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A Five-Drug Remission Induction Regimen With Intensive Consolidation for

Adults With Acute Lymphoblastic Leukemia: Cancer and Leukemia Group B
Study 8811

Article  in  Blood · April 1995

DOI: 10.1182/blood.V85.8.2025.bloodjournal8582025 · Source: PubMed

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A Five-Drug Remission Induction Regimen With Intensive Consolidation for
Adults With Acute Lymphoblastic Leukemia: Cancer and Leukemia
Group B Study 8811
By Richard A. Larson, Richard K. Dodge, C. Patrick Burns, Edward J. Lee, Richard M. Stone, Philip Schulman,
David Duggan, Frederick R. Davey, Robert E. Sobol, Stanley R. Frankel, Arthur L. Hooberman, Carol A. Westbrook,
Diane C. Arthur, Stephen L. George, Clara D. Bloomfield, and Charles A. Schiffer
The goal of this phase II multicenter clinical trial was t o
evaluate a new intensive chemotherapy program for adults
with untreated acute lymphoblastic leukemia (ALL) and t o
examine prospectively the impact of clinical and biologic
characteristics on the outcome. One hundred ninety-seven
eligible and evaluable patients (16 t o 80 years of age; me-
dian, 32 years of age) received cyclophosphamide, daunoru-
bicin, vincristine, prednisone, and L-asparaginase; 167 pa-
tients (85%) achieved a complete remission (CR),13(7%)
had refractory disease, and 17 (9%)died duringinduction. A
higher CR rate was observed in younger patients (94% for
those c 3 0 years old, 85% for those 30 t o 59 years old, and
39% for those r60 years old, P < .001) and in those who
had a mediastinal mass (100%) or blastswith a T-cell immu-
nophenotype. Eighty percent of B-lineage and 97% of T-cell
ALL patients achieved a CR ( P = .01). The coexpression of
myeloid antigens did not affect the response rate or dura-
tion. Seventy percent of those with cytogenetic or molecular
evidence of the Philadelphia (Ph) chromosome and 84% of
those without such evidence achieved a CR ( P = .11). Pa-
tients in remission received multiagent consolidation treat-
ment, central nervous system prophylaxis, late intensifica-
A LTHOUGH RECENT clinical trials have shown that
65% to 85% of adults with acute lymphoblastic leuke-
mia (ALL) may achieve a complete remission (CR), these
remissions have been disappointingly short, especially for
older adults.”’ Recent treatment strategies have focused on
increasingly intensive induction and postremission treatment
with multiple chemotherapy agents and also on multivariate
analyses of prognostic factors to individualize therapy.
Among the clinical and biologic characteristics that have
been found to have prognostic importance for adults with
ALL are age, initial white blood cell count ( W C ) , platelet
count, serum lactate dehydrogenase and albumin levels, the
presence of adenopathy or hepatosplenomegaly, perfor-
mance status, immunophenotype, cytogenetics, and time to
achieve CR.”5
Investigators at single institutions have reported favorable
results using intensive and prolonged remission consolida-
tion programs. At the Memorial Sloan-Kettering Cancer
Center, multiple courses of eight drugs were used in various
combinations in the L-l0 and L-1OM protocols; a CR rate
of 85% was reported among 72 patient^.^.' The median re-
mission duration was 51 months, and disease-free survival
at 5 years was estimated to be 45%. However, when evalu-
ated in a multi-institutional trial, the same chemotherapy
program was reported to yield a CR rate of 68% in 168
patients; the median duration of CR was 23 months.’ A
similar program tested in 59 consecutive patients at the Uni-
versity of Iowa showed a CR rate of 75%; the median dura-
tion of remission was about 50 months.’ Fifteen patients
(34%) remained in continuous remission longer than 5 years.
These results and others have suggested that additional initial
cytoreduction followed by multiagent intensification regi-
Blood, Vol 85, No 8 (April 15), 1995: pp 2025-2037
tion, and maintenance chemotherapy for a totalof 24
months. After a median follow-up time of 43 months, the
median survival for all197 patients is 36 months; the median
remission duration for the 167 CR patients is 29 months.
Favorable pretreatment characteristics relative t o remission
duration or survival are younger age, the presence of a medi-
astinal mass or lymphadenopathy, a white bloodcell count
(WBC) lessthan 3O,OOO/pL, L1 morphology, T or TMy immu-
nophenotype, and the absence of the Ph chromosome. The
estimates of the proportionsurviving at 3 yearsare 69% for
patients less than 30 years old, 39% for those 30 t o 59 years
old, 89% for those who had a mediastinal mass, 59% with
WBC less than 30,OOO/pL, 63% with L1 morphology, 69% for
T or TMy antigen expression, and 62%for those who lack the
Ph chromosome. Fifteen patients (8%) had no unfavorable
prognostic factors and have an estimatedprobability of sur-
vival at 5 years of 100% (95% confidence interval, 77% to
100%). This intensive chemotherapy regimen produces a
high remission rate and a high proportion ofdurable remis-
sions in adults with ALL.
0 7995 by The American Society of Hematology.
mens extending over a number of months or years may offer
the greatest likelihood for producing long-term disease-free
survival for adults with ALL.”
The goal of this study was to evaluate a new intensive
chemotherapy program for adults and to examine prospec-
tively the impact of clinical and biologic characteristics on
the outcome. This Cancer and Leukemia Group B (CALGB)
study of adults with ALL tested the feasibility of the direct
From the University of Chicago, Chicago, IL; the CALGB Statisti-
cal Center, Durham, NC; the University of Iowa, Iowa City, IA; the
University of Maryland Cancer Center, Baltimore, MD; the Dana
Farber Cancer Institute, Boston, MA;the North Shore University
Hospital, Manhasset, NY; the State University of New York Health
Science Center at Syracuse, NY; the University of California at San
Diego, CA; the Roswell Park Cancer Institute, Buffalo,NY;the
University of Minnesota, Minneapolis, MN; and CALGB, Lebanon,
NH.
Submitted September 27, 1994; accepted November 28, 1994.
Supported in pari by National Institutes of Health Grants No.
CA31946, CA33601, CA37027, CA37055, CA41287, and AGO353
and by the Coleman Leukemia Research Fund.
Presented in part at the 25th Annual Meeting of the American
Society of Clinical Oncology, San Diego, CA, May, 1992.
Address reprint requests to Richard A. Lurson, MD, university
of Chicago Medical Center, 5841 S Maryland Ave, MC2115, Chi-
cago, IL 60637.
The publication costs ofthisarticle 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.
0 1995 by The American Society of Hematology.
oooS-4971/95/8508-0003$3.00/0
2025
2026
application of treatment programs that have proven to be
very effective in high-risk childhood ALL. To achieve more
rapid cytoreduction, our protocol used a five-drug induction
regimen that was derived by adding a single dose of cyclo-
phosphamide (1,200 mg/m2) to a slight modification of the
four-drug regimen used in two previous CALGB studies
(7612 and 801 A similar five-drug induction program,
when used in high-risk childhood ALL (Children's Cancer
Group study CCG-l92P), yielded a CR rate of 96% with
only 2% deaths during ind~cti0n.I~ We modified the standard
consolidation program used in the German (Berlin-Frank-
furt-Munster [ B M ] ) multicenter trial for adults by increas-
ing the dose of cyclophosphamide from 600 to 1,000 mg/
m2 and adding 2 weeks of vincristine and L-asparaginase
treatment during the expected period of myelosuppression.'
To maintain maximum dose intensity, no dose reductions
nor delays were permitted for myelosuppression in the ab-
sence of fever or infection. In addition, earlier and more
extensive use of L-asparaginase was prescribed in this proto-
col than has commonly been used in adult ALL treatment
programs (biweekly administration for 7 weeks during the
first 12 weeks of therapy).
MATERIALS AND METHODS
Patients. Patients were eligible if they had untreated ALL of
any of the three French-American-British (FAB) subtypes or acute
undifferentiated leukemia.I4 Patients were registered by telephone
with the CALGB Statistical Office before treatment. The diagnosis
of ALL was confirmed by central review of blood smears and bone
marrow (BM) specimens for cytologic and cytochemical features
according to the FAB riter ria.'^.'^ Central immunophenotyping and
pathology review were required. It was recommended that pretreat-
ment blood and BM specimens be submitted for cytogenetic analysis,
including central review of the karyotypes (CALGB study 8461).
and for molecular analysis for the presence of the BCR-ABL fusion
gene (CALGB study 8762).",Is Leukemia cells were analyzed in a
central laboratory by Southern blot and pulsed-field gel electrophore-
sis for rearrangements within the BCR gene according to previously
reported methods, using conditions that will detect both the p190
and p210 subtypes." A lumbar puncture for spinal fluid examination
was not recommended at diagnosis for asymptomatic patients. How-
ever, patients with symptomatic central nervous system (CNS) leuke-
miawerenot excluded but received additional CNS therapy. All
patients were older than 15 years, had adequate renal and hepatic
function (less than twofold elevated above the normal range unless
felt to be caused by leukemia infiltration), and hadprovided informed
consent.
Immunophenotyping (CALGB study 8364) was performed in two
central CALGB laborat~ries.'~ In 10 cases in which the pretreatment
specimen was notevaluable in the central laboratory, immunopheno-
typing data from the local institutions were used after central review.
Flow cytometric analysis and a panel of monoclonal antibodies were
used for indirect immunofluorescence. The criterion for surface
marker positivity was expression by at least 20% of the leukemia
blast cell population. B-lineage antigen expression was defined as
CD19 or CD20 positivity; T-lineage antigen expression as CD5 or
CD2 reactivity; and myeloid antigen expression as CD13 or CD33
positivity. Expression of the common ALL antigen (CALLA) was
assessed by CD10 reactivity. Cases expressing combinations of both
B-lineage and T-lineage antigens were classified as BT, BTMy, or
miscellaneous. Cases expressing surface membrane Ig (SmIg) were
considered FAB-L3 (Burkitt-type ALL) andwerenot included
!ARSON ET AL
among the other B-lineage cases in subsequent analyses. Patients
with myeloperoxidase-negative blasts that expressed only myeloid
antigens (and not B- or T-lymphoid antigens) were reclassified as
acute myeloid leukemia (AML), subtype MO, and were deemed to
be ineligible (4patients).
Treatment protocol. The drugs and dosages used in the induc-
tion, consolidation, and maintenance phases of treatment are listed
in Table 1. The induction course used a single dose of cyclophospha-
mide on day 1, 3 consecutive days of daunorubicin, weekly vincris-
tine, biweekly L-asparaginase, and 3 weeks of prednisone. Before
each L-asparaginase injection, the serum amylase activity was mea-
sured. In addition, it was recommended that fresh frozen plasma or
cryoprecipitate be transfused to keep the fibrinogen level greater
than 100 mg/dL. Initially, there were no dose reductions for older
patients. After 1 year of accrual to the study (76 patients), one-third
dose reductions were implemented for patients older than 60 years
for the cyclophosphamide and daunorubicin and the prednisone ther-
apy was shortened to 7 days, because of a high induction death rate
caused by infection in this age group.
Early intensification (course 11) included 2 months of treatment
using cyclophosphamide, subcutaneous cytarabine, oral 6-mercapto-
purine (6-MP), vincristine, and more subcutaneous L-asparaginase.
Two years after the study opened (156 patients), the protocol was
amended so that CNS prophylaxis was initiated with the first two
doses of intrathecal methotrexate during course 11, rather than as
previously performed in course III, to provide earlier CNS prophy-
laxis.
In course 111, the CNS prophylaxis was completed with cranial
irradiation (2,400 cGy) and 5 weekly doses of intrathecal methotrex-
ate with daily 6-MP, followed by a brief maintenance period using
daily oral 6-MP andweekly oral methotrexate. Course IV was a
late intensification course lasting 8 weeks, followed by prolonged
maintenance treatment with daily 6-MP andweekly methotrexate
plus monthly pulses of vincristine and prednisone.
The total duration of treatment was 24 months. Testicular biopsies
were not required at the end of therapy, and testicular irradiation
was not administered prophylactically. Patients who had an isolated
CNS relapse while continuing in a marrow remission were counted
as failures; however, they continued to receive systemic chemother-
apy on protocol after suppression of cerebrospinal fluid (CSF)
lymphoblasts with additional intrathecal chemotherapy.
No hematopoietic growth factors were used. Cotrimoxazole or
aerosolized pentamidine were recommended for Pneumocystis pro-
phylaxis, starting in course 111. The use of oral nonabsorbable antibi-
otics, the management of febrile episodes and transfusions, and the
use of hospitalization were not prescribed by the protocol, but were
rather left to institutional guidelines.
Data audit. CALGB central data management personnel were
responsible for quality assurance for all clinical data submitted for
this study. Eligibility criteria were verified for all patients and an
evaluation of treatment, response, and toxicity was made by the
study chair (R.A.L.). In addition, as part of the group data monitoring
program, members of the CALGB Data Audit Committee made
periodic site visits to all institutions to verifycompliance with federal
regulations and protocol requirements, including eligibility, treat-
ment, response data, and follow-up.2oA random subset of 68 patients
(32%) treated on this study had such an on-site review of their
medical records. In addition, all radiotherapy portals and dosimetry
records for the cranial irradiation were centrally reviewed for quality
control by the Quality Assurance Review Center (Providence, RI).
Criteriafor response. Patients were considered tobeinCR
when the neutrophil count was greater than 1,50O/pL, the platelet
count was greater than 1OO,OOO/pL, the results of BM examination
were normal (including 4 % blasts and >25% cellularity), and all
extramedullary disease had resolved. Patients with greater than 25%
NT INTENSIVE ALL 2027

