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We aimed to use physiologically based pharmacokinetic (PBPK) modeling and simulation to predict imatinib steady‐state plasma exposure in patients with chronic myeloid leukemia (CML) to investigate variability in outcomes. A validated imatinib PBPK model (Simcyp Simulator) was used to predict imatinib AUCss, Css,min and Css,max for patients with CML (n = 68) from a real‐world retrospective observational study. Differences in imatinib exposure were evaluated based on clinical outcomes, (a) Early Molecular Response (EMR) achievement and (b) occurrence of grade ≥3 adverse drug reactions (ADRs), using the Kruskal‐Wallis rank sum test. Sensitivity analyses explored the influence of patient characteristics and drug interactions on imatinib exposure. Simulated imatinib exposure was significantly higher in patients who achieved EMR compared to patients who did not (geometric mean AUC0‐24,ss 51.2 vs. 42.7 μg h mL−1, p < 0.05; Css,min 1.1 vs. 0.9 μg mL−1, p < 0.05; Css,max 3.4 vs. 2.8 μg mL−1, p < 0.05). Patients who experienced grade ≥3 ADRs had a significantly higher simulated imatinib exposure compared to patients who did not (AUC0‐24,ss 56.1 vs. 45.9 μg h mL−1, p < 0.05; Css,min 1.2 vs. 1.0 μg mL−1, p < 0.05; Css,max 3.7 vs. 3.0 μg mL−1, p < 0.05). Simulations identified a range of patient (sex, age, weight, abundance of hepatic CYP2C8 and CYP3A4, α1‐acid glycoprotein concentrations, liver and kidney function) and medication‐related factors (dose, concomitant CYP2C8 modulators) contributing to the inter‐individual variability in imatinib exposure. Relationships between imatinib plasma exposure, EMR achievement and ADRs support the rationale for therapeutic drug monitoring to guide imatinib dosing to achieve optimal outcomes in CML. [ABSTRACT FROM AUTHOR]

Introduction: Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder characterized by the Philadelphia (Ph) chromosome. After the introduction of imatinib mesylate (IM) in 2000, the natural history of the disease changed. Data on the treatment of CML with IM are from randomized clinical trials. Establishing whether these results can be reproduced or if caution is needed when extrapolating data to the general population with CML is essential. Objectives: To evaluate the molecular response (MR) in patients with chronic-phase CML (CML-CP) not included in clinical studies and correlate them with the responses obtained in clinical trials. Methods: Between January 2007 and January 2017, 227 patients newly diagnosed with CML-CP treated with IM as first-line treatment were included. This study is an observational, retrospective, and single-center study. Results: At a median follow-up time of 7.3 years, 60.3% of the 227 patients who started IM were still on IM. Early molecular response (EMR) at 3 and 6 months was achieved by 74.2% and 65%, respectively. The median time to a MMR was nine months. The MR4.0 and MR4.5 were 67.2% and 51.1%, respectively. The overall survival (OS), progression-free survival (PFS), and event-free survival (EFS) of the patients who exclusively used IM were 91%, 91%, and 85.1%, respectively. Conclusion: The results presented are similar to those described in prospective and randomized trials, demonstrating that the outcomes are reproducible in the real world. EMR at 3 and 6 months reflects better long-term responses, including higher rates of deeper molecular responses. Considering treatment costs, the absence of literature evidence of an impact on overall survival demonstrated by first-line second-generation tyrosine kinase inhibitors (TKIs), and the global OS of 85.8%, imatinib mesylate (IM) is still an excellent therapeutic option. [ABSTRACT FROM AUTHOR]

Abstract We aimed to use physiologically based pharmacokinetic (PBPK) modeling and simulation to predict imatinib steady‐state plasma exposure in patients with chronic myeloid leukemia (CML) to investigate variability in outcomes. A validated imatinib PBPK model (Simcyp Simulator) was used to predict imatinib AUCss, Css,min and Css,max for patients with CML (n = 68) from a real‐world retrospective observational study. Differences in imatinib exposure were evaluated based on clinical outcomes, (a) Early Molecular Response (EMR) achievement and (b) occurrence of grade ≥3 adverse drug reactions (ADRs), using the Kruskal‐Wallis rank sum test. Sensitivity analyses explored the influence of patient characteristics and drug interactions on imatinib exposure. Simulated imatinib exposure was significantly higher in patients who achieved EMR compared to patients who did not (geometric mean AUC0‐24,ss 51.2 vs. 42.7 μg h mL−1, p

