Treatment of chronic myeloid leukemia

For decades, chronic myeloid leukemia (CML) has been recognized as a disease that can be effectively palliated for 3 to 5 years with relatively low doses of chemotherapy but that inevitably progresses into blast crisis and death. Such agents as hydroxyurea, and particularly interferon, can apparently extend the natural history of the disease, but few if any patients are cured. The first indication of curative therapy came 15 years ago with publications from England and Seattle (1,2). Both groups showed that the delivery of high-dose chemotherapy followed by allogeneic marrow stem cell rescue could lead to a high rate of remission, and in many cases cure. However, this new form of treatment is available only to patients fortunate enough to have an HLA-matched sibling and young enough to undergo the rigors of bone marrow transplant, with its attendant graft-versus-host disease (GVHD). Indeed, only 30% of patients have an HLA-matched sibling available in the family. This lack of donors led to the concept of establishing large registries of HLA-typed potential bone marrow donors, and there are more than 6.8 million HLA-typed unrelated donors available (Bone Marrow Donors Worldwide, available at: www.bmdw.org). Patients with CML are an obvious target for treatment using this donor source, not only because transplant is the only known form of curative treatment, but also because patients would be likely to remain in a stable, chronic phase during the time necessary to locate a matched donor. The National Marrow Donor Program has provided unrelated donor marrow for more than 3,000 patients with CML, 34% of all marrow provided (Data and Scientific Report of the National Marrow Donor Program, 1999). A number of early studies showed that transplantation from unrelated donors could be successful in patients with chronic myeloid leukemia (3). The paper in this issue of the American Journal of Medicine by Davies et al (4) and a previous paper from Seattle (5) convincingly show that patients transplanted from unrelated donors for the treatment of chronic myeloid leukemia can expect outcomes equivalent to the excellent outcomes experienced when HLA-matched siblings are used as marrow donors. The key data in the current paper show a 58% posttransplant 5-year survival for patients transplanted from matched siblings compared with a 53% survival for unrelated donors (P 5 0.4). For the more favorable group, transplanted within 1 year of diagnosis, the 5-year survivals were 76% and 70% (P 5 0.5). A detailed multivariate analysis showed no change in the probability of survival using an unrelated donor (relative risk 1.1, P 5 0.7). As often happens in medicine, however, such definitive results occur contemporaneously with major promising developments. The first and perhaps most highly publicized new therapeutic agent is a tyrosine kinase inhibitor (STI-571, or Glivec [Novartis]) developed specifically to interfere with the fusion protein generated by the 9:22 translocation characteristic of CML. The initial results of Drucker (6) showed high rates of complete response with minimal toxicity. As yet, there are no long-term data to indicate whether these early responses will translate into cures or delay the evolution to blast crisis. A second development in the treatment of CML is the attenuated, or nonmyeloablative, transplant regimen. This new approach to transplant derives from observations made 20 years ago (7) that patients who develop GVHD have a lower rate of relapse of their disease, assuming they survive the GVHD. This observation was followed by studies in Germany (8), where patients who relapsed after allogeneic transplant for CML were given lymphocytes from the original marrow donor; lasting, complete remissions were documented. This finally led to the concept that if one could simply establish allogeneic hematopoietic engraftment in patients, without giving high-dose chemotherapy to kill the leukemia, it might be possible to control the disease solely on an immunologic basis. These studies are now ongoing, with preliminary results showing low mortality and morbidity from GVHD, as well as high response rates for patients with CML (9). The good news for patients with CML is that there are now several effective options for treatment. The challenge to the medical profession is to optimize their use and sequencing.