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1.
Leukemia ; 2020 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-32382083

RESUMO

PTCL patients exhibit poor survival with existing treatments. We investigated the efficacy of CHOP combined with alemtuzumab in 116 PTCL patients age 61-80 in an open-label, randomized phase 3 trial. Alemtuzumab was given on day 1, to a total of 360 mg in 21 patients, or 120 mg in 37. Hematotoxicity was increased with A-CHOP resulting in more grade ≥3 infections (40% versus 21%) and 4 versus 1 death due to infections, respectively. CR/CRu rate was 60% for A-CHOP and 43% for CHOP, and OR rate was 72% and 66%, respectively. Three-year-EFS, PFS and OS were 27% [15%-39%], 28% [15%-40%], and 37% ([23%-50%] for A-CHOP, and 24% [12%-35%], 29% [17%-41%], and 56% [44%-69%] for CHOP, respectively, showing no significant differences. Multivariate analyses, adjusted for strata and sex confirmed these results (hazard ratio HREFS: 0.7 ([95% CI: 0.5-1.1]; p = 0.094), HRPFS: 0.8 ([95% CI: 0.5-1.2]; p = 0.271), HROS: 1.4 ([95% CI: 0.9-2.4]; p = 0.154). The IPI score was validated, and male sex (HREFS 2.5) and bulky disease (HREFS 2.2) were significant risk factors for EFS, PFS, and OS. Alemtuzumab added to CHOP increased response rates, but did not improve survival due to treatment-related toxicity.

2.
Nat Commun ; 11(1): 2465, 2020 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-32424289

RESUMO

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare lymphoma of B-cell origin with frequent expression of functional B-cell receptors (BCRs). Here we report that expression cloning followed by antigen screening identifies DNA-directed RNA polymerase beta' (RpoC) from Moraxella catarrhalis as frequent antigen of BCRs of IgD+ LP cells. Patients show predominance of HLA-DRB1*04/07 and the IgVH genes encode extraordinarily long CDR3s. High-titer, light-chain-restricted anti-RpoC IgG1/κ-type serum-antibodies are additionally found in these patients. RpoC and MID/hag, a superantigen co-expressed by Moraxella catarrhalis that is known to activate IgD+ B cells by binding to the Fc domain of IgD, have additive activation effects on the BCR, the NF-κB pathway and the proliferation of IgD+ DEV cells expressing RpoC-specific BCRs. This suggests an additive antigenic and superantigenic stimulation of B cells with RpoC-specific IgD+ BCRs under conditions of a permissive MHC-II haplotype as a model of NLPHL lymphomagenesis, implying future treatment strategies.

