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2.
Cancer ; 2022 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-35499819

RESUMO

The development of targeted therapies for the treatment of myelofibrosis highlights a unique issue in a field that has historically relied on symptom relief, rather than survival benefit or modification of disease course, as key response criteria. There is, therefore, a need to understand what constitutes disease modification of myelofibrosis to advance appropriate drug development and therapeutic pathways. Here, the authors discuss recent clinical trial data of agents in development and dissect the potential for novel end points to act as disease modifying parameters. Using the rationale garnered from latest clinical and scientific evidence, the authors propose a definition of disease modification in myelofibrosis. With improved overall survival a critical outcome, alongside the normalization of hematopoiesis and improvement in bone marrow fibrosis, there will be an increasing need for surrogate measures of survival for use in the early stages of trials. As such, the design of future clinical trials will require re-evaluation and updating to incorporate informative parameters and end points with standardized definitions and methodologies.

3.
Future Oncol ; 18(18): 2217-2231, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35388710

RESUMO

Aim: To assess real-world ruxolitinib treatment patterns and outcomes in patients diagnosed with primary or secondary myelofibrosis. Materials & methods: Patient medical records were reviewed in six countries. Results: Eligible patients (n = 469) had a mean age of 63.5 years, and most were male (66.5%) with primary myelofibrosis (78.5%). Median duration of ruxolitinib treatment was 13.1 months; 40% of patients initiated treatment at the recommended dose. The Kaplan-Meier estimate of median survival from ruxolitinib initiation was 44.4 months (95% CI, 38.8-50.2 months). Approximately one quarter (23%) of patients continued ruxolitinib after progression. Conclusion: These results suggest an unmet need for more effective treatments for patients with myelofibrosis who failed ruxolitinib.

4.
Br J Haematol ; 2022 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-35476316

RESUMO

Fedratinib, an oral Janus kinase-2 (JAK2) inhibitor, is approved for patients with myelofibrosis (MF) and platelet counts ≥50 × 109 /l, based on outcomes from the phase 3, placebo-controlled JAKARTA trial in JAK-inhibitor-naïve MF, and the phase 2, single-arm JAKARTA2 trial in patients previously treated with ruxolitinib. We evaluated the efficacy and safety of fedratinib 400 mg/day in patients with baseline platelet counts 50 to <100 × 109 /l ("Low-Platelets" cohorts), including 14/96 patients (15%) in JAKARTA and 33/97 (34%) in JAKARTA2. At 24 weeks, spleen response rates were not significantly different between the Low-Platelets cohort and patients with baseline platelet counts ≥100 × 109 /l ("High-Platelets" cohort), in JAKARTA (36% vs. 49%, respectively; p = 0.37) or JAKARTA2 (36% vs. 28%; p = 0.41). Symptom response rates were also not statistically different between the Low- and High-Platelets cohorts. Fedratinib was generally well-tolerated in both platelet-count cohorts. New or worsening thrombocytopaenia was more frequent in the Low-Platelets (44%) versus the High-Platelets (9%) cohort, but no serious thrombocytopaenia events occurred. Thrombocytopaenia was typically managed with dose modifications; only 3/48 Low-Platelets patients discontinued fedratinib due to thrombocytopaenia. These data indicate that fedratinib 400 mg/day is safe and effective in patients with MF and low pretreatment platelet counts, and no initial fedratinib dose adjustment is required for these patients.

