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Blood, Vol. 95 No. 11 (June 1), 2000:
pp. 3310-3322
CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
From the Department of Pediatric Hematology and Oncology,
Medizinische Hochschule Hannover, Federal Republic of Germany (FRG);
Department of Hematology, Oncology and Tumor Immunology, Charité,
Campus Berlin-Buch, Humboldt University, Berlin, FRG; Oncogenetic
Laboratory, University Children's Hospital, Gießen, FRG; Department
of Hematology and Oncology, University Göttingen; Germany;
Department of Pediatrics, University Freiburg, FRG; Ostschweizerisches
Kinderspital, St Gallen, Switzerland; Department of Pediatric
Hematology and Oncology, Charité, Humboldt University, Berlin,
FRG; Department of Pediatric Hematology and Oncology, University Jena,
FRG; Department of Pediatric Hematology and Oncology, University
Frankfurt, FRG; Department of Pediatric Hematology and Oncology,
University Münster, FRG; and St Anna Kinderspital, Wien, Austria.
A complete list of the members of the German-Austrian-Swiss ALL-BFM
Study Group appears at the end of this article.
Trial ALL-BFM 90 was designed to improve outcome in patients with
childhood acute lymphoblastic leukemia (ALL) by using a reduced
treatment regimen. Patients were stratified into a standard-risk group (SRG), a medium-risk group (MRG), both defined by adequate early
treatment response; and a high-risk group (HRG), defined by inadequate
response to the cytoreductive prednisone prephase, induction failure,
or Philadelphia-chromosome-positive ALL. Four treatment
modifications were evaluated: dose intensification in induction by a more rapid drug sequence; administration
of L-asparaginase during consolidation therapy in the
MRG (randomized); enforced consolidation by rotational elements in
the HRG; and reduction in the dose of anthracyclines and use of only
12-Gy preventive cranial radiotherapy in the MRG and HRG, with the aim
of avoiding toxicity. Among all 2178 patients (
Contemporary research on childhood acute lymphoblastic
leukemia (ALL) has focused on the identification of biologic and
clinical prognostic markers to generate better risk-adapted treatment
strategies.1-3 The identification of several chromosomal
aberrations and improved molecular detection techniques allow
definition of patient subsets with distinct prognostic
features.4-6 Nevertheless, treatment itself remains one of
the strongest prognostic factors, as has been shown in several
well-designed large clinical trials.7-15 Intrinsic drug
resistance is the major cause of treatment failure. So far, this
phenomenon has not been linked to any specific clonal abnormality.
However, knowledge gained from systematic measurements of in vitro and
in vivo drug resistance could be used for better identification of
patients at increased risk of treatment failure.3,16-23
With treatments for ALL having achieved long-term cure rates above 70%
in unselected patient populations, the acute and long-term toxicity of
such treatments identified by the end of the 1980s had to be taken into
account by researchers introducing new therapies.24-29 Thus, one major focus of the design of trial ALL-BFM 90 was a reduction
in the use of treatment elements with long-term toxicity; thus, during
induction, the cumulative anthracycline dose was reduced by 25%, from
160 mg/m2 of body-surface area (the dose used in trial
ALL-BFM 86) to 120 mg/m2. The elimination of preventive
cranial radiotherapy (CRT) in patients with low-risk ALL and the
successful stepwise reduction in CRT to 12 Gy in those with
intermediate-risk ALL (begun in previous ALL-BFM studies1)
was the basis for introducing the use of 12-Gy CRT in patients at
medium and high risk. To strengthen the extracompartmental treatment,
the ALL-BFM study group introduced high-dose methotrexate (HD-MTX) in
trial ALL-BFM 86.3
The experience from a series of large multicenter trials conducted by
the ALL-BFM study group (particularly, trial ALL-BFM 863)
made it evident that the BFM treatment concept could provide a cure
rate of more than 75% for approximately 90% of all patients. This
large patient subset was characterized by an adequate early response to
cytoreductive therapy with 7 days of prednisone (and 1 intrathecal dose
of methotrexate [MTX] on day 1). An adequate response was easily
measured as a leukemic blast-cell count of under 1000/µL in
peripheral blood (PB) on day 8 ("prednisone: good response"
[PGR]). Demonstration of in vivo prednisone resistance defined
high-risk patients, who comprised about 10% of the study population.16 Prognosis in this subset was unfavorable,
with an event-free survival (EFS) rate below 50%.3
Therefore, a new strategy for this well-defined patient subgroup was
developed, based on early intensification with treatment elements
derived from the strategy for treating ALL relapse.
