RESUMO
Myeloproliferative neoplasms (MPN) are characterized by uncontrolled expansion of myeloid cells, disease-related mutations in certain driver-genes including JAK2, CALR, and MPL, and a substantial risk to progress to secondary acute myeloid leukemia (sAML). Although behaving as stem cell neoplasms, little is known about disease-initiating stem cells in MPN. We established the phenotype of putative CD34+ /CD38- stem cells and CD34+ /CD38+ progenitor cells in MPN. A total of 111 patients with MPN suffering from polycythemia vera, essential thrombocythemia, or primary myelofibrosis (PMF) were examined. In almost all patients tested, CD34+ /CD38- stem cells expressed CD33, CD44, CD47, CD52, CD97, CD99, CD105, CD117, CD123, CD133, CD184, CD243, and CD274 (PD-L1). In patients with PMF, MPN stem cells often expressed CD25 and sometimes also CD26 in an aberrant manner. MPN stem cells did not exhibit substantial amounts of CD90, CD273 (PD-L2), CD279 (PD-1), CD366 (TIM-3), CD371 (CLL-1), or IL-1RAP. The phenotype of CD34+ /CD38- stem cells did not change profoundly during progression to sAML. The disease-initiating capacity of putative MPN stem cells was confirmed in NSGS mice. Whereas CD34+ /CD38- MPN cells engrafted in NSGS mice, no substantial engraftment was produced by CD34+ /CD38+ or CD34- cells. The JAK2-targeting drug fedratinib and the BRD4 degrader dBET6 induced apoptosis and suppressed proliferation in MPN stem cells. Together, MPN stem cells display a unique phenotype, including cytokine receptors, immune checkpoint molecules, and other clinically relevant target antigens. Phenotypic characterization of neoplastic stem cells in MPN and sAML should facilitate their enrichment and the development of stem cell-eradicating (curative) therapies.
Assuntos
Leucemia Mieloide Aguda , Transtornos Mieloproliferativos , Policitemia Vera , Animais , Camundongos , Calreticulina/genética , Janus Quinase 2/genética , Mutação , Transtornos Mieloproliferativos/genética , Células-Tronco Neoplásicas , Proteínas Nucleares/genética , Fenótipo , Policitemia Vera/genética , Fatores de Transcrição/genética , HumanosRESUMO
Although the RAS-pathway has been implicated as an important driver in the pathogenesis of chronic myelomonocytic leukemia (CMML) a comprehensive study including molecular and functional analyses in patients with progression and transformation has not been performed. A close correlation between RASopathy gene mutations and spontaneous in vitro myeloid colony (CFU-GM) growth in CMML has been described. Molecular and/or functional analyses were performed in three cohorts of 337 CMML patients: in patients without (A, n = 236) and with (B, n = 61) progression/transformation during follow-up, and in patients already transformed at the time of sampling (C, n = 40 + 26 who were before in B). The frequencies of RAS-pathway mutations (variant allele frequency ≥ 20%) in cohorts A, B, and C were 30%, 47%, and 71% (p < 0.0001), and of high colony growth (≥20/105 peripheral blood mononuclear cells) 31%, 44%, and 80% (p < 0.0001), respectively. Increases in allele burden of RAS-pathway mutations and in numbers of spontaneously formed CFU-GM before and after transformation could be shown in individual patients. Finally, the presence of mutations in RASopathy genes as well as the presence of high colony growth prior to transformation was significantly associated with an increased risk of acute myeloid leukemia (AML) development. Together, RAS-pathway mutations in CMML correlate with an augmented autonomous expansion of neoplastic precursor cells and indicate an increased risk of AML development which may be relevant for targeted treatment strategies.