Context Nilotinib is a second-generation BCR-ABL1 tyrosine kinase inhibitor used in the treatment of chronic myeloid leukemia (CML). Aims We aim to evaluate the responses and safety of upfront Nilotinib therapy in Indian CML patients. Setting and Design We retrospectively reviewed the medical records of CML patients who received Nilotinib as an upfront treatment at our center between January 1, 2011 and October 15, 2019.The follow-up was taken till March 31, 2020. Results Forty One patients (n = 36 chronic phase and five accelerated-phase CML) received frontline Nilotinib. Median age was 39 years (21–63) with male-to-female ratio of 1.1: 1. At 3 months, 96.9% patients achieved BCR-ABL of ≤10% at international scale. By the end of 12 months, 71.5% patients achieved major molecular response (BCR-ABL ≤0.1%) and 91.4% patients achieved complete cytogenetic response assessed by BCR-ABL polymerase chain reaction of ≤1%. Common toxicities observed were weight gain, thrombocytopenia, corrected QT prolongation, and elevated serum amylase in 14 (34.1%), 7(17.07%), 4(9.7%), and 4(9.7%) patients, respectively. Overall, five patients had loss of response with further progression and death in three patients. At a median of 43.7 months, 38 patients survived with estimated 3 year event-free survival and overall survival of 65 ± 9 and 93 ± 5%. Conclusion This study showed remarkable good response with upfront Nilotinib in Indian patients with CML.

Simple Summary: An early assessment of response to treatment is crucial to informing appropriate therapeutic management. Using a plasma-only strategy, we measured changes in circulating tumor DNA (ctDNA) levels after one or two cycles of chemotherapy in 92 patients with advanced non-small-cell lung cancer (NSCLC) treated with first-line chemo- or chemoradiation therapies. A ≤50% decrease in ctDNA level after one cycle of chemotherapy was associated with shorter progression-free survival and overall survival. A ≤50% decrease in ctDNA level after two cycles of chemotherapy also had shorter survival. Our findings demonstrate that using liquid biopsies to measure early changes in ctDNA levels in response to chemotherapy may help identify non-responders before standard-of-care imaging in advanced NSCLC. Monitoring treatment efficacy earlier and accurately can enable more personalized regimens to improve patient outcomes. Monitoring treatment efficacy early during therapy could enable a change in treatment to improve patient outcomes. We report an early assessment of response to treatment in advanced NSCLC using a plasma-only strategy to measure changes in ctDNA levels after one cycle of chemotherapy. Plasma samples were collected from 92 patients with Stage IIIB-IV NSCLC treated with first-line chemo- or chemoradiation therapies in an observational, prospective study. Retrospective ctDNA analysis was performed using next-generation sequencing with a targeted 198-kb panel designed for lung cancer surveillance and monitoring. We assessed whether changes in ctDNA levels after one or two cycles of treatment were associated with clinical outcomes. Subjects with ≤50% decrease in ctDNA level after one cycle of chemotherapy had a lower 6-month progression-free survival rate (33% vs. 58%, HR 2.3, 95% CI 1.2 to 4.2, log-rank p = 0.009) and a lower 12-month overall survival rate (25% vs. 70%, HR 4.3, 95% CI 2.2 to 9.7, log-rank p < 0.001). Subjects with ≤50% decrease in ctDNA level after two cycles of chemotherapy also had shorter survival. Using non-invasive liquid biopsies to measure early changes in ctDNA levels in response to chemotherapy may help identify non-responders before standard-of-care imaging in advanced NSCLC. [ABSTRACT FROM AUTHOR]

Objective: To determine the relationship of baseline quantitative BCR ABL1 gene percentage and therapeutic response i.e. Early Molecular Response (EMR) at 3 months with first generation Tyrosine kinase inhibitors (Imatinib) in patients with Chronic Myeloid Leukemia (CML) in chronic phase (CP). Study Design: Prospective observational study. Place and Duration of Study: Combined Military Hospital, Rawalpindi, Pakistan, and Armed Forces Institute of Pathology Rawalpindi, Pakistan from Oct 2017 to Oct 2019. Methodology: One hundred and seventy patients, 18 years of age or older with newly diagnosed Chronic Myeloid Leukemia (CML) in chronic phase (CP) with quantitative baseline BCR-ABL (IS) transcript were included in the study. All enrolled patients were placed on Imatinib therapy (400 mg/day) and Reverse transcription polymerase chain reaction (RT-PCR) for BCR ABL transcript was repeated at 3 months to document EMR (BCR-ABL (IS) 50% at baseline achieved early molecular response (p-value 50%, the rate of EMR was comparatively lower.

