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1.
BMJ Case Rep ; 14(1)2021 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-33509883
2.
Lancet Haematol ; 8(1): e34-e44, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33357480

RESUMO

BACKGROUND: Fit patients with mantle cell lymphoma aged 18-65 years are usually given cytarabine and rituximab-based induction regimens followed by autologous haematopoetic stem-cell transplantation (HSCT). We investigated whether post-autologous HSCT maintenance with lenalidomide improves progression-free survival in this population. METHODS: This open-label, randomised, multicentre, phase 3 trial was done at 49 haematology and oncology units in Italy and Portugal. Eligible patients had Ann Arbor stage III or IV treatment-naive mantle cell lymphoma (or stage II plus bulky disease [≥5 cm] or B symptoms), and had evidence of cyclin D1 overexpression or the translocation t(11;14)(q13;q32). Patients were aged 18-59 years with Eastern Cooperative Oncology Group (ECOG) performance status 0-3, or aged 60-65 years with ECOG 0-2. After an optional prephase with vincristine and steroids (intravenous vincristine 1·4 mg/m2 on day 1, oral prednisone 100 mg [total dose] on days 1-5), patients were given three courses of R-CHOP (21-day cycle, intravenous rituximab 375 mg/m2 on day 1; intravenous doxorubicin 50 mg/m2, vincristine 1·4 mg/m2, and cyclophosphamide 750 mg/m2 on day 2; oral prednisone 100 mg/m2 on day 2-6). Patients then received one cycle of high-dose CTX (intravenous cyclophosphamide 4 g/m2 on day 1, intravenous rituximab 375 mg/m2 on day 4). After restaging, patients received two cycles of R-HD-cytarabine (high-dose intravenous cytarabine 2 g/m2 every 12 h on days 1-3, intravenous rituximab 375 mg/m2 on days 4 and 10). Patients with complete remission or partial remission proceeded to autologous HSCT and responding patients (complete remission or partial remission) with haematological recovery were randomly assigned (1:1) to receive 24 courses of oral lenalidomide maintenance (15 mg per day for patients with platelets >100 × 109 cells per L or 10 mg per day for platelets 60-100 × 109 cells per L, days 1-21 every 28 days) for 24 months, or observation. The primary endpoint was progression-free survival, measured in the randomised population. This study is registered with EudraCT (2009-012807-25) and ClinicalTrials.gov (NCT02354313). FINDINGS: Between May 4, 2010, and Aug 24, 2015, 303 patients were screened for inclusion and 300 patients were enrolled (median age 57 years, IQR 51-62; 235 [78%] male). 95 patients were excluded before randomisation, mostly due to disease progression, adverse events, and inadequate recovery. 104 patients were randomly assigned to the lenalidomide maintenance group and 101 patients to the observation group. 11 (11%) of 104 patients assigned to lenalidomide did not start treatment (3 withdrew, 6 adverse events or protocol breach, 2 lost to follow-up). At a median follow-up of 38 months after randomisation (IQR 24-50), 3-year progression-free survival was 80% (95% CI 70-87) in the lenalidomide group versus 64% (53-73) in the observation group (log-rank test p=0·012; hazard ratio 0·51, 95% CI 0·30-0·87). 41 (39%) of 104 patients discontinued lenalidomide for reasons including death or progression. Treatment-related deaths were recorded in two (2%) of 93 patients in the lenalidomide group (1 pneumonia, 1 thrombotic thrombocytopenic purpura), and one (1%) of 101 in the observation group (pneumonia). 59 (63%) of 93 patients in the lenalidomide group had grade 3-4 haematological adverse events versus 12 (12%) of 101 patients in the observation group (p<0·0001). 29 (31%) of 93 patients in the lenalidomide group and eight (8%) of 101 patients in the observation group had grade 3-4 non-haematological adverse events (p<0·0001), of which infections were the most common.Serious adverse events were reported in 22 (24%) of 93 patients in the lenalidomide group and five (5%) of 101 patients in the observation group. Pneumonia and other infections were the most common serious adverse events. INTERPRETATION: Despite non-negligibile toxicity, lenalidomide after autologous HSCT improved progression-free survival in patients with mantle cell lymphoma, highlighting the role of maintenance in mantle cell lymphoma. FUNDING: Fondazione Italiana Linfomi and Celgene.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Lenalidomida/administração & dosagem , Linfoma de Célula do Manto , Quimioterapia de Manutenção , Adolescente , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Feminino , Humanos , Lenalidomida/efeitos adversos , Linfoma de Célula do Manto/sangue , Linfoma de Célula do Manto/mortalidade , Linfoma de Célula do Manto/terapia , Masculino , Pessoa de Meia-Idade , Contagem de Plaquetas , Prednisona/administração & dosagem , Prednisona/efeitos adversos , Rituximab/administração & dosagem , Rituximab/efeitos adversos , Taxa de Sobrevida , Transplante Autólogo , Vincristina/administração & dosagem , Vincristina/efeitos adversos
3.
Lancet Haematol ; 7(11): e798-e807, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32971036

