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600
Treatment of Patients with Acute Lymphoblastic
Leukemia with Bulky Extramedullary Disease and
T-Cell Phenotype or Other Poor Prognostic Features
Randomized Controlled Trial from the Children’s Cancer Group
Peter G. Steinherz, M.D.1
Paul S. Gaynon, M.D.2
John C. Breneman, M.D.3
Joel M. Cherlow, M.D.4
Neil J. Grossman, M.D.5
John H. Kersey, M.D.6
Helen S. Johnstone, M.D.7
Harland N. Sather, Ph.D.8
Michael E. Trigg, M.D.9
Fatih M. Uckun, M.D., Ph.D.6
W. Archie Bleyer, M.D.10
BACKGROUND. Children with acute lymphoblastic leukemia with multiple poor
prognostic factors and who have a lymphomatous mass at diagnosis, whether of
T- or non-T-immunophenotype, are at increased risk of short term remission and
extramedullary recurrence, and are in need of better therapies.
The authors thank Ms. Victoria Barbosa for secretarial assistance.
1
Department of Pediatrics, Memorial SloanKettering Cancer Center, New York, New York.
2
Department of Pediatrics, University of Wisconsin Medical Center, Madison, Wisconsin.
3
Division of Radiation Oncology, University of
Cincinnati Hospitals, Cincinnati, Ohio.
4
Department of Radiation Oncology, Miller Children’s Hospital, Long Beach, California.
5
Department of Hematology-Oncology, Children’s Hospital of Columbus, Columbus, Ohio.
6
Division of Pediatric Hematology-Oncology,
University of Minnesota Medical Center, Minneapolis, Minnesota.
7
Department of Pediatrics, University of Illinois,
Chicago, Illinois.
8
Department of Preventive Medicine, University of
Southern California School of Medicine, Los
Angeles, California.
9
Department of Bone Marrow Transplantation,
The University of Iowa Hospital and Clinics,
Iowa City, Iowa.
10
Chairman, Division of Pediatrics, University of
Texas, M. D. Anderson Cancer Center, Houston,
Texas.
Supported by grants from the Division of Cancer
Treatment, National Cancer Institute, National
Institutes of Health, U. S. Department of Health
and Human Services.
The following is a list of participating principal
investigators of the Children’s Cancer Group:
Group Operations Center Arcadia, CA: W. Archie
Bleyer, M.D., Anita Khayat, Ph.D., Harland Sather,
Ph.D., Mark Krailo, Ph.D., Jonathan Buckley,
M.B.B.S., Ph.D., Daniel Stram, Ph.D., and Richard
Sposto, Ph.D. (Grant CA 13539); University of
Michigan Medical Center, Ann Arbor, MI: Raymond Hutchinson, M.D. (Grant CA 02971); University of California Medical Center, San Francisco, CA: Katherine Matthay, M.D. (Grant CA
17829); University of Wisconsin Hospital, Madison, WI: Paul Gaynon, M.D. (Grant CA 05436);
Children’s Hospital & Medical Center, Seattle, WA:
Ronald Chard, M.D. (Grant CA 10382); Rainbow
Babies & Children’s Hospital, Cleveland, OH: Susan Shurin, M.D. (Grant CA 20320); Children’s
National Medical Center, Washington, DC: Gregory Reaman, M.D. (Grant CA 03888); Children’s
Memorial Hospital, Chicago, IL: Edward Baum,
M.D. (Grant CA 07431); Children’s Hospital of Los
Angeles, Los Angeles, CA: Jorge Ortega, M.D.
(Grant CA 02649); Children’s Hospital of Columbus, Columbus, OH: Frederick Ruymann, M.D.
(Grant CA 03750); Columbia Presbyterian College
of Physicians & Surgeons, New York, NY: Sergio
Piomelli, M.D. (Grant CA 03526); Children’s Hospital of Pittsburgh, Pittsburgh, PA: Joseph Mirro,
M.D. (Grant CA 36015); University of California
Medical Center (UCLA), Los Angeles, CA: Stephen
Feig, M.D. (Grant CA 27678); University of Iowa
Hospitals and Clinics, Iowa City, IA: Raymond
Tannous, M.D. (Grant CA 29314); Children’s Hospital of Denver, Denver, CO: Lorrie Odom, M.D.
(Grant CA 28851); Mayo Clinic and Foundation
Rochester, MN: Gerald Gilchrist, M.D. (Grant CA
28882); Izaak Walton Killam Hospital for Children,
Halifax, Nova Scotia, Canada: Dorothy Barnard,
M.D.; University of North Carolina, Chapel Hill,
q 1998 American Cancer Society
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NC: Joseph Wiley, M.D.; University of Medicine &
Dentistry of New Jersey, Camden, NJ: Milton Donaldson, M.D.; Children’s Mercy Hospital Kansas
City, MO: Maxine Hetherington, M.D.; University
of Nebraska Medical Center, Omaha, NE: Peter
Coccia, M.D.; Wyler Children’s Hospital Chicago,
IL: James Nachman, M.D.; M. D. Anderson Cancer
Center, Houston, TX: Beverly Raney, M.D.; New
York University Medical Center, New York, NY:
Aaron Rausen, M.D.; Children’s Hospital of Orange County, Orange, CA: Mitchell Cairo, M.D.;
Vanderbilt University School of Medicine, Nashville, TN: John Lukens, M.D. (Grant CA 26270);
Doernbecher Memorial Hospital for Children, Portland OR: Lawrence Wolff, M.D. (Grant CA 26044);
University of Minnesota Health Sciences Center,
Minneapolis, MN: William Woods, M.D. (Grant
CA 07306); University of Texas Health Sciences
Center, San Antonio, TX: Thomas Williams, M.D.
(Grant CA 36004); Children’s Hospital of Philadelphia, Philadelphia, PA: Anna Meadows, M.D.
