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Blood, 1 June 2001, Vol. 97, No. 11, pp. 3673-3675
CORRESPONDENCE
To the editor:
Treatment of children with acute myeloid leukemia
In a recent article, Woods et al report that postremission bone
marrow transplantation (BMT) produced better overall survival than
chemotherapy in children with acute myeloid leukemia
(AML).1 They also indicate that intensive timing induction
improved postremission survival. Their study is impressive in its
design, conduct, and magnitude, but their article raises
several questions. First, in comparing initial characteristics of patients in the
allogeneic BMT (allo-BMT) and chemotherapy groups, no mention is made
of ethnicity or socioeconomic and insurance status. Because these
appear to be important variables in accessibility to allo-BMT and may
also influence prognosis, should they not be taken into consideration?2 Is it possible that access to allo-BMT
itself is a selective factor for better prognosis? Second, the article compares overall survival after remission rather
than from diagnosis. As described elsewhere,3 the remission induction mortality due to drug toxicity was 12% for the
intensive timing group and 5% for the standard group. Is it possible
that this higher treatment-related mortality during induction removed
from the intensive-timing group patients with less favorable prognosis,
for example, patients more vulnerable to chemotherapy toxicity
and interruption during postremission chemotherapy? In other words, were the postremission intensive-timing patients selected for better prognosis by the mortality of the intensive-timing induction? Third, as the article points out, survival curves for AML do not
plateau until 6 or more years. Because the plateau is the closest
measure of cure or near-cure, the plateaus must be compared to
determine curability. Comparison of the 6- and 7-year survivals of the
allo-BMT and chemotherapy groups in Woods et al's Figure 2 reveals no
apparent significant difference. This is reflected in the configuration
of the 2 survival curves, which indicate that the wide gap at 3 years
progressively narrows in subsequent years. In children, should entire
survival curves or plateaus be used to compare success? To revive an
argument from the 1960s, is the prime goal of treatment to prolong
survival or to cure leukemia? Finally, the article justifiably celebrates progress in curing children
of AML. But for the sake of perspective, should not event-free survival
and overall survival from diagnosis be indicated, and should
not the treatment-related mortality and morbidity, late and early, be
summarized?4 From my reading of this article and similar reports cited by Woods et
al, I fail to reach their conclusion that allogeneic BMT is the
treatment of choice for children with AML in first remission who have a
matched related donor.
Donald Pinkel
Correspondence: Donald Pinkel, Driscoll Children's Hospital,
3533 South Alameda, PO Box 6530, Corpus Christi, TX 78466-6530
References
1.
Woods W G, Neudorf S, Gold S, et al.
A comparison of allogeneic bone marrow transplantation, autologous bone marrow transplantation, and aggressive chemotherapy in children with acute myeloid leukemia in remission: a report from the Children's Cancer Group.
Blood.
2001;97:56-62[Abstract/Free Full Text].
2.
Mitchell JM, Meehan KR, Kong J, Schulman KA.
Access to bone marrow transplantation for leukemia and lymphoma: the role of sociodemographic factors.
J Clin Oncol.
1997;15:2644-2651[Abstract/Free Full Text].
3.
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[Abstract/Free Full Text].
4.
Leung W, Hudson MM, Strickland DK, et al.
Late effects of treatment in survivors of childhood acute myeloid leukemia.
J Clin Oncol.
2000;18:3273-3279[Abstract/Free Full Text].
Response:
A comparison of allogeneic bone marrow transplantation (BMT),
autologous BMT, and chemotherapy in pediatric acute myeloid leukemia
We thank Drs Creutzig et al, Drs Horan and Korones, and Dr
Pinkel for their comments regarding our recently published
study.1 We would like to respond to several points that
were raised. As Creutzig et al point out, we2 and others have
documented that in every large, published, randomized trial of
postremission therapy in children with acute myeloid leukemia (AML) in
first remission, superior results, often significant, have been found in the allogeneic bone marrow transplantation (BMT) arm, including our
study. Several of these studies used advanced intensive treatment strategies, both in induction and in the chemotherapy postremission phase. Even the Medical Research Council (MRC) 10 trial,3
which Creutzig et al cite, shows a superiority in survival for
allogeneic BMT (70% versus 60%, at 7 years; P = .10).
