Imatinib In Chronic Myeloid Leukemia Research Articles

Risk Factors and Prognosis of Chronic Myeloid Leukemia in Saudi Arabia: A Systematic Review

Background: Among adult leukaemias, chronic myeloid leukaemia (CML) is one of the most prevalent types. The Philadelphia chromosome, which constitutively activates tyrosine kinase through the BCR-ABL1 oncoprotein, is central to the pathophysiology of CML.
 Objectives: To study the risk factors and prognosis of chronic myeloid leukemia in Saudi Arabia.
 Methods: PubMed, SCOPUS, Web of Science, and Science Direct were systematically searched for relevant literature. Rayyan QRCI was employed throughout this comprehensive process.
 Results and Interpretation: seven studies with a total of 658 patients and 357 (54.3) were males. Risk factors for the development of CML were shown to be limited to younger and middle-aged groups, with a slight male predominance. This study showed that imatinib for CML has both long-term efficacy and manageable side effects. Improved compliance, lower blast and basophil counts, increased haemoglobin, increased platelets, and a low-risk score were all associated with different molecular reactions to imatinib. Future research is required to assess the possible risk factors, management lines, and prognostic factors of CML in Saudi population.

Polymorphisms in Drug Transporter and Metabolism Genes Associated with Resistance to Imatinib in Chronic Myeloid Leukemia: A Systematic Review and Meta-Analysis

The aim of this study was to establish the relationship between different polymorphisms in drug transporter and metabolizer genes and resistance to imatinib in chronic myeloid leukemia (CML). For this purpose, an exhaustive search was carried out in the Scopus, Web of Science, and PubMed databases using different combinations of keywords with different inclusion and exclusion criteria. The meta-analysis included nine studies that met the established criteria. The results of the study showed that the polymorphic variants AG and GG of CYP3A5*3 are associated with response to treatment, presenting a significantly lower risk with resistance to imatinib. Likewise, the variants T1236C and G2677T/A of the ABCB1 gene show a significant association with treatment efficacy. In addition, the genetic polymorphism 1236T, homozygous CC of the MDR1 gene, significantly influences the increased risk of cytogenetic relapse and the polymorphic variant 361G>A GA of the SLCO1A2 gene significantly affects the complete molecular response.

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.

Stem Cell Responsiveness to Imatinib in Chronic Myeloid Leukemia

Stem Cell Responsiveness to Imatinib in Chronic Myeloid Leukemia

Temporal effect of imatinib adherence on time to remission in chronic myeloid leukemia patients.

Adherence to imatinib in chronic myeloid leukemia (CML) patients is estimated to be as low as 70% despite its clinical benefit, and our understanding of the impact of nonadherence in this population is limited. This study presents a novel application of the Alternating Conditional Estimation (ACE) algorithm in newly diagnosed CML patients to map the full dose-response curve (DRC) and determine how the strength of this curve varies over time. We applied the ACE algorithm alongside a backward elimination procedure to detect the presence of time dependence and nonlinearity in the relationship between imatinib adherence and time-to-remission. An extended Cox model allowing for the flexible modeling of identified effects via unpenalized B-splines was subsequently fit and assessed. The substantial improvement in model fit associated with the extended Cox approach suggests that traditional Cox proportional hazards model assumptions do not hold in this setting. Results indicate that the DRC for imatinib is non-linearly increasing, with an attenuated effect above a 74% adherence rate. The strength of this effect on remission varied over time and was strongest in the initial months of treatment, reaching a peak around 90 days post-initiation (log hazard ratio: 2.12, 95% confidence interval: 1.47 to 2.66). Most patients that achieved remission did so by 4 months (120 days) with consistently high adherence, suggesting that this could be a critical time and duration for realizing treatment benefit and patient monitoring. Findings regarding the relationship between adherence and remission can additionally help guide the design of future studies.

