Positive Chronic Myeloid Leukemia Research Articles

FDA Approval Summary: Asciminib for Ph+ CML in Chronic Phase Treated with Two or More Tyrosine Kinase Inhibitors and for the T315I Mutation.

On October 29, 2021, FDA granted accelerated approval to asciminib (Scemblix; Novartis), a tyrosine kinase inhibitor (TKI), for the treatment of adult patients with Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase (CP), previously treated with two or more TKIs, and granted traditional approval to asciminib for adult patients with Ph+ CML in CP with the T315I mutation. The first indication was approved based on major molecular response (MMR) at 24 weeks in the ASCEMBL Study, a randomized trial comparing asciminib with bosutinib in patients who had failed two or more TKIs. This indication was ultimately granted traditional approval on October 12, 2022, based on safety data and MMR rate at 96 weeks of 38% (95% CI: 30, 46) in the asciminib arm vs. 16% (95% CI: 8, 26) in the bosutinib arm (p-value: 0.001). The second indication was approved based on MMR rate by 96 weeks of 49% (95% CI: 34, 64) in the single-arm CABL001X2101 Study. The most common (≥20%) adverse reactions included upper respiratory tract infections, musculoskeletal pain, headache, fatigue, nausea, rash, and diarrhea. The most common (≥20%) laboratory abnormalities were thrombocytopenia, neutropenia, anemia, lymphopenia, hypertriglyceridemia, hyperuricemia, increases in creatine kinase, ALT, AST, lipase, and amylase. This manuscript describes the basis for approval of these indications.

Chronic myeloid leukemia with e6a2 fusion gene: a case report and literature review

Chronic myeloid leukemia (CML) with e6a2 transcript type is very rare in clinic,which is usually related to disease aggressiveness. Its clinical characteristics and relationship with tyrosine kinase inhibitor efficacy are still unclear. In this paper, the clinical characteristics and related laboratory tests of a patient with e6a2 fusion gene positive CML characterized by multiple osteolytic bone destruction throughout the body and eosinophil infiltration in gastrointestinal tract, lymph nodes and other organs were retrospectively analyzed, and the relevant literature was reviewed. The patient was Ph chromosome positive with chromosome +8, and the common BCR::ABL1 transcript of CML was negative, but e6a2 transcript was positive detected by RT-PCR. The patient was treated with dasatinib 100 mg/d. Three months later, the patients achieved CHR, CCyR and MR4.0. However, the e6a2 transcript is very rare in clinical practice, and more cases of e6a2 transcript need to be studied to clarify its clinical characteristics and improve the treatment effect of these rare cases.

Efficacy and safety of bosutinib in patients treated with prior imatinib and/or dasatinib and/or nilotinib: Subgroup analyses from the phase 4 BYOND study

The BYOND study evaluated the efficacy and safety of bosutinib 500 mg once daily in patients with chronic myeloid leukemia (CML) resistant/intolerant to prior tyrosine kinase inhibitors (TKIs). These post-hoc analyses assessed the efficacy and safety of bosutinib by resistance or intolerance to prior TKIs (imatinib-resistant vs dasatinib/nilotinib-resistant vs TKI-intolerant), and cross-intolerance between bosutinib and prior TKIs (imatinib, dasatinib, nilotinib), in patients with Philadelphia chromosome–positive chronic phase CML. Data are reported after ≥3 years’ follow-up. Of 156 patients with Philadelphia chromosome–positive chronic phase CML, 53 were imatinib-resistant, 29 dasatinib/nilotinib-resistant, and 74 intolerant to all prior TKIs; cumulative complete cytogenetic response rates at any time were 83.7%, 61.5%, and 86.8%, and cumulative major molecular response rates at any time were 72.9%, 40.7%, and 82.4%, respectively. Of 141, 95, and 79 patients who received prior imatinib, dasatinib, and nilotinib, 64 (45.4%), 71 (74.7%), and 60 (75.9%) discontinued the respective TKI due to intolerance; of these, 2 (3.1%), 5 (7.0%), and 0 had cross-intolerance with bosutinib. The response rates observed in TKI-resistant and TKI-intolerant patients, and low cross-intolerance between bosutinib and prior TKIs, further support bosutinib use for patients with Philadelphia chromosome–positive chronic phase CML resistant/intolerant to prior TKIs. Trial registrationClinicalTrials.gov: NCT02228382

Co-occurrence of JAK2-V617 F mutation and BCR::ABL1 translocation in chronic myeloproliferative neoplasms: a potentially confounding genetic combination.