RESUMO

BACKGROUND: Obinutuzumab monotherapy has shown promising efficacy in mantle cell lymphoma. We aimed to investigate the activity of obinutuzumab plus DHAP (dexamethasone, high-dose cytarabine, and cisplatin), measured by minimal residual disease quantitative (q)PCR status in the bone marrow after four cycles. METHODS: LyMa-101 was a prospective, open-label, single-arm, phase 2 trial. Participants were enrolled from 28 hospitals in France. Newly diagnosed patients with mantle cell lymphoma (aged 18 to <66 years) who were eligible for autologous stem-cell transplantation received four cycles of obinutuzumab plus DHAP (obinutuzumab 1000 mg/m2 intravenously on days 1, 8, and 15 at cycle 1 and day 1 at cycles 2, 3, and 4; dexamethasone 40 mg intravenously on days 1-4, cytarabine 2 g/m2 intravenously every 12 h on day 1, and according to local investigator, cisplatin 100 mg/m2 by continuous infusion over 24 h on day 1 or carboplatin area under the curve 5 or oxaliplatin 130 mg/m2) every 21 days before transplantation, and 3 years of obinutuzumab (1000 mg/m2 every 2 months) maintenance followed by minimal residual disease-based obinutuzumab on-demand maintenance. The primary outcome was minimal residual disease negativity in the bone marrow after four cycles of obinutuzumab plus DHAP at the end of induction, measured in the efficacy set (all minimal residual disease-informative [bone marrow or peripheral blood] patients who received at least one dose of obinutuzumab). Obinutuzumab plus DHAP was considered effective if bone marrow minimal residual disease negativity was 70% or more by intention to treat. The trial is closed to recruitment and registered with ClinicalTrials.gov, NCT02896582. FINDINGS: 86 patients were enrolled between Nov 29, 2016, and May 2, 2018. 81 patients completed induction, 73 underwent autologous stem-cell transplantation, and 69 started maintenance therapy. 55 (75%) of 73 patients in the efficacy set reached minimal residual disease negativity in bone marrow at end of induction. According to the protocol definition, 18 (25%) of 73 patients in the efficacy set were minimal residual disease-positive: 12 patients who were minimal residual disease-positive in the bone marrow, plus two patients who progressed during induction, and four patients who did not have minimal residual disease assessment. The most common grade 3-4 treatment-emergent adverse events were anaemia (grade 3, 26 [31%] of 85 patients; grade 4, three [4%] of 85 patients) and neutropenia (grade 3, 13 [15%] of 85 patients; grade 4, 32 [38%] of 85 patients). 58 serious adverse events occurred during the induction phase. There were no treatment-related deaths. INTERPRETATION: Obinutuzumab plus DHAP is a well tolerated regimen and has good activity for inducing minimal residual disease negativity in the bone marrow of transplant-eligible patients with mantle cell lymphoma. Obinutuzumab plus DHAP has potential activity as induction chemotherapy, with bone marrow minimal residual disease negativity potentially predicting long-term disease control. FUNDING: Roche SAS.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Citarabina/administração & dosagem , Transplante de Células-Tronco Hematopoéticas , Linfoma de Célula do Manto/tratamento farmacológico , Adolescente , Adulto , Anemia/etiologia , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Área Sob a Curva , Medula Óssea/patologia , Citarabina/efeitos adversos , Dexametasona/administração & dosagem , Humanos , Linfoma de Célula do Manto/patologia , Linfoma de Célula do Manto/terapia , Pessoa de Meia-Idade , Neoplasia Residual , Estudos Prospectivos , Curva ROC , Transplante Autólogo , Resultado do Tratamento , Adulto Jovem
5.
Ann Hematol ; 99(8): 1771-1778, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32601796

