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1.
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
2.
Transplant Cell Ther ; 27(8): 689-695, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34023569

RESUMO

Relapse after allogeneic hematopoietic cell transplantation (HCT) leads to poor survival in patients with acute myeloid leukemia (AML). A second HCT (HCT2) may achieve durable remission. To determine the outcomes of patients who received an HCT2 for relapsed AML and to evaluate the predictors of overall survival (OS) and progression-free survival (PFS). We retrospectively reviewed medical records of adult patients who underwent an HCT2 for relapsed AML at our institution during 2000 to 2019. Ninety-one patients were identified with a median age of 44 years (range 18-73) at HCT2. Donor types were HLA-identical sibling (n = 37 [41%]), HLA-matched-unrelated (n = 34 [37%]), haploidentical (n = 19 [21%]), and cord blood (n=1 [1%]). Donors were different at HCT2 in 53% of patients. The majority of patients received reduced intensity conditioning (n = 71 [78%]) and were in remission (n = 56 [61%]) at HCT2. The median remission duration after HCT1 was 8.4 months (range 1-70) and the median time between transplants was 14 months (range 3-73). The median follow-up of surviving patients after HCT2 was 66 months (range 2-171), with 32% alive at time of analysis. The most common cause of death was disease recurrence (n = 45 [73%]). At 2 years, the rates of OS, PFS, progression, and nonrelapse mortality were 36%, 27%, 42%, and 18%, respectively. The development of chronic graft-versus-host disease (GVHD) after first HCT and HCT comorbidity index (HCT-CI) ≥2 at HCT2 were associated with inferior PFS and OS after HCT2. A second HCT is feasible in selected patients with AML who have relapsed after HCT1. Long-term survival benefit is possible in patients without chronic GVHD after HCT1 and HCT-CI <2 at HCT2.


Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Adolescente , Adulto , Idoso , Humanos , Leucemia Mieloide Aguda/terapia , Pessoa de Meia-Idade , Estudos Retrospectivos , Condicionamento Pré-Transplante , Adulto Jovem
3.
Biol Blood Marrow Transplant ; 26(10): 1759-1769, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32623078

RESUMO

Immune effector cell (IEC) therapy is emerging as a promising approach in the field of cancer immunotherapy. Clinical IEC trials, predominantly using chimeric antigen receptor (CAR) T cells, have shown excellent responses in CD19+ B cell malignancies and multiple myeloma. In solid tumors, preclinical data are encouraging, but clinical data are in their infancy, and there are challenges in using CAR T therapy in this setting, including (1) on-target off-tumor toxicity, (2) optimal target identification, (3) effective trafficking into bulky tumor tissue, and (4) resistance to tumor immune evasion mechanisms. Novel techniques and modifications are being explored in both the preclinical and clinical settings, aiming to improve treatment efficacy and address the aforementioned obstacles to successful CAR T therapy in solid tumors. Here we review these challenges in a clinically oriented approach and summarize published clinical trials using CAR T therapy in a variety of solid tumors.


Assuntos
Imunoterapia Adotiva , Neoplasias , Antígenos CD19 , Humanos , Linfócitos , Neoplasias/terapia , Receptores de Antígenos de Linfócitos T , Microambiente Tumoral
4.
Cancer ; 126(10): 2183-2192, 2020 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-32101640

RESUMO

BACKGROUND: Despite the well-defined role of minimal residual disease (MRD) monitoring by real-time quantitative polymerase chain reaction (RT-PCR) for RUNX1/RUNX1T1 and CBFB-MYH11 transcripts in core binding factor (CBF) acute myeloid leukemia (AML) after intensive chemotherapy, there has been a paucity of data assessing the utility of MRD monitoring at and after allogeneic hematopoietic stem cell transplantation (HSCT). METHODS: Patients with CBF AML who underwent HSCT in complete remission (first or second) from January 2007 through December 2018 were included in this analysis. RESULTS: MRD by polymerase chain reaction at HSCT was assessed in 50 of 76 patients, and 44 (88%) had evidence of MRD (MRDpos). MRDpos patients had 3-year overall survival (OS) and leukemia-free survival (LFS) rates of 69.3% and 66.3%, respectively. Six MRD-negative patients had 3-year OS and LFS rates of 100% and 100%, respectively. Thirty-five of the 70 evaluable patients (50%) had a day +100 MRD assessment by RT-PCR, and 14 (40%) were MRDpos. The presence of MRD by RT-PCR on day +100 was not associated with lower estimates of LFS (75% vs 82.2%; P = .3) but was associated with a higher relapse incidence, although the difference did not reach statistical significance (27.6% vs 9.7%; P = .2). CONCLUSIONS: Durable complete remissions can be achieved in patients with CBF AML with HSCT even if they are MRDpos by RT-PCR at HSCT. The clinical impact of frequent MRD monitoring for identifying a group at high risk for early relapse and then for determining the best time point for therapeutic interventions to prevent impending relapse warrants investigation in prospectively designed clinical trials.