Myeloproliferative neoplasms (MPNs) are classified into Philadelphia (Ph) chromosome-positive chronic myeloid leukemia (CML) and Ph-negative MPNs. BCR::ABL1 translocation is the key genetic event of CML, whereas JAK2/MPL/CALR mutations are molecular aberrations of Ph-negative MPNs. Despite initially considered mutually exclusive genetic aberrations, the co-occurrence of BCR::ABL1 and JAK2 has been reported in a limited number of cases. The two genetic alterations may be identified either at the same time or JAK2 aberration may be detected in patients with a previous CML treated with tyrosine kinase inhibitors or, finally, BCR::ABL1 translocation occurs in patients with a history of JAK2-positive MPN. This combination of genomic alterations is potentially confounding with clinical manifestations often misinterpreted either as disease progression or drug resistance, therefore leading to inappropriate patient's treatment. Our systematic review aims to improve hematologist and pathologist knowledge on this rare subset of patients. Starting from the presentation of two additional cases from our routine daily practice, we focus mainly on clinical, laboratory, and bone marrow histological findings, which may represent useful clues of BCR::ABL1 and JAK2 co-occurrence. The interaction between JAK2 and BCR::ABL1 clones during the disease course as well as therapy and outcome are presented.

The study of the impact of additional chromosomal aberrations and c-MYC and BCR::ABL1 genes amplification on CML patient’s characteristics: relation to haematological parameters and patient outcome

BackgroundChronic myeloid leukaemia is characterised by genetic instability which results in additional cytogenetic aberrations that have been linked to progression to advanced phase. Genomic study linked amplified genes in the form of c-MYC and/or the rare BCR::ABL1 genes amplification to chronic myeloid leukaemia. The effect of these genes’ amplification on patients’ characteristics and disease progression still needs further study.This cross-sectional study aimed to investigate the frequency of additional chromosomal aberrations in addition to c-MYC and BCR::ABL1 genes amplification in chronic myeloid leukaemia patients and their impact on patient’s characteristics, disease progression, and level of remission. The study included cytogenetic analysis of 49 Philadelphia positive chronic myeloid leukaemia patients and investigation of c-MYC and BCR::ABL1 genes amplification by fluorescence in situ hybridization.ResultsPatients with additional chromosomal aberrations represented 36.7% and had significantly lower platelet count (P = 0.003) and higher blast count (P = 0.008). The acquisition of additional chromosomal aberrations was significantly higher in chronic myeloid leukaemia patients with advanced stages (P = 0.014). Follow-up of the patients for 6 months revealed significant higher frequency of additional chromosomal aberrations in patients with failure of remission (P < 0.0001). A highly significant association between cases with failure of molecular remission (P = 0.001) and co-existing additional chromosomal aberrations.Amplification of the c-MYC gene was detected in 6 cases. The cases with c-MYC amplification showed significantly higher peripheral blood and bone marrow blasts (P = 0.029 and P = 0.008, respectively) and significantly lower platelet count (P = 0.044). Amplification of c-MYC was significantly associated with additional chromosomal aberrations (P = 0.011). Molecular remission was not achieved in any of the instances with c-MYC amplification. A highly significant association between c-MYC amplification and poor patient outcome was detected (P = 0.002). BCR::ABL1 amplification was detected in three cases, and ABL amplification was detected in four cases. Patients with BCR::ABL1 amplification showed significantly higher blast count. BCR::ABL1 amplification was significantly associated with disease progression and failure of molecular remission (P = 0.002).ConclusionAdditional chromosomal aberrations, c-MYC amplification, and BCR:ABL1 amplification in chronic myeloid leukaemia stratify patients with disease progression, which may lead to better interventions and improved outcome in the future chronic myeloid leukaemia patients.

Dasatinib induced nephrotic range proteinuria in pediatric patient with acute lymphoblastic leukemia with hyper-eosinophilia

Tyrosine kinase inhibitors (TKIs) have improved outcomes for Philadelphia chromosome positive acute lymphoblastic leukemia (ALL) and chronic myeloid leukemia (CML). There has been reports of dasatinib induced proteinuria or nephrotic syndrome. We present a case of a 14-year-old male with high-risk B- ALL who developed nephrotic syndrome due to dasatinib. Proteinuria and nephrotic syndrome should be considered as related adverse effects from dasatinib. This is the first reported case of dasatinib induced nephrotic range proteinuria in a patient with high-risk B-ALL with hyper-eosinophilia.

