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Blood, Vol. 93 No. 9 (May 1), 1999:
pp. 3081-3087
Correlation of Bcl-2 Rearrangement With Clinical
Characteristics and Outcome in Indolent Follicular Lymphoma
By
Armando López-Guillermo,
Fernando Cabanillas,
Timothy I. McDonnell,
Peter McLaughlin,
Terry Smith,
William Pugh,
Fredrick Hagemeister,
M. Alma Rodríguez,
Jorge E. Romaguera,
Anas Younes,
Andreas H. Sarris,
H. Alejandro Preti, and
Ming-Seng Lee
From the Departments of Myeloma/Lymphoma, Pathology, Biomathematics,
and Laboratory Medicine, the University of Texas, M.D. Anderson Cancer
Center, Houston, TX.
 |
ABSTRACT |
The t(14;18) translocation, which involves the bcl-2
oncogene, occurs in follicular lymphomas (FL) at two common sites: the major breakpoint region (MBR) and the minor cluster region
(mcr). The biological and clinical significance of these
breakpoints is unknown. The bcl-2 breakpoint site was
determined in 247 previously untreated patients (49% men; median age
52 years) with indolent FL (155 grade I, 83 grade II, and 8 grade III)
to correlate it with pretreatment characteristics, response, and
outcome. The bcl-2 breakpoint site was determined by a
polymerase chain reaction method of peripheral blood (all cases), bone
marrows (149 cases), and fresh lymph node biopsy specimens (68 cases).
The breakpoint site occurred at MBR in 175 cases (71%) and at
mcr in 27 (11%). In 45 cases (18%), no breakpoint was
detected (germline). No significant relationship was found between the
rearrangements and the expression of BLC-2 and BAX
proteins. Patients' germline for MBR and mcr tended to
present more frequently with stage IV disease and higher  2-microglobulin (2M) levels, whereas mcr-rearranged
patients presented more frequently with early stage and normal 2M.
The complete response rate of germline patients was significantly lower
than that of MBR and mcr patients. An estimated 3-year
failure-free survival (FFS) for mcr, MBR, and germline cases
was 95%, 76%, and 57%, respectively (P < .001). The
bcl-2 breakpoint site was independent of serum 2M and
lactate dehydrogenase in its correlation with FFS. In conclusion, the
bcl-2 rearrangement site is an important prognostic factor in
indolent FL, useful to identify patients who may require different treatment.
© 1999 by The American Society of Hematology.
| |
INTRODUCTION |
FOLLICULAR LYMPHOMAS (FLs) are
characterized by the presence of the t(14;18)(q32;q21) translocation,
which causes a rearrangement of the bcl-2 oncogene. This
rearrangement normally occurs in chromosome 18, with the immunoglobulin
heavy-chain gene (IgH) in chromosome 14.1,2 The
consequence is an overexpression of a chimerical
bcl-2/IgH mRNA.3 Because the breakpoint is usually located outside the translated portion of the bcl-2
gene, the protein product is identical to the normal BCL-2
protein.4 The function of the BCL-2 protein is to
block apoptosis, probably by means of its interaction with other
bcl-2-family proteins such as bax.5-8 The
inhibition of apoptosis leads to accumulation of B lymphocytes, which
might later acquire additional mutations that eventually result in the
development of FL.
Approximately 70% of bcl-2 rearrangements in FL occur at the
major breakpoint region (MBR) located in the untranslated 3' end of the last exon,9-11 and in approximately 10% of
cases, the rearrangement occurs in the minor cluster region
(mcr) located approximately 30 kb downstream of the
bcl-2 gene.12 In a few cases, rearrangements occur
at other sites such as the variant cluster region at the 5' end of the
bcl-2 gene. In approximately 15% of patients, no t(14;18)
translocation can be detected by either cytogenetic, Southern blot
analysis, or polymerase chain reaction (PCR) techniques13
(germline configuration). Tight clustering of the breakpoints at
MBR and mcr, as well as the availability of consensus
sequences of the JH segments of the IgH make this a
particularly favorable target for PCR amplification.9-12 In fact, it is possible to use two universal primers (one for each breakpoint) along with a primer derived from JH region to amplify the
majority of the translocations at MBR and
mcr,9,14,18 with less than 5% of translocations
failing to be amplified.