Most relapses, however, occurred in medium-risk patients who did not
have any specific prognostic biologic or clinical
characteristics.3 Improvement in the largest patient subset
was therefore sought by using a more condensed induction regimen and
enforcement of the consolidation phase. This strategy had the following
features: to increase dose intensity, induction element protocol I was
shortened by 1 week by starting L-asparaginase on day 12 instead of day 19 (as in trial ALL-BFM 86); and to intensify
consolidation in medium-risk patients, 4 high-dose pulses of
L-asparaginase were added in a randomized manner to the
existing consolidation phase using HD-MTX and 6-mercaptopurine
(protocol M in trial ALL-BFM 86).
Trial ALL-BFM 90, which had 2178 unselected patients, was the largest
cooperative trial performed so far by the BFM study group and can thus
offer treatment results with regard to biologic and clinical variables
evaluated for their prognostic importance. To better assess the
importance of the advances and pitfalls in this trial, direct
comparisons with updated results of previous ALL-BFM trials were
performed. This was possible because patient populations in all ALL-BFM
trials are unselected and because treatment modifications were limited
and well defined.
Patients
Diagnosis
Immunophenotyping Immunophenotyping was done as described elsewhere.32,33 Surface antigens were considered positive if at least 20% of the leukemic cells expressed the antigen with more than 98% fluorescence intensity compared with negative control cells. Positivity for terminal deoxynucleotide transferase (TdT) and cytoplasmic (cy) antigens was defined as more than 10% of the cells exhibiting nuclear or intracytoplasmic fluorescence (TdT, cyIgM, and cyCD3). In 1994, 2-color flow cytometric analysis was introduced; the procedure uses appropriate monoclonal antibodies directly conjugated to fluorescein isothiocyanate or phycoerythrin. Immunophenotypic subgroups were defined according to the definition provided by the European Group for the Immunological Characterization of Leukemias, as follows: pro-B ALL, TdT+, CD19+, CD10 , cyIgM,
surface immunoglobulin (sIg); common ALL,
TdT+, CD19+, CD10+,
cyIgM, sIg; pre-B ALL,
TdT+, CD19+, CD10+/,
cyIgM+, sIg; and T-cell ALL (T-ALL),
TdT+, cyCD3+, CD7+.34
Coexpression of myeloid antigen was defined as simultaneous expression
of one or more of the myeloid-lineage associated molecules tested
(CD13, CD33, CD65s) on at least 20% of the lymphoblasts.