Physiologically Based Pharmacokinetic Modeling of Nilotinib for Drug-Drug Interactions, Pediatric Patients, and Pregnancy and Lactation.

Nilotinib is a second-generation BCR-ABL tyrosine kinase inhibitor for the treatment of Philadelphia chromosome-positive chronic myeloid leukemia in both adult and pediatric patients. The pharmacokinetics (PK) of nilotinib in specific populations such as pregnant and lactating people remain poorly understood. Therefore, the objectives of the current study were to develop a physiologically based pharmacokinetic (PBPK) model to predict nilotinib PK in virtual drug-drug interaction (DDI) studies, as well as in pediatric, pregnant, and lactating populations. The nilotinib PBPK model was built in PK-Sim, which is part of the free and open-source software Open Systems Pharmacology. The observed clinical data for the validation of the nilotinib models were obtained from the literature. The model reasonably predicted nilotinib concentrations in the adult population; the DDIs between nilotinib and rifampin or ketoconazole in the adult population; and the PK in the pediatric, pregnant, and lactating populations, although in the latter 2 populations plasma concentrations were slightly underestimated. The ratio of predicted versus observed PK parameters for the adult model ranged from 0.71 to 1.11 for area under the concentration-time curve and 0.55 to 0.95 for maximum concentration. For the DDI, the predicted area under the concentration-time curve ratio and maximum concentration ratio fell within the Guest criterion. The current study demonstrated the utility of using PBPK modeling to understand the mechanistic basis of PK differences between adults and specific populations, such as pediatrics, and pregnant and lactating individuals, indicating that this technology can potentially inform or optimize dosing conditions in specific populations.

Asciminib - ABL Kinase Inhibitor in the Treatment of Philadelphia Chromosome Positive Chronic Myeloid Leukemia: Chemistry and Pharmacology Perspectives

Abstract: Asciminib, also known as ACP-196, is the FDA-approved low-molecular ABL kinase inhibitor. The ABL kinase is a non-receptor tyrosine kinase that helps in cell growth and survival and is a key player in the development of chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL). The BCR-ABL fusion protein, which is formed by chromosomal translocation in CML and Ph+ ALL, results in the constitutive activation of ABL kinase, leading to uncontrolled cell growth and proliferation. To have a high binding affinity for the active site of the enzyme, structural biology and computer-aided drug design (CADD) concepts were applied to the design of asciminib so that it could specifically target the ABL kinase enzyme. The drug was synthesized and characterized in a laboratory. In its pharmacological studies, it has shown that asciminib is a potent and selective inhibitor of ABL kinase. Phase I clinical trials assessed its safety and efficacy, revealing that it is effective against tumors while causing minimal discomfort to patients. In addition to this, it was able to induce apoptosis and a cytogenetic response as well as inhibit the proliferation of CML and Ph+ALL cells in patients with CML. As this trial gave a positive response, phase II and III trials were conducted. In that sense, asciminib has shown to be highly effective, with response rates of over 90% in patients with these diseases. The safety and efficacy of asciminib were also evaluated in combination with other drugs, such as tyrosine kinase inhibitors and immunomodulatory drugs, and the results were promising. Overall, the discovery and development of asciminib showed that by using the concepts of pharmacology and CADD, a drug with a 90% positive rate response can be developed with a high tolerance level and lower side effects

Outcome of Philadelphia chromosome-positive chronic myeloid leukemia in the United States since the introduction of imatinib therapy-The Surveillance, Epidemiology, and End Results database, 2000-2019.

Since the introduction of BCR::ABL1 tyrosine kinase inhibitors (TKIs) in 2000, the treatment of Philadelphia chromosome (Ph)-positive chronic myeloid leukemia (CML) has improved significantly. This study aimed to evaluate Ph-positive CML outcomes in the TKI therapy era, considering factors like age, ethnicity, and income. Using the Surveillance, Epidemiology, and End Results (SEER) database, 2857 patients with Ph-positive CML diagnosed from 2000 to 2019 were analyzed. The overall 5-year survival rates in Ph-positive CML increased to above 80%, compared with pre-TKIs historical data reporting 5-year overall survival (OS) rates of less than 50%. The 5-year OS rate was 73% for patients diagnosed in 2000-2004, 82% in 2005-2009, and 78% in 2010-2014; the 4-year OS rate was 83% in 2015-2019. The 5-year OS rate for younger patients (<60years old) was 88% in 2000-2009 and 90% in 2010-2019 (p value .426). In older patients (60+ years old), the 5-year OS rates were 64% and 65%, respectively (p value, .303). Lower household income was associated with inferior survival across the 2000-2019. These results are inferior to European studies where TKIs are universally available and affordable, and relative OS in CML is similar to age-matched normal populations. Although the outcome of Ph-positive CML has improved significantly since 2000, the SEER data still shows differences in outcomes among patient subsets, some anticipated (worse OS in older patients accounted by the relative OS), but others that suggest less than universal access and affordability of this therapy (among poorer patients) in the United States.

