Tyrosine Kinase Inhibitors Research Articles

A Review on Systematic Treatment of Clear Cell Renal Cell Carcinoma Using Nivolumab and Cabozantinib

Since the introduction of anti-angiogenic and targeted therapies a decade ago, the management of advanced clear-cell renal cell carcinoma has seen significant advancements. Currently, the standard of care for colorectal cancer includes combinations of tyrosine kinase inhibitors (TKIs) and immunotherapy regimens like cabozantinib and nivolumab. The first-line treatment for RCC involves the combination of the anti-PD-1 monoclonal antibody nivolumab (OPDIVO®) and the multi-targeted TKI cabozantinib (Cabometyx®). Throughout the trial, the combination of cabozantinib and nivolumab consistently led to an enhanced health-related quality of life. Cabozantinib is used in the treatment of kidney cancer, hepatocellular carcinoma, and renal cell carcinoma. Nivolumab is typically employed when anti-angiogenic therapy proves ineffective. The combination of cabozantinib plus nivolumab, involving medications like sunitinib, ipilimumab, lenvatinib, and axtinib, is primarily utilized for its efficacy and survival benefits. The present review describes cabozantinib and nivolumab which are used for cancer treatment. This review helps people who are suffering from clear cell renal cell carcinoma.

Successful Treatment of Monoclonal Immunotactoid Glomerulopathy Associated with Chronic Lymphocytic Leukemia Using Ibrutinib.

A 71-year-old woman developed nephrotic syndrome during 10-year follow-up for chronic lymphocytic leukemia. A renal biopsy sample analysis revealed IgG1-lambda-positive monoclonal immunotactoid glomerulopathy (mITG). The patient was treated with ibrutinib, a Bruton tyrosine kinase inhibitor, and complete renal remission was achieved after 24 months. ITG is a rare disease that is characterized by glomerular deposition. In particular, mITG, which presents immune deposits that exhibit light-chain restriction, is often associated with hematologic disorders. Most patients with mITG receive immunosuppressive therapy and/or chemotherapy; however, to our knowledge, there have been no reports of treatment with ibrutinib.

Glofitamab in Relapsed/Refractory Mantle Cell Lymphoma: Results From a Phase I/II Study.

Patients with relapsed/refractory (R/R) mantle cell lymphoma (MCL) have a poor prognosis. The phase I/II NP30179 study (ClinicalTrials.gov identifier: NCT03075696) evaluated glofitamab monotherapy in patients with R/R B-cell lymphomas, with obinutuzumab pretreatment (Gpt) to mitigate the risk of cytokine release syndrome (CRS) with glofitamab. We present data for patients with R/R MCL. Eligible patients with R/R MCL (at least one previous therapy) received Gpt (1,000 or 2,000 mg) 7 days before the first glofitamab dose (single dose or split over 2 days if required). Glofitamab step-up dosing was administered once a day on days 8 (2.5 mg) and 15 (10 mg) of cycle 1, with a target dose of 16 or 30 mg once every 3 weeks from cycle 2 day 1 onward, for 12 cycles. Efficacy end points included investigator-assessed complete response (CR) rate, overall response rate (ORR), and duration of CR. Of 61 enrolled patients, 60 were evaluable for safety and efficacy. Patients had received a median of two previous therapies (range, 1-5). CR rate and ORR were 78.3% (95% CI, 65.8 to 87.9) and 85.0% (95% CI, 73.4 to 92.9), respectively. In patients who had received previous treatment with a Bruton tyrosine kinase inhibitor (n = 31), CR rate was 71.0% (95% CI, 52.0 to 85.8) and ORR was 74.2% (95% CI, 55.4 to 88.1). CRS after glofitamab administration occurred in 70.0% of patients, with a lower incidence in the 2,000 mg (63.6% [grade ≥2, 22.7%]) versus 1,000 mg (87.5%; grade ≥2, 62.5%) Gpt cohort. Four adverse events led to glofitamab withdrawal (all infections). Fixed-duration glofitamab induced high CR rates in heavily pretreated patients with R/R MCL; the safety profile was manageable with appropriate support.

Solvates and Polymorphs of Axitinib: Characterization and Phase Transformation.

