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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 95 No. 2 (January 15), 2000:
pp. 398-403
CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
Molecular analysis and clinical outcome of adult APL patients with
the type V PML-RAR isoform: results from Intergroup protocol 0129
James L. Slack,
Cheryl L. Willman,
Janet W. Andersen,
Yun-Ping Li,
David S. Viswanatha,
Clara D. Bloomfield,
Martin S. Tallman, and
Robert E. Gallagher
From the Department of Medicine, Roswell Park Cancer Institute,
Buffalo, NY; Department of Pathology, University of New Mexico Cancer
Center, Albuquerque, NM; Department of Biostatistics,
Harvard School of Public Health, Boston, MA; Departments of
Oncology and Medicine, Montefiore Medical Center and Albert Einstein
Cancer Center, Bronx, NY; Department of Medicine, The Ohio State
University Comprehensive Cancer Center, Columbus, OH; and Department of
Medicine, Northwestern University Medical School, Chicago, IL.
 |
Abstract |
The type V (for variable) promyelocytic leukemia
retinoic acid receptor (PML-RAR) transcript, found in approximately
8% of adult patients with acute promyelocytic leukemia (APL), is
defined molecularly by truncation of PML exon 6 and frequent insertion of genetic material from RAR intron 2. To more fully characterize the molecular features of PML-RAR V-type transcripts and to
determine whether V-form APL patients have a distinct clinical
presentation or prognosis, we analyzed 18 adult V-form APL patients
enrolled on Intergroup protocol 0129 (INT-0129). Truncations in PML
exon 6 ranged from 8 to 146 nucleotides, and 3 to 127 extra nucleotides (1 to 42 extra amino acids) were inserted at the PML exon 6/RAR exon
3 junction in 13 cases. No distinguishing morphologic, cytogenetic, or
immunophenotypic features of V-form blasts were identified. A total of
5 of 7 patients induced with ATRA and 8 of 11 patients who received
chemotherapy for induction achieved complete remission (CR). Six
patients have relapsed, 4 after chemotherapy induction and 2 after
ATRA. Nine patients (50%) are alive, 6 in continuous CR, 2 after
salvage therapy for relapsed or refractory disease, and 1 after
alternative treatment following early removal from protocol. Although
the failure rate for V-form APL patients was high (61%), the low power
of the current study to detect clinically significant differences
precludes a meaningful comparison of clinical outcomes between the 18 V-form cases and non-V-form adult APL patients enrolled on INT-0129.
(Blood. 2000;95:398-403)
© 2000 by The American Society of Hematology.
| |
Introduction |
Acute promyelocytic leukemia (APL) accounts for
approximately 10% of all cases of acute myeloid leukemia (AML). It is
highly curable with combined differentiation/cytotoxic
therapy1 and is perhaps the best understood subtype of AML
at the molecular level. The defining genetic feature of APL is
disruption of the retinoic acid receptor (RAR) gene, at 17q12, and
fusion of RAR with 1 of 4 partner genes.2 In more than
99% of APL cases, RAR is fused to a gene termed PML,
located at 15q22, and the resulting promyelocytic leukemia (PML)-RAR
fusion protein is felt to be responsible for the development of APL. At
the messenger RNA (mRNA) level, different numbers of PML 5' exons
are fused with RAR exons 3 through 9 to create 3 structurally
distinct PML-RAR fusion transcripts, the so-called L (long), V
(variable), and S (short) isoforms (Figure
1A). The oncogenic potential of all 3 PML-RAR isoforms derives from their ability to inhibit, in a
dominant negative fashion, both PML-dependent- and RAR-dependent signaling pathways. This inhibition of native PML and RAR function leads to a block of myeloid differentiation, inhibition of apoptosis, and ultimately to the APL phenotype.
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| Fig 1.
Schematic representation of PML breaksites and PML-RAR
fusion mRNAs.
(A) The 3 PML breakpoint cluster regions
(bcr-1, -2, and -3) are indicated by vertical arrowheads, and the
resultant L, V, and S PML-RAR isoforms are diagrammed. PML exons are
indicated by numbered, shaded rectangles. The positions of primers used
to amplify PML-RAR mRNA are indicated below their respective exons.
