Outcome of Treatment in Adults With Acute Lymphoblastic Leukemia:

Analysis of the LALA-94 Trial

Xavier Thomas, Jean-Michel Boiron, Franoise Huguet, Herv Dombret, Ken Bradstock, Norbert Vey, Tibor
Kovacsovics, Andr Delannoy, Nathalie Fegueux, Pierre Fenaux, Aspasia Stamatoullas, Jean-Paul Vernant, Olivier
Tournilhac, Agns Buzyn, Oumedaly Reman, Christiane Charrin, Claude Boucheix, Jean Gabert, Vronique
Lhritier, Denis FiereShow More

Purpose

We analyzed the benefits of a risk-adapted postremission strategy in adult lymphoblastic leukemia (ALL), and re-
evaluated stem-cell transplantation (SCT) for high-risk ALL.

Patients and Methods

A total of 922 adult patients entered onto the trial according to risk groups: standard-risk ALL (group 1), high-risk
ALL (group 2), Philadelphia chromosome-positive ALL (group 3), and CNS-positive ALL (group 4). All received a
standard four-drug/4-week induction course. Patients from group 1 who achieved a complete remission (CR) after
one course of induction therapy were randomly assigned between intensive and less intensive postremission
chemotherapy, whereas those who achieved CR after salvage therapy were then included in group 2. Patients in
groups 2, 3, and 4 with an HLA-identical sibling were assigned to allogeneic SCT. In groups 3 and 4, autologous
SCT was offered to all other patients, whereas in group 2 they were randomly assigned between chemotherapy and
autologous SCT.

Results

Overall, 771 patients achieved CR (84%). Median disease-free survival (DFS) was 17.5 months, with 3-year DFS at
37%. In group 1, the 3-year DFS rate was 41%, with no difference between arms of postremission randomization. In
groups 2 and 4, the 3-year DFS rates were 38% and 44%, respectively. In group 2, autologous SCT and
chemotherapy resulted in comparable median DFS. Patients with an HLA-matched sibling (groups 2 and 4) had
improved DFS. Three-year DFS was 24% in group 3.

Conclusion

Allogeneic SCT improved DFS in high-risk ALL in the first CR. Autologous SCT did not confer a significant
benefit over chemotherapy for high-risk ALL.

INTRODUCTION

During the last two decades, clinical trials have demonstrated an improved response rate in adult acute
lymphoblastic leukemia (ALL) using intensive chemotherapy. However, the duration of remission has been
disappointingly short.1 Similar to treatment in children, risk-adapted strategies are being applied to adults with ALL
to improve survival. Both single institutions and multicenter studies have shown that aggressive induction plus more
potent intensification programs with chemotherapy alone or chemotherapy plus stem-cell transplantation (SCT) may
improve treatment results.2-7

In a previous prospective multicenter trial (Leucmie Aigus Lymphoblastique de lAdulte [LALA]-87 trial), the
French LALA Group tested three different strategies for postinduction therapy with the first aim to evaluate
randomly, after consolidation chemotherapy, the benefits of autologous SCT compared with standard maintenance
chemotherapy, and second, to evaluate the role of allogeneic SCT in first remission. 3Analyzed on an intention-to-
treat basis, results showed an advantage of allogeneic SCT over chemotherapy. 8 The difference between allogeneic
SCT and the control arm was highly significant in high-risk ALL, with 10-year survival rates of 44% and 11%,
respectively.9 Conversely, it seemed that allogeneic SCT was not superior to chemotherapy or autologous SCT in
standard-risk ALL. When comparing autologous SCT with chemotherapy, there was only a trend for better results in
the autologous SCT arm.

On the basis of these results, we designed a new multicenter regimen (LALA-94 trial) with the aims to assess the
intensification of induction therapy to improve complete remission (CR) rates; to introduce a risk-adapted
postremission strategy by stratifying patients according to initial features and to initial response to therapy; and to
re-evaluate transplantation for high-risk ALL.

PATIENTS AND METHODS

Study Eligibility

Eligibility criteria included age 15 to 55 years, untreated ALL (excluding mature B-cell ALL), without prior
malignancy or psychiatric disease. All participants were registered at the time of entry onto the study through a
randomization between idarubicin (IDA) and daunorubicin (DNR) for induction therapy. Subsequent
randomizations occurred after the patients had achieved remission and were ready to start postremission therapy.
The study was approved by the Ethics Committee (Lyon, France). All patients gave signed informed consent.

Diagnostic Procedure
Morphologic and cytochemical studies.

The morphologic diagnosis was based on May-Grnwald-Giemsa and cytochemical staining of bone marrow
smears, and was classified according to the French-American-British classification.10

Immunologic studies.

