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Diffuse large B-cell lymphoma (DLBCL) is the most common and aggressive subtype of non-Hodgkin lymphoma. The overall risk of developing DLBCL is increased in patients with other lymphomas, such as mycosis fungoides (MF). In this report, we present an 81-year-old female with early-stage MF who simultaneously progressed to tumor stage, large-cell transformed (LCT) MF and developed a primary DLBCL in a lymph node (LN). She presented with a tumor on her leg and new lymphadenopathy in her right axilla. Skin biopsy of the tumor revealed infiltration of large atypical CD3+, CD4+, and CD30+ cells, and a smaller portion of CD8+ cells in the dermis, consistent with LCT MF. Biopsy of the axillary LN revealed diffuse sheets of CD20+, BCL-2+, c-MYC+, and CD10- cells, highly suggestive of double expressor DLBCL. High-throughput sequencing revealed monoclonal T cells in the skin tumor and a monoclonal B-cell population in the LN. The above findings led to simultaneous diagnoses of LCT MF and nodal double expressor DLBCL. Our case demonstrates the importance of performing a full pathological workup in cutaneous T-cell lymphoma patients presenting with lymphadenopathy.
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ABSTRACT: We report a 48-year-old man with CD30+ large cell transformation of mycosis fungoides (tMF) with distinctive anaplastic morphology. The patient initially presented with folliculotropic and syringotropic mycosis fungoides (MF) manifested as occipital scalp plaque and trunk and extremities patches. Six years later, he progressed to the tumor stage from his scalp lesion and developed cervical lymphadenopathy. Lymph node and scalp biopsies showed diffuse infiltration of CD30+ anaplastic cells with multinucleated, hallmark-like, Hodgkin-Reed-Sternberg-like, histiocytoid forms, indistinguishable from anaplastic large cell lymphoma (ALCL). T-cell receptor gamma gene (TCRg) rearrangement studies revealed identical clones in the initial MF scalp lesion and nodal anaplastic lesion, confirming the transformation. Ancillary studies showed absence of IRF4/DUSP22 and ALK rearrangements and positive RB1, SMARCA4, SOCS1, and TP53 mutations. The patient achieved partial response with systemic chemotherapy. Our case is an example of tMF presenting as the morphology and phenotype of ALCL. Because clinical behavior and therapeutic options of tMF and primary cutaneous ALCL may be different, it is clinically relevant to differentiate these 2 entities. The proof of clonal relationship may be useful in diagnostically challenging cases with features overlapping between tMF and primary cutaneous ALCL.
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Micose Fungoide , Neoplasias Cutâneas , Masculino , Humanos , Micose Fungoide/genética , Biópsia , Células Clonais , Extremidades , Neoplasias Cutâneas/genética , DNA Helicases , Proteínas Nucleares , Fatores de TranscriçãoRESUMO
The use of cyclophosphamide (CY) for bidirectional tolerization of recipient and donor T cells is associated with reduced rates of graft-versus-host disease (GVHD) and nonrelapse mortality (NRM) after HLA-matched hematopoietic stem cell transplantation (HSCT). However, recurrent disease remains the primary barrier to long-term survival. We extended our 2-step approach to HLA-matched related HSCT using a radiation-based myeloablative conditioning regimen combined with a high dose of T cells in an attempt to reduce relapse rates while maintaining the beneficial effects of CY tolerization. After conditioning, patients received their grafts in 2 components: (1) a fixed dose of 2 × 108/kg T cells, followed 2 days later by CY, and (2) a CD34-selected graft containing a small residual amount of non-CY-exposed T cells, at a median dose of 2.98 × 103/kg. Forty-six patients with hematologic malignancies were treated. Despite the myeloablative conditioning regimen and use of high T cell doses, the cumulative incidences of grade II-IV acute GVHD, chronic GVHD, and NRM at 1 year and 5 years were very low, at 13%, 9%, and 4.3%, respectively. This contributed to a high overall survival of 89.1% at 1 year and 65.8% at 5 years. Relapse was the primary cause of mortality, with a cumulative incidence of 23.9% at 1 year and 45.7% at 5 years. In a post hoc analysis, relapse rates were significantly lower in patients receiving greater than versus those receiving less than the group median of non-CY-exposed residual T cells in the CD34 product (19.3% versus 58.1%; P = .009), without a concomitant increase in NRM. In its current form, this 2-step regimen was highly tolerable, but strategies to reduce relapse, potentially the addition of T cells not exposed to CY, are needed.