Axitinib (AXTN) is an oral tyrosine kinase inhibitor for the treatment of early to advanced renal cell carcinoma. In this work, solvates of AXTN were prepared in five solvents and subjected to desolvation treatment. The crystal form A of AXTN can form solvates in acetonitrile, DMF, acetic acid, acetic acid + water, and methanol. Different ratios of AXTN and acetic acid will form different products (solvate or directly crystallized into another crystal form (form IV)). The characterization results of thermal analyses confirmed the types of the five solvates. The obtained solvates were desolvated using methods of solid-phase desolvation (heating, exposure to solvent steam, microwave) and solvent-mediated phase transformation (SMPT). The desolvated solids were characterized by PXRD, TGA, DSC, FT-IR, and SEM, and it was ultimately inferred that a new crystal form (form Z) of AXTN could be formed after desolvation. In addition, the solvates obtained in this work experienced mutual transformation via SMPT, which depends on the type of solvents or mixed solvents. The phase transformations of different solid forms were summarized. This study is instructive for exploring solvates and polymorphs of AXTN and understanding phase transitions under different environments.

Tolerability Assessment of Tyrosine Kinase Inhibitors in Patients With Solid Tumor Malignancies and Hypoalbuminemia.

Hypoalbuminemia is common in patients with advanced solid tumor malignancies. However, despite the increased use of highly protein-bound tyrosine kinase inhibitors (TKIs) in cancer treatments, the tolerability of these agents in patients with hypoalbuminemia is not fully known. Our aim is to assess whether patients on oral TKIs with hypoalbuminemia are at higher risk for experiencing medication-related adverse events, therefore requiring careful considerations. This is a single-center, retrospective study including patients ≥18 years of age with a solid tumor malignancy who had taken at least one dose of oral TKIs with a protein binding of ≥90% between June 1, 2016, and June 1, 2021. The primary outcome was to compare time to TKI discontinuation due to adverse events between patients with and without hypoalbuminemia. Key secondary outcomes include TKI discontinuation and dose reduction rates, time to TKI dose reduction, and severity of adverse events. Out of 282 included patients, 134 (48%) patients had hypoalbuminemia and 148 (52%) had normal albumin levels. Compared with patients without hypoalbuminemia, patients with hypoalbuminemia had shorter median time on treatment at 2.8 months (95% CI = 2.3-4.5 months) versus 4.3 months (95% CI = 2.8-6.4 months; P = 0.003). In patients who had TKI discontinuation, dose reduction was associated with longer time on treatment in patients in the normal albumin group compared with patients in the hypoalbuminemia group or patients without dose reduction (P < 0.0001). Patients in the hypoalbuminemia group experienced significantly more grade 3/4 adverse events compared with those in the normal albumin group (73% vs 27%, P < 0.0001). Hypoalbuminemia is a risk factor for both shorter time on treatment and more severe adverse events in patients with solid tumor malignancies taking highly protein-bound oral TKIs. This study highlights the need for closer monitoring of this patient population by health care providers.

Pirtobrutinib monotherapy in Bruton tyrosine kinase inhibitor-intolerant patients with B-cell malignancies: results of the phase I/II BRUIN trial.

Bruton tyrosine kinase inhibitors (BTKi) have transformed the treatment of B-cell malignancies, but intolerance has often led to their discontinuation. The phase 1/2 BRUIN study evaluated pirtobrutinib, a highly selective non-covalent (reversible) BTKi, in patients with R/R B-cell malignancies (NCT03740529). Pirtobrutinib was investigated in 127 patients with intolerance to at least one prior BTKi therapy in the absence of progressive disease. The most common adverse event (AE) leading to BTKi discontinuation was cardiac disorders (n=40, 31.5%), specifically atrial fibrillation (n=30, 23.6%). The median follow-up was 17.4 months and the median time on pirtobrutinib was 15.3 months. The most common reasons for pirtobrutinib discontinuation were progressive disease (26.8%), AE (10.2%), or death (5.5%). The most frequent treatment-emergent AEs were fatigue (39.4%) and neutropenia (37.0%). Among patients who discontinued a prior BTKi for a cardiac issue, 75% had no recurrence of their cardiac AE. No patient discontinued pirtobrutinib for the same AE that led to discontinuation of the prior BTKi. In 78 CLL/SLL and 21 MCL patients intolerant to prior BTKi, ORR to pirtobrutinib was 76.9% and 81.0%, respectively. Median PFS for CLL/SLL was 28.4 months and was not estimable for MCL. These results suggest that pirtobrutinib was safe, well-tolerated, and an efficacious option in patients with prior BTKi-intolerance.

