Prevalence and management of proteinuria associated with vascular endothelial growth factor receptor-targeted tyrosine kinase inhibitor treatment in advanced renal cell carcinoma, hepatocellular carcinoma, and thyroid cancer.

Vascular endothelial growth factor receptor-targeted tyrosine kinase inhibitors (VEGFR-TKIs) are often used for treatment of several types of cancer; however, they are associated with an increased risk of proteinuria, sometimes leading to treatment discontinuation. We searched PubMed and Scopus to identify clinical studies examining the incidence and risk factors for proteinuria caused by VEGFR-TKIs in patients with renal cell carcinoma, thyroid cancer, and hepatocellular carcinoma. The global incidence of proteinuria ranged from 6% to 34% for all grades of proteinuria, and from 1% to 10% for grade ≥3 proteinuria. The incidence of proteinuria did not differ significantly by cancer type, but in all three cancer types, there was a trend toward a higher incidence of proteinuria with lenvatinib than with other VEGFR-TKIs. In terms of risk factors, the incidence of proteinuria was significantly higher among Asians (including Japanese) compared with non-Asian populations. Other risk factors included diabetes mellitus, hypertension, and previous nephrectomy. When grade 3/4 proteinuria occurs, patients should be treated according to the criteria for dose reduction or withdrawal specified for each drug. For grade 2 proteinuria, treatment should be continued when the benefits outweigh the risks. Referral to a nephrologist should be considered for symptoms related to decreased renal function or when proteinuria has not improved after medication withdrawal. These management practices should be implemented universally, regardless of the cancer type.

Real-world analysis of adverse event rates after initiation of ibrutinib among Medicare beneficiaries with chronic lymphocytic leukemia.

BACKGROUND: The first-generation BTK inhibitor ibrutinib is a standard-of-care therapy in the treatment of chronic lymphocytic leukemia (CLL) despite potential side effects that often lead to discontinuation. METHODS: This study used 2013-2019 claims data to describe the incidence rate of adverse events (AEs) among elderly Medicare beneficiaries newly initiating ibrutinib for CLL. RESULTS: The final sample contained 11,870 Medicare beneficiaries with CLL (mean age 77.2) newly initiating ibrutinib, of whom 65.2% discontinued over mean follow-up of 2.3 years. The overall incidence rate of AEs was 62.5 per 1000 patient-months for all discontinuers and 32.9 per 1000 patient-months for non-discontinuers. Discontinuers had a higher incidence rate of AEs per 1000 patient-months compared with non-discontinuers for all AEs examined, including infection (22.8 vs. 14.5), atrial fibrillation (15.1 vs. 7.0), anemia (21.9 vs. 14.5), and arthralgia/myalgia (19.5 vs. 13.6). CONCLUSION: In this first real-world study of a national sample of elderly US patients treated with ibrutinib, we found a clear unmet need for improved management of ibrutinib-related AEs and/or new treatments to improve real-world outcomes in patients with CLL.

Maximizing the Value of Chronic Myeloid Leukemia Management Using Tyrosine Kinase Inhibitors in the USA: Potential Determinants and Consequences of Healthcare Resource Utilization and Costs, with Proposed Optimization Approaches.

