Correspondence
Interferon Alfa-2a for Chronic Myeloid Leukemia
N Engl J Med 1994; 331:401-402August 11, 1994
- Article
To the Editor:
The Italian Cooperative Study Group on Chronic Myeloid Leukemia demonstrated the substantial benefit of interferon in a compelling fashion (March 24 issue),1 but the cost of therapy in the interferon group was 200 times higher than that in the chemotherapy group, and the quality of life for the patients receiving interferon was not very good because of the high incidence of systemic adverse effects.
It would be interesting to compare the outcome in patients in the interferon group who had a hematologic response other than a complete or partial response after 8 months of therapy (Figure 3 in the article) or those who had a minimal cytogenetic response or none after 24 months of therapy (Figure 4 in the article) with the outcome in patients randomly assigned to the chemotherapy group. If there were no significant differences in survival or disease progression at 8 or 24 months, cessation of interferon at that time would prevent prolonged administration of the drug in patients unlikely to benefit from it. This curtailment of therapy would address some of the cost and quality-of-life issues.
Previous interferon therapy has not been found to have an adverse effect on the outcome of allogeneic bone marrow transplantation in patients with chronic myeloid leukemia2. However, delay between diagnosis and transplantation does affect the outcome adversely3,4. The Seattle team has reported a 60 percent rate of long-term disease-free survival in patients undergoing transplantation within a year after diagnosis, including those who were 50 to 60 years of age5. The encouraging results of the current study should not detract from the fact that early allogeneic bone marrow transplantation remains the only definitive therapy for chronic myeloid leukemia in patients with HLA-identical siblings.
5 ReferencesJayesh Mehta, M.D.
Royal Marsden Hospital, Sutton, Surrey SM2 5PT, United Kingdom1
The Italian Cooperative Study Group on Chronic Myeloid Leukemia
Full Text | Web of Science | Medline2
Giralt SA ,Kantarjian HM ,Talpaz M , et al. Effect of prior interferon alfa therapy on the outcome of allogeneic bone marrow transplantation for chronic myelogenous leukemia. J Clin Oncol 1993;11:1055-1061
Web of Science | Medline3
Thomas ED ,Clift RA ,Fefer A , et al. Marrow transplantation for the treatment of chronic myelogenous leukemia. Ann Intern Med 1986;104:155-163
Web of Science | Medline4
Goldman JM ,Szydlo R ,Horowitz MM , et al. Choice of pretransplant treatment and timing of transplants for chronic myelogenous leukemia in chronic phase. Blood 1993;82:2235-2238
Web of Science | Medline5
Clift RA ,Appelbaum FR ,Thomas ED . Treatment of chronic myeloid leukemia by marrow transplantation. Blood 1993;82:1954-1956
Web of Science | Medline
To the Editor:
The authors describe their comparison of interferon with chemotherapy for chronic myelogenous leukemia as an intention-to-treat analysis. However, the legend to their Figure 1 states that “data on 36 patients who underwent bone marrow transplantation were censored as of the date of transplantation.” This method of analysis may introduce a bias if the reason for or timing of transplantation differs between the groups.
In fact, the authors provide curiously little information on the patients who underwent transplantation. We are not even told the treatment-group assignments for five of the patients and are given no details on the reasons for transplantation. It would be interesting to know the proportion of patients in each group who underwent transplantation because of the progression of disease, toxic effects of the assigned treatment, or simply the identification of a suitable bone marrow donor. If the data on these patients are censored, it is crucial to know how they fared after transplantation.
Another way to handle this problem is to compare survival data between the groups without censoring data at the time of transplantation, and then determine whether the exclusion of data on the patients undergoing transplantation affects the results. I wonder whether the authors have such an analysis available.
Carl D. Atkins, M.D.
242 Merrick Rd., Rockville Centre, NY 11570To the Editor:
The Italian Cooperative Study Group reports that interferon alfa-2a given to 218 patients induced more karyotypic responses, delayed the progression of disease longer, and resulted in longer overall survival than conventional chemotherapy given to 104 patients. An extensive description of the dose schedule for interferon is given.
Hydroxyurea was given as the first-line drug to the patients who received conventional chemotherapy. The treatment dose and schedule for hydroxyurea were determined by the investigator. For a convincing randomized study, the hydroxyurea dose should have been standardized. It is conceivable that many of the patients received inadequate doses of the drug. The only reference to dosage was the statement of the total dose given to a 57-year-old woman. It is not clear whether the dose of hydroxyurea used in the study was the same as the recommended dose1,2.
A clinical trial comparing two therapies should use standard schedules for the agents employed. This study appears to have lacked careful control of the hydroxyurea doses and schedule.
2 ReferencesB.J. Kennedy, M.D.
University of Minnesota, Minneapolis, MN 554551
Kennedy BJ . Hydroxyurea therapy in chronic myelogenous leukemia. Cancer 1972;29:1052-1056
CrossRef | Web of Science | Medline2
Rushing D ,Goldman A ,Gibbs G ,Howe R ,Kennedy BJ . Hydroxyurea versus busulfan in the treatment of chronic myelogenous leukemia. Am J Clin Oncol 1982;5:307-313
CrossRef | Web of Science | Medline
Author/Editor Response
The authors reply:
To the Editor: We share Dr. Mehta's opinion. In our study the survival of the patients who had a less-than-partial hematologic response after 8 months of therapy or a less-than-minor karyotypic response after 24 months was identical to the survival of the patients treated with chemotherapy. Our study was designed in 1986, when nobody could be sure of a relation between response and survival. Eight years later, our data suggest that a detectable response within less than one year for many patients and within two years for all patients is predictive of a survival benefit.
In response to Dr. Atkins: bone marrow transplantation was recommended to all patients who had suitable donors; most of the patients underwent transplantation irrespective of their response to the assigned treatment. The median time from registration to transplantation was 12 months in both treatment groups. At the time of our report, 22 of the 36 who had undergone transplantation were alive. All the survival calculations were made in triplicate, first by censoring data at the date of transplantation, second without censoring any data, and third by excluding the data on the patients who underwent transplantation. The results of the three calculations were identical, the differences were identical, and only the first calculation was reported.
Dr. Kennedy points out that our treatment with hydroxyurea was not sufficiently standardized and suggests that the dose of hydroxyurea may influence survival. That point is at least controversial, and relevant information is not available. Our study was a comparison between long-term treatment with interferon alfa and conventional chemotherapy with hydroxyurea. Interferon therapy was superior, but this cannot exclude the possibility that better results can be obtained with either interferon or chemotherapy.
After all, the main sources of potential bias in this study were the inexperience with interferon alfa and the consistent proportion of patients (31 percent) who stopped receiving interferon alfa treatment but were included in any calculations. The direction of both biases was against interferon alfa.
Sante Tura, M.D.
University of Bologna, 40138 Bologna, ItalyMichele Baccarani, M.D.
University of Udine, 33100 Udine, Italy
