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Three classes of BCMA-directed therapy (BDT) exist: antibody drug-conjugates (ADCs), CAR-T, and T-cell engagers (TCEs), each with distinct strengths and weaknesses. To aid clinicians in selecting between BDTs, we reviewed myeloma patients treated at Mayo Clinic with commercial or investigational BDT between 2018-2023. We identified 339 individuals (1-exposure = 297, 2-exposures = 38, 3-exposures = 4) who received 385 BDTs (ADC = 59, TCE = 134, CAR-T = 192), with median follow-up of 21-months. ADC recipients were older, with more lines of therapy (LOT), and penta-refractory disease. Compared to ADCs, CAR-T (aHR = 0.29, 95%CI = 0.20-0.43) and TCEs (aHR = 0.62, 95%CI = 0.43-0.91) had better progression-free survival (PFS) on analysis adjusted for age, the presence of extramedullary (EMD), penta-refractory disease, multi-hit high-risk cytogenetics, prior BDT, and the number of LOT in the preceding 1-year. Likewise, compared to ADCs, CAR-T (aHR = 0.28, 95%CI = 0.18-0.44) and TCEs (aHR = 0.60, 95%CI = 0.39-0.93) had superior overall survival. Prior BDT exposure negatively impacted all classes but was most striking in CAR-T, ORR 86% vs. 50% and median PFS 13-months vs. 3-months. Of relapses, 54% were extramedullary in nature, and a quarter of these cases had no history of EMD. CAR-T demonstrates superior efficacy and where feasible, should be the initial BDT. However, for patients with prior BDT or rapidly progressive disease, an alternative approach may be preferable.
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Antígeno de Maduración de Linfocitos B , Mieloma Múltiple , Humanos , Mieloma Múltiple/terapia , Mieloma Múltiple/mortalidad , Mieloma Múltiple/tratamiento farmacológico , Antígeno de Maduración de Linfocitos B/antagonistas & inhibidores , Masculino , Femenino , Persona de Mediana Edad , Anciano , Inmunoterapia Adoptiva , Adulto , Inmunoconjugados/uso terapéutico , Anciano de 80 o más Años , Recurrencia Local de Neoplasia/terapia , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia , Estudios RetrospectivosRESUMEN
The high rates of protein synthesis and processing render multiple myeloma (MM) cells vulnerable to perturbations in protein homeostasis. The induction of proteotoxic stress by targeting protein degradation with proteasome inhibitors (PIs) has revolutionized the treatment of MM. However, resistance to PIs is inevitable and represents an ongoing clinical challenge. Our first-in-human study of the selective inhibitor of RNA polymerase I transcription of ribosomal RNA genes, CX-5461, has demonstrated a potential signal for anti-tumor activity in three of six heavily pre-treated MM patients. Here, we show that CX-5461 has potent anti-myeloma activity in PI-resistant MM preclinical models in vitro and in vivo. In addition to inhibiting ribosome biogenesis, CX-5461 causes topoisomerase II trapping and replication-dependent DNA damage, leading to G2/M cell-cycle arrest and apoptotic cell death. Combining CX-5461 with PI does not further enhance the anti-myeloma activity of CX-5461 in vivo. In contrast, CX-5461 shows synergistic interaction with the histone deacetylase inhibitor panobinostat in both the Vk∗MYC and the 5T33-KaLwRij mouse models of MM by targeting ribosome biogenesis and protein synthesis through distinct mechanisms. Our findings thus provide strong evidence to facilitate the clinical development of targeting the ribosome to treat relapsed and refractory MM.
