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1.
Lancet Haematol ; 11(5): e324-e335, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38583455

RESUMO

BACKGROUND: Whether high-dose cytarabine-based salvage chemotherapy, administered to induce complete remission in patients with poor responsive or relapsed acute myeloid leukaemia scheduled for allogeneic haematopoietic stem-cell transplantation (HSCT) after intensive conditioning confers a survival advantage, is unclear. METHODS: To test salvage chemotherapy before allogeneic HSCT, patients aged between 18 and 75 years with non-favourable-risk acute myeloid leukaemia not in complete remission after first induction or untreated first relapse were randomly assigned 1:1 to remission induction with high-dose cytarabine (3 g/m2 intravenously, 1 g/m2 intravenously for patients >60 years or with a substantial comorbidity) twice daily on days 1-3 plus mitoxantrone (10 mg/m2 intravenously) on days 3-5 or immediate allogeneic HSCT for the disease control group. Block randomisation with variable block lengths was used and patients were stratified by age, acute myeloid leukaemia risk, and disease status. The study was open label. The primary endpoint was treatment success, defined as complete remission on day 56 after allogeneic HSCT, with the aim to show non-inferiority for disease control compared with remission induction with a non-inferiority-margin of 5% and one-sided type 1 error of 2·5%. The primary endpoint was analysed in both the intention-to-treat (ITT) population and in the per-protocol population. The trial is completed and was registered at ClinicalTrials.gov, NCT02461537. FINDINGS: 281 patients were enrolled between Sept 17, 2015, and Jan 12, 2022. Of 140 patients randomly assigned to disease control, 135 (96%) proceeded to allogeneic HSCT, 97 (69%) after watchful waiting only. Of 141 patients randomly assigned to remission induction, 134 (95%) received salvage chemotherapy and 128 (91%) patients subsequently proceeded to allogeneic HSCT. In the ITT population, treatment success was observed in 116 (83%) of 140 patients in the disease control group versus 112 (79%) of 141 patients with remission induction (test for non-inferiority, p=0·036). Among per-protocol treated patients, treatment success was observed in 116 (84%) of 138 patients with disease control versus 109 (81%) of 134 patients in the remission induction group (test for non-inferiority, p=0·047). The difference in treatment success between disease control and remission induction was estimated as 3·4% (95% CI -5·8 to 12·6) for the ITT population and 2·7% (-6·3 to 11·8) for the per-protocol population. Fewer patients with disease control compared with remission induction had non-haematological adverse events grade 3 or worse (30 [21%] of 140 patients vs 86 [61%] of 141 patients, χ2 test p<0·0001). Between randomisation and the start of conditioning, with disease control two patients died from progressive acute myeloid leukaemia and zero from treatment-related complications, and with remission induction two patients died from progressive acute myeloid leukaemia and two from treatment-related complications. Between randomisation and allogeneic HSCT, patients with disease control spent a median of 27 days less in hospital than those with remission induction, ie, the median time in hospital was 15 days (range 7-64) versus 42 days (27-121, U test p<0·0001), respectively. INTERPRETATION: Non-inferiority of disease control could not be shown at the 2·5% significance level. The rate of treatment success was also not statistically better for patients with remission induction. Watchful waiting and immediate transplantation could be an alternative for fit patients with poor response or relapsed acute myeloid leukaemia who have a stem cell donor available. More randomised controlled intention-to-transplant trials are needed to define the optimal treatment before transplantation for patients with active acute myeloid leukaemia. FUNDING: DKMS and the Gert and Susanna Mayer Stiftung Foundation.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Indução de Remissão , Transplante Homólogo , Humanos , Transplante de Células-Tronco Hematopoéticas/métodos , Leucemia Mieloide Aguda/terapia , Leucemia Mieloide Aguda/tratamento farmacológico , Pessoa de Meia-Idade , Masculino , Feminino , Adulto , Idoso , Citarabina/uso terapêutico , Citarabina/administração & dosagem , Adulto Jovem , Adolescente , Mitoxantrona/uso terapêutico , Mitoxantrona/administração & dosagem , Terapia de Salvação/métodos , Resultado do Tratamento , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Recidiva
2.
Front Immunol ; 14: 1251593, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37965339

