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

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

Low-dose dasatinib 50 mg/day versus standard-dose dasatinib 100 mg/day as frontline therapy in chronic myeloid leukemia in chronic phase: A propensity score analysis.

Low-dose dasatinib is safe and effective in patients with chronic myeloid leukemia in chronic phase (CML-CP). No randomized trials have compared the outcome with standard-dose dasatinib. This study aims to compare the outcome of patients with CML-CP treated with frontline dasatinib 50 versus 100 mg/day. We analyzed 233 patients with newly diagnosed CML-CP treated with low-dose dasatinib (N = 83) or standard-dose dasatinib (N = 150). Propensity score analysis with 1:1 matching was performed and identified 77 patients in each cohort without significant baseline differences. Response rates were reported as the cumulative incidences of complete cytogenetic response, major molecular response (MMR), molecular response (MR)4, and MR4.5. Failure-free survival (FFS), event-free survival (EFS), transformation-free survival (TFS), and overall survival (OS) were also compared. Patients on low-dose dasatinib with suboptimal response by European LeukemiaNet (ELN) 2013 criteria had the option to increase the dose to 100 mg/day. The overall median follow-up time was 60 months. The 3-year MMR rates were 92% and 84% for low-dose and standard-dose dasatinib, respectively (p = .23). Dasatinib 50 mg/day induced higher cumulative incidence of MR4 (77% vs. 66%; p = .04) and MR4.5 (77% vs. 62%; p = .02) at 3 years. The 4-year FFS, EFS and OS rates were 89% versus 77% (p = .04), 95% versus 92% (p = .06), and 97% versus 96% (p = .78) with low-dose and standard-dose dasatinib, respectively. The rate of any grade pleural effusion was 5% with dasatinib 50 mg/day compared to 21% with 100 mg/day. Dasatinib 50 mg/day is at least as effective as 100 mg/day with a better safety profile and drug exposure.

Lower tumor burden is associated with better cognitive function in patients with chronic phase chronic myeloid leukemia.

Cognitive function was assessed in patients with chronic myeloid leukemia in the chronic phase (CML-CP) receiving tyrosine kinase inhibitor (TKI) therapy using the Montreal Cognitive Assessment (MoCA). Cross-sectional assessments of 100 newly diagnosed patients and 584 patients receiving TKI therapy for >1 year showed that 31 (31.0%) and 191 (32.7%) patients had mild cognitive impairment, respectively. In the multivariable analyses, higher percentages of blood blasts were associated with a worse MoCA score at diagnosis [ß = -0.29, 95% confidence interval (-0.54, -0.03), p = .027]; deeper molecular response [versus < major molecular response, ß = 0.74 (0.07, 1.40), p = .029], better MoCA score on TKI therapy. Increased MoCA scores were observed after 12 months of TKI therapy in 42 patients who were regularly followed up (p = .005). Lower tumor burden is associated with better cognitive function in CML-CP patients both at diagnosis and during TKI therapy.

Outcomes of adolescents and young adults with chronic-phase chronic myeloid leukaemia treated with tyrosine kinase inhibitors.

INTRODUCTION: Few studies have reported the outcomes of adolescents and young adults (AYAs) with chronic-phase chronic myeloid leukaemia (CML-CP) on tyrosine kinase inhibitors (TKIs). MATERIALS AND METHODS: We retrospectively analysed the clinical features, treatment response, and long-term outcomes of 42 AYA patients, in comparison to older patients. The initial therapies of AYA patients between 2001 and 2016 included imatinib (n = 24), dasatinib (n = 13) and nilotinib (n = 5). RESULTS: In AYA patients, the peripheral blood (PB) white blood cell count and percentage of blasts at the diagnosis were significantly higher, haemoglobin levels were lower and the spleen size was larger. The major molecular response (MMR), event-free survival (EFS) and overall survival (OS) rates were comparable. A sub-analysis comparing imatinib to second-generation TKIs as the initial therapy also showed that their prognosis was comparable. DISCUSSION: In conclusion, the tumour burden at the diagnosis of CML-CP is higher in AYA patients; however, their prognosis was not worse in comparison to older patients treated with TKIs. KEY MESSAGESFew studies have reported the outcomes of adolescents and young adults (AYAs) with chronic-phase chronic myeloid leukaemia (CML-CP) on tyrosine kinase inhibitors (TKIs). This study showed the tumour burden at the diagnosis of CML-CP is higher in AYA pa tients; however, their prognosis was not worse in comparison to older patients treated with TKIs. Understanding the biological and non-biological features of AYA patients with CML-CP on TKI therapy is essential for better management and to improve the outcomes.

