Tyrosine Kinase Inhibitor Therapy Research Articles

Skin reactions to tyrosine kinase inhibitors in pediatric patients with chronic myeloid leukemia.

Cutaneous adverse events are commonly reported in adult patients with chronic myeloid leukemia (CML) receiving tyrosine kinase inhibitors (TKIs); however, little is known about the cutaneous reactions in children receiving TKIs for CML. As pediatric patients may require lifelong TKI therapy, it is essential to understand the wide range of potential cutaneous toxicities. We examined all case studies, cohort studies, and clinical trials in PubMed/MEDLINE and Embase that reported cutaneous reactions to first-, second-, and third-generation TKIs in children 18 years or younger with CML. This review article focuses on the TKI drug types and doses, patient demographic characteristics, features of skin reactions, and clinical outcomes.

Treatment patterns in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma post covalent Bruton tyrosine kinase inhibitor treatment: a Japanese claims database study.

Standard treatment has not been established for patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) after discontinuation of covalent Bruton tyrosine kinase inhibitor (cBTKi) therapy. This retrospective, administrative database (Medical Data Vision) study described the patient characteristics, treatment patterns, and factors associated with receiving post-first-cBTKi treatment in Japanese patients with CLL/SLL. Patients aged ≥18 years with confirmed CLL/SLL diagnosis and treated with anti-neoplastic drugs indicated for CLL/SLL between March 2013 and February 2022 were included. Patient characteristics at baseline (first line), first cBTKi exposure (first-cBTKi), post-first-cBTKi treatment received, and the treatment sequence of CLL drugs received first line through third line, were described. Time-to-event analyses used the Kaplan-Meier method. Multivariable logistic regression analysis was used to explore factors associated with receiving post-first-cBTKi treatment among patients who discontinued first-cBTKi treatment. Among 2,424 eligible patients (median age: 72.0 years, 61.9% male), 450 (18.6%) received cBTKi in any treatment line. Among patients treated with cBTKi, 273 (60.7%) discontinued treatment; 56.0% of them (n = 153/273) received subsequent treatment. Median duration of post-first-cBTKi treatment was 2.2 months (95% confidence interval [CI]: 1.8, 3.5). The most common regimens post-first-cBTKi were cBTKi therapy (47.7%), bendamustine-based therapy (17.0%), and venetoclax-based therapy (13.1%). Patients aged <75 years (odds ratio [OR] [95% CI]: 2.0 [1.2, 3.4]) and those who did not receive blood transfusion during cBTKi treatment (OR [95% CI]: 2.3 [1.3, 4.1]) were more likely to receive post-first-cBTKi treatment. In conclusion, Japanese patients with CLL/SLL received various treatments for short duration after first-cBTKi discontinuation.

Relevance and mechanism of STAT3/miR-221-3p/Fascin-1 axis in EGFR TKI resistance of triple-negative breast cancer.

The epidermal growth factor receptor 1 (EGFR) plays a crucial role in the progression of various malignant tumors and is considered a potential target for treating triple-negative breast cancer (TNBC). However, the effectiveness of representative tyrosine kinase inhibitors (TKIs) used in EGFR-targeted therapy is limited in TNBC patients. In our study, we observed that the TNBC cell lines MDA-MB-231 and MDA-MB-468 exhibited resistance to Gefitinib. Treatment with Gefitinib caused an upregulation of Fascin-1 (FSCN1) protein expression and a downregulation of miR-221-3p in these cell lines. However, sensitivity to Gefitinib was significantly improved in both cell lines with either inhibition of FSCN1 expression or overexpression of miR-221-3p. Our luciferase reporter assay confirmed that FSCN1 is a target of miR-221-3p. Moreover, Gefitinib treatment resulted in an upregulation of phosphorylated signal transducer and activator of transcription 3 (p-STAT3) in MDA-MB-231 cells. Using Stattic, a small-molecule inhibitor of STAT3, we observed a significant enhancement in the inhibitory effect of Gefitinib on the growth, migration, and invasion of MDA-MB-231 cells. Additionally, Stattic treatment upregulated miR-221-3p expression and downregulated FSCN1 mRNA and protein expression. A strong positive correlation was noted between the expression of STAT3 and FSCN1 in breast cancer tissues. Furthermore, patients with high expression levels of both STAT3 and FSCN1 had a worse prognosis. Our findings suggest that elevated FSCN1 expression is linked to primary resistance to EGFR TKIs in TNBC. Moreover, we propose that STAT3 regulates the expression of miR-221-3p/FSCN1 and therefore modulates resistance to EGFR TKI therapy in TNBC. Combining EGFR TKI therapy with inhibition of FSCN1 or STAT3 may offer a promising new therapeutic option for TNBC.

Long-term survival and portal vein patency with novel PVTT surgery approach in advanced HCC patients with Vp3/4 PVTT following combination therapy of TKIs and PD-1 inhibitors

BackgroundIt is controversial whether patients with hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT) should undergo salvage surgery following the combination therapy of tyrosine kinase inhibitors (TKIs) and programmed cell death protein 1 (PD-1) inhibitors. This study aimed to elucidate the efficiency and safety of salvage surgery following combination therapy, while also summarizing a novel surgical approach for Vp3/4 PVTT.MethodsBetween April 2019 and December 2022, a consecutive series of unresectable HCC patients with PVTT who received salvage surgery following combination therapy were enrolled. Evaluation included perioperative and long-term follow-up outcomes. The complete removal of Vp3/4 PVTT was achieved using a novel surgical approach characterized by “longitudinal incision and transverse suturing” and “angle-to-straight conversion”.ResultsForty patients including 22 patients with Vp3 and 18 patients with Vp4 were included. Long-term follow-up showed similar rates of portal vein patency (Vp3: 95.5%, Vp4:94.4%, p = 0.900), and 3-year portal vein patency rates were 95.0%. There were no significant differences observed in combination therapy-related adverse events (p = 0.253) and perioperative complications (p = 0.613) between the Vp3 and Vp4 groups. The recurrence patterns were similar between the two groups (p = 0.131). There were no significant differences in overall survival (OS) and recurrence-free (RFS) survival between the Vp3 and Vp4 groups (OS p = 0.457, RFS p = 0.985). Patients who achieved a pathological complete response had significantly better RFS (p = 0.011).ConclusionSalvage surgery after combination therapy demonstrated favorable efficacy and safety. The novel surgical approach for PVTT can effectively achieve complete removal of PVTT and ensured long-term portal vein patency.