RESUMO

Mantle cell lymphoma has a dismal prognosis at relapse or in the refractory setting. Among therapies, mTor pathway targeting by temsirolimus has been the first strategy approved for relapse in Europe. While its efficacy in monotherapy has long been demonstrated, its use remains limited. In the T3 phase Ib clinical trial, we investigated the recommended dose of temsirolimus in association with R-CHOP (R-CHOP-T), or high-dose cytarabine plus rituximab (R-DHA-T), or fludarabine, cyclophosphamide plus rituximab (R-FC-T). From November 11, 2011 to February 26, 2015, forty-one patients were enrolled. Patients presented with high MIPI (47.5%) at relapse and a median number of treatments of 1 (1-3). Patients were treated by R-CHOP-T (n = 10), R-FC-T (n = 14), or R-DHA-T (n = 17) according to the choice of local investigators. The maximum tolerated dose (MTD) was 15 mg in the R-CHOP-T arm and has not been determined in other treatment arms because of toxicities. All patients experienced ≥ Grade 3 adverse events, mainly thrombocytopenia (76%). Twenty-six patients discontinued prematurely the treatment, mostly for toxicity (n = 12) and progression of the disease (n = 8). Of note, 6 patients of the R-DHA-T arm reached complete remission (35%). Temsirolimus with immuno-chemotherapy is associated with a high rate of toxicities. Determination of MTD could only be achieved for R-CHOP-T arm. Associations between temsirolimus and other targeted therapies may be warranted for R/R MCL patients.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Imunoterapia , Linfoma de Célula do Manto/terapia , Sirolimo/análogos & derivados , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Feminino , Humanos , Linfoma de Célula do Manto/mortalidade , Masculino , Pessoa de Meia-Idade , Prednisona/administração & dosagem , Prednisona/efeitos adversos , Rituximab/administração & dosagem , Rituximab/efeitos adversos , Sirolimo/administração & dosagem , Sirolimo/efeitos adversos , Taxa de Sobrevida , Trombocitopenia/induzido quimicamente , Trombocitopenia/mortalidade , Vincristina/administração & dosagem , Vincristina/efeitos adversos
6.
Int J Hematol ; 112(3): 385-394, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32519171

RESUMO

Mantle cell lymphoma (MCL) is a B-cell non-Hodgkin lymphoma often with extranodal involvement at diagnosis, and yet how this feature correlates with survival awaits elucidation. To address this issue, a correlative analysis between clinical features of 127 MCL patients and their overall survival (OS) was conducted. In this cohort, the median age at MCL diagnosis was 62 years and 81% were males. Eighty-four percent of patients were Ann Arbor stage 4, and 15% were blastoid variants. In patients with gastrointestinal MCL, approximately 40% had gastric involvement. In treatment, CHOP-based induction chemotherapy was given to 61.1% of patients. One-third of patients undertook autologous stem cell transplant (SCT), and 4.7% had allogeneic SCT. The median OS was 82 months and well-stratified in MIPI risk groups. In the multivariate analysis for OS, blastoid variants and gastric involvement were both independent risk factors whereas auto-SCT had a protective effect. Overall, this study corroborated with the current understandings and international therapeutic standards for MCL. Auto-SCT associated with a better OS while allo-SCT remained an option for blastoid variants and those who failed Auto-SCT. Interestingly, patients with gastric involvement tended to have worse survival, a finding that spawns more studies to investigate the mechanism.


Assuntos
Neoplasias Gastrointestinais/mortalidade , Neoplasias Gastrointestinais/terapia , Linfoma de Célula do Manto/mortalidade , Linfoma de Célula do Manto/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Estudos de Coortes , Ciclofosfamida/administração & dosagem , Doxorrubicina/administração & dosagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prednisona/administração & dosagem , Prognóstico , Indução de Remissão , Transplante de Células-Tronco , Taiwan/epidemiologia , Transplante Autólogo , Transplante Homólogo , Vincristina/administração & dosagem
7.
Hematol Oncol ; 38(4): 446-455, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32472610