Immunophenotyping was performed by indirect immunofluorescence using flow cytometry, focusing on the blast
cell population, and employed a panel of monoclonal antibodies to B-cell (CD10, CD19, CD20, CD22, CD79a, sIg,
cIg), T-cell (CD1, CD2, CD3, CD4, CD5, CD7, CD8), myeloid (CD13, CD14, CD15, CD33, CD65, CD117,
myeloperoxidase), and precursor cell (terminal deoxynucleotidyl transferase, CD34, HLA-DR) associated antigens.
Leukemic cells that expressed none of these markers were considered as undifferentiated. Myeloid-antigenpositive
ALL was defined as coexpression of lymphoid markers and at least two myeloid-lineageassociated antigens. An
arbitrary threshold of 20% of labeled blast cells was set as the positive cutoff for each marker.

Cytogenetics and molecular biology.

Cytogenetic examination was performed on bone marrow and/or blood samples. Chromosomal abnormalities were
classified according to structural and numerical changes. The presence of t(4;11), t(9;22), or t(1;19) chromosomal
translocations was assessed by conventional cytogenetics, and their respective gene rearrangements (MLL-
AF4, BCR-ABL, or E2A-PBX1) were assessed by reverse transcriptase polymerase chain reaction.

Risk Groups

Group 1 (standard-risk ALL) comprised all T-cell lineage ALL patients achieving CR after one course of
chemotherapy and B-cell lineage ALL patients defined by the absence of CNS-positive ALL; the absence of
Philadelphia (Ph) chromosome, t(4;11), t(1;19), or other abnormalities involving 11q23 rearrangements; a WBC
count less than 30 109/L; an immunophenotype characterized by CD10 +/CD19+, or CD20+/CD19+and the absence
of myeloid markers; and achievement of CR after one course of chemotherapy. Group 2 (high-risk ALL) was
defined as nonstandard-risk ALL without Ph-positive status or CNS involvement. Patients in whom any phenotypic
and/or karyotypic analyses could not be performed because of marrow fibrosis were systematically included in
group 2. Group 3 comprised Ph-positive and/or BCR-ABLpositive ALL. Group 4 included all patients with
evidence of CNS leukemia at diagnosis based on cranial nerve palsies, leukemic blasts in the CSF, and/or
mononuclear cell counts 5 106/L and leukemic blasts in stained centrifuged spinal fluid.

Treatment

Treatment schedule is indicated on Figure 1. The induction course was administered over a 4-week period and
consisted of prednisone, vincristine, cyclophosphamide (CPM), and DNR or IDA according to initial random
assignment. Colony-stimulating factor could be administered according to each centers policy. Marrow response
status was determined by bone marrow aspirates at about day 28 of induction chemotherapy.

Standard-risk ALL patients (group 1) were randomly assigned on day 35 and received either an intensive
consolidation chemotherapy combining mitoxantrone (MTZ) with intermediate-dose cytarabine (IDaraC), or a less
intensive consolidation course combining CPM with cytarabine (araC), and mercaptopurine. Then, patients with
standard-risk ALL followed a chemotherapy program for 2 years (Table 1) .
On day 35, high-risk ALL patients (groups 2, 3, and 4) were scheduled to receive a second course of intensive
chemotherapy (consolidation or salvage), consisting of MTZ and IDaraC. Patients who did not reach a CR after that
course were withdrawn from the protocol.

On the basis of an intention-to-treat principle, all patients with Ph-positive ALL or with CNS-positive ALL were
distributed in one of the two following SCT groups: matched related allogeneic bone marrow SCT if they had a
sibling donor, or autologous peripheral-blood SCT if they did not meet criteria for the first group. Transplantation
was planned to be performed at day 90 after initial random assignment. Donors were matched at the A, B, C, and
DR regions of the HLA loci (molecular typing at the HLA class II loci). Alternative donors were admitted for Ph-
positive ALL with related or unrelated donors who were mismatched at one or more of these loci. In group 2,
patients without a sibling donor were randomly assigned between the chemotherapy program and autologous SCT.
Patients eligible for SCT received one or two additional cycles of chemotherapy consisting of methotrexate (MTX)
and L-asparaginase. Granulocyte colony-stimulating factormobilized autologous peripheral-blood stem cells were
collected during the myeloid recovery following the consolidation course. The conditioning regimen, for both
autologous and allogeneic SCT, consisted of CPM 60 mg/kg on days 1 and 2, and total-body irradiation, either 10
Gy as a single dose or 12 Gy in six fractions.11 Etoposide 50 mg/kg on day 1 was added to the conditioning regimen
for patients with Ph-positive ALL. For allogeneic SCT, graft-versus-host disease prophylaxis mostly consisted of
cyclosporine plus MTX or cyclosporine alone, but did not include T-cell depletion. In groups 2 and 4, a maintenance
therapy combining mercaptopurine and MTX was planned for 2 years after autologous SCT. During the early study
period, few patients (n = 6) with Ph-positive ALL have undergone transplantation with purged autologous bone
marrow stem cells. In these patients, bone marrow purging was performed by complement-dependent lysis using
anti-CD19 and anti-CD20 monoclonal antibodies. A few patients (three patients in group 2, 10 patients in group 3,
and one patient in group 4) received matched unrelated allogeneic SCT. In the statistical analysis, the four patients
from groups 2 and 4 were analyzed in intention-to-treat according to their arm of randomization, whereas the 10
patients with Ph-positive ALL were analyzed in the allogeneic SCT arm.

