First-generation Tyrosine Kinase Inhibitors Research Articles

Validation of imatinib therapy failure score (IMTF) in chronic phase chronic myeloid leukemia in real life practice

The outcome of chronic myeloid leukemia (CML) patients improved in the last decade. Clinical prognostic scoring systems aim to provide information about survival in the long-term, without determining from baseline the subset of patients who require a strictly monitoring because at increased risk of failure. Imatinib, the first-generation tyrosine kinase inhibitor (TKI), is still widely used as frontline treatment: recently, the imatinib therapy failure (IMTF) score was proposed to identify the failure free survival. Aim of our study was to validate this index in a large cohort of patients treated with imatinib.

Clinical Outcomes of Patients with Chronic Myeloid Leukemia and COVID-19 Infection-A Single Center Survey.

Background: Previous research has shown different effects of hematological malignancies on the outcome of patients with COVID-19 infection depending on the type of disease and the treatment received. This research was aimed at examining the clinical outcome of COVID-19 infection in positive patients with chronic myeloid leukemia treated with tyrosine kinase inhibitors. Methods: We collected retrospective information on chronic myeloid leukemia patients who were treated and monitored in our institution during the pandemic period. Within this cohort, we recorded COVID-19 positive symptomatic patients and analyzed their basic characteristics, symptoms, severity, and outcome. Results: In the study cohort when COVID-19 was diagnosed, 86.7% of patients were on first-generation tyrosine kinase inhibitors therapy-imatinib. At the time of infection, 70% of patients were in molecular remission, 23.4% in complete cytogenetic remission, and 3.3% in complete hematological response. Most patients had symptomatic disease. Within the analyzed group, 56.7% of patients had asymptomatic/mild COVID-19 infection, 23.3% of patients had moderate symptoms which did not require hospitalization, and 20% of patients had severe/critical symptoms that required admission to the intensive care unit. More than half of the patients interrupted treatment with tyrosine kinase inhibitors temporarily during COVID-19. There were no deaths due to COVID-19 infection. Conclusions: In compliance with other larger clinical studies, analysis of the clinical outcome of COVID-19 infection in patients with chronic myeloid leukemia on tyrosine kinase inhibitors therapy in this study showed that they do not have an increased risk for COVID-19 infection and that they have a mild course of the disease with recovery.

Bioinformatic analysis of the expression profile and identification of RhoGDI2 as a biomarker in imatinib-resistant K562 cells

ABSTRACTObjectivesChronic myeloid leukemia (CML) is an aggressive malignancy originating from hematopoietic stem cells. Imatinib (IM), the first-generation tyrosine kinase inhibitor, has greatly improved theliving quality of CML patients. However, owing to the recurrence and treatment failure coming from tyrosine kinase inhibitor (TKIs) resistance, some CML patients still bear poor prognosis. Therefore, we aimed to seek potential signaling pathways and specific biomarkers for imatinib resistance.MethodsWe performed mRNA and miRNA expression profiling in imatinib-sensitive K562 cells (IS-K562) and imatinib-resistant K562 cells (IR-K562). Differentially expressed genes (DEGs) were identified and pathway enrichment analyses were performed to explore the potential mechanism. The protein–protein interaction (PPI) network and miRNA-mRNA regulatory network were constructed to explore potential relationships among these genes. RT-qPCR, western blot and CCK8 were used for further experiments.ResultsA total of 623 DEGs and 61 differentially expressed miRNAs were identified. GO revealed that DEGs were mainly involved in cell adhesion, cell migration, differentiation, and inflammatory response. KEGG revealed that DEGs were typically enriched in the Rap1 signaling pathway, focal adhesion, proteoglycans and transcriptional misregulation in cancer, signaling pathways regulating pluripotency of stem cells and some immune-related pathways. The protein–protein interaction (PPI) network and miRNA-mRNA regulatory network revealed a web of diverse connections among genes. Finally, we proved that RHoGDI2 played a critical role in imatinib resistance.ConclusionThe dynamic interplay between genes and signaling pathways is associated with TKIs resistance and RHoGDI2 is identified as a biomarker in IR-K562.

Therapeutical Options in ROS1-Rearranged Advanced Non Small Cell Lung Cancer.

ROS proto-oncogene 1 (ROS1) rearrangements occur in 0.9-2.6% of patients with non small cell lung cancer (NSCLC), conferring sensitivity to treatment with specific tyrosine-kinase inhibitors (TKI). Crizotinib, a first-generation TKI, was the first target-therapy approved for the first-line treatment of ROS1-positive NSCLC. Recently, entrectinib, a multitarget inhibitor with an anti-ROS1 activity 40 times more potent than crizotinib and better activity on the central nervous system (CNS), received approval for treatment-naive patients. After a median time-to-progression of 5.5-20 months, resistance mechanisms can occur, leading to tumor progression. Therefore, newer generation TKI with greater potency and brain penetration have been developed and are currently under investigation. This review summarizes the current knowledge on clinicopathological characteristics of ROS1-positive NSCLC and its therapeutic options.