(Grant CA 11796); Memorial Sloan-Kettering Cancer Center, New York, NY: Peter Steinherz, M.D.
(Grant CA 42764); James Whitcomb Riley Hospital for Children, Indianapolis, IN: Philip Breitfeld,
M.D. (Grant CA 13809); University of Utah Medical
Center, Salt Lake City, UT: Richard O’Brien, M.D.
(Grant CA 10198); Strong Memorial Hospital,
Rochester, NY: Harvey Cohen, M.D. (Grant CA
11174); University of British Columbia, Vancouver, British Columbia, Canada: Christopher Fryer,
M.D. (Grant CA 29013); Children’s Hospital Medical Center, Cincinnati, OH: Robert Wells, M.D.
(Grant CA 26126); and Harbor/UCLA & Miller Children’s Medical Center, Torrance/Long Beach, CA:
Jerry Finklestein, M.D. (Grant CA 14560).
Address for reprints: Peter G. Steinherz, M.D.,
Children’s Cancer Group, P.O. Box 60012, Arcadia, CA 91066-6012.
Received April 3, 1997; revision received July 30,
1997; accepted July 30, 1997.
Therapy of ALL with Lymphomatous Features/Steinherz et al.
601
METHODS. Six hundred and ninety-four eligible patients ranging in age from 1–
20 years were entered on the study. Sixty-five percent of the patients had Tcell immunophenotype. Of these, 678 were randomized to one of four regimens:
Regimen A: Berlin-Frankfurt-Munster (BFM) 76/79; Regimen B: LSA2-L2 with cranial irradiation; Regimen C: LSA2-L2 without cranial irradiation; and Regimen D:
the New York (NY) regimen.
RESULTS. Complete remission was induced in 97% of patients. The overall event
free survival (EFS) { the standard deviation was 60 { 4% 6 years after diagnosis,
in contrast to 36 { 6% in a comparable historic group. The EFS of the 371 T-cell
patients was 62 { 7%. EFS was best on the NY (67 { 7%) and the BFM (67 { 6%)
arms. These were significantly better than the EFS on the 2 LSA2-L2 regimens, with
an EFS of 53 { 8% (Regimen B) and 42 { 11% (Regimen C) (P Å 0.03 and 0.0003
for NY vs. Regimen B and NY vs. Regimen C; P Å 0.01 and 0.0001 for BFM vs.
Regimen B and BFM vs. Regimen C). Regimen C had a 3-fold greater central
nervous system (CNS) recurrence rate than the identical chemotherapy Regimen
B (16 { 5% vs. 6 { 4%; P Å 0.02), although the difference in overall EFS did not
reach the required level for significance. Testicular recurrence varied from 2–8%
in comparison with 20% in the historic group. EFS was not influenced by age,
gender, CNS disease at diagnosis, morphology, or immunophenotype. In addition
to treatment regimen and early response rate, initial leukocyte count, hemoglobin
level, liver, spleen, and lymph node enlargement, and the presence of a mediastinal
mass had univariate prognostic influence on EFS. In multivariate analysis, only
the kinetics of response, leukocyte count (unfavorably, P õ 0.0001), and mediastinal mass status (favorably, P Å 0.01) were prognostic.
CONCLUSIONS. The adverse prognostic implications of lymphomatous ALL can be
minimized by the NY and BFM regimens. Cranial irradiation resulted in better
CNS disease control when added to the LSA2-L2 regimen, but did not improve the
overall disease free survival. With improved systemic chemotherapy, there was no
excess of lymph node, testicular, or other local recurrence without prophylactic
irradiation to sites of initial bulk disease or to the testes. Cancer 1998;82:600–12.
q 1998 American Cancer Society.
KEYWORDS: acute lymphoblastic leukemia, T-cell leukemia, lymphomatous leukemia, poor prognosis, high risk.
A
nalysis of predictors of short term remission
among children with acute lymphoblastic leukemia (ALL) in past (1972 – 1982) Children’s Cancer
Group (CCG) studies identified a group of patients
differing from others, with a poor prognosis due to the
presence of bulky disease-bearing sites (lymphomatous mass) at diagnosis and by the predominance of
T-cell immunophenotype and by a high incidence of
extramedullary recurrence (Table 1).1 In 1983, the CCG
initiated a prospective, randomized, combined modality therapy trial (CCG-123) to improve event free survival (EFS) in this subgroup, and to identify the therapy
best suited to achieve that goal. Three protocols reported to result in better EFS than standard therapy
in patients with leukemia or lymphoma were compared: the CCG modified versions of the LSA2-L2 ,2 the
Berlin-Frankfurt- Munster (BFM) 76/79,3 and the New
York4 regimens. The need for irradiation to extraabdominal bulky disease sites and for central nervous
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system (CNS) prophylaxis also was evaluated. This
study presents the long term results with these therapies.
MATERIALS AND METHODS
Eligibility
All patients entered into this study had to meet individual institution human subjects review committee
approval and consent requirements in accordance
with the Department of Health and Human Services
and institutional policies.
The study group was defined based on analysis of
the results of 1537 patients on previous CCG trials
(101, 141, 141A, and 143) that enrolled patients between 1972 – 1978. The aim was to define a study subgroup with distinctive biologic or clinical features and
a predicted EFS of õ 40% in whom the risks of aggressive therapy would be justified. The prognostic significance of the group thus identified was confirmed
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CANCER February 1, 1998 / Volume 82 / Number 3
TABLE 1
Proportion and Outcome of Patients with ALL on CCG-101, 143, 141, 141A, 161, 162, and 163
CCG
no.