RESUMO

Introduction: Allogeneic stem cell transplantation is used to cure hematologic malignancies or deficiencies of the hematopoietic system. It is associated with severe immunodeficiency of the host early after transplant and therefore early reactivation of latent herpesviruses such as CMV and EBV within the first 100 days are frequent. Small studies and case series indicated that application of herpes virus specific T cells can control and prevent disease in this patient population. Methods: We report the results of a randomized controlled multi centre phase I/IIa study (MULTIVIR-01) using a newly developed T cell product with specificity for CMV and EBV derived from the allogeneic stem cell grafts used for transplantation. The study aimed at prevention and preemptive treatment of both viruses in patients after allogeneic stem cell transplantation targeting first infusion on day +30. Primary endpoints were acute transfusion reaction and acute-graft versus-host-disease after infusion of activated T cells. Results: Thirty-three patients were screened and 9 patients were treated with a total of 25 doses of the T cell product. We show that central manufacturing can be achieved successfully under study conditions and the product can be applied without major side effects. Overall survival, transplant related mortality, cumulative incidence of graft versus host disease and number of severe adverse events were not different between treatment and control groups. Expansion of CMV/EBV specific T cells was observed in a fraction of patients, but overall there was no difference in virus reactivation. Discussion: Our study results indicate peptide stimulated epitope specific T cells derived from stem cell grafts can be administered safely for prevention and preemptive treatment of reactivation without evidence for induction of acute graft versus host disease. Clinical trial registration: https://clinicaltrials.gov, identifier NCT02227641.


Assuntos
Infecções por Citomegalovirus , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Humanos , Infecções por Citomegalovirus/prevenção & controle , Infecções por Citomegalovirus/complicações , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Herpesvirus Humano 4/fisiologia , Linfócitos T , Transplante Homólogo/efeitos adversos
4.
Transplant Proc ; 53(4): 1365-1368, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33478746

RESUMO

A 53-year-old female patient with acute myeloid leukemia developed severe chronic graft vs host disease (cGVHD) of the oral mucosa after allogeneic hematopoietic stem cell transplantation with leukoplakia and relapsing oral squamous cell carcinoma (SCC) of the tongue. cGVHD needed long-lasting immunosuppressive therapy; SCC was treated with radiation and surgery. Acute myeloid leukemia remained in complete remission. The patient developed a myositis with pain of all muscles as well as paraparesis with elevated creatine kinase and C-reactive protein and detection of antiskeletal muscle autoantibodies 3500 days after hematopoietic stem cell transplantation. No other clinical features of chronic GVHD were apparent at this time. Symptoms disappeared after treatment with corticosteroids but relapsed while tapering. Weekly therapy with the B-cell-depleting antibody rituximab was started and administered for 6 weeks. Symptoms disappeared again but partly returned after some weeks, so therapy with azathioprine was started. During therapy with azathioprine slow tapering of corticosteroids was possible and clinical symptoms remained absent. Here we present a case report and review of the literature on alloimmune myositis as paraneoplastic complication of an oral SCC of the tongue after severe chronic GVHD or as late manifestation of chronic GVHD itself.


Assuntos
Doença Enxerto-Hospedeiro/diagnóstico , Neoplasias Bucais/diagnóstico , Miosite/diagnóstico , Carcinoma de Células Escamosas de Cabeça e Pescoço/diagnóstico , Autoanticorpos/sangue , Proteína C-Reativa/análise , Feminino , Doença Enxerto-Hospedeiro/tratamento farmacológico , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Imunossupressores/uso terapêutico , Leucemia Mieloide Aguda/terapia , Leucoplasia/complicações , Pessoa de Meia-Idade , Mucosa Bucal/patologia , Neoplasias Bucais/complicações , Neoplasias Bucais/radioterapia , Neoplasias Bucais/cirurgia , Carcinoma de Células Escamosas de Cabeça e Pescoço/complicações , Carcinoma de Células Escamosas de Cabeça e Pescoço/radioterapia , Carcinoma de Células Escamosas de Cabeça e Pescoço/cirurgia , Transplante Homólogo
5.
Lancet Haematol ; 7(1): e28-e39, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31606445