Comparison of cutaneous adverse events between second-generation tyrosine kinase inhibitors and imatinib for chronic myeloid leukemia: a systematic review and meta-analysis

Background Patients with chronic myeloid leukemia (CML) treated with tyrosine kinase inhibitors (TKIs) often experience cutaneous adverse events, such as rashes and pruritus. In this study, we aimed to compare the risks of cutaneous adverse events between imatinib- and second-generation TKI-treated patients with CML. Material and Methods Paired reviewers independently obtained studies from PubMed, Embase, and Cochrane Library published until 15 March 2022. The following terms were searched: (Leukemia, Myelogenous, Chronic and BCR-ABL Positive), chronic myeloid leukemia, tyrosine kinase inhibitor, TKI, imatinib, dasatinib, nilotinib, bosutinib, and radotinib. Two independent reviewers screened the results and selected articles on cutaneous adverse events. RevMan 5.4 and the Cochrane Collaboration tool were used to perform the meta-analysis and risk of bias assessment. Results and Conclusion Eleven trials involving 4502 patients were analyzed in this study. Patients treated with second-generation TKIs were significantly more likely to experience cutaneous adverse events than those treated with imatinib with a relative risk (RR) of 1.62 (95% confidence interval [CI], [1.25–2.09]). Except dasatinib (RR [95% CI], 1.39 [0.75–2.56]), the risk of adverse events was more with second-generation TKIs than with imatinib as follows: nilotinib (2.11 [1.53–2.90]), bosutinib (1.41 [1.07–1.86]), and radotinib (1.87 [1.33–2.63]). Rash was the most common cutaneous adverse event that was observed in 21.6% of cases across all grades, followed by pruritus (5.7%) and alopecia (4.3%). In conclusion, our findings suggest that cutaneous adverse events occur more frequently with second-generation TKIs than with imatinib. Therefore, effective management of the cutaneous outcome is necessary to achieve high patient adherence to medication and successful treatment with TKIs.

Birth Outcomes of Anticancer Drug Prescriptions during Pregnancy: A Case Series from a Japanese Claims Database

We aimed to evaluate the adverse birth outcomes of anticancer drug prescription during pregnancy using a Japanese claims database from 2005 to 2019. We applied validated claims-based algorithms to identify pregnant women with birth outcomes, and evaluated drug prescription during pregnancy. The causal relationship between anticancer drugs and adverse birth outcomes was evaluated using the Council for International Organizations of Medical Sciences Working Group VI criteria. Thirteen women with anticancer drugs prescription during pregnancy were identified (mean age: 34.6 years). Atrial/ventricular septal defect was observed in one infant after exposure to cyclophosphamide and doxorubicin for breast cancer in the second and third trimesters. One woman on several anticancer drugs (cyclophosphamide, cytarabine, daunorubicin, l-asparaginase, methotrexate, nelarabine, and vincristine) for acute lymphoblastic leukemia, one on imatinib for chronic myeloid leukemia, and one on cisplatin and fluorouracil for cervical cancer had miscarriages after exposure in the first trimester. A relationship between those anticancer drugs and miscarriage could not be ruled out, while no relationship was identified regarding the atrial/ventricular septal defect considering the period of exposure and organogenesis. Our results suggest increased risk of miscarriage with the use of several anticancer drugs such as methotrexate, imatinib, cisplatin, and fluorouracil in the first trimester.

Inhibitory Effect of Ouabain on Resistance to Imatinib in Chronic Myeloid Leukemia K562/G01 Cells

Inhibitory Effect of Ouabain on Resistance to Imatinib in Chronic Myeloid Leukemia K562/G01 Cells

Prevalence of therapeutic drug monitoring and adherence to imatinib in chronic myeloid leukemia in Japan.

The effectiveness of imatinib, a tyrosine kinase inhibitor recommended for the treatment of chronic myeloid leukemia, is associated with high adherence and trough plasma imatinib concentrations of ~1,000 ng/mL. However, adherence and therapeutic drug monitoring (TDM) for imatinib have hardly been reported. This study evaluated the prevalence of TDM and adherence to imatinib for chronic myeloid leukemia in Japan. Monthly insurance claims data for ~5.6million individuals aged 20-74 years between June 1, 2005 and December 31, 2017 were studied. Patients with at least one prescription for imatinib were included to calculate adherence and the annual mean prevalence of TDM for imatinib. A total of 498 patients with 9,620 prescriptions of imatinib were included. After 2013, the number of imatinib prescriptions and the number of patients treated with imatinib were over 1,000 and 200, respectively. The mean annual prevalence of TDM for imatinib was 12.2% (95% confidence interval (CI), 8.1-16.1%). Antihyperuricemic drugs and steroids increased the likelihood of TDM. The medication possession ratio for assessment of adherence was 93.5% (95% CI: 91.8-95.5%). The annual mean prevalence of TDM for imatinib was low, although adherence was high. To encourage the measurement of plasma concentrations of imatinib in clinical settings, adding a package insert, a summary of product characteristics, and a patient information leaflet regarding the implementation of TDM is justified and warrants further attention.