104
105
106
107
123
Risk group
% of
patients
Event free
survival
(5-yr)
Bone marrow
recurrence
(5-yr)
Overt isolated
CNS recurrence
(3-yr)a
Testicular
recurrenceb
(3-yr)a
Survival
(5-yr)
Good
Average
Poor
Infants
Lymphomatous
18
44
21
3
14
78%
55%
40%
21%
39%
10%
32%
8%
67%
46%
1–2%
5%
8%
3%
10%
4%
5%
12%
0%
20%
90%
72%
46%
27%
44%
ALL: acute lymphoblastic leukemia; CCG: Children’s Cancer Group; CNS: central nervous system.
a
Based on the results of the Children’s Cancer Group-160 studies.
b
Proportion in boys only.
The expected event free survival and type of recurrence by patient groups as defined by the eligibility for the Children’s Cancer Group (CCG)-100 series studies (104, 105, 106, 107, and 123) based on the experience
with similar patient populations on the two prior groupwide series of studies (101, 143, 141, 141A, 161, 162, and 163). The patients at high risk of recurrence were divided into three groups: infants age õ12
months (CCG-107), patients with lymphomatous features (CCG-123), and those patients with a poor prognosis because of leukocyte count ú50,000/ml or a leukocyte count of 10–50,000/ml with ú10% of patients
with L2 French–American–British morphology (CCG-106).
on a separate data base of 2225 patients accrued onto
CCG trials 161, 162, and 163 between 1978 – 1982.1 The
experience with these 3762 patients was referred to as
the ‘‘historic data.’’ 1 Patients were eligible for CCG123 if they had at least one site of bulky disease and,
in addition, they had at least one of three laboratory
criteria: T-cell phenotype, a leukocyte count ú 50,000/
mL, or hemoglobin ú 10 gm/dL. Bulky disease was
defined as: 1) a mediastinal mass ú 33% of the intrathoracic dimension at the level of the fifth thoracic
vertebra, 2) lymphadenopathy (ú 3 cm in dimension
for a single lymph node or ú 5 cm in dimension for
a group of contiguous lymph nodes), or 3) splenomegaly in the supine position with the spleen tip palpated
below the umbilicus. Infants age õ 12 months and
patients with French-American-British (FAB) classified
L3 leukemia were not eligible.
Therapy: CCG-123
Regimen A was the CCG modified version of the BFM
76/79 study.3 This therapy, described elsewhere in detail, included intensive induction/consolidation with
a reinduction/reintensification phase after a period of
interim maintenance and 1800 centigray (cGy) cranial
irradiation (10 doses of 180 cGy each) plus intrathecal
(IT) methotrexate for CNS prophylaxis. No radiotherapy (RT) to bulky disease sites was given (Fig. 1).
Regimens B and C were the CCG modified versions of the Memorial Sloan-Kettering Cancer Center
LSA2-L2 protocol (Fig. 2). This regimen as originally
described, and as used here in Regimen C, included
1500 cGy in 10 fractions to extraabdominal bulky disease sites (i.e., the neck, mediastinum, etc., but not to
liver, spleen, or intraabdominal lymph node sites), but
no prophylactic cranial radiotherapy (RT).2 Because of
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the propensity for extramedullary recurrence among
these patients on past therapies, there was concern
that intensive IT methotrexate alone would not be sufficient CNS prophylaxis. Therefore, patients were randomized to receive LSA2-L2 with (Regimen B) and
without (Regimen C) 1800 cGy cranial irradiation in
addition to the IT methotrexate. Patients with CNS
disease at diagnosis were not eligible for the Regimen
C (no cranial RT).
Regimen D was the New York (NY) regimen (Fig.
3).4 The protocol included a 5- drug remission induction with 1500 cGy to extraabdominal bulky disease
sites as in Regimen B and C. Cranial irradiation (1800
cGy) was given in addition to IT methotrexate during
a 4-drug consolidation phase and intensive rotating
pairs of drugs during maintenance.
Throughout maintenance chemotherapy patients
received IT methotrexate on the first day of each new
maintenance cycle (2 – 3-month intervals).
Subjects
There were a total of 708 patients entered on the study.
Of the 694 eligible patients, 678 agreed to randomization.
From April 1983 to October 1985, 260 patients
were randomized to Regimen A (88 patients), B (89
patients), and C (83 patients). In October 1985, there
appeared to be a disproportionate number of CNS recurrences on one of the coded regimens. Regimen C
(no CNS RT) was found to be the inferior regimen and
was closed to new patient entry in November 1985.
All isolated CNS events on Regimen C occurred early;
therefore, patients who received Regimen C for õ 6
months (14 patients) were recalled and given the
choice of receiving 1800 cGy cranial RT. With the clo-
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603
FIGURE 2. Overview of Regimens B and C-The Children’s Cancer Group
modified LSA2-L2 protocol. BCNU: carmustine, 30 mg/m2 intravenously
(IV); Ara-C: cytosine arabinoside, 150 mg/m2/day every 4 days; IT: intrathecal; SC: subcutaneously; IM: intramuscularly; PO: orally; CYT: cyclophosphamide, 600 mg/m2 IV; DNR: daunorubicin, 30 mg/m2 IV; VCR: vincristine, 2.0 mg/m2 IV; TG: thioguanine, 300 mg/m2/day orally every 4 days;
HU: hydroxyurea, 2400 mg/m2/day orally every 4 days; MTX: methotrexate,
10 mg/m2/day orally every 4 days.
FIGURE 1. Overview of Regimen A. The Children’s Cancer Group modified Berlin-Frankfurt-Munster 76/79. A dose of 1800 centigray (cGy) cranial
irradiation was delivered in 180-cGy fractions during Phase II. IT: intrathecal; IV: intravenously; IM: intramuscular; PO: orally; SC: subcutaneous; d:
day.
sure of Regimen C, Regimen D was added in December
1985, and the study continued as a three-arm randomization until April 1987, when patient entry to Regimen
B was discontinued. Randomization to Regimens A
and D ended in April 1989. A total of 678 patients
were randomized, to Regimens A (261 patients), B (163
patients), C (84 patients), and D (170 patients). The
results were last analyzed in July 1996, with a mini-
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mum follow-up of 6/ years for those not experiencing
an event. Events beyond this point are extremely rare,
and unlikely to effect the results. In fact, no adverse
events occurred on any of the study arms during the
last 2 years of observation.
