Correspondence

Treatment of Acute Myeloid Leukemia

N Engl J Med 1999; 340:1436-1439May 6, 1999

Article

To the Editor:

Cassileth et al. (Dec. 3 issue)1 report the results of a large study comparing chemotherapy with autologous or allogeneic bone marrow transplantation in the management of acute myeloid leukemia in first remission. Their study showed that autologous or allogeneic bone marrow transplantation offered no advantage over intensive chemotherapy in terms of overall survival. However, the study included patients with a variety of risk factors. Although there is no established prognostic index for acute myeloid leukemia, we believe that most institutions do not perform bone marrow transplantation in patients with either the M2 or the M3 type of acute myeloid leukemia in first remission, according to the French–American–British (FAB) classification, unless there are unfavorable factors, such as a high initial white-cell count or difficulty in achieving remission.

What we want to know is, who really requires bone marrow transplantation in first remission? In other words, for which patients should we reserve bone marrow transplantation until they have a relapse? Characterizing the patients who have had relapses with chemotherapy and in whom bone marrow transplantation as second-line therapy has failed will be informative in identifying eligible patients for further randomized studies. In such patients, bone marrow transplantation as consolidation therapy may be of benefit.

Yoshinobu Kanda, M.D.
Akiyoshi Miwa, M.D.
Atsushi Togawa, M.D.
International Medical Center of Japan, Tokyo 162-8655, Japan

1 References

1
Cassileth PA, Harrington DP, Appelbaum FR, et al. Chemotherapy compared with autologous or allogeneic bone marrow transplantation in the management of acute myeloid leukemia in first remission. N Engl J Med 1998;339:1649-1656
Full Text | Web of Science | Medline

To the Editor:

In the study by Cassileth et al., the mortality rate at 100 days in the autologous-transplantation group was 14 percent; most of these deaths were due to infection or graft failure. Autologous marrow grafts were purged with perfosfamide. This technique has been associated with delayed engraftment in a dose-dependent manner, even in patients with neoplasms that originated outside the bone marrow.1 In the study by Cassileth et al., purging with perfosfamide may have contributed to early death, and thus to the lack of a benefit in terms of leukemia-free survival and the relapse rate. Their results should be compared with those of studies in which unpurged marrow was used.2-4 The conclusions of Cassileth et al. should be viewed with caution when applied to the transplantation of unpurged cellular products.

Javier Pérez-Calvo, M.D.
Antonio Brugarolas, M.D.
University Clinic of Navarre, 31008 Pamplona, Spain

4 References

1
Shpall EJ, Jones RB, Blast RC Jr, et al. 4-Hydroperoxycyclophosphamide purging of breast cancer from the mononuclear cell fraction of bone marrow in patients receiving high-dose chemotherapy and autologous marrow support: a phase I trial. J Clin Oncol 1991;9:85-93
Web of Science | Medline

2
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

3
Harousseau JL, Cahn JY, Pignon B, et al. Comparison of autologous bone marrow transplantation and intensive chemotherapy as postremission therapy in adult acute myeloid leukemia. Blood 1997;90:2978-2986
Web of Science | Medline

4
Burnett AK, Goldstone AH, Stevens RM, et al. Randomised comparison of addition of autologous bone-marrow transplantation to intensive chemotherapy for acute myeloid leukaemia in first remission: results of MRC AML 10 trial. Lancet 1998;351:700-708
CrossRef | Web of Science | Medline

To the Editor:

In the study by Cassileth et al., patients were randomly assigned to undergo bone marrow transplantation or to receive high-dose cytarabine chemotherapy after one course of consolidation therapy consisting of two days of idarubicin and five days of cytarabine. No significant advantage in terms of disease-free survival was shown for bone marrow transplantation. In fact, the overall survival rate was better for the patients who received high-dose cytarabine chemotherapy than for those who underwent autologous marrow transplantation.

Although bone marrow transplantation has an aspect of immunotherapy through its graft-versus-leukemia effect, transplantation itself, especially autologous transplantation, is not a cytocidal therapy but a means of hematopoietic rescue after myeloablative chemotherapy. Therefore, the therapeutic effect of transplantation should be considered in the context of the remission-induction and consolidation chemotherapy and the preparative regimens the patients receive.