Although no one has published a formal meta-analysis, results would
clearly favor allogeneic BMT. Compliance with the allogeneic BMT arm
was 94% in our study,1(Fig1) precluding ethnic,
socioeconomic, or insurance status bias. Creutzig et al raise the interesting question of whether patients with
favorable cytogenetics or other good prognostic factors might not need
allogeneic BMT. Although beyond the scope of the overall
paper,1 in Children's Cancer Group trial (CCG)-2891 we
could not show the value of favorable cytogenetics, based on adult
trials, in determining postremission therapy. For example, in patients
with 16q abnormalities, 77% receiving allogeneic BMT are alive at 6 years, compared with 56% receiving aggressive postremission chemotherapy (P = .39). Even in our large trial, the
number of affected patients with specific cytogenetic abnormalities is
too small to make definitive conclusions. We certainly agree that patients with acute promyelocytic leukemia and t(15;17) should first be
treated with all-trans-retinoic acid (ATRA)-containing regimens. As
noted in our original CCG-2891 manuscript,4 since 1992 CCG
patients with acute promyelocytic leukemia have been enrolled in
ATRA-containing protocols not offering BMT, and this practice
continues. We furthermore advocate allogeneic BMT only when a matched
family donor is available, in children without Down syndrome. Our study emphasizes the importance of long-term follow-up with
survival as the ultimate, most important endpoint. All 3 of our postremission arms showed plateaus after 4 years in patients receiving intensively timed induction therapy.1(Fig4) This
is in contrast to the ongoing drop-off in survival in patients receiving standard timing.1(Fig2) Late-transplant deaths
were seen in standard-timing patients, both because of ongoing relapses
and from chronic graft-versus-host disease. This phenomenon has been
well described: although the initial, pioneering reports from the Fred
Hutchinson Cancer Research Center suggested survival in AML patients
undergoing allogeneic BMT of almost 65%,5 long-term
studies revealed outcomes closer to 45%,6 during an era
when less aggressive induction therapy was utilized. We agree with
Horan and Korones that no one has done a study critically examining
matched-related-donor (MRD) BMTs utilized in relapse. But results of
matched-unrelated-donor BMTs in second or subsequent remission may be
as efficacious as MRD BMT.7 To summarize, the largest
trial to date, which had an extremely high compliance rate and
utilized aggressive induction and postremission chemotherapy,
indicates that allogeneic BMT remains the treatment of choice for the
vast majority of children with AML in first remission. "Cure," not
prolonging survival, is the end-point. With respect to overall survival, 49% from diagnosis for the
539 patients receiving intensive-timing induction, results would have
been a bit higher had we not randomized 177 patients to autologous BMT.
It is highly unlikely that intensive timing "selects" for patients
more vulnerable to chemotherapy: the difference in induction deaths
between intensive and standard timing, 9% (12% versus 3%, respectively), is much less than the difference in survival after achieving remission, 17% (61% versus 44%). The Berlin-Frankfurt-Münster (BFM) studies cited by Creutzig et
al8,9 do not represent a comparable patient population to
our study, primarily performed in North America. CCG trials accept
patients up to the age of 21 and include a much more heterogeneous population than in either the German8,9 or
British3 studies. Only 67% of our patients are of
northern European descent, with 25% of patients either African
American or Hispanic, 3% Asian, and 5% "other." In the past 2 CCG
trials, including CCG-2891, African Americans and Hispanics have done
significantly worse (36% survival at 6 years, both induction arms,
versus 47% for whites; P < .001). Specific results will
be published in a future manuscript. It is well known that there are
striking differences in the incidence of AML subtypes among various
geographic locations.10 There are also major genetic
differences that determine outcome to therapy.11 It is
most difficult to compare outcome of patients in various geographic
areas when one is not controlling for important variables, including
genetic differences. We agree with Creutzig et al that "allogeneic BMT [in fact, all
treatment] should always be considered in context with the applied
protocol." Although the BFM Group has reported excellent results in
children receiving AML therapy, the routine use of cranial radiation to
achieve these results12 is questionable. The late,
deleterious effects of cancer and its treatment cannot be overestimated
in children. We have seen a dramatic decline in the short-term and
long-term morbidity and mortality associated with allogenic BMT. We
also use conditioning regimens that do not include total body
irradiation, hence sparing the brain exposure to an agent that is well
known to affect long-term development.13 Future North America-wide Children's Oncology Group trials
in childhood AML will continue to utilize allogeneic BMT in first remission for patients with matched family donors, while continuing to
look for favorable subtypes that may do well with less aggressive therapy.
