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1.
Blood Adv ; 2022 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-35008100

RESUMO

Secondary central nervous system large B-cell lymphoma (SCNSL) is rare with a generally poor prognosis. There is limited data about the role of autologous stem cell transplantation (ASCT) in these high-risk patients. We explored in this study treatment outcomes and prognostic factors for patients with SCNSL who underwent ASCT. We included all consecutive patients who underwent ASCT at our institution. Primary endpoints were progression free survival (PFS) and overall survival (OS). One-hundred two patients were identified. Median age at transplant was 56 (range, 21-71) years. With a median follow-up of 56 (range, 1-256) months, the median PFS and OS were 40 and 88 months, respectively. The 4-year PFS and OS were 48% and 57%, respectively. In univariate analysis, complete remission (CR) at transplant, prior lines of therapy (≤2), normal LDH, and parenchymal involvement were significantly associated with improved PFS. For OS, only CR at transplant and ≤2 prior lines of therapy were associated with improved survival. On multivariable analysis for PFS, CR at transplant (HR 0.278, 95% CI: 0.153-0.506; p=<0.0001) and ≤ 2 prior lines of therapy (HR 0.485, 95% CI: 0.274-0.859; p=0.0131) were significantly associated with superior PFS. Similarly, CR at transplant (HR 0.352, 95% CI: 0.186-0.663; p=0.0013) and ≤ 2 prior lines of therapy (HR 0.476, 95% CI: 0.257-0.882; p=0.0183) were associated with improved survival. In the largest single center study, our findings indicate that ASCT is associated with durable responses and prolonged survival in patients with SCNSL. Patients in CR at transplant and those received less than two lines of therapy have particularly excellent outcomes.

2.
Blood Adv ; 2022 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-35015825

RESUMO

About 70% of patients with large B-cell lymphoma (LBCL) treated with axicabtagene ciloleucel (axi-cel) who achieve a partial response (PR) or a stable disease (SD) on day 30 (D30) PET-CT scan progress, but predictive factors of progression are unknown. This a retrospective study of patients with LBCL treated with axi-cel at MD Anderson Cancer Center between 01/2018 and 02/2021. Among 50 patients with D30 PR/SD, 13 (26%) converted to complete response (CR). Among 95 patients with D30 CR, 72 (76%) remained in CR. On univariate analysis, the only day -5 characteristic associated with conversion from D30 PR/SD to subsequent CR was a higher platelet count (p=0.05). The only D30 factor associated with conversion from D30 PR/SD to subsequent CR was lower D30 SUVmax (p<0.001), and all patients with and D30 SUVmax ≥10 progressed. After a median follow-up of 12 months, no significant difference in median progression-free survival was observed when comparing patients who converted from D30 PR/SD to subsequent CR to those who had been in CR since D30 (p=0.19). Novel predictive and prognostic markers based on tissue biopsy and non-invasive diagnostic assays are needed to more effectively identify these patients and characterize the biology of their residual disease.

3.
Cancers (Basel) ; 13(22)2021 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-34830782

RESUMO

T-cell lymphomas are a relatively rare group of malignancies with a diverse range of pathologic features and clinical behaviors. Recent molecular studies have revealed a wide array of different mechanisms that drive the development of these malignancies and may be associated with resistance to therapies. Although widely accepted chemotherapeutic agents and combinations, including stem cell transplantation, obtain responses as initial therapy for these diseases, most patients will develop a relapse, and the median survival is only 5 years. Most patients with relapsed disease succumb within 2 to 3 years. Since 2006, the USFDA has approved five medications for treatment of these diseases, and only anti-CD30-therapy has made a change in these statistics. Clearly, newer agents are needed for treatment of these disorders, and investigators have proposed studies that evaluate agents that target these malignancies and the microenvironment depending upon the molecular mechanisms thought to underlie their pathogenesis. In this review, we discuss the currently known molecular mechanisms driving the development and persistence of these cancers and discuss novel targets for therapy of these diseases and agents that may improve outcomes for these patients.

