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1.
Br J Haematol ; 2022 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-35468225

RESUMO

Checkpoint inhibitors (CPIs) are routinely employed in relapsed/refractory classical Hodgkin lymphoma. Nonetheless, persistent long-term responses are uncommon, and one-third of patients are refractory. Several reports have suggested that treatment with CPIs may re-sensitize patients to chemotherapy, however there is no consensus on the optimal chemotherapy regimen and subsequent consolidation strategy. In this retrospective study we analysed the response to rechallenge with chemotherapy after CPI failure. Furthermore, we exploratively characterized the clonal evolution profile of a small sample of patients (n = 5) by employing the CALDER approach. Among the 28 patients included in the study, 17 (71%) were primary refractory and 26 (92%) were refractory to the last chemotherapy prior to CPIs. Following rechallenge with chemotherapy, response was recorded in 23 (82%) patients experiencing complete remission and 3 (11%) patients experiencing partial remission. The tumour evolution of the patients inferred by CALDER seemingly occurred prior to the first cycle of therapy and was characterized either by linear or branching evolution patterns. Twenty-five patients proceeded to allogeneic stem cell transplantation. At a median follow-up of 21 months, median PFS and OS were not reached. In conclusion, patients who fail CPIs can be effectively rescued by salvage chemotherapy and bridged to allo-SCT/auto-SCT.

2.
Blood Adv ; 6(6): 1855-1864, 2022 03 22.
Artigo em Inglês | MEDLINE | ID: mdl-35130339

RESUMO

Ruxolitinib (RUX) is extensively used in myelofibrosis (MF). Despite its early efficacy, most patients lose response over time and, after discontinuation, have a worse overall survival (OS). Currently, response criteria able to predict OS in RUX-treated patients are lacking, leading to uncertainty regarding the switch to second-line treatments. In this study, we investigated predictors of survival collected after 6 months of RUX in 209 MF patients participating in the real-world ambispective observational RUXOREL-MF study (NCT03959371). Multivariable analysis identified the following risk factors: (1) RUX dose <20 mg twice daily at baseline, months 3 and 6 (hazard ratio [HR], 1.79; 95% confidence interval [CI], 1.07-3.00; P = .03), (2) palpable spleen length reduction from baseline ≤30% at months 3 and 6 (HR, 2.26; 95% CI, 1.40-3.65; P = .0009), (3) red blood cell (RBC) transfusion need at months 3 and/or 6 (HR, 1.66; 95% CI, 0.95-2.88; P = .07), and (4) RBC transfusion need at all time points (ie, baseline and months 3 and 6; HR, 2.32; 95% CI, 1.19-4.54; P = .02). Hence, we developed a prognostic model, named Response to Ruxolitinib After 6 Months (RR6), dissecting 3 risk categories: low (median OS, not reached), intermediate (median OS, 61 months; 95% CI, 43-80), and high (median OS, 33 months; 95% CI, 21-50). The RR6 model was validated and confirmed in an external cohort comprised of 40 MF patients. In conclusion, the RR6 prognostic model allows for the early identification of RUX-treated MF patients with impaired survival who might benefit from a prompt treatment shift.


Assuntos
Mielofibrose Primária , Humanos , Nitrilas , Mielofibrose Primária/induzido quimicamente , Mielofibrose Primária/diagnóstico , Mielofibrose Primária/tratamento farmacológico , Prognóstico , Pirazóis/efeitos adversos , Pirimidinas , Estudos Retrospectivos
3.
Blood ; 139(16): 2499-2511, 2022 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-34995350

