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1.
Br J Haematol ; 2019 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-31702836

RESUMO

Lenalidomide maintenance therapy prolonged progression-free survival (PFS) versus placebo in elderly patients with diffuse large B-cell lymphoma (DLBCL) responding to induction chemotherapy in the phase 3 REMARC study. This subpopulation analysis assessed the impact of lenalidomide maintenance and treatment-emergent adverse events (TEAEs) on health-related quality of life (HRQOL). Global health status (GHS), and physical functioning and fatigue subscales were evaluated in patients who completed the European Organisation for Research and Treatment of Cancer quality-of-life questionnaire-C30 v3.0. The impact of TEAEs classified post hoc as subjective (patients can feel) or observable (only measurable by physicians) on dose reductions and discontinuations was assessed. Among 457 patients (lenalidomide, n = 229; placebo, n = 228), mean (standard deviation) GHS was similar between treatment arms [68·2 (20·7) Versus 72·0 (17·8)] at randomisation and remained similar during maintenance. Patients receiving lenalidomide experienced no meaningful changes in GHS, physical functioning, or fatigue. Observable TEAEs were more common (81·1% Versus 66·3%) and more likely to lead to dose reductions, than subjective TEAEs in both arms. PFS was superior in the lenalidomide arm regardless of dose reduction. Lenalidomide maintenance prolonged PFS and did not negatively impact HRQOL in patients with DLBCL despite TEAEs being more common, when compared with placebo.

2.
Artigo em Inglês | MEDLINE | ID: mdl-31570781

RESUMO

Plerixafor + granulocyte-colony stimulating factor (G-CSF) is administered to patients with lymphoma who are poor mobilizers of hematopoietic stem cells (HSCs) in Europe. This international, multicenter, non-interventional registry study (NCT01362972) evaluated long-term follow-up of patients with lymphoma who received plerixafor for HSC mobilization versus other mobilization methods. Propensity score matching was conducted to balance baseline characteristics between comparison groups. The following mobilization regimens were compared: G-CSF + plerixafor (G + P) versus G-CSF alone; G + P versus G-CSF + chemotherapy (G + C); and G-CSF + plerixafor + chemotherapy (G + P + C) versus G + C. The primary outcomes were progression-free survival (PFS), overall survival (OS), and cumulative incidence of relapse (CIR). Overall, 313/3749 (8.3%) eligible patients were mobilized with plerixafor-containing regimens. After propensity score matching, 70 versus 36 patients were matched in the G + P versus G-CSF alone cohort, 124 versus 124 in the G + P versus G + C cohort, and 130 versus 130 in the G + P + C versus G + C cohort. For both PFS and OS, the upper bound of confidence interval for the hazard ratio was >1.3 for all comparisons, implying that non-inferiority was not demonstrated. No major differences in PFS, OS, and CIR were observed between the plerixafor and comparison groups.

3.
J Clin Oncol ; : JCO1901389, 2019 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-31609651

RESUMO

PURPOSE: Patients with relapsed or refractory primary mediastinal large B-cell lymphoma (rrPMBCL) have a poor prognosis, and their treatment represents an urgent and unmet need. Because PMBCL is associated with genetic aberrations at 9p24 and overexpression of programmed cell death-1 (PD-1) ligands (PD-L1), it is hypothesized to be susceptible to PD-1 blockade. METHODS: In the phase IB KEYNOTE-013 (ClinicalTrials.gov identifier: NCT01953692) and phase II KEYNOTE-170 (ClinicalTrials.gov identifier: NCT02576990) studies, adults with rrPMBCL received pembrolizumab for up to 2 years or until disease progression or unacceptable toxicity. The primary end points were safety and objective response rate in KEYNOTE-013 and objective response rate in KEYNOTE-170. Secondary end points included duration of response, progression-free survival, overall survival, and safety. Exploratory end points included association between biomarkers and pembrolizumab activity. RESULTS: The objective response rate was 48% (7 complete responses; 33%) among 21 patients in KEYNOTE-013 and 45% (7 complete responses; 13%) among 53 patients in KEYNOTE-170. After a median follow-up time of 29.1 months in KEYNOTE-013 and 12.5 months in KEYNOTE-170, the median duration of response was not reached in either study. No patient with complete response experienced progression, including 2 patients with complete response for at least 1 year off therapy. Treatment-related adverse events occurred in 24% of patients in KEYNOTE-013 and 23% of patients in KEYNOTE-170. There were no treatment-related deaths. Among 42 evaluable patients, the magnitude of the 9p24 gene abnormality was associated with PD-L1 expression, which was itself significantly associated with progression-free survival. CONCLUSION: Pembrolizumab is associated with high response rate, durable activity, and a manageable safety profile in patients with rrPMBCL.

