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Blood, Vol. 93 No. 11 (June 1), 1999:
pp. 3983-3993
Prospective Karyotype Analysis in Adult Acute Lymphoblastic
Leukemia: The Cancer and Leukemia Group B Experience
By
Meir Wetzler,
Richard K. Dodge,
Krzysztof Mrózek,
Andrew J. Carroll,
Ramana Tantravahi,
AnneMarie W. Block,
Mark J. Pettenati,
Michelle M. Le Beau,
Stanley R. Frankel,
Carleton C. Stewart,
Ted
P. Szatrowski,
Charles A. Schiffer,
Richard A. Larson, and
Clara D. Bloomfield
From the Roswell Park Cancer Institute, Buffalo, NY; the Duke
University Medical Center, Durham, NC; the Comprehensive Cancer Center
of The Ohio State University, Columbus, OH; the University of Alabama
at Birmingham, Birmingham, AL; the Dana Farber Cancer Institute,
Boston, MA; the Wake Forest University School of Medicine,
Winston-Salem, NC; the University of Chicago, Chicago, IL; the
Georgetown University Medical Center, Washington, DC; the New York
Hospital-Cornell Medical Center, New York, NY; and the Karmanos Cancer
Institute, Wayne State University School of Medicine, Detroit, MI.
 |
ABSTRACT |
The Cancer and Leukemia Group B (CALGB) has been conducting a
prospective cytogenetic companion study (CALGB 8461) to all CALGB
treatment protocols for newly diagnosed adults with acute lymphoblastic
leukemia (ALL). These protocols underwent a significant change in 1988 when a new intensive chemotherapy program was introduced (CALGB 8811).
We asked whether karyotype continued to represent a significant
prognostic factor in adult ALL patients after the change. A total of
256 patients had adequate pretreatment cytogenetic analyses: 67 before
1988 and 189 subsequently. The complete remission (CR) rate for the
whole group was 80%. Patients with t(9;22), t(4;11),  7, or +8 had
significantly lower probabilities of continuous CR and survival at 5 years (.11 and .12) than patients with a normal karyotype (.38 and .37)
and patients with miscellaneous cytogenetic abnormalities (.52 and .49;
P < .001 for each comparison). When analyzed by treatment
period, the CR rate before CALGB 8811 was 63%; subsequently, it was
86% (P < .001). Patients with cytogenetic abnormalities
other than t(9;22), t(4;11), 7, or +8 had better CR rates,
disease-free survival (DFS), and survivals (P = .001, P = .04, and P = .004, respectively) after the
change to the more intensive chemotherapy regimens. Patients with
normal cytogenetics had improved CR rate but no improved DFS or
survival, whereas no significant benefit for patients with t(9;22),
t(4;11), 7, or +8 was seen. In a multivariate analysis, karyotype
retained its prognostic significance for DFS but not for survival; it
remained the most important factor for DFS. We conclude that
cytogenetic analysis at diagnosis should be used to guide treatment
decisions in adults with ALL.
© 1999 by The American Society of Hematology.
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INTRODUCTION |
THE CLONAL CHROMOSOME abnormalities
t(9;22)(q34;q11), t(4;11)(q21;q23), and the t(8;14)(q24;q32) are well
known in adults with acute lymphoblastic leukemia (ALL).1,2
The Cancer and Leukemia Group B (CALGB) has been conducting a
prospective cytogenetic companion study (CALGB 8461) to all CALGB
front-line ALL treatment protocols since 1984. These protocols (CALGB
8011, 8411, and 8513)3,4 underwent a significant change in
1988 when a new intensive chemotherapy program (CALGB 8811) was
introduced.5 The two subsequent protocols (CALGB 9111 and
CALGB 9311) were based on the same intensive regimen, with minor
modifications.6,7
We asked whether karyotype continued to represent a significant
prognostic factor in patients with ALL regardless of other initial
clinical characteristics, ie, age, white blood cell (WBC) count, the
presence of a mediastinal mass, French-American-British (FAB)
classification, and immunophenotype, even after the treatment regimens
had been intensified. Finally, we studied patients sequentially, at
diagnosis, and at relapse to determine whether a change in karyotype at
relapse occurred and, if so, if it had an impact on outcome.
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MATERIALS AND METHODS |
Patients.
Patients included in this analysis were enrolled on CALGB 8461, a
prospective study of karyotype in acute leukemia, which has been a
companion study to all CALGB ALL treatment protocols since 1984. Adults
who were 15 years or older with previously untreated ALL as defined by
the FAB classification system were eligible.8,9
Patients with prior or concomitant malignancy, uncontrolled or severe
cardiovascular disease, pre-existing liver disease, or uncontrolled
infection were ineligible for these studies. Central review of the
pathologic diagnosis was performed. The only patients excluded from
this analysis based on morphology were those with FAB L3
(Burkitt's-type ALL).
