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Blood, Vol. 95 No. 1 (January 1), 2000:
pp. 90-95
CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
Clinical description of 44 patients with acute promyelocytic
leukemia who developed the retinoic acid syndrome
Martin S. Tallman,
Janet W. Andersen,
Charles A. Schiffer,
Frederick R. Appelbaum,
James H. Feusner,
Angela Ogden,
Lois Shepherd,
Jacob
M. Rowe,
Christopher François,
Richard S. Larson, and
Peter H. Wiernik
From Eastern Cooperative Oncology Group, Northwestern University
Medical School, Robert H. Lurie Comprehensive Cancer Center, Chicago
IL; Eastern Cooperative Oncology Group, Harvard School of Public
Health, Division of Biostatistics, Boston MA; Cancer & Leukemia Group
B, Wayne State University, Barbara Ann Karmanos Cancer Center, Detroit,
MI; Southwest Oncology Group, University of Washington, Fred Hutchinson
Cancer Research Center, Seattle WA; Children's Cancer Group,
Children's Hospital Oakland, Oakland, CA; Pediatric Oncology Group,
Texas Children's Hospital, Houston TX; National Cancer Institute of
Canada Clinical Trials Group, Kingston, Ontario; Eastern Cooperative
Oncology Group, University of Rochester, Rambam Medical Center, Haifa,
Israel; Southwestern Oncology Group, University of New Mexico,
Department of Pathology, Albuquerque, NM; Eastern
Cooperative Oncology Group, Our Lady of Mercy Cancer Center, New York
Medical College, Bronx NY.
 |
Abstract |
We examined the incidence, clinical course, and outcome of patients
with newly diagnosed acute promyelocytic leukemia (APL) who developed
the retinoic acid syndrome (RAS) treated on the Intergroup
Protocol 0129, which prospectively evaluated the role of
alltrans retinoic acid (ATRA) alone during induction and as maintenance therapy. Forty-four of 167 (26%) patients receiving ATRA
for induction developed the syndrome at a median of 11 days of
ATRA (range, 2-47). The median white blood cell (WBC) count was
1450/µL at diagnosis and was 31 000/µL (range, 6800-72 000/µL) at the time the syndrome developed. ATRA was discontinued in 36 of the
44 patients (82%) and continued in 8 patients (18%), with subsequent
resolution of the syndrome in 7 of the 8. ATRA was resumed in 19 of the 36 patients (53%) in whom ATRA was stopped and not in 17 (47%). The syndrome recurred in 3 of those 19 patients, with 1 death
attributable to resumption of the drug. Ten of these 36 patients
received chemotherapy without further ATRA, and 8 achieved complete
remission (CR). Among 7 patients in whom ATRA was not restarted and
were not treated with chemotherapy, 5 achieved CR and 2 died. Two
deaths were definitely attributable to the syndrome. No patient
receiving ATRA as maintenance developed the syndrome. (Blood.
2000;95:90-95)
© 2000 by The American Society of Hematology.
| |
Introduction |
Randomized clinical trials have shown that the vitamin
A derivative all-trans retinoic acid (ATRA) significantly
improves the outcome of patients with acute promyelocytic leukemia
(APL).1,2 Although ATRA is generally well tolerated, some
patients develop the retinoic acid syndrome (RAS), manifested by
unexplained fever, weight gain, respiratory distress, interstitial
pulmonary infiltrates, pleural and pericardial effusions, episodic
hypotension, and acute renal failure.3 This syndrome is the
most serious toxicity of ATRA and is often, but not always, associated
with the development of hyperleukocytosis.4-6 It has been
suggested that patients who have a white blood cell count (WBC) that
exceeds 5000/µL on day 1, 6000/µL on day 5, 10 000/µL on day 10, or 15 000/µL on day 15 are at high risk for the development of
RAS.1
The pathogenesis of the syndrome is not completely understood. However,
several possible mediators have been identified, including cathepsin G,
a serine protease that enhances capillary permeability7; cell adhesion molecules on APL cells such as CD15s(Lex) and
integrins CD11a and CD11b, which interact with the
endothelial cell receptor ICAM (intercellular adhesion molecule)-1;
and hematopoietic growth factors such as interleukin (IL)-1 , tumor
necrosis factor (TNF) and IL-6, which promote leukocyte
activation.8-10 Increased expression of IL-1 in leukemic
promyelocytes may induce endothelial cell expression of
ICAM-1 and vascular cell adhesion molecule (VCAM)-1, which may
allow for leukemic cell binding to endothelium.11 Finally,
exposure of the promyelocytic leukemia cell line NB4 to ATRA promotes