The biological and clinical significance of these differences in
bcl-2 rearrangement sites in FL remain unclear. In fact, it has
been suggested that the presence of the t(14;18) translocation in FL
correlates with better,16 worse,17 and
similar18-21 clinical outcomes. However, these studies are
based on a small number of cases and frequently included high-grade and
intermediate-grade lymphomas. On the other hand, BCL-2-protein
expression recently has been associated with poor prognosis in patients
with diffuse large-cell lymphoma.22-24 Currently, the
treatment to indolent FL is based largely on the Ann Arbor stage of the
disease at the time of diagnosis.25 Management of patients
with advanced stage includes observation and single agent or
combination chemotherapy. A therapeutic approach based on the
patient's prognostic risk could be of practical help in the
decision-making process.26 Furthermore, knowledge of these
prognostic factors could lead to an improvement in the analysis of
clinical trials and in the understanding of the biology of these
disorders. Consequently, it is important to ascertain whether or not
the bcl-2 rearrangements are useful in predicting the outcome
of FL patients.
| |
MATERIALS AND METHODS |
Patients.
The presence of bcl-2 rearrangements was analyzed in the
pretreatment peripheral blood (PB) and/or bone marrow (BM) aspirates of
247 patients diagnosed with indolent FL during a 7-year period. The
median age was 52 years (range, 18 to 84 years); 120 patients (49%)
were men and 127 (51%) were women. The distribution, according to the
REAL classification, was follicular center cell lymphoma grade I, 155 cases; grade II, 83 cases; grade III, 8 cases, and unclassified, 1 case. Only eight patients had grade III histology and were included in
the study because their tumors predominantly contained cleaved cells
and for that reason were considered indolent. Twenty-two patients (9%)
presented with Ann Arbor stage I disease, 28 (11%) stage II, 44 (18%)
stage III, and 153 (62%) stage IV. Bulky disease was present in 21%
of the cases, extranodal involvement in 68%, and BM infiltration in
56%. The proportion of patients with elevated serum lactate
dehydrogenase (LDH) (top normal: 618 IU/L) and high 2-microglobulin
(2M) (top normal: 2 mg/L) was 16% and 42%, respectively.
Patients with stage IV disease received anthracycline-containing
chemotherapy regimens depending on the protocol being used at the time
they were diagnosed. The treatment consisted of an intensive
alternating triple therapy (ATT) regimen27 in 106 cases,
FND (fludarabine, Novantrone, and
dexamethasone)28 in 34 cases, and standard cyclophosphamide
doxorubicin, vincristine (oncovin), prednisone (CHOP) in 13 cases.
Patients with stage III disease were treated with ATT chemotherapy in
16 cases, with CHOP in 13, and with total nodal radiotherapy in 15. Patients with early stage received either radiotherapy alone (9 cases) or a combined modality of chemotherapy plus radiotherapy to the involved fields (41 cases).
Histologic and immunophenotypic studies.
The diagnosis of indolent FL was based on conventional examination of
paraffin-embedded slides and whenever possible on immunohistologic staining of frozen sections, according to currently accepted
criteria.29 In 47 cases, the expression of BCL-2
and BAX proteins was analyzed by an immunostaining method. The
results were expressed in a semiquantitative manner by comparing
BCL-2 or BAX-tumor expression with that of contiguous
interfollicular areas. Four patterns were distinguished: negative (0),
no tumor BCL-2 expression; weak (+), BCL-2-tumor expression present but weaker than in interfollicular areas; positive (++), positivity similar to interfollicular areas; and strongly positive (+++), BCL-2-tumor expression stronger than in the
interfollicular areas.
PCR methods for detecting bcl-2 rearrangements.