3.
Lancet ; 394(10216): 2271-2281, 2020 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-31868632

RESUMO

BACKGROUND: Six cycles of R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) are the standard treatment for aggressive B-cell non-Hodgkin lymphoma. In the FLYER trial, we assessed whether four cycles of CHOP plus six applications of rituximab are non-inferior to six cycles of R-CHOP in a population of patients with B-cell non-Hodgkin lymphoma with favourable prognosis. METHODS: This two-arm, open-label, international, multicentre, prospective, randomised phase 3 non-inferiority trial was done at 138 clinical sites in Denmark, Israel, Italy, Norway, and Germany. We enrolled patients aged 18-60 years, with stage I-II disease, normal serum lactate dehydrogenase concentration, ECOG performance status 0-1, and without bulky disease (maximal tumour diameter <7·5 cm). Randomisation was computer-based and done centrally in a 1:1 ratio using the Pocock minimisation algorithm after stratification for centres, stage (I vs II), and extralymphatic sites (no vs yes). Patients were assigned to receive either six cycles of R-CHOP or four cycles of R-CHOP plus two doses of rituximab. CHOP comprised cyclophosphamide (750 mg/m2), doxorubicin (50 mg/m2), and vincristine (1·4 mg/m2, with a maximum total dose of 2 mg), all administered intravenously on day 1, plus oral prednisone or prednisolone at the discretion of the investigator (100 mg) administered on days 1-5. Rituximab was given at a dose of 375 mg/m2 of body surface area. Cycles were repeated every 21 days. No radiotherapy was planned except for testicular lymphoma treatment. The primary endpoint was progression-free survival after 3 years. The primary analysis was done in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of assigned treatment. A non-inferiority margin of -5·5% was chosen. The trial, which is completed, was prospectively registered at ClinicalTrials.gov, NCT00278421. FINDINGS: Between Dec 2, 2005, and Oct 7, 2016, 592 patients were enrolled, of whom 295 patients were randomly assigned to receive six cycles of R-CHOP and 297 were assigned to receive four cycles of R-CHOP plus two doses of rituximab. Four patients in the four-cycles group withdrew informed consent before the start of treatment, so 588 patients were included in the intention-to-treat analysis. After a median follow-up of 66 months (IQR 42-100), 3-year progression-free survival of patients who had four cycles of R-CHOP plus two doses of rituximab was 96% (95% CI 94-99), which was 3% better (lower limit of the one-sided 95% CI for the difference was 0%) than six cycles of R-CHOP, demonstrating the non-inferiority of the four-cycles regimen. 294 haematological and 1036 non-haematological adverse events were documented in the four-cycles group compared with 426 haematological and 1280 non-haematological adverse events in the six-cycles group. Two patients, both in the six-cycles group, died during study therapy. INTERPRETATION: In young patients with aggressive B-cell non-Hodgkin lymphoma and favourable prognosis, four cycles of R-CHOP is non-inferior to six cycles of R-CHOP, with relevant reduction of toxic effects. Thus, chemotherapy can be reduced without compromising outcomes in this population. FUNDING: Deutsche Krebshilfe.


Assuntos
Antineoplásicos Imunológicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Rituximab/administração & dosagem , Administração Intravenosa , Administração Oral , Adulto , Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ciclofosfamida/administração & dosagem , Ciclofosfamida/uso terapêutico , Dinamarca , Doxorrubicina/administração & dosagem , Doxorrubicina/uso terapêutico , Esquema de Medicação , Feminino , Alemanha , Humanos , Cooperação Internacional , Israel , Itália , Linfoma Difuso de Grandes Células B/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Noruega , Prednisona/administração & dosagem , Prednisona/uso terapêutico , Estudos Prospectivos , Rituximab/uso terapêutico , Análise de Sobrevida , Resultado do Tratamento , Vincristina/administração & dosagem , Vincristina/uso terapêutico , Adulto Jovem
4.
Immun Inflamm Dis ; 7(4): 271-275, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31502765

RESUMO

OBJECTIVE: The present study aimed to investigate progranulin autoantibodies in systemic sclerosis and autoimmune connective tissue disorders. Progranulin is a physiologic tumor necrosis factor (TNF) antagonist. Progranulin antibodies decrease progranulin levels. METHODS: Serum samples of 123 patients with systemic sclerosis and various autoimmune connective tissue disorders (Sjoegren's syndrome [SjS], mixed connective tissue disorder, polymyositis [PM] and dermatomyositis [DM], antiphospholipid syndrome [APLS], and undifferentiated connective tissue disease [UCTD]) were tested for progranulin antibodies using enzyme-linked immunosorbent assay. RESULTS: Progranulin antibodies were found in 34 of 123 (27.6%) patients at least once during their disease. In detail, 2 of 8 (25%) patients with limited cutaneous systemic sclerosis, 10 of 31 (32.3%) patients with diffuse cutaneous systemic sclerosis, 9 of 22 (40.9%) patients with SjS, 1 of 3 (33.33%) patients with mixed connective tissue disease, 4 of 33 (12.1%) patients with DM or PM, 6 of 15 (40%) patients with APLS, and 2 of 11 (18.2%) patients with UCTD were positive for progranulin antibodies during the course of disease. CONCLUSIONS: Progranulin antibodies are frequently present in patients with systemic sclerosis and other autoimmune connective tissue disorders. Despite the lack of specificity for a given autoimmune disease, progranulin antibodies might not only indicate a potential subtype but also play a pathogenic role in patients with autoimmune connective disorders. Given the important role of TNF-α in inflammatory processes in autoimmune connective tissue disorders, progranulin antibodies might support the proinflammatory environment by neutralizing the TNF blocker progranulin.