RESUMO

Mantle cell lymphoma (MCL) is a lymphoproliferative disorder characterized by the t(11;14)(q13;q32) CCND1/IGH translocation. This lymphoma is however extremely heterogeneous in terms of molecular alterations. Moreover, the course of the disease can vary greatly between indolent forms with slow progression and aggressive conditions rapidly pejorative. The identification of early markers allowing to predict individual patients outcome has however been unsuccessful so far. The LyMa trial treated homogeneously a cohort of young MCL patients. This appeared as a good opportunity to search for biomarkers of response to therapy. DNA extracted from diagnostic paraffin-embedded lymph node biopsies from 100 patients with newly diagnosed MCL, homogeneously treated in this prospective clinical trial, were investigated for copy number alterations and copy neutral loss of heterozygosity using the Oncoscan SNP-array scanning the whole genome. An independent confirmatory cohort was used to strengthen the possibly relevant anomalies observed. Here we describe the recurrent anomalies identified with this technique. Deletions of 17p(TP53) and 9p(CDKN2A) were more frequent in refractory or early relapsing patients (10%), but had no significant impact in univariate analysis on progression-free (PFS) or overall survival (OS). Regardless of the presence of TP53 or CDKN2A deletions, gains in 7p22 (8,5%) were associated with better PFS in univariate but not in multivariate analysis including MCL International Prognostic Index and treatment. Gains of 11q(CCDN1), suggesting gains of the CCND1/IGH fusion, were associated with worse OS and PFS in univariate and multivariate analyses. This worse prognosis impact was confirmed by FISH in an independent confirmatory cohort. This work, using a whole genome approach, confirms the broad genomic landscape of MCL and shows that gains of the CCND1/IGH fusion can be considered as a new prognostic structural variant. Genomic abnormalities of prognostic impact could be useful to strengthen or de-escalate treatment schedules or choosing targeted therapies or CART-cells.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/genética , Variações do Número de Cópias de DNA , Genoma Humano , Linfoma de Célula do Manto/patologia , Recidiva Local de Neoplasia/patologia , Adulto , Idoso , Terapia Combinada , Ciclina D1/genética , Inibidor p16 de Quinase Dependente de Ciclina/genética , Feminino , Seguimentos , Humanos , Linfoma de Célula do Manto/genética , Linfoma de Célula do Manto/terapia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/terapia , Prognóstico , Estudos Prospectivos , Transplante de Células-Tronco , Taxa de Sobrevida , Translocação Genética , Proteína Supressora de Tumor p53/genética , Sequenciamento Completo do Genoma
8.
N Engl J Med ; 382(14): 1331-1342, 2020 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-32242358

RESUMO

BACKGROUND: Patients with relapsed or refractory mantle-cell lymphoma who have disease progression during or after the receipt of Bruton's tyrosine kinase (BTK) inhibitor therapy have a poor prognosis. KTE-X19, an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, may have benefit in patients with relapsed or refractory mantle-cell lymphoma. METHODS: In a multicenter, phase 2 trial, we evaluated KTE-X19 in patients with relapsed or refractory mantle-cell lymphoma. Patients had disease that had relapsed or was refractory after the receipt of up to five previous therapies; all patients had to have received BTK inhibitor therapy previously. Patients underwent leukapheresis and optional bridging therapy, followed by conditioning chemotherapy and a single infusion of KTE-X19 at a dose of 2×106 CAR T cells per kilogram of body weight. The primary end point was the percentage of patients with an objective response (complete or partial response) as assessed by an independent radiologic review committee according to the Lugano classification. Per the protocol, the primary efficacy analysis was to be conducted after 60 patients had been treated and followed for 7 months. RESULTS: A total of 74 patients were enrolled. KTE-X19 was manufactured for 71 patients and administered to 68. The primary efficacy analysis showed that 93% (95% confidence interval [CI], 84 to 98) of the 60 patients in the primary efficacy analysis had an objective response; 67% (95% CI, 53 to 78) had a complete response. In an intention-to-treat analysis involving all 74 patients, 85% had an objective response; 59% had a complete response. At a median follow-up of 12.3 months (range, 7.0 to 32.3), 57% of the 60 patients in the primary efficacy analysis were in remission. At 12 months, the estimated progression-free survival and overall survival were 61% and 83%, respectively. Common adverse events of grade 3 or higher were cytopenias (in 94% of the patients) and infections (in 32%). Grade 3 or higher cytokine release syndrome and neurologic events occurred in 15% and 31% of patients, respectively; none were fatal. Two grade 5 infectious adverse events occurred. CONCLUSIONS: KTE-X19 induced durable remissions in a majority of patients with relapsed or refractory mantle-cell lymphoma. The therapy led to serious and life-threatening toxic effects that were consistent with those reported with other CAR T-cell therapies. (Funded by Kite, a Gilead company; ZUMA-2 ClinicalTrials.gov number, NCT02601313.).


Assuntos
Antígenos CD19/uso terapêutico , Imunoterapia Adotiva , Linfoma de Célula do Manto/terapia , Receptores de Antígenos Quiméricos/antagonistas & inibidores , Adulto , Idoso , Antineoplásicos/uso terapêutico , Terapia Combinada , Humanos , Imunoterapia Adotiva/efeitos adversos , Infusões Intravenosas , Leucaférese , Linfoma de Célula do Manto/tratamento farmacológico , Linfoma de Célula do Manto/mortalidade , Pessoa de Meia-Idade , Recidiva , Análise de Sobrevida , Linfócitos T/transplante , Vidarabina/análogos & derivados , Vidarabina/uso terapêutico
10.
Am J Hematol ; 95(7): 775-783, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32243637