RESUMO

Prophylactic high-dose methotrexate (HD-MTX) is often used for diffuse large B-cell lymphoma (DLBCL) patients at high risk of central nervous system (CNS) relapse, despite limited evidence demonstrating efficacy or the optimal delivery method. We conducted a retrospective, international analysis of 1384 patients receiving HD-MTX CNS prophylaxis either intercalated (i-HD-MTX) (n = 749) or at the end (n = 635) of R-CHOP/R-CHOP-like therapy (EOT). There were 78 CNS relapses (3-year rate 5.7%), with no difference between i-HD-MTX and EOT: 5.7% vs 5.8%, P = .98; 3-year difference: 0.04% (-2.0% to 3.1%). Conclusions were unchanged on adjusting for baseline prognostic factors or on 6-month landmark analysis (n = 1253). In patients with a high CNS international prognostic index (n = 600), the 3-year CNS relapse rate was 9.1%, with no difference between i-HD-MTX and EOT. On multivariable analysis, increasing age and renal/adrenal involvement were the only independent risk factors for CNS relapse. Concurrent intrathecal prophylaxis was not associated with a reduction in CNS relapse. R-CHOP delays of ≥7 days were significantly increased with i-HD-MTX vs EOT, with 308 of 1573 (19.6%) i-HD-MTX treatments resulting in a delay to subsequent R-CHOP (median 8 days). Increased risk of delay occurred in older patients when delivery was later than day 10 in the R-CHOP cycle. In summary, we found no evidence that EOT delivery increases CNS relapse risk vs i-HD-MTX. Findings in high-risk subgroups were unchanged. Rates of CNS relapse in this HD-MTX-treated cohort were similar to comparable cohorts receiving infrequent CNS prophylaxis. If HD-MTX is still considered for certain high-risk patients, delivery could be deferred until R-CHOP completion.


Assuntos
Neoplasias do Sistema Nervoso Central , Linfoma Difuso de Grandes Células B , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Neoplasias do Sistema Nervoso Central/patologia , Neoplasias do Sistema Nervoso Central/prevenção & controle , Ciclofosfamida , Doxorrubicina , Humanos , Linfoma Difuso de Grandes Células B/patologia , Metotrexato , Recidiva Local de Neoplasia/tratamento farmacológico , Prednisona , Estudos Retrospectivos , Rituximab/uso terapêutico , Vincristina
4.
Blood Adv ; 6(1): 327-338, 2022 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-34644385

RESUMO

Lymphoma represents a heterogeneous hematological malignancy (HM), which is characterized by severe immunosuppression. Patients diagnosed of coronavirus disease 2019 (COVID-19) during the course of HM have been described to have poor outcome, with only few reports specifically addressing lymphoma patients. Here, we investigated the clinical behavior and clinical parameters of a large multicenter cohort of adult patients with different lymphoma subtypes, with the aim of identifying predictors of death. The study included 856 patients, of whom 619 were enrolled prospectively in a 1-year frame and were followed-up for a median of 66 days (range 1-395). Patients were managed as outpatient (not-admitted cohort, n = 388) or required hospitalization (n = 468), and median age was 63 years (range 19-94). Overall, the 30- and 100-days mortality was 13% (95% confidence interval (CI), 11% to 15%) and 23% (95% CI, 20% to 27%), respectively. Antilymphoma treatment, including anti-CD20 containing regimens, did not impact survival. Patients with Hodgkin's lymphoma had the more favorable survival, but this was partly related to significantly younger age. The time interval between lymphoma diagnosis and COVID-19 was inversely related to mortality. Multivariable analysis recognized 4 easy-to-use factors (age, gender, lymphocyte, and platelet count) that were associated with risk of death, both in the admitted and in the not-admitted cohort (HR 3.79 and 8.85 for the intermediate- and high-risk group, respectively). Overall, our study shows that patients should not be deprived of the best available treatment of their underlying disease and indicates which patients are at higher risk of death. This study was registered with ClinicalTrials.gov, NCT04352556.


Assuntos
COVID-19 , Linfoma , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Humanos , Linfoma/diagnóstico , Linfoma/terapia , Pessoa de Meia-Idade , Prognóstico , SARS-CoV-2 , Adulto Jovem
5.
Br J Haematol ; 196(3): 548-558, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34649298

