Use Of Tyrosine Kinase Inhibitors Research Articles

ALK inhibitors in cancer: mechanisms of resistance and therapeutic management strategies

Anaplastic lymphoma kinase (ALK ) gene rearrangements have been identified as potent oncogenic drivers in several malignancies, including non-small cell lung cancer (NSCLC). The discovery of ALK inhibition using a tyrosine kinase inhibitor (TKI) has dramatically improved the outcomes of patients with ALK-mutated NSCLC. However, the emergence of intrinsic and acquired resistance inevitably occurs with ALK TKI use. This review describes the molecular mechanisms of ALK TKI resistance and discusses management strategies to overcome therapeutic resistance.

Myocardial Infarction in Chronic Myeloid Leukemia: Results from Nationwide Readmission Database.

Background and Objective Chronic myeloid leukemia (CML) is a hematological malignancy with an excellent prognostic outcome. After advancements in CML treatment and the introduction of different tyrosine kinase inhibitors (TKI), the life expectancy of CML patients has become equivalent to that of the general population. As a result, coronary artery disease is anticipated to be the leading cause of death among CML patients. Moreover, TKI use is associated with a risk of endothelial dysfunction, thrombosis, and cardiovascular events, including myocardial infarction. In this study, we compare the outcomes of percutaneous coronary intervention (PCI) in patients with CML to their matched non-CML counterparts. and compare the events reported with different TKI. Method The Nationwide Readmission Database (NRD) was searched from January 2016 to December 2020. for the study population. Adults of age ≥ 18 years with or without CML hospitalized for with a primary diagnosis of acute myocardial infarction, ST-segment elevation myocardial infarction (STEMI), and non-ST-segment elevation myocardial infarction (NSTEMI) and underwent PCI were included. The patients were identified using ICD-10 codes. The baseline characteristics and outcomes of the CML and non-CML patients who underwent PCI were compared. The primary outcomes were in-hospital mortality and 30-day readmission rates. The secondary outcomes were the PCI complications rates. Data regarding TKI reports of STEMI and acute coronary syndrome were obtained from The FDA Adverse Event Reporting System (FARES). Results Out of 2,727,619 patients with myocardial infarction, 2,124 CML patients were identified. A total of 888 CML patients underwent PCI. The mean age was 68.34 ± 11.14, with 62.46 % above 65 years. The analysis showed no significant difference between CML and non-CML patients after PCI for death (OR? 0.93 (95% CI 0.49-1.80), P=0.527) and 30-day readmission (OR? 1.41 (95% CI 0.99-2.01), P=0.056) rates. CML patients were significantly older (mean age 68.34 ± 11.14 versus 64.40 ± 12.61, p < 0.001) than non-CML patients without a difference in sex distribution. Hypertension (85.45% versus 78.64%), diabetes (45.48% versus 37.29), stroke (11.84% versus 7.78) at baseline were significantly higher in CML group. Prior myocardial infarction events (20.51% versus 15.17%) and prior PCI procedure (24.47% versus 16.89%) were significantly higher in CML group. CML had a significantly longer hospital stay (4.66 ± 4.40 versus 3.75 ± 4.62 days, p = 0.001). The primary outcomes did not differ between the comparison groups. Conclusion This analysis showed no statistically significant difference in mortality, 30-day readmission, and complication rates post PCI between CML and non-CML patients. However, interestingly, CML patients may experience lower coronary artery dissection and ischemic stroke rates than those without CML diagnosis.

Targeted Therapy Following Metastasectomy for Metastatic Renal Cell Carcinoma: A Systematic Review and Meta-analysis

Purpose: The aim of this study was to assess the effects of tyrosine kinase inhibitors (TKIs) following metastasectomy in patients with metastatic renal cell carcinoma (mRCC).Materials and Methods: A systematic search of multiple electronic databases was conducted. The inclusion criteria encompassed randomized clinical trials evaluating the use of TKIs after metastasectomy in mRCC patients. Study outcomes were relapse-free survival (RFS)/disease-free survival (DFS), overall survival (OS), and adverse events of TKIs.Results: Two studies with 197 randomized participants that compared TKIs following metastasectomy versus metastasectomy alone were identified. According to these studies, TKIs following metastasectomy may result in little to no difference in RFS/DFS (hazard ratio [HR], 1.01; 95% confidence interval [CI], 0.65–1.57; I<sup>2</sup>=29%; low-certainty evidence). TKIs after metastasectomy may slightly increase OS, but the CI crossed the line of no effect (HR, 0.80; 95% CI, 0.06–9.87; I<sup>2</sup>=86%; low-certainty evidence). TKIs after metastasectomy likely resulted in a large increase in adverse events (risk ratio, 2.76; 95% CI: 1.65–4.62; I<sup>2</sup>=not applicable; moderatecertainty evidence).Conclusions: TKIs following metastasectomy did not improve RFS/DFS, but slightly improved OS. It is likely that TKIs following metastasectomy increase adverse events compared to surgery only. The certainty of evidence ranged from moderate (signaling confidence that the reported effect size is likely close to the true effect) to low (indicating that the true effect may be substantially different from the effect estimate). The findings of this study should help to inform future guidelines and clinical decision-making at the point of care.

Executive Summary of the American Radium Society Appropriate Use Criteria for Brain Metastases in EGFR-mutated and ALK-fusion Non-Small Cell Lung Cancer.

