RESUMO
Allogeneic hematopoietic stem cell transplantation (HSCT) remains the only curative option for patients with Myelodysplastic syndromes (MDS). For many years, the selection of patients to allogeneic HSCT has been largely based on use of the International Prognostic Scoring System-Revised (IPSS-R). However, the recent broader application of next generation sequencing in clinical practice provided an abundance of molecular data and led to the introduction of molecular prognostic scores as IPSS-Molecular (IPSS-M). In this paper, we retrospectively analyzed the outcomes of 57 consecutive MDS patients treated with allogeneic HSCT in our center. Re-stratification from IPSS-R to IPSS-M occurred in almost half of patients. The application of IPSS-M to our cohort demonstrated a stronger prognostic separation compared to IPSS-R and improved the C-index. Very high-risk IPSS-M patients showed worse outcomes following HSCT compared to high-risk patients. This study provides data supporting the need of integrating molecular information in the transplant decision making of patients with MDS. This allows an earlier and better identification of patients to whom the transplant should be advised.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Síndromes Mielodisplásicas , Humanos , Síndromes Mielodisplásicas/terapia , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/mortalidade , Síndromes Mielodisplásicas/diagnóstico , Estudos Retrospectivos , Transplante de Células-Tronco Hematopoéticas/métodos , Masculino , Feminino , Pessoa de Meia-Idade , Prognóstico , Idoso , Adulto , Tomada de Decisão Clínica , Transplante Homólogo , Sequenciamento de Nucleotídeos em Larga Escala , Adulto JovemAssuntos
Anticorpos Biespecíficos , Leucemia Linfocítica Crônica de Células B , Humanos , Anticorpos Biespecíficos/uso terapêutico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Masculino , Feminino , Linfócitos T/imunologia , Pessoa de Meia-Idade , Idoso , Reconstituição Imune , Adulto , Imunoterapia Adotiva/efeitos adversosRESUMO
Clinical or biological parameters useful to predict progression during treatment in real-life setting with ibrutinib, idelalisib and venetoclax in relapsed/refractory chronic lymphocytic leukemia (CLL) are still debated. We conducted a multi-center retrospective study on CLL patients treated with ibrutinib and/or idelalisib who were switched to venetoclax for progression or due to adverse events to identify any clinical and/or biological parameters useful to predict progression during treatment with venetoclax. Of all the 128 evaluable patients, 81 had received ibrutinib prior to switching to venetoclax, 35 had received idelalisib and 12 both. When comparing the three subgroups, we did not notice any statistical difference in terms of clinical or biological features. No variable at baseline and at different time points during the follow-up (at 6, 12, 18 and 24 months) was found to predict progression nor to have significance for Progression Free Survival (PFS) in the ibrutinib group and in the idelalisib group and in subgroups according to the line of treatment. Analyzing the data of the venetoclax treatment, after a median follow up of 14.3 months, median PFS was not reached and estimated 3-year PFS was 54%. Of the 128 patients treated with venetoclax, 28 (22%) experienced progressive disease. At multivariate analysis for predictive factors for progression, lymph node diameter >56.5 mm before starting treatment emerged as an independent risk factor for progression. The lymph node predictive role for progression during venetoclax treatment could be a new parameter that deserves to be investigate in future studies.