Real-world Management of CML: Outcomes and Treatment Patterns.

Chronic myeloid leukemia (CML) is a disease that previously signified a poor prognosis, but treatment options and outcomes have improved over the last several decades. Despite this, challenges remain in optimal management in clinical practice, as the characteristics in trial populations differ from patients who are treated in a real-world setting. This review describes recent updates in real-world treatment patterns and outcomes in patients with CML. Several analyses describing real-world practice patterns show that tyrosine kinase inhibitors (TKIs) are the most commonly prescribed agents in multiple lines of therapy. First-generation (1G) and second-generation (2G) TKIs are the most commonly prescribed, even in the third line and beyond. Third-generation (3G) TKIs are typically utilized in patients with resistant disease who are younger with fewer comorbidities. Hematopoietic stem cell transplant (HSCT) is utilized significantly less, given other treatment options available. The goals of treatment with CML have shifted to quality of life, cost savings, and treatment-free response (TFR). Despite clear guidelines for attempting TFR, discontinuation practice patterns remain inconsistent. TKIs are the mainstay of CML treatment, including those in later lines of therapy. In real-world practice, several challenges still remain with regard to optimal management. Specifically, ideal sequencing of treatments, side effect profiles of tyrosine kinase inhibitors (TKIs), current role and timing of transplant, and adherence to recommendations for attempting to achieve a treatment-free response (TFR). A national registry could characterize these practice patterns in order to find ways to optimize care for CML patients.

Cost-Effectiveness Analysis of Three Diagnostic Strategies for the Detection of EGFR Mutation in Advanced Non-Small Cell Lung Cancer.

In non-small cell lung cancer (NSCLC), epidermal growth factor receptor (EGFR) mutation testing of tumor tissue should be conducted at diagnosis. Alternatively, circulating tumor DNA can be used to detect EGFR mutation. We compared the cost and clinical effect of three strategies according to the application of the EGFR test. Decision models were developed to compare the cost-effectiveness of tissue-only, tissue-first, and plasma-first diagnostic strategies as first- and second-line treatments for NSCLC from the perspective of the Korean national healthcare payer. Progression-free survival (PFS), overall survival (OS), and direct medical costs were assessed. A one-way sensitivity analysis was performed. The plasma-first strategy correctly identified numerous patients in the first- and second-line treatments. This strategy also decreased the cost of biopsy procedures and complications. Compared with that when using the other two strategies, the plasma-first strategy increased PFS by 0.5 months. The plasma-first strategy increased OS by 0.9 and 1 month compared with that when using the tissue-only and tissue-first strategies, respectively. The plasma-first strategy was the least expensive first-line treatment but the most expensive second-line treatment. First-generation tyrosine kinase inhibitor and the detection rate of the T790M mutation in tissues were the most cost-influential factors. The plasma-first strategy improved PFS and OS, allowing for a more accurate identification of candidates for targeted therapy for NSCLC and decreased biopsy- and complication-related costs.

Sequential therapy with crizotinib and a second-generation ALK inhibitor versus direct therapy of a second-generation ALK inhibitor in ALK-positive advanced lung cancer: a real-world study.

There are few real-world studies in which the efficacy of sequential crizotinib and second-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) are compared with direct therapy of second-generation ALK TKI in ALK-positive advanced lung cancer. Between May 2014 and October 2022, 211 patients from the Zhejiang Cancer Hospital who harbored ALK rearrangement were analyzed. Of these patients, 115 received crizotinib with sequential second-generation ALK TKIs, and 96 patients received a second-generation ALK TKI directly. The survival analysis of median progression-free survival (PFS), overall survival (OS), and central nervous system time to progression (CNS TTP) in the various groups were calculated using the Kaplan-Meier method and compared by the log-rank test. Of the 211 lung cancer patients with ALK rearrangement, there were no statistical differences in PFS (25.27 vs. 20.47 months, P=0.644) and OS (70.27 months vs. not reached, P=0.991) between the 115 patients in the sequential therapy group and the 96 patients in the direct second-generation group. In the patients with baseline brain metastases at study entry (n=54), the sequential therapy group had a significantly shorter median CNS TTP than the direct second-generation group (10.40 vs. 22.40 months, P=0.040). Multivariate analyses revealed that the prognostic factors for PFS included performance status (PS, P=0.047) and brain metastases (P=0.010). For OS, the prognostic factors included PS (P=0.047) and liver metastases (P=0.021). There was no statistical difference in efficacy between first-generation sequential second-generation ALK TKIs and direct therapy of second-generation ALK TKI regimens. The CNS efficacy of the direct second-generation group was better than that of the sequential therapy group. The prognostic factors for PFS included PS and brain metastases, while the prognostic factors for OS, PS and liver metastases were included.

I13 overrides resistance mediated by the T315I mutation in chronic myeloid leukemia by direct BCR-ABL inhibition.

