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1.
J Natl Compr Canc Netw ; 19(11): 1218-1230, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34781267

RESUMO

In the last decade, a better understanding of the molecular pathogenesis of B-cell non-Hodgkin lymphomas has resulted in the development of novel targeted therapies, such as small molecule inhibitors of select kinases in the B-cell receptor pathway, antibody-drug conjugates, and small molecules that target a variety of proteins (eg, CD-19, EZH2, and XPO-1-mediated nuclear export). Anti-CD19 CAR T-cell therapy, first approved for relapsed/refractory (R/R) diffuse large B-cell lymphoma, has also emerged as a novel treatment option for R/R follicular lymphoma and mantle cell lymphoma. These NCCN Guideline Insights highlight the new targeted therapy options included in the NCCN Guidelines for B-Cell Lymphomas for the treatment of R/R disease.

2.
Int J Infect Dis ; 112: 327-329, 2021 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-34600133

RESUMO

This article reports a fatal case of human herpesvirus 6 (HHV-6) myelitis following CD19-targeted chimeric antigen receptor T-cell therapy. Infection from HHV-6 reactivation after haematopoietic stem cell transplant is established, and outside of this population is limited to case reports. The patient developed cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome that responded to corticosteroids both clinically and on imaging. Subsequently, ascending flaccid paralysis developed, leading to neuromuscular respiratory failure and, ultimately, death. Disease progression was refractory to foscarnet and multiple immunomodulating agents. HHV-6 should be considered in patients with encephalitis and myelitis after adoptive T-cell therapy.

3.
Blood Adv ; 5(14): 2799-2806, 2021 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-34264268

RESUMO

The Endothelial Activation and Stress Index (EASIX) score, defined as [(creatinine × lactate dehydrogenase [LDH])/platelets], is a marker of endothelial activation that has been validated in the allogeneic hematopoietic stem cell transplant setting. Endothelial activation is one of the mechanisms driving immune-mediated toxicities in patients treated with chimeric antigen receptor-T (CAR-T)-cell therapy. This study's objective was to evaluate the association between EASIX and other laboratory parameters collected before lymphodepletion and the subsequent onset of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) those patients. Toxicity data were collected prospectively on 171 patients treated with axicabtagene ciloleucel (axi-cel) for large B-cell lymphoma (LBCL). CRS grades 2 to 4 were diagnosed in 81 (47%) patients and ICANS grades 2 to 4 in 84 (49%). EASIX combined with ferritin (EASIX-F) identified 3 risk groups with CRS grades 2 to 4 cumulative incidence of 74% (hazards ratio [HR], 4.8; 95% confidence interval [CI], 2.1-11; P < .001), 49% (HR, 2.3; 95% CI, 1.02-5; P = .04), and 23% (reference), respectively. EASIX combined with CRP and ferritin (EASIX-FC) identified 3 risk groups with an ICANS grade 2 to 4 cumulative incidence of 74% (HR, 3.6; 95% CI, 1.9-6.9; P < .001), 51% (HR, 2.1; 95% CI, 1.1-3.9; P = .025), and 29% (reference). Our results indicate that common laboratory parameters before lymphodepletion correlate with CAR-T-related toxicities and can help support clinical decisions, such as preemptive toxicity management, hospitalization length, and proper setting for CAR-T administration.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Linfoma Difuso de Grandes Células B , Receptores de Antígenos Quiméricos , Síndrome da Liberação de Citocina , Ferritinas , Humanos
4.
Blood ; 137(23): 3272-3276, 2021 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-33534891

RESUMO

Corticosteroids are commonly used for the management of severe toxicities associated with chimeric antigen receptor (CAR) T-cell therapy. However, it remains unclear whether their dose, duration, and timing may affect clinical efficacy. Here, we determined the impact of corticosteroids on clinical outcomes in patients with relapsed or refractory large B-cell lymphoma treated with standard of care anti-CD19 CAR T-cell therapy. Among 100 patients evaluated, 60 (60%) received corticosteroids for management of CAR T-cell therapy-associated toxicities. The median cumulative dexamethasone-equivalent dose was 186 mg (range, 8-1803) and the median duration of corticosteroid treatment was 9 days (range, 1-30). Corticosteroid treatment was started between days 0 and 7 in 45 (75%) patients and beyond day 7 in 15 (25%). After a median follow-up of 10 months (95% confidence interval, 8-12 months), use of higher cumulative dose of corticosteroids was associated with significantly shorter progression-free survival. More importantly, higher cumulative dose of corticosteroids, and prolonged and early use after CAR T-cell infusion were associated with significantly shorter overall survival. These results suggest that corticosteroids should be used at the lowest dose and for the shortest duration and their initiation should be delayed whenever clinically feasible while managing CAR T-cell therapy-associated toxicities.