RESUMO

Patients affected by lymphoid malignancies (LM) are frequently immune-compromised, suffering increased mortality from COVID-19. This prospective study evaluated serological and T-cell responses after complete mRNA vaccination in 263 patients affected by chronic lymphocytic leukaemia, B- and T-cell lymphomas and multiple myeloma. Results were compared with those of 167 healthy subjects matched for age and sex. Overall, patient seroconversion rate was 64·6%: serological response was lower in those receiving anti-cancer treatments in the 12 months before vaccination: 55% vs 81·9% (P < 0·001). Anti-CD20 antibody plus chemotherapy treatment was associated with the lowest seroconversion rate: 17·6% vs. 71·2% (P < 0·001). In the multivariate analysis conducted in the subgroup of patients on active treatment, independent predictors for seroconversion were: anti-CD20 treatment (P < 0·001), aggressive B-cell lymphoma diagnosis (P = 0·002), and immunoglobulin M levels <40 mg/dl (P = 0·030). The T-cell response was evaluated in 99 patients and detected in 85 of them (86%). Of note, 74% of seronegative patients had a T-cell response, but both cellular and humoral responses were absent in 13·1% of cases. Our findings raise some concerns about the protection that patients with LM, particularly those receiving anti-CD20 antibodies, may gain from vaccination. These patients should strictly maintain all the protective measures.


Assuntos
/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , COVID-19 , Neoplasias Hematológicas , Imunidade Celular/efeitos dos fármacos , Transtornos Linfoproliferativos , SARS-CoV-2/imunologia , Linfócitos T/imunologia , /imunologia , Idoso , Anticorpos Antivirais/imunologia , COVID-19/imunologia , COVID-19/prevenção & controle , Feminino , Neoplasias Hematológicas/tratamento farmacológico , Neoplasias Hematológicas/imunologia , Humanos , Imunoglobulina M/imunologia , Transtornos Linfoproliferativos/tratamento farmacológico , Transtornos Linfoproliferativos/imunologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Soroconversão
7.
Blood ; 139(5): 732-747, 2022 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-34653238

RESUMO

Splenic marginal zone B-cell lymphoma (SMZL) is a heterogeneous clinico-biological entity. The clinical course is variable, multiple genes are mutated with no unifying mechanism, and essential regulatory pathways and surrounding microenvironments are diverse. We sought to clarify the heterogeneity of SMZL by resolving different subgroups and their underlying genomic abnormalities, pathway signatures, and microenvironment compositions to uncover biomarkers and therapeutic vulnerabilities. We studied 303 SMZL spleen samples collected through the IELSG46 multicenter international study (NCT02945319) by using a multiplatform approach. We carried out genetic and phenotypic analyses, defined self-organized signatures, validated the findings in independent primary tumor metadata and in genetically modified mouse models, and determined correlations with outcome data. We identified 2 prominent genetic clusters in SMZL, termed NNK (58% of cases, harboring NF-κB, NOTCH, and KLF2 modules) and DMT (32% of cases, with DNA-damage response, MAPK, and TLR modules). Genetic aberrations in multiple genes as well as cytogenetic and immunogenetic features distinguished NNK- from DMT-SMZLs. These genetic clusters not only have distinct underpinning biology, as judged by differences in gene-expression signatures, but also different outcomes, with inferior survival in NNK-SMZLs. Digital cytometry and in situ profiling segregated 2 basic types of SMZL immune microenvironments termed immune-suppressive SMZL (50% of cases, associated with inflammatory cells and immune checkpoint activation) and immune-silent SMZL (50% of cases, associated with an immune-excluded phenotype) with distinct mutational and clinical connotations. In summary, we propose a nosology of SMZL that can implement its classification and also aid in the development of rationally targeted treatments.


Assuntos
Linfoma de Zona Marginal Tipo Células B/genética , Neoplasias Esplênicas/genética , Idoso , Animais , Aberrações Cromossômicas , Feminino , Humanos , Imunofenotipagem , Linfoma de Zona Marginal Tipo Células B/diagnóstico , Masculino , Camundongos , Pessoa de Meia-Idade , Família Multigênica , Mutação , Baço/patologia , Neoplasias Esplênicas/diagnóstico , Transcriptoma , Microambiente Tumoral
9.
J Hematol Oncol ; 14(1): 168, 2021 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-34649563