Cytogenetic and molecular genetic analysis Cytogenetic studies were carried out by using standard techniques as described elsewhere.35 In November 1992, screening for BCR/ABL based on reverse transcriptase-polymerase chain reaction was initiated.36DNA index Cellular DNA content was determined by using flow cytometry as previously described.37 The DNA index of the leukemic blasts was defined as the ratio of DNA content in leukemic G0/G1 cells to that in normal diploid lymphocytes. A cut-off DNA-index value of 1.16 was used to distinguish prognostic categories.Estimation of the leukemic cell mass at diagnosis The leukemic cell mass estimate (the BFM-RF) was calculated with the following equation: BFM-RF = 0.2 × log (blood blasts/µL + 1) + 0.06 × liver size in centimeters below the costal margin + 0.04 × spleen size in centimeters below the costal margin.38Definition of prednisone response In all patients, treatment started with 7 days of monotherapy with prednisone and 1 intrathecal dose of MTX on day 1. The first day of treatment was the day of the first administration of prednisone. The dosage of prednisone was increased steadily to 60 mg/m2 daily in accordance with leukemic cell mass, renal, and metabolic variables to circumvent complications of acute cell lysis. The number of leukemic blasts in the blood on day 8 was calculated from the absolute leukocyte count and the percentage of blasts in PB smears determined by central review in the study center. The presence of at least 1000/µL blasts in PB on day 8 was defined as a "prednisone: poor response" (PPR); fewer than 1000/µL leukemic cells was required for a classification of PGR.16Patient stratification and treatment Patients were assigned to 1 of 3 branches: a standard-risk group (SRG), a medium-risk group (MRG), and a high-risk group (HRG). The main criteria for stratification were the leukemic cell mass estimate (BFM-RF) and the treatment response.3,38 Additional criteria included the presence of the T-cell immunophenotype, rearrangement BCR/ABL or translocation t(9;22), and CNS involvement.
Response criteria
Statistical analysis For the random assignment to treatment with L-asparaginase in branch MRG, the following estimate was made on the basis of results of previous studies: 30% of patients will be at risk for relapse after induction protocol I. Sample-size calculations then determined that 230 patients were needed in each of the randomization branches, MRG-1 and MRG-2, to detect a decrease from 30% to 20% in the relapse rate resulting from intensification of protocol M with a power of 0.80 ( error = 0.05).
Patient characteristics The median age of all 2178 evaluable patients was 4.6 years (range, 0.01-18.53 years); 2.7% of patients were infants under 1 year of age. The median WBC count at presentation was 11.8 × 109/L (range, 0.3-1496.0 × 109/L). Clinical and biologic characteristics of the whole study population and the 3 risk groups are summarized in Table 2. The major extramedullary disease manifestations were a mediastinal mass in 8% of patients, nodal involvement (without mediastinal involvement) in 36%, liver and spleen enlargement (organ palpable more than 4 cm below the costal margin) in 31% and 27%, respectively, and CNS involvement in 2.5%. Eight boys (0.6%) had testicular involvement. B-cell-precursor ALL predominated (86.5% of patients); 13.5% patients had T-ALL. Among patients with B-cell-precursor ALL, pro-B ALL was diagnosed in 6%, common ALL in nearly 75%, and pre-B ALL in 19%.
Treatment results EFS.
After a median observation time of 4.8 years (range, 0-8.1 years), the
estimate for EFS of all 2178 evaluable patients was 78% ± 1% at
6 years and 77% ± 1% at 8 years; 1.7% of all patients did not
have CR, 17.7% had relapse, 0.5% had a second malignancy diagnosed,
and 1.6% died of complications of therapy (Table
3). Among all 2300 patients enrolled, EFS
was 76% ± 1% at 8 years. The estimate of probability of
disease-free survival for all evaluable patients was 78% ± 1%,
and the estimate of probability of survival was 85% ± 1%. The
78% ± 1% 6-year EFS (CI, 76%-79%) in trial ALL-BFM 90 was
significantly higher than the EFS at 6 years in trials ALL-BFM 86 and
ALL-BFM 83, in which it was 72% ± 1% (CI, 69%-75%) and
64% ± 2% (CI, 60%-68%), respectively (P = .001 for
ALL-BFM 86 compared with ALL-BFM 90; P = .0001 for ALL-BFM 83 compared with ALL-BFM 90; Figure
2).
Remission failures.