Asymptomatic chronic-phase chronic myeloid leukemia BCR-ABL. (+) without splenomegaly: A case report.

Chronic Myeloid Leukemia (CML) is one of the myeloproliferative disorders characterized by Philadelphia chromosome presence. Contrary to Western countries, most CML patients in Indonesia present symptoms with splenomegaly as the most common finding. It is rare to find asymptomatic CML patients. We present a case of asymptomatic chronic-phase chronic myeloid leukemia BCR-ABL (+) without splenomegaly who achieved a hematologic and molecular response to imatinib.

BCR-ABL1 transcript doubling time as a predictor for treatment-free remission failure after imatinib discontinuation in chronic myeloid leukaemia in chronic phase.

The doubling time (DT) of the BCR-ABL1 quantitative polymerase chain reaction (qPCR) transcript level reflects the re-growing fraction of leukaemic cells after discontinuation of tyrosine kinase inhibitor (TKI). The present study analyzed monthly DT within six months after imatinib discontinuation in 131 patients. Monthly DT was calculated as x = ln(2)/K, where x is the DT and K is the fold BCR-ABL1 change from the previous value divided by the number of days between each measurement. The optimal DT value was determined as 12·75 days at two months using a recursive partitioning method. The patients were stratified into three groups: the high-risk group (DT<12·75 days but >0, with rapidly proliferating chronic myeloid leukaemia (CML) cells; n = 26) showed the lowest molecular relapse-free survival (mRFS) of 7·7% at 12 months, compared to 53·6% in the intermediate-risk group (DT≥12·75 days, with slowly proliferating CML cells; n = 16) or 90·0% in the low-risk group (DT≤0, i.e., without proliferating CML cells; n = 71; P < 0·001). Monthly assessment of DT helps identify high-risk patients for treatment-free remission failure with an imminent risk of molecular recurrence, and to define low-risk patients who can be spared the frequent monitoring of monthly molecular tests.

Serial evaluation of the pharmacokinetics of ponatinib in patients with CML and Ph + ALL.

Although tyrosine kinase inhibitors (TKIs) play a crucial role in the treatment of chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL), intolerance and resistance to TKIs have been serious problems. Due to a lack of research, the importance of the pharmacokinetics (PK) of TKIs is currently unclear. We examined the PK of the third-generation TKI ponatinib to monitor side effects and efficacy during treatments for one patient with CML-chronic phase (CP-CML) and two who received allogeneic hematopoietic stem cell transplantation (allo-HSCT), one for CML-blastic crisis (BC-CML) and one for Ph + ALL. The patient with CP-CML was intolerant to multiple TKIs (dasatinib, nilotinib, imatinib, and bosutinib) and thus was switched to ponatinib (15 mg/day). The patients who received allo-HSCT for BC-CML and Ph + ALL received ponatinib (15 mg/day) as maintenance therapy. Notably, serial evaluation of the PK of ponatinib showed that the median trough values (ng/ml) were 17.2 (12.2-34.5), 33.1 (21.2-40.3) and 27.7 (13.6-29.9) in patients 1, 2, and 3, respectively. These values were around the target concentration (23 ng/ml). All patients are maintaining complete remission without side effects. In conclusion, serial evaluation of PK of ponatinib may yield meaningful information about its safety and efficacy.

Higher red blood cell distribution width at diagnose is a simple negative prognostic factor in chronic phase-chronic myeloid leukemia patients treated with tyrosine kinase inhibitors: A retrospective study.

