RESUMO
We conducted a post hoc analysis of the FOLL12 trial to determine the impact of different initial immunochemotherapy (ICT) regimens on patient outcomes. Patients were selected from the FOLL12 trial, which included adults with stage II-IV follicular lymphoma (FL) grade 1-3a and high tumor burden. Patients were randomized 1:1 to receive either standard ICT followed by rituximab maintenance (RM) or the same ICT followed by a response-adapted approach. ICT consisted of rituximab-bendamustine (RB) or rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHOP), per physician's decision. A total of 786 patients were included in this analysis, 341 of whom received RB and 445 R-CHOP. RB was more frequently prescribed to older subjects, females, patients without bulky disease, and those with grade 1-2 FL. After a median of 56 months of follow-up, R-CHOP and RB had similar progression-free survival (PFS) (Hazard Ratio for RB 1.11, 95% CI 0.87-1.42, p = 0.392). Standard RM was associated with improved PFS compared to response-adapted management both after R-CHOP and RB. Grade 3-4 hematologic adverse events were more frequent with R-CHOP during induction treatment and more frequent with RB during RM. Grade 3-4 infections were more frequent with RB. RB was also associated with a higher incidence of transformed FL. R-CHOP and RB showed similar activity and efficacy, but with different safety profiles and long-term events, suggesting that the treating physician should carefully select the most appropriate chemotherapy regimen for each patient based on patient's individual characteristics, choices, and risk profile.
Assuntos
Linfoma Folicular , Adulto , Feminino , Humanos , Rituximab , Cloridrato de Bendamustina/uso terapêutico , Prednisona , Recidiva Local de Neoplasia/tratamento farmacológico , Vincristina , Ciclofosfamida , Doxorrubicina , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
Little is known of the course of COVID-19 and the antibody response to infection or vaccination in patients with hairy-cell leukaemia (HCL). Among a total of 58 HCL cases we studied in these regards, 37 unvaccinated patients, mostly enjoying a relatively long period free from anti-leukaemic treatment, developed COVID-19 between March 2020 and December 2021 with a usually favourable outcome (fatality rate: 5/37, 14%); however, active leukaemia, older age and more comorbidities were associated with a worse course. Postinfection (n = 11 cases) and postvaccination (n = 28) seroconversion consistently developed, except after recent anti-CD20 or venetoclax therapy, correlating with perivaccine B-cell count. Vaccination appeared to protect from severe COVID-19 in 11 patients with breakthrough infection.
Assuntos
COVID-19 , Leucemia de Células Pilosas , Leucemia , Humanos , COVID-19/prevenção & controle , SARS-CoV-2 , Vacinação , Anticorpos AntiviraisRESUMO
BACKGROUND: Hairy-cell leukemia (HCL) is a CD20+ indolent B-cell cancer in which a BRAF V600E kinase-activating mutation plays a pathogenetic role. In clinical trials involving patients with refractory or relapsed HCL, the targeting of BRAF V600E with the oral BRAF inhibitor vemurafenib led to a response in 91% of the patients; 35% of the patients had a complete response. However, the median relapse-free survival was only 9 months after treatment was stopped. METHODS: In a phase 2, single-center, academic trial involving patients with refractory or relapsed HCL, we assessed the safety and efficacy of vemurafenib (960 mg, administered twice daily for 8 weeks) plus concurrent and sequential rituximab (375 mg per square meter of body-surface area, administered for 8 doses over a period of 18 weeks). The primary end point was a complete response at the end of planned treatment. RESULTS: Among the 30 enrolled patients with HCL, the median number of previous therapies was 3. A complete response was observed in 26 patients (87%) in the intention-to-treat population. All the patients who had HCL that had been refractory to chemotherapy (10 patients) or rituximab (5) and all those who had previously been treated with BRAF inhibitors (7) had a complete response. Thrombocytopenia resolved after a median of 2 weeks, and neutropenia after a median of 4 weeks. Of the 26 patients with a complete response, 17 (65%) were cleared of minimal residual disease (MRD). Progression-free survival among all 30 patients was 78% at a median follow-up of 37 months; relapse-free survival among the 26 patients with a response was 85% at a median follow-up of 34 months. In post hoc analyses, MRD negativity and no previous BRAF inhibitor treatment correlated with longer relapse-free survival. Toxic effects, mostly of grade 1 or 2, were those that had previously been noted for these agents. CONCLUSIONS: In this small study, a short, chemotherapy-free, nonmyelotoxic regimen of vemurafenib plus rituximab was associated with a durable complete response in most patients with refractory or relapsed HCL. (Funded by the European Research Council and others; HCL-PG03 EudraCT number, 2014-003046-27.).