Table 1. Chemotherapy Regimen for ALL in Adults

Course I: Induction (4wk)

Cyclophosphamide* IV Day 1,200mglm’ 1
Daunorubicin* IV 45 mg/rn2 Days 1, 2,3
Vincristine IV Days 2 mg 22 15, 1, 8,
Prednisone* Days mglm’ld
ponv 60 1-21
L-asparaginase sc 6,000 IUlm’ Days 5,22
8. 11, 15, 18,
+For patients ~ 6 yr0 old:
Cyclophosphamide 800 mg/m2 Day 1
Daunorubicin 30 mg/m2 Days 1,2,3
Prednisone Days mg/m’/d 60 1-7
Course II: Early intensification (4wk, repeat once)
Intrathecal methotrexate 15 mg Day 1
Cyclophosphamide IV 1,000rnglm’ Day 1
6-Mercaptopurine PO mglm’ld 60 Days 1-14
Cytarabine sc 75 mg/m’/d Days 1-4. 18-1
Vincristine IV 2 mg Days 15,22
L-asparaginase sc 6,000 IU/m’ Days 15, 18.22, 25
Course 111: CNS prophylaxis and interim maintenance (12wk)
Cranial irradiation 2,400 cGy Days 1-12
Intrathecal methotrexate 15 mg Days 1, 8. 15, 22, 29
6-Mercaptopurine PO 60 mghn’/d Days 1-70
Methotrexate PO 20 mg/m2 Days 36, 43, 50, 57, 64
Course IV: Late intensification (8wk)
Doxorubicin IV 30 mg/m’ Days 1, 8, 15
Vincristine IV 2 mg Days 1.8. 15
Dexamethasone PO 10 mg/m2/d Days 1-14
Cyclophosphamide IV 1,000mg/m’ Day 29
6-Thioguanine PO 60 mglm‘/d Days 29-42
Cytarabine sc 75 mg/m2/d Days 29-32, 36-39
Course V: Prolonged maintenance (until 24 rno from diagnosis)
Vincristine IV 2 rng Day 1 of every 4 wk
Prednisone PO mg/m’/d 60 Days 1-5 of every 4 wk
Methotrexate PO 20 mglm‘ Days 1,s. 15, 22
6-Mercaptopurine PO mglm’ld 60 Days 1-28

