Treatment Of Chronic Myeloid Leukemia Patients Research Articles

ADAR1 Gene Polymorphism and Hematological Analysis in Responders and Relapse Patients with Chronic Myeloid Leukemia

Abstract Background: Chronic myeloid leukemia (CML) is defined by the Break point cluster region and Abelson Genes (BCR-ABL) fusion gene, which produces a continuously active tyrosine kinase known as the primary driver responsible for initiating and sustaining the disease. The RNA editing enzyme adenosine deaminase acting on double-stranded RNA 1 (ADAR1) converts adenosine into inosine in double-stranded RNA substrates. This enzymatic process is crucial in cellular RNA editing and can impact disease progression and therapeutic responses in CML. Objective: Analysis of ADAR1 gene polymorphisms, ADAR1 levels, and hematological parameters in Iraqi patients with CML. Materials and Methods: From January 2021 to February 2023, one hundred and twenty samples of whole blood were collected from patients with CML at the National Center of Hematology/Mustansiriyah University. The control group in this study comprised thirty samples of fresh whole blood. Total DNA genomic extraction was done to detect the ADAR1 gene polymorphism by sequencing. Furthermore, serum was used to detect ADAR1 enzyme level. Results: According to the age and male/female ratio, the patients’ groups were matching with control group. A group of CML patients on treatment, 65 out of 100 patients were on imatinib, while 35 were treated with other tyrosine kinase inhibitors. The patient groups in terms of age and gender ratio were matched with the control group. Among CML patients receiving treatment, 65 out of 100 were using imatinib, while 35 were treated with other tyrosine kinase inhibitors. In the newly diagnosed CML group, ADAR mutations were present in 35% of cases, and among treated CML patients, this proportion was 36%, whereas the control group showed no mutations (P < 0.001). The distribution of DNA polymorphisms—A/G, G/T, and G/G—was 42%, 30%, and 28%, respectively, among patients with CML, compared to 34%, 20%, and 46%, respectively, in the control group. There are significant differences between different groups according to genotyping of ADAR1 (P < 0.05). Based on ADAR1 mutation, there is a significant difference observed between the newly diagnosed CML group and the CML patients in the treatment group compared to the control group (P < 0.001). Specifically, the differences between the new diagnosis CML group and the treatment group were not statistically significant (P = 0.326). Furthermore, both the new diagnosis CML group and the relapse group showed significant differences compared to the control group (P < 0.001). The P value associated with the correlation between ADAR mutation and these groups is <0.001, indicating a highly significant correlation. Conclusion: The current findings suggest that ADAR1 polymorphisms and ADAR1 enzyme levels in Iraqi patients with CML could potentially influence disease progression and deepen our understanding of its mechanisms. These factors may also contribute to disease development and affect how patients respond to treatment.

Mebendazole effectively overcomes imatinib resistance by dual-targeting BCR/ABL oncoprotein and β-tubulin in chronic myeloid leukemia cells.

To target the pivotal BCR/ABL oncoprotein in chronic myeloid leukemia (CML) cells, tyrosine kinase inhibitors (TKIs) are utilized as landmark achievements in CML therapy. However, TKI resistance and intolerance remain principal obstacles in the treatment of CML patients. In recent years, drug repositioning provided alternative and promising perspectives apart from the classical cancer therapies, and promoted anthelmintic mebendazole (MBZ) as an effective anti-cancer drug in various cancers. Here, we investigated the role of MBZ in CML treatment including imatinib-resistant CML cells. Our results proved that MBZ inhibited the proliferation and induced apoptosis in CML cells. We found that MBZ effectively suppressed BCR/ABL kinase activity and MEK/ERK signaling pathway by reducing p-BCR/ABL and p-ERK levels with ABL1 targeting ability. Meanwhile, MBZ directly targeted the colchicine-binding site of β-tubulin protein, hampered microtubule polymerization and induced mitosis arrest and mitotic catastrophe. In addition, MBZ increased DNA damage levels and hampered the accumulation of ataxia-telangiectasia mutated and DNA-dependent protein kinase into the nucleus. This work discovered that anthelmintic MBZ exerts remarkable anticancer effects in both imatinib-sensitive and imatinib-resistant CML cells in vitro and revealed mechanisms underlying. From the perspective of drug repositioning and multi-target therapeutic strategy, this study provides a promising option for CML treatment, especially in TKI-resistant or intolerant individuals.

Frequency of comedication of proton pump inhibitors with crystalline dasatinib in chronic myeloid leukemia and effects on TKI-bioavailability.

