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Given the selection of elderly patients with AML in first complete remission (CR1) the advantage of consolidation with allogeneic hematopoietic cell transplantation (HCT) over chemotherapy is still unclear. Newly diagnosed AML patients in CR1 aged 60-75 years were registered and a donor search initiated. After one consolidation cycle, patients with a matched donor were randomized to HCT with fludarabine/lowdose total body irradiation and cyclosporine/mycophenolate mofetil immunosuppression or conventional non-HCT. Primary outcome was restricted mean leukemia-free survival (RM-LFS) up to five years. Between 2010 and 2017, 245 patients (median age 67 years) were registered at CR1. After one consolidation, 26.9% of patients failed inclusion criteria. Of the 179 (73%) patients still on study, 75.4% had an HLA identical donor. Ten ineligible patients were excluded, and 125 randomized to HCT (n=83) or non-HCT (n=42). The primary outcome RM-LFS up to 5 years was 24.5 months (95%CI:18.9-30.1) in the HCT and 15.6 months (95%CI:10.4-20.8) in the non-HCT arm (p=0.022) due to a decrease in cumulative relapse incidence from 91.1 (95%CI:80.7-100.0) after non-HCT to 37.8 (95%CI:27.2-48.4)% after HCT (p.
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BACKGROUND: Intensified systemic chemotherapy has the highest primary cure rate for advanced-stage, classical Hodgkin lymphoma but this comes with a cost of severe and potentially life long, persisting toxicities. With the new regimen of brentuximab vedotin, etoposide, cyclophosphamide, doxorubicin, dacarbazine, and dexamethasone (BrECADD), we aimed to improve the risk-to-benefit ratio of treatment of advanced-stage, classical Hodgkin lymphoma guided by PET after two cycles. METHODS: This randomised, multicentre, parallel, open-label, phase 3 trial was done in 233 trial sites across nine countries. Eligible patients were adults (aged ≤60 years) with newly diagnosed, advanced-stage, classical Hodgkin lymphoma (ie, Ann Arbor stage III/IV, stage II with B symptoms, and either one or both risk factors of large mediastinal mass and extranodal lesions). Patients were randomly assigned (1:1) to four or six cycles (21-day intervals) of escalated doses of etoposide (200 mg/m2 intravenously on days 1-3), doxorubicin (35 mg/m2 intravenously on day 1), and cyclophosphamide (1250 mg/m2 intravenously on day 1), and standard doses of bleomycin (10 mg/m2 intravenously on day 8), vincristine (1·4 mg/m2 intravenously on day 8), procarbazine (100 mg/m2 orally on days 1-7), and prednisone (40 mg/m2 orally on days 1-14; eBEACOPP) or BrECADD, guided by PET after two cycles. Patients and investigators were not masked to treatment assignment. Hierarchical coprimary objectives were to show (1) improved tolerability defined by treatment-related morbidity and (2) non-inferior efficacy defined by progression-free survival with an absolute non-inferiority margin of 6 percentage points of BrECADD compared with eBEACOPP. An additional test of superiority of progression-free survival was to be done if non-inferiority had been established. Analyses were done by intention to treat; the treatment-related morbidity assessment required documentation of at least one chemotherapy cycle. This trial was registered at ClinicalTrials.gov (NCT02661503). FINDINGS: Between July 22, 2016, and Aug 27, 2020, 1500 patients were enrolled, of whom 749 were randomly assigned to BrECADD and 751 to eBEACOPP. 1482 patients were included in the intention-to-treat analysis. The median age of patients was 31 years (IQR 24-42). 838 (56%) of 1482 patients were male and 644 (44%) were female. Most patients were White (1352 [91%] of 1482). Treatment-related morbidity was significantly lower with BrECADD (312 [42%] of 738 patients) than with eBEACOPP (430 [59%] of 732 patients; relative risk 0·72 [95% CI 0·65-0·80]; p<0·0001). At a median follow-up of 48 months, BrECADD improved progression-free survival with a hazard ratio of 0·66 (0·45-0·97; p=0·035); 4-year progression-free survival estimates were 94·3% (95% CI 92·6-96·1) for BrECADD and 90·9% (88·7-93·1) for eBEACOPP. 4-year overall survival rates were 98·6% (97·7-99·5) and 98·2% (97·2-99·3), respectively. INTERPRETATION: BrECADD guided by PET after two cycles is better tolerated and more effective than eBEACOPP in first-line treatment of adult patients with advanced-stage, classical Hodgkin lymphoma. FUNDING: Takeda Oncology.