RESUMO

Radiation is the most effective treatment for localized lymphoma, but treatment of multifocal disease is limited by toxicity. Radioimmunotherapy (RIT) delivers tumoricidal radiation to multifocal sites, further augmenting response by dose-escalation. This phase II trial evaluated high-dose RIT and chemotherapy prior to autologous stem-cell transplant (ASCT) for high-risk, relapsed or refractory (R/R) B-cell non-Hodgkin lymphoma (NHL). The primary endpoint was progression free survival (PFS). Secondary endpoints were overall survival (OS), toxicity, and tolerability. Patients age < 60 years with R/R NHL expressing CD20 were eligible. Mantle cell lymphoma (MCL) patients could proceed to transplant in first remission. Patients received I-131-tositumomab delivered at ≤25Gy to critical normal organs, followed by etoposide, cyclophosphamide and ASCT. A group of 107 patients were treated including aggressive lymphoma (N = 29), indolent lymphoma (N = 45), and MCL (N = 33). After a median follow-up of 10.1 years, the 10-year PFS for the aggressive, indolent, and MCL groups were 62%, 64%, 43% respectively. The 10-year OS for the aggressive, indolent, and MCL groups were 61%, 71%, 48% respectively. Toxicities were similar to standard conditioning regimens and non-relapse mortality at 100 days was 2.8%. Late myeloid malignancies were seen in 6% of patients. High-dose I-131-tositumomab, etoposide and cyclophosphamide followed by ASCT appeared feasible, safe, and effective in treating NHL, with estimated PFS at 10-years of 43%-64%. In light of novel cellular therapies for R/R NHL, high-dose RIT-containing regimens yield comparable efficacy and safety and could be prospectively compared.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Linfoma de Célula do Manto/mortalidade , Linfoma de Célula do Manto/terapia , Adulto , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Autoenxertos , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Intervalo Livre de Doença , Etoposídeo/administração & dosagem , Etoposídeo/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transplante de Células-Tronco , Taxa de Sobrevida
12.
Am J Hematol ; 95(6): 583-593, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32170769

RESUMO

Immunochemotherapy followed by autologous transplant (ASCT) in CALGB/Alliance 59909 achieved a median progression-free survival (PFS) in mantle cell lymphoma (MCL) of 5 years, but late recurrences occurred. We evaluated tolerability and efficacy of adding post-transplant bortezomib consolidation (BC) or maintenance (BM) to this regimen in CALGB/Alliance 50403, a randomized phase II trial. Following augmented-dose R-CHOP/ methotrexate, high-dose cytarabine-based stem cell mobilization, cyclophosphamide/carmustine/etoposide (CBV) autotransplant, and rituximab, patients were randomized to BC (1.3 mg/m2 IV days 1, 4, 8, 11 of a 3-week cycle for four cycles) or BM (1.6 mg/m2 IV once weekly × 4 every 8 weeks for 18 months) beginning day 90. The primary endpoint was PFS, measured from randomization for each arm. Proliferation signature, Ki67, and postinduction minimal residual disease (MRD) in bone marrow were assessed. Of 151 patients enrolled; 118 (80%) underwent ASCT, and 102 (68%) were randomized. Both arms met the primary endpoint, with median PFS significantly greater than 4 years (P < .001). The 8-year PFS estimates in the BC and BM arms were 54.1% (95% CI 40.9%-71.5%) and 64.4% (95% 51.8%-79.0%), respectively. Progression-free survival was significantly longer for transplanted patients on 50403 compared with those on 59909. Both the PFS and OS were significantly better for those who were MRD-negative post-induction. The high risk proliferation signature was associated with adverse outcome. Both BM and BC were efficacious and tolerable, although toxicity was significant. The comparison between studies 50403 and 59909 with long-term follow up suggests a PFS benefit from the addition of BC or BM post- transplant.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Bortezomib/administração & dosagem , Quimioterapia de Consolidação , Linfoma de Célula do Manto/terapia , Quimioterapia de Manutenção , Rituximab/administração & dosagem , Adolescente , Adulto , Idoso , Autoenxertos , Bortezomib/efeitos adversos , Carmustina/administração & dosagem , Ciclofosfamida/administração & dosagem , Etoposídeo/administração & dosagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
13.
Rev. esp. patol ; 53(1): 48-54, ene.-mar. 2020. ilus, tab
Artigo em Inglês | IBECS | ID: ibc-195576

