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Prepublished online as a Blood First Edition Paper on August 15, 2002; DOI 10.1182/blood-2002-02-0632.
CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
From Northwestern University, Feinburg School of
Medicine, Robert H. Lurie Comprehensive Cancer Center of Northwestern
University, Chicago, IL (Eastern Cooperative Oncology Group [ECOG],
Brookline, MA); Harvard School of Public Health, Boston, MA (ECOG);
Karmanos Cancer Center, Wayne State University, Detroit, MI (Cancer and
Leukemia Group B [CALGB], Chicago, IL); Fred Hutchinson Cancer
Research Center, University of Washington, Seattle (Southwest Oncology
Group [SWOG], San Antonio, TX); Children's Hospital of Northern
California-Oakland; Emory University/ Children's
Healthcare of Atlanta, GA; Texas Children's Cancer Center, Houston
(Pediatric Oncology Group [POG], Chicago, IL); Massachusetts General
Hospital, Harvard Medical School, Boston (POG); National Cancer
Institute of Canada Clinical Trials Group, Kingston, ON; University of
New Mexico, Albuquerque (SWOG); The Ohio State University, Columbus
(CALGB); Rambam Medical Center, Technion, Haifa, Israel
(ECOG); and Our Lady of Mercy Cancer Center, New York Medical College,
Bronx (ECOG).
We previously reported a benefit for all-trans retinoic
acid (ATRA) in both induction and maintenance therapy in patients with
acute promyelocytic leukemia (APL). To determine the durability of this
benefit and identify important prognostic factors, long-term follow-up
of the North American Intergroup APL trial is reported. A total of 350 patients with newly diagnosed APL were randomized to either
daunorubicin and cytarabine (DA) or ATRA for induction and then either
ATRA maintenance or observation following consolidation chemotherapy.
The complete remission (CR) rates were not significantly different
between the ATRA and DA groups (70% and 73%, respectively). However,
the 5-year disease-free survival (DFS) and overall survival (OS) were
longer with ATRA than with DA for induction (69% vs 29% and 69% vs
45%, respectively). Based on both induction and maintenance
randomizations, the 5-year DFS was 16% for patients randomized to DA
and observation, 47% for DA and ATRA, 55% for ATRA and observation,
and 74% for ATRA and ATRA. There was no advantage of either induction
regimen among any subgroups when CR alone was considered. However,
female sex, classical M3 morphology (vs the microgranular
variant [M3v]), and treatment-white blood cell count (WBC)
interaction (ATRA/WBC below 2 × 109/L [2000/µL]
best, DA/WBC above 2 × 109/L worst) were each
significantly associated with improved DFS (P < .05).
Treatment with ATRA, WBC below 2 × 109/L, and absence of
bleeding disorder were each significantly associated with improved OS.
Age more than 15 years, female sex, and
treatment-morphology interaction (DA/M3v worst, ATRA best regardless of
morphology) were each significantly associated with improved DFS based
on maintenance randomization. The improvement in outcome with ATRA in
APL was maintained with long-term follow-up.
(Blood. 2002;100:4298-4302) During the last decade a series of clinical trials
has contributed to the development of remarkably effective therapeutic strategies for patients with acute promyelocytic leukemia (APL). The
administration of all-trans retinoic acid (ATRA) for
patients with newly diagnosed APL, either alone or combined with
chemotherapy in induction, has improved the prognosis such that the
event-free survival (EFS) at 2 to 4 years is 55% to 85% and the
overall survival (OS) is 70% to 80%.1-9 The European APL
Group has compared concurrent ATRA plus chemotherapy with sequential
ATRA until complete remission (CR) followed by chemotherapy and reports
a significantly reduced relapse rate at 2 years among patients
receiving concurrent therapy (6% vs 16%,
P = .04).10 Two randomized trials, including
the first report of the North American Intergroup trial, with a median follow-up of 30 months show a benefit to maintenance therapy with ATRA.7,10 Furthermore, a combination of low-dose
chemotherapy given together with ATRA as maintenance appears better
than ATRA alone to prevent relapse, and either appears better than no
maintenance.5,10
Although all of these studies suggest an important role for ATRA in
both induction and maintenance, long-term follow-up is necessary to
determine whether these early benefits are sustained. Despite the
impact of ATRA in the treatment of APL, the induction mortality rate
remains approximately 10% and acquired retinoid resistance contributes
to relapse in approximately 20% to 30% of patients.1-10
Therefore, an analysis of prognostic factors that predict for success
or failure with contemporary treatment strategies may identify specific
subsets of patients who require an alternative approach. This report
provides long-term outcome results of the North American Intergroup
protocol in which patients with APL were randomized to either ATRA or
chemotherapy for induction and either ATRA maintenance or
observation.7 An analysis of prognostic factors is also
presented to identify patients at high risk of relapse.