Estimated Savings After Stopping Tyrosine Kinase Inhibitor Treatment Among Patients With Chronic Myeloid Leukemia

Patients with chronic myeloid leukemia (CML) who have a sustained deep molecular response using tyrosine kinase inhibitors (TKIs) can safely attempt to stop their use. As these medications are very costly, this change in treatment protocols may result in large savings. To estimate future savings from attempting to stop TKI use among patients with CML who have deep molecular response. A microsimulation model was developed for this decision analytical modeling study to estimate costs for US adults moving from using a TKI, to attempting discontinuation and then reinitiating TKI therapy, if clinically appropriate. Estimates were calculated for US patients who currently have CML and simulated newly diagnosed cohorts of patients over the next 30 years. Attempting to stop using a TKI. Estimated savings after attempted discontinuation of TKI use. A simulated population of individuals with CML in 2018 and future populations were created using estimates from the SEER*Explorer website. The median age at diagnosis was 66 years for men and 65 years for women. Between 2022 and 2052, the savings associated with eligible patients attempting discontinuation of TKI therapy was estimated at more than $30 billion among those currently diagnosed and over $15 billion among those who will develop CML in the future, for a total savings of over $54 billion by 2052 for drug treatment and polymerase chain reaction testing. The estimate is conservative as it does not account for complications and other health care-associated costs for patients continuing TKI therapy. The findings of this decision analytical modeling study of patients with CML suggest that attempting discontinuation of TKI therapy could save over $54 billion during the next 30 years. Further education for patients and physicians is needed to safely increase the number of patients who can successfully attain treatment-free remission.

Assessment of knowledge, attitudes, and practices of CML patients and their families toward TKI therapy in China.

The introduction of tyrosine kinase inhibitors (TKIs) has revolutionized chronic myeloid leukemia (CML) treatment. The knowledge, attitude, and practice (KAP) of patients and their families play a significant role in treatment adherence and effectiveness. This study aimed to investigate the KAP of CML patients and their families regarding TKI therapy in China. From November 1 to December 31, 2022, a cross-sectional study was conducted at the Affiliated Huai'an No. 1 People's Hospital in China. A total of 313 CML patients and 268 family caregivers were selected using convenience sampling. Participants answered a self-designed questionnaire. The questionnaire contained demographic/clinical data and assessed KAP toward CML and TKI therapy. Participants exhibited mean KAP scores of 8.91 (55.7%), 33.10 (73.6%), and 2.20 (73.3%), respectively. Family members had higher knowledge and practice scores than patients (both P < .05), with factors such as younger age, urban residency, higher education, employment, higher income, and interaction with peers correlating with better knowledge scores (P < .001). Although participants were well-informed about their diagnosis and medication (>80%), understanding of disease causes (<30%) and treatment prognosis and side effects (<50%) was limited, and cost concerns affected 80.55%. Anxiety and depression were reported more among caregivers (46.64% and 13.8%) than patients (29.71% and 11.51%). While 84.85% adhered to the doctor's instructions, only 68.50% actively sought more CML information. Positive correlations were observed among KAP scores, indicating their interdependence (knowledge-attitude: R = 0.397; knowledge-practice: R = 0.598; attitude-practice: R = 0.353; all P < .001). The findings underscore the importance of tailored education to fill knowledge gaps about CML and the need to address financial concerns and provide psychological support. The positive correlations among knowledge, attitudes, and practices emphasize the need for comprehensive interventions. In conclusion, this study highlights the importance of tailored education, addresses financial concerns, and provides emotional support for CML patients and caregivers in China, despite limitations such as convenience sampling and questionnaire design. Future research should evaluate the effectiveness of educational interventions and long-term outcomes to further enhance the overall well-being of this population.

Mutation Analysis of Epidermal Growth Factor Receptor Gene in Non-Small Cell Lung Cancer for Selection of Patients Eligible for Tyrosine Kinase Inhibitor Therapy

Introduction: Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor therapy is effective as a first-line treatment of advanced non-small-cell lung cancer (NSCLC). This research study investigated the distribution of EGFR mutations in patients diagnosed with NSCLC to assist in selecting patients who could benefit from tyrosine kinase inhibitor therapy. Materials and Methods: This cross-sectional study was conducted between July 2017 and November 2022. A real-time multiplex ​Polymerase Chain Reaction (PCR) assay supplied by Roche Diagnostics was used to examine DNA obtained from 682 tumor biopsies collected from NSCLC patients. DNA amplification was performed in a Cobas z 480 instrument for mutation analysis. The PCR assay was designed using specific primers and probes to detect 43 different mutations targeting exons 18-21. Results: Among the 682 samples, 466 (68.3%) were males, and 216 were females. The male-to-female ratio was 2.1. Twenty per cent of the male and 37% of the female samples were positive for EGFR mutations. The most common mutations were the in-frame deletion of exon 19, followed by L858R in exon 21, exon 20 insertion and S769I, exon 18 G719X. In addition, three mutations, namely del exon 19, T790M and exon 20 insertions were also detected in a patient, suggesting an actively progressive disease. Conclusions: This study showed that EGFR mutations are more common in Pakistani female patients than males. Secondly, in-frame deletion of exon 19 and exon 21 mutation L858R are prevalent in most of the NSCLC patients. The prevalence of common and rare EGFR mutations in Pakistani patients provides an opportunity for a subset of patients' chance of therapy.

Aleukemic Chronic Myeloid Leukemia Without Neutrophilia and Thrombocytosis: A Report From the BCR::ABL1 Pathology Group

Chronic myeloid leukemia (CML) is characterized by leukocytosis with left-shifted neutrophilia, basophilia, eosinophilia, and variable thrombocytosis. However, extremely rare cases of patients with CML without significant leukocytosis and thrombocytosis (aleukemic phase [ALP] CML, or CML-ALP) have been reported. Due to its rarity and limited awareness, there remains a significant knowledge gap concerning the pathologic diagnosis, disease progression, and optimal patient management and outcomes. In this multi-institutional study, we investigated 31 patients with CML-ALP. Over half (54.8%) of patients had a history of or concurrent hematopoietic or nonhematopoietic malignancies. At time of diagnosis of CML-ALP, approximately 26.7% of patients exhibited neutrophilia, 56.7% had basophilia, and 13.3% showed eosinophilia. The median number of metaphases positive for t(9;22)(q34;q11.2) was 15, with a median of 38.5% of interphase nuclei positive for BCR::ABL1 by fluorescence in situ hybridization. The median BCR::ABL1 level was 26.14%. Remarkably, 14 (45.2%) patients were initially misdiagnosed or not diagnosed before karyotype or fluorescence in situ hybridization information for BCR::ABL1 became available. Twenty-five patients received tyrosine kinase inhibitors (TKIs). One patient developed blast crisis while on TKI treatment 8 months after initial diagnosis. With a median follow-up time of 46.1 months, 20 of 22 patients who received TKI therapy and had detailed follow-up information achieved complete cytogenetic remission or deeper, 15 achieved major molecular remission or deeper, and 10 achieved molecularly undetectable leukemia. In conclusion, given the frequent occurrence of prior or concurrent malignancies, aleukemic presentation, and low level of t(9;22)(q34;q11.2)/BCR::ABL1, misdiagnosis or delayed diagnosis is common among these patients. While these patients generally respond well to TKIs, rare patients may develop blastic transformation. It is therefore important for pathologists and hematologists to be aware of this highly unusual presentation of CML to ensure timely diagnosis and appropriate management.