(B) PCR products were electrophoresed and visualized by
staining with ethidium bromide and then transferred to nylon membranes
and hybridized with junctional probe PR. In L-form APL, as well as in
the NB4 cell line, the PML breaksite is in intron 6 (bcr-1), and
full-length PML exon 6 is fused in-frame to exon 3 (Ex 3) of RAR.
In such cases, primers P2 and R2 generate a 283-bp chimeric PCR product
that is detected by hybridization to the junctional oligonucleotide
probe, designated PR (lanes L1, L2, NB4). V-form cases, by definition,
lack variable amounts of terminal exon 6 sequence and give
variable-sized bands with primer set P2/R2 (panel B, lanes V1-V5). In
most cases, due to loss of exon 6 sequence, the amplicon is smaller
than 283 bp (ie, V2, V3, V5); however, due to insertion of genomic DNA
from RAR intron 2, the amplified fragment can be larger (case V1) or
essentially the same size (case V4) as the 283-bp L-form fragment.
These latter V-form cases are distinguished from L-form cases by lack
of hybridization to the PR probe, and/or by sequencing the P2/R2
amplicon.
|
|
Although all 3 PML-RAR isoforms lead to APL in humans, there are
clinical and biochemical differences among them.3-6 The type V PML-RAR isoform, which is the subject of this report, is
found in approximately 8% of adult patients with APL3 but is significantly more common in pediatric APL.7,8 This
PML-RAR V isoform results from either an aberrant splicing event or
from a genomic break in PML exon 6 (or, rarely, in PML exon 5); the molecular consequence, in both cases, is loss of coding DNA from the
distal region of PML exon 6 (or loss of all of exon 6), often with
insertion of genomic DNA from RAR intron 2. The presence of
potential phosphorylation sites and of a caspase cleavage
site9 in the distal region of PML exon 6 lends scientific
support to the hypothesis that PML exon 6 truncations may influence the
function of the PML-RAR oncoprotein and thereby influence response
to treatment. Indeed, a recent study reported that the extent of truncation of PML exon 6 correlated with APL blast sensitivity to
all-trans retinoic acid (ATRA) in vitro.10 Because
adult V-form APL cases are rare, and because of the suggestion that some V-form APL blasts may be ATRA-resistant, we present here the
clinical and molecular features, and response to therapy, of 18 adult
V-form APL patients who were enrolled on Intergroup protocol 0129 (INT-0129).1 This is the largest combined molecular and
clinical study of the rare V-form subtype of APL, and our results
suggest that, although such patients have a high failure rate, they
nevertheless have a long-term survival that does not appear to differ
significantly from that of other adult APL cases.
| |
Materials and methods |
Patients
INT-0129 was a comparison of induction therapy of APL with ATRA
alone versus chemotherapy with daunorubicin and ara-C
(DA), with a subsequent randomization of patients achieving complete remission (CR) to 1 year of maintenance ATRA or
observation.1 A total of 401 patients were enrolled, and
350 were evaluable; 230 evaluable adult patients (82% of evaluable
adult patients) enrolled on INT-0129 by Cancer and Leukemia Group B
(CALGB), the Southwest Oncology Group (SWOG), and the Eastern
Cooperative Oncology Group (ECOG) had reverse-transcription polymerase
chain reaction (RT-PCR) performed on a pretreatment bone marrow or
blood sample. Among these 230 patients, 18 (8%) expressed the
PML-RAR V isoform and are described in detail here. The clinical
data in this report are based on information received at the ECOG data
management center as of January 23, 1999.
Flow cytometry, cytogenetics, and molecular analyses
Flow cytometric and cytogenetic analyses were performed by
laboratories affiliated with the respective cooperative groups. Karyotypes were reported according to guidelines of the International System for Human Cytogenetic Nomenclature,11 and
immunophenotypic analyses were carried out using standard antibody
combinations.12 The details of the RT-PCR procedure for
detection of PML-RAR and documentation of the V isoform have been
previously published.3
Statistics
The coding of CR is based on remission status on the initial
induction regimen. One patient randomized to ATRA who failed to achieve
a CR after 6 weeks of treatment is coded as a nonresponder even though
CR was achieved after cross over to DA. For purposes of this report, 1 patient randomized to ATRA who received only DA induction is analyzed
with the DA arm. Disease-free survival (DFS) is calculated from the
date of induction CR to documented relapse or to censoring. DFS was
censored if the subject was in continuing remission at the last update.