RESUMO

BACKGROUND: Patients with hematological malignancies (HM) are at high risk of mortality from SARS-CoV-2 disease 2019 (COVID-19). A better understanding of risk factors for adverse outcomes may improve clinical management in these patients. We therefore studied baseline characteristics of HM patients developing COVID-19 and analyzed predictors of mortality. METHODS: The survey was supported by the Scientific Working Group Infection in Hematology of the European Hematology Association (EHA). Eligible for the analysis were adult patients with HM and laboratory-confirmed COVID-19 observed between March and December 2020. RESULTS: The study sample includes 3801 cases, represented by lymphoproliferative (mainly non-Hodgkin lymphoma n = 1084, myeloma n = 684 and chronic lymphoid leukemia n = 474) and myeloproliferative malignancies (mainly acute myeloid leukemia n = 497 and myelodysplastic syndromes n = 279). Severe/critical COVID-19 was observed in 63.8% of patients (n = 2425). Overall, 2778 (73.1%) of the patients were hospitalized, 689 (18.1%) of whom were admitted to intensive care units (ICUs). Overall, 1185 patients (31.2%) died. The primary cause of death was COVID-19 in 688 patients (58.1%), HM in 173 patients (14.6%), and a combination of both COVID-19 and progressing HM in 155 patients (13.1%). Highest mortality was observed in acute myeloid leukemia (199/497, 40%) and myelodysplastic syndromes (118/279, 42.3%). The mortality rate significantly decreased between the first COVID-19 wave (March-May 2020) and the second wave (October-December 2020) (581/1427, 40.7% vs. 439/1773, 24.8%, p value < 0.0001). In the multivariable analysis, age, active malignancy, chronic cardiac disease, liver disease, renal impairment, smoking history, and ICU stay correlated with mortality. Acute myeloid leukemia was a higher mortality risk than lymphoproliferative diseases. CONCLUSIONS: This survey confirms that COVID-19 patients with HM are at high risk of lethal complications. However, improved COVID-19 prevention has reduced mortality despite an increase in the number of reported cases.


Assuntos
COVID-19/complicações , Neoplasias Hematológicas/complicações , Adulto , Idoso , Idoso de 80 Anos ou mais , COVID-19/diagnóstico , COVID-19/epidemiologia , COVID-19/terapia , Europa (Continente)/epidemiologia , Feminino , Neoplasias Hematológicas/epidemiologia , Neoplasias Hematológicas/terapia , Hospitalização , Humanos , Unidades de Terapia Intensiva , Masculino , Pessoa de Meia-Idade , Sistema de Registros , Fatores de Risco , SARS-CoV-2/isolamento & purificação , Adulto Jovem
10.
Haematologica ; 2021 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-34289655

RESUMO

Diffuse Large B-Cell Lymphoma (DLBCL) is a heterogeneous disease, including one-third of cases overexpressing MYC and BCL2 proteins (Double Expressor Lymphoma, DEL) and 5-10% of patients with chromosomal rearrangements of MYC, BCL2 and/or BCL-6 (Double/Triple-Hit Lymphomas, DH/TH). TP53 mutations are detected in 20-25% of DEL. We report the efficacy of dose-adjusted EPOCH and rituximab (DA-EPOCH-R) in a series of 122 consecutive patients, including DEL (n=81, 66%), DEL-MYC (n=9, 7%), DEL-BCL2 (n=13, 11%), or High-Grade Lymphomas (DH/TH) (n=19, 16%). Central nervous system (CNS) prophylaxis included intravenous methotrexate (n=66), intrathecal chemotherapy (IT) (n=40) or no prophylaxis (n=16). Sixty-seven pts (55%) had high-intermediate or high International Prognostic Index (IPI) and 30 (25%) had high CNS-IPI. The 2-year progressionfree survival (PFS) and overall survival (OS) for the entire study population were 74% and 84%, respectively. There was a trend for inferior OS for DH/TH (2-year OS: 66%, p=0.058) as compared to all the others. The outcome was significantly better for the IPI 0-2 versus IPI 3-5 (OS: 98% vs. 72%, p=0.002). DA-EPOCH-R did not overcome the negative prognostic value of TP53 mutations: 2-year OS of 62% versus 88% (p=0.036) were observed for mutated as compared to wild-type cases, respectively. Systemic CNS prophylaxis conferred a better 2-year OS (94%) as compared to IT or no prophylaxis (76% and 65%, respectively; p= 0.008). DA-EPOCH-R treatment resulted in a favorable outcome in patients with DEL and DEL with single rearrangement, whereas those with multiple genetic alterations such as DEL-DH/TH and TP53 mutated cases still have an inferior outcome.