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Doença Enxerto-Hospedeiro , Neoplasias Hematológicas , Transplante de Células-Tronco Hematopoéticas , Ciclofosfamida/uso terapêutico , Intervalo Livre de Doença , Doença Enxerto-Hospedeiro/prevenção & controle , Neoplasias Hematológicas/terapia , Humanos , Recidiva Local de Neoplasia , Linfócitos T , Condicionamento Pré-TransplanteRESUMO
BACKGROUND: Low-dose total skin electron beam therapy (TSEBT) for mycosis fungoides is popular because of reduced toxicity with effective palliation. We condensed TSEBT, reducing visits by half and overall treatment length by one third. OBJECTIVE: To determine the efficacy and safety of a novel condensed low-dose TSEBT for mycosis fungoides. METHODS: We conducted a cohort study (2014-2018) with a median follow-up of 22.8 months. We delivered 12 Gy per 6 fractions with the modified Stanford technique, 3 fractions per week, with boosts to shadowed sites at risk between treatments, completing in 2 weeks. Primary outcomes included clinical response, duration of and time to response, and toxicity. Secondary outcomes included patient-reported quality of life (pain, pruritus, and Dermatology Life Quality Index) and physician-scored disease burden (body surface area involvement and Modified Skin Weighted Assessment Tool). RESULTS: Of 25 patients, stage IB was most common at the time of TSEBT (36%). The overall response rate was 88%. Most common was a near complete response (36%), and complete response was achieved in 6 (24%) patients. The median duration of response was 17.5 months (3.5-44.2), and the median time to response was 2 months (range, 0.9-4.1). No patients had toxicity of grade 3 or greater. QOL and disease burden showed significant benefit after TSEBT (P < .001). LIMITATIONS: Cohort study with limited sample size. CONCLUSIONS: Condensed, low-dose TSEBT has favorable outcomes and toxicity with logistical convenience.
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Efeitos Psicossociais da Doença , Micose Fungoide/radioterapia , Qualidade de Vida , Adulto , Idoso , Idoso de 80 Anos ou mais , Fracionamento da Dose de Radiação , Elétrons/efeitos adversos , Elétrons/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Resultado do TratamentoRESUMO
Peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) is a World Health Organization (WHO)-defined diagnostic category within the highly heterogeneous group of mature post-thymic T-cell neoplasms. It is the most common subtype of mature post-thymic T-cell neoplasms globally, accounting for up to 35% of PTCL cases in Europe and North America. PTCL-NOS is a diagnosis of exclusion, comprising several disease entities that differ in biology, clinical presentation, and outcome. The diagnosis of PTCL-NOS is made based on the presence of typical histopathological features of lymphoma, an aberrant T-cell immunophenotype, often with a loss of CD5 and CD7, and a clonal T-cell receptor (TCR) gene rearrangement, in the appropriate clinical context. Unlike other types of T-cell lymphoma, recurrent mutations to assist with the diagnosis have not been identified. Patients often present with advanced stage. Prognosis is poor, with a 5-year overall survival (OS) of 20-30%. Anthracycline-based combination chemotherapy remains the most frequently used frontline strategy, with overall response rates (ORR) of 50-60%, and complete response rates (CRR) of 20-30%. Prospective studies with intent-to-treat analyses have shown that consolidation with high-dose chemotherapy and autologous stem cell transplant (ASCT) results in progression-free survivals (PFS) that compare favorably with historical cohorts and may improve OS in selected patient populations. However, randomized data are still lacking. Over the past decade, therapeutic agents approved in the relapsed and refractory setting have produced response rates of up to 33% and median PFS up to 18 months. Overall, outcomes remain poor and there is a dire need for more effective treatments. This review discusses the latest information on the diagnosis and treatment of PTCL-NOS.
