Correspondence
Treatment of Acute Myelogenous Leukemia
N Engl J Med 1995; 332:1717-1719June 22, 1995
- Article
To the Editor:
The report by Zittoun et al. (Jan. 26 issue)1 on a comparison of allogeneic or autologous transplantation and chemotherapy for acute myelogenous leukemia (AML) illustrates a flaw in the study design that is common in trials of treatment for acute leukemia and that limits the clinical usefulness of the conclusions that are drawn.
In the trial, all patients with histocompatible donors were assigned to the allogeneic-transplantation group and none were randomly assigned to the other two groups. This design is appropriate for studying the end point of duration of the first remission or of disease-free survival, but this is not an appropriate end point for a disease in which salvage therapy can cure some patients after a relapse. Long-term survival is the appropriate end point.
Allogeneic transplantation can result in a cure in a proportion of patients with AML who have a relapse. By not randomly assigning patients with histocompatible donors to the autologous-transplantation or chemotherapy group, Zittoun et al. did not allow the full potential of autologous transplantation and chemotherapy to be realized and thus did not provide a valid comparison of the three treatments. In future trials, patients with histocompatible donors should be randomly assigned to all groups in which salvage therapy by means of allogeneic transplantation is a treatment option, even if first-line allogeneic transplantation is one of the treatment strategies being investigated. Long-term survival, not the duration of the first remission, should be the primary end point. A corollary of this suggestion is that future trials should enroll very large numbers of patients to achieve sufficient statistical power.
1 ReferencesAlexander A. Morley, M.D.
Flinders Medical Centre, Bedford Park, SA 5042, Australia1
Zittoun RA ,Mandelli F ,Willemze R , et al. Autologous or allogeneic bone marrow transplantation compared with intensive chemotherapy in acute myelogenous leukemia. N Engl J Med 1995;332:217-223
Full Text | Web of Science | Medline
To the Editor:
In their informative report on a well-performed study, Zittoun et al. present data on disease-free and overall survival for all patients with AML, regardless of the cytogenetic features. However, the heterogeneity of AML is now well recognized, with subgroups and risk groups best defined on the basis of cytogenetic features.1 A cytogenetically oriented approach would therefore appear to be more appropriate in interpreting the outcome of AML according to the treatment administered. We and others have reported that patients with inv(16) and t(8;21) benefit from high doses of cytarabine rather than conventional doses.2,3 In a small study, this subgroup of patients, treated during their first relapse, was found to do equally well with bone marrow transplantation or chemotherapy.4 Patients with unfavorable cytogenetic characteristics (abnormalities of chromosome 5 or 7, trisomy 8, or abnormal 11q) have a poor response to standard chemotherapy. It remains to be determined whether this subgroup benefits disproportionately from bone marrow transplantation.
Since cytogenetic data are available for the cohort Zittoun et al. studied, it is important to answer this question. Since only 44 percent of the patients underwent cytogenetic analysis, the number of patients per cytogenetic subgroup might be too small for a meaningful comparison of the three treatments within each subgroup. Given the paucity of such data in the literature and the inherent difficulty of addressing this issue, however, presentation of the available data would still be beneficial. It should also be noted that since the median age of the patients in this study was 33 years, they cannot be considered representative of the typical patient with AML in the first complete remission (median age, 55 to 60 years), as stated in the report.
4 ReferencesHabib Ghaddar, M.D.
Paolo Anderlini, M.D.
Elihu Estey, M.D.
University of Texas M.D. Anderson Cancer Center, Houston, TX 770301
Keating MJ ,Smith TL ,Kantarjian H , et al. Cytogenetic pattern in acute myelogenous leukemia: a major reproducible determinant of outcome. Leukemia 1988;2:403-412
Web of Science | Medline2
Ghaddar HM ,Plunkett W ,Kantarjian HM , et al. Long-term results following treatment of newly-diagnosed acute myelogenous leukemia with continuous-infusion high-dose cytosine arabinoside. Leukemia 1994;8:1269-1274
Web of Science | Medline3
Bloomfield CD ,Lawrence D ,Arthur DC ,Berg DT ,Schiffer CA ,Mayer RJ . Curative impact of intensification with high-dose cytarabine in acute myeloid leukemia varies by cytogenetic group. Blood 1994;84:Suppl:111a-111a abstract.
Web of Science4
Keating MJ ,Kantarjian H ,Smith TL , et al. Response to salvage therapy and survival after relapse in acute myelogenous leukemia. J Clin Oncol 1989;7:1071-1080
Web of Science | Medline
To the Editor:
The observation that overall survival is nearly the same with chemotherapy and autologous or allogeneic transplantation after remission in patients with AML is similar to that in previous reports from smaller, randomized, or registry studies.1-3 A high dropout rate was reported (one third of the patients in remission did not complete the assigned therapy).
A similarly large, randomized study in the United States has just ended after nearly five years of accrual. Another recent study of postremission therapy in AML involved over 1000 patients.4
Though it may be heretical, I wonder about the wisdom of conducting large, expensive randomized trials of postremission therapies, since preliminary results have shown equivalent survival rates and since most patients with AML cannot benefit from the information these studies attempt to provide. Consider the following statistics. In the United States there are roughly 8000 new cases of adult AML annually. Only 45 percent of the patients are less than 60 years old, which is the approximate age limit for patients undergoing the most aggressive of these therapies. Only two thirds of patients have a remission, and in one third of those who do the intended postremission therapy is not administered because of an early relapse or toxic effects. This leaves only 1600 patients who might stand to benefit. Since only one third of patients have HLA-matched donors, only about 533 patients in this country would be able to undergo allogeneic transplantation in remission, even if it proved to be the best therapy.