11.
Leukemia ; 35(9): 2672-2683, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33658659

RESUMO

Anti-PD-1 monoclonal antibodies yield high response rates in patients with relapsed/refractory classic Hodgkin lymphoma (cHL), but most patients will eventually progress. Allogeneic hematopoietic cell transplantation (alloHCT) after PD-1 blockade may be associated with increased toxicity, raising challenging questions about the role, timing, and optimal method of transplantation in this setting. To address these questions, we assembled a retrospective cohort of 209 cHL patients who underwent alloHCT after PD-1 blockade. With a median follow-up among survivors of 24 months, the 2-year cumulative incidences (CIs) of non-relapse mortality and relapse were 14 and 18%, respectively; the 2-year graft-versus-host disease (GVHD) and relapse-free survival (GRFS), progression-free survival (PFS), and overall survival were 47%, 69%, and 82%, respectively. The 180-day CI of grade 3-4 acute GVHD was 15%, while the 2-year CI of chronic GVHD was 34%. In multivariable analyses, a longer interval from PD-1 to alloHCT was associated with less frequent severe acute GVHD, while additional treatment between PD-1 and alloHCT was associated with a higher risk of relapse. Notably, post-transplant cyclophosphamide (PTCy)-based GVHD prophylaxis was associated with significant improvements in PFS and GRFS. While awaiting prospective clinical trials, PTCy-based GVHD prophylaxis may be considered the optimal transplantation strategy for this patient population.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Transplante de Células-Tronco Hematopoéticas/mortalidade , Doença de Hodgkin/terapia , Inibidores de Checkpoint Imunológico/efeitos adversos , Recidiva Local de Neoplasia/terapia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Terapia de Salvação , Adolescente , Adulto , Idoso , Feminino , Seguimentos , Doença de Hodgkin/tratamento farmacológico , Doença de Hodgkin/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Transplante Homólogo , Adulto Jovem
14.
Hematol Oncol ; 38(4): 501-508, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32602970

RESUMO

Among patients with advanced-stage classical Hodgkin lymphoma (cHL) receiving ABVD chemotherapy, PET performed after the first two treatment cycles (PET-2) has prognostic value. However, 15% of patients with a negative PET-2 will experience treatment failure. Here we prospectively evaluated serum thymus and activation-regulated chemokine (TARC) levels, to improve risk assessment in patients treated according to HD0607 PET-driven trial (#NCT00795613). In 266 patients with available serum samples, who have agreed to participate in a sub-study for assessment of the role of TARC monitoring, serum TARC levels were measured at baseline and at time of PET-2 by commercially available ELISA test kits. The primary end-point was to evaluate the association between TARC after 2 ABVD cycles and PFS. Median TARC-2 values were significantly higher in PET-2-positive patients compared to PET-2-negative patients (P = .001), and in patients with treatment failure compared to those in continuous CR (P = .01). The 4-year PFS significantly differed between patients with TARC-2 >800 pg/mL vs ≤800 pg/mL (64% vs 86%, P = .0001). Moreover, among PET-2-negative patients, elevated TARC-2 identified those with a worse prognosis (74% vs 89%; P = .01). In multivariable analysis, TARC-2 >800 pg/mL was a significant independent predictor of PFS in the whole study population (HR 2.39, P = .004) and among the PET-2-negative patients (HR 2.49, P = .02). In conclusion, our results indicate that TARC-2 serum levels above 800 pg/mL suggest the need for a stringent follow-up in PET-2-negative patients, and the evaluation of new drugs in PET-2-positive, who will likely fail to respond to intensification with escalated BEACOPP.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/sangue , Quimiocina CCL17/sangue , Doença de Hodgkin/patologia , Tomografia por Emissão de Pósitrons/métodos , Adolescente , Adulto , Feminino , Seguimentos , Doença de Hodgkin/sangue , Doença de Hodgkin/diagnóstico por imagem , Doença de Hodgkin/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Taxa de Sobrevida , Adulto Jovem
15.
Eur J Hybrid Imaging ; 4(1): 9, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-34191173

