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2030
Clinical Significance of Philadelphia Chromosome
Positive Pediatric Acute Lymphoblastic Leukemia in
the Context of Contemporary Intensive Therapies
A Report from the Children’s Cancer Group
Fatih M. Uckun, M.D., Ph.D.1
James B. Nachman, M.D.2
Harland N. Sather, Ph.D.3,4
Martha G. Sensel, Ph.D.4
Peter Kraft, M.S.5
Peter G. Steinherz, M.D.6
Beverly Lange, M.D.7
Raymond Hutchinson, M.D.8
Gregory H. Reaman, M.D.9
Paul S. Gaynon, M.D.10
Nyla A. Heerema, Ph.D.11
1
Children’s Cancer Group ALL Biology Reference
Laboratory and Hughes Institute, St. Paul, Minnesota.
2
Section of Pediatric Hematology-Oncology, University of Chicago, Chicago, Illinois.
3
Department of Preventive Medicine, University of
Southern California, Los Angeles, California.
4
Group Operations Center, Children’s Cancer
Group, Arcadia, California.
5
Division of Biometry, University of Southern California, Los Angeles, California.
6
Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, New York.
7
Division of Oncology, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania.
8
Department of Pediatric Hematology-Oncology,
University of Michigan, Ann Arbor, Michigan.
BACKGROUND. Children with Philadelphia (Ph) chromosome positive (⫹) acute
lymphoblastic leukemia (ALL) represent a subgroup at very high risk for treatment
failure. In this report, the authors assessed the outcome of Ph⫹ ALL in a large
cohort of children treated on contemporary intensive chemotherapy protocols of
the Children’s Cancer Group (CCG).
METHODS. This study included 1322 children enrolled between 1988 –1995 on CCG
risk-adjusted studies for ALL who had centrally reviewed cytogenetic data. Thirty
patients had a t(9;22)(q34;q11) translocation and were referred to as Ph⫹; 1292
were Ph negative(⫺). Outcome analyses used standard life table methods.
RESULTS. Compared with Ph⫺ ALL patients, Ph⫹ ALL patients were more likely to
be black (P ⫽ 0.008), age ⬎10 years (P ⫽ 0.02), and have a leukocyte count
ⱖ50,000/L (P ⬍ 0.0001). Nearly all Ph⫹ (96.7%) and Ph⫺ (98.3%) patients achieved
remission after induction therapy, yet event free survival outcome was significantly
worse for Ph⫹ patients compared with Ph⫺ patients, with 4-year estimates of 20.1%
(standard deviation [SD] ⫽ 9.1%) and 75.8% (SD ⫽ 1.2%), respectively (P ⬍ 0.0001).
This difference was maintained among patients regardless of presenting leukocyte
count, age, or early response to therapy. Ten Ph⫹ patients underwent bone marrow
transplantation (BMT) at the time of first remission; six of these patients remained
event free at the time of analysis, and represent the majority (six of eight) of
patients surviving event free.
CONCLUSIONS. The findings of the current study confirm that Ph chromosome
positivity represents a significant independent adverse risk factor for childhood
ALL that has not been abrogated by current intensive chemotherapy programs.
BMT at the time of first remission, as well as other alternative strategies employing
biotherapeutic agents, should be considered in future front-line trials for pediatric
patients with Ph⫹ ALL. Cancer 1998;83:2030 –9.
© 1998 American Cancer Society.
KEYWORDS: Philadelphia chromosome, children, acute lymphoblastic leukemia,
cytogenetics.
9
Department of Hematology-Oncology, Children’s
National Medical Center and the George Washington University, Washington, D.C.
10
Department of Pediatric Hematology-Oncology,
University of Wisconsin, Madison, Wisconsin.
11
Department of Medical and Molecular Genetics,
Indiana University School of Medicine, Indianapolis, Indiana.
Supported in part by research grants, including Children’s Cancer Group Chairman’s grant
CA-13539, CA-51425 and CA-60437 from the Na© 1998 American Cancer Society
tional Cancer Institute, National Institutes of
Health.
Dr. F. M. Uckun is a Stohlman Scholar of the
Leukemia Society of America.
Address for reprints; Fatih M. Uckun, M.D.,
Ph.D., Children’s Cancer Group ALL Biology
Reference Laboratory and Hughes Institute,
2665 Long Lake Road, Suite 330, St. Paul, MN
55113.
Received February 4, 1998; revision received May
20, 1998; accepted June 5, 1998.
Ph Chromosome Positive Childhood ALL/Uckun et al.
