Schaer, Gary L.

Background: Refractory angina(Ang) effects 150 –250,000 pts in the US alone. These individuals have exhausted options for revasc and continue to have lifestyle limiting ang despite optimal medical Rx. Pre-clinical studies provided evidence that human CD34+ cells(CD34) can stimulate new blood vessel formation in ischemic myocardium(Myo), improving perfusion and function. We performed a phase 2 study of intraMyo injection of autologous CD34 in pts with CCS Class 3 and 4 Ang to obtain evidence for feasibility, safety and bioactivity. Methods: A phase 2 randomized, double-blind, placebo-controlled clinical trial was performed at 26 centers in the United States. There were 3 treatment groups: placebo, low dose (1×10^5 CD34/kg body wt) and high dose (5×10^5 CD34/kg). All pts underwent mobilization with GCSF 5 mcg/kg/day SC for 5 d, followed by apheresis on d5 to collect mononuclear cells. On day 6 CD34 were purified from the collected cells using the Isolex 300i device. After lot release testing, CD34 were injected endocardially at 10 locations in the ischemic Myo using the Myostar catheter following NOGA mapping. Placebo injections consisted of identical volumes of the diluent only. Results: A total of 167 pts were randomized and completed the injection procedure and 162 completed the 6 mo evaluation. The mean age of subjects was 61.0±8.9, there were 22 female and 145 male subjects. Trop was elevated in 26 pts at baseline and in 71 at some point following GCSF or injection. At 6 mo CD34 treated pts showed more reduction in ang frequency (−8.6 placebo vs 14.2 low dose) and improved ETT time (+69 sec placebo vs. +138 low dose). At 12m CD34 treated continue to show more reduction in angina (−8.2 placebo vs. −15.0 low dose) and improved ETT (+58 sec placebo vs. + 139 sec low dose). For key endpoints the high dose group results were inferior to low dose. The 12m data set has been locked and is being analyzed and the results of the completed analysis will be presented. Conclusions: Autologous CD34 cell therapy was associated with improved exercise tolerance and reduced angina in no-option pts with intractable angina. Ongoing analysis will determine endpoints, sample size and suitability of this therapy for a phase III study in no-option pts with refractory angina.

Background: Prior studies suggest an association between naturally high circulating levels of CD34+ cells (CD34) and better outcomes following ischemic events. Pts in the treatment arm of the PreSERVE-AMI study were infused with all CD34 yielded from their bone marrow harvest, resulting in pts with naturally higher CD34 cell counts being infused with a higher cell dose. To determine whether selection bias may have influenced results, we performed an analysis of the relationship between BM CD34 content and outcomes in PreSERVE-AMI. Methods: PreSERVE-AMI is a Phase 2, randomized, double-blind, placebo-controlled trial of autologous, BM derived CD34 (CLBS10) in pts with LV dysfunction (LVEF ≤48% by MRI) ≥4 days post-STEMI. All pts underwent mini BM harvest and were randomized 1:1 to intracoronary infusion of CD34 (minimum dose 10M±20% cells) or placebo (cell diluent). Primary safety endpoints included AEs, SAEs and MACE (CV mortality, HF hospitalization, reinfarction, revascularization). Secondary endpoints included LVEF change from baseline. Regression analyses were performed to assess the influence of BM CD34 content on outcomes. Results: 161 patients were randomized and received intracoronary infusion (Jan 2013-Dec 2014). Mean age was 57±10 and 82% were men. Mean follow-up time was 18 mo, and safety data are accruing. BM CD34 content was not associated with differences in baseline characteristics with the exception of diabetes prevalence being higher in those with higher BM CD34 count (p=0.03). In controls, regression analyses showed no association of BM CD34 content with rates of MACE (p=0.2), SAEs (p=0.4), or change in LVEF (p=0.9). However, in CD34 treated pts, there was a dose-dependent improvement in LV function (p=0.045) and dose-dependent trends in MACE and SAE reduction compared to controls. As previously reported SPECT perfusion improved to a similar degree in control and treated pts. Conclusions: These data suggest that intracoronary infusion of CD34 cells, rather than BM CD34 cell content, is responsible for the benefit observed in the CD34 treatment group. The finding of a dose-response relationship is an important advance for defining the CD34 as an active agent for tissue repair. Future studies will further define CD34 dosimetry.

An increasing number of patients have refractory angina despite optimal medical therapy and are without further revascularization options. Preclinical studies indicate that human CD34 + stem cells can stimulate new blood vessel formation in ischemic myocardium, improving perfusion and function. In ACT34-CMI ( N = 167), patients treated with autologous CD34 + stem cells had improvements in angina and exercise time at 6 and 12 months compared to placebo; however, the longer-term effects of this treatment are unknown. ACT34 was a phase II randomized, double-blind, placebo-controlled clinical trial comparing placebo, low dose (1 × 10 5 CD34/kg body weight), and high dose (5 × 10 5 CD34/kg) using intramyocardial delivery into the ischemic zone following NOGA ® mapping. To obtain longer-term safety and efficacy in these patients, we compiled data of major adverse cardiac events (MACE; death, myocardial infarction, acute coronary syndrome, or heart failure hospitalization) up to 24 months as well as angina and quality of life assessments in patients who consented for 24-month follow-up. A total of 167 patients with class III–IV refractory angina were randomized and completed the injection procedure. The low-dose-treated patients had a significant reduction in angina frequency ( p = 0.02, 0.035) and improvements in exercise tolerance testing (ETT) time ( p = 0.014, 0.017) compared to the placebo group at 6 and 12 months. At 24 months, patients treated with both low-and high-dose CD34 + cells had significant reduction in angina frequency ( p = 0.03). At 24 months, there were a total of seven deaths (12.5%) in the control group versus one (1.8%) in the low-dose and two (3.6%) in the high-dose ( p = 0.08) groups. At 2 years, MACE occurred at a rate of 33.9%, 21.8%, and 16.2% in control, low-, and high-dose patients, respectively ( p = 0.08). Autologous CD34 + cell therapy was associated with persistent improvement in angina at 2 years and a trend for reduction in mortality in no-option patients with refractory angina.