Progress on the EGFR pathway drives targeted therapy for NSCLC

Epidermal growth factor receptor (EGFR) is a key tyrosine kinase receptor that regulates cell survival, proliferation, division, and differentiation. The mutation of the EGFR gene is one of the most common gene mutations responsible for non-small cell lung cancer (NSCLC). Extensive research has been done in the field. Several key EGFR signaling pathways control cell activity, such as MAPK/EPK, PI3K/Akt/mTOR, and JAK/STAT pathways. Mutation of EGFR can cause abnormal activation of signaling cascades, leading to constant cell growth and division, eventually causing tumor growth. Understanding the function of epidermal growth factor receptor and EGFR signaling pathways contributes to the development of targeted treatment for lung cancer. Therefore, through recent research and analysis on the mechanism of action and related pathways of EGFR, this article finds that EGFR tyrosine kinase inhibitor (TKI), a commonly used drug to treat lung cancer, is one of the most effective treatment and it has high potential. However, resistance to TKIs caused by secondary mutations has become a crucial challenge. Novel generations of TKI and combination therapies are needed.

Abstract B024: KO-2806, a next-generation farnesyltransferase inhibitor, potentiates the antitumor activity of cabozantinib in clear cell renal cell carcinoma models

Abstract Conventional treatments for advanced clear cell renal cell carcinoma (ccRCC) include tyrosine kinase inhibitors (TKI) that target angiogenesis, a critical element for ccRCC tumor growth and survival. Cabozantinib, a TKI that inhibits VEGFR, AXL, and MET, is an approved therapy in advanced RCC. However, cabozantinib has limited therapeutic benefit; for example, patients with prior VEGFR TKI therapy had an overall response rate of 21% and median progression-free survival of 7.4 months. Thus, there is an urgent need to identify combination drug partners that can improve the depth and/or durability of clinical responses to cabozantinib. Here, we present preclinical evidence that supports combining the farnesyltransferase inhibitor (FTI), KO-2806, with cabozantinib in ccRCC. KO-2806 is a next-generation farnesyltransferase inhibitor with increased potency and improved pharmacokinetic properties relative to earlier FTI drug candidates and is poised to enter a first-in-human clinical trial. We demonstrate that addition of KO-2806 enhanced tumor growth inhibition of cabozantinib in multiple ccRCC cell line- and patient-derived xenograft models, resulting in either tumor stasis or regression. Immunohistochemical analysis of angiogenic markers in 786-O tumors revealed that, consistent with its mechanism of action, cabozantinib significantly reduced angiogenesis, an effect that was deepened by KO-2806. In support of this, cell viability experiments performed in primary human endothelial cells showed that the combination of KO-2806 and cabozantinib was more effective in reducing cell viability than cabozantinib alone. In addition, we investigated the mechanism underlying the improved response of tumors with the KO-2806-cabozantinib combination by analyzing the major growth signaling pathways in 786-O tumors. Cabozantinib alone reduced both MAPK and PI3K/AKT/mTOR signaling, but addition of KO-2806 resulted in enhanced inhibition of mTOR signaling and increased cell cycle arrest compared to either agent alone. We hypothesize that exposure to anti-angiogenic TKIs render ccRCC tumors more hypoxic, and thus more reliant on compensatory, oncogenic mechanisms like mTOR signaling that allow them to adapt to a nutrient- and oxygen-deprived environment. Mechanistically, KO-2806 potently inhibits the farnesylation, and hence the activity, of the farnesylation-dependent protein RHEB, a positive regulator of mTOR, suggesting that the improved anti-tumor efficacy of the combination may arise through RHEB inhibition in this model. Further in vitro and in vivo studies are underway to establish the scope and mechanistic underpinnings of the effects of the KO-2806-cabozantinib combination and strengthen the therapeutic rationale for the investigation of this approach in the treatment of patients with ccRCC. Citation Format: Jovylyn Gatchalian, Linda Kessler, Hetika Patel, Stacia Chan, Francis Burrows, Shivani Malik. KO-2806, a next-generation farnesyltransferase inhibitor, potentiates the antitumor activity of cabozantinib in clear cell renal cell carcinoma models [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B024.

Abstract C136: VHL, PBRM1, and BAP1 mutation variants and response to first-line therapies in patients with metastatic clear-cell renal cell carcinoma (mRCC)

Abstract Background VHL, PBRM1, and BAP1 are common mutations in clear-cell renal cell carcinoma (ccRCC). VHL and PBRM1 mutations result in downstream dysregulation of vascular endothelial growth factor receptor (VEGFR) that cause angiogenesis and uncontrolled cell growth. VEGFR tyrosine kinase inhibitors (TKI) are the mainstay of ccRCC treatment. The current first-line (1L) therapies for mRCC include combination anti-VEGFR TKI + anti-PD-1 immune checkpoint inhibitors (CPI), or combination CPI targeting PD-1 and CTLA-4. It is unknown whether VHL and PBRM1 mutations are predictive for response to 1L anti-VEGFR TKI, anti-VEGFR TKI + CPI, or combination CPI immunotherapy. In this retrospective observational study, we evaluated the real-world outcomes of 1L therapies in patients with mRCC with or without VHL, PBRM1, or BAP1 mutations. Methods This study used the nationwide de-identified Flatiron Health-Foundation Medicine RCC clinico-genomic database, originating from approximately 280 cancer clinics (~800 sites of care). Patients with metastatic ccRCC, diagnosed from 8/1996-8/2022, who received 1L therapy with anti-VEGFR TKI, anti-VEGFR TKI + PD-1/PD-L1, or anti-PD-1 + anti-CTLA-4 therapy, and who had comprehensive genomic profiling were included. The primary endpoint was real-world overall survival (rwOS) in mRCC patients with VHL mutations. Secondary endpoints included rwOS and real-world progression-free survival (rwPFS) in patients with BAP1 and PBRM1 mutations, and rwPFS in patients with VHL mutations. The cox proportional hazard model was used to conduct the multivariable analysis adjusting for demographic/clinical factors for rwOS and rwPFS. The Kaplan-Meier method were used to estimate the median survival time. Results149 patients with complete data sets were included, of whom 99 had VHL mutations, 65 had PBRM1 mutations, and 31 had BAP1 mutations. Eight patients (5%) had favorable International Metastatic RCC Database Consortium (IMDC) risk, 110 (74%) had intermediate IMDC risk, and 31 (21%) had poor IMDC risk. The adjusted hazard ratio (HR) for rwOS in patients with VHL mutations compared to those without who received 1L anti-VEGFR TKI, anti-VEGFR TKI + PD-1/PD-L1, or PD-1/PD-L1 + CTLA-4 therapy were 1.53 (95% CI: 0.78-3.00, p=0.221), 0.87 (95% CI: 0.29-2.61, p=0.798), and 1.64 (95% CI: 0.71-3.75,p=0.245), respectively. The median rwOS for patients with PBRM1 mutations who received anti-VEGFR TKI was 50.1 months (95% CI: 34.62-NR) and 30.6 months (95% CI: 19.4-63.2) in patients without PBRM1 mutations (adjusted HR 0.54, 95% CI: 0.29-1.00, p=0.049). The median rwPFS for BAP1 mutations with anti-VEGFR TKI therapy was 5.2 months (95% CI: 3.6-9.1) and 6.4 (95% CI: 4.7-10.8) in patients without BAP1 mutations (adjusted HR 2.45, 95% CI: 1.35-4.44, p=0.003). Conclusion No significant difference was observed in rwOS in mRCC patients with VHL mutations treated with first-line anti-VEGFR TKI, anti-VEGFR TKI + PD-1/PD-L1, or PD-1/PD-L1 + CTLA-4 therapy, compared to patients without VHL mutations. Additional studies are needed to confirm this finding. Citation Format: Jessica Zhu, Junxiao Hu, Elaine T Lam. VHL, PBRM1, and BAP1 mutation variants and response to first-line therapies in patients with metastatic clear-cell renal cell carcinoma (mRCC) [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C136.