4.
Cancer Immunol Immunother ; 68(10): 1561-1572, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31494742

RESUMO

Preclinical and clinical studies have suggested that cancer treatment with antitumor antibodies induces a specific adaptive T cell response. A central role in this process has been attributed to CD4+ T cells, but the relevant T cell epitopes, mostly derived from non-mutated self-antigens, are largely unknown. In this study, we have characterized human CD20-derived epitopes restricted by HLA-DR1, HLA-DR3, HLA-DR4, and HLA-DR7, and investigated whether T cell responses directed against CD20-derived peptides can be elicited in human HLA-DR-transgenic mice and human samples. Based on in vitro binding assays to recombinant human MHC II molecules and on in vivo immunization assays in H-2 KO/HLA-A2+-DR1+ transgenic mice, we have identified 21 MHC II-restricted long peptides derived from intracellular, membrane, or extracellular domains of the human non-mutated CD20 protein that trigger in vitro IFN-γ production by PBMCs and splenocytes from healthy individuals and by PBMCs from follicular lymphoma patients. These CD20-derived MHC II-restricted peptides could serve as a therapeutic tool for improving and/or monitoring anti-CD20 T cell activity in patients treated with rituximab or other anti-CD20 antibodies.


Assuntos
Antígenos CD20/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfoma/tratamento farmacológico , Animais , Feminino , Cadeias HLA-DRB1/imunologia , Humanos , Interferon gama/biossíntese , Linfoma/imunologia , Camundongos , Rituximab/uso terapêutico
7.
Health Qual Life Outcomes ; 17(1): 115, 2019 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-31266501

RESUMO

BACKGROUND: Long-term lymphoma survivors often complain of persistent fatigue that remains unexplained. While largely reported in Hodgkin lymphoma (HL), long-term fatigue is poorly documented in non-Hodgkin lymphomas (NHL). Data collected in two cohort studies were used to illustrate the fatigue level changes with time in the two populations. METHODS: Two cross-sectional studies were conducted in 2009-2010 (HL) and in 2015 (NHL) in survivors enrolled in European Organisation for Research and Treatment of Cancer (EORTC) Lymphoma Group and Lymphoma Study Association (LYSA) trials. The same protocol and questionnaires were used in both studies including the Multidimensional Fatigue Inventory (MFI) tool to assess fatigue and a checklist of health disorders. Multivariate linear regression models were used in the two populations separately to assess the influence of time since diagnosis and primary treatment, age, gender, education level, cohabitation status, obesity and health disorders on fatigue level changes. Fatigue level changes were compared to general population data. RESULTS: Overall, data of 2023 HL and 1619 NHL survivors with fatigue assessment available (99 and 97% of cases, respectively) were analyzed. Crude levels of fatigue were similar in the two populations. Individuals who reported health disorders (61% of HL and 64% of NHL) displayed higher levels of fatigue than those who did not (P <  0.001). HL survivors showed increasing fatigue level with age while in NHL survivors mean fatigue level remained constant until age 70 and increased beyond. HL survivors showed fatigue changes with age higher than those of the general population with health disorders while NHL survivors were in between those of the general population with and without health disorders. CONCLUSIONS: Among lymphoma survivors progressive increase of fatigue level with time since treatment completion is a distinctive feature of HL. Our data suggest that changes in fatigue level are unlikely to only depend on treatment complications and health disorders. Investigations should be undertaken to identify which factors including biologic mechanisms could explain why a substantial proportion of survivors develop high level of fatigue.


