RESUMO
Plasmablastic lymphoma (PBL) is a rare and clinically aggressive neoplasm that typically occurs in immunocompromised individuals, including those with HIV infection and solid organ allograft recipients. Most prior studies have focused on delineating the clinicopathologic features and genetic attributes of HIV-related PBLs, where MYC deregulation and EBV infection, and more recently, mutations in JAK/STAT, MAP kinase, and NOTCH pathway genes have been implicated in disease pathogenesis. The phenotypic spectrum of post-transplant (PT)-PBLs is not well characterized and data on underlying genetic alterations are limited. Hence, we performed comprehensive histopathologic and immunophenotypic evaluation and targeted sequencing of 18 samples from 11 patients (8 males, 3 females, age range 12-76 years) with PT-PBL; 8 de novo and 3 preceded by other types of PTLDs. PT-PBLs displayed morphologic and immunophenotypic heterogeneity and some features overlapped those of plasmablastic myeloma. Six (55%) cases were EBV+ and 5 (45%) showed MYC rearrangement by fluorescence in situ hybridization. Recurrent mutations in epigenetic regulators (KMT2/MLL family, TET2) and DNA damage repair and response (TP53, mismatch repair genes, FANCA, ATRX), MAP kinase (KRAS, NRAS, HRAS, BRAF), JAK/STAT (STAT3, STAT6, SOCS1), NOTCH (NOTCH1, NOTCH3, SPEN), and immune surveillance (FAS, CD58) pathway genes were observed, with EBV+ and EBV- cases exhibiting similarities and differences in their mutational profiles. Clinical outcomes also varied, with survival ranging from 0-15.9 years postdiagnosis. Besides uncovering the biological heterogeneity of PT-PBL, our study highlights similarities and distinctions between PT-PBLs and PBLs occurring in other settings and reveals potentially targetable oncogenic pathways in disease subsets.
Assuntos
Infecções por Vírus Epstein-Barr , Infecções por HIV , Linfoma Plasmablástico , Adolescente , Adulto , Idoso , Criança , Feminino , Humanos , Imunofenotipagem , Hibridização in Situ Fluorescente , Masculino , Pessoa de Meia-Idade , Linfoma Plasmablástico/etiologia , Linfoma Plasmablástico/genética , Adulto JovemAssuntos
Embolização Terapêutica , Púrpura Trombocitopênica Idiopática , Ruptura Esplênica , Trombocitopenia , Vacinas , Embolização Terapêutica/efeitos adversos , Humanos , Púrpura Trombocitopênica Idiopática/complicações , Púrpura Trombocitopênica Idiopática/terapia , Ruptura Esplênica/diagnóstico por imagem , Ruptura Esplênica/etiologia , Ruptura Esplênica/cirurgia , Trombocitopenia/induzido quimicamente , Trombocitopenia/complicações , Trombocitopenia/terapia , Vacinas/efeitos adversosRESUMO
Peripheral T-cell lymphomas (PTCL) represent a heterogeneous disease group accounting for 10% of non-Hodgkin lymphomas. PTCL patients have typically poorer outcomes compared with aggressive B-cell lymphomas. However, such outcomes are heavily dependent on subtype. Although anthracycline-based regimens such as cyclophosphamide, doxorubicin, vincristine and prednisone remain the standard first-line treatment for most aggressive PTCL, there are important variations including incorporation of novel agents, use of radiotherapy and judicious consideration of stem cell transplantation. Relapsed or refractory disease represents a significant area of unmet need where chemotherapy intensification has limited efficacy and novel agents such as brentuximab vedotin and pralatrexate provide additional opportunities for attainment of remission and potential stem cell transplant. In the future, pre-therapy prognostic biomarkers including genomic characterisation, may aid in risk stratification and help guide initial patient management to improve survival. There is an urgent need to understand better the pathogenesis of PTCL to facilitate novel drug combinatorial approaches to improve survival. This position statement represents an evidence-based synthesis of the literature for application in Australian and New Zealand practice.