However, if off-study treatment was initiated in a patient in CR, DFS
was censored at that date. Data regarding off-study treatment (ie, bone
marrow transplant) were not available in most instances. Univariate
analyses testing the association of categorical variables were
performed with the Fisher exact test. DFS and survival curves were
estimated by the method of Kaplan and Meier.13
| |
Results |
Molecular analysis
Figure 1 shows the position of primers used in RT-PCR to identify
APL patients with the PML-RAR V isoform. The initial
PCR was performed with primers from PML exon 3 and RAR
exon 3 (P1/R1), followed by a nested PCR with primers from
the proximal regions of PML exon 6 and RAR exon 3 (P2/R2; Figure
1A). Electrophoretic analysis, hybridization with a junctional probe
(Figure 1B) and, ultimately, sequencing of PCR products allowed
determination of the extent of PML exon 6 truncation and of the nature
of inserted sequences, if any. Table 1
presents detailed molecular data for the 18 INT-0129 V-form APL
patients. In 4 cases (C902, E003, E011, and E801) and in 4 of 12 previously described V-form cases,10,14-16 PML exon 6 was
truncated at nucleotide 1685, 54 base pairs (bp) upstream of the normal
exon 6/intron 6 boundary; there were no inserted bases in any of these
8 cases. Because a 5' splice site donor consensus sequence
(gtgag) follows nucleotide 1685, it is likely that the PML
genomic breakpoint in these cases is 3' to nucleotide 1685, possibly in PML intron 6, and that the truncated PML exon 6-RAR exon
3 fusion results from an aberrant splicing event. This proposed event,
diagrammed in Figure 2A, results in the
loss of 54 nucleotides (18 amino acids) from PML exon 6 and in the
production of a novel threonine residue at the PML-RAR junction
(Figure 2A and Table 1).
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| Fig 2.
Proposed mechanisms of PML exon 6 truncations in V-form
APL.
In (A), represented by cases C902, E003, E011, and E801, the PML
exon 6 fusion site is 54 bp 5' of the normal PML exon
6/intron 6 boundary (at nucleotide 1685), but the PML genomic
breakpoint is 3' of nucleotide 1685, either in the distal
region of PML exon 6 or in intron 6. The loss of 54 nucleotides
from exon 6 occurs as a result of an aberrant splicing event. The
cryptic 5' splice donor site (gtgag) is shown. Only
the relevant PML and RAR exons are shown for clarity. In (B), the
molecular events responsible for case S386 are diagrammed. The PML
genomic break is in exon 6 at nucleotide 1711, and the RAR
break is in intron 2 at bp -287 relative to the exon
3 boundary. The processed mRNA contains a 19-nucleotide insertion
from RAR intron 2 (underlined) that results from use of a cryptic 5'
splice donor site (gtgat) 19 bp downstream from the breaksite. Genomic
sequence that is spliced out is shown in lowercase type. Six
novel amino acids and a new junctional amino acid (Ser) are
incorporated in the final PML-RAR protein and are shown in
bold.
|
|
In 13 of the remaining 14 V-form INT-0129 cases, and in 6 additional
cases reported previously,15,16 the PML breaksite is within
PML exon 6, and there are variable numbers of additional nucleotides
inserted between the PML exon 6/RAR exon 3 junction (Table 1). By
comparison to DNA sequence deposited in GenBank, the origin of the
inserted sequences could be ascertained in 5 of the 8 cases in which
there were more than 10 inserted nucleotides. The inserted DNA in cases
C205 and S386 originates from the distal portion of RAR intron 2, 19, and 287 nucleotides 5' of the intron 2/exon 3 boundary,
respectively (GenBank accession AF088 890.1). Cases S448 and E036
contain an identical stretch of 18 nucleotides that maps to the
proximal region of RAR intron 2313 nucleotides from the exon
2/intron2 boundary (GenBank AF088 889.1). The RAR intron 2 breaksites in these 2 cases are 7 bp apart, and the resulting PML-RAR isoforms contain an identical stretch of 6 novel amino acids
(AspThrGlnValGlyAla; Table 1). The inserted sequence in case C183 is
homologous (39 out of 40 identical bases) to exon 1 of mouse and rat
RAR isoform 2,17 mapping the genomic breakpoint in this
case to exon 1 of human RAR isoform 2. Thirteen amino acids from
this exon are included in the resulting C183 PML-RAR fusion protein.
