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BACKGROUND & AIMS: Patients with autoimmune hepatitis (AIH) almost invariably require lifelong immunosuppressive treatment. There is genuine concern about the efficacy and tolerability of the current standard combination therapy of prednisolone and azathioprine. Mycophenolate mofetil (MMF) has emerged as an alternative option. The aim of this study was to compare MMF to azathioprine as induction therapy for AIH. METHODS: In this 24-week, prospective, randomised, open-label, multicentre superiority trial, 70 patients with treatment-naive AIH received either MMF or azathioprine, both in combination with prednisolone. The primary endpoint was biochemical remission defined as normalisation of serum levels of alanine aminotransferase and IgG after 24 weeks of treatment. Secondary endpoints included safety and tolerability. RESULTS: Seventy patients (mean 57.9 years [SD 14.0]; 72.9% female) were randomly assigned to the MMF plus prednisolone (n = 39) or azathioprine plus prednisolone (n = 31) group. The primary endpoint was met in 56.4% and 29.0% of patients assigned to the MMF group and the azathioprine group, respectively (difference, 27.4 percentage points; 95% CI 4.0 to 46.7; p = 0.022). The MMF group exhibited higher complete biochemical response rates at 6 months (72.2% vs. 32.3%; p = 0.004). No serious adverse events occurred in patients who received MMF (0%) but serious adverse events were reported in four patients who received azathioprine (12.9%) (p = 0.034). Two patients in the MMF group (5.1%) and eight patients in the azathioprine group (25.8%) discontinued treatment owing to adverse events or serious adverse events (p = 0.018). CONCLUSIONS: In patients with treatment-naive AIH, MMF with prednisolone led to a significantly higher rate of biochemical remission at 24 weeks compared to azathioprine combined with prednisolone. Azathioprine use was associated with more (serious) adverse events leading to cessation of treatment, suggesting superior tolerability of MMF. IMPACT AND IMPLICATIONS: This randomised-controlled trial directly compares azathioprine and mycophenolate mofetil, both in combination with prednisolone, for the induction of biochemical remission in treatment-naive patients with autoimmune hepatitis. Achieving complete remission is desirable to prevent disease progression. Patients assigned to the mycophenolate mofetil group reached biochemical remission more often and experienced fewer adverse events. The findings in this trial may contribute to the re-evaluation of international guidelines for the standard of care in treatment-naive patients with autoimmune hepatitis. TRIAL REGISTRATION NUMBER: #NCT02900443.
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Azatioprina , Hepatitis Autoinmune , Humanos , Femenino , Masculino , Azatioprina/uso terapéutico , Ácido Micofenólico/efectos adversos , Hepatitis Autoinmune/tratamiento farmacológico , Estudios Prospectivos , Resultado del Tratamiento , Inmunosupresores/efectos adversos , Prednisolona/efectos adversos , Inducción de RemisiónRESUMEN
We conducted a phase I trial in newly diagnosed acute myeloid leukaemia (AML) to investigate the combination of two novel targeted agents, gemtuzumab ozogamicin (GO) and midostaurin, with intensive chemotherapy in FLT3-mutated AML and CBF leukaemia. Three dose levels of midostaurin and one to three sequential doses of 3 mg/m2 GO in combination with '7 + 3' induction were evaluated. Based on safety findings in 12 patients, our results show that 3 mg/m2 GO on Days 1 + 4 and 100 mg midostaurin on Days 8-21 can be safely combined with IC in newly diagnosed AML.