6.
Bone Marrow Transplant ; 54(6): 877-884, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30413811

RESUMO

Salvage chemotherapy induces disease remissions in patients with relapsed or refractory (r/r) T-cell lymphomas, but fails to provide lasting tumor control. We analyzed the outcome after peripheral blood stem and bone marrow transplantation (PBSCT, n = 80; BMT, n = 4) from matched related (MRD, n = 22) or matched and unmatched unrelated donors (MUD and MMD, n = 53 and n = 9, respectively) following conditioning with fludarabine, busulfan, and cyclophosphamide (FBC) for 84 consecutive patients with r/r T-cell malignancies. At start of conditioning LDH was elevated in 50% of cases, and residual tumor (PD, SD, PR) was detectable in 84% of patients. In total, 38% (95% CI 33-44) of the patients were alive and disease-free after a median observation time of 14.5 (range 1.8 to 114) months. Univariate and multivariate analyses identified low ECOG status, as well as occurrence of acute GvHD as favorable factors for outcome. Lymphoma-directed conditioning with fludarabin, busulfan and cyclophosphamid (FBC-12), and allogeneic stem cell transplantation resulted in long-term survival for a proportion of patients with r/r peripheral T-cell lymphoma, including those with PR and SD only after salvage therapy.

7.
Br J Haematol ; 184(5): 760-768, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30520013

RESUMO

To further improve outcome in young high-risk patients with diffuse large B-cell lymphoma (DLBCL) the number of rituximab (R) infusions was doubled in combination with standard CHOEP (cyclophosphamide, doxorubicin, etoposide, vincristine, prednisone) chemotherapy. Seventy-seven patients (aged 18-60 years) with an age-adjusted International Prognostic Index of 2-3 received 12 × R (375 mg/m2 ) on days 0, 1, 4, 8, 15, 22, 29, 43, 57, 71, 85 and 99 together with eight cycles of CHOEP-14. Results were retrospectively compared to those of patients receiving 6 × R and 8 × CHOEP-14 in the standard arm of the randomized R-MegaCHOEP trial. Two-year overall survival (OS) was 82% [95% confidence interval (CI) 73%-92%]; 2-year event-free (EFS) and progression-free survival (PFS) was 69% (95% CI 59-80%) and 76% (95% CI 66%--6%), respectively. Comparing 12 to six doses of R revealed no differences (univariate/multivariate) in EFS (at 2 years: 69% vs. 71%), PFS (76% vs. 75%) and OS (82% vs. 85%), with P = 0·766, P = 0·871 and P = 0·843, respectively. Doubling the number of R infusions concomitant to CHOEP did not improve treatment outcomes. Nonetheless, OS and PFS of young high-risk patients who received only six infusions of R combined with CHOEP remain excellent and were confirmed in an independent cohort of patients.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/mortalidade , Rituximab/administração & dosagem , Adolescente , Adulto , Fatores Etários , Ciclofosfamida/administração & dosagem , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Etoposídeo/administração & dosagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prednisolona/administração & dosagem , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida , Vincristina/administração & dosagem
8.
Br J Haematol ; 184(3): 384-391, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30450574

RESUMO

Patients with Gaucher disease (GD) have an increased risk of monoclonal gammopathies for which antigenic targets might play a role in their pathogenesis. Here we report the identification of saposin C (sapC) as high-titre (1:1 000 000) target structure of 7/16 GD-associated paraproteins. Anti-sapC immunoglobulin (Ig) showed identity with the paraprotein Ig type and subclass in each patient that showed anti-sapC immunoreactivity. Absorption and depletion studies completely removed the paraprotein from the sera of GD patients. No immunoreactivity against sapC was detected in healthy donors and in other plasma cell dyscrasias, demonstrating that anti-sapC reactivity is highly restricted to GD. Several uncharacterized forms of post-translational modified sapC were detected but their role in the pathogenesis is not clear. We confirm the frequent presence of low-titre (1:250) anti-lysolipid reactivities in the sera of GD patients but we could show that this immunoreactivity is not mediated by the paraprotein and is not restricted to GD patients.