William G. Woods, Beverly J. Lange, Franklin O. Smith, and Todd A. Alonzo
Correspondence: William G. Woods, Children's Cancer Group, PO
Box 60012, Arcadia, CA 91066-6012
References
1.
Woods WG, Neudort S, Gold S, et al.
A comparison of allogeneic bone marrow transplantation, autologous bone marrow transplantation, and aggressive chemotherapy in children with acute myeloid leukemia in remission: a report from the Children's Cancer Group.
Blood.
2001;97:56-62.
2.
Woods WG, Sanders JE, Neudorf S.
Treatment of acute myeloid leukemia [letter].
New Engl J Med.
1999;340:1437-1438.
3.
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][Medline]
[Order article via Infotrieve].
4.
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.
5.
Thomas ED, Buckner CD, Clift RA, et al.
Marrow transplantation for acute non-lymphoblastic leukemia in first remission.
New Engl J Med.
1979;301:597-599[Medline]
[Order article via Infotrieve].
6.
Clift RA, Buckner CD, Thomas ED, et al.
The treatment of acute non-lymphoblastic leukemia by allogeneic marrow transplantation.
Bone Marrow Transplantation.
1987;2:243-258[Medline]
[Order article via Infotrieve].
7.
Davies SM, Wagner JE, Shu XO, et al.
Unrelated donor bone marrow transplantation for children with acute leukemia.
J Clin Oncol.
1997;15:557-565[Abstract/Free Full Text].
8.
Creutzig U, Ritter J, Zimmerman M, et al.
Idarubicin improves blast cell clearance during induction therapy in children with AML: results of the study AML-BFM 93.
Leukemia.
2001;15:348-354[CrossRef][Medline]
[Order article via Infotrieve].
9.
Creutzig U, Zimmermann M, Ritter J, et al.
Definition of a standard-risk group in children with AML.
Br J Haematol.
1999;104:630-639[CrossRef][Medline]
[Order article via Infotrieve].
10.
Cantu-Rajnoldi A, Biondi A, Jankovic M, et al.
Diagnosis and incidence of acute promyelocytic leukemia (FAB M3 and M3 variant) in childhood.
Blood.
1993;81:2209-2210[Free Full Text].
11.
Davies SM, Robison LL, Buckley JD, et al.
Glutathione-S transference polymorphisms and outcome of chemotherapy in childhood AML.
J Clin Oncol.
2001;19:1279-1287[Abstract/Free Full Text].
12.
Creutzig U, Ritter J, Zimmerman M, Schellong G.
Does cranial irradiation reduce the risk for bone marrow relapse in acute myelogenous leukemia? unexpected results of the childhood acute myelogenous leukemia study BFM-87.
J Clin Oncol.
1993;11:279-286[Abstract/Free Full Text].
13.
Jankovic M, Brouwers P, Valsecchi MG, et al.
Association of 1800 cGy cranial irradiation with intellectual function in children with acute lymphoblastic leukaemia.
Lancet.
1994;344:224-227[CrossRef][Medline]
[Order article via Infotrieve].
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A comparison of allogeneic bone marrow transplantation, autologous bone marrow transplantation, and aggressive chemotherapy in children with acute myeloid leukemia in remission: a report from the Children's Cancer Group
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Blood 2001 97: 56-62.
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