In most previous prospective studies, bone marrow transplantation was performed after no consolidation therapy, or after only one cycle of it, and these studies showed no or only marginal benefits of transplantation. However, two large-scale, randomized trials of autologous marrow transplantation for acute myeloid leukemia, in which the transplant was given after at least one cycle of intensive consolidation chemotherapy, showed a significant improvement in disease-free survival in the patients assigned to receive transplants.1,2 Although these studies failed to show any difference in overall survival, a study in which patients undergo transplantation after multiple cycles of intensive consolidation chemotherapy might well demonstrate an advantage of transplantation. The effect of transplantation should be evaluated in the context of induction and postremission chemotherapy before one draws a negative conclusion about the value of transplantation.

Ritsuro Suzuki, M.D.
Masao Seto, M.D.
Yasuo Morishima, M.D.
Aichi Cancer Center, Nagoya 464-8681, Japan

2 References

1
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

2
Burnett AK, Goldstone AH, Stevens RM, et al. Randomised comparison of addition of autologous bone-marrow transplantation to intensive chemotherapy for acute myeloid leukaemia in first remission: results of MRC AML 10 trial. Lancet 1998;351:700-708
CrossRef | Web of Science | Medline

To the Editor:

The study by Cassileth et al. has two major flaws. The first concerns compliance with the study, its effect on the intention-to-treat analysis, and the use of the O'Brien–Fleming boundary. Although 116 patients were assigned to undergo autologous bone marrow transplantation, only 63 (54 percent) actually did so. We believe that for an intention-to-treat analysis, it is unacceptable to retain in the analysis the 21 patients (18 percent of the group) who, after randomization, withdrew from the study, when only 5 patients in the cytarabine group and 3 in the allogeneic-transplantation group withdrew. This raises the question of a bias of the participating physicians against autologous bone marrow transplantation. The decision to close the study when there was no difference between groups in the rate of leukemia-free survival, the primary end point, is not allowed when the O'Brien–Fleming boundary is used.

The second flaw concerns cytogenetic features, the most important independent prognostic factors in patients with acute myeloid leukemia. Cassileth et al. report only the distribution of karyotypes to show that there was no difference between the treatment groups. A Medical Research Council study of acute myeloid leukemia (MRC AML 10)1 concluded that the value of each therapeutic strategy depended on cytogenetic features, with worse results of allogeneic bone marrow transplantation only in patients with a good prognosis.

We believe that Cassileth et al. convey the misleading message that any type of bone marrow transplantation is not advisable in patients with acute myeloid leukemia in first remission.

Norbert-Claude Gorin, M.D.
Hôpital Saint-Antoine, 75012 Paris, France

Myriam Labopin, M.D.
European Cooperative Group for Blood and Marrow Transplantation, 75006 Paris, France

1 References

1
Burnett AK, Goldstone AH, Stevens RM, et al. Randomised comparison of addition of autologous bone-marrow transplantation to intensive chemotherapy for acute myeloid leukaemia in first remission: results of MRC AML 10 trial. Lancet 1998;351:700-708
CrossRef | Web of Science | Medline

To the Editor:

In his editorial on the role of bone marrow transplantation in patients with acute myeloid leukemia in first remission (Dec. 3 issue),1 Dr. Burnett states, “It already appears justifiable to reserve transplantation for second-line treatment in patients with a favorable karyotype and for children.” We dispute this statement with respect to children. Every large comparative study reported to date has demonstrated superior survival among children assigned to undergo allogeneic bone marrow transplantation.2-5 For example, the Children's Cancer Group showed that children and adolescents with HLA-compatible family donors had significantly longer disease-free survival and overall survival after a remission had been achieved than patients with no HLA-compatible donors who were randomly assigned to undergo autologous bone marrow transplantation or chemotherapy.2,3 The compliance rate in this large trial, in which 656 patients in remission were eligible for randomization, was 75 percent.

These results confirm those of two previous Children's Cancer Group trials involving 800 patients in remission,6,7 as well as the results of the St. Jude,8 Italian Association of Pediatric Hematology and Oncology (AIEOP), Pediatric Oncology Group, and Medical Research Council (MRC) trials.1,4,5 Although we agree that the role of autologous bone marrow transplantation in first remission remains questionable, children with HLA-compatible family donors clearly benefit from undergoing allogeneic bone marrow transplantation in first remission.