5.
Blood Adv ; 6(6): 1855-1864, 2022 03 22.
Artigo em Inglês | MEDLINE | ID: mdl-35130339

RESUMO

Ruxolitinib (RUX) is extensively used in myelofibrosis (MF). Despite its early efficacy, most patients lose response over time and, after discontinuation, have a worse overall survival (OS). Currently, response criteria able to predict OS in RUX-treated patients are lacking, leading to uncertainty regarding the switch to second-line treatments. In this study, we investigated predictors of survival collected after 6 months of RUX in 209 MF patients participating in the real-world ambispective observational RUXOREL-MF study (NCT03959371). Multivariable analysis identified the following risk factors: (1) RUX dose <20 mg twice daily at baseline, months 3 and 6 (hazard ratio [HR], 1.79; 95% confidence interval [CI], 1.07-3.00; P = .03), (2) palpable spleen length reduction from baseline ≤30% at months 3 and 6 (HR, 2.26; 95% CI, 1.40-3.65; P = .0009), (3) red blood cell (RBC) transfusion need at months 3 and/or 6 (HR, 1.66; 95% CI, 0.95-2.88; P = .07), and (4) RBC transfusion need at all time points (ie, baseline and months 3 and 6; HR, 2.32; 95% CI, 1.19-4.54; P = .02). Hence, we developed a prognostic model, named Response to Ruxolitinib After 6 Months (RR6), dissecting 3 risk categories: low (median OS, not reached), intermediate (median OS, 61 months; 95% CI, 43-80), and high (median OS, 33 months; 95% CI, 21-50). The RR6 model was validated and confirmed in an external cohort comprised of 40 MF patients. In conclusion, the RR6 prognostic model allows for the early identification of RUX-treated MF patients with impaired survival who might benefit from a prompt treatment shift.


Assuntos
Mielofibrose Primária , Humanos , Nitrilas , Mielofibrose Primária/induzido quimicamente , Mielofibrose Primária/diagnóstico , Mielofibrose Primária/tratamento farmacológico , Prognóstico , Pirazóis/efeitos adversos , Pirimidinas , Estudos Retrospectivos
6.
Antioxidants (Basel) ; 11(1)2022 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-35052617

RESUMO

Myelofibrosis (MF) is the Philadelphia-negative myeloproliferative neoplasm characterized by the worst prognosis and no response to conventional therapy. Driver mutations in JAK2 and CALR impact on JAK-STAT pathway activation but also on the production of reactive oxygen species (ROS). ROS play a pivotal role in inflammation-induced oxidative damage to cellular components including DNA, therefore leading to greater genomic instability and promoting cell transformation. In order to unveil the role of driver mutations in oxidative stress, we assessed ROS levels in CD34+ hematopoietic stem/progenitor cells of MF patients. Our results demonstrated that ROS production in CD34+ cells from CALR-mutated MF patients is far greater compared with patients harboring JAK2 mutation, and this leads to increased oxidative DNA damage. Moreover, CALR-mutant cells show less superoxide dismutase (SOD) antioxidant activity than JAK2-mutated ones. Here, we show that high plasma levels of total antioxidant capacity (TAC) correlate with detrimental clinical features, such as high levels of lactate dehydrogenase (LDH) and circulating CD34+ cells. Moreover, in JAK2-mutated patients, high plasma level of TAC is also associated with a poor overall survival (OS), and multivariate analysis demonstrated that high TAC classification is an independent prognostic factor allowing the identification of patients with inferior OS in both DIPSS lowest and highest categories. Altogether, our data suggest that a different capability to respond to oxidative stress can be one of the mechanisms underlying disease progression of myelofibrosis.

7.
Blood Adv ; 6(4): 1162-1174, 2022 02 22.
Artigo em Inglês | MEDLINE | ID: mdl-34933330

RESUMO

Idasanutlin, an MDM2 antagonist, showed clinical activity and a rapid reduction in JAK2 V617F allele burden in patients with polycythemia vera (PV) in a phase 1 study. This open-label phase 2 study evaluated idasanutlin in patients with hydroxyurea (HU)-resistant/-intolerant PV, per the European LeukemiaNet criteria, and phlebotomy dependence; prior ruxolitinib exposure was permitted. Idasanutlin was administered once daily on days 1 through 5 of each 28-day cycle. The primary end point was composite response (hematocrit control and spleen volume reduction > 35%) in patients with splenomegaly and hematocrit control in patients without splenomegaly at week 32. Key secondary end points included safety, complete hematologic response (CHR), patient-reported outcomes, and molecular responses. All patients (n = 27) received idasanutlin; 16 had response assessment (week 32). Among responders with baseline splenomegaly (n = 13), 9 (69%) attained any spleen volume reduction, and 1 achieved composite response. Nine patients (56%) achieved hematocrit control, and 8 patients (50%) achieved CHR. Overall, 43% of evaluable patients (6/14) showed a ≥50% reduction in the Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (week 32). Nausea (93%), diarrhea (78%), and vomiting (41%) were the most common adverse events, with grade ≥ 3 nausea or vomiting experienced by 3 patients (11%) and 1 patient (4%), respectively. Reduced JAK2 V617F allele burden occurred early (after 3 cycles), with a median reduction of 76%, and was associated with achieving CHR and hematocrit control. Overall, the idasanutlin dosing regimen showed clinical activity and rapidly reduced JAK2 allele burden in patients with HU-resistant/- intolerant PV but was associated with low-grade gastrointestinal toxicity, leading to poor long-term tolerability. This trial was registered at www.clinincaltrials.gov as #NCT03287245.