Analysis of treatment benefits and prognostic factors for posttransplant HCC recurrence in a large Euro-American-Asian cohort.

Posttransplant HCC recurrence significantly impacts survival, yet its management is challenging due to limited evidence. With recent advancements in HCC treatment, updated data on managing recurrent diseases are needed. In this retrospective study across 6 centers (2000-2022), we employed Cox proportional-hazards regression and log-rank tests to assess survival differences. A prognostic score model was developed to categorize patient survival. The efficacy of tyrosine kinase inhibitors was evaluated through propensity score matching. In our study, 431 of 3349 (14%) patients with HCC who underwent transplantation developed recurrence within a median interval of 18 (IQR: 9-32) months. One hundred forty-seven (34%) underwent curative-intent treatments, 207 (48%) received palliative treatments, and 77 (18%) were given best-supportive care. Patients undergoing curative-intent treatments had better survival from the time of recurrence with a median survival of 45 (95% CI: 36-63) months and 1/3/5-year survival of 90%/56%/43% compared to those receiving noncurative treatments (median: 11 [95% CI: 10-13] mo, 1/3/5-y survival of 46%/10%/7%, log-rank p < 0.001). Patients with recurrence diagnosed in the era 2018-2022 showed improved survival over the previous era (HR 0.64 [95% CI: 0.47-0.86]). Multivariable analysis identified 5 prognostic factors: ineligibility for curative-intent treatment (HR: 3.5 [95% CI: 2.7-4.6]), recurrence within 1 year (HR: 1.7 [95% CI: 1.3-2.1]), poor tumor differentiation (HR: 1.5 [95% CI: 1.1-1.9]), RETREAT score ≥3 (HR: 1.4 [95% CI: 1.1-1.8]), and alpha-fetoprotein at recurrence ≥400ng/mL (HR: 1.4 [95% CI: 1.1-1.9]). These factors contributed to a prognostic scoring system (0-9) that stratified patients into 3 prognosis groups. Both propensity score-matched analysis and multivariable regression indicated that lenvatinib was not statistically superior to sorafenib in terms of efficacy. Curative-intent treatments should be advocated for patients with posttransplant recurrence whenever possible. Prognostic factors linked to aggressive tumor biology significantly influence survival. Advancements in HCC management have improved survival outcomes over the past 5 years.

Discovery of Oral Degraders of the ROS1 Fusion Protein with Potent Activity against Secondary Resistance Mutations.

The development of therapeutic resistance in the majority of patients limits the long-term benefit of ROS1 inhibitor treatment. On-target mutations of the ROS1 kinase domain confer resistance to crizotinib and lorlatinib in more than one-third of acquired resistance cases with no current effective treatment option. As an alternative to stoichiometric inhibition, proteolytic degradation of ROS1 could provide an effective tool to combat resistance generated by these mutations. Our study has identified a potent, orally active ROS1 degrader with an excellent pharmacokinetics profile. The degrader can effectively inhibit ROS1-dependent cell proliferation and tumor growth by degrading the ROS1 kinase, thereby eliminating the active phospho-ROS1. More importantly, the degradation-based therapeutic modality can overcome on-target mutation resistance to tyrosine kinase inhibitors by efficient degradation of the mutated kinase to achieve greater potency than inhibition.