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm caused by a BCR-ABL fusion gene. Imatinib has significantly improved the treatment of CML as a first-generation tyrosine kinase inhibitor (TKIs). The T315I mutant form of BCR-ABL is the most common mutation that confers resistance to imatinib or the second-generation TKIs, resulting in poor clinical prognosis. In this work, we assessed the effect of a potent histone deacetylase (HDAC) inhibitor, I13, on the differentiation blockade in CML cells harboring T315I-mutated and wild-type BCR-ABL by MTT assay, flow cytometery, cell colony formation assay, mRNA Sequencing, Quantitative real-time PCR and Western blotting analysis. We found that I13 possessed highly potent activity against T315I-mutated BCR-ABL mutant-expressing cells and wild-type BCR-ABL-expressing cells. I13 induced cell differentiation and significantly suppressed the proliferation of these CML cells via the cell cycle G0/G1-phase accumulation. Moreover, it was revealed that I13 triggered the differentiation of BaF3-T315I cells, which was attributed to the block of the chronic myeloid leukemia signaling pathway via the depletion of BCR-ABL that was mediated by the inhibition of HDAC activity presented by the acetylation of histones H3 and H4. Taken together, I13 efficiently depleted BCR-ABL in CML cells expressing the BCR-ABL-T315I mutation, which blocked its function, serving as a scaffold protein that modulated the chronic myeloid leukemia signaling pathway mediating cell differentiation. The present findings demonstrate that I13 is a BCR-ABL modulator for the development of CML therapy that can override resistance caused by T315I-mutated BCR-ABL.

Abstract 4022: Preclinical intracranial activity of NVL-655 in an alectinib-resistant patient-derived model harboring EML4-ALK fusion with G1202R mutation

Abstract Introduction: NVL-655 is a brain-penetrant, ALK-selective tyrosine kinase inhibitor (TKI) designed to maintain activity against ALK and ALK mutations that confer resistance to currently approved therapies, and to avoid neurological adverse events and dose-limiting toxicities associated with TRK inhibition. Brain metastases are common in ALK-positive non-small cell lung cancer (NSCLC), with an incidence of ~40% at diagnosis and ~60% after progressive disease on the first-generation ALK TKI (crizotinib) due to its limited brain penetration. Second- (ceritinib, alectinib, brigatinib, and ensartinib) and third-generation (lorlatinib) ALK TKIs have higher intracranial responses than crizotinib but are still limited by emergence of resistance mutations, most commonly G1202R-containing single and compound mutations. We previously reported that NVL-655 has intracranial activity in a preclinical model of Ba/F3 EML4-ALK v1 G1202R/L1196M. Here we further demonstrate the intracranial activity of NVL-655 in a preclinical patient-derived model harboring EML4-ALK v3 G1202R. Methods: The YU-1077 cell line was established from a patient with ALK-positive NSCLC after relapse on alectinib and was confirmed to harbor EML4-ALK v3 G1202R alteration. ALK TKIs (crizotinib, ceritinib, alectinib, brigatinib, ensartinib, lorlatinib, and NVL-655) were profiled against YU-1077 cells in 3-day viability assays and signaling assays. YU-1077 cells were intracranially implanted in Balb/c nude mice and treated with NVL-655 orally twice daily. Brain tumor burden was monitored weekly using magnetic resonance imaging (MRI). Results: NVL-655 suppressed the viability of YU-1077 cells bearing EML4-ALK v3 G1202R (IC50 < 1 nM) with potency >10-fold that of lorlatinib. NVL-655 at ≤10 nM fully inhibited ALK signaling as measured by ALK, ERK, and S6 phosphorylation, compared to ≥100 nM of lorlatinib required to achieve similar inhibition. Other ALK TKIs tested had limited activity against YU-1077 cells in viability and signaling assays, consistent with the G1202R mutation conferring resistance to first- and second-generation ALK TKIs. In mice intracranially implanted with YU-1077 cells, MRI scans confirmed rapid tumor regression upon treatment with 0.5 and 1.5 mg/kg NVL-655. Conclusion: Patient-derived models are widely viewed as among the most disease-relevant models for evaluating new therapies and drug resistance. Using a xenograft model derived from an alectinib-relapsed patient, we showed that NVL-655 had high intracranial activity against brain tumors bearing the ALK G1202R mutation that confers resistance to multiple ALK TKIs. NVL-655 is being evaluated in a Phase 1/2 clinical trial for patients with advanced NSCLC and other solid tumors harboring ALK rearrangement or activating ALK mutation (ALKOVE-1): NCT05384626. [J. Lee and M. Yu contributed equally.] Citation Format: Jii Bum Lee, Mi Ra Yu, Mi Ran Yun, You Won Lee, Seung Yeon Oh, Eun Ji Lee, Anupong Tangpeerachaikul, Henry E. Pelish, Byoung Chul Cho. Preclinical intracranial activity of NVL-655 in an alectinib-resistant patient-derived model harboring EML4-ALK fusion with G1202R mutation. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4022.

