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ABSTRACT: Posttransplant lymphoproliferative disorder (PTLD) is a rare complication of solid organ transplantation, and cytotoxic chemotherapy is associated with treatment-related morbidity and mortality. Current treatment takes a sequential, risk-stratified approach, and patients with low-risk disease after initial immunotherapy can avoid escalation to immunochemotherapy. TIDaL is a prospective, single-arm phase 2 trial investigating the activity and tolerability of ibrutinib combined with risk-stratified therapy for first-line treatment of PTLD. Eligible patients were adults with newly diagnosed CD20+ B-cell PTLD after solid organ transplant and performance status 0 to 2. Initial treatment comprised 49 days of ibrutinib 560 mg once daily, with 4 doses of weekly rituximab. Treatment response on interim scan and baseline International Prognostic Index were used to allocate patients to either a low-risk arm (who continued ibrutinib, alongside 4 further doses of 3-weekly rituximab) or high-risk (escalation to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone [R-CHOP] immunochemotherapy, with ibrutinib continuing in patients aged <65 years). The primary outcome was complete response on interim scan, achieved by 11 of 38 patients (29%; 95% confidence interval [CI], 15-46). This did not reach the prespecified threshold for clinically significant activity. Secondary outcomes included allocation to the low-risk arm (41% of patients), 2-year progression-free survival (58%; 95% CI, 44-76), and 2-year overall survival (76%; 95% CI, 63-91). Adverse events were mostly hematological, gastrointestinal, and infective. Although TIDaL does not support adding ibrutinib into first-line treatment of PTLD, increasing the proportion of patients who can be treated without cytotoxic chemotherapy remains an important aim of future research. This trial was registered at www.clinicaltrials.gov as #ISRCTN32667607.
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Adenina , Protocolos de Quimioterapia Combinada Antineoplásica , Trastornos Linfoproliferativos , Piperidinas , Rituximab , Humanos , Piperidinas/uso terapéutico , Piperidinas/efectos adversos , Piperidinas/administración & dosificación , Persona de Mediana Edad , Femenino , Masculino , Adenina/análogos & derivados , Adenina/uso terapéutico , Trastornos Linfoproliferativos/tratamiento farmacológico , Trastornos Linfoproliferativos/etiología , Anciano , Adulto , Rituximab/efectos adversos , Rituximab/administración & dosificación , Rituximab/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Trasplante de Órganos/efectos adversos , Ciclofosfamida/administración & dosificación , Ciclofosfamida/uso terapéutico , Ciclofosfamida/efectos adversos , Vincristina/administración & dosificación , Vincristina/efectos adversos , Vincristina/uso terapéutico , Doxorrubicina/efectos adversos , Doxorrubicina/uso terapéutico , Doxorrubicina/administración & dosificación , Prednisona/administración & dosificación , Prednisona/efectos adversos , Prednisona/uso terapéutico , Estudios Prospectivos , Pirazoles/uso terapéutico , Pirazoles/efectos adversos , Pirazoles/administración & dosificaciónRESUMEN
BACKGROUND: Relapsed or refractory follicular lymphoma (rrFL) is an incurable disease associated with shorter remissions and survival after each line of standard therapy. Many promising novel, chemotherapy-free therapies are in development, but few are licensed as their role in current treatment pathways is poorly defined. METHODS: The REFRACT trial is an investigator-initiated, UK National Cancer Research Institute, open-label, multi-centre, randomised phase II platform trial aimed at accelerating clinical development of novel therapies by addressing evidence gaps. The first of the three sequential novel therapy arms is epcoritamab plus lenalidomide, to be compared with investigator choice standard therapy (ICT). Patients aged 18 years or older with biopsy proven relapsed or refractory CD20 positive, grade 1-3a follicular lymphoma and assessable disease by PET-CT are eligible. The primary outcome is complete metabolic response by PET-CT at 24 weeks using the Deauville 5-point scale and Lugano 2014 criteria. Secondary outcomes include overall metabolic response, progression-free survival, overall survival, duration of response, and quality of life assessed by EQ-5D-5 L and FACT-Lym. The trial employs an innovative Bayesian design with a target sample size of 284 patients: 95 in the ICT arm and 189 in the novel therapy arms. DISCUSSION: Whilst there are many promising novel drugs in early clinical development for rrFL, understanding the relative efficacy and safety of these agents, and their place in modern treatment pathways, is limited by a lack of randomised trials and dearth of published outcomes for standard regimens to act as historic controls. Therefore, the aim of REFRACT is to provide an efficient platform to evaluate novel agents against standard therapies for rrFL. The adaptive Bayesian power prior methodology design will minimise patient numbers and accelerate trial delivery. TRIAL REGISTRATION: ClinicalTrials.gov: NCT05848765; 08-May-2023. EUDRACT: 2022-000677-75; 10-Feb-2022.