5.
Leuk Lymphoma ; 62(6): 1361-1369, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33480830

RESUMO

We addressed the prognostic impact of cell-of-origin (COO), MYC and Bcl-2 overexpression as well as isolated MYC rearrangement among 111 patients with limited stage diffuse large B-cell lymphoma (DLBCL) treated with consolidative radiation therapy (RT) after a metabolic complete response to immunochemotherapy. With a median follow-up of 31.1 months (95% CI 27.4 - 34.8), 4 relapses occurred. The 3-year progression free survival (PFS), overall survival (OS), and loco-regional relapse free survival (LRFS) for the cohort were 95%, 96%, and 100%, respectively. There were no differences in OS, PFS, or LRFS based on COO or MYC/Bcl-2 dual expression (DE). Similarly, patients with MYC translocations without BCL2 or BCL6 rearrangements did not have worse outcomes. Consolidative RT produced excellent local control, regardless of DLBCL biology, with one late in-field failure.


Assuntos
Linfoma Difuso de Grandes Células B , Proteínas Proto-Oncogênicas c-myc , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Terapia Combinada , Ciclofosfamida/uso terapêutico , Doxorrubicina/uso terapêutico , Humanos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/terapia , Recidiva Local de Neoplasia/genética , Prognóstico , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-6/genética , Proteínas Proto-Oncogênicas c-myc/genética
8.
Haematologica ; 106(10): 2667-2672, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32732355

RESUMO

Chimeric antigen receptor (CAR) T-cell therapy targeting CD19 may be associated with long-term adverse effects such as cytopenia and immune deficiency. In order to characterize these late events, we analyzed 31 patients with relapsed or refractory large B-cell lymphoma treated with axicabtagene ciloleucel at our institution on two clinical trials, ZUMA-1 (clinicaltrials gov. Identifier: NCT02348216) and ZUMA-9 (clinicaltrials gov. Identifier: NCT03153462). Complete blood counts, lymphocyte subsets, and immunoglobulin levels were measured serially until month 24 or progression. Fifteen (48%) patients had grade 3-4 cytopenia, including anemia (five, 16%), neutropenia (nine, 29%), or thrombocytopenia (13, 42%) at day 30. Cytopenia at day 30 was not significantly associated with later diagnosis of myelodysplasia. Among patients with ongoing remission, grade 3-4 cytopenia was observed in one of nine (11%) at 2 years. While peripheral CD8+ T cells recovered early, CD4+ T-cell recovery was delayed with a count of <200/mL in three of nine (33%) patients at 1 year and two of seven (29%) at 2 years. Immunoglobulin G levels normalized in five of nine (56%) patients at 2 years. Thirteen (42%) patients developed grade 3-4 infectious complications, including herpes zoster and Pneumocystis jiroveci pneumonia. These results suggest the need for prolonged monitoring and prophylaxis against opportunistic infections in these patients, to improve the longterm safety of axicabtagene ciloleucel therapy.

10.
Clin Cancer Res ; 26(21): 5579-5587, 2020 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-33055173

RESUMO

PURPOSE: Preclinical and early clinical data suggested that combining histone deacetylase (HDAC) and mTOR inhibitors can synergistically inhibit Hodgkin lymphoma. PATIENTS AND METHODS: During the dose-escalation study (ClinicalTrials.gov number: NCT01087554) with the HDAC inhibitor vorinostat and the mTOR inhibitor sirolimus (V+S), a patient with Hodgkin lymphoma refractory to nine prior therapies demonstrated a partial response (PR) lasting for 18.5 months, which promoted additional enrollment of patients with Hodgkin lymphoma as well as exploration of an alternative combination of vorinostat and mTOR inhibitor everolimus (V+E). RESULTS: A total of 40 patients with refractory Hodgkin lymphoma received V+S (n = 22) or V+E (n = 18). Patients received a median of five prior therapies, including brentuximab (n = 39), autologous stem cell transplantation (n = 26), and allogeneic stem cell transplantation (n = 12). The most frequent grade ≥3 treatment-related adverse event was thrombocytopenia in 55% and 67% of patients treated with V+S and V+E, respectively. Complete response was reported in 6 (27%) patients treated with V+S and 2 (11%) patients treated with V+E, and PR was reported in 6 patients (27%) treated with V+S and 4 (22%) patients treated with V+E (objective response rate of 55% and 33%, respectively). In summary, combined HDAC and mTOR inhibition had encouraging activity in heavily pretreated patients with relapsed/refractory Hodgkin lymphoma and warrants further investigation. CONCLUSIONS: Combined HDAC and mTOR inhibition has salutary activity in patients with relapsed refractory Hodgkin lymphoma and warrants further investigation.