T
he Philadelphia (Ph) chromosome, a cytogenetic
abnormality that is characterized by deletion or
translocation of 22q11, was described first in cases of
chronic myelogenous leukemia (CML)1,2 but is now
known to occur in 2–5% of all cases of childhood and
in 16 –25% of adult acute lymphoblastic leukemia
(ALL).2–5 In ALL, the Ph chromosome arises most often
through a t(9;22)(q34;q11), with translocation of the
c-abl proto-oncogene on chromosome 9 to either of
the two breakpoint regions within the BCR gene on
chromosome 22, which results in production of either
a 210-kDa or a 190-kDa fusion protein with tyrosine
kinase activity.6 – 8
Presence of a Ph chromosome appears to be an
independent adverse risk factor for children with
ALL3–5 despite the fact that it is associated with unfavorable presenting features, such as high leukocyte
count, older age, and French–American–British (FAB)
L2 morphology. Recent studies have suggested that
small subsets of Ph positive (Ph⫹) patients who have
low leukocyte count at diagnosis,9 show a “prednisone
good response,”10 or are treated with reinforced early
therapy followed by rotational therapy with noncross-resistant agents11 may have improved outcomes. The majority of children with Ph⫹ ALL, however, continue to experience extremely poor outcomes
despite treatment on contemporary intensive treatment regimens that are effective for most other children with ALL. In the current report, we have assessed
the incidence, prognostic significance, and treatment
outcome of Ph⫹ ALL in a large cohort of children
enrolled on risk-adjusted, contemporary, intensive
treatment protocols of the Children’s Cancer Group
(CCG). Our findings confirm that Ph chromosome
positivity represents a significant adverse risk factor
for ALL that has not been negated by current intensive
chemotherapy regimens and that bone marrow transplantation (BMT) appears to represent a promising
treatment modality for such patients.
MATERIALS AND METHODS
Patients
Diagnosis of ALL was based on morphologic, biochemical, and immunologic features of the leukemic
cells, including lymphoblast morphology on Wright–
Giemsa-stained bone marrow smears, positive nuclear
staining for terminal deoxynucleotidyl transferase
(TdT), negative staining for myeloperoxidase, and cell
surface expression of two or more lymphoid differentiation antigens, as described below. Between 1988
and 1995, a total of 3937 children (⬍21 years of age)
were entered on the CCG studies included in this
analysis (see below). Among these, 1322 patients had
centrally reviewed and accepted cytogenetic data: 30
2031
(2.3%) had t(9;22) and are referred to as Ph⫹, and 1292
(97.7%) were Ph negative (Ph⫺).
On CCG risk-adjusted ALL protocols, National
Cancer Institute (NCI) standard risk patients12 were
assigned either to CCG 1881, a low risk protocol for
children 2–9 years of age and leukocyte count
⬍10,000/␮L, or to CCG 1891, an intermediate risk
protocol for children 2–9 years of age and leukocyte
count 10,000 – 49,999/␮L or 1 year of age and leukocyte count ⬍50,000/␮L. Patients who would be classified as NCI poor risk12 were assigned to CCG 1883, a
protocol for infants less than 1 year of age, CCG 1882,
a high risk protocol for patients 1–9 years of age with
leukocyte count ⱖ50,000/␮L of age ⱖ10 years; or CCG
1901, a high risk protocol for patients with lymphomatous features. Definition of organomegaly (moderate or marked enlargement) and lymphomatous features were as described by Steinherz et al.13 Each
protocol was approved by the NCI and the Institutional Review Boards of the participating CCG-affiliated institutions. Informed consent was obtained
from parents, patients, or both, as deemed appropriate, according to Department of Health and Human
Services guidelines. From 1988 to mid-1993, no specific provisions were made for referring Ph⫹ patients
to BMT centers. In mid-1993, however, a CCG protocol
(CCG 1921) employing allogeneic BMT in first remission was initiated for treatment of high risk patients,
including those who were Ph⫹. Three patients in the
current analysis were transferred to CCG 1921.
Cytogenetic Analysis
Cytogenetic analysis of leukemic cells was performed
at diagnosis prior to initiation of therapy by local
institutions. The recommended procedure called for
preparation of banded chromosomes from unstimulated peripheral blood or direct and 24-hour-cultured
preparations of fresh bone marrow, as described previously.14 Chromosome abnormalities were designated by using the 1995 International System for Human Cytogenetics Nomenclature.15 Abnormal clones
were defined as two or more metaphase cells with
identical structural abnormalities or extra chromosomes or three or more metaphase cells with identical
missing chromosomes. Diagnosis of a normal karyotype required complete analysis of a minimum of 20
banded metaphases from bone marrow only. At least
two original karyotypes of each abnormal clone or, in
the case of normal cytogenetics, normal cells were
reviewed by at least two members of the CCG cytogenetics committee. The term “primary clone” was used
to identify the simplest karyotype, and assignment of
ploidy group and other groupings were based on the
primary clone. Deletions of chromosome 22 or 22q
2032
CANCER November 1, 1998 / Volume 83 / Number 9
were not considered to be cases of a Philadelphia
chromosome and were not included in this analysis.