CML-344 Adherence to Imatinib Mesylate in Patients Newly Diagnosed With Chronic Myeloid Leukemia in India Over the First Year of Treatment and How to Improve Compliance

Chronic myeloid leukemia (CML) is treated with the first-line agent imatinib; however, it was seen that adherence to treatment had been poor in many patients. Therefore, a study was carried out to find causative reasons for the discontinuation of treatment, with the ultimate goal to improve rates of compliance. The aim of the study was to identify reasons for adherence failure in patients treated with imatinib for CML and to detect a way to improve adherence. A prospective review of 160 patients with newly diagnosed Philadelphia chromosome-positive CML was undertaken to check for rates of adherence to treatment with imatinib. The patients were equally distributed with 77 men and 83 women and had an average age of 40 years. Due to imatinib being the only option for most patients in India for CML, those who discontinued it were reinforced about the importance of being compliant with treatment. The rates of patients who restarted imatinib after reinforcement were recorded. It was found that out of 160 patients over the initial year of treatment, 87 patients (54.3%) continued to take imatinib and 73 patients (45.6%) discontinued treatment. The most common reasons for discontinuation of treatment were due to adverse drug events such as headaches, weight gain, musculoskeletal symptoms, and GI disturbances. Of the 73 patients, 60 (82.3%) stopped taking imatinib due to adverse drug events, 10 (13.6%) patients were lost to follow-up, and 3 (4.1%) patients wanted to pursue holistic methods of treatment. The 60 patients who stopped taking imatinib due to adverse drug events were counseled on the benefits of pursuing treatment despite some adverse effects. Out of the 60 patients who stopped imatinib due to adverse effects after counseling, 43 (71.6%) patients restarted imatinib. The patients' adherence to imatinib in our study was found to be 46%, with the majority of patients discontinuing treatment due to adverse effects. However, after counseling patients on the overall benefits of taking imatinib, compliance improved. The authors believe that compliance can be improved by taking the time to educate patients on the benefits of treatment with reinforcement.

Vandetanib drives growth arrest and promotes sensitivity to imatinib in chronic myeloid leukemia by targeting ephrin type‐B receptor 4

The oncogenic role of ephrin type‐B receptor 4 (EPHB4) has been reported in many types of tumors, including chronic myeloid leukemia (CML). Here, we found that CML patients have a higher EPHB4 expression level than healthy subjects. EPHB4 knockdown inhibited growth of K562 cells (a human immortalized myelogenous leukemia cell line). In addition, transient transfection of EPHB4 siRNA led to sensitization to imatinib. These growth defects could be fully rescued by EPHB4 transfection. To identify an EPHB4‐specific inhibitor with the potential of rapid translation into the clinic, a pool of clinical compounds was screened and vandetanib was found to be most sensitive to K562 cells, which express a high level of EPHB4. Vandetanib mainly acts on the intracellular tyrosine kinase domain and interacts stably with a hydrophobic pocket. Furthermore, vandetanib downregulated EPHB4 protein via the ubiquitin‐proteasome pathway and inhibited PI3K/AKT and MAPK/ERK signaling pathways in K562 cells. Vandetanib alone significantly inhibited tumor growth in a K562 xenograft model. Furthermore, the combination of vandetanib and imatinib exhibited enhanced and synergistic growth inhibition against imatinib‐resistant K562 cells in vitro and in vivo. These findings suggest that vandetanib drives growth arrest and overcomes the resistance to imatinib in CML via targeting EPHB4.

Role of ADME gene polymorphisms on imatinib disposition: results from a population pharmacokinetic study in chronic myeloid leukaemia.

