Chronic Myeloid Leukemia Therapy Research Articles

BCR-ABL1 Levels at First Month after TKI Discontinuation Predict Subsequent Maintenance of Treatment-Free Remission: A Study from the “Gruppo Triveneto LMC”

Introduction: the possibility to discontinue TKI therapy and maintaining molecular response, the so called "treatment-free remission" (TFR) has become common clinical practice and a goal of therapy in chronic myeloid leukemia (CML). It is now accepted to attempt TFR in patients with sustained deep molecular response (DMR) and resume therapy if major molecular response (MMR) is lost. The reported TFR rates range between 30% and 70%, but, at present, it remains difficult to identify factors that may predict TFR and, after TKI stop, to early detect patients who will eventually relapse. The present study was designed to evaluate BCR-ABL1 expression in patients attempting TFR, to investigate if baseline values and/or trends after TKI suspension could predict CML recurrence. Methods: we analyzed the BCR-ABL1 RNA expression at therapy discontinuation (baseline), monthly during the first 6 months, bi-monthly between 6 and 12 months and three-monthly thereafter in 166 CML patients stopping imatinib (n=110) or 2nd generation TKI (n=56). Patients were divided among those who maintained MMR (group 1, n=120) and those who were deemed necessary to restart therapy for MMR loss (group 2, n=46). Molecular response was classified according to the standardized International Scale, DMR was defined as MR4 or deeper. Results: median time from TKI stop and restart in group 2 was 5 months (range: 3-12). Mean BCR-ABL1 RNA expression at drug discontinuation for groups 1 and 2 was 0.0010±0.0020 and 0.0018±0.0029, respectively (p=0.052); difference in molecular response at stop did not reach statistical significance neither in the imatinib cohort (group 1: 0.0007±0.0019, group 2: 0.0016±0.0026; p=0.08) nor in the 2G-TKI one (group 1: 0.0015±0.0023, group 2: 0.0022±0.0032; p=0.64). Mean BCR-ABL1 RNA levels one month after discontinuation were significantly higher in group 2 (0.0060±0.0107) than in group 1 (0.0010±0.0026; p=0.0005); this difference was confirmed and more evident two months after TKI stop as mean BCR-ABL1 value was 0.1354±0.4259 in group 2 compared to 0.0020±0.0076 in group 1 (p<0.0001) (Figure 1). The same trend was found in the imatinib group at month 1 (group 1: 0.0010±0.0028, group 2: 0.0059±0.0106; p=0.003) and at month 2 (group 1: 0.0021±0.0088, group 2: 0.0489±0.0913; p<0.0001) and in the 2G-TKI group at month 1 (group 1: 0.0009±0.0020, group 2: 0.0020±0.0037; p=0.014) and at month 2 (group 1: 0.0061±0.0113, group 2: 0.2707±0.6621; p=0.0001). Moreover, even the slopes obtained with the values at baseline, one and two months (0.0006±0.0043 in group 1 vs 0.0237±0.0450 in group 2; p<0.0001) highlight the difference between patients with or without sustained MMR. These data were confirmed both for imatinib (-0.0043±0.0370 in group 1 vs 0.0237±0.0450 in group 2; p<0.0001) and for 2G-TKI (0.0002±0.0018 in group 1 vs 0.1132±0.3057 in group 2; p=0.0007). For the determination of a threshold value of BCR-ABL1 RNA at one month after discontinuation, the ROC analysis was performed, defining an AUC=0.6430 (IC 95%: 0.5361-0.7498 p=0.0066): the cut-off value for BCR-ABL1 was defined as 0.0051%. The chosen range has 92.2% specificity, 31.7% sensitivity and a likelihood ratio of 4.087. Conclusions: our data suggest that the chance of a successful TFR could be foreseen already at one month after TKI discontinuation, both for patients stopping imatinib or 2G-TKI. The 0.0051% BCR-ABL1 cut-off value identify patients who will maintain MMR; this could allow for a lengthening of molecular monitoring. Figure 1 Disclosures Krampera: Janssen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Semenzato:Roche: Honoraria; Abbvie: Honoraria; Takeda: Honoraria.