Assuntos
Fatores de Ligação ao Core/genética , Leucemia Mieloide Aguda/diagnóstico , Neoplasia Residual/diagnóstico , Reação em Cadeia da Polimerase em Tempo Real/métodos , Adulto , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Subunidade beta de Fator de Ligação ao Core/genética , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , Cadeias Pesadas de Miosina/genética , Neoplasia Residual/genética , Neoplasia Residual/terapia , Proteínas de Fusão Oncogênica/genética , Prognóstico , Proteína 1 Parceira de Translocação de RUNX1/genética , Transplante Homólogo
5.
Br J Haematol ; 188(3): 404-412, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31468521

RESUMO

Hypomethylating agents (HMAs) are standard of care for higher-risk myelodysplastic syndromes (MDS). However, less than half of patients achieve objective responses and most eventually lose their response. Pracinostat is a pan-histone deacetylase inhibitor with demonstrated activity in advanced myeloid malignancies. This phase II study explored the benefit of adding pracinostat to HMAs in MDS patients who did not respond to single-agent HMA treatment. The goal was to estimate the clinical improvement rate [complete remission (CR), marrow CR, partial response (PR) and haematological improvement]. Group 1 included patients with primary/secondary HMA failures; Group 2 included those who did not achieve response but had stable disease (SD) after single-agent HMAs. Forty-five patients (39 Group 1, 6 Group 2) received a median of 3 cycles. Among all patients, 1 (2%) had CR, 7 (16%) had marrow CR and 18 (40%) had SD; disease progression occurred in 3 (7%). Median overall survival was 5·7/5·6 months for Group 1/2. Grade ≥3 adverse events occurred in 38 patients (84%) leading to treatment discontinuation in 12 (33%). Adding pracinostat to HMAs did not improve outcomes in patients previously treated with HMAs. Frequent dose modifications/early discontinuation resulted in suboptimal drug exposure. A reduced pracinostat dose may improve tolerability and efficacy.


Assuntos
Benzimidazóis/administração & dosagem , Inibidores de Histona Desacetilases/administração & dosagem , Síndromes Mielodisplásicas/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Medula Óssea/metabolismo , Medula Óssea/patologia , Quimioterapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/metabolismo , Síndromes Mielodisplásicas/patologia
6.
Drugs ; 79(12): 1287-1304, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31313099

RESUMO

Apoptosis, the process of programmed cell death, occurs normally during development and aging. Members of the B-cell lymphoma 2 (BCL2) family of proteins are central regulators of apoptosis, and resistance to apoptosis is one of the hallmarks of cancer. Targeting the apoptotic pathway via BCL2 inhibitors has been considered a promising treatment strategy in the past decade. Initial efforts with small molecule BH3 mimetics such as ABT-737 and ABT-263 (navitoclax) pioneered the development of the first-in-class Food and Drug Administration (FDA)-approved oral BCL2 inhibitor, venetoclax. Venetoclax was approved for the treatment of chronic lymphocytic leukemia and acute myeloid leukemia, and is now being studied in a number of hematologic malignancies. Several other inhibitors targeting different BCL2 family members are now in early stages of development.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Hematológicas/tratamento farmacológico , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Compostos de Anilina/uso terapêutico , Apoptose/efeitos dos fármacos , Compostos de Bifenilo/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Aprovação de Drogas , Humanos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Terapia de Alvo Molecular , Nitrofenóis/uso terapêutico , Piperazinas/uso terapêutico , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Sulfonamidas/uso terapêutico , Estados Unidos , United States Food and Drug Administration
8.
EBioMedicine ; 31: 174-181, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29728305