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Linfoma Folicular , Humanos , Linfoma Folicular/tratamiento farmacológico , Tomografía Computarizada por Tomografía de Emisión de Positrones , Brazo/patología , Teorema de Bayes , Calidad de Vida , Resultado del Tratamiento , Ensayos Clínicos Controlados Aleatorios como Asunto , Estudios Multicéntricos como Asunto , Ensayos Clínicos Fase II como AsuntoRESUMEN
Current therapies for myeloproliferative neoplasms (MPNs) improve symptoms but have limited effect on tumor size. In preclinical studies, tamoxifen restored normal apoptosis in mutated hematopoietic stem/progenitor cells (HSPCs). TAMARIN Phase-II, multicenter, single-arm clinical trial assessed tamoxifen's safety and activity in patients with stable MPNs, no prior thrombotic events and mutated JAK2V617F, CALRins5 or CALRdel52 peripheral blood allele burden ≥20% (EudraCT 2015-005497-38). 38 patients were recruited over 112w and 32 completed 24w-treatment. The study's A'herns success criteria were met as the primary outcome ( ≥ 50% reduction in mutant allele burden at 24w) was observed in 3/38 patients. Secondary outcomes included ≥25% reduction at 24w (5/38), ≥50% reduction at 12w (0/38), thrombotic events (2/38), toxicities, hematological response, proportion of patients in each IWG-MRT response category and ELN response criteria. As exploratory outcomes, baseline analysis of HSPC transcriptome segregates responders and non-responders, suggesting a predictive signature. In responder HSPCs, longitudinal analysis shows high baseline expression of JAK-STAT signaling and oxidative phosphorylation genes, which are downregulated by tamoxifen. We further demonstrate in preclinical studies that in JAK2V617F+ cells, 4-hydroxytamoxifen inhibits mitochondrial complex-I, activates integrated stress response and decreases pathogenic JAK2-signaling. These results warrant further investigation of tamoxifen in MPN, with careful consideration of thrombotic risk.
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Trastornos Mieloproliferativos , Neoplasias , Humanos , Trastornos Mieloproliferativos/tratamiento farmacológico , Trastornos Mieloproliferativos/genética , Trastornos Mieloproliferativos/patología , Janus Quinasa 2/genética , Janus Quinasa 2/metabolismo , Células Madre Hematopoyéticas/metabolismo , Transducción de Señal , Neoplasias/metabolismo , Tamoxifeno/uso terapéutico , Tamoxifeno/metabolismo , Mutación , Calreticulina/genética , Calreticulina/metabolismoRESUMEN
INTRODUCTION: The usage of a T-cell depleted, reduced intensity conditioning (RIC) approach to haematopoietic cell transplantation (HCT) in adult patients with acute lymphoblastic leukaemia (ALL) over 40 years of age and in first complete remission (CR) has resulted in encouraging rates of event-free and overall survival in a population of adults with high risk disease. However, relapse rates remain high-with disease progression being the major cause of treatment failure. Using different, more powerful conditioning approaches is the logical next step in examining the role of RIC allogeneic HCT in adult ALL. METHODS AND ANALYSIS: The ALL-RIC trial is a two-arm, phase II, multicentre, randomised clinical trial in adult patients with ALL in first or second CR, who are undergoing allogeneic HCT. Comparison of a novel RIC transplant conditioning regimen using reduced-dose total body irradiation (TBI), cyclophosphamide and alemtuzumab, is made against a standardised RIC approach using fludarabine, melphalan and alemtuzumab. The primary outcome of the study is disease-free survival at 3 years, defined as time from randomisation to the first of either relapse or death from any cause. Patients who are still alive and progression-free at the end of the trial will be censored at their last date known to be alive. Secondary outcomes include overall survival and non-relapse mortality. ETHICS AND DISSEMINATION: The protocol was approved by the East Midlands-Leicester Central Research Ethics committee (18/EM/0112). Initial approval was received on 12 June 2018. Current protocol version (V.6.0) approval obtained on 18 November 2019. The Medicines and Healthcare products Regulatory Agency (MHRA) also approved all protocol versions. The results of this trial will be disseminated through national and international presentations and peer-reviewed publications. TRIAL REGISTRATION NUMBER: EudraCT Number: 2017-004800-23.ISRCTN99927695.