Do Not Miss Karyotyping at Chronic Myeloid Leukemia Diagnosis: An Italian Campus CML Study on the Role of Complex Variant Translocations

Background. The Philadelphia (Ph) chromosome (chr.) is the hallmark of chronic myeloid leukemia (CML) and typically results from the reciprocal translocation t(9;22)(q34;11.2). Complex variant translocations (CVT) involving one or more additional chr. are identified in less than 5% of newly diagnosed CML. There are conflicting reports about the prognostic impact of CVT in the achievement of optimal response to tyrosine kinase inhibitor (TKI), and very few studies addressed the role of frontline treatment with imatinib or second generation (2G)-TKI in patients with CVT. Aims. To assess the response to imatinib or 2G-TKI in a large cohort of newly diagnosed CML with CVT, and to explore the impact of the different chr. translocations on outcome. Methods. This observational retrospective study was conducted in 19 hematologic centers in the framework of Campus CML, a network of Italian physicians involved in the management of CML patients. All newly diagnosed CML from 2000 to 2019 were evaluated and patients with CVT were selected for the present analysis. Karyotypes were defined according to the 2016 International System for Human Cytogenetic Nomenclature. Responses to frontline treatment were retrospectively categorized according to the 2013 ELN recommendations, as they include cytogenetic milestones. Deep molecular response (DMR, i.e. MR4or better) was defined as BCR-ABLIS ratio ≤0.01% or undetectable disease with ≥10,000 ABL copies. Patients with DMR lasting ≥2 years and at least a Q-PCR test every 6 months were defined as stable DMR responders. Failure-free survival (FFS) was calculated from the start of frontline TKI treatment to progression to advanced phase, death, or switch to other treatments for resistance. For FFS calculation, patients were censored at TKI stop for treatment-free remission (TFR) or in case of switch for intolerance only. Differences between subgroups according to the partner chr. were presented for descriptive purposes. Results. CVT were identified in 109 (3.2%) patients from a whole population of 3,361 subjects with newly diagnosed CML. Ninety-five out of 109 patients (87%) exhibited three-way translocations, with chr. 1, 4, 6, 10, 11, 12, 14, 15 and 17 representing the most common additional partners (figure). Four- and five-way translocations were identified in 13 and 1 patients, respectively. Additional chr. abnormalities (ACA) in the Ph+ cells were observed in 15/109 (13.8%) patients and were more common in older individuals (p=0.018). Overall, median age at diagnosis was 50.6 years (range 20-90). Risk distribution according to the ELTS score was 54%, 28% and 8% for L, I and H risk, respectively (10% missing). Cytogenetic result was available before the choice of frontline treatment in 45% of cases and represented a decisive factor in 28% of them (i.e. clinicians selected a 2G-TKI or high-dose imatinib, according to the available options). Frontline TKI treatment was imatinib in 80 cases (73%) and 2G-TKI (nilotinib n=22, dasatinib n=6, bosutinib n=1) in the remaining cases. The frequency of optimal response at 3, 6 and 12 months was 48%, 45% and 53%, respectively, for imatinib-treated patients, and 76%, 83% and 76%, respectively, for the 2G-TKI cohort (p<0.05 for all comparisons). Stable DMR was achieved by 39% of patients and 42% of them attempted a TFR. After a median follow-up of 91.3 months (range 1-236), 5-year FFS was 66% (95%CI: 53.4-76.4) and 84% (95%CI: 62.4-93.6) for imatinib and 2G-TKI treated patients, respectively (p=ns). The estimated 10-year OS for the entire cohort was 84.4% (95%CI: 73.6-91). The subtype of CVT had an impact on response and long-term outcome. Patients with CVT involving chr. 1, 4, 6, 11 or 12 had a higher frequency of MMR at 12 months than patients with CVT involving chr. 10, 14, 15 or 17 (75.8% vs 30.4%, respectively, p=0.001), higher frequency of stable DMR (48.7% vs 22.2%, respectively; p=0.04) and tended to have better median FFS (p=0.07), regardless of the type of frontline TKI and of the ELTS score. Conclusions. Due to its retrospective nature, this study does not allow to define which is the optimal therapy for CML harboring CVT at diagnosis. However, our data reinforce the usefulness of bone marrow karyotyping in CML. The observed differences between partner chr. may also depend on the breaking points, which are variable. Further dissection of CVT will help to identify which are associated to a poor response to TKIs. Figure Disclosures D'Adda: Incyte: Other: Advisory board; Novartis: Other: Advisory board; Pfizer: Other: Advisory board. Galimberti:Novartis: Speakers Bureau; Incyte: Honoraria. Crugnola:Celgene: Honoraria; Janssen: Honoraria; BMS: Honoraria; Novartis: Honoraria. Bocchia:Incyte: Honoraria; CELGENE: Honoraria. Krampera:Janssen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Breccia:Incyte: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Abbvie: Consultancy; Bristol-Myers Squibb/Celgene: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Saglio:Novartis: Research Funding; Ariad: Research Funding; Pfizer: Research Funding; Bristol-Myers Squibb: Research Funding; Incyte: Research Funding; Roche: Research Funding.