Assuntos
Sobreviventes de Câncer , Fadiga/etiologia , Doença de Hodgkin/complicações , Linfoma não Hodgkin/complicações , Qualidade de Vida , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos Transversais , Feminino , Doença de Hodgkin/psicologia , Humanos , Modelos Lineares , Linfoma não Hodgkin/psicologia , Masculino , Pessoa de Meia-Idade , Inquéritos e Questionários , Adulto Jovem
8.
Lancet Haematol ; 6(8): e429-e437, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31296423

RESUMO

BACKGROUND: Lenalidomide plus rituximab is approved to treat patients with relapsed or refractory follicular lymphoma. Obinutuzumab has been shown to enhance antibody-dependent cellular cytotoxicity, phagocytosis, and direct B-cell killing better than rituximab. Our aim was to determine the activity and safety of lenalidomide plus obinutuzumab in previously treated patients with relapsed or refractory follicular lymphoma. METHODS: In this multicentre, single-arm, phase 2 study, patients were enrolled from 24 Lymphoma Academic Research Organisation centres in France. Eligible patients (age ≥18 years) had histologically confirmed CD20-positive relapsed or refractory follicular lymphoma of WHO grade 1, 2, or 3a; an ECOG performance status of 0-2; and received at least one previous rituximab-containing therapy. Patients received oral lenalidomide (20 mg) plus intravenously infused obinutuzumab as induction therapy (1000 mg; six 28-day cycles), 1-year maintenance with lenalidomide (10 mg; 12 28-day cycles; days 2-22) plus obinutuzumab (1000 mg; alternate cycles), and 1-year maintenance with obinutuzumab (1000 mg; six 56-day cycles; day 1). The primary endpoint was the proportion of patients who achieved an overall response at induction end as per investigator assessment using the 1999 international working group criteria. The secondary endpoints were event-free survival, progression-free survival, overall survival, and safety. Analyses were per-protocol; the efficacy population included all patients who received at least one dose of both obinutuzumab and lenalidomide, and the safety population included all patients who received one dose of either investigational drug. The study is registered with ClinicalTrials.gov, number NCT01582776, and is ongoing but closed to accrual. FINDINGS: Between June 11, 2014, and Dec 18, 2015, 89 patients were recruited and 86 patients were evaluable for efficacy and 88 for safety. Median follow-up was 2·6 years (IQR 2·2-2·8). 68 (79%) of 86 evaluable patients (95% CI 69-87) achieved an overall response at induction end, meeting the prespecified primary endpoint. At 2 years, event-free survival was 62% (95% CI 51-72), progression-free survival 65% (95% CI 54-74), duration of response 70% (95% CI 57-79), and overall survival 87% (95% CI 78-93). Complete response was achieved by 33 (38%, 95% CI 28-50) of 86 patients at induction end, and the proportion of patients achieving a best overall response was 70 (81%, 95% CI 72-89) and 72 (84%, 74-91) of 86 patients during induction and treatment, respectively. The most common adverse events were asthenia (n=54, 61%), neutropenia (n=38, 43%), bronchitis (n=36, 41%), diarrhoea (n=35, 40%), and muscle spasms (n=34, 39%). Neutropenia was the most common toxicity of grade 3 or more; four (5%) patients had febrile neutropenia. 57 serious adverse events were reported in 30 (34%) of 88 patients. The most common serious adverse events were basal cell carcinoma (n=5, 6%), febrile neutropenia (n=4, 5%), and infusion-related reaction (n=3, 3%). One patient died due to treatment-related febrile neutropenia. INTERPRETATION: Our data shows that lenalidomide plus obinutuzumab is active in previously treated patients with relapsed or refractory follicular lymphoma, including those with early relapse, and has a manageable safety profile. Randomised trials of new immunomodulatory regimens, such as GALEN or using GALEN as a backbone, versus lenalidomide plus rituximab, are warranted. FUNDING: Lymphoma Academic Research Organisation, and Celgene and Roche.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Lenalidomida/uso terapêutico , Linfoma de Células B/tratamento farmacológico , Linfoma Folicular/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/efeitos adversos , Antígenos CD20/metabolismo , Antineoplásicos Imunológicos/efeitos adversos , Intervalo Livre de Doença , Esquema de Medicação , Quimioterapia Combinada , Feminino , Humanos , Lenalidomida/efeitos adversos , Linfoma de Células B/mortalidade , Linfoma de Células B/patologia , Linfoma Folicular/mortalidade , Linfoma Folicular/patologia , Masculino , Pessoa de Meia-Idade , Neutropenia/etiologia , Recidiva , Taxa de Sobrevida , Resultado do Tratamento
9.
Cancer ; 2019 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-30901086