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Protocolos de Quimioterapia Combinada Antineoplásica , Gemtuzumab , Leucemia Mieloide Aguda , Estaurosporina , Humanos , Estaurosporina/análogos & derivados , Estaurosporina/administración & dosificación , Estaurosporina/uso terapéutico , Estaurosporina/efectos adversos , Gemtuzumab/administración & dosificación , Gemtuzumab/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Masculino , Persona de Mediana Edad , Femenino , Anciano , Adulto , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/efectos adversos , Quimioterapia de Inducción , Tirosina Quinasa 3 Similar a fms/genética , Aminoglicósidos/administración & dosificación , Aminoglicósidos/uso terapéuticoRESUMEN
BACKGROUND: Several international high-volume centers have reported good outcomes after resection of locally advanced pancreatic cancer (LAPC) following chemo(radio)therapy, but it is unclear how this translates to nationwide clinical practice and outcome. This study aims to assess the nationwide use and outcome of resection of LAPC following induction chemo(radio)therapy. PATIENTS AND METHODS: A multicenter retrospective study including all patients who underwent resection for LAPC following chemo(radio)therapy in all 16 Dutch pancreatic surgery centers (2014-2020), registered in the mandatory Dutch Pancreatic Cancer Audit. LAPC is defined as arterial involvement > 90° and/or portomesenteric venous > 270° involvement or occlusion. RESULTS: Overall, 142 patients underwent resection for LAPC, of whom 34.5% met the 2022 National Comprehensive Cancer Network criteria. FOLFIRINOX was the most commonly (93.7%) used chemotherapy [median 5 cycles (IQR 4-8)]. Venous and arterial resections were performed in 51.4% and 14.8% of patients. Most resections (73.9%) were performed in high-volume centers (i.e., ≥ 60 pancreatoduodenectomies/year). Overall median volume of LAPC resections/center was 4 (IQR 1-7). In-hospital/30-day major morbidity was 37.3% and 90-day mortality was 4.2%. Median OS from diagnosis was 26 months (95% CI 23-28) and 5-year OS 18%. Surgery in high-volume centers [HR = 0.542 (95% CI 0.318-0.923)], ypN1-2 [HR = 3.141 (95% CI 1.886-5.234)], and major morbidity [HR = 2.031 (95% CI 1.272-3.244)] were associated with OS. CONCLUSIONS: Resection of LAPC following chemo(radio)therapy is infrequently performed in the Netherlands, albeit with acceptable morbidity, mortality, and OS. Given these findings, a structured nationwide approach involving international centers of excellence would be needed to improve selection of patients with LAPC for surgical resection following induction therapy.
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Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/cirugía , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Quimioterapia de Inducción , Estudios Retrospectivos , Fluorouracilo/uso terapéutico , Leucovorina/uso terapéutico , Países Bajos/epidemiologíaRESUMEN
BACKGROUND: The use of surgery in patients with locally advanced pancreatic cancer (LAPC) following induction chemotherapy is increasing. However, most series do not report on the total cohort of patients undergoing surgical exploration; therefore, this single-center study investigates outcomes among all consecutive patients with LAPC who underwent surgical exploration. METHODS: We conducted a retrospective, single-center analysis including all consecutive patients with LAPC (Dutch Pancreatic Cancer Group criteria) who underwent surgical exploration with curative intent (January 2014-June 2023) after induction therapy. Primary outcomes were resection rate and overall survival (OS) from the time of diagnosis. RESULTS: Overall, 127 patients underwent surgical exploration for LAPC, whereby 100 patients (78.7%) underwent resection and 27 patients (21.3%) underwent a non-therapeutic laparotomy due to the extent of vascular involvement (n = 11, 8.7%) or occult metastases (n = 16, 12.6%). The overall in-hospital/30-day mortality rate was 0.8% and major morbidity was 31.3% (in patients after resection: 1.0% and 33.3%, respectively). The overall 90-day mortality rate was 5.5%, which included 3.1% mortality due to disease progression. Resection was associated with longer median OS {29 months (95% confidence interval [CI] 26-43) vs. 17 months (95% CI 11-26); p < 0.001} compared with patients undergoing non-therapeutic laparotomy, with corresponding 5-year OS rates of 28.4% and 7.7%. In Cox proportional hazard regression analysis, only pancreatic body/tail tumors independently predicted OS (hazard ratio 1.788 [95% CI 1.042-3.068]). CONCLUSION: This single-center series found a resection rate of 78.7% in patients with LAPC selected for surgical exploration, with a low risk of mortality and morbidity in all explored patients and a 5-year OS rate after resection of 28.4%.
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Protocolos de Quimioterapia Combinada Antineoplásica , Quimioterapia de Inducción , Pancreatectomía , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/cirugía , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/mortalidad , Masculino , Femenino , Estudios Retrospectivos , Tasa de Supervivencia , Persona de Mediana Edad , Anciano , Estudios de Seguimiento , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Pronóstico , Terapia Neoadyuvante/mortalidad , AdultoRESUMEN
BACKGROUND: Definitive chemoradiotherapy is recommended as the primary treatment for cervical esophageal carcinoma (CEC). However, local control rates remain unsatisfactory for some patients. Therefore, in this study, we introduced a new treatment paradigm for individuals with CEC, customizing the choice between subsequent local treatments based on their response to induction chemotherapy and immunotherapy. PATIENTS AND METHODS: Induction treatment comprised two to four cycles of chemotherapy combined with programmed cell death protein 1 (PD-1) inhibitors. Patients achieving complete response (CR) or near CR after induction treatment underwent definitive chemoradiotherapy (dCRT), while those not achieving CR or near CR underwent surgical resection. RESULTS: Among the 40 eligible patients, 14 (35.0%) achieved a CR or near CR after induction treatment. Of the ten patients achieving a CR or near CR, one developed an esophageal fistula after dCRT (10.0%). Among the eight non-CR or non-near CR patients receiving chemoradiotherapy, six developed esophageal fistula (75.0%). Among the 26 patients who did not achieve CR or near CR after induction treatment, the 1-year cancer specific survival (CSS) rates were 93.3% [95% confidence interval (CI) 0.815-1%] for the 18 patients in the surgery group, and 71.4% (95% CI 0.447-1%) for the 8 patients in the chemoradiotherapy group (p = 0.027). The overall laryngeal preservation rate was 85.0% (34/40), with a functional laryngeal preservation rate of 77.5% (31/40). CONCLUSION: The approach consisting of combined immunotherapy and chemotherapy successfully identified patients who were responding well to induction treatment and who were sensitive to radiotherapy, for chemoradiotherapy; thus, improving laryngeal preservation rates. In addition, it also identified patients with poor responses to induction treatment and radiotherapy, for timely surgery; hence, reducing radiotherapy complications and enhancing survival.
