Previous studies using autologous bone marrow mononuclear cells (BMCs) in patients with ischemic cardiomyopathy have demonstrated safety and suggested efficacy. To determine if administration of BMCs through transendocardial injections improves myocardial perfusion, reduces left ventricular end-systolic volume (LVESV), or enhances maximal oxygen consumption in patients with coronary artery disease or LV dysfunction, and limiting heart failure or angina. A phase 2 randomized double-blind, placebo-controlled trial of symptomatic patients (New York Heart Association classification II-III or Canadian Cardiovascular Society classification II-IV) with a left ventricular ejection fraction of 45% or less, a perfusion defect by single-photon emission tomography (SPECT), and coronary artery disease not amenable to revascularization who were receiving maximal medical therapy at 5 National Heart, Lung, and Blood Institute-sponsored Cardiovascular Cell Therapy Research Network (CCTRN) sites between April 29, 2009, and April 18, 2011. Bone marrow aspiration (isolation of BMCs using a standardized automated system performed locally) and transendocardial injection of 100 million BMCs or placebo (ratio of 2 for BMC group to 1 for placebo group). Co-primary end points assessed at 6 months: changes in LVESV assessed by echocardiography, maximal oxygen consumption, and reversibility on SPECT. Phenotypic and functional analyses of the cell product were performed by the CCTRN biorepository core laboratory. Of 153 patients who provided consent, a total of 92 (82 men; average age: 63 years) were randomized (n = 61 in BMC group and n = 31 in placebo group). Changes in LVESV index (-0.9 mL/m(2) [95% CI, -6.1 to 4.3]; P = .73), maximal oxygen consumption (1.0 [95% CI, -0.42 to 2.34]; P = .17), and reversible defect (-1.2 [95% CI, -12.50 to 10.12]; P = .84) were not statistically significant. There were no differences found in any of the secondary outcomes, including percent myocardial defect, total defect size, fixed defect size, regional wall motion, and clinical improvement. Among patients with chronic ischemic heart failure, transendocardial injection of autologous BMCs compared with placebo did not improve LVESV, maximal oxygen consumption, or reversibility on SPECT. clinicaltrials.gov Identifier: NCT00824005.

Cell therapy may eventually become a therapeutic option for patients after acute myocardial infarction (AMI), potentially preventing the transition to end-stage heart failure for which cardiac transplantation is currently the only curative procedure available. Recent meta-analyses of bone marrow mononuclear cell (BMC) delivery to the infarct zone after AMI have shown small improvements in left ventricular function after successful reperfusion.¹ However, despite a growing number of trials, many fundamental questions such as optimal timing of BMC delivery remain unanswered.

Purpose: To determine the maximum-tolerated dose (MTD), safety, pharmacokinetic and pharmacodynamic profiles, and clinical activity of an oral formulation of azacitidine in patients with myelodysplastic syndromes (MDSs), chronic myelomonocytic leukemia (CMML), or acute myeloid leukemia (AML). Patients and Methods: Patients received 1 cycle of subcutaneous (SC) azacitidine (75 mg/m²) on the first 7 days of cycle 1, followed by oral azacitidine daily (120 to 600 mg) on the first 7 days of each additional 28-day cycle. Pharmacokinetic and pharmacodynamic profiles were evaluated during cycles 1 and 2. Adverse events and hematologic responses were recorded. Cross-over to SC azacitidine was permitted for nonresponders who received ≥ 6 cycles of oral azacitidine. Results: Overall, 41 patients received SC and oral azacitidine (MDSs, n = 29; CMML, n = 4; AML, n = 8). Dose-limiting toxicity (grade 3/4 diarrhea) occurred at the 600-mg dose and MTD was 480 mg. Most common grade 3/4 adverse events were diarrhea (12.2%), nausea (7.3%), vomiting (7.3%), febrile neutropenia (19.5%), and fatigue (9.8%). Azacitidine exposure increased with escalating oral doses. Mean relative oral bioavailability ranged from 6.3% to 20%. Oral and SC azacitidine decreased DNA methylation in blood, with maximum effect at day 15 of each cycle. Hematologic responses occurred in patients with MDSs and CMML. Overall response rate (ie, complete remission, hematologic improvement, or RBC or platelet transfusion independence) was 35% in previously treated patients and 73% in previously untreated patients. Conclusion: Oral azacitidine was bioavailable and demonstrated biologic and clinical activity in patients with MDSs and CMML.

The myelodysplastic syndromes (MDSs) are hematologically diverse hematopoietic stem cell malignancies primarily affecting older individuals. The incidence of MDS in the United States is estimated at 3.3 per 100 000; however, evidence suggests underreporting of MDS to centralized cancer registries. Contrary to clinical recommendations, registry guidelines from 2001-2010 required the capture of only one malignancy in the myeloid lineage and did not require blood count (BC) or bone marrow (BM) biopsy for MDS confirmation. To address these potential limitations, we constructed 4 claims-based algorithms to assess MDS incidence, applied the algorithms to the 2000-2008 Surveillance Epidemiology and End Results (SEER)–Medicare database, and assessed algorithm validity using SEER-registered MDS cases. Each algorithm required one or more MDS claims and accounted for recommended diagnostic services during the year before the first claim: 1+, 2+, 2 + BC, and 2 + BCBM (ordered by sensitivity). Each had moderate sensitivities (78.05%-92.90%) and high specificities (98.49%-99.84%), with the 2 + BCBM algorithm demonstrating the highest specificity. Based on the 2 + BCBM algorithm, the annual incidence of MDS is 75 per 100 000 persons 65 years or older—much higher than the 20 per 100 000 reported by SEER using the same sample.