Outcomes and patterns of treatment in chronic myeloid leukemia, a global perspective based on a real-world data global network.
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ABSTRACT:
SUBMITTER: Sanz A
PROVIDER: S-EPMC9232604 | biostudies-literature | 2022 Jun
REPOSITORIES: biostudies-literature
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Outcomes and patterns of treatment in chronic myeloid leukemia, a global perspective based on a real-world data global network.
Sanz A A Ayala R R Hernández G G Lopez N N Gil-Alos D D Gil R R Colmenares R R Carreño-Tarragona G G Sánchez-Pina J J Alonso R A RA García-Barrio N N Pérez-Rey D D Meloni L L Calbacho M M Cruz-Rojo J J Pedrera-Jiménez M M Serrano-Balazote P P de la Cruz J J Martínez-López J J
Blood cancer journal 20220624 6
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Project description:ObjectivesMaintenance therapy is one strategy to prolong survival in patients with acute myeloid leukemia (AML) following hematopoietic stem cell transplantation (HSCT). We evaluated real-world treatment patterns and outcomes in patients with newly diagnosed FLT3-mutated AML receiving HSCT after complete remission with first-line chemotherapy.MethodsA global, retrospective chart review to evaluate maintenance therapy and outcomes in patients with FLT3-mutated AML after HSCT.ResultsData from 1208 charts from eight countries showed that most patients (n = 765 [63.3%]) received no maintenance therapy after HSCT, 219 (18.1%) received FLT3 inhibitor maintenance therapy, and 224 (18.5%) received other types of maintenance therapy. No systematic differences were observed in healthcare resource utilization across the three groups. Clinical benefit was observed with FLT3 inhibitor maintenance over no maintenance therapy with relapse-free survival (adjusted hazard ratio [HR] 0.57 [95% CI 0.34-0.94], P < .05). FLT3 inhibitor and other maintenance also demonstrated overall survival benefit over no maintenance (adjusted HR 0.50 [95% CI 0.28-0.89] and 0.46 [95% CI 0.23-0.91], respectively; both P < .05).ConclusionsReal-world maintenance therapies after HSCT in patients with FLT3-mutated AML were heterogeneous. While overall use of healthcare resources was not significantly increased in patients receiving maintenance therapy versus those who did not, clinical outcomes were improved.
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Project description:Tyrosine kinase inhibitors (TKI) have revolutionized the treatment of chronic myeloid leukemia (CML), but patients still experience treatment-limiting toxicities or therapeutic failure. To investigate the real-world use and outcomes of imatinib in patients with CML in Australia, a retrospective cohort study of patients with CML commencing imatinib (2001-2018) was conducted across two sites. Prescribing patterns, tolerability outcomes, and survival and molecular response were evaluated. 86 patients received 89 imatinib treatments. Dose modifications were frequently observed (12-month rate of 58%). At last follow-up, 62 patients (5-year rate of 55%) had permanently discontinued imatinib treatment, of which 44 switched to another TKI (5-year rate of 46%). Within 3 months of starting imatinib, 43% (95% CI, 32%-53%) of patients experienced imatinib-related grade ≥3 adverse drug reactions (ADRs). Higher comorbidity score, lower body weight, higher imatinib starting dose, and Middle Eastern or North African ancestry were associated with a higher risk of grade ≥3 ADR occurrence on multivariable analysis (MVA). Estimated overall survival and event-free survival rates at 3 years were 97% (95% CI, 92%-100%) and 81% (95% CI, 72%-92%), respectively. Cumulative incidence of major molecular response (MMR) at 3 years was 63% (95% CI, 50%-73%). On MVA, imatinib starting dose, ELTS score, BCR-ABL1 transcript type, pre-existing pulmonary disease, and potential drug-drug interactions were predictive of MMR. In conclusion, imatinib induced deep molecular responses that translated to good survival outcomes in a real-world setting, but was associated with a higher incidence of ADRs, dose modifications and treatment discontinuations than in clinical trials.
| S-EPMC9475133 | biostudies-literature
Project description: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.
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Project description:Core-binding factor acute myeloid leukemia (CBF-AML) is characterized by the presence of inv(16)/t(16;16) or t(8;21) and is classified as a favorable risk by the 2022 European LeukemiaNet (ELN) guidelines. The CD33-targeting antibody-drug conjugate, gemtuzumab ozogamicin (GO), is commonly added to intensive chemotherapy (IC) in CBF-AML. We sought to compare outcomes in patients treated with IC with or without GO in CBF-AML. We included 200 patients with CBF-AML treated with IC across seven academic centers. Induction treatment regimens were categorized as IC alone, IC with GO, or IC with KIT inhibitor (dasatinib or midostaurin). Median follow-up for the whole cohort was 2.5 years. Three-year overall survival (OS) was 70% and 3-year event-free survival (EFS) was 51%. Patients treated with IC with GO experienced a 3-year EFS of 50% compared to those treated with IC alone who experienced a 3-year EFS of 47%, with no statistically significant difference (p = 0.62). Similarly, those treated with IC with GO did not experience an improved OS compared to those treated with IC alone (p = 0.67). Patients treated with IC with KIT inhibitor experienced a significantly improved 3-year EFS of 85% compared to those with IC with or without GO (p = 0.04). We find in our study that there is no survival benefit in patients treated with IC with the addition of GO; improved EFS was seen in patients with CBF-AML treated with IC plus KIT inhibitors, consistent with outcomes noted in prospective studies utilizing this approach.