Comparison of efficacy of gefitinib and osimertinib for untreated EGFR mutation-positive non-small-cell lung cancer in patients with poor performance status

BackgroundThere is a dearth of studies on the efficacy and safety of the tyrosine kinase inhibitors osimertinib (OSI) and gefitinib (GEF) in treating epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC), even in patients with poor performance status (PS). MethodsWe retrospectively reviewed and compared data of 113 patients with EGFR mutation-positive NSCLC with Eastern Cooperative Oncology Group PS 2–4 who were administered OSI 80 mg/day or GEF 250 mg/day from May 2016 to March 2022. ResultsThe GEF group (39 patients; median age: 74 years) included 20 patients with a PS of 2, 17 with a PS of 3, and 2 with a PS of 4. The OSI group (74 patients; median age: 76 years) included 48 patients with a PS of 2, 24 with a PS of 3, and 2 with a PS of 4. The overall response rates were 69% and 66% in the GEF and OSI groups, respectively. The disease control and PS improvement rates were 89% and 51% in both groups, respectively. The median progression-free survival in the GEF and OSI groups was 6.9 and 9.2 months, respectively (p = 0.15). The OSI group experienced better overall survival than the GEF group (median: 20.9 vs. 13.0 months, p = 0.0031). The incidence of pneumonitis was 10% and 11% in the GEF and OSI groups, respectively. One treatment-related death owing to pneumonitis occurred in the GEF group. ConclusionsOSI may be a useful treatment for untreated EGFR mutation-positive NSCLC with poor PS.

Efficacy and safety of olverembatinib in adult BCR::ABL1-positive ALL with T315I mutation or relapsed/refractory disease.

Third-generation tyrosine kinase inhibitors (TKIs) have much potential for the treatment of BCR::ABL1-positive leukaemia, particularly that harbouring the ABL1 T315I mutation. Olverembatinib (HQP1351), a novel third-generation TKI, has favourable efficacy and safety profiles in chronic myeloid leukaemia. Here, we present the clinical findings from 31 BCR::ABL1-positive acute lymphoblastic leukaemia (ALL) patients who received olverembatinib. Among the 14 patients with overt relapsed/refractory (R/R) disease (including 10 with the T315I mutation), 71.4% achieved an overall response. Of the other 17 patients with minimal residual disease (MRD)-positive ALL (including 14 with the T315I mutation), 60.0% and 47.1% achieved MRD flow negativity and complete molecular remission, respectively. With a median follow-up time of 16.3 months, the median event-free survival and overall survival were 3.9 and 8.3 months respectively, in overt R/R patients, and 11.5 and 18.4 months in MRD-positive patients. Allogeneic haematopoietic stem cell transplantation further improved outcomes among responders. The safety profile was generally manageable. This study suggests that olverembatinib-based therapy is another promising option for BCR::ABL1-positive ALL in addition to ponatinib, especially for patients with MRD-positive disease and a single T315I mutation.

First-line treatment of EGFR-mutated non-small cell lung cancer with brain metastases: a systematic review and meta-analysis

This systematic review and network meta-analysis evaluates first-line treatment options for patients with EGFR-mutant non-small cell lung cancer (NSCLC) and brain metastases. We analyzed 24 randomized controlled trials (RCTs) involving 2,682 patients, comparing various EGFR tyrosine kinase inhibitors (TKIs) and combination therapies. Direct comparisons showed that the addition of bevacizumab or chemotherapy to first-generation (1G) EGFR-TKIs improved overall survival (OS) compared to 1G TKIs alone, with HRs of 0.704 (95% CI: 0.433–0.973) and 0.682 (95% CI: 0.464–0.899), respectively. However, third-generation (3G) TKI monotherapy did not significantly improve OS compared with 1G TKIs, with an HR of 0.855 (95% CI: 0.511–1.198). Indirect comparisons suggested that the combination of 3G TKIs with chemotherapy provided the most significant improvements in OS and progression-free survival (PFS), significantly outperforming 3G TKIs, with HRs of OS 1.69 (95% CI: 1.14–3.4) and PFS 2.13 (95% CI: 1.28–3.54). Intracranial PFS was best with 1G TKIs plus bevacizumab. Our findings suggest that 3G EGFR-TKIs in combination with chemotherapy may be the most effective strategy for patients with EGFR-mutant NSCLC and brain metastases, though further head-to-head trials are needed for validation.

Detection and Response Evaluation of Extramedullary and Medullary Blast Crisis in Chronic Myeloid Leukemia on 18F-FDG PET/CT.