Management and therapy of patients with chronic myeloid leukaemia (CML) has changed significantly over the past twenty years. Quantitative RT-PCR detection of the BCR-ABL1 transcript level has become the gold standard for evaluating response to tyrosine kinase inhibitors (TKI) treatment. Demand for standardization of methodologies resulted in the international harmonisation of test result interpretation by expressing these on an international scale and assigning conversion factors to individual laboratories based on their comparison with reference sites. Early molecular response to treatment significantly influences the disease course and selects patients with good prognosis. Some of the patients who do not experience an early response still have good prospects in terms of disease course, as it is possible to take into consideration the kinetics of transcript level early decrease in order to exclude the high-risk group. The "halving time" concept indicates a high success rate for predicting disease sensitivity to the treatment given. In the era of long-term TKI therapy, attempts at a treatment-free remission (TFR) are being cited more frequently. This strategy involves the possibility of interrupting treatment without disease recurrence, decreasing adverse effects and the economic burden. Even today, identification of patients who are able to achieve this goal is hard and stable TFR is achieved only in a minority of patients. Treatment strategy may thus involve opting for a maximum possible reduction of TKI dose while still preserving treatment response. CML is not only a paradigm because of targeted treatment and its success rate but also because of its amenability for mathematical modelling of an oncological disease, given the simplicity of tumour load examination from peripheral blood and its real-time observation. This allows for easily acquired accurate data to be entered into the models. Using such models, we can simulate the origin of CML from the leukemic stem cell, TKI influence on these cells, various dosage regimens, attempts at TFR or the immune system response to presence of the disease. The following paper provides an overview of the principles of molecular measurement of treatment response, the consequences of early response and its kinetics on patient prognosis, and mathematical models of CML in the organism. [ABSTRACT FROM AUTHOR]

Sokal, Hasford, and EUTOS prognostic scoring systems are widely used for chronic myeloid leukemia (CML) patients. However, whether one of these scoring systems was better predicting therapeutic responses among patients treated with tyrosine kinase inhibitor (TKI) remains elusive. This study was aimed to assess the correlation of each prognostic score with therapeutic responses--complete hematologic response (CHR) and early molecular response (EMR) after treated with Imatinib mesylate. 40 CML patients with the mean of age of 40 ± 11 years from Indonesian population were followed-up prospectively. The CHR at 3 months was seen in 40.7%, 18.6%, and 40.7% in Sokal low-, intermediate- and high-risk groups respectively, 26.0%, 40.7%, and 33.3% in Hasford low-, intermediate- and high-risk groups respectively, 100% and 0% EUTOS low- and high-risk groups respectively. The EMR at 3 months was seen in 41.7%, 16.6%, and 41.7% in Sokal low-, intermediate- and high-risk groups respectively, 29.2%, 37.5% and 33.3% in Hasford low-, intermediate- and high-risk groups respectively, 100% and 0% in EUTOS low- and high-risk groups respectively. However, none of these scoring systems predicted CHR and EMR at 3 months among CML patients treated with Imatinib. [ABSTRACT FROM AUTHOR]

Objective: To determine the relationship of baseline quantitative BCR ABL1 gene percentage and therapeutic response i.e. Early Molecular Response (EMR) at 3 months with first generation Tyrosine kinase inhibitors (Imatinib) in patients with Chronic Myeloid Leukemia (CML) in chronic phase (CP) Study Design: Prospective observational study. Place and Duration of Study: Combined Military Hospital, Rawalpindi, Pakistan, and Armed Forces Institute of Pathology Rawalpindi, Pakistan from Oct 2017 to Oct 2019. Methodology: One hundred and seventy patients, 18 years of age or older with newly diagnosed Chronic Myeloid Leukemia (CML) in chronic phase (CP) with quantitative baseline BCR-ABL (IS) transcript were included in the study. All enrolled patients were placed on Imatinib therapy (400 mg/day) and Reverse transcription polymerase chain reaction (RT-PCR) for BCR ABL transcript was repeated at 3 months to document EMR (BCR-ABL (IS) <10%). Patients who were in accelerated/blast phase, or already taking any Tyrosine Kinase Inhibitors (TKI) or chemotherapy were excluded from the study Results: In our study 101 (59.4%) patients achieved early molecular response. Out of these 80 (70.8%) patients with BCR-ABL<50% at baseline value showed early molecular response. However, only 21 (36.8%) with BCRABL >50% at baseline achieved early molecular response (p-value <0.001). Conclusion: A significant number of patients achieved early molecular response with Imatinib therapy that had BCR ABL below 50%, however those with baseline BCR ABL >50%, the rate of EMR was comparatively lower. [ABSTRACT FROM AUTHOR]