A total of 2140 patients (98.3%) achieved first CR. The CR rate was
lowest in the HRG (92.2%) because all patients with induction failure
were, by definition, stratified into that group. Thirty-eight of the
2178 evaluable patients did not have remission because of early death
or resistant disease. Before and during the first 5 weeks of induction,
22 patients died. Ten of these patients died of complications
(hyperleukocytosis, cardiomyopathy, encephalopathy, or bleeding) before
or within the first few days of treatment, and 12 patients died of
complications that were more closely related to the treatment (sepsis
or pneumonia, 10 patients; massive bleeding from an ulcer, 1 patient;
and hepatopathy and cardiomyopathy after 3 doses of vincristine and
daunorubicin, 1 patient). Thus, the early mortality rate was 1.0%
(Table 3). Sixteen patients, of whom 4 were initially classified as MRG
patients with PGR, did not have remission at day 33 and were also not
in CR after the third HR pulse (nonresponse). Six of the 16 nonresponse
patients had CR very late Deaths in CR.
Thirty-four patients (1.6%) died in first CR from complications (Table
3). Four of these patients died because of toxicity related to
allogeneic BMT (branch HR), 19 died of infection (sepsis and
pneumonia in 18 patients and cytomegalovirus infection in 1), 5 patients died as a result of massive unexpected bleeding during
induction, and 5 died of organ failure (1 patient each of
cardiomyopathy, hepatopathy, and ileus and 2 of encephalopathy). One
patient was found dead at home and an autopsy was not performed. Twenty-six of the 30 deaths not related to BMT occurred within 12 months of diagnosis, ie, during the intensive-treatment phase or early
in the maintenance-treatment phase. Two patients died in the second
year of therapy, and 2 died at the end of maintenance therapy (1 patient with Down syndrome who died of pneumonia and 1 patient
who died of cytomegalovirus encephalitis).
Relapses.
Relapse occurred in 385 patients (17.7%; Table 3). Thirty-three
percent of all recurrences were in the HRG, 48% were in the MRG, and
19% were in the SRG. Most relapses (85%) in the HRG occurred within
the first 2 years of diagnosis, ie, during therapy. In contrast, most
relapses in the SRG and MRG occurred after the end of treatment (Figure
3). Systemic failures were more frequent among HRG patients; they
developed in 39.1% of patients in that group but in only 6.9% of SRG
patients and 9.2% of MRG patients. There were, however, no differences
in the rates of extramedullary recurrences among the 3 risk groups. The
overall incidence of isolated and combined CNS relapse was 1.0% and
1.9%, respectively. Most of the other extramedullary relapses involved
lymph nodes or mediastinal sites (or both), the thymus, or the testes.
Second malignancy.
In 10 patients, a secondary malignancy developed at a median time of
40.2 months (range, 15-68 months) after diagnosis. Secondary malignancies occurred in all 3 risk groups; there was no evidence of a
higher incidence among more intensely treated patients (Table 3). Five
second malignancies were acute myelogenous leukemia (AML),
2 were brain tumors, 1 was Hodgkin disease, 1 was basal cell carcinoma,
and 1 was malignant histiocytosis.
Impact of new or modified treatment elements: intensification of
consolidation in MRG patients by high-dose L-asparaginase.
The probability of EFI among MRG patients randomly assigned to receive
4 courses of 25 000 IU/m2 L-asparaginase
(branch MRG-2, n = 528) was 83% ± 2%. In patients receiving
the standard consolidation without L-asparaginase
(n = 557), the probability of EFI was 81% ± 2%. The
difference in EFI in the 2 groups was not significant
(P = .67). In the Cox regression including all variables
found to be relevant for prognosis, no significant influence of
additional L-asparaginase treatment was found.
Impact of new or modified treatment elements: intensive early
consolidation with rotational high-dose pulses and reduced preventive
CRT in HRG patients.