FDG PET/CT imaging is usually not routinely undertaken in patients of chronic myeloid leukemia (CML). We present a case of CML on tyrosine kinase inhibitor treatment with disease control indicated by BCR-ABL1 quantitative reverse transcription-polymerase chain reaction, who underwent PET/CT for evaluation of recent onset vision deterioration with subretinal exudates on ophthalmological examination. PET CT detected FDG-avid sinonasal thickening and bilateral marrow lesions. These lesions on histopathological sampling, examination revealed extramedullary and intramedullary CML blast crisis. Patient was then treated with steroids and change of tyrosine kinase inhibitor for the CML blast crisis. FDG PET/CT done subsequently was able to demonstrate morphological and metabolic response in the lesions.

Understanding Treatment Decisions and Management for Patients with Advanced Renal Cell Carcinoma Using Hypothetical Case Studies: A Vodcast.

In recent years, the armamentarium of therapies for the management of advanced renal cell carcinoma (aRCC) has grown. Combination therapies, including immuno-oncology (IO) agents and tyrosine kinase inhibitors [TKIs (IO-TKI)], and IO-IO combinations, are now approved for first-line treatment of aRCC. Decisions regarding the use of these combinations, IO-IO versus IO-TKI, can be challenging, as they have not been compared in a randomized trial; each of these combinations have been compared with sunitinib alone. In addition, patient-, disease-, and treatment-based factors must be evaluated in the decision-making process. More important is the consideration of patient management during treatment and optimal detection and management of toxicities to ensure continued benefit. In this vodcast, two experts in the field of kidney cancer will present case studies that represent typical patients seen in practice. The faculty will discuss treatment approaches, adverse event management, and which factors to consider during the treatment decision-making process. Viewers of the vodcast will get a better understanding of clinical trial outcomes related to an IO-TKI combination, such as axitinib plus pembrolizumab, that they can apply to their practice immediately. In addition, they will gain real-world insight into how experts approach the treatment of patients with aRCC and, more importantly, therapy management.

Ibrutinib Promotes Atrial Fibrillation by Disrupting A-Kinase Anchoring Protein 1-Mediated Mitochondrial Quality Surveillance in Cardiomyocytes.

Background: Ibrutinib, a potent Bruton's tyrosine kinase inhibitor with marked efficacy against hematological malignancies, is associated with the heightened risk of atrial fibrillation (AF). Although ibrutinib-induced AF is linked to enhanced oxidative stress, the underlying mechanisms remain unclear. Objective: This research aimed to explore the molecular mechanism and regulatory target in ibrutinib-induced AF. Methods: We performed invivo electrophysiology studies using ibrutinib-treated mice, and then employed proteomic and single-cell transcriptomic analyses to identify the underlying targets and mechanisms. The effects of A-kinase anchoring protein 1 (AKAP1) depletion on mitochondrial quality surveillance (MQS) were evaluated using both invivo and exvivo AKAP1 overexpression models. Results: Atrial AKAP1 expression was significantly reduced in ibrutinib-treated mice, leading to inducible AF, atrial fibrosis, and mitochondrial fragmentation. These pathological changes were effectively mitigated in an overexpression model of ibrutinib-treated mice injected with an adeno-associated virus carrying Akap1. In ibrutinib-treated atrial myocytes, AKAP1 down-regulation promoted dynamin-related protein 1 (DRP1) translocation into mitochondria by facilitating DRP1 dephosphorylation at Ser637, thereby mediating excessive mitochondrial fission. Impaired MQS was also suggested by defective mitochondrial respiration, mitochondrial metabolic reprogramming, and suppressed mitochondrial biogenesis, accompanied by excessive oxidative stress and inflammatory activation. The ibrutinib-mediated MQS disturbance can be markedly improved with the inducible expression of the AKAP1 lentiviral system. Conclusions: Our findings emphasize the key role of AKAP1-mediated MQS disruption in ibrutinib-induced AF, which explains the previously observed reactive oxygen species overproduction. Hence, AKAP1 activation can be employed to prevent and treat ibrutinib-induced AF.