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Protocolos de Quimioterapia Combinada Antineoplásica , Doença de Hodgkin , Adulto , Feminino , Humanos , Masculino , Adulto Jovem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Brentuximab Vedotin/administração & dosagem , Brentuximab Vedotin/efeitos adversos , Brentuximab Vedotin/uso terapêutico , Ciclofosfamida/uso terapêutico , Ciclofosfamida/efeitos adversos , Ciclofosfamida/administração & dosagem , Dacarbazina/uso terapêutico , Dacarbazina/administração & dosagem , Dacarbazina/efeitos adversos , Dexametasona/administração & dosagem , Dexametasona/uso terapêutico , Dexametasona/efeitos adversos , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Doxorrubicina/uso terapêutico , Etoposídeo/administração & dosagem , Etoposídeo/efeitos adversos , Etoposídeo/uso terapêutico , Doença de Hodgkin/tratamento farmacológico , Doença de Hodgkin/diagnóstico por imagem , Doença de Hodgkin/patologia , Doença de Hodgkin/mortalidade , Estadiamento de Neoplasias , Tomografia por Emissão de Pósitrons , Resultado do TratamentoRESUMO
BACKGROUND: Anti-BCMA-directed chimeric antigen receptor (CAR) T cells are effective treatment for patients with refractory/relapsed multiple myeloma (RRMM). However, little is known about the impact of previous allogeneic hematopoietic stem cell transplantation (allo-HSCT) on lymphocyte collection for production of CAR T cells and subsequent treatment with CAR T cells. PATIENTS AND METHODS: We performed a retrospective analysis of cellular composition of lymphocyte collections, CAR T cell expansion and treatment outcomes of RRMM patients undergoing therapy with idecabtagene vicleucel (ide-cel) with and without history of allo-HSCT. 27 patients (11/27 female) with median age 63 (range 39-75) years were analyzed. Five patients (19%) had the history of allo-HSCT median of 5.5 years before ide-cel. RESULTS: Prior to apheresis, the white blood cell, absolute lymphocyte counts, CD3+ cells and monocytes did not differ in patients with and without prior allo-HSCT. We also noticed no differences in the collected CD3+ yields or cellular compositions of lymphocyte collections. One year after ide-cel infusion, the progression-free survival and overall survival of patients with and without previous allo-HSCT did not differ with 60% and 45% respectively (P = .58) and 66.7% and 74% respectively (P = .84). The highest expansion of CAR T was detected between day 7 after infusion and showed no difference regarding previous allo-HSCT (P = .71). No graft-versus-host disease during the follow-up was detected. CONCLUSION: Our data confirm that the treatment with ide-cel is feasible for patients with prior allo-HSCT. Furthermore, allo-HSCT did not influence cellular composition of lymphocyte collections, clinical outcome or in vivo expansion of ide-cel.
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Markers that predict response and resistance to chimeric antigen receptor (CAR) T cells in relapsed/refractory multiple myeloma are currently missing. We subjected mononuclear cells isolated from peripheral blood and bone marrow before and after the application of approved B cell maturation antigen-directed CAR T cells to single-cell multiomic analyses to identify markers associated with resistance and early relapse. Differences between responders and nonresponders were identified at the time of leukapheresis. Nonresponders showed an immunosuppressive microenvironment characterized by increased numbers of monocytes expressing the immune checkpoint molecule CD39 and suppressed CD8+ T cell and natural killer cell function. Analysis of CAR T cells showed cytotoxic and exhausted phenotypes in hyperexpanded clones compared to low/intermediate expanded clones. We identified potential immunotherapy targets on CAR T cells, like PD1, to improve their functionality and durability. Our work provides evidence that an immunosuppressive microenvironment causes resistance to CAR T cell therapies in multiple myeloma.