Cytogenetic analyses.
Chromosomal analyses of bone marrow (232 samples) and blood (24 samples) were performed in institutional CALGB cytogenetics laboratories, and karyotypes from all cases were centrally reviewed. Specimens were obtained at diagnosis from all patients. Specimens were
processed using direct methods and unstimulated short-term (24-, 48-, and 72-hour) cultures. G-banding was usually performed, although
Q-banding was acceptable for inclusion in this series. A minimum of 20 bone marrow metaphase cells were analyzed in each patient designated as
having a normal karyotype, with the exception of 1 case in which 19 normal cells were analyzed. The criteria to describe a cytogenetic
clone and description of karyotype followed the recommendations of the
International System for Human Cytogenetic Nomenclature.10
Immunophenotyping.
Before April 1991, cases were classified by uniparameter flow cytometry
using the criteria previously published.11 Subsequently, cases were classified by multiparameter flow cytometry.12
In these cases, criteria for surface marker positivity was coexpression of an antigen by at least 10% of the leukemia blast population. Ten
percent positivity was selected as a cutoff to eliminate the possibility that coexpression was due to a nonspecific binding process.
B-lineage (B) antigen expression was defined as CD19 or CD20
positivity. T-lineage (T) antigen expression was defined as either (1)
CD2 or CD7 positivity with CD1 or CD3 or CD4 or CD5 or CD8 positivity
or (2) CD5 positivity without CD19 or CD20 positivity. Myeloid (My)
antigen expression was defined as CD13 and/or CD33 positivity
coexpressed with either B- or T-lineage antigens. Cases expressing
combinations of myeloid antigens with either B- or T-lineage antigens
were classified as BMy or TMy. Patients with myeloid antigens only were
classified as acute myeloid leukemia and excluded from this analysis.
Treatment.
All patients were treated on one of the following six treatment
studies. On CALGB 8011, patients received daunorubicin, prednisone, vincristine, L-asparaginase, and intrathecal methotrexate for induction.3 After attainment of complete remission (CR),
patients were randomized to receive either intensive cytarabine and
daunorubicin or cycles of mercaptopurine and methotrexate, followed by
mercaptopurine, methotrexate, vincristine, and prednisone for 3 years
of maintenance therapy. In CALGB 8411 mitoxantrone, vincristine and
prednisone were used for induction.4 CALGB 8513 compared
daunorubicin versus mitoxantrone in induction followed by a multidrug
intensification over 8 months.4 In CALGB 8811, the
induction regimen was redesigned to include cyclophosphamide,
daunorubicin, vincristine, prednisone, and L-asparaginase. Patients who
achieved CR received multidrug consolidation treatment, central nervous
system prophylaxis, late intensification, and maintenance chemotherapy
for a total of 24 months.5 CALGB 9111 used exactly the same
chemotherapy regimen as CALGB 8811, but, in addition, patients were
assigned in a double-blind fashion to receive granulocyte
colony-stimulating factor (G-CSF) or a placebo during the induction and
early intensification courses.6 CALGB 9311 also used
exactly the same chemotherapy regimen as CALGB 8811, but, in addition,
all patients received G-CSF after induction and, after the first
consolidation course, patients with B-lineage ALL received
anti-B4-blocked ricin therapy and patients with T-lineage ALL received
high-dose cytarabine.7
Definition of response.
The definition of hematologic CR in these studies adhered to the
criteria established previously.5 CR required a neutrophil count greater than 1,500/µL, platelet count greater than
100,000/µL, normal bone marrow cellularity (>25%) with trilineage
hematopoiesis with less than 5% blasts, and resolution of all
extramedullary disease. Patients with less than 25% lymphoblasts in
the bone marrow after course I were allowed to continue through course II but were removed from the treatment protocols if they had not achieved CR by that time point. Patients with greater than 25% lymphoblasts in the bone marrow after course I were removed from the
treatment studies.
Definition of relapse, disease-free survival (DFS), and survival
duration.
Relapse was defined by the reappearance of more than 5% leukemic cells
in bone marrow aspirates or extramedullary leukemia in patients with a
previously documented CR. In patients who achieved CR, DFS was measured
from the date of documented CR to ALL relapse (bone marrow or
extramedullary) or death from any cause. Overall survival was
measured from the time of entry on the treatment study to the time of
death. Patients were censored for DFS and for survival only at the date
last known to be in remission or alive, respectively.
Statistical analyses.