RESUMO

Composite lymphoma with mantle and follicular cell components is a challenging diagnosis. Flow cytometry, immunohistochemistry and molecular genetics are required to distinguish the two components, as often the more aggressive one is predominant and masks the other. A 58-year-old man with history of nodal composite lymphoma presented with right exophthalmos and diplopia. A head CT scan showed an orbital tumor. A biopsy of the tumor revealed a mantle cell lymphoma predominating over a follicular lymphoma. Immunoglobulin heavy chain and light chain rearrangements analysis by PCR proved that both components of the orbital tumor were recurrences of the same nodal composite lymphoma diagnosed two years earlier. The nodal lymphoma was composed of a follicular lymphoma and an in situ mantle cell neoplasia. Consensus view is that dominant lymphoma should be treated when needed but taking into account if the mantle cell lymphoma is an in situ neoplasia and if it expresses CD5 and SOX11


El diagnóstico de linfoma compuesto con componentes del manto y folicular es desafiante y requiere de técnicas como citometría de flujo, inmunohistoquímica y genética molecular, porque a menudo el componente linfoide más agresivo predomina sobre el otro, enmascarándolo. Un varón de 58 años con historia de linfoma compuesto ganglionar presentó exoftalmos derecho y diplopia. La TAC de cabeza mostró un tumor orbitario. Una biopsia del tumor reveló un linfoma del manto predominando sobre un linfoma folicular. El reordenamiento genético mediante PCR de la cadena pesada y cadenas ligeras de inmunoglobulina demostró que ambos componentes del tumor orbitario eran recurrentes del mismo linfoma compuesto ganglionar diagnosticado 2 años antes. El linfoma ganglionar estaba compuesto por linfoma folicular y neoplasia del manto in situ. El consenso es que el linfoma dominante debe ser tratado cuando sea necesario considerando si el linfoma del manto es in situ y si expresa CD5 y SOX11


Assuntos
Humanos , Masculino , Pessoa de Meia-Idade , Linfoma de Célula do Manto/diagnóstico , Linfoma de Célula do Manto/terapia , Neoplasias Orbitárias/diagnóstico , Neoplasias Orbitárias/terapia , Tomografia Computadorizada por Raios X , Reação em Cadeia da Polimerase , Imuno-Histoquímica , Biópsia
14.
Ann Hematol ; 99(2): 223-228, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31853704

RESUMO

Limited-stage (Ann Arbor stage I or II) mantle cell lymphoma (MCL) is an extremely rare disease. Thus, there is little data on the clinical features and treatment outcomes of patients with early-stage MCL. We examined consecutive stage I or II MCL 41 cases diagnosed between 2000 and 2016 in 16 institutions of the Consortium for Improving Survival of Lymphoma group. All cases were pathologically confirmed and systemic evaluation was performed for staging. The clinical features were reviewed, and the treatment outcomes were analyzed. The median age of patients was 66 years (range 19-85 years); there were more men (n = 31, 75.6%) than women. Most patients (n = 28, 68.3%) had stage 2 disease, and 29 (70.7%) were symptomatic. The elevation of lactate dehydrogenase (n = 2, 4.9%) was not common; thus, 39 patients (95.1%) had a low-risk score (0 or 1) for the International Prognostic Index, and 28 (68.3%) had a low-risk score (1-3) for the MCL International Prognostic Index. Most patients (n = 37, 90.1%) received chemotherapy as the first therapeutic strategy, while some received radiotherapy (n = 2), surgical resection (n = 1), or no treatment (n = 1). Of the patients who received chemotherapy, 23 (56.9%) received a rituximab-containing regimen, and R-CHOP (n = 17) and R-bendamustine (n = 5) were commonly used. The best response was noted in 97.4% (n = 38) of patients, including 32 who showed a complete response (78%). With a median follow-up duration of 40.6 months, the 42 months relapse-free survival was 59.1%, and the 5-year overall survival rate was 80.4%. Limited-state MCL showed indolent clinical and low-risk prognostic features. Chemotherapy could be effective for controlling localized MCL lesions, with high complete response rates.


