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From www.bloodjournal.org by guest on October 28, 2014. For personal use only.
1996 88: 754-755
High-dose cytarabine induction for acute myeloid leukemia [letter;
comment]
JD Shepherd, MJ Barnett and GL Philips
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154
CORRESPONDENCE
High-Dose Cytarabine Induction for Acute Myeloid Leukemia
To the Editor:
REFERENCES
In a recent article, Bishop et al’ state that high-dose cytarabine has
not previously been used as induction for untreated acute myeloid
leukemia (AML). In fact, high-dose cytarabine has been used by
itself: with am~acrine,~
and with daunorubicin4 in this role. Additionally, doses of cytarabine significantly above those considered
standard had previously been used by other groups for initial induction’ with daunorubicin.
The report by Bishop et all builds on these previous experiences
and clearly supports a role for high-dose cytarabine as initial therapy,
as we and other groups have reported.
John D. Shepherd
Michael J. Barnett
LeukemidBone Marrow Transplantation Program
of British Columbia
Vancouver, British Columbia
Canada
Gordon L. Phillips
Markey Cancer Center
University of Kentucky
Lexington, KY
1. Bishop JF, Matthews JP, Young GA, Szer J , Gillet A, Joshua
D, Bradstock K, Enno A, Wolf MM, Fox R, Cobcroft R, Hemnann
R, Van Der Weyden M, Lowenthal RM, Page F, Garson OM, Juneja
S: A randomized study of high-dose cytarabine in induction in acute
myeloid leukemia. Blood 87:1710, 1996
2. Preisler HD, Raza A, Barcos M, Azarnia N, Larson R, Walker
1, Browman M, Grunwald H, D’Arrigo P, Doeblin T, Bloom M,
Stein A, Logue G, Goldberg J, Kirshner J, Gottlieb A, Bennett J:
High-dose cytosine arabinoside as the initial treatment of poor-risk
patients with acute nonlymphocytic leukemia: A Leukemia Intergroup study. J Clin Oncol 5:75, 1987
3. Hines JD, Mazza JJ, Oken MM, Adelstein DJ, Keller A, Bennett JM, O’Connell MJ: Prolonged survival after high-dose cytosine
arabinoside and amsacrine induction in patients with previously untreated de novo acute nonlymphocytic leukemia. Semin Oncol14:37,
1987
4. Phillips GL, Reece DE, Shepherd JD, Barnett MJ, Brown RA,
Frei-Lahr DA, Klingemann H-G, Boswell BJ, Spinelli JJ, Herzig
RH, Herzig GP: High-dose cytarabine and daunorubicin induction
and postremission chemotherapy for the treatment of acute myelogenous leukemia in adults. Blood 77:1429, 1991
5. Vaughan WP, Karp JE, Burke PJ: Two-cycle timed-sequential
chemotherapy for adult acute nonlymphocytic leukemia. Blood
64:975, 1984
Response: Induction Endpoints in AML
Shepherd et al are quite right. High-dose cytarabine has been used
in a number of single-ann studies in the induction therapy of AML.
However, our report is one of the first published papers of a phase
111 randomized study of high-dose cytarabine in the induction of de
novo AML.’ The South-West Oncology Group (SWOG) is soon to
publish its randomised study of high-dose cytarabine induction with
similar results.’
We believe the distinction between phase 111 randomized and
phase 11 single ann studies is important for the usual reasons that
large randomized comparisons are the appropriate clinical trial methodology to avoid bias when comparing treatments. However, in
addition, single-arm studies reporting high response rates in AML
are difficult to interpret. A number of recent randomized trials of
AML induction intensified with high-dose cytarabine’.* or etopohave shown no difference in complete remission (CR) rate but
clinically important, statistically significant differences in remission
duration, relapse-free survival, or survival.
An explanation for this discrepancy may be that most modem
standard-dose induction chemotherapy is probably as successful as
more intensive regimens in reducing marrow blasts to less than 5%.
CR as measured by blasts in bone marrow on morphology (CR-BM)
fails to detect clinically important residual disease in about 50% of
patients who subsequently relapse. Thus, when reporting clinical
trials it would be useful to routinely report cytogenetic CR (CR-C)
or loss of a molecular marker (CR-M) to better understand the likely
burden of residual subclinical disease.
The important observation that intensified induction therapy prolongs remission may also provide a useful clinical tool to evaluate
a number of new induction therapies, all of which could produce
high rates of CR. We have recently defined a new endpoint, time
to failure, for evaluating induction treatment. This endpoint incorporates early deaths, failure to achieve CR, relapse after CR, and death
in CR.5 This endpoint allows the individual types of failure to be
studied as competing risks and is a valuable method for comparing
induction regimens.
James F. Bishop
Graham A. Young
Royal Prince Alfred Hospital
Sydney, Australia
Jane P. Matthews
Peter MacCallum Cancer Institute
Melbourne, Australia
Ken Bradstock
Westmead Hospital
Sydney, Australia
REFERENCES
1. Bishop JF, Matthews JP, Young GA, Szer J, Gillet A, Joshua
D, Bradstock K, Enno A, Wolf MM, Fox R, Cobcroft R, Henmann
R, Van Der Weyden M, Lowenthal RM, Page F, Garson OM, Juneja
S: A randomized study of high-dose cytarabine in induction in acute
myeloid leukemia. Blood 87:1710, 1996
2. Weick J, Kopecky J, Appelbaum F, Head D, Elias L, Kinsbury
L, Daniels D, Balcerzak SP, Mills GM, Hynes HE, Coltman C,
Grever M: A randomised investigation of high dose versus standard
From www.bloodjournal.org by guest on October 28, 2014. For personal use only.
CORRESPONDENCE
dose cytarabine arabinoside with daunorubicin in patients with acute
myelogenous leukemia. hoc Am Soc Clin Oncol 11:261, 1992
(abstr)
3. Bishop JF, Lowenthal RM, Joshua D, Matthews JP, Todd D,
Cobcroft R, Whiteside MG, Kronenberg H, Ma D, Dodds A: Etoposide in acute non-lymphocytic leukemia. Blood 75:27, 1990
4. Vogler WR, McCarley DH, Stagg M, Bartolucci AA, Moore
755
J, Martelo 0, Omura GA: A phase ID trial of high dose cytarabine
arabinoside with or without etoposide in relapsed and refractory
acute myelogenous leukemia. Leukemia 9: 1847, 1994
5. Bishop JF, Matthews JP, Young GA, Bradstock K Factors influencing poor outcome in induction therapy of acute myeloid leukemia using a new endpoint, time to failure. 26th Congress of the
International Society of Hematology, 1996. Int J Hematol (in press)