The long-term efficacy and safety of nilotinib in pediatric patients with CML: a 5-year update of the DIALOG study

AbstractThe efficacy and safety of nilotinib in pediatric patients with imatinib/dasatinib resistant/intolerant (R/I) or newly diagnosed (ND) Philadelphia chromosome–positive (Ph+) chronic myeloid leukemia in chronic phase (CML-CP) was demonstrated in the phase 2, open-label DIALOG study. In this final analysis, long-term efficacy and safety are presented for patients who completed 66 cycles (of 28 days) of treatment with nilotinib (230 mg/m2 twice daily) or discontinued early. Overall, 59 patients were enrolled and 58 were treated (R/I, n = 33; ND, n = 25; median time on treatment: 60.5 and 51.9 months, respectively). In the R/I cohort, the cumulative major molecular response (MMR; BCR::ABL1 international scale [IS] ≤ 0.1%) rate was 60.6%, and no patients had a confirmed loss of MMR. Among ND patients, the best overall MMR rate was 76.0%; 3 patients had a confirmed loss of MMR. The cumulative molecular response MR4 (BCR::ABL1IS ≤ 0.01%) and MR4.5 (BCR::ABL1IS ≤ 0.0032%) rates by 66 cycles were 27.3% and 12.1% in the R/I cohort, and 56.0% and 44.0% in the ND cohort, respectively. The safety profile of nilotinib was consistent with those of earlier reports. No on-treatment deaths occurred. These long-term (up to ∼5 years) data support the efficacy and safety of nilotinib in pediatric patients with Ph+ CML-CP. This trial was registered at www.clinicaltrials.gov.uk as #NCT01844765.

Concomitant BCR-ABL and JAK2 V617F in a Patient with Myeloproliferative Neoplasm: A Case Report

Myeloproliferative neoplasm (MPN) is a clonal proliferation of the haematopoietic stem cells leading to activated tyrosine kinase signaling activity. Myeloproliferative neoplasm is classified into BCR-ABL positive chronic myeloid leukemia (CML) and BCR-ABL negative MPN which harbors JAK2 V617F mutation in most cases. The genetic combination of BCR-ABL and JAK2 V617F mutation is rare with estimated frequency of 0.4% based on recent study. Herein, we reported a case of a man diagnosed with CML detected by fluorescence in-situ hybdridisation (FISH) showing atypical BCR-ABL fusion pattern in 29% nucleated cells (cut-off levels ≥5% for positive signals) in the presence of JAK2 V617F mutation. However, the BCR-ABL transcript was not detected by the conventional reverse transcriptase-polymerase chain reaction (RT-PCR) method which was specific for major fragments. Interestingly, complete hematological remission was not achieved despite initiation of tyrosine kinase inhibitor (Imatinib). In conclusion, it is imperative to scrutinise CML cases for concomitant JAK2 V617F mutation especially patients with atypical clinical or laboratory findings. Therefore, close monitoring with clinical and ancillary technique especially FISH and molecular methods such as DNA sequencing were crucial to help achieve complete hematological, cytogenetic and deep molecular response alongside targeted therapy.