A novel role for WZ3146 in the inhibition of cell proliferation via ERK and AKT pathway in the rare EGFR G719X mutant cells

Mutations in the epidermal growth factor receptor (EGFR) gene are common driver oncogenes in non-small cell lung cancer (NSCLC). Studies have shown that afatinib is beneficial for NSCLC patients with rare EGFR mutations. However, the effectiveness of tyrosine kinase inhibitors (TKIs) against the G719X (G719A, G719C and G719S) mutation has not been fully established. Herein, using the CRISPR method, the EGFR G719X mutant cell lines were constructed to assess the sensitivity of the rare mutation G719X in NSCLC. WZ3146, a novel mutation-selective EGFR inhibitor, was conducted transcriptome sequencing and in vitro experiments. The results showed that WZ3146 induced cytotoxic effects, inhibited growth vitality and proliferation via ERK and AKT pathway in the EGFR G719X mutant cells. Our findings suggest that WZ3146 may be a promising treatment option for NSCLC patients with the EGFR exon 18 substitution mutation G719X.

An analysis of the clinical significance of the TKI-resistant gene ZNF687 for hepatocellular carcinoma patients.

Novel treatments such as monotherapy and combined immunotherapy significantly extend overall survival (OS) for hepatocellular carcinoma (HCC) patients, but HCC is susceptible to treatment resistance during long-term therapy. The resistance mechanism to targeted drugs in HCC remains ambiguous, making research on HCC drug resistance targets crucial for the development of precision medicine. To investigate the transcriptional features, biological functions and potential clinical value of the tyrosine kinase inhibitor (TKI)-resistant gene ZNF687 in HCC. The TKI-resistant genes of HCC were identified using clustered regularly interspaced short palindromic repeats (CRISPR) in vitro screening. Then, the dependence of HCC cell lines on ZNF687 was investigated in silico. We collected global mRNA datasets of HCC tissue, integrated the mRNA expression characteristics of ZNF687 in HCC and explored the impact of ZNF687 on HCC patient prognoses using the Kaplan-Meier method (in silico). The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways analyses were then conducted, and a connectivity map and molecular docking technology were applied to find the underlying agent opposing ZNF687. In vitro, the guide RNA corresponding to ZNF687 was weakly detected in HCC cells, and ZNF687 deficiency was found to inhibit growth in HCC cell lines. ZNF687 mRNA was overexpressed and had a high discriminatory ability for HCC in 2,975 HCC samples, contrasting with 2,340 non-HCC samples. Moreover, an excessive ZNF687 transcript level was related to a worse overall survival (OS) prognosis. Histone modification, spliceosome, transcription coregulator activity, and nucleocytoplasmic transport were the most significant pathways for ZNF687 differential-related gene enrichment. Chaetocin was found to be a candidate compound and presented a strong affinity to ZNF687. ZNF687 represents a TKI-resistant and growth-dependent gene for HCC, the overexpression of which indicates poor OS for HCC patients. Additionally, ZNF687 is expected to be a druggable target for overcoming TKI resistance, and chaetocin may be a candidate therapeutic compound for ZNF687.

