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Interferon-α1 for chronic myeloid leukaemia
settings. Such was the case in Goma, and the high mortality rates there could have been avoided if the refugees had not been crowded into such a small area. But the arrival of 1 million people-more than the entire population of a San Francisco or a Glasgow-over a fourday period in an isolated area without any infrastructure
non-responders, but only as strongly suggestive of it. The only way of getting further and unbiased evidence on this would be to randomise the non-responders to stop or
overcrowded
offered little
or no
choice.
Mohamed W Dualeh Programme and Technical Support Section, UNHCR,
CH-1202 Geneva, Switzerland
Interferon-&agr;1 for chronic myeloid leukaemia SiR-In the Medical Research Council trial
on
interferon-all
for the treatment of chronic myelogenous leukaemia, Allan and colleagues (June 3, p 1392) suggest that the survival among cytogenetic non-responders in the interferon (IFN)-a group is better than in the no-IFN-a group. Although 96 of 208 non-responders in the IFN-a group died compared with 134 of 261 in the no IFN-a group, Allan et al fail to mention that this difference is not significant (p=0267, Fisher’s exact test). Furthermore, they state that the results were not affected by stratification according to the induction treatment. In table 3, however, it seems that in the group induced by hydroxyurea, the difference between the IFN-a group and the no-IFN-a group was not significant (95% CI 0-52-1-11). Further, in the patients who had induction with hydroxyurea, the number of patients who died in the IFN-a group did not differ from that in the no-IFN-a group (53 of 152 vs 59 of 152, p=055, Fishers exact test). Likewise, combining the two treatment groups, those induced by busulphan fared significantly worse compared with the hydroxyurea treated patients (174 of 283 died vs 112 of 304 died, p<00005). It therefore seems that the apparent benefit attained from the use of IFN-a could just as well be a disadvantage of the use of busulphan, as has been reported by others.’1 Allan and co-workers imply that the true treatment effect of the IFN-a group might be greater than that reported on the basis of the intention-to-treat principle. They might just as well report the fate of the patients in the IFN-a group who received the drug as compared with those who did not. Finally, they suggest that the dose of IFN-a could be reduced without loss of benefit, as have others.2 What were the reasons for non-compliance or less intense than intended treatment? In that respect it is surprising that the researchers do not consider side-effects of the treatments. *Troels
Ring, Mogens Krogh Jensen
Department of Haematology, Aalborg Sygehus, 9100 Aalborg, Denmark 1
2
Hehlmann R, Heimpel H, Hasford J, et al. Randomized comparison of interferon-&agr; with busulfan and hydroxyurea in chronic myelogenous leukemia. Blood 1994; 84: 4064-77. Schofield JR, Robinson WA, Murphy JR, Rovira DK. Low doses of interferon-&agr; are as effective as higher doses of inducing remissions and prolonging survival in chronic myeloid leukemia. Ann Intern Med 1994; 121: 736-44.
Authors’
reply
SiR-All the survival analyses in our report were done by the rank method,’ which takes into account time to death and length of time at risk for each patient, and hence has greater statistical power than the use of only numbers of deaths. The comparison of the non-responders with the no-IFN group was marginally significant (2p=006) but this p-value was not given since this is not strictly a valid comparison, although the possible biases are likely to favour the no-IFN group. Even if the p value were smaller this could not be regarded as proof of benefit of IFN for
log
1370
continue IFN. It is true that the effect of IFN was significant in the busulphan-treated group and not in the hydroxyurea-treated group, but this is subgroup analysis and a formal test for heterogeneity of effect was not significant. Indeed, the results within each subgroup are perfectly compatible with the hypothesis that the true effect in each subgroup is the same as the overall estimate, since the odds ratio of 0-67 is within the 95% CI for each subgroup (0-45-0-82 and 052-111). This is supported by the Italian trial which showed a significant benefit for IFN versus hydroxyureaIn addition, one cannot compare from this paper hydroxyurea versus busulphan alone because patients randomised to busulphan or hydroxyurea as well as those who elected busulphan or hydroxyurea therapy as allowed in the protocol would be included. Analysis of only the randomised patients shows a trend for better survival for hydroxyurea, but this is not
statistically significant.