The patient characteristics at diagnosis are shown
in Table 2. With the exception of immunoglobulin (Ig)
levels, the patients on this study differed significantly
in all parameters listed from those patients entered on
the other concurrent ALL studies (CCG-104, 105, 106,
and 107 for good, average, or poor prognosis patients
and infants, respectively). Of the patients on this study,
71% were male. Age at diagnosis ranged from 13
months to 20 years. Approximately 31% of patients
were age ú 10 years. Approximately 79% of patients
were white, 9% were black, and 12% were of other
ethnic origins. The most frequent site of bulky extra-
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CANCER February 1, 1998 / Volume 82 / Number 3
TABLE 2
Diagnostic Characteristics of Patients on CCG-123 and Concurrent
ALL Trials
FIGURE 3. Overview of Regimen D-The New York protocol. The lower
half of the figure depicts the repeating 56-day maintenance cycles. Doxorubicin (adriamycin) was discontinued after the first 10 maintenance cycles
for a maximum total anthracycline dose of 300 mg/m2 of doxorubicin and
120 mg/m2 of daunomycin. Ara-C: cytarabine; IT: intrathecal; IV: intravenously; SC: subcutaneously; IM: intramuscular; PO: orally; TG: thioguanine;
q: every.
medullary disease qualifying a patient for study entry
was the spleen (48% of patients). Lymphadenopathy
exceeding study eligibility criteria was present in 46%
and a large mediastinal mass was diagnosed in 40%
of patients.
The most frequent laboratory criterion allowing
study entry was T-cell immunophenotype (65%). Immunophenotyping was performed centrally by the
CCG reference laboratory as reported previously.5 Leukemic cells from 54% of the patients reacted with an
antibody cocktail against T-lineage antigens CD2,
CD5, and CD7. CD2, CD5, and CD7 antigens in ú 30%
of lymphoblasts were expressed in 59%, 61%, and 71%
of the cases, respectively. However, in only 4.7% of
patients was T-cell phenotype alone the determining
laboratory factor for study eligibility. CD24 (BA-1),
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Male
Age (yrs)
õ2
2–5
6–9
¢10
Leukocyte count
õ20,000/mL
20–49,000
50–99,000
¢100,000
Platelet count
õ50,000/mL
50–150,000
ú150,000
Hemoglobin ú10 gm/dL
FAB
L1
L1/L2
L2/L1
L2
CNS disease
Anti T-cocktail positive
T-lineage immunophenotype
Race
White
Black
Hispanic
Other
Immunoglobulins normal
Massive hepatomegaly
splenomegaly
mediastinal mass
lymphadenopathy
CCG-123
(n Å 694)
CCG-100s
(n Å 3018)a
P value
71%
56%
õ0.0001
7%
29%
33%
31%
12%
46%
22%
20%
2.5%
13%
23%
39%
60%
17%
10%
13%
35%
36%
29%
59%
50%
31%
19%
16%
74%
12%
8%
6%
5.2%
54%
65%
85%
8%
4%
3%
1.7%
17%
8%
79%
9%
9%
3%
65%
19%
48%
40%
46%
79%
5%
11%
5%
64%
3%
5%
0.2%
2%
õ0.0001
õ0.0001
õ0.0001
õ0.0001
õ0.0001
õ0.0001
õ0.0001
õ0.0001
õ0.0001
0.38
õ0.0001
õ0.0001
õ0.0001
õ0.0001
CCG: Children’s Cancer Group; ALL: acute lymphoblastic leukemia; FAB: French–American–British;
CNS: central nervous system.
a
CCG 104, 105, 106, and 107 for good, average, and poor prognosis patients, and for infants, respectively.
CD9 (BA-2), and CD10 (common acute lymphocytic
leukemia antigen) positivity was observed in 42 – 45%.
Human leukocyte antigen (HLA)-DR was positive in
44%. Occasional patients were positive with either myeloid antibody CD13 or CD33 (5%), or were cytoplasmic or surface Ig positive (5 – 10%). The derivation
of the lymphoblasts involved in the leukemic process
was believed to be: B lineage, 32.8%; T lineage, 60.4%;
biphenotypic (both T and B), 4.8%; and mixed lineage
(lymphoid and myeloid), 2%. Leukocytosis ú 50,000/
mL was observed in 62% of patients. Approximately
20% had a leukocyte count ú 200,000/mL. Hemoglobin
ú 10 gm/dL was present in 59% of patients. Two or
more sites of mass disease were observed in 29.7%,
and 56.8% had ¢ 2 laboratory criteria for study entry.
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Although 19.6% of patients had all 3 laboratory features, only 3.9% had mass disease at all 3 sites. Of the
6 eligibility criteria, ¢ 4 characteristics were present
in 34.3% of the population, but only 6 patients (0.9%)
had all 6 characteristics.
One or more of the Igs were depressed at diagnosis
in 35% of patients (IgG, 19%; IgM, 18%; and IgA, 15%).
FAB morphology by central review classified blasts
from 74% of cases as L1 and 26% as L2 (ú 10% were
L2).
Approximately 5% of the patients had CNS disease
at diagnosis. CNS disease was defined as ú5 cells/mL
in the cerebrospinal fluid (CSF ) with blasts on the
cytospin preparation. In the case of red blood cell contamination, the ratio of leukocytes to red blood cells
in the CSF had to be more than that in the peripheral
blood.
The patient characteristics of the four randomized
regimens were quite similar, indicating that the randomization achieved very comparable groups.
Early response of the bone marrow aspirate was
evaluated on Days 7 and 14 of remission induction in
the last cohort of 319 patients entered on study. The
bone marrow response was termed M1 , M2 , or M3 if
the residual blast percent was õ 5%, 5 – 25%, or ú 25%,
respectively. Slow early response was defined as ú
25% blasts on Day 7.