BACKGROUND AND OBJECTIVES: The introduction and widespread use of effective and well-tolerated tyrosine kinase inhibitors for chronic myeloid leukemia have been associated with marked increments in life expectancy and disease prevalence. These changes have been accompanied by elevations in costs of tyrosine kinase inhibitors, which typically must be taken ad vitam after diagnosis and tend to be more expensive than medical therapies for many other hematologic malignancies. The aims of this review included evaluating the potential associations and consequences of healthcare resource utilization and costs of tyrosine kinase inhibitors and possible clinical management approaches to mitigate them. METHODS: A PubMed search of English-language US study reports was conducted that covered the interval of 2001 (US approval of imatinib) through 17 April, 2023 augmented by manual reviews of published bibliographies from the referenced articles and searches of other databases: Google Scholar and Scopus. RESULTS: On the basis of this analysis of chiefly real-world evidence (administrative claims database studies), healthcare resource utilization and costs can be considered indicators of ineffective chronic myeloid leukemia management, including potentially mutation-driven treatment resistance and costly tyrosine kinase inhibitor switches, non-adherence, and suboptimal tolerability, which may culminate in the progression of disease from the chronic to an accelerated or blast phase, with additional excess costs. Costs of tyrosine kinase inhibitors are also associated with reduced treatment adherence. At a willingness-to-pay threshold of $50,000-$200,000 per quality-adjusted life-year, tyrosine kinase inhibitors can be considered cost effective from a US payer perspective. Potential clinical approaches to mitigate costs include regular molecular monitoring with proactive assessments of BCR::ABL1 gene mutations to avoid costly treatment switches, as well as interventions to enhance treatment adherence and tyrosine kinase inhibitor tolerability. CONCLUSIONS: Healthcare resource utilization and costs of chronic myeloid leukemia care may be considered barometers of ineffective management, including mutation-driven tyrosine kinase inhibitor resistance and switching as well as non-adherence and intolerance. Future prospective research is warranted to help determine whether costs can be reduced and other treatment outcomes optimized via more proactive and effective diagnostic interventions (i.e., regular molecular monitoring and proactive mutational testing) and treatment approaches. The strengths and limitations of this review include its emphasis on observational research, which, on one hand, offers a naturalistic "real-world" perspective on current chronic myeloid leukemia management, but, on the other hand, is associational in nature and cannot be used to determine causality and/or its direction.

PRECYCLE: multicenter, randomized phase IV intergroup trial to evaluate the impact of eHealth-based patient-reported outcome (PRO) assessment on quality of life in patients with hormone receptor positive, HER2 negative locally advanced or metastatic breast cancer treated with palbociclib and an aromatase inhibitor or palbociclib and fulvestrant.

BACKGROUND: Efficacy and quality of life (QoL) are key criteria for therapy selection in metastatic breast cancer (MBC). In hormone receptor positive (HR +) human epidermal growth factor receptor 2 negative (HER2 -) MBC, addition of targeted oral agents such as everolimus or a cycline-dependent kinase 4/6 (CDK 4/6) inhibitor (e.g., palbociclib, ribociclib, abemaciclib) to endocrine therapy substantially prolongs progression-free survival and in the case of a CDK 4/6i also overall survival. However, the prerequisite is adherence to therapy over the entire course of treatment. However, particularly with new oral drugs, adherence presents a challenge to disease management. In this context, factors influencing adherence include maintaining patients' satisfaction and early detection/management of side effects. New strategies for continuous support of oncological patients are needed. An eHealth-based platform can help to support therapy management and physician-patient interaction. METHODS: PreCycle is a multicenter, randomized, phase IV trial in HR + HER2 - MBC. All patients (n = 960) receive the CDK 4/6 inhibitor palbociclib either in first (62.5%) or later line (37.5%) together with endocrine therapy (AI, fulvestrant) according to national guidelines. PreCycle evaluates and compares the time to deterioration (TTD) of QoL in patients supported by eHealth systems with substantially different functionality: CANKADO active vs. inform. CANKADO active is the fully functional CANKADO-based eHealth treatment support system. CANKADO inform is a CANKADO-based eHealth service with a personal login, documentation of daily drug intake, but no further functions. To evaluate QoL, the FACT-B questionnaire is completed at every visit. As little is known about relationships between behavior (e.g., adherence), genetic background, and drug efficacy, the trial includes both patient-reported outcome and biomarker screening for discovery of forecast models for adherence, symptoms, QoL, progression free survival (PFS), and overall survival (OS). DISCUSSION: The primary objective of PreCycle is to test the hypothesis of superiority for time to deterioration (TTD) in terms of DQoL = "Deterioration of quality of life" (FACT-G scale) in patients supported by an eHealth therapy management system (CANKADO active) versus in patients merely receiving eHealth-based information (CANKADO inform). EudraCT Number: 2016-004191-22.

The EMA Assessment of Asciminib for the Treatment of Adult Patients With Philadelphia Chromosome-Positive Chronic Myeloid Leukemia in Chronic Phase Who Were Previously Treated With at Least Two Tyrosine Kinase Inhibitors.