Assuntos
Linfoma de Células T Periférico , Humanos , Linfoma de Células T Periférico/diagnóstico , Linfoma de Células T Periférico/terapia , Vincristina/uso terapêutico , Brentuximab Vedotin , Prednisona , Consenso , Seguimentos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Austrália/epidemiologia , Ciclofosfamida/uso terapêutico , Doxorrubicina/uso terapêutico , BiomarcadoresRESUMO
We report the case of a 59-year-old woman with stage IV erythrodermic mycosis fungoides (MF) and large cell transformation who, despite failing multiple previous treatments, achieved complete remission through a combination of pralatrexate and romidepsin followed by allogeneic hematopoietic stem cell transplantation (alloSCT). Further studies are needed in focussing on this combined regimen in treating cutaneous T-cell lymphoma (CTCL) and its efficacy as a bridging regimen in facilitating successful alloSCT.
Assuntos
Aminopterina/análogos & derivados , Antibióticos Antineoplásicos/uso terapêutico , Depsipeptídeos/uso terapêutico , Transplante de Células-Tronco Hematopoéticas , Micose Fungoide/terapia , Neoplasias Cutâneas/terapia , Aminopterina/uso terapêutico , Feminino , Humanos , Pessoa de Meia-Idade , Micose Fungoide/patologia , Indução de Remissão , Neoplasias Cutâneas/patologia , Resultado do TratamentoRESUMO
Primary cutaneous lymphomas represent a heterogeneous group of T- and B-cell lymphomas with distinct clinical presentations, histopathologic features, treatment approaches and outcomes. The cutaneous T-cell lymphomas, which include mycosis fungoides and Sézary syndrome, account for the majority of the cutaneous lymphomas. This Clinical Practice Statement is reflective of the current clinical practice in Australia. An expanded form of the Clinical Practice Statement (and updates), along with helpful patient resources and access to support groups, can be found at the following (http://www.australasianlymphomaalliance.org.au).
Assuntos
Micose Fungoide/diagnóstico , Micose Fungoide/terapia , Síndrome de Sézary/diagnóstico , Síndrome de Sézary/terapia , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/terapia , Biópsia , Testes Hematológicos , Humanos , Micose Fungoide/mortalidade , Estadiamento de Neoplasias , Prognóstico , Síndrome de Sézary/mortalidade , Pele/patologia , Neoplasias Cutâneas/mortalidade , Taxa de SobrevidaRESUMO
We present a retrospective multicenter study of pralatrexate treatment outcomes in an Australian practice setting for patients with relapsed/refractory T-cell lymphoma who had failed 1+ systemic therapies, treated via a compassionate access program. Endpoints assessed included response rates, toxicities, and subsequent therapies. Progression-free survival (PFS), time to next treatment (TTNT), event-free survival (EFS), overall survival (OS), and time to best response, were assessed by Kaplan-Meier analysis. The study included 31 patients, with median age 69 years. We demonstrated ORR of 35.5% (n = 11), including 4 complete responses (13%) and 7 partial responses (23%). The predicted median OS was 10 months, with EFS of 9 months, and PFS of 9 months. Median TTNT was 8 months. Mucositis was the most commonly observed toxicity. This study - the second largest real-world cohort reported to date - underscores the importance of pralatrexate in relapsed/refractory T-cell lymphoma, as well as its acceptable toxicity profile.
Assuntos
Linfoma de Células T , Recidiva Local de Neoplasia , Idoso , Aminopterina/análogos & derivados , Austrália/epidemiologia , Humanos , Linfoma de Células T/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Estudos Retrospectivos , Resultado do TratamentoAssuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Sistema Nervoso Central/efeitos dos fármacos , Fígado/patologia , Linfoma de Células T/tratamento farmacológico , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo , Baço/patologia , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Sistema Nervoso Central/patologia , Doenças do Sistema Nervoso Central/induzido quimicamente , Doenças do Sistema Nervoso Central/diagnóstico por imagem , Resistencia a Medicamentos Antineoplásicos , Evolução Fatal , Feminino , Humanos , Injeções Espinhais , Linfoma de Células T/metabolismo , Linfoma de Células T/patologia , Imageamento por Ressonância Magnética/métodos , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodosRESUMO
OBJECTIVES: To describe three further cases of anaplastic large cell lymphoma (ALCL) occurring in patients with preexisting chronic lymphocytic leukemia (CLL). We also reviewed the literature of previously published cases. METHODS: We discuss the clinical features, histopathology, and outcomes for three patients with ALCL and CLL from Perth, Australia. The cases were also included in a literature review of existing cases and comparisons were made with our cohort. RESULTS: The three patients included two men (aged 77 and 74 years) and one woman (aged 66 years). All had a history of untreated CLL with diagnosis established 4 to 16 years before. They had lymphadenopathy and/or cutaneous/soft tissue lesions that proved to be ALCL, ALK+ (one case) or ALCL, ALK- (two cases). CONCLUSIONS: Further research is required in this area to establish prognostic and management recommendations. Increasing numbers of cases are being described. Positron emission tomography with computed tomography was not useful in our cohort for diagnosing progression.