Assuntos
Doença de Gaucher/sangue , Gamopatia Monoclonal de Significância Indeterminada/sangue , Mieloma Múltiplo/sangue , Paraproteínas/metabolismo , Saposinas/sangue , Feminino , Humanos , Masculino
9.
Br J Haematol ; 185(1): 42-52, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30592027

RESUMO

About 30% of all Hodgkin lymphoma (HL) patients are ≥60 years old. As lenalidomide has promising single agent activity in multiple relapsed HL, we replaced bleomycin in ABVD with lenalidomide in this phase-I trial. Patients aged ≥60 years with early-unfavourable- or advanced-stage HL (Eastern Cooperative Oncology Group performance status ≤2, Cumulative Illness Rating Scale for Geriatrics score 0-7) received 4-8 cycles of AVD (doxorubicin, vinblastine, dacarbazine) and lenalidomide in escalation with overdose control. Dose-limiting toxicities (DLTs) included thromboembolism ≥grade 2, severe haematological toxicity, neutropenic fever and prolonged therapy delay. Twenty-five patients with a median age of 68 years were included, 68% had advanced-stage HL. A pre-defined stopping criterion for dose escalation after DLT evaluation of 20/24 patients suggested a recommended phase II dose (RPTD) of 20 mg. DLTs occurred in 10/24 evaluable patients, all treated with ≥20 mg, however, median relative dose intensity was 97% (interquartile range 49-104%). Grade 3 or higher toxicities occurred in all 22 patients at ≥20 mg lenalidomide but no treatment-related deaths occurred. Overall response rate was 80% for all patients (20/25) and 86% (19/22) at ≥20 mg lenalidomide. Three-year estimates for progression-free survival and OS were 69·7% (95% CI: 50·3-89·1%) and 83·8% (95%-CI: 69·3-98·4%), respectively. In conclusion, AVD with lenalidomide 20 mg is feasible and highly effective in older HL patients.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Doença de Hodgkin/tratamento farmacológico , Fatores Etários , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Dacarbazina/administração & dosagem , Doxorrubicina/administração & dosagem , Feminino , Doença de Hodgkin/diagnóstico , Doença de Hodgkin/mortalidade , Humanos , Lenalidomida/administração & dosagem , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Resultado do Tratamento , Vimblastina/administração & dosagem
10.
Leukemia ; 33(1): 148-158, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29955130

RESUMO

The predominant usage of VH4-34 and V3-21 and reports of stereotyped CDR3s suggest a shared antigenic target of B-cell receptors (BCR) from mantle cell lymphomas (MCL). To identify the target antigens of MCL-BCRs, BCRs from 21 patients and seven MCL cell lines were recombinantly expressed and used for antigen screening. The BCRs from 8/21 patients and 2/7 MCL cell lines reacted specifically with the autoantigen low-density lipoprotein receptor-related protein-associated protein 1 (LRPAP1). High-titered and light chain-restricted anti-LRPAP1 serum antibodies were found in MCL patients, but not in controls. LRPAP1 induced proliferation by BCR pathway activation, while an LRPAP1-ETA' toxin-conjugate specifically killed MCL cells with LRPAP1-specific BCRs. Our results suggest a role of LRPAP1 in lymphomagenesis and maintenance of a considerable proportion of MCL cases by chronic autoantigenic stimulation, likely evolving from a chronic autoreactive B-cell response. Importantly, LRPAP1 can be used for a novel therapeutic approach that targets MCL with LRPAP1-reactive BCRs with high specificity.