In SilicoStudy of Potential Cross-Kingdom Plant MicroRNA Based Regulation in Chronic Myeloid Leukemia

Background:Chronic Myeloid Leukaemia (CML) is associated with the BCRABL1 gene, which plays a central role in the pathogenesis of CML. Thus, it is crucial to suppress the expression of BCR-ABL1 in the treatment of CML. MicroRNA is known to be a gene expression regulator and is thus a good candidate for molecularly targeted therapy for CML.Objective:This study aims to identify the microRNAs from edible plants targeting the 3’ Untranslated Region (3’UTR) of BCR-ABL1.Methods:In this in silico analysis, the sequence of 3’UTR of BCR-ABL1 was obtained from Ensembl Genome Browser. PsRNATarget Analysis Server and MicroRNA Target Prediction (miRTar) Server were used to identify miRNAs that have binding conformity with 3’UTR of BCR-ABL1. The MiRBase database was used to validate the species of plants expressing the miRNAs. The RNAfold web server and RNA COMPOSER were used for secondary and tertiary structure prediction, respectively.Results:In silico analyses revealed that cpa-miR8154, csi-miR3952, gma-miR4414-5p, mdm-miR482c, osa-miR1858a and osa-miR1858b show binding conformity with strong molecular interaction towards 3’UTR region of BCR-ABL1. However, only cpa-miR- 8154, osa-miR-1858a and osa-miR-1858b showed good target site accessibility.Conclusion:It is predicted that these microRNAs post-transcriptionally inhibit the BCRABL1 gene and thus could be a potential molecular targeted therapy for CML. However, further studies involving in vitro, in vivo and functional analyses need to be carried out to determine the ability of these miRNAs to form the basis for targeted therapy for CML.

Repurposing of Acriflavine to Target Chronic Myeloid Leukemia Treatment.

Drug repurposing has lately received increasing interest in several diseases especially in cancers, due to its advantages in facilitating the development of new therapeutic strategies, by adopting a cost-friendly approach and avoiding the strict Food and Drug Administration (FDA) regulations. Acriflavine (ACF) is an FDA approved molecule that has been extensively studied since 1912 with antiseptic, trypanocidal, anti-viral, anti-bacterial and anti-cancer effects. ACF has been shown to block the growth of solid and hematopoietic tumor cells. Indeed, ACF acts as an inhibitor of various proteins, including DNA-dependent protein kinases C (DNA-PKcs), topoisomerase I and II, hypoxia-inducible factor 1α (HIF-1α), in addition to its recent discovery as an inhibitor of the signal transducer and activator of transcription (STAT). Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder characterized by the expression of the constitutively active tyrosine kinase BCR-ABL. This protein allows the activation of several signaling pathways known for their role in cell proliferation and survival, such as the JAK/STAT pathway. CML therapy, based on tyrosine kinase inhibitors (TKIs), such as imatinib (IM), is highly effective. However, 15% of patients are refractory to IM, where in some cases, 20-30% of patients become resistant. Thus, we suggest the repurposing of ACF in CML after IM failure or in combination with IM to improve the anti-tumor effects of IM. In this review, we present the different pharmacological properties of ACF along with its anti-leukemic effects in the hope of its repurposing in CML therapy.

Adherence trajectories in oral therapy for chronic myeloid leukemia: Overview of a research protocol.

Over a quarter of chemotherapy regimens now include oral agents. Individuals living with cancer are now responsible for administering this lifesaving therapy at home by taking every dose as prescribed. One type of oral chemotherapy, tyrosine kinase inhibitors (TKIs), is the current recommended treatment for chronic myeloid leukemia. This targeted therapy has markedly improved survival but comes with significant side effects and financial costs. In the study described in this protocol, the investigators seek to understand the dynamic nature of TKI adherence experienced by individuals diagnosed with CML. Using a mixed-method approach in this prospective observational study, funded by the National Cancer Institute, we seek to describe subjects' adherence trajectories over 1 year. We aim to characterize adherence trajectories in individuals taking TKIs using model-based cluster analysis. Next, we will determine how side effects and financial toxicity influence adherence trajectories. Then we will examine the influence of TKI adherence trajectories on disease outcomes. Additionally, we will explore the experience of patients taking TKIs by interviewing a subset of participants in different adherence trajectories. The projected sample includes 120 individuals taking TKIs who we will assess monthly for 12 months, measuring adherence with an objective measure (Medication Event Monitoring System). Identifying differential trajectories of adherence for TKIs is important for detecting subgroups at the highest risk of nonadherence and will support designing targeted interventions. Results from this study can potentially translate to other oral agents to improve care across different types of cancer.

INNO-406 inhibits the growth of chronic myeloid leukemia and promotes its apoptosis via targeting PTEN.