4.
Blood ; 2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34780598

RESUMO

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening inflammatory syndrome that may complicate hematologic malignancies (HM). The appropriateness of current criteria for diagnosing HLH in the context of HMs is unknown because they were developed for children with familial HLH (HLH-2004) or derived from adult patient cohorts in which HMs were underrepresented (HScore). Moreover, many features of these criteria may directly reflect the underlying HM rather than an abnormal inflammatory state. To improve and potentially simplify HLH diagnosis in patients with HMs, we studied an international cohort of 225 adult patients with various HMs both with and without HLH and for whom HLH-2004 criteria were available. We used classification and regression tree and receiver operating curve analysis to identify the most useful diagnostic and prognostic parameters and optimize laboratory cutoff values. Combined elevation of soluble CD25 (>3,900 U/ml) and ferritin (>1,000 ng/ml) best identified HLH-2004 defining features (sensitivity 84%, specificity 81%). Moreover, this combination, which we term the 'optimized HLH inflammatory' (OHI) index, was highly predictive of mortality (hazard ratio 4.3; confidence interval 3.0-6.2) across diverse HMs. Furthermore, the OHI index identified a large group of patients with high mortality risk that were not defined as having HLH by HLH-2004/HScore. Finally, the OHI demonstrates diagnostic and prognostic value when used for routine surveillance of patients with newly diagnosed HMs as well as those with clinically suspected HLH. Thus, we conclude that the OHI index identifies HM patients with an inflammatory state associated with a high mortality risk and warrants further prospective validation.

5.
Ann Hematol ; 2021 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-34668982

RESUMO

Peripheral T-cell lymphomas (PTCL) are a unique subset of lymphomas with a poor prognosis due to limited treatment options. We performed a phase 1 study of carfilzomib in patients with relapsed/refractory PTCL to determine the safety profile and the maximum tolerated dose (MTD) of this agent. The study was a classical 3 + 3 phase 1 design with intra-patient dose escalation allowed beginning on day 8 of cycle 1 and subsequently. Dose-limiting toxicity (DLT) was defined as the occurrence of any grade 3/4 adverse event. Carfilzomib was given on days 1, 2, 8, 9, 15, and 16 of a 28-day cycle. Fifteen patients were enrolled from 3 centers. The median age of patients was 62. The median number of prior therapies for subjects on this trial was five. The MTD of carfilzomib was 36 mg/m2. Dose-limiting toxicities included anemia and sepsis. Serious adverse events were seen in 45% of patients. Single-agent carfilzomib leads to a complete response in one patient and a partial response in one patient. Overall, the drug was reasonably tolerated for a heavily pretreated population, but the limited response rate and short duration of response demonstrate a lack of promise for carfilzomib as a single agent in this patient population.

8.
Clin Cancer Res ; 27(21): 5847-5856, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34380640

RESUMO

PURPOSE: To compare outcomes between patients with relapsed follicular lymphoma who received a nonmyeloablative allogeneic stem cell transplant (alloSCT) and those who received an autologous transplant (autoSCT). PATIENTS AND METHODS: We evaluated 194 patients with follicular lymphoma who received an alloSCT (n = 98) or autoSCT (n = 96) at MD Anderson Cancer Center (Houston, TX). The transplant type used was based on donor availability and by Medicare reimbursement guidelines. Patients who received an alloSCT were enrolled in four consecutive trials in which they received fludarabine, cyclophosphamide (or bendamustine), and rituximab conditioning. autoSCT patients received R-BEAM (rituximab, carmustine, etoposide, cytarabine, and melphalan). RESULTS: The median follow-up of survivors was 108 months for the alloSCT group and 102 months for the autoSCT group. Overall survival was significantly better for patients who received an alloSCT compared with those who received an autoSCT (62% vs. 46%; P = 0.048). Similarly, progression-free survival rates were 52% in patients who received an alloSCT and 31% in those who received an autoSCT (P < 0.001), and the 8-year relapse rates were 11% and 43%, respectively (P < 0.0001). Only three patients in the alloSCT group relapsed beyond 3.5 years. In the alloSCT group, the rates for grade 2 to 4 acute graft-versus-host disease (GVHD), grade 3 to 4 acute GVHD, and extensive chronic GVHD were 22%, 9%, and 38%, respectively. In the autoSCT group, the 8-year incidence of secondary myelodysplasia was 11%. Nonrelapse mortality was similar between the two groups (15% vs. 11% at 8 years; P = 0.27). CONCLUSIONS: This study shows that alloSCT is curative and confers superior survival compared with autoSCT in patients with follicular lymphoma.

9.
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
10.
Mod Pathol ; 34(12): 2154-2167, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34226673

RESUMO

Breast implant anaplastic large cell lymphoma (ALCL) is a T-cell neoplasm arising around textured breast implants that was recognized recently as a distinct entity by the World Health Organization. Rarely, other types of lymphoma have been reported in patients with breast implants, raising the possibility of a pathogenetic relationship between breast implants and other types of lymphoma. We report eight cases of Epstein-Barr virus (EBV)-positive large B-cell lymphoma associated with breast implants. One of these cases was invasive, and the other seven neoplasms were noninvasive and showed morphologic overlap with breast implant ALCL. All eight cases expressed B-cell markers, had a non-germinal center B-cell immunophenotype, and were EBV+ with a latency type III pattern of infection. We compared the noninvasive EBV+ large B-cell lymphoma cases with a cohort of breast implant ALCL cases matched for clinical and pathologic stage. The EBV+ large B-cell lymphoma cases more frequently showed a thicker capsule, and more often were associated with calcification and prominent lymphoid aggregates outside of the capsule. The EBV+ B-cell lymphoma cells were more often arranged within necrotic fibrinoid material in a layered pattern. We believe that this case series highlights many morphologic similarities between EBV+ large B-cell lymphoma and breast implant ALCL. The data presented suggest a pathogenetic role for breast implants (as well as EBV) in the pathogenesis of EBV+ large B-cell lymphoma. We also provide some histologic findings useful for distinguishing EBV+ large B-cell lymphoma from breast implant ALCL in this clinical setting.