6561 Background: Tyrosine kinase inhibitors (TKI), including dasatinib, have profoundly improved clinical outcome in chronic myeloid leukemia (CML). However, solubility, bioavailability and systematic exposure of the crystalline formulation of dasatinib (Sprycel) is reduced at higher gastric pH levels. This is problematic for comedication with acid reducing agents as lower bioavailability may reduce clinical response. Methods: We investigated proton pump inhibitor (PPI) and TKI comedication, including dasatinib, in a large real world CML cohort. Furthermore, we assessed the influence of timing of PPI comedication on the absorption and bioavailability of dasatinib. Results: Using the Swedish CML- and Prescribed Drug-Registries, we identified 1,328 chronic phase CML patients, diagnosed 2002-2018. 1,261 (95%) had received specified/known TKI treatment and 685 of those (54%) were prescribed a PPI (ATC-code: “A02BC”) at some point after CML diagnosis. TKIs and PPIs prescribed within 12 months of CML diagnosis were prescribed by different HCPs in 66% of cases (284/432). Of the 388 patients treated with dasatinib, 91 (23.5%) received a concomitant PPI. The PPI prescription rate increased to 53% (204/388) in the dasatinib cohort after dasatinib treatment had ended. Further, we assessed the drug-drug interaction (DDI) in 18 healthy volunteers given crystalline dasatinib (100mg) alone or together with omeprazole (40mg, at steady state) administered 9 hours apart; a time point when a high effect on bioavailability is expected. Compared to dosing with crystalline dasatinib alone, Cmax and AUC0-24 were reduced by 96% and 88% by omeprazole comedication (Table). Conclusions: Despite warnings, comedication with PPI is common among dasatinib treated CML patients. Further, an even larger proportion of patients need PPI co-treatment, which however, cannot fully be administered due to its negative impact on dasatinib pharmacokinetics. Moreover, with an optimized study design, we observed a higher than previously reported negative interaction of PPI comedication on crystalline dasatinib bioavailability. This may compromise clinical efficacy and risk CML disease progression. For patients in need of PPI, selection of a non-crystalline, less pH-sensitive formulation of dasatinib therefore appears more appropriate. Clinical trial information: NCT06145217 . [Table: see text]

Clinical applications of abnormal DNA methylation in chronic myeloid leukemia.

DNA methylation, a crucial biochemical process within the human body, fundamentally alters gene expression without modifying the DNA sequence, resulting in stable changes. The changes in DNA methylation are closely related to numerous biological processes including cellular proliferation and differentiation, embryonic development, and the occurrence of immune diseases and tumor. Specifically, abnormal DNA methylation plays a crucial role in the formation, progression, and prognosis of chronic myeloid leukemia (CML). Moreover, DNA methylation offers substantial potential for diagnosing and treating CML. Accordingly, understanding the precise mechanism of DNA methylation, particularly abnormal changes in the methylation of specific genes in CML, can potentially promote the development of novel targeted therapeutic strategies. Such strategies could transform into clinical practice, effectively aiding diagnosis and treatment of CML patients.

Some Hematological Indices as Predictors of Survival in Chronic Myeloid Leukemia Patients

Abstract Background: Despite the promising of introduction of tyrosine kinase inhibitors (TKIs), chronic myeloid leukemia (CML) remains a significant cause of annual mortality. Red blood cell distribution width (RDW), neutrophil/lymphocyte ratio (NLR), and platelet/lymphocyte ratio (PLR) are parameters derived from a complete blood count (CBC) commonly used to diagnose anemia, autoimmune diseases, and inflammation. These parameters have been reported to have a strong association with various diseases, including hematologic malignancies. Objectives: The study aims to identify whether RDW, NLR, and PLR can act as predictors of survival in newly diagnosed and treated CML patients. Materials and Methods: The study involved 60 Iraqi patients (37 males, 23 females, aged 17–69 years) with CML at chronic phase, who were referred to the National Center of Hematology/Mustansiriyah University, Baghdad, from February 2022 to December 2022. Twenty were newly diagnosed (T0), and 40 were under TKI treatment (T+), with 20 on imatinib and 20 on nilotinib. Additionally, a control group of 20 age- and gender-matched healthy subjects was included. CBC assessed red blood cell (RBC) indices across all groups. Results: There was no significant difference in the age of CML patients at the onset of disease between males (34.5 ± 11.7 years) and females (34 ± 11.9 years). Likewise, there was no significant difference in the treatment of CML patients with imatinib or nilotinib between males (48% and 52%) and females (53.3% and 47.7%), respectively. Most RBC indices for patients and controls were within normal ranges without significant differences. However, RDW% in T0 was markedly elevated (20.4%), with about 80% showing anisocytosis, surpassing both T+ and controls, and exceeding the upper limit of normal. The total and differential white blood cell (WBC) counts were significantly higher in T0 compared to T+, exceeding their normal ranges. Additionally, the NLR was significantly higher in T0 (8.13) compared with T+ and controls (1.80 and 1.87, respectively). Platelet count, mean platelet volume, and platelet distribution width (PDW%) differed significantly among the three groups but remained within the normal range. However, PLR in T0 (31 ± 24) was significantly lower than those in T+ and controls (130 ± 43 and 102 ± 27, respectively). Conclusion: It can be concluded that the monitoring of some parameters in peripheral blood in CBC test (as a simple and inexpensive test) such as RDW%, NLR%, and PLR% during the therapy course of CML patients may act as predictive markers to evaluate the prognosis of disease in CML patients and the degree of response to certain TKI treatment.