Assuntos
Policitemia Vera , Pirrolidinas , para-Aminobenzoatos , Humanos , Hidroxiureia/farmacologia , Náusea/induzido quimicamente , Policitemia Vera/tratamento farmacológico , Policitemia Vera/genética , Proteínas Proto-Oncogênicas c-mdm2 , Pirrolidinas/efeitos adversos , Esplenomegalia/induzido quimicamente , Vômito/induzido quimicamente , para-Aminobenzoatos/efeitos adversos
8.
Lancet Haematol ; 9(4): e301-e311, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35358444

RESUMO

Polycythaemia vera is associated with a reduced quality of life, a high rate of vascular events, and an intrinsic risk of disease evolution. The results of several randomised trials for the treatment of this disorder are now available, and both a new ropegylated formulation of interferon alfa-2b (ropeginterferon alfa-2b; 2018) and ruxolitinib (2015) have been approved in Europe. European LeukemiaNet (ELN) investigators have therefore deemed it appropriate to provide recommendations for the use of these drugs in clinical practice. An expert panel of 14 senior haematologists from ELN centres that had actively participated in previous ELN projects or relevant randomised trials, chaired by a member of the ELN Steering Committee, developed a list of clinical questions, and a methodologist established three patient, intervention, comparator, outcome (PICO) questions and systematically reviewed the evidence. Recommendations were approved by six Delphi consensus rounds and two virtual meetings (on Jan 26, 2021, and June 24, 2021). The expert panel recommended that patients with polycythaemia vera who are younger than 60 years and have not had previous thrombotic events should start cytoreductive drug therapy if at least one of the following criteria are fulfilled: strictly defined intolerance to phlebotomy, symptomatic progressive splenomegaly, persistent leukocytosis (>15 × 109 white blood cells per L), progressive leukocytosis (at least 100% increase if baseline count is <10 × 109 cells per L or at least 50% increase if baseline count is >10 × 109 cells per L), extreme thrombocytosis (>1500 × 109 platelets per L), inadequate haematocrit control requiring phlebotomies, persistently high cardiovascular risk, and persistently high symptom burden. Recombinant interferon alfa, either in the form of ropeginterferon alfa-2b or pegylated interferon alfa-2a, is the recommended cytoreductive treatment for these patients. The expert panel suggested that either interferon alfa or ruxolitinib should be considered for patients who are being treated with hydroxyurea but require a therapy change.


Assuntos
Policitemia Vera , Procedimentos Cirúrgicos de Citorredução , Humanos , Hidroxiureia/uso terapêutico , Policitemia Vera/tratamento farmacológico , Qualidade de Vida , Esplenomegalia/tratamento farmacológico
9.
Haematologica ; 2021 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-34911284

RESUMO

Vaccines against SARS-CoV-2 have shown remarkable efficacy and thus constitute an important preventive option against COVID-19, especially in fragile patients. We aimed to systematically analyse the outcomes of patients with haematological malignancies who received vaccination and to identify specific groups with differences in outcomes. The primary end point was antibody response after full vaccination (two doses of mRNA or one dose of vector-based vaccines). We identified 49 studies comprising 11086 individuals. Overall risk of bias was low. The pooled response for haematological malignancies was 64% (95% confidence interval [CI], 59-69; I²=93%) vs 96% (95% CI, 92-97; I²=44%) for solid cancer and 98% (95% CI, 96-99; I²=55%) for healthy controls (P<0.001). Outcome was different across haematological malignancies (P<0.001). The pooled response was 50% (95% CI, 43-57; I²=84%) for chronic lymphocytic leukaemia, 76% (95% CI, 67-83; I²=92%) for multiple myeloma, 83% (95% CI, 69-91; I²=85%) for myeloproliferative neoplasms, 91% (95% CI, 82-96; I²=12%) for Hodgkin's lymphoma, and 58% (95% CI, 44-70; I²=84%) for aggressive and 61% (95% CI, 48-72; I²=85%) for indolent non-Hodgkin's lymphoma. The pooled response for allogeneic and autologous haematopoietic cell transplantation was 82% and 83%, respectively. Being in remission and prior COVID-19 showed significantly higher responses. Low pooled response was identified for active treatment (35%), anti-CD20 therapy ≤1 year (15%), Bruton kinase inhibition (23%), venetoclax (26%), ruxolitinib (42%), and chimeric antigen receptor T-cell therapy (42%). Studies on timing, value of boosters, and long-term efficacy are needed. This study is registered with PROSPERO (CRD42021279051).