11.
Ophthalmic Epidemiol ; : 1-12, 2021 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-34167454

RESUMO

Aim: To assess the impact of practice patterns amongst global ophthalmologists during severe acute respiratory syndrome Coronavirus 2 (SARS Cov2) causing Corona virus disease (COVID-19) and understand the various modifications made to address emergency surgeries and practice needs.Methods: An online survey was sent to practicing ophthalmologists around the world through email, Whatsapp™ ListServ17.0™ (for pediatric ophthalmologists), WeChat™ (China) and ophthalmology associations (Indonesia, Philippines, Ireland). All queries were collected and categorized. Responses to the queries were given according to the recommendations by the Ophthalmology association. Practices ability to deal with the COVID were also classified according to country and type of access to PPE. Statistical analyses of the association between these data and queries, where appropriate were carried out.Results: One thousand nine hundred sixteen ophthalmologists were invited to participate in a survey between April 10th and April 30th, 2020 of which 1207 responded, which is a response rate of approximately 63%. The majority of respondents were from India, Indonesia, China, Singapore and the USA. Our study indicates a precipitous drop in surgical procedures with 46% (n = 538) ophthalmologists ceased to operate on their patients and almost 40% (n = 486) were doing less than 25% of their original number of surgeries. The intent to resume elective surgeries was a consideration in 41% (n = 495) after an evaluation of the situation and in consultation with professional bodies. More than 2/3 of the respondents (n = 703) made it a priority to use and mandate their patients to practice physical distancing, wearing masks, and hand dis-infection for protection to limit the spread of infection.Conclusion: This global survey provides a real-world assessment of diverse practices that were in various forms of "shut down mode" and circumstances with varying capabilities to deal with COVID. It is unprecedented that the collective wisdom for a curtailment of practice has had an enormous immediate and far reaching implications on the livelihoods of ophthalmologists, their staff, and their families. Nevertheless, ophthalmologists and their staff remain resilient and have adapted to these changes pragmatically.

12.
Surg Pathol Clin ; 14(2): 177-194, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34023099

RESUMO

Primary cutaneous T-cell lymphomas pose a diagnostic challenge for dermatopathologists, hematopathologists, and general surgical pathologists. Recognition of gamma/delta phenotype in cutaneous T proliferations has been enhanced by the availability of antibodies against TCRgamma and delta for immunohistochemistry. Thus, reporting gamma/delta phenotype in a cutaneous T-cell lymphoid proliferation may indicate a significant change in therapy and a challenge for dermatologists and oncologists who treat these patients. Herein, we discuss primary cutaneous gamma/delta T-cell lymphoma, its differential diagnosis, and other skin lymphoid proliferations that may show gamma/delta phenotype. Awareness of the occurrence of gamma/delta phenotype in both T-cell lymphomas and benign lymphoid proliferations involving skin is crucial for a better interpretation of histopathologic findings. Integration of clinical presentation, morphology, immunoprofile, and molecular findings is key for a correct diagnosis and appropriate therapy of lesions displaying gamma/delta T-cell phenotype.


Assuntos
Linfoma Cutâneo de Células T , Neoplasias Cutâneas , Humanos , Linfoma Cutâneo de Células T/diagnóstico , Linfoma Cutâneo de Células T/genética , Fenótipo , Receptores de Antígenos de Linfócitos T gama-delta/genética , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/genética , Linfócitos T
13.
Leukemia ; 35(4): 956-967, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33664464

RESUMO

T-cell lymphomas (TCL) are a group of biologically and clinically heterogenous neoplasms derived from mature T lymphocytes. Recent findings in biology have advanced the classification of these neoplasms; however, clinical investigations based on biologic features have yet to be designed. Two biomarker-driven treatments for TCL are promising: brentuximab vedotin (BV) in combination with chemotherapy or as monotherapy is the standard treatment for newly diagnosed CD30-positive TCL and relapsed/refractory anaplastic large cell lymphoma (ALCL), while ALK inhibitors have induced responses in ALK+ ALCLs. Common genetic alterations in TCL, such as aberrations in PI3K/mTOR, JAK/STAT, and epigenetic regulators are also targetable by pathway inhibitors and HDAC/DNMT inhibitors; however, responses to these treatments as monotherapy are neither satisfactory nor durable, even in patients pre-stratified by several biomarkers. Additional work is needed to extend biology/biomarker-driven treatment in these neoplasms. As T-cell lymphomagenesis is multistep and multifactorial, trials are ongoing to evaluate combination treatments. The focus of this article is to summarize the status and the current role of targeted-based therapy in nodal TCL.


