Introduction Of Imatinib Research Articles

Expression of B7-H3 and B7-H4 in Gastric Gastrointestinal Stromal Tumors.

Gastric gastrointestinal stromal tumors (GISTs) are mesenchymal neoplasms with variable behavior characterized by differentiation toward the interstitial cells of Cajal occurring anywhere in the gastrointestinal stromal tract. The management of GIST was revolutionized by the introduction of imatinib, a KIT inhibitor, which has become the standard first-line treatment for metastatic GIST. However, despite a clinical benefit rate of 80%, the majority of patients with GIST experience disease progression after 2 to 3 years of imatinib therapy. This shows the need for novel treatment approaches for imatinib refractory GISTs. The checkpoint proteins B7-H3 and B7-H4 inhibit the activation and function of T cells by potently suppressing the proliferation, cytokine production, and cytotoxicity of activated T cells, which is a mechanism for immune escape. This study aims to clarify B7-H3 and B7-H4 expression in gastric GISTs using immunohistochemistry and reverse transcription polymerase chain reaction (RT-PCR). We confirmed B7-H3 expression (H-score ≥50 points) in 92% and B7-H4 expression in 0% of GIST samples. We examined B7-H3 mRNA expression in 3 representative GIST samples, each having their respective immunostained areas detected by RT-PCR. B7-H3 is expressed at a particularly high rate in GISTs. This suggests that B7-H3 might operate as part of an immune checkpoint in GISTs.

Long-term efficacy of high-dose imatinib in Hispanic patients without access to second-generation tyrosine kinase inhibitors treated in LATAM centers.

6512 Background: Treatment for patients with chronic myeloid leukemia (CML) had a benchmark with the introduction of imatinib, a tyrosine kinase inhibitor (TKI). Nevertheless, resistance due to genetic mutations in the BCR::ABL1 kinase receptor remains relatively common for many patients, leading to failure, lack of response, or suboptimal response. Ideally, to bypass genetic resistance, guidelines recommend switching to a second-generation TKI, but for many developing countries, socioeconomic barriers hinder the possibility of switching medication. Despite this scenario, scarce information is available to evaluate the clinical prognosis of these patients. Methods: We conducted a retrospective cohort analysis to compare the overall mortality of patients with CML who developed a suboptimal response to standard-dose imatinib and were treated with either high-dose imatinib or a second-generation TKI. We created a marginal structural model with inverse probability weighting and stabilized weights and depicted the survival curves and median using the Kaplan-Meier estimator. Our primary outcome was overall survival (OS) at 150 months, defined as the number of deaths once patients had reached treatment response based on parameters of the European Leukemia Net Guidelines for CML. Our secondary outcomes were disease-free survival (DFS) at 150 months, defined as the number of months after patients achieved either major molecular response or deep molecular response, and adverse events that included gastrointestinal, dermatologic, hematologic, and others. Results: The cohort included 148 patients, of which 32 received high-dose imatinib and 116 a second-generation TKI. While we found no difference in the 150-month risk in both OS and DFS (Table), patients receiving second-generation TKI had an increase in median survival of OS ( p-value = 0.009). No difference was found in the median survival of DFS ( p-value = 0.55). No difference was found in either hematologic, gastrointestinal, dermatologic, or other adverse events (p-values of 0.39, 0.94, 0.24, and 0.33, respectively). Conclusions: Ideally, patients who develop a suboptimal response to imatinib should be switched to a second-generation TKI. However, If impossible, our findings suggest that patients treated with high-dose imatinib have a similar OS and DFS prognosis to those receiving a second-generation TKI. [Table: see text]

The Progress of Small Molecule Targeting BCR-ABL in the Treatment of Chronic Myeloid Leukemia.

