Bone Marrow Mesenchymal Stem Cell-Derived Extracellular Vesicle Infusion for the Treatment of Respiratory Failure From COVID-19: A Randomized, Placebo-Controlled Dosing Clinical Trial.

BACKGROUND: Bone marrow mesenchymal stem cell (BM-MSC)-derived extracellular vesicles (ExoFlo) convey the immunomodulatory and regenerative properties of intact BM-MSCs. This study aimed to determine the safety and efficacy of ExoFlo as treatment for moderate to severe ARDS in patients with severe COVID-19. RESEARCH QUESTION: Do two doses of ExoFlo safely reduce mortality in COVID-19-associated moderate to severe ARDS compared with placebo? STUDY DESIGN AND METHODS: A prospective phase 2 multicenter double-anonymized randomized placebo-controlled dosing trial was conducted at five sites across the United States with infusions of placebo, 10 mL of ExoFlo, or 15 mL of ExoFlo on days 1 and 4. Patients (N = 102) with COVID-19-associated moderate to severe ARDS were enrolled and randomized to treatment. Adverse events were documented throughout the study. The primary outcome measure was all-cause 60-day mortality rate. Secondary outcomes included time to death (overall mortality); the incidence of treatment-emergent serious adverse events; proportion of discharged patients at 7, 30, and 60 days; time to hospital discharge; and ventilation-free days. RESULTS: No treatment-related adverse events were reported. Mortality (60-day) in the intention-to-treat population was reduced with 15 mL ExoFlo mixed with 85 mL normal saline (ExoFlo-15) compared with placebo (not significant, χ2, P = .1343). For the post hoc subgroup analyses, 60-day mortality was decreased with ExoFlo-15 compared with placebo (relative risk, 0.385; 95% CI, 0.159-0.931; P = .0340; n = 50). With ExoFlo-15, a relative risk of 0.423 (95% CI, 0.173-1.032; P = .0588; n = 24) was determined for participants aged 18 to 65 years with moderate to severe ARDS. Ventilation-free days improved with ExoFlo-15 (P = .0455; n = 50) for all participants aged 18 to 65 years. INTERPRETATION: The 15 mL dose of ExoFlo was found to be safe in patients with severe or critical COVID-19-associated respiratory failure. In participants aged 18 to 65 years, the risk reduction in 60-day mortality was further improved from subjects of all ages in the intention-to-treat population after two doses of 15 mL of ExoFlo compared with placebo. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; No.: NCT04493242; URL: www. CLINICALTRIALS: gov.

Prognostic Factors for Complete Response to Ibrutinib in Patients With Chronic Lymphocytic Leukemia: A Pooled Analysis of 2 Clinical Trials.

Importance: Ibrutinib, a first-in-class Bruton tyrosine kinase inhibitor taken once daily, is approved in the United States for patients with chronic lymphocytic leukemia/small lymphocytic lymphoma and allows for treatment without chemotherapy. Extended treatment with ibrutinib has demonstrated increased complete response (CR) rates over time. Objective: To analyze baseline factors that predict CR in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma treated with ibrutinib. Design, Setting, and Participants: Univariate and multivariate analyses of pooled data from 2 clinical trials were used to assess the prognostic value of baseline factors associated with CR in 327 patients from the PCYC-1102 and PCYC-1112 studies treated with single-agent ibrutinib. Participants were followed up in academic and community medical centers in the United States, the United Kingdom, Australia, France, Italy, Ireland, Poland, Spain, and Austria. Main Outcomes and Measures: Odds ratio (OR) of CR rate. Results: The 327 patients included in this analysis had a median age of 67 years (range, 30-86 years) and 227 (69.4%) were male. At baseline, 185 patients (56.6%) had bulky disease (lymph node ≥5 cm), 184 (56.3%) had advanced-stage disease, and 182 (55.7%) had an Eastern Cooperative Oncology Group performance status of 1 or higher. Thirty-one patients (9.5%) were in the first-line setting; 38 (11.6%) had undergone 1 previous therapy, 81 (24.8%) had undergone 2, and 177 (54.1%) had undergone 3 or more; patients with relapsed/refractory disease had undergone a median of 3 (range, 0-12) previous therapies. Median time on study was 26.4 months (range, 0.3-55.6 months). Thirty-two of the 327 patients (9.8%) treated with ibrutinib had a CR (PCYC-1102: relapsed/refractory, 12 of 101 [11.9%]; treatment-naive, 8 of 31 [25.8%]; and PCYC-1112: 12 of 195 [6.2%]). The median time to CR for these patients was 14.7 months (range, 4.6-47.1 months). Univariate analysis of baseline factors showed that bulky disease, clinical stage, number of previous therapies, and ß2-microglobulin concentration had a significant effect on the odds of CR. The final multivariate model showed that patients with no previous therapy vs patients with at least 1 previous therapy (OR, 2.65; 95% CI, 1.01-6.95; P = .047) and patients without bulky disease (lymph node <5 cm) vs those with bulky disease (lymph node ≥5 cm [OR, 4.97; 95% CI, 1.91-12.91; P = .001]) had an increased likelihood of CR. Conclusions and Relevance: Patients receiving ibrutinib as a first-line therapy for chronic lymphocytic leukemia and those without bulky disease had a better likelihood of CR to treatment. The CR rate with continued longer-term ibrutinib treatment was higher than in previous reports. Trial Registration: clinicaltrials.gov Identifiers: NCT01105247 and NCT01578707.

Response-independent survival benefit in metastatic colorectal cancer: a comparative analysis of N9741 and AVF2107.

PURPOSE: In the phase III study AVF2107g, bevacizumab (BV) demonstrated a survival benefit when added to irinotecan, fluorouracil, and leucovorin (IFL) in first-line metastatic colorectal cancer (mCRC). In a parallel phase III study, Intergroup N9741, oxaliplatin plus fluorouracil and leucovorin (FOLFOX) also demonstrated a survival benefit compared with IFL. As these two superior therapies have differing mechanisms of action, we explored whether the improved survival associated with the superior therapy was dependent on tumor response. PATIENTS AND METHODS: For these retrospective, exploratory analyses, patients were defined as responders or nonresponders by whether complete or partial response was achieved with first-line therapy. RESULTS: Compared with IFL alone, BV plus IFL and FOLFOX each demonstrated statistically significant improvements in progression-free survival (PFS) and overall survival (OS) regardless of objective tumor response. BV-treated nonresponders had a hazard ratio (HR) of 0.63 (P = .0001) for PFS and 0.76 (P = .0188) for OS compared with IFL-treated nonresponders. FOLFOX-treated nonresponders had an HR of 0.75 (P = .0029) for PFS and 0.74 (P = .0030) for OS compared with IFL-treated nonresponders. CONCLUSION: In both AVF2107g and N9741, objective response did not predict the magnitude of PFS or OS benefit from the superior therapy; nonresponders, despite a poorer prognosis than responders, achieved extended PFS and OS from BV plus IFL or FOLFOX compared with IFL. On the basis of these data, tumor response in metastatic colorectal cancer is not a necessary factor for a therapy to provide benefit to an individual patient.