11.
Blood Adv ; 4(16): 3943-3951, 2020 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-32822484

RESUMO

Neurotoxicity or immune effector cell-associated neurotoxicity syndrome (ICANS) is the second most common acute toxicity after chimeric antigen receptor (CAR) T-cell therapy. However, there are limited data on the clinical and radiologic correlates of ICANS. We conducted a cohort analysis of 100 consecutive patients with relapsed or refractory large B-cell lymphoma (LBCL) treated with standard of care axicabtagene ciloleucel (axi-cel). ICANS was graded according to an objective grading system. Neuroimaging studies and electroencephalograms (EEGs) were reviewed by an expert neuroradiologist and neurologist. Of 100 patients included in the study, 68 (68%) developed ICANS of any grade and 41 (41%) had grade ≥3. Median time to ICANS onset was 5 days, and median duration was 6 days. ICANS grade ≥3 was associated with high peak ferritin (P = .03) and C-reactive protein (P = .001) levels and a low peak monocyte count (P = .001) within the 30 days after axi-cel infusion. Magnetic resonance imaging was performed in 38 patients with ICANS and revealed 4 imaging patterns with features of encephalitis (n = 7), stroke (n = 3), leptomeningeal disease (n = 2), and posterior reversible encephalopathy syndrome (n = 2). Abnormalities noted on EEG included diffuse slowing (n = 49), epileptiform discharges (n = 6), and nonconvulsive status epilepticus (n = 8). Although reversible, grade ≥3 ICANS was associated with significantly shorter progression-free (P = .02) and overall survival (progression being the most common cause of death; P = .001). Our results suggest that imaging and EEG abnormalities are common in patients with ICANS, and high-grade ICANS is associated with worse outcome after CAR T-cell therapy in LBCL patients.


Assuntos
Síndromes Neurotóxicas , Síndrome da Leucoencefalopatia Posterior , Antígenos CD19/uso terapêutico , Humanos , Imunoterapia Adotiva , Síndromes Neurotóxicas/diagnóstico por imagem , Síndromes Neurotóxicas/etiologia
14.
Lancet Haematol ; 7(3): e209-e217, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32027862

RESUMO

BACKGROUND: Siltuximab is recommended by international consensus as a first-line treatment for idiopathic multicentric Castleman disease on the basis of durable efficacy and safety data. This study was done to assess the long-term safety and activity of siltuximab over up to 6 years of treatment. METHODS: This study is a prespecified open-label extension analysis of a phase 1 trial (NCT00412321) and a phase 2 trial (NCT01024036), done at 26 hospitals worldwide. Patients in both studies were at least 18 years old with histologically confirmed, symptomatic Castleman disease. This extension study enrolled 60 patients who completed the previous trials without disease progression on siltuximab. Patients received siltuximab infusions of 11 mg/kg every 3 weeks (which could be extended to 6 weeks) for up to 6 years. Descriptive statistics were used to summarise the data. No formal hypothesis testing was performed. The primary endpoint was the safety of siltuximab, assessed at each dosing cycle. The study was registered with ClinicalTrials.gov, number NCT01400503 and with EudraCT, number 2010-022837-27. FINDINGS: Patient enrolment into the phase 1 trial was from June 20, 2005, to Sept 15, 2009, and enrolment into the phase 2 trial was from Feb 9, 2010, to Feb 3, 2012. Patients were enrolled in this long-term extension from April 1, 2011, to Jan 15, 2014. Median follow-up was 6 years (IQR 5·11-7·76). Median treatment duration, from the beginning of the previous trials to the end of the present study, was 5·5 years (IQR 4·26-7·14). Siltuximab was well tolerated; however, adverse events of grade 3 or worse were reported in 36 (60%) of 60 patients with the most common being hypertension (eight [13%]), fatigue (five [8%]), nausea (four [7%]), neutropenia (four [7%]), and vomiting (three [5%]). 25 (42%) patients reported at least one serious adverse event, which most commonly was an infection (eight [13%]). Only two serious adverse events, polycythaemia and urinary retention, were considered related to siltuximab treatment. 18 patients discontinued before study completion, either to receive siltuximab locally (eight) or because of progressive disease (two), adverse events (two), or other reasons (six). No deaths were reported. INTERPRETATION: These results show that siltuximab is well tolerated long term and provides important evidence for the feasibility of the life-long use required by patients with idiopathic multicentric Castleman disease. FUNDING: Janssen R&D and EUSA Pharma.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Hiperplasia do Linfonodo Gigante/tratamento farmacológico , Adulto , Hiperplasia do Linfonodo Gigante/patologia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Segurança do Paciente , Prognóstico
15.
Leuk Lymphoma ; 61(6): 1380-1387, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-31971032