lymphoblasts remaining in the BM after course I were removed from
this protocol. All patients were required to have achieved a CR by
half-way through course I1 to remain on the study.
Staristical methods. The proportion of patients achieving a CR
to the induction regimen was the primary outcome measure on this
study. The duration of CR and length of survival were additional
outcome measures. Differences in proportions of CRs among patient
subgroups were analyzed using Fisher’s exact test. The duration of
CR was defined to be the time from achieving a CR to relapse (bone
marrow, blood, CNS, or testicular), death, or date of last follow-up.
Patients still at risk, lost to follow-up, or withdrawn for BM trans-
plant (BMT) were censored for the analysis of remission duration.
Survival was defined as the time from study entry to death or date
of last follow-up. Probabilities of surviving and remaining in CR
were estimated by the Kaplan-Meier method.” Ninety-five percent
confidence intervals (CI) for these probabilities and the median sur-
vival times were obtained using the method of Simon and Lee?’
Median follow-up time was estimated by reversing the codes for the
censoring indicator in a Kaplan-Meier analysis. In instances in which
the median was not defined, the estimate was reported to be greater
than the smallest possible time. Differences in survival or remission
duration between patient subgroups were tested using the logrank
statistic, adjusted for multiple comparisons where appr~priate.’~.”
In accordance with the study objectives, the prognostic signifi-
cance of age, WBC count, platelet count, mediastinal mass, organ-
omegaly, lymphadenopathy, FAB classification, immunophenotype,
cytogenetics, and molecular analysis were assessed with respect to
CR rate and duration and survival. For the joint analysis of these
variables, regression analyses were used. The analysis of CR rate
was performed using the logistic regression model, whereas the anal-
yses ofCR duration and survival were performed using the Cox
proportional hazards regression These were performed
using the SAS procedures LOGISTIC and PHREG, respectively.”
For the regression analyses, all variables that attained a univariate
P value of .20 or less were considered in the variable selection
process. All reported P values are nominal two-sided values unless
otherwise stated. The analysis was based on all data available as of
August 4, 1994.
RESULTS
Patient accrual. BetweenSeptember1988and June
1991, 214 patients were entered onCALGBstudy 8811
from 25 main member institutions and 41 of their affiliated
hospitals. One patient withdrew before beginning treatment
and 16 patients were judged ineligible after central review
of all data (14 with AML and
with
2 lymphocytic
lymphoma). Thus, 197 patients were eligible and evaluable
for this report.
Patient characteristics. The 197 eligible patients ranged
in age from 16 to 80 years, with a median age of 32 years.
Eighteen patients (9%) were 60 years or older. There were
124 men (63%) and 73 women. Eighteen patients were Afri-
2028
Table 2. Results of Cytogenetics and Molecular Assays
for Ph Positivity in Adult ALL
BCR Rearrangement In)
ph Chromosome
Negative
Positive
Unknown
Total
Positive 15 2 8
Negative 3 29 28
Unknown 2 26 04
Total 20 57 120t
* Includes not done (n = 81) and not evaluable (n = 31).
t Includes not done (n = 114) and not evaluable (n = 6).
can-American, 4 were Hispanic, and 1 wasAsian. Initial
WBC counts ranged from 500 to 475,000/pL (median,
17,00O/pL), platelet counts ranged from 8,000 to 557,000/
pL (median, 55,500/pL), and hemoglobin levels ranged from
4.0 to 16.6 g/dL (median, 9.6 g/&).
Thirty-four percent of patients had WBCcounts =-30,000/
pL, 13% had WBC counts greater than lOo,OOO/pL, and 6%
had more extreme hyperleukocytosis with WBC counts in
excess of200,OOO/pL. Fifty-six percent of patients had a
fever or infection before chemotherapy. Only 1 patient had
symptomatic CNS disease at diagnosis. Thirty patients
(15%) had a mediastinal mass, 60 (31%) had palpable sple-
nomegaly, and 47 (24%) had hepatomegaly. Palpable lymph-
adenopathy was present in 78 patients (40%).
One hundred sixty-six patients (84%) could be classified
by the pathology review committee using the FAB criteria;
71 cases (43%) were L1, 87 (52%) were L2, and 8 ( 5 % )
were L3. Morphologic subtyping could not be accomplished
in 24 cases, usually because of inadequate marrow aspirate
samples, and these were considered unclassifiable acute leu-
kemia. Seven cases were not evaluable for central review.
Central immunophenotyping was successfully performed
in 130 cases. Where these determinants were missing, local
institutional imrnunophenotyping data were used in 10 cases
to assess the lymphocyte surface marker profile. Excluding
the 8 patients with L3 ALL, there was surface expression of
at least one B-lineage antigen in 86 cases (61%). Thirty-nine
cases (28%) expressed at least one T-lineage antigen and 27
cases (19%) expressed at least one myeloid (My) antigen.
Five subsets were defined: pure B lineage, 67 cases (48%);
BMy, 19 cases (14%); pure T lineage, 3 1 cases (22%); TMy,
8 cases (6%); and a miscellaneous group with other marker
profiles (SmIg positive, BT, BTMy, and unclassified), 15
cases ( I 1%). The miscellaneous group was not included in
further analyses by immunophenotype. Sixty-five percent of
the T or TMy patients had a mediastinal mass, compared
with only 4% of the non-T-lineage patients. Eighty-three
percent of patients with a mediastinal mass had a T or TMy
immunophenotype.
Eighty-five (73%) of the 116 cases submitted for cytoge-
netic analyses were evaluable after central reviewof the
karyotypes. The Philadelphia (Ph) chromosome was identi-
fied in 25 patients (29%). Molecular analyses for a BCR
gene rearrangement from pretreatment blood and/or marrow
specimens were performed in 77 cases; 20 (26%) were posi-
tive. Table 2 shows the results from these two analytic tech-
LARSON ET AL
niques. When the results of both cytogenetic and molecular
tests were combined, 30 patients were positive for either the
Ph chromosome or BCR-ABL rearrangement (Ph-positive
h )
ALL). Forty-nine patients were analyzed by both methods:
15 were positive and 29 were negative by both tests (90%
25 concordance). Eighty-three patients were negative by at least
60 one test (and not positive by the other). Thus, approximately
112'
27% of the 113 patients studied had Ph-positive ALL. Forty
197
percent of patients with B-lineage ALL were Ph-positive,
compared with 5% of those with T-lineage ALL.
Remission induction. One hundred sixty-seven (85%) of
197 eligible patients achieved a CR (Table 3). One hundred
twenty-three (74%) of the responders were in CR within 30
days from the first treatment; 44 (26%) required more than
30 days, either because of slow recovery of marrow cellu-
larity and blood counts in 29 patients or because additional
chemotherapy (ie, course 11) was required in15 patients.
Eighty-eight percent of remissions were achieved within 42
days. Eight patients (4%) had no response to induction che-
motherapy (ie, >25% lymphoblasts persisting in the mar-
row) and were taken off study after 4 weeks. Five patients
(3%) had at best only a partial response and were taken off
study after 8 weeks. Of these 13 patients with refractory
disease, 5 are known to have had a Ph chromosome or BCR
rearrangement, 1 had a t(4; 1l), and 1 had Burkitt-type (L3)
ALL. Despite additional treatment, all but 1 (who received
an allogeneic marrow transplant) have died.
Seventeen patients (9%) died before hematopoietic recov-
ery from the induction chemotherapy; 1 of these was less
than 30 years old (1% of the age cohort), 7 were 30 to
59 years old (8%), and 9 were 260 years old (50%). The
predominant cause for induction mortality was infection with
either enteric gram-negative bacteria, Streptococcus pneu-
moniae or Candida species, occumng during week 2 or 3 of
treatment. There were two episodes of clinically severe tu-
mor lysis syndrome, and l of these patients died.
Treatment response was a function of age (Table 4).
Eighty-two of the 87 patients (94%) less than 30 years old
achieved a CR, compared with 78 of 92 (85%) between 30
and 59 years of age and only 7 of 18 (39%) of those 60
years and older (P< .001). Four percent to 10% of patients
within each age group had either a partial remission or no
response to induction chemotherapy. After the protocol was
amended to institute a one-third reduction of the chemother-
apy doses for patients 2 6 0 years old (see Materials and
Methods and Table l), the CR rate for this older group
Table 3. Results of Therapy
Patients entered 214
Patients eligible 197
Induction deaths 17 (9%)
Refractory disease 13 (7%)
CR 167 (85%)
Died in remission (6%) 10
Censored for BMT in first CR (3%)
5
Relapsed 77 (46%)
CCR (45%) 75
ENT INTENSIVE FOR ADULT ALL 2029

Table 4. Clinical and Biologic Characteristicsin Relation to CR Rates, Remission Duration, and Survival
Survival Duration Remission

CR Probability of CCR Survival of Probability

Median Median
Variable n (%) n (%l P (mo) at 3 yr (95% Cl) P (mol at 3 yr (95% Cl) P
Total 197 (0.42-0.58)
167 (85) 0.50 (0.37-0.55)
29 0.46 36
Age (yr)
<30 87 (44) c.001 36 0.51 (0.38-0.63) .2 1 >42 0.69 (0.57-0.78) <.001
30-59 92 (47) 25 0.43 (0.30-0.57) 25 0.39 (0.28-0.51)
260 18 (9) 12 0.43 (0.16-0.75) 1 0.17 (0.06-0.39)
Gender
Male 124 (63) .69 34 0.48(0.37-0.59) .56 33 0.49 (0.40-0.59) .76
Female 73 (37) 28 0.44 (0.30-0.60) 38 0.52 (0.39-0.651
Performance status
0-1 166 (84) .58 34 0.48 (0.38-0.581 .23 38 0.51 (0.43-0.60) .40
2-4 31 (16) 15 0.36 (0.18-0.57) 21 0.45 (0.26-0.66)
Fever or infection
+ 110 (56) .43 36 0.51 (0.39-0.63) .46 39 0.53 (0.43-0.64) .50
- 85 (44) 27 0.42 (0.29-0.56) 28 0.46 (0.35-0.60)
Mediastinal mass
+ 30 (15) .01 >33 0.71 (0.49-0.87) ,002 >42 0.89 (0.70-0.96) <.001
- 166 (85) 26 0.41 (0.32-0.52) 24 0.43 (0.35-0.52)
Lymphadenopathy
+ 78 140) .07 36 0.51 (0.38-0.64) .49 >38 0.60 (0.47-0.71) .04
- 117 (60) 28 0.43 (0.31-0.56) 26 0.44 (0.34-0.55)
Splenomegaly
i W (31) .20 27 0.47 (0.33-0.62) .93 32 0.50 10.36-0.63) .69
- 135 (69) 29 0.46 (0.35-0.58) 37 0.51 (0.41-0.60)
Hepatomegaly
+ 47 (24) .65 24 0.41 (0.26-0.58) 27 32 0.51(0.35-0.66) .76
147 (76) 34 0.49 (0.38-0.60) 37 0.50 (0.41-0.60)
Leukocytes
<30,000 130 (66) .m 37 0.51 (0.40-0.62) .05 244 0.59 (0.49-0.68) .M)1
230,000 66 (34) 19 0.36 (0.22-0.53) 19 0.34 (0.23-0.47)
Platelets
<50,000 81 (41) .l6 27 0.43 (0.30-0.58) .36 23 0.44 (0.33-0.57) .11
r
5 0.
0 00 115 159) 34 0.48 (0.37-0.60) 41 0.54 10.44-0.64)
FAB
L1 71 (37) .35 38 0.54 (0.39-0.68) .l6 >44 0.63 (0.50-0.74) .03
L2 87 (46) 26 0.46 (0.33-0.59) 25 0.45 (0.34-0.57)

L3 8 14) 3 0.17 (0.03-0.56) 6 0.38 (0.11-0.74)

Unclassified 24 (13) 23 0.35 (0.16-0.60) 11 0.31(0.15-0.541
lmmunophenotype
8 67 (48) .02 25 0.42 (0.27-0.581 .l4 19 0.36 10.25-0.49) ,004
T 31 (22) >za 0.57 10.37-0.76) >40 0.67 10.47-0.82)

BMY 19 (14) 27 0.38 (0.18-0.64) 27 0.47 (0.26-0.69)

TMY 8 (6) >40 0.86 (0.49-0.97) >40 0.75 (0.41-0.93)
Other 15 (11) 31 0.53 (0.28-0.76) 43 0.60 (0.36-0.80)

B or BMy 86 (61) .01 25 0.41 (0.28-0.55) .04 21 0.38 (0.28-0.50) .001

T or TMy 39 (28) >32 0.63 (0.44-0.78) >40 0.69 (0.51-0.82)

BMy or TMy 27 (19) >31 0.55 (0.33-0.75) 233 0.55 (0.36-0.73)