Imatinib is a substrate of CYP3A4, ABCB1 and ABCG2, and is known to have wide variability in pharmacokinetics (PK). At the same time, a clear relationship between drug levels and response also exists for imatinib in chronic myeloid leukaemia (CML). Therefore, pharmacogenetic-based dosing of imatinib is an attractive proposition. This study aims to characterize the population pharmacokinetics of imatinib in order to identify significant covariates including pharmacogenetic variants. Forty-nine patients with CML were enrolled in the study after being on imatinib for at least 4 consecutive weeks. Steady-state pharmacokinetic sampling was performed either in a sparse (4 samples each, n = 44) or intensive manner (9 samples each, n = 5). An additional pharmacogenetic sample was also collected from all patients. Plasma imatinib levels were estimated using a validated HPLC method. Pharmacogenetic variants were identified using the PharmacoScan array platform. Population pharmacokinetic analysis was carried out using NONMEM v7.2. Seven SNPs within CYP3A4, ABCB1 and ABCG2 genes were evaluated for covariate effect on the clearance of imatinib. Imatinib PK was well characterized using a one-compartment model with zero-order absorption. The clearance and volume of distribution were found to be 10.2 L/h and 389 L respectively. Only SNP rs1128503 of the ABCB1 gene had a small but insignificant effect on imatinib clearance, with a 25% reduction in clearance observed in patients carrying the polymorphism. Twenty-three out of forty-nine patients (47%) carried the polymorphic allele, of whom 17 were heterozygous and six were homozygous. Our study conclusively proves that genetic polymorphisms in the CYP3A4 and ABC family of transporters do not have any role in the personalized dosing of imatinib in CML.

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

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. 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. 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). 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.

Evaluating Real-World Effectiveness and Safety of Generic and Brand-Name Imatinib in Chronic Myeloid Leukemia

Introduction: Generic formulations of imatinib were approved and commercially available in the United States starting in 2016, introducing vast cost savings to the standard treatment of chronic myeloid leukemia (CML). While bioequivalence studies of generic formulations are required for Food and Drug Administration approval, the safety of generic drug supply chains have come into question. There is limited real-world data comparing the effectiveness and safety profiles of generic formulations to the original. This study aimed to evaluate the effectiveness and safety of generic imatinib compared to the branded product.Methods: This retrospective study included patients treated at UNC Medical Centers who were diagnosed with CML and treated with imatinib at any time during their course of treatment. Data was retrieved from the institution's electronic health record and collected over the first 6 months of imatinib treatment to include both safety and effectiveness outcomes. The primary endpoint was to compare generic versus branded product effectiveness, as defined by the European LeukemiaNet (ELN) guidelines (achieving BCR-ABL/ABL ratio of <10% and <1% at 3 and 6 months, respectively). The secondary endpoints included comparisons of generic vs branded product safety, measured via patient adverse drug events (ADEs), all-cause hospitalizations, and early treatment discontinuation. Patients were excluded from primary endpoint evaluation and only included for safety endpoint analysis if they were not treated with imatinib first-line and if duration of imatinib treatment was less than 6 months.Results: Fifty-one CML patients met criteria with no significant differences in age or gender between the generic (n = 23) and brand (n = 28) imatinib groups (Table 1). First-line therapy was composed of 83% of patients on generic imatinib and 29% of patients on brand imatinib. Of those receiving first-line imatinib therapy, there was no difference in molecular responses at 3 and 6 months between generic and brand imatinib (p = 0.71). Brand imatinib was associated with numerically lower CML-related emergency department visits and hospitalizations when compared to generic imatinib, although this difference was not statistically significant (p = 0.12). Rates of discontinuation were numerically lower for brand imatinib although overall time to discontinuation was shorter for generic imatinib (Table 1).Conclusions: This study demonstrates real-world treatment effectiveness and safety of generic and brand imatinib in clinical practice. Generic imatinib appears to be associated with higher rates of CML-related ED visits and hospitalizations although sample size was small and statistical significance was not reached. Further analyses of comparisons and continuation of data collection will provide a more robust assessment to compare the effectiveness and safety of generic and brand imatinib in the real-world setting. [Display omitted] DisclosuresMuluneh: Novartis: Other: Spouse works for Novartis.

DNA Fingerprint Analysis of Raman Spectra Captures Global Genomic Alterations in Imatinib-Resistant Chronic Myeloid Leukemia: A Potential Single Assay for Screening Imatinib Resistance.