Research Advance of BCR-ABL Mutation and the Efficacy of Second and Third Generation TKI in Chronic Myeloid Leukemia--Review

The treatment of chronic myeloid leukemia (CML) was revolutionized with the advent of the first-generation tyrosine kinase inhibitors (TKIs), but drug resistance developed during treatment, leading to the development of the second-generation (dasatinib, nilotinib, and bosutinib) and third-generation (ponatinib) TKI. Compared with previous treatment regimens, specific TKI can significantly improve the response rate, overall survival rate and prognosis of CML. Only a few patients with BCR-ABL mutation are insensitive to the second-generation TKIs, so it is suggested to select the second-generation TKIs for patients with specific mutations. For patients with other mutations and without mutations, the second-generation TKI should be selected according to the patient's medical history, while the third-generation TKIs should be selected for mutations that are insensitive to the second-generation TKIs, such as T315I mutation that is sensitive to ponatinib. Due to different BCR-ABL mutations in patients with different sensitivity to the second and third-generation TKIs, this paper will review the latest research progress of the efficacy of the second and third-generation TKIs in CML patients with BCR-ABL mutations.

Red blood cell distribution width at diagnosis as a predictor factor in chronic phase-chronic myeloid leukemia patients treated with first-generation tyrosine kinase inhibitors

BACKGROUND: Chronic myelogenous leukemia is a hematological disorder of stem cells resulting from uncontrolled and unregulated growth of myeloid cells in the bone marrow. Since the introduction of tyrosine kinase inhibitors (TKIs), therapy has dramatically improved survival in these patients. TKIs treatment targeting BCR-ABL significantly improves the prognosis of patients with chronic myelogenous leukemia. To date, the validity of scoring systems is insufficient for predicting prognosis, and there are few studies of scoring systems for predicting treatment response and clinical efficacy of TKIs. OBJECTIVES: The objective of this study was to evaluate the ability of the red blood cell distribution width (RDW) to predict treatment response in chronic myeloid leukemia-chronic phase (CP) patients treated with first-generation TKI. PATIENTS AND METHODS: A prospective and retroprospective cohort study was conducted on chronic myeloid leukemia-CP patients treated with first-generation TKI at Iraqi Hematological Centers. The collection period was from December 2020 to November 2021. Patients were treated with first-generation TKIs as initial therapy and were followed up to assess the response by polymerase chain reaction (PCR). The assessment of RDW was done at baseline and then at 3, 6, 12, and 18 months after initiation of therapy. RESULTS: There were 150 patients included in this study. The mean age of patients was 43.7 ± 14 years (range: 18–84 years). Males were representing 48.6% and females 51.3%. The classification of baseline RDW showed that the majority of patients (53%) had high RDW. The RDW showed significant change over time, in which, it was significantly decreasing over time (P < 0.05). Association between PCR over time and baseline RDW category showed that the high baseline RDW was associated with higher mean PCR at 3, 6, 12, and 18 months (P < 0.05). The correlation between RDW at baseline and PCR at 3, 6, 12, and 18 months showed that there was a significant positive weak correlation between baseline RDW and PCR at 6, 12, and 18 months. The association between baseline RDW and the response showed that high baseline RDW was associated with higher failure rate at 6 and 12 months (P < 0.05). CONCLUSION: RDW could be used in the prediction of response to treatment. Furthermore, high RDW showed significant association with high disease activity score, high white blood cell count, and lower hemoglobin, in addition to association and correlation with PCR level.

Survival benefit of thoracic radiotherapy plus EGFR-TKIs in patients with non-oligometastatic advanced non-small-cell lung cancer: a single-center retrospective study.

The study aims to evaluate the efficacy and safety of thoracic radiotherapy in epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI)-treated patients with stage IV non-small-cell lung cancer (NSCLC). Patients with non-oligometastatic NSCLC harboring EGFR mutations were recruited. All patients received the first-generation TKI treatment with or without radiotherapy. The irradiated sites included primary and/or metastatic lesions. Of all the patients who underwent thoracic radiotherapy, some received radiotherapy before EGFR-TKI resistance, others received radiotherapy after progressive disease. No statistically significant difference was observed in progression-free survival (PFS) (median 14.7 versus 11.2 months, p = 0.075) or overall survival (OS) (median 29.6 versus 40.6 months, p = 0.116) between patients treated with EGFR-TKIs alone and those with additional radiotherapy to any sites. However, EGFR inhibitors with thoracic radiation significantly improved OS (median 47.0 versus 31.0 months, p < 0.001) but not PFS (median 13.9 versus 11.9 months, p = 0.124). Moreover, longer PFS (median 18.3 versus 8.5 months, p < 0.001) was achieved in the preemptive thoracic radiation cohort than in the delayed thoracic radiation cohort. However, OS was similar between the two cohorts (median 40.6 versus 52.6 months, p = 0.124). The lower incidence rate of grade 1-2 pneumonitis occurred in preemptive radiation cohort (29.8% versus 75.8%, p < 0.001). Non-oligometastatic NSCLC patients with EGFR mutations benefited from thoracic radiotherapy while using EGFR inhibitors. Preemptive thoracic radiotherapy could be a competitive first-line therapeutic option due to superior PFS and favorable safety.

Therapeutic Management of Metastatic Clear Cell Renal Cell Carcinoma: A Revolution in Every Decade.