Cytogenetics
Ph' 25 (29) .l5 10 0.14 (0.05-0.34) ,006 11 0.19 (0.08-0.37) ,008
Ph- W (71) >33 0.53 (0.39-0.68) 34 0.50 (0.37-0.63)
Molecular
BCR-ABL' 20 (26) .l1 7 0.10 (0.03-0.30) c.001 11 0.13 (0.05-0.33) <.m1
BCR-ABL- 57 (74) 234 0.64 (0.48-0.781 >39 0.63 (0.49-0.75)
Cytogenetics and molecular
Ph+ or BCR-ABL' 30 (27) .l 1 7 0.11 (0.04-0.28) 1.001 11 0.16 (0.07-0.32) <.001
Negative by 1 test+ 83 (73) 233 0.56(0.434.69) 44 0.56 (0.45-0.67)
Ph' or BCR-ABL+ 30 (51) .2 1 7 0.1 1 (0.04-0.28) <.W1 11 0.16 (0.07-0.32) <.W1
Negative by both tests 29 (49) >40 0.72 (0.51-0.86) >40 0.62 (0.44-0.78)
Time to CR (d)
530 123 (74) 37 0.51 (0.40-0.62) 24 244 0.59 (0.49-0.69) .40
>30 44 (26) 26 0.33 (0.20-0.50) 39 0.56 (0.40-0.71)
Cases evaluated by cytogenetics or molecularmethods but not by both tests.

changed from 3 of 10 to 4 of 8 because of fewer induction or the presence or absence of fever or infection, splenomeg-
deaths (6 [60%1v 3 [38%1, respectively). aly, or hepatomegaly (Table 4). The presence of a rnediasti-
Subset analyses. The remission induction rate did not nal mass or lymphadenopathy were favorable features asso-
vary significantly by gender, performance status (0-1 v 2-4), ciated with CR rates of 100% and 91%, respectively. The
2030
0.0
o 1 2 3 4 5
rears
Fig 1. The duration of complete remission is shown for the 167
CR patients after a median follow-up
time of 3.5 years. The estimated
probability of remaining in continuousCR at 3 years is 46% (95% Cl,
37% to 55%).
presenting platelet count (greater than or less than 50,000/
pL) did not affect the CR rate. Patients with a WBC less
than 30,OOO/pL had a higher CR rate (88%) than those with
a greater WBC count (77%), but this difference was not
statistically significant ( P = .06). The CR rate was 80% for
the 25 patients with initial WBC counts greater than 100,000/
pL and 73% for the 11withWBC counts greater than
200,OOO/pL. The CR rate did not vary according to the pre-
treatment marrow cellularity or the fraction of lymphoblasts
in the marrow. The CR rate was 90% for patients with FAB
L1 morphology, 84% for L2, and 75% for L3 ( P = .35 for
L1 v L2).
There were significant differences in the CR rates ac-
cording to immunophenotype and genetic subtype. One hun-
dred percent of 3 1 patients with a pure-T-lineage phenotype
achieved a CR, compared with 82%of the 67 with a pure-B-
lineage phenotype ( P = .02). The coexpression of myeloid
antigens had no impact on the CR rate, ie, 78% for these 27
patients overall (88% for 8 TMy patients and 74% for 19
BMy patients). There were no differences in these results
when only the cases with central immunophenotyping were
analyzed.
The CR rate was 68% for the 25 patients with a t(9;22)
by cytogenetic analysis and 65% for the 20 patients in whom
a BCR-ABL rearrangement was detected. One hundred thir-
teen patients were studied by at least one genetic method.
The CR rate was 70% for the 30 patients identified by one
or both tests as having Ph-positive ALL and 84% for those
who were negative ( P = .11).
Using a logistic regression model and adjusting for age,
the lack of T-cell antigen expression ( P = .03) and the
absence of a mediastinal mass ( P = .04) were indicators of
a poor remission induction outcome. No other factors were
related to the response rate after adjusting for age.
Remission duration. The remission duration estimates
for the 167 patients who achieved a CR are shown in Fig 1.
The median duration of CR for all responders is 29 months
after a median follow-up time of 40 months (range, 23 to
63 months). Approximately 46% of all responders are esti-
mated to remain in continuous CR (CCR) at 3 years (95%
CI, 37% to 55%). Fifty-one percent of patients younger than
LARSON ET AL
30 years at diagnosis are estimated to remain in CCR at 3
years, compared with 43% of middle-aged and 43% of older
patients, but these differences are not statistically significant.
Remission durations were longer for patients presenting
with a WBC less than 30,00O/pL( P = .05). Remission dura-
tion was not associated with the initial platelet count but
was significantly longer in those with a mediastinal mass ( P
= .002).
Biologic features were correlated with outcome. The esti-
I
mated probability of CCR at 3 years is 54% for patients with
6 L1 morphology, 46% for L2, and 17% for L3 ( P = .l6 for
L1 v L2). The median remission durations are 38, 26, and
3 months, respectively. Sixty-three percent of those with
expression of T-cell antigens remain in CCRat 3 years,
compared with 41% of those expressing B-lineage antigens
( P = .04). Patients withmyeloidantigen expression have
had an intermediate outcome overall with 55% in CCR at 3
years, but they do not differ from the patients without my-
eloid antigen expression within the same lymphoid lineage.
Only 11% of patients with Ph-positive (or BCR+) ALL
were estimated to remain in CCR at 3 years (95% CI, 4%
to 28%), compared with 56% (95% CI, 43%to 69%) of
those who were negative byat least one genetic test and
72% (95% CI, 51% to 86%) of those who were negative by
both cytogenetic and molecular analyses ( P < .001 for each
comparison).
Fifty-one percent of patients who achieved a CR within
30 days were estimated to remain in CR after 3 years, com-
pared with 33% of those who needed longer than 30 days
to enter remission, but this difference was not statistically
significant ( P = .24). Similarly, those 20 patients who re-
quired more than 42 days to achieve CR have not had sig-
nificantly shorter remission durations (median, 26 months v
29 months for rapid responders, P = .62).
After adjusting for age in a logistic regression model, the
WBC count retained statistical significance with respect to
CR duration ( P = .006). After controlling for these two
factors, mediastinal mass was the most significant variable
with respect to remission duration ( P < .001). After ad-
justing for all three factors, FAB subtype (L1 v L2) attained
prognostic significance for CR duration ( P = .005), as did
immunophenotype (T or TMy v others; P = .04), whereas
adverse cytogenetics [the detection of Ph, or the BCR/ABL
gene, or a t(4; 1l)] retained significance ( P = M ) . Among
T or TMy patients, the WBC count did not have prognostic
significance for CR duration, but a mediastinal mass was
significantly associated with longer remission duration ( P =
.04).
Overallsurvival. The estimated median survival for all
197 treated patients is 36 months after a median follow-up
time of 43 months (range, 24 to 64 months; Fig2). The
median survival for the 167 patients who achieved a CR has
not been reached but is longer than 45 months. The survival
on this study is significantly better than that observed on
any of the three previous CALGB studies ( P < ,001 for all
3 comparisons); CALGB 8513 had a median survival of 19
months, and CALGB studies 7612 and 8011 had medians
of 16 months (Fig 3).".'*,**
Patient age is significantly associated with survival ( P <
INTENSIVETREATMENT FOR ADULT ALL
0.2
0.0
Years
Fig2. The survivalof all 197eligiblepatientsisshown after a
median follow-up time of 3.5 years. The estimated probability of
survival at 3 years is 50% (95% Cl, 42% to 58%).
.OOl). The probability of survival at 3 years is estimated to
be 69% for those less than 30 years old, 39% for those 30
to 59 years old, and 17% for those 2 6 0 years old (Fig 4).
Survival is significantly longer for patients presenting with
a WBC less than 30,OOO/pL ( P = .001). Among patients
with high WBC counts, the median survivals are 24 months
for those with 30,000 to 59,00O/pL, 14 months with 60,000
to 99,OOO/pL, and 11 months with greater than lOO,OOO/pL,
but these are not significantly different. Despite a high CR
rate, of the 25 patients with an initial WBC count greater
than 100,OOO/pL, only 7 (27%) remain alive at last contact.
Patients who achieved a remission within 30 days are no
more likely to be alive at 3 years than those who required
more than 30 days to achieve a CR (59% v 56%).
Survival is associated with morphology and immunophe-
notype. The probability of survival at 3 years is estimated
to be 63% for L1 and 45% for L2 ( P = .03). The patients
with L1 morphology had a median WBC count of 19,2001
pL (range, 800 to 401,OOO/pL); 39% had T or TMy immuno-
phenotypes and 20% were Ph positive. The L2 patients had
a median WBC count of 17,2001pL (range, 700 to 328,5001
pL); 21% had T or TMy immunophenotypes and 44% were
Ph positive. The 8 patients with L3 morphology were consid-
ered as a separate FAB group but were not compared with
1.0
0.8
P O
R 0.8'
B 0.6
0
i 0.4
O
N ;
(1.2
0.0
0 1 2 3 4 3 6 7 8 9 1 0
Years
Fig 3. The survival of all 197 eligible patients treated on CALGB
study8811 is comparedwith the survival of patients treated on three
previous CALQB studies: 7612 (185 patients), 8011 (308 patients), andWpe (median. >40 months) is significantly longer
8513 (171 patients).
2031
N
0.2- I 60. years(n-18)
0.oi (.
0 1 2 3 4 5 6
years
Fig 4. The survival of the 87 patients less than 30 years old (me-
dian, >42 months) is significantly longer than that of the 92 patients
30 to 59 years old (median, 25 months) or the 18 patients260 years
old (median, 1 month) (all comparisons, P < .001).
the L1 or L2 patients because of the small sample size. Their
median WBC was 9,100/pL (range, 1 , 6 0 0 to 31,3OO/pL)
and none had a T or TMy immunophenotype or the Ph
chromosome. These patients have had a short median sur-
vival (6 months). Although 3 patients survived longer than
2 years, 2 have relapsed and 1of these subsequently received
a BMT.
Survival is also influenced by immunophenotype: 38% at
3 years for those with the expression of B-lineage antigens
compared with 69% for those with T-lineage antigen expres-
sion ( P = .001; Fig 5 ) . The myeloid antigen-positive cases
have had an intermediate survival (55% at 3 years) but not
statistically different from that of patients without myeloid
antigen expression within the same lymphoid lineage.
Similar to its impact on remission duration, the detection
of the t(9;22) has a statistically significant adverse effect on
survival. Only 16% (95% CI, 7% to 32%) of those with
either a Ph chromosome or a BCR-ABL rearrangement are
estimated to survive for 3 years, compared with 62% of
those who were negative by both genetic tests (P < .OOl).
In the multivariate analysis, after adjusting for age, WBC
count retained statistical significance with respect to survival
(P< .00l). Among T or TMy patients, the WBC count did
not have prognostic significance for survival, but a mediasti-
'l1-
P
R
0.6-
O
R Buy (n-19)
0.4-
O
N
"1'
0.0
I
0 3 1 2 1 5 6
Years
Fig 5. The survival for 39 patientswith a T or TMy immunophano-
( P = . M I ) than for
88 patients with a B or BMy immunophenotype (median, 21 months).
2032 LARSON ET AL