Evaluation of the modified approach for high-risk patients had to be
performed by comparing results with those in the matching subset of
patients in trial ALL-BFM 86.3 The only difference at
diagnosis between the high-risk patients in the 2 trials was the
distribution of age subgroups: there were more infants (< 1 year of
age) in trial ALL-BFM 86 and more patients older than 6 years of age in
trial ALL-BFM 90. The EFS for high-risk patients in trial ALL-BFM 86 (group EG) was 47% ± 5%, whereas it was 34% ± 3% in
trial ALL-BFM 90 (P = .04). The difference was due to the
higher number of systemic recurrences in high-risk patients in ALL-BFM
90: the cumulative incidence of isolated BM relapse at 6 years was
42.7% ± 4% in ALL-BFM 90, but 24.7% ± 6% in ALL-BFM 86 (P = .01). Despite the reduction in CRT, the cumulative
incidence of isolated and combined CNS relapse was only 1.8% and
2.7%, respectively, in ALL-BFM 90, whereas it was 7.4% and 5.4%,
respectively, in ALL-BFM 86 (P not significant).
Impact of new or modified treatment elements: outcome in
standard-risk and medium-risk patients according to modified induction
in patients with PGR.
EFS among all patients with PGR (n = 1935) at 6 years was
82% ± 1%. As shown in Figure 5,
this was a significant improvement over results in comparable patients
in trials ALL-BFM 83 (n = 467; 6-year EFS, 69% ± 2%;
P = .0001) and ALL-BFM 86 (n = 783; 6-year EFS,
77% ± 2%; P = .0012 [standard-risk patients treated without reinduction in ALL-BFM 83 and ALL-BFM 86 were excluded to
reduce bias1,3]). To identify the subset in which the
greatest improvement occurred, patients from the most comparable
trials, ALL-BFM 86 and ALL-BFM 90, were analyzed according to risk
groups. In SRG patients, no difference was found: EFS was
85 ± 2% in trial ALL-BFM 90 (Figure 3) and 84% ± 3% in
ALL-BFM 86 (n = 175; only patients who received reinduction were
included). In MRG patients, a significant improvement was noted: EFS at
6 years was 82% ± 1% in trial ALL-BFM 90 and 75% ± 2%
in ALL-BFM 86 (P = .001). This difference was due to a
reduced cumulative incidence of isolated BM relapses in trial ALL-BFM
90, which at 6 years, was 10.1% ± 0.9% in the MRG in ALL-BFM 90 and 15.1% ± 1.5% in the respective subset in trial ALL-BFM 86 (P = .006). The reduction in isolated BM recurrences was
achieved exclusively in patients with B-cell-precursor ALL.
Accordingly, the 6-year EFS among medium-risk patients with
B-cell-precursor ALL was 82% ± 1% in trial ALL-BFM 90 and
73% ± 2% in trial ALL-BFM 86 (P = .0001). The 6-year
EFS among patients with T-ALL was 80% ± 3% in the MRG in
ALL-BFM 90 and 84% ± 4% in the corresponding subgroup
in ALL-BFM 86 (P = .45).
Impact of new or modified treatment elements: reduction of
preventive CRT in MRG patients with a BFM-RF of 1.2 or higher.
The impact of reducing CRT to 12 Gy in trial ALL-BFM 90 was analyzed by
comparing the higher risk patients within the MRG (those with a large
cell load [BFM-RF
Outcome according to prednisone response.
The 6-year EFS in patients with PGR in trial ALL-BFM 90 was
82% ± 1%. Among patients with PPR, the EFS was 34% ± 3%
(Figures 4 and 5). The overall proportion of patients with PPR was
9.5% but varied widely among subsets of patients (Table
4). PPR was infrequent among patients who
were 1 to 9 years of age (7.2%), had a WBC count below
50 × 109/L (4.3%), had pre-B ALL (4%) or common
ALL (5%), or met standard-risk criteria developed by the National
Cancer Institute (NCI) consensus conference (3.5%).46 With
regard to 6-year EFS rates among patients with PPR, a homogeneous
profile emerged: in no such defined subgroup was EFS above 50%. Within
each subset, patients with PPR had an outcome that was significantly
worse than that in the corresponding group with PGR.
