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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 92 No. 8 (October 15), 1998:
pp. 2712-2718
Incidence, Clinical Features, and Outcome of All
Trans-Retinoic Acid Syndrome in 413 Cases of Newly Diagnosed
Acute Promyelocytic Leukemia
By
S. De Botton,
H. Dombret,
M. Sanz,
J. San Miguel,
D. Caillot,
R. Zittoun,
M. Gardembas,
A. Stamatoulas,
E. Condé,
A. Guerci,
C. Gardin,
K. Geiser,
D. Cony Makhoul,
O. Reman,
J. de la Serna,
F. Lefrere,
C. Chomienne,
C. Chastang,
L. Degos,
P. Fenaux, and
the
European APL Group
From the Service d'Hematologie of the Centre Hospitalier
Universitaire (CHU) of Lille, Paris St Louis, Dijon, Paris Hotel Dieu,
Angers, Roven, Nancy, Paris Beaujon, Bordeaux, Caen, and Paris
Cochin, France; the Departments of Hematology of Valencia, Salamanca,
Santander, and Madrid, Spain; and the Department of Hematology, Bern,
Switzerland.
 |
ABSTRACT |
All trans-retinoic acid (ATRA) syndrome is a
life-threatening complication of uncertain pathogenesis that can occur
during the treatment of acute promyelocytic leukemia (APL) by ATRA.
Since its initial description, however, no large series of ATRA
syndrome has been reported in detail. We analyzed cases of ATRA
syndrome observed in an ongoing European trial of treatment of newly
diagnosed APL. In this trial, patients 65 years of age or less with an
initial white blood cell count (WBC) less than 5,000/µL were
initially randomized between ATRA followed by chemotherapy (CT)
(ATRA CT group) or ATRA with CT started on day 3; patients
with WBC greater than 5,000/µL received ATRA and CT from day 1;
patients aged 66 to 75 received ATRACT. In patients with
initial WBC less than 5,000/µL and allocated to ATRACT, CT
was rapidly added if WBC was greater than 6,000, 10,000, 15,000/µL by
days 5, 10, and 15 of ATRA treatment. A total of 64 (15%) of the 413 patients included in this trial experienced ATRA syndrome during
induction treatment. Clinical signs developed after a median of 7 days (range, 0 to 35 days). In two of them, they were in fact present
before the onset of ATRA. In 11 patients, they occurred upon
recovery from the phase of aplasia due to the addition of CT.
Respiratory distress (89% of the patients), fever (81%), pulmonary
infiltrates (81%), weight gain (50%), pleural effusion (47%), renal
failure (39%), pericardial effusion (19%), cardiac failure (17%),
and hypotension (12%) were the main clinical signs, and 63 of the 64 patients had at least three of them. Thirteen patients required
mechanical ventilation and two dialysis. A total of 60 patients
received CT in addition to ATRA as per protocol or based on increasing WBC; 58 also received high dose dexamethasone (DXM); ATRA was stopped
when clinical signs developed in 30 patients. A total of 55 patients
(86%) who experienced ATRA syndrome achieved complete remission (CR),
as compared with 94% of patients who had no ATRA syndrome (P
= .07) and nine (14%) died of ATRA syndrome (5 cases), sepsis (2 cases), leukemic resistance (1 patient), and central nervous system
(CNS) bleeding (1 patient). None of the patients who
achieved CR and received ATRA for maintenance had ATRA
syndrome recurrence. No significant predictive factors of ATRA
syndrome, including pretreatment WBC, could be found. Kaplan Meier
estimates of relapse, event-free survival (EFS), and survival at 2 years were 32% ± 10%, 63% ± 8%, and 68% ± 7% in patients
who had ATRA syndrome as compared with 15% ± 3%, 77% ± 2%, and
80% ± 2% in patients who had no ATRA syndrome (P
= .05, P = .003, and P = .03), respectively.
In a stepwise Cox model that also included pretreatment prognostic
variables, ATRA syndrome remained predictive for EFS and survival. In
conclusion, in this multicenter trial where CT was rapidly added to
ATRA in case of high or increasing WBC counts and DXM generally also
used at the earliest clinical sign, the incidence of ATRA syndrome was
15%, but ATRA syndrome was responsible for death in only 1.2% of the
total number of patients treated. However, occurrence of ATRA syndrome
was associated with lower EFS and survival.