Assuntos
Leucemia Linfocítica Crônica de Células B , Linfadenopatia , Humanos , Leucemia Linfocítica Crônica de Células B/patologia , Estudos Retrospectivos , Linfadenopatia/induzido quimicamente , Linfadenopatia/tratamento farmacológico , Compostos Bicíclicos Heterocíclicos com Pontes/efeitos adversos , Recidiva , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosAssuntos
COVID-19 , Leucemia Linfocítica Crônica de Células B , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Compostos Bicíclicos Heterocíclicos com Pontes/efeitos adversos , Humanos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Pandemias , SulfonamidasAssuntos
COVID-19/complicações , Leucemia Linfocítica Crônica de Células B/terapia , SARS-CoV-2/imunologia , Vacinação/métodos , Idoso , COVID-19/prevenção & controle , COVID-19/transmissão , COVID-19/virologia , Gerenciamento Clínico , Feminino , Humanos , Itália/epidemiologia , Leucemia Linfocítica Crônica de Células B/epidemiologia , Leucemia Linfocítica Crônica de Células B/virologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Fatores de TempoRESUMO
Chronic lymphocytic leukemia (CLL) is a disease of the elderly, characterized by immunodeficiency. Hence, patients with CLL might be considered more susceptible to severe complications from COVID-19. We undertook this retrospective international multicenter study to characterize the course of COVID-19 in patients with CLL and identify potential predictors of outcome. Of 190 patients with CLL and confirmed COVID-19 diagnosed between 28/03/2020 and 22/05/2020, 151 (79%) presented with severe COVID-19 (need of oxygen and/or intensive care admission). Severe COVID-19 was associated with more advanced age (≥65 years) (odds ratio 3.72 [95% CI 1.79-7.71]). Only 60 patients (39.7%) with severe COVID-19 were receiving or had recent (≤12 months) treatment for CLL at the time of COVID-19 versus 30/39 (76.9%) patients with mild disease. Hospitalization rate for severe COVID-19 was lower (p < 0.05) for patients on ibrutinib versus those on other regimens or off treatment. Of 151 patients with severe disease, 55 (36.4%) succumbed versus only 1/38 (2.6%) with mild disease; age and comorbidities did not impact on mortality. In CLL, (1) COVID-19 severity increases with age; (2) antileukemic treatment (particularly BTK inhibitors) appears to exert a protective effect; (3) age and comorbidities did not impact on mortality, alluding to a relevant role of CLL and immunodeficiency.
Assuntos
Betacoronavirus , Infecções por Coronavirus/patologia , Leucemia Linfocítica Crônica de Células B/complicações , Pneumonia Viral/patologia , Adenina/análogos & derivados , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , COVID-19 , Comorbidade , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/mortalidade , Feminino , Humanos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Pandemias , Piperidinas , Pneumonia Viral/diagnóstico , Pneumonia Viral/mortalidade , Prognóstico , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/farmacologia , Pirazóis/uso terapêutico , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Estudos Retrospectivos , SARS-CoV-2 , Índice de Gravidade de Doença , Inquéritos e QuestionáriosAssuntos
Deferasirox/uso terapêutico , Quelantes de Ferro/uso terapêutico , Sobrecarga de Ferro/tratamento farmacológico , Sobrecarga de Ferro/etiologia , Síndromes Mielodisplásicas/complicações , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Transfusão de Sangue , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/terapia , Resultado do Tratamento , Adulto JovemRESUMO
Adverse drug reactions (ADRs) reduce patients' quality of life, increase mortality and morbidity, and have a negative economic impact on healthcare systems. Nevertheless, the importance of ADR reporting is often underestimated. The project "FarmaREL" has been developed to monitor and evaluate ADRs in haematological patients and to increase pharmacovigilance culture among haematology specialists. In 13 haematology units, based in Lombardy, Italy, a dedicated specialist with the task of encouraging ADRs reporting and sensitizing healthcare professionals to pharmacovigilance has been assigned. The ADRs occurring in haematological patients were collected electronically and then analysed with multiple logistic regression. Between January 2009 and December 2011, 887 reports were collected. The number of ADRs was higher in older adults (528; 59%), in male (490; 55%), and in non-Hodgkin lymphoma patients (343; 39%). Most reactions were severe (45% required or prolonged hospitalization), but in most cases, they were fully resolved at the time of reporting. According to Schumock and Thornton criteria, a percentage of ADRs as high as 7% was found to be preventable versus 2% according to reporter opinion. Patients' haematological diagnosis, not age or gender, resulted to be the variable that most influenced ADR, in particular severity and outcome. The employment of personnel specifically dedicated to pharmacovigilance is a successful strategy to improve the number and quality of ADR reports. "FarmaREL", the first programme of active pharmacovigilance in oncohaematologic patients, significantly contributed to reach the WHO "Gold Standard" for pharmacovigilance in Lombardy, Italy.
Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/diagnóstico , Neoplasias Hematológicas/complicações , Farmacovigilância , Qualidade de Vida/psicologia , Idoso , Feminino , Humanos , Itália , Masculino , Pessoa de Meia-IdadeRESUMO
5-Azacytidine is an effective therapy in high risk MDS and oligoblastic AML. This "real life" analysis was made on 185 patients treated with 5-azacytidine in 10 centers afferent to REL ("Rete Ematologica Lombarda"), a network in Lombardia region. The aim was to assess the influence of disease and comorbidity risk assessments on the survival. The results confirm the utility of 5-azacitidine in prolonging OS regardless of advanced age and the presence of comorbidities. They also encourage an early treatment since patients with IPSS-R High risk MDS have better outcome with respect to Very High risk ones. According to the IPSS cytogenetic risk, there was no difference in the outcome between Intermediate and High risk patients. Nevertheless, a poorer cytogenetic risk, according to the IPSS-R cytogenetic stratification, negatively influenced the outcome.
Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Azacitidina/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Síndromes Mielodisplásicas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Comorbidade , Feminino , Humanos , Estimativa de Kaplan-Meier , Leucemia Mieloide Aguda/epidemiologia , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/epidemiologia , Síndromes Mielodisplásicas/patologia , Curva ROC , Estudos Retrospectivos , Fatores de Risco , Adulto JovemRESUMO
OBJECTIVE: The primary objective of this study was to evaluate the health-related quality of life (HRQOL) in lower-risk, transfusion-dependent patients with myelodysplastic syndromes (MDS) treated with deferasirox. A secondary objective was to investigate the relationship between HRQOL, serum ferritin levels and transfusion dependency. PATIENTS AND METHODS: This was a prospective multicentre study enrolling 159 patients, of whom 152 received at least one dose of deferasirox. HRQOL was assessed with the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) at baseline and then at 3, 6, 9 and 12â months. Primary analysis was performed estimating mean HRQOL scores over time by a linear mixed model on selected scales. RESULTS: The median age of treated patients was 72â years (range 24-87â years). No statistically significant changes over time were found in mean scores for global health status/quality of life (p=0.564), physical functioning (p=0.409) and fatigue (p=0.471) scales. Also, no significant changes were found for constipation (p=0.292), diarrhoea (p=0.815) and nausea and vomiting (p=0.643). Serum ferritin levels were not associated with HRQOL outcomes. A higher patient-reported baseline pain severity was an independent predictive factor of an earlier achievement of transfusion independence with a HR of 1.032 (99% CI 1.004 to 1.060; p=0.003). CONCLUSIONS: HRQOL of transfusion-dependent patients with MDS receiving deferasirox therapy remains stable over time. HRQOL assessment might also provide important predictive information on treatment outcomes. TRIAL REGISTRATION NUMBER: NCT00469560.