Treatment outcome of the tyrosine kinase inhibitor (bosutinib) in previously treated chronic myeloid leukemia patients (sample of Iraqi patients)

Abstract: BACKGROUND: Chronic myeloid leukemia (CML) is a type of myeloproliferative neoplasm characterized by the excessive accumulation of malignant myeloid cells in the bone marrow and peripheral blood. This condition is primarily triggered by a specific chromosomal translocation known as t(9;22) (q34.13;q11.23), which leads to the formation of the BCR-ABL fusion gene. The treatment landscape for CML has undergone significant changes with the approval of tyrosine kinase inhibitors (TKIs) targeting the BCR-ABL1 kinase activity. One such inhibitor is bosutinib, which has been available for several years to treat patients with chronic, accelerated, and blast-phase CML who have shown resistance or intolerance to previous therapies. OBJECTIVES: The aim of this study was to assess efficacy and safety of Bosutinib as a 2nd line therapy in CML patients, in addition to effect of adherence to treatment on patients response. PATIENTS AND METHODS: Eighty-five patients with CML were enrolled in a prospective cohort study from October 2021 to October 2022 at Hematology Center in Medical City Complex – Baghdad. All patients failed to at least one TKI, and all of them started escalated dose of bosutinib. The patients were followed-up by assessing molecular and cytogenetic response at 3 and 6 months and monitored carefully for adverse events (AEs) which were graded by common terminology IX criteria for AEs version 5. Adherence to bosutinib was also monitored by a specific adherence scale to optimize the response rate to treatment. RESULTS: The mean age of patients was 47.3 ± 14.9 (range: 18–77), with male:female ratio 1.4:1. Status of CML patients showed that 89.4% were in the chronic phase, 5.8% in accelerated phase, and 4.7% in blast phase. Regarding the number of previous TKIs before bosutinib, 72.9% of patients failed to prior one TKI (imatinib). At 6 months (72.3%), patients achieve optimal response according to European Leukemia Net criteria 2013. Gastrointestinal symptoms and dermatological manifestations were the most common nonhematological AEs of bosutinib. According to 9-item Morisky Medication Adherence Scale, 42% of patients were adherent to medication which showed a significant association with a higher number of optimal response (P = 0.0001). CONCLUSION: Bosutinib is effective with a high and promising response as a subsequent line treatment in CML patients, and it is generally safe and associated with mild-to-moderate tolerable and manageable AEs. Adherence to the drug plays a significant role in optimal response to bosutinib.

KF1601, a Novel Orally Bioavailable Inhibitor of BCR-ABL1 T315I without Inducing Thrombotic Microangiopathy

Targeting Bcr-Abl with tyrosine kinase inhibitors (TKIs) has revolutionized the treatment of chronic myeloid leukemia (CML) by significantly improving patients' survival. However, the gatekeeper mutation T315I confers resistance to TKIs targeting Bcr-Abl, presenting a formidable task in CML's clinical management. Ponatinib significantly reduces the mortality of CML patients with Bcr-Abl T315I, but often accompanies severe, life-threatening side effects. Herein, we report KF1601, a novel orally bioavailable TKI: 1) KF1601 inhibited kinase functions of both Bcr-Abl WT and Bcr-Abl T315I with nanomolar IC 50 values; 2) KF1601 and ponatinib had similar potency in terms of inhibiting CRKL phosphorylation, which correlates to major molecular responses in CML patients. 3) In murine models using Ba/F3 Bcr-Abl T315I cell line, it showed promising in vivo antitumor efficacy, comparable to that of ponatinib; 4) In animal models, it did not cause thrombotic microangiopathy, a major mechanism of ponatinib's toxicity. In summary, KF1601 is a promising drug candidate for safely treating CML patients with drug-resistant Bcr-Abl T315I mutation.