Expression of genes potentially involved in loss of response in patients with chronic myeloid leukemia

Chronic Myeloid Leukemia (CML) is a hematological malignancy characterized by the presence of the BCR::ABL1 fusion gene, which leads to uncontrolled cell growth and survival. Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of CML, but a significant proportion of patients develop resistance or lose response to these drugs. Understanding the molecular mechanisms underlying treatment response and resistance is crucial for improving patient outcomes. This study aimed to analyze the expression patterns of genes involved in treatment response and resistance in CML patients receiving TKI therapy. The expression levels of MET, FOXO3, p15, p16, HCK, and FYN genes were examined in CML patients and compared to healthy donors. Gene expression levels were compared between optimal responders (OR) and resistant patients (R) vs. healthy donors (HD). The MET and FOXO3 OR group showed significant differences compared with the HD, (p < 0.0001) and (p = 0.0003), respectively. p15 expression showed significant differences between OR and HD groups (p = 0.0078), while no significant differences were found in p16 expression between the HD groups. FYN showed a statistically significant difference between R vs. HD (p = 0.0157). The results of HCK expression analysis revealed significant differences between OR and HD (p = 0.0041) and between R and HD (p = 0.0026). When we analyzed OR patients with undetectable BCR::ABL1 transcripts, a greater expression of HCK was observed in the R group. These findings suggest that monitoring the expression levels of MET and FOXO3 genes could be valuable in predicting treatment response and relapse in CML patients. Our study provides important insights into the potential use of gene expression analysis as a tool for predicting treatment response and guiding treatment decisions in CML patients. This knowledge may ultimately contribute to the development of personalized treatment strategies to improve patient outcomes in CML.

New Pattern of Emerging Somatic Mutations in Optimal Responders Following Tyrosine Kinase Inhibitor Therapy in Chronic Myeloid Leukemia Patients Evidenced from Mutational Kinetic Analysis Based on Pairwise Comparison

Introduction Recent advances in genomics in chronic myeloid leukemia (CML) patients (pts) provide new insights in understanding somatic mutation (SM) and their prognostic implications following tyrosine kinase inhibitor (TKI) therapy. DNMT3A, TET2, or ASXL1 (DTA) mutations are most frequently detected following TKI therapy and have adverse prognosis. Five longitudinal patterns of changes in SM after TKI therapy were suggested with its clinical significance (Kim, Blood 2017): Pattern 1, persistent mutation burden despite optimal TKI response; Pattern 2, emerging mutation which correlates with TKI resistance/CML progression; Pattern 3, mutational clearance with mixed clinical outcomes; and Pattern 4 and 5 having some mutation in germline control as well as CML cells. Clonal evolution (CE) in Philadelphia negative (Ph -) clone is found in up to 10% of CML pts who respond to TKI therapy optimally but develop +8 or -7 changes in Ph - clone. This is diagnosed only by metaphase cytogenetic test on bone marrow samples. Alternatively, fluorescence in situ hybridization (FISH) test can be used. With recent advances in next-generation sequencing (NGS), we hypothesize that SM profiling can capture a clone carrying a SM in the Ph - population. We sequenced and analyzed mutation profiles in paired samples taken prior to TKI therapy and at longitudinal follow-up. Patients and methods The present study adopted single molecule-tagging and molecular inversion probe (smMIP)-based sequencing methods to analyze the DNA extracted from the mononuclear cell fraction of peripheral blood samples collected from CML pts at initial diagnosis and during follow-up. While conventional NGS has a relatively high intrinsic sequencing error rate and is limited in detecting mutations with a variant allele frequency (VAF) of less than 2%, smMIP-based sequencing overcomes this issue by tracking all sequence reads from a single strand and can detect mutations with a limit of detection up to 0.1%. The in-house CML-specific smMIP panel used in this study included 40 genes with 332 amplicon probes covering genes involved in epigenetic modifiers, activation signaling, myeloid transcription factor, spliceosome, tumor suppressor, cohesion, and miscellaneous functions. To evaluate kinetics of mutations, we calculated doubling time of mutations. Using the mutational VAFs from 2 time points, t1 and t2, the doubling time was calculated according to the following equation: = (-2 -1) log(2) /log(-2) - log(-1), where VAF1 and VAF2 is the VAF of the mutant at time points t1 and t2, respectively. Results We performed targeted deep sequencing on a total of 119 serial samples from 51 CML pts (median of 405.5 days following TKI therapy). 41 pts had an optimal response, 7 were non-responders, and 3 were non-evaluable for response. Pattern 2 was observed in 1 of 7 non-responders. In 12 pts pattern 3 (mutation clearance with mixed clinical outcomes) was observed. 22 pts carried 36 mutations. At baseline 9 pts had somatic mutations. Emergence of somatic mutations in optimal responders was observed in 13 out of total 51 (25%) pts, with DNMT3A (n=5), TET2 (n=4), ASXL1 (n=4), and EZH2 (n=2). While JAK2, SF3B1, U2AF1, PHF6, TP53, BRAF, and CBL were observed in one patient each (Figure 1). Particularly, those with emerging DTA mutation were all optimal responders to TKI therapy. This pattern of mutational change is novel and has never been described before. The median doubling time was 77 days (range 21-1909 days) in the group with emergence of somatic mutation in follow-up samples. The doubling time was 56.1, 93.7, 74.8 days in DNMT3A, ASXL1, and TET2 mutations, respectively. Based on kinetics of mutations (doubling time), to capture 10-fold increase (i.e. 1 log increase) of certain mutation, NGS profile can be monitored every 6-7 months. This pattern of emergence of mutations (mostly DTA mutation) in pts responding optimally to TKI therapy is new and does not fit into the five patterns mentioned in our previous paper (Kim, Blood 2017). Thus, we propose this sixth novel pattern called “Emerging mutational clones in CML pts responding optimally to TKI therapy”. Conclusion We suggest a new pattern of emerging mutations in optimal responders to TKI therapy, which could derive from expansion of Ph- clone carrying some clones with emerging mutations. Longitudinal NGS monitoring in CML patients is feasible with frequency every 6-7 months.