Table 5. Severe or Life-Threatening Toxicity a pulmonary embolism. Fatigue and malaise were common
Durina Treatment for ALL during L-asparaginase therapy; mental confusion was rare.
Induction Intensification Maintenance All patients were hospitalized during course I and many
Leukopenia (<2,000 yL) 98% 97% 75% patients required hospitalization during courses I1 and IV for
Thrombocytopenia (<50,OOO/fiL) 94 84 32 the treatment of fever while granulocytopenic. Otherwise,
Anemia (Hgb <8 g/dL) 65 84 26 hospitalization was seldom necessary. Increases in the levels
Hemorrhage 5 (1) 4 (2) 0 of hepatic transaminases were common and often required
infection 54 (7) 49 (4) 25 dose adjustments of maintenance chemotherapy. The treat-
Fever without infection 4 8 2 ment program was rigorous; 19 patients withdrew from the
Nausea/vomiting 8 17 8 prescribed therapy because of severe but less-than-life-
Stomatitis 7 9 7 threatening toxicity. These patients continued to be observed
Diarrhea 4 3 1
until relapse and death. Three patients underwent allogeneic
Hepatic 25 28 30
4
BMT in first remission; 2 of these have died. Two of the
Pulmonary 8 5 (1)
Cardiac 5 (1) 1 6 transplant patients had Ph-positive ALL; 1 reiapsed after
Genitourinary 8 (1) 2 1 BMT and has died and the other is alive and free of disease
CNS 6 13 6 more than 3 years after diagnosis. One patient underwent an
Peripheral nervous system 7 12 7 autologous BMT in first remission, relapsed 6 months later,
Skin 4 1 2 and died. A second patient, an 18-year-old manwithPh-
Allergy 0 1 1 positive ALL, underwent an autologous BMT in first remis-
The table liststhe frequencies (%) of grade 3 and 4 toxicities during sion followed by interferon therapyandwas alive atlast
each phaseof treatment using the CALGB Expanded Common Toxic- contact 14 months later. Two second cancers have been dis-
ity Criteria. The percentage of patients with lethal toxicity is shown covered, 1 renal and 1 breast carcinoma.
in parentheses. Patterns of failure. As described above, 28 patients
(14%) died while undergoing treatment on this study. Treat-
ment-related mortality was strongly related to increasing age
and was most often the result of infection.
nal mass was significantly associated with longer survival Twelve of the 13 patients who survived the induction
(P= .01). After controlling for age, WBC count, and medias- chemotherapy but failed to achieve a CR have died despite
tinal mass, FAB subtype retained prognostic significance additional therapy. One 19-year-old manhad Ph-positive
with respect to survival ( P = .001). If cytogenetic abnormali- ALL that was refractory to this protocol therapybut has
ties are accounted for first, then age, WBC count, and medi- remained free of disease for longer than 1 year after an
astinal mass continue to be significant. allogeneic BMT.
Toxicity. The major toxicities encountered during the in- Of 19 patients in remission who withdrew voluntarily or
duction and consolidation phases of this study were myelo- on their physician’s advice because of toxicity before com-
suppression and infection (Table 5). Seventeen patients (9%) pleting 2 years of the protocol therapy, 10 have experienced
died during the induction course, and most of these deaths a relapse of ALL and 8 of these have died. However, 7
were from infection with gram-negative bacteria or fungi. patients who did not complete the prescribed therapy remain
Nine of these patients were older than 60 years. There was alive with no evidence of disease. A11 7 have now been in
1 death from renal failure after tumor lysis syndrome during CCR longer than 3 years.
the induction phase. To date, 77 of the 167 patients (46%) who achieved a CR
Eleven patients (3 older than 60 years) died later, while have experienced a marrow and/or CNS relapse of ALL.
in remission and receiving consolidation or maintenance che- The minimum estimate of CNS relapse is 15% (25 patients).
motherapy. Six deaths were caused by infection, and l pa- Follow-up CSF examinations were not always reported, but
tient died after a colon perforation. Eleven patients were at least 7 patients have had concurrent relapses in the marrow
diagnosed to have Pneumocystis carinii pneumonia at some and the CNS. Only one patient, a 53-year-old man with Ph-
point during the 2 years of treatment; 1 of these patients positive ALL, had neurologic symptoms and CSF
died 3 weeks after the completion of all Chemotherapy.There lymphoblasts at diagnosis. Despite achieving a CR with in-
were 3 deaths from bleeding among patients in remission duction chemotherapy, intrathecal methotrexate, and cranial
who were receiving additional Chemotherapy: 2 hemorrhagic irradiation, he suffered a BM and CNS relapse 4 months
strokes and 1 gastrointestinal hemorrhage. after diagnosis and died 3 months later.
The L-asparaginase treatment was generally well toler- For 18 patients, CNS relapse preceded evidence of BM
ated. Several patients had local cutaneous reactions that did relapse by more than 1 month (range, 1 to 19 months). These
not recur when Erwinia L-asparaginase was substituted for latter patients had various features previously associated with
the initial Escherichia coli-derived drug. Treating physicians an increased risk of CNS leukemia: 5 had L3 morphology,
were required to evaluate the patient’s serum amylase level 5 had Ph-positive ALL, 3 had T-cell ALL, and 8 (including
before each L-asparaginase injection. Eight episodes of clini- 2 Ph-positive and 2 T-ALL cases) had greater than 30,000
cally significant pancreatitis were reported during courses I WBC/pL at diagnosis. Initially on this study, asymptomatic
and I1 during the 7 weeks of L-asparaginase therapy. One patients underwent their first lumbar puncture for spinal fluid
patient had inferior vena cava thrombosis and another had examination and intrathecal methotrexate at the beginning
NT INTENSIVE FOR ADULT ALL
Table 6. The Impact of Unfavorable Pretreatment Characteristics onthe Survival of 197 Adults With ALL
Adverse Features
No. of Adverse No. of Age WBC
Features Patients ~ 6 yr0 s30,WO/pL
None 15 - -
Exactly 1 42 0 6
1 Known 61 0 9
2 Known 55 7 55
31
3 Known 19 6 19
15
4 Known 5 5 5 1
Totals
18 197 66
The group reported to have one adverse feature is subdivided into 42 patients who had complete data regarding all five characteristics
(“exactly 1”) and 61 patients who had some missing data (mostly cytogenetics) but only one known adverse feature. Ph denotes Ph-positive
ALL detected by cytogenetics or by molecular assays.
of course HI, 3 months after diagnosis, when the BM was
already in remission. Seven asymptomatic patients were dis-
covered to have CSF lymphoblasts at that time. Isolated CSF
disease was also discovered in three patients who developed
neurologic symptoms while receiving consolidation chemo-
therapy in course 11. Although most responded to intrathecal
chemotherapy and cranial irradiation and several maintained
a subsequent CR for longer than l year, all eventually suf-
fered a BM relapse or died from recurrent CNS leukemia.
After the protocol was amended so that intrathecal metho-
trexate was administered starting at the beginning of course
I1 (see Table l), there were fewer cases of early CNS leuke-
mia observed (2 patients).
Six patients have had late isolated CNS relapses (without
simultaneous BM relapse), occumng after more than 1 year
in CR. Four relapses occurred while receiving maintenance
chemotherapy and 2 occurred 2 and 4 months after comple-
tion of 2 years of therapy. All 6 have died, 3 after subsequent
BM relapses. One 34-year-old man with T-cell ALL had an
isolated testicular relapse 5 months after completing 2 years
of therapy. He achieved a second CR after local irradiation
and received additional systemic chemotherapy; he suffered
a BM relapse 11 months later and died.
During the 24 months of treatment, 68 patients relapsed
or died in remission. The risk of failure was greater for
patients with Ph-positive or L3 ALL than for those with T-
lineage or B-lineage ALL butlacking the Ph or L3 character-
istics. When considering only B-lineage (not including Ph-
positive or L3) versus T-lineage ALL cases, the risk of
relapse was comparable throughout the 2 years of therapy.
As yet, only 3 relapses have been observed among 50 pa-
tients in CR for longer than 3 years.
Of 30 patients identified to have the Ph chromosome or
BCR-ABL rearrangement, 21 (70%) achieved a CR, but 16
of these have relapsed and died. Three others (39, 74, and
80 years old) have died in remission, and 1 is alive with no
evidence of disease after a BMT. Only 1 patient (46 years
old) has remained on study and continues in first remission
for longer than 4 years.
Patients with a t(4; 11) have been identified as a second
cytogenetic group with a poor outcome.’’ Two such patients
were known to be enrolled on this study. One woman (64
years old; WBC 392,2001pL) died during induction and 1
2033
FAB Ph or No Mediastinal % Estimated Survival at
L3 t(4; 11) Mass 3 yr (95% Cl)
- - - 100 (77-100)
0 0 36 74 (58-85)