© 1998 by The American Society of Hematology.
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INTRODUCTION |
ACUTE PROMYELOCYTIC leukemia (APL) is a
specific type of acute myeloid leukemia (AML) characterized by the
morphology of blast cells (M3 in the French-American-British
classification of AML,1,2 the t(15;17)
translocation,3 which fuses the PML gene on chromosome 15 to the retinoic acid receptor (RAR) alpha gene on chromosome 17,4,5 and by a coagulopathy combining disseminated
intravascular coagulation (DIC) and fibrinolysis.6,7 Until
recently, intensive chemotherapy (CT), usually combining an
anthracycline and cytosine arabinoside (AraC), was the only effective
treatment for APL.8-11
All trans-retinoic acid (ATRA) can differentiate APL blasts in
vivo and in vitro.12-14 Treatment by ATRA followed by
anthracycline-AraC CT has improved the outcome of APL by slightly
improving the complete remission (CR) rate, but more importantly by
reducing the incidence of relapse.15-21
ATRA is usually well tolerated, but a few major side effects can be
observed, ATRA syndrome being the most important of them. Frankel et
al22 gave the first description of this syndrome in nine of
35 (25%) newly diagnosed APL patients they treated with ATRA. Signs
occurred after 2 to 21 days of treatment and were generally associated
with increasing white blood cell (WBC) count and combined fever, weight
gain, dyspnea, pleural effusion, and pulmonary infiltrates on chest
radiograph and, in some patients, renal failure, hypotension, and
pericardial effusion. Five of the nine patients required transfer to an
intensive care unit and mechanical ventilation, and three patients
died.
In the present report, we analyzed characteristics and outcome of cases
of ATRA syndrome that occurred in 413 patients with newly diagnosed APL
treated by ATRA in a multicenter European trial (APL 93 trial).
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PATIENTS AND METHODS |
Patients with newly diagnosed APL who were included in the APL 93 trial
and developed ATRA syndrome during ATRA treatment form the basis of
this study.
Diagnosis of APL.
Inclusion criteria were as follows: (1) diagnosis of APL, based on
morphological criteria,1,2 (2) age 75 years or less, and
(3) informed consent. Diagnosis had to be subsequently confirmed by the
presence of t(15;17) or PML-RAR gene rearrangement. In the absence
of t(15;17) and if no analysis of the rearrangement could be made,
review of initial marrow slides by an independent morphologist was
mandatory.
APL 93 trial.
Objectives of the APL 93 trial were to assess the optimal timing of
ATRA treatment (before or combined with CT) and the role of maintenance
therapy.
Induction treatment was stratified on age and initial WBC count.
Patients aged  65 years with WBC less than 5,000/µL were randomized
between ATRA followed by CT (ATRACT group) and ATRA plus CT
(ATRA + CT). In the ATRACT group, patients received ATRA 45 mg/m2/d orally until CR or for a maximum of 90 days. After
CR achievement, they received a course of Daunorubicin (DNR) 60 mg/m2/d for 3 days and AraC 200 mg/m2/d for 7 days (course I). However,course I was added to ATRA if WBC raised above
6,000/µL, 10,000/µL, or 15,000/µL by days 5, 10, and 15 of ATRA
treatment, respectively, as from our experience, patients were at risk
of ATRA syndrome above those thresholds.21 CT was also to
be immediately added if clinical signs of ATRA syndrome developed,
irrespective of the WBC count.
Patients randomized to the ATRA + CT group received the same
combination of ATRA and CT, but CT course I was started on day 3 of
ATRA treatment. Patients with WBC >5,000/µL at presentation or aged
66 to 75 and with WBC less than 5,000/µL were not randomized and
received ATRA plus CT course I from day 1 (high WBC group) and the same
treatment as in the ATRACT group (elderly group), respectively.
Patients who achieved CR received two chemotherapy consolidation
courses, including course II (identical to course I) and course III,
consisting of DNR 45 mg/m2/d for 3 days and AraC 1 g/m2 every 12 hours for 4 days. The elderly group, however,
only received course II. Patients were then offered a second
randomization testing both intermittent ATRA (45 mg/m2/d,
15 days every 3 months) and continuous CT with 6 mercaptopurine (90 mg/m2/d orally) and methotrexate (15 mg/m2/week
orally), both scheduled for 2 years, using a(2x2) design. Randomization
was performed through a centralized telephone procedure.