RESUMO

BACKGROUND: According to published data, radiomics features differ between lesions of refractory/relapsing HL patients from those of long-term responders. However, several methodological aspects have not been elucidated yet. PURPOSE: The study aimed at setting up a methodological framework in radiomics applications in Hodgkin's lymphoma (HL), especially at (a) developing a novel feature selection approach, (b) evaluating radiomic intra-patient lesions' similarity, and (c) classifying relapsing refractory (R/R) vs non-(R/R) patients. METHODS: We retrospectively included 85 patients (male:female = 52:33; median age 35 years, range 19-74). LIFEx (www.lifexsoft.org) was used for [18F]FDG-PET/CT segmentation and feature extraction. Features were a-priori selected if they were highly correlated or uncorrelated to the volume. Principal component analysis-transformed features were used to build the fingerprints that were tested to assess lesions' similarity, using the silhouette. For intra-patient similarity analysis, we used patients having multiple lesions only. To classify patients as non-R/R and R/R, the fingerprint considering one single lesion (fingerprint_One) and all lesions (fingerprint_All) was tested using Random Undersampling Boosting of Tree Ensemble (RUBTE). RESULTS: HL fingerprints included up to 15 features. Intra-patient lesion similarity analysis resulted in mean/median silhouette values below 0.5 (low similarity especially in the non-R/R group). In the test set, the fingerprint_One classification accuracy was 62% (78% sensitivity and 53% specificity); the classification by RUBTE using fingerprint_All resulted in 82% accuracy (70% sensitivity and 88% specificity). CONCLUSIONS: Lesion similarity analysis was developed, and it allowed to demonstrate that HL lesions were not homogeneous within patients in terms of radiomics signature. Therefore, a random target lesion selection should not be adopted for radiomics applications. Moreover, the classifier to predict R/R vs non-R/R performed the best when all the lesions were used.

16.
Hemasphere ; 3(5): e284, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31942539

RESUMO

Diffuse Large B-Cell Lymphoma (DLBCL) is a clinically and biologically heterogeneous disease. The revised Classification of Lymphoproliferative diseases published in 2016 (WHO, 2016) refined the previous DLBLC subtypes and identified four categories: DLBCL not otherwise specified (NOS), other lymphomas of large B cells, high grade B-cell lymphoma, and B-cell lymphoma unclassifiable. High grade B-cell lymphomas include the entities carrying MYC, BCL2 and/or BCL6 translocations or cases with blastoid morphology without DH translocations. This classification also acknowledges the cell of origin (COO) classification, that has only a limited impact on the choice of frontline treatment for DLBCL, as most patients still receive R-CHOP chemoimmunotherapy. Attempts to improve the outcomes of specific subgroups, especially COO groups, have so far had limited success. Newer analyses have further subdivided DLBCL into genomically distinct subsets, not yet incorporated in the WHO classification, which may facilitate targeted approaches to therapy. In this review, we discuss the subgroups that are recognized by the WHO 2016 classification, review the newer genomic data, and speculate on how this could alter the treatment landscape of DLBCL in the future. We also discuss novel approaches to salvage therapy in the broad context of the heterogeneity of DLBCL.