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Trasplante de Células Madre Hematopoyéticas , Leucemia-Linfoma Linfoblástico de Células Precursoras , Adulto , Humanos , Persona de Mediana Edad , Melfalán/uso terapéutico , Alemtuzumab , Irradiación Corporal Total/métodos , Recurrencia Local de Neoplasia/tratamiento farmacológico , Ciclofosfamida/uso terapéutico , Trasplante de Células Madre Hematopoyéticas/métodos , Enfermedad Aguda , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Ensayos Clínicos Controlados Aleatorios como Asunto , Estudios Multicéntricos como Asunto , Ensayos Clínicos Fase II como AsuntoRESUMEN
PURPOSE: Polycythemia vera (PV) is characterized by JAK/STAT activation, thrombotic/hemorrhagic events, systemic symptoms, and disease transformation. In high-risk PV, ruxolitinib controls blood counts and improves symptoms. PATIENTS AND METHODS: MAJIC-PV is a randomized phase II trial of ruxolitinib versus best available therapy (BAT) in patients resistant/intolerant to hydroxycarbamide (HC-INT/RES). Primary outcome was complete response (CR) within 1 year. Secondary outcomes included duration of response, event-free survival (EFS), symptom, and molecular response. RESULTS: One hundred eighty patients were randomly assigned. CR was achieved in 40 (43%) patients on ruxolitinib versus 23 (26%) on BAT (odds ratio, 2.12; 90% CI, 1.25 to 3.60; P = .02). Duration of CR was superior for ruxolitinib (hazard ratio [HR], 0.38; 95% CI, 0.24 to 0.61; P < .001). Symptom responses were better with ruxolitinib and durable. EFS (major thrombosis, hemorrhage, transformation, and death) was superior for patients attaining CR within 1 year (HR, 0.41; 95% CI, 0.21 to 0.78; P = .01); and those on ruxolitinib (HR, 0.58; 95% CI, 0.35 to 0.94; P = .03). Serial analysis of JAK2V617F variant allele fraction revealed molecular response was more frequent with ruxolitinib and was associated with improved outcomes (progression-free survival [PFS] P = .001, EFS P = .001, overall survival P = .01) and clearance of JAK2V617F stem/progenitor cells. ASXL1 mutations predicted for adverse EFS (HR, 3.02; 95% CI, 1.47 to 6.17; P = .003). The safety profile of ruxolitinib was as previously reported. CONCLUSION: The MAJIC-PV study demonstrates ruxolitinib treatment benefits HC-INT/RES PV patients with superior CR, and EFS as well as molecular response; importantly also demonstrating for the first time, to our knowledge, that molecular response is linked to EFS, PFS, and OS.
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Policitemia Vera , Humanos , Policitemia Vera/tratamiento farmacológico , Policitemia Vera/genética , Policitemia Vera/complicaciones , Resultado del Tratamiento , Hidroxiurea/efectos adversos , Nitrilos/uso terapéutico , Hemorragia/complicaciones , Hemorragia/tratamiento farmacológicoRESUMEN
Allogeneic stem-cell transplant allows for the delivery of curative graft-versus-leukemia (GVL) in patients with acute myeloid leukemia/myelodysplasia (AML/MDS). Surveillance of T-cell chimerism, measurable residual disease (MRD) and blast HLA-DR expression may inform whether GVL effectiveness is reduced. We report here the prognostic impact of these biomarkers in patients allografted for AML/MDS. One hundred eighty-seven patients from FIGARO, a randomized trial of reduced-intensity conditioning regimens in AML/MDS, were alive and relapse-free at the first MRD time-point and provided monitoring samples for flow cytometric MRD and T-cell chimerism, requested to month+12. Twenty-nine (15.5%) patients had at least 1 MRD-positive result posttransplant. MRD-positivity was associated with reduced overall survival (OS) (hazard ratio [HR], 2.18; P = .0028) as a time-varying Cox variable and remained significant irrespective of pretransplant MRD status in multivariate analyses (P < .001). Ninety-four patients had sequential MRD with T-cell chimerism results at months+3/+6. Patients with full donor T-cell chimerism (FDTC) had an improved OS as compared with patients with mixed donor T-cell chimerism (MDTC) (adjusted HR=0.4; P = .0019). In patients with MDTC (month+3 or +6), MRD-positivity was associated with a decreased 2-year OS (34.3%) vs MRD-negativity (71.4%) (P = .001). In contrast, in the group with FDTC, MRD was infrequent and did not affect the outcome. Among patients with posttransplant MRD-positivity, decreased HLA-DR expression on blasts significantly reduced OS, supporting this as a mechanism for GVL escape. In conclusion, posttransplant MRD is an important predictor of the outcome in patients allografted for AML/MDS and is most informative when combined with T-cell chimerism results, underlining the importance of a GVL effect in AML/MDS.