Assuntos
Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Leucemia Mielomonocítica Crônica/genética , Leucemia Mielomonocítica Crônica/metabolismo , Mutação , Transdução de Sinais , Proteínas ras/genética , Proteínas ras/metabolismo , Análise Citogenética , Progressão da Doença , Regulação Leucêmica da Expressão Gênica , Humanos , Leucemia Mielomonocítica Crônica/mortalidade , Leucemia Mielomonocítica Crônica/patologia , Estadiamento de Neoplasias , Células-Tronco Neoplásicas/metabolismo , Prognóstico , Estudos RetrospectivosRESUMO
The aim of this study was to evaluate the efficacy and feasibility of intensified consolidation therapy employing fludarabine and ARA-C in cycle 1 and intermediate-dose ARA-C (IDAC) in cycles 2 through 4, in elderly acute myeloid leukemia (AML) patients and to analyze the effects of pegfilgrastim on the duration of neutropenia, overall toxicity, and hospitalization-time during consolidation in these patients. Thirty nine elderly patients with de novo AML (median age 69.9 years) who achieved complete remission (CR) after induction-chemotherapy were analyzed. To examine the effect of pegfilgrastim on neutropenia and hospitalization, we compared cycles 2 and 4 where pegfilgrastim was given routinely from day 6 (IDAC-P) with cycle 3 where pegfilgrastim was only administered in case of severe infections and/or prolonged neutropenia. All four planned cycles were administered in 23/39 patients (59.0%); 5/39 patients (12.8%) received 3 cycles, 3/39 (7.7%) 2 cycles, and 8/39 (20.5%) one consolidation-cycle. The median duration of severe neutropenia was 7 days in cycle 2 (IDAC-P), 11.5 days in cycle 3 (IDAC), and 7.5 days in cycle 4 (IDAC-P) (P < .05). Median overall survival was 1.1 years and differed significantly between patients aged <75 and ≥75 years (P < .05). The probability to be alive after 5 years was 32%. Together, intensified consolidation can be administered in AML patients ≥60, and those who are <75 may benefit from this therapy. Routine administration of pegfilgrastim during consolidation shortens the time of neutropenia and hospitalization in these patients.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimioterapia de Consolidação/métodos , Citarabina/uso terapêutico , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Vidarabina/análogos & derivados , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Quimioterapia de Consolidação/efeitos adversos , Citarabina/administração & dosagem , Citarabina/efeitos adversos , Intervalo Livre de Doença , Esquema de Medicação , Estudos de Viabilidade , Filgrastim , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Fator Estimulador de Colônias de Granulócitos/efeitos adversos , Hospitalização/estatística & dados numéricos , Humanos , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Neutropenia/epidemiologia , Polietilenoglicóis , Prognóstico , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/uso terapêutico , Vidarabina/administração & dosagem , Vidarabina/efeitos adversos , Vidarabina/uso terapêuticoRESUMO
The 2016 revised WHO criteria for the diagnosis of pre-fibrotic/early primary myelofibrosis (pre-PMF) require at least one of the following four borderline expressed minor clinical criteria: anemia, leukocytosis, elevated lactate dehydrogenase and splenomegaly. In this study, we evaluated the relative frequency of these four criteria in a group of 170 pre-PMF patients and compared them to 225 ET cases. More than 91% of pre-PMF cases showed one or more of these features required for diagnosis, by contrast with only 48% of ET patients. According to clinical data the cumulative risk of progression to advanced/overt PMF in pre-PMF was 36.9% after 15 years. After fitting cox regression models to analyze the impact of the minor criteria on overall survival, only leukocytosis remained as a significant predictor of survival in both pre-PMF and ET. Molecular characterization showed differences in survival in pre-PMF but not ET, with CALR being a more favorable mutation than JAK2. The different outcome of pre-PMF versus ET and associated molecular genetic data supports the concept of two different entities, rather than a continuum of the same disease. Although slightly less than 50% of ET patients also show one or more minor clinical criteria, accurate distinction between ET and pre-PMF is possible by following an integrated approach including histomorphological diagnosis and presence of minor clinical criteria.