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BACKGROUND: Hypersensitivity reactions (HR) are common in mastocytosis. However, little is known about triggers and risk factors. The registry of the European Competence Network on Mastocytosis (ECNM) enables reliable studies in a larger cohort of mastocytosis patients. We assessed prevalence, triggers and risk factors of HR in adults with mastocytosis in the ECNM registry. METHODS: Data were collected in 27 ECNM centers. We analyzed potential triggers (Hymenoptera venoms, food, drug, inhalant and others) and risk factors at diagnosis and during follow-up. The study group consisted of 2485 adults with mastocytosis, 1379 women (55.5%) and 1106 men (44.5%). Median age was 48.2 years (range 18-91 years). RESULTS: Nine hundred and forty eight patients (38.1%) reported one or more HR`. Most common triggers were Hymenoptera venoms in cutaneous mastocytosis (CM) and indolent systemic mastocytosis (ISM), whereas in advanced SM (advSM), most common elicitors were drugs, including nonsteroidal anti-inflammatory agents and penicillin. In multivariate analyses, tryptase level < 90 ng/mL, <15% infiltration by mast cells in bone marrow biopsy-sections, and diagnosis of ISM were identified as independent risk factors for HR. For drug-induced HR, prominent risk factors were advSM and high tryptase levels. New reactions were observed in 4.8% of all patients during 4 years follow-up. CONCLUSIONS: HR are mainly triggered by Hymenoptera venoms in patients with CM and ISM and by drugs in patients with advSM. Tryptase levels <90 ng/mL, mast cell bone marrow infiltration <15%, and WHO category ISM are predictors of HR. New HR occur in 4.8% of all patients within 4 years.
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Blinatumomab is a BiTE® (bispecific T-cell engager) molecule that redirects CD3+ T-cells to engage and lyse CD19+ target cells. Here we demonstrate that subcutaneous (SC) blinatumomab can provide high efficacy and greater convenience of administration. In the expansion phase of a multi-institutional phase 1b trial (ClinicalTrials.gov, NCT04521231), heavily pretreated adults with relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL) received SC blinatumomab at two doses: (1) 250 µg once daily (QD) for week 1 and 500 µg three times weekly (TIW) thereafter (250 µg/500 µg) or (2) 500 µg QD for week 1 and 1000 µg TIW thereafter (500 µg/1000 µg). The primary endpoint was complete remission/complete remission with partial hematologic recovery (CR/CRh) within two cycles. At the data cutoff of September 15, 2023, 29 patients were treated: 14 at the 250 µg/500 µg dose and 13 at 500 µg/1000 µg dose. Data from two ineligible patients were excluded. At the end of two cycles, 12 of 14 patients (85.7%) from the 250 µg/500 µg dose achieved CR/CRh of which nine patients (75.0%) were negative for measurable residual disease (MRD; <10-4 leukemic blasts). At the 500 µg/1000 µg dose, 12 of 13 patients (92.3%) achieved CR/CRh; all 12 patients (100.0%) were MRD-negative. No treatment-related grade 4 cytokine release syndrome (CRS) or neurologic events (NEs) were reported. SC injections were well tolerated and all treatment-related grade 3 CRS and NEs responded to standard-of-care management, interruption, or discontinuation. Treatment with SC blinatumomab resulted in high efficacy, with high MRD-negativity rates and acceptable safety profile in heavily pretreated adults with R/R B-ALL.
