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1.
Ann Hematol ; 100(11): 2733-2744, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34477953

RESUMO

Patients with high-risk or relapsed aggressive B-cell lymphomas are characterized by poor prognosis. High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) can induce durable remissions in these patients and is potentially curative. Two hundred forty-seven patients with aggressive B-cell lymphomas treated with high-dose chemotherapy and ASCT, either as consolidation after first-line therapy or after salvage therapy for relapsed disease, between 2002 and 2019 at the University Hospital Muenster, were analyzed. The median follow-up of surviving patients was 36 months (range 0-163). Progression-free survival (PFS) and overall survival (OS) after 3 years was 63% and 68%, respectively. After ASCT, 28% of all patients experienced a relapse. The cumulative incidence of non-relapse mortality at day 100 after ASCT was 4%. Multivariate analysis identified remission status at ASCT, age at ASCT, and the numbers of infused CD34+ cells as independent prognostic factors for both PFS and OS. Patients with mantle cell lymphoma (MCL) or primary CNS lymphoma (PCNSL) treated with ASCT in first-line had a superior OS and PFS when compared to patients treated with ASCT in relapsed disease. For patients with diffuse large B-cell lymphoma (DLBCL) and Hodgkin lymphoma (HL), early relapse (< 12 months) after first-line therapy showed a trend towards an inferior PFS and OS. Deaths after ASCT were predominantly caused by lymphoma relapse and/or progression (64%) or due to infections (23%). In conclusion, high-dose chemotherapy followed by ASCT in the era of novel targeted agents remains a feasible and effective approach for patients with high-risk or relapsed aggressive B-cell lymphomas. Remission status and age at ASCT, and the number of infused stem cells were of prognostic relevance.


Assuntos
Linfoma de Células B/terapia , Transplante de Células-Tronco de Sangue Periférico , Adulto , Idoso , Aloenxertos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Terapia Combinada , Feminino , Humanos , Estimativa de Kaplan-Meier , Linfoma de Células B/tratamento farmacológico , Linfoma de Células B/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Intervalo Livre de Progressão , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Terapia de Salvação , Transplante Autólogo , Resultado do Tratamento , Irradiação Corporal Total , Adulto Jovem
3.
Transpl Infect Dis ; 22(1): e13224, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31782899

RESUMO

Here, we present the unique case of a 51-year-old German patient with multiple myeloma excreting Ascaris lumbricoides in his stool five weeks after allogeneic hematopoietic stem cell transplantation. Stool analysis remained negative for the presence of eggs, and there was no eosinophilia in the peripheral blood at any time around stem cell transplantation. The patient was commenced on a three-day treatment with mebendazole, which was well tolerated. No serious interactions with the concomitant post-transplant medication or negative effects on the hematopoiesis were observed, and the myeloma still is in complete remission. To our knowledge, this is the first report on excretion of A lumbricoides in the context of allogeneic stem cell transplantation. The case is remarkable with view to the fact that the parasite has supposedly survived all courses of myeloma treatment including autologous and allogeneic conditioning. Parasitosis with A lumbricoides has a worldwide prevalence of about a billion and is extremely rare in northern Europe. Possibly the patient got infected during a trip to Egypt years before multiple myeloma was diagnosed.


Assuntos
Ascaríase/diagnóstico , Fezes/parasitologia , Transplante de Células-Tronco Hematopoéticas , Mebendazol/uso terapêutico , Animais , Ascaris lumbricoides , Egito , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/parasitologia , Mieloma Múltiplo/terapia , Contagem de Ovos de Parasitas , Transplante de Células-Tronco , Condicionamento Pré-Transplante , Transplante Homólogo
4.
Blood ; 125(2): 261-72, 2015 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-25395422