William G. Woods, M.D.
South Carolina Cancer Center, Columbia, SC 29203

Jean E. Sanders, M.D.
Fred Hutchinson Cancer Research Center, Seattle, WA 98109-1024

Steven Neudorf, M.D.
Children's Hospital, Pittsburgh, PA 15213

8 References

1
Burnett AK. Transplantation in first remission of acute myeloid leukemia. N Engl J Med 1998;339:1698-1700
Full Text | Web of Science | Medline

2
Woods WG, Kobrinsky N, Buckley JD, et al. Timed-sequential induction therapy improves postremission outcome in acute myeloid leukemia: a report from the Children's Cancer Group. Blood 1996;87:4979-4989
Web of Science | Medline

3
Woods WG, Neudorf S, Gold S, et al. Aggressive post-remission chemotherapy is better than autologous bone marrow transplantation and allogeneic BMT is superior to both in children with acute myeloid leukemia. Prog Proc Am Soc Clin Oncol 1996;15:368-368 abstract.

4
Ravindranath Y, Yeager AM, Chang MN, et al. Autologous bone marrow transplantation versus intensive consolidation chemotherapy for acute myeloid leukemia in childhood. N Engl J Med 1996;334:1428-1434
Full Text | Web of Science | Medline

5
Stevens RF, Hann IM, Wheatley K, Gray RG. Marked improvements in outcome with chemotherapy alone in paediatric acute myeloid leukaemia: results of the United Kingdom Medical Research Council's 10th AML trial. Br J Haematol 1998;101:130-140
CrossRef | Web of Science | Medline

6
Nesbit ME, Buckley JD, Feig SA, et al. Chemotherapy for induction of remission of childhood acute myeloid leukemia followed by marrow transplantation or multiagent chemotherapy: a report from the Childrens Cancer Group. J Clin Oncol 1994;12:127-135
Web of Science | Medline

7
Wells RJ, Woods WG, Buckley JD, et al. Treatment of newly diagnosed children and adolescents with acute myeloid leukemia: a Childrens Cancer Group Study. J Clin Oncol 1994;12:2367-2377
Web of Science | Medline

8
Dahl GV, Kalwinsky DK, Mirro J Jr, et al. Allogeneic bone marrow transplantation in a program of intensive sequential chemotherapy for children and young adults with acute nonlymphocytic leukemia in first remission. J Clin Oncol 1990;8:295-303
Web of Science | Medline

Author/Editor Response

The authors reply:

To the Editor: We agree with Kanda et al. that therapy should be guided by prognostic factors, but we believe that cytogenetic features are more precise prognostic indicators than the FAB classification. Drs. Gorin and Labopin note that we failed to correlate cytogenetic features with therapeutic outcomes. The initial version of our manuscript included such an analysis. It was deleted because the Journal's reviewers believed that the differences observed among the cytogenetic subgroups1 were of limited reliability because of the small number of patients in each subgroup. We strongly agree that decisions about therapy in individual patients should be based on an evaluation of the patient's prognosis rather than on the results of our study for the population of patients as a whole.

In our article, we acknowledge the potential flaw cited by Drs. Gorin and Labopin — namely, that only a fraction of patients in our study, as in other studies, actually underwent the assigned autologous bone marrow transplantation. In our article, we explain the rationale for our intention-to-treat analysis and describe the biases that influence analyses that include only patients who actually undergo the procedure. We are aware that the use of the O'Brien–Fleming boundary involves rules for stopping the study early when the data support the conclusion that there are significant treatment differences. As we stated, however, the data monitoring committee of the Eastern Cooperative Oncology Group directed the study team to unblind the results when it became clear that the chance of observing a significant difference in disease-free survival was exceedingly small.

Perez-Calvo and Brugarolas suggest that the results of this study, in which chemotherapy-purged bone marrow was transplanted, should not be compared with the results of studies in which unpurged bone marrow was used.2-4 Only two of the studies they cite2,4 reported a benefit in terms of disease-free survival after autologous bone marrow transplantation as compared with chemotherapy; overall survival was not improved in two of the studies2,3 and was only marginally improved in the other study.4 The lack of substantive improvement in survival reported in these studies is consistent with our results. Perez-Calvo and Brugarolas also believe that the mortality rate of 14 percent in our group of patients who underwent autologous transplantation with purged bone marrow adversely affected the disease-free survival and overall survival of this group as a whole. This may be true and, as we noted, may suggest a way to improve the results of autologous bone marrow transplantation, with the use, for example, of peripheral-blood stem cells.

The caveat of Suzuki et al. is well taken. Our results can be applied only to patients who receive the induction and consolidation therapy we used. Other approaches to preremission and postremission therapy, preparative regimens for transplantation, and stem-cell transplantation may have different results. New therapeutic strategies need to be compared with conventional therapy in randomized studies that analyze the data according to prognostic subgroups.

