ASHPatients with chronic myelogenous leukemia (CML) who are eligible for transplant but lack a matched sibling donor should begin their search for an unrelated donor as soon as possible after diagnosis, A. James Morton, MD, said at the plenary session of the annual meeting of the American Society of Hematology (ASH) in San Diego.
Once a donor is found, he said, patients should progress to immediate transplantation rather than continuing alfa-interferon (IFN) therapy.
Dr. Morton, of the Fred Hutchinson Cancer Research Center, reported the results of a study providing the rationale for this recommendation. The Hutchin-son researchers found that pretransplant treatment with alfa-interferon for 6 or more months in CML patients was associated with a higher incidence of severe acute graft-versus-host disease (GVHD) unresponsive to standard prednisone therapy and with increased mortality from chronic GVHD.
The study involved 184 patients with CML in chronic phase who underwent an unrelated donor transplant at Hutchinson between 1988 and 1994.
Of the 70 patients who had received pre-transplant interferon therapy, 22 had received the agent for 1 to 5 months, 23 for 6 to 12 months, and 25 for more than 12 months, for a median of 10 months; 114 transplant patients received no interferon. For purposes of the study, patients were grouped into those who had received the agent for 0 to 5 months (136 patients) or 6 or more months (48 patients).
Five-year overall survival was significantly better in those patients whose pretransplant interferon use was 5 months or less (60% vs 43% in those who received the agent for 6 months or more prior to transplant).
The reduced survival in those receiving a longer course of interferon was related to a significantly increased risk of severe GVHD. The incidence of grade 3-4 GVHD was 55% for those patients who received 6 or more months of interferon, compared with 34% for those who were on the drug for 5 months or less.
Five-year nonrelapsed mortality was higher in the group that received interferon for 6 or more months before transplant (56% vs 38% for those in the 0 to 5 month group). The major increase in mortality occurred between day 100 and day 365 post-transplant and was due to development of severe GVHD unresponsive to prednisone and subsequent fatal chronic GVHD.
In addition to interferon for less than 5 months, other factors associated with better survival after transplant included age 50 years or less, prophylaxis for CMV and fungal infections, and a donor matched for HLA-A, HLA-B, DRB1, and DQB1.
In fact, Dr. Morton said, in patients with all these factors undergoing unrelated donor transplant for CML in chronic phase, 5-year overall survival was 87%. This figure is equivalent to the best published results with sibling transplants and is remarkably similar to survival figures seen in cytogenetic responders to alfa-interferon therapy, he said.
The Fork in the Road
In his comments on the paper, Fred Appelbaum, MD, also of Hutchinson, cited previous studies showing improved 5-year overall survival with interferon versus conventional chemotherapy (57% vs 42%). Although interferon is more toxic and more expensive, this 15% improvement in overall survival led to the emergence of alfa-interferon as the preferred form of nontransplant therapy.
However, he said, there have also been advances in transplantation using unrelated matched donors, with reports of 65% five-year overall survival. Further, he said, today, matched unrelated donors can be found in as many as 75% of patients with European ancestry.
These developments raised the question as to the best strategy for patients with recently diagnosed CML, under 55 years of age, and with a matched unrelated donor. The answer is not necessarily interferon vs transplantation, but rather how to devise a strategy providing the benefits of both, Dr. Appelbaum said.
He cited the solution of Yogi Berra, the sage and former New York Yankee catcher, who once said, If you come to a fork in the road, take it. The new study suggests, Dr. Appelbaum said, that physicians can now offer their newly diagnosed CML patients more precise treatment recommendations.