Response to letter to the editor by Kovacic et al

We are sorry Kovacic et al were surprised by our editorial, but we believe it to be accurate, constructively critical, and necessary at this time in the development of cardiovascular stem cell clinical trials. Although a number of novel concepts were introduced in GAIN 1, the trial complexity resulted in a different protocol for nearly every patient.1, 2 If indeed the take home message was that granulocyte-colony stimulating factor (G-CSF) should be titrated to a white blood cell (WBC) response, then the authors could have emphasized this in the article, and we are not aware of data correlating WBC response to outcome. The authors themselves note that “a 5 μg/kg/d starting dose may be more appropriate for future studies.”1

Kovacic et al criticized our phase I clinical trial, a well-designed, placebo-controlled trial with clearly defined safety and efficacy end points based on rigorous preclinical investigation.3 The phase I trial led to the first large multicenter placebo-controlled cell therapy trial (ACT-34) for patients with refractory angina using G-CSF 5 μg/kg per day for 5 days followed by apheresis with intramyocardial injection of CD34+ cells into the ischemic zone, which has completed enrollment. In the phase I trial, only 1 patient had a WBC >36.6 × 103 mL, and no patient sustained myocardial infarction or injury. In ACT-34, the regimen appears to have been well tolerated again. Kovacic et al raised the possibility that adverse events are related to extreme leukocytosis, but 7 of 8 patients with myocardial injury in GAIN 1 had a WBC <40.0 × 103 mL.1 An alternative explanation not explored by the authors would be an inadequate antiplatelet regimen.

In regard to “the red flag” events with high-dose G-CSF, the NIH trial was presented November 2003 at the AHA and referenced in Lancet in March of 2004.4 It was also documented on the clinicaltrials.gov Web site as prematurely terminated.

It is a critical time in the development of cardiovascular stem cell therapy.2 We continue to believe, “It is imperative that we design future cell therapy trials to provide clear insights into safety and efficacy and allow the field to advance: ‘running with scissors’ is no longer an option.”