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Linfoma de Células T Periférico , Protocolos de Quimioterapia Combinada Antineoplásica , Humanos , Linfoma de Células T Periférico/diagnóstico , Linfoma de Células T Periférico/tratamento farmacológico , Prognóstico , Estudos Prospectivos , Transplante de Células-Tronco , Resultado do TratamentoRESUMO
CD8 T-cell lymphomas comprise a wide spectrum of lymphomas, many which have yet to be formally classified. We present a case of a 43-year-old woman with an enlarging tumor distal to the distal interphalangeal joint of the fourth finger, compressing the underlying nail matrix. Magnetic resonance imaging showed bony involvement of the underlying distal phalanx. Histology showed a dense epidermotropic and pandermal infiltrate composed of medium-sized, uniformly pleomorphic lymphocytes with cleaved nuclei, which raised the possibility of primary cutaneous CD8 aggressive epidermotropic cytotoxic T-cell lymphoma. However, the patient's clinical photograph was inconsistent with this diagnosis. Other diagnoses, such as primary cutaneous acral CD8 T-cell lymphoma-a provisional entity, were also considered but did not capture all the features of this patient's lymphoma. We propose to classify this case as a primary cutaneous CD8 T-cell lymphoma, an indolent and locally aggressive form.
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Linfócitos T CD8-Positivos/patologia , Linfoma Cutâneo de Células T/patologia , Paroniquia/diagnóstico , Neoplasias Cutâneas/diagnóstico , Adulto , Diagnóstico Diferencial , Feminino , Dedos/patologia , Humanos , Linfoma Cutâneo de Células T/diagnóstico , Paroniquia/patologia , Neoplasias Cutâneas/patologiaRESUMO
Haploidentical stem cell transplantation (SCT) offers a transplantation option to patients who lack an HLA-matched donor. We developed a 2-step approach to myeloablative allogeneic hematopoietic stem cell transplantation for patients with haploidentical or matched related (MR) donors. In this approach, the lymphoid and myeloid portions of the graft are administered in 2 separate steps to allow fixed T cell dosing. Cyclophosphamide is used for T cell tolerization. Given a uniform conditioning regimen, graft T cell dose, and graft-versus-host disease (GVHD) prophylaxis strategy, we compared immune reconstitution and clinical outcomes in patients undergoing 2-step haploidentical versus 2-step MR SCT. We retrospectively compared data on patients undergoing a 2-step haploidentical (n = 50) or MR (n = 27) peripheral blood SCT for high-risk hematological malignancies and aplastic anemia. Both groups received myeloablative total body irradiation conditioning. Immune reconstitution data included flow cytometric assessment of T cell subsets at day 28 and 90 after SCT. Both groups showed comparable early immune recovery in all assessed T cell subsets except for the median CD3/CD8 cell count, which was higher in the MR group at day 28 compared with that in the haploidentical group. The 3-year probability of overall survival was 70% in the haploidentical group and 71% in the MR group (P = .81), while the 3-year progression-free survival was 68% in the haploidentical group and 70% in the MR group (P = .97). The 3-year cumulative incidence of nonrelapse mortality was 10% in the haploidentical group and 4% in the MR group (P = .34). The 3-year cumulative incidence of relapse was 21% in the haploidentical group and 27% in the MR group (P = .93). The 100-day cumulative incidence of overall grades II to IV acute GVHD was higher in the haploidentical group compared with that in the MR group (40% versus 8%, P < .001), whereas the grades III and IV acute GVHD was not statistically different between both groups (haploidentical, 6%; MR, 4%; P = .49). The cumulative incidence of cytomegalovirus reactivation was also higher in the haploidentical group compared to the MR group (haploidentical, 68%; MR, 19%; P < .001). There were no deaths from GVHD in either group. Using an identical conditioning regimen, graft T cell dose, and GVHD prophylaxis strategy, comparable early immune recovery and clinical outcomes were observed in the 2-step haploidentical and MR SCT recipients.
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Anemia Aplástica/terapia , Doadores de Sangue , Doença Enxerto-Hospedeiro/prevenção & controle , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco de Sangue Periférico , Linfócitos T/transplante , Condicionamento Pré-Transplante , Doença Aguda , Adulto , Idoso , Aloenxertos , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Taxa de SobrevidaRESUMO
Haploidentical hematopoietic stem cell transplantation (HSCT) is an attractive alternative donor option based on the rapid availability of an acceptable donor for most patients and decreased cost compared with costs of other alternative donor strategies. The safety of haploidentical HSCT has increased in recent years, making it ethically feasible to offer to patients with earlier stage disease. We developed a 2-step approach to haploidentical HSCT that separates the lymphoid and myeloid portions of the graft, allowing fixed T cell dosing to improve consistency in outcome comparisons. In the initial 2-step trial, the subset of patients without morphologic disease at HSCT had high rates of disease-free survival. To confirm these results, 28 additional patients without evidence of their disease were treated and are now 15 to 45 (median, 31) months past HSCT. To date, the 2-year cumulative incidence of nonrelapse mortality is 3.6%, with only 1 patient dying of nonrelapse causes, confirming the safety of this approach. Based on low regimen toxicity, the probabilities of disease-free and overall survival at 2 years are 74% and 77%, respectively, consistent with the findings in the initial trial and supporting the use of this approach in earlier stage patients lacking a matched related donor.