formation of leukoaggregates via LFA-1/ICAM-2 interaction, providing
another potential mechanism contributing to the syndrome.12
The best approach to predict, prevent, or treat the syndrome has
not been established. To further characterize this complication, we
examined the incidence, clinical manifestations, lung pathology, clinical course, and outcome of patients with newly diagnosed APL
who developed RAS treated on the National Cancer Institute Intergroup
Protocol 0129, which prospectively evaluated the role of ATRA alone
during induction and as maintenance therapy.2
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Materials and methods |
Treatment with ATRA
Intergroup Protocol 0129 was a prospective trial conducted between
April 1992 and February 1995 in which patients with newly diagnosed APL
established by morphology were randomized to either ATRA 45 mg/m2/d divided into 2 daily doses orally or daunorubicin
45mg/m2 by intravenous (IV) bolus on days 1 to 3 and
cytosine arabinoside 100 mg/m2 by continuous IV infusion on
days 1 to 7 for induction.2 Patients who achieved a
complete remission (CR) received 2 cycles of consolidation chemotherapy. They were then randomized to either maintenance therapy
with daily ATRA 45 mg/m2/d for 1 year or observation.
Patients < 3 years of age were randomized to receive ATRA as just
described or daunorubicin 1.5 mg/kg/d by IV bolus on days 1 to 3 plus
cytosine arabinoside 3.3 mg/kg/d by continuous IV infusion on days 1 to
7. All patients on the ATRA induction arm were required to have a WBC
 10 000/µL either at presentation, or after hydroxyurea, prior to
initiating ATRA. Hydroxyurea was given any time the WBC increased to
 30 000/µL. Patients failing to respond to ATRA for induction
after a maximum of 90 days, or failing before 90 days of ATRA because
of toxicity or progressive disease, were allowed to cross over to the
chemotherapy arm. Patients randomized to induction chemotherapy who did
not achieve CR after 2 cycles did not cross over to the ATRA arm but were removed from the study and treated at the physician's discretion.
Patients
A total of 172 patients were evaluable for analysis on the ATRA arm.
Details of the patient characteristics and outcome have been previously
reported.2 Five of these patients never received ATRA (2 patients crossed over before any treatment, 2 patients were randomized
to ATRA but received chemotherapy, and 1 patient died of
intracerebral hemorrhage after the first dose) and are excluded from this analysis. Forty-four of the remaining 167 (26%; 95% CI, 20%-34%) patients developed definite RAS during induction therapy with ATRA.
Diagnosis of the retinoic acid syndrome
The diagnosis of RAS was made clinically by the presence of
otherwise unexplained fever, weight gain, respiratory distress, interstitial pulmonary infiltrates, and pleural or pericardial effusions during treatment with ATRA. No single sign or symptom itself
was considered diagnostic of the syndrome.3 Cases were identified by reviewing records of patients reported to have a grade 2 or higher pulmonary or cardiac toxicity as well as by reviewing cases
identified by the institution as having the syndrome from adverse drug
reporting. Seven other patients had signs or symptoms consistent with
the syndrome, but all had concurrent medical problems, such as
bacteremia, sepsis, or congestive heart failure, making accurate
diagnosis of RAS impossible. Therefore, these 7 patients were
indeterminate3 and are not included in the cohort of
patients categorized as definitely having the syndrome.
Forty-eight patients treated with chemotherapy who developed grade 2 or
worse pulmonary or cardiac toxicity were analyzed for the presence of a
cardiorespiratory distress syndrome similar to that associated with
ATRA, which has been reported rarely.13 One patient
developed Streptococcal mitus bacteremia with
adult respiratory distress syndrome, 1 had an arrhythmia, 8 sustained substantial declines in the left ventricular ejection fraction, 4 had
fungal pneumonia, 1 had sternal heaviness, and the remainder had either
pneumonia, pulmonary infiltrates of undetermined etiology, fluid
overload, or pleural effusion. One patient had pulmonary infiltrates 2 days prior to study entry with a WBC 34 600/µL and an oxygen
saturation of 85%. On day 1 of chemotherapy, the patient underwent
leukapheresis for a WBC of 42 500/µL and the pulmonary symptoms
resolved, reflecting disease-related pulmonary symptoms.