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Leucemia Mieloide Aguda , Síndromes Mielodisplásicos , Humanos , Quimerismo , Linfocitos T , Leucemia Mieloide Aguda/terapia , AloinjertosRESUMEN
BACKGROUND: In utero repair of open neural tube defects using an open hysterotomy approach (hereafter referred to as "open") has been shown to reduce the need for ventriculoperitoneal shunting and to improve motor outcomes for affected infants. Laparotomy-assisted fetoscopic repair (hereafter referred to as "hybrid") is an alternative approach that may confer similar neurologic benefits while reducing the incidence of hysterotomy-related complications. OBJECTIVE: This study aimed to analyze procedure-related maternal and fetal complications of in utero repair using the Clavien-Dindo classification, and to compare the outcomes of the hybrid and open approaches. STUDY DESIGN: This was a retrospective cohort study conducted in a single center between September 2011 and July 2021. All patients who met the Management of Myelomeningocele Study criteria and who underwent either hybrid or open fetal surgery were included. Maternal complications were classified using a unique adaptation of the Clavien-Dindo scoring system, allowing the development of a comprehensive complication index score specific to fetal surgery. Primary fetal outcome was defined as gestational age at delivery and summarized according to the World Health Organization definitions of preterm delivery. RESULTS: There were 146 fetuses with open neural tube defects who were eligible for, and underwent, in utero repair during the study period. Of these, 102 underwent hybrid fetoscopic repair and 44 underwent open hysterotomy repair. Gestational age at the time of surgery was higher in the hybrid group than in the open group (25.1 vs 24.8 weeks; P=.004). Maternal body mass index was lower in the hybrid than in the open group (25.4 vs 27.1 kg/m2; P=.02). The duration of hybrid fetoscopic surgery was significantly longer in the hybrid than in the open group (250 vs 164 minutes; P<.001). There was a significantly lower Clavien-Dindo Grade III complication rate (4.9% vs 43.2%; P<.001) and a significantly lower overall comprehensive maternal complication index (8.7 vs 22.6; P=.021) in the hybrid group than in the open group. Gestational age at delivery was significantly higher in the hybrid group than in the open group (38.1 vs 35.8 weeks; P<.001), and this finding persisted when gestational age at delivery was analyzed using the World Health Organization definitions of preterm delivery. CONCLUSION: Use of our adaptation of the standardized Clavien-Dindo classification to assess the maternal complications associated with in utero open neural tube defect repair provides a new method for objectively assessing different fetal surgical approaches. It also provides a much-needed standardized tool to allow objective comparisons between methods, which can be used when counseling patients. The hybrid open neural tube defect repair was associated with lower rates of maternal adverse events , and later gestational age at delivery compared with the open approach.
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Meningomielocele , Defectos del Tubo Neural , Nacimiento Prematuro , Embarazo , Recién Nacido , Lactante , Femenino , Humanos , Nacimiento Prematuro/etiología , Estudios Retrospectivos , Feto/cirugía , Meningomielocele/cirugía , Fetoscopía/métodos , Edad Gestacional , Defectos del Tubo Neural/cirugíaRESUMEN
COVID-19 causes significant thrombosis and coagulopathy, with elevated D-dimer a predictor of adverse outcome. The precise mechanism of this coagulopathy remains unclear; one hypothesis is that loss of angiotensin-converting enzyme 2 activity during viral endocytosis leads to pro-inflammatory angiotensin-II accumulation, loss of angiotensin-1-7 and subsequent vascular endothelial activation. We undertook a double-blind randomized, placebo-controlled experimental medicine study to assess the effect of TRV027, a synthetic angiotensin-1-7 analogue on D-dimer in 30 patients admitted to hospital with COVID-19. The study showed a similar rate of adverse events in TRV027 and control groups. There was a numerical decrease in D-dimer in the TRV027 group and increase in D-dimer in the placebo group; however, this did not reach statistical significance (P = .15). A Bayesian analysis demonstrated that there was a 92% probability that this change represented a true drug effect.
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Trastornos de la Coagulación Sanguínea , COVID-19 , Humanos , Teorema de Bayes , Proyectos Piloto , Angiotensinas , Método Doble Ciego , Resultado del TratamientoRESUMEN
BACKGROUND: For patients with acute myeloid leukaemia (AML), the only potentially curative treatment is intensive chemotherapy (IC). This is highly toxic, particularly for patients > 60 years, potentially leading to prolonged hospitalisations requiring intensive supportive care, and sometimes treatment-related death. This also results in extensive healthcare costs and negatively impacts quality of life (QoL). Venetoclax with low-dose cytarabine (VEN + LDAC) is a novel, low-intensity treatment for AML patients who cannot receive IC. VEN + LDAC is given as an outpatient and toxicity appears significantly lower than with IC. Analysis of clinical trials performed to date are promising for patients with the genotype NPM1mutFLT3 ITDneg, where remission and survival rates appear comparable to those achieved with IC. METHODS: VICTOR is an international, two-arm, open-label, multi-centre, non-inferiority, randomised-controlled phase II trial to assess VEN + LDAC compared to standard of care (IC) as first-line treatment in older patients (initially aged ≥ 60 years) with newly diagnosed AML. The trial will recruit patients with a NPM1mutFLT3 ITDneg genotype; those with a favourable risk in relation to the experimental treatment. University of Birmingham is the UK co-ordinating centre, with national hubs in Aarhus University Hospital, Denmark, and Auckland District Health Board, New Zealand. The primary outcome is molecular event-free survival time where an event is defined as failure to achieve morphological complete response (CR) or CR with incomplete blood count recovery after two cycles of therapy; molecular persistence, progression or relapse requiring treatment change; morphological relapse, or; death. Secondary outcomes include cumulative resource use at 12- and 24-months, and QoL as assessed by EORTCQLQ-C30 and EQ-5D-3L at 3-, 6-, 12-, 18- and 24-months. The trial employs an innovative Bayesian design with target sample size of 156 patients aged > 60 years. DISCUSSION: The principle underpinning the VICTOR trial is that the chance of cure for patients in the experimental arm should not be compromised, therefore, an adaptive design with regular checks on accumulating data has been employed, which will allow for a staged expansion of the trial population to include younger patients if, and when, there is sufficient evidence of non-inferiority in older patients. TRIAL REGISTRATION: EudraCT: 2020-000,273-24; 21-Aug-2020. ISRCTN: 15,567,173; 08-Dec-2020.