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Neoplasias Hematológicas/mortalidade , Neoplasias Hematológicas/terapia , Adulto , Idoso , Aloenxertos , Intervalo Livre de Doença , Feminino , Neoplasias Hematológicas/patologia , Transplante de Células-Tronco Hematopoéticas , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Taxa de Sobrevida , Doadores de TecidosRESUMO
BACKGROUND: The panniculitic T-cell lymphomas (TCLs) comprise 2 distinct entities, αß subcutaneous panniculitis-like TCL (SPTCL) and the γδ cutaneous TCLs with pannicular involvement primary cutaneous γδ (PCGD)-TCL. Although outcomes for most patients with SPTCL are favorable, those with PCGD-TCLs generally have an inferior outcome, and treatment strategies have not been well defined. Allogeneic hematopoietic stem cell transplantation (HSCT) has been shown to be a potentially curative strategy in aggressive TCLs and in refractory and advanced-stage mycosis fungoides. OBJECTIVE: We sought to analyze the outcomes of HSCT for panniculitic cutaneous TCL. RESULTS: Fourteen patients (4 SPTCL, 10 PCGD-TCL) presented with primarily pannicular T-cell infiltrates. Seven patients underwent allogeneic HSCT from matched-related donors and matched-unrelated donors of which 4 (57%) are alive (1 SPTCL, 3 PCGD-TCL) at 7.8, 6.9, 6.2, and 0.25 years. Two patients underwent autologous HSCT (1 SPTCL, 1 PCGD-TCL) and both are alive at a median follow-up of 1.91 years. LIMITATIONS: This study is limited by its retrospective nature and small sample size because of the rarity of SPTCL and PCGD-TCL. CONCLUSION: Aggressive therapy followed by allogeneic HSCT is a promising treatment modality for patients with PCGD-TCL.
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Transplante de Células-Tronco Hematopoéticas/métodos , Linfoma Cutâneo de Células T/cirurgia , Linfoma de Células T/cirurgia , Paniculite/cirurgia , Neoplasias Cutâneas/cirurgia , Adulto , Idoso , Aloenxertos , Autoenxertos , Biópsia por Agulha , Feminino , Seguimentos , Rejeição de Enxerto , Sobrevivência de Enxerto , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Imuno-Histoquímica , Linfoma de Células T/diagnóstico por imagem , Linfoma de Células T/patologia , Linfoma Cutâneo de Células T/diagnóstico por imagem , Linfoma Cutâneo de Células T/patologia , Masculino , Pessoa de Meia-Idade , Paniculite/diagnóstico por imagem , Paniculite/patologia , Tomografia por Emissão de Pósitrons/métodos , Estudos Retrospectivos , Medição de Risco , Estudos de Amostragem , Neoplasias Cutâneas/diagnóstico por imagem , Neoplasias Cutâneas/patologia , Resultado do TratamentoRESUMO
Immune deficiency, together with its associated risks such as infections, is becoming an increasingly important clinical problem owing to the ageing of the general population and the increasing number of patients with HIV/AIDS, malignancies (especially those treated with intensive chemotherapy or radiotherapy) or transplants (of either solid organs or haematopoietic stem cells). Of all immune cells, T cells are the most often affected, leading to a prolonged deficiency of T cells, which has important clinical consequences. Accordingly, strategies to improve the recovery and function of T cells, as we discuss here, should have a direct impact on reducing the morbidity and mortality of many patients and should increase the efficacy of therapeutic and prophylactic vaccinations against microbial pathogens or tumours.