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Anticorpos Biespecíficos , Antineoplásicos , Linfoma de Células B , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Leucemia-Linfoma Linfoblástico de Células Precursoras , Adulto , Humanos , Indução de Remissão , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Anticorpos Biespecíficos/efeitos adversos , Linfoma de Células B/tratamento farmacológico , Resposta Patológica Completa , Doença Aguda , Neoplasia Residual , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Antineoplásicos/efeitos adversosRESUMO
PURPOSE: Although chimeric antigen receptor T therapy (CAR-T) cells are an established therapy for relapsed/refractory multiple myeloma (RRMM), there are no established models predicting outcome to identify patients who may benefit the most from CAR-T. PATIENTS AND METHODS: This is an international retrospective observational study including patients with RRMM infused with currently available commercial or academically produced anti-B-cell maturation antigen (BCMA) CAR-T. We describe characteristics and outcomes in Europe (n = 136) and the United States (n = 133). Independent predictors of relapse/progression built a simple prediction model (Myeloma CAR-T Relapse [MyCARe] model) in the training cohort (Europe), which was externally validated (US cohort) and tested within patient- and treatment-specific subgroups. RESULTS: The overall response rate was 87% and comparable between both cohorts, and complete responses were seen in 48% (Europe) and 49% (the United States). The median time to relapse was 5 months, and early relapse <5 months from infusion showed poor survival across cohorts, with the 12-month overall survival of 30% (Europe) and 14% (the United States). The presence of extramedullary disease or plasma cell leukemia, lenalidomide-refractoriness, high-risk cytogenetics, and increased ferritin at the time of lymphodepletion were independent predictors of early relapse or progression. Each factor received one point, forming the three-tiered MyCARe model: scores 0-1 (low risk), scores 2-3 (intermediate risk), and a score of 4 (high risk). The MyCARe model was significantly associated with distinct 5-month incidence of relapse/progression (P < .001): 7% for low-risk, 27% for intermediate-risk, and 53% for high-risk groups. The model was validated in the US cohort and maintained prognostic utility for response, survival, and outcomes across subgroups. CONCLUSION: Outcomes of patients with RRMM after CAR-T are comparable between Europe and the United States. The MyCARe model may facilitate optimal timing of CAR-T cells in patient-specific subgroups.
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Antígeno de Maturação de Linfócitos B , Imunoterapia Adotiva , Mieloma Múltiplo , Humanos , Mieloma Múltiplo/terapia , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/imunologia , Pessoa de Meia-Idade , Masculino , Estudos Retrospectivos , Feminino , Idoso , Imunoterapia Adotiva/métodos , Antígeno de Maturação de Linfócitos B/imunologia , Estados Unidos , Adulto , Receptores de Antígenos Quiméricos/imunologia , Europa (Continente) , Resultado do Tratamento , Recidiva Local de Neoplasia/terapiaRESUMO
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.
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Receptores de Antígenos Quiméricos , Humanos , Imunoterapia Adotiva , Alemanha , Pacientes , Terapia Baseada em Transplante de Células e TecidosRESUMO
B-cell maturation antigen (BCMA)-targeting chimeric antigen receptor (CAR) T cells revolutionized the treatment of relapsed/refractory multiple myeloma (RRMM). However, data on cellular (CAR) T cell dynamics and the association with response, resistance or the occurrence of cytokine release syndrome (CRS) are limited. Therefore, we performed a comprehensive flow cytometry analysis of 27 RRMM patients treated with Idecabtagene vicleucel (Ide-cel) to assess the expansion capacity, persistence and effects on bystander cells of BCMA-targeting CAR T cells. Additionally, we addressed side effects, like cytokine release syndrome (CRS) and cytopenia. Our results show that in vivo expansion of CD8+ CAR T cells is correlated to response, however persistence is not essential for durable remission in RRMM patients. In addition, our data provide evidence, that an increased fraction of CD8+ T cells at day of leukapheresis in combination with successful lymphodepletion positively influence the outcome. We show that patients at risk for higher-grade CRS can be identified already prior to lymphodepletion. Our extensive characterization contributes to a better understanding of the dynamics and effects of BCMA-targeting CAR T cells, in order to predict the response of individual patients as well as side effects, which can be counteracted at an early stage or even prevented.