RESUMO

Somatic mutations contribute to the heterogeneous prognosis of chronic myelomonocytic leukemia (CMML). Hypomethylating agents (HMAs) are active in CMML, but analyses of small series failed to identify mutations predicting response or survival. We analyzed a retrospective multi-center cohort of 174 CMML patients treated with a median of 7 cycles of azacitidine (n = 68) or decitabine (n = 106). Sequencing data before treatment initiation were available for all patients, from Sanger (n = 68) or next generation (n = 106) sequencing. Overall response rate (ORR) was 52%, including complete response (CR) in 28 patients (17%). In multivariate analysis, ASXL1 mutations predicted a lower ORR (Odds Ratio [OR] = 0.85, p = 0.037), whereas TET2mut/ASXL1wt genotype predicted a higher CR rate (OR = 1.18, p = 0.011) independently of clinical parameters. With a median follow-up of 36.7 months, overall survival (OS) was 23.0 months. In multivariate analysis, RUNX1mut (Hazard Ratio [HR] = 2.00, p = .011), CBLmut (HR = 1.90, p = 0.03) genotypes and higher WBC (log10(WBC) HR = 2.30, p = .005) independently predicted worse OS while the TET2mut/ASXL1wt predicted better OS (HR = 0.60, p = 0.05). CMML-specific scores CPSS and GFM had limited predictive power. Our results stress the need for robust biomarkers of HMA activity in CMML and for novel treatment strategies in patients with myeloproliferative features and RUNX1 mutations.


Assuntos
Azacitidina/análogos & derivados , Azacitidina/administração & dosagem , Subunidade alfa 2 de Fator de Ligação ao Core , Proteínas de Ligação a DNA , Leucemia Mielogênica Crônica BCR-ABL Positiva , Mutação , Proteínas Proto-Oncogênicas , Proteínas Repressoras , Idoso , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Subunidade alfa 2 de Fator de Ligação ao Core/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Decitabina , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Masculino , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo
9.
Biol Blood Marrow Transplant ; 24(9): 1920-1927, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29550629

RESUMO

Given the increasing incidence of chronic graft-versus-host disease (cGVHD) and its rapidly escalating costs due to many lines of drug treatments, we aimed to perform a meta-analysis to assess the comparative effectiveness of various treatment options. Using these results, we then conducted a cost-effectiveness analysis for the frequently utilized agents in steroid-refractory cGVHD. We searched for studies examining tacrolimus, sirolimus, rituximab, ruxolitinib, hydroxychloroquine, imatinib, bortezomib, ibrutinib, extracorporeal photopheresis, pomalidomide, and methotrexate. Studies with a median follow-up period shorter than 6 months and enrolling fewer than 5 patients were excluded. Meta-analysis for overall and organ system-specific GVHD response (overall response [ORR], complete response [CR], and partial response [PR]) was conducted for each intervention. Cost per CR and cost per CR + PR were calculated as the quotient of the 6-month direct treatment cost by CR and CR + PR. Forty-one studies involving 1047 patients were included. CR rates ranged from 7% to 30% with rituximab and methotrexate, respectively, and ORR ranged from 30% to 85% with tacrolimus and ruxolitinib, respectively. Cost per CR ranged from US$1,187,657 with ruxolitinib to US$680 with methotrexate. Cost per ORR ranged from US$453 for methotrexate to US$242,236 for ibrutinib. The most cost-effective strategy was methotrexate for all of the organ systems. Pomalidomide was found to be the least cost-effective treatment for eye, gastrointestinal, fascia/joint, skin, and oral GVHD, and imatinib was found to be the least cost-effective treatment for liver and extracorporeal photopheresis for lung GVHD. We observed huge cost-effectiveness differences among available agents. Attention to economic issues when treating cGVHD is important to recommend how treatments should be sequenced, knowing that many patients will cycle through available agents.


Assuntos
Análise Custo-Benefício/tendências , Doença Enxerto-Hospedeiro/economia , Doença Crônica , Feminino , Custos de Cuidados de Saúde , Humanos , Masculino
10.
Am J Hematol ; 93(1): 65-73, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29023992