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia de Células Pilosas/tratamento farmacológico , Rituximab/administração & dosagem , Vemurafenib/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Medula Óssea/patologia , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Neoplasia Residual , Neutropenia/induzido quimicamente , Intervalo Livre de Progressão , Recidiva , Indução de Remissão , Rituximab/efeitos adversos , Trombocitopenia/induzido quimicamente , Vemurafenib/efeitos adversosRESUMO
BACKGROUND: BRAF V600E is the genetic lesion underlying hairy-cell leukemia. We assessed the safety and activity of the oral BRAF inhibitor vemurafenib in patients with hairy-cell leukemia that had relapsed after treatment with a purine analogue or who had disease that was refractory to purine analogues. METHODS: We conducted two phase 2, single-group, multicenter studies of vemurafenib (at a dose of 960 mg twice daily)--one in Italy and one in the United States. The therapy was administered for a median of 16 weeks in the Italian study and 18 weeks in the U.S. study. Primary end points were the complete response rate (in the Italian trial) and the overall response rate (in the U.S. trial). Enrollment was completed (28 patients) in the Italian trial in April 2013 and is still open (26 of 36 planned patients) in the U.S. trial. RESULTS: The overall response rates were 96% (25 of 26 patients who could be evaluated) after a median of 8 weeks in the Italian study and 100% (24 of 24) after a median of 12 weeks in the U.S. study. The rates of complete response were 35% (9 of 26 patients) and 42% (10 of 24) in the two trials, respectively. In the Italian trial, after a median follow-up of 23 months, the median relapse-free survival was 19 months among patients with a complete response and 6 months among those with a partial response; the median treatment-free survival was 25 months and 18 months, respectively. In the U.S. trial, at 1 year, the progression-free survival rate was 73% and the overall survival rate was 91%. Drug-related adverse events were usually of grade 1 or 2, and the events most frequently leading to dose reductions were rash and arthralgia or arthritis. Secondary cutaneous tumors (treated with simple excision) developed in 7 of 50 patients. The frequent persistence of phosphorylated ERK-positive leukemic cells in bone marrow at the end of treatment suggests bypass reactivation of MEK and ERK as a resistance mechanism. CONCLUSIONS: A short oral course of vemurafenib was highly effective in patients with relapsed or refractory hairy-cell leukemia. (Funded by the Associazione Italiana per la Ricerca sul Cancro and others; EudraCT number, 2011-005487-13; ClinicalTrials.gov number NCT01711632.).
Assuntos
Antineoplásicos/administração & dosagem , Indóis/administração & dosagem , Leucemia de Células Pilosas/tratamento farmacológico , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Proteínas Proto-Oncogênicas B-raf/genética , Sulfonamidas/administração & dosagem , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Artralgia/induzido quimicamente , Biomarcadores/sangue , Medula Óssea/patologia , Intervalo Livre de Doença , Resistencia a Medicamentos Antineoplásicos/genética , Exantema/induzido quimicamente , Feminino , Humanos , Indóis/efeitos adversos , Leucemia de Células Pilosas/genética , Leucemia de Células Pilosas/patologia , Masculino , Pessoa de Meia-Idade , Mutação , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas p21(ras) , Recidiva , Indução de Remissão , Sulfonamidas/efeitos adversos , Vemurafenib , Proteínas ras/genéticaRESUMO
BACKGROUND AND AIMS: In hepatitis B virus (HBV) carriers receiving chemotherapy, the risk of reactivation is high, particularly if rituximab is given alone or in combination with steroids. The aim of this study was to assess the incidence, prevalence, and clinical course of HBV infection in a cohort of patients with hematological malignancies receiving cytotoxic therapy as well as to propose a strategy for managing HBV reactivation. METHODS: This is a prospective observational study. All consecutive patients with hematological malignancies receiving intravenous cytotoxic chemotherapy between October 2005 and June 2010 and followed up for at least six months were enrolled in the study. Viral hepatitis markers and liver function indexes were monitored prospectively. RESULTS: We enrolled 478 patients, including 263 males (55%) and 465 (97.3%) Italians. Non-Hodgkin's lymphoma was the most frequent diagnosis (66%). At least one HBV marker was positive in 96 patients (20%): 21 (4.4%) patients were HBsAg positive, 17 (3.5%) were anti-HBc positive, and 58 (12.1%) were anti-HBc/anti-HBs positive. All but one HBsAg-positive patient received therapy with nucleoside/nucleotide analogs prior to chemotherapy. All but three reached complete virological suppression at six months from the start of treatment. Of the 17 HBsAg-negative/anti-HBc-positive patients, three (18%) had reactivation with seroreversion. All three obtained viral suppression with adefovir. Regarding the 58 anti-HBc/anti-HBs-positive patients, two (3.4%) experienced seroreversion and were treated successfully with nucleoside analogs; both were taking rituximab. No severe ALT flares were observed during or after antiviral therapy. CONCLUSION: Our data suggest that pre-treatment screening of patients at risk of viral reactivation yields benefit and therefore should be practiced by clinicians treating patients with malignancies.