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Imunoterapia Adotiva , Mieloma Múltiplo , Humanos , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/métodos , Mieloma Múltiplo/tratamento farmacológico , Linfócitos T CD8-Positivos , Síndrome da Liberação de Citocina , Antígeno de Maturação de Linfócitos BRESUMO
OBJECTIVES: Treatment intensification (including consolidative high-dose chemotherapy with autologous stem cell transplantation [HDT-ASCT]) significantly improved outcome in primary central nervous system lymphoma (PCNSL) patients. METHODS: We conducted a multicenter, retrospective analysis of newly diagnosed PCNSL patients, treated with intensified treatment regimens. The following scores were evaluated in terms of overall survival (OS) and progression-free survival (PFS): Memorial Sloan-Kettering Cancer Center (MSKCC), International Extranodal Lymphoma Study Group (IELSG), and three-factor (3F) prognostic score. Further, all scores were comparatively investigated for model quality and concordance. RESULTS: Altogether, 174 PCNSL patients were included. One hundred and five patients (60.3%) underwent HDT-ASCT. Two-year OS and 2-year PFS for the entire population were 73.3% and 48.5%, respectively. The MSKCC (p = .003) and 3F score (p < .001), but not the IELSG score (p = .06), had the discriminatory power to identify different risk groups for OS. In regard to concordance, the 3F score (C-index [0.71]) outperformed both the MSKCC (C-index [0.64]) and IELSG (C-index [0.53]) score. Moreover, the superiority of the 3F score was shown for PFS, successfully stratifying patients in three risk groups, which also resulted in the highest C-index (0.66). CONCLUSION: The comparative analysis of established PCNSL risk scores affirm the clinical utility of the 3F score stratifying the widest prognostic spectrum among PCNSL patients treated with intensified treatment approaches.
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Neoplasias do Sistema Nervoso Central , Transplante de Células-Tronco Hematopoéticas , Linfoma , Humanos , Transplante de Células-Tronco Hematopoéticas/métodos , Prognóstico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias do Sistema Nervoso Central/terapia , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Estudos Retrospectivos , Transplante Autólogo , Linfoma/terapia , Linfoma/tratamento farmacológicoRESUMO
The introduction of chimeric antigen receptor (CAR) T cells revolutionized treatment of relapsed and refractory multiple myeloma (RRMM) in recent years. Currently, two CAR T cell products-idecabtagene vicleucel and ciltacabtagene autoleucel-are approved in the United States and the European Union to treat patients with three prior lines of therapy, including a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 antibody. Moreover, seminal phase III trials of both agents in earlier lines of therapy have been published recently. Despite unprecedented rates of deep and lasting remissions in RRMM, there are still areas of uncertainty regarding the optimal use and distribution of CAR T cells in multiple myeloma. In the current review, we discuss the available data on approved CAR T cell products as well as unmet clinical needs and ongoing developments to optimize usage of this promising treatment modality in multiple myeloma.