Immunophenotyping
Immunophenotypic analysis of leukemic cells was
performed for a subset of patients in the current analysis. Mononuclear cell fractions comprised primarily
(ⱖ90%) of leukemic cells were isolated from pretreatment bone marrow aspirate samples by centrifugation
on Ficoll–Hypaque gradients. Immunophenotyping
was performed centrally in the CCG ALL Biology Reference Laboratory by indirect immunofluorescence
and flow cytometry, using monoclonal antibodies reactive with the following differentiation antigens: CD2,
CD3, CD5, CD7, CD10, CD19, CD24, and CD34, as
previously described.16 Patients were classified as B
lineage if ⱖ30% of their leukemic cells were positive
for CD19 or CD24 and if ⬍30% of their leukemic cells
were positive for CD2, CD5, or CD7. Patients were
classified as T lineage if ⱖ30% of their leukemic cells
were positive for CD2, CD5, or CD7 and if ⬍30% of
their leukemic cells were positive for CD19 or CD24.
Statistical Methods
Data analysis used patient information current to November, 1996. Patients with or without t(9;22) translocations were compared with respect to various clinical, demographic, and laboratory features by using
chi-square tests for homogeneity of proportions. In
selected cases, we also compared B-lineage t(9;22)⫹
and t(9;22)⫺ patients according to recently published
NCI risk-classification criteria. The cohort of patients
with accepted cytogenetic data was also compared
with concurrently enrolled patients with unaccepted
cytogenetic data. Most of the outcome analyses used
life table methods and associated statistics. The primary endpoint examined was event free survival (EFS)
from entry on study. EFS events included induction
failure (nonresponse to therapy or death during induction), leukemic relapse at any site, death during
remission, or second malignant neoplasm, which ever
occurred first. Patients who did not experience an
event at the time of EFS analysis were censored at the
time of their last contact. A secondary endpoint, disease free survival (DFS), was the time to the first
occurrence of an event (relapse at any site, death in
remission, or second malignant neoplasm) from the
start of the consolidation phase (i.e., postinduction).
Patients without an event were censored at the time of
last contact. Life table estimates were calculated by
the Kaplan–Meier (KM) procedure, and the standard
deviation (SD) of the life table estimate was obtained
by using Greenwood’s formula.17 To indicate precision, the KM estimate of EFS and its SD are provided
at selected time points. An approximate 95% confidence interval can be obtained from the life table
estimate ⫾1.96 SDs. Life table comparisons of EFS
outcome patterns for patient groups generally used
the log rank statistic.18,19 P values for life table comparisons are based on the patterns of outcome across
the entire period of patient follow-up but also may be
given at specific time points for comparative purposes. P values ⱕ0.05 are referred to as significant.
RESULTS
Presenting Features of Phⴙ Patients
Patients with Ph⫹ ALL were similar to Ph⫺ patients
with respect to many presenting characteristics, yet
several important differences were noted (Table 1).
Compared with Ph⫺ ALL patients, Ph⫹ patients were
more likely to be black (P ⫽ 0.008), older than 10 years
of age (P ⫽ 0.02), and more likely to have leukocyte
counts ⱖ50,000/␮L (P ⬍ 0.0001) and splenomegaly
(P ⬍ 0.001). Indeed, the majority of Ph⫹ patients were
clustered in the combined group with age ⱖ10 years
and leukocyte counts ⱖ50,000/␮L. Among Ph⫹ patients with immunophenotypic data, 25 of 26 had
B-lineage ALL. Moreover, 90.9% of B-lineage Ph⫹ patients had the immature, B-progenitor immunophenotype CD10⫹CD19⫹CD34⫹ compared with only
63.4% of B-lineage Ph⫺ patients. The majority of Ph⫹
ALL patients (86.7%) were assigned to high risk CCG
protocols due to their unfavorable clinical features;
only four Ph⫹ patients were assigned to the low or
intermediate risk CCG studies, and no Ph⫹ patients
were infants. Within the B-lineage subset, 84.0% of
Ph⫹ patients met the NCI poor risk criteria. Most Ph⫹
patients (70.0%) had pseudodiploid karyotypes and,
notably, only one had ⬎50 chromosomes in the primary clone.
Presenting features for the entire cohort of patients for whom cytogenetic data were accepted generally were similar to those of concurrently enrolled
patients for whom cytogenetic data were unaccepted
or unavailable. However, patients with accepted cytogenetics were less likely to be in the “other” race group
(P ⬍ 0.0001), more likely to have elevated hemoglobin
(P ⬍ 0.0001) and platelet (P ⫽ 0.007) levels, and more
likely to have T-lineage ALL (P ⫽ 0.02).