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Hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory syndrome with high mortality rate. The response to induction therapy is an important factor affecting survival. The purpose is to investigate laboratory predictors for induction response in adult patients with HLH, which are convenient, practical, and timeliness. Clinical data from January 2017 to December 2020 was retrospectively analyzed, and 269 patients were included. Patients were divided into remission and non-remission groups according to their induction response, 177 in the remission group, and 92 in the non-remission group. We reviewed general characteristics and analyzed the predictive value of serum ferritin, triglycerides, alanine aminotransferase (ALT), and blood cells before and 1-4 weeks after induction therapy for induction response by univariate analysis, ROC curves, etc. There was a correlation between serum ferritin, ALT, leukocytes, neutrophils, hemoglobin, platelets, and induction response (P < 0.05). Serum ferritin and platelets 1-4 weeks after induction therapy, respectively, might be a good predictor for induction response in adults with HLH, with AUC values close to or greater than 0.7. We established a new clinical model of the ferritin/platelet ratio. The results showed that the ferritin/platelet ratio at 1-4 weeks after induction therapy might be a practical index for predicting induction response, which significantly improved the area under the ROC curve (AUC > 0.75). Patients with a ferritin/platelet ratio > 16.08 at 2 weeks after induction therapy may have a relatively poor induction response. Ferritin/platelet ratio after induction therapy can be a good predictor for induction response in adult patients with HLH.
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Linfohistiocitosis Hemofagocítica , Adulto , Humanos , Linfohistiocitosis Hemofagocítica/diagnóstico , Estudios Retrospectivos , Ferritinas , Curva ROC , LeucocitosRESUMEN
BACKGROUND: The use of induction therapy (IT) agents in the early post-heart transplant period remains controversial. The following recommendations aim to provide guidance on the use of IT agents, including Basiliximab and Thymoglobulin, as part of routine care in heart transplantation (HTx). METHODS: We recruited an international, multidisciplinary panel of 15 stakeholders, including patient partners, transplant cardiologists and surgeons, nurse practitioners, pharmacists, and methodologists. We commissioned a systematic review on benefits and harms of IT on patient-important outcomes, and another on patients' values and preferences to inform our recommendations. We used the GRADE framework to summarize our findings, rate certainty in the evidence, and develop recommendations. The panel considered the balance between benefits and harms, certainty in the evidence, and patient's values and preferences, to make recommendations for or against the routine post-operative use of Thymoglobulin or Basiliximab. RESULTS: The panel made recommendations on three major clinical problems in HTx: (1) We suggest against the routine post-operative use of Basiliximab compared to no IT, (2) we suggest against the routine use of Thymoglobulin compared to no IT, and (3) for those patients for whom IT is deemed desirable, we suggest for the use of Thymoglobulin as compared to Basiliximab. CONCLUSION: This report highlights gaps in current knowledge and provides directions for clinical research in the future to better understand the clinical utility of IT agents in the early post heart transplant period, leading to improved management and care.