Assuntos
Benzoatos/uso terapêutico , Quelantes de Ferro/uso terapêutico , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/psicologia , Qualidade de Vida , Reação Transfusional , Triazóis/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Benzoatos/administração & dosagem , Deferasirox , Feminino , Humanos , Quelantes de Ferro/administração & dosagem , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/metabolismo , Estudos Prospectivos , Resultado do Tratamento , Triazóis/administração & dosagem , Adulto JovemAssuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Feminino , Seguimentos , Humanos , Leucemia Linfocítica Crônica de Células B/sangue , Leucemia Linfocítica Crônica de Células B/patologia , Masculino , Pessoa de Meia-Idade , Pentostatina/administração & dosagem , Pentostatina/efeitos adversosRESUMO
Current treatment of chronic lymphocytic leukemia (CLL) patients often results in life-threatening immunosuppression. Furthermore, CLL is still an incurable disease due to the persistence of residual leukemic cells. These patients may therefore benefit from immunotherapy approaches aimed at immunoreconstitution and/or the elimination of residual disease following chemotherapy. For these purposes, we designed a simple GMP-compliant protocol for ex vivo expansion of normal T cells from CLL patients' peripheral blood for adoptive therapy, using bispecific Ab blinatumomab (CD3 × CD19), acting both as T cell stimulator and CLL depletion agent, and human rIL-2. Starting from only 10 ml CLL peripheral blood, a mean 515 × 10(6) CD3(+) T cells were expanded in 3 wk. The resulting blinatumomab-expanded T cells (BET) were polyclonal CD4(+) and CD8(+) and mostly effector and central memory cells. The Th1 subset was slightly prevalent over Th2, whereas Th17 and T regulatory cells were <1%. CMV-specific clones were detected in equivalent proportion before and after expansion. Interestingly, BET cells had normalized expression of the synapse inhibitors CD272 and CD279 compared with starting T cells and were cytotoxic against CD19(+) targets in presence of blinatumomab in vitro. In support of their functional capacity, we observed that BET, in combination with blinatumomab, had significant therapeutic activity in a systemic human diffuse large B lymphoma model in NOD-SCID mice. We propose BET as a therapeutic tool for immunoreconstitution of heavily immunosuppressed CLL patients and, in combination with bispecific Ab, as antitumor immunotherapy.
Assuntos
Anticorpos Biespecíficos/farmacologia , Técnicas de Cultura de Células , Imunoterapia Adotiva , Subpopulações de Linfócitos T/efeitos dos fármacos , Subpopulações de Linfócitos T/imunologia , Animais , Antígenos de Superfície/metabolismo , Linhagem Celular Tumoral , Citotoxicidade Imunológica , Modelos Animais de Doenças , Feminino , Humanos , Imunofenotipagem , Interleucina-2/farmacologia , Leucemia Linfocítica Crônica de Células B/imunologia , Leucemia Linfocítica Crônica de Células B/mortalidade , Leucemia Linfocítica Crônica de Células B/terapia , Camundongos , Fenótipo , Receptor de Morte Celular Programada 1/metabolismo , Subpopulações de Linfócitos T/metabolismoRESUMO
BACKGROUND: In the absence of randomized, controlled trial data to support iron chelation therapy in transfusion-dependent patients with myelodysplastic syndromes (MDS), continued evidence from large prospective clinical trials evaluating the efficacy and safety of iron chelation therapy in this patient population is warranted. METHODS: The safety and efficacy of deferasirox was examined in a prospective, open-label, single-arm, multicenter trial of transfusion-dependent patients with International Prognostic Scoring System low- or intermediate-1-risk MDS and evidence of transfusion-related iron overload. The effects of deferasirox therapy on hematological response and disease progression were also examined. RESULTS: Of 159 participants enrolled from 37 Italian centers, 152 received ≥1 dose of deferasirox (initiated at 10-20 mg/kg/day and titrated as appropriate), and 68 completed the study. Of 84 patients who discontinued deferasirox therapy, 22 died during the trial, and 28 withdrew due to an adverse event (AE). Fourteen treatment-related grade 3 AEs occurred in 11 patients, whereas no grade 4 or 5 drug-related AEs were reported. Significant risks for dropout were a higher serum ferritin level at baseline, a higher MDS-Specific Comorbidity Index, and a shorter diagnosis-enrollment interval. Median serum ferritin level fell from 1966 ng/mL to 1475 ng/mL (P < 0.0001). The cumulative incidence of transfusion independence, adjusted for death and disease progression, was 2.6%, 12.3%, and 15.5% after 6, 9, and 12 months, respectively. CONCLUSIONS: Deferasirox therapy in transfusion-dependent patients with MDS was moderately well tolerated and effectively lowered serum ferritin levels. Positive hematological responses were observed, and a subset of patients achieved transfusion independence.