One of the main objectives of this study was to investigate the
prognostic significance of karyotypic subgroups in the presence of
other clinical and laboratory factors that have been shown to influence
outcome. The other factors included age, WBC count, mediastinal mass,
FAB subtype, immunophenotype, and treatment.6 The
relationships between these factors and DFS or survival were analyzed
using the Cox regression model.13 In the multivariate analysis, karyotype, categorized into the three risk groups, was analyzed as a variable with two degrees of freedom. Age was considered as a continuous variable and dichotomized as less than 60 years and
 60 years; WBC count was dichotomized as less than 30,000/µL and
30,000/µL, as well as used as a continuous variable by taking the
natural logarithm; mediastinal mass was dichotomized as present or
absent; FAB subtype was dichotomized as L1 or L2; and immunophenotype was dichotomized as expression of B or B+myeloid (BMy) markers versus T
or T+myeloid (TMy) markers. Treatment was dichotomized into earlier
protocols (8011, 8411, and 8513) and later protocols (8811, 9111, and
9311). The distribution of time to a specific endpoint was estimated by
the method of Kaplan and Meier,14 and 95% confidence
intervals for estimated probabilities of surviving or remaining in CR
were calculated by the method of Simon and Lee.15
Differences among groups with respect to the distribution of times were
tested with the logrank statistic.16 Two-group comparisons
of pretreatment characteristics between the unfavorable risk group and
the normal group and the miscellaneous risk group and the normal group
were considered with the Wilcoxon rank sum test for medians and
Fisher's exact test for proportions.
| |
RESULTS |
Patient characteristics.
For the six CALGB treatment studies examined, 551 patients with ALL
were registered between July 1984 and September 1994. No cytogenetic
sample was available on 29 patients, 8 had missing data, 20 patients
were ineligible for the treatment study due to non-ALL morphology after
central review, and 210 patients had inadequate cytogenetic analyses.
Inadequate cytogenetic analysis was defined by either poor quality of
the banding, no mitoses, a normal karyotype but less than 20 cells
analyzed from marrow, or a normal karyotype analyzed only by direct
methods, ie, without culture. After central karyotype
review, a total of 284 patients had adequate pretreatment cytogenetic
analyses. Twelve of the 284 patients had the t(8;14)(q24;q32) or its
variant and were excluded as Burkitt's leukemia. Sixteen were
classified as acute myeloid leukemia (usually FAB-M0) by central review
of immunophenotype and were therefore excluded from this analysis. The
remaining evaluable 256 patients were treated on ALL treatment studies
CALGB 8011 (n = 12), 8411 (n = 4), 8513 (n = 51), 8811 (n = 70), 9111 (n = 82), and 9311 (n = 37). The median follow-up time of living patients is estimated to be 5.5 years (range, 1.6 to 12.3 years).
A comparison of patients with adequate cytogenetic analysis to those
with inadequate samples showed that there was a higher proportion of
patients with inadequate samples in the initial treatment period (40%
v 26%; P = .002). There were no significant differences between the adequate versus inadequate cytogenetics groups
with respect to age (P = .15), mediastinal mass (P = .87), WBC count (P = .24), CR rate (P = .91), DFS
(P =.48), or survival (P = .62).
Cytogenetic groups.
Table 1 presents the frequency of the
chromosome abnormalities and gives some indication of the frequency of
multiple abnormalities. Table 2 gives
clinical outcome, with respect to DFS and overall survival, for those
abnormalities with at least 9 patients as well as for patients with a
normal karyotype. A clonal cytogenetic abnormality was detected in 177 (69%) patients, and 79 (31%) patients had a normal karyotype. The
clinical outcome for each specific abnormality is compared with the
normal group.
Unfavorable cytogenetic groups.
Groups with unfavorable outcome are the t(9;22), +8, and t(4;11)
(P < .001, P = .007, and P = .002 for DFS and
P < .001, P = .004, and P < .001 for
survival, respectively). In addition, the 7 group had an
unfavorable outcome (P = .01 for survival). It may seem
that the group with +8 abnormality fared poorly by having 12 of 23 (52%) of the patients with a t(9;22) as well. However, as shown in
Fig 1, those with a +8 abnormality without t(9;22) fared just as poorly (P = .87). Similarly,
there were 14 patients with the 7 chromosome abnormality, 9 of
whom had t(9;22) as well. The 5 patients with 7 abnormality but
without t(9;22) fared as poorly. Hence, the unfavorable cytogenetic
group was defined to be composed of the 100 patients with either
t(9;22), t(4;11), 7, or +8 abnormality.
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| Fig 1.
DFS for patients with the +8 cytogenetic abnormality.
Those coharboring the t(9;22) have a similar outcome to those without
the t(9;22) (P = .87).
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Miscellaneous and normal.
The 77 other patients with a chromosome abnormality were combined to
form a miscellaneous risk group. The most common type of miscellaneous
abnormalities included +21, del(9p) or t(9p), del(12p) or t(12p),
t(14q11-q13), t(14q32) other than t(8;14), and del(6q) (Table 1). There
were 5 patients with a hyperdiploid karyotype (>50 chromosomes but
without any structural abnormalities). They all died at a median of 8 months (range, 3 months to 3.1 years). Patients without a detectable
cytogenetic abnormality were classified as a normal group. The
pretreatment characteristics of the 256 patients are summarized in
Table 3 according to cytogenetic risk
group.