Chronic myelogenous leukemia (CML) is a malignant myeloproliferative disease. According to the American Cancer Society's 2021 cancer data report, new cases of CML account for about 15% of all leukemias. CML is generally divided into three stages: chronic phase, accelerated phase, and blast phase. Nearly 90% of patients are diagnosed as a chronic phase. Allogeneic stem cell transplantation and chemotherapeutic drugs, such as interferon IFN-α were used as the earliest treatments for CML. However, they could generate obvious side effects, and scientists had to seek new treatments for CML. A new era of targeted therapy for CML began with the introduction of imatinib, the first-generation BCR-ABL kinase inhibitor. However, the ensuing drug resistance and mutant strains led by T315I limited the further use of imatinib. With the continuous advancement of research, tyrosine kinase inhibitors (TKI) and BCR-ABL protein degraders with novel structures and therapeutic mechanisms have been discovered. From biological macromolecules to classical target protein inhibitors, a growing number of compounds are being developed to treat chronic myelogenous leukemia. In this review, we focus on summarizing the current situation of a series of candidate small-molecule drugs in CML therapy, including TKIs and BCR-ABL protein degrader. The examples provided herein describe the pharmacology activity of small-molecule drugs. These drugs will provide new enlightenment for future treatment directions.

Arterio-occlusive events among patients with chronic myeloid leukemia on tyrosine kinase inhibitors

AbstractTyrosine kinase inhibitors (TKIs) are standard therapy for patients with chronic myeloid leukemia. Each of these drugs has a specific profile of tyrosine kinases that they inhibit and, although all are clinically effective, they each have unique toxicity profiles. With the introduction of ponatinib, arterio-occlusive events were first noted and later found to occur with all TKIs to various extents. The recognition of this “class effect” was delayed considering ponatinib was introduced 10 years after the introduction of imatinib. The reasons for the delay in identification of this class effect are likely multifaceted. Importantly, there is an inconsistency in adverse event reporting criteria among the major clinical trials of the various TKIs, likely resulting in mixed reporting of arterio-occlusive events. Reporting events based on a frequency threshold, lack of sufficient follow-up, attempts at causality attribution, and the primary focus on molecular response may all have played an additional role. Considering the increasing rate of arterio-occlusive events over time, the termination of many trials after only 5 years prevents full assessment of the impact of these events. A comprehensive evaluation of TKI adverse effects using uniform Medical Dictionary for Regulatory Activities terms and comprehensive adjudication of these events may be helpful in better assessing the real risk for patients with each TKI. Future clinical trials should use a uniform and comprehensive approach to reporting adverse events without attempting to assign causality to the study drug.

Therapeutic options for chronic myeloid leukemia following the failure of second-generation tyrosine kinase inhibitor therapy.

The management of chronic myeloid leukemia in the chronic phase (CML-CP) has witnessed significant advancements since the identification of a common chromosomal translocation anomaly involving chromosomes 9 and 22, which results in the formation of the Philadelphia chromosome driven by the BCR-ABL1 fusion protein. This discovery paved the way for the development of tyrosine kinase inhibitors (TKIs) that target the adenosine triphosphate (ATP) binding site of ABL1 through the BCR-ABL-1 fusion protein. Following the approval of Imatinib by the Food and Drug Administration (FDA) as the first TKI for CML treatment in 2001, the median overall survival (OS) for chronic phase CML (CML-CP) has significantly improved, approaching that of the general population. However, achieving this milestone crucially depends on reaching certain treatment response milestones. Since the introduction of imatinib, five additional TKIs have been approved for CML-CP treatment. Despite the availability of these treatments, many patients may experience treatment failure and require multiple lines of therapy due to factors such as the emergence of resistance, such as mutations in the ATP binding site of ABL, or intolerance to therapy. This review will primarily focus on exploring treatment options for patients who fail second-generation TKI therapy due to true resistance.

Sorafenib combination with imatinib enhances apoptotic and cell cycle arrest effects with no effect on viability and BCR-ABL expression of K-562 cells

Chronic myeloid leukemia (CML) is one of the myeloproliferative disorders that affect hematopoiesis. Historically, many therapies have been used for the management of this disease with moderate response. The discovery of tyrosine kinase inhibitors (TKIs), marked by the introduction of imatinib, revolutionized the therapy of CML. Resistance to imatinib, however, marks CML cells in refractory disease. Additionally, advanced stages of CML may still be refractory to available therapies. Sorafenib is an inhibitor of multiple intracellular and receptor protein kinases that is approved by the FDA for the treatment of advanced hepatocellular carcinoma patients and renal cell cancer. Other TKIs, such as erlotinib and sunitinib, are under study for the treatment of CML patients. In this study, the synergistic effect of the combination of imatinib and sorafenib on the K-562 CML cell line was evaluated. We used viability assay, cell cycle analysis, apoptosis assay, reverse transcription quantitative real-time PCR detect the expression of Breakpoint Cluster Region – abelson fusion oncogene and to evaluate the interaction of the combination. The study showed that the addition of sorafenib to imatinib did not produce a significant synergistic effect on the viability of cells. The combination, however, had a significant effect on cell cycle arrest and induction of apoptosis with no effect on the reduction of BCR-ABL mRNA expression on K-562 cells.