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ABSTRACT: CD19-directed chimeric antigen receptor T cells (CAR-T) achieve high response rates in patients with relapsed/refractory mantle cell lymphoma (MCL). However, their use is associated with significant toxicity, relapse concern, and unclear broad tractability. Preclinical and clinical data support a beneficial synergistic effect of ibrutinib on apheresis product fitness, CAR-T expansion, and toxicity. We evaluated the combination of time-limited ibrutinib and CTL019 CAR-T in 20 patients with MCL in the phase 2 TARMAC study. Ibrutinib commenced before leukapheresis and continued through CAR-T manufacture for a minimum of 6 months after CAR-T administration. The median prior lines of therapy was 2; 50% of patients were previously exposed to a Bruton tyrosine kinase inhibitor (BTKi). The primary end point was 4-month postinfusion complete response (CR) rate, and secondary end points included safety and subgroup analysis based on TP53 aberrancy. The primary end point was met; 80% of patients demonstrated CR, with 70% and 40% demonstrating measurable residual disease negativity by flow cytometry and molecular methods, respectively. At 13-month median follow-up, the estimated 12-month progression-free survival was 75% and overall survival 100%. Fifteen patients (75%) developed cytokine release syndrome; 12 (55%) with grade 1 to 2 and 3 (20%) with grade 3. Reversible grade 1 to 2 neurotoxicity was observed in 2 patients (10%). Efficacy was preserved irrespective of prior BTKi exposure or TP53 mutation. Deep responses correlated with robust CAR-T expansion and a less exhausted baseline T-cell phenotype. Overall, the safety and efficacy of the combination of BTKi and T-cell redirecting immunotherapy appears promising and merits further exploration. This trial was registered at www.ClinicalTrials.gov as #NCT04234061.
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Adenina/análogos & derivados , Linfoma de Células del Manto , Piperidinas , Receptores Quiméricos de Antígenos , Adulto , Humanos , Linfoma de Células del Manto/tratamiento farmacológico , Receptores Quiméricos de Antígenos/uso terapéutico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Linfocitos T , Inmunoterapia Adoptiva/métodos , Antígenos CD19RESUMEN
PURPOSE: Health care professionals (HCP) play a vital role in effectiveness of prehabilitation programs, but information is limited about what assists HCP deliver an effective service. This study evaluated HCP perceptions of enablers and barriers to two behaviours: referral for, and delivery of, multidisciplinary prehabilitation prior to autologous stem cell transplant. METHODS: Based on the Theoretical Domains Framework (TDF) of behaviour change, we conducted semi-structured interviews, purposively sampling 14 participants (from various healthcare disciplines) at a tertiary cancer centre. Discipline-specific topic guides were created based on the TDF and the behaviours appropriate to each discipline. Interviews were audio-recorded, transcribed verbatim, anonymised, content analysed (grouping, then labelling, thematically similar responses), and classified into theoretical domains. Structured decision rules were used to classify themes as high, medium, or low priority. RESULTS: Fifty enablers and 31 barriers were identified; of these 26 enablers and 16 barriers classified as high priority. Four domains had the most frequent high-priority enablers: Social professional role and identity (e.g. multidisciplinary teamwork); Beliefs about consequences (e.g. patient benefit); Memory, attention, and decision processes (e.g. refer as early as possible); and Environmental context and resources (e.g. electronic medical records are beneficial). High-priority barriers were most frequent in four domains: Memory, attention, and decision processes (e.g. conflicting views about who should be referred); Environmental context and resources (e.g. lack of time); Social influences (e.g. families); and Emotions (e.g. patient distress). CONCLUSION: Participants reported more enablers than barriers. Findings can support delivery of prehabilitation programs in hospital settings where uptake remains low.
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Personal de Salud , Ejercicio Preoperatorio , Humanos , Derivación y Consulta , Actitud del Personal de Salud , Investigación CualitativaRESUMEN
In patients early post-autologous stem cell transplant, seroprotection rates were high for Hemophilus influenzae type B and tetanus toxoid (70%-90%) but lower for Streptococcus pneumoniae (30%-50%) including after revaccination. There were high rates of seropositivity (67%-86%) to measles, mumps, and rubella and varicella zoster virus. Durability of protection requires assessment.
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Trasplante de Células Madre Hematopoyéticas , Mieloma Múltiple , Humanos , Mieloma Múltiple/tratamiento farmacológico , Lenalidomida/uso terapéutico , Bortezomib/uso terapéutico , Supervivencia sin Enfermedad , Trasplante Autólogo , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Quimioterapia de Mantención , Dexametasona/uso terapéuticoRESUMEN
Cytarabine-containing chemoimmunotherapy followed by autologous transplantation and rituximab maintenance achieves durable remissions for most patients with mantle cell lymphoma (MCL). However, patients with TP53-mutated disease have poor outcomes with standard approaches. We previously reported that allogeneic stem cell transplantation (alloSCT) achieved durable remissions in MCL, however follow-up among patients with TP53-mutated disease was limited. Here we report extended follow-up of the overall cohort (n = 36) and TP53-mutated subset (n = 13) (median follow-up 10.8 and 4.2 years, respectively). Estimated overall survival was 56% at 10 years for the overall cohort and 59% at 4 years for the TP53-mutated subset. Among patients with TP53-mutated disease, no relapses occurred beyond 6 months post-transplant. Survival after post-alloSCT disease relapse was poor (median 2.1 years). These data confirm that alloSCT can be curative in MCL, including patients with TP53-mutated disease, and should be considered for earlier utilization in this subgroup for whom conventional chemoimmunotherapy is ineffective.