RESUMO

BACKGROUND: Long-term survivors of non-Hodgkin lymphoma (NHL) must cope with treatment complications and late toxicities that affect their health-related quality of life. Little is known about the risk-to-benefit ratio of new agents like rituximab. The impact of treatment regimens and health disorders on long-term fatigue levels was investigated in a cross-sectional study. METHODS: Two self-administered questionnaires, the 20-item Multidimensional Fatigue Inventory (MFI-20) and a Life Situation Questionnaire, were mailed in 2015 to NHL survivors enrolled onto 12 successive clinical studies (1993-2010) conducted by the Lymphoma Study Association. Private addresses were obtained for 3317 survivors, of whom 1671 (50%) returned the questionnaires. Severe fatigue was defined as MFI-20 scores ≥60 on dimension scales scored from 0 to 100. Linear regression models were used to assess factors that were linked to increased fatigue levels. RESULTS: The study population included 906 men and 765 women, and the median age was 64 years (age range, 24-95 years). Overall, 811 survivors had received cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP)-like chemotherapy, 518 had received high-dose CHOP, and 342 had undergone upfront autologous stem cell transplantation; 829 survivors also had received rituximab. In total, 1100 survivors (66%) reported 1 or more late health disorders. Severe fatigue was reported by 602 survivors (37%). Increased fatigue levels were associated (P < .001) with increased age, obesity, and the presence of health disorders, but not with initial treatment or rituximab. CONCLUSIONS: The survey confirms that high proportions long-term NHL survivors have severe fatigue. The results suggest that initial treatment and the receipt of rituximab have no influence on the development of long-term fatigue.

10.
Cell Metab ; 29(6): 1243-1257.e10, 2019 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-30827861

RESUMO

Diffuse large B cell lymphoma (DLBCL) is a heterogeneous disease treated with anti-CD20-based immuno-chemotherapy (R-CHOP). We identified that low levels of GAPDH predict a poor response to R-CHOP treatment. Importantly, we demonstrated that GAPDHlow lymphomas use OxPhos metabolism and rely on mTORC1 signaling and glutaminolysis. Consistently, disruptors of OxPhos metabolism (phenformin) or glutaminolysis (L-asparaginase) induce cytotoxic responses in GAPDHlow B cells and improve GAPDHlow B cell-lymphoma-bearing mice survival, while they are low or not efficient on GAPDHhigh B cell lymphomas. Ultimately, we selected four GAPDHlow DLBCL patients, who were refractory to all anti-CD20-based therapies, and targeted DLBCL metabolism using L-asparaginase (K), mTOR inhibitor (T), and metformin (M) (called KTM therapy). Three out of the four patients presented a complete response upon one cycle of KTM. These findings establish that the GAPDH expression level predicts DLBCL patients' response to R-CHOP treatment and their sensitivity to specific metabolic inhibitors.