Mortality rate and social disparity trends with tyrosine kinase inhibitory availability in chronic myelogenous leukemia: An analysis in the US from 1999 to 2020.

7055 Background: We analyzed CML mortality from 1999 to 2020 in the US in relation to FDA approval of tyrosine kinase inhibitors (TKIs). These agents were introduced in the 2000s, revolutionizing the treatment of CML and providing a paradigm for targeted therapy in oncology. Starting with imatinib in 2001, followed by dasatinib (2006), nilotinib (2007), and bosutinib (2012). TKIs have increased tolerability and efficacy for the treatment of CML as compared to previous treatment modalities. We investigated age-adjusted mortality rates (AAMR) and annual percent change (APC) in this population in relation to TKI approval. Methods: Using the CDC WONDER database, we examined mortality trends from 1999 to 2020 for CML in the US. AAMRs were calculated per 100,000 people and stratified by sex, race/ethnicity, and census region. AAMR groups were listed as pre-TKI era and 1 year post-FDA approval of different TKI agents. We computed the APC trends for the respective stratification with Joinpoint, a regression analysis program. Results: Between 1999 and 2020 there were 35,268 deaths from CML. In 1999, overall AAMR initially was 0.8, which improved to 0.5 by 2020 with a respective APC of -2.5%. In our subgroup analysis there was a consistent and significant decrease in AAMR since the introduction of Imatinib in 2001. With additional TKI releases, AAMR continued to decline in all subgroups. APC for mortality rates was similar between all subgroups [-2.0 to -2.8%] indicating a similar benefit regardless of subgroup. Male AAMR was consistently higher than female AAMR. Black and white patients (0.5, 2020) have a 2.5x higher AAMR (0.2, 2020) compared to Asian patients. Census region did not show a significant difference between each other. Conclusions: Since the FDA approval of imatinib in 2001 and the subsequent release of TKIs there has been a significant impact on reducing AAMR for patients with CML. The decline was seen in sex, race, and census region. The APCs were similar between all subgroups indicating a consistent improvement in survival. Possible etiologies of disparities in AARM for males in comparison to females and for black and white patients in comparison to Asian patients include gender and race-associated gene polymorphisms possibly inducing differences in drug metabolism. Further gender and race specific pharmacokinetic studies would be useful to further elucidate etiology of the disparity and may lead to changes in TKI dosing strategies. [Table: see text]

Effect of tumor location on the efficacy of chemotherapy for gastrointestinal stromal tumors.

790 Background: Gastrointestinal stromal tumors (GISTs) arise from multiple sites within the gastrointestinal tract. Since the introduction of imatinib in 2002, patients have seen improved overall survival. However, a recent National Cancer Database (NCDB) study suggested no survival benefit to adjuvant imatinib for colorectal GIST patients. Another recent study showed that small bowel GISTs have larger median tumor size and higher incidence of tumors with at least 5 mitoses compared to gastric GISTs. These findings suggest a differential tumor biology for GISTs arising from different primary tumor sites, potentially conferring differential response to imatinib. In this NCDB study, we compare overall survival outcomes with and without chemotherapy, stratifying by primary tumor site. Methods: We queried the NCDB from 2004-2018 for patients with GIST histology. We excluded patients with age <40, age>80, high comorbidity score, and patients who received additional therapy other than surgery or chemotherapy. Of the 22,846 patients meeting criteria for our study, 27 patients had tumors originating from the anus, 454 from the colon, 173 from the esophagus, 15,296 from the stomach, 556 from the rectum, 32 from the rectosigmoid junction, and 6,308 from the small intestine. 8,983 (39%) received chemotherapy. Treatment with chemotherapy was used to extrapolate response to imatinib, the mainstay of treatment. Results: Cox proportional hazards analysis demonstrated increased hazard of death for chemotherapy, increasing age, and comorbidity score of 1. Positive predictive factors for survival included female sex and later year of diagnosis. For anal, esophageal, gastric, and rectosigmoid GIST patients, there was no statistically significant overall survival benefit for any treatment modality. For colonic GISTs, neoadjuvant chemotherapy combined with surgery improved overall survival. For rectal GISTs, adjuvant chemotherapy with surgery also provided survival benefit. For small intestinal GISTs, surgery alone or surgery with neoadjuvant, adjuvant, or both neoadjuvant and adjuvant chemotherapy improved overall survival. Conclusions: While our study is retrospective and limited as a NCDB study, our Kaplan-Meier survival analysis demonstrated survival benefit for chemotherapy only in patients with colon, rectal, or small intestinal GIST tumors. Our Cox proportional analysis demonstrated an overall negative survival impact for chemotherapy. These findings lend further support to the idea that differential tumor biology at each primary site may lead to differential response to imatinib. Overall, our study provides rationale for further investigating the heterogeneity of GIST tumor microenvironments, as these differences could contribute to the differential treatment outcomes.