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Trasplante de Corazón , Quimioterapia de Inducción , Humanos , Metaanálisis en Red , Basiliximab , Trasplante de Corazón/efectos adversos , CorazónRESUMEN
BACKGROUND: This study aimed to compare the efficacy and safety of basiliximab (BAS) versus a single dose of anti-thymocyte globulin (r-ATG) induction therapy in pediatric kidney transplant recipients (KTRs). METHODS: This single-center retrospective comparative cohort study included all pediatric KTRs from May 2013 to April 2018 and followed up to 12 months. In the first period, all recipients received BAS, while from May 2016, a single 3 mg/kg dose of r-ATG was instituted. Maintenance therapy consisted of a calcineurin inhibitor plus prednisone plus azathioprine or mycophenolate. RESULTS: A total of 227 patients were included (BAS, n = 113; r-ATG, n = 114). The main combination of immunosuppressive drugs was tacrolimus, prednisone, and azathioprine in both groups (87% vs. 88%, p = .718). Patients receiving r-ATG showed superior survival-free of the composite endpoint (acute rejection, graft loss, or death; 76% vs. 61%, p = .003; HR 2.08, 1.29-3.34, p = .003) and lower incidence of biopsy-proven acute rejection (10% vs. 21%, p = .015). There was no difference in the overall incidence of CMV infection (33% vs. 37%, p = .457), PTLD (1% vs. 3%, p = .309), 30-day hospital readmissions (24% vs. 23%, p = .847), and kidney function at 12 months (86 ± 29 vs. 84 ± 30 mL/min/1.73m2, p = .614). CONCLUSIONS: These data suggest that induction therapy with a single 3 mg/kg dose of r-ATG is associated with higher efficacy for preventing acute rejection and similar safety profile compared to BAS.
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Suero Antilinfocítico , Trasplante de Riñón , Humanos , Niño , Basiliximab/uso terapéutico , Suero Antilinfocítico/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Prednisona/uso terapéutico , Estudios Retrospectivos , Estudios de Cohortes , Azatioprina , Quimioterapia de Inducción , Rechazo de Injerto/prevención & control , Rechazo de Injerto/epidemiología , Inmunosupresores/uso terapéutico , Proteínas Recombinantes de Fusión/uso terapéutico , Receptores de TrasplantesRESUMEN
Although granulocyte colony-stimulating factor (G-CSF) reduces the incidence, duration, and severity of neutropenia, its prophylactic use for acute myeloid leukemia (AML) remains controversial due to a theoretically increased risk of relapse. The present study investigated the effects of G-CSF as primary prophylaxis for AML with remission induction therapy. A detailed literature search for related studies was performed using PubMed, Ichushi-Web, and the Cochrane Library. Data were independently extracted and assessed by two reviewers. A qualitative analysis of pooled data was conducted, and the risk ratio with corresponding confidence intervals was calculated in the meta-analysis and summarized. Sixteen studies were included in the qualitative analysis, nine of which were examined in the meta-analysis. Although G-CSF significantly shortened the duration of neutropenia, primary prophylaxis with G-CSF did not correlate with infection-related mortality. Moreover, primary prophylaxis with G-CSF did not affect disease progression/recurrence, overall survival, or adverse events, such as musculoskeletal pain. However, evidence to support or discourage the use of G-CSF as primary prophylaxis for adult AML patients with induction therapy remains limited. Therefore, the use of G-CSF as primary prophylaxis can be considered for adult AML patients with remission induction therapy who are at a high risk of infectious complications.
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Factor Estimulante de Colonias de Granulocitos , Leucemia Mieloide Aguda , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Inducción de Remisión , Guías de Práctica Clínica como Asunto , Quimioterapia de Inducción , Japón , Neutropenia/inducido químicamente , Neutropenia/prevención & controlRESUMEN
OBJECTIVE: Although sporadic case reports have demonstrated successful management of eosinophilic granulomatosis with polyangiitis (EGPA) by anti-IL-5 therapy, larger-scale monocentric studies for the efficacy of mepolizumab (MEP), an IL-5 monoclonal antibody, are still lacking in Taiwan. METHODS: Hospitalized EGPA patients aged at least 18 years were enrolled from November 1998 to October 2023, and analyzed for demographic, clinical, laboratory, medication and outcome data, focusing on the efficacy and safety of biologics use, particularly induction therapy with MEP. RESULTS: Twenty-seven EGPA patients aged 10-70 years (43 ± 15) at disease diagnosis were recruited with 21 under combined corticosteroids/cyclophosphamide induction therapy. Seventeen patients received biologics with 13 under MEP therapy. Ten patients aged 19-71 years (48 ± 15) completed 12-month induction therapy with a 100 mg quadri-weekly subcutaneous injection regimen indicated for active or relapse disease. There were reduced BVAS with complete remission in 6 and partial remission in 4 patients, lower CRP levels, decreased eosinophil counts with an inhibition of 92â¼96 %, and tapered prednisolone dosages from 5 to 25 (13.0 ± 6.3) to 0-10 (3.3 ± 3.1) mg/day. Only one patient had an adverse event of injection site reactions. Nine patients received the same regimen for annual maintenance therapy. All had a persistent clinical remission. In these patients, 13-56 injections (41 ± 15) were prescribed with a follow-up period of 12â¼52 months (38 ± 14). CONCLUSION: In this retrospective study, induction therapy with a 12-month 100 mg MEP quadri-weekly subcutaneous injection regimen demonstrates the efficacy and safety for active and relapsing EGPA patients.