11.
Clin Hematol Int ; 3(3): 77-82, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34820612

RESUMO

The use of convalescent plasma (CP) from individuals recovered from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a promising therapeutic modality for the coronavirus disease 2019 (COVID-19). CP has been in use for at least a century to provide passive immunity against a number of diseases, and was recently proposed by the World Health Organization for human Ebola virus infection. Only a few small studies have so far been published on patients with COVID-19 and concomitant hematological malignancies (HM). The Italian Hematology Alliance on HM and COVID-19 has found that HM patients with COVID-19 clinically perform more poorly than those with either HM or COVID-19 alone. A COVID-19 infection in patients with B-cell lymphoma is associated with impaired generation of neutralizing antibody titers and lowered clearance of SARS-CoV-2. Treatment with CP was seen to increase antibody titers in all patients and to improve clinical response in 80% of patients examined. However, a recent study has reported impaired production of SARS-CoV-2-neutralizing antibodies in an immunosuppressed individual treated with CP, possibly supporting the notion of virus escape, particularly in immunocompromised individuals where prolonged viral replication occurs. This may limit the efficacy of CP treatment in at least some HM patients. More recently, it has been shown that CP may provide a neutralising effect against B.1.1.7 and other SARS-CoV-2 variants, thus expanding its application in clinical practice. More extensive studies are needed to further assess the use of CP in COVID-19-infected HM patients.

13.
Blood Adv ; 2021 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-34749396

RESUMO

Patients receiving chimeric antigen receptor T cells (CAR-T cells) therapy may be particularly susceptible to coronavirus disease 2019 (COVID-19) because of several factors including the immunosuppression associated to the underlying disease and delayed cytopenias. Regrettably, data on outcomes of CAR-T recipients with COVID-19 are extremely scarce. The aim of this study was to investigate the characteristics and outcomes of COVID-19 in patients treated with CAR-T therapy. The European Hematology Association - Scientific Working Group Infection in Hematology endorsed a survey to collect and analyze data from patients developing COVID-19 after CAR-T therapy. Overall, 459 patients treated with CAR-T cells were reported from 18 European centers. The prevalence of COVID-19 cases was 4.8%. Median time from CAR-T therapy and COVID-19 diagnosis was 169 days. Severe infection occurred in 66.7% of patients and 43.3% of the subjects required admission to ICU. The COVID-19 mortality was 33%. In multivariable analysis, the disease status at the time of COVID-19 trended marginally towards adverse outcome (P=0.075). In conclusion, we documented a high fatality rate for CAR-T patients with COVID-19, supporting the need to design successful interventions to mitigate the risk of infection in this vulnerable group of patients.

15.
Cancers (Basel) ; 13(19)2021 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-34638230

RESUMO

Long non-coding RNAs (lncRNAs) have been recently described as key mediators in the development of hematological malignancies. In the last years, circulating lncRNAs have been proposed as a new class of non-invasive biomarkers for cancer diagnosis and prognosis and to predict treatment response. The present study is aimed to investigate the potential of circulating lncRNAs as non-invasive prognostic biomarkers in myelofibrosis (MF), the most severe among Philadelphia-negative myeloproliferative neoplasms. We detected increased levels of seven circulating lncRNAs in plasma samples of MF patients (n = 143), compared to healthy controls (n = 65). Among these, high levels of LINC01268, MALAT1 or GAS5 correlate with detrimental clinical variables, such as high count of leukocytes and CD34+ cells, severe grade of bone marrow fibrosis and presence of splenomegaly. Strikingly, high plasma levels of LINC01268 (p = 0.0018), GAS5 (p = 0.0008) or MALAT1 (p = 0.0348) are also associated with a poor overall-survival while high levels of LINC01268 correlate with a shorter leukemia-free-survival. Finally, multivariate analysis demonstrated that the plasma level of LINC01268 is an independent prognostic variable, suggesting that, if confirmed in future in an independent patients' cohort, it could be used for further studies to design an updated classification model for MF patients.