The mRNA Expression of PTEN, LEF1, JAK3, LC3 and p62/SQSTM1 Genes in Patients with Chronic Myeloid Leukemia.

Chronic myeloid leukemia (CML) is a progressive myeloproliferative disorder resulting from forming a chimeric BCR-ABL gene. The proteins derived from this gene can affect some genes from various signaling pathways such as PI3K/AKT/Wnt/catenin/JAK/Stat involved in proliferation, differentiation, cell death, and genes related to autophagy. Imatinib is the first-line treatment for CML patients, with durable and proper responses in Iranian children and adult CML patients. Hence, we aimed to evaluate the mRNA expression of some selected key genes from those pathways in patients with CML before and under treatment. In the case-control study, the mRNA expression of PTEN, LEF1, JAK3, LC3 and p62 genes were measured in 51 CML patients (6 patients before treatment and 45 patients under treatment with imatinib mesylate) and 40 healthy controls using the Real-time PCR method. The mRNA expression of PTEN and P62 were significantly higher in newly diagnosed patients than in controls (P<0.0001 and P = 0.0183, respectively), while the expression of the LC3 gene was significantly lower in the untreated newly diagnosed group than in control subjects (P = 0.0191). The expression level of PTEN, LEF1, JAK3 and P62 genes were significantly decreased in patients under treatment than in the group before treatment (P = 0.0172, P = 0.0002, P = 0.0047 and P = 0.0038, respectively). A positive correlation was seen between the gene expression of P62 and BCR-ABL in the patients under treatment (r 0529, P = 0.016). Our findings showed that the changes in expression of these genes were related to the patient's treatment. Due to the key role of these genes in proliferation, differentiation and tumor suppression, it is proposed that these genes may be helpful for follow-up of treatment in CML patients.

BH3 mimetics and TKI combined therapy for Chronic Myeloid Leukemia.

Chronic myeloid leukemia (CML) was considered for a long time one of the most hostile leukemia that was incurable for most of the patients, predominantly due to the extreme resistance to chemotherapy. Part of the resistance to cell death (apoptosis) is the result of increased levels of anti-apoptotic and decreased levels of pro-apoptotic member of the BCL-2 family induced by the BCR-ABL1 oncoprotein. BCR-ABL1 is a constitutively active tyrosine kinase responsible for initiating multiple and oncogenic signaling pathways. With the development of specific BCR-ABL1 tyrosine kinase inhibitors (TKIs) CML became a much more tractable disease. Nevertheless, TKIs do not cure CML patients and a substantial number of them develop intolerance or become resistant to the treatment. Therefore, novel anti-cancer strategies must be developed to treat CML patients independently or in combination with TKIs. Here, we will discuss the mechanisms of BCR-ABL1-dependent and -independent resistance to TKIs and the use of BH3-mimetics as a potential tool to fight CML.

The role of CSE1L silencing in the regulation of proliferation and apoptosis via the AMPK/mTOR signaling pathway in chronic myeloid leukemia

ABSTRACTObjectivesChromosome segregation 1-like (CSE1L) is abundant and strongly expressed in solid tumors. However, the expression and role of CSE1L in chronic myeloid leukemia(CML) remain largely unknown.Materials and methodsThe relative expression levels of CSE1L in bone marrow granulocytes from patients with primary CML and non-hematologic controls were measured by flow cytometry. Cell counting kit-8 analysis, DNA Content Quantitation Assay, and Annexin V-PE/7-AAD staining were applied to assess the effects of CSE1L knockdown on cell proliferation, cell cycle progression, and apoptosis.ResultsElevated expression of CSE1L was detected in bone marrow granulocytes of patients with primary CML. In the CML cell line K562 cells, CSE1L knockdown impaired cell proliferation blocked the cell cycle shift from G0/G1 phase to the S phase, and promoted apoptosis. Knockdown of CSE1L reduced Bcl-2 protein expression and increased Bax protein expression. Meanwhile, knockdown of CSE1L enhanced the expression of phospho-AMPK protein and decreased the expression of phospho-mTOR protein. The expression of total AMPK and mTOR proteins was not affected. In addition, CSE1L expression levels were decreased in imatinib-treated K562 cells.ConclusionsCSE1L plays a pivotal role in K562 cell survival and growth. These functions may be partially dependent on the AMPK/mTOR signaling pathway to achieve. In addition, CSE1L may have had a future impact on the treatment of CML patients.