Baseline pretreatment PB samples were collected in 242 patients as part
of a study aimed at assessing minimal residual disease in FL (in five
cases, the PCR result was not assessable). In addition, a BM aspirate
for PCR analysis was obtained in 154 cases. Finally, fresh material
from the original lymph node biopsy specimen was available for
bcl-2 rearrangement studies in 68 patients.
DNA was isolated from PB, BM, and/or lymph node material by using
conventional methods. A PCR technique was used to detect the
bcl-2 of MBR and mcr. PCR amplification was
performed with 1 µg of purified DNA that was subjected to a 45-cycle
PCR amplification.14,15 The primers
MBR+, mcr+, and
JH have been previously described.12,14,15
Twenty percent of the PCR products were size fractionated in a 2%
NuSieve gel (FMC Bioproducts, Rockland, ME) and then transferred to a
nylon membrane. Membranes were hybridized with 5' end radiolabeled
oligonucleotide probes MBR or
mcr.15
To ensure the reliability of the PCR assay, we routinely included a
weak, positive control (100 pg of positive DNA), a negative control
(normal DNA), a reagent control, and an internal control. These
controls helped us detect contamination, avoid false negativity caused
by suboptimal PCR efficiency, and standardize the variation in PCR efficiency.
Statistical considerations.
FFS was the outcome variable of major interest. FFS was defined as the
time interval from the start of initial therapy to the first evidence
of relapse or death from toxicity. Response to therapy and associations
between bcl-2-breakpoint site and other pretreatment patient
characteristics were also reported. Differences in patient
characteristics and response were tested with the chi-square or
Fisher's exact tests. Survival curves were estimated by using the
Kaplan and Meier methods30 and differences among curves
were tested by using the Wilcoxon test.31 A multivariate analysis was performed by the Cox's stepwise proportional hazard regression method.32 However, because there was an apparent lack of proportionality of hazard rates, a stratified test was used to
assess the independent prognostic value of the bcl-2-breakpoint site. For this purpose, because a standard score system for FLs does
not exist, the patients were divided into three sets according to the
most important prognostic variables in MDACC series, serum LDH, and
2M levels. We analyzed the prognostic value of the
bcl-2-breakpoint sites in each group.
| |
RESULTS |
Distribution of the bcl-2 rearrangement site.
The breakpoint site ocurred at MBR in 175 patients (71%), at
the mcr in 27 patients (11%), and no rearrangement was
detected for both MBR and mcr in the remaining 45 patients (18%). These results were obtained in PB and BM samples from
the same patients in 149 cases and in PB only in 98 cases. In those
patients in whom the bcl-2 rearrangement was observed in blood
or BM samples only, they were graded as positive.
Assessment of bcl-2 rearrangement in lymph node, PB, and BM
samples.
To ascertain if the results obtained from PB and BM samples were
representative of those obtained from the tumor itself, we studied by
PCR a subset of 68 samples (from the 247 patients) obtained from the
lymph nodes or masses involved by lymphoma. The results showed that 46 patients (68%) had MBR rearrangements, 4 (6%) had mcr
rearrangements, and 18 (27%) were germline for both MBR and
mcr. These results are similar to those obtained from blood and
marrow analyses. When comparing tumor samples with blood or marrow, the
only discrepancy found was in 4 of the 18 germline lymph node biopsy
samples in which MBR (1) or mcr (3) rearrangements were
found in PB, the BM, or both. In the remaining 64 cases (94.2% of all
cases), there was agreement between the results of lymph node and PB/BM
analyses. Of particular note, all patients germline for MBR or
mcr in PB or BM also showed a germline pattern in lymph node
tissue. Therefore, the rate of agreement between blood/marrow and tumor
tissue was 94%.
On the other hand, we also compared the results obtained in PB and BM
in 149 patients in whom paired blood and marrow were available (Table
1). MBR or mcr
rearrangements were observed in 87 paired samples of blood and marrow,
and no rearrangement was seen in another 31 paired samples. In 23 cases
(15%), a bcl-2 rearrangement was found in the PB sample and
not in BM, whereas in 8 cases (5%) it was observed in BM but not in
blood.