Abstract 4040: Asciminib activates erythroid differentiation in K562 cell line

Abstract Background: Asciminib an allosteric tyrosine kinase inhibitor (TKI) was recently approved by the FDA for managing Philadelphia positive chronic myeloid leukemia (CML) patients in chronic phase who had failed to respond to previous TKIs. In this study, we used human erythroleukemic K562 cell line to investigate the role of asciminib as an inducer of erythroid differentiation. Additionally, imatinib, which has previously been reported as a potential inducer of erythroid differentiation, was also tested on these cells, both independently as well as in combination, in order to investigate the degree of erythroid differentiation in a K562 cell line. Methodology: In this study, we investigated the effect of asciminib (5-20nM) with and without imatinib (50-200nM) in differentiating the erythroleukemic cell line K562 towards erythroid lineage. K562 cells were cultured over a 12-day period in basic (IMDM) media and an EPO-based differentiation media to select optimal medium conditions. In addition, an in-vitro drug cytotoxicity experiment (XTT) was used to determine the preliminary toxicity of asciminib with IMDM media and EPO-based differentiation media CD235a and CD71 surface marker expressions were analyzed by flow cytometry at all time-points to determine the degree of differentiation achieved by each of the conditions Moreover, to analyze and identify hemoglobin producing cells ensuing differentiation, benzidine staining was performed at indicated time points. Results: Our results suggest that asciminib, imatinib or a combination of both drugs in EPO-based differentiation media results in efficient erythroid differentiation with high levels of GPA expression (approx. 90%) and significant upregulation of globin genes (p value = 0.0001). These results were further confirmed by benzidine staining, where drug addition and dose escalation significantly increased benzidine-positive cells. Our results also demonstrated that asciminib was able to achieve maximum differentiation at a much earlier time point as compared to imatinib. Moreover, asciminib, when combined with another TKI such as imatinib, can also aid in lowering the drug concentrations being used, hence resulting in lessening the toxicity of the drug when used alone required at high doses. Conclusion: The results from this study highlighted the novel role of asciminib in erythroid differentiation using an in-vitro K562 model that can give high-levels of surface markers and globin expression. Potential clinical application of asciminib in hematological diseases that are associated specifically with a failure in the expression of globin genes should be evaluated. Keywords:K562, erythroid differentiation, asciminib, imatinib, glycophorin A, transferrin receptor, hemoglobin Citation Format: Hammad Hassan, Sarah Yousuf, Syed Muhammad Ahmed, Karim Ruknuddin, Hadiqa Raees, Sadia Habib, Fizza Iftikhar, Afsar Ali Mian, Elnasir Lalani. Asciminib activates erythroid differentiation in K562 cell line. [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 4040.

Asciminib monotherapy in patients with CML-CP without BCR::ABL1 T315I mutations treated with at least two prior TKIs: 4-year phase 1 safety and efficacy results

Asciminib is approved for patients with Philadelphia chromosome–positive chronic-phase chronic myeloid leukemia (CML-CP) who received ≥2 prior tyrosine kinase inhibitors or have the T315I mutation. We report updated results of a phase 1, open-label, nonrandomized trial (NCT02081378) assessing the safety, tolerability, and antileukemic activity of asciminib monotherapy 10–200 mg once or twice daily in 115 patients with CML-CP without T315I (data cutoff: January 6, 2021). After ≈4-year median exposure, 69.6% of patients remained on asciminib. The most common grade ≥3 adverse events (AEs) included increased pancreatic enzymes (22.6%), thrombocytopenia (13.9%), hypertension (13.0%), and neutropenia (12.2%); all-grade AEs (mostly grade 1/2) included musculoskeletal pain (59.1%), upper respiratory tract infection (41.7%), and fatigue (40.9%). Clinical pancreatitis and arterial occlusive events (AOEs) occurred in 7.0% and 8.7%, respectively. Most AEs occurred during year 1; the subsequent likelihood of new events, including AOEs, was low. By data cutoff, among patients without the indicated response at baseline, 61.3% achieved BCR::ABL1 ≤ 1%, 61.6% achieved ≤0.1% (major molecular response [MMR]), and 33.7% achieved ≤0.01% on the International Scale. MMR was maintained in 48/53 patients who achieved it and 19/20 who were in MMR at screening, supporting the long-term safety and efficacy of asciminib in this population.

Response to Tyrosine Kinase Inhibitors in Patients with BCR-ABL1 Positive Chronic Myeloid Leukemia; 13.5 Years’ Experience at Patan Hospital, Nepal