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Antineoplásicos , Leucemia Mieloide Aguda , Humanos , Adulto , Anciano , Citarabina , Calidad de Vida , Teorema de Bayes , Nivel de Atención , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Recurrencia Local de Neoplasia/tratamiento farmacológico , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Antineoplásicos/uso terapéutico , Proteínas Nucleares , Ensayos Clínicos Fase II como Asunto , Estudios Multicéntricos como AsuntoRESUMEN
Acute myeloid leukaemia is prevalent in older patients that are often ineligible for intensive chemotherapy and treatment options remain limited with azacitidine being at the forefront. Azacitidine has been used in the clinic for decades, however, we still lack a complete understanding of the mechanisms by which the drug exerts its anti-tumour effect. To gain insight into the mechanism of action, we defined the mutational profile of sequential samples of patients treated with azacitidine. We did not identify any mutations that could predict response and observed lack of a uniform pattern of clonal evolution. Focusing on responders, at remission, we observed three types of response: (1) an almost complete elimination of mutations (33%), (2) no change (17%), and (3) change with no discernible pattern (50%). Heterogeneous patterns were also observed at relapse, with no clonal evolution between remission and relapse in some patients. Lack of clonal evolution suggests that non-genetic mechanisms might be involved. Towards understanding such mechanisms, we investigated the immune microenvironment in a number of patients and we observed lack of a uniform response following therapy. We identified a higher frequency of cytotoxic T cells in responders and higher frequency of naïve helper T cells in non-responders.
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Treating adverse risk myelodysplastic syndromes with azacitidine exacerbates thrombocytopenia. We report a study of eltrombopag in combination with azacitidine using a 3 + 3 cohort design. Patients with baseline platelets of <150 × 109 /l received eltrombopag ranging from 25 to 300 mg. An 8-day pre-phase of eltrombopag was followed by two cycles of combined therapy. Amongst 31 patients, there were no dose-limiting toxicities. The maximum tolerated dose (MTD) was 300 mg. Transient increases in bone marrow blasts at day 8 were common but no patient had protocol-defined progression following eltrombopag monotherapy. Marrow response rates after three and six treatment cycles were 32% and 29% respectively. In all, 70% of patients treated below and 36% treated at the MTD achieved a modified International Working Group 2006 platelet response at the end of cycle two. Of the platelet transfusion independent patients at baseline, 67% treated at the MTD became transfusion dependent during the first two cycles of treatment. Apart from lack of disease progression, our findings concur with a previously reported Phase III study (A StUdy of eltromboPag in myelodysPlastic SyndrOmes Receiving azaciTidine [SUPPORT]). We conclude that eltrombopag/azacitidine is safe in terms of conventional measures defined by adverse-event reporting. However, in light of SUPPORT and our own descriptive findings regarding efficacy, further combination studies in high-risk disease should be considered with caution.