Treatment of the retinoic acid syndrome
At the earliest sign or symptom of the syndrome, ATRA was to be
discontinued and dexamethasone initiated at 10 mg IV twice daily. If
the syndrome resolved, ATRA was to be reinstituted at 75% of the
initial dose and then escalated to the full dose after 3 to 5 days if
the syndrome did not recur. All but 3 patients were given 10 mg per day
of dexamethasone. Two patients were given 20 mg per day, and 1 was
given 1 mg per day. Among the patients receiving 10 mg per day, the
mean duration of dexamethasone was 9 days (range, 1-49 days). One of
the 2 patients given 20 mg per day of dexamethasone received 1 day of
the drug; the other received 7 days of the drug; and the single patient
treated with 1 mg per day received 17 days of the drug.
Statistical methods
Univariate analyses of the association between ever-developing RAS
and dichotomous predictors were conducted with Fisher's exact test.
Evaluations of the association of continuous predictors and of
multicovariate models were performed with logistic regression (SAS
V6.12). P values <.05 were considered to be significant.
| |
Results |
Clinical characteristics of patients with the retinoic acid
syndrome
Table 1 presents the initial
characteristics of the patients with and without RAS. Briefly, the
median age was 42 years among patients who developed RAS and 35 years
among those who did not. The WBC at diagnosis was slightly lower among
those who developed RAS than those who did not, with medians of
1450/µL and 2000/µL, respectively. One patient (2%) among those
who developed RAS was reported to have the microgranular variant M3v of
APL in the original data set.2 However, more detailed
review for this analysis indicated that another patient had M3v.
Twenty-one (17%) of the cases who did not develop RAS had M3v. Among
those who were evaluated, slightly more than 50% in each group had the
long form of the PML/RAR fusion protein. Three (7%) patients
received hydroxyurea prior to ATRA among those who developed RAS,
compared to 19 (15%) among those who did not. No patients receiving
ATRA for maintenance developed the syndrome.
There was no significant difference in the CR rate between those who
developed RAS (64%) and those who did not (76%), and there was no
difference in disease-free survival between the 2 groups among those
who did achieve a CR (74% and 66% at 3 years, respectively).
Timing of the retinoic acid syndrome
RAS developed after a median of 11 days of ATRA (range, 2-47 days).
White blood cell count at the time of the retinoic acid
syndrome
The maximum WBC count among the 44 patients who developed the
syndrome ranged from 6800/µL to 72 000/µL (median,
31 000/µL).
Major manifestations of the retinoic acid syndrome
The major manifestations (10% incidence) of RAS included
respiratory distress, fever, pulmonary edema, pulmonary infiltrates, pleural or pericardial effusions, hypotension, bone pain, headache, congestive heart failure, and acute renal failure. (Table
2). Mechanical ventilation was required in
26% of patients with the syndrome.
Outcome of the retinoic acid syndrome
All but 2 of the 44 patients were treated with dexamethasone. ATRA
was discontinued when the syndrome developed in 36 of the 44 patients
(82%) and was continued in 8 patients (18%) (Figure 1). The syndrome resolved in all 8 patients
in whom ATRA was continued, but 1 patient died of
intracerebral hemorrhage attributable to the underlying
disease. Among the 36 patients in whom ATRA was stopped, it was resumed
in 19 (53%), 11 (58%) under coverage of steroids. Ten of these 36 patients crossed over to chemotherapy without restarting ATRA, and 8 achieved CR. The syndrome recurred in 3 of 19 patients after
reinstitution of ATRA (2 under coverage of steroids), with 1 death attributable to recurrence of the syndrome, 1 death due to
cardiorespiratory arrest and sepsis, and 17 CRs. Among the 7 patients
in whom ATRA was not resumed and who were not crossed over to
chemotherapy, 5 achieved CR after having received 14, 16, 19, 24, and
26 days of ATRA, and 2 patients died, 1 of intracerebral
hemorrhage due to progressive disease and 1 of multiorgan failure
attributable to the syndrome.