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Trasplante de Células Madre Hematopoyéticas , Linfoma de Células del Manto , Adulto , Humanos , Linfoma de Células del Manto/terapia , Linfoma de Células del Manto/tratamiento farmacológico , Recurrencia Local de Neoplasia , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Rituximab/uso terapéutico , Trasplante Autólogo , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Trasplante de Células Madre , Proteína p53 Supresora de Tumor/genéticaRESUMEN
Mantle cell lymphoma is an uncommon subtype of lymphoma characterised by clinical and biological heterogeneity. Although most patients with mantle cell lymphoma have durable responses after chemoimmunotherapy, there is a need to prospectively identify high-risk subsets of patients for whom disease control with standard chemotherapy will be short lived. Among the available prognostic factors, TP53 mutations are uniquely informative owing to their strong association with early disease progression and death among patients receiving conventional chemoimmunotherapy, with the highest negative prognostic value compared with other established risk indicators, including the mantle cell lymphoma international prognostic index, histological features, elevated Ki-67, and other genetic lesions. The poor outcomes for patients with TP53-mutated mantle cell lymphoma receiving chemoimmunotherapy and second-line Bruton tyrosine kinase inhibitors represent an urgent need for alternative approaches. In this Review, we synthesise the available data to inform the management of this high-risk subset of patients and present a treatment strategy prioritising clinical trials and early use of cellular therapies.
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Linfoma de Células del Manto , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Inmunoterapia , Linfoma de Células del Manto/tratamiento farmacológico , Linfoma de Células del Manto/genética , Pacientes , Pronóstico , Proteína p53 Supresora de Tumor/genéticaAsunto(s)
Lesión Renal Aguda , Enfermedad Injerto contra Huésped , Neoplasias Hematológicas , Trasplante de Células Madre Hematopoyéticas , Humanos , Índice de Masa Corporal , Etopósido/efectos adversos , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Neoplasias Hematológicas/terapia , Neoplasias Hematológicas/etiología , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/diagnóstico , Acondicionamiento Pretrasplante/efectos adversos , Enfermedad Injerto contra Huésped/etiologíaAsunto(s)
Trasplante de Células Madre Hematopoyéticas , Linfoma Cutáneo de Células T , Linfoma de Células T , Paniculitis , Neoplasias Cutáneas , Humanos , Paniculitis/diagnóstico , Paniculitis/etiología , Paniculitis/terapia , Linfoma de Células T/diagnóstico , Linfoma de Células T/terapia , Linfoma de Células T/patología , Neoplasias Cutáneas/patologíaRESUMEN
BACKGROUND: Management of neutropenic fever in high-risk haematology patients is challenging; there are often few localising clinical features, and diagnostic tests have poor sensitivity and specificity. We aimed to compare how [18F]flurodeoxyglucose ([18F]FDG)-PET-CT scans and conventional CT scans affected the guidance of antimicrobial management and the outcomes of patients with persistent or recurrent neutropenic fever. METHODS: We did a multicentre, open-label, phase 3, randomised, controlled trial in two tertiary referral hospitals in Australia. We recruited adults aged 18 years or older who were receiving conditioning chemotherapy for haematopoietic stem-cell transplantation or chemotherapy for acute leukaemia and had persistent (>72 h) or recurrent (new fever beyond 72 h of initial onset interspersed with >48 h defervescence) neutropenic fever. Exclusion criteria were pregnancy, allergy to iodinated contrast, or estimated glomerular filtration rate of less than 30 mL/min. Patients were randomly assigned by computer-generated randomisation chart (1:1) to [18F]FDG-PET-CT or conventional CT. Masking was not possible because of the nature of the investigation. Scans were done within 3 days of random assignment. The primary endpoint was a composite of starting, stopping, or changing the spectrum (broadening or narrowing) of antimicrobial therapy-referred to here as antimicrobial rationalisation-within 96 h of the assigned scan, analysed per protocol. This trial is registered with clinicaltrials.gov, NCT03429387, and is complete. FINDINGS: Between Jan 8, 2018, and July 23, 2020, we assessed 316 patients for eligibility. 