The American Radium Society (ARS) Central Nervous System (CNS) committee reviewed literature on epidermal growth factor receptor mutated (EGFRm) and ALK-fusion (ALK+) tyrosine kinase inhibitors (TKIs) for the treatment of brain metastases (BrMs) from non-small cell lung cancers (NSCLC) to generate appropriate use guidelines addressing use of TKIs in conjunction with or in lieu of radiotherapy (RT). The panel developed three key questions to guide systematic review: can radiotherapy be deferred in patients receiving EGFR or ALK TKIs at 1) diagnosis or 2) recurrence? Should TKI be administered concurrently with RT (3)? Two literature searches were performed (May 2019 and December 2023). The panel developed 8 model cases and voted on treatment options using a 9-point scale, with 1-3, 4-6 and 7-9 corresponding to usually not appropriate, may be appropriate, and usually appropriate (respectively), per the UCLA/RAND Appropriateness Method. Consensus was achieved in only 4 treatment scenarios, all consistent with existing ARS-AUC guidelines for multiple BrM. The panel did not reach consensus that RT can be appropriately deferred in patients with BrM receiving CNS penetrant ALK or EGFR TKIs, though median scores indicated deferral may be appropriate under most circumstances. Whole brain RT with concurrent TKI generated broad disagreement except in cases with 2-4 BrM, where it was considered usually not appropriate. We identified no definitive studies dictating optimal sequencing of TKIs and RT for EGFRm and ALK+ BrM. Until such studies are completed, the committee hopes these cases guide decision-making in this complex clinical space.

Planned Discontinuation of Tyrosine Kinase Inhibitor Therapy in Metastatic Renal Cell Carcinoma: Lessons for the Era of Immunotherapy.

Several regimens combining immunotherapy and tyrosine kinase inhibitors (TKIs) have recently been validated for the first-line treatment of patients with metastatic renal cell carcinoma (mRCC). While immunotherapy is typically discontinued after 2 years in patients who neither progress nor experience limiting toxicity, according to the protocols of most recent phase III clinical trials, TKIs are to be continued until disease progression or the emergence of limiting toxicity. However, the prolonged use of TKIs is associated with significant toxicity and financial costs. This has sparked considerable debate about whether TKIs can be safely discontinued, particularly in mRCC patients who have achieved a verified complete response. This concise review examines the available evidence on TKI discontinuation in the context of mRCC management.

Characteristics and Survival Outcomes of Patients With Metastatic RET Fusion-Positive Solid Tumors Receiving Non-RET Inhibitor Standards of Care in a Real-World Setting.

RET fusions are oncogenic drivers across different solid tumors. However, the genomic landscape and natural history of patients with RET fusion-positive solid tumors are not well known. We describe the clinical characteristics of RET tyrosine kinase inhibitor (TKI)-naïve patients with RET fusion-positive solid tumors (excluding non-small-cell lung cancer [NSCLC]), treated in a real-world setting and assess the prognostic effect of RET fusions. Data for RET TKI-naïve patients with metastatic solid tumors (excluding NSCLC) who had ≥one Foundation Medicine comprehensive genomic profiling test (January 1, 2011-March 31, 2022) were obtained from a deidentified nationwide (US-based) clinicogenomic database. The primary objective of this study was to compare the overall survival (OS) of patients with RET fusion-positive tumors versus matched patients with RET wild-type (RET-WT) tumors. Patients with RET-WT solid tumors were matched (4:1) to patients with RET fusion-positive tumors on the basis of preselected covariates. The study population included 26 patients in the RET fusion-positive cohort, 7,220 patients in the RET-WT cohort (before matching), and 104 patients in the matched RET-WT cohort. Co-occurring genomic alterations were rare in the RET fusion-positive cohort. Median OS was consistently lower in patients with RET fusion-positive tumors versus those with RET-WT tumors, using three different analyses (hazard ratios, 2.0, 1.7, and 2.2). These data suggest that RET fusions represent a negative prognostic factor in patients with metastatic solid tumors and highlight the need for wider genomic testing and use of RET-specific TKIs that could improve patient outcomes. Our study also highlights the value of real-world data when studying rare cancers or cancers with rare genomic alterations.

Keratosis Pilaris-like Eruption during Treatment of Chronic Myeloid Leukemia with Tyrosine Kinase Inhibitors: Literature Review and Report of a Case Related to Imatinib.

The advent of tyrosine kinase inhibitors (TKIs) blocking BCR-ABL activity has revolutionized the therapeutic management of patients with chronic myeloid leukemia (CML). Adverse cutaneous reactions (ACRs) are common nonhematologic adverse events associated with the use of BCR-ABL TKIs. A characteristic pattern of eruption resembling keratosis pilaris (KP) has been described in patients treated with these drugs, especially nilotinib and dasatinib. The pathogenesis of this ACR is still unknown. This type of reaction appears to be uncommon with imatinib. Here, we report the case of an elderly patient with an asymptomatic KP-like eruption, which appeared one month after starting treatment with imatinib for CML. The case presentation is accompanied by a review of similar reactions in patients with CML treated with BCR-ABL inhibitors, attempting to make an excursus on the molecular targets of such drugs and possible mechanisms underlying this ACR.