Clear cell renal cell carcinoma (RCC) oncogenesis is mainly driven by VHL gene inactivation, leading to overexpression of vascular endothelial growth factor (VEGF). The use of tyrosine-kinase inhibitors (TKIs) directed against VEGF and its receptor (VEGFR) revolutionised the management of metastatic renal cancer in the 2000s. The more recent development of next-generation TKIs such as cabozantinib or lenvatinib has made it possible to bypass some of the mechanisms of resistance to first-generation anti-VEGFR TKIs. During the decade 2010-2020, the development of immune checkpoint blockade (ICB) therapies revolutionised the management of many solid cancers, including RCC, in first- and subsequent-line settings. Dual ICB or ICB plus anti-VEGFR TKI combinations are now the standard of care for patients with advanced clear cell RCC. To optimise these combination therapies while preserving patient quality of life, escalation and de-escalation strategies are being evaluated in prospective randomised trials, based on patient selection according to their prognosis risk. Finally, new therapeutic approaches, such as targeting hypoxia-inducible factor (HIF) and the development of innovative treatments using antibody-drug conjugates (ADCs), CAR-T cells, or radiopharmaceuticals, are all potential candidates to improve further patient survival.

Evidence-Based Minireview: What is the optimal tyrosine kinase inhibitor for adults with newly diagnosed Philadelphia chromosome–positive acute lymphoblastic leukemia?

The incorporation of BCR::ABL1 tyrosine kinase inhibitors (TKIs) to intensive chemotherapy significantly improved the outcomes of patients with Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL). This was first shown with the addition of the first-generation TKI imatinib, which allowed more patients to be bridged to an allogeneic stem cell transplant (SCT) and led to superior long-term outcomes compared with chemotherapy alone. The use of second-generation TKIs (eg, dasatinib and nilotinib) has led to further improvement in outcomes of patients with Ph- positive ALL, with a long-term survival of 40% to 60% in several studies. Ponatinib is a third-generation, more potent TKI that results in high rates of molecular response and promising long-term survival even when allogeneic SCT is not routinely performed. While randomized data to support the TKI selection in Ph-positive ALL are lacking, data from single-arm studies suggest deeper molecular responses and superior survival outcomes with each successive generation of TKI. More recently, chemotherapy-free regimens with blinatumomab and TKIs have shown excellent results in the frontline setting and may represent an emerging paradigm shift in the treatment of Ph-positive ALL.

Novel third-generation tyrosine kinase inhibitor for newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia: a case study.

Although Philadelphia chromosome-positive acute leukemia (Ph + -ALL) has been revolutionized with tyrosine kinase inhibitors (TKIs), resistance and mutation are universal events during treatment with first-generation and second-generation TKIs. The present third-generation TKI has a dose-dependent, increased risk of serious cardiovascular events and the sensitivity is poor for patients with ≥2 mutations accompanied by the T315I mutation. Thus, novel and well-tolerated TKIs should be explored. This study analyzes the efficacy and advert effects of olverembatinib, a novel third TKI, in the treatment of newly diagnosed adult Ph + -ALL in induction therapy. Four adult patients with newly diagnosed Ph + -ALL were treated with olverembatinib as the first-line treatment. For induction therapy, these patients received 40 mg of oral olverembatinib quaque omni die for 28 days, 1 mg/kg/d of prednisone for 14 days, then tapered and stopped at 28 days and vindesine 4 mg/d at days 1, 8 and 15. After induction therapy, these patients received median or high-dose of cytarabine and methotrexate combined with oral olverembatinib as consolidation therapy. Then the allogeneic hematopoietic stem cell transplantation (allo-HSCT) was performed. All patients reached complete remission with a complete cytogenetic response after induction therapy. Two patients reached major molecular remission and one with complete molecular remission. Before allo-HSCT, all the patients achieved complete molecular remission. All the patients have survived disease-free for 3-6 months. No severe advert effects were observed. It is well-tolerated and effective for olverembatinib in the treatment of newly diagnosed adult patients with Ph + -ALL. A prospective study should be performed to further testify the role.

Targeted Next-Generation Sequencing Identifies Additional Mutations Other Than BCR-ABL in Chronic Myeloid Leukemia Patients: A Chinese Monocentric Retrospective Study