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Table 1.
Results of the PCR Analysis for Bcl-2
Rearrangement Performed in 149 Patients With Both PB and BM
Pretreatment
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Expression of BCL-2 and BAX proteins.
In an attempt to determine if there was any correlation between the
bcl-2-breakpoint site and the expression of BCL-2 and BAX proteins, we analyzed such expression in a subset of 47 patients for whom tumor tissue was available. In 40 of 47 patients,
BCL-2-protein expression was found in tumor tissue, whereas no
expression was observed in 7 patients. Although not statistically
significant, the proportion of cases expressing positive or strongly
positive BCL-2 protein was higher among germline cases (89%)
than among MBR (73%) and mcr cases (60%). No
differences were found regarding BAX-protein expression.
Bcl-2 breakpoints and their correlation with pretreatment
features.
The correlation of the bcl-2-breakpoint site with pretreatment
features is summarized in Table 2. Germline
patients tended to be older, to have higher LDH and 2M values, and
to have a higher incidence of advanced stage. Patients with an
mcr breakpoint tended to be younger, to have lower LDH and
2M values, and to have a lower rate of advanced stage. Differences
in distribution of patient characteristics among breakpoint groups were
not statistically significant at the .05 level with the exception of
Ann Arbor stage (P = .03) and 2M values
(P = .02). Differences between mcr and MBR
patients did not reach statistical significance.
Response to therapy.
Among the 228 patients with evaluable response, 200 (88%) achieved
complete response (CR) and 26 (11%) achieved partial response CR rates
for mcr, MBR, and germline groups were 96%, 90%, and 71%, respectively (P < .01). The trend for fewer responses
among germline cases held true when consideration was restricted to patients with stage IV disease (Table 3).
Differences between mcr and MBR patients did not reach
statistical significance.
Failure-free survival.
At the time of analysis, 56 patients (23%) had experienced relapse or
progression; 7 patients experienced histologic transformation into
large-cell lymphoma at relapse (5 cases MBR, 2 cases germline). Estimated FFS at 3 years after initiation of therapy was 0.74 (standard
error: 0.04) (Fig 1).
There was one relapse among 27 patients with mcr breakpoint, 42 among 175 patients with MBR breakpoint and 13 among 45 germline patients. An estimated 3-year FFS for these groups was 0.95 (standard error = 0.05), 0.76 (standard error = 0.04), and 0.57 (standard error = 0.10), respectively. The overall difference among FFS curves
was statistically significant (P < .001; Fig
2). These results suggested a trend for
superior FFS among patients with mcr breakpoint and unfavorable
outcomes for germline cases. The large group of MBR-breakpoint
cases was of particular interest because of the apparent low risk of
failure in early follow-up, with a subsequent increase in the rate of
failure. This observation was verified in an analysis of smoothed
hazard rates (not shown), which indicated for the
MBR-breakpoint group a gradually increasing risk of failure
during the first 24 months after treatment. Although treatment failure
among patients in the germline group was higher, there was no real
evidence that the rate changed over time, at least through the first 36 months. The single failure in the mcr group did not allow
characterization of their risk of failure over time.
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| Fig 2.
FFS in 247 patients with FL according to the
bcl-2-breakpoint site MBR, mcr, and germline for both
MBR and mcr (P < .001).
