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Purpose: This study aimed to explore the health-related quality of life (HRQoL) and associated variables in children with chronic myeloid leukemia in the chronic phase (CML-CP) receiving tyrosine kinase inhibitors (TKIs)., Methods: A cross-sectional questionnaire was given to children with CML and their parents, who were < 18 years at diagnosis of CML and < 19 years at study. The questionnaire comprised three parts, including demographic information, clinical information, and the Chinese version of Pediatric Quality of Life Inventory ™ (PedsQL ™ ) Cancer Module 3.0 as HRQoL questionnaire., Results: A total of 240 respondents data were analyzed. Multivariate analysis showed that children with symptoms had worse pain (- 10.2; P < 0.001), nausea (- 17.3; P = 0.001), more treatment anxiety (- 7.2; P = 0.005), worse self-assessment appearance (- 7.1; P = 0.001), communication problems (- 6.4; P = 0.001), and worse HRQoL (- 7.0; P < 0.001). Children with mothers having low educational qualifications had worse pain (- 6.0; P = 0.014), more worried about future (- 5.4; P = 0.042), worse cognition problems (- 7.1; P = 0.002), worse communication problems (- 5.5; P = 0.008), and worse HRQoL (- 4.3; P = 0.005). Younger age children at study had more procedural anxiety (2.7; P = 0.001), treatment anxiety (- 1.7; P = 0.014) and cognition problem (3.6; P < 0.001), as well as worse HRQoL (1.8; P = 0.008). However, older age children at diagnosis were more worried about future (- 2.8; P = 0.001), worse self-assessment appearance (- 1.1; P = 0.042) and worse HRQoL (- 1.8; P = 0.007). Other variables significantly associated with worse HRQoL included female gender, rural household registration and their father's low education level. Parents reported more gastrointestinal disorders, were worried about the future and had less concern about appearance than their children., Conclusions: Female gender, older age at diagnosis, younger age at study, lower mother's education level, and TKI-related symptoms are significantly associated with worse HRQoL in Children with CML. Children and their parents have different priorities in the HRQoL., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

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.

Objectives: SIMPLICITY (NCT01244750) is an observational study of patients with chronic-phase chronic myeloid leukemia (CP-CML) in routine clinical practice receiving first-line tyrosine kinase inhibitors (TKIs). We evaluated TKI treatment changes and how switching affects clinical response in patients recruited in Europe with ≥3 years of follow-up., Methods: The SIMPLICITY European cohort (France, Germany, Italy, the Netherlands, Russia, and Spain) included 431 patients. 370 (86%) were followed for ≥3 years., Results: Proportions of patients experiencing treatment interruptions, TKI switching, and discontinuations decreased over 3 years' follow-up. Intolerance was a key driver for treatment changes. Complete cytogenetic response (CCyR) was achieved in 87.5% of patients switching TKI within 3 years of initiation vs 91.7% of non-switchers. Major molecular response (MMR) was achieved in 82.4% of switchers vs 92.9% of non-switchers. Over 3 years, not switching TKI was a strong predictor for achieving CCyR or MMR (both P < .05). Three-year survival remained high, irrespective of treatment changes (95.3% switchers, 96.4% non-switchers)., Conclusions: European patients with CP-CML who do not switch TKI are more likely to achieve clinical response, while intolerance is a key driver for switching. Successful CML management may require careful selection of initial TKI, with early monitoring of response and intolerance., (© 2020 The Authors. European Journal of Haematology published by John Wiley & Sons Ltd.)

Tyrosine kinase inhibitor (TKI) therapy discontinuation practice in patients with chronic myeloid leukemia chronic phase (CML-CP) was assessed in real-world practice prior to the release of recommendations on discontinuation. Data were collected from US oncologists/hematologists (through web-based physician survey and patient chart review) on TKI therapy discontinuation practice including monitoring, adequate response for discontinuation, relapse, and symptoms following discontinuation. From the physician survey, 34% of oncologists/hematologists attempted discontinuation, with two-thirds doing so outside of a trial. From the chart review, TKI therapy was discontinued in 3.4% of patients after they achieved an adequate response with the intention to remain CML-therapy-free until disease relapse. Among these patients, 21% relapsed and 17% had symptoms following discontinuation. There was a lack of consensus on the definition of adequate response suggesting that discontinuation was attempted without clear guidelines and under suboptimal conditions underscoring the need for physician education regarding guidelines for TKI therapy discontinuation.