Diagnosis and treatment of the ATRA syndrome.
In the absence of biological diagnostic criteria of ATRA syndrome,
diagnosis of ATRA syndrome was made on clinical grounds by the
association of at least three of the following signs, in the absence of
other causes: fever, weight gain, respiratory distress, lung
infiltrates, pleural or pericardial effusion, hypotension, and renal
failure.22
When ATRA syndrome was suspected, recommendation was made to
immediately start treatment with dexamethasone (DXM) (10 mg/12 hours
intravenously) for at least 3 days. Furthermore, addition of the first
course of CT was scheduled, if CT had not already been started.
Discontinuation of ATRA was recommended if the patient had received at
least 20 days of ATRA. In patients who had received less than 20 days
of ATRA, immediate discontinuation of the drug was also recommended if
ATRA syndrome was life-threatening and did not rapidly improve with CT
and DXM.
Statistical methods.
Predictive factors of ATRA syndrome and the prognostic value of ATRA
syndrome on event-free survival (EFS), relapse and survival, were
analyzed. The following pretreatment parameters were studied: age, sex,
WBC count, platelet count, absolute number of circulating blasts,
M3 subtype (classical M3 v
microgranular variant M3), and fibrinogen level. The
 2 test, Fisher's exact test, and a Cox model were
used. Relapse, EFS, and survival curves were estimated by the
Kaplan Meier method and compared by the log rank test.23-25
| |
RESULTS |
Incidence and clinical features of the ATRA syndrome in APL 93 trial.
Between April 1, 1993 and December 31, 1996, 439 patients from 93 centers were entered in the APL 93 trial. Diagnosis of APL was
confirmed in 413 cases by the presence of t(15;17) translocation (352 cases), PML-RAR rearrangement (30 cases), and review of initial bone
marrow slides (31 cases where cytogenetic analysis was a failure and
molecular analysis could not be performed).
Of the 413 patients, 64 (15%, 95% exact confidence interval [CI]:
12% to 19%) experienced ATRA syndrome during induction treatment. In
two of them, with WBC counts of 186,000 and 38,000/µL upon admission,
respectively, dyspnea, hypoxia, and pulmonary infiltrates were already
present, before the onset of ATRA. Worsening of those signs occurred
within hours on ATRA onset. In the other patients, signs developed
after 1 to 35 days (median, 7 days) of ATRA treatment. They occurred
later than day 14 of ATRA treatment in 21 (33%) patients. In 11 of
those 21 patients, ATRA syndrome was observed upon recovery from the
phase of aplasia that followed the addition of CT (indicated because of
high WBC counts at diagnosis or during treatment).
Twenty-four (16%) of the 151 patients included in the ATRACT
group and the elderly group, ie, who presented with less than 5,000 WBC/µL and were initially treated with ATRA alone, experienced ATRA
syndrome. ATRA syndrome in 22 of them was preceded by an increase in
WBC, which fell in 18 cases (75% of the 24 patients) within our
criteria for adding CT. In the other groups (ATRA + CT and high WBC
groups), the correlation between WBC counts and occurrence of the ATRA
syndrome was difficult to determine because CT had been systemically
rapidly added to ATRA, resulting in a decrease in WBC counts.
Clinical features of ATRA syndrome observed in the 64 patients included
respiratory distress in 57 patients (89%), pulmonary infiltrates in 52 (81%), fever in 52 (81%), weight gain in 32 (50%), pleural effusion
in 30 (47%), renal failure in 25 (39%), pericardial effusion in 12 (19%), cardiac failure in 11 (17%), and hypotension in 8 (12%). All
but one of the patients had at least three of those clinical signs, and
no other explanation to those signs (especially infection). The last
patient had only unexplained fever and pericardial effusion, but this
rapidly resolved with intravenous DXM. He was therefore considered to
have ATRA syndrome and included in the series.
Outcome of ATRA syndrome.
Sixty of the 64 patients who developed ATRA syndrome received CT, based
on WBC counts >5,000/µL at diagnosis, randomization to the ATRA + CT group, or WBC increase with ATRA (above 6,000, 10,000, 15,000/µL
by day 5, 10, or 15 of ATRA treatment, respectively, according to
protocol guidelines). In 53 of the patients, addition of CT had been
made before the onset of clinical signs of ATRA syndrome, whereas in
seven, CT was added when symptoms of ATRA syndrome occurred. In three
of those seven patients, addition of CT should, in fact, have been made
earlier according to protocol guidelines, because of increasing WBC
counts. Finally, four patients did not receive CT even when ATRA
syndrome occurred. In two of them, WBC had increased above thresholds
defined for starting CT before ATRA syndrome developed.