Statistical Methods
Chi-square tests for homogeneity of proportions were
used to compare patient characteristics on the randomized treatment regimens and to correlate various
characteristics and treatment groups on induction
outcome. The majority of the study analyses used life
table methods and associated statistics for describing
patient outcome. Life table estimates were calculated
by the Kaplan-Meier (KM) procedure and the standard
deviation (SD) of the life table estimate was obtained
using Greenwood’s formula.6 Often, the KM estimate
{ 2 SDs was provided, which gives an approximate
95% confidence interval estimate of the life table outcome being described. The primary endpoint examined was EFS from randomization or date on study.
EFS events included induction failure (nonresponse to
therapy or death during induction), leukemic recurrence at any site, death during remission, or second
malignant neoplasm, whichever occurred first. Patients not experiencing an event at the time of analysis
were censored in the EFS analysis at the time of their
last contact. Other life table endpoints examined include survival from randomization or date on study
and site specific recurrence occurring as isolated initial events (duration of hematologic remission, CNS
remission, and testicular remission). The site specific
analyses only examined the subset of patients who
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605
achieved initial remission of their disease and were
measured from the time of remission. Patients who
initially recurred of a cause other than the one being
examined in a site specific analysis were censored at
the time of that event. Sixteen eligible patients refused
randomization and were nonrandomly treated on 1 of
the regimens. These patients were not included in any
of the regimen comparisons, but were included in
analyses of prognostic factors for this population. All
comparisons of the randomized regimens used the
‘‘intent to treat’’ approach of comparing patients according to their originally randomized assignment, irrespective of whether they complied with the treatment approach throughout. Only 5 of the 678 randomized patients switched to another treatment on
randomization (2 patients on Regimen B and 1 each
on Regimens A, C, and D). When patients went off
study due to protocol noncompliance, they were still
followed for the occurrence of events and that information was used in the analyses.
Most of the life table comparisons of outcome pattern between randomized regimens and for prognostic
factors used the log rank statistic.7,8 Stratified log rank
tests occasionally were used to adjust for the possible
modifying effect of other single factors on the comparisons of interest.8,9 Multivariate regression analyses
used the Cox proportional hazards model.10 Estimates
of the life table relative hazard rate (RHR) for a particular event were calculated by the observed to expected
ratio method for log rank analyses and by the regression coefficient method in proportional hazards regression.11 P values for life table comparisons were
based on the pattern of outcome across the entire
period of patient follow-up, although life table estimates at specific time values frequently were given for
comparative purposes.
Because multiple regimens were being compared
in this study, there was a greater chance of false-positive results than in a simple two-regimen design. To
handle that possibility, a Bonferroni multiple comparison correction was used in determining the P values
reported here for all pairwise regimen comparisons.
The study design essentially was conducted in two
periods, each involving a randomization among three
regimens: 1) the initial randomization to Regimens A,
B, and C until Regimen C was dropped from the study,
and 2) the later period of randomization to Regimens
A, B, and D (although Regimen B was eliminated from
this randomization before completion of the study).
The Bonferroni correction that was used was based on
a three-regimen comparison that modified the simple
unadjusted pairwise comparison P value by multiplying it by three (e.g., the unadjusted P value of 0.03
would become 0.09). For the conventional 5% significance level that was used in these analyses, the Bonfer-
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606
CANCER February 1, 1998 / Volume 82 / Number 3
roni correction would limit the chance of any falsepositive conclusion among the three regimens to õ
5%. Patients from both periods of the study were used
in regimen comparisons because examination of the
data showed good homogeneity of outcome for those
regimens used in both periods (Regimens A and B)
and provided better statistical power for detecting differences. Comparison of Regimens C and D also was
provided for information; however, none of those patients actually were randomized during the same time
period because Regimen D only was added to the
study after Regimen C was eliminated. Because Regimen C did not include patients with CNS disease at
diagnosis (there was a separate stratified randomization of those patients to just Regimens A, B, and D),
all comparisons of other regimens with Regimen C
included only patients without CNS disease at diagnosis.
RESULTS
The remission induction rate for the entire study was
97%, with 97%, 97%, 98%, and 97% for Regimens A,
B, C, and D, respectively. Three patients receiving Regimen A and two receiving Regimen B did not achieve
remission. The other induction failures were due to
early deaths. Leukocyte count was the only patient
characteristic that had a prognostic influence on the
achievement of remission (P Å 0.004). Patients with a
leukocyte count õ 50,000/mL had an induction failure
rate of 1.2%, whereas 4.6% of the remaining patients
failed induction.
The EFS for the entire CCG-123 study was 60 {
4% ({ 2 SD) and overall survival was 67 { 4% 6 years
after diagnosis (Fig. 4) compared with 36 { 6% in the
historic group.1 The EFS was similar for the NY and
BFM regimens (67 { 7% and 67 { 6%, respectively)
(Fig. 5). These therapies had better EFS than either of
the 2 LSA2-L2 regimens (P Å 0.03 and 0.0003, respectively, for NY vs. B and NY vs. C; P Å 0.01 and 0.0001,
respectively, for BFM vs. B and BFM vs. C). The difference in EFS between the two randomized LSA2-L2 arms
was small (RHR was 1.3 times higher for Regimen C;
P Å 0.34) (Table 3). If all Regimen B patients were
included in the analyses and if Regimen C patients
who received cranial irradiation were censored, the
difference in EFS on the 2 regimens approached significance (P Å 0.1) and CNS remission duration remained significantly different (P Å 0.008).
Figure 6 depicts the CNS events on the four randomized regimens. All isolated meningeal recurrences
as first events were represented, but the results were
very similar when isolated plus concurrent CNS and
systemic recurrences were compared. In patients randomized to the initial 3 regimens, the observed/expected event ratios were 0.85, 0.93, and 3.22 for Regi-
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FIGURE 4. Event free survival (EFS) (60 { 4% at 6 years) and overall
survival (67 { 4%) of the entire Children’s Cancer Group- 123 study.