Assuntos
Leucemia Linfocítica Crônica de Células B/patologia , Linfoma Anaplásico de Células Grandes/patologia , Neoplasias Primárias Múltiplas/patologia , Idoso , Feminino , Humanos , MasculinoRESUMO
We present an analysis of 98 consecutive patients with peripheral T-cell lymphoma (PTCL) treated over a 10-year period within Western Australia. The most common frontline therapies were CHO(E)P (47%), HyperCVAD (21%), and reduced intensity therapy or supportive care alone (19%). Median and 4-year overall survival (OS) for the whole cohort were 1.59 years and 34%. Amongst CHO(E)P and HyperCVAD-treated patients, elevated LDH, advanced stage, IPI >1, and non-ALK + ALCL histology predicted inferior progression-free survival (PFS). Inferior OS was predicted by elevated LDH, age >60, IPI >1, and non-ALK + ALCL histology. Response rates and PFS were not significantly different between patients treated with CHO(E)P or HyperCVAD. OS was longer in the HyperCVAD group, however this was not significant on multivariable analysis and appears to relate to the younger age and more aggressive therapy at relapse in this group. Our data confirmed the prognostic utility of the IPI in patients with PTCL and do not demonstrate a clear benefit of HyperCVAD.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma Anaplásico de Células Grandes/mortalidade , Linfoma de Células T Periférico/mortalidade , Recidiva Local de Neoplasia/mortalidade , Transplante de Células-Tronco/métodos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Terapia Combinada , Feminino , Seguimentos , Humanos , Linfoma Anaplásico de Células Grandes/patologia , Linfoma Anaplásico de Células Grandes/terapia , Linfoma de Células T Periférico/patologia , Linfoma de Células T Periférico/terapia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/terapia , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Austrália Ocidental , Adulto JovemRESUMO
Chronic Lymphocytic Leukaemia (CLL), the most common leukaemia in the Western world, has a characteristic phenotype and prognosis largely defined by the presence of cytogenetic aberrations. The gold standard for detecting these cytogenetic abnormalities is interphase fluorescence in situ hybridisation (FISH) performed on cell smears or tissue sections on glass slides. Fluorescently labelled DNA probes bind to specific chromosomal regions and the signal detected by fluorescent microscopy. Generally only 200 cells are assessed and the limit of sensitivity is 3% positive cells. Here we report the development and use of imaging flow cytometry to assess chromosomes by FISH in phenotyped CLL cells in suspension. Thousands of CLL cells, identified by their phenotype, are assessed for specific FISH probe signals using an automated, high throughput imaging flow cytometer. The "extended depth of field" capability of the imaging flow cytometer enables FISH probe signals ("spots") to be resolved and localised within the (stained) nucleus of the immunophenotyped cells. We report the development of the automated "immuno-flowFISH" on normal blood using the Amnis ImageStreamX mark II platform and illustrate the clinical application of the method for the assessment of chromosome 12 in CLL. It is a powerful new method which has potential to be applied at diagnosis for disease stratification, and following treatment to assess residual disease. These applications will assist clinicians in optimising therapeutic decision making and thereby improve patient outcome.