Monitoring the development of resistance to the tyrosine kinase inhibitor (TKI) imatinib in chronic myeloid leukemia (CML) patients in the initial chronic phase (CP) is crucial for limiting the progression of unresponsive patients to terminal phase of blast crisis (BC). This study for the first time demonstrates the potential of Raman spectroscopy to sense the resistant phenotype. Currently recommended resistance screening strategy include detection of BCR-ABL1 transcripts, kinase domain mutations, complex chromosomal abnormalities and BCR-ABL1 gene amplification. The techniques used for these tests are expensive, technologically demanding and have limited availability in resource-poor countries. In India, this could be a reason for more patients reporting to clinics with advanced disease. A single method which can identify resistant cells irrespective of the underlying mechanism would be a practical screening strategy. During our analysis of imatinib-sensitive and -resistant K562 cells, by array comparative genomic hybridization (aCGH), copy number variations specific to resistant cells were detected. aCGH is technologically demanding, expensive and therefore not suitable to serve as a single economic test. We therefore explored whether DNA finger-print analysis of Raman hyperspectral data could capture these alterations in the genome, and demonstrated that it could indeed segregate imatinib-sensitive and -resistant cells. Raman spectroscopy, due to availability of portable instruments, ease of spectrum acquisition and possibility of centralized analysis of transmitted data, qualifies as a preliminary screening tool in resource-poor countries for imatinib resistance in CML. This study provides a proof of principle for a single assay for monitoring resistance to imatinib, available for scrutiny in clinics.

RanBP3 Regulates Proliferation, Apoptosis and Chemosensitivity of Chronic Myeloid Leukemia Cells via Mediating SMAD2/3 and ERK1/2 Nuclear Transport.

Abnormal subcellular localization of proteins is an important cause of tumorigenesis and drug resistance. Chromosome region maintenance 1 (CRM1), the nuclear export regulator of most proteins, has been confirmed to be over-expressed in various malignancies and is regarded as an efficient target. But the potential role of the CRM1 cofactor RanBP3 (Ran Binding Protein 3) is left unrevealed in chronic myeloid leukemia (CML). Here, we first detected the level of RanBP3 in CML and found an elevated RanBP3 expression in CML compared with control. Then we used shRNA lentivirus to down-regulated RanBP3 in imatinib sensitive K562 cells and resistant K562/G01 cells and found RanBP3 silencing inhibited cell proliferation by up-regulating p21, induced caspase3-related cell apoptosis, and enhanced the drug sensitivity of IM in vitro. Notably, we observed that RanBP3 silencing restored imatinib sensitivity of K562 cells in NOD/SCID mice. Mechanistically, the nuclear aggregation of SMAD2/3 revealed that tumor suppressor axis (TGF-β)-SMAD2/3-p21 was the anti-proliferation program related to RanBP3 knockdown, and the decrease of cytoplasmic ERK1/2 caused by RanBP3 interference leaded to the down-regulation of anti-apoptosis protein p(Ser112)-BAD, which was the mechanism of increased cell apoptosis and enhanced chemosensitivity to imatinib in CML. In summary, this study revealed the expression and potential role of RanBP3 in CML, suggesting that targeting RanBP3 alone or combined with TKIs could improve the clinical response of CML.

Persistence with Generic Imatinib for Chronic Myeloid Leukemia: A Matched Cohort Study

Background: Generic imatinib (GI) has been approved for use in Canada and other countries based on bioequivalence. A high rate of GI discontinuation has been reported to be related to intolerance (Islamagic E, et al. Clin Lymphoma Myeloma Leuk. 2017;17:238) but no clinical studies have been conducted to determine whether GI is clinically comparable to branded imatinib (BI) for chronic myeloid leukemia (CML). In Quebec, GI was approved and reimbursed in early 2013 and was mandated to replace BI for patients with public drug coverage later the same year. We compared persistence on GI to that on BI in a matched cohort study.Methods: Patients who started GI between 2013 and 2016 were selected from the Quebec CML registry. Each was matched with a BI user who had recorded use of BI at the same calendar date, had the closest duration of prior BI use and closest age. In both cohorts, patients who previously received therapy other than imatinib for their CML were excluded. Matched pairs were followed until switch in therapy, death, withdrawal of consent or end of study (31 December 2016). Kaplan-Meier curves were constructed to evaluate persistence, defined as time until switch in therapy, between GI and BI users. Cox proportional hazards models were used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) for treatment discontinuation or switch with GI, comparing GI with BI, adjusting for sex, obesity, smoking, alcohol consumption, and Charlson comorbidity index.Results: A total of 167 matched pairs were included; mean age (SD) and mean duration (SD) of prior BI therapy was similar between GI and BI users (57.2 (14.4) and 58.3 (13.4) years and 6.1 (4.2) and 5.7 (4.5), respectively). At 42 months, 72.8% (95% CI, 63.4.5%-81.7%) of GI users and 88.9% (95% CI, 82.8%-93.6%) of BI users persisted with their TKI (Figure, P= 0.03). Overall, GI use was associated with an increased risk of switch (HR, 2.13; 95% CI, 1.18-3.86), compared with BI. In GI users, 36 patients switched therapy, 11 for suboptimal response (defined as loss of response, including loss of MMR or failure to achieve a milestone) and 25 for intolerance, which included 21 switching back to BI. Most (63.5%) of the switches occurred in the first year of GI use, and most for intolerance (66.7%, n=24). Of note, there were seven grade 3 adverse events in GI users (fatigue, weakness, nausea and vomiting, diarrhea, muscle cramps). Among BI users, 17 patients switched for suboptimal response (n=8), and intolerance (n=9). Of note, in GI and BI users respectively, 13 and 4 patients stopped therapy in deep molecular response.Discussion: In this matched cohort study with close to 4 years of follow-up, GI users were twice more likely to stop their TKI than users of BI users, marking lower persistence. In most terminations of GI use, the patients reverted to BI, and intolerance was the main cause for TKI switch. Future studies are warranted to investigate the safety profile of GI. [Display omitted] DisclosuresBusque:Pfizer: Honoraria; Paladin: Honoraria; Bristol Myer Squibb: Honoraria; Novartis Canada Inc.: Honoraria. Assouline:Novartis Canada Inc.: Honoraria; Bristol Myer Squibb: Speakers Bureau; Pfizer: Speakers Bureau; Paladin: Speakers Bureau; Janssen: Honoraria.