Clinical significance of serum prohibitin in chronic myeloid leukemia patients on first-line tyrosine kinase inhibitors

Abstract Background Prohibitin is a widely expressed intracellular protein that is distributed in various compartments, where they exert different biological functions accordingly. Prohibitins have displayed both protumorigenic and antitumorigenic roles in cancer formation. Depending on the type of cancer and the localization of prohibitin, studies have shown that it exerts a different biological role. Aim This study aims to investigate prohibitin level in Egyptian patients with chronic myeloid leukemia (CML) and to evaluate its correlation with disease activity and response to first-line tyrosysine kinase inhibitor treatment. Patients and methods Prohibitin level was measured using enzyme-linked immunosorbent assay in 80 CML patients in the chronic phase. They were recruited from the clinical hematology division of Internal Medicine Department, Ain Shams University Hospitals. They were matched to 10 healthy volunteers as a control group. Results In our study, we have demonstrated that prohibitin levels were significantly higher in patients with CML than in the control participants (P=0.002). Prohibitin levels were significantly higher in CML patients with an active disease status (P=0.001). In addition, significantly higher levels of prohibitin in CML patients were associated with poor response to first generation TKIs (P=0.001). Receiver-operating characteristic curve was applied. A serum level of prohibitin higher than 289 is a good predictor for poor response to first generation TKIs as per response assessment by PCR for BCR-ABL (area under the curve=0.67, sensitivity and specificity 58.33 and 80.56, respectively). Conclusion Prohibitin is overexpressed in CML patients and has a possible impact on disease activity and response to treatment in CML patients that warrants further investigations.

A review of the therapeutic role of the new third-generation TKI olverembatinib in chronic myeloid leukemia.

Several tyrosine kinase inhibitors (TKIs) have been developed as targeted therapies to inhibit the oncogenic activity of several tyrosine kinases in chronic myeloid leukemia (CML), acute lymphoid leukemia (ALL), gastrointestinal stromal tumor (GIST), and other diseases. TKIs have significantly improved the overall survival of these patients and changed the treatment strategy in the clinic. However, approximately 50% of patients develop resistance or intolerance to imatinib. For second-generation TKIs, approximately 30%-40% of patients need to change therapy by 5 years when they are used as first-line treatment. Clinical study analysis showed that the T315I mutation is highly associated with TKI resistance. Developing new drugs that target the T315I mutation will address the dilemma of treatment failure. Olverembatinib, as a third-generation TKI designed for the T315I mutation, is being researched in China. Preliminary clinical data show the safety and efficacy in treating CML patients harboring the T315I mutation or who are resistant to first- or second-line TKI treatment. Herein, we review the characteristics and clinical trials of olverembatinib. We also discuss its role in the management of CML patients.

CML-125 Clinical Significance of Serum Prohibitin in Chronic Myeloid Leukemia Patients on First-Line Tyrosine Kinase Inhibitors

Prohibitin is a widely expressed intracellular protein that is distributed in various compartments, where they exert different biological functions accordingly. Prohibitins have displayed both pro-tumorigenic and antitumorigenic roles in cancer formation. Depending on the type of cancer and the localization of prohibitin, studies have shown that it exerts a different biological role. To investigate prohibitin level in Egyptian patients with chronic myeloid leukemia (CML) and to evaluate its correlation with disease activity and response to first-line tyrosine kinase inhibitor treatment. A case-control prospective study. Clinical Haematology division of Internal Medicine Department, Ain Shams University Hospitals. 80 CML patients in the chronic phase. They were matched to 10 healthy volunteers as a control group. Prohibitin level was measured using an enzyme-linked immunosorbent assay. We reported a significant value of prohibtin level in CML patients and a significant correlation between its level and disease activity and response to treatment. We have demonstrated that prohibitin levels were significantly higher in patients with CML than in the control participants (P=0.002). Prohibitin levels were significantly higher in CML patients with an active disease status (P=0.001). In addition, significantly higher levels of prohibitin in CML patients were associated with poor response to first-generation TKIs (P=0.001). A serum level of prohibitin higher than 289 is a good predictor of poor response to first-generation TKIs as per response assessment by PCR for BCR-ABL (area under the curve=0.67, sensitivity and specificity 58.33 and 80.56, respectively). Prohibitin is overexpressed in CML patients and has a possible impact on disease activity and response to treatment in CML patients that warrants further investigations.

