or PD-1/PD-L1 + CTLA-4 therapy, compared to patients without VHL mutations. Additional studies are needed to confirm this finding. Citation Format: Jessica Zhu, Junxiao Hu, Elaine T Lam. VHL, PBRM1, and BAP1 mutation variants and response to first-line therapies in patients with metastatic clear-cell renal cell carcinoma (mRCC) [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C136.

Characteristics, Outcomes, Tfr Rates in Young Adults with Chronic Myeloid Leukemia in the Tyrosine Kinase Inhibitor Era: A French Observational Study

Introduction. Chronic myeloid leukemia (CML) is a myeloproliferative disorder with a median age of approximately 60 years. Our study emphasizes the fact that CML can present at younger ages. These patients have significantly different life challenges compared with older patients. The 2020 update of the ELN recommendations mentioned that“ TFR may be the main goal for any patient, irrespective of age, but it is clear that the younger the patient the stronger the case for achieving TFR”. We report here the main characteristics and TFR data in CML young adults. Methods. The French CML group (FI-LMC) initiated an observational study (CCTIRS no. 14.745) to describe the characteristics of CML in young adult patients in terms of characteristics at diagnosis, treatment choices, tolerance, adherence, therapeutic response, evolution and survival. Patients ranging from 18 to &amp;lt; 30 years with newly diagnosed CML in chronic phase (CP) or accelerated phase (AP) treated with a tyrosine kinase inhibitor (TKI) in first line were eligible for enrolment. Results. The observatory included 253 unselected young adults from 22 centers with newly diagnosed CML in CP (n=246) or in AP (n=7) among which 51.6% were treated within a first line trial. At the time of CML diagnosis, the median patient age was 24 years (range, 18-29 years); 165 patients were males (63%). Median (range) values were: WBC 154.3 G/L (6.5; 841); platelets 374 G/L (51; 1799), hemoglobin 11.3 g/dL (4.1; 18.3), blast cells 1 % (0; 20), spleen below costal margin 4 cm (0; 30). In CP patients, Sokal score was low in 132 (53.6%) patients, intermediate in 46 (18.7%), high in 37 (15.1%) and unknown in 31 (12.6%) and ELTS score was low in 142 (57.7%) patients, intermediate in 48 (19.5%), high in 22 (9%) and unknown in 34 (13.8%). Initial TKI was imatinib alone (52.4%) or in combination with IFN (2.4%) or Ara-C (0.8%), nilotinib alone (24.6%) or in combination with IFN (4%), dasatinib alone (8.2%) or in combination with IFN (0.4%), bosutinib (1.2%), ponatinib (4.8%) or asciminib (1.2%). Median follow-up is 106.2 months (range: 0.03; 279.2). Ninety-nine (39.3%) patients remained under first-line TKI at latest follow-up and 21 pts (8.3%) underwent bone marrow transplantation (BMT) for resistance or transformation. Median overall survival at 9 years is 96.9% [95% CI: 94.5- 99.4]. Event free survival without death, transformation, or BMT at 9 years is 93.1% [95% CI: 89.7- 96.7]. Six patients died, 1 from sarcoma, 5 from CML including 1 before any therapy (brain hemorrhage). We investigated the TFR strategy. In 169 patients treated for at least 5 years, 56 (33.1%) attempted TKI discontinuation. TKI free survival at 24 months is 57.9% [95% CI: 45.8- 73.2] (Figure 1). Complete analysis comparing characteristics and outcome between the 2 groups of patients (TFR vs no TFR), will be available for ASH presentation. Conclusion. Despite aggressive features including prominent splenomegaly, high WBC counts and high blast cell percentage, TFR seems achievable in young adults with CML.