Karyotypes of Phⴙ Patients
Karyotypes of the 30 Ph⫹ ALL patients are shown in
Table 2. With the exception of patient 19, all patients
in this series presented with a balanced t(9;22)(q34;
q11). Patient 19 had a complex rearrangement involving chromosome arms 7p, 7q, 9q, 19p, and 22q, resulting in an apparent Ph chromosome. In nine cases
(patients 1, 6, 8, 18, 20, 22, 23, 25, and 30), a balanced
Ph Chromosome Positive Childhood ALL/Uckun et al.
2033
TABLE 1
Presenting Features of Children with Phⴙ and Phⴚ Acute Lymphoblastic Leukemia
Phⴚ (n ⴝ 1292)
Phⴙ (n ⴝ 30)
Variable
Category
No.
(%)
No.
%
P value*
Age (yr)
⬍1
1–9
ⱖ10
⬍20
20–49
ⱖ50
Male
Female
White
Black
Other
Yes
No
Normal
Mod. enlargeda
Markedly enlarged
Normal
Mod. enlarged
Markedly enlarged
Normal
Mod. enlarged
Markedly enlarged
Absent
Small
Large
1.0–7.9
8.0–10.9
ⱖ11.0
1–49
50–149
ⱖ150
Yes
No
L1, L1/L2
L2/L1, L2
B lineage
T lineage
Standard
Poor
Low
Intermediate
High
Lymphomatous
Infant
Normal (46)
Hypoploid (⬍46)
Pseudodiploid (46)
Hyperdiploid (47–50)
Hyperdiploid (⬎46)
56
919
317
756
190
346
715
577
1046
85
159
30
1261
630
608
50
580
611
101
655
536
101
1171
47
73
650
422
207
605
387
295
56
1227
1121
170
789
168
470
278
257
392
433
154
56
399
69
347
143
334
4.3
71.1
24.5
58.5
14.7
26.8
55.3
44.7
81.1
6.6
12.3
2.3
97.7
48.9
47.2
3.9
44.9
47.3
7.8
50.7
41.5
7.8
90.7
3.6
5.7
50.8
33.0
16.2
47.0
30.1
22.9
4.4
95.6
86.8
13.2
82.4
17.6
62.8
37.2
19.9
30.3
33.5
11.9
4.3
30.9
5.3
26.9
11.1
25.9
0
16
14
5
3
22
15
15
23
6
1
0
30
14
14
2
3
25
2
11
18
1
30
0
0
17
8
4
19
4
7
1
29
25
5
25
1
4
21
1
3
23
3
0
0
5
21
3
1
0.0
53.3
46.7
16.7
10.0
73.3
50.0
50.0
76.7
20.0
3.3
0.0
100.0
46.7
46.7
6.7
10.0
83.3
6.7
36.7
60.0
3.3
100.0
0.0
0.0
58.6
27.6
13.8
63.3
13.3
23.3
3.3
96.7
83.3
16.7
96.2
3.8
16.0
84.0
3.3
10.0
76.7
10.0
0.0
0.0
16.7
70.0
10.0
3.3
0.02
Leukocyte count (⫻109/liter)
Sex
Race
Down’s syndrome
Liver
Spleen
Lymph nodes
Mediastinal mass
Hemoglobin (g/dL)
Platelets (⫻109/liter)
CNS disease at diagnosis
FAB morphology
Immunophenotype
NCI risk groupb
CCG study group
Chromosome number
⬍0.0001
0.69
0.008
0.82
0.74
⬍0.001
0.12
0.22
0.71
0.11
0.78
0.77
0.12
⬍0.0001
⬍0.0001
⬍0.0001
Ph⫹: Philadelphia chromosome positive; Ph⫺: Philadelphia chromosome negative; central nervous system: FAB: French–American–British; NCI: National Cancer Institute; CCG: Children’s Cancer group.
a
Degree of organomegaly and size of mediastinal mass were determined as described in Materials and Methods.
b
Patients with B lineage acute lymphoblastic leukemia only.
* Global chi-square test for homogeneity.