After ATRA syndrome was suspected, 58 of the 64 patients also received
intravenous DXM during a median of 6 days (range, 3 to 23 days). The
duration of DXM treatment was greater than 10 days in nine patients,
due to very slow improvement of signs of ATRA syndrome in five cases,
or very progressive tapering of the doses in the remaining four cases.
In 30 of the 64 patients, ATRA was stopped when ATRA syndrome developed
after 2 to 26 days of ATRA treatment. Thirteen patients required
mechanical ventilation and two hemodialysis.
Fifty-five (86%) of the patients who experienced ATRA syndrome
achieved CR and nine (14%) had early death, after 3 to 21 days of ATRA
(median, 17 days), from ATRA syndrome in five cases, from CNS bleeding in one patient (who had moderate ATRA syndrome), from
sepsis after resolution of ATRA syndrome in two cases, and from
leukemic resistance in the remaining case. Fatal cases due to ATRA
syndrome included one of the four cases and one of the six cases where
addition of CT and DXM, respectively, was not made, and one of the four
cases where addition of CT was delayed. The CR rate was not
significantly lower in patients who experienced the ATRA syndrome than
in patients who had no ATRA syndrome (86% v 94%, P = .07 by Fisher's test). Patients who experienced ATRA syndrome had a
Kaplan Meier estimate of relapse at 2 years of 32% ± 10% as
compared with 15% ± 3% in patients who had no ATRA syndrome
(relative risk [RR]: 1.97; 95% CI: 0.98 to 3.96; P = .05 by
the log rank test). Kaplan Meier estimate of EFS and survival at 2 years were 63% ± 8% and 68% ± 7% in patients who had ATRA syndrome as compared with 77% ± 2% and 80% ± 2% in patients
who had no ATRA syndrome: for EFS, RR = 1.97 (95% CI: 1.25 to 3.11), P = .003 by the log rank test (Fig
1); for survival, RR = 1.78 (95% CI: 1.05 to 3.01), P = .03 by
the log rank test.
Using a stepwise Cox model with ATRA syndrome and all prognostic
baseline covariates, we found that ATRA syndrome remained predictive
for poorer EFS (P = .004; RR = 1.99; 95% CI: 1.12 to 3.23)
along with older age and higher circulating blast counts, for poorer
survival (P = .02; RR = 1.9; 95%CI: 1.12 to 3.23) along with
older age and higher circulating blast counts, but not for relapse
(P = .33; RR = 1.43; 95% CI: 0.7 to 2.95) when considering male gender and higher circulating blast counts.
Of the 55 patients who achieved CR, 17 subsequently received ATRA for
maintenance, but no recurrence of ATRA syndrome was seen in any case.
Predictive factors of ATRA syndrome.
As seen in Table 1, no predictive factor of
ATRA syndrome could be found. There was a nonsignificant trend for
higher incidence of ATRA syndrome in patients randomized to
ATRACT as compared with those randomized to ATRA + CT
(P = .17). No difference was observed according to initial WBC
count or PML/RAR isoform (bcr1, bcr2, bcr3). CD13
expression was not assessed in a sufficient number of patients to
evaluate its prognostic value on the occurrence of ATRA syndrome.
On the other hand, severe cases of ATRA tended to be more frequent in
the high WBC group: 8 of the 13 cases of ATRA syndrome requiring
mechanical ventilation (P = .17) and 8 of the 12 cases of
pericarditis (P = .07) occurred in that group.