The present study aimed to assess the clinical impact of BCR‐ABL1 transcript levels determined at an earlier time point than the 3‐month early molecular response (EMR) in chronic‐phase chronic myeloid leukemia (CML‐CP) patients. BCR‐ABL1 transcript levels of CML‐CP patients (n = 258; median age, 43 [range, 18‐81] years) treated with various tyrosine kinase inhibitors (TKIs) were determined at 4 weeks (28 ± 3 days) and at every 3 months of treatment initiation. At 4 weeks, receiver operating characteristic curves revealed that cutoff values of BCR‐ABL1 transcripts for achieving major molecular responses (MMRs) by 12 and 60 months were 40.89% and 39.16%, respectively (95% CI, 0.658‐0.772 and 95% CI, 0.643‐0.758; P < 0.0001). With 40% of BCR‐ABL1 transcripts at 4 weeks (very early MR; VEMR), patients with VEMR achieved higher 3‐month EMR and 4‐week VEMR significantly associated with higher cumulative incidences of 5‐year MMR (89.1% vs 72.3%; P < 0.001) and 5‐year deep molecular response (DMR) (56.5% vs 29.4%; P = 0.001). Furthermore, event‐free survival (EFS)‐a (93.0% vs 84.8%; P = 0.068) and EFS‐b (71.1% vs 57.9%; P = 0.061) by 5 years were also marginally significant. VEMR and 3‐month EMR were achieved in 89 patients, with significantly superior outcomes. In multivariate analyses, lower leukocyte count (P = 0.008) and frontline second‐generation TKI therapy size (P < 0.001) were significantly associated with VEMR achievement, but not baseline BCR‐ABL1 level and CML duration. In conclusion, the 4‐week BCR‐ABL1 transcript levels including VEMR could be important to predict long‐term outcomes and may provide additional information about innate intrinsic sensitivity to CML among individuals. The very early molecular response assessment could be important to predict long‐term outcomes and may provide additional information about innate intrinsic sensitivity to individual CML clone. As it also allows for the prediction of DMR, VEMR can be used as one of the important tools to select candidates for treatment‐free remission. [ABSTRACT FROM AUTHOR]

An editorial is presented on the developments in the treatment of chronic myeloid leukaemia (CML) with the introduction of BCR-ABL1 tyrosine kinase inhibitors (TKIs). It expresses the view that CML is a highly controllable disease with the availability of TKIs, and treatment-free remission is a new therapeutic goal for the eligible patients.

Chronic myeloid leukemia (CML) respond dramatically to molecular target therapy; imatinib (IM), a first generation tyrosine kinase inhibitor (TKIs). Quantitation of cytokines like Interleukin-6, Interleukin-7 and Transforming growth factor-α plasma levels before IM therapy, could assess early molecular response (EMR) to IM and predict imatinib failure. A case-control study of 30 CML patients and 30 controls. Levels of IL-6, IL-7 and TGF-α were assayed by ELISA (R&D systems, USA) for both controls and patients. The patients' BCR-ABL1 transcript was assayed by real time-quantitative polymerase chain reaction, using ipsogen® BCR-ABL1 Mbcr Kit on the Rotor-Gene Q MDx (Qiagen, USA). Cytokines and BCR-ABL1 levels were done both before therapy and at 3 months follow up. Three months following IM therapy, the patients were divided into improved (n= 27) and non-improved (n= 3) groups; based on the establishment of EMR. Plasma levels of IL-7, IL-6 and TGF-α were significantly higher in CML patients (p< 0.05). Cytokines plasma levels dropped significantly after IM therapy (p< 0.05). Correlation studies revealed a strong positive correlation between pretreatment levels of both IL-6 and TGF-α and posttreatment levels of BCR-ABL transcript (r= 0.89 and 0.84, respectively). IL-7 showed a poor correlation with posttreatment levels of BCR-ABL transcript (r= 0.32). Our study revealed a possible role of IL-6, IL-7 and TGF-α as mediators of CML. The initial high levels of IL-6 and TGF-α was associated with the failure of achieving EMR. The initial high levels of IL-7 in CML patients appears to facilitate the disease process. [ABSTRACT FROM AUTHOR]