Twenty years of evolution of CML therapy: how the treatment goal is moving from disease to patient.

The introduction of imatinib in 2000 opened the era of tyrosine kinase inhibitors (TKIs) for CML therapy and has revolutionized the life expectancy of CML patients, which is now quite like the one of the healthy aged population. Over the last 20 years, both the TKI therapy itself and the objectives have undergone evolutions highlighted and discussed in this review. The main objective of the CML therapy in the first 10 years after TKI introduction was to abolish the disease progression from the chronic to the blastic phase and guarantee the long-term survival of the great majority of patients. In the second 10 years (from 2010 to the present), the main objective of CML therapy moved from survival, considered achieved as a goal, to treatment-free remission (TFR). Two phenomena emerged: no more than 50-60% of CML patients could be candidates for discontinuation and over 50% of them molecularly relapse. The increased cumulative incidence of specific TKI off-target side effects was such relevant to compel to discontinue or reduce the TKI administration in a significant proportion of patients and to avoid a specific TKI in particular settings of patients. Therefore, the treatment strategy must be adapted to each category of patients. What about the patients who do not get or fail the TFR? Should they be compelled to continue the TKIs at the maximum tolerated dose? Alternative strategies based on the principle of minimal effective dose have been tested with success and they are now re-evaluated with more attention, since they guarantee survival and probably a better quality of life, too. Moving from treating the disease to treating the patient is an important change of paradigm. We can say that we are entering a personalized CML therapy, which considers the patients' age, their comorbidities, tolerability, and specific objectives. In this scenario, the new techniques supporting the monitoring of the patients, such as the digital PCR, must be considered. In the present review, we present in deep this evolution and comment on the future perspectives of CML therapy.

Adverse events and dose modifications of tyrosine kinase inhibitors in chronic myelogenous leukemia.

The prognosis of chronic myelogenous leukemia (CML-CP) in chronic phase has improved dramatically since the introduction of imatinib. In addition to imatinib, second- and third-generation tyrosine kinase inhibitors (TKIs) and a novel allosteric inhibitor, asciminib, are now available. During long-term TKI therapy, the optimal selection of TKI therapy for individual patients requires the understanding of specific patterns of toxicity profile to minimize chronic toxicity and the risk of adverse events, including pulmonary arterial hypertension, pleural effusion, and cardiovascular events. Given the high efficacy of TKI therapy, dose modifications of TKI therapy reduce the risk of toxicities and improves quality of life during therapy. In this review article, we summarize the characteristics and adverse event profile of each TKI and dose modifications in patients with CML-CP and discuss future perspectives in the treatment of CML-CP.

The Impact of SKP2 Gene Expression in Chronic Myeloid Leukemia.