RESUMO

In 2 randomized phase 3 trials BR resulted in longer progression-free survival (PFS) than frontline R-CHOP in patients with indolent and mantle cell lymphoma. However, in subset analyses of follicular lymphoma (FL), the results were incongruent. We conducted a retrospective matched-pair analysis to compare the outcome of patients with advanced stage FL, receiving frontline BR (N = 73) or R-CHOP (N = 73), matched by age, gender, stage, and FL International Prognostic Index score. On multivariable analysis, baseline maximum standardized uptake value (SUVmax) >13 was associated with use of R-CHOP (p = .001). After a median follow-up of 69 months for the BR arm and 126 months for the R-CHOP arm, 5-year PFS was 80% and 70%, respectively (p = .07). After adjusting for SUVmax >13, the trend for better PFS in BR was not maintained. Prospective studies are needed to validate the role of pretreatment SUVmax as a stratification factor in future randomized therapeutic trials in FL.


Assuntos
Linfoma Folicular , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ciclofosfamida/uso terapêutico , Doxorrubicina/uso terapêutico , Humanos , Linfoma Folicular/tratamento farmacológico , Prednisona/uso terapêutico , Estudos Prospectivos , Estudos Retrospectivos , Rituximab/uso terapêutico , Vincristina/efeitos adversos
16.
Leuk Lymphoma ; 61(2): 328-336, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31533521

RESUMO

CD5+ diffuse large B-cell lymphoma (DLBCL), NOS represents a distinct subset of DLBCL associated with poorer outcomes and extranodal disease. We analyzed characteristics and outcomes for 102 CD5+ DLBCL patients diagnosed between 2001-2016. The majority had poor-risk disease based on R-IPI scores; 80% had extranodal disease at diagnosis. CNS relapse occurred 23% of the time. Median PFS and OS was 18.9 months and 112 months, respectively. Four-year PFS rates were 100%, 53%, and 41% for patients with R-IPI scores of very good, good, and poor, respectively. CD5+ DLBCL represents a subset of patients with poor outcomes despite rituximab and anthracycline-based regimens. There is a need for novel therapies and clinical trials for this high-risk group of patients. Given high rates of CNS relapse, better CNS prophylaxis with frontline therapy requires more study.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Linfoma Difuso de Grandes Células B , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Humanos , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Recidiva Local de Neoplasia , Rituximab/uso terapêutico
17.
Haematologica ; 105(7): 1907-1913, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-31601688

RESUMO

The impact of pre-treatment maximum standardized uptake value (SUVmax) on the outcome of follicular lymphoma (FL) following specific frontline regimens has not been explored. We performed a retrospective analysis of 346 patients with advanced stage follicular lymphoma (FL) without histological evidence of transformation, and analyzed the impact of SUVmax on outcome after frontline therapy. Fifty-two (15%) patients had a SUVmax >18, and a large lymph node ≥6 cm was the only factor associating with SUVmax >18 on multivariate analysis (odds ratio 2.7, 95% confidence interval [CI]: 1.3-5.3, P=0.006). The complete response rate was significantly lower among patients treated with non-anthracycline-based regimens if SUVmax was >18 (45% vs 92%, P<0.001), but not among patients treated with R-CHOP (P=1). SUVmax >18 was associated with significantly shorter progression-free survival among patients treated with non-anthracycline-based regimens (77 months vs. not reached, P=0.02), but not among patients treated with R-CHOP (P=0.73). SUVmax >18 associated with shorter overall survival (OS) both in patients treated with R-CHOP (8-year OS 70% vs. 90%, P=0.02) and non-anthracycline-based frontline regimens (8-year OS 50% vs 85%, P=0.001). In conclusion, pre-treatment PET scan has prognostic and predictive value in patients with advanced stage FL receiving frontline treatment.


