Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

PRIORITY PRESS - American Transplant Congress 2009

Boston, Massachusetts / May 30-June 3, 2009

Two-year data from the Spare-the-Nephron (STN) trial continue to support better outcomes for patients converted from a calcineurin inhibitor (CNI)-based regimen to a sirolimus (SRL)-based regimen vs. those who continued on a CNI regimen.

At one year, patients who were converted to SRL plus mycophenolate mofetil (MMF) from a CNI-based regimen had almost a 30% mean increase in their glomerular filtration rate (GFR) from baseline compared to an 8% mean increase for those on a CNI/MMF-based regimen, the majority of whom were on tacrolimus.

Rates of biopsy-proven acute rejection (BPAR) and graft loss were low at one year and comparable in both arms. At two years, BPAR rates were slightly lower in the SRL/MMF arm at 9.5% vs. 11.3% for the CNI/MMF arm, with less latent acute rejection occurring between years 1and 2 in the mTOR conversion arm (2.9%) vs. the CNI continuation arm (8%). Graft loss at two years—including death—was also lower in the SRL/MMF arm at 2% vs. 4% for the CNI/MMF arm, while there were no deaths in the SRL/MMF arm vs. a 3% death rate in the CNI/MMF arm (P=0.03).

Per cent change in measured GFR from baseline at two years had narrowed from values seen at one year to a difference of 8.6% in the SRL/MMF arm vs. a difference of 3.4% in the CNI/MMF arm (P=0.054), as observed by Dr. Matthew Weir, Professor of Medicine, University of Maryland Hospital, Baltimore. By the end of the second year, 21% of patients had discontinued treatment in the SRL/MMF arm compared with 13% in the CNI/MMF arm. “Tolerability is always a key issue,” Dr. Weir noted. The adverse event (AE) profile was different between the two regimens but overall, rates of serious AEs in both arms were “quite similar.”

“Conclusions from this study suggest that maintenance immunosuppression with a MMF-based regimen in combination with SRL provides improvement in renal function when compared to a CNI-containing regimen without any increased risk of acute rejection or treatment failure,” Dr. Weir concluded.

As reported by Dr. Lewis Teperman, Director and Vice Chair of Surgery, New York University School of Medicine, renal dysfunction is a “terrible problem” in liver transplant recipients, with studies indicating a cumulative incidence of chronic renal failure in approximately 25% of liver transplant patients 10 years after transplantation. Consequently, the STN trial extended its inclusion criteria to liver transplant recipients.

After between four and 12 weeks on tacrolimus/MMF, 293 liver transplant patients were randomized to the SRL/MMF regimen or to remain on the CNI-based regimen. “Most patients had either hepatitis C (HCV) or hepatomas,” Dr. Teperman noted. The mean time from transplant to randomization was roughly equal at approximately 50 days.

From baseline to month 12, investigators observed almost a 20% mean increase in the calculated GFR in the SRL/MMF group compared to a 1.2% increase in the CNI/MMF group (P=0.0012). For hepatoma patients, there was a 25% mean increase in calculated GFR from baseline compared to a significant decrease in the CNI group (P=0.0016). HCV patients also had a significant increase in their calculated GFR at a mean of 25.6% over baseline vs. virtually no change in the CNI/MMF group (P=0.034).

BPAR rates were higher in the SRL/MMF arm at 12% compared with 4% in the CNI/MMF arm (P=0.016)—“but this did not result in death or graft loss,” Dr. Teperman told delegates. Graft loss in turn was more common in the CNI/MMF group at 8% vs. 3% in the SRL/MMF group (P=0.044). “Interestingly enough, graft loss in the CNI arm in HCV patients was much more common with nine out of 43 grafts being lost at one year compared with one out of 44 in the SRL/MMF group (P=0.004),” Dr. Teperman added.

As part of the protocol, investigators were required to do a biopsy at baseline and at month 12. “Again interestingly enough,” Dr. Teperman remarked, “31% of patients in the SRL arm did not have any fibrosis vs. 20% of the CNI group who similarly had no fibrosis.”