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Mieloma Múltiplo , Humanos , Mieloma Múltiplo/terapia , Imunoterapia Adotiva , Antivirais , Terapia de Alvo Molecular , Inibidores de ProteassomaRESUMO
Introduction: In patients with a clinical indication for autologous hematopoietic stem cell transplantation (ASCT), sufficient mobilization of CD34+ precursor cells into peripheral blood is essential to ensure adequate hematopoietic stem cell (HSC) collection prior to intensive therapy. However, with standard granulocyte-colony stimulating factor (G-CSF)-based mobilization schemes, an important minority of patients fail to mobilize sufficient (e.g., >10/µL) CD34+ cell counts into the peripheral blood and are considered as poor mobilizers (PM). Because failure to achieve sufficient CD34+ cell mobilization can negatively affect important clinical treatment endpoints, the use of plerixafor (PLX) was approved to increase CD34+ mobilization in PM patients. Methods: The German non-interventional, multicenter, open-label, prospective OPTIMOB study evaluated HSC mobilization strategies prior to planned ASCT in adult patients with hematologic malignancies (lymphomas or multiple myeloma [MM]) focusing on PM patients. PM patients were defined as follows: (1) never achieving ≥20 CD34+ cells/µL before 1st apheresis, (2) receiving PLX at any timepoint of mobilization, (3) their initially planned stem cell yield had to be reduced, or (4) they had not received apheresis due to low CD34+ count in peripheral blood. Results: 168 of 475 MM patients (35%) participating in the OPTIMOB study were classified as PM, and 155 of them (92%) received PLX (PM+PLX) during the study. PM patients were 40-78 years old, slightly more often male (n = 97, 58%), mostly newly diagnosed (n = 146, 87%) and received highly individualized previous treatments. Ninety-four of the PMs underwent chemotherapy mobilization (65%), and 51 patients (35%) received steady-state mobilization with G-CSF only during 1st mobilization attempt. 92% of the total PM population (n = 155) underwent apheresis, 78% of them (n = 117) achieved >2.0 × 106 CD34+ cells/kg body weight on the 1st day of apheresis. PM+PLX had a higher median total collection result than those PM patients without PLX support (7.2 vs. 5.7 × 106 CD34+ cells/kg body weight). In total, ASCT was performed in 136 PM+PLX (88%) versus 8 PM-PLX patients (62%). Conclusion: The OPTIMOB study showed that a considerable proportion of adult MM patients in Germany are PMs. Even though most of PMs were supported with PLX in the OPTIMOB study, PM-PLX also successfully mobilized HSCs, allowing ASCT in majority of all PMs. However, further analyses are required for treatment optimization in PMs.
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Background: Hematological cancer patients must comply with extensive medical instructions to prevent cancer progression or relapse. Psychological comorbidities and patient characteristics have been shown to affect compliance. However, the impact of posttraumatic stress disorder (PTSD) and adjustment disorder (AjD) on compliance in cancer patients remains unclear. This study aims to evaluate compliance in hematological cancer patients more comprehensively and to investigate its association with PTSD and AjD symptomatology as well as sociodemographic and medical factors. Methods: Hematological cancer patients were cross-sectionally assessed via validated questionnaires for PTSD (PCL-5) and AjD (ADMN-20), and three internally developed items on compliance with medical regimen, with two referring to compliance behavior and one item assessing perceived difficulties with complying. Each compliance item was analyzed descriptively. Multiple linear regression models tested the association between compliance and PTSD and AjD symptomatology, sociodemographic and medical factors. Results: In total, 291 patients were included (response rate 58%). Nine out of ten patients reported to either never (67%) or rarely (25%) change their medical regimen. However, 8% reported to change it once in a while or often. Compliance behavior was mostly rated as very easy (36%) or easy (45%) to implement. Nevertheless, 19% perceived it to be partly difficult or difficult to follow medical regimen. Symptoms of AjD (ß = 0.31, p < 0.001) were associated with more difficulties to comply. Higher compliance behavior in turn was associated with stem cell transplantation (SCT) treatment (ß = -0.21, p < 0.001) and lower education (ß = -0.19, p = 0.002). Conclusion: Although most patients indicated that they comply with medical regimen, a considerable subgroup of patients indicated subjectively perceived difficulties and thus seem to require additional support in implementing medical instructions possibly through improved medical communication and patient health literacy or shared decision-making.