Favorable cytogenetic groups.
In Table 2, the group with del(12p) or t(12p) (n = 11) is suggestive of
having better survival compared with the normal group [probability of
survival at 5 years, .82 v .37; P = .10; excluding the
2 cases with t(9;22)]. A possible explanation is that these patients
are somewhat younger than the normal group (median ages, 21 v
30 years; P = .06). Another group that may have a favorable prognosis compared with the normal group is t(14q11-q13) [n = 9; excluding 2 patients with t(9;22)]. This group was composed of 8 patients with t(14q11-q13) and 1 patient with inv(14)(q11q32). Among them, 4 patients had t(10;14)(q24;q11), all of whom remain in
continuous CR from 6.2 to 8.0 years. Longer survival (P = .04) and DFS (P = .05) was observed in the group with t(14q11-q13), which is usually associated with T-cell ALL. In this study, among the
11 patients, phenotype was performed in 9; 7 patients had T-lineage,
whereas 2 had B-lineage [including 1 patient with t(9;22)].
The CR rate for the 256 patients was 80%, with 52 patients not
achieving CR. When analyzed by treatment period, the CR rate before
initiation of CALGB 8811 was 63%; subsequently, it was 86% (P < .001). When all patients were considered, the CR rate was 79% for
the unfavorable risk group, 78% for the miscellaneous abnormalities
group, and 82% for the normal group (P = .77). The probability
of continuous CR (CCR) at 5 years was .11 for the unfavorable risk
group, .52 for the miscellaneous abnormalities group, and .38 for the
normal group (Fig 2 and
Table 4). The probability of
survival at 5 years was .12 for the unfavorable risk group, .49 for the
miscellaneous abnormalities group, and .37 for the normal group
(Fig 3 and Table 4). The unfavorable risk
group differs significantly from both of the other groups for both
endpoints (P < .001 for each comparison). However, the miscellaneous group had comparable CCR and survival to the normal group
(P = .53 and P = .91, respectively). The 9 long-term
(at least 3 years) survivors who had either t(9;22) or t(4;11) all underwent allogeneic bone marrow transplantation (BMT), except for 2 patients with t(4;11) who are alive and in continuous CR 4.5 and 4.8 years after chemotherapy alone (CALGB 9111). There are 3 long-term
survivors who had +8; they are surviving 3.0, 4.5, and 5.8 years and
only 1 [with t(9;22), surviving 3.0 years] is known to have undergone
allogeneic BMT. Because of the importance of allogeneic BMT in
prolonging survival for these patients, we have analyzed our data for
those less than 60 years of age who were treated with the more
intensive regimens. Figure 4A and B show
similar results to Figs 2 and 3, respectively.
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| Fig 2.
DFS by cytogenetic risk group for 204 complete
responders. The unfavorable risk group (n = 79), consisting of
patients with the t(4;11), t(9;22), 7, or +8, had a median
duration of nearly 10 months, whereas the miscellaneous abnormality
group (n = 60) had a median of 5.5 years and the normal group (n = 65) had a median of 2.3 years.
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| Fig 3.
Survival by cytogenetic risk group for 256 ALL patients.
The unfavorable risk group (n = 100), consisting of patients with
t(4;11), t(9;22), 7, or +8, had a median survival of 1.2 years,
whereas the miscellaneous abnormality group (n = 77) had a median of
3.1 years and the normal group (n = 79) had a median of 2.9 years.
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| Fig 4.
DFS and overall survival of patients less than 60 years
of age treated on the intensive treatment protocols (8811) by
cytogenetic risk group. (A) DFS; (B) overall survival.
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Table 5 compares the outcome by treatment
protocols and by cytogenetic risk groups. When only the three earlier
protocols (before 8811) are considered, the CR rates are 68% for the
unfavorable risk group, 50% for the miscellaneous abnormalities group,
and 68% for the normal group (P = .40). The probability of CCR
at 5 years was .00 for the unfavorable risk group (all patients failed before 2 years), .30 for the miscellaneous abnormalities group, and .35 for the normal group (P < .001 for comparison of unfavorable and normal; P = .15 for comparison of unfavorable and
miscellaneous; and P = .82 for comparison of miscellaneous and
normal). The probability of survival at 5 years was .05 for the
unfavorable risk group, .25 for the miscellaneous abnormalities group,
and .26 for the normal group (P = .005 for comparison of
unfavorable and normal; P = .63 for comparison of unfavorable
and miscellaneous; and P = .55 for comparison of miscellaneous
and normal). For the later protocols (8811 and after), the CR rates are
82% for the unfavorable risk group, 88% for the miscellaneous
abnormalities group, and 89% for the normal group (P = .52).