Assuntos
Linfonodos/patologia , Linfoma de Células T/diagnóstico , Linfoma de Células T/tratamento farmacológico , Terapia de Alvo Molecular , Biomarcadores Tumorais , Gerenciamento Clínico , Suscetibilidade a Doenças , Aprovação de Drogas , Predisposição Genética para Doença , Genômica/métodos , Humanos , Imunofenotipagem , Linfonodos/metabolismo , Linfoma de Células T/etiologia , Linfoma de Células T/metabolismo , Terapia de Alvo Molecular/efeitos adversos , Terapia de Alvo Molecular/métodos , Fenótipo , Transdução de Sinais/efeitos dos fármacos
15.
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.

16.
Ann Hematol ; 100(3): 667-673, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33439304

RESUMO

The severe pneumonia caused by the human coronavirus (hCoV)-SARS-CoV-2 has inflicted heavy casualties, especially among the elderly and those with co-morbid illnesses irrespective of their age. The high mortality in African-Americans and males, in general, raises the concern for a possible X-linked mediated process that could affect the viral pathogenesis and the immune system. We hypothesized that G6PD, the most common X-linked enzyme deficiency, associated with redox status, may have a role in severity of pneumonia. Retrospective chart review was performed in hospitalized patients with COVID19 pneumonia needing supplemental oxygen. A total of 17 patients were evaluated: six with G6PD deficiency (G6PDd) and 11 with normal levels. The two groups (normal and G6PDd) were comparable in terms of age, sex, co-morbidities, and laboratory parameters-LDH, IL-6, CRP, and ferritin, respectively. Thirteen patients needed ventilatory support ; 8 in the normal group and 5 in the G6PDd group (72% vs.83%). The main differences indicating increasing severity in normal vs. G6PDd groups included G6PD levels (12.2 vs. 5.6, P = 0.0002), PaO2/FiO2 ratio (159 vs. 108, P = 0.05), days on mechanical ventilation (10.25 vs. 21 days P = 0.04), hemoglobin level (10 vs. 8.1 P = 0.03), and hematocrit (32 vs. 26 P = 0.015). Only one patient with G6PDd died; 16 were discharged home. Our clinical series ascribes a possible biological role for G6PDd in SARS-CoV2 viral proliferation. It is imperative that further studies are performed to understand the interplay between the viral and host factors in G6PDd that may lead to disparity in outcomes. KEY POINTS: • COVID19 studies show higher mortality in men, due to severe pneumonia and ARDS, indicating possible X-linked mediated differences • G6PD, the most common X-linked enzymopathy, highly prevalent in African Americans and Italians, maintains redox homeostasis. • Preclinical studies using G6PD deficient (G6PDd) cells infected with human coronavirus (hCoV), show impaired cellular responses, viral proliferation and worsening oxidative damage. • Retrospective chart review in hospitalized patients with COVID19 pneumonia needing supplemental oxygen shows differences between the two groups (Normal and G6PDd) in hematological indices; the G6PDdgroup demonstrated prolonged PaO2/FiO2 ratio, and longer days on mechanical ventilation indicating the severity of the pneumonia.


Assuntos
COVID-19/complicações , Deficiência de Glucosefosfato Desidrogenase/complicações , Síndrome do Desconforto Respiratório/etiologia , SARS-CoV-2 , Afro-Americanos , COVID-19/sangue , COVID-19/diagnóstico , Teste de Ácido Nucleico para COVID-19 , Contraindicações de Medicamentos , Cuidados Críticos , Feminino , Predisposição Genética para Doença , Deficiência de Glucosefosfato Desidrogenase/sangue , Deficiência de Glucosefosfato Desidrogenase/etnologia , Deficiência de Glucosefosfato Desidrogenase/fisiopatologia , Humanos , Hidroxicloroquina/efeitos adversos , Hidroxicloroquina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Estresse Oxidativo , Respiração Artificial , Síndrome do Desconforto Respiratório/sangue , Síndrome do Desconforto Respiratório/terapia , Estudos Retrospectivos , SARS-CoV-2/isolamento & purificação , Índice de Gravidade de Doença , Distribuição por Sexo
18.
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
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