| |
DISCUSSION |
The pathophysiology of ATRA syndrome is still poorly understood, but
the proposed mechanisms could involve changes in the cytokine secretion
and adhesive qualities of APL cells during ATRA-induced
differentiation. Some clinical manifestations of the ATRA syndrome
(fever, hypotension, effusions) indeed suggest a role for cytokines,
and the release of several cytokines, including interleukin-1
(IL-1), IL-6, IL-8, and tumor necrosis factor (TNF) , by APL
cells undergoing differentiation with ATRA has been
demonstrated.26-28 Organ infiltration by APL cells found in postmortem studies in ATRA syndrome suggests that ATRA induces APL
cells to acquise leukemic cell-endothelial cell adhesion followed by
extravascular extravasation.22 In vitro, ATRA also leads to
aggregation of APL cells, which appears to be mediated by induction by
ATRA of the expression of high-affinity 2 integrins (especially leukocyte function-associated antigen-1 [LFA-1] and
their counterstructure on the cell surface (in particular intercellular
adhesion molecule [ICAM]-2). Methyl prednisolone rapidly
inhibits APL cell aggregation in a dose-dependent manner, consistent
with its prompt clinical effectiveness in vivo.29
In this multicenter trial that included 413 patients with newly
diagnosed APL, the incidence of ATRA syndrome was 15%. In previously
published reports, this incidence ranged from 6% to 27%30-33 (Table 2). Reasons
for variable incidences among series possibly include differences in
prophylactic approaches. A higher incidence in recent series could also
be due to better recognition of the syndrome since its precise
description by Frankel et al.22 Because diagnosis of ATRA
syndrome remains purely clinical, it may be in some cases difficult to
distinguish from other complications of the disease, particularly
sepsis.
Date of onset of signs of ATRA syndrome was variable in
our experience, as in that of Frankel et al.22 Median time
to occurrence of ATRA syndrome was 10 to 12 days in published series
and 7 days in our experience. A few cases where a clinical picture
resembling ATRA syndrome was observed before the onset of ATRA have
been reported.34 Likewise, in two of our
patients with high WBC counts at presentation, dyspnea, hypoxia, and
pulmonary infiltrates were present before the onset of ATRA, although
they worsened within hours of ATRA onset. Conversely, in 11% of the
cases presented here, ATRA syndrome occurred upon recovery from the
phase of aplasia secondary to the addition of CT (indicated because of
high WBC counts at diagnosis or during ATRA treatment), a circumstance where ATRA syndrome had not been so far reported, to our knowledge.
The clinical picture we observed in the present series of cases of ATRA
syndrome, the largest reported so far, was similar to that reported by
Frankel et al,22 with a great variety in the intensity of
signs, ranging from moderate pleural effusion discovered on chest x-ray
film to major respiratory distress requiring mechanical ventilation.
In the present study, most of the patients who experienced ATRA
syndrome had high WBC counts at diagnosis or had an increase in WBC
counts with ATRA. However, in six of the 24 cases (25%) of ATRA
syndrome that occurred in the ATRACT group and elderly group,
ie, in patients who initially had low WBC counts and were started on
ATRA alone, ATRA syndrome occurred at low WBC counts, below thresholds
established by our group for starting CT. Those thresholds therefore
applied to only 75% of the patients who developed ATRA syndrome in
those two treatment groups (a correlation between evolution of WBC
counts under ATRA and occurrence of ATRA syndrome could not be
determined in other induction treatment groups, where CT was
systematically started early). The WBC count at diagnosis was not a
significant predictive factor of ATRA syndrome, and no other baseline
predictor of ATRA syndrome could be found in our study. On the other
hand, patients presenting with high WBC counts tended to have more
severe forms of ATRA syndrome, more often associated with pericardial
effusion and more often requiring mechanical ventilation. Vahdat et
al30 also found no correlation between preteatment WBC
counts and ATRA syndrome, but observed a correlation between the peak
WBC count and the development of ATRA syndrome. Four of the 21 cases of
ATRA syndrome they observed occurred at WBC counts below
10,000/µL,30 but in three of them, WBC were greater than
5,000/µL when symptoms occurred. These investigators found that the
threshold used by our group for adding CT to ATRA could predict 64% of
the cases of ATRA syndrome, a figure similar to our 75%. Vahdat et
al30 also found that basal expression of CD13 on APL blasts
was strongly associated with both development of the ATRA syndrome, as
well as an elevated WBC count.
We found, in patients who experienced the ATRA syndrome, a trend for a
higher risk of relapse by comparison to other patients with borderline
significance. This finding had not been previously reported, to our
knowledge. Thus, APL blasts, which when exposed to ATRA have biologic
responses capable of triggering ATRA syndrome, may also be more
resistant to the combination of ATRA and CT. Although this is
speculative, cases developing ATRA syndrome may be associated with the
induction of higher expression of adhesion molecules on APL cell
surface by ATRA.29 This would give those cells a higher
tendency to infiltrative disease, especially at extramedullary sites.