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm. INNO-406 is a novel tyrosine kinase inhibitor (TKI) that possess specific Lyn kinase inhibitory activity with no or limited activity against other sarcoma (Src) family member kinases. The present study aimed to confirm the anti-tumor effect of INNO-406 on CML cells, and elucidate the underlying molecular mechanism. CML cells were treated by INNO-406 at the concentration of 5, 25, 50, 100μM at the indicated time. Cell proliferation was measured by MTT. Cell apoptosis were detected by Western blot and flow cytometry, respectively. As suggested by the findings, INNO-406 significantly inhibited the proliferation and induced apoptosis of CML cells. In addition, INNO-406 promoted the expression level of PTEN. Rescue experiment revealed that PTEN knockdown reversed the effect of INNO-406 which indicated the correlation between INNO-406 and PTEN. Further study determined that PTEN inhibited the phosphorylation of AKT and 4EBP1 and subsequently altered the expression of apoptotic proteins including bax, cytoplasmic cytochrome c (cyto-c), cleaved caspase3 and bcl-2. In vivo study further confirmed that INNO-406 inhibited the growth of CML cells by targeting PTEN. Based on the above findings, this work extended our understanding of INNO-406 in the therapy of CML and its molecular mechanism.

Patient adherence to tyrosine kinase inhibitor therapy in chronic myeloid leukemia: influence of coping strategies and psychological factors

BACKGROUND: Medication non-adherence is associated with poor health outcomes and increased healthcare costs. Although the use of tyrosine kinase inhibitor (TKI) for chronic myeloid leukemia (CML) treatment is satisfactory in clinical results, it is subject to non-adherence. In this study, we intend to verify if there are psychological factors, such as anxiety, depression, and coping style that can influence medication adherence. METHODS: The study was conducted on 120 patients with CML receiving long-term TKI therapy. The sample was collected in the years 2016-2017 at Department of Oncology-Hematology in Pescara, Italy. Adherence behaviour was measured with the eight-item Morisky Medication Adherence Scale (MMAS-8) and psychological factors investigated included: anxiety and depression symptoms [Hospital Anxiety and Depression Scale (HADS)] and coping strategies [abbreviated version of the Coping Orientation to Problems Experienced (Brief-COPE)]. T-test and logistic regression analyses were performed to investigate factors associated with medication adherence. RESULTS: The participants, 74 men and 46 women, reported a mean age of 56.65 ± 15.80 years. The results showed that 71.67% of the patients were adherent while 28.33% were non-adherent. Furthermore, adherence was positively associated with active coping (P < 0.050) and instrumental support (P < 0.001). Also, depression symptoms were risk factor for non-adherence (P < 0.050). CONCLUSION: This study suggests that active coping strategies with a good level of instrumental support are factors associated with greater adherence to long-term therapy. The results of this study support paying attention to factors identified as being helpful in monitoring patients with a risk of non-adherence. There is a need to provide increased psychosocial support for patients with chronic disease by planning effective client‐focused interventions.

Circ_0080145 Enhances Imatinib Resistance of Chronic Myeloid Leukemia by Regulating miR-326/PPFIA1 Axis.

Background: Acquired multidrug resistance is often blamed for the failure of chemotherapy in patients with malignant tumors, including chronic myeloid leukemia (CML). In this study, the authors investigated the role of circular RNA 0080145 (circ_0080145) in imatinib (IM) resistance of CML. Materials and Methods: Quantitative real-time polymerase chain reaction was applied to measure the expression of circ_0080145, microRNA-326 (miR-326), and PTPRF interacting protein alpha 1 (PPFIA1) mRNA. 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay was used to determine the half maximal inhibitory concentration (IC50) of IM and cell proliferation. Flow cytometry analysis was utilized to assess cell apoptosis. The levels of glucose uptake and lactate production were examined using specific kits. Protein levels were detected through Western blot assay. The targeting relationship between miR-326 and circ_0080145 or PPFIA1 was verified by dual-luciferase reporter assay. The murine xenograft model was constructed to investigate the effect of circ_0080145 in vivo. Results: circ_0080145 was upregulated in IM-resistant CML patients and cells. circ_0080145 silencing suppressed IM resistance, cell growth, and glycolysis and induced apoptosis in IM-resistant CML cells in vitro. Moreover, circ_0080145 knockdown blocked tumor growth and IM resistance in vivo. miR-326 was a target of circ_0080145, and miR-326 inhibition restored the effects of circ_0080145 silencing on cell progression and IM resistance. In addition, PPFIA1 was a target gene of miR-326. The suppressive roles in IM resistance, cell growth and glycolysis, and the promotional role in apoptosis mediated by miR-326 were abolished by PPFIA1 overexpression in IM-resistant CML cells. Conclusion: circ_0080145 contributes to IM resistance via modulating miR-326/PPFIA1 axis, which might provide a novel avenue for CML therapy.