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Doenças do Sistema Imunitário/terapia , Linfócitos T/imunologia , Transferência Adotiva , Animais , Citocinas/imunologia , Substâncias de Crescimento/uso terapêutico , Hormônios/uso terapêutico , Humanos , Doenças do Sistema Imunitário/imunologia , Camundongos , Transplante de Células-Tronco , Timo/imunologiaRESUMO
The poor prognosis for patients with diffuse large B cell lymphoma (DLBCL) who relapse within 1 year of initial diagnosis after first-line rituximab-based chemo-immunotherapy has created controversy about the role of autologous transplantation (HCT) in this setting. We compared autologous HCT outcomes for chemosensitive DLBCL patients between 2000 and 2011 in 2 cohorts based on time to relapse from diagnosis. The early rituximab failure (ERF) cohort consisted of patients with primary refractory disease or those with first relapse within 1 year of initial diagnosis. The ERF cohort was compared with those relapsing >1 year after initial diagnosis (late rituximab failure [LRF] cohort). ERF and LRF cohorts included 300 and 216 patients, respectively. Nonrelapse mortality (NRM), progression/relapse, progression-free survival (PFS), and overall survival (OS) of ERF versus LRF cohorts at 3 years were 9% (95% confidence interval [CI], 6% to 13%) versus 9% (95% CI, 5% to 13%), 47% (95% CI, 41% to 52%) versus 39% (95% CI, 33% to 46%), 44% (95% CI, 38% to 50%) versus 52% (95% CI, 45% to 59%), and 50% (95% CI, 44% to 56%) versus 67% (95% CI, 60% to 74%), respectively. On multivariate analysis, ERF was not associated with higher NRM (relative risk [RR], 1.31; P = .34). The ERF cohort had a higher risk of treatment failure (progression/relapse or death) (RR, 2.08; P < .001) and overall mortality (RR, 3.75; P <.001) within the first 9 months after autologous HCT. Beyond this period, PFS and OS were not significantly different between the ERF and LRF cohorts. Autologous HCT provides durable disease control to a sizeable subset of DLBCL despite ERF (3-year PFS, 44%) and remains the standard-of-care in chemosensitive DLBCL regardless of the timing of disease relapse.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/métodos , Linfoma Difuso de Grandes Células B/terapia , Condicionamento Pré-Transplante/métodos , Adulto , Idoso , Anticorpos Monoclonais Murinos/administração & dosagem , Estudos de Coortes , Progressão da Doença , Intervalo Livre de Doença , Feminino , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Prognóstico , Rituximab , Condicionamento Pré-Transplante/efeitos adversos , Transplante Autólogo , Falha de Tratamento , Resultado do Tratamento , Adulto JovemRESUMO
Anaplastic large cell lymphoma (ALCL) is a CD30+ peripheral T-cell lymphoma with a clinical spectrum including cutaneous and systemic presentations. While primary cutaneous ALCL (pcALCL) has a favorable prognosis, systemic ALCL (sALCL) has poorer survival outcomes. Expression of anaplastic lymphoma kinase (ALK) by malignant cells has been suggested to distinguish sALCL from pcALCL. However, there have been documented cases of ALK-positive ALCL confined to the skin. The present study reviewed characteristics of published cutaneous ALK-positive ALCL cases to distinguish between these two entities. In 23 identified adults with ALK-positive pcALCL, 26% developed systemic involvement and 74% had skin-limited disease. In 14 pediatric patients, 36% had both cutaneous and systemic involvement and 64% had cutaneous disease only. This analysis revealed that pcALCL and sALCL could not reliably be distinguished by ALK expression or nuclear vs. cytoplasmic localization. Localized treatment with frequent monitoring may be sufficient in ALK-positive pcALCL until there is evidence of progression. Physicians should be aware of the overall spectrum of ALCL, including cutaneous limited disease, systemic disease, disease with NPM-ALK translocation, disease with ALK positivity and disease with skin recurrence.
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Immunoincompetence after allogeneic hematopoietic stem cell transplantation (HSCT) affects in particular the T-cell lineage and is associated with an increased risk for infections, graft failure and malignant relapse. To generate large numbers of T-cell precursors for adoptive therapy, we cultured mouse hematopoietic stem cells (HSCs) in vitro on OP9 mouse stromal cells expressing the Notch-1 ligand Delta-like-1 (OP9-DL1). We infused these cells, together with T-cell-depleted mouse bone marrow or purified HSCs, into lethally irradiated allogeneic recipients and determined their effect on T-cell reconstitution after transplantation. Recipients of OP9-DL1-derived T-cell precursors showed increased thymic cellularity and substantially improved donor T-cell chimerism (versus recipients of bone marrow or HSCs only). OP9-DL1-derived T-cell precursors gave rise to host-tolerant CD4+ and CD8+ populations with normal T-cell antigen receptor repertoires, cytokine secretion and proliferative responses to antigen. Administration of OP9-DL1-derived T-cell precursors increased resistance to infection with Listeria monocytogenes and mediated significant graft-versus-tumor (GVT) activity but not graft-versus-host disease (GVHD). We conclude that the adoptive transfer of OP9-DL1-derived T-cell precursors markedly enhances T-cell reconstitution after transplantation, resulting in GVT activity without GVHD.