Deaths due to the retinoic acid syndrome
There were 2 deaths definitely attributed to RAS. A 52-year-old man
presented with a WBC count of 3100/µL and developed patchy bilateral
pulmonary infiltrates, fever, and pleural effusions on day 4 of ATRA,
with a peak WBC count of 56 100/µL on day 6. ATRA was discontinued
on day 4, and dexamethasone was administered. ATRA was resumed on day
12 at 75% dose after the syndrome resolved, and the WBC had decreased
to 11 700/µL while he was still receiving tapering doses of
dexamethasone (<10 mg every 12 hours), but ATRA was discontinued
again on day 18 because the syndrome recurred. The WBC had
increased in 24 hours from 8800/µL to 21 300/µL when ATRA was
discontinued the second time and to 55 800/µL on the day of death.
He sustained a myocardial infarction and died on day 20. The second
patient was a 4-year-old girl who presented with a WBC count of
6000/µL and developed a peak WBC count of 58 100/µL on day 10, when hydroxyurea was begun. RAS developed on day 29. Despite 17 days of
dexamethasone (initially started on day 13 for increased intracranial
pressure due to pseudotumor cerebri and tapered beginning on day 27),
she died on day 30 with pulmonary infiltrates and
hypotension.14
Histologic findings in cases with fatal retinoic acid syndrome
We obtained formalin-fixed postmortem lung tissue for histologic
evaluation from the 2 patients who died. The histologic findings in the
lungs of these 2 patients were consistent with the concept that ATRA
therapy led to differentiation, endothelial cell damage, and leukocyte
infiltration into the lung (Figure 2). ATRA
promotes in vitro differentiation of APL cells over a period of days
and, indeed, circulating myeloid precursors at various stages of
differentiation were present in the microvasculature of both cases. An
intra-alveolar myeloid infiltrate was prominent in 1 case and mild in
the other, consistent with the hypothesis that ATRA exposure alters
adhesive properties of differentiating APL cells that may lead to
interaction with the endothelium and extravasation from the
blood.11,12 In the case with a prominent intra-alveolar
infiltrate, additional findings indicative of endothelial cell damage
were present and included intra-alveolar edema, interalveolar
hemorrhage, and fibrinous exudates.
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| Fig 2.
Histologic findings in cases with fatal retinoic acid
syndrome.
(A) Histologic appearance of normal lung tissue. L shows lung
alveolae in normal lung; * indicates normal neutrophil in
microvasculature. (B) Lung tissue showing infiltration of alveolae with
leukocytes from a patient who succumbed to the retinoic acid
syndrome. W shows myeloid cells in the airspace (most
leukocytes to left of "w"); the lobated nuclei of myeloid cells
is prominently seen. Arrows indicate fibrinous exudate due to vascular
leak of serum fibrin.
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Prognostic factors for the development of RAS
It has been suggested that patients with a WBC that exceeds
5000/µL on day 1, 6000/µL on day 5, 10 000/µL on day 10, or
15 000/µL on day 15 are at increased risk for RAS.2
Table 3 presents the number of patients who
met these criteria and whether they ever developed RAS.
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Table 3.
Number of patients whose white blood cell count met
criteria predicting the development of the retinoic acid syndrome
(RAS)
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A total of 110 of 167 patients (66%) met at least 1 of
the criteria, only 31 of whom ever developed RAS. Thus, the sensitivity (probability of meeting the criteria given that a patient ever developed RAS) is 31/44, or 70% (95% CI, 55%-83%), and the
specificity (probability of not meeting the criteria given that a
patient never developed RAS) is only 44/123, or 36% (95% CI,
27%-45%). The overall false-positive rate is 64%, and a number of
patients met 2 or more criteria without ever developing RAS. There is
no discrimination between those who developed RAS and those who did not
with these criteria in this large population. In addition, a
time-varying model that considered the predictive value of WBC at entry
and days 5, 10, and 15 for development of RAS in a subsequent 5-day
period also showed no discrimination between patients who developed RAS
and those who did not.