11.
J Clin Oncol ; 37(15): 1285-1295, 2019 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-30901302

RESUMO

PURPOSE: Ibrutinib has shown activity in non-germinal center B-cell diffuse large B-cell lymphoma (DLBCL). This double-blind phase III study evaluated ibrutinib and rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in untreated non-germinal center B-cell DLBCL. PATIENTS AND METHODS: Patients were randomly assigned at a one-to-one ratio to ibrutinib (560 mg per day orally) plus R-CHOP or placebo plus R-CHOP. The primary end point was event-free survival (EFS) in the intent-to-treat (ITT) population and the activated B-cell (ABC) DLBCL subgroup. Secondary end points included progression-free survival (PFS), overall survival (OS), and safety. RESULTS: A total of 838 patients were randomly assigned to ibrutinib plus R-CHOP (n = 419) or placebo plus R-CHOP (n = 419). Median age was 62.0 years; 75.9% of evaluable patients had ABC subtype disease, and baseline characteristics were balanced. Ibrutinib plus R-CHOP did not improve EFS in the ITT (hazard ratio [HR], 0.934) or ABC (HR, 0.949) population. A preplanned analysis showed a significant interaction between treatment and age. In patients age younger than 60 years, ibrutinib plus R-CHOP improved EFS (HR, 0.579), PFS (HR, 0.556), and OS (HR, 0.330) and slightly increased serious adverse events (35.7% v 28.6%), but the proportion of patients receiving at least six cycles of R-CHOP was similar between treatment arms (92.9% v 93.0%). In patients age 60 years or older, ibrutinib plus R-CHOP worsened EFS, PFS, and OS, increased serious adverse events (63.4% v 38.2%), and decreased the proportion of patients receiving at least six cycles of R-CHOP (73.7% v 88.8%). CONCLUSION: The study did not meet its primary end point in the ITT or ABC population. However, in patients age younger than 60 years, ibrutinib plus R-CHOP improved EFS, PFS, and OS with manageable safety. In patients age 60 years or older, ibrutinib plus R-CHOP was associated with increased toxicity, leading to compromised R-CHOP administration and worse outcomes. Further investigation is warranted.

12.
Semin Hematol ; 55(4): 179-181, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30502843

RESUMO

We here report for the first time that low levels of interleukin (IL)-10 do not exclude lymphomatous meningitis (LM) in B-cell lymphoproliferative disorders (CLPD). Unexpectedly, IL-10 levels and IL-10:IL-6 ratio in CLPD differed from the levels observed in diffuse large B-cell lymphoma (DLBCL). We report the usefulness of adding the IL-10:IL-6 ratio in order to potentially reveal more aggressive lymphomas: either a transformation or an association with another "hidden" lymphoma such as primary CNS lymphoma (PCNSL).

13.
Br J Haematol ; 183(5): 755-765, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30407629

RESUMO

Splenectomy in addition to immunotherapy with rituximab can provide quick and sometimes durable disease control in patients with splenic marginal zone lymphoma (SMZL). However, systemic chemotherapy is ultimately required in many cases. The BRISMA (Bendamustine-rituximab as first-line treatment of splenic marginal zone lymphoma)/IELSG (International Extranodal Lymphoma Study Group)36 trial is an open-label, single arm phase II study designed by the IELSG in cooperation with the Fondazione Italiana Linfomi and the lymphoma Study Association according to Simon's two-stage method. The primary endpoint was complete response rate. Fifty-six patients with SMZL diagnosis confirmed on central revision were treated with bendamustine (90 mg/m2  days 1, 2) and rituximab (375 mg/m2  day 1) every 28 days for six cycles (B-R). The overall response and CR rates were 91% and 73%, respectively. Duration of response, progression-free survival and overall survival at 3 years were 93% (95% confidence interval [CI] 81-98), 90% (95% CI 77-96) and 96% (95% CI 84-98), respectively. Toxicity was mostly haematological. Neutropenia grade ≥3 was recorded in 43% of patients; infections and febrile neutropenia in 5·4% and 3·6%. Overall, 14 patients (25%) experienced serious adverse events. Five patients (9%) went off-study because of toxicity and one patient died from infection. In conclusion, B-R resulted in a very effective first-line regimen for SMZL. Based on the results achieved in the BRISMA trial, B-R should be considered when a chemotherapy combination with rituximab is deemed necessary for symptomatic SMZL patients.

14.
Eur J Intern Med ; 2018 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-30472108

RESUMO

In older patients lymphoma is a frequent disease and diffuse large B-cell lymphoma (DLBCL) represents >60% of all lymphomas. Elderly patients with DLBCL are a heterogeneous population and the definition of elderly varies within the literature. Even though the combination of rituximab, cyclophosphamide, doxorubicine, vincristine and prednisone (R-CHOP) is considered standard therapy for DLBCL, management of elderly patients remains challenging. Accurate selection of patients able to tolerate proper immune-chemotherapy is crucial and the comprehensive geriatric assessment based on age, comorbidities and functional abilities of daily living, may help to discriminate among fit, unfit or frail patients. Unfit and frail patients need to be treated with chemotherapy at reduced intensity. Novel compounds with a favorable toxicity profile may represent a promising first-line therapeutic option in combination with standard immune-chemotherapy or as single agent in the relapse/refractory setting.

