Safety Concerns Disqualify Scleroderma/PH Patients for Stem Cell Trial

Patients with systemic sclerosis hoping to enroll in clinical trials investigating hematopoietic stem cell transplantation may be disqualified if they have pulmonary hypertension. During the Autologous Stem Cell Transplantation International Scleroderma (ASTIS) trial, reasons for turning away interested patients included pulmonary hypertension and left ventricular ejection fraction less than 45%.

Outlined by a Letter to the Editor regarding the ASTIS trial, disqualification on this basis may have been problematic. First, the ASTIS trial defined pulmonary hypertension as mean pulmonary pressure greater than 50 mmHg, measured by echocardiogram or cardiac catheterization–the accepted definition is actually a mean pulmonary artery pressure of 25 mmHg or greater, measured by hemodynamic testing.

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This leads to a second problem. Echocardiograms are known to unreliably measure mean pulmonary artery pressure–they can instead estimate pulmonary artery systolic pressure. Pulmonary artery systolic pressure cannot be used to designate a patient as having pulmonary hypertension, as there is poor correlation between the two.

Therefore, Richard K. Burt, MD, author of the letter, stated, “Regardless of what each of the 29 centers did in terms of cardiac evaluation, these criteria were not adequate for exclusion of pulmonary arterial hypertension.”

In response to the letter, investigators in the ASTIS trial — Jacob M. van Laar, MD, PhD, Dominique Farge, MD, PhD, and Alan Tyndall, MD — wrote a reply letter defending their choice of disqualification. “When the ASTIS trial was launched in 2001, phase 1/2 data indicated that patients with systemic sclerosis and a mean pulmonary arterial pressure greater than 50 mmHg measured by right heart catheterization had an unacceptable risk of treatment-related mortality and were therefore excluded from the ASTIS trial,” they wrote.

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As it was, treatment-related mortality was 10% during the trial. Reasons for high mortality were attributed to using cancer-specific cardiac screening rather than rigorous cardiac assessment. However, no mortalities were reported during a similar clinical trial, called American Scleroderma Stem Cell vs Immune Suppression Trial (ASSIST).

It can be noted that excluding pulmonary hypertension-afflicted systemic sclerosis patients could disqualify a large part of the scleroderma community from key clinical trials and experimental therapies, as a large percentage develop pulmonary hypertension throughout the course of disease. It may be interesting for the future to develop a safe stem cell therapy for patients with concurrent pulmonary hypertension and systemic sclerosis.