Discontinuation rates were high in both arms due to a number of AEs, such that only 55% of patients receiving SRL/MMF and 66% of patients receiving CNI/MMF who completed one year of treatment could tolerate the regimen.

CONCEPT Study

The CONCEPT study involved 235 kidney transplant recipients who were either switched to SRL at three months or continued on cyclosporine microemulsion (CsA). Steroids were to be withdrawn at month 8 in both groups, a goal which was achieved in over 70% of patients. At one year, estimated GFR (eGFR) rates were 61.9 mL/min/1.73 m² in the SRL arm compared with 53.8 mL/min/1.73 m2 in the CsA arm (P=0.0002). Some 160 out of 181 patients who completed the core study were eligible for follow-up and 154 were evaluable at month 30—72 in the SRL arm and 82 in the CsA arm.

Prof. Yvon Lebranchu, Université François-Rabelais, Tours, France, reported findings on behalf of CONCEPT investigators. At 30 months, eGFR were still higher in the SRL arm at 58.3 mL/min/1.73 m² compared with 52.6 mL/min/1.73 m² (P=0.027). The difference was even more pronounced in patients who remained on treatment according to protocol, with a 20% difference in renal function at 30 months in favour of the SRL-containing arm. There was one graft loss in each group and one death in the CsA group. There were six malignancies by month 30 in the CsA arm vs. one in the SRL arm. Proteinuria levels were similar in both arms at one year and at 30 months, although a higher percentage of SRL patients had proteinuria in excess of 0.5 g/day. At month 30, 60% of patients remained on the SRL/MMF regimen vs. 80% in the CsA group.

“Early introduction of SRL maintained similar graft and patient survival and better renal function than CsA despite a higher rate of rejection in the first year,” Prof. Lebranchu concluded.

Addressing Skin Cancer

Cancer is the second most common cause of mortality in kidney transplant recipients. In Australia, virtually all transplant patients are at risk for non-melanoma skin cancer (NMSC) because of intense ultraviolet (UV) light exposure. As an mTOR inhibitor, SRL is known to have antineoplastic activity, suggesting that conversion from a CNI-based regimen to a SRL-based regimen may help prevent disease.

In the first study specifically designed to assess the effect of such a conversion on the incidence of NMSC, Australian investigators converted 39 kidney transplant recipients with a prior history of skin cancer to a SRL-based regimen while 47 patients remained on their CNI regimen. The primary end point was the number of new biopsy-proven NMSC lesions per patient-year.

At a follow-up of approximately 1.7 years, the rate of new NMSC lesions in the ITT population was 1.31 per patient-year in the SRL group and 2.48 in the CNI continuation group (P=0.022). Dr. Graeme Russ, Director of Nephrology and Transplantation, Queen Elizabeth Hospital, Woodville, South Australia, explained during the scientific sessions, “Looked at another way, 80.9% of patients who remained on the CNI regimen developed a new NMSC over this follow-up interval vs. 56.4% of those who were converted to SRL (P=0.015).”

These findings held true for both basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) where 35.9% of patients in the SRL arm developed a new BCC vs. 51.1% of the CNI continuation arm (P=0.016), while 41% of SRL patients developed a new SCC vs. 70.2% of their CNI counterparts (P=0.006).

As Dr. Russ noted, the withdrawal rate in the SRL conversion arm due to AEs was higher (n=18) than in the CNI arm (n=0). However, this was primarily because patients underwent conversion to SRL almost 10 years after receiving their transplant at a time when renal function was relatively poor and they were less able to tolerate the conversion.

Dr. Russ stated, “The way around this is to pre-emptively convert patients prone to develop skin cancer to SRL when renal function is better.” He added that in his own unit, they pre-emptively convert transplant patients to SRL at approximately six months post-transplant.

Summary

Advances in immunosuppressive protocols have been made in recent years that help preserve renal function in transplant recipients at risk for renal failure. Using the same strategies, it is also now possible to prevent skin cancer in a significant proportion of transplant patients. These gains are not trivial as with increasing longevity, long-term consequences of immunosuppression become more important than the risk of acute rejection.