Asciminib is an allosteric high-affinity tyrosine kinase inhibitor (TKI) of the BCR-ABL1 protein kinase. This kinase is translated from the Philadelphia chromosome in chronic myeloid leukemia (CML). Marketing authorization for asciminib was granted on August 25, 2022 by the European Commission. The approved indication was for patients with Philadelphia chromosome-positive CML in the chronic phase which have previously been treated with at least 2 TKIs. Clinical efficacy and safety of asciminib were evaluated in the open-label, randomized, phase III ASCEMBL study. The primary endpoint of this trial was major molecular response (MMR) rate at 24 weeks. A significant difference in MRR rate was shown between the asciminib treated population and the bosutinib control group (25.5% vs. 13.2%, respectively, P = .029). In the asciminib cohort, adverse reactions of at least grade 3 with an incidence ≥ 5% were thrombocytopenia, neutropenia, increased pancreatic enzymes, hypertension, and anemia. The aim of this article is to summarize the scientific review of the application which led to the positive opinion by the European Medicines Agency's Committee for Medicinal Products for Human Use.

An Analysis of Dasatinib Treatment Patterns in Patients with Chronic Myeloid Leukemia after Experiencing Pleural Effusion during Dasatinib Therapy.

INTRODUCTION: Treatment with dasatinib for chronic myeloid leukemia (CML) has been associated with development of pleural effusion; however, data regarding its optimal management are limited. We examined treatment patterns and healthcare resource utilization (HCRU) and costs among patients with CML treated with dasatinib who experienced a subsequent pleural effusion. METHODS: Adults with CML and ≥1 pharmacy claim for dasatinib in 2015-2018 who experienced pleural effusion after dasatinib were identified using data from claims databases. RESULTS: Overall, 123 patients were eligible. After 1 year, of the 38.2% of patients with a dose modification, 72.3% did not switch treatment; among these patients, 70.6% continued treatment. Among patients with a stable dose after pleural effusion (61.8%), 57.9% later switched to another TKI. The mean (SD) duration of dasatinib treatment after pleural effusion was 262.0 (124.0) days for patients with a dose modification versus 149.1 (155.2) days for those with a stable dose (p < 0.001). HCRU and costs were similar between groups. CONCLUSION: Dasatinib dose modification after pleural effusion was not always required; however, patients with dose modifications continued therapy for a longer duration with a lower rate of switching to another TKI versus patients who remained on a stable dose.

Drug-drug interactions of protein kinase inhibitors in chronic myeloid leukaemia patients: A study using the French health insurance database.

The introduction of protein kinase inhibitors (PKIs) for chronic myeloid leukaemia (CML) has considerably improved prognosis of the disease but has also demonstrated a great potential for drug-drug interactions. Using the French health insurance databases, we aim to investigate the frequency, identify the associated factors and describe the potential consequences of potential drug-drug interactions (pPKI-DIs) between PKIs and concurrent medications in CML. A retrospective cohort study has been performed among patients with CML identified in the French healthcare database from 2011 to 2014. A pPKI-DI is defined as the presence of drugs listed as 'interacting' on the same day as PKI dispensing (co-dispensing) or in its coverage period (co-medication) during the first year of follow-up. The list of interacting drugs is based on the summary of products characteristics (SPCs) and Thesaurus of interactions. We performed specific nested case-control comparisons to investigate the association between PKI-DI and each of the three potential outcomes (death, hospitalisation for adverse drug reactions and switch to another PKI). We included 3480 patients; 1429 (41%) had a co-dispensing pPKI-DI, and 2153 (62%) had a co-medication pPKI-DI; 50% of the pPKI-DIs were 'to be taken into account', and 17% were 'not recommended'. The PKI with the most interactions was imatinib, and additional common drug classes included statins, benzodiazepines and proton pump inhibitors. Multivariate analysis demonstrated that the use of a higher number of additional drugs, comorbidities at baseline, high number of prescribers and higher ages were potential risk factors. Nilotinib and dasatinib showed a tendency towards a higher risk of pPKI-DI compared to imatinib. Despite the fact that some PKI-DIs were potentially clinically relevant, we did not find any significant association with death, hospitalisation for adverse drug reactions and switching. These findings should increase awareness to help reduce the prevalence of PKI-drug interactions and thereby ensure better management of CML patients.