Specificity of dermatological adverse events of BCR-ABL tyrosine kinase inhibitors and their effect on quality of life of patients with chronic myeloid leukemia

Introduction. BCR-ABL tyrosine kinase inhibitors are currently used to successfully treat chronic myeloid leukemia (CML). Drug therapy is carried out in a continuous daily mode throughout the patient’s life. Treatment with this group of drugs is associated with specific dermatological adverse events (dAE), which can lead to a change in the regimen of effective, vital therapy for CML patients.Purpose. To study the characteristics of dermatological adverse events, the severity and influence on the quality of life of BCR-ABL tyrosine kinase inhibitors.Patients and methods. The observational study included 93 patients. The clinical manifestations of dAE, their severity were evaluated, their photographs and pathomorphological studies of skin biopsy samples were performed, cases of dose reduction or drug withdrawal due to dAE were recorded. The quality of life of patients with dAE was determined based on the assessment of the dermatological index of quality of life.Results. Imatinib therapy was accompanied by a maculopapular rash in 43.3 % of patients, nilotinib caused follicular keratosis in 12.9 % of patients. In 3.2 % of patients, dasatinib caused hyperpigmentation, in 2.2 % of patients lichenoid rashes of the II degree occurred during treatment with bosutinib. Ponatinib treatment was followed by dAE in 9.7 % of patients. All dAE have an impact on the quality of life of patients, but the maculopapular rash and dyskeratotic changes are most pronounced. In a pathomorphological study, these dAE have specific features corresponding to immuno-mediated dermatitis.Conclusions. The most frequent and pronounced dAE that significantly affect the quality of life of patients with CML are a maculopapular rash and dyskeratotic skin changes: psoriasiform and lichenoid dermatitis. Clinical and pathomorphological characteristics of skin reactions make it possible in the future to determine effective methods of supportive therapy for dAE.

Amulticenter retrospective evaluation of Chronic Myeloid Leukemia (CML) therapy in Austria assessing the impact of early treatment response on patient outcomes in areal-life setting : R-EFECT study.

SummaryBackgroundSeveral clinical trials in chronic phase (CP) chronic myeloid leukemia (CML) showed that early response to tyrosine kinase inhibitor (TKI) treatment results in an improved long-term survival and progression-free survival. This study assessed whether patients achieving early treatment response (ETR; partial cytogenetic response or BCR-ABL1 mRNA ≤10% at 3 months) in daily practice also have a long-term survival benefit.MethodsThe Retrospective Evaluation of Early response in CML for long-term Treatment outcome (R-EFECT), a multicenter, retrospective chart review, documented patients with newly diagnosed CML-CP starting first-line TKI therapy in routine clinical practice. The primary aim was to assess the 5‑year overall survival rate.ResultsOf the 211 patients from 12 centers across Austria (January 2004–May 2010), 176 (median age, 56 years) were included in the analysis. All patients received first-line therapy with imatinib. Overall, 136 patients (77.3%) achieved ETR (ETR+ group), whereas 40 (22.7%) did not reach ETR (ETR− group). The ETR+ group had higher 5‑year overall survival (92.5% vs. 77.5%, P = 0.018) and progression-free survival (95.6% vs. 87.5%, P = 0.06) rates compared with the ETR− group. As expected, more patients in the ETR− group were switched to another TKI. At the last contact, 120 patients were still on imatinib and 44 had switched to another TKI (25 to nilotinib, 15 to dasatinib, and 4 to bosutinib).ConclusionThe data are in line with randomized trials demonstrating that ETR is associated with improved survival and thus confirmed these results in patients treated in daily clinical routine.

Cytogenetic Response Assessment to Imatinib Mesylate Therapy for Chronic Myeloid Leukemia in Iraqi Patients

Cytogenetic Response Assessment to Imatinib Mesylate Therapy for Chronic Myeloid Leukemia in Iraqi Patients

Molecular Response of Chronic Myeloid Leukaemia Patients to Tyrosine Kinase Inhibitors

Background: The goal of therapy in Chronic Myeloid Leukaemia (CML) with tyrosine kinase inhibitors (TKIs) has been to achieve the molecular responses, as measured by the reduction or elimination of BCR-ABLl transcript. Objective: The aim of the study is to observe the molecular response status of CML patients to TKIs. Methodology: This is an observational study and was conducted in the department of Haematology, Bangabandhu Sheikh Mujib Medical University (BSMMU) from February 2018 to January 2019. A total of 30 diagnosed CML patients on TKIs therapy was checked for quantitative BCR-ABL1 (by qRT-PCR) level. The laboratory monitoring of BCR-ABL1 RNA with RQ-PCR was likely become the model for successful molecular diagnostic monitoring of CML patients to both assess and prognosticate the efficacy of these targeted treatments. Result: Among 30 diagnosed CML patients, the mean age was found 36.1±11.7 years with range from 20 to 70 years. Males were predominant 19 (63.3%), male: female ratio was 1.7:1. Almost two third (63.3%) patients were found optimal (?10%) after 3-month BCR ABL. Age, sex, religion, marital status, occupational status, BMI, monthly income, number of family member, symptoms and sings were not statistically significant (p&gt;0.05) when compared between BCR ABL optimal (?10%) and warning (&gt;10%) group. Mean haemoglobin, total leukocyte count, platelet count, basophil, myelocyte and baseline BCR&#x0D; ABL1 were not statistically significant (p&gt;0.05) however atypical cells was found statistically significant&#x0D; (p

Discontinuation of tyrosine kinase inhibitor (TKI) therapy in chronic myeloid leukemia in chronic phase (CML-CP) in US clinical practice after guideline updates.