15.
Nat Genet ; 2018 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-30429576

RESUMO

In the version of this article originally published, the main-text sentence "In three patients of European ancestry, we identified the germline variant encoding p.Ile97Met in TIM-3, which was homozygous in two (P12 and P13) and heterozygous in one (P15) in the germline but with no TIM-3 plasma membrane expression in the tumor" misstated the identifiers of the two homozygous individuals, which should have been P13 and P14. The error has been corrected in the HTML, PDF and print versions of the paper.

16.
Nat Genet ; 50(12): 1650-1657, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30374066

RESUMO

Subcutaneous panniculitis-like T cell lymphoma (SPTCL), a non-Hodgkin lymphoma, can be associated with hemophagocytic lymphohistiocytosis (HLH), a life-threatening immune activation that adversely affects survival1,2. T cell immunoglobulin mucin 3 (TIM-3) is a modulator of immune responses expressed on subgroups of T and innate immune cells. We identify in ~60% of SPTCL cases germline, loss-of-function, missense variants altering highly conserved residues of TIM-3, c.245A>G (p.Tyr82Cys) and c.291A>G (p.Ile97Met), each with specific geographic distribution. The variant encoding p.Tyr82Cys TIM-3 occurs on a potential founder chromosome in patients with East Asian and Polynesian ancestry, while p.Ile97Met TIM-3 occurs in patients with European ancestry. Both variants induce protein misfolding and abrogate TIM-3's plasma membrane expression, leading to persistent immune activation and increased production of inflammatory cytokines, including tumor necrosis factor-α and interleukin-1ß, promoting HLH and SPTCL. Our findings highlight HLH-SPTCL as a new genetic entity and identify mutations causing TIM-3 alterations as a causative genetic defect in SPTCL. While HLH-SPTCL patients with mutant TIM-3 benefit from immunomodulation, therapeutic repression of the TIM-3 checkpoint may have adverse consequences.

17.
Ann Hematol ; 2018 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-30315345

RESUMO

Follicular lymphoma (FL) and marginal zone lymphoma (MZL) are two subtypes of indolent B cell non-Hodgkin lymphoma (NHL) that account for approximately 20% and 12% of all NHLs, respectively. FL and MZL are rare conditions with orphan disease designations. We conducted a comprehensive review of the burden of FL and MZL that encompasses the epidemiological, real world clinical, economic, and humanistic impact of these diseases globally. A targeted literature search identified 31 eligible studies for review. Epidemiological coverage was poor, with data obtained for studies from only seven countries. The incidences of both subtypes were low: age-standardized incidence rates of FL ranged from 2.1/100,000 in France to 4.3/100,000 in the USA, while for MZL it varied geographically from 0.5/100,000 in Australia to 2.6/100,000 in the UK. The cumulative total direct healthcare costs for FL were higher for patients with progressive disease compared to those without ($30,890 vs. $8704 at 12 months, respectively) and main driver of costs related to the use of chemotherapy. Five-year overall survival was improved in patients with FL compared with MZL (e.g., 76.5% vs 60.7% in one study that reported on both subtypes). Mortality rates were particularly lower in female patients with FL aged < 60 years. However, limited outcome data for MZL patients were identified. FL and MZL contribute significant burden on healthcare systems and on patients globally, with delays in progression potentially leading to cost savings. More rigorous characterization of these two NHL subtypes, new and more effective treatments, and standardization of reporting would lead to a more robust understanding of future data in this disease area.