Inequalities in survival and care across social determinants of health in a cohort of advanced lung cancer patients in Quebec (Canada): A high-resolution population-level analysis.

BACKGROUND: Advanced lung cancer patients exposed to breakthrough therapies like EGFR tyrosine kinase inhibitors (EGFR-TKI) may experience social inequalities in survival, partly from differences in care. This study examined survival by neighborhood-level socioeconomic and sociodemographic status, and geographical location of advanced lung cancer patients who received gefitinib, an EGFR-TKI, as first-line palliative treatment. Differences in the use and delay of EGFR-TKI treatment were also examined. METHODS: Lung cancer patients receiving gefitinib from 2001 to 2019 were identified from Quebec's health administrative databases. Accounting for age and sex, estimates were obtained for the median survival time from treatment to death, the probability of receiving osimertinib as a second EGFR-TKI, and the median time from biopsy to receiving first-line gefitinib. RESULTS: Among 457 patients who received first-line treatment with gefitinib, those living in the most materially deprived areas had the shortest median survival time (ratio, high vs. low deprivation: 0.69; 95% CI: 0.47-1.04). The probability of receiving osimertinib as a second EGFR-TKI was highest for patients from immigrant-dense areas (ratio, high vs. lowdensity: 1.95; 95% CI: 1.26-3.36) or from Montreal (ratio, other urban areas vs. Montreal: 0.39; 95% CI: 0.16-0.71). The median wait time for gefitinib was 1.27 times longer in regions with health centers peripheral to large centers in Quebec or Montreal in comparison to regions with university-affiliated centers (95% CI: 1.09-1.54; n = 353). CONCLUSION: This study shows that real-world variations in survival and treatment exist among advanced lung cancer patients in the era of breakthrough therapies and that future research on inequalities should also focus on this population.

Assessment of Imatinib as a Primary Treatment of Chronic Myeloid Leukemia in Chronic Phase: a Cohort Study.

PURPOSE: The study aimed to assess the effectiveness of Imatinib in chronic myeloid leukaemia (CML) in our hospital population. In addition to identify which brand of imatinib (Gleevec/Veenat) is cost effective for CML patients and to assess the possible adverse drug reactions during the treatment for chronic myeloid leukaemia. METHODS: A non-interventional (observational), both retrospective and prospective study was carried out in the department of Medical Oncology and Haematology of our hospital. A total of 152 patients were enrolled in the study. Patients who satisfied the inclusion and exclusion criteria were selected for the study. RESULTS: Evaluation of baseline characteristics of study population (n = 152) showed predominance of males (65.1%). The mean age was 49.80 ± 16.561 years. The overall clinical outcome of the sample population, BCR ABL value responses during 3,6 and 12 months are the main indicators for the prediction of outcome in CML -CP patients. Using Independent sample t test, it was found that the difference in response to Imatinib therapy during 3,6 & 12 months were statistically significant and showed a statistically significant difference between the good and adverse outcome (p < 0.001). CONCLUSION: Our study concluded that Imatinib showed a benefit in treating the condition without any life-threatening adverse events and also the drug exhibits a complete haematological and optimal response based on European Leukaemia Net criteria during the period of study. From which, it can be concluded that imatinib appears to be a safe and well-tolerated treatment for the chronic-phase chronic myeloid leukaemia population.

The influence of drug prices, new availability of inexpensive generic imatinib, new approvals, and post-marketing research on the treatment of chronic myeloid leukaemia in the USA.