RESUMO

Donor-derived immunity against tumor-associated antigens (TAAs) may exert selective antileukemic activity reprieving the allogeneic recipient from graft-versus-host disease. As TAAs are highly expressed in placental tissues we hypothesized that pregnancy could drive respective immunity in healthy individuals. Thus, we investigated the frequency and level of immune responses against clinically relevant TAAs in 114 blood donors and 44 women during their first pregnancy. Quantitative reverse-transcription polymerase chain reaction was employed to detect low levels of interferon-γ after primary peptide stimulation of CD8(+) T lymphocytes. In blood donors, primary immune responses of low and/or high avidity were found against WT1 (15%), MUC1 (14%), PRAME (7%), and HER2/neu (5%) and exerted killing functions against leukemic cells. Men had higher responses than women, likely due to gonadal cancer-testis-antigen expression. Interestingly, a history of prior delivery was not associated with increased responses, whereas the strongest responses during pregnancy were found in early trimesters to disappear after delivery. This boost and loss of TAA-specific immunity suggests that virtually every donor harbors the potential to mount antileukemic immune responses in a recipient. However, in the absence of the driving target and a permissive environment, they are short-lived and thus require supplemental strategies such as vaccination or immunomodulation to facilitate their persistence.


Assuntos
Antígenos de Neoplasias/imunologia , Imunoterapia , Gravidez/imunologia , Adulto , Linfócitos T CD8-Positivos/imunologia , Estudos Transversais , Feminino , Doença Enxerto-Hospedeiro/imunologia , Antígeno HLA-A2/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Adulto Jovem
5.
Br J Clin Pharmacol ; 82(5): 1171-1179, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27245261

RESUMO

Inhibition of the mechanistic target of rapamycin (mTOR) has been exploited largely both in solid tumour oncology and solid organ transplantation. More recently mTOR inhibitors such as sirolimus and everolimus have been introduced to the field of allogeneic haematopoietic stem cell transplantation where their unique combination of immunosuppressive purposes offering reduced nephrotoxicity and potential antimalignant effects reflect a unique drug profile that has led to their widespread use in both prophylaxis and therapy of graft-versus-host disease (GVHD). On the other hand haematological insufficiency, infectious complications as well as vasculopathies, have been frequently reported as limiting toxicities. Here, we review both the retrospective and prospective experience available to date and stress the need for prospective registration trials to reduce off label use and improve patient safety by optimizing dosing and enhancing pharmacovigilance. Furthermore, we speculate on the future role of mTOR inhibitors in allogeneic haematopoietic stem cell transplantation.


Assuntos
Doença Enxerto-Hospedeiro/tratamento farmacológico , Transplante de Células-Tronco Hematopoéticas/métodos , Imunossupressores/uso terapêutico , Serina-Treonina Quinases TOR/antagonistas & inibidores , Humanos , Imunossupressores/efeitos adversos
7.
Clin Transplant ; 28(12): 1410-5, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25287756

RESUMO

Compromised quality of life (QoL) is a frequent consequence of treatment-refractory chronic graft-versus-host disease (cGvHD). Here, we report on the assessment of QoL in a subgroup of 22 patients with a median age of 54 (17-70) yr receiving an everolimus-based salvage therapy at a single center for their steroid-refractory cGvHD. Five patients suffered from mild, 13 from moderate, and four from severe cGvHD according to NIH consensus criteria when everolimus was introduced. Median treatment duration was 390 d ranging from 86 to 814 d. We performed actual and retrospective assessments of QoL (EuroQol EQ-5D questionnaire) and degree of bother experienced by cGvHD symptoms (Lee cGvHD Symptom Scale). Seventeen of 22 patients showed an improved QoL according to the EQ-5D visual analog scale (37.5% vs. 70.0%; p < 0.001), and a decline in the median Lee cGvHD Symptom Scale was noted in 20 of 22 patients (28 vs. 17; p < 0.001). Furthermore, an improvement was noted in each of the five dimensions of the EQ-5D descriptive system. These data even when limited by their retrospective nature suggest that beyond physical responses everolimus may have contributed to the rebuilding of patients' QoL.