Median follow-up was 76 months for those patients not experiencing an
event.
mens A, B, and C, respectively, indicating a ú 3-fold
excess risk for patients receiving LSA2-L2 without cranial RT. The 6-year CNS recurrence free survival was
95%, 94%, and 84% for the 3 regimens (P Å 0.006). The
comparison of CNS remission duration for Regimen B
versus Regimen C was significant (P Å 0.02). The 2year EFS after meningeal recurrence was 22%. Of the
12 Regimen C patients recalled for cranial RT, 2 recurred in the CNS and 3 in the bone marrow.
The bone marrow recurrence rate of patients receiving the identical systemic chemotherapies (Regimens B and C) was 32 { 8% and 39 { 12%, respectively, 72 months after diagnosis (Table 3). The bone
marrow recurrence rate for patients receiving Regimens A and D was 17 { 5% and 19 { 7%, respectively.
Fewer bone marrow recurrences accounted for the
major advantage of Regimens A and D over the other
regimens (P Å 0.001). The testicular recurrence rate
was low on all the regimens (Table 3) in comparison
with the 20% rate in the historic group of lymphomatous ALL patients (Table 1).
On Day 7 with the 4-drug remission induction
(Regimen A) 56%, 15%, and 29% of patients were early
response classification M1 , M2 , or M3 , respectively,
with an EFS of 78%, 66%, and 52%, respectively. The
5-drug induction (Regimens B and D) resulted in 68%,
14%, and 18% of patients classified as early response
M1 , M2 , and M3 , respectively, with an EFS of 77%,
61%, and 49%, respectively. On Day 14 84% of patients
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607
FIGURE 5.
Event free survival (EFS)
of each treatment regimen. Regimen
A: Berlin-Frankfurt-Munster; Regimen
B: LSA2-L2 with cranial (central nervous system [CNS]) radiotherapy
(RT); Regimen C: LSA2-L2 without cranial RT; Regimen D: New York. P values: A vs. B, 0.004; A vs. C, 0.0001;
A vs. D, 0.97; B vs. C, 0.34; B vs. D,
0.01; and D vs. C, 0.001.
TABLE 3
Outcome of Patients (Events { 2 SD (%) 6 Years after Diagnosis)
Entire study CCG-123
Historical data (5 yrs)2
Regimen A (BFM)
Regimen B (LSA2 / cranial RT)
Regimen C (LSA2)
Regimen D (NY)
EFS
Survival
BM reca
Test reca
CNS reca
60 { 4
39
67 { 6
53 { 8
42 { 0
67 { 7
67 { 4
44
74 { 6
59 { 8
53 { 11
73 { 7
24 { 4
46
17 { 5
32 { 8
39 { 12
19 { 7
6{3
20
7{4
9{6
2{4
3{4
6{2
10
5{3
6{4
18 { 9
3{3
SD: standard deviations; EFS: event free survival; BM: bone marrow; rec: recurrence; test: testicular; CNS: central nervous system; CCG: Children’s Cancer Group; BFM: Berlin-Frankfurt-Munster; RT: radiotherapy.
a
Bone marrow, central nervous system, and testicular recurrence rates include only isolated recurrence as a first event.
receiving the 4-drug induction and 87% of patients
receiving the 5-drug induction were M1 and only 6 –
8% were M2 or M3 with any of the regimens.12
Patients receiving Regimen A who did not receive
irradiation to extraabdominal bulky disease sites at
diagnosis did not have an excess of local recurrences
in those sites compared with patients receiving Regimens B and C. There were very few other extramedullary recurrences (other than the CNS) on any of the
regimens. Only two cases of second malignancy were
reported at last follow-up.
No significant influence on the EFS rate was observed with the presence or absence of any of the
surface markers tested. The lack of significance of the
T-cell phenotype can be observed in Figure 7. The EFS
of males, females, teenagers, and of the different FAB
subtypes was similar. In addition to the influence of
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therapy, EFS was related inversely to the initial leukocyte count (P õ 0.0001, trend test) (Fig. 8). The significant influence of early bone marrow response on EFS
has been reported previously.12
Several other factors showed significant influence
on EFS in univariate analyses, including hepatomegaly, splenomegaly, lymphadenopathy, and mediastinal
mass. The initial three factors all indicated that the
greater the enlargement, the poorer the outcome.
However, patients with very large mediastinal masses
did not have a worse EFS than those with smaller
masses or no mass at all. In fact, among those regimens that provided for RT, if the mass exceeded 33%
of the intrathoracic dimension at the level of the T-5
vertebra (Regimens B, C, and D), the outcome actually
was better for patients with a larger mass than for
patients with a small mass or no mass (P Å 0.002) (Fig.
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CANCER February 1, 1998 / Volume 82 / Number 3
FIGURE 6. Freedom from isolated central nervous system (CNS) recurrence on the four therapeutic regimens. CNS control on the 3 regimens
containing 1800 centigray (cGy) cranial irradiation (CNS RT) was significantly better than on LSA2-L2 without cranial irradiation. P values: A vs.
B, 0.69; A vs. C, 0.0007; A vs. D, 0.3; B vs. C, 0.01; B vs. D, 0.2; and D
vs. C, 0.0002. BFM: Berlin-Frankfurt-Munster.
FIGURE 8. Event free survival (EFS) based on leukocyte count (WBC)
at diagnosis. An adverse effect of the WBC was demonstrated (P for trend
õ 0.0001).
9). A previous report dealing with the RT aspects of
this study noted that there were 18 patients with large
mediastinal masses receiving Regimen B or C who did
not receive the mediastinal irradiation prescribed by
the protocol due to protocol violation by the treating
physician.13 These patients had a somewhat worse
outcome (P Å 0.06) than the 66 patients with large
FIGURE 9. The effect of mediastinal mass on event free survival on the
FIGURE 7. Event free survival (EFS) by immunophenotype. T-cell immunophenotype did not adversely affect the EFS. Data include patients on
the two inferior regimens. The EFS for the 371 patients with T-cell disease
was 60.0 { 7% 7 years after diagnosis.
