Critical Appraisal of Published Indirect Comparisons and Network Meta-Analyses of Competing Interventions for Multiple Myeloma

ObjectivesIn the field of relapsed or refractory multiple myeloma (RRMM), between-trial or indirect comparisons are required to estimate relative treatment effects between competing interventions based on the available evidence. Two approaches are frequently used in RRMM: network meta-analysis (NMA) and unanchored matching-adjusted indirect comparison (MAIC). The objective of the current study was to evaluate the relevance and credibility of published NMA and unanchored MAIC studies aiming to estimate the comparative efficacy of treatment options for RRMM.MethodsTwelve relevant studies were identified in the published literature (n = 7) and from health technology assessment agencies (n = 5). Data from trials were extracted to identify between-trial differences that may have biased results. Credibility of the performed analyses and relevance of the research questions were critically appraised using the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) checklist and feedback based on consultations with clinical experts.ResultsThe identified studies concerned NMAs of randomized controlled trials (RCTs; n = 7), unanchored MAICs (n = 4), or both types of analyses (n = 1). According to clinical expert consultation, the majority of the identified NMAs did not consider differences in prior therapies or treatment duration across the RCTs included in the analyses, thereby compromising the relevance.ConclusionBased on the results and feedback from clinicians, the majority of NMAs did not consider prior treatment history or treatment duration, which resulted in nonrelevant comparisons. Furthermore, it may have compromised the credibility of the estimates owing to differences in effect-modifiers between the different trials. Pairwise comparisons by means of unanchored MAICs require clear justification given the reliance on non-randomized comparisons.     

p53-Induced inflammation exacerbates cardiac dysfunction during pressure overload

The rates of death and disability caused by severe heart failure are still unacceptably high. There is evidence that the sterile inflammatory response has a critical role in the progression of cardiac remodeling in the failing heart. The p53 signaling pathway has been implicated in heart failure, but the pathological link between p53 and inflammation in the failing heart is largely unknown. Here we demonstrate a critical role of p53-induced inflammation in heart failure. Expression of p53 was increased in cardiac endothelial cells and bone marrow cells in response to pressure overload, leading to up-regulation of intercellular adhesion molecule-1 (ICAM1) expression by endothelial cells and integrin expression by bone marrow cells. Deletion of p53 from endothelial cells or bone marrow cells significantly reduced ICAM1 or integrin expression, respectively, as well as decreasing cardiac inflammation and ameliorating systolic dysfunction during pressure overload. Conversely, overexpression of p53 in bone marrow cells led to an increase of integrin expression and cardiac inflammation that reduced systolic function. Norepinephrine markedly increased p53 expression in endothelial cells and macrophages. Reducing β₂-adrenergic receptor expression in endothelial cells or bone marrow cells attenuated cardiac inflammation and improved systolic dysfunction during pressure overload. These results suggest that activation of the sympathetic nervous system promotes cardiac inflammation by up-regulating ICAM1 and integrin expression via p53 signaling to exacerbate cardiac dysfunction. Inhibition of p53-induced inflammation may be a novel therapeutic strategy for heart failure.     

IKZF1 Deletion Subtyping and Outcome Analysis in BCR–ABL1-Negative Pediatric B-Cell Acute Lymphoblastic Leukemia: A Single-Institution Experience from North India

BackgroundIKZF1 deletions are associated with adverse outcomes in B-cell acute lymphoblastic leukemia (B-ALL). We assessed the prevalence and clinical impact of functional subtypes of IKZF1 deletions in pediatric BCR–ABL1-negative B-ALL. Patients andMethodsThis retrospective study of IKZF1 deletions was done in cases of pediatric BCR–ABL1-negative B-ALL. The genomic DNA of cases, over a 53-month period, was analyzed using multiplex ligation-dependent probe amplification and multiplex fluorescent polymerase chain reaction. The deletions were divided into functional subgroups: (1) loss-of-function/haploinsufficiency, (2) dominant-negative, and (3) a combination of both types of deletion. The post-induction remission status, event-free survival (EFS), and overall survival (OS) were noted.ResultsOut of 320 cases, 47 (14.7%) had IKZF1 deletions. Thirty-six of the 47 (77%) had loss-of-function deletions, 10 (21%) had dominant-negative deletions, and one (2%) had a combination of both types. The post-induction remission rates in cases with loss-of-function deletions (22/30, 73%; P = .060) and dominant-negative deletions (4/5, 80%; P = .517) were lower compared with those without deletions (215/248, 86.7%). These cases also had worse median EFS: 21.1 months (P = .006) for loss-of-function and 15.4 months (P = .156) for dominant-negative deletions, compared with 46.4 months in cases without IKZF1 deletions. They also had worse median OS: 23.4 months (P = .012) for loss-of-function deletions and 15.7 months (P = .233) for dominant-negative deletions, compared with median not reached in cases without IKZF1 deletions.ConclusionThe IKZF1 deletions were seen in 14.7% of BCR–ABL1-negative pediatric B-ALL. Most of these deletions (77%) were loss-of-function type. The cases with loss-of-function deletions had lower remission rates and poor EFS and OS compared with cases without IKZF1 deletions. A similar trend of poor outcome was seen in the few cases with dominant-negative IKZF1 deletions.