A-170 Hypereosinophilic Syndrome and t(5;15): Case Report and Literature Review

Abstract Background Hypereosinophilic syndrome (HES) is a myeloproliferative disorder characterized by persistent eosinophilia (absolute eosinophil count &amp;gt;1,500/mm3), classified into primary/clonal, reactive and idiopathic. After ruling out secondary causes of eosinophilia (parasitic infections, allergic conditions, vasculitis and collagenosis, drugs, eosinophilic lung disease, allergic gastroenteritis and metabolic conditions such as adrenal insufficiency), the main hypotheses become oncohematological diseases. Main entities to consider are myeloid/lymphoid neoplasms associated with eosinophilia and rearrangement of PDGFRA, FDGFRB, FGFR1 or PCM1-JAK2 and chronic eosinophilic leukemia. Conventional and molecular cytogenetics are the basis for classification and diagnosis of various hematological malignancies. This report describes a rare case of HES with t(5;15) (q33;q22). Methods A 29-year-old male patient was admitted with leukocytosis with the following exams: hemoglobin 6.5g/dL, hematocrit 21.7%, platelets 71,000/mm3, leukocytes 56,190/mm3 (60% neutrophils with a left shift to pro-myelocyte; 6% monocytes and 24% eosinophils), DHL 277 U/L, B12 vitamin 932 pg/mL, folic acid 1.72ng/mL, ferritin 913ng/mL. Non-reactive results were detected for antinuclear antibody, rheumatoid Factor, HIV, hepatitis B and C, syphilis and chagas disease. Bone marrow was hypercellular for age with absolute granulocytic predominance (G:E ratio 64:1) and eosinophilia (38%) in all maturational stages without dysplasia. Bone marrow flow cytometry did not detect neither increases in blasts nor anomalous immunophenotype. Bone marrow biopsy demonstrated 99% cellularity with normal blasts. Cytogenetics with translocation between the long arms of chromosome 5 and 15 in 15 of 20 metaphases analyzed - 46,XY,t(5;15)(q33;q22). No other molecular tests were available for this patient. Results In the case described t(5;15)(q33;q22) was found, which may be related to the TP53BP1::PDGFRB gene rearrangement. This breakpoint generates a chimeric oncoprotein similar to other tyrosine kinase fusions responsive to Imatinib. 53BP1 is a cellular DNA damage response component that binds wild type (non-mutant) p53. Oncogenesis occurs since the coiled-coil domains of TP53BP1 can mediate the homodimerization of PDGFRB and the constitutive activation of its tyrosine kinase activity; on the other hand, the DNA damage response of TP53BP1 may be disrupted. Gene rearrangements involving PDGFRA and FDGFRB are associated with response to tyrosine kinase inhibitors. Elevated vitamin B12 is a common finding in myeloproliferations with eosinophilia due to the increased production of haptocorrins, which binds to vitamin B12 in serum and in other tissues. Conclusions To our knowledge, in the literature there is only one described case of Myeloproliferative Neoplasia with Eosinophilia related to t(5;15)(q33;q22).

Outcomes of First-Line Microwave Ablation of Treatment-Naive Epidermal Growth Factor Receptor–Mutated Advanced Lung Adenocarcinoma Treated with Tyrosine Kinase Inhibitors

PurposeTo investigate the outcomes of first-line image-guided microwave ablation (MWA) plus tyrosine kinase inhibitors (TKIs) in untreated epidermal growth factor receptor (EGFR)–mutant advanced lung adenocarcinoma (LUAD) and to compare with TKIs alone. Materials and MethodsThis retrospective cohort study included patients between December 2015 and December 2021 and was divided into 2 groups (Group A: first-line MWA+TKIs; Group B: TKIs alone). Progression-free survival (PFS) was the primary end point, whereas overall survival (OS) was the secondary end point and were compared via the Kaplan–Meier methods. Univariate and multivariate analyses were used to investigate the predictors of PFS and OS. Propensity score matching (1:1 ratio) was applied between Group B and the subgroup of complete ablation in Group A. ResultsA total of 117 patients were included (Group A: n = 43; Group B: n = 74). In a mean follow-up of 47.0 months (SD ± 19.4), Group A had significantly longer median PFS (19.0 vs 10.0 months; P < .001) and OS (41.0 vs 25.0 months; P = .044) than Group B. Predictors of PFS included first-line MWA (P < .001) and tumor stage (P = .020), while that of OS included first-line MWA (P = 0.039), tumor stage (P = 0.014), and usage of third-generation TKIs (P = 0.001). There were 23 pairs of patients obtained after propensity score matching (Group A1: complete ablation+TKIs; Group B1: TKIs alone). Group A1 had significantly longer median PFS (24.0 vs 10.0 months; P < .001) and OS (48.0 vs 24.0 months; P = .012) than Group B1. ConclusionsFirst-line MWA significantly improved the outcomes of patients with untreated EGFR-mutant advanced LUAD treated with TKIs. Complete ablation predicts a better prognosis.

Tyrosine kinase inhibitors in the treatment of leptomeningeal carcinomatosis.