The biases introduced by reporting results only for patients who actually receive their allocated treatment, rather than on the intention-to-treat principle, are well known. However, although biases are eliminated by this method, it may weaken the result. The major reason for not starting IFN was the availability of a donor for bone marrow transplantation (BMT). All survival analyses were repeated censoring at time of BMT without significantly altering the outcome.
of dose is being directly addressed by the Dutch and MRC high-dose versus low-dose randomised trials. Finally, as we stated, this was a preliminary report and further information on side-effects, reasons for non-compliance and quality of life will be reported later.
The
question
current
*N C
Allan, S M Richards, P C A Shepherd
MRC Human Genetics Unit, Western General Hospital, Crewe Road, Edinburgh EH4 2XU
1
2
Peto R, Pike MC, Armitage P, et al. Design and analysis of randomised clinical trials requiring prolonged observation of each patient. II. Analysis and Examples. Br J Cancer 1977; 35: 1-39. The Italian Cooperative Study Group on Chronic Myeloid Leukemia. Interferon alfa-2a as compared with conventional chemotherapy for the treatment of chronic myeloid leukemia. N Engl J Med 1994; 330: 820-25.
Detection of parasite DNA in disease
Chagas’ heart
SiR-Chronic Chagas’ heart disease (cChHD) resulting from infection with Trypanosoma cruzi is a slowly evolving inflammatory cardiomyopathy. Histopathology reveals mononuclear cell infiltration, myocyte damage, and fibrosis. Since parasite cells are rarely found at sites of myocarditis, autoimmunity has been postulated as the cause of cChHD. We have searched for anti-T cruzi antibodies that differentiate the serological profile of chronically infected individuals with or without cChHD.’ We have used the from a cChHD reference patient with high serum of anti-T cruzi concentrations antibodies as an immunological probe for isolating parasite recombinant antigens from a T cruzi expression library.’ The reference serum came from JL, a deceased 27-year-old male, New York Heart Association functional class IV, whose electrocardiogram at admission in 1985, at age 25, was: firstdegree atrioventricular block, left anterior fascicular block and anterior electrical inactivation area. After one year of
non-responders, but only as strongly suggestive of it. The only way of getting further and unbiased evidence on this would be to randomise the non-responders to stop or
overcrowded
offered little
or no
choice.
Mohamed W Dualeh Programme and Technical Support Section, UNHCR,
CH-1202 Geneva, Switzerland
Interferon-&agr;1 for chronic myeloid leukaemia SiR-In the Medical Research Council trial
on
interferon-all
for the treatment of chronic myelogenous leukaemia, Allan and colleagues (June 3, p 1392) suggest that the survival among cytogenetic non-responders in the interferon (IFN)-a group is better than in the no-IFN-a group. Although 96 of 208 non-responders in the IFN-a group died compared with 134 of 261 in the no IFN-a group, Allan et al fail to mention that this difference is not significant (p=0267, Fisher’s exact test). Furthermore, they state that the results were not affected by stratification according to the induction treatment. In table 3, however, it seems that in the group induced by hydroxyurea, the difference between the IFN-a group and the no-IFN-a group was not significant (95% CI 0-52-1-11). Further, in the patients who had induction with hydroxyurea, the number of patients who died in the IFN-a group did not differ from that in the no-IFN-a group (53 of 152 vs 59 of 152, p=055, Fishers exact test). Likewise, combining the two treatment groups, those induced by busulphan fared significantly worse compared with the hydroxyurea treated patients (174 of 283 died vs 112 of 304 died, p<00005). It therefore seems that the apparent benefit attained from the use of IFN-a could just as well be a disadvantage of the use of busulphan, as has been reported by others.’1 Allan and co-workers imply that the true treatment effect of the IFN-a group might be greater than that reported on the basis of the intention-to-treat principle. They might just as well report the fate of the patients in the IFN-a group who received the drug as compared with those who did not. Finally, they suggest that the dose of IFN-a could be reduced without loss of benefit, as have others.2 What were the reasons for non-compliance or less intense than intended treatment? In that respect it is surprising that the researchers do not consider side-effects of the treatments. *Troels
Ring, Mogens Krogh Jensen
Department of Haematology, Aalborg Sygehus, 9100 Aalborg, Denmark 1
2
Hehlmann R, Heimpel H, Hasford J, et al. Randomized comparison of interferon-&agr; with busulfan and hydroxyurea in chronic myelogenous leukemia. Blood 1994; 84: 4064-77. Schofield JR, Robinson WA, Murphy JR, Rovira DK. Low doses of interferon-&agr; are as effective as higher doses of inducing remissions and prolonging survival in chronic myeloid leukemia. Ann Intern Med 1994; 121: 736-44.