Estimated Savings After Stopping Tyrosine Kinase Inhibitor Treatment Among Patients With Chronic Myeloid Leukemia

Patients with chronic myeloid leukemia (CML) who have a sustained deep molecular response using tyrosine kinase inhibitors (TKIs) can safely attempt to stop their use. As these medications are very costly, this change in treatment protocols may result in large savings. To estimate future savings from attempting to stop TKI use among patients with CML who have deep molecular response. A microsimulation model was developed for this decision analytical modeling study to estimate costs for US adults moving from using a TKI, to attempting discontinuation and then reinitiating TKI therapy, if clinically appropriate. Estimates were calculated for US patients who currently have CML and simulated newly diagnosed cohorts of patients over the next 30 years. Attempting to stop using a TKI. Estimated savings after attempted discontinuation of TKI use. A simulated population of individuals with CML in 2018 and future populations were created using estimates from the SEER*Explorer website. The median age at diagnosis was 66 years for men and 65 years for women. Between 2022 and 2052, the savings associated with eligible patients attempting discontinuation of TKI therapy was estimated at more than $30 billion among those currently diagnosed and over $15 billion among those who will develop CML in the future, for a total savings of over $54 billion by 2052 for drug treatment and polymerase chain reaction testing. The estimate is conservative as it does not account for complications and other health care-associated costs for patients continuing TKI therapy. The findings of this decision analytical modeling study of patients with CML suggest that attempting discontinuation of TKI therapy could save over $54 billion during the next 30 years. Further education for patients and physicians is needed to safely increase the number of patients who can successfully attain treatment-free remission.

Safety and Efficacy of Bezuclastinib (CGT9486), a Novel, Highly Selective, Potent KIT D816V Tyrosine Kinase Inhibitor, in Patients with Advanced Systemic Mastocytosis (AdvSM): Results from Part 1 of the Phase 2 Apex Trial

Background: Systemic mastocytosis (SM) is a rare disease characterized by the aberrant proliferation of mast cells (MC). In about 95% of adult patients, SM is driven by a gain-of-function mutation (D816V) in exon 17 of KIT. Advanced SM (AdvSM) is a life-threatening form of SM and includes three subtypes: aggressive SM (ASM), SM with an associated hematologic neoplasm (SM-AHN), and Mast Cell leukemia (MCL). Bezuclastinib is an oral, potent, and selective tyrosine kinase inhibitor (TKI) with activity against KIT D816V. Preliminary results from the on-going Apex study in patients with AdvSM (NCT04996875) were presented previously (DeAngelo et al. [abstract] In: Blood (ASH) 2022; 140 (Supplement 1): 1512-13). Methods: Apex is a randomized Phase 2, open-label, multicenter trial in adult patients diagnosed with AdvSM per 2022 WHO criteria with a baseline serum tryptase of ≥20 ng/mL. In Part 1, patients were randomized 1:1:1:1 to bezuclastinib 50mg BID, 100mg BID, 200mg BID, or 400mg QD. Patients with a history of prior TKI therapy (e.g., avapritinib, midostaurin) are permitted in the trial. Data from Part 1 informed dose selection for Part 2 of the trial. The primary efficacy endpoint for this trial is overall response rate (complete response [CR], CR with incomplete hematologic recovery [CRh], partial response [PR] and clinical improvement [CI]) as assessed by a central review committee based on mIWG-MRT-ECNM response criteria. Results: As of April 2023, Part 1 was fully enrolled with 33 AdvSM patients. Patients were randomized to 50mg BID (n=8), 100mg BID (n=8), 200mg BID (n=8), or 400mg QD (n=9). Disease subtypes included ASM (n=7), MCL (n=2), and SM-AHN (n=24); AHN subtypes included CMML (n=18), MDS (n=3), MPN (n=1), and MDS/MPN-U (n=2). The majority of patients were male (64%), ECOG PS 0-1 (82%) and KITD816V positive at baseline (91%). At baseline, 67% of patients were TKI-naïve; 33% had prior midostaurin, and 15% had prior avapritinib. Median (range) BM MC burden, serum tryptase, and KIT D816V VAF at baseline were 30% (5-90), 163 ng/mL (35-1578), and 7% (0-47), respectively. Of the 33 patients enrolled, 25 patients (76%) had C-findings evaluable per mIWG-MRT-ECNM criteria; 20 patients (61%) were positive for SRSF2/ASXL1/RUNX1 mutation which are associated with poor survival in SM. Conclusion: Enrollment in Part 1 of the Apex trial is complete. Patients enrolled in Part 1 of the Apex trial are generally representative of the population of patients with AdvSM based on patient characteristics and markers of disease. Part 1 includes a small subset of patients with prior use of TKIs. Safety, clinical activity, and clinical objective response for all patients in Part 1 will be presented.

Tyrosine Kinase Inhibitor (TKI) Treatment Patterns in 5,261 Chronic Phase (CP) Chronic Myeloid Leukemia (CML) Patients in “Real-Life” Settings: A Population-Based Study Using a Nationwide Claim Database