7548 Background: NCCN CML practice guidelines were updated in 11/2016 and in 9/2019 to include considerations for discontinuation of TKI therapy in patients (pts) with CML-CP. This study characterized TKI discontinuation practices in the US after these updates and drew parallels with a similar study conducted prior to these guideline updates (Ritchie et al. Leuk Lymphoma. 2019). Methods: Pt charts of adult CML-CP pts with TKI discontinuation (1/2017-12/2018) outside a clinical trial after achieving an adequate response were abstracted (11/2019-12/2019) via an online case report form by US oncologists/hematologists. Physicians’ assessment of adequate response (TKI duration, molecular response [MR], MR duration) and relapse were described. Results: 61 physicians (academic: 43%; community-based practices: 57%) contributed 153 pt charts. Most physicians were from large practices (57%), had &gt; 10 years (y) experience since completing subspecialty training (59%), and treated a median of 30 CML pts in the last 2y; 56% did not have access to precise molecular response monitoring for BCR-ABL of ≥4.5 log when attempting TKI discontinuation. Pts with TKI discontinuation had mean age 56 years, were mostly male (60%), white (69%), and had TKI discontinued in first-line (96%). Most common reasons for TKI discontinuation were pt request (54%) and adverse events (18%), besides achieving an adequate response. Physicians’ assessment of adequate response for TKI discontinuation are reported in the Table. 21% of pts (academic: 12%; community: 30%) relapsed after TKI discontinuation (treatment-free remission [TFR] failure; 66% relapsed within 1y). Conclusions: Although NCCN CML practice guidelines provide guidance for discontinuation of TKI therapy, there remains heterogeneity in US practice and TKI discontinuation is predominantly attempted in first-line (similar to Ritchie et al. 2019). TKI discontinuation is being practiced without adequate sensitive tools mandated by practice guidelines to monitor response. Broader application of practice guidelines for optimal TKI therapy discontinuation in CML-CP pts is needed, particularly in community-based practices, to improve long-term TFR rates. [Table: see text]

Evaluation of Imatinib Concentrations in Samples Submitted for BCR-ABL1 or Imatinib Testing-Evidence to Support Therapeutic Drug Monitoring for Dose Optimization?

Imatinib is one of the first-line therapies for chronic myeloid leukemia. Achieving a major molecular response early in treatment, as indicated by a BCR-ABL1 major international scale result of ≤0.1% within 6 months, is associated with better patient outcomes and is statistically associated with a trough imatinib concentration of approximately 1000 ng/mL. Adherence to therapy, drug resistance, drug-drug interactions, and pharmacokinetic/pharmacodynamic factors may hinder attaining this target. Therapeutic drug monitoring of imatinib is not currently standard-of-care, but may help to evaluate adherence and optimize treatment of patients with chronic myeloid leukemia. This study aimed to evaluate imatinib concentrations in real-world patient plasma samples to identify the proportion of imatinib-treated patients who achieved the therapeutic target of 1000 ng/mL. This was a retrospective, observational study that measured imatinib in residual plasma samples used for BCR-ABL1 tests (n = 1022) and analyzed clinician-ordered imatinib tests for therapeutic drug monitoring (n = 116). Imatinib was measured by competitive immunoassay. The frequency of imatinib concentrations achieving the therapeutic target was determined and correlated with BCR-ABL1 major international scale, age, and sex. Seventy-two percent of patients tested for BCR-ABL1 may not have been prescribed or were not adherent to imatinib therapy. In the 29% of patients who did not achieve major molecular response, but had quantifiable imatinib concentrations, the therapeutic concentration was not met. For clinician-ordered imatinib tests, 45% of samples did not exceed the therapeutic target and 4% had potentially toxic plasma concentrations (>3000 ng/mL). Therapeutic drug monitoring for imatinib may assist clinicians in the identification of patients who may not be adherent to therapy, display variable pharmacokinetics or pharmacodynamics, or may be experiencing toxicity or treatment failure.