1 0 51 58 (42-72)
6 11 25 (14-39)
0 17 26 (12-49)
4 5 0
8 32 166 50 (42-58)
man (61 years old; W C 209,800/pL) had refractory disease
and died 2 months after diagnosis.
High-risk patients. Groups of high-risk patients were
identified by the presence of one or more of the following
unfavorable characteristics: age 2 6 0 years, WBC count
=30,00O/pL, FAB L3 morphology, absence of a mediastinal
mass, and the presence of Ph or t(4; 11). Table 6 lists the
numbers of patients with each of these features and their
survival estimates. Fifteen patients (8%) had no unfavorable
features; 100% of these patients are estimated to be alive at
5 years (95% CI, 77% to 100%). Eight male and 7 female
patients comprised this favorable group. Their median age
was 30 years (range, 16 to 39 years) and the median WBC
count was 10,700/pL (range, 1,400 to 24,9OO/pL). Five had
L1 morphology and 10 had L2. Eighty-three percent had a
T or TMy phenotype. All had a mediastinal mass (by defini-
tion), 5 had splenomegaly, and 3 had hepatomegaly.
One hundred three patients (52%) had onlya single known
adverse feature; in 87, this was the absence of a mediastinal
mass. Fifty-nine percent of these patients were alive at last
follow-up. For this analysis, missing values were imputed as
“no adverse feature,” which has undoubtedly caused some
underreporting of multiple adverse features, especially with
respect to cytogenetics. For example, only 49% of the pa-
tients listed with one unfavorable feature had cytogenetic
data available. Hence, we separated those patients with com-
plete information (“exactly one adverse feature”) from
those with missing data and labeled the latter group as “one
known adverse feature.” No patient is considered to be high
risk based solely on age. Patients known to have L3 morphol-
ogy or unfavorable cytogenetics appear to have multiple
other adverse features. There are no survivors among the 5
patients known to have four adverse features.
DISCUSSION
One major goal of this study was to achieve initial cytore-
duction as rapidly as possible, using five lymphocytotoxic
drugs during the induction course. The fraction of patients
who subsequently achieved a CR (85%) was the highest yet
observed in a CALGB trial and compares favorably with
the outcomes reported from the best, large, single-institution
trials.2,6,7,9 The two preceding CALGB trials (8011 and
8513), enrolling unselected patients at the same centers with
 2034
an equivalent age distribution, had shown CR rates of 64%
71%,
and Other recent multicenter trials
have also reported lower CRrates:74% for the German
ALL trial (GMALL-01). 75% for GMALL-02, 68% for the
SWOG trial, and 64% for the ECOG trial, despite median
ages for the patients in each of these trials approximately 5
years younger than in the three CALGB trial^.^.'"^'' A recent
Medical Research Council trial reported an 87% CR rate for
patients with ALL, but that study included patients as young
as 14 years old and 40% of the patients were less than 20
years old.3’
Among patients less than 30 years old, the CR rate of
94% in our study also exceeds the remission rates of 75%
to 87% observed in other multicenter adult trials and ap-
proaches the 96% CR rate observed by the Children’s Cancer
Group using the same induction schedule for high-risk child-
hood ALL.I3 Unfortunately, the response rate for patients
more than 60 years old in our study was markedly affected
by the high early death rate. Thus, the question of whether
the poor overall outcome of older adults with ALL is caused
by inability to withstand treatment or to chemotherapy resis-
tance remains to be answered. However, once remission was
achieved, the probability of continuing in CR at 3 years was
not different between patients 30 to 59 years old and those
older than 60 years, although the number of older patients
was small.
Another objective of our trial was to provide the highest
possible dose intensity of treatment during courses I and I1
after initial rapid cytoreduction. For that reason, no delays
in treatment or dose reductions were permitted because of
pancytopenia in the absence of fever or obvious infection.
Nevertheless, on average, patients required 4 months to com-
plete the first 3 months of scheduled therapy. We cannot
determine whether the apparent success of this treatment
program is the result of the initial rapid cytoreduction or the
dose intensity of the later therapy.
Preliminary data from three randomized clinical trials sug-
gest that the concurrent use of filgrastim (granulocyte col-
ony-stimulating factor [G-CSF]) may improve the ability to
deliver intensive chemotherapy more s a f e l ~ . ~The~ . ’ follow-
~ tinal enlargement as an important factor. A trend similar to
up periods for these trials are still short, and the full impact
of the use of G-CSF during the treatment of adults with ALL
remains to be determined.
Modem chemotherapy regimens for ALL have evolved
empirically in such a fashion as to make it difficult to con-
clude which part of the total therapy is most effective or,
alternatively, even deleterious. Few randomized clinical tri-
als have been performed. In this regard, it is important to
note the results of the recent GIMEMA ALL-0288 trial, as
yet published only in abstract form.35 Here, 541 patients
between 12 and 65 years of age were randomly assigned to
remission induction treatment with daunorubicin, vincristine,
prednisone, and L-asparaginase with or without cydophos-
phamide. Thus, one arm received the same five agents that
weused in CALGB 881 1. However, those investigators
found no difference in the CR rates (80%) on each m,
calling into question the added benefit of the cyclophospha-
mide.
Patients with large-cell lymphoma whose disease responds
LARSON ET AL
more rapidly to chemotherapy have more durable remis-
sions.16 Likewise, some studies of both childhood and adult
ALL have shown that patients obtaining a more rapid re-
sponse of their leukemia to induction therapy have a higher
CR rate and longer disease-free s ~ r v i v a l . ”However,
~~~ others
have found that time to achieve remission was not predictive
of progn~sis.~’ In our study, we did not observe a statistically
significant difference in long-term outcome for the 27% of
CR patients who required more than 30 days to enter remis-
sion. This finding might be explained by the fact that delay
in achieving CR is a function both of drug resistance of the
disease as well as myelotoxicity from the treatment.
It would appear that the use of a more intensive remission
induction program has overcome the negative prognostic
importance previously associated with the expression of my-
eloid surface antigens or with any delay in achieving CR for
longer than 30 days.'^'^,^^ When we carefully excluded pa-
tients with minimally differentiated AML (FAB type MO),
we found no significant differences in the response rates,
remission duration, or survival of ALL patients whohad
coexpression of CD13 or CD33. In general, the course of
these patients appeared to be determined by their lymphoid
lineage, ie, B or T cell.
The TMy immunophenotype may identify a distinct subset
with a favorable prognosis. We treated 8 such patients, all
of whom were men. Their ages ranged from 17 to 46 years
(median, 32 years). The median WBC count was 14,90O/pL
(range, 1,OOO to 132,80O/pL). Three had splenomegaly, but
only 1 had a mediastinal mass. Three had L1 morphology,
3 had L2 morphology, and 2 were unclassified. None of the
7 studied had the t(9;22) by cytogenetics or by molecular
assays. Seven (88%) achieved a CR; as yet, only l of these
has relapsed and died. After 3 years, 86% remain in continu-
ous CR and 75% of the overall group remain alive.
Fifteen percent of our patients had an enlarged mediasti-
num. Surprisingly, we found that this was predictive of a
favorable outcome, with an influence on remission rate, dura-
tion of remission, and survival in multivariate analyses. Most
previous studies of adult ALL have failed to identify medias-
ours seemed apparent in an older German study, but it did
not reach statistical significance.’ Furthermore, in our study,
lymphadenopathy, another manifestation of leukemia mass,
had a favorable effect on remission rate and survival in a
univariate but not multivariate analysis. This favorable effect
of mediastinal node enlargement may be caused in part by
the favorable effect of the T-lineage immunophenotype, be-
cause 83% of the patients with an enlarged mediastinum had
T or TMy disease, or of L1 morphology (41% of these
patients). The median age of the patients with a mediastinal
mass was 32 years (range, 16 to 54 years) and the median
WBC count was 24,lOOIpL (range, 1,400 to 475,000/&).
None had the Ph chromosome.
Biologic characteristics of the disease continue to be pow-
erful determinants of response. The use of molecular meth-
ods to detect the BCR-ABL rearrangement will reliably de-
tect the approximately 30% of adults with ALL witha
t(9;22).I8 Despite a nearly equivalent CR rate, the disease-