The probability of CCR at 5 years was .14 for the unfavorable risk
group, .57 for the miscellaneous abnormalities group, and .39 for the
normal group (P = .004 for comparison of unfavorable and
normal; P < .001 for comparison of unfavorable and
miscellaneous; and P = .43 for comparison of miscellaneous and
normal). The probability of survival at 5 years was .15 for the
unfavorable risk group, .57 for the miscellaneous abnormalities group,
and .43 for the normal group (P = .001 for comparison of
unfavorable and normal; P < .001 for comparison of
unfavorable and miscellaneous; and P = .56 for comparison of miscellaneous and normal). Figure 5A
through H shows the comparison between early and later protocols with
respect to DFS and survival for each risk group. Thus, the change in
therapy had its major impact in patients with miscellaneous cytogenetic
abnormalities. It improved the CR rate for patients with normal
cytogenetics and had no significant impact for patients with
unfavorable risk cytogenetics.
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| Fig 5.
DFS and overall survival by cytogenetic risk groups and
treatment periods (earlier protocols: 8011, 8411, and 8513; later
protocols: 8811, 9111, and 9311). (A through D) DFS; (E through H)
overall survival. (A and E) all patients; (B and F) unfavorable risk
group; (C and G) miscellaneous cytogenetic abnormalities group; (D and
H) normal cytogenetics group.
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Univariate analyses.
Table 4 depicts the results of univariate analyses for DFS and
survival. For each category of the variables considered, the median
times and estimated probabilities of remaining in CR for more than 5 years and surviving for at least 5 years are given, with 95%
confidence intervals. With respect to DFS, the following variables were
found to be significantly related to shorter remissions: unfavorable
cytogenetic group (P < .001), higher log WBC count (P < .001), absence of a mediastinal mass (P < .001), age as a continuous variable (P < .001), and B or BMy immunophenotype
(P = .01). Similarly, with respect to survival,
unfavorable cytogenetic group (P < .001), higher log WBC
count (P < .001), higher age when considered as a continuous
variable (P < .001), absence of a mediastinal mass (P < .001), and B or BMy immunophenotype (P = .004)
were significantly related to a poorer outcome.
Multivariate analyses.
To determine the relationship of these variables when considered
jointly, stepwise multivariate analyses were performed with the Cox
regression model. Because nearly complete data were available for all
variables except FAB and immunophenotype, the first approach excluded
these two variables. For DFS, analysis of 199 cases identified unfavorable cytogenetic group as the most significant factor related to
shorter remission (P < .001). After adjusting for cytogenetic risk group, the other significant factors, in order selected to the
model, were higher log WBC count (P < .001), absence of a mediastinal mass (P = .002), age (P = .008), and
treatment protocol (P = .03), where the P values are
adjusted for factors already in the model.
Table 6 shows these results and gives the
adjusted hazard ratios for each variable in the final model. For DFS,
in a model also including immunophenotype (n = 161), expression of B or
BMy markers was not associated with outcome after adjustment was
made for these five significant factors (P = .16). In a model adding FAB (L1 or L2) (n = 184) instead of immunophenotype, there was
additional prognostic information (L2 was associated with poor DFS)
after adjusting for the five variables listed above (P = .03).
For survival, analysis of 251 cases identified age as the most
significant factor related to poor outcome (P < .001). After
adjusting for age, the other significant factors, in the order selected
to the model, were higher log WBC count (P < .001), absence of a mediastinal mass (P = .001), and treatment
protocol (P = .02), where the P values are
adjusted for factors already in the model (Table 6). After adjusting
for age and log WBC, cytogenetics retains marginal prognostic
significance (P = .051). For survival, in a model
adding immunophenotype (n = 203), expression of B or BMy markers was
not associated with outcome after adjustment was made for age, WBC,
mediastinal mass, and treatment protocol (P = .20). In a model
adding FAB (L1 or L2) (n = 228) instead, there was also no
additional prognostic information after adjusting for these same
variables listed above (P = .07).
Sequential chromosome analyses.