If the difference in survival between patients treated with transplantation and those treated with standard chemotherapy were as large as 20 percent, the number of increased cures would be only 107 with allogeneic transplantation. Since autologous transplantation does not require a matched donor, 321 patients might benefit from this approach. Far more is at stake in discerning even slight differences among various adjuvant therapies for breast cancer, to cite just one example.
Although some of these calculations might be disputed, the basic premise holds: important advances in the study of AML will emanate not from large studies conducted to detect small differences in postremission therapy but from studies of the much larger number of patients of all ages who do not enter remission. This is not to say that efforts to optimize postremission therapy in patients with AML are not important, but when resources are limited, time and effort should be invested where the rewards are likely to be greatest.
4 ReferencesBarry Meisenberg, M.D.
Scripps Clinic and Research Foundation, La Jolla, CA 920371
Schiller GJ ,Nimer SD ,Territo MC ,Ho WG ,Champlin RE ,Gajewski JL . Bone marrow transplantation versus high-dose cytarabine-based consolidation chemotheray for acute myelogenous leukemia in first remission. J Clin Oncol 1992;10:41-46
Web of Science | Medline2
Archimbaud E ,Thomas X ,Michallet M , et al. Prospective genetically randomized comparison between intensive postinduction chemotherapy and bone marrow transplantation in adults with newly diagnosed acute myeloid leukemia. J Clin Oncol 1994;12:262-267
Web of Science | Medline3
Cassileth OA ,Andersen J ,Lazarus HM , et al. Autologous bone marrow transplant in acute myeloid leukemia in first remission. J Clin Oncol 1993;11:314-319
Web of Science | Medline4
Mayer RJ ,Davis RB ,Schiffer CA , et al. Intensive postremission chemotherapy in adults with acute myeloid leukemia. N Engl J Med 1994;331:896-903
Full Text | Web of Science | Medline
Author/Editor Response
The authors reply:
To the Editor: We agree with Dr. Morley that long-term survival should be the main end point of randomized trials. In our study, autologous transplantation performed in patients who had relapses after consolidation chemotherapy resulted in an overall survival equivalent to that associated with immediate transplantation. The value of this approach must be confirmed by longer follow-up. Randomization of patients with HLA-identical siblings would hardly have been feasible, and very few patients have undergone transplantation twice. The prognosis for patients with recurrent leukemia remains poor,1 and the true rate of cure when allogeneic or autologous transplantation is performed after the first relapse is unknown. Only randomized studies comparing delayed with immediate transplantation will permit conclusions on this issue.2
Ghaddar and colleagues raise the question of treatment allocation according to cytogenetic categories. Their study, as well as a recent analysis by the Cancer and Leukemia Group B (CALGB), suggests that high-dose cytarabine may be the optimal postremission treatment in low-risk cases. In our series, the estimated relative risk of an event, whether a relapse or death, was 0.12 for patients treated with transplantation instead of consolidation chemotherapy, including high-dose cytarabine. But as we point out, this consolidation regimen may have been suboptimal. In addition, the number of successful cytogenetic examinations in our series was relatively limited, and the 99 percent confidence interval for the above figure is 0.01 to 1.43. For these reasons, we did not present these analyses in our article. A meta-analysis of the benefit of transplantation according to various risk factors would allow confirmation of Ghaddar et al.'s hypothesis or show that even in the low-risk subgroups, transplantation remains a better option.
By “typical,” we mean that our patient population corresponds to those age groups in which intensive treatments are undertaken. It is important to emphasize that this type of limitation has been observed by the CALGB in their study of intensive consolidation chemotherapy with high-dose cytarabine.3
We are surprised by the conclusions drawn by Dr. Meisenberg from his calculations. To cure 107 more patients annually in the United States is far from negligible, and the number might be much higher if he also considered patients in other countries. The allocation of resources was not the focus of our study. Determining the cost effectiveness of treatment for acute leukemia is quite a delicate matter because of the high cost of both transplantation and management of incurable disease; the problem has seldom been adequately addressed. It is difficult to develop therapeutic strategies for patients who do not have a remission, and it takes a long time before approaches with positive results can be implemented as first-line treatments. These efforts should not compete with prospective trials aimed at comparing the actual postremission strategies.
3 ReferencesRobert Zittoun, M.D.
Hôtel-Dieu, 75004 Paris, FranceFranco Mandelli, M.D.
Università La Sapienza, 00185 Rome, ItalyStefan Suciu, M.S
European Organization for Research and Treatment of Cancer Data Center, 1000 Brussels, Belgium1
Davis CL ,Rohatiner AZ ,Lim J , et al. The management of recurrent acute myelogenous leukaemia at a single centre over a fifteen-year period. Br J Haematol 1993;83:404-411
CrossRef | Web of Science | Medline2
Clift RA ,Buckner CD ,Appelbaum FR , et al. Allogeneic marrow transplantation during untreated first relapse of acute myeloid leukemia. J Clin Oncol 1992;10:1723-1729
Web of Science | Medline3
Mayer RI ,Davis RB ,Schiffer CA , et al. Intensive postremission chemotherapy in adults with acute myeloid leukemia. N Engl J Med 1994;331:896-903
Full Text | Web of Science | Medline