The on-study characteristics listed in Table 1 were analyzed for their
predictive value for the development of RAS. As noted above, only 1 of
44 patients who developed RAS was confirmed to have M3v at the time the
original manuscript was prepared. However, the subsequent detailed
review for this analysis identified a second patient who had M3v. In
multicovariate logistic regression models, only M3v status was
significantly associated with protection from developing RAS whether
considering 1 of 44 (P = .01) or 2 of 44 (P = .042). Age (P = .27), gender
(P = .60), performance status (P = .60), molecular
break point (P = .82), and receipt of hydroxyurea
prior to ATRA (P = .20) were not associated with the
development of RAS in this population. There was no association of WBC
at diagnosis with duration of the syndrome.
| |
Discussion |
All-trans retinoic acid represents a major advance that has
made APL the most curable subtype of acute myeloid leukemia (AML) in
adults.1,2 However, a major toxicity of ATRA has been RAS.3 Neither the pathogenesis nor the optimal way to
prevent or treat the syndrome has been established.
Among 167 patients with newly diagnosed APL treated with ATRA alone for
induction, RAS developed in 26%. An additional 7 patients may have had
RAS, but this could not be determined because of concurrent medical
problems. None of these indeterminate cases were treated with
corticosteroids. Although the syndrome usually resolved rapidly with
the early administration of dexamethasone even among patients who
continued ATRA, the deaths of 2 patients (5%) were definitely
attributable to the syndrome. The incidence of the syndrome has varied
in other reports from 5% to 27% and the mortality from 5% to
29%.6,13-19 (Table 4). A
cohort of patients similar to that reported here, treated with ATRA
alone, had a similar incidence of 27%.6 However, the
mortality rate of patients with the syndrome in the present report is
substantially lower (5% vs 29%), likely reflecting the earlier
recognition and institution of dexamethasone, as experience with ATRA
has accumulated.
The concurrent administration of chemotherapy with ATRA may decrease
the incidence of the syndrome. However, this has not clearly been
established. In the first report of the AIDA (all-trans retinoic acid plus idarubicin) trial, in which all patients receive idarubicin concurrently with ATRA, the incidence of the syndrome was
10%.17 As the experience with concurrent ATRA plus
idarubicin expanded, the incidence of the syndrome
decreased.18 Among 240 patients treated with the AIDA
regimen in the most recent trials, only 6 (3%) patients developed the
syndrome and 1 patient died. An additional 11 patients had a
constellations of signs and symptoms that led to an
"indeterminate" classification. The incidence of the syndrome in
the Japanese Adult Leukemia Study Group (JALSG) trial, in which
chemotherapy was introduced early for the prevention of
hyperleukocytosis, was 11 of 196 patients (6%) with 1 death, which
occurred early in the trial when there was less experience with the
syndrome.19 An overall incidence of 15% was reported by
the European APL group, with a mortality rate of 8% of patients with
the syndrome.13 No difference in the incidence of the
syndrome was observed among patients treated with concurrent versus
sequential ATRA and chemotherapy. In this trial, some patients received
concurrent chemotherapy for a rapidly rising WBC count. These series
suggest that although the incidence of RAS may be reduced, the
mortality rate due to the syndrome is low and is not different than the mortality in our series when the syndrome is recognized and treated early.
There were no pretreatment variables predictive of the syndrome,
including median age, gender, WBC count, or breakpoint
location20 except for M3v. Patients with M3v appear to be
protected from the syndrome, but the reason(s) is not clear.
Furthermore, we did not find a WBC count above 5000/µL on day 1, or
above 6000/µL, 10 000/µL, or 15 000/µL on days 5, 10, or 15 of
ATRA, respectively, predictive for the development of the syndrome, as
was observed by Fenaux and colleagues.21 Similarly, Vahdat
and colleagues found that the initial WBC count as well as the rate of
rise was not statistically correlated with the development of the
syndrome.6
The pathogenesis of the syndrome has not been completely determined.
However, the autopsy findings reported here provide insight. The
constellation of histologic findings (edema, hemorrhage, fibrinous exudates, and leukocyte infiltration) likely results from
microvasculature damage, because similar histologic findings are seen
in a variety of diseases, including trauma, sepsis, and the adult
respiratory distress syndrome.22-27 The final common
pathway is an insult to the endothelium followed by a predictable
series of events, including edema, hemorrhage, fibrinous exudates,
neutrophilic infiltration, and respiratory failure.
Patients with AML and hyperleukocytosis with pulmonary compromise may
have indistinguishable clinical presentations from patients with APL
who develop RAS. However, in cases of AML with hyperleukocytosis, pulmonary compromise appears to result primarily from formation of
leukoaggregates in the circulation.28 In contrast, Frankel et al reported leukocytic infiltration without leukoaggregate formation
in 2 cases of RAS.3 The histologic findings in the 2 fatal
cases of RAS reported here were identical to those described by Frankel
et al.3 Taken together, these observations indicate that
different cellular and molecular mechanisms cause RAS in contrast to
leukostasis in AML, although the clinical scenario is similar.