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Introduction: Successful mobilization and collection of peripheral hematopoietic stem cells (HSCs) are necessary for lymphoma patients eligible for myeloablative chemotherapy with subsequent autologous stem cell transplantation (ASCT). Albeit G-CSF alone or combined with chemotherapy is well-established methods for HSC mobilization, up to 40% of the patients fail to mobilize (poor mobilizer, PM). Plerixafor (PLX) is commonly used in PM patients resulting in increased migration of HSCs into peripheral blood and thus improves the collection outcome. Methods: The prospective, multicenter, open-label, non-interventional OPTIMOB study assessed mobilization and collection parameter of patients with lymphoma or multiple myeloma to get deep insights in the treatment of those patients in clinical routine focusing on PM patients. PM was defined as follows: (1) no achievement of ≥20 CD34+ progenitor cells/µL before first apheresis, (2) PLX administration at any time point during the observational period, (3) reduction of the initially planned CD34+ progenitor cell yield as necessity due to failed mobilization or HSC collection, and (4) no performance of apheresis due to low CD34+ progenitor level. Primary objective of the study was to assess mobilization success by the proportion of PM patients achieving >2 × 106 CD34+ progenitor cells/kg body weight on the first day of apheresis. Here, the data of the lymphoma cohort are presented. Results: Out of 238 patients with lymphoma documented in the study, 32% were classified as PM. 87% of them received PLX. Demographic data revealed no obvious differences between PM and good mobilizing (GM) patients. All patients were treated highly individualized prior to mobilization. Majority of all PM patients were able to undergo apheresis (95%) and reached their individual requested CD34+ progenitor cell target (72%). 57% of the PM patients achieved >2.0 × 106 CD34+ progenitor cells/kg body weight on day 1 of apheresis and nearby 70% of them underwent ASCT. Median time to engraftment was similar in PM and GM patients of the lymphoma cohort. Conclusions: Majority of PM patients with lymphoma were successfully mobilized and underwent ASCT. Most of them received PLX during the study.
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BACKGROUND: The incorporation of anti-CD38 monoclonal antibodies (mAb) in induction regimens of newly diagnosed transplant-eligible multiple myeloma (MM) patients has been established as a new standard. However, the optimal strategy of stem cell mobilization in this context is not yet clear. STUDY DESIGN AND METHODS: From May 2020 till September 2022, we retrospectively reviewed patients receiving anti-CD38 mAb-based induction therapy followed by stem cell mobilization either in a steady-state protocol (SSM) using 10 µg/kg granulocyte colony-stimulating factor (G-CSF) for 5 days or in a chemotherapy-based protocol (CM) using 1-4 g/m2 cyclophosphamide and G-CSF. RESULTS: Overall, 85 patients (median age 61 years) were included in the analysis. In total, 90 mobilization attempts were performed, 42 with SSM and 48 with CM. There was no significant difference in the median concentration of CD34+ cells in peripheral blood (PB) prior to apheresis between SSM and CM (61/µL vs. 55.4/µL; p = .60). Cumulative CD34+ yields did not differ between the groups with median of 6.68 and 6.75 × 106 /kg body weight, respectively (p = .35). The target yield (≥4 × 106 CD34+ cells/kg body weight) was reached in 88% (CM) and 86% (SSM), with a high proportion even after a single apheresis session (76% vs. 75%). Plerixafor was found to be more frequently used in SSM (52%) than in CM (23%; p < .01). A total of 83 patients underwent autologous transplantation and all were engrafted. CONCLUSIONS: Stem cell collection in patients undergoing anti-CD38-based induction therapy is feasible with either CM or SSM, although SSM more frequently requires plerixafor.