Patients
A total of 350 evaluable patients were randomized to ATRA 45 mg/m2/d orally until CR or 1 to 2 cycles of daunorubicin 45 mg/m2 by intravenous bolus on days 1 to 3 plus cytarabine
100 mg/m2 by continuous intravenous infusion on days 1 to
7. Patients younger than 3 years of age were randomized to receive
either ATRA as just described or daunorubicin 1.5 mg/kg/d by
intravenous infusion on days 1 to 3 plus cytarabine 3.3 mg/kg/d by
continuous intravenous infusion on days 1 to 7. If the white blood cell
count (WBC) was more than 10 × 109/L
(10 000/µL), hydroxyurea was given prior to ATRA. Patients who
failed to achieve CR after a maximum of 90 days of ATRA crossed over to
chemotherapy. ATRA was supplied by the National Cancer Institute,
Bethesda, MD. Patients who failed to achieve CR with 2 cycles of
induction chemotherapy received no further protocol therapy and were
treated at the physician's discretion. Patients who achieved CR with
either chemotherapy or ATRA received 2 cycles of consolidation
chemotherapy. The first cycle was identical to the chemotherapy
administered in induction. The second cycle consisted of high-dose
cytarabine 2.0 mg/m2 as a 1-hour intravenous
infusion every 12 hours for 4 consecutive days with daunorubicin 45 mg/m2 by intravenous infusion on days 1 and 2. For patients
less than 3 years of age, the second cycle included cytarabine 67 g/kg
as a 1-hour intravenous infusion every 12 hours for 4 consecutive days
and daunorubicin 1.5 mg/kg/d by intravenous infusion on days 1 and 2. Patients in CR after both cycles of consolidation chemotherapy, irrespective of induction therapy, underwent a second randomization to
either maintenance ATRA 45 mg/m2/d orally given in divided
doses every 12 hours for 1 year or observation. Patients intolerant of
ATRA in induction were directly assigned to observation.
Fifty-one of the 401 patients registered were excluded because
either they did not have APL after central pathology review (23), their
medical condition deteriorated before any treatment was given (14),
they did not fulfill entry criteria (7), or there was not adequate
on-study data available (7). Four patients who were excluded from the
initial analysis because of administrative reasons are now evaluable
and included. Therefore, 350 patients are evaluable for this analysis.
The WBCs used in the analyses here were the earliest recorded at
diagnosis and prior to the introduction of hydroxyurea.
Response criteria
Statistical methods Univariate associations between dichotomous variables were evaluated with the Fisher exact test. Associations involving ordered categoric variables were evaluated with a Wilcoxon rank sum test.13 Analyses of the primary induction end points were stratified by age. Analyses of the joint association of multiple variables with response were evaluated with logistic regression. Univariate and multivariate analyses of disease-free survival (DFS) and overall survival (OS) were evaluated with proportional hazards regression. Disease-free survival is defined as the time from achievement of CR to relapse or death from any cause. Overall survival is defined as the time from registration to death. Survival distributions were produced using the methods of Kaplan and Meier.14 Outcome analyses are based on the treatment the patient was intended to receive by the randomization.
Patient characteristics Patient characteristics have been previously published and are presented in Table 1.7 There were no significant differences between the 2 arms.
Treatment outcome Complete remission.
A total of 123 (70%) of the 176 patients randomized to chemotherapy
achieved CR, as did 127 (73%) of the 174 patients randomized to ATRA
(P = .56). The CR rates are presented in Table
2 by age, WBC, morphology, and
sex. Overall, there was no difference in CR rates between
patients treated with ATRA or daunorubicin plus cytarabine
(DA). Furthermore, there were no significant differences for any of the
variables when CR alone was considered as the outcome (Table
2).
Disease-free survival based on induction randomization.