Introduction The introduction of TKI in CP-CML enabled responders to reach a similar survival to that of the general population. However, recent small-sized real-life studies showed that 1 in 5 CP-CML patients (pts) received at least 3 lines of TKI, mainly due to resistance or the onset of adverse events (AE). The objective of this study is to document real-life TKI treatment patterns nationwide in CML pts with a long-term follow-up, with a focus on pts who initiated at least a 3 rd line and associated disease burden. Methods This real-life non-interventional study was conducted using the French nationwide claim database (SNDS, Système National des Données de Santé), covering over 99% of French beneficiaries. Pts who initiated their first TKI with an indication for CML (imatinib, dasatinib, nilotinib, bosutinib, ponatinib) between January 2010 and December 2018, aged 18 years old or older at TKI initiation (index date T 0), and with healthcare resource use (HCRU) markers of CML - i.e., reasons for hospitalization and reported Long-Term Disease - without markers of confounding disease for the use of TKIs, were included. Treatment patterns were assessed from T 0 to December 2020 or death, through the description of TKI treatment sequences (TKI lines), adherence - discontinuations (≥ 3 months) during a TKI line and Medication Possession Ratio (MPR) -, and line duration (Time to Next Treatment (TTNT) estimates). TTNT was calculated as cumulative incidence of TKI switches, with death as competing risk; switches were defined as discontinuation of a TKI followed by the start of a different TKI. Results A total of 5,261 CML pts initiated their 1 st line TKI, with a median age at T 0 of 59.5 years (IQR: 23.2) and a M/F ratio of 1.2. The median follow-up from T 0 was 5.6 years (IQR: 4.6). Respectively 2,299, 1,017 and 426 pts initiated 2 nd, 3 rd and 4 th TKI line. Most frequent TKIs used as 1 st and 2 nd lines were imatinib (73.1%), and dasatinib (60.4%; Figure 1), respectively. From the 3 rd line, TKI patterns changed following the reimbursement of bosutinib in 2015 and ponatinib in 2016, and subsequently stabilized; shares in pts treated in 3 rd line and more at the beginning of 2020 were roughly equally distributed between marketed TKIs. TKI discontinuations rates during a line varied from 76.2% for 1 st line to 56.2% for 4 th lines. The median cumulative duration of discontinuations tended to decrease across lines (2.9, 2.5, 2.3 and 2.1 months for 1 st, 2 nd, 3 rd, and 4 th line, respectively); IQRs across lines were similar. The proportion of pts with a good medication adherence (MPR ≥ 80%) was around 80% for all TKI lines. TTNT was similar across all TKIs and all lines; 10-year TTNT rates were 48% (95CI: [47%; 50%]), 56% [53%; 59%], 56% [51%; 61%], 48% [42%; 54%] for 1 st, 2 nd, 3 rd, and 4 th lines. For pts who switched, most of switches occurred during the first year following line initiation (51% of switches observed in the first year for both 1 st, 2 nd, 3 rd, and 4 th lines), 24% occurred during the second year, and 10% during the third year. The 10-year cumulative incidences of death were 12% (95CI: [11%; 14%]), 9% [8%; 11%], 12% [9%; 16%], 14% [6%; 25%] for 1 st, 2 nd, 3 rd, and 4 th lines, respectively. The proportion of CML pts who initiated at least 3 lines of TKIs was 19.3% from raw estimates (n=1,017/5,261) and would be 27% based on TTNT estimates. Their characteristics were similar to pts who initiated 1 st line TKI (sociodemographic, comorbidities). Regarding HCRU, respectively 37.2% and 29.8% of pts had at least one hospitalization during 1 st and 6 th semesters following 3 rd line initiation; 7.9% to 5.8% visited emergency room, and around 10% had at least one sick leave per semester. Conclusion Using one of the largest cohorts of CML pts ever studied, with a follow-up period up to 10 years (median 5.6 years), this real-life study confirmed that multiple TKI switches are now common. We confirmed that at least 1 out of 5 CML patient fails at least two TKI lines. From TTNT estimates, surrogate marker for the duration of clinical benefit, lines of TKI would be effective over the long-term for around half of pts, and half of the switches occur within the first two years, regardless of line position. Finally, this real-world study illustrates the need for permanent care of these pts and alternative treatment options to avoid resistance or intolerance and induce a similar survival as the general population of the same age.

Chronic Myeloid Leukemia and Myocardial Infarction: A Nationwide Readmission Database Analysis

Introduction Chronic myeloid leukemia (CML) is a hematological malignancy with an excellent outcome. After advancements in CML treatment and the introduction of different Tyrosine kinase inhibitors (TKI), their life expectancy is equivalent to the normal population. As a result of that, coronary artery disease is anticipated to be the leading cause of death among CML patients. It was particularly noted that TKI use is associated with the risk of endothelial dysfunction and it associated risk of cardiovascular events, including myocardial infarction. In this study, we compare the outcome of PCI in patients with CML to their matched non-CML group. Method The National readmission database (NRD) was searched from January 2016 to December 2020 for the study population. Adults above (age ≥ 18 years) with chronic myeloid leukemia hospitalized with a primary diagnosis of myocardial infarction, ST Elevation Myocardial Infarction (STEMI), and Non-ST-elevation myocardial infarction (NSTEMI) were identified using ICD 10 code. The primary outcomes were in-hospital mortality and 30-day readmission, and the secondary outcome was to compare the complications. The weighting of patient-level observations was implemented to obtain national estimates. Multivariate regression analysis models were built by including all confounders significantly associated with the outcome on univariable analysis with a cutoff P-value of 0.2. Variables deemed important determinants of the outcomes based on literature were forced into the models. For readmission comparison, we used the time-to-event Cox regression analysis. Propensity matching was done by the Greedy method. Proportions were compared using the Mantel-Haenszel Chi-square test or Fisher exact test, and continuous variables were compared using the Student t-test. All P values were two-sided, with .05 as the threshold for statistical significance. Results Out of 2727619 patients with myocardial infarction, 2124 CML patients were identified, and 888 CML patients had Percutaneous Coronary Intervention (PCI). Patients' baseline characteristics and major outcomes were compared (table 1). The mean age of CML patients was 68.34 ± 11.14 (P<0.001). The analysis showed no significant difference between CML and non-CML patients after PCI for the primary outcome of death 0.93 (CI 0.49-1.80) P value 0.527 and 30 days readmission rate 1.41 (0.99-2.01) P value 0.056. Also, there was no statistical significance in developing major complications, including cardiac arrest, coronary artery dissection, cardiac tamponade, stroke, thrombosis, major bleeding, AKI, and dialysis. Discussion and Conclusion Patients with hematologic malignancies, including chronic myeloid leukemia, are at increased risk of thrombosis. In CML, thrombosis can be venous or arterial (myocardial infarction, cerebrovascular accidents, and peripheral artery disease). Arterial thrombosis in CML is primarily linked to using different TKIs, and thrombotic events were reported with the second-generation TKIs like nilotinib, dasatinib, and ponatinib more often than with first-generation TKIs. The mechanism of TKI use-associated thrombosis is likely related to TKI-associated endothelial dysfunction and vascular toxicity that lead to accelerated atherosclerosis and subsequent vascular thrombosis. This increased risk might lead to an assumption of an increased risk of complications with vascular intervention like PCI. Some studies showed that PCI for hematological cancer patients with STEMI have no significant difference regarding in-hospital mortality. This analysis of patients with CML with myocardial infarction ( STEMI and NSTEMI ) showed no statistically significant difference in outcome after PCI between the two groups. There were no significant differences in mortality, 30 days readmission rate, and other complications post PCI. Therefore, diagnosis of chronic myeloid leukemia shouldn't prevent patients from receiving routine therapy and intervention because of the theoretical risk of thrombosis. This information aid in patient counseling and achieving the objective of maintaining a normal quality of life for chronic myeloid leukemia patients.

