Measurable Residual Disease and Clinical Outcomes in Chronic Lymphocytic Leukemia: A Systematic Review and Meta-Analysis.

Importance: Measurable residual disease (MRD) refers to the presence of disease at low levels not detected by conventional pathologic analysis. The association of MRD status as a surrogate end point of clinical outcome in chronic lymphocytic leukemia (CLL) has not been established in the era of targeted agents. Assessing the association of MRD with progression-free survival (PFS) may improve its role as a surrogate marker and allow its use to accelerate drug development. Objective: To assess the association between MRD and PFS in CLL using data from prospective clinical trials that studied targeted agents or obinutuzumab-based treatment. Data Sources: Clinical studies on CLL were identified via searches of PubMed, Embase, Scopus, and Web of Science from inception through July 31, 2023. Study Selection: Prospective, single-arm, and randomized clinical trials that assessed targeted agents or obinutuzumab-based treatment and reported PFS by MRD status were included. Studies with insufficient description of MRD information were excluded. Data Extraction and Synthesis: Study sample size, median patient age, median follow-up time, line of treatment, MRD detection method and time points, and survival outcomes were extracted. Main Outcomes and Measures: Analyses of survival probabilities and hazard ratios (HRs) were conducted for PFS according to MRD status. Meta-analyses were performed using a random-effects model. Results: A total of 11 prospective clinical trials (9 randomized and 2 nonrandomized) including 2765 patients were analyzed. Achieving undetectable MRD (uMRD) at 0.01% was associated with an HR of 0.28 (95% CI, 0.20-0.39; P < .001) for PFS. Median PFS was not reached in both groups (uMRD vs MRD), but the estimated 24-month PFS was better in the uMRD group (91.9% [95% CI, 88.8%-95.2%] vs 75.3% [95% CI, 64.7%-87.6%]; P < .001). The association of uMRD with PFS was observed in subgroup analyses in the first-line treatment setting (HR, 0.24; 95% CI, 0.18-0.33), relapsed or refractory disease setting (HR, 0.34; 95% CI, 0.16-0.71), and trials using time-limited therapy (HR, 0.28; 95% CI, 0.19-0.40). Conclusions and Relevance: The findings of this systematic review and meta-analysis suggest that assessing MRD status as an end point in clinical trials and as a surrogate of PFS may improve trial efficiency and potentially allow for accelerated drug registration.

Measurable Residual Disease in Chronic Lymphocytic Leukemia: Current Understanding and Evolving Role in Clinical Practice.

OPINION STATEMENT: Treatment of chronic lymphocytic leukemia (CLL) has evolved dramatically during the last decade, from chemoimmunotherapy (CIT)-based therapies to newer B-cell receptor (BCR) signaling targeting agents, which are sometimes given as continuous schemes. Response to treatment was traditionally defined according to clinical variables designed to assign a response category. Interest in assessing for deeper responses in CLL by the means of measurable residual disease (MRD) testing has been the subject of research during the last several years. Analyses and sub-analyses of clinical trials have shown that achieving undetectable MRD (uMRD) in CLL is an important prognostic factor. In this review, we summarize the available evidence about MRD in CLL, from the various assays available for measurement, the compartment to test, the impact of reaching uMRD according to the treatment regimen, and the results of fixed duration treatment guided by MRD trials. Finally, we summarize how MRD can be incorporated in clinical practice and how it may guide fixed duration treatment in the future should evidence continue to accumulate in that direction.

Outcomes in Temporary ICUs Versus Conventional ICUs: An Observational Cohort of Mechanically Ventilated Patients With COVID-19-Induced Acute Respiratory Distress Syndrome.

Throughout the COVID-19 pandemic, thousands of temporary ICUs have been established worldwide. The outcomes and management of mechanically ventilated patients in these areas remain unknown. OBJECTIVES: To investigate mortality and management of mechanically ventilated patients in temporary ICUs. DESIGN SETTING AND PARTICIPANTS: Observational cohort study in a single-institution academic center. We included all adult patients with severe COVID-19 hospitalized in temporary and conventional ICUs for invasive mechanical ventilation due to acute respiratory distress syndrome from March 23, 2020, to April 5, 2021. MAIN OUTCOMES AND MEASURES: To determine if management in temporary ICUs increased 30-day in-hospital mortality compared with conventional ICUs. Ventilator-free days, ICU-free days (both at 28 d), hospital length of stay, and ICU readmission were also assessed. RESULTS: We included 776 patients (326 conventional and 450 temporary ICUs). Thirty-day in-hospital unadjusted mortality (28.8% conventional vs 36.0% temporary, log-rank test p = 0.023) was higher in temporary ICUs. After controlling for potential confounders, hospitalization in temporary ICUs was an independent risk factor associated with mortality (hazard ratio, 1.4; CI, 1.06-1.83; p = 0.016).There were no differences in ICU-free days at 28 days (6; IQR, 0-16 vs 2; IQR, 0-15; p = 0.5) or ventilator-free days at 28 days (8; IQR, 0-16 vs 5; IQR, 0-15; p = 0.6). We observed higher reintubation (18% vs 12%; p = 0.029) and readmission (5% vs 1.6%; p = 0.004) rates in conventional ICUs despite higher use of postextubation noninvasive mechanical ventilation (13% vs 8%; p = 0.025). Use of lung-protective ventilation (87% vs 85%; p = 0.5), prone positioning (76% vs 79%; p = 0.4), neuromuscular blockade (96% vs 98%; p = 0.4), and COVID-19 pharmacologic treatment was similar. CONCLUSIONS AND RELEVANCE: We observed a higher 30-day in-hospital mortality in temporary ICUs. Although both areas had high adherence to evidence-based management, hospitalization in temporary ICUs was an independent risk factor associated with mortality.