Assuntos
Autoantígenos/imunologia , Linfócitos B/imunologia , Proteína Associada a Proteínas Relacionadas a Receptor de LDL/imunologia , Linfoma de Célula do Manto/imunologia , Receptores de Antígenos de Linfócitos B/imunologia , Autoantígenos/metabolismo , Linfócitos B/metabolismo , Linfócitos B/patologia , Proliferação de Células , Humanos , Proteína Associada a Proteínas Relacionadas a Receptor de LDL/metabolismo , Linfoma de Célula do Manto/metabolismo , Linfoma de Célula do Manto/patologia , Receptores de Antígenos de Linfócitos B/metabolismo , Células Tumorais Cultivadas
11.
Blood ; 132(26): 2744-2753, 2018 12 27.
Artigo em Inglês | MEDLINE | ID: mdl-30249786

RESUMO

To address the role of chronic antigenic stimulation in primary central nervous system lymphoma (PCNSL), we searched for autoantigens and identified sterile α-motif domain containing protein 14 (SAMD14) and neural tissue-specific F-actin binding protein I (neurabin-I) as autoantigenic targets of the B-cell receptors (BCRs) from 8/12 PCNSLs. In the respective cases, SAMD14 and neurabin-I were atypically hyper-N-glycosylated (SAMD14 at ASN339 and neurabin-I at ASN1277), explaining their autoimmunogenicity. SAMD14 and neurabin-I induced BCR pathway activation and proliferation of aggressive lymphoma cell lines transfected with SAMD14- and neurabin-I-reactive BCRs. Moreover, the BCR binding epitope of neurabin-I conjugated to truncated Pseudomonas exotoxin-killed lymphoma cells expressing the respective BCRs. These results support the role of chronic antigenic stimulation by posttranslationally modified central nervous system (CNS) driver autoantigens in the pathogenesis of PCNSL, serve as an explanation for their CNS tropism, and provide the basis for a novel specific treatment approach.


Assuntos
Antígenos de Neoplasias/imunologia , Autoantígenos/imunologia , Neoplasias do Sistema Nervoso Central/imunologia , Linfoma Difuso de Grandes Células B/imunologia , Proteínas dos Microfilamentos/imunologia , Proteínas de Neoplasias/imunologia , Proteínas do Tecido Nervoso/imunologia , Proteínas Repressoras/imunologia , Antígenos de Neoplasias/genética , Autoantígenos/genética , Linhagem Celular Tumoral , Neoplasias do Sistema Nervoso Central/genética , Neoplasias do Sistema Nervoso Central/patologia , Neoplasias do Sistema Nervoso Central/terapia , Glicosilação , Células HEK293 , Humanos , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/patologia , Linfoma Difuso de Grandes Células B/terapia , Proteínas dos Microfilamentos/genética , Proteínas de Neoplasias/genética , Proteínas do Tecido Nervoso/genética , Proteínas Repressoras/genética
12.
Cancer Immunol Immunother ; 67(11): 1709-1718, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30132083

RESUMO

Vitamin D3 (25-OH-D3) deficiency impairs rituximab-dependent cellular cytotoxicity and the outcome of patients with diffuse large B-cell and follicular lymphomas (DLBCL). Since the optimum 25-OH-D3 serum levels for NK cell-mediated antibody-dependent cellular cytotoxicity (ADCC) are unknown, we determined the 25-OH-D3 serum levels associated with maximum NK cell-mediated ADCC. CD20 antibody-loaded CD20+ B-cell lymphoma cell lines were cultured with NK cells and ADCC activity was determined by lactate dehydrogenase release assays. Using a newly developed formula, pre-defined 25-OH-D3 serum levels were achieved with high individual precision over a wide range. NK cells from 20 healthy individuals killed antibody-treated CD20+ lymphoma cells in a concentration- and E:T ratio-dependent manner with obinutuzumab displaying a stronger ADCC activity than rituximab. Maximum NK-cell activity and ADCC were observed at 65 ng/ml 25-OH-D3, the middle of the normal range (30-100 ng/ml). 25-OH-D3 serum levels around this range should be the target in interventional trials aiming at improving NK cell-mediated ADCC by 25-OH-D3 substitution. Lower levels do not provide significant ADCC improvements in individuals with 25-OH-D3 deficiency or insufficiency and might result in the failure of interventions with 25-OH-D3.


Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Citotoxicidade Celular Dependente de Anticorpos/imunologia , Colecalciferol/sangue , Citotoxicidade Imunológica/imunologia , Células Matadoras Naturais/imunologia , Linfoma Difuso de Grandes Células B/imunologia , Rituximab/farmacologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Imunológicos/farmacologia , Estudos de Casos e Controles , Colecalciferol/imunologia , Feminino , Voluntários Saudáveis , Humanos , Ativação Linfocitária , Linfoma Difuso de Grandes Células B/sangue , Linfoma Difuso de Grandes Células B/patologia , Masculino , Pessoa de Meia-Idade
13.
J Clin Oncol ; 36(25): 2593-2602, 2018 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-29975624

RESUMO

Purpose Overall survival (OS) is the definitive and best-established primary efficacy end point to evaluate diffuse large B-cell lymphoma (DLBCL) therapies, but it requires prolonged follow-up. An earlier end point assessed post-treatment would expedite clinical trial conduct and accelerate patient access to effective new therapies. Our objective was to formally evaluate progression-free survival (PFS) and PFS at 24 months (PFS24) as surrogate end points for OS in first-line DLBCL. Patients and Methods Individual patient data were analyzed from 7,507 patients from 13 multicenter randomized controlled trials of active treatment in previously untreated DLBCL, published after 2002, with sufficient PFS data to predict treatment effects on OS. Trial-level surrogacy examining the correlation of treatment effect estimates of PFS/PFS24 and OS was evaluated using both linear regression ( R2WLS) and Copula bivariable ( R2Copula) models. Prespecified criteria for surrogacy required either R2WLS or R2Copula ≥ 0.80 and neither < 0.7, with lower-bound 95% CI > 0.60. Results Trial-level surrogacy for PFS was strong ( R2WLS = 0.83; R2Copula = 0.85) and met the predefined criteria for surrogacy. At the patient level, PFS strongly correlated with OS. The surrogate threshold effect had a hazard ratio of 0.89. Surrogacy was consistent across comparisons with or without rituximab and with rituximab maintenance trials. Trial-level surrogacy for PFS24 was relatively strong ( R2WLS = 0.77; R2Copula = 0.78) but did not meet prespecified criteria. At the patient level, PFS24 significantly correlated with OS. The surrogate threshold effect had an odds ratio of 1.51. Conclusion This large pooled analysis of individual patient data supports PFS as a surrogate end point for OS in future randomized controlled trials evaluating chemoimmunotherapy in DLBCL. Use of this end point may expedite therapeutic development with the intent of bringing novel therapies to this patient population years before OS results are mature.


Assuntos
Antineoplásicos/uso terapêutico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/mortalidade , Biomarcadores , Humanos , Estudos Multicêntricos como Assunto , Intervalo Livre de Progressão , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
14.
Nat Med ; 24(8): 1292, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29955181

RESUMO

In the version of this article originally published, some text above the "Tri-nucleotide sequence motifs" label in Fig. 2a appeared incorrectly. The text was garbled and should have appeared as nucleotide codes.Additionally, the labels on the bars in Fig. 2c were not italicized in the original publication. These are gene symbols, and they should have been italicized.The colored labels above the graphs in Fig. 4b were also erroneously not italicized. These labels represent gene names and loci, and they should have been italicized.