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Transferência Adotiva , Transplante de Células-Tronco Hematopoéticas , Células-Tronco/fisiologia , Linfócitos T/imunologia , Linfócitos T/fisiologia , Animais , Técnicas de Cocultura , Fator 7 de Crescimento de Fibroblastos/farmacologia , Doença Enxerto-Hospedeiro/imunologia , Efeito Enxerto vs Tumor/imunologia , Listeriose/imunologia , Depleção Linfocítica , Camundongos , Regeneração , Linfócitos T/efeitos dos fármacosRESUMO
Chemotherapy remains a primary treatment for younger AML patients, though many relapse. Data from our group have shown that highly phosphorylated S6 in blasts may predict response to sirolimus given with chemotherapy. We report the results of a phase I study of this combination in newly diagnosed AML and the pharmacodynamic analysis of pS6 before and after treatment. Subjects received sirolimus (12 mg on day 1, 4 mg daily, days 2-10), then idarubicin and cytarabine (days 4-10). Response was assessed at hematologic recovery or by day 42 using a modified IWG criteria. Fifty-five patients received sirolimus. Toxicity was similar to published 7 + 3 data, and 53% had high-, 27% intermediate-, and 20% favorable-risk disease. Forty-four percent of the high-risk patients entered into CR/CRp. Seventy-nine percent of the intermediate-risk subjects had a CR/CRp. All favorable-risk patients had a CR by day 42; 9/11 remained alive and in remission with a median follow-up of 660 days. Additionally, 41/55 patients had adequate samples for pharmacodynamic analysis. All patients demonstrated activation of S6 prior to therapy, in contrast to 67% seen in previous studies of relapsed AML. mTORC1 inhibition was observed in 66% of patients without enrichment among patients who achieved remission. We conclude that sirolimus and 7 + 3 is a well-tolerated and safe regimen. mTORC1 appears to be activated in almost all patients at diagnosis of AML. Inhibition of mTORC1 did not differ based on response, suggesting that AML cells may have redundant signaling pathways that regulate chemosensitivity in the presence of mTORC1 inhibition.
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Lymphomas are not infrequently associated with the Epstein-Barr virus (EBV), and EBV positivity is linked to worse outcomes in several subtypes. Nanatinostat is a class-I selective oral histone deacetylase inhibitor that induces the expression of lytic EBV BGLF4 protein kinase in EBV+ tumor cells, activating ganciclovir via phosphorylation, resulting in tumor cell apoptosis. This phase 1b/2 study investigated the combination of nanatinostat with valganciclovir in patients aged ≥18 years with EBV+ lymphomas relapsed/refractory to ≥1 prior systemic therapy with no viable curative treatment options. In the phase 1b part, 25 patients were enrolled into 5 dose escalation cohorts to determine the recommended phase 2 dose (RP2D) for phase 2 expansion. Phase 2 patients (n = 30) received RP2D (nanatinostat 20 mg daily, 4 days per week with valganciclovir 900 mg orally daily) for 28-day cycles. The primary end points were safety, RP2D determination (phase 1b), and overall response rate (ORR; phase 2). Overall, 55 patients were enrolled (B-non-Hodgkin lymphoma [B-NHL], [n = 10]; angioimmunoblastic T-cell lymphoma-NHL, [n = 21]; classical Hodgkin lymphoma, [n = 11]; and immunodeficiency-associated lymphoproliferative disorders, [n = 13]). The ORR was 40% in 43 evaluable patients (complete response rate [CRR], 19% [n = 8]) with a median duration of response of 10.4 months. For angioimmunoblastic T-cell lymphoma-NHL (n = 15; all refractory to the last prior therapy), the ORR/CRR ratio was 60%/27%. The most common adverse events were nausea (38% any grade) and cytopenia (grade 3/4 neutropenia [29%], thrombocytopenia [20%], and anemia [20%]). This novel oral regimen provided encouraging efficacy across several EBV+ lymphoma subtypes and warrants further evaluation; a confirmatory phase 2 study (NCT05011058) is underway. This phase 1b/2 study is registered at www.clinicaltrials.gov as #NCT03397706.