The discovery of tyrosine kinase inhibitors (TKIs) has drastically changed the treatment of chronic myeloid leukemia (CML) patients. However, a proportion of patients still show resistance or intolerance to TKI therapy. These patients often carry somatic variants related to myeloid malignancies, indicating that additional mutations other than BCR-ABL1 may lead to TKI treatment failure or disease progression. We retrospectively evaluated 151 CML patients receiving TKI therapy and performed next-generation sequencing (NGS) analysis of 22 CML patients to explore the mutation spectrum other than BCR-ABL1 affecting the achievement of molecular responses. We also performed a comprehensive evaluation of clinical characteristics, distinct TKI options and scoring systems in the correlation with the molecular response of TKI. In total, 161 variants were detected by NGS, most of which were nonsynonymous SNVs (Figure A). The coexistence pattern among high-frequency variants was quite intricate(Figure B). Among 25 genes with allele mutation frequency (VAF) ≥5%, the most frequently mutated gene was ASXL1 (40.9%), followed by KMT2C (27.3%), DIS3 (18.2%), ATM (13.6%), DNMT3A (13.2%) and NOTCH3 (13.6%) (Figure C). NOTCH3 and RELN mutations were only carried by subjects failing to achieve a major molecular response (MMR) at 12 months, suggesting CML patients with NOTCH3 and RELN mutations might have poor long-term treatment effects (Figure D, Figure E). The distribution frequency of ASXL1 mutations was higher in the group that did not achieve MR4.0 at 36 months (P=0.023), indicating that ASXL1 mutation was an adverse factor for the achievement of MR4.0. Furthermore, subjects in this group possessed more mutations related to activation signaling pathway genes (P=0.003) and chromatin modification genes (P=0.029) (Figure F). In the group that failed to achieve MR4.5 at 12 months, there were more subjects carrying >2 gene mutations (9.1% vs. 63.6%, P=0.024), implying that it is less likely to achieve MR4.5 with the increase in the number of mutated genes and that the existence of more than two mutations is a poor prognostic factor for achieving deep molecular response (DMR) (Figure G, Figure H). However, no statistical significance was found in the effects of mutations in ASXL1 (P=0.371), KMT2C (P=0.079), DIS3 (P=0.467), ATM (P=0.280), DNMT3A (P=0.479) and NOTCH3 (P=0.479) on PFS. In the analysis of clinical characteristics, multivariate analysis identified hemoglobin concentration (HB) (relative risk, [RR], 1.023; P=0.08) and BCR-ABLIS level at 12 months (RR, 2.485; P＜0.001) as independent predictive covariates for MR4.5(Figure I). Subjects who received initial second-generation TKI (2GTKI) were more likely to achieve early molecular response (EMR) at 3 months (P=0.012), BCR-ABLIS ≤1% at 6 months (P=0.012) and MMR at 12 months (P=0.018) than initial first-generation TKI (1GTKI). And there did not show statistical significance in achieving BCR-ABLIS≤1% at 6 months, MMR at 12 months and MR4.5 between original 1GTKI (Group A1, Glevic, Novartis, Switzerland) and generic 1GTKI (Group A2, Genike, Chiatai Tianqing Pharmaceutical Group Co., Ltd.). As for scoring system, ELTS score was sensitive in differentiating whether patients could achieve EMR (P=0.001) and MMR (P=0.004). EUTOS scoring system had a significant difference in achieving MMR at 12 months (P=0.049). However, there was no significant difference in subjects stratified by the Hasford and Sokal scoring systems. In conclusion, ASXL1 mutation, activation signal pathway genes, chromatin modification genes and the presence of >2 mutations were adverse factors in achieving molecular response with TKI treatment. HB and MMR were independent factors for DMR, and initial 2GTKI therapy was better than 1GTKI in the achievement of molecular response. For the scoring system, we found that the ELTS score was the best in predicting the efficacy of TKI therapy. Acknowledgement: The work was supported by the Key R&D Program of Zhejiang (No. 2022C03137.), Public Technology Application Research Program of Zhejiang, China (No. LGF21H080003.), the Key Project of Jinhua Science and Technology Plan, China (No. 2020-3-011.), the 2019-2022 Key Medical Discipline (Haematology) Fund of Jinhua, China. Correspondence to: Dr Jian Huang, The First Affiliated Hospital of Zhejiang University School of Medicine. No. 79 Qingchun Road. Hangzhou, Zhejiang, PR China. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Long-Term Molecular Testing and Clinical Response of Tyrosine Kinase Inhibitors in Patients with Chronic Myeloid Leukemia in the Chronic Phase: 5-Year Follow-up from SIMPLICITY, a Prospective, Observational Study