169 patients were excluded and 147 patients were randomly assigned to either [18F]FDG-PET-CT (n=73) or CT (n=74). Nine patients did not receive a scan per protocol, and two participants in each group were excluded for repeat entry into the study. 65 patients received [18F]FDG-PET-CT (38 [58%] male; 53 [82%] White) and 69 patients received CT (50 [72%] male; 58 [84%] White) per protocol. Median follow up was 6 months (IQR 6-6). Antimicrobial rationalisation occurred in 53 (82%) of 65 patients in the [18F]FDG-PET-CT group and 45 (65%) of 69 patients in the CT group (OR 2·36, 95% CI 1·06-5·24; p=0·033). The most frequent component of antimicrobial rationalisation was narrowing spectrum of therapy, in 28 (43%) of 65 patients in the [18F]FDG-PET-CT group compared with 17 (25%) of 69 patients in the CT group (OR 2·31, 95% CI 1·11-4·83; p=0·024). INTERPRETATION: [18F]FDG-PET-CT was associated with more frequent antimicrobial rationalisation than conventional CT. [18F]FDG-PET-CT can support decision making regarding antimicrobial cessation or de-escalation and should be considered in the management of patients with haematological diseases and persistent or recurrent high-risk neutropenic fever after chemotherapy or transplant conditioning. FUNDING: National Health and Medical Research Council Centre of Research Excellence (APP1116876), Melbourne Health foundation, Gilead Research Fellowship grants supported this study.
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Antiinfecciosos , Fluorodesoxiglucosa F18 , Adulto , Femenino , Humanos , Masculino , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Tomografía de Emisión de Positrones , Acondicionamiento PretrasplanteRESUMEN
PURPOSE: Evaluate the impact of a new multidisciplinary allied health prehabilitation service in haematologic cancer patients receiving high-dose chemotherapy with autologous stem cell transplant (AuSCT). METHODS: In a tertiary cancer centre, 12 months of prospectively collected data was retrospectively analysed. Patients were referred to an allied health service for individualised exercise prescription, nutrition intervention and, if indicated through screening, psychological intervention. Impact and operational success were investigated using the RE-AIM framework: patient uptake of the service and sample representativeness (reach); effectiveness in terms of changes in outcomes from initial to pre-transplant assessment; adoption of the service by key stakeholders; fidelity of the prescribed exercise program (implementation); and the extent to which the new service had become routine practice (maintenance). RESULTS: One hundred and eighty-three patients were referred to the AuSCT service over 12 months, of whom 133 (73%) were referred into the prehabilitation service, 128 (96%) were eligible and 116 (91%) participated. Patients were representative of Australian AuSCT patients. Eighty-nine patients reached pre-transplant assessment by data censoring; 6-min walk distance (n = 45/89, 51%) improved a mean (95% CI) of 39.9 m (18.8 to 61.0, p = < 0.005) from baseline. Fidelity of exercise prescription was moderate with 72% of eligible patients receiving the intended exercise interventions. The referral trend over time (maintenance) was high after the initiation period. CONCLUSION: The prehabilitation service was well adopted by clinicians. Clinically relevant improvements in outcomes were demonstrated. Recommendations, including development of well-integrated discipline-specific assessment intervention and measurement protocols, are highlighted for service improvement. Prehabilitation should be routinely considered to support patients undergoing AuSCT.