2034
CANCER November 1, 1998 / Volume 83 / Number 9
TABLE 2
Karyotypes of Children with Phⴙ Acute Lymphoblastic Leukemia
Patient
Karyotypea
1
2b
3b
4b,c
5c
6
7a
8
9d
10b
11
12b
13b
14c
15b
16d
17b
18
19b
20
21b
22
23
24b
25
26c
27
28b,d
29
30
46,XX,t(9;22)(q34;q11)
45,XY,dic(7;9)(p11;p11),t(9;22)(q34;q11)
46,XX,ider(9)(q10)t(9;22)(q34;q11),der(22)t(9;22)(q34;q11)
47,XY,del(9)(p22),t(9;22)(q34;q11),⫹der(22)t(9;22)(q34;q11)/46,idem,⫹9,⫺del(9)(p22)
55,XX,⫹X,⫹2,⫹4,⫹6,t(9;22)(q34;q11.2),⫹14,⫹18,⫹21,⫹21,⫹der(22)t(9;22)/55,idem,dup(1)(pter3q21::q323q21::q253q32::q253qter)
46,XY,t(9;22)(q34;q11)
46,XX,t(9;22)(q34;q11)/47,idem,t(8;11)(p10;q10),⫹der(22)t(9;22)
46,XY,t(9;22)(q34;q11)
45,XX,⫺7,t(9;22)(q34;q11)
46,XX,der(9)del(9)(p?21)t(9;22)(q34;q11),der(22)t(9;22)(q34;q11)/45,idem,⫺15
46,XY,t(9;22)(q34;q11)/46,idem,add(19)(p13)/46,idem,der(19)del(19)(p11)add(19)(q13)
46,XY,del(9)(p13),t(9;22)(q34;q11)
46,XY,t(9;22)(q34;q11)/46,idem,i(9)(q10),del(11)(q13q23)
46,XX,t(3;15)(p21;q15),t(9;22)(q34;q11)/47,idem,⫹der(22)t(9;22)
46,XX,der(9)del(9)(p?21)t(9;22)(q34;q11),der(22)t(9;22)(q34;q11)
45,XY,⫺7/45,idem,t(9;22)(q34;q11)
45,XX,del(9)(p13p24),t(9;22)(q34;q11),⫺15,der(20)t(15;20)(q13;q13.3)
46,XX,t(9;22)(q34;q11.2)
46,XY,der(7)t(7;19)(p15;p13.1)t(7;22)(q11.2;q11),ider(9)(q10)t(7;9)(p15;q34),der(19)t(7;19)(q11.2;p13.1),der(22)t(9;22)(q34;q11)
46,XX,t(9;22)(q34;q11.2)
47,XY,⫹8,ider(9)(q10)t(9;22)(q34;q11),der(22)t(9;22)(q34;q11)/48,idem,⫹mar
46,XX,t(9;22)(q34;q11)
46,XX,t(9;22)(q34;q11.2)
46,XX,del(1)(q32q42),⫺9,t(9;22)(q34;q11),⫹mar
46,XY,t(9;22)(q34;q11)
46,XX,t(9;22)(q34;q11)/58,idem,⫹X,⫹4,⫹4,⫹6,⫹10,⫹14,⫹14,⫹17,⫹18,⫹18,⫹21,⫹der(22)t(9;22)
49,XY,⫹X,t(9;22)(q34;q11),⫹17,⫹mar
45,X,⫺Y,⫺7,del(9)(p22),t(9;22)(q34;q11.2),del(10)(q22q24),der(12)t(Y;12)(q12;p13),⫹mar
46,XY,der(1)t(1;1)(p36;q21),t(9;22)(q34;q11)
46,XY,t(9;22)(q34;q11)
a
Karyotypic nomenclature according to ISCN guidelines15; additional abnormalities are indicated.
9p del.
c
⫹der(22)t(9;22).
d
Monosomy 7.
b
t(9;22)(q34;q11) was the sole abnormality. Four additional cases (patients 7, 11, 13, and 26) with multiple
clones had a clone with t(9;22) as the sole abnormality.
Five patients (4, 5, 7, 14, and 26) had a duplicate Ph
chromosome, i.e., ⫹der(22)t(9;22); all of these patients
had complex karyotypes with additional abnormalities. Monosomy 7 was observed in only three patients
(9, 16, and 28); it is noteworthy that this abnormality
was the primary clone in patient 16, because ten cells
had monosomy 7 as the sole abnormality, and three
cells also had a Ph chromosome. Deletions of the short
arm of chromosome 9 were observed in 12 patients
including the complex rearrangement of patient 19.
Four of these patients (3, 13, 19, and 21) had an i(9q),
three of the der(9)t(9;22) and one of the homolog. In 5
of the 12 cases, the der(9)t(9;22) also had deletion or
loss of 9p; the other 7 cases had deletion or loss of the
homolog. Only one patient (5) was high hyperdiploid
(⬎50), although a second patient (26) had a high hy-
perdiploid clone secondary to a pseudodiploid primary clone.
Treatment Outcome
EFS outcome for the entire cohort of patients for
whom cytogenetic data were available resembled that
of concurrently enrolled patients for whom cytogenetics data were not available (P ⫽ 0.66; data not shown).
Thus, patients who were included in the analysis of
EFS outcome were representative of all patients concurrently enrolled in CCG ALL treatment programs.
Although the majority of both Ph⫹ (96.7%) and Ph⫺
(98.3%) patients achieved remission following induction therapy, EFS outcome was significantly worse for
Ph⫹ patients compared with Ph⫺ patients, with 4-year
estimates of 20.1% (SD ⫽ 9.1%) and 75.8% (SD ⫽
1.2%), respectively (P ⬍ 0.0001; Fig. 1). Median follow-up for all event free survivors was 39 months
(range, 24 – 61 months). Of the eight patients who sur-
Ph Chromosome Positive Childhood ALL/Uckun et al.