Healthcare costs are rising due to an increase in chronic diseases, including chronic myeloid leukemia (CML) due to improved survival. In CML care, patient adherence and physician adherence are key elements. We assessed the potential health gain and cost savings when both are improved, using a decision analytic model that integrated various sources of evidence. The current situation was compared to a theoretical situation in which either patient or physician adherence is improved, in terms of costs and quality-adjusted life years (QALYs). Current patient adherence rate is 74%, improvement to 100% resulted in 0.1031 QALYs gained and a saving of €17,509 per patient over a 25-year period. Improving physician adherence from 72% to 100%, resulted in 0.0380 QALYs and €7606. Enhancement of either adherence results in substantial health gain and cost savings. Regarding the rising healthcare costs, new strategies should focus on improving adherence to keep healthcare affordable in the future.

Scarce information is available on the use of ponatinib as second-line treatment in chronic phase chronic myeloid leukemia (CP-CML) patients resistant and/or intolerant to prior tyrosine kinase inhibitor (TKI) therapy. We collected data from 29 CML patients, with a median age of 54 years (range 32-72). Eleven patients had received dasatinib, 15 patients received nilotinib, and 3 patients received imatinib as first-line treatment. Forty-five percent of patients started ponatinib for secondary resistance, 38% for primary resistance, 7% for severe intolerance associated to a molecular warning, 7% due to the presence of a T315I mutation, and 3% for severe intolerance. Ponatinib was started at a dose of 45 mg in 60% of patients, 30 mg in 38%, and 15 mg in 2% of patients. Overall, at a median follow-up of 12 months, 85% of treated patients improved the level of response as compared to baseline, with 10 patients achieving a deep molecular response (MR4-4.5). No thrombotic events were recorded. The dose was reduced during treatment in 2 patients due to intolerance and in 8 patients in order to reduce the cardiovascular risk. Ponatinib seems a valid second-line treatment option for chronic phase CML, in particular for patients who failed a front-line second-generation TKI due to BCR-ABL-independent mechanisms of resistance.

Data are limited in developing countries regarding the clinicopathologic features and response to therapy of chronic myeloid leukemia (CML) in the era of imatinib (IM). The objective of this study is to report on the clinicoepidemiologic features of CML in Tunisia, to evaluate the long-term outcome of patients in chronic (CP) or accelerated phase (AP) treated with IM 400 mg daily as frontline therapy, and to determine imatinib's efficacy and safety. From October 2002 to December 2014, 410 CML patients were treated with IM in six Tunisian departments of hematology. Response (hematologic, cytogenetic, and molecular responses) and outcome-overall survival (OS), event-free survival (EFS), and progression-free survival (PFS)-were evaluated. The following prognostic factors were analyzed for their impact on the European leukemia net (ELN) response, OS, EFS, and PFS at 5 years: age, sex, leukocyte count, Sokal score, European Treatment and Outcome Study (EUTOS) score, CML phase, time to starting IM, and impact of adverse events. The median age was 45 years (3-85 years). Two hundred ten (51.2%) patients were male. Splenomegaly was present in 322 of the 410 (79%). Additional cytogenetic abnormalities were encountered in 25 (6.3%) patients. At diagnosis, 379 (92.4%) patients were in CP, 31 (7.6%) were in AP. The Sokal risk was low in 87 (22.5%), intermediate in 138 (35.7%), and high in 164 patients (41.9%). The EUTOS risk was low in 217 (74%), and high in 77 (26%) patients. The rates of cumulative complete cytogenetic response (CCyR), major molecular response (MMR), and molecular response 4/5 log (MR4.5) in CP/AP-CML patients were 72, 68.4, and 46.4%, respectively. The median time to reach CCyR, MMR, and MR4.5 was 6 months (3-51), 18 months (3-72), and 24 months (3-100), respectively. According to the ELN criteria, optimal, suboptimal response, and failure were noted in 206 (51.8%), 61 (15.3%), and 125 (31.4%) patients, respectively. Five-year event-free survival (EFS), progression-free survival (PFS), and overall survival (OS) were 81, 90, and 90%, respectively. By multivariate analysis, AP, high EUTOS risk, and baseline WBC ≥ 150G/l remained independent predictive factors of non-optimal response to IM. The adverse events (AE) of IM were moderate and tolerable. With the caveats that the monitoring of the disease was not optimal, response rates were similar to those reported in previous studies. It is clear to us that improvements should be made in treatment of AP-CML and high Sokal risk group of CP-CML. The frontline use of second-generation tyrosine kinase inhibitor (TKI) is expected to improve the results of the first-line treatment of these high-risk Tunisian patients, but cost and accessibility of this therapy remain the problems in developing countries.