Sars-Cov-2 and Chronic Myeloid Leukemia: A Systematic Review

Introduction Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the virus causing the coronavirus disease of 2019. Numerous mutations had developed in SARS-CoV-2 virus that resulted in strains (Alfa Beta Delta Omicron) with varying degrees of virulence disease severity. In coronavirus disease of 2019 (COVID-19) patients with chronic myeloid leukemia (CML), there is a controversy regarding the effect of tyrosine kinase inhibitors (TKI) on SARS-CoV-2 infection and patients' outcomes. Some studies showed that CML patients with COVID-19 had better outcomes; other reports showed no significant difference. Method Following the PRISMA (preferred reporting items for systematic reviews and meta-analyses) guidelines, PubMed, Scopus, and Google Scholar databases were searched for published articles through 20 April 2023 for qualified studies. The search included retrospective, prospective studies, reviews, case series, and case reports. The inclusion criteria were English literature with CML patients above 18 years who had SARS-CoV-2 infection. Articles in languages other than English and articles with non-sufficient information were excluded, and patients with bone marrow transplants were excluded. Search terms were (chronic myeloid leukemia) OR (chronic myelogenous leukemia) AND (SARS-CoV-2) OR (COVID-19). Two eligibility checks were done on the included studies. Title and abstract screening was completed first, and the full text of articles that met the requirements for inclusion was subsequently obtained. The search included all articles published up to 20 April 2023. The review is registered in PROSPERO (registration number is: CRD42022326674). Results We reviewed 36 articles of published literature up to April 2023 and collected data for a total of 686 CML patients with COVID-19. The vast majority of patients were in the chronic phase; seven patients were in the accelerated phase, and eight patients were in the blast phase. Disease severity was classified according to WHO criteria. Twenty-seven patients were managed at home, and 21 patients were in ICU (intensive care unit) during the hospital course. Twenty-six patients required oxygen therapy; among them, seven patients required intubation and mechanical ventilation, and six patients required non-invasive ventilation. Mortality was seen in 47 patients, and there were no reports of thrombotic events, but some patients developed AKI, autoimmune hemolytic anemia, rhabdomyolysis, and DKA during COVID-19. Limitations The major limitation is the lack of details about the use or hold of TKIs during SARS-CoV-2 infection in the majority of the reports. Also, the specific or predominant strain of SARS-CoV-2 was not mentioned. Few studies mentioned the variant of the virus, which make it difficult to compare the outcome of the different variant of the SARS-CoV-2 virus in patients with CML. Discussion/Conclusions Hematological cancers are associated with an increased risk of thrombosis. Thrombosis risk is expected to increase in patients with COVID-19; interestingly, patients with CML have not been reported to have a significant increase in the risk of thrombosis during COVID-19. The crucial point is, does TKI continuation during COVID-19 beneficial or harmful? Few patients continued TKIs during Covid-19 without serious adverse events. For patients who had the TKI continued, there were no mortality or serious adverse events. In vitro, TKIs were found to have a significant effect on inhibiting viral replication, which might be the reason behind the better outcome in CML patients infected with SARS-CoV-2 virus. On the other hand, there is a theoretical risk of increased severe infection in CML patients taking TKI due to targeted inhibition of kinases involved in immune cell function. This might result in suppressed cellular immune response that facilitates viral replication. Despite that, CML patients with COVID-19 have no significant increase in mortality or ICU admission compared to other hematological malignancies. in fact, our review showed that the mortality of CML patients with COVID-19 has significantly improved from 0.12% in the pre-vaccination period to 0.04% in the post-vaccination era. The available data indicates that, COVID-19's effect on patients with chronic myeloid leukemia (CML) still needs to be better understood due to the limited data.