Assuntos
Glucocorticoides/uso terapêutico , Doença Enxerto-Hospedeiro/tratamento farmacológico , Qualidade de Vida/psicologia , Sirolimo/análogos & derivados , Serina-Treonina Quinases TOR/antagonistas & inibidores , Adolescente , Adulto , Idoso , Doença Crônica , Everolimo , Feminino , Seguimentos , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/psicologia , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas , Humanos , Imunossupressores/uso terapêutico , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Terapia de Salvação , Índice de Gravidade de Doença , Sirolimo/uso terapêutico , Inquéritos e Questionários , Transplante Homólogo , Adulto Jovem
8.
Oncol Res Treat ; 47(3): 65-75, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38198763

RESUMO

INTRODUCTION: Chimeric antigen receptor positive T cell (CAR-T cell) treatment became standard therapy for relapsed or refractory hematologic malignancies, such as non-Hodgkin's lymphoma and multiple myeloma. Owing to the rapidly progressing field of CAR-T cell therapy and the lack of generally accepted treatment guidelines, we hypothesized significant differences between centers in the prevention, diagnosis, and management of short- and long-term complications. METHODS: To capture the current CAR-T cell management among German centers to determine the medical need and specific areas for future clinical research, the DAG-HSZT (Deutsche Arbeitsgemeinschaft für Hämatopoetische Stammzelltransplantation und Zelluläre Therapie; German Working Group for Hematopoietic Stem Cell Transplantation and Cellular Therapy) performed a survey among 26 German CAR-T cell centers. RESULTS: We received answers from 17 centers (65%). The survey documents the relevance of evidence in the CAR-T cell field with a homogeneity of practice in areas with existing clinical evidence. In contrast, in areas with no - or low quality - clinical evidence, we identified significant variety in management in between the centers: management of cytokine release syndrome, immune effector cell-related neurotoxicity syndrome, IgG substitution, autologous stem cell backups, anti-infective prophylaxis, and vaccinations. CONCLUSION: The results indicate the urgent need for better harmonization of supportive care in CAR-T cell therapies including clinical research to improve clinical outcome.


Assuntos
Receptores de Antígenos Quiméricos , Humanos , Imunoterapia Adotiva , Alemanha , Pacientes , Terapia Baseada em Transplante de Células e Tecidos
9.
Cureus ; 15(11): e49473, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-38152773

RESUMO

Pure white cell aplasia (PWCA) is a very rare hematological disorder with a nearly total absence of granulocytes and their precursor cells. While the disease is rarely diagnosed incidentally in otherwise asymptomatic individuals, most patients suffer from sometimes life-threatening infections. Due to its very low incidence, the precise pathomechanism of PWCA still needs to be elucidated. While most cases reported in the literature have been associated with an underlying thymic or autoimmune disease, some other factors including the intake of certain drugs such as antimicrobial agents or immune checkpoint inhibitors have been identified as potential triggers. Since PWCA is commonly refractory to treatment with granulocyte colony-stimulating factors (G-CSF), the main focus lies in identifying and eliminating the underlying trigger. Here, we report a unique case where the development of PWCA in a 56-year-old man with an upper respiratory tract infection has to be attributed to the long-term unprotected exposure to an industrial detergent containing high concentrations of the preservatives benzalkonium chloride (BAC) and 2-phenoxyethanol (2-PE). As a matter of fact, certain hematotoxic potential has been described in the literature for both BAC and 2-PE.

10.
Curr Drug Saf ; 18(3): 404-412, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-35670337

RESUMO

BACKGROUND: Metamizole is one of the most used analgesic, antipyretic, and spasmolytic agents in many countries worldwide. While metamizole-induced agranulocytosis is an, albeit seldom, well-known adverse event, metamizole-associated drug-induced liver injury has been reported rarely in the literature and hence often remains unconsidered. Here, we present a unique case where metamizole-induced hepatotoxicity got unmasked by the simultaneous development of characteristic agranulocytosis. CASE REPORT: A 22-year-old woman without known conditions presented with a new onset of fever, jaundice, and maculopapular rash and explicitly denied intake of any new substances. Laboratory tests showed liver injury, granulopenia, and positive anti-nuclear and anti-mitochondrial (AMA-M2) antibodies. Liver biopsy revealed a histological pattern characteristic of drug-induced liver injury and bone marrow biopsy, the classical picture of metamizole-induced agranulocytosis. Indeed the in-depth interview of the patient unveiled metamizole consumption over the last two months. Therefore, we could diagnose metamizole-induced hepato- and myelotoxicity. Accordingly, steroid therapy led to normalization of liver parameters and stimulation with granulocyte colony- stimulating factor to leukocyte recovery. CONCLUSION: This case report is intended to increase the awareness of metamizole-associated druginduced liver injury which should always be kept in mind due to its occasionally life-threatening course. Diagnosis can be difficult particularly if anamnesis and written records are without hints for prior metamizole intake.