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Anticuerpos Monoclonales Humanizados , Granulomatosis con Poliangitis , Interleucina-5 , Humanos , Persona de Mediana Edad , Masculino , Femenino , Adulto , Interleucina-5/antagonistas & inhibidores , Anciano , Adolescente , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/administración & dosificación , Adulto Joven , Granulomatosis con Poliangitis/tratamiento farmacológico , Taiwán , Niño , Resultado del Tratamiento , Estudios Retrospectivos , Ciclofosfamida/uso terapéutico , Ciclofosfamida/administración & dosificación , Síndrome de Churg-Strauss/tratamiento farmacológico , Inducción de Remisión , Eosinófilos , Quimioterapia de Inducción , Quimioterapia CombinadaRESUMEN
Introduction: Eurotransplant established the acceptable mismatch (AM) program to facilitate timely kidney transplantations of highly sensitized patients, but long-term granular clinical and immunological outcomes regarding overall graft survival and de novo DSA (dnDSA) formation are still intensively researched. The right choice of induction therapy in patients with differing immunological risk is not conclusively determined, as well as the impact of human leukocyte antigen (HLA) epitope matching on dnDSA formation. Methods: This monocentric, retrospective study analyzed 94 patients transplanted within the AM program between 2000 and 2019 compared to case-control matched cohorts of non- (PRA 0-5%; PRA-0) and intermediately sensitized (PRA 6-84%; PRA-6/84) patients transplanted through Eurotransplant Kidney Allocation System. Results: Estimated 10-year overall graft survival between the PRA-0 and AM cohorts was similar, whereas PRA-6/84 was significantly disadvantageous compared to PRA-0. Estimated 10-year incidence of antibody-mediated rejection rates was significantly lower in the PRA-0 group compared to AM and PRA-6/84 groups. Compared to the AM group, estimated incidence of de novo donor-specific antibody (dnDSA) was significantly lower in PRA-0 patients, with no differences between the AM and PRA-6/84 cohorts. The PRA-6/84 cohort was the only subgroup in which interleukin-2 receptor antagonist (IL2RA) induction was associated with longer overall graft survival, patient survival, and graft survival compared to depleting induction (ATG or OKT3). Broad HLA-A, -B, -DR mismatches (mmABDR) and HLA epitope mismatches determined by Eplets and PIRCHE-II were predictive for dnDSA formation in the total cohort, and the AM subgroup. Discussion: The high efforts expended on AM patients are justified to allow timely organ transplantation with acceptable risk profile and non-inferior outcomes. IL2RA induction in intermediately sensitized patients is associated with superior overall graft survival, patient survival, and graft survival compared to ATG/OKT3 induction, without negative effects on rejection episodes or dnDSA formation. In silico epitope matching might further help reduce dnDSA formation, particularly in high-risk AM patients.
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BACKGROUND: Lupus nephritis (LN) is a common serious presentation of systemic lupus erythematosus. Cyclophosphamide (CYC) and mycophenolate mofetil (MMF) are listed as the first-line drugs in induction therapy for LN. OBJECTIVE: This study aimed to compare high- and low-dose CYC in a cohort of Egyptian LN patients. PATIENTS AND METHODS: The data of 547 patients with class III/IV active LN who received CYC as induction therapy were retrospectively analyzed. Whereas 399 patients received 6monthly 0.5-1â¯g/m2 CYC doses, 148 patients received six biweekly 500â¯mg CYC doses. Demographic data, laboratory test results, and disease activity index were recorded and compared at presentation and at 6, 12, 18, 24, and 48 months of follow-up. RESULTS: After 48 months, the proportion of patients maintaining normal creatinine levels was higher in the group receiving induction therapy with high-dose CYC (67.9%, 60.4%, pâ¯= 0.029), and these patients also had higher proteinuria remission at 36 (26.6%, 14.8%, pâ¯= 0.014) and 48 months (24.3%, 12.8%, pâ¯= 0.006). Comparison of patient outcomes according to both induction and maintenance therapy showed the best results in patients who received high-dose CYC and continued MMF as maintenance therapy. CONCLUSION: High- and low-dose CYC are comparable in early phases of treatment. However, after a longer duration of follow-up, high-dose CYC was associated with higher remission rates in the current cohort.