Objectives: The primary goal in management of chronic phase (CP) chronic myeloid leukaemia (CML) is to prevent disease progression to accelerated phase (AP) or blast crisis (BC). We have evaluated progression rates in a decentralised healthcare setting and characterised patients progressing to AP/BC on TKI treatment., Methods: Using data from the Swedish CML register, we identified CP-CML patients diagnosed 2007-2011 who progressed to AP/BC within 2 yrs from diagnosis (n = 18) as well as patients diagnosed in advanced phase during 2007-2012 (n = 36) from a total of 544 newly diagnosed CML cases. We evaluated baseline characteristics, progression rates, outcome and adherence to guidelines for monitoring and treatment., Results: The cumulative progression rate at 2 yrs was 4.3%. All 18 progression cases had been treated with imatinib, and six progressed within 6 months. High-risk EUTOS score was associated to a higher risk of progression. Insufficient cytogenetic and/or molecular monitoring was found in 33%. Median survival after transformation during TKI treatment was 1.4 yrs. In those presenting with BC and AP, median survival was 1.6 yrs and not reached, respectively., Conclusion: In this population-based setting, progression rates appear comparable to that reported from clinical trials, with similar dismal patient outcome. Improved adherence to CML guidelines may minimise the risk of disease progression., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The availability of tyrosine kinase inhibitors has extended therapeutic options for chronic myeloid leukaemia (CML) patients. Monitoring recommendations and clinical response goals have recently been updated. The objective of this study was to describe the profile of CML patients in chronic phase currently receiving first-line therapy, including treatment, monitoring and response kinetics. A multicentre, cross-sectional, epidemiological survey in unselected chronic phase CML patients in France attending consultations during a one-month period was performed. 438 of 697 (62·8%) reported patients were currently receiving first-line treatment and were analysed. Imatinib was the most frequently received treatment (72·4% of patients). Retrospective cytogenetic and molecular assessments at 3, 6, 12 or 18 months were available in 88·4% of patients. At the 12-month assessment, 32·2% were not in major molecular response (MMR). At last assessment, among 355 patients with duration of treatment ≥ 12 months, 91·5% had achieved MMR and 66·5% were in deep molecular response. This study, performed in everyday practice population of CML patients, suggests that monitoring of molecular responses in real-life practice is aligned with European LeukaemiaNet recommendations. The majority of patients still receiving first-line treatment are in optimal response, with a few being classified as in the warning area or responding to failure., (© 2016 John Wiley & Sons Ltd.)

This study elicited time trade-off (TTO) and standard gamble (SG) preference values associated with four health states corresponding to response levels in chronic phase chronic myeloid leukemia (CML) from members of the general public in the UK (n = 235). Health states studied were treatment-free remission (TFR), complete molecular response (CMR, i.e. undetectable disease on treatment), molecular response and reappearance of detectable disease (i.e. relapse from TFR to molecular response requiring treatment). TFR was the most preferred health state (mean utility of 0.97 [TTO] and 0.87 [SG]) followed by CMR (mean utility of 0.96 [TTO] and 0.85 [SG]) followed by molecular response (mean utility of 0.94 [TTO] and 0.80 [SG]) followed by reappearance of detectable disease (mean utility of 0.90 [TTO] and 0.72 [SG]). SG values were significantly lower than TTO values (p < 0.001). The study demonstrated that different treatment responses may impact on the health-related quality of life of patients with chronic phase CML.