The Impact of Adding Rituximab to the Standard Chemotherapy + TKI Regimen in Adults with Philadelphia-Positive B Acute Lymphoblastic Leukemia: A Multicenter Retrospective Study

Introduction: The addition of rituximab to the treatment of CD20-positive (CD20+) Philadelphia chromosome (Ph)-negative acute lymphoblastic leukemia (ALL) patients has demonstrated considerable benefits in terms of event-free survival in a large randomized clinical trial, as well as overall survival (OS) in retrospective analyses. Consequently, it is now an integral part of the standard care chemotherapy regimen for these patients. Conversely, Ph-positive (Ph+) B-ALL patients have been excluded from these trials and are typically managed with tyrosine-kinase inhibitors (TKI) in combination with chemotherapy, steroids, or novel agents such as blinatumomab. However, the potential benefits and concerns of adding rituximab to CD20+ Ph+ B-ALL patients remain uncertain, as there are worries about prolonged immunosuppression and potential infectious complications. Methods: We conducted a multicenter retrospective study involving five tertiary care centers in Mexico. The study included patients older than 16 years with newly diagnosed Ph-positive B ALL between January 2009 and June 2022, according to the WHO criteria. CD20+ was defined as CD20 expression ≥20% by flow cytometry. The decision to administer rituximab was based on the physician's discretion. The primary objective was to compare the 3-year OS between CD20-negative patients and CD20-positive patients who received or did not receive rituximab, and as secondary objectives to evaluate infection rates and mortality during induction with the addition of rituximab. Results: The study comprised 119 patients who met the inclusion criteria. The median age at diagnosis was 38 years (16 - 73), with 52.1% being male. The median white blood cell count (WBC) count was 114 x 10 9/L (0.5 - 466). Of these, 45 patients (37.8%) had CD20+ B-ALL, and 24 of them (53.3%) received rituximab. A total of 111 patients (93.2%) received TKI treatment, with imatinib being the most common (79%), followed by dasatinib (13.4%) and ponatinib (0.8%). The majority of the patients received either Hyper-CVAD (41.2%) or a local adult regimen (31.9%). There were no significant differences in age, WBC count, or treatment/TKI between patients who received rituximab and those who did not. Table 1 presents the characteristics of the population based on CD20 expression and treatment. Early mortality was 5.8%, with no significant difference observed between patients who received rituximab and those who did not (0% vs. 7.4%; OR 0.78, 95% CI 0.71 - 0.86, p=0.342). The rate of neutropenic fever during induction was 72.3%, and it was lower in patients who received rituximab (50.0% vs. 77.9%; OR 0.28, 95% CI 0.11 - 0.72, p=0.010). The intensive care unit (ICU) admission rate during induction was 11.8%, with no significant difference observed between patients with or without rituximab (8.3% vs. 12.6%; OR 0.62, 95% CI 0.13 - 3.01, p=0.733). Molecular response at 3 months was measured in 72 patients and the use of rituximab was associated with a non-significant higher rate: 83.3% vs 57.4% with an OR of 3.71 (95% CI, 0.96-14.33, p=0.056).The median OS for the entire cohort was 20 months (95% CI, 13.34 - 26.65), with a 3-year OS of 35.7%. The leading cause of death was disease progression (77.3%), while 10.7% died in remission: 7.7% of CD20- patients, 21.4% of CD20+ patients without rituximab, and 11.1% of CD20+ patients receiving rituximab (p=0.436). There was a trend towards a better OS in CD20+ patients who received rituximab: median OS not reached vs. 21 months (95% CI 13.27 - 28.72) in CD20- patients, and 13 months (95% CI 9.7 - 16.29) in CD20+ patients without rituximab. The 3-year OS rates for these groups were 52.7%, 34%, and 24.6%, respectively (p=0.222; Figure 1). Conclusions: In real-world practice, rituximab is added to the chemotherapy regimen and TKI in 53.3% of CD20+ Ph+ B-ALL cases. Rituximab is not associated with a higher incidence of infections, ICU admission, early mortality, or deaths in remission. Although there is no significant benefit observed, there is a trend towards better OS with the addition of rituximab to the standard treatment of CD20+ Ph+ ALL. There is an unmet need to explore the concomitant use of rituximab and TKI in prospective studies.

First-line treatment option for patients with ALK-positive metastatic NSCLC

Non-small cell lung cancer (NSCLC) that occupies a leading place in the pattern of cancer incidence and mortality is a highly heterogeneous group of diseases. The presence of a wide spectrum of NSCLC driver mutations has led to a fundamentally different understanding of the treatment strategy for this cohort of patients and a significant improvement in long-term oncological outcomes, even in the metastatic process. Chromosomal rearrangements involving the anaplastic lymphoma kinase (ALK) gene loci on chromosome 2 are found in approximately 3–5% of patients with metastatic NSCLC (mNSCLC) and in most cases are associated not only with a number of specific clinical features, but also with high sensitivity to targeted therapy with tyrosine kinase inhibitors (TKI). Crizotinib was the first approved ALK inhibitor, but although most patients achieved response within the first two years after start of the treatment, disease progression occurred often due to intracranial injury. The development of second-(ceritinib, alectinib), brigatinib and third-generation (lorlatinib) drugs has led to a statistically significant improvement in progression-free survival (PFS) rates, as well as control over intracranial manifestations of the disease and a change in the initial treatment strategy for these patients. In addition, new-generations of TKIs were developed to solve the problem of acquired resistance, as well as to achieve the best outcomes in the presence of such unfavourable factors as the presence of a TP53 mutation and/or ALK inhibitor low-sensitive translocation variants of the intracellular kinase domain of EML4 (echinoderm microtubule‐associated protein‐like 4)‐ALK (anaplastic lymphoma kinase) protein. Thus, advances in the therapeutic options for ALK-positive mNSCLC has completely changed the course of the disease, resulting in a significant increase in overall survival (OS) rates not only with the sequential use of different generation TKIs, but also with the choice of the most effective first-line option. In this article, we present an analysis of data on the efficacy and toxicity of lorlatinib, a third-generation TKI, in the first-line treatment for ALK+ mNSCLC.