A diagram of the molecular events responsible for these cases, using
S386 as an example, is shown in Figure 2B. Case E091 is anomalous in
that it does not contain additional inserted sequence, nor does it
appear to have a cryptic splice donor site.
Patient data
The 18 V-form patients included 10 women and 8 men (Table
2). The median age was 33.5, and the median
white blood cell count at presentation was
4.05 × 109/L (range,
0.70 × 109/L to
68.6 × 109/L). Eight of 18 (44%)
V-form patients had white cell counts >5 × 109L,
and 5 (28%) had white cell counts >10 × 109L.
For comparison, 35 of 92 (38%) S-form, and 25 of 121 (21%) L-form
cases, had white cell counts >5 × 109L
(P = .04, L vs V). Three patients had an ECOG performance
status  2 (Table 2).
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|
Table 2.
Pretreatment demographic, hematologic, and cytogenetic
characteristics of 18 V-form APL patients on Intergroup protocol
0129
|
|
Cytogenetic analysis was successfully completed in 15 patients (Table
2). Although 13 patients had the t(15;17)(q22;q12), the other 2 patients lacked this abnormality patient E003 had an apparently normal
karyotype (although only 8 metaphases were available for analysis), and
patient E011 had primarily normal metaphases with a minor clone showing
trisomy 13. Four of the 13 t(15;17)-positive patients (30%) had 1 or
more additional chromosomal abnormalities (Table 2), and all 4 either
failed induction therapy or relapsed (Table
3). Immunophenotypic information was
available for most patients; no consistent differences in surface
antigen expression could be detected between the V-form patients and
APL patients described in other series. Two cases (E003 and E091) had
relatively high CD11b expression (expression on 72% and 32% of blast
cells, respectively), which is uncommon in APL. One patient (E003)
expressed CD2, and another (C205) expressed CD34 at high levels. All
cases examined were HLA-DR-negative, and no case expressed CD56.
Treatment and outcome
Among the 18 V-form patients, 11 received chemotherapy (DA)
induction, and 7 received ATRA (Table 3). One patient (E086) was
randomized to receive ATRA for induction but did not receive the drug
and was given DA because of hydrea-resistant leukocytosis. Twelve of
the 18 patients overall (67%) achieved a documented CR5 of the 7 ATRA-treated patients and 7 of the 11 patients induced with DA (95%
CI, 41%-87%). One additional patient (C205) achieved an undocumented
CR. Six of the 13 CR patients (46%) have relapsed at a median of 20 months after attainment of CR4 after induction with DA and
2 after induction with ATRA (Table 3). As of the date of this
analysis (January 23, 1999), 9 of the 18 patients are alive.
Figure 3 shows DFS and overall survival of
the V-form cases. Of the total group of 18 V-form patients, 11 (61%)
either failed induction therapy or relapsed after achieving CR. The
median DFS for all patients is 36 months.
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| Fig 3.
Kaplan-Meier analysis of DFS and overall survival of
V-form APL cases on INT-0129.
DFS survival is indicated by the solid line, overall survival, by the
dotted line.
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Influence of PML exon 6 break/fusion site on response to ATRA
In a previous study,10 blasts from V-form patients with
large PML exon 6 truncations were found to be relatively resistant to
ATRA in vitro. Thus, it was of interest to examine whether such
"E6-short" (E6S) patients (defined here as patients with loss of
54 nucleotides from PML exon 6) had a poorer clinical response to
ATRA than patients with loss of fewer than 54 nucleotides from PML exon
6 ("E6-long," or E6L patients) or if E6S patients had an overall
poorer prognosis. There were 9 patients in each subgroup. The median
age was 25 (range, 19-66) for the E6S patients and 41 (range,
19-57) for the E6L group (P = .07). The median white cell counts were 4.8 × 109/L (range,
0.90 × 109/L to 77.4 × 109/L)
and 3.3 × 109/L (range,
0.90 × 109/L to 68.6 × 109/L),
respectively (P = 0.6). Of the 9 E6S patients, 3 failed
induction, and 2 of these failures were in response to ATRA (patients
E076 and E003; Table 3). Patient E076, whose blasts were relatively ATRA-resistant in vitro,10 received only 3 weeks of ATRA
due to development of a fungal infection. Case E003, which has been discussed in detail elsewhere,10 received ATRA for 42 days
without achievement of CR but attained CR after crossover to
DA. At diagnosis, no t(15;17)-positive cells were seen out of 8 metaphases examined (material was not available for fluorescence in
situ hybridization [FISH] analysis). At relapse, PML-RAR was not
detected, suggesting that patient E003 may have had a chimeric form of
APL from the outset. The other case whose blasts were tested and found
to be ATRA-resistant in vitro (E011) received induction with DA (Table 3), and thus the ATRA sensitivity of this case in vivo could not be
assessed. In the E6L group, there were 2 induction failures, both in
response to DA (of 6 who received DA induction), and all 3 E6L patients
treated with ATRA achieved CR. A total of 4 and 5 patients of 9 are
alive, respectively, in the E6S and E6L subgroups (Table
3).