Introduction: The prognosis of chronic myeloid leukemia (CML) patients has been dramatically improved with the introduction of imatinib (IM), the first tyrosine kinase inhibitor (TKI). TKI resistance is a serious problem in IM-based therapy. The human S-phase kinase-associated protein 2 (SKP2) gene may play an essential role in the genesis and progression of CML. Aim of the study: We try to explore the diagnostic/prognostic impact of SKP2 gene expression to predict treatment response in first-line IM-treated CML patients at an early response stage. Patients and methods: The gene expression and protein levels of SKP2 were determined using quantitative RT-PCR and ELISA in 100 newly diagnosed CML patients and 100 healthy subjects. Results: SKP2 gene expression and SKP2 protein levels were significantly upregulated in CML patients compared to the control group. The receiver operating characteristic (ROC) analysis for the SKP2 gene expression level, which that differentiated the CML patients from the healthy subjects, yielded a sensitivity of 86.0% and a specificity of 82.0%, with an area under the curve (AUC) of 0.958 (p < 0.001). The ROC analysis for the SKP2 gene expression level, which differentiated optimally from the warning/failure responses, yielded a sensitivity of 70.59% and a specificity of 71.21%, with an AUC of 0.815 (p < 0.001). Conclusion: The SKP2 gene could be an additional diagnostic and an independent prognostic marker for predicting treatment responses in first-line IM-treated CML patients at an early time point (3 months).

Long-term progression-free survival achieved in the skull base metastasis of gastrointestinal stromal tumor with introduction of tyrosine kinase inhibitor: illustrative case.

BACKGROUNDGastrointestinal stromal tumors (GISTs) are common subepithelial tumors that rarely metastasize to the intracranial space. Because the standard treatment for metastatic intracranial GISTs has not been established, multimodal therapies are needed, especially in the case of skull base metastasis. However, its outcome has not always been favorable. The authors report the longest known surviving case of skull base metastasis of GIST treated with imatinib only.OBSERVATIONSA 52-year-old male with a history of GIST presented with left facial swelling and numbness. Examinations revealed a 70-mm tumor occupying the left middle cranial fossa and the orbit. The authors performed transnasal endoscopic tumor biopsy for definitive diagnosis and reintroduced imatinib treatment. The tumor significantly decreased in size early after the introduction of imatinib, and symptoms completely disappeared within several weeks. The lesion has remained shrunk radiologically for 63 months, and the patient is continuously being followed up under imatinib treatment.LESSONSThe authors reported a rare case of skull base metastasis of GIST successfully treated solely with systemic therapy with a tyrosine kinase inhibitor, achieving tumor control for over 5 years. This case suggests that tyrosine kinase inhibitors might play a key role in the multidisciplinary treatment for skull base metastases of GIST.

Patient characteristics and management practices in chronic myeloid leukemia in Turkey: reflections from an expert meeting

ABSTRACT Introduction The therapeutic landscape of chronic myeloid leukemia (CML) has evolved significantly since the introduction of imatinib. The European LeukemiaNet (ELN) recommendations serve as a guide for diagnosis, treatment, and monitorization of CML, but availability and accessibility of diagnostic tools and medications affect their applicability. Areas covered This article provides an overview of the current clinical management of CML in Turkey with reference to the key outputs of the online expert meeting held in November 2020. The applicability of the ELN 2020 recommendations for treating CML in clinical practice was also discussed. Expert opinion Imatinib is the only reimbursed and the most preferred first-line treatment in CML restricting the upfront use of second-generation tyrosine kinase inhibitors (TKIs), thereby limiting the applicability of treatment-free remission approach in Turkey. The ELN recommendations about using the EUTOS Long-Term Survival (ELTS) score for risk assessment and focusing on patient reported outcomes and quality of life can be enhanced with educational activities. The widespread availability of standardized technical infrastructure for diagnosing and monitoring CML will contribute to better disease management. Establishing a sustainable national database for CML is valuable for observing patient characteristics and disease outcomes as well as the impact of treatment patterns over time.

Incidence of cardiovascular events in patients with chronic myeloid leukaemia treated with tyrosine kinase inhibitors

Background The introduction of imatinib and tyrosine kinase inhibitors as therapeutic strategy for Philadelphia chromosome-positive chronic myeloid leukaemia (CML) has represented an important step forward for treatment of this disease. The aim of this study was therefore to evaluate the incidence of cardiovascular adverse events (CVEs) in patients affected by CML treated with TKI in an observational prospective study. Methods All consecutive patients affected by CML and treated with TKI in our Institution were enrolled in the study from February 2005 to September 2018 with a clinical, laboratory and instrumental follow-up. Results Sixty-one consecutive patients were enrolled, 29 with imatinib, 15 with nilotinib, 11 with dasatinib, 3 with bosutinib and 3 with ponatinib. Neither patients in therapy with bosutinib nor with nilotinib had CVE during follow-up. Incidence rates per person/year were 0 for bosutinib and nilotinib, 0.15 for dasatinib, 0.19 for imatinib and 1.69 for ponatinib (Log Rank p < 0.05); differences in terms of incidence of adverse outcomes remained significant also after multivariate correction. Conclusions In patients with CML treated with TKIs, therapy with ponatinib was associated with a higher risk of CVE than other TKIs. The lowest incidence of CVE was associated with bosutinib and nilotinib.