Chromosome analyses from diagnosis and at the time of first relapse
were evaluable on 34 patient samples to study clonal evolution. Only
samples obtained from the same tissue at diagnosis and at relapse, ie,
either bone marrow or blood, were included. These patients were divided
into two major groups. One group of 23 (68%) patients had a karyotype
change upon relapse. These changes could be separated into four groups:
(1) abnormal karyotype at diagnosis that changed to a normal karyotype
at the time of relapse (n = 4); (2) abnormal karyotype at diagnosis
that underwent clonal regression (n = 4); (3) abnormal karyotype at
diagnosis that underwent clonal progression (n = 11); and (4) normal
karyotype that evolved to an abnormal karyotype (n = 4). The second
group consisted of 11 (32%) patients who had no change in karyotype
upon relapse. This included 5 patients with abnormal karyotype at
diagnosis that remained the same at the time of relapse and 6 patients
with normal karyotype at diagnosis. Of 34 patients, 13 (38%) were in the unfavorable cytogenetic group [1 with t(4;11), 9 with t(9;22) of
whom 1 had also +8 and another had 7, 1 with 7, and 2 with +8 and other structural abnormalities]. Ten of these 13 were in the group that developed a karyotypic change upon relapse; the other 3 had no karyotypic change upon relapse.
Survival after relapse was suggested to be longer for patients without
a karyotype change (median, 9.0 months) than for those who had a
different karyotype at the time of relapse (median, 3.6 months;
P = .07; Fig 6A). Survival after
relapse by cytogenetic group is shown in Fig 6B. The survival after
relapse in the normal group is similar to that in the no karyotype
group (Fig 6A) and is suggested to be longer than that for the
miscellaneous and unfavorable groups (P = .09). There are 2 patients in the normal group who are surviving after relapse for at
least 3 years. There was no difference in survival from study entry for
these same patients (P = .18).
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| Fig 6.
Survival after relapse by karyotype at first relapse. (A)
Patients without a karyotype change (n = 11) had a median survival
after relapse of 9.0 months, whereas those with a change (n = 23) had
a median of 3.6 months (P = .07). (B) Survival after relapse
by cytogenetic risk group.
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| |
DISCUSSION |
There are few reported studies looking at the prognostic significance
of chromosome analysis in a large number of adult ALL patients.17-19 Our study emphasizes that karyotype remained
an independent prognostic factor in adult ALL even after more
intensified treatment regimens were introduced. However, in a
multivariate analysis, karyotype retained its prognostic significance
only for DFS and not for overall survival. We do not think that this discrepancy resulted from induction mortality, because the distribution of these events was comparable between the risk groups. After adjusting
for age and log WBC, cytogenetics retains marginal prognostic significance with respect to survival.
Little data exist on the effect of the karyotypes after different
treatments. The overall improvement in CR rate in the treatment protocols since 1988 is most probably related to the addition of
cyclophosphamide. Furthermore, these more intensive regimens improved
the outcome of patients with normal karyotype or miscellaneous cytogenetic abnormalities. However, they did not markedly change the
poor outcome of patients with t(9;22), t(4;11), 7, or +8, for
whom novel therapeutic approaches are urgently needed. The data suggest
that karyotype should continue to be analyzed at diagnosis for all
adult ALL patients and treatment be assigned according to the karyotype.
It is known that adult ALL patients with t(9;22) have a short CR
duration and survival. Investigators at the University of Minnesota and
Memorial Sloan-Kettering Cancer Center, using a variety of treatment
regimens for induction and maintenance, showed a similar short median
survival for patients with this translocation.20,21 Using
vincristine, doxorubicin, and dexamethasone for an induction regimen
followed by a 2-year rotating chemotherapy maintenance program and
concluding with autologous BMT, investigators at M.D. Anderson Cancer
Center also showed a median CR duration of only 7 months for patients
with the t(9;22).22 Similar data were described in a
clinical trial at the University of California at San Francisco, where
multiple courses of non-cross-resistant chemotherapy were used after
attainment of CR; the presence of the t(9;22) was associated with 100%
risk of relapse within 3 years.23 Our results for patients
with t(9;22) were similar whether they were treated before or after the
initiation of CALGB 8811. Therefore, the t(9;22) continues to be a poor
prognostic factor for patients with ALL and a major challenge for new therapies.
Patients with the t(4;11) are also known to have a poor outcome. They
either fail to achieve remission or their disease relapses within the
first year of therapy.24 The Groupe Francais de
Cytogenetique Hematologique studied 443 adult patients and correlated
the cytogenetic analyses with clinical data and outcome.18
In their series, patients with t(9;22) and t(4;11) had median
event-free survivals of 5 and 7 months, respectively. There were no
long-term surviving patients in the t(9;22) and in the t(4;11) groups
beyond 3 years and 1 year, respectively.
