1,720,999 research outputs found
Title: Cladribine, idarubicin and cytarabine (CLIA1) in patients with acute myeloid leukemia (AML): a phase 2 single-arm trial.
No full textIntroduction: Several studies have demonstrated that the addition of cladribine (CdA) to standard cytarabine containing induction regimens improve outcomes for patients with newly diagnosed and relapsed/refractory (RR) acute myeloid leukemia (AML) patients. Based on this experience, we conducted a phase-2 clinical trial to study the efficacy of CdA combined with a higher dose of cytarabine (ARA-C) and idarubicin (IDA) as induction and consolidation treatment in younger patients with AML. Aim and Methods: In this single-arm, open-label, single-centre phase 2 study, we enrolled 153 patients aged ≤ 65 years with AML who had adequate organ function and an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less. Patients were enrolled under three cohorts: frontline, secondary AML (s-AML), and relapsed/refractory (R/R). All patients). All patients underwent cytogenetic analysis and molecular testing at baseline using a customized next generation sequencing (NGS) panel including known AML related mutations. All patients received induction treatment. Induction regimen consisted of CdA 5 mg/m2 intravenously (IV) over 30 minutes on days 1-5, followed by ARA-C 1 g/m2 IV on days 1-5, and IDA 10 mg/m2 IV days 1-3 (CLIA). Patients who had remission during this induction regimen moved on to consolidation therapy (up to 5 more cycles of CdA 5 mg/m2 IV over 30 minutes on days 1-3 with ARA-C 750 mg/m2 IV on days 1-3 and IDA 8 mg/m2 IV on days 1-2). Sorafenib was added in FLT3-ITD mutated patients during induction and consolidation treatments. The primary outcome measure was overall response rate. Secondary outcomes were overall survival, relapse free survival, toxicity, and induction mortality. All patients were included in the analyses. This trial is ongoing and is registered with ClinicalTrials.gov, number NCT02115295. Results: Between May 31, 2014, and June 2, 2017, 153 patients were enrolled and treated, among whom 65 (42%) belonged to frontline, 15 (10%) to s-AML, and 73 (48%) to R/R cohorts, respectively. In the frontline cohort, the molecular subgroup presenting the higher CR rate was the NPM1 (94%), followed by CEPBA (90%), IDH2 (83%), RAS (81%) and FLT3-ITD (78%). The lower CR rate was observed in patients harboring DNMT3A (69%), TP53 (67%) and ASXL1 (33%) mutation. According to the cytogenetic risk stratification, patients with an adverse risk at baseline showed an ORR of 71%, while patients with in favorable and intermediate risk the ORR was 89% and 93%, respectively (p=0.01). Among R/R patients cohort the ORR rates in NPM1, IDH1, IDH2 and FLT3-ITD cohorts were 58%, 40%, 58% and 70%, respectively. None of patients with TP53 mutation responded to treatment. Also in this cohort, cytogenetic adverse risk (p=0.0028) and complex karyotype (p=0.0092) at baseline significantly affected the ORR rate. At a median study follow up of 24.8 months among survivors, median overall survival estimates were NR, 4.5, and 7.8 months for the frontline, s-AML, and R/R cohorts, respectively. In the frontline group, FLT3-ITD patients, showed a 1- and 2- year OS of 86% and 75% and a CR rate of 95% at 1- and 2-year with a median duration of CR duration not reached. Among R/R setting, patients with complex karyotype had a significantly shorter median OS compared to others (3.3 vs 12.1 months; p=0.0001); according to molecular mutations, no difference was shown in patients harboring FLT3-ITD (8.8 vs 6.7 months; p=0.843), NPM1 (4.7 vs 8.1 months; p=0.213) IDH1 (5.5 vs 7.8 months; p=0.567), and DNMT3A (6.7 vs 10.9 months; p=0.739) compared to their negative molecular counterpart in terms of survival. According to Papaemmanuil genomic classification, the groups of AML with NPM1 mutation and AML with no driver mutations were associated with improved OS when compared to other groups (TP53/aneuploidy, driver mutations but no detected class-defining lesions, mutated chromatin, RNA splicing genes) either in the whole population (p=0.002) or in the R/R setting (p=0.017). Conclusions:: The combination of CLIA constitutes an effective and safe induction regimen in younger AML patients either in frontline or in relapse/refractory setting. Genomic subgrouping identifies high-risk AML groups, particularly TP53/aneuploidy, driver mutations, and chromatin/RNA-splicing genes, in which there exists a critical need for risk-adapted therapeutic approaches
Prognostic Significance of Transcript-Type BCR-ABL1 in Chronic Myeloid Leukemia
No full textChronic myeloid leukemia (CML) is characterized by the presence of the
BCR-ABL1 fusion gene. In more than 95\% of CML patients, the typical
BCR-ABL1 transcript subtypes are e13a2 (b2a2), e14a2 (b3a2), or the
simultaneous expression of both. Other less frequent transcript
subtypes, such as e1a2, e2a2, e6a2, e19a2, e1a3, e13a3, and e14a3, have
been sporadically reported. The main purpose of this review is to assess
the possible impact of different transcripts on the response rate to
tyrosine kinase inhibitors (TKIs), the achievement of stable deep
molecular responses (s-DMR), the potential maintenance of treatment-free
remission (TFR), and long-term outcome of CML patients treated with
TKIs. According to the majority of published studies, patients with
e13a2 transcript treated with imatinib have lower and slower cytogenetic
and molecular responses than those with e14a2 transcript. They should be
considered a high-risk group that would most benefit from frontline
treatment with second-generation TKIs (2GTIKIs). Although few studies
have been published, similar significant differences in response rates
to 2GTKIs have been not reported. The e14a2 transcript seems to be a
favorable prognostic factor for obtaining s-DMR, irrespective of the TKI
received, and is also associated with a very high rate of TFR
maintenance. Indeed, patients with e13a2 transcript achieve a lower rate
of s-DMR and experience a higher probability of TFR failure. According
to most reported data in the literature, the type of transcript does not
seem to affect long-term outcomes of CML patients treated with TKIs. In
TFR, the e14a2 transcript appears to be related to favorable responses.