Designing Novel BCR-ABL Inhibitors for Chronic Myeloid Leukemia with Improved Cardiac Safety.

Development of tyrosine kinase inhibitors (TKIs) targeting the BCR-ABL oncogene constitutes an effective approach for the treatment of chronic myeloid leukemia (CML) and/or acute lymphoblastic leukemia. However, currently available inhibitors are limited by drug resistance and toxicity. Ponatinib, a third-generation inhibitor, has demonstrated excellent efficacy against both wild type and mutant BCR-ABL kinase, including the “gatekeeper” T315I mutation that is resistant to all other currently available TKIs. However, it is one of the most cardiotoxic of the FDA-approved TKIs. Herein, we report the structure-guided design of a novel series of potent BCR-ABL inhibitors, particularly for the T315I mutation. Our drug design paradigm was coupled to iPSC–cardiomyocyte models. Systematic structure–activity relationship studies identified two compounds, 33a and 36a, that significantly inhibit the kinase activity of both native BCR-ABL and the T315I mutant. We have identified the most cardiac-safe TKIs reported to date, and they may be used to effectively treat CML patients with the T315I mutation.

Priapism as the Initial Presentation in Chronic Myeloid Leukemia Is a Red Flag Sign

Chronic myeloid leukemia (CML) is a myeloproliferative disorder of the hemopoietic stem cells, which may occasionally present with symptoms of leukostasis secondary to hyperleukocytosis, which includes headache, priapism, and dreaded ones such as stroke and myocardial infarction. This is a case of a 23-year-old man who presented with priapism and was subsequently found to have CML. The patient later developed stroke and succumbed to it. This case demonstrates that the importance of treating CML patients presenting with signs of hyperleukocytosis promptly and cautiously to prevent the impending grievous complications.

OCT-1 Expression in Patients with Chronic Myeloid Leukemia: A Comparative Analysis with Respect to Response to Imatinib Treatment.

The introduction of tyrosine kinase inhibitors (TKI) has resulted in a significant improvement in the treatment of CML patients. However, some CML patients are resistant to imatinib therapy, the initial TKI therapy in the CML. Therefore, it is important to find prognostic markers for resistance. The OCT-1 gene involved in imatinib uptake is also suspected to cause imatinib resistance. The aim of this study was to investigate the role of OCT-1 in imatinib resistance by comparing OCT-1 expression levels in imatinib resistant and imatinib sensitive patients with chronic myeloid leukemia (CML). This study was conducted on 101 patients with CML [imatinib sensitive (n = 51) and imatinib resistant (n = 50)] who were treated with imatinib. Gene expression analysis was done using QRT-PCR. The relative expression levels of OCT-1 were calculated using 2(-ΔΔCT) method. OCT1 mRNA expression levels were 0.149 (0.011-2.532) and 0.119 (0.008-2.868) in imatinib-sensitive group and imatinib-resistant group, respectively. OCT-1 expression levels were not significantly different in the imatinib-sensitive group when compared to imatinib resistant group (p > 0.05). OCT-1 expression was also similar in BCR-ABL1 kinase domain mutation positive and negative cases (p > 0.05). The imatinib-resistant group had a higher rate of hydroxyurea or interferon-alpha treatment prior to imatinib therapy and a lower rate for first-line imatinib as the only treatment than the imatinib-sensitive group (p = 0.002 and p = 0.002, respectively). According to the results of our study, OCT-1 does not have a biomarker feature in the evaluation of imatinib response. In addition, the study should be performed in larger patient groups.

Pro-Inflammatory and Pro-Oxidative Changes During Nilotinib Treatment in CML Patients: Results of a Prospective Multicenter Front-Line TKIs Study (KIARO Study).