Assuntos
Mielofibrose Primária/diagnóstico , Mielofibrose Primária/mortalidade , Trombocitemia Essencial/diagnóstico , Trombocitemia Essencial/mortalidade , Idoso , Calreticulina/genética , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Janus Quinase 2/genética , Masculino , Pessoa de Meia-Idade , Mutação , Mielofibrose Primária/genética , Mielofibrose Primária/terapia , Fatores de Risco , Taxa de Sobrevida , Trombocitemia Essencial/genética , Trombocitemia Essencial/terapia , Organização Mundial da SaúdeRESUMO
PURPOSE: Chemotherapy-induced febrile neutropenia (FN) causes treatment delays and interruptions and can have fatal consequences. Current guidelines provide recommendations on granulocyte colony-stimulating factors (G-CSF) for prevention of FN, but guidance is unclear regarding use of short- vs long-acting G-CSF (e.g., filgrastim vs pegfilgrastim/lipegfilgrastim, respectively). An international panel of experts convened to develop guidance on appropriate use of pegfilgrastim for prevention of chemotherapy-induced FN. METHODS: Guidance recommendations were developed following a literature review, survey, evaluation of current practice, and an expert meeting. Consensus was established using an anonymous Delphi-based approach. RESULTS: Guidance recommendations for prevention of treatment-associated FN were as follows: for treatment with curative intent, maintenance of dose intensity using G-CSF to prevent dose delays/reduction should be standard of care; for treatment-associated FN risk ≥ 20%, short-acting G-CSF/pegfilgrastim should be given from cycle 1 onwards; and for treatment-associated FN risk < 20%, short-acting G-CSF/pegfilgrastim should be given if factors suggest overall risk (including treatment-related and patient-related risk factors) is ≥ 20%. It was agreed that pegfilgrastim and 11 days' filgrastim have similar efficacy and safety and that pegfilgrastim is preferred to < 11 days' filgrastim (and may be preferred to ≥ 11 days' filgrastim based on adherence and convenience); pegfilgrastim is not appropriate in weekly chemotherapy; in split-dose chemotherapy, pegfilgrastim is recommended 24 h after last chemotherapy dose; and during palliative chemotherapy, patient adherence and convenience may favor pegfilgrastim. CONCLUSION: In this era of targeted therapies, additional trials with G-CSF are still required. These recommendations should be used with existing guidelines to optimize pegfilgrastim use in clinical practice.
Assuntos
Neutropenia Febril Induzida por Quimioterapia/prevenção & controle , Filgrastim/uso terapêutico , Polietilenoglicóis/uso terapêutico , Neutropenia Febril Induzida por Quimioterapia/tratamento farmacológico , Consenso , Feminino , Filgrastim/administração & dosagem , Filgrastim/farmacologia , Humanos , Masculino , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/farmacologiaRESUMO
In chronic myelomonocytic leukemia (CMML), colony-forming units granulocyte/macrophage (CFU-GM), which grow in vitro in the absence of exogenous growth factors, arise from the abnormal clone that is responsible for the overproduction of granulomonocytic cells. Previous in vitro findings including ours suggest that divergent molecular aberrations in CMML seem to converge within the GM-CSF signaling pathway. As JAK2 is a sentinel kinase in this pathway, JAK2 inhibition may be an attractive treatment approach in CMML. We investigated the in vitro effects of the specific JAK2 inhibitor TG101209 on the autonomous CFU-GM formation from peripheral blood mononuclear cells of patients with CMML. TG101209 was found to either block or strongly inhibit spontaneous CFU-GM growth in all 10 patients tested. This inhibitory effect was dose dependent and significantly more pronounced as compared to the inhibitory effect on stimulated CFU-GM growth from normal individuals. In a CMML patient with splenomegaly, who was treated with the JAK1/2 inhibitor ruxolitinib off label, we can demonstrate a spleen response and the disappearance of constitutional symptoms which was associated with a decrease in autonomous CFU-GM formation ex vivo. Pharmacological JAK2 inhibition may be an interesting approach to be systematically studied in patients with CMML.