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Nefritis Lúpica , Humanos , Nefritis Lúpica/diagnóstico , Nefritis Lúpica/tratamiento farmacológico , Inmunosupresores/uso terapéutico , Estudios Retrospectivos , Egipto/epidemiología , Resultado del Tratamiento , Ciclofosfamida/efectos adversos , Ácido Micofenólico/efectos adversos , Inducción de RemisiónRESUMEN
While the bone marrow (BM) microenvironment is significantly remodelled in acute myeloid leukaemia (AML), molecular insight into AML-specific alterations in the microenvironment has been historically limited by the analysis of liquid marrow aspirates rather than core biopsies that contain solid-phase BM stroma. We assessed the effect of anthracycline- and cytarabine-based induction chemotherapy on both haematopoietic and non-haematopoietic cells directly in core BM biopsies using RNA-seq and histological analysis. We compared matched human core BM biopsies at diagnosis and 2 weeks after cytarabine- and anthracycline-based induction therapy in responders (<5% blasts present after treatment) and non-responders (≥5% blasts present after treatment). Our data indicated enrichment in vimentin (VIM), platelet-derived growth factor receptor beta (PDGFRB) and Snail family transcriptional repressor 2 (SNAI2) transcripts in responders, consistent with the reactivation of the mesenchymal population in the BM stroma. Enrichment of osteoblast maturation-related transcripts of biglycan (BGN), osteopontin (SPP1) and osteonectin (SPARC) was observed in non-responders. To the best of our knowledge, this is the first report demonstrating distinct osteogenic and mesenchymal transcriptome profiles specific to AML response to induction chemotherapy assessed directly in core BM biopsies. Detailing treatment response-specific alterations in the BM stroma may inform optimised therapeutic strategies for AML.
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Médula Ósea , Leucemia Mieloide Aguda , Humanos , Médula Ósea/patología , Transcriptoma , Leucemia Mieloide Aguda/tratamiento farmacológico , Citarabina/uso terapéutico , Células de la Médula Ósea/patología , Antraciclinas/uso terapéutico , Biopsia , Microambiente TumoralRESUMEN
Intensive chemotherapy is the backbone of induction treatment in patients with acute myeloid leukemia (AML). However, AML patients with concomitant cardiac disease may not be eligible for anthracycline-based therapies. In a small cohort of patients, we have previously shown that anthracycline-free, amsacrine-based chemotherapy TAA (thioguanine, cytarabine, amsacrine) may be as effective as cytarabine/daunorubicin for induction therapy in these patients. In this systematic retrospective single-center analysis, we documented the outcome of 31 patients with significant cardiac comorbidities including coronary heart disease or cardiomyopathy receiving TAA as induction chemotherapy. Median (range) ejection fraction (EF) was 48% (30-67%) in this cohort. Patients with EF below 30% were considered unfit for intensive induction therapy. Event-free survival (EFS), overall survival (OS), and relapse-free survival (RFS) were 1.61, 5.46, and 13.6 months respectively. Poor outcome was primarily related to a high early mortality rate within the first 30 days of therapy, mainly caused by infectious complications. TAA cannot be recommended as a substitute of standard induction for AML patients with significant concomitant cardiac disease. In the era of novel agents, alternative strategies (e.g., hypomethylating agents plus venetoclax) should be considered when anthracycline-based regimens are not suitable.
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Cardiopatías , Leucemia Mieloide Aguda , Humanos , Amsacrina , Quimioterapia de Inducción , Estudios Retrospectivos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Leucemia Mieloide Aguda/complicaciones , Leucemia Mieloide Aguda/tratamiento farmacológico , Inducción de Remisión , Cardiopatías/epidemiología , Cardiopatías/etiología , Antraciclinas/efectos adversos , CitarabinaRESUMEN
A randomized inter-group trial comparing more intensive treatment strategies to a common standard arm 3 + 7 (CSA) was conducted in patients with non-M3 AML. Untreated patients ≥ 60 years were allocated to the CSA (n = 132) or to the study group arms (n = 1154) of the AMLCG (TAD/HAM versus HAM/HAM ± G-CSF followed by TAD and maintenance) and the OSHO (intermediate-dose ara-C/mitoxantrone followed by ara-C/mitoxantrone). Median age of the 1147 eligible patients was 69 (range 60-87) years. CR/CRi status at 90 days was not significantly different between the CSA (54% (95%CI: 45-64)) and the study group arms (53% (95%CI: 47-60) and 59% (95%CI: 58-63)). The five-year event-free survival (EFS) probability (primary endpoint) was 6.2% (95%CI: 2.7-14.0) in the CSA, 7.6% (95%CI: 4.5-12.8) in study group A and 11.1% (95%CI: 9.0-13.7) in B. The 5-year OS was 17.2% (95%CI: 11.0-26.9), 17.0% (95%CI: 2.0-23.9), and 19.5% (95%CI: 16.7-22.8) in CSA, study group A and B, respectively. Neither study group differed significantly from the CSA regarding EFS, OS, or relapse-free survival. In multivariate analyses, allocation to the treatment strategy was not significantly associated with the time-to-event endpoints. The evaluation of more intensive treatment strategies did not show clinically relevant outcome differences when compared to CSA.