Introduction Tyrosine kinase inhibitors (TKIs) are commonly used as first-line therapy for the treatment of patients with chronic myeloid leukemia in the chronic phase (CML-CP). Molecular response is monitored regularly after initiating TKI therapy and less frequently after achieving BCR::ABL1 ≤ 0.1%. Although responses to TKIs have been extensively evaluated in clinical trials, utilization of molecular testing and clinical response associated with TKI therapy is not as well understood in real-world settings. SIMPLICITY (NCT01244750) is a prospective observational study assessing TKI use, molecular testing patterns, and clinical response in patients with CML-CP in routine clinical practice. Methods The SIMPLICITY study followed patients with CML-CP from routine clinical practice who received first-line treatment with the first-generation TKI imatinib (IM) or second-generation TKIs dasatinib (DAS) or nilotinib (NIL) in the USA and Europe. As this was an observational study, molecular testing was performed at the discretion of the treating team without directives from the study protocol. The cumulative proportion of US patients who underwent ≥ 1 molecular test as well as the rates of major molecular response (MMR; BCR::ABL1 ≤ 0.1%) and deep (4.5-log) molecular response (MR4.5; BCR::ABL1 < 0.0032%) were evaluated through 3 and 6 months, and yearly through 5 years, after starting TKI treatment. Patients were stratified by index TKI (IM or DAS/NIL). Descriptive statistics are presented. Results At data cutoff (January 28, 2020), a total of 810 prospective US patients were enrolled and included in this analysis, of whom 244 received IM and 566 received DAS/NIL. The median age (range) at diagnosis was 56 (18-91) years (IM, 58 [18-90] years; DAS/NIL, 55 [19-91] years). A total of 796 (98.3%) patients were followed through 3 months from the start of index TKI treatment, 792 (97.8%) through 6 months, 762 (94.1%) through 1 year, 704 (86.9%) through 2 years, 652 (80.5%) through 3 years, 590 (72.8%) through 4 years, and 538 (66.4%) through 5 years. Of those followed, the overall proportion of patients tested for molecular response ranged from 20.7% through 3 months to 92.2% through 5 years (Figure). The proportion of assessed patients who achieved MMR at least once increased over time; MMR was achieved in 15.8% of patients assessed through 3 months (IM, 11.1%; DAS/NIL, 17.1%), 35.0% through 6 months (IM, 28.7%; DAS/NIL, 36.8%), 58.2% through 1 year (IM, 51.6%; DAS/NIL, 60.5%), 77.4% through 2 years (IM, 72.9%; DAS/NIL, 79.2%), 86.6% through 3 years (IM, 84.8%; DAS/NIL, 87.3%), 92.5% through 4 years (IM, 90.6%; DAS/NIL, 93.4%), and 95.4% through 5 years (IM, 95.9%; DAS/NIL, 95.2%). The proportion of patients who achieved MR4.5 at least once also increased over time; MR4.5 was achieved in 6.1% of patients assessed through 3 months (IM, 2.8%; DAS/NIL, 7.0%), 15.9% through 6 months (IM, 9.2%; DAS/NIL, 17.9%), 32.5% through 1 year (IM, 23.4%; DAS/NIL, 35.6%), 50.2% through 2 years (IM, 41.3%; DAS/NIL, 53.6%), 63.8% through 3 years (IM, 54.9%; DAS/NIL, 67.4%), 73.8% through 4 years (IM, 67.9%; DAS/NIL, 76.3%), and 79.2% through 5 years (IM, 75.9%; DAS/NIL, 80.6%). Among all 810 enrolled patients, 473 (58.4%) and 393 (48.5%) achieved MMR and MR4.5, respectively, and remained in the study through 5 years. Mean (standard deviation) time from index TKI to best response in tested patients was 2.4 (0.5) months among patients assessed through 3 months and 24.4 (15.4) months among those assessed through 5 years. Conclusions At 5-year follow-up in US patients from the SIMPLICITY study, there was a consistent increase in the proportion of assessed patients who achieved MMR and MR4.5 over time for all patients treated with TKIs, with the caveat that patients who remained on treatment at each subsequent time point were more likely to respond. In general, a consistently higher proportion of patients treated with DAS/NIL achieved MR4.5 across the time points assessed compared with IM in this non-controlled study. Further studies evaluating molecular response to IM, DAS, NIL, and other TKIs beyond 5 years can help delineate further differences in outcomes and determine whether molecular testing frequency correlates with outcomes. Study support This study was funded by Bristol Myers Squibb. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

CML-337 Therapeutic Results of Second-Generation TKIs in a CML Multicentric Study in the West Region of Algeria

Historically, treatments for chronic myeloid leukemia (CML) are palliative, except for bone marrow allograft. Despite the results obtained using imatinib, a first-generation tyrosine kinase inhibitor (TKI), some patients (pts) have weak responses. The second-generation TKIs dasatinib and nilotinib are therapeutic alternatives in pts resistant to imatinib. This retrospective, multicenter study included 7 hematology centers in western Algeria. Pts older than 15 years treated with dasatinib or nilotinib as second-line therapy were included. The analysis of prognostic factors and the study of therapeutic responses were conducted according to ELN 2013. Event-free survival, progression-free survival, and overall survival (OS) were calculated according to the Kaplan-Meier method. Between January 2007 and December 2018, we collected 494 pts with CML, 154 of whom were treated with second-generation TKIs at a median age of 45 years (16, 83). The sex ratio was 0.87. The average splenic overflow was 8 cm. The average leukocytosis was 100 Giga/L. The average hemoglobin level was 10 g/dl (5.5-15). The average platelet rate was 35.5 Giga/L (27-1120). The majority of pts (120, 80%) had intermediate or high Sokal scores. The myelocytic phase was detected in 132 pts (86%), accelerated phase in 19 pts (13%), and acute transformation phase in 1 pt (1%). The indication for second-generation TKI was pts in accelerated phase in 70% of cases, failure to respond to first-generation TKI in 25% of cases, and intolerance in 5% of cases. Dasatinib was used in 75 pts (50%), nilotinib in 44 pts (30%), and dasatinib then nilotinib in 33 pts (20%). Evaluable pts (154) included 61% in MMR and 39% in failure, 25 pts died, and 25 pts were lost to follow-up. Toxicity was primarily hematological and digestive. OS was 80% at 5 years. The results obtained in our series are encouraging because second-generation TKIs as second-line therapy allowed treatment of 62% of pts who were intolerant or failing to respond to imatinib with acceptable digestive and hematological toxicity.