Outcome in subgroups defined by NCI consensus risk criteria.
To facilitate comparability of the results, we adopted the risk
criteria of the NCI consensus conference46 and found 2 distinct subgroups (Table 5 and Figure
7). The largest group, the NCI SRG (WBC
count < 50 × 109/L and age 1-10 years), comprised 64% of all patients, and its 6-year EFS was
86% ± 1%. This was significantly better than the EFS in the NCI
HRG (WBC count
Prognostic factors
With 2178 evaluable patients, trial ALL-BFM 90 was the
largest of the 6 trials conducted by the ALL-BFM study group so far. It
was done in 3 countries with nearly 100 participating centers. Because
of the trial's unselected study population, a large panel of clinical
and biologic characteristics could be analyzed with respect to early
response and treatment outcome. The 6-year EFS of 78% ± 1% is
the most favorable treatment result ever achieved in an ALL-BFM
trial.1,3,47 More remarkably, for approximately 90% of the
patients in the trial (ie, for all patients who had a low burden of
leukemic cells in the PB after 1 week of prednisone therapy [the PGR
group]), an EFS rate of 80% or greater was achieved with the more
condensed induction phase. The reduction of the anthracycline dose in
induction and the reduced preventive CRT for patients with a larger
cell mass were appropriate because no adverse effects of these therapy
changes on outcome were found. The intensified consolidation therapy
with high-dose L-asparaginase did not provide an additional
improvement in medium-risk patients.
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Top
Abstract
Introduction
18 years of age),
the 6-year event-free survival (EFS) rate (± SE) was
78% ± 1%, with a median observation time of 4.8 years. EFS was
85% ± 2% in the SRG (n = 636) and 82% ± 1% in the
MRG (n = 1299). L-asparaginase did not improve outcome
in the MRG: the event-free interval was 83% ± 2% with
L-asparaginase (n = 528) and 81% ± 2% without it
(n = 557). Because there were more systemic relapses in the HRG
(n = 243), EFS was 34% ± 3%, an outcome inferior to that in
the HRG in a previous trial, ALL-BFM 86, in which EFS was
47% ± 5% (P = .04). The rates of isolated central
nervous system relapse in the MRG and HRG were 0.8% and 1.6%,
respectively; thus, the 12-Gy preventive cranial radiotherapy regimen
apparently provided sufficient central nervous system prophylaxis.
The overall improvement over the results in ALL-BFM 86 (6-year EFS,
72%; P = .001) was based on fewer recurrences among
patients in the MRG with B-cell-precursor ALL, indicating an advantage
of more condensed induction therapy. In multivariate analysis,
inadequate in vivo response emerged as the strongest adverse prognostic variable.
(Blood. 2000;95:3310-3322)
2 test for
categorized variables and the Wilcoxon rank sum test for continuous
variables. Differences between EFS distributions for patient
subpopulations were evaluated by using 2-sided log-rank tests.
4 after allogeneic BMT and 1 after extended
chemotherapy
1.2] but no initial CNS involvement) with the
respective subset of patients in trial ALL-BFM 86, who were treated
with 18 Gy. The 6-year EFS was 77% ± 2% in this subset of
patients in ALL-BFM 90 (n = 570) and 68% ± 3% in the
subset in ALL-BFM 86 (n = 259; P = .003). The cumulative
incidence of relapse with CNS involvement was 4.0% in ALL-BFM 90 and
6.7% in ALL-BFM 86 (P = .19); that of non-CNS recurrences
was 16% ± 1.8% in ALL-BFM 90 and 23.6% ± 2.8% in
ALL-BFM 86 (P = .02). Thus, the reduction in CRT did not
adversely affect the rate of CNS recurrences in MRG patients in trial
ALL-BFM 90 who had no CNS involvement and a BFM-RF of 1.2 or higher
(Figure 