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Antineoplásicos , Transplante de Células-Tronco Hematopoéticas , Compostos Heterocíclicos , Mieloma Múltiplo , Humanos , Pessoa de Meia-Idade , Mieloma Múltiplo/tratamento farmacológico , Mobilização de Células-Tronco Hematopoéticas/métodos , Quimioterapia de Indução , Estudos Retrospectivos , Compostos Heterocíclicos/uso terapêutico , Antineoplásicos/uso terapêutico , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Fator Estimulador de Colônias de Granulócitos/farmacologia , Antígenos CD34/metabolismo , Transplante Autólogo , Peso CorporalRESUMO
Recent evidence revealed important interactions between clonal hematopoiesis (CH) and cellular therapies established for the treatment of hematologic malignancies. The impact of CH on safety, efficacy, and outcome of chimeric antigen receptor (CAR) T-cell therapy is currently under investigation. We analyzed 110 patients with relapsed/refractory B-cell non-Hodgkin lymphoma (n = 105) or acute lymphoblastic leukemia (ALL) (n = 5), treated with Axicabtagene-Ciloleucel (39%), Tisagenlecleucel (51%), or Brexucabtagene autoleucel (10%). Using error-corrected targeted sequencing, a high CH prevalence of 56.4% (variant allele frequency [VAF] ≥1%) at the time of CAR T-cell infusion was detected. The most frequently mutated gene was PPM1D followed by DNMT3A, TET2, ASXL1, and TP53. Variant allele frequencies were significantly lower in B and T cells compared with monocytes and granulocytes. CH did not increase the risk of CAR T-related toxicities. The incidences of cytokine release syndrome and immune effector-cell-associated neurotoxicity syndrome were similar between CHpos and CHneg patients, regardless of clone size, age, or CAR T product. Prolonged cytopenias were not associated with CH. Best overall response rates (ORRs) were numerically but not significantly higher in CHpos patients (ORR 76.7% versus 62.2%; P = 0.13). Furthermore, CH status did not predict progression-free survival or overall survival. Lastly, sequential analysis showed a modest VAF increase of 1.3% and acquisition of novel mutations within 100 days postinfusion. CH was frequent in large B-cell lymphoma/ALL patients receiving CAR T-cells but did not affect toxicity nor treatment response or outcome.
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The outcome of patients with large B cell lymphoma (LBCL) who relapse or progress after CD19-directed chimeric antigen receptor T cell therapy (CAR-T) administered as salvage therapy beyond the second treatment line is poor. However, a minority of patients become long-term survivors despite CAR-T failure. The German Lymphoma Alliance (GLA) has proposed a hierarchical management algorithm for CAR-T failure in LBCL, aimed at allogeneic hematopoietic cell transplantation (alloHCT) as definite therapy in eligible patients. The purpose of this study was to investigate characteristics, relapse patterns, and management strategies in long-term survivors after CAR-T failure, with a particular focus on the feasibility and outcome of alloHCT. This was a retrospective analysis of all evaluable patients with a relapse/progression event (REL) observed in a previously reported GLA sample between November 2018 and May 2021. REL occurred in 214 of 356 patients (60%) who underwent CAR-T for LBCL in the previous GLA study. An evaluable dataset was available for 143 of these 214 patients (67%). Twenty-six of 143 patients (18%) survived 12 months or longer from REL, 109 (76%) died within the first year after REL, and 8 (6%) were alive but had not reached the 12-month landmark. Long-term survivors had more favorable pre-CAR-T features, had a longer interval between CAR-T and REL, and had more often received a tumor biopsy after CAR-T failure, whereas the choice of the first salvage regimen had no impact. AlloHCT was feasible in 40 of 53 patients (75%) intended and resulted in a 12-month post-transplantation overall survival of 36% in those patients who underwent transplantation with sensitive or untreated REL. AlloHCT after CAR-T failure in LBCL is feasible and may be an important contributor to long-term survival, although selection bias must be taken into account. Thus, alloHCT should be considered as a reasonable treatment option for eligible patients in this setting. However, because the overall outlook after CAR-T failure remains poor, novel effective therapeutic approaches are needed, either to allow long-term disease control per se or to improve the preconditions for successful alloHCT.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Linfoma Difuso de Grandes Células B , Receptores de Antígenos Quiméricos , Humanos , Estudos Retrospectivos , Recidiva Local de Neoplasia/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Linfoma Difuso de Grandes Células B/terapia , Sistema de Registros , Recidiva , SobreviventesRESUMO
Type B insulin resistance (TBIR) is a rare, often fulminant form of insulin resistance caused by autoantibodies against the insulin receptor. If left untreated, its mortality is high. Various immunosuppressive regimens have shown efficacy, but treatment effects are variable and time-delayed, and drug-induced complications may arise. We report a patient with TBIR arising as a complication of Wiskott-Aldrich syndrome. Stable remission of TBIR was achieved through allogeneic peripheral blood stem cell transplantation (PBSCT) over a follow-up period of more than 1.5 years. We thus demonstrate that PBSCT can be considered a treatment option in TBIR where conventional immunosuppressive therapy is ineffective or contraindicated.