2GTKIs as frontline therapy might be a convenient approach in patients
with e13a2 transcript to achieve optimal long-term outcomes
Insights into the optimal use of ponatinib in patients with chronic phase chronic myeloid leukaemia
No full textThere are five tyrosine kinase inhibitors (TKIs) that are currently approved (in the European Union and the United States) for the treatment of chronic myeloid leukaemia (CML) in the chronic phase (CP) and each of them has its own efficacy and toxicity profile. Oral ponatinib (Iclusig((R))) is a third-generation TKI structurally designed to inhibit native BCR-ABL1 tyrosine kinase and several BCR-ABL1 mutants, including T315I. Ponatinib is now approved for patients with CML who are resistant or intolerant to prior TKI therapy (European Union) or for whom no other TKI therapy is indicated (United States). Despite achieving results in heavily treated patients, which led to its approval, the drug may induce cardiovascular events, requiring a careful baseline assessment of predisposing risk factors and specific management during treatment. Pharmacokinetic analysis has indicated the possibility of reducing the starting dose of ponatinib to 15 mg/day and preliminary data showed advantages in terms of safety while maintained its efficacy. This review summarizes the results achieved and drug-related side effects reported in all clinical trials and real-life experiences, testing ponatinib in patients with CP-CML. In addition, we focus on the appropriate use of ponatinib in clinical practice suggesting some useful recommendations on the proper management of this drug
Improvement of bone marrow fibrosis with ruxolitinib: Will this finding change our perception of the drug?
No full textRuxolitinib, a JAK1 and JAK2 inhibitor, has been tested and approved for the treatment of primary and secondary myelofibrosis. Reduction of spleen volume and improvement of constitutional symptoms and quality of life have been reported as the major findings in sponsored randomized clinical trials. Recent data indicated that the drug improves bone marrow fibrosis and that different targets may be involved in this response. These new data, which require confirmation in prospective trials, may change our perspectives and therapeutic strategies for this disease.Ruxolitinib, a JAK1 and JAK2 inhibitor, has been tested and approved for the treatment of primary and secondary myelofibrosis. Reduction of spleen volume and improvement of constitutional symptoms and quality of life have been reported as the major findings in sponsored randomized clinical trials. Recent data indicated that the drug improves bone marrow fibrosis and that different targets may be involved in this response. These new data, which require confirmation in prospective trials, may change our perspectives and therapeutic strategies for this disease
Insights into the optimal use of ponatinib in patients with chronic phase chronic myeloid leukaemia
No full textThere are five tyrosine kinase inhibitors (TKIs) that are currently
approved (in the European Union and the United States) for the treatment
of chronic myeloid leukaemia (CML) in the chronic phase (CP) and each of
them has its own efficacy and toxicity profile. Oral ponatinib
(Iclusig((R))) is a third-generation TKI structurally designed to
inhibit native BCR-ABL1 tyrosine kinase and several BCR-ABL1 mutants,
including T315I. Ponatinib is now approved for patients with CML who are
resistant or intolerant to prior TKI therapy (European Union) or for
whom no other TKI therapy is indicated (United States). Despite
achieving results in heavily treated patients, which led to its
approval, the drug may induce cardiovascular events, requiring a careful
baseline assessment of predisposing risk factors and specific management
during treatment. Pharmacokinetic analysis has indicated the possibility
of reducing the starting dose of ponatinib to 15 mg/day and preliminary
data showed advantages in terms of safety while maintained its efficacy.
This review summarizes the results achieved and drug-related side
effects reported in all clinical trials and real-life experiences,
testing ponatinib in patients with CP-CML. In addition, we focus on the
appropriate use of ponatinib in clinical practice suggesting some useful
recommendations on the proper management of this drug
Is There a Better Therapeutic Time Window from Diagnosis to Treatment for Elderly Acute Myeloid Leukemia Patients Receiving Hypomethylating Agents?
No full textCorrelation between Charlson comorbidity index and outcome in patients with chronic phase chronic myeloid leukemia treated with second-generation tyrosine kinase inhibitors upfront
No full text
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
- …