Peter A. Cassileth, M.D.
University of Miami Sylvester Comprehensive Cancer Center, Miami, FL 33136

Frederick R. Appelbaum, M.D.
Fred Hutchinson Cancer Research Center, Seattle, WA 98109-1024

Peter H. Wiernik, M.D.
Our Lady of Mercy Comprehensive Cancer Center, Bronx, NY 10466

4 References

1
Slovak ML, Kopecky KJ, Cassileth PA, et al. Karyotypic analysis predicts outcome of pre- and post-remission therapy in adult acute myeloid leukemia (AML): a SWOG/ECOG intergroup study. Blood 1998;92:Suppl 1:678a-678a abstract.
Web of Science

2
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

3
Harousseau JL, Cahn JY, Pignon B, et al. Comparison of autologous bone marrow transplantation and intensive chemotherapy as postremission therapy in adult acute myeloid leukemia. Blood 1997;90:2978-2986
Web of Science | Medline

4
Burnett AK, Goldstone AH, Stevens RM, et al. Randomised comparison of addition of autologous bone-marrow transplantation to intensive chemotherapy for acute myeloid leukaemia in first remission: results of MRC AML 10 trial. Lancet 1998;351:700-708
CrossRef | Web of Science | Medline

Author/Editor Response

Any benefit of bone marrow transplantation for acute myeloid leukemia depends on how effective the comparative chemotherapy is. In the AIEOP trial,1 the chemotherapy group had a poorer outcome (rate of disease-free survival, 27 percent) than that expected with contemporary treatment in children. Improvements in chemotherapy continue to improve the results, as reported by Dr. Woods and colleagues on behalf of the Children's Cancer Group2 and by the United Kingdom MRC Paediatric Leukaemia Working Party, which recently reported a 56 percent rate of overall survival at seven years in recipients of chemotherapy alone; in fact, this study showed no superiority of transplantation.3 When the data in the MRC study were “time-adjusted” so that survival was calculated from day 155 of remission, which was the median elapsed time between the induction of clinical remission and transplantation, 66 percent of the patients who received chemotherapy alone (range, 58 to 74 percent) were alive at seven years, as compared with 73 percent of those who underwent transplantation (range, 62 to 84 percent). The overall rate of survival at seven years did not differ significantly between the patients with donors and those without donors (70 percent and 60 percent, respectively; P=0.1).

Even when children with favorable karyotypes were excluded from the MRC analysis, there was no advantage of bone marrow transplantation. In the MRC study of acute myeloid leukemia (MRC AML 10), from which this experience was derived, the rate of second remission among children who had relapses after chemotherapy was 90 percent, and the survival rate among those with relapses was 34 percent. Given that this is the only time-adjusted comparison of children with donors and those without donors that has been reported so far and that it showed no significant advantage of transplantation with respect to survival, it is important to take into account the associated morbidity and possible late adverse effects, as well as the fact that these children have an excellent chance of a second remission. Under these circumstances, it does seem justifiable to delay transplantation.

This approach has been adopted by the MRC Paediatric Leukaemia Working Party in its current trial, which is showing a further improvement in survival. The results of the Children's Cancer Group study2 and the Pediatric Oncology Group study4 may indeed conflict with the MRC data when a time-adjusted comparison of children with donors and those without donors is performed, in which case the value of allogeneic transplantation is uncertain and should continue to be examined in the context of a prospective trial.

Alan K. Burnett, M.D.
University of Wales College of Medicine, Cardiff CF4 4XN, United Kingdom

4 References

1
Amadori S, Testi AM, Arico M, et al. Prospective comparative study of bone marrow transplantation and postremission chemotherapy for childhood acute myelogenous leukemia. J Clin Oncol 1993;11:1046-1054
Web of Science | Medline

2
Woods WG, Neudorf S, Gold S, et al. Aggressive post-remission chemotherapy is better than autologous bone marrow transplantation and allogeneic BMT is superior to both in children with acute myeloid leukemia. Prog Proc Am Soc Clin Oncol 1996;15:368-368 abstract.

3
Stevens RF, Hann IM, Wheatley K, Gray RG. Marked improvements in outcome with chemotherapy alone in paediatric acute myeloid leukemia: results of the United Kingdom Medical Research Council's 10th AML trial. Br J Haematol 1998;101:130-140
CrossRef | Web of Science | Medline

4
Ravindranath Y, Yeager AM, Chang MN, et al. Autologous bone marrow transplantation versus intensive consolidation chemotherapy for acute myeloid leukemia in childhood. N Engl J Med 1996;334:1428-1434
Full Text | Web of Science | Medline