Among the 250 patients achieving CR, the 5-year DFS is 29% (95%
confidence interval [CI], 20-38) and 69% (95% CI, 52-72)
for patients randomized to chemotherapy or ATRA induction, respectively (P < .0001; Figure 1). The
associations between DFS and a number of presenting characteristics
(race, sex, platelet count, WBC, hemoglobin, percent marrow
promyelocytes, percent of patients with extramedullary disease at
entry, the presence of bleeding, and microgranular variant [M3v]
morphology) and the corresponding treatment-factor interactions were
evaluated. Previous reports in APL suggest a WBC of
10 × 109/L (10 000/µL) and above is an adverse
prognostic factor.6,9 Analyses carried out here considered
10 × 109/L (10 000/µL) and above,
5 × 109/L (5000/µL), and 2 × 109/L
(2000/µL) and found a WBC of 2 × 109/L to be a highly
prognostic cut point. Female sex, classical morphology, and
treatment-WBC interaction (where patients with a WBC below
2 × 109/L [2000/µL] who received ATRA did best;
patients with a WBC above 2 × 109/L who received ATRA
and those with a WBC below 2 × 109/L who received DA
fared intermediately well; and those with a WBC above
2 × 109/L and received DA did worst) were each
significantly associated with improved DFS when adjusted for the others
based on a P
Overall survival based on induction randomization.
With a median follow-up for survival from study entry for all patients
of 6.2 years (range, 0-8.5 years), the OS at 5 years was 45%
(95% CI, 36-52) for patients randomized to induction chemotherapy and
69% (95% CI, 62-76) for patients randomized to ATRA
(P = .0001; Figure 2). The
associations between OS from induction randomization and the presenting
characteristics listed above were evaluated. Treatment with ATRA for
induction, WBC below 2 × 109/L [2000/µL], and
absence of clinical bleeding at study entry were each significantly
associated with improved OS when adjusted for the others.
Disease-free survival based on maintenance randomization.
Five-year DFS based on maintenance randomization was 61% (95% CI,
49-70) for patients randomized to ATRA and 36% (95% CI, 23-44) for
observation (P < .0001; Figure
3). The associations between DFS from
maintenance and presenting characteristics were evaluated. Age older
than 15 years, female sex, and a treatment-morphology interaction (DA/M3v worst, ATRA best regardless of morphology) were
each significant in a multicovariate analysis stratified by induction
randomization.
Disease-free survival based on both induction and maintenance
randomization.
When both induction and maintenance randomizations were taken into
account, the 5-year DFS was 16% (95% CI, 06-26) for patients randomized to chemotherapy and observation; 47% (95% CI, > 31-62) for patients randomized to chemotherapy for induction and ATRA for
maintenance; 55% (95% CI, 35-67) for ATRA and observation; and 74%
(95% CI, 61-87) for ATRA induction and ATRA maintenance (Figure
4).
Late relapses. Late relapses defined as relapse occurring after at least 2 years of continuous CR were documented in 23 patients (9% of patients achieving CR) primarily in the marrow, but 3 in the central nervous system (all of whom received DA for induction). Fourteen (64%) of these 23 patients were male, 2 (9%) had the M3v, and the median WBC at presentation was 1.6 × 109/L (1600/µL; range, 0.3 × 109/L to 29.9 × 109/L [300/µL to 29 900/µL]). The latest relapse occurred 7.5 years from CR. Thirteen (56%) of the 23 patients survived after relapse. Five of the patients relapsing late were randomized to chemotherapy for induction and then observation, 6 to ATRA and then observation, 8 to chemotherapy and then ATRA, and only 1 to ATRA for induction and ATRA for maintenance. Two of the 23 received ATRA for induction and were not randomized to maintenance.
The most important finding of this long-term follow-up report is that among patients with newly diagnosed APL, ATRA therapy conferred a sustained significant DFS and OS benefit. Patients treated with ATRA for induction have an excellent outcome, with a 5-year DFS and OS of 69%, and may well be cured of their disease. The patients reported here have among the longest follow-up published, and the results for patients treated with ATRA during induction compare favorably with the best outcomes with similar therapy and follow-up.8-10,15 Although in the study reported here there was a median follow-up of more than 6 years, we cite 5-year proportions surviving or disease free to facilitate comparisons with other studies. We also found a durable benefit for maintenance with ATRA. The 5-year DFS for patients randomized to ATRA maintenance was 61% compared with 36% for patients observed after consolidation. Furthermore, the best outcome was observed for patients randomized to ATRA for both induction and maintenance who had a 5-year DFS of 74%. Additional support for the importance of maintenance comes from the Program a Espanol para el Tratamiento de las Hemopatias Malignas (PETHEMA) Cooperative Group in Spain, which has recently shown that cytarabine may be omitted from induction and consolidation in patients treated with ATRA and anthracyclines for induction plus maintenance therapy with ATRA and low-dose chemotherapy without compromising the outcome.15 It is noteworthy that similarly favorable results may also be observed with increased dose intensity