It is clear that other treatment modalities are needed for adults with
t(9;22) and t(4;11) ALL. Allogeneic transplantation is currently the
treatment of choice, providing CCR in 22% to 46% of transplanted
patients with t(9;22).25-28 Similar data are available for
patients with t(4;11) (IBMTR, unpublished data). Our data
are compatible with this, because all our long-term survivors underwent
BMT except for 1 patient. However, patients should be relatively young
(<60 years old) and have a healthy and histocompatible donor to be
candidates for allogeneic BMT. For those who do not meet these
criteria, other treatment modalities are needed. Novel approaches have
been suggested for patients with the t(9;22). These include the use of
interleukin-4 that has been shown to exert inhibitory activity against
cells with the t(9;22)29; CGP 57148, a synthetic protein
kinase inhibitor that has been shown to induce complete inhibition of
proliferation of colonies with the t(9;22) with no inhibition of normal
colony formation30; and specific inhibitors of the fusion
BCR/ABL mRNA such as ribozymes and antisense
oligonucleotides.31,32 Clearly, novel approaches are also
needed for patients with the t(4;11). In the meantime, allogeneic BMT
is the only potentially curative therapy for these patients.
This is the first report to show that patients with trisomy 8 represent
an unfavorable prognostic group in adult ALL even if they do not have
t(9;22). Previous reports have presumably included patients with +8
along with patients who had miscellaneous cytogenetic abnormalities
instead of analyzing them separately. Trisomy 8 as the sole abnormality
is infrequent and has been described in 4 of 413 (1.0%), 3 of 350 (0.9%), and 2 of 256 (0.4%) adult ALL patients (The Groupe Francais
de Cytogenetique Hematologique,18 Secker-Walker et
al,19 and this study). A study of a larger cohort of
patients analyzing the effect of 7 and +8 as independent prognostic factors in adult ALL patients is warranted.
Our study supports the concept that there may be some favorable
cytogenetic abnormalities in adult ALL. Deletions or translocations of
the short arm of chromosome 12 have been shown to represent a group
with favorable prognosis in adult ALL, regardless of other prognostic
factors, by Secker-Walker et al.19 In our study, it seems
that this group was younger than the normal group. Because age is a
known independent statistical prognostic factor for survival in adult
ALL, additional studies looking at larger groups of patients with
del(12p) or t(12p) are warranted. Similar to our data, the Groupe
Francais de Cytogenetique Hematologique demonstrated that t(10;14)(q24;q11) conferred a better prognosis for adult
ALL.18 However, to study the effect of rearrangement
involving t(14q11-q13) as an independent prognostic factor, a larger
study is needed. Identifying groups with favorable outcome has the
potential of reducing treatment intensiveness and thus toxicity without
negatively affecting treatment outcome.
Karyotypic changes at first relapse occurred in 68% of patients in the
current study. Normal karyotype changing to an abnormal karyotype or
the reverse may be the result of failing to identify the abnormal
clone. However, because other groups reported sequential studies in
patients with normal karyotype, we did the same. Although the number of
patients analyzed at diagnosis and at relapse represents only a
fraction of the total number of patients who relapsed, this is
nevertheless the largest such series published. Similar degrees of
karyotypic change have been described by Chucrallah et al33
in 21 of 32 patients (66%) and by Secker-Walker et al34 in
11 of 21 patients (53%). The stability of unfavorable risk karyotypes
as compared with miscellaneous karyotypes has been studied by all three
groups, although the other groups did not include 7 or +8 as an
unfavorable risk group. Similar to our findings, Chucrallah et
al33 demonstrated that 5 of 6 patients with unfavorable
risk cytogenetics were in the group that developed karyotypic changes
at relapse, whereas only 1 patient in the unfavorable risk cytogenetic
group had a stable clone at relapse. In contrast, Secker-Walker et
al34 demonstrated that 4 of 4 patients with unfavorable
risk abnormalities had stable clones at relapse. The numbers are small,
but when combined, there were 23 patients with unfavorable risk
abnormalities in all three series (Chucrallah et al,33
Secker-Walker et al,34 and this study). Of these, 15 (65%)
had a karyotypic change at relapse and 8 (35%) had stable karyotypes
at relapse. Therefore, having an unfavorable risk karyotype does not
necessarily suggest a higher probability for a change in karyotype at
relapse. This implies that additional changes other than those
detectable cytogenetically may be involved in the early relapse seen in
these patients.
Our data support the observations reported by the M.D. Anderson Cancer
Center group33 that survival after relapse was shorter for
patients with changes in the karyotype. Our data were of marginal statistical significance but show a similar trend, based on relatively few patients. Our data do not support the findings of shorter survival
from time of study entry. Continued cytogenetic evaluation at relapse
is needed to evaluate further the significance of clonal evolution.
We conclude that adult patients with ALL with the t(9;22), t(4;11),
7, and +8 have a poor outcome even when more intensive therapeutic regimens are used. New treatment modalities are clearly needed for this group of patients. For relapsed ALL, patients with
additional karyotypic changes may also represent an unfavorable risk group.
| |
APPENDIX |
The following CALGB institutions, principal investigators, and
cytogeneticists participated in this study (in alphabetical order):
Columbia University (New York, NY), Rose R. Ellison and Ram S. Verma
(Grant No. CA12011); Dana Farber Cancer Institute (Boston, MA), George
P. Canellos and Ramana Tantravahi (Grant No. CA32291); Dartmouth
Medical School (Lebanon, NH), Herbert Maurer and T.K. Mohandas (Grant
No. CA04326); Duke University Medical Center (Durham, NC), Jeffrey
Crawford and Mazin Qumsiyeh (Grant No. CA47577); Eastern Maine Medical
Center (Bangor, ME), Thomas Ervin and Laurent Beauregard (Grant No.
