Mortality risk has declined dramatically for patients undergoing allogeneic hematopoietic-cell transplantation in recent years, and long-term survival has improved substantially, according to a report in the Nov. 25 issue of the New England Journal of Medicine.
The improved outcomes appear to be related to marked reductions in organ damage, infection, and severe acute graft-vs.-host disease (GVHD), said Ted A. Gooley, Ph.D., and his associates at the Fred Hutchinson Cancer Research Center and the University of Washington, Seattle.
The investigators hypothesized that several changes in the care of transplant patients have likely improved outcomes in recent years, and they tested their hypothesis by comparing several outcome measures between two large patient cohorts at their cancer center: 1,418 patients who received their first allogeneic transplants in 1993-1997 and 1,148 who did so in 2003-2007.
Overall mortality decreased by 41% between the two time periods.
The overall risk of death not preceded by relapse decreased by 52%, and the risk of death not preceded by relapse within 200 days of transplant decreased by 60%.
The rate of relapse or progression of the malignant condition decreased by 21%.
These improvements were seen consistently across numerous subgroups of patients. They occurred across diagnostic categories including acute lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, and myelodysplastic syndrome. And they were seen in patients who received transplants from a matched donor sibling, a mismatched sibling, a relative who was not a sibling, or an unrelated donor.
Almost every complication associated with transplantation showed improvement over time.
Concerning organ damage, the odds of developing jaundice dropped by more than 70%, and the odds of respiratory failure decreased by 36%. The risk of developing acute renal injury also declined significantly.
Regarding infections, the rate of early cytomegalovirus infection declined by 48%. The rate of bacteremia with a gram-negative organism decreased by 39%, that of invasive mold infection dropped by 51%, and the rate of invasive candida infection was cut by an impressive 88% between the two study periods.
At the same time, the proportion of patients with any degree of acute GVHD – mild, moderate, or severe – also decreased significantly. In particular, the odds of developing grade 3 or 4 GVHD declined 67%, even though the use of peripheral-blood hematopoietic cells instead of bone marrow has increased.
All of these improvements occurred despite the fact that during this time interval, transplantation was expanded to include patients who were older, were more seriously ill, and had more advanced disease, Dr. Gooley and his associates said (N. Engl. J. Med. 2010;363[22]:2091-101).
"Several changes in our transplantation practice appear to have contributed to improved outcomes," they noted.
Patients who have coexisting medical conditions now receive a less toxic conditioning regimen to preserve their organ function. In some patients, the dose of total-body irradiation is limited, fludarabine is substituted for cyclophosphamide, or cyclophosphamide dosing is individualized to head off organ failure.
The decrease in GVHD is due in part to the introduction of ursodiol prophylaxis, which prevents cholestasis and accounts for the near-disappearance of stage 4 hepatic GVHD. Treatment of emergent GVHD also has changed, with universal prednisone therapy being replaced by a more individualized approach. This reduced the average exposure to prednisone by 48%, which in turn cut the rate of prednisone-related CMV, fungal, and bacterial infections.
The increased use of peripheral-blood donor cells allowed significantly faster neutrophil engraftment and earlier recovery of immunity against fungal and bacterial infection. In addition, antibacterial prophylaxis in neutropenic patients switched from cephalosporins to quinolones, and "preemptive antiviral therapy is now based on a more sensitive diagnostic test for CMV viremia," the investigators said.
"In conclusion, our data show clear improvement in outcomes of transplantation between the period from 1993 through 1997 and the period from 2003 through 2007. The data also indicate areas of transplantation biology and patient care in which research is needed to achieve further progress – specifically, GVHD and graft-versus-tumor effects, immunologic tolerance, and the management of infection and recurrent malignant conditions," they said.
Dr. Gooley and his associates reported numerous ties to pharmaceutical and device manufacturers.