Assuntos
Citometria de Fluxo/métodos , Hibridização in Situ Fluorescente/métodos , Leucemia Linfocítica Crônica de Células B/diagnóstico por imagem , Linhagem Celular Tumoral , Núcleo Celular/genética , Aberrações Cromossômicas , Humanos , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/patologiaRESUMO
Peripheral T-cell lymphoma (PTCL) is a disease with poor prognosis and limited treatment options. Recent advances in cancer biology suggest that PTCL may be characterized by gross epigenetic dysregulation, which may help explain its sensitivity to histone deacetylase (HDAC) inhibitors. HDAC inhibitors have demonstrated significant activity in T-cell neoplasms and recently, the BELIEF trial evaluated belinostat leading to its approval in the US. This review discusses the development of belinostat, its mechanism of action, pivotal clinical trials, drug toxicity and its recent approval for patients with relapsed or refractory PTCL. Key clinical trials covered include phase I/II evaluation of belinostat in hematologic malignancies, cutaneous T-cell lymphoma (CTCL) and PTCL. In addition, the BELIEF trial in PTCL leading to FDA approval of belinostat is reviewed in detail.
RESUMO
The post-transplant lymphoproliferative disorders (PTLD) comprise a heterogeneous group of lymphocytic and plasma cell proliferations occurring in recipients of tissue allografts in the setting of immunosuppression. We describe our experience of 120 patients with PTLD seen between 1990 and 2009, one of the largest series reported by a single institution. Post-transplant lymphoproliferative disorders characteristics were analysed with regard to paediatric and adult patients, and with regard to the decade of diagnosis, 1990-1999 (pre-rituximab era) versus 2000-2009 (the rituximab era). We present a new prognostic score using the recursive partitioning model, consisting of the Eastern Cooperative Oncology Group (ECOG) score (0-1 vs. 2-4), age [paediatrics (<16 years old), adults (16-60 years old) and elderly (>60 years old)] and CD20 status (positive vs negative); separating patients into 4 risk categories based on overall survival. Low-risk included paediatric patients with ECOG score of 0-1; intermediate-low-risk included adults aged 16-60 years with an ECOG score of 0-1; intermediate-high-risk included elderly patients with an ECOG score 0-1 or paediatric patients and adults aged 16-60 years with an ECOG score of 2-4 and CD20 positive; high-risk group included patients of any age with an ECOG score of 2-4 and CD20 negative, and elderly patients with an ECOG score of 2-4 with CD20-positive PTLD.
Assuntos
Transtornos Linfoproliferativos/mortalidade , Transplante de Órgãos , Complicações Pós-Operatórias/mortalidade , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Terapia Combinada , Infecções por Vírus Epstein-Barr/transmissão , Feminino , Humanos , Imunossupressores/efeitos adversos , Lactente , Transtornos Linfoproliferativos/tratamento farmacológico , Transtornos Linfoproliferativos/terapia , Transtornos Linfoproliferativos/virologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Transplante de Órgãos/efeitos adversos , Complicações Pós-Operatórias/tratamento farmacológico , Complicações Pós-Operatórias/virologia , Prognóstico , Medição de Risco , Rituximab/uso terapêutico , Índice de Gravidade de Doença , Adulto JovemRESUMO
PURPOSE: Pan-class histone deacetylase (HDAC) inhibitors are effective treatments for select lymphomas. Isoform-selective HDAC inhibitors are emerging as potentially more targeted agents. HDAC6 is a class IIb deacetylase that facilitates misfolded protein transport to the aggresome for degradation. We investigated the mechanism and therapeutic impact of the selective HDAC6 inhibitor ACY-1215 alone and in combination with bortezomib in preclinical models of lymphoma. EXPERIMENTAL DESIGN: Concentration-effect relationships were defined for ACY-1215 across 16 lymphoma cell lines and for synergy with bortezomib. Mechanism was interrogated by immunoblot and flow cytometry. An in vivo xenograft model of DLBCL was used to confirm in vitro findings. A collection of primary lymphoma samples were surveyed for markers of the unfolded protein response (UPR). RESULTS: Concentration-effect relationships defined maximal cytotoxicity at 48 hours with IC50 values ranging from 0.9 to 4.7 µmol/L. Strong synergy was observed in combination with bortezomib. Treatment with ACY-1215 led to inhibition of the aggresome evidenced by acetylated α-tubulin and accumulated polyubiquitinated proteins and upregulation of the UPR. All pharmacodynamic effects were enhanced with the addition of bortezomib. Findings were validated in vivo where mice treated with the combination demonstrated significant tumor growth delay and prolonged overall survival. Evaluation of a collection of primary lymphoma samples for markers of the UPR revealed increased HDAC6, GRP78, and XBP-1 expression as compared with reactive lymphoid tissue. CONCLUSIONS: These data are the first results to demonstrate that dual targeting of protein degradation pathways represents an innovative and rational approach for the treatment of lymphoma.