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Azacitidina , Benzoatos , Hidrazinas , Síndromes Mielodisplásicos , Pirazoles , Azacitidina/uso terapéutico , Benzoatos/uso terapéutico , Combinación de Medicamentos , Humanos , Hidrazinas/uso terapéutico , Síndromes Mielodisplásicos/tratamiento farmacológico , Pirazoles/uso terapéutico , Resultado del TratamientoRESUMEN
Azacitidine (AZA) is important in the management of patients with acute myeloid leukaemia (AML) who are ineligible for intensive chemotherapy. Romidepsin (ROM) is a histone deacetylase inhibitor which synergises with AZA in vitro. The ROMAZA trial established the maximum tolerated dose (MTD) of combined ROM/AZA therapy in patients with AML, as ROM 12 mg/m2 on Days 8 and 15, with AZA 75 mg/m2 administered for 7/28 day cycle. Nine of the 38 (23·7%) patients treated at the MTD were classified as responders by Cycle 6 (best response: complete remission [CR]/incomplete CR n = 7, partial response n = 2). Correlative next-generation sequencing studies demonstrated important insights into therapy resistance.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/tratamiento farmacológico , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Azacitidina/administración & dosificación , Toma de Decisiones Clínicas , Análisis Citogenético , Depsipéptidos/administración & dosificación , Manejo de la Enfermedad , Susceptibilidad a Enfermedades , Femenino , Humanos , Leucemia Mieloide Aguda/etiología , Masculino , Terapia Molecular Dirigida , Pronóstico , Resultado del Tratamiento , Adulto JovenRESUMEN
Chronic graft-versus-host disease (cGvHD) is a major cause of non-relapse morbidity and mortality following allogeneic stem cell transplant. Over half of patients with moderate or severe cGvHD fail to respond adequately to first-line treatment with systemic steroids, and although a range of second-line options have been employed, a lack of prospective evidence means there is no standard of care. The AZTEC trial is a prospective, single-arm, phase II study investigating the safety and activity of azacitidine for the treatment of cGvHD in patients who are resistant to, or intolerant of, systemic steroid therapy. The co-primary outcomes were treatment tolerability, and activity measured as objective response according to modified National Institutes of Health criteria. Fourteen patients were recruited to the first stage of the trial, of whom seven completed the planned six cycles of azacitidine 36 mg/m2 days 1-5 per 28-day cycle. Azacitidine was tolerated by 13/14 patients, and 7/14 showed an objective response. Clinical responses were mirrored by improvements in patient-reported cGvHD symptoms and quality of life. AZTEC demonstrates that azacitidine is a safe and promising option for the treatment of cGvHD, and continued evaluation in the second stage of this phase II efficacy study is supported.
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Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Azacitidina/farmacología , Azacitidina/uso terapéutico , Enfermedad Crónica , Enfermedad Injerto contra Huésped/etiología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Estudios Prospectivos , Calidad de Vida , Esteroides/uso terapéuticoRESUMEN
Relapsed or refractory primary central nervous system lymphoma (rrPCNSL) confers a poor prognosis with no accepted standard of care. Very few prospective studies have been conducted in this patient group. This study was a multicenter phase 1/2 study that investigated thiotepa in combination with ifosfamide, etoposide, and rituximab (TIER) for the treatment of PCNSL relapsed or refractory to high-dose methotrexate-based chemotherapy. A 3 + 3 design investigated the recommended phase 2 dose of thiotepa for a single-stage phase 2 cohort by assessing the activity of 2 cycles of TIER against rrPCNSL. The primary outcome was overall response rate. The dose-finding study demonstrated that 50 mg/m2 of thiotepa could be safely delivered within the TIER regimen. No dose-limiting toxicities were encountered in phase 1, and TIER was well-tolerated by the 27 patients treated in phase 2. The most common grade 3 to 4 toxicities were neutropenia (56% of patients) and thrombocytopenia (39%). An overall response was confirmed in 14 patients (52%), which met the prespecified threshold for clinically relevant activity. The median progression-free survival was 3 months (95% confidence interval [CI], 2 to 6 months) and overall survival 5 months (95% CI, 3 to 9 months). Exploratory analyses suggest a greater benefit for thiotepa-naïve patients. Six patients successfully completed autologous stem cell transplantation (ASCT) consolidation, with 4 experiencing durable remissions after a median follow-up of 50 months. The TIER regimen can be delivered safely and is active against rrPCNSL. When it is followed by ASCT, it can provide durable remission and long-term survival. However, for the majority of patients, prognosis remains poor, and novel treatment strategies are urgently needed. This trial was registered at https://www.clinicaltrialsregister.eu/ctr-search/search as EudraCT 2014-000227-24 and ISRCTN 12857473.
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Trasplante de Células Madre Hematopoyéticas , Linfoma no Hodgkin , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Terapia Combinada , Humanos , Linfoma no Hodgkin/tratamiento farmacológico , Estudios Prospectivos , Tiotepa/uso terapéutico , Trasplante AutólogoRESUMEN
BACKGROUND: Cancer cachexia causes significant morbidity and mortality in advanced lung cancer patients. Clinical benefit of ß-hydroxy-ß-methylbutyrate, arginine, and glutamine (HMB/Arg/Gln) was assessed in newly diagnosed patients. METHODS: NOURISH, a prospective, two-arm, open-label, multi-centre, randomised controlled phase II trial compared cachexia in patients who received HMB/Arg/Gln with those who did not. All patients received structured nutritional, exercise and symptom control via a Macmillan Durham Cachexia Pack. Conducted in five UK centres, patients aged > 18 years, with newly diagnosed advanced small cell lung cancer (SCLC) or non-small cell lung cancer (NSCLC), who were able to take oral nutrition, with a performance status of 0-to-2 and a life expectancy > 4 months were eligible for trial entry. Patients suitable for treatment with curative intent were ineligible. The trial was designed as a signal-seeking pilot study with target recruitment of 96 patients. One-to-one randomisation was stratified by diagnosis (SCLC or NSCLC), stage of disease (locally advanced or metastatic) and performance status. The primary outcome measure was treatment success defined as a patient being alive without significant loss of lean body mass (not > 5%) by 12 weeks. Secondary outcome measures included quality of life. RESULTS: Between February-2012 and February-2013, 38 patients were recruited, 19 to each arm. Baseline characteristics were balanced. The trial was halted due to slow accrual and partial adherence. Trial data demonstrated no evidence of treatment benefit. No serious adverse events were reported during the trial. CONCLUSIONS: Further evaluation of HMB/Arg/Gln in this setting could not be recommended on the basis of this trial. CLINICAL TRIAL REGISTRATION: ISRCTN registry: 39911673; 14-Apr-2011 https://doi.org/10.1186/ISRCTN39911673 .