Assuntos
Agranulocitose , Doença Hepática Crônica Induzida por Substâncias e Drogas , Doença Hepática Induzida por Substâncias e Drogas , Feminino , Humanos , Adulto Jovem , Adulto , Dipirona/efeitos adversos , Anti-Inflamatórios não Esteroides/efeitos adversos , Agranulocitose/induzido quimicamente , Agranulocitose/diagnóstico , Agranulocitose/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Doença Hepática Induzida por Substâncias e Drogas/etiologia
11.
Front Oncol ; 12: 905103, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36003787

RESUMO

Background: JC virus reactivation causing progressive multifocal leukoencephalopathy (PML) occurs preferentially in human immunodeficiency virus (HIV) positive individuals or patients suffering from hematologic neoplasms due to impaired viral control. Reactivation in patients suffering from solid malignancies is rarely described in published literature. Case Presentation: Here we describe a case of PML in a male patient suffering from esophageal cancer who underwent neoadjuvant radiochemotherapy and surgical resection in curative intent resulting in complete tumor remission. The radiochemotherapy regimen contained carboplatin and paclitaxel (CROSS protocol). Since therapy onset, the patient presented with persistent and progredient leukopenia and lymphopenia in absence of otherwise known risk factors for PML. Symptom onset, which comprised aphasia, word finding disorder, and paresis, was apparent 7 months after therapy initiation. There was no relief in symptoms despite standard of care PML directed supportive therapy. The patient died two months after therapy onset. Conclusion: PML is a very rare event in solid tumors without obvious states of immununosuppression and thus harbors the risk of unawareness. The reported patient suffered from lymphopenia, associated with systemic therapy, but was an otherwise immunocompetent individual. In case of neurologic impairment in patients suffering from leukopenia, PML must be considered - even in the absence of hematologic neoplasia or HIV infection.

12.
Nat Commun ; 13(1): 3881, 2022 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-35794096

RESUMO

While survival has improved for Burkitt lymphoma patients, potential differences in outcome between pediatric and adult patients remain unclear. In both age groups, survival remains poor at relapse. Therefore, we conducted a comparative study in a large pediatric cohort, including 191 cases and 97 samples from adults. While TP53 and CCND3 mutation frequencies are not age related, samples from pediatric patients showed a higher frequency of mutations in ID3, DDX3X, ARID1A and SMARCA4, while several genes such as BCL2 and YY1AP1 are almost exclusively mutated in adult patients. An unbiased analysis reveals a transition of the mutational profile between 25 and 40 years of age. Survival analysis in the pediatric cohort confirms that TP53 mutations are significantly associated with higher incidence of relapse (25 ± 4% versus 6 ± 2%, p-value 0.0002). This identifies a promising molecular marker for relapse incidence in pediatric BL which will be used in future clinical trials.


Assuntos
Linfoma de Burkitt , Adulto , Linfoma de Burkitt/genética , Linfoma de Burkitt/patologia , Proteínas de Ciclo Celular/genética , Criança , DNA Helicases/genética , Genes cdc , Humanos , Mutação , Taxa de Mutação , Recidiva Local de Neoplasia/genética , Proteínas Nucleares/genética , Fatores de Transcrição/genética
13.
Nat Commun ; 12(1): 5183, 2021 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-34465776

RESUMO

Plasmablastic lymphoma (PBL) represents a rare and aggressive lymphoma subtype frequently associated with immunosuppression. Clinically, patients with PBL are characterized by poor outcome. The current understanding of the molecular pathogenesis is limited. A hallmark of PBL represents its plasmacytic differentiation with loss of B-cell markers and, in 60% of cases, its association with Epstein-Barr virus (EBV). Roughly 50% of PBLs harbor a MYC translocation. Here, we provide a comprehensive integrated genomic analysis using whole exome sequencing (WES) and genome-wide copy number determination in a large cohort of 96 primary PBL samples. We identify alterations activating the RAS-RAF, JAK-STAT, and NOTCH pathways as well as frequent high-level amplifications in MCL1 and IRF4. The functional impact of these alterations is assessed using an unbiased shRNA screen in a PBL model. These analyses identify the IRF4 and JAK-STAT pathways as promising molecular targets to improve outcome of PBL patients.