16.
Leukemia ; 32(7): 1621-1630, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29720733

RESUMO

In this phase Ib/IIa study (ClinicalTrials.gov Identifier: NCT00850382) of the German-Austrian AML Study Group (AMLSG) the multikinase inhibitor dasatinib was added to intensive induction and consolidation chemotherapy and administered as single agent for 1-year maintenance in first-line treatment of adult patients with core-binding factor (CBF) acute myeloid leukemia (AML). The primary combined end point in this study was safety and feasibility, and included the rates of early (ED) and hypoplastic (HD) deaths, pleural/pericardial effusion 3°/4° and liver toxicity 3°/4°, and the rate of refractory disease. Secondary end points were cumulative incidence of relapse (CIR) and death in complete remission (CID), and overall survival (OS). Eighty-nine pts [median age 49.5 years, range: 19-73 years; t(8;21), n = 37; inv (16), n = 52] were included. No unexpected excess in toxicity was observed. The rates of ED/HD and CR/CRi were 4.5% (4/89) and 94% (84/89), respectively. The 4-year estimated CIR, CID, and OS were 33.1% [95%-CI (confidence interval), 22.7-43.4%], 6.0% (95% CI, 0.9-11.2%), and 74.7% (95% CI, 66.1-84.5%), respectively. On the basis of the acceptable toxicity profile and favorable outcome in the AMLSG 11-08 trial, a confirmatory randomized phase III trial with dasatinib in adults with CBF-AML is ongoing (ClinicalTrials.gov Identifier: NCT02013648).


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Fatores de Ligação ao Core/genética , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Biomarcadores Tumorais , Fatores de Ligação ao Core/metabolismo , Dasatinibe/administração & dosagem , Feminino , Humanos , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Mutação , Proteínas Proto-Oncogênicas c-kit/genética , Recidiva , Indução de Remissão , Resultado do Tratamento , Adulto Jovem
17.
Nat Med ; 24(5): 679-690, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29713087

RESUMO

Diffuse large B cell lymphoma (DLBCL), the most common lymphoid malignancy in adults, is a clinically and genetically heterogeneous disease that is further classified into transcriptionally defined activated B cell (ABC) and germinal center B cell (GCB) subtypes. We carried out a comprehensive genetic analysis of 304 primary DLBCLs and identified low-frequency alterations, captured recurrent mutations, somatic copy number alterations, and structural variants, and defined coordinate signatures in patients with available outcome data. We integrated these genetic drivers using consensus clustering and identified five robust DLBCL subsets, including a previously unrecognized group of low-risk ABC-DLBCLs of extrafollicular/marginal zone origin; two distinct subsets of GCB-DLBCLs with different outcomes and targetable alterations; and an ABC/GCB-independent group with biallelic inactivation of TP53, CDKN2A loss, and associated genomic instability. The genetic features of the newly characterized subsets, their mutational signatures, and the temporal ordering of identified alterations provide new insights into DLBCL pathogenesis. The coordinate genetic signatures also predict outcome independent of the clinical International Prognostic Index and suggest new combination treatment strategies. More broadly, our results provide a roadmap for an actionable DLBCL classification.


Assuntos
Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/patologia , Variações do Número de Cópias de DNA/genética , Rearranjo Gênico/genética , Genes Neoplásicos , Heterogeneidade Genética , Humanos , Mutação/genética , Taxa de Mutação , Resultado do Tratamento
18.
Eur J Haematol ; 101(1): 38-47, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29652096

RESUMO

OBJECTIVE: As reconstitution of virus-specific T-cells is critical to control cytomegalovirus (CMV)-viremia following stem-cell transplantation (SCT), we characterized the dynamics in CMV-specific T-cell reconstitution after SCT. METHODS: Cytomegalovirus-specific T-cells from 51 SCT-recipients were prospectively quantified and phenotypically characterised by intracellular cytokine-staining after specific stimulation and HLA class-I-specific pentamers using flow cytometry. RESULTS: Cytomegalovirus-specific CD4 T-cells reconstituted after a median of 2.3 (IQR, 2.0-3.0) weeks following autografting, and 4.0 (IQR, 3.0-5.6) weeks after allografting, with CMV-specific T-cells originating from donors and/or recipients. The time for reconstitution of CMV-specific CD4 and CD8 T-cells did not differ (P = .58). Factors delaying the time to initial reconstitution of CMV-specific CD4 T-cells included a negative recipient serostatus (P = .016) and CMV-viremia (P = .026). Percentages of CMV-specific CD4 T-cells significantly increased over time and reached a plateau after 90 days (P = .043). Relative CMV-specific CD4 T-cell levels remained higher in long-term transplant recipients compared with those in controls (P < .0001). However, due to persisting lymphopenia, absolute numbers of CMV-specific T-cells were similar as in controls. CONCLUSION: Cytomegalovirus-specific T-cells rapidly reconstitute after SCT and their percentages remain high in the long term. In the face of persistent lymphopenia, this results in similar absolute numbers of CMV-specific T-cells as in controls to ensure sufficient pathogen control.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Infecções por Citomegalovirus/imunologia , Citomegalovirus/imunologia , Transplante de Células-Tronco Hematopoéticas , Linfopenia/imunologia , Adulto , Idoso , Linfócitos T CD4-Positivos/virologia , Linfócitos T CD8-Positivos/virologia , Infecções por Citomegalovirus/patologia , Infecções por Citomegalovirus/virologia , Feminino , Humanos , Reconstituição Imune , Contagem de Linfócitos , Linfopenia/patologia , Linfopenia/virologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Tempo , Transplante Autólogo , Transplante Homólogo
19.
Biol Blood Marrow Transplant ; 24(6): 1172-1179, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29605716