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Arginina/uso terapéutico , Caquexia/tratamiento farmacológico , Glutamina/uso terapéutico , Neoplasias Pulmonares/complicaciones , Neoplasias Pulmonares/tratamiento farmacológico , Arginina/farmacología , Femenino , Glutamina/farmacología , Humanos , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Resultado del TratamientoRESUMEN
PURPOSE: miRNA-155 is an oncogenic miRNA highly expressed in B-cell malignancies, particularly in the non-germinal center B-cell or activated B-cell subtype of diffuse large B-cell lymphoma (ABC-DLBCL), where it is considered a potential diagnostic and prognostic biomarker. Thus, miR-155 inhibition represents an important therapeutic strategy for B-cell lymphomas. In this study, we tested the efficacy and pharmacodynamic activity of an oligonucleotide inhibitor of miR-155, cobomarsen, in ABC-DLBCL cell lines and in corresponding xenograft mouse models. In addition, we assessed the therapeutic efficacy and safety of cobomarsen in a patient diagnosed with aggressive ABC-DLBCL. EXPERIMENTAL DESIGN: Preclinical studies included the delivery of cobomarsen to highly miR-155-expressing ABC-DLBCL cell lines to assess any phenotypic changes, as well as intravenous injections of cobomarsen in NSG mice carrying ABC-DLBCL xenografts, to study tumor growth and pharmacodynamics of the compound over time. To begin to test its safety and therapeutic efficacy, a patient was recruited who underwent five cycles of cobomarsen treatment. RESULTS: Cobomarsen decreased cell proliferation and induced apoptosis in ABC-DLBCL cell lines. Intravenous administration of cobomarsen in a xenograft NSG mouse model of ABC-DLBCL reduced tumor volume, triggered apoptosis, and derepressed direct miR-155 target genes. Finally, the compound reduced and stabilized tumor growth without any toxic effects for the patient. CONCLUSIONS: Our findings support the potential therapeutic application of cobomarsen in ABC-DLBCL and other types of lymphoma with elevated miR-155 expression.
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Linfoma de Células B Grandes Difuso/tratamiento farmacológico , MicroARNs/antagonistas & inhibidores , Oligonucleótidos Antisentido/farmacología , Oligonucleótidos/farmacología , Animales , Apoptosis/efectos de los fármacos , Apoptosis/genética , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Proliferación Celular/genética , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/patología , Ratones , MicroARNs/metabolismo , Oligonucleótidos/uso terapéutico , Oligonucleótidos Antisentido/uso terapéutico , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
PURPOSE: Reduced-intensity conditioning (RIC) regimens have extended the curative potential of allogeneic stem-cell transplantation to older adults with high-risk acute myeloid leukemia (AML) and myelodysplasia (MDS) but are associated with a high risk of disease relapse. Strategies to reduce recurrence are urgently required. Registry data have demonstrated improved outcomes using a sequential transplant regimen, fludarabine/amsacrine/cytarabine-busulphan (FLAMSA-Bu), but the impact of this intensified conditioning regimen has not been studied in randomized trials. PATIENTS AND METHODS: Two hundred forty-four patients (median age, 59 years) with high-risk AML (n = 164) or MDS (n = 80) were randomly assigned 1:1 to a fludarabine-based RIC regimen or FLAMSA-Bu. Pretransplant measurable residual disease (MRD) was monitored by flow cytometry (MFC-MRD) and correlated with outcome. RESULTS: There was no difference in 2-year overall survival (hazard ratio 1.05 [85% CI, 0.80 to 1.38] P = .81) or cumulative incidence of relapse (CIR) (hazard ratio 0.94 [95%CI, 0.60 to 1.46] P = .81) between the control and FLAMSA-Bu arms. Detectable pretransplant MFC-MRD was associated with an increased CIR (2-year CIR 41.0% v 20.0%, P = .01) in the overall trial cohort with a comparable prognostic impact when measured by an unsupervised analysis approach. There was no evidence of interaction between MRD status and conditioning regimen intensity for relapse or survival. Acquisition of full donor T-cell chimerism at 3 months abrogated the adverse impact of pretransplant MRD on CIR and overall survival. CONCLUSION: The intensified RIC conditioning regimen, FLAMSA-Bu, did not improve outcomes in adults transplanted for high-risk AML or MDS regardless of pretransplant MRD status. Our data instead support the exploration of interventions with the ability to accelerate acquisition of full donor T-cell chimerism as a tractable strategy to improve outcomes in patients allografted for AML.