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Abnormal pretreatment LDH and 2M levels have been reported as poor
prognostic factors in FL, and their association with FFS was verified
in this patient group (results not shown). Because these poor features
also occurred more commonly in the MBR group and particularly
in the germline group, it was possible that these factors accounted for
differences in FFS among the breakpoint groups. To investigate this
question, patients were divided into three risk groups: those whose LDH
and 2M were both normal, those in whom only one of these factors was
normal, and those in whom both factors were abnormal. FFS for patients
with mcr and MBR breakpoints and those with germline
rearrangements are plotted in Fig 3
separately within the three risk groups. Although the number of
patients was small, the same pattern of FFS differences by breakpoint
was noted within each risk group as observed in the overall group. A
Wilcoxon test stratified by risk group resulted in a P value of
.08. These results suggest that the breakpoint site is an
independent prognostic variable from LDH and 2M values in predicting
FFS. Although there was an apparent lack of proportionality of hazard
rates, we performed a proportional hazard model analysis32 that confirmed the same results as the stratified test previously reported; the presence of bcl-2 rearrangement (at mcr or
MBR) maintained its prognostic importance along with serum
2M and LDH levels.
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| Fig 3.
FFS according to the bcl-2-breakpoint site
(mcr, MBR, and germline) in three subsets of patients with
different risks: (A) patients with normal serum LDH and 2M (no
significant difference among breakpoints), (B) patients with high LDH
or 2M (P = .02), and (C) patients with high LDH and
2M (P = .03).
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Patients with stage IV disease treated with the intensive ATT regimen
fared somewhat better than those who received the FND regimen. In an
attempt to consider the possibility that a treatment effect could have
influenced the FFS as related to the breakpoint site, FFS was compared
for those patients with stage IV disease treated with ATT and FND.
Although the number of patients was small, the same ordering of FFS
curves was preserved within the homogeneously treated subsets of ATT
and FND.
Overall survival.
There have been 17 deaths so far in this group of patients. The cause
of death was directly or indirectly related to lymphoma in 11 cases
(progressive disease in 9 cases, toxicity in 2). The remaining six
patients died in CR from other causes such as concurrent tumors in two
cases (glioblastoma multiforme, disseminated breast cancer), myocardial
infarction in one case, gunshot wound in one case, and unknown
(probably cardiovascular disease) in two cases.
| |
DISCUSSION |
Most patients with FL, even those in early stages, have circulating
cells that carry the bcl-2 rearrangement providing a unique opportunity to identify and classify them according to their
bcl-2 rearrangement without necessarily having to directly
study their tumor tissue. However, in a considerable number of cases
(one third of the whole series) we performed the same analysis directly on tissue involved by the malignant lymphoma to ascertain if the results obtained from PB and BM samples were representative of those
obtained from the tumor. The agreement between the results from PB/BM
and lymph node was 94.2%. No patient with a bcl-2
rearrangement assessed in lymph-node tissue failed to be detected when
combining PB and BM determinations. Of note is the fact that in 5.8%
of the cases, a bcl-2 rearrangement was detected in PB or BM by
PCR but was not observed in tumor tissue. Possible explanations for this discrepancy are (1) the tumor sample studied was only partially infiltrated by lymphoma, (2) some technical problems could have occurred in extracting DNA from tumor tissue, (3) the blood/marrow results could be spurious and could perhaps represent contamination, or
(4) the bcl-2 rearrangement detected was real but did not
correspond to the tumor tissue. This latter alternative cannot be
completely ruled out in these four cases, because bcl-2
rearrangements have been described in PB of healthy
individuals.33-35 However, when only 1 µg of DNA is
loaded, as we have done in this study, the bcl-2 rearrangement
in blood is only detected in 6% of normal individuals.33
When whole PB white cells are tested and not B lymphocytes, as in our
study, this proportion is expected to be much lower.
Relatively good concordance between the detection of lymphoma cells in
blood and BM at diagnosis has been previously observed by different
groups.36-38 However, in one fifth of the patients tested,
the bcl-2 rearrangement was detected only in the PB or in BM
but not in both. Two thirds of these cases were positive in blood, but
negative in BM. Because BM infiltration in FL is characteristically
patchy and frequently not observed in marrow aspirates, this finding is
not viewed as unusual. In fact, Gribben et al39 previously
observed that the results of PCR from BM biopsy specimens varied
according to the site where the biopsy was performed.