RESUMO

BACKGROUND: Further improvement of preparative regimens before allogeneic haemopoietic stem cell transplantation (HSCT) is an unmet medical need for the growing number of older or comorbid patients with acute myeloid leukaemia or myelodysplastic syndrome. We aimed to evaluate the efficacy and safety of conditioning with treosulfan plus fludarabine compared with reduced-intensity busulfan plus fludarabine in this population. METHODS: We did an open-label, randomised, non-inferiority, phase 3 trial in 31 transplantation centres in France, Germany, Hungary, Italy, and Poland. Eligible patients were 18-70 years, had acute myeloid leukaemia in first or consecutive complete haematological remission (blast counts <5% in bone marrow) or myelodysplastic syndrome (blast counts <20% in bone marrow), Karnofsky index of 60% or higher, and were indicated for allogeneic HSCT but considered at an increased risk for standard myeloablative preparative regimens based on age (≥50 years), an HSCT-specific comorbidity index of more than 2, or both. Patients were randomly assigned (1:1) to receive either intravenous 10 g/m2 treosulfan daily applied as a 2-h infusion for 3 days (days -4 to -2) or 0·8 mg/kg busulfan applied as a 2-h infusion at 6-h intervals on days -4 and -3. Both groups received 30 mg/m2 intravenous fludarabine daily for 5 days (days -6 to -2). The primary outcome was event-free survival 2 years after HSCT. The non-inferiority margin was a hazard ratio (HR) of 1·3. Efficacy was assessed in all patients who received treatment and completed transplantation, and safety in all patients who received treatment. The study is registered with EudraCT (2008-002356-18) and ClinicalTrials.gov (NCT00822393). FINDINGS: Between June 13, 2013, and May 3, 2016, 476 patients were enrolled (240 in the busulfan group received treatment and transplantation, and in the treosulfan group 221 received treatment and 220 transplanation). At the second preplanned interim analysis (Nov 9, 2016), the primary endpoint was met and trial was stopped. Here we present the final confirmatory analysis (data cutoff May 31, 2017). Median follow-up was 15·4 months (IQR 8·8-23·6) for patients treated with treosulfan and 17·4 months (6·3-23·4) for those treated with busulfan. 2-year event-free survival was 64·0% (95% CI 56·0-70·9) in the treosulfan group and 50·4% (42·8-57·5) in the busulfan group (HR 0·65 [95% CI 0·47-0·90]; p<0·0001 for non-inferiority, p=0·0051 for superiority). The most frequently reported grade 3 or higher adverse events were abnormal blood chemistry results (33 [15%] of 221 patients in the treosulfan group vs 35 [15%] of 240 patients in the busulfan group) and gastrointestinal disorders (24 [11%] patients vs 39 [16%] patients). Serious adverse events were reported for 18 (8%) patients in the treosulfan group and 17 (7%) patients in the busulfan group. Causes of deaths were generally transplantation-related. INTERPRETATION: Treosulfan was non-inferior to busulfan when used in combination with fludarabine as a conditioning regimen for allogeneic HSCT for older or comorbid patients with acute myeloid leukaemia or myelodysplastic syndrome. The improved outcomes in patients treated with the treosulfan-fludarabine regimen suggest its potential to become a standard preparative regimen in this population. FUNDING: medac GmbH.