Incremental Healthcare Resource Utilization and Costs Associated with Non-Optimal Treatment in Patients with Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Treated with Tyrosine Kinase Inhibitors (TKI) in Early Lines of Therapy in the United States (US)

Introduction: TKIs are the standard of care for CML-CP. Although effective TKI options are available in early lines of therapy of CML, patients may experience intolerance or resistance to TKI leading to non-optimal treatment (NOPT). This retrospective cohort study assessed the incremental healthcare resource utilization (HRU) and medical costs associated with NOPT in patients with CML treated in first-line (1L) or second-line (2L) TKI therapy in the US. Methods: Adult patients with CML who received 1L TKI therapy with imatinib, dasatinib, nilotinib, or bosutinib (1L cohort), and those who received 2L TKI therapy with imatinib, dasatinib, nilotinib, bosutinib, or ponatinib (2L cohort), in 2012 or later, were selected from the OptumInsight Clinformatics database (01/2007-06/2022). Patients were required to have ≥2 years of continuous health plan coverage post-1L/2L initiation (1L/2L index date). Patients were classified in NOPT subgroup if they met one of the following criteria: 1) treatment discontinuation/switch within the first 6 months post-index, or 2) temporary treatment interruption and/or dose reduction within the first 6 months post-index followed by treatment discontinuation within the first 12 months post-index, or 3) low treatment adherence (proportion of days covered [PDC] ≤50%). Patients were classified in the reference (REF) subgroup if they met one of the following criteria: 1) high treatment adherence (PDC &amp;gt;90%) and no treatment discontinuation, 2) high treatment adherence (PDC &amp;gt;90%) and treatment discontinuation occurring more than 12 months post-index. All-cause HRU (inpatient [IP] admissions, outpatient [OP] visits, and emergency department [ED] visits) and associated medical costs (2022 USD) were measured during the 2 years post-index and reported per-patient-per-year (PPPY). Incremental HRU and costs of NOPT (vs. REF) were estimated using multivariable Poisson regressions and two-part models (adjusted for age, gender, race, region, health plan type, time from CML diagnosis to index date, and Darkow Disease Complexity Index), respectively. Adjusted incidence rate ratios (IRR) and mean cost differences (Δ) were reported along with p-value, estimated using bootstrap technique. All analyses were conducted separately in the 1L and 2L cohorts. Results: Of 2,043 patients that initiated 1L TKI therapy in 2012 or later, 197 patients were included in NOPT subgroup (median age: 69 years; 52.3% female; 68.5% White) and 284 in REF subgroup (median age: 62 years; 40.1% female; 74.6% White). Patients in NOPT subgroup had 80% more IP admissions (adjusted IRR=1.8; p &amp;lt;0.001) with twice more IP days (adjusted IRR=2.0; p=0.024), 30% more OP visits (adjusted IRR=1.3; p=&amp;lt;0.001) in the first 2 years post-index, as compared to REF subgroup. Consistently, patients in NOPT subgroup had higher medical costs (adjusted Δ=$13,551 PPPY; p=0.012) mainly driven by higher IP costs (adjusted Δ =$5,989 PPPY; p=0.028) along with numerically higher OP costs (adjusted Δ=$5,483 PPPY; p=0.060) in the first 2 years post-index, as compared to REF subgroup ( Figure 1). Of 586 patients that initiated 2L TKI therapy in 2012 or later, 69 patients were included in NOPT subgroup (median age: 67 years; 60.9% female; 76.8% White) and 72 in REF subgroup (median age: 68 years; 51.4% female; 69.4% White). Patients in NOPT subgroup had 3 times more IP admissions (adjusted IRR=3.1; p &amp;lt;0.001) with almost 7 times more IP days (adjusted IRR=6.7; p&amp;lt;0.001), 80% more ED visits (adjusted IRR=1.8; p=0.036), and numerically more OP visits (adjusted IRR=1.2; p=0.056) in the first 2 years post-index, as compared to REF subgroup. Consistently, patients in NOPT subgroup had higher medical costs (adjusted Δ=$30,962 PPPY; p=0.008) mainly driven by higher OP costs (adjusted Δ=$8,380 PPPY; p=0.016) and higher ED costs (adjusted Δ=$4,332 PPPY; p=0.012) along with numerically higher IP costs (adjusted Δ=$14,063 PPPY; p=0.100) in the first 2 years post-index, as compared to REF subgroup ( Figure 1). Conclusions: In this study of patients with CML-CP non-optimal treatment resulting in early treatment discontinuation/switch or dose interruptions/reduction in the first 6 months from treatment initiation or low adherence with the currently approved TKIs in 1L and 2L therapy for CML was associated with significant incremental economic burden. This highlights the need for more tolerable therapeutic options early in the treatment course.

Phase 2 Study of Dasatinib with and without Venetoclax in Patients with Early Chronic Phase Chronic Myeloid Leukemia (ECP-CML)