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Amsacrina/administración & dosificación , Busulfano/administración & dosificación , Citarabina/administración & dosificación , Inmunosupresores/uso terapéutico , Leucemia Mieloide Aguda/terapia , Agonistas Mieloablativos/administración & dosificación , Síndromes Mielodisplásicos/terapia , Trasplante de Células Madre , Acondicionamiento Pretrasplante , Vidarabina/análogos & derivados , Adulto , Anciano , Amsacrina/efectos adversos , Busulfano/efectos adversos , Citarabina/efectos adversos , Femenino , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/prevención & control , Humanos , Inmunosupresores/efectos adversos , Leucemia Mieloide Aguda/mortalidad , Leucemia Mieloide Aguda/patología , Masculino , Persona de Mediana Edad , Agonistas Mieloablativos/efectos adversos , Síndromes Mielodisplásicos/mortalidad , Síndromes Mielodisplásicos/patología , Supervivencia sin Progresión , Recurrencia , Trasplante de Células Madre/efectos adversos , Trasplante de Células Madre/mortalidad , Factores de Tiempo , Acondicionamiento Pretrasplante/efectos adversos , Acondicionamiento Pretrasplante/mortalidad , Trasplante Homólogo , Reino Unido , Vidarabina/administración & dosificación , Vidarabina/efectos adversos , Adulto JovenAsunto(s)
Transfusión Sanguínea , Deferasirox , Síndromes Mielodisplásicos , Anciano , Anciano de 80 o más Años , Deferasirox/administración & dosificación , Deferasirox/efectos adversos , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/sangre , Síndromes Mielodisplásicos/mortalidad , Síndromes Mielodisplásicos/terapia , Estudios Prospectivos , Tasa de SupervivenciaRESUMEN
BACKGROUND: Transformation of chronic lymphocytic leukaemia (CLL) to diffuse large B-cell lymphoma (DLCBL) type Richter's syndrome (RS) carries a dismal prognosis. Standard-of-care chemoimmunotherapy for de novo RS is inadequate with median survival of less than one year. Patients are frequently elderly or have co-morbidities limiting dose-intense chemotherapy. Treatment of relapsed/refractory (R/R) RS and RS emerging after CLL-directed therapy represent urgent unmet clinical needs. Agents targeting Bruton's tyrosine kinase (BTK) deliver improved outcomes for patients with high-risk CLL and expand effective treatments to frailer patients. Acalabrutinib is an oral, second-generation BTK inhibitor with a favourable toxicity profile and demonstrated activity in CLL and B-cell lymphomas. Combination of acalabrutinib with standard-of-care CHOP-R chemoimmunotherapy offers a sound rationale to test in a prospective trial for de novo RS. METHODS: The prospective multicentre STELLAR study is designed in two elements, consisting of a randomised study to evaluate the safety and activity of CHOP-R chemoimmunotherapy in combination with acalabrutinib in newly diagnosed RS and single-arm studies of novel agents for other RS patient cohorts. Eligible patients with newly diagnosed DLBCL-type RS are randomised between six cycles of CHOP-R therapy and six cycles CHOP-R plus acalabrutinib, followed by acalabrutinib maintenance. The primary endpoint of the randomised component is progression free survival (PFS). Cohort 1 enrols RS patients with progressive disease following chemoimmunotherapy for acalabrutinib monotherapy. Patients with RS diagnosed while on ibrutinib may enrol in Cohort 2, a single-arm study of CHOP-R plus acalabrutinib. The primary endpoint for the single-arm studies is overall response rate (ORR). Secondary endpoints for all cohorts are overall survival (OS), quality of life and proportion of patients proceeding to stem cell transplantation. The study will be accompanied by exploratory analysis of the mutational landscape of RS and the relationship between dynamic changes in sequential circulating tumour DNA samples and clinical outcomes. DISCUSSION: The STELLAR randomised trial evaluates the role of CHOP-R plus acalabrutinib in newly diagnosed RS patients. The single-arm platform studies enable the incorporation of promising novel therapies into the protocol. The STELLAR study has potential to identify novel biomarkers of treatment response in this high-risk malignancy. TRIAL REGISTRATION: EudraCT: 2017-004401-40 , registered on the 31-Oct-2017. IRSCTN: https://www.isrctn.com/ISRCTN52839057 , registered on the 04-Mar-2019. ClinicalTrials.gov : NCT03899337 , registered on 02-April-2019.