FIGURE 1. Event free survival for children with Philadelphia (Ph) chromosome positive (Ph⫹) and negative (Ph⫺) acute lymphoblastic leukemia. Percentages of 30 Ph⫹ and 1292 Ph⫺ patients surviving event free during
follow-up. Numbers of patients remaining in follow-up at 0, 1, 2, 3, 4, or 5
years were 30, 16, 15, 11, 3, and 1, respectively, for Ph⫹ and 1292, 1186,
1091, 923, 665, and 393, respectively, for Ph⫺.
vived event free at the time of the analysis, six underwent BMT in first remission (see below), and two
received only chemotherapy. Seven of these eight patients (including all six who underwent BMT) remain
event free with additional follow-up of 100 – 400 days;
the other patient, who received only chemotherapy,
had a marrow relapse at 3.8 years. By comparison,
overall 7-year EFS for the entire cohort of patients
enrolled on CCG studies during this treatment era was
70.7% (SD ⫽ 0.9%). Overall survival, although more
favorable than EFS, was also significantly worse for
Ph⫹ patients compared with Ph⫺ patients, with 4-year
estimates of 56% (SD ⫽ 9.2%) and 85.3% (SD ⫽ 1.0%),
respectively (P ⫽ ⬍ 0.0001). Six Ph⫹ patients remain
alive after an event and range in follow-up from 1 year
to 3.3 years postrelapse. One of these six patients has
had a second relapse.
The difference in outcome observed for Ph⫹ versus Ph⫺ patients was maintained within the subgroup
of patients (n ⫽ 456) assigned to the high risk CCG
1882 study, with 4-year EFS of 11.3% (SD ⫽ 9.8%) and
73.4% (SD ⫽ 2.3%) for Ph⫹ and Ph⫺ patients, respectively (P ⬍ 0.0001). Among the three Ph⫹ patients
enrolled on CCG-1901 (study for ALL with lymphomatous features), only one patient experienced an event;
however, one of the patients who remained event free
2035
underwent BMT in first remission (see below). There
were three patients enrolled on CCG 1891 (intermediate risk ALL) and one patient enrolled on CCG 1881
(low risk ALL); three of these four patients had events,
and the one event free survivor underwent BMT in
first remission.
Poor outcome was observed for Ph⫹ patients regardless of age at diagnosis, with 4-year EFS rates of
21.2% (SD ⫽ 12.1%) and 28.6% (SD ⫽ 24.1%) for Ph⫹
patients ages ⬍10 years and ⱖ10 years, respectively
(P ⬍ 0.25; Fig. 2). Likewise, the 4-year EFS for Ph⫹
patients with leukocyte count ⱖ50,000/␮L was 17.9%
(SD ⫽ 10.3%), and six of the 8 Ph⫹ patients with
leukocyte counts ⬍50,000/␮L experienced an event,
with an estimated median EFS of 3.4 years (range
0.7–5.6 years; Fig. 3). Five patients had leukocyte
counts ⱕ25,000/␮L; three of these patients had events
at 3.4 years, 5.6 years, and 11 months after diagnosis.
Furthermore, for the subset of 23 Ph⫹ ALL patients
with Day 7 marrow status data who achieved a remission to induction therapy, initial response to treatment did not affect outcome: four-year DFS rates were
22.2% (SD ⫽ 12.8%) and 27.3%) for rapid early responders (ⱕ25% marrow blasts on Day 7 of induction
chemotherapy)20 and slow early responders (⬎25%
marrow blasts on Day 7 of induction chemotherapy),
respectively (Fig. 4).
It is interesting to note that among all older patients with leukocyte counts ⱖ50,000/␮L, those with
B-lineage ALL had worse outcomes than those with
T-lineage ALL (P ⫽ 0.005; data not shown). The worse
treatment outcome of this subset of B-lineage patients
can be attributed to the presence of the Ph chromosome (Fig. 5): Ph⫹ B-lineage patients had significantly
worse outcome than that of either T-lineage or P⫺
B-lineage patients (P ⬍ 0.001 and P ⫽ 0.001, respectively).
Outcome for the five patients harboring two copies of the Ph chromosome (patients 4, 5, 7, 14, and 26)
did not appear to be different from that of the other
Ph⫹ patients. Two of the five patients died 1.5 years or
less from study entry. Three of the five patients remain
alive: One underwent BMT in first remission and has
remained event free 2.6 years post-BMT, one underwent BMT after a late marrow relapse and has survived 0.7 years post-BMT, and one received chemotherapy only and had survived 3.4 years. Among the
three patients with monosomy 7, two had a marrow
relapse, and the third died in remission due to a grampositive micrococcal infection. The patient with the
high hyperdiploid clone (patient 5) also underwent
BMT in first remission and is one of the event free
survivors.