| |
Discussion |
Almost all cases of APL result from a chromosomal translocation that
fuses the RAR gene, at 17q12, with the PML gene, located at
15q22. The genomic breakpoints in RAR are distributed within the
second intron of that gene, in an apparent random distribution; although the issue has received limited attention, there is no compelling evidence for recombination "hotspots" flanking the RAR breakpoint sites. In contrast, the breakpoints in the PML gene are found in 3 distinct breakpoint cluster
regions: bcr-1, which encompasses PML intron 6; bcr-2, which
includes PML exons 5 and 6; and bcr-3, which spans the small (about 1 kb) PML intron 3.14,15,18 The clustering of breakpoint
sites in the PML genomic locus produces 3 distinct types of PML-RAR
transcriptsthe short (S), long (L) and
variable (V) isoformsthat appear to have subtly different
behavior both in vitro5,6,10 and in vivo. For example,
compared with L-form cases, both S- and V-isoform APL patients tend to
have higher presenting white cell counts;3 in addition,
S-form cases have more frequent secondary cytogenetic changes,4 and express a different profile of cell surface
antigens, than L-form cases.8,19 The distal region of PML
exon 6, which is variably lost in V isoform cases, and is always lost
in S-form APL, is serine/proline-rich and thus likely to be heavily
phosphorylated; it also contains a caspase cleavage site that has been
shown to mediate retinoid-induced, caspase-mediated, degradation of
PML-RAR.9 When overexpressed in vitro, the S isoform is
resistant to retinoid-induced degradation,5 possibly due to
loss of the PML exon 6 caspase cleavage site. Although no in vitro data
are available regarding the specific issues of stability or function of
the different V-form PML-RAR transcripts, it is possible that
altered phosphorylation or loss (or altered function) of the caspase
cleavage site imparts subtle biological differences to V-form APL
blasts, as previously suggested in studies of leukemic samples from
V-form patients.10 In addition, and although speculative,
the insertion of entirely foreign amino acids in many V-form
transcripts might be expected to generate a more robust immune response
in these patients.
The rarity of adult V-form APL, and its frequent inclusion with L-form
(bcr-1) patients in other series, has until now prevented a
comprehensive description of such cases at both a clinical and molecular level and has precluded an analysis of response to therapy and outcome of V-form APL patients after modern retinoid-based therapy.
The median age (33.5 years) of V-form APL patients in this study, while
somewhat lower than generally seen in other adult APL series, was not
statistically different from the median age of L- or S-form patients
enrolled on INT-0129 from the 3 adult cooperative groups.3
Nevertheless, a trend toward younger age of V-form cases is consistent
with the more frequent occurrence of V-form APL in children, an
observation that remains unexplained.7,8 As noted earlier,
there was also a trend toward higher presenting WBC counts in V-form
patients as compared with L-form patients. These 2 trends were
the only distinguishing clinical features that tended to separate
V-form APL patients from other patients with APL.
The striking difference occurs at a submicroscopic level and involves
molecular events that produce individually unique PML-RAR isoforms.
The analyses of V-isoform cases reported here and
elsewhere10,14-16 document these molecular events and
highlight 2 possible mechanisms of PML exon 6 truncations. In the first
mechanism, diagrammed in Figure 2A, the distal region of exon 6 is lost
due to an aberrant splicing event that removes the terminal 54 nucleotides. It is presumed, though not formally proven, that the PML
genomic break in these cases is in the distal region of PML exon 6, or
possibly in PML intron 6 (ie, in bcr-1). In the second mechanism,
diagrammed in Figure 2B, the PML breaksite lies within exon 6 (or, in 1 case, in exon 5; reference 16). The truncated exon lacks an acceptable splice donor site, but the situation is remedied by use of an "unnatural" but functional splice donor site in RAR intron 2. The reading frame is preserved by inclusion of variable numbers of
bases from RAR intron 2 in the final, processed PML-RAR
transcript and inclusion of variable numbers of "foreign" amino
acids in the final PML-RAR fusion protein. As discussed above,
whether the presence of these additional amino acids affects the
function of the resultant PML-RAR protein is unknown.
