Interferon-a Improves Survival in Chronic Myeloid Leukemia
January 1, 1998
Interferon-a Improves Survival in Chronic Myeloid Leukemia
ABSTRACT & COMMENTARY
Synopsis: Meta-analysis of seven prospective, randomized trials including patients with Philadelphia chromosome positive chronic myeloid leukemia demonstrated that regimens including interferon-a produced significantly better five-year survival than regimens with busulfan or hydroxyurea.
Source: Chronic Myeloid Leukemia Trialists’ Collaborative Group. J Natl Cancer Inst 1997;89:1616-1620.
Chronic myeloid leukemia (cml) is a disease of the pluripotent hematopoietic stem cell usually characterized by the expression of a Philadelphia chromosome, a cytogenetic marker generated by the translocation between chromosomes 9 and 22 resulting in the fusion of the BCR and ABL genes to create an oncogene. The disease is typified by an indolent phase, an accelerated phase in which genetic lesions seem to accumulate, followed by a transformation to acute myeloid leukemia that is generally refractory to therapy. The average course of disease is about four years.
The only treatment approach that has been demonstrated to cure patients with CML is allogeneic bone marrow transplantation, and it is more effective if performed in the chronic phase of disease than in the accelerated or transformed states. However, many CML patients do not have a suitable bone marrow donor, and others are too old to be considered as candidates for allogeneic bone marrow transplantation. The optimal management of patients with CML who cannot receive allogeneic bone marrow transplantation is controversial. High-dose therapy with autologous bone marrow transplantation must be considered experimental. Although a large percentage of patients so treated may be reinduced to chronic phase, it is not yet clear that this produces a significant survival advantage.
Other therapies for CML are recognized as mainly palliative. Historically, two chemotherapeutic agents have commonly been used to reduce peripheral white blood cell countsbusulfan and hydroxyurea. However, it was observed that interferon-a was also capable of controlling peripheral white blood counts, with the additional advantage that the fraction of bone marrow metaphases expressing the Philadelphia chromosome seemed to decline in patients treated with interferon, sometimes dramatically. It is unclear whether this selective effect on the malignant clone of cells was related to selective killing or rather to inhibition of proliferation such that these cells did not enter the cell cycle and, therefore, were not analyzed. Molecular, rather than cytogenetic, methods of detecting the abnormality tended to reflect that the antitumor effects of interferon were not as great as they seemed based upon cytogenetics; however, interferon was clearly an active single agent in the disease.
Several randomized trials have been reported that compare the use of interferon to the use of chemotherapy in patients with chronic phase CML. Recently, a group called the Chronic Myeloid Leukemia Trialists’ Collaborative Group performed a meta-analysis of all seven published studies in an effort to assess reliably the size and persistence of any survival benefit for interferon-treated patients. Furthermore, meta-analysis permitted the authors to ask whether certain subgroups of patients appeared to benefit more from interferon therapy.
Individual patient data were available for 1554 patients who had been randomly assigned to treatment on seven different studies (German, Italian, British, French, Japanese, and the "Benelux" trials). Patients receiving interferon had an overall reduction in their annual death rate of 26% compared to patients receiving hydroxyurea and a reduction in annual death rate of 36% compared to patients receiving busulfan. The cumulative effect on survival is that median survival is prolonged by one or two years. Five-year survival rates for patients receiving chemotherapy are 42%; for those receiving interferon, five-year survival is 57%. The 15% difference in five-year survival is statistically significant. In general, the improvement in survival for interferon over hydroxyurea is less than interferon vs. busulfan, but there are no significant differences between hydroxyurea and busulfan.
When results were analyzed for subgroups based upon Sokal stage, age, or sex, benefit from interferon over chemotherapy was observed in all groups.
COMMENTARY
The treatment of choice for patients with CML remains allogeneic bone marrow transplantation. However, for those patients without a matched donor or who are over age 60, and, thus, usually considered ineligible for allogeneic transplant, it would appear that interferon is preferable treatment to either busulfan or hydroxyurea. Interferon appears to significantly improve survival about 15% at five years. Interferon therapy is associated with normalization of the peripheral blood counts in 70-80% of patients and major cytogenetic responses in 5-20%.
A recent preliminary report from a French multicenter study suggested that inteferon plus cytarabine 20 mg/m2 subcutaneously daily for 10 days each month produced a higher incidence of cytogenetic response and longer survival than interferon alone.1 It will be of interest to see if this result can be confirmed.
An early report that patients who were treated with interferon were less likely to be cured by allogeneic transplantation2 has not been substantiated in a very large retrospective analysis carried out by the International Bone Marrow Transplant Registry.3 Thus, one probably does not need to be concerned about beginning treatment with interferon while one is searching for a compatible bone marrow donor in patients who would otherwise be considered candidates for allogeneic transplantation. The success of allogeneic transplantation in this setting provides encouragement that CML may be a disease susceptible to immunologic manipulation. Novel approaches based upon vaccinating patients against the bcr-abl fusion protein may make curative therapy available to those without a matched sibling bone marrow donor and those too old to safely undergo allogeneic marrow transplant.
References
1. Guilhot F, et al. N Engl J Med 1997;337:223-229.
2. Goldman JM, et al. Blood 1993;82:2235-2238.
3. Beelen DW, et al. Blood 1995;85:2981-2990.
A 67-year-old man presents with Philadelphia chromosome- positive chronic myeloid leukemia. He has no siblings who are HLA identical to him. How should he be treated?
a. With careful observation
b. With matched unrelated donor allogeneic bone marrow transplant
c. With busulfan therapy
d. With interferon-alpha
e. With high-dose therapy and autologous stem-cell transplantation
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