Assuntos
Antineoplásicos/farmacologia , Janus Quinase 2/antagonistas & inibidores , Leucemia Mielomonocítica Crônica/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Proliferação de Células/efeitos dos fármacos , Ensaio de Unidades Formadoras de Colônias , Relação Dose-Resposta a Droga , Feminino , Células Progenitoras de Granulócitos e Macrófagos/efeitos dos fármacos , Humanos , Janus Quinase 2/genética , Leucemia Mielomonocítica Crônica/diagnóstico , Leucemia Mielomonocítica Crônica/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Mutação , Nitrilas , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/farmacologia , Pirazóis/uso terapêutico , Pirimidinas , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND: Allogeneic haematopoietic stem cell transplantation (HSCT) is the only curative rescue therapy for patients (pts) with chemotherapy-refractory acute leukaemia. Disease control prior to HSCT is essential for long-term disease-free survival after HSCT. PATIENTS AND METHODS: We have retrospectively analysed the outcome of 20 pts aged 21-64 years with refractory leukaemia (acute myeloid leukaemia, n = 16; acute lymphatic leukaemia, n = 4) who received debulking therapy with clofarabine (10 mg/m², days 1-4) and cyclophosphamide (200 mg/m², days 1-4; ClofCy) prior to HSCT. RESULTS: Clofarabine/cyclophosphamide (1-4 cycles) was well tolerated and resulted in a substantial reduction of leukaemic cells in all pts. HSCT was performed in 15 of 20 pts. After HSCT (myeloablative, n = 9; dose-reduced, n = 6), all pts showed engraftment and full donor chimerism (related donors, n = 4 or unrelated donors, n = 11) and all pts achieved complete haematologic remission (CR). The median survival after HSCT is 531 days (range: 48-1462 days), and six pts are still alive after a median of 1245 days. Seven pts died after they had relapsed between days +152 and +1496. One patient died from acute graft-versus-host disease (day +48) and one from systemic fungal infection (day +87). CONCLUSION: Clofarabine/cyclophosphamide is a novel effective treatment approach for pts with chemotherapy-refractory acute leukaemia prior to HSCT. Whether this novel debulking protocol leads to improved long-term outcome in pts with refractory leukaemias remains to be determined in forthcoming clinical studies.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/métodos , Leucemia Mieloide Aguda/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Nucleotídeos de Adenina/administração & dosagem , Adulto , Arabinonucleosídeos/administração & dosagem , Clofarabina , Ciclofosfamida/administração & dosagem , Esquema de Medicação , Feminino , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/mortalidade , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/mortalidade , Humanos , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Estudos Retrospectivos , Transplante Homólogo , Resultado do Tratamento , Adulto JovemRESUMO
Data on efficacy and safety of azacitidine in acute myeloid leukemia (AML) with >30 % bone marrow (BM) blasts are limited, and the drug can only be used off-label in these patients. We previously reported on the efficacy and safety of azacitidine in 155 AML patients treated within the Austrian Azacitidine Registry (clinicaltrials.gov identifier NCT01595295). We herein update this report with a population almost twice as large (n = 302). This cohort included 172 patients with >30 % BM blasts; 93 % would have been excluded from the pivotal AZA-001 trial (which led to European Medicines Agency (EMA) approval of azacitidine for high-risk myelodysplastic syndromes (MDS) and AML with 20-30 % BM blasts). Despite this much more unfavorable profile, results are encouraging: overall response rate was 48 % in the total cohort and 72 % in patients evaluable according to MDS-IWG-2006 response criteria, respectively. Median OS was 9.6 (95 % CI 8.53-10.7) months. A clinically relevant OS benefit was observed with any form of disease stabilization (marrow stable disease (8.1 months), hematologic improvement (HI) (9.7 months), or the combination thereof (18.9 months)), as compared to patients without response and/or without disease stabilization (3.2 months). Age, white blood cell count, and BM blast count at start of therapy did not influence OS. The baseline factors LDH >225 U/l, ECOG ≥2, comorbidities ≥3, monosomal karyotype, and prior disease-modifying drugs, as well as the response-related factors hematologic improvement and further deepening of response after first response, were significant independent predictors of OS in multivariate analysis. Azacitidine seems effective in WHO-AML, including patients with >30 % BM blasts (currently off-label use). Although currently not regarded as standard form of response assessment in AML, disease stabilization and/or HI should be considered sufficient response to continue treatment with azacitidine.
Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Azacitidina/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/epidemiologia , Sistema de Registros , Organização Mundial da Saúde , Adulto , Idoso , Idoso de 80 Anos ou mais , Áustria/epidemiologia , Estudos de Coortes , Feminino , Humanos , Leucemia Mieloide Aguda/diagnóstico , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Taxa de Sobrevida/tendências , Resultado do TratamentoRESUMO
Approximately 15% of newly diagnosed breast cancer patients have neither hormone receptors expression nor HER2 overexpression and/or HER2/neu gene amplification. This subtype of breast cancer is known as Triple Negative Breast Cancer (TNBC), and carries a significantly elevated risk of local and distant recurrence. In comparison with other breast cancer subtypes, there is a higher rate of visceral and brain metastases. The majority of metastases of TNBC are diagnosed within three years after initial breast cancer diagnosis. While there have been major advances in hormone-receptor- positive and in human epidermal growth factor receptor 2 (HER2)-positive disease over the past two decades, only limited improvements in outcomes for patients with triple negative breast cancer (TNBC) have been observed. A group of Austrian breast cancer specialists therefore convened an expert meeting to establish a comprehensive clinical risk-benefit profile of available mTNBC therapies and discuss the role sacituzumab govitecan may play in the treatment algorithm of the triple-negative breast cancer patients.
RESUMO
A group of Austrian breast cancer specialists met in December 2020 to establish a comprehensive clinical benefit-risk profile of available HER2-targeted therapies based on recent data and to develop an updated treatment algorithm by consensus over several months in 2021. A total of four scenarios were developed in which treatment strategies appropriate for specific patient profiles were evaluated. Consensus was established by detailed discussions of each scenario and by reaching full consensus.
Assuntos
Neoplasias da Mama , Algoritmos , Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica , Áustria , Neoplasias da Mama/tratamento farmacológico , Feminino , Humanos , Receptor ErbB-2/genética , Receptor ErbB-2/uso terapêutico , Trastuzumab/uso terapêuticoRESUMO
Basophilia is a crucial prognostic variable in Ph-chromosome-positive chronic myeloid leukemia (CML). The ectoenzyme CD203c is an activation-linked surface antigen that is expressed specifically on basophil-committed progenitor cells and mature basophils. We examined the expression of CD203c on progenitors and/or basophils in 21 healthy donors and 44 patients with CML. As expected, the numbers of CD203c+ blood leukocytes were significantly higher in CML patients compared to controls (percentage of CD203c+ cells among viable cells in CML at diagnosis: 4.19 ± 3.68% vs. controls: 0.53 ± 0.23%, p < 0.05). Moreover, CML basophils expressed higher levels of CD203c compared to normal basophils (median staining-index in CML at diagnosis: 29.41 ± 19.14 versus controls: 20.44 ± 13.45). We also found that the numbers and percentage of circulating CD203c+ cells at diagnosis correlate with the disease-related risk-profile. Incubation of CML basophils with an anti-IgE-antibody resulted in further upregulation of CD203c. After successful treatment with imatinib and/or other BCR::ABL1 inhibitors leading to major or complete molecular responses, the numbers of CD203c+ basophils decreased substantially in our CML patients compared to pre-treatment values. Together, CD203c is overexpressed on CML basophils, is further upregulated by IgE receptor cross-linking, and may serve as a biomarker to quantify basophilia in patients with CML at diagnosis and during therapy.