BCL-2 Inhibition as Treatment for Chronic Lymphocytic Leukemia.

At the end of the 1990s, with the advent of imatinib for chronic myeloid leukemia and rituximab for B cell lymphoproliferative diseases with CD20 expression, there was a great conceptual evolution in the treatment of onco-hematological diseases. Researchers from around the world and the pharmaceutical industry began to focus their efforts on the so-called target therapy used alone or associated with classic chemotherapeutic drugs. In chronic lymphocytic leukemia, the development of second-generation anti-CD20 antibodies, biosimilars, PI3K (phosphatidylinositol 3-kinases) inhibitors, BTK (Bruton's tyrosine kinase) inhibitors, and anti-bcl 2 drugs represented mainly by venetoclax brought new, broader, and more effective opportunities in the treatment of this disease. This breakthrough occurred mainly regarding patients with alteration in 17p or mutation of the p53 gene for whom selecting the new drugs that act on B cell signaling (BTK and PI3K inhibitors) in the first line is mandatory. In fit patients with immunoglobulin heavy chain mutation, it is still acceptable to use the chemotherapy regimen with fludarabine, cyclophosphamide, and rituximab (FCR) and, in those who do not fit or are not IgVH-mutated, bendamustine-rituximab regimen. However, the first-line use of ibrutinib or venetoclax associated with immunotherapy within the concepts of infinite (ibrutinib) or finite (venetoclax) treatment has been increasingly used. In the second line, venetoclax, ibrutinib, and idelalisib have become the preferred treatments. I believe that a process of instruction and decision shared with patients considering the risks-benefits-cost and access to treatments should guide the choices within these concepts. Another fundamental aspect to discuss is the objective of the treatment for chronic lymphocytic leukemia (CLL) for a specific patient: the increase progression-free survival and overall survival and/or the achievement of minimal residual disease. CLL is the most common leukemia in adults with a median age at diagnosis of 72 years. The clinical course is heterogeneous, and outcomes are influenced by individual clinical presentation and disease biology. Molecular and genomic factors, including fluorescence in situ hybridization (FISH) testing, karyotype, and immunoglobulin heavy chain variable region gene (IGHV) mutational status, are important to treatment decisions and to predict the clinical course. However, despite disease biology, the presence of active disease is the most important criteria to initiate treatment. In the past decade, target therapies that inhibit B cell receptor signaling pathways and, more recently, BCL2 antagonists have emerged as a new treatment paradigm: chemo-free with fixed duration therapy. Bruton's tyrosine kinase inhibitors (BTK) are a class of oral medications approved for frontline and relapsed disease, effective for achieving lasting response and disease control with a good safety profile. BTK inhibitors are an attractive option for high-risk patients who are not candidates for an intensive regimen. However, it is a continuous therapy, and drug resistance or severe adverse events could lead to treatment suspension. BCL2 antagonists are an attractive alternative to BTK inhibitors. Anti-apoptotic BCL2 is associated with tumor genesis and chemotherapy resistance. The BCl2, an anti-apoptotic protein located in the mitochondrial membrane, is a major contributor to the pathogenesis of lymphoid malignancies and is overexpressed in CLL cells promoting clonal cell survival. Venetoclax is a potent and selective member of the BH3 mimetic drugs and a physiologic antagonist of BCL2. Venetoclax has demonstrated quick and durable responses in naïve and relapsed or refractory CLL (r/r CLL) patients, including high-risk patients. Furthermore, it has shown deeper responses, achieving a higher incidence of negative minimal residual disease (MRD) with a fixed duration therapy. In the past decade, there was a remarkable progress in CLL treatment. However, neither of the new target therapies is considered curative or free of toxicity. This article will focus on the treatment approach of CLL patients with BCl2 antagonists. Treatment strategy (combined versus monotherapy; continuous versus limited duration therapy), toxicity profile, and future directions will be exposed in this review.