2036
CANCER November 1, 1998 / Volume 83 / Number 9
Event free survival for children with Ph⫹ and Ph⫺ acute
lymphoblastic leukemia with white blood count (WBC) ⱖ 50,000/␮L at
diagnosis. Number of patients remaining in follow-up at 0, 1, 2, 3, 4, or 5
years were 22, 10, 9, 6, 2, and 0 for Ph⫹ and 346, 298, 261, 199, 135,
and 86 for Ph⫺.
FIGURE 3.
FIGURE 2. Event free survival for children with Ph⫹ and Ph⫺ acute lymphoblastic leukemia according to age. (A) Age ⬍ 10 years. Number of patients
remaining in follow-up at 0, 1, 2, 3, 4, or 5 years were 16, 11, 10, 8, 2, and 0 for
Ph⫹ and 975, 907, 837, 474, 537, and 323 for Ph⫺. (B) Age ⱖ 10 years. Number
of patients remaining in follow-up at 0, 1, 2, 3, 4, or 5 years were 14, 5, 5, 3, 1
and 1 for Ph⫹ and 317, 279, 254, 176, 128, and 70 for Ph⫺.
Outcome After BMT for Phⴙ ALL
Fifteen (50%) Ph⫹ patients in the overall cohort underwent BMT (matched sibling donor, n ⫽ 5; matched
or partially matched unrelated donor, n ⫽ 7; unspecified, n ⫽ 3). Ten of the 15 patients (1882; n ⫽ 8; 1891,
n ⫽ 1901, n ⫽ 1) underwent BMT in first remission
that ranged from 87 days to 488 days (median 135
days). These patients ranged in age from 1 year to 16.3
years (median, 7.6 years) and had leukocyte counts
ranging from 9,900/␮L to 800,000/␮L (median, 99,400/
␮L); all but two patients had leukocyte counts
ⱖ50,000/␮L. Among these ten patients, four had
events. Notably, the six patients (1882, n ⫽ 4; 1891,
n ⫽ 1; 1901, n ⫽ 1) who remain event-free after a first
remission BMT comprise the majority (6 of 8) of those
Ph⫹ patients who did not experience an event; moreover, median follow-up for these six patients is 38
months (range, 24 – 60 months), suggesting that long
term survival may be achieved. All of these patients, as
mentioned above, remain event free after an additional 100 – 400 days of follow-up. Five patients underwent BMT after an initial relapse; three of these have
died, and two remain in second remission for 0.7 and
3 years post-BMT.
DISCUSSION
We have determined the incidence and treatment outcome for Ph⫹ ALL in large cohort of children enrolled
on contemporary, intensive risk adjusted treatment
protocols of the CCG. Similar to reports by others,3–5
Ph Chromosome Positive Childhood ALL/Uckun et al.
2037
acute lymphoblastic
leukemia according to early marrow status. Numbers of patients remaining in
follow-up at 0, 1, 2, 3, 4, or 5 years, respectively, were 12, 7, 6, 6, 2, and 1
for patients with M1 or M2 marrow status at Day 7 of induction therapy and 11,
5, 5, 2, 1, and 0 for patients with M3 marrow status at Day 7 of induction
therapy.
FIGURE 5. Event free survival for children ⱖ10 years of age according to
immunophenotype and Philadelphia chromosome status. Percentages of 39 T
lineage (T), 9 Ph⫹ B-lineage, and 25 Ph⫺ B lineage (B) patients surviving
disease free during follow-up. Numbers of patients remaining in follow-up at 0,
1, 2, 3, 4, or 5 years, respectively, were 39, 34, 33, 26, 21, and 15 for T
lineage; 9, 1, 1, 0, 0, 0, and 0 Ph⫹ B lineage; and 25, 20, 17, 12, 7, and 4 for
Ph⫺ B lineage.
Ph⫹ ALL patients comprised 2.3% of all patients with
accepted to cytogenetic data. Other groups have reported that molecular genetic techniques may reveal
additional cases with BCR-ABL fusion genes that were
not apparent with cytogenetic analysis.21 We did not
employ such techniques for diagnosis of Ph⫹ ALL in
this series but are doing so for identification of Ph⫹
ALL in our ongoing trials. Any differences in outcome
of patients diagnosed with molecular techniques await
completion of the ongoing trials. In the cohort analyzed herein, patients were older and had higher leukocyte counts than their Ph⫺ counterparts. Unlike
previous studies,3–5 we did not find an increased frequency of FAB L2 morphology but did note that Ph⫹
patients were more likely to be black than Ph⫺ patients. Consistent with previous reports,4,5 Ph⫹ ALL
occurred preferentially among patients with a B-lineage immunophenotype.