Several research and market developments in the past 5 years could influence front-line and subsequent-line strategies in chronic myeloid leukaemia. These developments include the increased availability of effective and safe generic imatinib at affordable prices, studies showing that doses of tyrosine kinase inhibitors (TKIs) lower than the approved dose are effective and less toxic, studies showing that dose-adjusted ponatinib therapy at a reduced dose is effective and substantially safer than approved doses, and the approval of asciminib as third-line therapy in 2021. With the availability of an affordable generic imatinib, all patients with chronic myeloid leukaemia globally should be able to access a lifetime supply. The availability of reduced-dose schedules of generic second-generation TKIs, which are less toxic and produce faster deep molecular response than imatinib, might make them more appealing to use as front-line therapy. In the subsequent-line setting, the role of different TKIs as second, third, and later lines of therapy depends on the evolving front-line use. Dose-adjusted ponatinib schedules have shown better efficacy and safety with long-term follow-up. Ponatinib is the favoured therapy for patients with second-generation-TKI resistance or chronic myeloid leukaemia with 944C→T (Thr315Ile)-mutated BCR-ABL1. Studies of asciminib are needed in larger numbers of patients and with longer follow-up than has been done previously to better assess its comparative efficacy, safety, and survival data (vs ponatinib). The role of third-generation TKIs as second-line therapy following front-line resistance to second-generation TKIs needs to be evaluated. New and mature data with TKI therapy in chronic myeloid leukaemia are producing observations that encourage continuous discussion of the optimal treatment recommendations and frameworks in chronic myeloid leukaemia.

Efficacy and Safety of Generic Dasatinib in Patients With Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase: A Multicenter Prospective Study in China.

BACKGROUND: Brand-name dasatinib was approved for newly diagnosed chronic myeloid leukemia-chronic phase (CML-CP) patients due to its deeper and faster molecular response than imatinib. Generics, as the alternative, low-cost forms, are much in demand. This study aimed to evaluate the efficacy and safety of generic dasatinib (Yinishu) as a first-line treatment in CML-CP. MATERIALS AND METHODS: This was a prospective, multicenter, single-arm study from May 2016 to October 2018 with a 2-year follow-up analysis. All patients were given 100 mg/d (initial dose) of the generic dasatinib once a day. The primary endpoint was the major molecular response (MMR) calculated based on the BCR-ABL1 gene mutation rate of ≤ .1% at 12 months. RESULTS: Among 55 patients in CP observed for at least 3 months, 80.4% achieved MMR at 12 months. The cumulative MR4.5 was 58.2% by 24 months. Responses occurred rapidly, with 69.1% of patients achieving complete cytogenetic response (CCyR) by 3 months and 70.9% achieving CCyR by 6 months. The estimated 2-year PFS and OS were both 96%, with a median follow-up time of 24 months. Grade 3 neutropenia occurred in 8.5% of patients, and thrombocytopenia occurred in 11.9% of patients. Nonhematologic toxicity was usually mild and manageable. Pleural effusion occurred in 20.3% of patients, and only 1 patient (1.7%) had a grade 3 pleural effusion. No grade 4 adverse events were observed. CONCLUSION: Generic dasatinib is an effective option for newly diagnosed CML-CP patients, producing an MMR early in a greater number of patients during their therapy.

KIT-Associated Familial GIST Syndrome: Response to Tyrosine Kinase Inhibitors and Implications for Risk Management.

Sporadic gastrointestinal stromal tumors (GIST) are rare tumors, with a median age at diagnosis of 60 years. Familial GISTs are very rare and typically associated with earlier onset, with an average age at diagnosis of 48 years. To date, just over 50 familial cases associated with a germline variant KIT or PDGFRa genes have been published. Therefore, there are many challenges in managing these patients, including the timing of starting systemic treatment, considering that most patients have been asymptomatic for a long period before being diagnosed, as well as the choice of tyrosine kinase inhibitor and the plan for surveillance. It is uncertain if early diagnosis through screening of asymptomatic individuals improves overall survival. Screening could start from the age of 18 years but may be considered at earlier ages depending on the underlying genotype and family history. The long-term benefit of early diagnosis or palliative/prophylactic treatment with tyrosine kinase inhibitors is unknown as there are no data available. Long-term side effects of treatment with imatinib are rare but well documented and could be damaging in patients who have no or minimal disease. We present the case of a 53-year-old Caucasian patient who was diagnosed with multifocal GIST and subsequently found to be a carrier of a pathogenic germline KIT variant in exon 11. We discuss the implication of treatment and genetic testing in this case and in familial KIT associated GISTs.

Real world incidence and management of adverse events in patients with HR+, HER2- metastatic breast cancer receiving CDK4 and 6 inhibitors in a United States community setting.