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Infecções por Vírus Epstein-Barr , Linfoma não Hodgkin , Linfoma de Células T , Linfoma , Trombocitopenia , Humanos , Adolescente , Adulto , Valganciclovir/uso terapêutico , Herpesvirus Humano 4 , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/tratamento farmacológico , Inibidores de Histona Desacetilases/uso terapêutico , Recidiva Local de Neoplasia , Linfoma não Hodgkin/tratamento farmacológico , Linfoma/tratamento farmacológico , Trombocitopenia/patologiaRESUMO
We established double-haploidentical (DH) hematopoietic stem cell transplantation (HSCT) murine models to explore competitive engraftment, graft-versus-graft effect and graft-versus-host disease (GVHD). T cell-depleted (TCD) bone marrow (BM) cells from B6SJF1 (donor 1 [D1]) and B6D2F1 (donor 2 [D2]) mice achieved >90% donor engraftment when transplanted into B6CBAF1 mice. B6CBAF1 recipients survived without evidence of GVHD when undergoing HSCT with TCD-BM from 2 haploidentical donors, D1 and D2. DH-HSCT recipients had significantly higher leukocyte and neutrophil counts than single-haploidentical HSCT recipients from either D1 or D2. DH recipients consistently showed successful mixed chimerism in both BM and spleen. Two other DH-HSCT models, B6D2F1 + C3D2F1âB6C3F1 and B6CBAF1 + B6SJLF1âB6D2F1, showed similar engraftment patterns. Low-dose T cell infusion from both D1 and D2 increased the degree of early engraftment of the respective donors in BM and spleen; however, this early engraftment pattern did not determine long-term engraftment dominance. In the long term, minimally engrafted D1 BM recovered and comprised >50% of all donor- derived B, T, and natural killer cells. We conclude that early BM engraftment is determined by donor T cell immunodominance, but long-term engraftment is related to the engraftment potential of stem cells after DH-HSCT.
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Células da Medula Óssea/imunologia , Transplante de Medula Óssea/imunologia , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/métodos , Animais , Modelos Animais de Doenças , Feminino , Sobrevivência de Enxerto/imunologia , Haplótipos , Camundongos , Camundongos Endogâmicos C57BL , Doadores de TecidosRESUMO
Alloreactive T cells are crucial for graft-versus-host disease (GVHD) pathophysiology, and modulating their trafficking patterns has been efficacious in ameliorating experimental disease. We report in this paper that P-selectin, a glycoprotein found on resting and inflamed endothelium, is important for donor alloreactive T cells trafficking into GVHD target organs, such as the intestines and skin. Compared with wild-type (WT) recipients of allogeneic bone marrow transplantation, P-selectin(-/-) recipients exhibit decreased GVHD mortality and decreased GVHD of the skin, liver, and small bowels. This was associated with diminished infiltration of alloactivated T cells into the Peyer's patches and small bowels, coupled with increased numbers of donor T cells in the spleen and secondary lymphoid organs (SLOs). Surprisingly, however, donor T cells deficient for P-selectin glycoprotein ligand 1, the most well described P-selectin ligand, mediated GVHD similar to WT T cells and accumulated in SLO and target organs in similar numbers as WT T cells. This suggests that P-selectin may be required for trafficking into inflamed tissues but not SLO and that donor T cells may use multiple P-selectin ligands apart from P-selectin glycoprotein ligand 1 to interact with P-selectin and traffic into inflamed tissues during GVHD. We conclude that targeting P-selectin may be a viable strategy for GVHD prophylaxis or treatment.
Assuntos
Transplante de Medula Óssea/imunologia , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/terapia , Selectina-P/genética , Animais , Modelos Animais de Doenças , Endotélio Vascular/imunologia , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Doença Enxerto-Hospedeiro/fisiopatologia , Mediadores da Inflamação/metabolismo , Mediadores da Inflamação/fisiologia , Ligantes , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Glicoproteínas de Membrana/deficiência , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Selectina-P/metabolismo , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/patologia , Subpopulações de Linfócitos T/transplante , Transplante HomólogoRESUMO
Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a rare subtype of cutaneous T-cell lymphoma that usually presents with tender subcutaneous nodules on the trunk and extremities. Immunosuppressive therapy is considered first-line treatment for SPTCL, while multiagent chemotherapy is used for SPTCL complicated by hemophagocytic lymphohistiocytosis (HLH). Here, we report a 42-year-old Hispanic man that presented with a 5-year history of recurrent painful subcutaneous lesions in the absence of constitutional symptoms, lymphadenopathy, and hepatosplenomegaly. A punch biopsy revealed an atypical lymphoid infiltrate in between subcutaneous adipose lobules. Lymphocytes expressed CD3, CD8, and Beta F-1 and did not express CD4 and CD56. Based on clinical and histologic findings, the patient was diagnosed with SPTCL. In addition, laboratory findings did not demonstrate any evidence of HLH. He was initially started on both prednisone and hydroxychloroquine with no improvement. A trial of cyclosporine and methotrexate yielded no clinical improvement. As the lesions failed to resolve after treatment with multiple immunosuppressive agents, romidepsin, an intravenous histone deacetylase (HDAC) inhibitor, was initiated. After two cycles of romidepsin, the patient achieved complete clinical response. He continues to be in remission 12 months later with monthly maintenance therapy. This case illustrates that romidepsin can be useful as monotherapy for refractory SPTCL without HLH.
