Immune effector cell-associated hematotoxicity (ICAHT): EHA/EBMT consensus grading and best practice recommendations

Hematological toxicity represents the most common adverse event following chimeric antigen receptor (CAR) T-cell therapy. Cytopenias can be profound, long-lasting, and can predispose for severe infectious complications. In a recent worldwide survey, we demonstrated that there remains considerable heterogeneity in regards to current practice patterns. Here, we sought to build consensus on the grading and management of Immune Effector Cell Associated Hemato-Toxicity (ICAHT) following CAR-T therapy. For this purpose, a joint effort between the European society for Blood and Marrow Transplantation (EBMT) and the European Hematology Association (EHA) involved an international panel of 36 CAR-T experts who met in a series of virtual conferences, culminating in a 2-day meeting in Lille, France. On the basis of these deliberations, best practice recommendations were developed. For the grading of ICAHT, a classification system based on depth and duration of neutropenia was developed for early (day 0-30) and late cytopenia (after day +30). Detailed recommendations on risk factors, available pre-infusion scoring systems (e.g. CAR-HEMATOTOX score), and diagnostic work-up are provided. A further section focuses on identifying hemophagocytosis in the context of severe hematotoxicity. Finally, we review current evidence and provide consensus recommendations for the management of ICAHT, including growth factor support, anti-infectious prophylaxis, transfusions, autologous hematopoietic cell boost, and allogeneic hematopoietic cell transplantation. In conclusion, we propose ICAHT as a novel toxicity category following immune effector cell therapy, provide a framework for its grading, review literature on risk factors, and outline expert recommendations for the diagnostic work-up and short- and long-term management

Trastuzumab nel trattamento del tumore della mammella: un farmaco davvero rivoluzionario’ dal punto di vista della sanità pubblica? Meta-analisi di efficacia , sicurezza e appropriatezza prescrittiva

OBIETTIVI: I farmaci biotech, prodotti attraverso la biologia molecolare, costituiscono una grande innovazione in oncologia. Il loro alto costo pu\uf2 tuttavia rappresentare una criticit\ue0 per la sostenibilit\ue0 del servizio sanitario nazionale ed \ue8 pertanto rilevante valutarne con attenzione i benefici ed i rischi, per giustificarne l\u2019utilizzo e definirne appropriatezza prescrittiva ed implicazioni di politica sanitaria. Attraverso la tecnica della revisione sistematica della letteratura e della meta-analisi abbiamo analizzato l\u2019efficacia, la sicurezza e l\u2019appropriatezza del Trastuzumab, importante farmaco biotech per la terapia del tumore della mammella. MATERIALI: Sono stati analizzati tutti gli studi randomizzati controllati (RCT) che hanno valutato l\u2019efficacia e la sicurezza del Trastuzumab da solo o in associazione versus chemioterapia standard in donne di ogni et\ue0, con tumore mammario HER-2 positivo. La ricerca degli studi si \ue8 svolta su MEDLINE, EMBASE, TOXNET, BIOSIS, ASCO e sul registro del Cochrane Breast Cancer Group. Due revisori hanno valutato la qualit\ue0 degli RCT. I risultati sono stati sintetizzati e inseriti nelle meta-analisi dividendo gli studi in sottogruppi: tumore precoce e metastatico, alta e bassa qualit\ue0, durata del trattamento, somministrazione sequenziale e concomitante. I risultati sono espressi come hazard ratio (HR) per i dati di sopravvivenza e rischio relativo (RR) per gli outcome binari e riportano gli intervalli di confidenza al 95% (IC). RIASSUNTO: Sono stati inclusi 8 RCT riguardanti il tumore mammario precoce e 4 sul tumore metastatico. I dati sulla sopravvivenza e sopravvivenza libera da malattia o da progressione favorivano significativamente i regimi contenenti Trastuzumab sia nel tumore precoce (HR 0.66, IC 0.57-0.77 e HR 0.60, IC 0.50-0.71) che in quello metastatico (HR 0.79, IC 0.67-0.94 e HR 0.56, IC 0.48-0.64). Si evidenziava peraltro anche un aumentato rischio di scompenso cardiaco grave (RR 5.11, IC 2.70-9.66 e RR 3.75, IC 1.68-8.39), ! soprattu tto nelle pazienti trattate per pi\uf9 di 6 mesi. L\u2019efficacia del trattamento non era influenzata dallo stato linfonodale od ormonale, dalle dimensioni del tumore o dall\u2019et\ue0. CONCLUSIONI: Il Trastuzumab migliora certamente la sopravvivenza delle pazienti. Ci troviamo per\uf2 insicuri riguardo alla magnitudine del beneficio del farmaco ed alla durata dello stesso nel tempo. I dati rivelano, infatti, che il farmaco \ue8 gravato da un\u2019importante cardiotossicit\ue0, che erode il beneficio netto. Gli studi analizzati, inoltre, sono caratterizzati da bias, che potrebbero enfatizzare erroneamente l\u2019efficacia reale. \uc8 necessario pertanto definire con cautela l\u2019appropriatezza prescrittiva di questo farmaco

Unplanned crossover in randomised controlled trials : consequences for efficacy and safety outcomes

Background: If a randomized controlled trial (RCT) shows results in favour of an intervention, investigators might surmise that the equipoise principle has vanished. As a consequence, control patients may be offered to cross over to the experimental arm even if it was unplanned. Objectives: We assessed: a) the prevalence of the unplanned crossover in oncology; b) how it is dealt when analysing data; c) the potential magnitude and direction of bias. Methods: RCTs published between 2000 and 2011 in the NEJM, JNCI, Lancet, Lancet Oncology, JCO, Annals of Oncology, assessing the efficacy and safety of treatments in oncologic patients were searched. We explored the relationship between the effect and: a) the time when the crossover occurred; b) the fraction of patients who decided to cross over; c) their clinical characteristics. The magnitude and direction of bias were investigated through simulations. Results: Out of 164 papers analyzed so far, in 11 RCTs investigators gave patients the opportunity to crossover to the experimental arm. The phenomenon is more frequent in the second half of the decade. All studies compared outcomes by using ITT and 20% used an additional censored analyses. Simulations suggest that ITT analyses dilute the treatment effect size for efficacy and safety, whereas the magnitude and direction of the bias caused by the censored analysis seem to be less predictable. The inverse probability of censoring weighted model was also used, but it is highly speculative since it is dependant on the characteristics of those patients who decided to cross over. Conclusions: While investigators justify the unplanned crossover of patients on ethical grounds, it can leave the scientific community with increased uncertainty of study results, and may be a condition to inflate the net benefit and risk of an intervention of clinical relevance