free survival of these patients is clearly inferior to those
INTENSIVETREATMENT FOR ADULT ALL
without this genetic mutation. Indeed, once this subgroup
was reliably identified and considered separately, the esti-
mated 3-year survival of the remaining 3 1B-lineage patients
improved to 48% (95% CI, 32% to 65%). This was not
significantly different (P = .13) from the survival of the 27
similarly evaluated patients with T-lineage disease (62%;
95% CI, 42% to 79%). As yet, no chemotherapy regimen
has effectively cured patients with the Ph chromosome. In
our study, only 16% (95% CI, 7% to 32%) are estimated to
survive at 3 years. The proportion of patients with the Ph
chromosome increases with age.40 Thus, this abnormality
may be in part responsible for the poor prognosis of older
adults with ALL. Recent data suggest that approximately one
third of Ph-positive patients can be cured using allogeneic
BMT?’ At this time, allogeneic transplantation early in first
CR should be considered the treatment of choice for Ph-
positive patients of suitable age.
Burkitt-type (L3) B-ALL also had a poor outcome using
this treatment program. Approximately 5% of adults with
ALL have this subtype, which is characterized by the t(8; 14)
or one of its variants, t(2;8) or t(8;22). Although 75% of
our L3 patients achieved a CR, remissions were very short
(median, 3 months) and 5 of the 6 patients have relapsed.
Recent trials using short intensive chemotherapy programs
with high doses of cyclophosphamide or ifosfamide and
high-dose methotrexate and cytarabine have produced dis-
ease-free survival rates of 57% to 76% in children and adults
with L3 ALL or Burkitt’s lymph~ma:~-~~
Patients with FAB L2 morphology appear to do worse
than those with Ll, but it is not clear that L2 by itself can
be considered a poor-risk group. Indeed, in our multivariate
analyses, of 10 patients whose only adverse feature would
have been L2 morphology, all are alive at the most recent
follow-up. Patients with L3 morphology or adverse cytoge-
netics [Ph or t(4; l l)] appear to have other adverse features
and should be considered at high risk for treatment failure
regardless of the known number of other adverse features.
Complete data should be obtained at diagnosis to identify
the risk profile of individual patients with ALL to assist in
treatment planning.
In 23% of our patients who have relapsed, lymphoblasts
were observed in the spinal fluid 1 to 19 months before a
BM relapse and another 9% had simultaneous CNS and BM
relapses. Despite further treatment, all but 3 of these patients
have died. In our amended protocol, the first specific CNS
treatment begins in course 11, after achieving a BM response.
It is likely that systemic cyclophosphamide, prednisone, and
L-asparaginase provide some transarachnoid benefit during
the induction course. However, the CSF appears to remain
an important sanctuary site for ALL. Many of the CNS recur-
rences occurred in patients with previously described high-
risk features for CNS involvement: Ph chromosome, L3 mor-
phology, T-cell phenotype, or high initial WBC count. More
intensive systemic chemotherapy, such as high-dose metho-
trexate or high-dose cytarabine, or higher radiation doses,
such as 3,000 cGy to the cranium and perhaps to the entire
spinal axis, might be appropriate for these poor-prognosis
patient^.^.^.^'
In summary, we report the results of a multi-institutional
2035
study supporting the usefulness of a dose-intense multicourse
2-year therapy program for adults with ALL. The CR rate
is high, and for the younger than 30-year-old adult patients
approaches that achieved in high-risk childhood ALL. The
median survival has not been reached for younger patients;
it is greater than 2 years even for those in the 30- to 59-
year-old age group. Two subgroups have had particularly
favorable outcomes: those with amediastinal mass and those
with a TMy immunophenotype. We have identified five pa-
tient characteristics that are related to adverse prognosis and
found that patients with multiple adverse features appear to
have an increased risk. This observation requires validation
using other data sets. Future efforts should be directed to-
ward designing innovative approaches to those patients with
the identified adverse prognostic factors, especially older age
and adverse cytogenetic/molecular biologic features.
ACKNOWLEDGMENT
We thank Gwennelle Clark andAudrey Byrd for expert data
coordination at the CALGB Data Management Center and Susan
Jarman for the preparation of the manuscript. The following main
member CALGB institutions (principal investigator; N M grant sup-
port) participated in this study, and we thank the many treating
physicians, cytogeneticists, research nurses, data managers, and pa-
tients without whom it could not have been completed Bowman
Gray School of Medicine (M. Robert Cooper, MD; CA 03927);
Central Massachusetts Oncology Group-University of Massachusetts
Medical Center (Mary E. Costanza, MD); Dana-Farber Cancer Insti-
tute (George P. Canellos, MD; CA 32291); Dartmouth Medical
School-Noms Cotton Cancer Center (L. Herbert Maurer, MD; CA
04326); Duke University Medical Center (Jeffrey Crawford, MD;
CA 47577); Long Island Jewish Medical Center (Kanti R. Rai, MD;
CA 11028); Massachusetts General Hospital (Philip Amrein, MD;
CA 12449);McGill Department of Oncology (Brian Leyland-Jones,
MD; CA 3 1809);Mount Sinai Hospital (James F. Holland, MD; CA
04457); New York Hospital-Come11 Medical Center (Richard T.
Silver, MD; CA 07968); North Shore University Hospital (Daniel
R. Budman, MD;CA 35279); Rhode Island Hospital (Louis A.
Leone, MD; CA 08025); Roswell Park Cancer Institute (Clara D.
Bloomfield, MD; CA 59518); SUNY Health Science Center at Syra-
cuse (David B. Duggan, MD; CA 21060); University of Alabama,
Birmingham (George A. Omura, MD; CA 47545); University of
California at San Diego (Mark R. Green, MD; CA 11789); Univer-
sity of Chicago (Nicholas J. Vogelzang, MD; CA 41287); University
of Iowa Hospitals (Gerald Clamon, MD, CA 47642), university of
Maryland Cancer Center (Joseph Aisner, MD; CA 31983); Univer-
sity of Minnesota (Bruce A. Peterson, MD; CA 16450); University
of MissourEllis Fischel Cancer Center (Michael C. Peny, MD; CA
12046); University of North Carolina at Chapel Hill (Thomas C.
Shea, MD, CA 47545); University of Tennessee, Memphis (Alvin
M. Mauer, MD; CA 47555); Walter Reed A m y Medical Center
(Raymond B. Weiss, MD; CA 26806); and Barnes Hospital (Joanne
Mortimer, MD; CA 47546).
REFERENCES
1. Hoelzer DF: Therapy of the newly diagnosed adult with acute
lymphoblastic leukemia. Hematol Oncol Clin North Am 7:139, 1993
2. Kantarjian H M , Walters RS, Keating MJ, Smith TL, O’Brien
S, Estey EH, Huh YO, Spinolo J, Dicke K, Barlogie B, McCredie
KB, Freireich EJ: Results of the vincristine, doxorubicin, and dexa-
methasone regimen in adults with standard- and high-risk acute
lymphocytic leukemia. J Clin Oncol 8:994, 1990
2036
3. Hoelzer D, Thiel E, Ldffler, Buchner T, Ganser A, Heil G ,
Koch P, Freund M, Diedrich H, Riihl H, Maschmeyer G, Lipp T,
Nowrousian MR. Burkert M, Gerecke D, Pralle H, Mtiller U, Luns-
cken Ch. Fulle H, Ho AD, KiichlerR, Busch F W , Schneider W,
Gorg Ch, Emmerich B, Braumann D, Vaupel HA, von Paleske A,
Bartels H, Neiss A, Messerer D: Prognostic factors in a multicenter
study for treatment of acute lymphoblastic leukemia in adults. Blood
71:123, 1988
4. Gaynor J, Chapman D, Little C, McKenzie S, Miller W, An-
dreeff M, Arlin Z, Berman E, Kempin S, Gee T, Clarkson B: A
cause-specific hazard rate analysis of prognostic factors among 199
adults with acute lymphoblastic leukemia: The Memorial Hospital
experience since 1969. J Clin Oncol 61014, 1988
5. Linker CA, Levitt L J , O’Donnell M, Forman SJ, Ries CA:
Treatment of adult acute lymphoblastic leukemia with intensive cy-
clical chemotherapy: A follow-up report. Blood 78:2814, 1991
6. Schauer P, Arlin ZA, Mertelsmann R, Cirrincione C, Friedman
A, Gee TS, Dowling M, Kempin S, Straus DJ, Koziner B, McKenzie
S, Thaler Tzvi H, Dufour P, Little C, Dellaquila C, Ellis S, Clarkson
B: Treatment of acute lymphoblastic leukemia in adults: Results of
the L-IO and L-1OM protocols. J Clin Oncol 1:462, 1983
7. Clarkson B, Ellis S, Little C, Gee T, Arlin Z, Mertelsmann R,
Andreeff M, Kempin S, Cimncione C, Gaynor J: Acute lymphoblas-
tic leukemia in adults. Semin Oncol 12:160, 1985
8. Hussein KK, Dahlberg S , Head D, Waddell CC, DabichL,
Weick JK, Morrison F, Saiki JH, Metz E, Rivkin SE, Grever MR,
Boldt D, and the Southwest Oncology Group: Treatment of acute
lymphoblastic leukemia in adults with intensive induction, consoli-
dation, and maintenance chemotherapy. Blood 7357, 1989
9. Radford JE Jr. Bums CP, Jones MP, Gingrich RD, Kemp JD,
Edwards RW, McFadden DB, Dick FR. Wen B-C: Adult acute
lymphoblastic leukemia: Results of the Iowa HOP-L protocol. J Clin
Oncol 758, 1989
10. Hoelzer D: Treatment of acute lymphoblastic leukemia.
Semin Hematol 31:1, 1994
11. Gottlieb AJ, Weinberg V, Ellison RR, Henderson ES, Tere-