Assuntos
Linfoma de Célula do Manto , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Cloridrato de Bendamustina/administração & dosagem , Ciclofosfamida/administração & dosagem , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Feminino , Seguimentos , Humanos , Linfoma de Célula do Manto/diagnóstico , Linfoma de Célula do Manto/mortalidade , Linfoma de Célula do Manto/patologia , Linfoma de Célula do Manto/terapia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prednisona/administração & dosagem , Radioterapia , Estudos Retrospectivos , Fatores de Risco , Rituximab/administração & dosagem , Taxa de Sobrevida , Fatores de Tempo , Vincristina/administração & dosagem
15.
Br J Haematol ; 189(1): 106-116, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31721156

RESUMO

The prognosis for mantle cell lymphoma (MCL) remains poor. Our aim was to assess the impact of comorbidities on survival and causes of death. For 1,385 MCL patients (1,009 males, 376 females) diagnosed in 2000-2014 (median age 71 years, range 22-96) comorbidities ≤ 10 years of diagnosis were classified according to the Charlson comorbidity index (CCI; 0, 1, 2+). Hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated to compare lymphoma-specific and all-cause mortality rates. Model-based predictions were used to obtain probabilities of death. Overall, 44% had any comorbidity (CCI 1+) and 28% severe comorbidity (CCI 2+). Over a median follow-up of 3·7 years (range 0-16), 633 (46%) died, the majority (76%) from lymphoma. Severe comorbidity was independently associated with higher all-cause [hazard ratio (HR) = 1·52; 95% CI: 1·24-1·85) and lymphoma-specific mortality (HR = 1·31; 95% CI: 1·04-1·65). Particularly among patients with connective tissue, renal and psychiatric diseases, and dementia. Among females with any comorbidity, non-lymphoma deaths represented a larger proportion of all deaths, compared to males with any comorbidity. In general, more efficient lymphoma treatments need to be considered also for patients with severe comorbidity. However, among females with any comorbidity, the likelihood of non-lymphoma death was still considerable, perhaps favouring a more liberal use of a "wait and watch" approach.


Assuntos
Linfoma de Célula do Manto/mortalidade , Linfoma de Célula do Manto/terapia , Modelos Biológicos , Sistema de Registros , Caracteres Sexuais , Adulto , Idoso , Idoso de 80 Anos ou mais , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Taxa de Sobrevida
16.
Am J Clin Pathol ; 153(1): 49-57, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31433838

RESUMO

OBJECTIVES: Mantle cell lymphoma (MCL) is a mature B-cell lymphoma characterized by CCND1/IGH rearrangement. We reported a case of MCL harboring both CCND1/IGH and MYC/IGH rearrangements that also presented with an aggressive clinical course. METHODS: Biopsy specimens were evaluated by morphological staining, immunohistochemistry, flow cytometry, conventional cytogenetics, fluorescence in situ hybridization (FISH), and next-generation sequencing (NGS). RESULTS: Morphological and immunohistochemical staining of gallbladder samples demonstrated blastoid variant MCL. However, in the bone marrow sample, FISH indicated rearrangements in CCND1/IGH and MYC/IGH. Flow cytometry identified two groups of malignant lymphocytes. We sorted these two groups of cells. NGS then revealed that both cell types carried CCND1/IGH rearrangements and TP53 mutations. Furthermore, the CD19+/CD10+ cells carried additional MYC/IGH rearrangement and NOTCH2 mutation. CONCLUSIONS: The rearrangement of MYC and a mutation in NOTCH2 probably induced the transformation of MCL cells in this patient. This uncommon double-hit MCL case clearly demonstrates a transformation process.


Assuntos
Ciclina D1/genética , Linfoma de Células B/patologia , Linfoma de Célula do Manto/patologia , Proteínas de Fusão Oncogênica/genética , Proteínas Proto-Oncogênicas c-myc/genética , Transformação Celular Neoplásica , Citogenética , Evolução Fatal , Feminino , Rearranjo Gênico , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Linfoma de Células B/diagnóstico por imagem , Linfoma de Células B/genética , Linfoma de Célula do Manto/diagnóstico por imagem , Linfoma de Célula do Manto/genética , Linfoma de Célula do Manto/terapia , Pessoa de Meia-Idade , Mutação
17.
J Oncol Pharm Pract ; 26(2): 273-278, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30940050

RESUMO

INTRODUCTION: The aim of this study was to investigate the influence of high-dose cytosine arabinoside (HDAC)-containing treatments followed by autologous hematopoietic stem cell transplantation on the survival of patients with mantle cell lymphoma. MATERIAL AND METHODS: The data of 27 MCL patients who were followed-up between January 2009 and December 2015 were analyzed retrospectively. RESULTS: The median age of the patients was 63 (range, 45-82) with 22 (81.4%) males and 5 (18.6%) females. Eight of 27 patients were treated with HDAC-containing regimens either as induction or salvage chemotherapy followed by autologous hematopoietic stem cell transplantation (AHSCT). The patients who received HDAC-containing regimen followed by AHSCT were found to have better one-year survival compared to others (p = 0.03). Median follow-up of patient cohort was 27.6 months and median overall survival (OS) was not reached. The probability of one-year OS for all patients was 76.8%. CONCLUSION: Our findings suggest that HDAC treatment followed by AHSCT seems to provide the best outcome for young-fit patients presenting with mantle cell lymphoma.