PCN126 COST-EFFECTIVENESS OF SECOND GENERATION TKIS COMPARED WITH IMATINIB FOR CHRONIC MYELOID LEUKAEMIA: IMPLICATIONS OF TREATMENT-FREE REMISSION

Although second generation Tyrosine kinase inhibitor (TKIs) nilotinib and dasatinib are associated with higher rates of sustained deep molecular response (SDMR) compared to imatinib, the later remains as frontline therapy for chronic myeloid leukaemia (CML) in Brazil due to lower prices of generic formulations. However, as treatment free remission (TFR) became feasible for CML patients, second generation TKIs might be a valuable option for frontline therapy since SDMR is the main eligibility criterion for treatment suspension. This study compared the cost-effectiveness of first and second generation TKIs as frontline CML treatment considering TRF as a possibility. We constructed a Markov model to compare the ten year cost-effectiveness of imatinib frontline therapy versus nilotinib or dasatinib from a Brazilian third payer perspective, assuming 5% annual discounting. The model included six health states: first line treatment, second line treatment, TFR, treatment resume, disease progression and death. Transition probabilities were obtained from eligible studies. Only direct medical costs were considered including those related to drugs acquisition, medical visits and laboratory tests (exchange rate 1 BRL = 4 USD). The main outcome was progression-free life-years (PF-LY). We assessed different price scenarios for second generation TKIs. Nilotinib-first strategy offered 0.85 additional PF-LY with an ICER of US$ 29,541.98/PF-LY compared to imatinib. Dasatinib frontline was the most costly strategy with an ICER of US$ 81,355.07/PF-LY. These results were robust to probabilistic sensitivity analysis. The scenarios analysis showed that a 25% reduction in nilotinib price would make it the dominant strategy. Although TFR was included as a health state in the model, imatinib remained as the most economically advantageous frontline CML treatment, mainly because of the low price of its generic formulations. However, a decrease in the price of nilotinib could significantly change this scenario.

Mutation Analysis of ABL1 Gene and its Relation to the Achievement of Major Molecular Response in Indonesian Chronic Myeloid Leukemia Patients

Background: Imatinib mesylate is the first tyrosine kinase inhibitor approved for chronic myeloid leukemia (CML) therapy. Imatinib is an effective drug. However, previous studies have shown that about 20-30% of patients eventually would develop resistance to imatinib. Approximately 40% of imatinib resistance is associated with BCRABL kinase domain mutation. One of the most common and serious variations account for imatinib response is T315I of ABL1 gene. Objective: The study aimed to examine the association of T315I mutation with the ABL1 gene and its relation to major molecular response (MMR) achievement in CML patients. This study also examined other mutations adjacent to T315I, i.e., F311I, F317L, and different possible variations in the ABL1 gene. Methods: This was a cross-sectional study on Indonesian CML patients in chronic phase. We analyzed 120 blood samples from patients in chronic phase who have received imatinib mesylate (IM) for ≥12 months. Results: There were no T315I, F311I, and F317L mutations found in this study. However, we found another variation, which was 36 substitutions from A to G at position 163816 of ABL1 gene (according to NG_012034.1). Conclusions: We found no T315I, F311I, and F317L mutations in this study. Our findings suggest that there might be other factors that influenced the MMR achievement in our study patients. However, there were 36 substitutions from A to G at position 163.816 (according to NG_012034.1) that needed further examination to explore the significance of this mutation in clinical practice.

Complete Molecular Response in Chronic Myeloid Leukemia After Six Months of Imatinib: A Single Center Experience.

Introduction: The hallmark of chronic myeloid leukemia (CML) is the development of the fusion gene, BCR-ABL which has unopposed tyrosine kinase activity. The first tyrosine kinase inhibitor (TKI) imatinib is claimed to have superior efficacy and side effect profile as compared to traditional treatment options. This study was conducted to see our patients’ molecular response to imatinib treatment. The objective of this study was to determine the frequency of complete molecular response in patients after six months of imatinib therapy.Methods: A descriptive case series was designed and conducted in Oncology department, Jinnah hospital Lahore (May-November 2016). Newly diagnosed patients of CML aged between 20 and 65 years were enrolled. They were prescribed 400 mg imatinib daily and complete molecular response was assessed after six months of treatment.Results: Mean age was 39.76 ± 9.072 years. Some 66 of them were males while 69 were females. Some 40 patients (29.6%) were found to be in complete molecular response after six months of imatinib therapy.Conclusion: Imatinib at a dose of 400 mg/day is optimal as the primary therapy for CML.