Authors’
reply
SiR-All the survival analyses in our report were done by the rank method,’ which takes into account time to death and length of time at risk for each patient, and hence has greater statistical power than the use of only numbers of deaths. The comparison of the non-responders with the no-IFN group was marginally significant (2p=006) but this p-value was not given since this is not strictly a valid comparison, although the possible biases are likely to favour the no-IFN group. Even if the p value were smaller this could not be regarded as proof of benefit of IFN for
log
1370
continue IFN. It is true that the effect of IFN was significant in the busulphan-treated group and not in the hydroxyurea-treated group, but this is subgroup analysis and a formal test for heterogeneity of effect was not significant. Indeed, the results within each subgroup are perfectly compatible with the hypothesis that the true effect in each subgroup is the same as the overall estimate, since the odds ratio of 0-67 is within the 95% CI for each subgroup (0-45-0-82 and 052-111). This is supported by the Italian trial which showed a significant benefit for IFN versus hydroxyureaIn addition, one cannot compare from this paper hydroxyurea versus busulphan alone because patients randomised to busulphan or hydroxyurea as well as those who elected busulphan or hydroxyurea therapy as allowed in the protocol would be included. Analysis of only the randomised patients shows a trend for better survival for hydroxyurea, but this is not
statistically significant.
The biases introduced by reporting results only for patients who actually receive their allocated treatment, rather than on the intention-to-treat principle, are well known. However, although biases are eliminated by this method, it may weaken the result. The major reason for not starting IFN was the availability of a donor for bone marrow transplantation (BMT). All survival analyses were repeated censoring at time of BMT without significantly altering the outcome.
of dose is being directly addressed by the Dutch and MRC high-dose versus low-dose randomised trials. Finally, as we stated, this was a preliminary report and further information on side-effects, reasons for non-compliance and quality of life will be reported later.
The
question
current
*N C
Allan, S M Richards, P C A Shepherd
MRC Human Genetics Unit, Western General Hospital, Crewe Road, Edinburgh EH4 2XU
1
2
Peto R, Pike MC, Armitage P, et al. Design and analysis of randomised clinical trials requiring prolonged observation of each patient. II. Analysis and Examples. Br J Cancer 1977; 35: 1-39. The Italian Cooperative Study Group on Chronic Myeloid Leukemia. Interferon alfa-2a as compared with conventional chemotherapy for the treatment of chronic myeloid leukemia. N Engl J Med 1994; 330: 820-25.
Detection of parasite DNA in disease
Chagas’ heart
SiR-Chronic Chagas’ heart disease (cChHD) resulting from infection with Trypanosoma cruzi is a slowly evolving inflammatory cardiomyopathy. Histopathology reveals mononuclear cell infiltration, myocyte damage, and fibrosis. Since parasite cells are rarely found at sites of myocarditis, autoimmunity has been postulated as the cause of cChHD. We have searched for anti-T cruzi antibodies that differentiate the serological profile of chronically infected individuals with or without cChHD.’ We have used the from a cChHD reference patient with high serum of anti-T cruzi concentrations antibodies as an immunological probe for isolating parasite recombinant antigens from a T cruzi expression library.’ The reference serum came from JL, a deceased 27-year-old male, New York Heart Association functional class IV, whose electrocardiogram at admission in 1985, at age 25, was: firstdegree atrioventricular block, left anterior fascicular block and anterior electrical inactivation area. After one year of