Assuntos
Fluordesoxiglucose F18 , Linfoma Folicular , Humanos , Linfonodos , Linfoma Folicular/diagnóstico , Linfoma Folicular/tratamento farmacológico , Tomografia por Emissão de Pósitrons , Prognóstico , Estudos Retrospectivos
19.
Clin Lymphoma Myeloma Leuk ; 19(11): 709-714, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31446000

RESUMO

BACKGROUND: Rosai-Dorfman disease (RDD) is a rare disorder composed of a proliferation of histiocytes with varied clinical manifestations. PATIENTS AND METHODS: In this retrospective observational study, we obtained demographic, clinical, and outcome data from the medical records of 10 adult patients with RDD seen in the Department of Lymphoma and Myeloma at MD Anderson Cancer Center between 1995 and 2015. RESULTS: Patients had a median age of 56 years (range, 20-81 years) with equal gender distribution. Five patients were initially treated with systemic therapy. Five received cladribine as initial therapy or for relapse. Other therapeutic agents included clofarabine, lenalidomide, and steroids. The overall response rate was 80% in patients receiving cladribine, with a median progression-free survival of 29 months. Surgery, radiotherapy, and observation were also treatment options for localized disease. With a median follow-up of 65 months, none of the patients have died. CONCLUSION: Currently, there is no standard of care for RDD. Treatment should be personalized for each patient depending on the clinical presentation, course of the disease, and prior treatment history. Purine analogues provide excellent responses; however, surgical resection and observation are also suitable for specific cases.


Assuntos
Histiocitose Sinusal/epidemiologia , Centros Médicos Acadêmicos , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia , Institutos de Câncer , Terapia Combinada , Gerenciamento Clínico , Feminino , Histiocitose Sinusal/diagnóstico , Histiocitose Sinusal/história , Histiocitose Sinusal/terapia , História do Século XX , História do Século XXI , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Estudos Retrospectivos , Avaliação de Sintomas , Texas/epidemiologia , Resultado do Tratamento , Adulto Jovem
20.
J Natl Compr Canc Netw ; 17(6): 650-661, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-31200358

RESUMO

Diffuse large B-cell lymphomas (DLBCLs) and follicular lymphoma (FL) are the most common subtypes of B-cell non-Hodgkin's lymphomas in adults. Histologic transformation of FL to DLBCL (TFL) occurs in approximately 15% of patients and is generally associated with a poor clinical outcome. Phosphatidylinositol 3-kinase (PI3K) inhibitors have shown promising results in the treatment of relapsed/refractory FL. CAR T-cell therapy (axicabtagene ciloleucel and tisagenlecleucel) has emerged as a novel treatment option for relapsed/refractory DLBCL and TFL. These NCCN Guidelines Insights highlight important updates to the NCCN Guidelines for B-Cell Lymphomas regarding the treatment of TFL and relapsed/refractory FL and DLBCL.


Assuntos
Linfoma Folicular/terapia , Linfoma Difuso de Grandes Células B/terapia , Oncologia/normas , Recidiva Local de Neoplasia/terapia , Adulto , Assistência ao Convalescente/normas , Antineoplásicos Imunológicos/normas , Antineoplásicos Imunológicos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Humanos , Imunoterapia Adotiva/métodos , Imunoterapia Adotiva/normas , Linfoma Folicular/imunologia , Linfoma Folicular/mortalidade , Linfoma Folicular/patologia , Linfoma Difuso de Grandes Células B/imunologia , Linfoma Difuso de Grandes Células B/mortalidade , Linfoma Difuso de Grandes Células B/patologia , Oncologia/métodos , Recidiva Local de Neoplasia/imunologia , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Inibidores de Fosfoinositídeo-3 Quinase/normas , Inibidores de Fosfoinositídeo-3 Quinase/uso terapêutico , Receptores de Antígenos Quiméricos/imunologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Estados Unidos
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