Background: Since the advent of Tyrosine Kinase Inhibitor (TKI), well controlled studies in developed world have shown that the life expectancy of patients with CML is comparable to normal people without the disease. But long-term follow up studies are lacking in resource poor setting.&#x0D; Methods: This is a retrospective follow up study looking at the molecular response and resistance to Tyrosine Kinase Inhibitors (TKI) in patients enrolled in the Max Access Program since February 2003 till March 2017. Patients with two or more BCR-ABL1 levels by Karyotyping/ fluorescent in situ hybridization (FISH) / reverse transcriptase polymerase chain reaction (RT-PCR) were included. At baseline, complete blood count (CBC), renal function test (RFT), and liver function test (LFT) were evaluated. Bone marrow aspiration and biopsy for morphology, cytogenetic analysis by Karyotyping/FISH and/or molecular analysis by RT-PCR were also done if these tests were not performed earlier. FISH or RT-PCR was done on peripheral blood every 3–12 months as necessary if the patient could afford. Patients with warning response/failure underwent BCR-ABL1 Resistance Mutation Analysis (IRMA).&#x0D; Results: Three hundred and forty six (346) patients had two or more BCR-ABL1 monitoring tests done. Optimal response was seen in 49.42%. Similarly, suboptimal response and failure were seen in 16.5% and 34% respectively. Overall Survival is 89.6% (at 1.8 -165 months, mean 62 months) . If only CML related events is considered survival is 95.9%. Seventy seven (77) patients with a total of 80 BCR-ABL1 domain Imatinib Resistance Mutation Analyses (IRMA) showed 19 different types of mutations with the most common being T315I mutation (8 and 19.5%). About 22.25% of the total patients showed resistance to Glivec out of which 10.98% showed mutations. Nine patients underwent trial for treatment free response (TFR) and 5 of them relapsed between 2-8 months.&#x0D; Conclusions: Despite all the odds of having financial problem, accessibility problem due to distances, transportation, etc. and difficulty monitoring with routine BCR-ABL1 and IRMA, our findings show that the outcome of TKI therapy in our CML patients is comparable to well controlled studies done elsewhere. Overall survival, molecular and cytogenetic responses and mutations in our patients who developed resistance as well as TFR are also similar to other studies. The resistance rate of 22.25% is slightly higher compared to other studies in developed world. This is mainly because of poor monitoring due to unavailability of the test including IRMA in our country and affordability until 2012. It proves that TKI is very effective in CML even in a resource-poor, developing country.

Cardiotoxicity of Tyrosine Kinase Inhibitors in Philadelphia-Positive Leukemia Patients

In the past twenty years, tyrosine kinase inhibitors (TKIs) have substantially changed the therapeutic landscape and the clinical outcome of several cancers, including Philadelphia-chromosome positive chronic myeloid leukemia and acute lymphoblastic leukemia, chronic eosinophilic syndromes, gastrointestinal stromal tumors, and others. Despite the obvious advantages offered in terms of efficacy and the overall safety profile, this new class of agents presents novel side effects, sometimes different from those induced by conventional chemotherapy. Among others, the potential cardiac toxicity, characterized by possible arrhythmias and the highest rates of cardiac ischemic disease and heart failure, were predominantly investigated. In this article, the authors review the most significant evidence in this regard, highlighting the overall benefit of TKI usage and the need for careful monitoring, especially in elderly patients.

SPHINX-Based Combination Therapy as a Potential Novel Treatment Strategy for Acute Myeloid Leukaemia.

Introduction: Dysregulated alternative splicing is a prominent feature of cancer. The inhibition and knockdown of the SR splice factor kinase SRPK1 reduces tumour growth in vivo. As a result several SPRK1 inhibitors are in development including SPHINX, a 3-(trifluoromethyl)anilide scaffold. The objective of this study was to treat two leukaemic cell lines with SPHINX in combination with the established cancer drugs azacitidine and imatinib. Materials and Methods: We selected two representative cell lines; Kasumi-1, acute myeloid leukaemia, and K562, BCR-ABL positive chronic myeloid leukaemia. Cells were treated with SPHINX concentrations up to 10μM, and in combination with azacitidine (up to 1.5μg/ml, Kasumi-1 cells) and imatinib (up to 20μg/ml, K562 cells). Cell viability was determined by counting the proportion of live cells and those undergoing apoptosis through the detection of activated caspase 3/7. SRPK1 was knocked down with siRNA to confirm SPHINX results. Results: The effects of SPHINX were first confirmed by observing reduced levels of phosphorylated SR proteins. SPHINX significantly reduced cell viability and increased apoptosis in Kasumi-1 cells, but less prominently in K562 cells. Knockdown of SRPK1 by RNA interference similarly reduced cell viability. Combining SPHINX with azacitidine augmented the effect of azacitidine in Kasumi-1 cells. In conclusion, SPHINX reduces cell viability and increases apoptosis in the acute myeloid leukaemia cell line Kasumi-1, but less convincingly in the chronic myeloid leukaemia cell line K562. Conclusion: We suggest that specific types of leukaemia may present an opportunity for the development of SRPK1-targeted therapies to be used in combination with established chemotherapeutic drugs.