17.
Leuk Lymphoma ; 60(1): 101-109, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29716416

RESUMO

This monocentric retrospective study included 70 consecutive relapsed/refractory Hodgkin lymphoma (RR-HL) patients receiving reduced-intensity allogeneic stem cell transplantation (alloSCT). We evaluated overall and progression-free survival (OS, PFS), graft-versus host disease/relapse-free survival (GFRS), and chronic GVHD-free OS (cGVHD-free OS) defined as OS without moderate-to-severe cGVHD. Patients had a median age of 33 years (range, 18-60 years), 23% had refractory disease (SD/PD). Donors were HLA identical (39%), unrelated (30%), or haploidentical (31%). Median follow-up was 6.2 years. Five-year OS was 59% and PFS was 49%. NRM was 16% at 1 year. 44% of patients had cGVHD, and 14% moderate-to-severe cGVHD at last follow-up. GFRS and cGVHD-free OS were 26 and 48% at 5 years. In multivariate analysis, resistant disease at alloSCT impacted survival and GFRS. In conclusion, disease response before alloSCT impacts survival and GFRS. GVHD outcomes may help comparing the long-term effects of the new salvage treatments that bridge patients to alloSCT.


Assuntos
Doença Enxerto-Hospedeiro/epidemiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Doença de Hodgkin/terapia , Recidiva Local de Neoplasia/epidemiologia , Terapia de Salvação/métodos , Adolescente , Adulto , Criança , Resistencia a Medicamentos Antineoplásicos , Feminino , Seguimentos , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/prevenção & controle , Doença de Hodgkin/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/prevenção & controle , Intervalo Livre de Progressão , Qualidade de Vida , Estudos Retrospectivos , Terapia de Salvação/efeitos adversos , Índice de Gravidade de Doença , Análise de Sobrevida , Fatores de Tempo , Condicionamento Pré-Transplante/métodos , Transplante Homólogo/efeitos adversos , Adulto Jovem
18.
Expert Opin Biol Ther ; 18(8): 841-849, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29999431

RESUMO

INTRODUCTION: Hodgkin's lymphoma (HL) patients refractory to first-line therapy or relapsed after autologous stem cell transplantation have a dismal prognosis, and their treatment represents an unmet medical need. Brentuximab vedotin (BV) is a second-generation antibody-drug conjugate (ADC) constituted by an anti-CD30 antibody linked to the cytotoxic drug monomethyl auristatin E. The first administration of BV in relapsed and refractory HL patients in a phase I study showed an impressive antilymphoma activity and prompted development of the drug. Areas covered: This article reviews pharmaceutical characteristics of ADC and specific chemical features of BV related to mechanism of action and mechanism of resistance. Administration recommendation and main toxicities will also be described. Antilymphoma efficacy of BV alone and in combination with conventional chemotherapy and new compounds in different settings of HL patients will be examined. Expert opinion: BV seems to be an effective and safe option for treatment of HL patients. BV alone or in association with chemotherapy as salvage regimen or as bridge to autologous or allogeneic transplant showed encouraging results. Exploration of new drug combinations and new settings of treatment is warranted in order to reduce long-term therapy-related toxicities and ameliorate survival of poor prognosis patients.


Assuntos
Doença de Hodgkin/tratamento farmacológico , Imunoconjugados/uso terapêutico , Antineoplásicos/uso terapêutico , Brentuximab Vedotin , Quimioterapia Adjuvante , Transplante de Células-Tronco Hematopoéticas , Doença de Hodgkin/epidemiologia , Doença de Hodgkin/terapia , Humanos , Prognóstico , Terapia de Salvação/métodos , Resultado do Tratamento
19.
Haematologica ; 103(8): 1351-1358, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29748443