Background Treatment-free remission (TFR) is a therapeutic goal for patients with ECP-CML once patients maintain a deep molecular remission (DMR) on tyrosine kinase inhibitors (TKIs). Only a fraction of patients (pts) achieved sustained (3+ years) molecular remission with 4.0- to 4.5-log reduction (MR4.5). Preclinical studies showed that BCL-2 is a key survival factor for CML stem/progenitor cells. Therefore, the combination of TKIs and venetoclax, targeting BCR::ABL1 and BCL-2, has the potential to significantly improve DMR and subsequently the rates of TFR. The aim of this study is to evaluate the safety and efficacy of the combination. Methods Patients with ECP-CML or accelerated phase (AP; defined by clonal evolution only) were eligible; pts with &amp;lt; 1 month of prior TKI therapy were eligible. Pts received single-agent dasatinib 50 mg/d for the first 3 months. From Month 4 and onwards, venetoclax was administered from Days 1 to 14 each month concomitantly with dasatinib for a total of 3 years. The first 16 patients received venetoclax 200 mg/d, with a rapid ramp-up starting 50 mg on Day 1, then 100 mg on Day 2, then 200 mg daily on Day 3 and onwards. Due to neutropenia observed with continuous dose of venetoclax 200 mg/d, the protocol was ameded: from patient #17 and onwards, venetoclax was administered at 200 mg/d for 14 days per month and upon achievement of MR4.5, venetoclax was reduced to 100 mg/d for 7 days per month. After 3 years of combination, patients received single-agent dasatinib. TFR was offered after ≥ 3 years of DMR. The primary endpoint was the rate of major molecular response (MMR) by 12 months of the combination. The secondary endpoints were the 12-month rate of MR4.5 and the cumulative overall rate of MR4.5; the rates of MR4.5 at 6-, 12-, 18-, 24, and 36-months of the combination; the proportion of patients with sustained MR4.5 of 3 years and more; the TFR rate; overall survival; and the safety of the combination. Cumulative response rates were calculated with treatment failure as a competing event. Failure-free survival (FFS) was calculated from the initiation of therapy to loss of major cytogenetic response (MCyR), transformation to AP or blast phase, discontinuation of therapy for any reason except of TFR, or death. Results Sixty-five pts were enrolled and treated between April 2018 and August 2021. The median age at treatment initation was 46 years (range, 23-73) and 57% of the pts were females. Twenty-one (32%) pts had splenomegaly, 46 (71%) had low Sokal risk disease and 3 (5%) had high Sokal risk disease (Table 1). By 12 months of the combination, 85% of the pts had achieved MMR or deeper response. The median time to MMR, MR4, and MR4.5 were 6.2 months, 13 months, and 23.9 months from the time of TKI start, respectively. After a median follow-up of 25.7 months (range, 8.7-48.1), two pts discontinued therapy due to adverse events (GI intolerance, and pleural effusion); the 2 -year FFS was 96%. One pt switched TKI therapy due to the lack of 18-month complete cytogenetic response (CCyR); no loss of CCyR, transformation, or death was observed. We then compared the outcomes with the combination to the outcomes of 85 pts treated with single-agent dasatinib. From the start of TKI therapy, the 12-month cumulative MMR rates were 78% and 79% in the dasatinib single-agent and dasatinib + venetoclax groups, respectively. The cumulative 24-month rates of CCyR, MMR, MR4, and MR4.5 are summarized in Table 2. In the dasatinib single-agent group, 3 pts switched TKI therapy due to the lack of 12-month MCyR, 18-month CCyR, and the acquisition of ABL1 mutation (1 each); 3 pts switched TKI therapy due to loss of CCyR; 2 pts died during therapy (deaths unrelated to CML). Within one year of therapy, the incidence of grade 1/2 neutropenia (absolute neutrophil count, below lower range of normal to 1,000 x10 9/L) was 21% and 52% in the dasatinib single agent and dasatinib + venetoclax groups, respectively ( P&amp;lt;0.001); the incidence of grade 3/4 neutropenia (absolute neutrophil count, below 1,000 x10 9/L) was 8% and 17%, respectively ( P&amp;lt;0.001). There was no incidence of neutropenic fever in the dasatinib + venetoclax. Conclusion The combination of dasatinib 50 mg/d and venetoclax is safe and effective in pts with ECP-CML. With a median follow-up of 2 years, the cumulative resposne of dasatinib + venetoclax is similar to that of dasatinib single-agent without adding significant toxicities. Further follow-up is needed for the evaluation of TFR.

The Efficacy and Safety of Olverembatinib Combined with Monoclonal Antibodies As Salvage Therapy for RR B ALL with ABL1 Fusion Gene Positive

Background: B cell acute Lymphoblastic Leukemia （B ALL） with ABL1 fusion gene(FG) positive（ABL1+B ALL） is classified as Ph or Ph like ALL and has a poor prognosis. With the therapy of tyrosine kinase inhibitors(TKI)CD19- or CD22-specific chimeric antigen receptor (CAR) T-cell therapy,more patients(pts)can achieve complete remission(CR) even relapsed after hematopoietic stem cell transplantation(HSCT). However, the pts relapsed/recurrence（RR）after HSCT /CART/ TKIs even ponatinib or cannot receive CART due to any reason have the worst prognosis. Recently, such pts have new hope with the wide application of a novel third-generation TKI Olverembatinib developed in China and Blinatumomab（CD19 antibody,BITE）and INOTUZUMAB OZOGAMICIN(CD22 antibody,Ino.). Aims: Observe the efficacy and safety of Olverembatinib combined with BITE or INO. therapy in RR ABL1+B ALL pts after chemotherapy combined with TKI or CART or even after transplantation. Methods: Four RR ABL1+B ALL pts received Olverembatinib with BITE or INO from June 2022 to July 2023. During treatment, the dose of Olverembatinib was adjusted and chemotherapy or veneclax may be given at the same time,and give appropriate treatment depending on the patient's condition.After treatment, efficacy was assessed by complete remission (CR) rate, minimal residual disease(MRD)neg (&amp;lt;0.01%) rate by MFC and complete molecular remission(CMR )(FG transcript&amp;lt;10-5) rate by real-time quantitative polymerase chain reaction (RT-qPCR). Results:Four pts were male, the median age was 45 (range13-72) years, 3 pts were BCR-ABL1 FG positive, 1 pts was AML1-ABL1 FG positive. Before treatment,3 pts presented with 5.5%-35.5% leukemic blasts in bone marrow（BM） and only 1 pts was MRD positive by MFC.And all pts's leukemic cell showed CD19 and CD22 expression confirmed by MFC.2 pts did not undergo HSCT: both them have T315I mutation occurred during disease progression. Pts 1 was 72 years and relapsed after chemotherapy combined with TKI( include ponatinib);Pts 2 was 61 years and relapsed after chemotherapy, TKI( include ponatinib), venetoclax ,BITE and CD19-CART CD22-CART treatments. 2 pts were eventually treated with Olverembatinib combined with INO. and chemotherapy and venetoclax. The other two pts relapsed after HSCT: neither of them had T315I mutation.Pts 3 was 29 years and had recurrence after chemotherapyTKIvenetoclax HSCT and three times CART. Pts 4 was 13 years and had reccurence after chemotherapyHSCTthree times CART and TKI( include ponatinib)venetoclax DLI. 2 pts were eventually treated with Olverembatinib combined with BITE and venetoclax.All pts survived safely and achieved CR:3 pts CMR,1 pts MRDneg by MFC and BCR::ABL1:0.0023%. Pts.2 bridged HSCT;pts.3 and 4 continued oral Olverembatinib combined with venetoclax. The longest follow-up time for 3 pts was one year nearly until today. Unfortunately, pts 1 died due to a secondary fungal infection post-COVID-19 and recurrence of ALL. Conclusions:For heavily treated RR ABL1+B ALL pts,including those after treatment with ponatinib and other TKICART and HSCT, Olverembatinib combined with monoclonal antibodies is effective and safe. In my cases, it is particularly noteworthy that one pts ,Ph like ALL with ABL1 FG, received Olverembatinib combination BITE and achieved a surprising response, so Olverembatinib may also be effective and safe for such pts. In addition, venetoclax may be used as a sensitizer for TKI or other antitumor drugs. Of course, the above needs more clinical practice to verify.