We conducted this study to identify the factors for predicting poor outcomes in chronic myeloid leukemia patients who failed to achieve a 3-month early molecular response (EMR). Of the 413 newly diagnosed, chronic phase, chronic myeloid leukemia patients receiving imatinib (IM), 120 (29.1%) failed to achieve a 3-month EMR. With a median follow-up of 67.0 months, 39 patients continued IM treatment with at least complete cytogenetic response (CCyR), and 81 patients permanently discontinued IM treatment. The cumulative incidence rates of CCyR and major molecular response (MMR) by 3 years were 90.1 ± 3.9% and 53.7 ± 7.3%, respectively. After adjusting for potential factors, multivariate analyses showed that a transcript type of e13a2, compared with e14a2, and a larger spleen size were independent factors for failure of overall MMR. The predictive factors outlined in this study may provide valuable information for high-risk patients who would benefit from early decision-making regarding therapy change. [ABSTRACT FROM AUTHOR]

A reduction in BCR-ABL1/ABL1IS transcript levels to BCR-ABL1 thresholds in predicting treatment outcomes for 184 subjects diagnosed with CML and treated with standard-dose imatinib mesylate (IM). With a median follow-up of 61 months, patients with concordant BCR-ABL1/ABL1IS transcripts below the defined thresholds (10% at 3 months and 1% at 6 months) displayed significantly superior rates of event-free survival (86.1% vs. 26.6%) and deep molecular response (≥ MR4; 71.5% vs. 16.1%) compared to individuals with BCR-ABL1/ABL1IS levels above these defined thresholds. We then analyzed the outcomes of subjects displaying discordant molecular transcripts at 3- and 6-month time points. Among these patients, those with BCR-ABL1/ABL1IS values >10% at 3 months but BCR-ABL1/ABL1IS 1% at 6 months (event-free survival 68.2% vs. 32.7%; p < 0.001). Likewise, subjects with BCR-ABL1/ABL1IS at 3 months >10% but 4 compared to patients with BCR-ABL1/ABL1IS 1% at 6 months (75% vs. 18.2%; p < 0.001). Finally, lower BCR-ABL1/GUSIS transcripts at diagnosis were associated with BCR-ABL1/ABL1IS values p < 0.001). Our data suggest that when assessing early molecular responses to therapy, the 6-month BCR-ABL1/ABL1IS level displays a superior prognostic value compared to the 3-month measurement in patients with discordant oncogenic transcripts at these two pivotal time points.

Purpose of Review: Although tyrosine kinase inhibitors (TKIs) spectacularly improve the disease burden and the overall survival of chronic myeloid leukemia patients, early identification of a subset of poor TKI responders has been recognized as a critical goal to prevent disease progression in these patients. We herein review the past and recent evidence on the impact of early response. Recent Findings: In the recent years, the achievement of an early molecular response (EMR, defined as 3-month BCR-ABL1 transcript <10% IS) has emerged as a useful tool to identify poor-risk patients. Although several groups have reported the importance of such milestone, clinical intervention based on it remains controversial partly due to its low specificity to predict progression, which may be partially improved by using the rate of decline in BCR-ABL1 transcript level (halving time or velocity of ratio reduction). Summary: Standardization of halving time or velocity of ratio reduction will likely help establishing more stringent recommendation and modify current clinical practices. [ABSTRACT FROM AUTHOR]

Achieving a BCR-ABL/ABL ratio <10% at 3 months has become an important goal of treatment for chronic myeloid leukemia (CML) patients treated with tyrosine kinase inhibitors. Several evidences showed that this early molecular response (EMR) is associated with positive long-term outcome in terms of overall survival and progression-free survival, but a consensus has not been reached when this goal is not achieved. European LeukemiaNet recommendations defined patients as treatment failure only after the 6- month time point. Not all patients that lack EMR have similar outcome and it became important to identify patients before this time point of 3 months. Several groups introduced the concept of “halving time” or “velocity of ratio reduction” that could anticipate the possibility to recognize patients deserving a switch to another treatment. Aim of this review is to summarize all evidences reported on the significance of EMR and how this evaluation changed our perspectives and modified our therapeutic strategies. [ABSTRACT FROM AUTHOR]