Assuntos
Antineoplásicos/uso terapêutico , Bussulfano/análogos & derivados , Bussulfano/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/métodos , Leucemia Mieloide Aguda/terapia , Síndromes Mielodisplásicas/terapia , Condicionamento Pré-Transplante/métodos , Vidarabina/análogos & derivados , Adulto , Idoso , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Vidarabina/uso terapêutico
6.
Sci Rep ; 9(1): 19911, 2019 12 27.
Artigo em Inglês | MEDLINE | ID: mdl-31882648

RESUMO

Patients undergoing allogeneic hematopoietic stem cell transplantation have a high morbidity and mortality, especially after admission to intensive care unit (ICU) during peri-transplant period. The objective of this study was to identify new clinical and biological parameters and validate prognostic scores associated with ICU, short-and long-term survival. Significant differences between ICU survivors and ICU non-survivors for the clinical parameters invasive mechanical ventilation, urine output, heart rate, mean arterial pressure, and amount of vasopressors have been measured. Among prognostic scores (SOFA, SAPSII, PICAT, APACHE II, APACHE IV) assessing severity of disease and predicting outcome of critically ill patients on ICU, the APACHE II score has shown most significant difference (p = 0.002) and the highest discriminative power (area under the ROC curve (AUC) 0.74). An elevated level of lactate at day of admission was associated with poor survival on ICU and the most significant independent parameter (p < 0.001). In our cohort kidney damage with low urine output has a highly relevant impact on ICU, short- and long-term overall survival. The APACHE II score was superior predicting ICU mortality compared to all other tested prognostic scores for patients on ICU during peri-transplant period.


Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , APACHE , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Unidades de Terapia Intensiva/estatística & dados numéricos , Rim/patologia , Masculino , Pessoa de Meia-Idade , Pró-Calcitonina/metabolismo , Prognóstico , Curva ROC , Estudos Retrospectivos
7.
Mol Ther ; 27(1): 261-271, 2019 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-30528087

RESUMO

Genetic engineering of T cells with a T cell receptor (TCR) targeting tumor antigen is a promising strategy for cancer immunotherapy. Inefficient expression of the introduced TCR due to TCR mispairing may limit the efficacy and adversely affect the safety of TCR gene therapy. Here, we evaluated the safety and therapeutic efficiency of an optimized single-chain TCR (scTCR) specific for an HLA-A2.1-restricted (non-mutated) p53(264-272) peptide in adoptive T cell transfer (ACT) models using our unique transgenic mice expressing human p53 and HLA-A2.1 that closely mimic the human setting. Specifically, we showed that adoptive transfer of optimized scTCR-redirected T cells does not induce on-target and off-target autoimmunity. Furthermore, ACT resulted in full tumor protection and led to a long-lived effective, antigen-specific memory T cell response in syngeneic and xenograft models. Taken together, the study demonstrated that our scTCR specific for the broadly expressed tumor-associated antigen p53(264-272) can eradicate p53+A2.1+ tumor cells without inducing off-target or self-directed toxicities in mouse models of ACT. These data strongly support the improved safety and therapeutic efficacy of high-affinity p53scTCR for TCR-based immunotherapy of p53-associated malignancies.


Assuntos
Autoimunidade/fisiologia , Receptores de Antígenos de Linfócitos T/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Animais , Terapia Genética , Antígeno HLA-A2/genética , Antígeno HLA-A2/metabolismo , Humanos , Camundongos , Receptores de Antígenos de Linfócitos T/imunologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Proteína Supressora de Tumor p53/genética
8.
Blood ; 115(25): 5154-63, 2010 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-20378753

RESUMO

Transfer of tumor antigen-specific T-cell receptors (TCRs) into human T cells aims at redirecting their cytotoxicity toward tumors. Efficacy and safety may be affected by pairing of natural and introduced TCRalpha/beta chains potentially leading to autoimmunity. We hypothesized that a novel single-chain (sc)TCR framework relying on the coexpression of the TCRalpha constant alpha (Calpha) domain would prevent undesired pairing while preserving structural and functional similarity to a fully assembled double-chain (dc)TCR/CD3 complex. We confirmed this hypothesis for a murine p53-specific scTCR. Substantial effector function was observed only in the presence of a murine Calpha domain preceded by a TCRalpha signal peptide for shuttling to the cell membrane. The generalization to a human gp100-specific TCR required the murinization of both C domains. Structural and functional T-cell avidities of an accessory disulfide-linked scTCR gp100/Calpha were higher than those of a dcTCR. Antigen-dependent phosphorylation of the proximal effector zeta-chain-associated protein kinase 70 at tyrosine 319 was not impaired, reflecting its molecular integrity in signaling. In melanoma-engrafted nonobese diabetic/severe combined immunodeficient mice, adoptive transfer of scTCR gp100/Calpha transduced T cells conferred superior delay in tumor growth among primary and long-term secondary tumor challenges. We conclude that the novel scTCR constitutes a reliable means to immunotherapeutically target hematologic malignancies.