Acute heart failure following pazopanib treatment: a literature review featuring two case reports.

Tyrosine kinase inhibitors (TKIs) have transformed cancer treatment but are associated with cardiovascular toxicity, including heart failure. This review examines the cardiotoxicity of pazopanib, a VEGFR-TKI, through two case reports and explores potential mechanisms. The importance of vigilant clinical monitoring to prevent cardiac dysfunction in cancer patients receiving pazopanib is emphasized. We present two cases of acute heart failure following pazopanib treatment. Case 1 involves a comorbidity-free, 62-year-old woman with metastatic renal cell carcinoma who experienced irreversible heart failure. In case 2, a 40-year-old woman with a history of anthracycline-containing chemotherapy developed reversible left ventricular systolic dysfunction following pazopanib discontinuation. Both patients received appropriate management for their heart failure symptoms. Case 1's condition rapidly deteriorated, leading to her unfortunate demise 3 months after starting pazopanib. In contrast, case 2's cardiac function improved after discontinuing pazopanib. The advent of TKIs has revolutionized cancer treatment, but their association with cardiovascular toxicity necessitates meticulous monitoring of patients. The cases presented here highlight the importance of recognizing and managing cardiotoxicity, particularly in patients without prior cardiovascular risk factors. Understanding the underlying mechanisms and risk factors for TKI-induced heart failure is crucial to optimize patient care and treatment outcomes. Oncologists should be vigilant in identifying clinical symptoms and closely monitoring cardiac function throughout TKI therapy.

Restoration of Mir-185 in Combination with BCR-ABL Downregulation By Therapeutic Delivery of siRNA with Lipid Nanoparticle Carriers Targets Drug Resistant Leukemic Stem/Progenitor Cells

Background: Despite development of effective tyrosine kinase inhibitors (TKIs) for chronic myeloid leukemia (CML), TKI therapy is not curative as some patients develop drug resistance or are at risk of disease relapse. Importantly, CML leukemic stem cells (LSCs) remain largely unresponsive and represent a key population for sustaining disease and relapse. We previously demonstrated that miR-185 levels were significantly reduced in CD34 + stem/progenitor cells from TKI-nonresponders compared to TKI responders. Further, restoration of miR-185 levels in CML LSCs and their progenitors impaired their survival and sensitized them to TKI in vitro and in vivo. However, the therapeutic potential of downregulating BCR-ABL using siRNA in combination with miR-185 mimic treatment to target CML LSCs have yet to be elucidated. Objective: Downregulation of BCR-ABL using siRNA represents a promising therapeutic approach to inhibit its kinase and non-kinase functions to combat drug-resistant CML and overcome limitations of current therapy. Additionally, previous work suggests that restoring miR-185 levels may improve therapeutic outcomes from complimentary therapies in CML, particularly in combination with BCR-ABL inhibition. Therefore, we aim to investigate the therapeutic outcomes and mechanism of action of inhibiting BCR-ABL using siRNA in combination with miR-185 mimic treatment in drug-resistant CML. Methods: To assess the effects of BCR-ABL downregulation in combination with miR-185 restoration, we encapsulated siRNA targeting BCR-ABL and a miR-185 mimic using an optimized lipid nanoparticle (LNP) formulation. Biological effects and mechanistic changes of this novel RNA combination was evaluated using various CML cell lines expressing b2a2, b3a2, T315I mutated BCR-ABL and CD34 + stem/progenitor cells from non-responder patients. Results: A total of 7 siRNA sequences targeting various fusion regions of BCR-ABL were designed and tested to effectively target primitive CML cells. The highest performing BCR-ABL siRNA encapsulated showed significant knockdown in various CML models expressing b2a2, b3a2 and T315I mutated BCR-ABL (65-99% knockdown). After 48 hours of 0.5 μg/mL BCR-ABL siRNA LNP treatment, BCR-ABL protein levels and its direct downstream target p-CrkL are undetectable by immunoblotting. The robust downregulation of BCR-ABL results in a dose-dependent decrease in cell viability (down to 28% and 9.4% viable cells at a dose of 1 μg/mL) and increase in apoptotic cells (70% and 78% Annexin-V positive) in imatinib resistant K562 and T315I mutated cells, respectively after 72 hours. Similarly, encapsulated miR-185 mimic downregulates its main downstream target PAK6 transcript levels down to 50% in drug sensitive and drug-resistant cell lines and in TKI nonresponder CD34 + stem/progenitor cells. More importantly, our RNA LNP formulation demonstrated significant uptake (&amp;gt; 80% Cy5 positive) of fluorescent-labelled siRNA in TKI nonresponder CD34 + stem/progenitor cells and decreased BCR-ABL mRNA transcript levels by 60%. The combined BCR-ABL inhibition and miR-185 mimic treatment were determined to be highly synergistic when analysed using the Chou-Talalay (combination index less than 1), ZIP, Bliss and HSA methods (synergy scores larger than 10) in both drug-sensitive and drug-resistant CML cells. Furthermore, treatment of BCR-ABL siRNA and miR-185 using LNPs decreased the colony forming units of nonresponder patient cells by 50%. Interestingly, this effect was further enhanced when combined with TKIs, decreasing colony forming units to 20% compared to control after 14 days. Conclusion: We have uncovered a LNP formulation that is able to effectively deliver therapeutic BCR-ABL siRNA and miR-185 mimic into primitive CML cells. This combination treatment significantly reduces the levels of oncogenic BCR-ABL and PAK6, decreasing the viability clonogenic potential and increases apoptosis in CML cell line models and primary patient cells. Importantly, this combination strategy overcomes TKI resistance in CD34 + stem/progenitor cells suggesting a feasible and effective model for patients suffering from clinical resistance and relapse.

Improvement of Treatment-Free Remission Rate Following Discontinuation of BCR::ABL1 Tyrosine Kinase Inhibitors in Chronic Phase, Chronic Myeloid Leukemia