This trend for a higher hazard of relapse, combined with the trend for
lower CR rate, explained why patients who experienced ATRA syndrome had
significantly lower EFS and survival than other patients. Furthermore,
using a stepwise Cox model that also included prognostic baseline
covariates, we found that ATRA syndrome remained predictive for EFS and
survival.
Mortality of the ATRA syndrome ranged from 7% to 28% in the
literature and was 8% in the current trial, ie, 1% of all treated patients. In the two other published series that involved more than 100 patients, the overall mortality from ATRA syndrome in APL was in the
range of 1% (Table 2). Because of the severity of
prognosis of the ATRA syndrome once full blown signs have developed, prophylaxis or at least early treatment at the first signs of the
syndrome, are mandatory. Leukaphereses are incapable of sufficiently lowering WBC counts and preventing the ATRA syndrome in
APL,22 and other approaches are required.
One approach, used mainly by European and Japanese
groups,15-18 is to add anthracycline-AraC CT to ATRA from
the onset of ATRA treatment in patients presenting with high WBC counts
or during ATRA treatment if increases in the WBC are seen (Table
2).21 The thresholds used by those groups for adding CT, as
seen above, did not predict all cases of ATRA syndrome. However, the
European and Japanese approach proved effective on a multicenter basis, as the ATRA syndrome seen in 64 of the 413 patients in the APL 93 trial
and seven of 109 patients treated by the Japanese group,18 was fatal in only six of those 522 patients. A disadvantage of this
approach is that about two thirds of the patients treated with ATRA
also received early CT. However, we found that in this case, the
duration of neutropenia and thrombocytopenia was significantly shorter
than when CT was administered alone, an effect that may be linked to
the effect of ATRA on normal granulocytic proliferation and
differentiation.15 Furthermore, intensive CT, if not
administered early, would have to be aministered later on as
consolidation treatment. Finally, first interim analysis of results of
the present APL93 trial suggest a reduction in the incidence of relapse
after ATRA + CT, as compared with ATRA
CT.35 These findings support very early
introduction of CT during induction treatment of APL. Along with these
findings, the Italian GIMEMA group32 and the MD Anderson
group36 are using a prophylactic approach to
the ATRA syndrome where CT is systematically added to ATRA after 2 to 4 days of treatment.
Another approach, mainly used by the New York group and Australian
group,19,30,31 is to prevent fatal cases of ATRA syndrome by administration of high dose intravenous corticosteroids (DXM at 10 mg intravenously twice daily for 3 or more days) as soon as the first
symptoms occur. This treatment proved effective in the New York
experience; although six of the 78 patients treated died of ATRA
syndrome, only one death had occurred in the last 21/2 years of
the study. The Australian group, using the same approach, observed
fatal toxicity from the ATRA syndrome in one of 19 newly diagnosed
patients who received ATRA. This approach avoids the early use of CT
and its side effects. However, it has mainly been used by a few
experienced groups and has not been tested on a large multicenter
basis.
The US intergroup study33 used a somewhat intermediate
approach where single agent CT with hydroxyurea was administered before
ATRA in cases presenting with WBC above 10,000/µL or was added to
ATRA if WBC rose above 30,000/µL, intravenous DXM being started at
the earliest clinical sign of ATRA syndrome. The incidence of ATRA
syndrome (27%) was slightly higher than in European and Japanese
studies, but the outcome was similar (overall incidence of death due to
the ATRA syndrome of about 1%).
All of those approaches are obviously not exclusive. Our group
recommends adding DXM to CT at the earliest sign of ATRA syndrome in
cases presenting with leukopenia, but with rising WBC counts under
ATRA. Finally, there is now a consensus over the fact that patients
presenting with high WBC counts (eg, more than 15,000 to 20,000/µL)
will very often develop severe ATRA syndrome with ATRA alone and should
receive CT and intravenous DXM from the onset of treatment as
prophylactic measures before any symptoms of ATRA syndrome develop.
In conclusion, the advent of ATRA has been a breakthrough in the
treatment of APL. ATRA syndrome, its major side effect, is now well
described. Prophylaxis of severe forms of ATRA syndrome by rapid
addition of CT and/or early use of DXM has reduced the mortality of ATRA syndrome to about 1% of the APL patients treated with ATRA. On the other hand, occurrence of ATRA syndrome still appears
to be associated with lower EFS and survival in APL.
| |
FOOTNOTES |
Submitted January 29, 1998;
accepted June 8, 1998.