OBJECTIVE: To examine the real-world incidence and management of select adverse events (AEs) among female patients with hormone receptor positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC), receiving a cyclin-dependent kinase 4 and 6 (CDK4 and 6) inhibitor (palbociclib, abemaciclib, or ribociclib). METHODS: This retrospective study analyzed data from the US Oncology Network iKnowMed electronic health record database for 396 patients with an initial MBC diagnosis on/after 1 January 2014 and receipt of first CDK4 and 6 regimen between 1 January 2017 and 31 December 2018. In this descriptive study, the proportion of patients who experienced select AEs and associated dose modifications or discontinuations were reported. The occurrence of select healthcare resource utilization categories was also reported. RESULTS: Median follow-up time was 451, 262, and 355 days for patients in the palbociclib, abemaciclib, and ribociclib cohorts, respectively. The most common AEs were neutropenia (palbociclib, 44.8%; abemaciclib, 10.6%; ribociclib, 36.3%), diarrhea (palbociclib, 8.0%; abemaciclib, 43.0%; ribociclib, 8.8%), and fatigue (palbociclib, 12.9%; abemaciclib, 17.6%; ribociclib, 16.5%). AEs resulted in a treatment hold among 91 (23.0%), a dose reduction among 86 (21.7%), and permanent discontinuation among 48 (12.1%) patients overall. CONCLUSIONS: This real-world study provides insight into the occurrence of AEs which varied by CDK4 and 6 inhibitor. Compared to clinical trials, frequencies of AEs were numerically lower but dose reductions due to AEs were numerically higher. It is possible these differences reflect proactive management of AEs on the part of clinicians to help patients remain on therapy.

Cyclin-dependent kinase 4 and 6 inhibitors (CDK4 and 6 inhibitors) have changed the landscape for the treatment of metastatic breast cancer (MBC) among patients who are hormone receptor positive (HR+) and human epidermal growth factor receptor 2 negative (HER2−). An understanding of the real-world management of adverse events (AEs) will help optimize treatment strategies. Here, data from the US Oncology Network electronic health record database for 396 HR+, HER2−, MBC patients receiving a CDK4 and 6 inhibitor were examined to describe the proportion of patients who experienced select AEs and the associated outcomes of these AEs. Compared to clinical trials, frequencies of AEs were numerically lower but dose reductions due to AEs were numerically higher. It is possible that these differences reflect a proactive management of AEs on the part of clinicians to help patients remain on therapy.

Utilization and costs of epidermal growth factor receptor mutation testing and targeted therapy in Medicare patients with metastatic lung adenocarcinoma.

BACKGROUND: Guidelines in 2013 and 2014 recommended Epidermal Growth Factor Receptor (EGFR) testing for metastatic lung adenocarcinoma patients as the efficacy of targeted therapies depends on the mutations. However, adherence to these guidelines and the corresponding costs have not been well-studied. METHODS: We identified 2362 patients at least 65 years old newly diagnosed with metastatic lung adenocarcinoma from January 2013 to December 2015 using the SEER-Medicare database. We examined the utilization patterns of EGFR testing and targeted therapies including erlotinib and afatinib. We further examined the costs of both EGFR testing and targeted therapy in terms of Medicare costs and patient out-of-pocket (OOP) costs. RESULTS: The EGFR testing rate increased from 38% in 2013 to 51% and 49% in 2014 and 2015 respectively. The testing rate was 54% among the 394 patients who received erlotinib, and 52% among the 42 patients who received afatinib. The median Medicare and OOP costs for testing were $1483 and $293. In contrast, the costs for targeted therapy were substantially higher with median 30-day costs at $6114 and $240 for erlotinib and $6239 and $471 for afatinib. CONCLUSION: This population-based study suggests that testing guidelines improved the use of EGFR testing, although there was still a large proportion of patients receiving targeted therapy without testing. The costs of targeted therapy were substantially higher than the testing costs, highlighting the need to improve adherence to testing guidelines in order to improve clinical outcomes while reducing the economic burden for both Medicare and patients.

[Prevalence of Adverse Effects of Tyrosine Kinase Inhibitors Used in Management of Chronic Myeloid Leukemia at Sidi Bel-Abbès University Hospital Center]. / Prévalence des Effets Indésirables des Inhibiteurs de Tyrosine Kinase Utilisés dans le Traitement de la Leucémie Myéloïde Chronique au CHU de Sidi Bel-Abbès.