The most significant and interesting observation in this study is the
intriguing correlation between the bcl-2 breakpoint site and
the clinical outcome. As a group, the mcr+ patients so far
have shown an excellent prognosis. Their pretreatment prognostic
variables were more favorable than those of the other groups (earlier
Ann Arbor stage and lower serum 2M levels); in addition, they also
had a higher CR rate and superior FFS. So far, only 1 of 27 patients
have relapsed at a median follow-up of 27 months. On the other hand,
those patients with germline bcl-2 had a poor prognosis. Their
response to therapy was suboptimal (<70% of CR rate), and their
relapse rate was highest of all. It is interesting to note that the
relapse pattern of MBR+ cases appears different
when compared with germline cases. The MBR+ cases
display the typical FFS curve of FL, which consists of a slow but
relentless relapse pattern, without any hint of a plateau. Interestingly, the germline cases have a FFS curve that mimics that of
aggressive lymphomas: early and frequent relapses for the first 3 years
but no more relapses. A longer follow-up will be necessary to confirm
this observation.
The type of treatment delivered to patients with advanced stage was
associated with some differences in FFS. Those who received the
intensive ATT regimen experienced a better FFS than those treated with
FND. However, the two groups of patients might not be strictly
comparable because the median follow-up is different. This is because
of the fact that FND recently has been introduced for advanced,
previously untreated FL in our institution.40 In fact, in a
current prospective randomized study comparing FND with ATT, no
statistically significant differences have been found between these two
regimens.40
Table 4 summarizes previous
studies16-21 on the prognostic importance of bcl-2
rearrangements in FL. In most of these series, the number of patients
was small. Furthermore, most authors included all FL-cell types,
whereas Yunis et al17 only considered mixed and large cell
FL, and one half of Johnson's cases16 were of "high-grade" histology. This indicates a predominance of large cell as well as a diffuse pattern on the biopsy specimen. These subgroups are not comparable with typical indolent FL and probably a
large number of FL transformed to large cell lymphoma have been included in these series. In large cell lymphomas, the presence of a
bcl-2 rearrangement has been related to a poor
outcome,41 supposedly because these patients correspond to
transformed FL, which traditionally have had a poor outcome. On the
other hand, Johnson et al16 found bcl-2
rearrangement to be a favorable factor for survival, but only for
patients with the indolent cell types.
Finally, it is difficult to explain the differences in outcome of the
patients according to the bcl-2 rearrangement. In fact, the
expression of BCL-2 and BAX proteins, assessed by a
semiquantitative immunostaining technique in a significant number of
patients, did not show significant differences according to the
bcl-2 rearrangement, although the proportion of germline cases
with positive or strongly positive bcl-2 expression was higher
than that of MBR and mcr cases. Because the number of
patients tested is small, we have to be cautious in the interpretation
of these results. On the other hand, p53 mutations,42 c-myc
rearrangements43 or, more recently, different p16
alterations44 have been related to aggressive behavior in
FL, mostly by histologic transformation of FL. However, there is no
proved link between such alterations and the bcl-2 rearrangement so far.
In conclusion, the type of bcl-2 rearrangement appears to be an
important biological feature that correlates well with the outcome in
patients with FL, especially when combined with other classical
prognostic factors such LDH and 2M. The biological explanation for
the clinical differences we have identified remains unclear. More
studies on bcl-2, bax, and other related molecules, including a
more detailed analysis of such proteins and their mRNA would be useful
to better understand the pathogenesis of FL.
| |
FOOTNOTES |
Submitted June 30, 1998; accepted January 5, 1999.
Supported in part by National Cancer Institute, Grants No. CA62518 and
No. CA62597 and by the Herschel and Hilda Rich Fund for Lymphoma
Research. A.L.G. was supported by the Hospital Clínic of
Barcelona and the Spanish Ministry of Education (EX 95/43390399).
The publication costs of this
article were defrayed in part by
page charge payment. This article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
Address reprint requests to Fernando Cabanillas, MD, Chairman,
Department of Myeloma/Lymphoma, Box 68, The University of Texas, MD
Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030.
| |
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