Response to frontline BCR-ABL1-targeted tyrosine kinase inhibitor (TKI) therapy is associated with an improved prognosis for patients with chronic myeloid leukemia (CML). Accordingly, the National Comprehensive Cancer Network (NCCN) and European LeukemiaNet (ELN) recommend the use of specific response milestones (eg, BCR-ABL1 ≤ 10% on the International Scale at 3 months) to assess treatment success and inform follow-up care, including potentially switching to another TKI therapy. However, prior to any treatment change, the potential benefits and risks of each TKI and the goals of the patient must be considered. Here we review current NCCN and ELN response recommendations for patients with CML, highlight the impact of early responses on long-term prognosis, and discuss several reasons patients may consider a switch in TKI therapy. We also review completed and ongoing clinical studies involving a switch in frontline therapy for patients with CML, including those with a treatment-free remission phase. [ABSTRACT FROM AUTHOR]

Multiple BCR-ABL tyrosine kinase inhibitors (TKIs) are available for the treatment of chronic myeloid leukemia in chronic phase (CML-CP), and several baseline and on-treatment predictive factors have been identified that can be used to help guide TKI selection for individual patients. In particular, early molecular response (EMR;BCR-ABL ≤10% on the International Scale at 3 months) has become an accepted benchmark for evaluating whether patients with CML-CP are responding optimally to frontline TKI therapy. Failure to achieve EMR is considered an inadequate initial response according to the National Comprehensive Cancer Network guidelines and a warning response according to the European LeukemiaNet recommendations. Here we review data supporting the importance of achieving EMR for improving patients’ long-term outcomes and discuss key considerations for selecting a frontline TKI in light of these data. Because a higher proportion of patients achieve EMR with second-generation TKIs such as nilotinib and dasatinib than with imatinib, these TKIs may be preferable for many patients, particularly those with known negative prognostic factors at baseline. We also discuss other considerations for frontline TKI choice, including toxicities, cost-effectiveness, and the emerging goals of deep molecular response and treatment-free remission. [ABSTRACT FROM PUBLISHER]

Patients with chronic myeloid leukemia in chronic phase who achieve early molecular response ( EMR; generally defined as BCR- ABL ≤ 10% on the International Scale at 3 or 6 months) have improved outcomes. However, there is no consensus on whether EMR failure at 3 months requires a change in therapy, and the value of the 6-month time point remains under debate. Some patients who do not achieve EMR at 3 months achieve significant decreases in BCR- ABL levels by 6 months, whereas others have progressive disease. For patients who do not achieve EMR at either time point, the risk of disease progression is higher both between 3 and 6 months and over the longer term, underlining the therapeutic relevance of the 3- to 6-month time period. For patients with EMR failure at 3 months, although there is currently no consensus on whether to switch therapy or wait until the 6-month assessment, some patients may benefit from an early change in treatment. This review synthesizes key clinical data demonstrating improved outcomes associated with the achievement of EMR and discusses the relevance of the 3- and 6-month time points on survival and the risk of disease progression. Several potential clinical situations are also presented to explore when a change in therapy may be considered. [ABSTRACT FROM AUTHOR]

Early molecular response (MR) defined by BCR-ABLIS levels has prognostic impact in chronic myeloid leukemia (CML). MR was evaluated at 3 and 6 months after switching to nilotinib or dasatinib in 115 patients with resistance to imatinib. Three groups were delineated at 3 months (< 1%, 1-10% or > 10% BCR-ABLIS levels) with different outcomes at 3 years regarding major molecular response (MMR, 91%, 47%, 22%, p < 0.001), failure-free survival (FFS), progression-free survival (PFS, 96%, 89% and 78%, p = 0.05) and overall survival (OS). After 6 months, patients with MR < 1% had higher 3-year MMR (83% vs. 16%, p < 0.001), FFS, PFS (94% vs. 84%, p = 0.05) and OS. Four patients had 3-month and 6-month MR > 10% and < 1%, respectively (3-year FFS 50%). Thirteen had 3-month and 6-month MR < 10% and ≥ 1%, respectively (3-year FFS 38%). These findings confirm the strong predictive value of 3-month and 6-month BCR-ABLIS levels in imatinib-resistant patients. [ABSTRACT FROM AUTHOR]