Assuntos
Basófilos , Leucemia Mielogênica Crônica BCR-ABL Positiva , Humanos , Doença Crônica , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Receptores de IgE/metabolismo , Regulação para CimaAssuntos
Neoplasias Hematológicas , Transtornos Mieloproliferativos , Neoplasias , Humanos , Nitrilas , Pirazóis , PirimidinasRESUMO
According to the World Health Organization (WHO) classification, essential (primary) thrombocythemia (ET) is one of several Bcr-Abl negative chronic myeloproliferative neoplasms (MPN). The classical term MPN covers the subcategories of MPN: ET, polycythemia vera (PV), primary myelofibrosis (PMF), and prefibrotic PMF (pPMF). ET is marked by clonal proliferation of hematopoietic stem cells, leading to a chronic overproduction of platelets. At the molecular level a JAK2 (Janus Kinase 2), calreticulin, or MPL mutation is found in the majority of patients. Typical ongoing complications of the disease include thrombosis and hemorrhage. Primary and secondary prevention of these complications can be achieved with platelet function inhibitors and various cytoreductive drugs including anagrelide, hydroxyurea and interferon. After a long follow up, in a minority of ET patients the disease transforms into post-ET myelofibrosis or secondary leukemia. Overall, life expectancy with ET is only slightly decreased.
Assuntos
Transtornos Mieloproliferativos , Policitemia Vera , Mielofibrose Primária , Trombocitemia Essencial , Áustria , Humanos , Mutação , Trombocitemia Essencial/diagnóstico , Trombocitemia Essencial/tratamento farmacológico , Trombocitemia Essencial/genéticaRESUMO
BACKGROUND: Pancreatic cancer (PC) ranks among the deadliest malignancies worldwide. In the MPACT study, first-line nab-paclitaxel plus gemcitabine (nab-P/G) demonstrated activity (median overall survival [OS], 8.7 months) and tolerability in patients with metastatic PC (mPC). However, the clinical evidence of nab-P/G in the elderly (>70 years), who account for the majority of patients with mPC, is limited. This is the first prospective, multicentre, non-interventional study evaluating the tolerability and effectiveness of nab-P/G in younger (≤70 years) versus elderly (>70 years) patients with mPC in the daily clinical routine. METHODS: Eligible patients with mPC were treated with nab-P/G and observed until disease progression or unacceptable toxicity. The primary objectives were safety and tolerability of nab-P/G, and the secondary objectives were efficacy and real-life dosing. RESULTS: A total of 317 patients with mPC (median age, 70 years) were recruited, of which 299, aged ≤70 (n = 162) and >70 (n = 137) years, were eligible for analysis. Baseline characteristics and the safety profile were comparable between the groups. However, fatigue (22.8% versus 13.0%) and decreased appetite (8.8% versus 1.2%) were more frequent in elderly patients. Younger versus elderly patients equally benefited in terms of objective response rate (36% versus 48%), median progression-free survival (5.6 versus 5.5 months; hazard ratio [HR] = 1.03; p = 0.81) and OS (10.6 versus 10.2 months; HR = 0.89; p = 0.4). In addition, the median treatment duration (5 versus 4 cycles), relative dose intensity (70% versus 74%) or reasons for treatment discontinuation were similar. Most patients (56.2% versus 47.4%) benefited from a second-line therapy. CONCLUSION: This prospective real-world analysis confirms the feasibility and tolerability of nab-P/G treatment and reveals OS data similar for younger patients and elderly patients aged >70 years. CLINICALTRIALS. GOV REGISTRATION: NCT02555813. AUSTRIAN NIS REGISTRY: NIS005071.