Treatment outcomes of non-small cell lung cancers treated with EGFR tyrosine kinase inhibitors: a real-world cohort study

Background Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) are a standard of care treatment options in non-small cell lung cancer (NSCLC). The present study investigated real-world EGFR TKI use and patient outcomes in NSCLC. Material and methods We collected all the patients who had reimbursement for EGFR TKIs in Finland 2011–2020 and had data available at Finnish Cancer Registry. Survival and time-on-treatment (ToT) were analyzed from the first EGFR TKI purchase and patients were stratified according to the TKIs. Results Whole patient cohort consisted of 1498 individuals who were treated with erlotinib (n = 998), afatinib (n = 258), or gefitinib (n = 238). In the EGFR mutant cohort (all gefitinib users and afatinib users with non-squamous histology; n = 466), survival was comparable to registrational trials while patients treated with afatinib had improved survival (HR 0.67 CI 95% 0.53–0.85) and longer ToT (13.9 vs 11.9 months, NS) compared to those treated with gefitinib. Females treated with afatinib had improved survival (HR 0.61 CI 95% 0.44–0.83) and longer ToT (15.1 vs 12.5 months, NS) compared to gefitinib while similar was not observed in males. Later line osimertinib treatment was applied for 78 patients. Approximately 20% of the individuals treated with previous gefitinib or afatinib had later line osimertinib treatment. Efficacy analysis of osimertinib treated showed similar ToT and survival regardless of the first line EGFR TKI. Conclusions EGFR mutants treated with afatinib have improved outcomes compared to gefitinib while later-line osimertinib was applied only for around 20% of the individuals. The study further highlights the good real-world performance of EGFR TKIs and sheds light on therapy sequencing.

A Scoping Review on Tyrosine Kinase Inhibitors in Cats: Current Evidence and Future Directions.

Tyrosine kinase inhibitors (TKIs) have become invaluable in the treatment of human and canine malignancies, but their role in feline oncology is less defined. While toceranib phosphate and masitinib mesylate are licensed for use in dogs, no TKI is yet approved for cats. This review systematically maps the research conducted on the expression of tyrosine kinases in neoplastic and non-neoplastic domestic feline tissues, as well as the in vitro/in vivo use of TKIs in domestic cats. We identify and discuss knowledge gaps and speculate on the further research and potential indications for TKI use in cats. A comprehensive search of three electronic databases and relevant paper reference lists identified 139 studies meeting the inclusion criteria. The most commonly identified tumors were mast cell tumors (MCTs), mammary and squamous cell carcinomas and injection-site sarcomas. Based on the current literature, toceranib phosphate appears to be the most efficacious TKI in cats, especially against MCTs. Exploring the clinical use of TKIs in mammary carcinomas holds promise. Despite the progress, currently, the evidence falls short, underscoring the need for further research to discover new indications in feline oncology and to bridge the knowledge gaps between human and feline medicine.

Precision Deuteration in Search of Anticancer Agents: Approaches to Cancer Drug Discovery.

Cancer chemotherapy has been shifted from conventional cytotoxic drug therapy to selective and target-specific therapy after the findings about DNA changes and proteins that are responsible for cancer. A large number of newer drugs were discovered as targeted therapy for particular types of neoplastic disease. The initial discovery includes the development of the first in the category, imatinib, a Bcr-Abl tyrosine kinase inhibitor (TKI) for the treatment of chronic myelocytic leukemia in 2001. But the joy did not last for long as the drug developed a point mutation within the ABL1 kinase domain of BCR-ABL1, which subsequently led to the discovery of many other TKIs. Resistance was observed for newer TKIs a few years after their launching, but the use of TKIs in life-threatening cancer therapy is considered as far better compared with the risks of disease because of its target specificity and hence less toxicity. In search of a better anticancer agent, the physiochemical properties of the lead molecule have been modified for its efficacy toward disease and delay in the development of resistance. Deuteration in the drug molecule is one of such modifications that alter the pharmacokinetic properties, generally its metabolism, as compared with its pharmacodynamic effects. Precision deuteration in many anticancer drugs has been carried out to search for better drugs for cancer. In this review, the majority of anticancer drugs and molecules for which deuteration was applied to get better anticancer molecules were discussed. This review will provide a complete guide about the benefits of deuteration in cancer chemotherapy.

Gastrointestinal Stromal Tumors: Our Ten-Year Experience of a Single-Center Tertiary Hospital.

Gastrointestinal stromal tumors (GISTs) are the most frequent mesenchymal neoplasms of the gastrointestinal tract. They have variable clinical presentation, prognosis, and molecular characteristics. Here, we present the results of our retrospective study including patients operated on for GIST during the last decade. All the patients who underwent GIST resection during the decade 2008-2018 were included in the study. The diagnosis was based on the pathology report. All the data were collected and analyzed statistically using the Statistical Package for Social Science v25.0. Finally, after having applied the proper search terms, a comprehensive review of articles published in the Medline database was held. Thirty-two patients (sixteen women) were included in the study with a mean age of 69.6 years old (SD = 13.9). Twenty-one patients had a GIST in the stomach, eight in the small intestine, and three had an extra GIST. Of the 29 patients contacted, 21 were alive with a mean survival time of 74.3 months (SD = 49.6 months, min: 3.0 months, max: 161.0 months), whereas eight patients passed away. Finally, 13 patients were treated with tyrosine kinase inhibitors (TKIs) of whom only one died, while 9 patients passed away from those treated with surgery alone (p = 0.031). Our results were in concordance with the existing data in the literature. GISTs require patient-based therapeutical management depending on the histology of the tumors. Gastric tumors present a better prognosis than those localized in the intestine, while the use of TKIs has led to an improvement in patient survival rate.