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Project description:BackgroundLaboratory testing and treatments for chronic lymphocytic leukemia (CLL) have changed dramatically within the last decade. The authors evaluated changes in patterns of real-world testing and treatment over time by comparing 2 population-based cohorts.MethodsThe National Cancer Institute-sponsored Patterns of Care study was conducted among patients with CLL who were sampled from 14 Surveillance, Epidemiology, and End Results (SEER) program registries. Demographics, testing, and treatment data were abstracted from medical records within 24 months of diagnosis.ResultsA total of 1008 patients diagnosed in 2008 and 1367 patients diagnosed in 2014 were included. There was a significant increase in fluorescence in situ hybridization (FISH) testing, immunoglobulin heavy-chain variable region gene (IgVH ) mutation analyses, and lymph node biopsies between 2008 and 2014. FISH testing was performed in the majority of, but not all, treated patients (53% in 2008, which increased to 62% in 2014). Some differences in the receipt of FISH testing by age and insurance status were observed over time (older patients and Medicare patients without private insurance were less likely to be tested in 2014). There were contrasting testing patterns noted by practice type and year, with nonteaching hospitals more likely to perform bone marrow biopsies in 2008, and teaching hospitals more likely to perform FISH and IgVH testing in 2014. There also were differences in treatments over time, with the use of bendamustine and rituximab being more common in 2014, at the expense of fludarabine, cyclophosphamide, and rituximab.ConclusionsThere have been rapidly changing practices in the testing and treatment patterns of patients with CLL within the last decade.
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Project description:Evaluations of the 'real-world' efficacy and safety of tyrosine kinase inhibitors in patients with chronic myeloid leukemia are scarce. A nationwide, population-based, chronic myeloid leukemia registry was analyzed to evaluate (deep) response rates to first and subsequent treatment lines and eligibility for a treatment cessation attempt in adults diagnosed between January 2008 and April 2013 in the Netherlands. The registry covered 457 patients; 434 in chronic phase (95%) and 15 (3%) in advanced disease phase. Seventy-five percent of the patients in chronic phase were treated with imatinib and 25% with a second-generation tyrosine kinase inhibitor. At 3 years 44% of patients had discontinued their first-line treatment, mainly due to intolerance (21%) or treatment failure (19%). At 18 months 73% of patients had achieved a complete cytogenetic response and 63% a major molecular response. Deep molecular responses (MR4.0 and MR4.5) were achieved in 69% and 56% of patients, respectively, at 48 months. All response milestones were achieved faster in patients treated upfront with a second-generation tyrosine kinase inhibitor, but ultimately patients initially treated with imatinib also reached similar levels of responses. The 6-year cumulative incidence of eligibility for a tyrosine kinase cessation attempt, according to EURO-SKI criteria, was 31%. Our findings show that in a 'real-world' setting the long-term outcome of patients treated with tyrosine kinase inhibitors is excellent and the conditions for an attempt to stop tyrosine kinase inhibitor therapy are met by a third of the patients.
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Project description:Tyrosine kinase inhibitors (TKIs) have been improving the prognosis of patients with chronic myeloid leukemia (CML), but there are still large differences in survival among European countries. This raises questions on the added value of results from population-based studies, which use real-world data, compared to results of randomized controlled trials (RCTs) involving patients with CML. There are also questions about the extent of the findings on RCTs effectiveness for patients in the general population. We compare survival data extracted from our previous systematic review and meta-analysis of CML RCTs with the latest updated population-based survival data of EUROCARE-6, the widest collaborative study on cancer survival in Europe. The EUROCARE-6 CML survival estimated in patients (15-64 years) diagnosed in 2000-2006 vs. 2007-2013 revealed that the prognostic improvement highlighted by RCTs was confirmed in real-world settings, too. The study shows, evaluating for the first time all European regions, that the optimal outcome figures obtained in controlled settings for CML are also achievable (and indeed achieved) in real-world settings with prompt introduction of TKIs in daily clinical practice. However, some differences still persist, particularly in Eastern European countries, where overall survival values are lower than elsewhere, probably due to a delayed introduction of TKIs. Our results suggest an insufficient adoption of adequate protocols in daily clinical practice in those countries where CML survival values remain lower in real life than the values obtained in RCTs. New high-resolution population-based studies may help to identify failures in the clinical pathways followed there.