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Leucemia Mieloide Aguda , Mitoxantrona , Anciano , Anciano de 80 o más Años , Humanos , Persona de Mediana Edad , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Citarabina/uso terapéutico , Daunorrubicina/efectos adversos , Supervivencia sin Enfermedad , Leucemia Mieloide Aguda/tratamiento farmacológico , Mitoxantrona/efectos adversos , Pronóstico , Inducción de RemisiónRESUMEN
OBJECTIVES: To describe the clinico-pathological characteristics of non-muscle-invasive bladder cancer (NMIBC) treated in metropolitan France over 1 year when bacille Calmette-Guérin (BCG) was subject to a national quota, and to document, in the context of recurrent shortages of intravesical BCG for NMIBC, the real-life indications for adjuvant treatment. MATERIALS AND METHODS: Between February 2021 and February 2022, the French National Agency for the Safety of Medicines (ANSM) asked the French Association of Urology to propose a science-based quota solution for BCG using a clinical score. The ANSM then asked the distributor of the drug, MEDAC, to collect the scores for all patients for whom BCG was requested by healthcare institutions and to prioritize the requests for patients with the highest scores. Tumour stage, grade, size, number, time to recurrence, carcinoma in situ, age, accessibility of alternative treatments (total cystectomy, radio-chemotherapy, thermo-chemotherapy) and BCG treatment progress (initiation or maintenance) were documented for each intravesical BCG prescription. A descriptive analysis of the data collected during the quota year was performed. RESULTS: During the 1-year quota, 25 878 requests for BCG were made for 19 024 patients, 60.5% of whom were aged ≥70 years. Requests for induction and maintenance treatment accounted for 12 704 (49.1%) and 13 174 prescriptions (50.9%), respectively. NMIBC treated with BCG maintenance therapy was more frequently high-risk NMIBC (91.7% vs 90.2%; P < 0.0001) than NMIBC for which induction therapy was requested. The number of cases of NMIBC leading to BCG adjuvant treatment was estimated at 12 704 cases/66 062 188 inhabitants over 1 year in metropolitan France. CONCLUSIONS: Our data suggest that the incidence of NMIBC at high risk of recurrence and progression is underestimated in reference epidemiological studies. These results should help to better define future care needs.
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Neoplasias Vesicales sin Invasión Muscular , Neoplasias de la Vejiga Urinaria , Humanos , Administración Intravesical , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/patología , Vejiga Urinaria/patología , Adyuvantes Inmunológicos/uso terapéutico , Francia/epidemiología , Vacuna BCG/uso terapéutico , Invasividad Neoplásica/patología , Recurrencia Local de Neoplasia/patologíaRESUMEN
OBJECTIVES AND METHODS: Venous thromboembolic (VTE) events are emerging as frequent complications in acute myeloid leukemia (AML); however, there is insufficient data regarding epidemiology, risk factors, and impact on outcomes. The optimal approach to balance risks of thrombosis and hemorrhage remains unclear. This retrospective single-center study in AML patients undergoing induction chemotherapy between 2007 and 2018 assessed incidence, risk factors, features, and outcomes of early-onset VTE. RESULTS: 423 patients (median age 59 years) were enrolled. VTE was diagnosed in 31 patients (7.3%) within 3 months of admission. The median time to VTE was 3 days. Non-central venous catheter (CVC)-related VTE occurred in 19 patients (61%). Main risk factor for VTE was leukocytosis at admission, independent of platelet counts/INR. Four patients (13%) exhibited VTE recurrence. No deaths directly related to VTE or major bleeding events associated with platelet-adjusted anticoagulation in patients with VTE were recorded. There was no clear impact of VTE on 1-year overall survival; however, non-CVC-related VTE may be associated with adverse outcomes. CONCLUSIONS: Early-onset VTE is a common complication in newly diagnosed AML patients admitted for induction chemotherapy. Leukocytosis is an independent VTE risk factor. The potentially adverse impact of non-CVC-related VTE merits further study.