To explore the factors for achieving early molecular responses (EMR; BCR-ABL1 ≤10% at 3 months, ≤1% at 6 months) by imatinib (IM), baseline characteristics including individual BCR-ABL1 transcript level, dose intensity, and IM trough level on day 29 were analyzed in 286 chronic phase chronic myeloid leukemia patients. Distinct predictive factors for achieving EMR at 3 months and 6 months were noted. Blast count at diagnosis and IM trough level on day 29 were significantly associated with an achievement of 3-month EMR. Early decline of BCR-ABL1 transcript, low Sokal risk, and mean daily dose (≥350 mg/day) by 6 months were associated with an achievement of 6-month EMR. Understanding the predictive factors for EMR may provide additional information to guide clinical decisions on the changing therapies at each landmark. [ABSTRACT FROM AUTHOR]

Context Nilotinib is a second-generation BCR-ABL1 tyrosine kinase inhibitor used in the treatment of chronic myeloid leukemia (CML). Aims We aim to evaluate the responses and safety of upfront Nilotinib therapy in Indian CML patients. Setting and Design We retrospectively reviewed the medical records of CML patients who received Nilotinib as an upfront treatment at our center between January 1, 2011 and October 15, 2019.The follow-up was taken till March 31, 2020. Results Forty One patients ( n = 36 chronic phase and five accelerated-phase CML) received frontline Nilotinib. Median age was 39 years (21-63) with male-to-female ratio of 1.1: 1. At 3 months, 96.9% patients achieved BCR-ABL of ≤10% at international scale. By the end of 12 months, 71.5% patients achieved major molecular response (BCR-ABL ≤0.1%) and 91.4% patients achieved complete cytogenetic response assessed by BCR-ABL polymerase chain reaction of ≤1%. Common toxicities observed were weight gain, thrombocytopenia, corrected QT prolongation, and elevated serum amylase in 14 (34.1%), 7(17.07%), 4(9.7%), and 4(9.7%) patients, respectively. Overall, five patients had loss of response with further progression and death in three patients. At a median of 43.7 months, 38 patients survived with estimated 3 year event-free survival and overall survival of 65 ± 9 and 93 ± 5%. Conclusion This study showed remarkable good response with upfront Nilotinib in Indian patients with CML., Competing Interests: Conflict of interest The authors declare that they have no conflict of interest., (MedIntel Services Pvt Ltd. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

A reduction in BCR-ABL1/ABL1IS transcript levels to <10% after 3 months or <1% after 6 months of tyrosine kinase inhibitor therapy are associated with superior clinical outcomes in chronic myeloid leukemia (CML) patients. In this study, we investigated the reliability of multiple BCR-ABL1 thresholds in predicting treatment outcomes for 184 subjects diagnosed with CML and treated with standard-dose imatinib mesylate (IM). With a median follow-up of 61 months, patients with concordant BCR-ABL1/ABL1IS transcripts below the defined thresholds (10% at 3 months and 1% at 6 months) displayed significantly superior rates of event-free survival (86.1% vs. 26.6%) and deep molecular response (≥ MR4; 71.5% vs. 16.1%) compared to individuals with BCR-ABL1/ABL1IS levels above these defined thresholds. We then analyzed the outcomes of subjects displaying discordant molecular transcripts at 3- and 6-month time points. Among these patients, those with BCR-ABL1/ABL1IS values >10% at 3 months but <1% at 6 months fared significantly better than individuals with BCR-ABL1/ABL1IS <10% at 3 months but >1% at 6 months (event-free survival 68.2% vs. 32.7%; p < 0.001). Likewise, subjects with BCR-ABL1/ABL1IS at 3 months >10% but <1% at 6 months showed a higher cumulative incidence of MR4 compared to patients with BCR-ABL1/ABL1IS <10% at 3 months but >1% at 6 months (75% vs. 18.2%; p < 0.001). Finally, lower BCR-ABL1/GUSIS transcripts at diagnosis were associated with BCR-ABL1/ABL1IS values <1% at 6 months (p < 0.001). Our data suggest that when assessing early molecular responses to therapy, the 6-month BCR-ABL1/ABL1IS level displays a superior prognostic value compared to the 3-month measurement in patients with discordant oncogenic transcripts at these two pivotal time points. [ABSTRACT FROM AUTHOR]