INTRODUCTION: Chronic myeloid leukemia (CML) is a malignant hemopathy within the framework of chronic myeloproliferative syndromes, predominant on the granular line. Her drug treatment is based on tyrosine kinase inhibitors (TKIs) which inhibit the abnormal BCR-ABL protein kinase that causes CML and thus block the signals that cause cancer cells to multiply abnormally. However, other proteins are also inhibited, so they can cause a wide range of adverse effects (AEs). The objective of this study was to study the prevalence of AEs of TKIs used in the therapeutic management of CML by the hematology department of University Hospital Center (UHC) of Sidi Bel-Abbes in Algeria and that of the ITK discontinuation following an AE. MATERIALS AND METHODS: It was a retrospective descriptive study carried out over a period of four months, from April 01st, 2021 to July 31st, 2021, on CML patients treated with TKI in the hematology department of Sidi Bel-Abbes HUC in Algeria. The primary outcome measure was the prevalence of AEs associated with the use of normal dosages or overdose of the following TKIs: Imatinib, Dasatinib and Nilotinib. Data were collected from patient charts, filled by doctors of hematology department, using questionnaire, and analyzed by Statistical Package for the Social Sciences software, version 20. RESULTS: A total of 40 patients were included, including 22 women, mean age 51.55±11.66years (23-78). Twenty-six patients reported at least one AE. Among the 106 AEs declared, 69 AEs (65.09 %) declared with Imatinib, 26 AEs (24.53 %) with Dasatinib and 11 AEs (10.38 %) with Nilotinib. A predominance of musculoskeletal effects 43 (40.56 %), followed by general disorders 18 (17 %), myelosuppression 14 (13.20 %) and digestive system 12 (11.32 %). AEs were responsible for permanent discontinuation of ITK in three cases (11.54 %), including two cases (07.70 %) on Imatinib because of neutropenia and one case (03.84 %) onDasatinibsuffering from pleural effusion. AEs could be controlled in 13 (50 %) of cases, including 9 (34.62%) by temporary discontinuation and 4 (15.38 %) by reducing the dosage, allowing improvement of symptoms and continuation or reintroduction of treatment. CONCLUSION: The prevalence of AEs was high in the studied population, their occurrence was inevitable, good management of AEs from the start of treatment is necessary to avoid switching to another TKI, especially in good responders. It is recommended to establish a low-sodium diet beforehand for all TKIs and a low-carbohydrate diet, especially for Nilotinib, and not to rush to stop the TKI because most often, EIs regress over time in order to allow good therapeutic adherence and obtain better results.

A systematic review on disease-drug-drug interactions with immunomodulating drugs: A critical appraisal of risk assessment and drug labelling.

AIM: Use of immunomodulating therapeutics for immune-mediated inflammatory diseases may cause disease-drug-drug interactions (DDDIs) by reversing inflammation-driven alterations in the metabolic capacity of cytochrome P450 enzymes. European Medicine Agency (EMA) and US Food and Drug Administration (FDA) guidelines from 2007 recommend that the DDDI potential of therapeutic proteins should be assessed. This systematic analysis aimed to characterize the available DDDI trials with immunomodulatory drugs, experimental evidence for a DDDI risk and reported DDDI risk information in FDA/EMA approved drug labelling. METHOD: For this systematic review, the EMA list of European Public Assessment Reports of human medicine was used to select immunomodulating monoclonal antibodies (mAbs) and tyrosine kinase inhibitors (TKIs) marketed after 2007 at risk for a DDDI. Selected drugs were included in PubMed and Embase searches to extract reported interaction studies. The Summary of Product Characteristics (SPCs) and the United States Prescribing Information (USPIs) were subsequently used for analysis of DDDI risk descriptions. RESULTS: Clinical interaction studies to evaluate DDDI risks were performed for 12 of the 24 mAbs (50%) and for none of the TKIs. Four studies identified a DDDI risk, of which three were studies with interleukin-6 (IL-6) neutralizing mAbs. Based on (non)clinical data, a DDDI risk was reported in 32% of the SPCs and in 60% of the USPIs. The EMA/FDA documentation aligned with the DDDI risk potential in 35% of the 20 cases. CONCLUSION: This systematic review reinforces that the risk for DDDI by immunomodulating drugs is target- and disease-specific. Drug labelling information designates the greatest DDDI risk to mAbs that neutralize the effects of IL-6, Tumor Necrosis Factor alfa (TNF-α) and interleukin-1 bèta (IL-1ß) in diseases with systemic inflammation.