Assuntos
Albuminas/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Desoxicitidina/análogos & derivados , Paclitaxel/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológico , Idoso , Albuminas/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Desoxicitidina/farmacologia , Desoxicitidina/uso terapêutico , Feminino , Humanos , Masculino , Paclitaxel/farmacologia , Neoplasias Pancreáticas/patologia , GencitabinaRESUMO
BACKGROUND: Several clinical trials in chronic phase (CP) chronic myeloid leukemia (CML) showed that early response to tyrosine kinase inhibitor (TKI) treatment results in an improved long-term survival and progression-free survival. This study assessed whether patients achieving early treatment response (ETR; partial cytogenetic response or BCR-ABL1 mRNA ≤10% at 3 months) in daily practice also have a long-term survival benefit. METHODS: The Retrospective Evaluation of Early response in CML for long-term Treatment outcome (R-EFECT), a multicenter, retrospective chart review, documented patients with newly diagnosed CML-CP starting first-line TKI therapy in routine clinical practice. The primary aim was to assess the 5year overall survival rate. RESULTS: Of the 211 patients from 12 centers across Austria (January 2004-May 2010), 176 (median age, 56 years) were included in the analysis. All patients received first-line therapy with imatinib. Overall, 136 patients (77.3%) achieved ETR (ETR+ group), whereas 40 (22.7%) did not reach ETR (ETR- group). The ETR+ group had higher 5year overall survival (92.5% vs. 77.5%, Pâ¯= 0.018) and progression-free survival (95.6% vs. 87.5%, Pâ¯= 0.06) rates compared with the ETR- group. As expected, more patients in the ETR- group were switched to another TKI. At the last contact, 120 patients were still on imatinib and 44 had switched to another TKI (25 to nilotinib, 15 to dasatinib, and 4 to bosutinib). CONCLUSION: The data are in line with randomized trials demonstrating that ETR is associated with improved survival and thus confirmed these results in patients treated in daily clinical routine.
Assuntos
Antineoplásicos , Leucemia Mielogênica Crônica BCR-ABL Positiva , Leucemia Mieloide de Fase Crônica , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Áustria , Dasatinibe/uso terapêutico , Feminino , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mieloide de Fase Crônica/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: The pretreatment De Ritis ratio [aspartate transaminase (AST)/alanine transaminase (ALT)] has been shown to be an adverse prognostic marker in various cancer entities. However, its relevance to advanced pancreatic ductal adenocarcinoma (PDAC) has not yet been studied. In the present study we investigated the AST/ALT ratio as a possible predictor of treatment response and disease outcome in patients with advanced PDAC treated with first-line gemcitabine/nab-paclitaxel. METHODS: A post hoc analysis of a prospective, multicenter, noninterventional study was performed. A total of 202 patients with advanced PDAC treated with first-line gemcitabine/nab-paclitaxel for whom the AST/ALT ratio was measured were included in this analysis. RESULTS: Median and 1-year progression-free survival estimates were 4.8 months and 5.1%, respectively in patients with an AST/ALT ratio above the 75th percentile of its distribution, and 6.0 months and 18.7%, respectively in patients with an AST/ALT ratio less than or equal to this cutoff, respectively (log-rank p = 0.004). In univariable Cox regression, a doubling of the AST/ALT ratio was associated with a 1.4-fold higher relative risk of progression or death [hazard ratio = 1.38, 95% confidence interval (CI): 1.06-1.80, p = 0.017]. The prognostic association was also found in multivariable analysis adjusting for Eastern Cooperative Oncology Group performance status and lung metastases (hazard ratio per AST/ALT ratio doubling = 1.32, 95% CI: 1.00-1.75, p = 0.047). In treatment response analysis, a doubling of the AST/ALT ratio was associated with a 0.5-fold lower odds of objective response (odds ratio = 0.54, 95% CI: 0.31-0.94, p = 0.020). CONCLUSIONS: The pretreatment serum AST/ALT ratio predicts poor disease outcome and response rate in patients with advanced PDAC treated with gemcitabine/nab-paclitaxel and might represent a novel and inexpensive marker for individual risk assessment in the treatment of pancreatic cancer.