Asciminib vs bosutinib in chronic-phase chronic myeloid leukemia previously treated with at least two tyrosine kinase inhibitors: longer-term follow-up of ASCEMBL

Asciminib, the first BCR::ABL1 inhibitor that Specifically Targets the ABL Myristoyl Pocket (STAMP), is approved worldwide for the treatment of adults with Philadelphia chromosome–positive chronic myeloid leukemia in chronic phase (CML-CP) treated with ≥2 prior tyrosine kinase inhibitors (TKIs). In ASCEMBL, patients with CML-CP treated with ≥2 prior TKIs were randomized (stratified by baseline major cytogenetic response [MCyR]) 2:1 to asciminib 40 mg twice daily or bosutinib 500 mg once daily. Consistent with previously published primary analysis results, after a median follow-up of 2.3 years, asciminib continued to demonstrate superior efficacy and better safety and tolerability than bosutinib. The major molecular response (MMR) rate at week 96 (key secondary endpoint) was 37.6% with asciminib vs 15.8% with bosutinib; the MMR rate difference between the arms, after adjusting for baseline MCyR, was 21.7% (95% CI, 10.53–32.95; two-sided p = 0.001). Fewer grade ≥3 adverse events (AEs) (56.4% vs 68.4%) and AEs leading to treatment discontinuation (7.7% vs 26.3%) occurred with asciminib than with bosutinib. A higher proportion of patients on asciminib than bosutinib remained on treatment and continued to derive benefit over time, supporting asciminib as a standard of care for patients with CML-CP previously treated with ≥2 TKIs.

Pediatric and adolescent chronic myeloid leukemia: A follow-up study in Western India.

Chronic myeloid leukemia (CML) is relatively rare in pediatric and adolescent age groups. The purpose of this study was to evaluate the clinical, hematopathological, and biochemical parameters of CML in pediatric and adolescent age groups, along with an assessment of the treatment response with first-line tyrosine kinase inhibitors (TKI) and its correlation with the prognostic scoring systems of adults. A retrospective study of 44 Breakpoint Cluster Region-Abelson leukemia virus (BCR-ABL1)-positive pediatric and adolescent CML cases registered at our hospital was done. The clinical and laboratory parameters were evaluated using hospital software. The treatment response was monitored and scoring was performed using mathematical calculations. The mean age was 11.6 (±4.7) years. The median hemoglobin was 8.4 g/dL and 63.6% of the cases showed white blood cell (WBC) counts >250,000/μL. The average follow-up was 21 months. A total of 97.7 and 78.1% cases achieved complete hematological response (CHR) and molecular response, respectively, during the treatment course. The maximum number of patients had low Sokal and European treatment and Outcomes Study (EUTOS) scores. Seventy-five per cent of the cases achieved CHR at 3 months, while 73.6 and 78.6% CML-Chronic phase (CP) cases with low Sokal and EUTOS scores achieved CHR at 3 months, respectively. This study revealed that the CML cases in pediatric and adolescent age groups are normally present with higher WBC counts at the time of diagnosis. The association of the prognostic scoring system with treatment response was statistically insignificant. However, a larger cohort study is needed to determine the treatment response of TKI in children and adolescent CML and its correlation with the prognostic scoring systems.

Efficacy and Safety of Vodobatinib in Patients (pts) with Chronic Phase Philadelphia Positive Chronic Myeloid Leukemia (Ph+ CML): A Sub Group Analysis By Lines of Tyrosine Kinase Inhibitor (TKI) Therapy

Efficacy and Safety of Vodobatinib in Patients (pts) with Chronic Phase Philadelphia Positive Chronic Myeloid Leukemia (Ph+ CML): A Sub Group Analysis By Lines of Tyrosine Kinase Inhibitor (TKI) Therapy

A Dasatinib-Induced Chylothorax Persisting After the Discontinuation of Dasatinib

Dasatinib is a rare cause of chylothorax.Chylothorax should be included in the differential diagnosis in patients developing pleural effusions when treated with dasatinib.The cornerstone of the treatment is tapering the dose or discontinuing the dasatinib therapy and changing it to another tyrosine kinase inhibitor.