A phase 3b study of venetoclax and azacitidine or decitabine in an outpatient setting in patients with acute myeloid leukemia.

Venetoclax, a highly selective BCL-2 inhibitor, combined with hypomethylating agents (HMAs) azacitidine or decitabine, is approved for the treatment of newly diagnosed acute myeloid leukemia (ND AML) in patients who are ineligible to receive intensive chemotherapy. Previous clinical studies initiated venetoclax plus HMA in an inpatient setting owing to concerns of tumor lysis syndrome (TLS). This study (NCT03941964) evaluated the efficacy and safety of venetoclax plus HMA in a United States community-based outpatient setting in patients with ND AML (N = 60) who were treatment naïve for AML, ineligible to receive intensive chemotherapy, had no evidence of spontaneous TLS at screening, and were deemed as appropriate candidates for outpatient initiation of venetoclax plus HMA by the investigator. Patients received venetoclax in combination with azacitidine (75 mg/m2) or decitabine (20 mg/m2) for up to 6 cycles during the study. With a median time on study of 18.3 weeks, the best response rate of composite complete remission was 66.7%, and the overall post-baseline red blood cell (RBC) and platelet transfusion independence rate was 55.0%, consistent with results of studies in which treatment was initiated in an inpatient setting. Key adverse events included nausea, anemia, thrombocytopenia, neutropenia, and white blood cell count decrease of any grade (≥50% of patients). The observed safety profile was generally consistent with that of venetoclax plus HMA observed in inpatient AML studies. With close monitoring, 2 cases of TLS were identified, appropriately managed, and the patients were able to continue study treatment. CLINICAL TRIALS REGISTRATION: This study is registered at ClinicalTrials.gov. The registration identification number is NCT03941964.

Early results and lessons learned from a multicenter, randomized, double-blind trial of bone marrow aspirate concentrate in critical limb ischemia.

OBJECTIVES: Despite advances in endovascular therapies, critical limb ischemia (CLI) continues to be associated with high morbidity and mortality. Patients without direct revascularization options have the worst outcomes. We sought to explore the feasibility of conducting a definitive trial of a bone marrow-derived cellular therapy for CLI in this "no option" population. METHODS: A pilot, multicenter, prospective, randomized, double-blind, placebo-controlled trial for "no option" CLI patients was performed. The therapy consisted of bone marrow aspirate concentrate (BMAC), prepared using a point of service centrifugation technique and injected percutaneously in 40 injections to the affected limb. Patients were randomized to BMAC or sham injections (dilute blood). We are reporting the 12-week data. RESULTS: Forty-eight patients were enrolled. The mean age was 69.5 years (range, 42-93 years). Males predominated (68%). Diabetes was present in 50%. Tissue loss (Rutherford 5) was present in 30 patients (62.5%), and 18 (37.5%) had rest pain without tissue loss (Rutherford 4). Patients were deemed unsuitable for conventional revascularization based on multiple prior failed revascularization efforts (24 [50%]), poor distal targets (43 [89.6%]), and medical risk (six [12.5%]). Thirty-four patients were treated with BMAC and 14 with sham injections. There were no adverse events attributed to the injections. Renal function was not affected. Effective blinding was confirmed; blinding index of 61% to 85%. Subjective and objective outcome measures were effectively obtained with the exception of treadmill walking times, which could only be obtained at baseline and follow-up in 15 of 48 subjects. This pilot study was not powered to demonstrate statistical significance but did demonstrate favorable trends for BMAC versus control in major amputations (17.6% vs 28.6%), improved pain (44% vs 25%), improved ankle brachial index (ABI; 32.4% vs 7.1%), improved Rutherford classification (35.3% vs 14.3%), and quality-of-life scoring better for BMAC in six of eight domains. CONCLUSIONS: In this multicenter, randomized, double-blind, placebo-controlled trial of autologous bone marrow cell therapy for CLI, the therapy was well tolerated without significant adverse events. The BMAC group demonstrated trends toward improvement in amputation, pain, quality of life, Rutherford classification, and ABI when compared with controls. This pilot allowed us to identify several areas for improvement for future trials and CLI studies. These recommendations include elimination of treadmill testing, stratification by Rutherford class, and more liberal inclusion of patients with renal insufficiency. Our strongest recommendation is that CLI studies that include Rutherford 4 patients should incorporate a composite endpoint reflecting pain and quality of life.

Dose-dense vinorelbine and docetaxel with Filgrastim support in patients with advanced nonsmall cell lung carcinoma.

BACKGROUND: Vinorelbine and docetaxel are active single agents in the treatment of nonsmall cell lung carcinoma (NSCLC) and may provide enhanced activity when combined in a dose-dense fashion. The efficacy and safety of this combination was assessed when it was administered every 14 days with Filgrastim support in a community practice setting. METHODS: This open-label study was conducted at 12 community oncology practices in the United States. Sixty-one chemotherapy-naive patients with Stage IIIB/IV NSCLC received vinorelbine 45 mg/m2 followed by docetaxel 60 mg/m2 on Day 1 and Filgrastim 5 mcg/kg beginning on Day 2, with cycles repeated every 14 days. RESULTS: Among 61 enrolled patients, 44% of patients had either a complete or partial response as their best response, and 27% of patients had confirmed complete or partial responses. The median time to confirmed response was 1.9 months (95% confidence interval [95% CI], 0.9-2.3 mos), and the median duration of confirmed response was 6.0 months (95% CI, 3.1-14.4 mos). The median time to disease progression was 4.9 months (95% CI, 3.8-5.8 mos). With a median follow-up of 14.3 months, the median survival was 12.9 months (95% CI, 8.1-14.3 mos), and the 1-year survival rate was 56% (95% CI, 43-69%). The relative dose intensity was 94% for vinorelbine and 93% for docetaxel. Febrile neutropenia occurred in 9 patients (15%) and during 9 of 351 cycles (3%). CONCLUSIONS: It was possible to administer dose-dense vinorelbine and docetaxel chemotherapy with Filgrastim support, beginning in the first cycle, to patients with NSCLC who were treated in a community practice setting.