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Project description:BackgroundThe real-world experience of Swiss chronic myeloid leukemia (CML) patients treated with tyrosine kinase inhibitors (TKIs) is largely unknown, in particular with regard to achievement of response per European Leukemia Net (ELN) criteria and adherence to ELN recommendations.MethodsThis was a retrospective, non-interventional, multicenter chart review of patients with newly diagnosed CML who had received first-line TKI and were solely treated with TKIs between 2010 and 2015, with a minimum follow-up of 18 months, at six Swiss hospitals. Effectiveness was evaluated according to ELN 2013 milestone achievements at 3, 6, 12 and 18 months, and at last follow-up.ResultsData from 63 patients (56% men; median age at diagnosis 55 years) were collected (first-line imatinib [n = 27], nilotinib [n = 27], dasatinib [n = 8], or ponatinib [n = 1]). TKI switches (49 times) and dosing changes (165 times) due to intolerance or insufficient response were frequent. Compared with patients receiving first-line imatinib, a higher proportion of patients receiving first-line nilotinib or dasatinib achieved optimal response at all timepoints, irrespective of subsequent TKI therapy, and a higher proportion of patients treated with first-line nilotinib and dasatinib reached deep molecular response (BCR-ABL1IS ≤ 0.01%) at 18 months (42 and 38%, respectively, versus 27%). Patients who received nilotinib or dasatinib switched therapies less frequently than patients treated with imatinib, irrespective of subsequent TKI therapy.ConclusionsAlthough patient numbers were small, this real-world evidence study with patients with CML confirms that ELN guidelines are generally implemented in Swiss clinical practice, with a large proportion of patients achieving ELN 2013 milestones. While TKI use involved all inhibitors approved at the time of the study, an unexpectedly high number of TKI therapy switches suggests a clear difference in TKI use between registration trials and clinical practice.
| S-EPMC9675134 | biostudies-literature
Project description:BackgroundWe evaluated the frequency of genomic testing and treatment patterns by age category in patients with newly diagnosed (ND) acute myeloid leukemia (AML) treated in both academic- and community-based health systems within a single Midwestern State.MethodsRetrospective analysis of data from the Indiana University Health System Enterprise Data Warehouse and two local cancer registries, of 629 patients aged ≥18 years with ND AML during 2011-2018. Primary outcome variables were, proportion of patients with genomic analysis and frequency of mutations. Chemotherapy was categorized as "standard induction" or "other chemotherapy"/targeted therapy, and hypomethylating agents.ResultsOverall, 13% of ND AML patients between 2011 and 2018 had evidence of a genomic sequencing report with a demonstrated increase to 37% since 2016. Genomic testing was more likely performed in patients: aged ≤60 years than >60 years (45% vs. 30%; p = 0.03), treated in academic versus community hospitals (44% vs. 26%; p = 0.01), and in chemotherapy recipients than non-therapy recipients (46% vs. 19%; p < 0.001). Most common mutations were ASXL1, NPM1, and FLT3. Patients ≥75 years had highest proportion (46%) of multiple (≥3) mutations. Overall, 31.2% of patients with AML did not receive any therapy for their disease. This subgroup was older than chemotherapy recipients (mean age: 71.4 vs. 55.7 years, p < 0.001), and was highest (66.2%) in patients ≥75 years.ConclusionsOur results highlight the unmet medical need to increase access to genomic testing to afford treatment options, particularly to older AML patients in the real-world setting, in this new era of targeted therapies.
| S-EPMC10524030 | biostudies-literature
Project description:Despite emerging molecular information on chronic myelomonocytic leukemia (CMML), patient outcome remains unsatisfactory and little is known about the transformation to acute myeloid leukemia (AML). In a single-center cohort of 219 CMML patients, we explored the potential correlation between clinical features, gene mutations, and treatment regimens with overall survival (OS) and clonal evolution into AML. The most commonly detected mutations were TET2, SRSF2, ASXL1, and RUNX1. Median OS was 34 months and varied according to age, cytogenetic risk, FAB, CPSS and CPSS-Mol categories, and number of gene mutations. Hypomethylating agents were administered to 37 patients, 18 of whom responded. Allogeneic stem cell transplantation (alloSCT) was performed in 22 patients. Two-year OS after alloSCT was 60.6%. Six patients received targeted therapy with IDH or FLT3 inhibitors, three of whom attained a long-lasting response. AML transformation occurred in 53 patients and the analysis of paired samples showed changes in gene mutation status. Our real-world data emphasize that the outcome of CMML patients is still unsatisfactory and alloSCT remains the only potentially curative treatment. However, targeted therapies show promise in patients with specific gene mutations. Complete molecular characterization can help to improve risk stratification, understand transformation, and personalize therapy.
| S-EPMC9455040 | biostudies-literature