Background: A large number of chronic myeloid leukemia (CML) patients are treated with imatinib mesylate outside of clinical trials, which may not be representative of common clinical practice. The age of CML patients enrolled within controlled clinical studies is lower with respect to patients included in population-based registries., Patients and Methods: To describe the safety and tolerability of imatinib in very elderly CML patients in chronic phase, 211 chronic-phase CML patients aged >75 years were retrospectively analyzed using data collected from 31 institutions in Italy., Results: The median age at imatinib start was 78.6 years [interquartile range (IR) 76.3-81.4], median time from diagnosis to imatinib start was 1.2 months (IR 0.5-3.7). The starting dose of imatinib was 400 mg/day in 144 patients (68.2 %), >400 mg/day in 4 patients (2.0 %), and <400 mg/day in 63 patients (29.8 %); overall, 94 patients (44.5 %) needed a dose reduction and 27 (12.7 %) discontinued imatinib for toxicity. Grade 3-4 hematologic and extrahematologic toxicities were observed in 40 (18.9 %) and 45 (21.3 %) patients, respectively. After a median observation of 29.8 months (IR 13.0-55.6), 203/211 patients had at least 6 months of observation on imatinib or discontinued before and were evaluable for response and outcome; of them, 183 patients (90.2 %) achieved a complete hematologic response (CHR). Among these 183 patients in CHR, 14 refused any other karyotypic or molecular evaluation, 24 achieved CHR only, and 145 (71.4 %) achieved a cytogenetic response (CyR) of any grade, which was complete (CCyR) in 129 (63.5 %). Among the 129 patients with CCyR, 95 (46.7 %) achieved a major molecular response (MMolR). By multivariate regression analysis, late chronic phase (p = 0.001) and grade 3-4 extrahematologic toxicity (p = 0.007) maintained a negative independent prognostic impact for CCyR, while late chronic phase (p = 0.026), grade 3-4 extrahematologic toxicity (p = 0.007), and lower initial dose of imatinib (p = 0.044) maintained a negative independent prognostic impact for MMolR. The 2-year and 4-year overall survival were 92.6 % (95 % CI 88.7-96.5) and 78.0 % (95 % CI 71.2-84.8), respectively., Conclusions: Results from this large cohort of patients show that no upper age limit should be applied for the administration of imatinib to patients with chronic-phase CML; the very elderly, including those with concomitant severe diseases, should be offered this treatment. The role of a reduced starting dose of imatinib warrants further studies.

This study estimated time trade-off preference values associated with the four chronic myelogenous leukemia (CML) chronic phase-related health states (i.e. untreated, hematologic response, cytogenetic response and molecular response) among members of the general public in the UK (n = 241). All four health states were associated with decreases in preference values from full health. The molecular response to treatment was the most preferred health state (mean utility of 0.94). The second-most preferred health state was cytogenetic response followed by hematologic response (mean utilities were 0.89 and 0.80, respectively). The least preferred health state was untreated chronic phase CML (mean utility of 0.72). The utility values for each state were significantly different from one another (p < 0.001). This study demonstrated and quantified the impact that more robust treatment responses have on the health-related quality of life of patients with chronic phase CML.

CML in Asia seems to affect the younger age group and more patients are in the high and intermediate Sokal risk group. Cytogenetic study and molecular testing are done mostly at diagnosis, but monitoring the response is limited due to the cost and accessibility. The treatment of chronic phase CML has changed dramatically within the last decade and imatinib has become the standard treatment for CP, CML. Since the cost of imatinib is quite high, most Asian patients cannot afford it. Patients in several countries get imatinib through Glivec International Patient Assistant Program. Patients who are intolerant or resistant to imatinib usually get the second generation tyrosine kinase inhibitors (TKIs), either nilotinib or dasatinib. The National Health Insurance covers all or most of the cost of imatinib in South Korea, Hong Kong and Taiwan. Both nilotinib and dasatinib are partially or fully covered by national insurance in Australia, Japan, Singapore and Taiwan as the second-line therapy. TKIs treatment remains out of reach for many Asian CML patients, especially those in the rural areas and those who are not eligible for patient access programs or covered by the national insurance. The cytogenetic response to imatinib in Asian CML patients varies considerably, from as low as 24% to as high as 96%. The Asia CML Study Alliance was briefly presented.