18.
Ann Hematol ; 2018 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-30218163

RESUMO

T cell non-Hodgkin lymphomas (T-NHLs) are aggressive malignancies which have a high risk of life-threatening complications. However, their prognosis in the intensive care unit (ICU) setting has not yet been assessed. We conducted a study including 87 ICU patients either with newly diagnosed T-NHLs or those undergoing first-line therapy admitted between January 1, 2000, and December 31, 2014. The primary subtypes were peripheral T cell lymphoma (PTCL) (n = 41, 47%), anaplastic large-cell lymphoma (ALCL) (n = 13, 15%), and adult T-leukaemia/lymphoma (ATLL) (n = 11, 13%). Six in every ten patients had malignancy-related complications (haemophagocytic syndrome 37%, tumour lysis syndrome 18% and hypercalcaemia 9%), while infections accounted for one quarter of ICU admissions. Nine fungal infections were documented, including six invasive aspergillosis. Urgent chemotherapy was started in the ICU in 59% of the patients, and urgent surgery was required in 13%. ICU and day-90 mortality were 22% and 41%, respectively. Multivariate analysis showed that SOFA score at day 1, age, sepsis and haemophagocytic syndrome were independent predictors of day-90 mortality. Compared to 66 ICU-matched controls with non-Hodgkin B cell lymphomas, patients with T-NHLs had a similar ICU survival. Overall survival rates of patients with T cell NHLs and B cell NHLs were 20% and 46%, respectively (hazard ratio for death associated with T cell NHLs 2.00 [1.12-3.58]). Patients with T cell NHLs had a very poor long-term outcome. Although the high rate of short-term survival suggests that an ICU trial is a reasonable option for patients newly diagnosed for the malignancy, extended stay in the ICU or further readmission should be considered only for highly selected patients who respond to the haematological treatment.

19.
Best Pract Res Clin Haematol ; 31(3): 199-208, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30213389

RESUMO

Diffuse large B-cell lymphoma (DLBCL) is a group of lymphomas comprising heterogeneous molecular and biological subtypes, reflected in a broad range of clinical outcomes. With the standard R-CHOP regimen of cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab administered every 21 days, the treatment failure rate remains unacceptably high in certain DLBCL subsets. Here we review possible avenues for optimizing initial therapy. The role of functional imaging and biological features, such as double-hit lymphomas, defined by the dual translocation of MYC and BCL2, and dual protein-expresser lymphomas, defined by the overexpression of MYC and BCL2, activated B-cell (ABC)-like DLBCL, to better define these high-risk patient subsets, and their use to guide and personalize treatment decisions are discussed. Secondly, the implications of varying dose-intensification of the various agents administered, and the link to imaging are reviewed. Thirdly, the results of the addition of novel drugs to standard R-CHOP will be analyzed, when added at induction or in maintenance. Finally, with CNS relapse in DLBCL representing a major and devastating unmet medical need, an overview and future directions for CNS prophylaxis is presented.

20.
Blood ; 132(14): 1486-1494, 2018 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-30068505

RESUMO

Obinutuzumab is a type II anti-CD20 monoclonal antibody that enhances antibody-dependent cellular cytotoxicity better than rituximab. Given promising results with lenalidomide and rituximab, this phase 1b study assessed the safety and efficacy of lenalidomide combined with obinutuzumab (GALEN). Patients age ≥18 years with relapsed or refractory (R/R) follicular lymphoma (FL) after rituximab-containing therapy received escalating doses (10 [n = 7], 15 [n = 3], 20 [n = 6], and 25 mg [n = 3]) of daily oral lenalidomide on days 1 to 21 of cycle 1 and on days 2 to 22 of cycles 2 to 6 (28-day cycles). Obinutuzumab 1000 mg IV was administered on days 8, 15, and 22 (cycle 1) and on day 1 (cycles 2-6). Dose was escalated in a 3 + 3 design based on dose-limiting toxicity (DLT) during cycle 1 to establish the maximum tolerated dose (MTD). We observed 164 adverse events (AEs), of which 139 were grade 1/2. The most common AEs were constipation (52.6%), neutropenia (47.4%), and asthenia (36.8%); 64.3% (9 of 14) of the grade 3/4 AEs were neutropenia/neutrophil decrease, but without any febrile neutropenia. Four DLTs occurred in 2 patients, all deemed unrelated to treatment. MTD was not reached. Twelve patients (63.2%) responded: 8 complete, 3 unconfirmed complete, and 1 partial response. Oral lenalidomide plus obinutuzumab is well tolerated and effective in R/R FL. The recommended dose of lenalidomide was established at 20 mg based on the risk of grade 3/4 neutropenia from cycle 2. This trial was registered at www.clinicaltrials.gov as #NCT01582776.

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