Assuntos
Benzoatos/uso terapêutico , Transfusão de Sangue , Quelantes de Ferro/uso terapêutico , Sobrecarga de Ferro/tratamento farmacológico , Sobrecarga de Ferro/etiologia , Síndromes Mielodisplásicas/complicações , Síndromes Mielodisplásicas/terapia , Triazóis/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Benzoatos/efeitos adversos , Deferasirox , Feminino , Ferritinas/sangue , Humanos , Quelantes de Ferro/efeitos adversos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Reação Transfusional , Resultado do Tratamento , Triazóis/efeitos adversos , Adulto JovemRESUMO
BACKGROUND: The JAK2(V617F) mutation is present in the majority of patients with polycythaemia vera and in approximately half of patients with essential thrombocythaemia and primary myelofibrosis. In this study we compare the results of JAK2(V617F) mutation detection using three different molecular techniques in the same group of patients affected by essential thrombocythaemia. PATIENTS AND METHODS: The JAK2 mutation was investigated with a qualitative method in 115 consecutive outpatients with a diagnosis of essential thrombocythaemia made according to WHO 2001 criteria. In 48/115 (41.7%) the allele burden was also evaluated with two different qualitative methods, of which one was a method developed in-house and the other was a commercially available method. RESULTS: The JAK2(V617F) mutation was detected by the qualitative method in 81/115 (69.6%) of the patients. Among the 48/115 patients in whom all three methods were applied, the qualitative method detected the mutation in 38 (79%). According to the quantitative method developed in-house, the mutation was present in 35/48 (73%) of the patients: of these, 2/35 (5.7%) patients were homozygous for the JAK2(V617F) mutation. The commercial quantitative method showed the mutation in 37/48 (77%) patients: of these, 9/37 (18%) patients were homozygous. Three of the 13 patients in whom no mutation was detected by the in-house method were positive for the JAK2(V617F) according to the commercial method. In one patient the search for the JAK2(V617F) mutation was positive with the in-house method but negative with the commercial kit. CONCLUSION: Detection of the JAK2(V617F) mutation may depend on the molecular technique used. Considering that detection of this mutation will not only have a diagnostic value, but also a role in treatment given the development of JAK2(V617F) pathway inhibiting drugs, indications on a reference molecular diagnostic technique for JAK2(V617F) assessment and quantification of its allele burden from a panel of experts are warranted.
Assuntos
Janus Quinase 2/genética , Mutação de Sentido Incorreto , Policitemia Vera/genética , Reação em Cadeia da Polimerase/métodos , Mielofibrose Primária/genética , Trombocitemia Essencial/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Substituição de Aminoácidos , Análise Mutacional de DNA/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Policitemia Vera/diagnóstico , Mielofibrose Primária/diagnóstico , Sensibilidade e Especificidade , Trombocitemia Essencial/diagnósticoRESUMO
Invasive pulmonary aspergillosis (IPA) is a frequently fatal complication in patients with acute leukaemia. Because diagnosis is still difficult, non-invasive diagnostic criteria were recently proposed by MSG/IFICG/EORTC for study purposes. We have analysed their usefulness in the clinical management of acute leukaemic patients with pulmonary infiltrates. Twenty-seven infiltrates developed during 174 chemotherapy cycles given to 50 consecutive patients. According to diagnostic criteria, IPA was diagnosed in 42% of patients and 77.8% of pulmonary infiltrates. AML diagnosis and the first induction cycle were significant risk factors. "Proven" IPA was rare, occurring in one patient (2%). The diagnosis of "probable" IPA was made in seven patients (14%) and was strongly supported by the significant association of characteristic radiological lesions ("major" clinical criterion) with the positivity of one microbiological criterion (P = 0.026). Conversely, "possible" IPA was frequent (26%) because its pertinent diagnostic criteria were fulfilled in 48.1% of pulmonary infiltrates. However, in 84.6% of cases, the diagnosis of "possible IPA" aspecifically derived from the association of two conditions, a new pulmonary infiltrate with symptoms of lower respiratory tract infection ("minor clinical criterion"), together with the definition of "susceptible" host, which applied to 100% of our leukaemic patients. We conclude that, according to MSG/IFICG/EORTC criteria, a high number of pulmonary infiltrates would be diagnosed as IPA, but only a diagnosis of "proven/probable" IPA should be considered reliable in the clinical management of suspected IPA.