16.
Cancers (Basel) ; 13(19)2021 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-34638236

RESUMO

An outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) started in December 2019 in China and then become pandemic in February 2020. Several publications investigated the possible increased rate of COVID-19 infection in hematological malignancies. Based on the published data, strategies for the management of chronic Philadelphia-negative chronic myeloproliferative neoplasms (MPNs) are provided. The risk of severe COVID-19 seems high in MPN, particularly in patients with essential thrombocythemia, but not negligible in myelofibrosis. MPN patients are at high risk of both thrombotic and hemorrhagic complications and this must be accounted in the case of COVID-19 deciding on a case-by-case basis. There are currently no data to suggest that hydroxyurea or interferon may influence the risk or severity of COVID-19 infection. Conversely, while the immunosuppressive activity of ruxolitinib might pose increased risk of infection, its abrupt discontinuation during COVID-19 syndrome is associated with worse outcome. All MPN patients should receive vaccine against COVID-19; reassuring data are available on efficacy of mRNA vaccines in MPNs.

17.
J Hematol Oncol ; 14(1): 168, 2021 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-34649563

RESUMO

BACKGROUND: Patients with hematological malignancies (HM) are at high risk of mortality from SARS-CoV-2 disease 2019 (COVID-19). A better understanding of risk factors for adverse outcomes may improve clinical management in these patients. We therefore studied baseline characteristics of HM patients developing COVID-19 and analyzed predictors of mortality. METHODS: The survey was supported by the Scientific Working Group Infection in Hematology of the European Hematology Association (EHA). Eligible for the analysis were adult patients with HM and laboratory-confirmed COVID-19 observed between March and December 2020. RESULTS: The study sample includes 3801 cases, represented by lymphoproliferative (mainly non-Hodgkin lymphoma n = 1084, myeloma n = 684 and chronic lymphoid leukemia n = 474) and myeloproliferative malignancies (mainly acute myeloid leukemia n = 497 and myelodysplastic syndromes n = 279). Severe/critical COVID-19 was observed in 63.8% of patients (n = 2425). Overall, 2778 (73.1%) of the patients were hospitalized, 689 (18.1%) of whom were admitted to intensive care units (ICUs). Overall, 1185 patients (31.2%) died. The primary cause of death was COVID-19 in 688 patients (58.1%), HM in 173 patients (14.6%), and a combination of both COVID-19 and progressing HM in 155 patients (13.1%). Highest mortality was observed in acute myeloid leukemia (199/497, 40%) and myelodysplastic syndromes (118/279, 42.3%). The mortality rate significantly decreased between the first COVID-19 wave (March-May 2020) and the second wave (October-December 2020) (581/1427, 40.7% vs. 439/1773, 24.8%, p value < 0.0001). In the multivariable analysis, age, active malignancy, chronic cardiac disease, liver disease, renal impairment, smoking history, and ICU stay correlated with mortality. Acute myeloid leukemia was a higher mortality risk than lymphoproliferative diseases. CONCLUSIONS: This survey confirms that COVID-19 patients with HM are at high risk of lethal complications. However, improved COVID-19 prevention has reduced mortality despite an increase in the number of reported cases.


Assuntos
COVID-19/complicações , Neoplasias Hematológicas/complicações , Adulto , Idoso , Idoso de 80 Anos ou mais , COVID-19/diagnóstico , COVID-19/epidemiologia , COVID-19/terapia , Europa (Continente)/epidemiologia , Feminino , Neoplasias Hematológicas/epidemiologia , Neoplasias Hematológicas/terapia , Hospitalização , Humanos , Unidades de Terapia Intensiva , Masculino , Pessoa de Meia-Idade , Sistema de Registros , Fatores de Risco , SARS-CoV-2/isolamento & purificação , Adulto Jovem
18.
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