belo H, Rafla S, Cuttner J, Silver RT, Carey RW, Levy RN, Hutchin-
son JL, Raich P, Cooper MR, Wiernik P, Anderson JR, Holland JF:
Efficacy of daunorubicin in the therapy of adult acute lymphocytic
leukemia: A prospective randomized trial by Cancer and Leukemia
Group B. Blood 64:267, 1984
12. Ellison RR, Mick R, Cuttner J, Schiffer CA, Silver RT, Hen-
derson ES, Woliver T, Royston I, Davey FR, Glicksman AS, Bloom-
field CD, Holland J F The effects of postinduction intensification
treatment with cytarabine and daunorubicin in adult acute lympho-
cytic leukemia: A prospective randomized clinical trial by Cancer
and Leukemia Group B. J Clin Oncol 9:2002, 1991
13. Steinherz PG, Gaynon P, Miller DR, Reaman G , Bleyer A,
Finklestein J, Evans RG, Meyers P, Steinherz LJ, Sather H, Ham-
mond D: Improved disease-free survival of children with acute
lymphoblastic leukemia at high risk for early relapse with the New
York regimen -A new intensive therapy protocol: A report from
the Children’s Cancer Study Group. J Clin Oncol 4:744, 1986
14. Cheson BD, Cassileth PA, Head DR, Schiffer CA, Bennett
JM, Bloomfield CD, Brunning R, Gale RP, Grever MR, Keating
MJ, Sawitsky A, Stass S, Weinstein H, Woods WG: Report of the
National Cancer Institute-sponsored workshop on definitions of diag-
nosis and response in acute myeloid leukemia. J Clin Oncol 8:813,
1990
15. Bennett JM, Catovsky D, Daniel M-T, Flandrin G , Galton
DAG, Gralnick HR, Sultan C: Proposals for the classification of
the acute leukemias. French-American-British (FAB) Co-operative
Group. Br J Haematol 33:451, 1976
16. Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton
DAG, Gralnick HR, Sultan C: The morphologic classification of
LARSON ET AL
acute lymphoblastic leukemia. Concordance among observers and
clinical correlations. Br J Haematol 47553, 1981
17. Bloomfield CD, Wurster-Hill D, Peng G, Le Beau M, Tantra-
vahi R, Testa J, Davey FR, Ellison RR, Cuttner J, Schiffer C, Sobol
RE, Lunghofer B, Carey M, Mick R, Arthur D: Prognostic signifi-
cance of the Philadelphia chromosome in adult acute lymphoblastic
leukemia, in Gale RP, Hoelzer D (eds): Acute Lymphoblastic Leuke-
mia. UCLA Symposium on Molecular and Cellular Biology, New
Series, v01 108. New York, NY, Wiley-Liss, 1990, p 101
18. Westbrook CA, Hooberman AL. Spin0 C, Dodge RK, Larson
RA, Davey F, Wurster-Hill DH, Sobol RE, Schiffer C, Bloomfield
CD: Clinical significance of the BCR-ABL fusion gene in adult
acute lymphoblastic leukemia: A Cancer and Leukemia Group B
Study (8762). Blood 80:2983, 1992
19. Sobol RE, Mick R, Royston 1, Davey FR, Ellison RR, New-
manR, Cuttner J, Griffin JD, Collins H, Nelson DA, Bloomfield
CD: Clinical importance of myeloid antigen expression in adult acute
lymphoblastic leukemia. N Engl J Med 316:1111, 1987
20. Weiss RB, Vogelzang NJ, Peterson BA, Panasci LC, Carpen-
ter JT, Gavignan M, Sartell K, Frei E, McIntyre OR: A successful
system for scientific data audits for clinical trials: A report from the
Cancer and Leukemia Group B. JAMA 270:459, 1993
21. Kaplan EL, Meier P Nonparametric estimation from incom-
plete observations. J Am Stat Assoc 53:457, 1958
22. Simon R, Lee YJ: Nonparametric confidence limits for sur-
vival probabilities and median survival time. Cancer Treat Rep
66:37, 1982
23. Mantel N: Evaluation of survival data and two new rank order
statistics arising in its consideration. Cancer Chemother Rep 50: 163,
1966
24. Koziol JA, Reid N: On multiple comparisons among k sam-
ples subject to unequal patterns of censorship. Comrnun Stat Theor
Methods A6: 1149, 1977
25. Hosmer DW, Lemeshow S: Applied Logistic Regression.
New York, NY, Wiley, 1989
26. Cox D R Regression models and life tables. J R Stat SOCB
34:187, 1972
27. SAS Technical Report P-229, SASISTAT Software: Changes
and Enhancements, Release 6.07. Cary, NC, SAS Institute, 1992, p
243 and 433
28. Pui CH: Acute luekemias withthe t(4;11)(q21;q23). Leuk
Lymphoma 7:173, 1992
29. Cuttner J, Mick R, Budman DR, Mayer RI, Lee EJ, Hender-
son ES, Weiss RB, Paciucci PA, Sobol R, Davey F, Bloomfield C,
Schiffer C: Phase 111 trial of brief intensive treatment of adult acute
lymphocytic leukemia comparing daunorubicin and mitoxantrone:
A CALGB Study. Leukemia 5425, 1991
30. Cassileth PA, Andersen W , Bennett JM, Hoagland HC,
Mazza JJ, O’Connell MC, Paietta E, Wiernik P, for the Eastern
Cooperative Oncology Group: Adult acute lymphocytic leukemia:
The Eastem Cooperative Oncology Group experience. Leukemia
6: 178, 1992 (suppl 2)
3 1. Durrant IJ, Richards SM: Results of Medical Research Coun-
cil trial UKALL IX in acute lymphoblastic leukaemia in adults:
Report from the Medical Research Council Working Party on Adult
Leukaemia. Br J Haematol 85:84, 1993
32. Larson RA, Linker CA, Dodge RK, George SL, Davey F R ,
Frankel SR, Powell BL, Schiffer CA: Granulocyte-colony stimulat-
ing factor (filgrastim; G-CSF) reduces the time to neutrophil recov-
ery in adults with acute lymphoblastic leukemia receiving intensive
remission induction chemotherapy: Cancer and Leukemia Group B
Study 91 11. Proc Am SOCClin Oncol 13:305, 1994 (abstr 995)
33. Ottmann OG, Hoelzer D, Gracien E, Kelly K, Ganser A,
Reutzel R, Lipp T, Busch F W , Schwonzen M, Wandt H, Heil G ,
Koch P, Hey11A, Meyer P, Bentz M, Peter S, Diedrich H, Kolbe
 INTENSIVETREATMENT FOR ADULT ALL
K: Concomitant R-metHuG-CSF (filgrastim) and intensive chemora-
diotherapy as induction treatment in adult ALL:A randomized
multicenter phase I1 trial. Blood 82:193a, 1993 (abstr 757, suppl l )
34. Ohno R, Tomonaga M, Kobayashi T, Kanamaru A, Shirakawa
S , Masaoka T, Omine M, OhH, Nomura T, Sakai Y, Hirano M,
Yokomaku S , Nakayama S, Yoshida Y, Miura AB, Morishima Y,
DohyH, Niho Y, Hamajima N, Takaku F Effect of granulocyte
colony-stimulating factor after intensive induction therapy in re-
lapsed or refractory acute leukemia. N Engl J Med 323:871, 1990
35. Mandelli F, Annino L, Vegna ML, Camera A, Ciolli S, De-
plan0 W, Fabian0 F, Ferrara F, Ladogana S , Muti G, Peta A, Recchia
A, Sica S , Stasi R, Tabilio A, Visani G, Baccarani M for the GI-
MEMA group: GIMEMA ALL 0288: A multicentric study on adult
acute lymphoblastic leukemia. Preliminary results. Leukemia 6 182,
1992 (suppl 2)
36. Armitage JO, Weisenburger DD, Hutchins M, Moravec DF,
Dowling M, Sorensen S, Mailliard J, Okerbloom J, Johnson PS,
Howe D, Bascom GK, Casey J, Linder J, Purtilo DT: Chemotherapy
for diffuse large-cell lymphoma: Rapidly responding patients have
more durable remissions. J Clin Oncol 4:160, 1986
37. Miller DR, Coccia PF, Bleyer WA, Lukens JN, Siege1 SE,
Sather HN, Hammond GD: Early response to induction therapy as
a predictor of disease-free survival and late recurrence of childhood
acute lymphoblastic leukemia: A report from the Children’s Cancer
Study Group. J Clin Oncol 7:1807, 1989
38. Hoelzer D: Therapy of acute lymphoblastic leukemia in
adults. Leukemia 6:132, 1992 (suppl 2)
39. Drexler HG, Thiel E, Ludwig W-D: Review of the incidence
and clinical relevance of myeloid antigen-positive acute lymphoblas-
tic leukemia. Leukemia 5:637, 1991
40. Secker-Walker LM, Craig JM, Hawkins JM, Hornrand AV:
Philadelphia positive acute lymphoblastic leukemia in adults: Age
View publication stats
2037
distribution, BCR breakpoint and prognostic significance. Leukemia
5196, 1991
41. Barrett AJ, Horowitz MM, Ash RC, Atkinson K, Gale RP,
Goldman JM, Henslee-Downey PJ, Herzig RH, Speck B, Zwaan FE,
Bortin MM: Bone marrow transplantation for Philadelphia chromo-
some-positive acute lymphoblastic leukemia. Blood 79:3067, 1992
42. Reiter A, Schrappe M, Ludwig W-D, Lampert F, Harbott J,
Henze G, Niemeyer CM, Gadner H, Muller-Weihrich S , Ritter J,
Edenwald E, Riehm H: Favorable outcome of B-cell acute lympho-
blastic leukemia in childhood: A report of three consecutive studies
of the BFM Group. Blood 802471, 1992
43. Schwenn MR, Blattner SR, Lynch E, Weinstein HU: HiC-
COM: A 2-monthintensive chemotherapy regimen for children with
stage I11 and IV Burkitt’s lymphoma and B-cell acute lymphoblastic
leukemia. J Clin Oncol 9:133, 1991
44. P a w C, Philip T, Rodary C, Zucker J-M, Behrendt H, Gentet
J-C, Lamagdre J-P, Otten J, Dufillot D, Pein F, Caillou B, Lemerle
J: High survival rate in advanced-stage B-cell lymphomas and leuke-
mias without CNS involvement with a short intensive polychemo-
therapy: Results from the French Pediatric Oncology Society of a
randomized trial of 216 children. J Clin Oncol 9:123, 1991
45. Fenaux P, Lai JL, Miaux 0, Zandecki M, Jouet JP, Bauters
F: Burkitt cell acute leukaemia (L3 ALL) in adults: A report of 18
cases. Br J Haematol 71:371, 1989
46. Cassileth PA, Andersen JW, Hoagland HC: High-dose cytara-
bine therapy in adult acute lymphocytic leukemia, in Gale RP,
Hoelzer D (4s): Acute Lymphoblastic Leukemia. New York, NY,
Liss, 1990, p 197
47. Wiernik PH, Dutcher JP, Paietta E, Gucalp R, Markus S ,
Weinberg V, Azar C, Gar1 S, BensonL: Long-term follow-up of
treatment and potential cure of adult acute lymphocytic leukemia
withMOAD:A non-anthracycline containing regimen. Leukemia
7:1236, 1993