MDR1 gene polymorphisms and imatinib response in chronic myeloid leukemia: A meta-analysis

Our study aimed to investigate the association between multidrug resistance (MDR1) C1236T, C3435T and G2677T/A polymorphisms and the response to imatinib (IM) in chronic myeloid leukemia (CML). An electronic databases in PubMed, Embase, Web of Knowledge, Scopus and Cochrane were searched using combinations of keywords relating to MDR1 polymorphisms and the response to IM in CML. Studies retrieved from database searches were screened using strict inclusion and exclusion criteria. In total, 37 studies were initially identified, and 17 studies, involving 4494 CML patients, were eventually included in this meta-analysis.Results of our study revealed significant association between MDR1 G2677T/A and C3435T polymorphisms and response to IM in Caucasian population under recessive model (T or A vs G; OR = 1.43,95%CI [1;06-1.93]; T vs C;OR = 1.13; 95%IC [0.79; 1.63]), dominant (T or A vs G; OR = 0.94; 95%CI [0.74-1.21]; T vs C; OR = 1.49; 95%CI [1.02-2.17]) and heterozygous models (T or A vs G; OR = 0.83; 95%CI [0.64; 1.09]; T vs C; OR = 1.52; 95%CI [1.01-2.28]); respectively. However, never significative association was found between IM response and the MDR1 C1236T polymorphism (OR = 1.25; 95%CI [0.46; 3.33]). The MDR1 G2677T/A and C3435T polymorphisms might be a risk factor for resistance to IM in Caucasian CML patients.

Glutathione S-transferase gene polymorphic sequence variations: Association with risk and response to Imatinib among Chronic Myeloid Leukemia patients of Kashmir.

Glutathione S-transferase (GST) gene deletion or polymorphic sequence variations lead to decreased enzyme activity that influences susceptibility and response to tyrosine kinase inhibitors in chronic myeloid leukemia (CML). We aimed to analyze relation of different GST gene sequence variants with susceptibility and response to Imatinib in CML. A total of 150CML cases and equal number of age and gender matched healthy controls were genotyped for five GST polymorphisms by multiplex-PCR and PCR-RFLP techniques. BCR-ABL1 transcripts were quantified by quantitative Real Time PCR (qRT-PCR). GSTT1, GSTO1, and GSTO2 SNPs revealed no association, while as GSTM1null genotype was observed to protect against the development of CML (OR=0.53, P=.01). GSTP1 variant genotypes AG (OR=2.1, P=.003) and GG (OR=5.6, P<.001), significantly associated with increased risk of CML. Combined genotype analysis showed protective impact of GSTT1present /GSTM1null (OR=0.44, P=.003) while as GSTT1present /GSTP1-GG (OR=6.92, P<.001) and GSTM1present /GSTP1-GG (OR=6.33, P<.001), significantly increased CML risk. GSTM1null genotype individually and in combination with GSTT1present associated with superior rate of major molecular response (MMR) and event free survival (EFS) (log-rank P=.029). GSTO2-AG+GG genotype associated with significantly inferior MMR rates at 3, 6, and 12months. Also, patients with GSTO2-GG genotype showed significantly reduced EFS (log-rank P=.025). Multivariate analysis confirmed GSTM1null as a better (HR:0.19, P=.029) and GSTO2-GG genotype as an independent poor prognostic factor (HR:2.29, P=.037). GSTM1null genotype seems to have a better prognostic role while GSTP1 variants significantly increase CML risk. Also, results support a correlation between disease outcome and GSTO2 polymorphism.