ABSTRACT: The aim of this study was to evaluate the ability of the red blood cell distribution width (RDW) to predict prognosis and treatment response in chronic myeloid leukemia (CML)-chronic phase (CP) patients treated with tyrosine kinase inhibitor (TKIs).We retrospectively enrolled 93 newly diagnosed CML-CP patients treated with TKIs from 2009 to 2018 at the First Hospital of Lanzhou University. Patients were divided into 2 groups using an RDW of 18.65% determined by receiver operating characteristic curve analysis. We analyzed the correlation of treatment responses and the RDW compared to common scoring systems, as well as the correlation of the RDW with disease outcome, including overall survival (OS) and progression-free survival (PFS), and demographic and laboratory factors affecting outcome. Univariate analysis and Cox regression analysis were used.The median age of patients was 40 years, and 51 patients (54.8%) were men. A high RDW could predict treatment response at 3 months (P = .03) and 6 months (P = .02). The RDW was significantly lower in patients who achieved molecular response by 3 months (P < .001) and complete cytogenetic response by 6 months (P = .001) than in those who did not respond. Patients with a high RDW (>18.65%, n = 35) had significantly worse 5-year OS (77.1% vs 96.6%; P = .008) and PFS (80.0% vs 98.3%; P = .002) than those with a low RDW (≤18.65%, n = 58). Multivariate analysis demonstrated that a high RDW was an adverse predictor of OS (P = .005, HR (hazard ratio) = 9.741) and PFS (P = .009, HR = 16.735).The RDW is a readily available prognostic marker of outcome in patients with CML-CP and can predict treatment response to TKIs. Further larger and prospective studies are required.

Efficacy and safety profile of generic imatinib in patients with newly diagnosed chronic myeloid leukemia-chronic phase: sharing experience of a hemato-oncology center from eastern India.

In India, CML is the commonest adult leukemia. Imatinib is the gold standard for frontline treatment of newly diagnosed CML-CP patients. The present study was conducted to assess the efficacy and safety of generic imatinib in newly diagnosed CML-CP patients. In this prospective study, 76 newly diagnosed CML-CP patients received generic imatinib. They were monitored as per the ELN2013 recommendation. Karyotyping and BCR-ABL transcript level were done at specified time points. Adverse effects, if any, were documented as per the NCI-CTCAE criteria v4.03. Statistical analysis was done using standard methods. A total of 76 patients included in the study; median age was 36 years. The most common (71%) presenting symptom was fatigue; splenomegaly was found in all patients. CHR was achieved in 97% cases. At 3 months, 64.5% patients achieved ERM. At 6 months, CCyR and MCyR had seen in 65% and 68% cases, respectively. MMR achieved at 12 months in 44% cases. Most common hematological and non-hematological toxicity were anemia and skin changes seen in 89.5% and 71% cases, respectively. With generic imatinib therapy, the results of treatment outcome and safety profile were comparable with original imatinib. The added advantage was gross reduction in cost of therapy meeting unmet needs in CML patients in countries with resource constraints.

Optimizing patient selection for treatment-free remission.

The advent of BCR-ABL1 tyrosine kinase inhibitors has revolutionized the treatment and prognosis of chronic myeloid leukemia. Life expectancy for patients with chronic phase chronic myeloid leukemia now nears that of the healthy population; however, optimal outcomes require continuous tyrosine kinase inhibitor administration, which can impact patient quality of life. Consequently, the concept of treatment-free remission has been explored in patients achieving and sustaining a deep molecular response. Heterogeneous data exist with multiple tyrosine kinase inhibitors; however, nilotinib is currently the only therapy that has been approved by the US Food and Drug Administration for treatment-free remission. The decision to pursue treatment-free remission is one that relies heavily on both patient- and disease-related factors. Herein, we will discuss relevant considerations to be made when determining an optimal candidate for treatment-free remission.

Switch from branded to generic imatinib: impact on molecular responses and safety in chronic-phase chronic myeloid leukemia patients.

Since July 2017, different generic imatinib formulations have been introduced in Italy for the treatment of patients with chronic myeloid leukemia (CML). We analyzed 168 chronic phase CML patients treated with branded imatinib for a median of 12 years (range 1-16) at a single institution who switched to a single generic formulation in order to assess the safety and impact on molecular response. The Sokal risk was low/intermediate/high in 63%, 33%, and 4% of patients, respectively. The median duration of generic imatinib treatment was 19 months (range 4-22). Twenty-seven percent of patients were in MMR and 73% were in deep molecular responses (MR4-4.5) at the time of the switch. After 12 months of treatment with generic imatinib, 140 patients were evaluable for response: 23.6% and 76.4% were respectively in MMR and in deep molecular response. When the degree of response was compared with the best molecular response observed with branded imatinib, it was found that 84% of patients maintained the response previously achieved, 6% improved it, and 10% of patients had a molecular fluctuation from the previous deep molecular response to MMR. Only 1 patient lost the MMR and no patient switched to another TKI for inefficacy. In terms of safety, 20% of patients reported new or worsening side effects, but only 2 patients returned to branded imatinib for toxicity. Our data show that the switch to generic imatinib in patients who have been previously treated with branded imatinib appears to maintain efficacy, although a proportion of patients experience new or worsening side effects.