Tyrosine kinase inhibitors (TKI) may offer a normal life expectancy to Chronic Myeloid Leukemia (CML) patients. However, a higher than expected incidence of arterial occlusive events (AOEs) was observed during treatment with nilotinib. We previously showed an “inflammatory status” during nilotinib that may explain the increased incidence of AOEs. Thus, we conducted this prospective KIARO study involving 186 CML patients (89 imatinib, 59 nilotinib, 38 dasatinib). Interleukin 6 (IL6), interleukin 10 (IL10), Tumor Necrosis Factor-α (TNFα), oxLDL, and high-sensitivity C-reactive protein (hs-CRP) plasma levels were measured at diagnosis and during treatment, with the aim to investigate changes in the inflammatory status favoring AOEs of each patient. Clinical and biochemical pro-atherothrombotic profiles and the 10-year SCORE chart were also evaluated. We showed a pro-inflammatory/pro-oxidative milieu increasing along treatment with nilotinib compared with imatinib or dasatinib, as demonstrated by higher hs-CRP and oxLDL levels and increased IL6/IL10 and TNFα/IL10 ratios only in nilotinib cohort. After median follow-up of 23.3 months starting from TKI, 10/186 patients (5.4%) suffered an AOE. Approximately 5/10 (50%) AOEs occurred during nilotinib treatment despite a lower 10-year SCORE and a lower median age in this subgroup. A longer follow-up is needed to further confirm the active role of nilotinib in AOEs pathogenesis.

Pro-Inflammatory and Pro-Oxidative Changes during Nilotinib Treatment in CML Patients: Results of a Prospective Multicenter Front-Line TKIs Study (KIARO Study)

Background: Tyrosine kinase inhibitors (TKI) may offer a normal life expectancy to Chronic Myeloid Leukemia (CML) patients. However, during treatment with nilotinib, a higher than expected incidence of arterial occlusive events (AOEs) was observed. We retrospectively showed an “inflammatory status” during nilotinib treatment that may explain this increased incidence of AOEs. Here, we report results of a prospective multicenter (KIARO) study including 186 CML patients (89 imatinib, 59 nilotinib, 38 dasatinib) in which pro/anti-inflammatory cytokines were measured at diagnosis and during treatment, with the aim to investigate potential changes in each patient's inflammatory status possibly favoring AOEs.Aims: The aims of this study are: 1) to analyze prospectively inflammation status during TKI treatment; 2) to record AOEs; 3) to calculate the SCORE and evaluate its predictive role for AOEs; 4) to analyze possible associations of AOEs with altered inflammation status.Methods: Inflammatory status was evaluated by measuring IL6, IL10, TNFα, oxLDL and hs-CRP plasma levels at diagnosis and during treatment (+1, +3, +6, +12 months); additionally, clinical and biochemical pro-atherothrombotic profiles and the 10-year SCORE chart were also evaluated.Results: 186 newly-diagnosed CML patients starting either imatinib, nilotinib or dasatinib treatment, entered this study. Regarding the inflammation status, we observed that TNFα and IL6 levels were high at diagnosis and decreased during the first 12 months of treatment regardless the type of TKI; instead, IL10 levels were comparable among the 3 TKI cohorts at baseline, but showed a remarkably different evolution during treatment. In fact, IL10 levels were significantly higher after 6 and 12 months of imatinib (p=0.012 and p=0.009, respectively) and dasatinib (p=0.032 and p=0.014, respectively) compared to nilotinib. Consequently, TNFα/IL10 ratio was significantly higher in nilotinib cohort at 6 and 12 months respect to imatinib (p=0.044 at 6 months and p=0.041 at 12 months) and dasatinib (p=0.040 at 6 months and p=0.044 at 12 months). As well, IL6/IL10 ratio was significantly higher in nilotinib cohort compared to imatinib and dasatinib both at 6 (p=0.042 and p=0.049, respectively) and 12 months (p=0.040 and p=0.041, respectively) (Figure 1). OxLDL levels were similar in the 3 groups for the first 6 months. At 12 months we detected a significant increase of oxLDL levels in the nilotinib cohort (p=0.041), respect to imatinib and dasatinib. We did not find significant differences in hs-CRP levels across the 3 TKIs, although a trend for higher levels was observed in nilotinib cohort. Overall, these results suggest a TKI-driven pro-inflammatory status in nilotinib treated patients.After a median follow-up of 23.3 months of TKI treatment, 10 patients (5.4%) suffered an AOE, specifically: 6 ACS, 2 PAOD, 1 TIA and 1 stroke. 5 events (50%) occurred in patients treated with nilotinib, either in first line (4 patients) or in third line (1 patient, after failure following brief treatment with imatinib and dasatinib). In this subgroup of 10 patients experiencing an AOE, we observed a trend of increased IL6 and TNFα median values both at diagnosis and at each time point, compared with the remaining no-AOE patients. IL10 and oxLDL had similar median concentrations in both AOE and no-AOE cohorts, except for oxLDL at 12 months which resulted higher in patients who experienced AOEs. Moreover, regarding AOEs, nilotinib treatment showed a 3.1 times increased risk compared to other TKIs (HR 3.1, 95% CI 2.6-4.4 p< 0.001), whereas 10-year SCORE was not predictive in the whole cohort (HR 0.6, 95% CI 0.33-0.94 p= 0.094) or in any subgroup (imatinib HR 0.8, 95% CI 0.49-1.03 p= 0.067; nilotinib HR 0.4, 95% CI 0.29-0.76 p= 0.112, dasatinib HR 0.6, 95% CI 0.37-0.92 p= 0.082).Conclusions: Our results showed a pro-inflammatory/oxidative milieu increasing along treatment with nilotinib compared with imatinib or dasatinib, as demonstrated by higher IL6/IL10 and TNFα/IL10 ratios, higher levels of oxLDL and a trend for higher hs-CRP only in nilotinib cohort. However, due to the low number of observed events, a formal statistical analysis for any association between AOEs and pro/anti-inflammatory cytokines levels was not possible. Therefore, a longer follow-up is needed to further confirm the active role of nilotinib in AOEs pathogenesis. [Display omitted] DisclosuresAbruzzese: Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria. Galimberti: Incyte: Speakers Bureau; AbbVie, Janssen: Honoraria, Other: Travel grants. Stagno: Pfizer: Consultancy, Honoraria, Other: Support for attending meetings and/or travel; InCyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Other: Support for attending meetings and/or travel, Research Funding.