First-line nilotinib in chronic myeloid leukemia is more effective than imatinib to achieve early and deep molecular responses, despite poor tolerability or failure observed in one-third of patients. The toxicity and efficacy of tyrosine kinase inhibitors might depend on the activity of transmembrane transporters. However, the impact of transporters genes polymorphisms in nilotinib setting is still debated. We investigated the possible correlation between single nucleotide polymorphisms of hOCT1 (rs683369 [c.480C>G]) and ABCB1 (rs1128503 [c.1236C>T], rs2032582 [c.2677G>T/A], rs1045642 [c.3435C>T]) and nilotinib efficacy and toxicity in a cohort of 78 patients affected by chronic myeloid leukemia in the context of current clinical practice. The early molecular response was achieved by 81% of patients while 64% of them attained deep molecular response (median time, 26 months). The 36-month event-free survival was 86%, whereas 58% of patients experienced toxicities. Interestingly, hOCT1 and ABCB1 polymorphisms alone or in combination did not influence event-free survival or the adverse events rate. Therefore, i n contrast to data obtained in patients treated with imatinib, hOCT1 and ABCB1 polymorphisms do not impact on nilotinib efficacy or toxicity. This could be relevant in the choice of the first-line therapy: patients with polymorphisms that negatively condition imatinib efficacy might thus receive nilotinib as first-line therapy., Competing Interests: CONFLICTS OF INTEREST SG, ADP, AI, GS, GRC, MP, CF participated to advisory boards sponsored by Novartis. Nevertheless, all authors declare no conflicts of interest concern this spontaneous, not industry-sponsored study.

Introduction: With the discovery of imatinib mesylate nearly 20 years ago, tyrosine kinase inhibitors (TKIs) were found to be effective in chronic myeloid leukemia (CML). TKI therapy has since revolutionized the treatment of CML and has served as a paradigm of success for targeted drug therapy in cancer. Several new TKIs for CML have been approved over the last two decades that exhibit improved potency over imatinib and have different off-target profiles, providing options for individualized therapy selection. Areas covered: Current management of chronic phase CML, including guidance on the sequential use of imatinib and newer-generation TKIs and evolving treatment strategies such as TKI discontinuation. Relevant literature was identified by searching biomedical databases (i.e. PubMed) for primary research material. Expert commentary: Although survival outcomes have drastically improved for CML patients, treatment for CML has grown more complex with the introduction of next-generation TKIs and the advent of treatment-free remissions (TFR). Goals of therapy have shifted accordingly, with increased focus on improving quality of life, managing patient expectations and optimizing patient adherence.

An early molecular response has a strong predictive value in chronic myeloid leukemia (CML). Recently, the halving time (velocity of early BCR-ABL1 transcript elimination) has been shown to represent an additional prognostic index. Our objective was the evaluation of the prognostic significance of the 3-month point in our population. We retrospectively collected BCR-ABL1 transcript data at different time points, events, and survival data of patients with CML treated at the Division of Hematology, San Luigi Hospital, University of Turin, Turin, Italy. Of 71 patients diagnosed from January 2005 to March 2015 in our center and treated with front-line tyrosine kinase inhibitors (imatinib, nilotinib and dasatinib), we selected those who had undergone a molecular evaluation at 3 months. The event-free survival (EFS) by the median follow-up time was the primary endpoint. The data from 50 patients with CML chronic phase were analyzed. Overall, 34 of the 50 patients (68%) had a transcript ≤ 10% at 3 months. Of those in the > 10% group, 63% had experienced an event compared with 12% in the ≤ 10% group by the median follow-up point (P < .001). The halving time threshold for discriminating between EFS was 17 days. None of the patients with a transcript > 10% at 3 months had a halving time of ≤ 17 days. Patients with BCR-ABL1 ≤ 10% and a halving time of ≤ 17 days had significantly better EFS than that of patients with BCR-ABL1 ≤ 10% and a halving time > 17 days and of patients with BCR-ABL1 > 10% (96% group 1 vs. 60% group 2 vs. 27% group 3; P < .001). Irrespective of the tyrosine kinase inhibitor used, the prognosis was significantly superior for patients with BCR-ABL1 ≤ 10% and halving time of ≤ 17 days. Our data revealed that the use of ABL1 as a control gene is reliable for the determination of the halving time in the clinical setting and highlight the importance of measuring the BCR-ABL1 transcript at CML diagnosis., (Copyright © 2016 Elsevier Inc. All rights reserved.)