Comparative Assessment of Echocardiographic Patterns Among Chronic Myeloid Leukemia Patients on Tyrosine Kinase Inhibitor and Healthy Controls.

PURPOSE: Chronic myeloid leukemia (CML) is one of the common hematological malignancies in Nigeria. Cardiac abnormalities are associated with CML irrespective of treatment with tyrosine kinase inhibitors such as imatinib, which is available gratis in Nigeria. OBJECTIVE: To assess the prevalence and patterns of cardiac dysfunction among patients with CML irrespective of treatment with imatinib using transthoracic echocardiography, and 12-lead surface electrocardiography. PATIENTS AND METHODS: CML patients without Imatinib, CML patients with imatinib, and apparently healthy (age- and sex-matched) controls were 70 each in the study. Various echocardiographic parameters were measured and data obtained were analyzed, and the level of significance was taken as p < 0.05. RESULTS: Of 70 CML patients with imatinib, 54.3% were men and 45.7% were women, while the CML group without imatinib had 62.9% men and 37.1% women, non-CML control had 54.3% men and 45.7% women. The average hematocrit was significantly lower in the CML group without Imatinib compared with the other groups (p<0.001). And, 12.9% and 17.1% of CML groups with and without imatinib had LVH, respectively, and none of the non-CML controls had LVH (P<0.041). Impaired left ventricular relaxation in 25.71% and 28.57% of CML patients with and without imatinib respectively but only 8.57% of the non-CML control had impaired left ventricular relaxation (p=0.236). Mitral valve regurgitation was the most frequent valvular abnormality across the groups. Pulmonary hypertension in 17.4% and 20% of CML patients with and without imatinib, respectively, but none of the non-CML controls had pulmonary hypertension (p<0.001). Pericardial effusion in 32.86% and 45.71% of CML patients with and without imatinib, respectively, but none of the non-CML controls had pericardial effusion (p<0.001). There was no significant difference in the QTC interval across the three groups. CONCLUSION: Cardiac abnormalities are present in CML patients with or without Imatinib treatment, with significant prevalence than what is seen in the non-CML control group.

Ex vivo platelet morphology assessment of chronic myeloid leukemia patients before and after Imatinib treatment.

Chronic myeloid leukemia (CML) is a myeloproliferative disease and the first line treatment is through the administration of Imatinib, a first generation tyrosine kinase inhibitor. Thrombocytosis and bleeding irregularities are common in CML, however, the morphological variations in CML patients' platelets are not well documented. In this study, ex vivo platelet morphology of control participants, as well as CML patients were assessed before and after Imatinib treatment. The topographical and structural morphology of platelets were determined via scanning electron microscopy (SEM) and transmission electron microscopy (TEM). Qualitative data of SEM and TEM revealed that CML patient's platelets were prone to aggregation and coagulation at time of diagnosis; the samples that were not aggregated at time of diagnosis showed typical discoid shaped platelets, which was comparable to control participants' platelets. TEM results of CML patients' platelets at diagnosis showed that internal granular constituents including dense bodies were decreased in comparison to control participants. In all CML patients, platelets appeared activated after 6 months of treatment with Imatinib with membrane structure abnormalities and constituent variations. Research to date has primarily focused on the effects of CML on leukocyte populations, however, the results of the current study implicate the impact of CML pathogenesis on platelets, seemingly as a result of alterations in normal hematopoiesis. In addition, the impact of Imatinib treatment on platelet morphology was also established, indicating an increase in platelet activation. Recognizing and understanding the impact of CML disease progression on platelets is of importance to aid improved patient treatment. RESEARCH HIGHLIGHTS: In the study, results from SEM and TEM indicated that CML patient's platelets were prone to aggregation at time of diagnosis, and activation after Imatnib treatment. Platelet samples that did not aggregate had decreased internal granular constituents.