Assuntos
Antineoplásicos/farmacologia , Bortezomib/farmacologia , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/metabolismo , Ácidos Hidroxâmicos/farmacologia , Linfoma/tratamento farmacológico , Pirimidinas/farmacologia , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sinergismo Farmacológico , Chaperona BiP do Retículo Endoplasmático , Desacetilase 6 de Histona , Humanos , Linfoma/metabolismo , Camundongos , Camundongos SCID , Proteólise , Tubulina (Proteína)/metabolismoRESUMO
Despite enormous advances in our understanding of aggressive lymphomas, it is clear that progress in the peripheral T-cell lymphomas (PTCL) has lagged well behind other B-cell malignancies. Although there are many reasons for this, the one commonly cited notes that the paradigms for diffuse large B-cell lymphoma (DLBCL) were merely applied to all patients with PTCL, the classic "one-size-fits-all" approach. Despite these challenges, progress is being made. Recently, the FDA has approved four drugs for patients with relapsed/refractory PTCL over the past 5 years, and if one counts the recent Japanese approval of the anti-CCR4 monoclonal antibody for patients with adult T-cell leukemia/lymphoma, five drugs have been approved worldwide. These efforts have led to the initiation of no fewer than four randomized clinical studies exploring the integration of these new agents into standard CHOP (cyclophosphamide-Adriamycin-vincristine-prednisone)-based chemotherapy regimens for patients with newly diagnosed PTCL. In addition, a new wave of studies are exploring the merits of novel drug combinations in the disease, an effort to build on the obvious single-agent successes. What has emerged most recently is the recognition that the PTCL may be a disease-characterized by epigenetic dysregulation, which may help explain its sensitivity to histone deacetylase (HDAC) inhibitors, and open the door for even more creative combination approaches. Nonetheless, advances made over a relatively short period of time are changing how we now view these diseases and, hopefully, have poised us to finally improve its prognosis. See all articles in this CCR Focus section, "Paradigm Shifts in Lymphoma."
Assuntos
Linfoma de Células T Periférico/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Predisposição Genética para Doença , Transplante de Células-Tronco Hematopoéticas , Humanos , Linfoma de Células T Periférico/etiologia , Linfoma de Células T Periférico/patologia , Recidiva Local de NeoplasiaRESUMO
PURPOSE: We report that hemodialysis clears Ara-U from the blood after high-dose Ara-C treatment in a patient with lymphoma and end-stage renal failure. METHODS: The patient received two doses of Ara-C 1 g/m(2) 24 h apart and was hemodialyzed at about 6 h after each dose and subsequently as per her usual dialysis schedule. Multiple blood samples were collected after dosing. Blood and dialyzate were also collected from the dialysis circuit during a second identical treatment cycle. Ara-C and its metabolite Ara-U in plasma and dialyzate were measured chromatographically, and the data subjected to pharmacokinetic analysis. RESULTS: The distribution and elimination half-lives, steady-state volume of distribution and clearance values were 0.5 h, 7 h, 181 L and 307 l/h for Ara-C and 4.1 h, 34 h, 118 L and 2.64 l/h for Ara-U, respectively. The dialysis sessions immediately after the first and second doses cleared 39 and 52% (as Ara-U) of the respective Ara-C doses. Some 63% of Ara-U in plasma was extracted by dialysis. The patient showed no signs of neurotoxicity or other drug-related adverse effects. CONCLUSION: Hemodialysis is very effective in clearing Ara-U from the plasma in renal failure, and this maneuver could easily be used routinely to prevent Ara-U accumulation and minimize adverse effects in patients with renal failure.