Tackling resistance in chronic myeloid leukemia: Novel cell death modulators with improved efficacy.

The development of resistance poses a serious problem in the therapy of cancer due to the necessity of a multiple-drug and unlimited treatment of affected patients. In chronic myeloid leukemia (CML), the introduction of imatinib has revolutionized the therapy. The persistence of an untreatable cancer stem cell pool and other resistance-causing factors, however, also impede the cure of this malignancy. New therapeutic approaches are therefore essential to overcome current treatment drawbacks. In this regard, an intervention in the STAT5 signaling pathway can significantly improve drug response, as this central signaling node induces the formation of highly resistant CML cells. In the present study, we continued the design of efficient chemosensitizers derived from the partial PPARγ agonist telmisartan. The developed 2-carbonitriles or 2-carboxymethyl esters showed improved potency in sensitizing K562-resistant cells to imatinib treatment, even at concentrations, which are considered patient-relevant. At 5μM, for instance, 2d sensitized the cells in such a manner that the resistance was fully overcome and the recovered efficacy of imatinib resulted in >76% cell death. Importantly, all compounds were non-cytotoxic per se. A transactivation experiment showed that only the carbonitriles are partial agonists of PPARγ, which does not seem to be involved in the mode of action. Yet, immunoassays revealed a suppression of the STAT5 phosphorylation status by co-application of the most active derivatives with imatinib. This mechanism consequently resulted in reduced cell proliferation and induction of cell death in resistant CML cells.

Lack of Association between C1236T, G2677T/A and C3435T Variants of the ABCB1 Gene and Imatinib Response in Iranian Chronic Myeloid Leukemia Patients

Imatinib introduction caused to improve the clinical outcomes of chronic myeloid leukemia (CML) patients. Despite the significant effects of Imatinib, pharmacogenetic variables induced treatment resistant is also observed.. Imatinib is known as a P-glycoprotein (P-gp) efflux pump substrate encoded by the ABCB1 gene. The ABCB1 C1236T, G2677T/A and C3435T variants are possibly correlated with interindividual variation in pharmacokinetic response to Imatinib therapy. The present study aimed to examine the effect of ABCB1 gene variants on the therapeutic response of Imatinib in CML patients. Sixty-nine Iranian CML patients treated with Imatinib or Nilotinib were selected and divided into two groups of sensitive and resistant to Imatinib. C1236T and G2677T/A variants were genotyped by high resolution melting (HRM) analysis, and C3435T variant was genotyped using polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP). Then, the results were compared between the two groups of patients. Our results showed that there were no significant differences between C1236T, G2677T/A and C3435T variants of ABCB1 gene and clinical response to Imatinib in the Iranian CML patients. According to the results of this study, genotyping of ABCB1 C1236T, G2677T/A and C3435T variants couldn’t help to predict the outcomes of Imatinib treatment in CML patients. So, these variants are not useful to make decisions about treatment, but it is suggested to do further investigations.

Wczesny nawrót molekularny po odstawieniu terapii nilotynibem

Pojawienie się imatynibu, a następnie kolejnych inhibitorów kinaz tyrozynowych (TKI), doprowadziło do zrównania długości życia chorych na przewlekłą białaczkę szpikową (CML) z czasem przeżycia oczekiwanym w zdrowej populacji. Obecnie celem terapeutycznym dla dużej grupy pacjentów jest uzyskanie remisji wolnej od leczenia. Wyniki licznych badań wskazują, że spośród pacjentów, którzy osiągnęli stabilną głęboką odpowiedź molekularną (DMR) i odstawili leczenie TKI, 40–50% może pozostać w remisji. Kluczowe jest to, że pacjenci, u których następuje nawrót molekularny, nie doświadczają progresji choroby do fazy zaawansowanej i prawie zawsze odzyskują DMR po ponownym wdrożeniu leczenia. Poniżej przedstawiono opis przypadku pacjenta z CML, u którego z powodu nietolerancji imatynibu wdrożono nilotynib, a po kilku latach terapii lek odstawiono. Cztery tygodnie po przerwaniu leczenia u pacjenta doszło do utraty większej odpowiedzi molekularnej. Niezwłocznie wznowiono terapię nilotynibem i już po 3 miesiącach chory odzyskał DMR.