Dasatinib is a highly potent BCR-ABL inhibitor with established efficacy and safety in imatinib-resistant/-intolerant patients with chronic myeloid leukemia (CML). In the phase 3 DASISION trial, patients with newly diagnosed chronic-phase (CP) CML were randomized to receive dasatinib 100 mg (n = 259) or imatinib 400 mg (n = 260) once daily. Primary data showed superior efficacy for dasatinib compared with imatinib after 12 months, including significantly higher rates of complete cytogenetic response (CCyR), confirmed CCyR (primary end point), and major molecular response (MMR). Here, 24-month data are presented. Cumulative response rates by 24 months in dasatinib and imatinib arms were: CCyR in 86% versus 82%, MMR in 64% versus 46%, and BCR-ABL reduction to ≤ 0.0032% (4.5-log reduction) in 17% versus 8%. Transformation to accelerated-/ blast-phase CML on study occurred in 2.3% with dasatinib versus 5.0% with imatinib. BCR-ABL mutations, assessed after discontinuation, were detected in 10 patients in each arm. In safety analyses, fluid retention, superficial edema, myalgia, vomiting, and rash were less frequent with dasatinib compared with imatinib, whereas pleural effusion and grade 3/4 thrombocytopenia were more frequent with dasatinib. Overall, dasatinib continues to show faster and deeper responses compared with imatinib, supporting first-line use of dasatinib in patients with newly diagnosed CML-CP. This study was registered at ClinicalTrials.gov: NCT00481247.

Objective: To determine the frequency of three phases of chronic myeloid leukaemia at first presentation., Study Design: Case series., Place and Duration of Study: Department of Oncology, Combined Military Hospital (CMH), Rawalpindi, from June 2006 to December 2007., Methodology: Forty-five patients of either gender with Chronic Myeloid Leukaemia (CML) at their first presentation in outpatient department were included in the study by consecutive sampling technique. All patients were diagnosed on blood complete picture and bone marrow examination including aspiration, trephine and cytogenetics at Armed Forces Institute of Pathology (AFIP). Each phase was defined on the basis of World Health Organization (WHO) criteria., Results: Out of 45, there were 31 (68.9%) male and 14 (31.1%) female patients. The mean age of presentation was 37.9 years. The pattern of presentation revealed 35 (77.8%) in Chronic Phase (CP), 7 (15.5%) in Accelerated Phase (AP) and 3 (6.7%) in Blast Crisis (BC). Philadelphia chromosome was detected in 39 (86.7%) cases on culture method. Splenomegaly was observed in 37 (82.2%) patients. The mean total leukocyte count, platelet count, haemoglobin and marrow blast were 214.3 x 10(9)/L, 551.4 x 10(9)/L, 9.94 g/dl and 9.3% respectively., Conclusion: CML presented at a younger age in the chronic phase.

This study sets out to investigate whether the proportion of patients with chronic myeloid leukemia (CML) in the chronic phase who achieve a major cytogenetic response (MCR) can be used as the basis for estimating long-term survival through the use of modeling. Data from seven randomized controlled trials of drugs to treat patients with CML in the chronic phase were used to explore the association between MCR and survival by way of regression analysis. The estimated weighted odds ratio for the survival of those who achieved an MCR when compared with those who did not was 7 (95% CI 5 - 11) at 2 years and 5 (95% CI 3 - 8) at 4 years. Four long-term survival models were subsequently constructed. All models were found to be robust to variations in the data included. Model D was favored using the 'Ockham's razor' principle; it suggests that the median survival may be increased by 1.8 years for every 25 percentage point increase in MCR rate. The results support the use of the proportion of patients with CML in the chronic phase with an MCR to estimate overall long-term survival.

Chronic phase duration was analyzed in 148 Japanese patients with Ph-positive chronic myelocytic leukemia (CML) treated only with busulfan, and multivariate proportional hazard models were constructed to infer the prognosis of a given patient, and to evaluate the prognostic importance of the clinical findings. To make an accurate estimation of an individual patient's prognosis, we introduced a piecewise linear model for describing a hazard function in each prognostic variable. Of the 11 prognostic variables initially analyzed, the absolute count of peripheral basophils was revealed as the most important prognostic factor. A high basophil count was clearly a factor in cases with poor prognosis. The statistical model selection based on the criteria of model approximation finally suggested a model with three covariates; absolute count of peripheral basophils, platelet count, and presence or absence of additional chromosome abnormalities superimposed on the translocation of 9;22. By analyses based on the above model, we estimated that the median of the chronic phase duration for the patients with poor and good prognosis was 12 and 75 months, respectively. The piecewise linear model was well suited for an accurate estimation of an individual patient's prognosis. Thus, the model constructed here would become a reliable control to evaluate investigational approaches, such as hydroxyurea, interferons, and/or bone marrow transplantation.