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LSA2-L2 (Regimens B and C) and New York (Regimen D) regimens. Patients with large mediastinal masses who received 1500 centigray fared
significantly better (P Å 0.002) than those with no mass and those with
a small mass that was not irradiated.
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Therapy of ALL with Lymphomatous Features/Steinherz et al.
mediastinal masses on these regimens who were irradiated. In Regimen A, which did not call for bulk disease site RT, the presence of a mediastinal mass,
whether large or small, had no prognostic significance
(P Å 0.92). However, in multivariate analysis only leukocyte count and early response remained as strong
independent prognostic factors for EFS (P õ 0.0001).
Liver, spleen, and lymph node enlargement became
nonsignificant when adjusted for leukocyte count. Mediastinal mass still retained some prognostic influence
(P Å 0.02), but the favorable prognostic influence of a
large mediastinal mass was limited to those regimens
in which patients with large mediastinal masses received mediastinal irradiation (Regimens B, C, and D).
Toxicity of the four regimens was similar. The
mean number of days of hospitalization during the
induction and consolidation phases of the four regimens was 30, 28, 28, and 30 days for Regimens A, B,
C, and D, respectively. Nonhematologic toxicities after
induction were rare on all the regimens. The patients
spent 5 to 14 days hospitalized after consolidation during the 2 – 3 year period of maintenance chemotherapy. There were more interruptions of maintenance
chemotherapy for hepatotoxicity on the BFM regimen
(Regimen A) than on the LSA2 (Regimens B and C)
or New York regimen (Regimen D). Survivors of both
Regimens A and D were reported to have fathered or
delivered normal babies.
DISCUSSION
Since the recognition of the significance of prognostic
factors on the outcome of children with ALL in the
1970s, attempts have been made to improve outcome
by risk group-directed therapies.14 In these trials, various therapy intensifications were directed at patient
groups whose outcome on prior therapies was inferior.
In 1980, Camitta et al,15 as well as other investigators,16 – 18 noted the ‘‘failure of early intensive chemotherapy to improve prognosis.’’ 15 It was not until the
encouraging results of the BFM 76/793 and the New
York regimens4 that a breakthrough was achieved. This
was the state-of-the-art in 1983, when this study was
initiated.
Each of the three experimental therapies evaluated in this study previously had demonstrated promise in the treatment of patients with aggressive lymphoblastic disease. The LSA2-L2 regimen resulted in a 65%
disease free survival in a group of children with Stage
IVB lymphoma (non-Hodgkin’s lymphoma [NHL])19
and was the better regimen for lymphoblastic disease
in the CCG-551 NHL therapy study.2 Although the Pediatric Oncology Group (POG) modified version resulted in only 40% EFS in patients with T-cell leukemia, the results still represented marked improvement
over the results of earlier reports of that population.20
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609
The results of the BFM 76/79 were a significant improvement over that of prior therapies. It was one of
the first studies that implied that adequate therapy
could diminish the effects of such powerful adverse
prognostic factors as the initial leukocyte count.21 The
pilot study of the New York regimen included 39 patients with lymphomatous presentation. Their 5-year
EFS was 64%.4
The results of this current study establish the superiority of the NY and BFM regimens over the CCG
modified version of the LSA2-L2 regimen and over the
results of past therapies. Better EFS and control of CNS
disease was achieved. All three regimens were notable
for the lack of testicular and other extramedullary recurrence outside the CNS (2 – 7%) (Table 3). The low
incidence of residual testicular disease after remission
induction does not warrant the use of testicular biopsies for asymptomatic patients. It also argues against
the use of prophylactic testicular irradiation used in
some protocols22 at that time for similar populations.
There were no excess recurrences at sites of bulky disease-bearing areas that did not receive RT on the BFM
regimen.
The results of LSA2-L2 appear to be improved
slightly with the addition of cranial RT, but this may
not necessarily be extrapolated to other regimens. It
is possible that better systemic chemotherapy can reduce the need for cranial irradiation. However, the
major site of therapy failure still is in the bone marrow,
and further improvement of EFS from the current rate
of 65 – 70% 7 years after diagnosis with improved chemotherapy is a more important goal than a possible
reduction in toxicity that may result from the elimination of cranial RT. However, the need for cranial irradiation with the New York or BFM regimens in this group
of patients cannot be established from this study.
The reasons for improved results with the BFM
and NY regimens compared with LSA2-L2 plus cranial
irradiation are difficult to pinpoint. They used two different treatment approaches. The strength of the BFM
regimen appears to be in large part in the reinduction/
reintensification phase.23 The NY regimen has a more
effective consolidation phase than LSA2-L2 and the intensive rotating pairs of drugs during maintenance
have been modified to substitute the drugs that have
been found to be less active in ALL (hydroxyurea and
carmustine) with more efficacious drug combinations.
The NY regimen also utilizes methotrexate much more
effectively (by pushing the dose to biologic tolerance)
than it was used in the earlier generation LSA2-L2 .
However, in a multiagent, multimodality therapy, it is
impossible to evaluate the contribution of any one
component of the therapy to the overall EFS without
a randomized study evaluating only that one particular
change.