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We retrospectively analyzed SARS-CoV-2 vaccination antibody responses in a cohort of 273 patients with lymphoproliferative disorders or plasma cell dyscrasias who were seen at a single tertiary cancer center. Semi-quantitative anti-spike protein serologic testing was performed with enzyme immunoassay method. We found that the antibody response rate to SARS-CoV-2 vaccination was 74.7% in our patient cohort with no difference based on gender, age or race. The highest response rate was found in patients with Multiple Myeloma (MM) (95.5%). The response rates found in Diffuse Large B-Cell Lymphoma (DLBCL), Chronic Lymphocytic Leukemia (CLL), and Low-Grade Non-Hodgkin Lymphoma (LG-NHL) were 73.2%, 61.5% and 53% respectively. We also evaluated the effects of receiving active chemo-immunotherapy on SARS-CoV-2 vaccination antibody response. We found that the patients on treatment had lower response than the patients off treatment (62.1% versus 84.4% p<0.001). Thirty-four of 58 LG-NHL patients were receiving anti-lymphoma treatment with a lower SARS-CoV-2 vaccination response as compared to the patients who were not on treatment (29.4% v 87.5% p<0.001). We observed a similar pattern in CLL patients receiving treatment (48.1 v 76.0 p:0.049). We found that only disease type and treatment status (on-treatment vs. off- treatment), but not gender, age or race were significant predictors of non-response in the multivariable logistic regression model. The interaction between disease type and treatment status was not statistically significant by multivariate analysis. In conclusion, receiving anti-cancer treatment was found to play a significant role in decreasing the response to COVID-19 vaccination.
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Background: Lymphopenia at diagnosis is considered a negative prognostic factor for patients with extra-nodal natural killer (NK)/T-cell lymphoma (ENKTL), especially that of the absolute cluster of differentiation 4+ T cell count (ACD4C), which has previously been identified as an independent prognostic factor in other hematologic malignancies. However, there is limited data available regarding the prognostic value of peripheral blood T lymphocyte subsets in ENKTL patients. The purpose of this study was to investigate the prognostic value of lymphocyte subsets, especially the ACD4C in ENKTL as a clinical biomarker. Methods: We analyzed the clinical data of 176 patients who met the inclusion criteria in Cancer Center of Integrated Hospital of Traditional Chinese Medicine, Southern Medical University from 2000 to 2018, including baseline clinical factors and ACD4C detected by flow cytometry, and examined the correlation between the results and clinical parameters and long-term outcomes. Results: The complete response rate of the high ACD4C group was 57.6%, which was significantly higher than that of the low ACD4C group (15.1%, P<0.001). The univariate analysis results showed that at a median follow-up time of 58.2 months, patients with a high ACD4C had significantly superior progression-free survival (PFS) and overall survival (OS) (P=0.034 and P=0.001, respectively). The multivariate analysis results revealed that Eastern Cooperative Oncology Group performance status (ECOG PS) and the ACD4C were independent prognostic factors for OS [RR (95% CI): 2.288 (1.209-4.328), P=0.011 and RR (95% CI): 2.058 (1.070-3.968), P=0.031, respectively]. ECOG PS was also an independent prognostic factor for PFS [RR (95% CI): 1.858 (1.064-3.244), P=0.029], while ACD4C tended to be independently correlated with PFS (P=0.085). Conclusions: In this large cohort study, we found that the ACD4C was associated with survival outcomes in ENKTL patients. It is a potential biomarker, which may potentially be applied to clinical.