Leptomeningeal carcinomatosis (LMC) is a devastating complication of advanced cancers, such as lung cancer and breast cancer, which is usually indicative of a poor prognosis. The current treatments for LMC include palliative care, with others aiming to prolong survival and relieve neurological symptoms. Traditional treatments for LMC include radiotherapy, systemic chemotherapy, and intrathecal injection. Furthermore, the application of molecularly targeted agents, such as antiepidermal growth factor receptor (anti-EGFR), antihuman epidermal growth factor receptor 2 (anti-HER2), and anti-PD-1 monoclonal antibody, have prolonged the survival of LMC patients. Targeted therapy with tyrosine kinase inhibitors has also been proven to be an effective treatment. Tyrosine kinases can be overactive or expressed at high levels in some cancer cells; therefore, the use of tyrosine kinase inhibitors may prevent the activation of tumor-related pathways, preventing cancer cell growth. The EGFR family are cell surface receptors directly related to tumor occurrence with tyrosine kinase activity; it is the most widely used target for tyrosine kinase inhibitors in the treatment of LMC. In this review, we introduced the clinical manifestation and diagnostic criteria of LMC, clarified the treatment mechanism of tyrosine kinase inhibitors for LMC with mutations in EGFR, HER2, or anaplastic lymphoma kinase, reviewed the current application of various generation tyrosine kinase inhibitors in patients with LMC, and discussed new clinical trials and the future directions of tyrosine kinase inhibitor therapy.

PERICARDIAL TUBERCULOSIS IN A PATIENT WITH REFRACTORY PERICARDIAL EFFUSION AND USE OF DASATINIB: CASE REPORT

AbstractCardiovascular events have been reported in patients with chronic myeloid leukemia (CML) using tyrosine kinase inhibitors (TKIs). This study reports the occurrence of pericardial effusion (PE) refractory to usual therapy, with a final diagnosis of extrapulmonary tuberculosis (TB). IntroductionBy suppressing cellular immunity and compromising T lymphocyte signal transduction, TKIs are associated with tuberculosis. In vitro, dasatinib's action on Src-family kinases can impair cellular function and increase lysosomal acidification in macrophages, reducing Mycobacterium tuberculosis (Mtb) intracellular proliferation. In parallel, pleural effusion is a significant adverse effect of dasatinib. Its pathophysiology may involve increased vascular permeability via endothelial ABL kinases, Src kinases, and off-target inhibition of PDGFR-β. IgE-mediated histamine release by basophils has also been observed in vitro and may participate in dasatinib-related PE. ReportA 45-year-old male patient was diagnosed with low-risk CML in 2019 (EUTOS, SOKAL, HASFORD). After loss of major molecular response to imatinib and grade 4 toxicity to nilotinib, he was started on dasatinib 100 mg/day. Two years and eight months later, he presented with moderate pleural and marked pericardial effusion with hemodynamic repercussions. The medication was discontinued, with pleural effusion improvement after ten days of diuretics and prednisone. Conversely, the pericardial effusion persisted. Pericardiocentesis was performed, draining 460 ml of citrine fluid. Analysis revealed glucose 126 mg/dL (serum 165 mg/dL); RBC < 10, WBC 196 cells/μL, MN 95%, PMN 3.9%; pH 7.49; Xpert MTB/RIF assay: negative. After clinical improvement and a brief reintroduction of reduced-dose dasatinib, a new severe PE occurred. Partial pleurectomy and pleuropericardial window were performed, draining 500 ml of serohematic fluid. Cytology disclosed macrophages and Xpert MTB/RIF assay trace result. The diagnosis of pericardial tuberculosis prompted the initiation of an alternative treatment with levofloxacin, isoniazid, pyrazinamide, and ethambutol due to the rifampicin-TKI interaction. Treatment resumed with bosutinib 100 mg/day, increasing to 300 mg/day, with satisfactory tolerance. A new BCR::ABL1 evaluation is in progress. DiscussionDasatinib affects Src kinases expressed by lymphocytes and macrophages, which are crucial in the response to Mycobacterium tuberculosis. The incidence of TB during TKI use varies geographically, and its incidence with dasatinib is not yet known. Nonetheless, extrapulmonary TB has been reported. The median time to development of TB after initiation of TKI treatment is not established. Dasatinib is associated with PE in 1-4% of cases. The complication usually occurs 8-12 months after treatment initiation. In severe cases, management includes dose interruption or reduction, diuretics, corticosteroids, and pericardiocentesis. ConclusionDasatinib is effective in CML, but its immunological effect requires further study. The incidence of TB varies geographically and possibly among TKIs since the dual action of dasatinib appears to interfere with cellular immunity and reduce Mtb growth in vitro. Cavitary effusions are reported at all doses of dasatinib and are generally mild and manageable, even if grade ≥3. Refractory effusions should raise suspicion of infection, especially in areas with a high prevalence of TB.