Assuntos
Transferência Adotiva , Antígenos de Neoplasias/imunologia , Melanoma/terapia , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Linfócitos T/imunologia , Proteína Supressora de Tumor p53/imunologia , Animais , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/metabolismo , Linhagem Celular Tumoral , Humanos , Imunidade Celular , Melanoma/genética , Melanoma/imunologia , Melanoma/metabolismo , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Transplante de Neoplasias , Fosforilação/genética , Estrutura Terciária de Proteína , Receptores de Antígenos de Linfócitos T alfa-beta/biossíntese , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Linfócitos T/metabolismo , Linfócitos T/transplante , Transdução Genética , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
9.
J Exp Med ; 206(2): 463-75, 2009 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-19171765

RESUMO

Adoptive transfer of T lymphocytes transduced with a T cell receptor (TCR) to impart tumor reactivity has been reported as a potential strategy to redirect immune responses to target cancer cells (Schumacher, T.N. 2002. Nat. Rev. Immunol. 2:512-519). However, the affinity of most TCRs specific for shared tumor antigens that can be isolated is usually low. Thus, strategies to increase the affinity of TCRs or the functional avidity of TCR-transduced T cells might be therapeutically beneficial. Because glycosylation affects the flexibility, movement, and interactions of surface molecules, we tested if selectively removing conserved N-glycoslyation sites in the constant regions of TCR alpha or beta chains could increase the functional avidity of T cells transduced with such modified TCRs. We observed enhanced functional avidity and improved recognition of tumor cells by T cells harboring TCR chains with reduced N-glycosylation (DeltaTCR) as compared with T cells with wild-type (WT) TCR chains. T cells transduced with WT or DeltaTCR chains bound tetramer equivalently at 4 degrees C, but tetramer binding was enhanced at 37 degrees C, predominantly as a result of reduced tetramer dissociation. This suggested a temperature-dependent mechanism such as TCR movement in the cell surface or structural changes of the TCR allowing improved multimerization. This strategy was effective with mouse and human TCRs specific for different antigens and, thus, should be readily translated to TCRs with any specificity.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Modelos Moleculares , Neoplasias/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Transferência Adotiva , Animais , Linfócitos T CD4-Positivos/metabolismo , Linhagem Celular Tumoral , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Glicosilação , Humanos , Camundongos , Ligação Proteica/imunologia , Receptores de Antígenos de Linfócitos T/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Temperatura
10.
Biologics ; 2(4): 619-33, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19707443

RESUMO

Besides traditional cytostatic drugs the introduction of monoclonal antibodies has substantially influenced current treatment concepts of non-Hodgkin's lymphoma (NHL). Rituximab, a monoclonal anti-CD20 chimeric antibody, now has been widely evaluated in the various B-cell lymphatic neoplasms. Large phase III studies helped to prove the value of this drug in follicular lymphoma as part of induction or relapse treatment as well as maintenance treatment. The addition of rituximab to the well established CHOP regimens has increased achievable cure rates in diffuse large cell lymphoma, and this combination is now accepted worldwide as standard of care. Although conflicting results are available, rituximab is widely used for the treatment of mantle cell lymphoma. For the less frequent lymphoma entities phase 2 studies show a considerable efficiency for most of these B-NHL variants. Current research focuses on combined chemoimmunotherapy approaches, optimization of dosing regimens, and combination with novel agents.

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