Factors Associated with Achieving Hematological Response in CML (Chronic Myeloid Leukemia) Patient

Background: The goal of CML therapy is to achieve complete hematological response first, then cytogeneticresponse andcomplete molecular response at the very end. Achieving a complete hematological responseis the easiest and relatively inexpensive to detect. Several factors are thought to have an association withachieving hematological response. This study sought to determine the factors associated with achievinghematological response in CML patientsMethod: We conducted an observational retrospective cohort study of CML patients at Wahidin SudirohusodoHospital and its network on 2018-2019 period. Diagnosis was done by positive BMP (Bone Marrow Punctie)results for CML, then a monthly blood check until a hematological response was achieved.Results: There wer 39 research subjects, 19 male (48.7%) and 20 female (51.3%). No association foundbetween age, gender and achievement of hematological response. Type of therapy was significantlycorrelated with the achievement of hematological response, with the highest number found in Nilotinibtherapy compared to other group. (54,1%; p = 0.046) Subjects who achieve hematological response had alower percentage of blast cells. (6.1% vs. 7.9% ; p = 0.016)Conclusion: The use of Nilotinib therapy was significantly associated with a succesful achievementof hematological response. A lower percentage of blast cells was found in CML patients who achievedhematological response.

Analysis of the Mortality of Russian Patients With Chronic Myeloid Leukemia in the Multicenter EUTOS ELN Population-based Study (EUTOS-PBS)

IntroductionRussia took part in the multicenter population-based study (Europe) and included 6.8% adult patients with newly diagnosed chronic myeloid leukemia (CML). The objective of this study was to analyze the mortality in the Russian cohort of patients with newly diagnosed CML in the EUTOS PBS observational study. Patients and MethodsThe analyzed cohort consisted of 197 patients (>18 years) with Ph+/BCR-ABL1+ CML diagnosed in the period from October 1, 2009 through December 31, 2012 from 6 regions of Russia. The distribution of the phases of CML were: chronic phase (CP), 93.4% and accelerated phase (AP) + blast crisis (BC), 6% + 0.6%. The median age was 50 years (range, 18-82 years); the male/female ratio was equal. ResultsThe overall survival (OS) at 5, 6, and 7 years was 80% (95% confidence interval [CI], 72%-86%), 78% (95% CI, 65%-80%), and 73% (95% CI, 65%-80%), respectively (P < .001). The 5-year OS in patients with AP and BC was 39%. In Russia, the study was prolonged, with a median follow-up of 77 months (range, 0.7-108 months): 141 (71.5%) patients were alive, 47 (24%) patients died, and the status of 9 (4.5%) patients is was unknown. Forty-seven (23.8%) patients died during the follow-up period. The largest number of deaths was observed in the first year after the CML diagnosis: 17 (36%) of 47 cases, 3 of 17 died refusing the CML treatment. At the seventh year of CML therapy, 1 patient died after allogenic hematopoietic stem cell transplantation. The causes of death were: (1) progression of CML to AP/BC in 20 (43%) patients; (2) death in remission in 5 (11%) patients with complete cytogenetic response (CCyR) and/or major molecular response; and (3) death without progression to AP/BC but with signs of leukemia in 22 (46%) patients. The 5-year cumulative incidence of death from all reasons was 20%; the cumulative incidence of CML-related and non–CML-related death at the fifth year was 18% and 11%, respectively. ConclusionIn general, the results of treatment in the Russian population sample of non-selected patients with CML were comparable with the data of the total European cohort. The CML-related deaths prevailed in the first year of CML therapy. The appropriate monitoring and therapy interventions during the first year of CML treatment are apparently important for the long-term treatment results.

Imatinib mesylate affects extracellular ATP catabolism and expression of NTPDases in a chronic myeloid leukemia cell line.

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm, characterized by the occurrence of the t(9;22)(q34;q11) translocation. First-line therapy for CML consists of treatment with imatinib mesylate, which selectively inhibits the BCR-ABL protein by competing for its ATP-binding site. Adenine nucleotide signaling is modulated by the ectonucleotidases and this pathway is related to tumorigenic processes. Considering the relationship between ATP and cancer, we aimed to evaluate the influence of imatinib mesylate on the expressions and functions of the NTPDase and ecto-5'-nucleotidase (CD73) enzymes in imatinib-sensitive and -resistant K-562 cell lines. mRNA analysis showed that K-562 cells express all ENTPDs and NT5E. However, when treated with imatinib mesylate for 24h, the expression of ENTPD1, -2, -3 and -5 increased, leading to a higher nucleotides hydrolysis rate. HPLC analysis identified increased ATP degradation in cells after 24h of treatment, with consequent ADP and AMP formation, corroborating the increase in gene and protein expression of ectonucleotidases as observed in previous results. On the other hand, we observed that imatinib-resistant K-562 cells presented a decrease in nucleotide hydrolysis and expressions of ENTPD1 and -5. These results suggest an involvement of imatinib in modulating ectonucleotidases in CML that will need further investigation. Since these ectonucleotidases have important catalytic activities in the tumor microenvironment, their modulation in CML cells may represent an important therapeutic approach to regulate levels of extracellular adenine nucleotides.