Assuntos
Linfoma Plasmablástico/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Amplificação de Genes , Dosagem de Genes , Perfilação da Expressão Gênica , Humanos , Fatores Reguladores de Interferon/genética , Fatores Reguladores de Interferon/metabolismo , Janus Quinases/genética , Janus Quinases/metabolismo , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Linfoma Plasmablástico/metabolismo , Linfoma Plasmablástico/mortalidade , Linfoma Plasmablástico/terapia , Fatores de Transcrição STAT/genética , Fatores de Transcrição STAT/metabolismo , Translocação Genética , Sequenciamento do Exoma , Adulto Jovem
15.
J Clin Pharmacol ; 59(11): 1433-1442, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31433499

RESUMO

Metamizole, also known as dipyrone, was introduced to the market nearly a century ago. Due to its excellent analgesic, antipyretic, and spasmolytic properties combined with its mostly favorable gastrointestinal tolerability, the drug was extensively applied worldwide during the first decades after its market introduction. Although rare, agranulocytosis is a well-known adverse event of metamizole and led to its withdrawal from the market in a number of countries beginning in the 1960s. Nevertheless, metamizole is still a frequently used drug worldwide either legally (by prescription in some countries, over the counter in other countries) or without official approval (especially by immigrants knowing the drug from their home countries) or even illegally (due to its growing application as an adulterant in illicit drugs). Metamizole undergoes extensive metabolism in the liver and cases of potential metamizole-associated hepatotoxicity have been described. Here, the literature is extensively reviewed for the first time regarding hepatic effects associated with the use of metamizole.


Assuntos
Anti-Inflamatórios não Esteroides/efeitos adversos , Dipirona/efeitos adversos , Dipirona/metabolismo , Fígado/efeitos dos fármacos , Agranulocitose , Analgésicos , Anti-Inflamatórios não Esteroides/metabolismo , Antipiréticos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Humanos , Fígado/metabolismo , Medicamentos sem Prescrição
16.
Cancer Res Treat ; 49(2): 548-552, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27456945

RESUMO

Progressive multifocal leukoencephalopathy (PML) is a devastating neurological disease observed nearly exclusively in immunocompromised patients. Recently, the introduction of monoclonal antibodies significantly inhibiting the immune system such as rituximab has led to an increase in PML cases. Although rituximab-based immunochemotherapy remains the standard of treatment for chronic lymphocytic leukemia (CLL), the importance of Bruton's tyrosine kinase inhibitors such as ibrutinib is steadily increasing. However, long-term experiences regarding possible side effects of these new substances are rare. Here, we report the development of eventually fatal PML possibly associated with ibrutinib therapy for CLL after multiple prior treatment lines, including rituximab. To the best of our knowledge, this is the first study to report such findings. Since the last course of rituximab was applied over 3 years ago, it is conceivable that the strong B cell inhibition by ibrutinib led to PML. With increased awareness of this potential side effect, further clinical studies are certainly warranted to evaluate this possible association.


Assuntos
Antineoplásicos/efeitos adversos , Leucemia Linfocítica Crônica de Células B/complicações , Leucoencefalopatia Multifocal Progressiva/diagnóstico , Leucoencefalopatia Multifocal Progressiva/etiologia , Inibidores de Proteínas Quinases/efeitos adversos , Pirazóis/efeitos adversos , Pirimidinas/efeitos adversos , Adenina/análogos & derivados , Idoso , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Progressão da Doença , Evolução Fatal , Humanos , Leucemia Linfocítica Crônica de Células B/diagnóstico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucoencefalopatia Multifocal Progressiva/tratamento farmacológico , Masculino , Mefloquina/uso terapêutico , Mianserina/análogos & derivados , Mianserina/uso terapêutico , Mirtazapina , Imagem Multimodal/métodos , Piperidinas , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico
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