Migration of leukocytes into tissue such as lung is important in the
pathogenesis of RAS, but leukemic cell adhesion to each other and the
formation of leukoaggregates may be important in leukostasis in AML.
Strategies to prevent the syndrome have been explored. Wiley and Firkin
tested the prophylactic administration of corticosteroids in 12 patients whose WBC rose above 10 000/µL on
ATRA.15 None of these 12 patients developed
any pulmonary toxicity despite a peak WBC count of up to 112 000/µL.
Although this decreased incidence compared to other trials suggests a
benefit, the number of patients studied was small, and no prospective
randomized trial has been conducted.16-18 Two groups of
investigators have reported the use of a lower dose of ATRA. Castaigne
and colleagues showed that the administration of a lower dose of ATRA
of 25 mg/m2/d resulted in a similar CR rate and similar
toxicity profile, including a similar incidence of RAS as the standard
dose.29 However, an even lower dose of 15-20 mg/m2/d appeared to result in less frequent development of
the syndrome.30 Whether novel retinoids such as
9-cis retinoic acid and AM-80 will be associated with a
decreased incidence of the syndrome is not known.31,32
Several observations regarding the clinical course of patients with the
syndrome can be made. First, ATRA need not necessarily be discontinued
if RAS develops, providing that dexamethasone is instituted at the
earliest sign or symptom. ATRA was continued in 8 patients and, in 7 of
the 8 patients, the syndrome resolved and CR was achieved uneventfully.
However, the success of that approach may depend on the severity of the
syndrome and the rapidity of institution of dexamethasone. Second, ATRA
can be successfully reintroduced following resolution of the syndrome
without concomitant steroids. The ability to resume ATRA may be
attributable to suppression of cytokines by corticosteroids together
with a continuous reduction in the cell burden. However, the syndrome
can recur despite prophylactic steroids, and it led to the death of 1 patient in this series. Third, there does not appear to be a risk of
the syndrome when ATRA is given as maintenance therapy to patients in
CR. This issue is important because recent data suggest the value of
maintenance ATRA, even in patients who present with WBC counts
5000/µL.2,16 Finally, mortality from the syndrome is
now very low.
What, then, is the recommended approach to prevent and treat the
syndrome? Because recent data suggest that concurrent ATRA plus
chemotherapy may prevent relapse, and because the incidence of the
syndrome may be lower, this approach is emerging as a
routine strategy for all patients.16 Prophylactic
corticosteroids cannot be recommended for routine use at the
present time. Studies evaluating the role of corticosteroid prophylaxis
are underway. If moderate or severe RAS develops, it is prudent to
discontinue ATRA. Prompt administration of dexamethasone is critical,
not only when the diagnosis is definitively established, but also at
the first sign of unexplained dyspnea, fever, weight gain, or pulmonary
infiltrate. When the syndrome resolves, ATRA can safely be restarted in
most patients; however, continued close observation is warranted.
Further studies of growth factor expression and modulation of adhesion molecules may provide further insights into the pathogenesis of the
syndrome and lead to its prevention.
| |
Footnotes |
Submitted March 29, 1999; accepted September 1, 1999.
Study was coordinated by the Eastern Cooperative Oncology Group (Robert
L. Comis, Chair) and supported in part by US Public Health Service
grants CA17145, CA23318, CA31983, CA20319, CA03161, CA11083, CA32102,
CA14958, CA66636, and CA21115 from the National Cancer Institute,
National Institutes of Health, Bethesda, MD, and the US Department of
Health and Human Services. Its contents are solely the responsibility
of the authors and do not necessarily represent the official views of
the National Cancer Institute.
Reprints: Martin S. Tallman, Northwestern University
Medical School, Division of Hematology/Oncology, Department of Medicine, Robert H. Lurie Comprehensive Cancer Center, 233 East Erie
St, #700, Chicago, IL 60611; e-mail: m-tallman{at}nwu.edu.
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 meeting of the American Society of
Hematology, San Diego, CA, December 1997.
| |
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Abstract
Introduction