CML Chapter.

The discovery of the tyrosine kinase inhibitor (TKI) imatinib in the early 2000's revolutionized the treatment and prognosis of patients with chronic myeloid leukemia (CML) [Hochhaus et al. in N Engl J Med 376:917-927, 2017]. The treatment of patients with CML has changed dramatically since the approval of imatinib and other TKIs. Before the TKI era, newly diagnosed patients would undergo HLA typing to try to identify a well-matched donor, and then proceed quickly to allogeneic hematopoietic cell transplantation (HCT). With the introduction of imatinib followed a few years later by dasatinib, nilotinib, then bosutinib, treatment approaches changed in a dramatic way. Transplantation is no longer an upfront treatment option for newly diagnosed CML patients, and in fact, it is very rarely used in the management of a patient with CML currently. The management of CML patients has been a model of personalized medicine or targeted therapy that is being emulated in the treatment of many other hematologic malignancies and solid tumors such as lung cancer [Soverini et al. in Mol Cancer 17:49, 2018]. The Philadelphia Chromosome (Ph) which leads to the formation of the BCR-ABL fusion gene and its product the BCR-ABL protein is the cause of CML. With effective targeting of this protein with the available TKIs, the disease is completely controllable if not curable for most patients. Life expectancy for patients with CML is essentially normal. Quality of life becomes an important goal including the potential for pregnancy, and ultimately the chance to discontinue all TKI therapy permanently. The three cases outlined below serve to highlight some of the important issues in the management of patients with CML in the post-TKI era.

Advances in the management of gastrointestinal stromal tumors (GISTs)

Gastrointestinal stromal tumors are rare neoplasms developing from cells of Cajal in the gastrointestinal tract. The mainstay of such tumors treatment is surgery, whenever possible. The therapeutic management of inoperable and metastatic disease is based on tyrosine kinase inhibitors and imatinib is the main drug recommended for first line treatment. The introduction of imatinib and other inhibitors improved survival outcomes for this disease, but due to primary and secondary resistance there is still the urgent need for new medications. This paper presents the progress in the systemic therapy of GISTs based on the latest scientific data. The newly developed agents (ripretinib, avapritinib) meet the need to treat patients after the failure of previously available therapies and those with PDGFRA mutation D842V associated with resistance to imatinib.

Tyrosine kinase inhibitors significantly improved survival outcomes in patients with metastatic gastrointestinal stromal tumour: a multi-institutional cohort study.

The real-world impact of tyrosine kinase inhibitors (tkis) in clinical practice for gastrointestinal stromal tumour (gist) has not been extensively reported. We sought to assess how outcomes have changed over the eras and to evaluate the effect of access to imatinib and sunitinib on survival in patients with unresectable or metastatic gist in British Columbia. Patients with metastatic or unresectable gist were allocated to one of three eras: pre-2002, 2002-2007, and post-2007 based on treatment availability (pre-imatinib, post-imatinib, and post-sunitinib). Overall survival (os) and progression-free survival (pfs) were compared between eras. Univariate and multivariate analyses were performed to determine the effects of tumour, patient, and treatment characteristics on survival outcomes. Of 657 patients diagnosed with gist throughout British Columbia during 1996-2016, 196 had metastatic disease: 23 in the pre-imatinib era, 67 in the post-imatinib era, and 106 in the post-sunitinib era. A significant increase in os, by 53.6 months (p = 0.0007), and pfs, by 29.1 months (p = 0.044), was observed after the introduction of imatinib. The introduction of sunitinib did not significantly affect os or pfs. Implementation of tkis has drastically improved survival outcomes for patients with metastatic gist by up to 4.55 years in the real-world setting. Our study demonstrates that implementation of tkis in clinical practice has outperformed their benefit predicted in clinical trials.