Address reprint requests to P. Fenaux MD, PhD, Service des Maladies du
Sang, CHU, 1 Place de Verdun, 59037 Lille, France; e-mail:
pfenaux.Lille{at}invivo.edu.
The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" is accordance with 18 U.S.C. section 1734 solely to indicate this fact.
| |
APPENDIX |
Dr P. Fenaux and Dr L. Degos served as cochairmen and Dr C. Chastang
(Department of Biostatistics, Hopital St Louis, Paris) as
biostatiscian. The following clinical departments participated in the
APL 93 trial.
French APL group.
S. Castaigne, H. Dombret (Paris, St Louis), R. Zittoun (Paris,
Hôtel Dieu), E. Archimbaud (Lyon), P. Travade (Clermont Ferrand), C. Gardin (Clichy), A. Guerci (Nancy), P. Fenaux (Lille), A.M. Stoppa
(Marseille), F. Dreyfus (Paris, Cochin), F. Stamatoulas (Rouen), F. Rigal-Huguet (Toulouse), H. Guy (Dijon), J.J. Sotto (Grenoble), F. Maloisel (Strasbourg), J. Reiffers (Pessac), A. Gardembas (Angers), D. Bordessoule (Limoges), N. Fegueux (Montpellier), A. Buzyn (Paris,
Necker), T. Lamy (Rennes), M. Hayat (Villejuif), E. Deconinck
(Besançon), E. Guyotat (St Etienne), M. Martin (Annecy), E. Cony-Makhoul (Bordeaux), J.P. Abgrall (Brest), O. Reman (Caen), B. Desablens (Amiens), J.L. Harousseau (Nantes), Y. Bastion (Lyon), J.P.
Pollet (Valenciennes), J. Pulik (Argenteuil), M. Lepeu (Avignon), M. Renoux (Bayonne), P. Morel (Lens), P. Henon (Mulhouse), N. Gratecos
(Nice), P. Colombat (Tours), D. Machover (Villejuif), A. Dor (Antibes),
P. Casassus (Bobigny), J. Donadio (Castelnou), B. Salles (Chalon), B. Legros (Clermont Ferrand), P. Audhuy (Colmar), A. Dutel
(Compiègne), N. Philippe (Lyon), B. Benothman (Meaux), C. Christian (Metz), C. Margueritte (Montpellier), F. Witz (Nancy), A. Pesce (Nice), A. Baruchel (Paris, St Louis), L. Sutton (Paris, Pitié Salpétrière), C. Quetin (Pointe à Pitre),
B. Pignon (Reims), E. Vilmer (Paris), E. Bourquard (St Brieuc), J.P.
Marolleau (Paris, St Louis), P. Robert (Toulouse), B. Despax
(Toulouse), G. Nedellec, P. Auzanneau (Paris), and M. Janvier (St
Cloud).
Spanish AML group.
O. Rayon (Oviedo), M. Sanz (Valencia), J. San Miguel (Salamanca), J. Montagud (Valencia), E. Condé (Santander), P. Javier de la Serna
(Madrid), G. Martin (Valencia), M. Perez Encinas (Santiago), J.P.
Torres Carrete (Juan Canalejo), J. Zuazu (Barcelone), J. Odriozola
(Madrid), E. Gomez-Sanz (Madrid), L. Palomera (Zaragoza), L. Villegas
(Almeria), A. Deben (Juan Canalejo), and P. Besalduch (Palma de
Mallorca).
Cooperative AML study group, Germany.
H. Link (Hannover), A. Ganser (Frankfurt), E. Wandt (Nurnberg), A. Breitenbach (Stuttgart), B. Brennscheidt (Freiburg), D. Herrmann (Ulm),
H. Soucek (Dresden), and H. Strobel (Erlangen).
SAKK Swiss AML group.
K. Geiser (Berne), M. Fey (Berne), T. Egger (Berne), and E. Jacky.
Belgian group.
J.L. Michaux (Bruxelles), A. Bosly (Yvoir), E. Meeus (Anvers), and A. Boulet (Mons).
Dutch group.
P. Daenen (Groningen), and P. Muus (Nijmegen).
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Abstract
Introduction
Abstract