Regulation of miR-126 and miR-122 Expression and Response of Imatinib Treatment on Its Expression in Chronic Myeloid Leukemia Patients

Background: MicroRNAs (miRNAs) have been observed to exhibit altered expression patterns in chronic myeloid leukemia (CML). Therefore, this study was aimed to evaluate the clinical importance of miR-126 and miR-122 expression in concert to imatinib response in CML patients. Methods: The present study included 100 CML and 100 healthy subjects. The expression of the 2 miRNAs was performed using TaqMan probe chemistry, and snU6 was used as internal control. Results: The expression of miR-126 and miR-122 was downregulated in CML patients, with a mean fold change ± SD 0.20 ± 0.33 and 0.22 ± 0.37, respectively. While the expression of both miRNAs was analysed before and after imatinib treatment, it was observed that the expression levels of both were increased after imatinib treatment by 26.25-fold (5.33 against 0.20) and 13.95-fold (3.07 against 0.22) and the increase was statistically significant (p < 0.0001 and p < 0.0001, respectively). The expression of miR-126 was not conclusive when compared in different clinical stages of the CML disease as it showed a decreased expression in patients with accelerated phase compared to chronic phase (mean fold change = 0.03 and 0.27, respectively), but patients with chronic phase and blastic phase had comparable expression (mean fold change = 0.27 and 0.24, respectively). We also observed an increased expression of both miRNAs after imatinib therapy in each clinical phase. Conclusion: The study concludes that expression of miR-126 and miR-122 increases after imatinib treatment in CML patients and that miR-126 defines the good responders of imatinib therapy.

Abstract 1462: KF1601, a novel orally bioavailable inhibitor of Bcr-Abl T315I, without inducing thrombotic microangiopathy

Abstract Targeting Bcr-Abl with tyrosine kinase inhibitors (TKIs) has revolutionized the treatment of chronic myeloid leukemia (CML) by significantly improving patients' survival. However, the gatekeeper mutation T315I confers resistance to TKIs targeting Bcr-Abl, presenting a formidable task in CML's clinical management. Ponatinib is the only approved drug for Bcr-AblT315I, but often accompanies severe, life-threatening side effects. Herein, we report KF1601, a novel orally bioavailable TKI: 1) KF1601 inhibited kinase functions of both Bcr-AblWT and Bcr-AblT315I with nanomolar IC50 values; 2) In xenograft models using Ba/F3 Bcr-AblT315I cell line, it showed promising in vivo antitumor efficacy, comparable to that of ponatinib; 3) In animal models, it did not cause thrombotic microangiopathy, a major mechanism of ponatinib's toxicity. In summary, KF1601 is a promising drug candidate for safely treating CML patients with drug-resistant Bcr-AblT315I mutation. Citation Format: HyunJin Kwon, Sung-Min Ahn, Kiho Chang, WooSik Kim, Amir Khan, Doohyun LEE, Seungyeon Lee, Ye Ri Han, Chun Young Im. KF1601, a novel orally bioavailable inhibitor of Bcr-Abl T315I, without inducing thrombotic microangiopathy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1462.