Cytogenetically, the majority of Ph⫹ patients were
pseudodiploid, and only one patient exhibited the favorable characteristic of hyperdiploidy ⬎50. Similar to
other reports,4,5,22 one patient in the current analysis
had a variant Ph chromosome, and 29 patients had a
balanced t(9;22)(q34;q11) either alone or in combination with other cytogenetic abnormalities. Five pa-
tients harbored a second copy of the Ph chromosome,
i.e., ⫹der(22)t(9;22). Although such patients with a
second Ph chromosome might be expected to exhibit
more aggressive disease progression than those with
only a single Ph chromosome, we found no evidence
for such a result in the current analysis. Monosomy 7,
which has been reported to occur frequently and to
confer increased risk in Ph⫹ ALL,23 was observed in
only three patients, all of whom experienced events.
Larger numbers of patients must be studied to determine unequivocally the significance of this cytogenetic abnormality in the context of Ph chromosome
positivity. We observed a del(9p), which has been observed frequently in lymphomatous ALL24 and T-lineage ALL,25 and was associated with poor outcome in
B-lineage ALL,26 in 12 of our 30 patients. It is noteworthy that only one of the eight patients without events
had a deletion of 9p, whereas 11 of the 22 patients with
events had a deletion of 9p.
The majority of Ph⫹ patients in the current study
achieved remission following induction therapy. EFS
outcome, however, was poor for the overall group of
Ph⫹ patients, with an estimated 4-year EFS of only
20%. Although t(9;22) was observed primarily among
patients with older age and higher leukocyte counts at
FIGURE 4. Disease free survival for children with Ph
⫹
2038
CANCER November 1, 1998 / Volume 83 / Number 9
diagnosis, this translocation nevertheless was a significant risk factor for patients presenting with leukocyte
counts ⬍50,000/␮L or age 1–9 years. Ribeiro et al.9
have reported that Ph⫹ ALL pediatric patients with
leukocyte counts ⱕ25,000/␮L had improved outcomes
compared with other Ph⫹ children. In our cohort,
even Ph⫹ patients with leukocyte counts ⱕ25,000/␮L
had a high rate of relapse. Larger numbers of patients
would be required to determine the true prognostic
significance of leukocyte counts in Ph⫹ ALL. In contrast to a recent report on children with Ph⫹ ALL who
achieved a good response to initial prednisone therapy.10 Ph⫹ patients in the current study who had a
rapid early response to induction therapy nevertheless
had poor DFS outcome. The poor outcome for those
with rapid early response in this series compared with
other studies may be attributable to differences in
treatment. For example, Arico et al. employed high
dose methotrexate as part of central nervous system
therapy for high risk patients including those with Ph⫹
ALL.10
Presence of the Ph chromosome appeared to be
the primary factor responsible for the worse outcome
observed in the CCG among older B-lineage ALL patients with high leukocyte counts compared with their
T-lineage ALL counterparts. The majority of Ph⫹ ALL
patients were treated on intensive chemotherapy protocols designed for higher risk patients, although
treatment regimens differed. Regardless of the individual treatment regimen, outcome was uniformly
poor for all Ph⫹ patients. It is noteworthy that these
intensive chemotherapy programs have proven successful for the majority of patients formerly deemed
high risk, including those with a T-lineage immunophenotype,27 those with lymphomatous presentation,28 those showing slow early response (SER) to
induction therapy,29 and the majority of those with a
t(1;19) translocation.30 Furthermore, the negative impact of the Ph chromosome apparently outweighed
the previously observed, favorable effect of the CD10⫹
CD19⫹ CD34⫹ B-progenitor immunophenotype,31 because this profile was observed in the majority of our
Ph⫹ patients. These findings confirm and extend reports by others that Ph⫹ ALL continues to confer adverse risk despite contemporary intensive chemotherapy regimens that yield successful outcomes for the
majority of ALL patients.3,4
BMT has been employed with some success
among small numbers of pediatric Ph⫹ ALL patients.3–5,32 In the current cohort, ten patients received a BMT in first remission, and it is notable
that although the pretransplant conditioning regimens were not uniform, six of these ten patients
remained event free for extended periods following
BMT. Moreover, these six patients represent the
majority (6 of 8) of those patients who have not
experienced an event. These data are suggestive of a
beneficial effect of first remission BMT compared
with chemotherapy alone for patients with Ph⫹ ALL.
In summary, the presence of a Philadelphia chromosome remains a significant adverse risk factor for
childhood ALL that has not been abrogated by contemporary intensive therapies. These results emphasize the need for improved treatment programs for
Ph⫹ ALL and strongly support the notion that this
patient population should be considered for BMT in
first remission. The application of alternative treatment strategies, such as reinforced early therapy/rotational continuation therapy,11 targeted inhibition of
BCR-ABL tyrosine kinase activity,33–36 or experimental
therapies, such as use of antisense BCR-ABL oligonucleotides,37 perhaps in the context of BMT, also warrant future consideration for treatment of patients
with Ph⫹ ALL.
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