CML-475 Real-World Treatment Patterns Among Patients With Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Cycling Through Multiple Tyrosine Kinase Inhibitors (TKIs) in the United States (US)

While TKIs are mainstay therapy for patients with CML-CP, many are refractory/intolerant to treatment. To describe real-world treatment patterns of CML-CP patients receiving third or later lines of therapy (3L+). Retrospective chart review of data collected through online case report forms completed between 03/05/2021-06/14/2021 by physicians from a panel of US oncologists/hematologists treating ≥1 adult with CML-CP who reached 3L+ between 01/01/2013-11/30/2018. In total, 64 physicians (academic: 36%; community: 64%) compiled data for 164 patients in 3L+ (median age: 58; females: 45%; White: 65%; Sokal score: intermediate: 47%, and high: 13%). In 1L (median duration: 13 months), most patients received the first-generation TKI (1G-TKI) imatinib (82%), and 12% received a second-generation TKI (2G-TKI) among which dasatinib was most common (9%). In 2L (median duration: 12 months), 92% received 2G-TKI including dasatinib (47%), nilotinib (31%) and bosutinib (13%). In 3L (median duration: 33 months), 2% received 1G-TKI, 49% 2G-TKI, 41% the third-generation TKI (3G-TKI, ponatinib), and 7% other CML-CP treatments. At data collection, most patients were undergoing 3L (67%), 15 patients were observed with a 4L and 3 with 5L. Main reasons for treatment discontinuation in earlier lines, based on physicians' interpretation, were lack of efficacy (1L: 34%; 2L: 26%), resistance (both 27%), and intolerance (1L: 21%; 2L: 26%). Proportion of patients with last molecular response (MR; achieved and sustained) of MR2 or better was 44% in 1L and 53% in 2L, and MR3 or better was 32% in both lines. Patients mainly cycled from 1G-TKI in 1L to 2G-TKI in 2L (81%), with 46% receiving imatinib and dasatinib in 1L/2L. From 2L to 3L, 46% cycled between 2G-TKIs and 39% switched from 2G-TKI to 3G-TKI. Patients with CML-CP in 3L+ have rapidly cycled between 1G-TKI and 2G-TKI in 1L and 2L. Rates of MR3 did not improve between earlier lines, with lack of efficacy/resistance being the most important reasons for discontinuation; intolerance became more prevalent in 2L. Findings highlight the need for novel therapeutics with improved safety/efficacy to prolong treatment in earlier lines and for patients in later lines who exhaust treatment options quickly.

CML-423 Trial in Progress: A Phase III Study of Asciminib vs an Investigator-Selected Tyrosine Kinase Inhibitor (TKI) in Patients With Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase (CML-CP)

Four TKIs are approved for first-line (1L) use in CML-CP: the first-generation TKI imatinib and the second-generation (2G) TKIs bosutinib, dasatinib, and nilotinib. However, in 1L CML-CP, >50% of patients treated with imatinib develop resistance/intolerance to therapy, and 30%-40% of patients treated with a 2G TKI need to change therapy by 5 years. While 2G TKIs yield a higher major molecular response (MMR) than imatinib, they are associated with more adverse events (AEs). Asciminib is a recently approved BCR::ABL1 inhibitor that targets the ABL1 myristoyl pocket. In the phase III ASCEMBL trial in patients with CML-CP treated with ≥2 prior TKIs, asciminib resulted in improved MMR (25.5% vs 13.2%) at week 24 and fewer treatment discontinuations due to AEs (5.8% vs 21.1%) vs bosutinib. We present a phase III trial evaluating asciminib vs an investigator-selected approved TKI in 1L CML-CP. As of March 28, 2022, 69 patients were randomized and receiving treatment. To assess the efficacy of asciminib vs investigator-selected TKI and asciminib vs imatinib within the stratum of patients who selected imatinib as the prerandomization TKI, via the primary endpoint of MMR at week 48. The study will be positive if either of these objectives is met. This is a multicenter, open-label, randomized, phase III study (NCT04971226). Newly diagnosed adults with CML-CP who have not received prior TKI therapy for CML, except for ≤2 weeks of imatinib, bosutinib, dasatinib, or nilotinib therapy, are eligible. Prior to randomization, patients and investigators will select a prerandomization TKI; 50% of patients who select imatinib and 50% who select a 2G TKI as their prerandomization TKI will be randomized to the investigator-selected TKI arm; the remaining 50% from each group will be randomized to receive asciminib. End of Study (EOS) is 5 years from the last patient first treatment. Asciminib 80mg once daily (QD), or an investigator-selected TKI (imatinib, bosutinib, dasatinib, or nilotinib at their approved doses) until EOS or premature discontinuation. MMR at week 48 is the primary endpoint, with MMR at week 96, safety, and deep molecular responses as secondary endpoints.