RESUMO

Patients with follicular lymphoma (FL) and progression of disease (POD) within 24 months after frontline treatment (POD24) have poor overall survival (OS). The optimal salvage treatment for these patients is unknown. We assessed the role of high-dose therapy and autologous stem cell transplantation (ASCT) in transplant-eligible patients. We analyzed 162 patients with advanced-stage FL who had received frontline treatment within the GLSG1996 or GLSG2000 trials. All patients had POD at age ≤ 65 years and had not received a prior transplant. Second-line treatment was not specified by study protocols. Survival was calculated from time of second-line treatment. Eighteen patients (11%) progressed (n = 16) or died (n = 2) during cytoreductive second-line treatment (considered "cytoreduction failure"); none received ASCT, and their median second-line OS was <1 year. A total of 113 patients had POD24 (70%), whereas 49 had POD after 24 months (30%). Sixty-three patients without cytoreduction failure received ASCT (39%), and 81 received no transplant (50%). In patients with POD24, a significant survival benefit was associated with ASCT with a 5-year second-line progression-free survival for ASCT versus no transplant of 51% versus 19% (hazard ratio, .38; 95% confidence interval, .24 to .62; P < .0001) and a 5-year second-line OS of 77% versus 59% (hazard ratio, .54, 95% confidence interval, .30 to .95; P= .031). Thus, ASCT is an effective treatment option for transplant-eligible patients with high-risk FL as identified by POD24 and should be evaluated in prospective clinical trials.


Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Linfoma Folicular/terapia , Transplante Autólogo/mortalidade , Adulto , Idoso , Progressão da Doença , Feminino , Seguimentos , Alemanha , Transplante de Células-Tronco Hematopoéticas/mortalidade , Humanos , Linfoma Folicular/mortalidade , Masculino , Pessoa de Meia-Idade , Terapia de Salvação/métodos , Análise de Sobrevida , Transplante Autólogo/normas
20.
Leukemia ; 32(5): 1222-1228, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29479070

RESUMO

Major molecular remission (MMR) is an important therapy goal in chronic myeloid leukemia (CML). So far, MMR is not a failure criterion according to ELN management recommendation leading to uncertainties when to change therapy in CML patients not reaching MMR after 12 months. At monthly landmarks, for different molecular remission status Hazard ratios (HR) were estimated for patients registered to CML study IV who were divided in a learning and a validation sample. The minimum HR for MMR was found at 2.5 years with 0.28 (compared to patients without remission). In the validation sample, a significant advantage for progression-free survival (PFS) for patients in MMR could be detected (p-value 0.007). The optimal time to predict PFS in patients with MMR could be validated in an independent sample at 2.5 years. With our model we provide a suggestion when to define lack of MMR as therapy failure and thus treatment change should be considered. The optimal response time for 1% BCR-ABL at about 12-15 months was confirmed and for deep molecular remission no specific time point was detected. Nevertheless, it was demonstrated that the earlier the MMR is achieved the higher is the chance to attain deep molecular response later.


Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Modelos Teóricos , Indução de Remissão/métodos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Mesilato de Imatinib/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/mortalidade , Aprendizado de Máquina , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Falha de Tratamento , Adulto Jovem
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