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Leucemia Mieloide Aguda , Tromboembolia Venosa , Trombosis de la Vena , Humanos , Persona de Mediana Edad , Tromboembolia Venosa/epidemiología , Estudios Retrospectivos , Quimioterapia de Inducción , Leucocitosis , Trombosis de la Vena/etiología , Leucemia Mieloide Aguda/tratamiento farmacológico , Hemorragia/tratamiento farmacológico , Factores de Riesgo , Anticoagulantes/efectos adversosRESUMEN
BACKGROUND: Induction immunosuppression in heart transplant recipients varies greatly by center. Basiliximab (BAS) is the most commonly used induction immunosuppressant but has not been shown to reduce rejection or improve survival. The objective of this retrospective study was to compare rejection, infection, and mortality within the first 12 months following heart transplant in patients who received BAS or no induction. METHODS: This was a retrospective cohort study of adult heart transplant recipients given BAS or no induction from January 1, 2017 to May 31, 2021. The primary endpoint was incidence of treated acute cellular rejection (ACR) at 12-months post-transplant. Secondary endpoints included ACR at 90 days post-transplant, incidence of antibody-mediated rejection (AMR) at 90 days and 1 year, incidence of infection, and all-cause mortality at 1 year. RESULTS: A total of 108 patients received BAS, and 26 patients received no induction within the specified timeframe. There was a lower incidence of ACR within the first year in the BAS group compared to the no induction group (27.7 vs. 68.2%, p < .002). BAS was independently associated with a lower probability of having a rejection event during the first 12-months post-transplant (hazard ratio (HR) .285, 95% confidence interval [CI] .142-.571, p < .001). There was no difference in the rate of infection and in mortality after hospital discharge at 1-year post-transplant (6% vs. 0%, p = .20). CONCLUSION: BAS appears to be associated with greater freedom from rejection without an increase in infections. BAS may be a preferred to a no induction strategy in patients undergoing heart transplantation.
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Anticuerpos Monoclonales , Trasplante de Corazón , Humanos , Adulto , Basiliximab , Anticuerpos Monoclonales/uso terapéutico , Estudios Retrospectivos , Inmunosupresores/uso terapéutico , Inmunosupresores/farmacología , Rechazo de Injerto/etiología , Proteínas Recombinantes de Fusión/uso terapéuticoRESUMEN
Extracorporeal photopheresis (ECP) is an immunomodulatory therapy based on the infusion of autologous cellular products exposed to ultraviolet light (UV) in the presence of a photosensitizer. The study evaluates the ECP efficacy as induction therapy in a full-mismatch kidney transplant rat model. Dark Agouti to Lewis (DA-L) kidney transplant model has been established. ECP product was obtained from Lewis rat recipients after DA kidney graft transplantation (LewDA). Leukocytes of those LewDA rats were exposed to 8-methoxy psoralen, and illuminated with UV-A. The ECP doses assessed were 10 × 106 and 100 × 106 cells/time point. Lewis recipients received seven ECP infusions. DA-L model was characterized by the appearance of donor-specific antibodies (DSA) and kidney function deterioration from day three after kidney transplant. The dysfunction progressed rapidly until graft loss (6.1 ± 0.5 days). Tacrolimus at 0.25 mg/kg prolonged rat survival until 11.4 ± 0.7 days (p = 0.0004). In this context, the application of leukocytes from LewDA sensitized rats accelerated the rejection (8.7 ± 0.45, p = 0.0012), whereas ECP product at high dose extended kidney graft survival until 26.3 ± 7.3 days, reducing class I and II DSA in surviving rats. ECP treatment increases kidney graft survival in full-mismatch rat model of acute rejection and is a suitable immunomodulatory therapy to be explored in kidney transplantation.
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Trasplante de Riñón , Fotoféresis , Ratas , Animales , Supervivencia de Injerto , Ratas Endogámicas Lew , Rechazo de Injerto/prevención & control , AnticuerposRESUMEN
The choice between Basiliximab (BSX) or Anti-Thymocyte Globulin (ATG) as induction therapy in non-immunized kidney transplant recipients remains uncertain. Whilst ATG may allow steroid withdrawal and a decrease in tacrolimus, it also increases infectious complications. We investigated outcomes in non-immunized patients receiving a very low dosage of ATG versus BSX as induction. Study outcomes were patient/graft survival, cumulative probabilities of biopsy proven acute rejection (BPAR), infectious episode including CMV and post-transplant diabetes (PTD). Cox, logistic or linear statistical models were used depending on the studied outcome and models were weighted on propensity scores. 100 patients received ATG (mean total dose of 2.0 mg/kg) and 83 received BSX. Maintenance therapy was comparable. Patient and graft survival did not differ between groups, nor did infectious complications. There was a trend for a higher occurrence of a first BPAR in the BSX group (HR at 1.92; 95%CI: [0.77; 4.78]; p = 0.15) with a significantly higher BPAR episodes (17% vs 7.3%, p = 0.01). PTD occurrence was significantly higher in the BSX group (HR at 2.44; 95%CI: [1.09; 5.46]; p = 0.03). Induction with a very low dose of ATG in non-immunized recipients was safe and associated with a lower rate of BPAR and PTD without increasing infectious complications.