CA31946); Finsen Institute (Copenhagen, Denmark), Nis I. Nissen and
Preben Philip; Long Island Jewish Medical Center (New Hyde Park, NY),
Marc Citron and Prasad R.K. Koduru (Grant No. CA11028); Massachusetts
General Hospital (Boston, MA), Michael L. Grossbard and Leonard Atkins (Grant No. CA12449); McGill Department of Oncology (Montreal, Quebec,
Canada), Brian Leyland-Jones and Jacqueline Emond (Grant No. CA31809);
Medical Center of Delaware Christiana Hospital (Newark, DE), Irving
Berkowitz and Digamber Borgaonkar (Grant No. CA45418); Medical College
of Virginia (Richmond, VA), John D. Roberts, Colleen Jackson-Cook and
Judith A. Brown (Grant No. CA52784); Medical University of South
Carolina (Charleston, SC), Mark R. Green and Eduardo Cantú; Mount
Sinai Hospital (New York, NY), James F. Holland and Vesna Najfeld
(Grant No. CA04457); New York Hospital-Cornell Medical Center (New
York, NY), Ted P. Szatrowski and Ram S. Verma (Grant No. CA07968);
North Shore University Hospital (Manhasset, NY), Daniel R. Budman and
Prasad R.K. Koduru (Grant No. CA35279); Parkview Memorial Hospital
(Fort Wayne, IN), David Sciortino and Patricia I. Bader; Rhode Island
Hospital (Providence, RI), Louis A. Leone and Hon Fong Louie Mark
(Grant No. CA08025); Roswell Park Cancer Institute (Buffalo, NY), Ellis
G. Levine and AnneMarie W. Block (Grant Nos. CA37027 and CA59518); SUNY
Health Science Center at Syracuse (Syracuse, NY), Stephan Graziano and
Constance K. Stein (Grant No. CA21060); SUNY-Methodist Hospital of
Brooklyn (New York, NY), Sameer Rafla and Ram S. Verma; University of
Alabama at Birmingham (Birmingham, AL), Robert Diasio and Andrew J. Carroll (Grant No. CA47545); University of California at San Diego (San Diego, CA), Stephen Seagren and Renee Bernstein (Grant No. CA11789); University of Chicago Medical Center (Chicago, IL), Nicholas Vogelzang, Michelle M. LeBeau and D. Roulston (Grant No. CA41287); University of
Iowa Hospitals (Iowa City, IA), Gerald Clamon and Shivanand R. Patil
(Grant No. CA47642); University of Maryland Cancer Center (Baltimore,
MD), Ernest Borden and Judith Stamberg (Grant No. CA31983); University
of Massachusetts Medical Center (Worcester, MA), F. Marc Stewart and
Vikram Jaswaney (Grant No. CA37135); University of Minnesota
(Minneapolis, MN), Bruce A. Peterson and Diane C. Arthur (Grant No.
CA16450); University of Missouri/Ellis Fischel Cancer Center (Columbia,
MO), Michael Perry and Tim Huang (Grant No. CA12046); University of
North Carolina at Chapel Hill (Chapel Hill, NC), Thomas C. Shea and
Kathleen W. Rao (Grant No. CA47559); University of Tennessee (Memphis,
TN), Alvin M. Mauer and Sugandhi A. Tharapel (Grant No. CA47555); Wake
Forest University School of Medicine (Winston-Salem, NC), Robert M. Cooper and Mark J. Pettenati (Grant No. CA03927); Walter Reed Army
Medical Center (Washington, DC), Nancy Dawson and Ratwal B. Surana
(Grant No. CA26806); Washington University-Barnes Hospital (St Louis,
MO), Daniel C. Ihde and Michael Watson (Grant No. CA47456).
| |
FOOTNOTES |
Submitted September 11, 1998; accepted February 4, 1999.
Supported in part by National Cancer Institute Grants No. CA77658,
CA16058, and CA31946 and by the Coleman Leukemia Research Fund (St
Paul, MN). The contents are solely the responsibility of the authors
and do not necessarily represent the official views of the National
Cancer Institute.
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 Meir Wetzler, MD, Division of Medicine,
Roswell Park Cancer Center, Buffalo, NY 14263; e-mail:
wetzler{at}SC3101.med.buffalo.edu.
| |
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TOP
ABSTRACT
INTRODUCTION