RESUMO

This phase II, single-arm, multicenter study examined the efficacy and safety of coltuximab ravtansine (an anti-CD19 antibody drug conjugate) in 61 patients with histologically documented (de novo or transformed) relapsed or refractory diffuse large B-cell lymphoma who had previously received rituximab-containing immuno-chemotherapy. Patients had received a median of 2.0 (range 0-9) prior treatment regimens for diffuse large B-cell lymphoma and almost half (45.9%) had bulky disease (≥1 lesion >5 cm) at trial entry. Patients received coltuximab ravtansine (55 mg/m2) in 4 weekly and 4 biweekly administrations until disease progression or unacceptable toxicity. Forty-one patients were eligible for inclusion in the per protocol population. Overall response rate (International Working Group criteria) in the per protocol population, the primary end point, was 18/41 [43.9%; 90% confidence interval (CI:) 30.6-57.9%]. Median duration of response, progression-free survival, and overall survival (all treated patients) were 4.7 (range 0.0-8.8) months, 4.4 (90%CI: 3.02-5.78) months, and 9.2 (90%CI: 6.57-12.09) months, respectively. Common non-hematologic adverse events included asthenia/fatigue (30%), nausea (23%), and diarrhea (20%). Grade 3-4 adverse events were reported in 23 patients (38%), the most frequent being hepatotoxicity (3%) and abdominal pain (3%). Eye disorders occurred in 15 patients (25%); all were grade 1-2 and none required a dose modification. Coltuximab ravtansine monotherapy was well tolerated and resulted in moderate clinical responses in pre-treated patients with relapsed/refractory diffuse large B-cell lymphoma. (Registered at: clinicaltrials.gov identifier: 01472887).


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Maitansina/análogos & derivados , Terapia de Salvação/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/farmacologia , Antígenos CD19/análise , Antígenos CD19/efeitos dos fármacos , Antígenos CD19/imunologia , Feminino , Humanos , Imunoconjugados/uso terapêutico , Imunoterapia/métodos , Linfoma Difuso de Grandes Células B/imunologia , Linfoma Difuso de Grandes Células B/mortalidade , Masculino , Maitansina/efeitos adversos , Maitansina/farmacologia , Maitansina/uso terapêutico , Pessoa de Meia-Idade , Rituximab/uso terapêutico , Análise de Sobrevida , Resultado do Tratamento
20.
Clin Cancer Res ; 20(22): 5641-51, 2014 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-25239609

RESUMO

PURPOSE: To evaluate safety and activity of perifosine and sorafenib combination therapy in patients with lymphoproliferative diseases. EXPERIMENTAL DESIGN: Patients with relapsed and refractory lymphoproliferative diseases received perifosine (50 mg twice daily) for 1 month. Patients achieving less than partial response (PR) after perifosine alone were administered the combination therapy [perifosine plus sorafenib (400 mg twice daily)] until progressive disease (PD) or unacceptable toxicity occurred. The pERK and pAKT in peripheral blood lymphocytes as well as serum cytokine levels were investigated as predictive biomarkers of response. RESULTS: Forty patients enrolled in this study. After 1 month of perifosine alone, 36 who achieved less than PR went on to combination therapy, whereas four patients with chronic lymphocytic leukemia (CLL) who achieved PR continued with perifosine alone for a median of 10 months (range, 4-21). The most common drug-related toxicities were grade 1-2 anemia (17%), thrombocytopenia (9%), diarrhea (25%), joint pain (22%), and hand-foot skin reaction (25%). Three patients experienced grade 3 pneumonitis. Eight patients (22%) achieved PR, 15 (42%) achieved stable disease, and 13 (36%) experienced PD. A 28% PR rate was recorded for 25 patients with Hodgkin lymphoma. Among all patients, median overall survival and progression-free survival were 16 and 5 months, respectively. Early reductions in pERK and pAKT significantly correlated with the probability of clinical response. CONCLUSIONS: Perifosine and sorafenib combination therapy is feasible with manageable toxicity and demonstrates promising activity in patients with Hodgkin lymphoma. The predictive value of pERK and pAKT should be confirmed in a larger patient cohort.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transtornos Linfoproliferativos/tratamento farmacológico , Transtornos Linfoproliferativos/patologia , Adolescente , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Biomarcadores/sangue , Biomarcadores/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Humanos , Transtornos Linfoproliferativos/diagnóstico , Transtornos Linfoproliferativos/metabolismo , Transtornos Linfoproliferativos/mortalidade , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Estadiamento de Neoplasias , Niacinamida/administração & dosagem , Niacinamida/análogos & derivados , Compostos de Fenilureia/administração & dosagem , Fosforilcolina/administração & dosagem , Fosforilcolina/análogos & derivados , Proteínas Proto-Oncogênicas c-akt/metabolismo , Recidiva , Sorafenibe , Resultado do Tratamento , Adulto Jovem
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