Tyrosine Kinase Inhibitor Dosing Patterns in Elderly Patients With Chronic Myeloid Leukemia.

INTRODUCTION: Tyrosine kinase inhibitors (TKIs) improve the survival rate of patients with chronic myeloid leukemia (CML). However, elderly patients often experience adverse events and require dose adjustments, leading to dose interruptions or treatment discontinuation. We therefore investigated TKI dosing patterns and subsequent outcomes in elderly CML patients. PATIENTS AND METHODS: Using the National Health Information Database, we identified patients with CML aged ≥ 70 years who were prescribed TKIs (imatinib, dasatinib, nilotinib, or radotinib) during 2007-2013. Data on age, sex, prescribed medication, and date of death were extracted. RESULTS: Among the 378 patients, the median age was 75 (range, 70-92) years; the median follow-up period was 53 (range, 1-133) months. Imatinib, dasatinib, nilotinib, and radotinib were prescribed to 324 (85.7%), 110 (29.1%), 93 (24.6%), and 15 (4.0%) patients, respectively. In 42 patients (12.2%), the initial dose was lower than the recommended dose for chronic-phase CML. At last follow-up, 249 patients (65.9%) were receiving a reduced dose. The mean ± standard deviation dose densities of imatinib, dasatinib, nilotinib, and radotinib were 207 ± 121.6, 29 ± 26.7, 235 ± 197, and 123 ± 95.4 mg/day, respectively. The estimated 5-year overall survival probability was 61.0%. Initial TKI dose or dose reduction within first year did not affect the overall survival (P = .0571 and .1826, respectively). CONCLUSION: Dose reduction was observed in 65.9% of the patients at their last visit; except for imatinib, TKI dose densities were < 50% of the recommended dose for the chronic phase. Therefore, the recommended TKI doses might be too high for elderly patients with CML.

Ten-year outcome of chronic-phase chronic myeloid leukemia patients treated with imatinib in real life.

Imatinib, the first BCR/ABL kinase inhibitor approved for the treatment of chronic myeloid leukemia (CML), has changed the long-term outcome of patients affected by this disease. The aim of our analysis was to report, after a median follow-up of 10.2 years (range 5.8-14.8), the long-term outcome, efficacy, and safety of imatinib treatment (frontline and after interferon failure) in a single institution cohort of 459 patients with CML in chronic phase treated outside of clinical trials. The 10-year overall survival of the whole cohort was 77.1%, while the 10-year probability of dying due to CML and other causes was 7.8% and 16%, respectively. The prognostic value of the BCR-ABL1 ratio at 3 months (⩽ 10%) and of complete cytogenetic response and major molecular response at 1 year was confirmed also in the real-life practice. The EUTOS long-term survival score better stratified the baseline risk of dying of CML compared with other risk scores. Two hundred thirty-six (51.4%) patients achieved a deep molecular response during imatinib treatment after a median time of 4.57 years, and 95 (20.6%) had a stable deep molecular response maintained for at least 2 consecutive years. Imatinib was associated with a low rate of serious cardiovascular events and second neoplasia. This 10-year real-life follow-up study shows that imatinib maintains efficacy over time and that long-term administration of imatinib is not associated with notable cumulative or late toxic effects.

Differentiating factors in treatment-free remission trials: impact of study design on results and clinical applications.

For patients with chronic myeloid leukemia in chronic phase with sustained deep molecular responses on long-term tyrosine kinase inhibitor (TKI) therapy, treatment-free remission (TFR) feasibility has been established. TFR is now a treatment goal for patients meeting specific criteria; NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for CML have developed criteria for attempting TFR outside clinical trials, and TFR was added to the US Food and Drug Administration-approved nilotinib label. Importantly, TFR studies vary in design and characteristics of participating patients. We discuss key study design elements to consider when assessing results from TFR trials, including criteria for attempting TFR, characteristics of enrolled patients, use of a consolidation phase (whereby patients continue TKI treatment on study before attempting TFR), and criteria for restarting TKI therapy. Finally, we review the criteria outlined in the NCCN Guidelines® for TFR outside clinical trials and compare to criteria used in TFR studies.