of anthracyclines. In a trial conducted by the Medical Research Council (MRC), patients received considerably more anthracycline exposure (daunorubicin 50 mg/m2 for 3 days for 2 cycles in all patients followed by daunorubicin 50 mg/m2/d for 2 cycles in some patients and mitoxantrone 10 mg/m2 for 5 days in others) than in other trials.8 The excellent results reported by the MRC with ATRA in induction, but without ATRA maintenance, is consistent with the well-recognized unusual sensitivity of leukemic promyelocytes to anthracyclines.16-18 In a Southwest Oncology Group (SWOG) trial conducted prior to the availability of ATRA, daunorubicin was administered at a dose of 70 mg/m2 for 3 days during induction and consolidation, and the 9-year DFS was 72%.16 The present trial began prior to the availability of the SWOG results, and the dose of daunorubicin was the standard dose for induction in AML. This unusual sensitivity may be attributable to an inherent lack of expression of multidrug resistance proteins.19-21 We have identified certain subgroups of patients that
particularly benefit from ATRA. In a multivariate analysis in the
current study, the prognostic factors predictive of prolonged DFS
stratified by age include female sex, classical morphology,
and the interaction of WBC with therapy. Notably, the prognostic
importance of the WBC is based on the presenting WBC before the
introduction of hydroxyurea. Historically, patients with M3v treated
have a less favorable prognosis than those with classical
morphology.22,23 In the maintenance analysis, we found
that ATRA improved the outlook for such patients to a degree similar to
that achieved with ATRA for patients with classical morphology. High
WBC at presentation, M3v morphology, and older age are factors reported
in other trials to confer an unfavorable
prognosis.6,8,10,24-26 Sanz and colleagues have identified
patients who can be classified in risk groups based on presenting WBC
and platelet counts. Those patients were treated with ATRA plus
idarubicin for induction, noncytarabine-containing consolidation, and
maintenance with ATRA plus 6-MP and methotrexate.27 Sanz
et al have classified patients with an initial WBC above 10 × 109/L (10 000/µL) as high risk, and because the
outcome for such patients is less favorable than that of patients with
a WBC below 10 × 109/L,15,25,26 alternative
strategies to improve the cure rate are necessary. The analysis
reported here shows the prognostic importance of a presenting WBC of
2.0 × 109/L (2000/µL) or less. The expression of CD56
occurs in approximately 20% of patients with newly diagnosed
AML.28 This antigen has been associated with
extramedullary disease, megakaryocytic differentiation, and a poor
outcome in certain subtypes of AML.29-32 Recently, 2 groups have reported that CD56 expression is associated with the S
isoform of the PML-RAR Although APL has become the most curable subtype of adult AML, approximately 20% of patients still die of the disease due to early death or relapse. The detection of minimal residual or recurrent disease by molecular techniques appears to be useful in guiding therapy. Treatment of molecular relapse is associated with a better outcome than if treatment is delayed until relapse is detected by morphology.35,36 The remarkable activity of arsenic trioxide in patients with relapsed and refractory APL suggests it may have a role in initial therapy or as consolidation.37-41 In the current North American Intergroup study, newly diagnosed patients induced with ATRA, daunorubicin, and cytarabine are randomized to either 2 courses of arsenic trioxide followed by 2 courses of daunorubicin consolidation or just to the 2 courses of daunorubicin consolidation. Patients are then randomized to 1 of 2 maintenance regimens. This trial will determine if arsenic trioxide can improve the cure rate, particularly in high-risk patients. All-trans retinoic acid with anthracycline-based chemotherapy is now the treatment of choice for patients with APL. With long-term follow-up, the advantages of ATRA in induction and maintenance are sustained.
Coordinated by the Eastern Cooperative Oncology Group (Robert L. Comis, group chair).
Submitted February 27, 2002; accepted June 17, 2002.
Prepublished online as Blood First Edition Paper, August 15, 2002; DOI 10.1182/blood-2002-02-0632.
Supported in part by Public Health Service grants from the National Cancer Institute, National Institutes of Health (grants CA17145, CA23318, CA11083, CA21115, and CA66636, ECOG; CA31983, CA31946, and CA37027, CALGB; CA20319 and CA32102, SWOG; CA03161, POG; and CA77658, CA16058, and CA14958); and the Department of Health and Human Services.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Presented in part at the 39th meeting of the American Society of Hematology, New Orleans, LA, December 1999. Reprints: Martin S. Tallman, Northwestern University, Feinburg School of Medicine, Department of Medicine, Division of Hematology/Oncology, Robert H. Lurie Comprehensive Cancer Center, 676 N St Clair St, Suite 850, Chicago, IL 60611; e-mail: m-tallman{at}northwestern.edu.
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© 2002 by The American Society of Hematology.
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Top
Abstract
Introduction
.05 criterion for retention.
fusion transcript and a poor
outcome.