RESUMO

Therapy related myeloid neoplasms (t-MN) including therapy related myelodysplastic syndromes (t-MDS) and acute myeloid leukemia (t-AML) are associated with aggressive disease biologies and poor outcomes. In this large (n = 497) and informative (inclusive of molecular and cytogenetic information) chronic myelomonocytic leukemia (CMML) patient cohort, we demonstrate key biological insights and an independent prognostic impact for t-CMML. T-CMML was diagnosed in 9% of patients and occurred approximately 7 years after exposure to prior chemotherapy and/or radiation therapy. In comparison to de novo CMML, t-CMML patients had higher LDH levels, higher frequency of karyotypic abnormalities and had higher risk cytogenetic stratification. There were no differences in the distribution of gene mutations and unlike t-MDS/AML, balanced chromosomal translocations, abnormalities of chromosome 11q23 (1%) and Tp53 mutations (<2%) were uncommon. Molecularly integrated CMML prognostic models were not effective in risk stratifying t-CMML patients and responses to hypomethylating agents were dismal with no complete responses. Median overall (OS) and leukemia free survival (LFS) was shorter for t-CMML in comparison to d-CMML (Median OS 10.9 vs 26 months and median LFS 50 vs 127 months) and t-CMML independently and adversely impacted OS (P = .0001 HR 2.1 95% CI 1.4-3.0). This prognostic impact was retained in the context of the Mayo Molecular Model (P = .001, HR 2.4, 95% CI 1.5-3.7) and the GFM prognostic model (P < .0001, HR 2.15, 95% CI 1.5-3.7). In summary, we highlight the unique genetics and independent prognostic impact of t-CMML, warranting its inclusion as a separate entity in the classification schema for both CMML and t-MN.


Assuntos
Citogenética/métodos , Leucemia Mielomonocítica Crônica/terapia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Leucemia Mielomonocítica Crônica/genética , Masculino , Pessoa de Meia-Idade , Prognóstico , Adulto Jovem
11.
Biol Blood Marrow Transplant ; 23(9): 1478-1484, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28495641

RESUMO

Acute graft-versus-host disease (aGVHD) is the leading cause of morbidity and mortality after allogenic hematopoietic cell transplantation (HCT). Corticosteroids are the first-line treatment; however, less than one-half of patients achieve durable remission. Studies suggest that TNF-α, a cytokine released from the bone marrow during conditioning, is involved in the pathogenesis of aGVHD. We retrospectively evaluated the outcome of anti-TNF-α therapy with infliximab in 35 patients with steroid refractory (SR) aGVHD. Infliximab was administered intravenously at 10 mg/kg for a median of 4 doses (range, 1 to 6) on a weekly basis. The overall response rates were 40% (17% complete response [CR], 23% partial response [PR]) at 4 weeks, 23% (9% CR, 14% PR) at 8 weeks, and 17% (all CR) at 12 weeks. Twenty-nine (83%) patients had infectious complications within 12 weeks of initiation of infliximab. These infections included 40 bacterial infections, 6 invasive fungal infections, and 5 viral reactivations. Twelve patients (34%) died secondary to infections. Overall survival at 12 weeks and 6 months from the start of infliximab therapy was 37% (13 of 35) and 17% (6 of 35), respectively; with most deaths secondary to complications from GVHD and infections. In conclusion; the use of infliximab therapy in patients with SR-aGVHD is associated with a modest poorly sustained response along with a heightened risk of severe infections. Future studies with more effective and less toxic therapies are needed for these patients.


Assuntos
Doença Enxerto-Hospedeiro/terapia , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas , Infliximab/administração & dosagem , Agonistas Mieloablativos/efeitos adversos , Condicionamento Pré-Transplante/efeitos adversos , Doença Aguda , Corticosteroides/uso terapêutico , Adulto , Idoso , Infecções Bacterianas/etiologia , Infecções Bacterianas/imunologia , Infecções Bacterianas/mortalidade , Infecções Bacterianas/patologia , Medula Óssea/efeitos dos fármacos , Medula Óssea/imunologia , Medula Óssea/patologia , Esquema de Medicação , Feminino , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/mortalidade , Doença Enxerto-Hospedeiro/patologia , Neoplasias Hematológicas/imunologia , Neoplasias Hematológicas/mortalidade , Neoplasias Hematológicas/patologia , Humanos , Infliximab/efeitos adversos , Injeções Intravenosas , Masculino , Pessoa de Meia-Idade , Micoses/etiologia , Micoses/imunologia , Micoses/mortalidade , Micoses/patologia , Estudos Retrospectivos , Análise de Sobrevida , Transplante Homólogo , Resultado do Tratamento , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/biossíntese , Fator de Necrose Tumoral alfa/imunologia , Viroses/etiologia , Viroses/imunologia , Viroses/mortalidade , Viroses/patologia
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