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CANCER February 1, 1998 / Volume 82 / Number 3
Although several patient characteristics appear to
have prognostic influence in this population, few exhibit independent prognostic influence when examined in a multivariate sense. However, initial leukocyte
count had a strong independent ordering effect, with
a nearly 3-fold higher relative event rate among those
patients with counts ú 200,000/mL compared with
those with counts õ 50,000/mL. Response to therapy
was the only other prognostic factor in multivariate
analysis with independent prognostic value. Early response did not explain the different results of the regimens. With the 5-drug induction (Regimen D) 12%
more patients were early response classification M1 on
Day 7 than with the 4-drug Regimen A. Unfortunately,
this increase in the number of early responders has
not been reflected in better long term EFS for the fivedrug regimen. Regimen D appears to have an advantage for the first 2 – 3 years, but then the EFS curves
come together. The five-drug induction Regimen B
was inferior to both Regimens A and D, indicating
that although the rapidity of cytoreduction is crucial,
postinduction therapy also plays on important role in
disease control.
In this study, patients with a large mediastinal
mass at diagnosis had a better outcome than those
without, whereas the EFS of those with small masses
fell below that of patients with no mediastinal mass.
This finding can be explained by the protocol requirement of mediastinal irradiation for patients with a
large mediastinal mass but not for those with small
masses receiving Regimens B, C, and D, in which a
strong prognostic effect was found and the absence of
this effect on Regimen A, in which mediastinal irradiation was not given. The improved outcome was not
due to better local disease control but to fewer bone
marrow recurrences in those patients who received
mediastinal irradiation. Although this abscopal effect
of mediastinal irradiation is difficult to explain, it has
been observed by others. Mott et al24 reported significant EFS advantage with 1500 cGy mediastinal irradiation in a group of T-cell leukemia/lymphoma patients.
Tubergen et al23 found fewer systemic recurrences in
children who received 1800 cGy cranial irradiation for
CNS prophylaxis than in a group given the identical
chemotherapy without irradiation. Alternatively, irradiation of the thymus may effect some unknown influence of that organ in the behavior of leukemia. The
suggestion that the thymus may have a regulatory role,
at least in T-cell ALL, has been made before. There
was even an unsuccessful trial of thymectomy in patients with T-cell ALL before more effective systemic
therapy became available.22
The results on all three regimens in this report
were better than those achieved in similar groups of
patients on past CCG studies. It is true that there has
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01-13-98 21:29:37
been a general improvement in the EFS of patients
with ALL with the better therapies of the 1980s. However, at least in the CCG experience, this was due in
large part to the superior results on the two studies
(CCG-106 and 123) for patients at high risk of recurrence on prior therapies. One of these is the subject
of the current report. Lymphomatous ALL patients on
CCG studies that accrued patients from 1972 – 1982
had 46% bone marrow, 10% CNS, and 20% testicular
actual recurrence rates (Table 1) compared with the
67% EFS on the best arm of the current study. The
lack of prognostic influence for immunophenotype in
this population observed in the historic group1 was
confirmed prospectively in the current study. The majority, but not all of the patients, had T-cell immunophenotype and one can only speculate regarding the
basic genetic lesion giving rise to this subtype of ALL.
It is difficult to compare the results achieved here with
those reported by others in the literature because the
study populations are different. The closest comparable group would be T-cell leukemia patients with mass
disease. On the POG 8035 study, with a therapy modeled after the LSA2-L2 , patients with a low leukocyte
count and T-cell immunophenotype with splenomegaly had a 39% EFS.25 This result is comparable to that
observed with the LSA2-L2 regimen without cranial RT,
the least effective arm of this study. The overall EFS
for T-cell immunophenotype patients, all of whom
also had mass disease, was 60 { 7% 7 years after diagnosis. Although initial leukocyte count retained its
prognostic significance, as in all reported studies, patients with a leukocyte count of 50 – 199,000/mL still
had a ú 60% EFS. Only patients with a leukocyte count
ú 200,000/mL had a õ 50% EFS. More recent interventions for patients with T-cell ALL, many of whom did
not have additional mass disease (as was the case with
our patients), reported variable results. Although the
EFS in some studies remains in the 40 – 50% range,26 –
29
there are reports of an EFS of 70 – 75% with 4 – 7
years of follow-up.30 – 32
In 1983, when this study was designed, the different mode of clinical and biologic presentation and the
different patterns of recurrence in the study patient
population appeared to justify a separate trial that included both a successful leukemia and a lymphoma
therapy in an attempt to determine which one would
better improve survival. There have been numerous
separate trials for patients with T-cell immunophenotype, with a mediastinal mass, with leukocytosis, with
unfavorable DNA index, or with an increased leukemic
cell mass as calculated by a ‘‘risk index.’’ Yet all these
patients are heterogeneous with considerable overlap
and their disease also crosses biologic boundaries.
Now that the current study has demonstrated that the
New York and BMF regimens are the most effective
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Therapy of ALL with Lymphomatous Features/Steinherz et al.
in patients with a lymphomatous presentation, T-cell
leukemia, and the other high risk ALL,33 – 35 the groups
again can be combined in future studies using those
regimens.
The adverse prognostic implications of lymphomatous presentation in patients with ALL can be minimized with aggressive multimodal therapy. T-cell disease no longer has independent adverse prognostic
significance. The New York regimen and the CCG
modified BFM 76/79 regimen resulted in better EFS
than the LSA2-L2 regimen. The rate of isolated CNS
and testicular recurrence used to be higher in this
group of patients than others with ALL. These problems have been reduced to 2.5% and 3.4%, respectively, on the best arm of this study. There is no need
for prophylactic testicular irradiation or testicular biopsy screening. Prophylactic cranial irradiation on the
LSA2-L2 regimen reduced CNS recurrence significantly,
whereas bone marrow recurrences occurred at similar
rates. EFS was similar on both LSA2-L2 regimens because the CNS recurrence rate is only a portion of the
total recurrences. The role of mediastinal irradiation
should be reconsidered. It had a beneficial effect in
patients receiving Regimens B, C, and D, but a similar
EFS was achieved by Regimen A without mediastinal
irradiation. More effective systemic therapy may improve disease control further at all sites. Until a superior regimen is described, we believe patients with
lymphomatous presentation ALL should be treated
with either the New York or the BFM 76/79 regimens.
7.
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