Management of chronic myelogenous leukemia with COVID-19 and hepatitis B.

The application of immunosuppressive agents and targeted drugs has opened a novel approach for the treatment of hematological tumors, and the application of tyrosine kinase inhibitors for the treatment of chronic myeloid leukemia is one of the landmark breakthroughs that has considerably improved the prognosis of CML patients. However, with the extensive use of TKI, the co-infection of CML patients has become increasingly apparent, especially regarding infectious diseases such as hepatitis B and COVID-19. The underlying mechanism may be related to the inhibition of the immune function by TKI. Poor management, including disease progression due to the infectious disease or TKI dose reduction or discontinuation, may lead to adverse clinical outcomes and can even be life-threatening. Therefore, this review principally provides an overview of the pathogenesis and standardized management principles of CML patients with comorbid COVID-19 or hepatitis B in order to improve clinicians' awareness of the risks so as to more effectively diagnose and treat CML and improve the survival rate and quality of life of patients. In the past two decades, owing to the advent of imatinib, chronic myeloid leukemia (CML) has transformed into a chronic controllable disease, and even treatment-free remission can be anticipated. Earlier studies have indicated that tyrosine kinase inhibitor (TKI) exerts a peculiar inhibitory effect on the body's immune function. Therefore, with the widespread application of TKI, more and more attention has been paid to the comorbidity of infectious diseases in CML patients, especially in patients with progressive disease or non-remission. Despite some studies revealing that the proportion and severity of SARS-CoV-2 infection in CML patients receiving TKI treatment are lower than in patients with other hematological malignancies, CML patients with stable disease are still recommended to be vaccinated against SARS-CoV-2, while TKI may or may not be discontinued. Meanwhile, the management of CML patients during the epidemic of coronavirus disease 2019 (COVID-19) still necessitates further discussion. This article also provides an overview of TKI-related hepatitis B reactivation. If not managed, patients may face adverse consequences such as hepatitis B reactivation-related hepatitis, liver failure, and progression of CML after forced withdrawal of medication. Therefore, this review aimed to comprehensively describe the management of CML patients with comorbid COVID-19, the pathogenesis of hepatitis B reactivation, the indicated population for prophylactic antiviral therapy, the time of antiviral drug discontinuation, and drug selection.

ALK Inhibitor Treatment Patterns and Outcomes in Real-World Patients with ALK-Positive Non-Small-Cell Lung Cancer: A Retrospective Cohort Study.

Randomized trials have demonstrated that anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) can be safe and efficacious treatments for patients with ALK-positive advanced non-small-cell lung cancer (aNSCLC). However, their safety, tolerability, effectiveness, and patterns of use in real-world patients remain understudied. We sought to assess the overall treatment pattern characteristics, safety, and effectiveness outcomes of real-world patients with ALK-positive aNSCLC receiving ALK TKIs. This retrospective cohort study using electronic health record data included adult patients with ALK-positive aNSCLC receiving ALK TKIs between January 2012 and November 2021 at a large tertiary medical center, University of California, San Francisco (UCSF), with alectinib or crizotinib as the initial ALK TKI therapy. Our primary endpoints included the incidence of treatment changes (treatment dose adjustments, interruptions, and discontinuations) during the initial ALK TKI treatment, the count and type of subsequent treatments, rates of serious adverse events (sAEs), and major adverse events (mAEs) leading to any ALK TKI treatment changes. Secondary endpoints included the hazard ratios (HRs) for median mAE-free survival (mAEFS), real-world progression-free survival (rwPFS), and overall survival (OS) when comparing alectinib with crizotinib. The cohort consisted of 117 adult patients (70 alectinib and 47 crizotinib) with ALK-positive aNSCLC, with 24.8%, 17.9%, and 6.0% experiencing treatment dose adjustments, interruptions, and discontinuation, respectively. Of the 73 patients whose ALK TKI treatments were discontinued, 68 received subsequent treatments including newer generations of ALK TKIs, immune checkpoint inhibitors, and chemotherapies. The most common mAEs were rash (9.9%) and bradycardia (7.0%) for alectinib and liver toxicity (19.1%) for crizotinib. The most common sAEs were pericardial effusion (5.6%) and pleural effusion (5.6%) for alectinib and pulmonary embolism (6.4%) for crizotinib. Patients receiving alectinib versus crizotinib as their first ALK TKI treatment experienced significantly prolonged median rwPFS (29.3 versus 10.4months) with an HR of 0.38 (95% CI 0.21-0.67), while prolonged median mAEFS (not reached versus 91.3months) and OS (54.1 versus 45.8months) were observed in patients receiving alectinib versus crizotinib but did not reach statistical significance. Yet, it is worth noting that there was a high degree of cross-over post-progression, which could significantly confound the overall survival measures. We found that ALK TKIs were highly tolerable, and alectinib was associated with favorable survival outcomes with longer time to adverse events (AE) requiring medical interventions, disease progression, and death, in the context of real-world use. Proactive monitoring for adverse events such as rash, bradycardia, and hepatotoxicity may help further promote the safe and optimal use of ALK TKIs in the treatment of patients with aNSCLC.