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Antivirais/uso terapêutico , Vírus da Hepatite B/fisiologia , Ativação Viral , Adenina/análogos & derivados , Adenina/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Murinos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Quimioterapia Combinada , Feminino , Hepatite B , Antígenos de Superfície da Hepatite B/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Organofosfonatos/uso terapêutico , Estudos Prospectivos , Recidiva , Rituximab , Resultado do TratamentoRESUMO
BACKGROUND: Hairy-cell leukemia (HCL) is a well-defined clinicopathological entity whose underlying genetic lesion is still obscure. METHODS: We searched for HCL-associated mutations by performing massively parallel sequencing of the whole exome of leukemic and matched normal cells purified from the peripheral blood of an index patient with HCL. Findings were validated by Sanger sequencing in 47 additional patients with HCL. RESULTS: Whole-exome sequencing identified five missense somatic clonal mutations that were confirmed on Sanger sequencing, including a heterozygous mutation in BRAF that results in the BRAF V600E variant protein. Since BRAF V600E is oncogenic in other tumors, further analyses were focused on this genetic lesion. The same BRAF mutation was noted in all the other 47 patients with HCL who were evaluated by means of Sanger sequencing. None of the 195 patients with other peripheral B-cell lymphomas or leukemias who were evaluated carried the BRAF V600E variant, including 38 patients with splenic marginal-zone lymphomas or unclassifiable splenic lymphomas or leukemias. In immunohistologic and Western blot studies, HCL cells expressed phosphorylated MEK and ERK (the downstream targets of the BRAF kinase), indicating a constitutive activation of the RAF-MEK-ERK mitogen-activated protein kinase pathway in HCL. In vitro incubation of BRAF-mutated primary leukemic hairy cells from 5 patients with PLX-4720, a specific inhibitor of active BRAF, led to a marked decrease in phosphorylated ERK and MEK. CONCLUSIONS; The BRAF V600E mutation was present in all patients with HCL who were evaluated. This finding may have implications for the pathogenesis, diagnosis, and targeted therapy of HCL. (Funded by Associazione Italiana per la Ricerca sul Cancro and others.).
Assuntos
Leucemia de Células Pilosas/genética , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Adulto , Idoso , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Humanos , Leucemia de Células Pilosas/metabolismo , Leucemia de Células Pilosas/patologia , Linfoma de Células B/genética , Linfoma de Células B/patologia , MAP Quinase Quinase Quinases/metabolismo , Masculino , Pessoa de Meia-Idade , Análise de Sequência de DNARESUMO
Haploidentical stem cell transplantation has became a clinical reality in the last 10 years as it provides the chance of transplant for about 50% of patients with hematological malignancies who do not have a matched related or unrelated donor. Proper graft preparation for this type of transplant is crucial and this paper analyses our work over the past decade in the search for the optimal graft processing procedure moving from E-rosetting and soybean agglutination, through a combination of negative or positive selection of hematopoietic stem cells to the current method of one-step positive selection. In preparing a graft for haploidentical transplant, three essential requisites must be met. It must contain (1) a megadose (>10 x 10(6) x kg recipient b.w.) of hematopoietic stem cells to overcome the HLA histocompatibility barrier; (2) very few T-lymphocytes (CD3+ cells < 3 x 10(4)/kg recipient b.w.) to prevent severe acute and chronic graft-versus-host disease (GvHD); (3) very few B-lymphocytes to prevent Epstein-Barr virus-related lymphoproliferative disorders. With current graft processing technologies based on positive selection of hematopoietic stem cells, these requirements can be met. A 70-80% hematopoietic stem cell recovery ensures the target megadose is achieved in over 70% of cases with a T-cell depletion of more than 4 logs and a B-cell depletion of over 3 logs. Progress in graft processing has ensured primary, sustained engraftment rates of over 90% and has significantly reduced the incidence of severe acute GvHD and EBV-related lymphoproliferative disorders. Modern time-saving automated graft processing devices ensure reproducibility, reliability, and biological safety, which make widespread application of the haploidentical transplant currently feasible.