One of the purposes of this report was to follow up on a previous
correlative laboratory observation that blasts from a subset of APL
V-form patients, primarily those with the largest exon 6 deletions,
were ATRA-resistant in vitro.10 In the current clinical
study, 7 patients received induction therapy with ATRA alone, and 5 of
these patients achieved CR. Of the 2 patients who failed ATRA therapy,
1 (E076) received an abbreviated 3-week course due to development of a
fungal infection. The other patient (E003) appeared to be truly
ATRA-resistant but had a highly unusual, possibly chimeric, type of
leukemia. In this case, the PML-RAR-positive clone appears to have
been successfully eradicated because, at relapse, the patient had no
detectable PML-RAR-positive cells. The PML-RAR transcripts from
patients E076 and E003 had relatively large exon 6 truncations (61 and
54 nucleotides, respectively), and blasts from both patients were
relatively ATRA-resistant in vitro.10 Overall, however, too
few patients with large PML exon 6 truncations were treated with ATRA
alone on this study to adequately test the hypothesis that such
patients as a group are ATRA-resistant in vivo. In this analysis of 18 V-form cases, which is the largest reported series to date, there was
no suggestion that the extent of PML exon 6 truncation, or the type of
insertion, had a significant influence on clinical outcome.
Our previous suggestion20 that V-form APL patients as a
group might have a poor prognosis is both supported and challenged by
the mature outcome data reported here. Although the incidence of
treatment failure in the V-isoform patients was high (11 of 18, or
61%, either failed induction or relapsed), 9 of 18 (50%) remain
alive6 in continuous CR, 2 after salvage therapy, and 1 after
receiving therapy off protocol. Because 8 of the 18 patients never
received ATRA on protocol (although several of the 8 may have received
ATRA for salvage therapy) and because the prognosis of APL patients
treated with chemotherapy alone remains poor,1 the high
failure rate of the V-form patients seen here may reflect their
overall minimal exposure to ATRA. Despite the high early failure rate,
the 50% overall survival of V-form cases cannot, given the small
numbers of patients and the caveat just noted, be considered different
from the survival of non-V-form adult APL patients enrolled on
INT-0129. Thus, although it remains possible that V-form APL patients
are a poor prognosis group, further study of larger numbers of
uniformly treated patients will be required to confirm or refute this
hypothesis. Such a study might most profitably be pursued in the
pediatric population, where the incidence of V-form APL is
significantly higher than in adults.
| |
Acknowledgments |
The authors thank the individuals at each participating CALGB, SWOG,
and ECOG institution for their role in patient care and in procurement
and analysis of specimens for this study. We specifically thank Drs
David Head (SWOG), Frederick Davey (CALGB), and John M. Bennet (ECOG)
for pathologic analysis and Drs Elizabeth Paietta (ECOG) and Carlton
Stewart (CALGB) for immunophenotype data.
| |
Footnotes |
Submitted July 23, 1999; accepted September 21, 1999.
Supported by National Cancer Institute grants CA59518-04, CA23318,
CA31946, CA77658, CA16058, and CA56771 and the Coleman Leukemia
Research Fund.
Reprints: James L. Slack, Roswell Park Cancer Institute,
Department of Medicine, Elm and Carlton Sts, Buffalo, NY 14263; e-mail:
james.slack{at}roswellpark.org.
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 38th annual meeting of the American Society of
Hematology, Orlando, FL, December 6-10, 1996, and was
published in abstract form in Blood 1996;88:635a (abstract 2528). This
study is based on an Intergroup clinical trial (INT-0129) involving
participation of the Cancer and Leukemia Group B (Richard L. Schilsky,
Group Chair), Eastern Cooperative Oncology Group (Robert L. Comis,
Group Chair), and the Southwest Oncology Group (Charles A. Coltman,
Group Chair).
| |
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Abstract
Introduction