Assuntos
Antimetabólitos Antineoplásicos/administração & dosagem , Citarabina/administração & dosagem , Transplante de Células-Tronco Hematopoéticas/métodos , Linfoma de Célula do Manto/terapia , Idoso , Idoso de 80 Anos ou mais , Terapia Combinada/métodos , Feminino , Transplante de Células-Tronco Hematopoéticas/mortalidade , Humanos , Linfoma de Célula do Manto/tratamento farmacológico , Linfoma de Célula do Manto/mortalidade , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Taxa de Sobrevida/tendências , Transplante Autólogo/métodos , Resultado do Tratamento
18.
Hematology Am Soc Hematol Educ Program ; 2019(1): 30-40, 2019 12 06.
Artigo em Inglês | MEDLINE | ID: mdl-31808882

RESUMO

Mantle cell lymphoma (MCL) is a distinct subtype of B-cell non-Hodgkin lymphoma characterized by the t(11;14)(q13;q32) translocation leading to cyclin D1 overexpression and cell cycle dysregulation. Molecular profiling with gene expression and deep sequencing analyses has identified genomic and epigenomic alterations in pathways regulating the cell cycle, DNA damage response, proliferation, and survival, which contribute to disease progression with important prognostic and therapeutic implications. Clinically, the nonnodal MCL subset is notable for leukemic presentation, indolent behavior, and association with hypermutated IGHV and lack of SOX11 expression, which differentiates it from the conventional nodal MCL. In addition to the Mantle Cell Lymphoma International Prognostic Index score and proliferative gene signatures, 17p/TP53 and 9p/CDKN2A alterations, and genomic complexity have emerged as clinically useful biomarkers of high-risk disease associated with aggressive disease behavior, resistance to chemotherapy, and poor overall survival. Although intensive chemoimmunotherapy regimens that incorporate high-dose cytarabine and stem cell transplantation have improved survival in young and fit MCL patients, the introduction of Bruton tyrosine kinase inhibitors and other novel agents has made effective outpatient-based treatment accessible to nearly all MCL patients. Optimizing combinations of novel agents in the relapsed setting and moving novel agents to the first-line setting have the potential to fundamentally change the MCL therapeutic landscape for the better, especially for patients ineligible for chemotherapy or those with high-risk mutations that are resistant to chemotherapy.


Assuntos
Linfoma de Célula do Manto/genética , Linfoma de Célula do Manto/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ciclo Celular/genética , Proliferação de Células/genética , Dano ao DNA , Regulação Neoplásica da Expressão Gênica , Humanos , Linfoma de Célula do Manto/patologia , Masculino , Pessoa de Meia-Idade , Neoplasia Residual/genética , Neoplasia Residual/patologia , Pacientes Ambulatoriais
20.
Curr Treat Options Oncol ; 20(12): 85, 2019 11 27.
Artigo em Inglês | MEDLINE | ID: mdl-31776787

RESUMO

OPINION STATEMENT: Mantle cell lymphoma (MCL) encompasses nearly 6% of all the non-Hodgkin lymphomas. It is considered an incurable neoplastic process arising from B cells. The cytogenetic abnormality t(11;14) (q13; q32) leading to cyclin D1 overexpression is the sentinel genetic event and provides an exceptional marker for diagnosis. MCL is generally considered to have an aggressive course as compared with other indolent lymphomas with traditionally reported median survival of 3-5 years. According to the 2016 WHO classification, there are two major known variants of MCL: classical which affects the lymph nodes and extra nodal sites and leukemic non-nodal MCL (L-NN-MCL) which characteristically involves the bone marrow, peripheral blood, and the spleen. It is important to distinguish between classical and leukemic non-nodal MCL since the latter variant of MCL follows a rather indolent course with a wait and watch approach in order to avoid overtreatment. However, a subset of patients with L-NN-MCL can transform into a more aggressive course requiring treatment. Current evidence suggests those patients with alteration in TP53 gene do not respond to standard chemotherapy agents and may need targeted therapy. In this review, we describe the characteristics of L-NN-MCL, its diagnosis, and management.


Assuntos
Linfoma de Célula do Manto/diagnóstico , Linfoma de Célula do Manto/terapia , Terapia Combinada , Diagnóstico Diferencial , Gerenciamento Clínico , Progressão da Doença , Suscetibilidade a Doenças , Humanos , Linfoma de Célula do Manto/etiologia , Gradação de Tumores , Estadiamento de Neoplasias , Resultado do Tratamento
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