RESUMO
Correction to:Wien Klin Wochenschr 2018 https://doi.org/10.1007/s00508-018-1365-5 The original version of this article unfortunately contained a mistake. Table Nr. 1 was inconsistent. The corrected version of Table 1 is given below. We apologize for any inconveniences this may have .
RESUMO
In the Austrian biodatabase for chronic myelomonocytic leukemia (ABCMML) clinicolaboratory real-life data have been captured from 606 CMML patients from 14 different hospitals over the last 30 years. It is the only large biodatabase worldwide in which functional methods such as semisolid in vitro cultures complement modern molecular methods such as next generation sequencing. This provides the possibility to comprehensively study the biology of CMML. The aim of this study was to compare patient characteristics with published CMML cohorts and to validate established prognostic parameters in order to examine if this real-life database can serve as a representative and useful data source for further research. After exclusion of patients in transformation characteristics of 531 patients were compared with published CMML cohorts. Median values for age, leukocytes, hemoglobin, platelets, lactate dehydrogenase (LDH) and circulating blasts were within the ranges of reported CMML series. Established prognostic parameters including leukocytes, hemoglobin, blasts and adverse cytogenetics were able to discriminate patients with different outcome. Myeloproliferative (MP) as compared to myelodysplastic (MD)-CMML patients had higher values for circulating blasts, LDH, RAS-pathway mutations and for spontaneous myelomonocytic colony growth in vitro as well as more often splenomegaly. This study demonstrates that the patient cohort of the ABCMML shares clinicolaboratory characteristics with reported CMML cohorts from other countries and confirms phenotypic and genotypic differences between MP-CMML and MD-CMML. Therefore, results obtained from molecular and biological analyses using material from the national cohort will also be applicable to other CMML series and thus may have a more general significance.
Assuntos
Pesquisa Biomédica , Leucemia Mielomonocítica Crônica , Adulto , Idoso , Idoso de 80 Anos ou mais , Áustria , Feminino , Humanos , Armazenamento e Recuperação da Informação , Masculino , Pessoa de Meia-Idade , Prognóstico , Adulto JovemRESUMO
INTRODUCTION: Despite the availability of effective iron chelators, transfusion-related morbidity is still a challenge in chronically transfused patients with myelodysplastic syndromes (MDS). In these patients, transfusion-induced iron overload may lead to organ dysfunction or even organ failure. In addition, iron overload is associated with reduced overall survival in MDS. Areas covered: During the past 10 years, various guidelines for the management of MDS patients with iron overload have been proposed. In the present article, we provide our updated recommendations for the diagnosis, prevention and therapy of iron overload in MDS. In addition, we propose refined treatment response criteria. As in 2006 and 2007, recommendations were discussed and formulated by participants of our Austrian MDS platform in a series of meetings in 2016 and 2017. Expert commentary: Our updated recommendations should support early recognition of iron overload, optimal patient management and the measurement of clinical responses to chelation treatment in daily practice.
Assuntos
Transfusão de Sangue , Sobrecarga de Ferro , Síndromes Mielodisplásicas , Reação Transfusional , Humanos , Sobrecarga de Ferro/sangue , Sobrecarga de Ferro/prevenção & controle , Síndromes Mielodisplásicas/sangue , Síndromes Mielodisplásicas/terapia , Guias de Prática Clínica como Assunto , Reação Transfusional/sangue , Reação Transfusional/prevenção & controleRESUMO
The oral Janus associated kinase (JAK1/2) inhibitor ruxolitinib has been available for treatment of patients with intermediate or high-risk myelofibrosis in Europe since 2012. Since its introduction, the expertise of prescribing doctors with respect to ruxolitinib function, efficacy and adverse effects has consistently been augmented, resulting in therapy modalities that are better tailored to individual patients as well as in increased safety of the treatment. The present consensus on ruxolitinib therapy management has been elaborated by Austrian experts in myeloproliferative neoplasms in line with international treatment guidelines. Our recommendations aim to contribute to an improved management of patients with myelofibrosis treated with ruxolitinib.