Backgrounds: Several studies have shown that approximately one-half of patients with chronic phase chronic myeloid leukemia (CP-CML) who receive sufficient tyrosine kinase inhibitors (TKIs) and achieve and maintain a deep molecular response (DMR) are able to successfully discontinue therapy. The main factors affecting Treatment free remission (TFR) are the duration of TKIs treatment and the duration of DMR maintenance during TKI treatment. Aims: To investigate impact of longer duration of DMR, we analyzed the outcome of patients with CP-CML who maintained DMR for more than 6 years during TKIs treatment and discontinued TKIs. The clinical and molecular immunological application criteria were also investigated for safer and more successful TFR. Methods: Among patients newly diagnosed with CP-CML and treated at least one of TKIs (Imatinib, Nilotinib, Dasatinib, Bosutinib, and Radotinib) as the first treatment, patients who maintained MR4.5 (BCR::ABL1 IS ≤0.0032%) continuously for at least 6 years through qRT-PCR tests were enrolled in this study. After discontinuation, molecular responses were monitored for up to six months per month, up to 12 months every two months, and every three months thereafter using the qRT-PCR method. In the case of relapse, defined as loss of major molecular response (MMR), the last TKI therapy was reintroduced and molecular responses after resumption were monitored monthly until achievement of MMR using qRT-PCR. Results: Altogether 116 patients (50 males and 66 females) discontinued TKI. Median age at diagnosis was 43.0 years (range, 40.8-45.3) and the percentages of patients with low, intermediate and high Sokal risk scores ware 58 (50.0%), 35 (30.2%) and 18 (15.5%) patients, respectively with unknown Sokal risk scores in 5 (4.3%) patients. Prior to discontinuation, all patients received TKIs for a median of 120.6 months (range, 113.9-127.3), and the duration of sustained MR4.5 was 75.0 months (range, 70.7-79.3). At the time of discontinuation, 93 patients (80.2%) were receiving their first TKI (70 imatinib, 13 nilotinib, 6 radotinib, and 4 dasatinib) while 13 (11.2 %) and 10 (8.6%) patients were receiving their second and more than three TKIs respectively. All patients who received more than one TKI had changed to adverse events. After a median follow-up from treatment discontinuation of 42.2 months (range, 35.3-49.1), 28 (24.1%) patients have lost their response at a median of 8.4 months (range, 4.9-11.9) after discontinuation; 18 (64.3%) patients had molecular relapse within 6 months of TKI discontinuation and 7 (25.0%) patients lost MMR after 12 months from discontinuation. TFR rates at 12, 24, and 48 months were 81.9%, 76.0%, and 71.0%, respectively. No progression toward advanced-phase CML occurred, and when 28 patients who lost MMR were retreated with same TKI, 26 patients (92.9%) re-achieved MMR with a median of 5.6 months (range, 4.0-7.2). By univariate analysis, a TKI treatment duration of 10 years or more was the only significant predictor for maintained response (P&amp;lt;0.048). Conclusion: Our result demonstrates that TFR rate can be improved in patients who received TKI treatment for approximately 10 years and maintained DMR for more than 6 years regardless of the type of TKI. Based on results, we can confirm one of important factors for safer TFR in CP-CML patients.

Propensity Score Matching Comparing Asciminib Versus Ponatinib in Chronic Myeloid Leukemia Patients Who Failed Prior Tyrosine Kinase Inhibitor Therapy

Background ASCEMBL trial has demonstrated superior efficacy of Asciminib (ASC) over Bosutinib in terms of molecular response, and event-free survival. Furthermore, ASC could reduce discontinuation rates due to lower occurrences of adverse events (7% vs 25%). However, it remains to be established how ASC would compare to Ponatinib (PON), which is frequently used in chronic myeloid leukemia (CML) practice for patients (pts) failing multiple lines of tyrosine kinase inhibitor (TKI) therapy. No prospective study has been performed or is ongoing comparing ASC vs PON, but alternatively, observational data can provide valuable insight on this topic. The propensity score is the probability of therapy assignment conditional on observed baseline characteristics. We performed a propensity score matching (PSM) analysis to balance the variables affecting the treatment choice among ASC vs PON therapy. The present study aimed to compare the therapeutic efficacy of ASC to PON in CML pts who failed prior TKIs concerning molecular response, failure-free survival (FFS), progression, and overall survival (OS). Patients and methods A total of 426 CML pts who had been treated with ASC or PON in 6 countries (Canada, Netherlands, Czech Republic, France, Argentine, and Italy) were included. In this preliminary report, data from 394 pts were analyzed. Primary endpoint was FFS at 1 year which was defined as the interval from TKI therapy start until treatment failure or death. Treatment outcomes were assessed for molecular response and long-term outcomes such as MR2 (BCR::ABL1 &amp;lt;1%IS or molecular response 2 log or deeper), MMR (BCR::ABL1 &amp;lt;0.1%IS or molecular response 3 log or deeper), MR4 (BCR::ABL1 &amp;lt;0.01%IS or molecular response 4 log or deeper), FFS, Progression, and OS. These parameters were evaluated in the overall population (n=394), resistant (n=254), or intolerant subgroups (n=126), T315I mutated (n=89) or non-T315I mutated subgroups (n=304), those having a past history of cardiovascular disease (CVD) (n=89) or not (n=304). For propensity score calculation, the following pre-treatment variables were selected using a binary logistic regression model: age, history of cardiovascular disease (CVD), disease phase, T315I mutation, and reason for failure to prior TKI line. 160 pts (i.e. 80 case-control pairs) were finally extracted through the PSM process within 0.2 of caliper difference. Results Significant differences were observed in various factors between ASC vs PON group, such as age (p&amp;lt;0.01), past history of CVD (p&amp;lt;0.01), previous TKI lines (p&amp;lt;0.01), presence of mutations (p=0.034), and reason for failure to prior TKI line (p&amp;lt;0.01). These differences ceased to exist when PSM was applied (Table 1). In the overall population, at 12 months, FFS was 46.7%, 95%CI [40.0-52.0%], MR2 62.6% [57.1-67.6%], MMR 44.7% [39.2-50.1%], MR4 28.6% [23.9-33.6%]), and OS 88.1% [84.1-91.1%]. In the overall population, PON group showed a lower FFS than ASC group (HR of PON 1.61, 95%CI [1.14-2.28], p=0.006), but, this difference was no significant when limited to the PSM selected pts. Figure 1 illustrates FFS in Asciminib vs Ponatinib-treated patients. In a subgroup of pts without T315I mutation, those on ASC showed higher FFS (HR of PON 1.82, [1.21-2.71], p=0.003), higher MR2 rate (HR of PON 0.69, [0.511-0.94], p=0.020), and higher MMR rate (HR of PON 0.677, [0.47-0.97], p=0.035). Additionally, in a subgroup of pts with a history of CVD those on ASC showed higher FFS (HR of PON 2.21, [1.19-4.10], p=0.011). Also, in pts in the chronic phase, ASC group showed higher FFS (HR of PON 1.77, [1.18-2.65], p=0.005), MR2 rate (HR of PON 0.73, [0.55-0.97], p=0.032), and MMR rate (HR of PON 0.71, [0.52-0.99], p=0.047). In the PSM balanced population, only MR2 rate was found to be significantly higher in favor of ASC (HR of PON 0.6, [0.39-0.93], p=0.022), while no significant differences were observed in all the other endpoints of interest. Conclusion From our current preliminary results, it can be established that ASC has at least equal efficacy to PON regarding FFS, MMR, MR4, progression, and OS which was confirmed in a PSM cohort. These findings contribute valuable insights to the understanding of ASC and PON treatments in pts with specific disease characteristics and may have implications for personalized therapy decisions in the absence of clinical trials comparing these drugs. Our aim is to expand our PSM cohort.