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Neoplasias , Ejercicio Preoperatorio , Australia , Ejercicio Físico , Humanos , Cuidados Preoperatorios , Estudios RetrospectivosRESUMEN
BACKGROUND: High-intensity chemotherapy and advances in novel immunotherapies have seen the emergence of cytomegalovirus (CMV) infections in cancer patients other than allogeneic haemopoietic cell transplantation (HCT). Aim To evaluate the epidemiology, clinical characteristics and outcomes of CMV infection in this population. METHODS: A retrospective review of cancer patients other than allogeneic HCT who had CMV DNAemia and/or disease from July 2013 till May 2020 at a quaternary cancer centre was performed. RESULTS: Of 11 485 cancer patients who underwent treatment during this period, 953 patients had CMV DNA testing performed and 238 of them had CMV DNAemia. After excluding patients with allogeneic HCT, 62 patients with CMV DNAemia were identified, of whom 10 had concurrent CMV disease. The most frequent underlying malignancies were B-cell lymphoproliferative disease (LPD) (31%; 19/62), T-cell LPD (21%; 13/62), chronic lymphocytic leukaemia (11%; 7/62) and multiple myeloma (10%; 6/62). Most patients had lymphopenia (77%; 48/62), multiple cancer therapies (63%; 39/62 received ≥2 previous therapies), co-infection (56%; 35/62 had ≥1 co-infection) and corticosteroid therapy (48%; 30/62) within 1 month before CMV diagnosis. CMV DNAemia and disease were observed in patients receiving novel immunotherapies, including bispecific antibody therapy, chimeric-antigen receptor T-cell therapy and immune checkpoint inhibitors. CONCLUSION: Patients with haematological malignancy, particularly B-cell LPD, T-cell LPD, chronic lymphocytic leukaemia and multiple myeloma, were frequently identified to have CMV DNAemia and disease. Lymphopenia, multiple cancer therapies, co-infection and recent receipt of systemic corticosteroids were also commonly observed. Future studies are necessary to determine optimal identification and management of CMV in these patients.
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Coinfección , Infecciones por Citomegalovirus , Trasplante de Células Madre Hematopoyéticas , Leucemia Linfocítica Crónica de Células B , Linfopenia , Mieloma Múltiple , Humanos , Citomegalovirus/genética , Inhibidores de Puntos de Control Inmunológico , ADN Viral , Infecciones por Citomegalovirus/diagnóstico , Infecciones por Citomegalovirus/epidemiología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Linfopenia/etiología , Receptores de Antígenos , CorticoesteroidesRESUMEN
BACKGROUND: Multiple Myeloma (MM) accounts for 1-2% of all malignancies but is the second most common hematological malignancy. It is characterized by a proliferation of malignant plasma cells. The treatment paradigm of MM in Australia is traditionally hospital-based, complex, and costly. While MM comprises 1-2% of cancer diagnoses, it appears in the top 10 cancer diagnoses requiring hospital admission. The cumulative time spent receiving treatment is a significant burden for patients. The ability to receive treatment at home and maximize time away from hospital-based settings is a key preference for patients receiving anticancer therapies over a prolonged period of time. METHODS: The Peter MacCallum Cancer Centre and Royal Melbourne Hospital's combined Clinical Hematology Unit has collaborated with their Hospital in the Home departments to develop several innovative programs to address this. RESULTS: We describe our current active programs and potential developments in home-based MM therapy. CONCLUSION: We have enabled large numbers of patients to receive complex therapies in their own home and the COVID-19 pandemic has increased the pace of the roll out without any compromise in safety. We anticipate that the next raft of immunotherapies will be able to transition into the @Home treatment setting in the coming years.
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COVID-19 , Mieloma Múltiple , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bortezomib/uso terapéutico , Dexametasona/uso terapéutico , Humanos , Mieloma Múltiple/tratamiento farmacológico , Pandemias , SARS-CoV-2Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Linfoma de Células del Manto , Adulto , Humanos , Linfoma de Células del Manto/genética , Linfoma de Células del Manto/terapia , Trasplante de Células Madre , Linfocitos T/patología , Trasplante Homólogo , Proteína p53 Supresora de Tumor/genéticaRESUMEN
Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of lymphomas that are frequently associated with a poor prognosis. For many decades, the standard-of-care has been CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone)-based therapy, but it is well-recognized that survival outcomes are unsatisfactory, especially when compared with B-cell lymphomas. Major recent advances in cancer diagnosis and management have the potential to significantly improve PTCL outcomes. These include: (1) improved diagnostic techniques that incorporate molecular genetic data to further refine diagnosis and subtyping; (2) the development of novel agents; and (3) improved monitoring modalities, such as 18F-fluorodeoxyglucose positron emission tomography-computed tomography scans and circulating tumor DNA. In this review, we aim to explore these 3 advances in the context of frontline management of PTCL.