CNS Prophylaxis and Therapy

CNS prophylaxis consisted of eight intrathecal injections (four during the first induction course and four during
continuation therapy) combining araC 40 mg, MTX 15 mg, and methylprednisolone 40 mg. In addition, patients
treated only with chemotherapy received a dose of 18 Gy cranial x-ray therapy (five 1.8-Gy sessions per week for 2
weeks).

In patients with CNS disease at diagnosis (group 4), therapy consisted of 18 triple intrathecal injections associated
with a pretransplant 15-Gy cranial irradiation.

Criteria for Response and Relapse

Morphologic response was evaluated after induction therapy and eventually after the salvage therapy course.
Response was classified as CR or failure, including resistant disease and early death. Patients were considered to be
in CR when the neutrophil count was more than 1.5 10 9/L, the platelet count was more than 150 109/L, the bone
marrow examination was normal, and all extramedullary disease had resolved.

In addition, patients had to be classified as early responders or nonresponders on a bone marrow aspiration and
peripheral-blood examination performed at day 8 of induction course. Early response was defined as the absence of
peripheral-blood blasts associated with fewer than 5% marrow blasts or a hypoplastic bone marrow.

Relapse was defined as the reappearance of leukemic cells in the bone marrow and/or clinical evidence of disease.
Toxicity of induction therapy was evaluated according to WHO criteria.12

Statistical Analyses

Random assignment of patients was stratified by center for the first randomization, but also by initial induction arm
for later randomizations. Reasons for discontinuing participation in the study were noncompliance of the patient, no
CR after salvage regimen, excessive extramedullary drug toxicity, death, relapse, major protocol violation, or lost to
follow-up. The planned accrual was 1,000 patients. An interim analysis was performed after 400 patients were
enrolled. The primary study objective was disease-free survival (DFS) rates according to the different postremission
therapeutic options. Secondary objectives included assessment of response rates to induction chemotherapy and
overall survival (OS) rates according to the different postremission strategies.

Associations between pretreatment characteristics and response to induction and the assessment of comparability of
characteristics for the two initial randomized groups were evaluated by the Pearson 2 test. All tests were two sided
with statistical significance set at .05. All analyses were performed on an intention-to-treat basis. Intent-to-treat
groups were applied after initial CR achievement, rather than at baseline. Intent-to-treat in group 1 was based only
on patients without high-risk features at diagnosis and who also achieved a CR after primary induction therapy,
whereas in group 2 it was based on those with high-risk features at diagnosis who achieved a CR and those without
high-risk features at diagnosis and who failed to respond after primary induction therapy, but achieved a CR after
salvage therapy. Patients with CR who were randomly assigned but never received the allocated treatment were not
excluded from the comparative analyses.

OS was defined as the time from study entry to death or last patient contact. DFS was defined from date of CR to
date of relapse or death, or last contact with patient in continuous CR. DFS and OS distributions were estimated by
the method of Kaplan and Meier. The analyses in CR patients included only those who were randomly assigned: in
group 1 (early consolidation v no early consolidation), in groups 2 and 4 (donor v no donor), in group 2 (autologous
SCT v chemotherapy), and in groups 3 and 4 (autologous SCT v allogeneic SCT). All treatment and subgroup
comparisons were performed by the log-rank test. Simultaneous effects of multiple covariates were estimated with
the maximum-likelihood logistic regression model for response and with the Cox model for DFS and OS, and tested
by the likelihood-ratio test, which was also used in univariate analyses for continuous variables. Estimated hazard
ratios are reported as relative risks with 95% CIs. Cumulative incidence of relapse and transplant-related mortality
(TRM) were calculated as previously described.13 All computations were made using BMDP software (BMDP
Statistical Software, Los Angeles, CA).

RESULTS
Patient Entry

Between June 1994 and January 2002, 1,000 patients entered onto the LALA-94 trial. Eleven patients were
withdrawn (error in entry [three ALL patients were older than 55 years, one patient had lymphoblastic lymphoma,
one patient had natural killer-cell lymphoma, four patients had late diagnosis of L3 subtype], patient refusal [one
patient], and physician decision [one patient treated according to a pediatric schedule]). Seven additional patients
were ineligible because of misdiagnosis (acute myeloid leukemia) and were not treated on this protocol. Data from
60 patients were not received or incomplete at the time of analysis. Thus we report on 922 eligible patients. The
cutoff date was January 1, 2004. The median follow-up of this cohort was 5.2 years.

Pretreatment Characteristics

Pretreatment characteristics are summarized in Table 2. Median age was 33 years. Male-to-female ratio was 1.8.
Immunophenotype was available for 902 patients: 72% of patients had B lineage, 26% had T lineage, and the
remaining 2% had undifferentiated ALL. Five percent of patients displayed myeloid markers. Cytogenetic and/or
molecular biology evaluation was performed in 863 patients. The Philadelphia chromosome and/or the BCR-
ABL rearrangement were found in 198 patients (23%), t(4;11)/MLL-AF4 was found in 36 patients, and t(1;19)/E2A-
PBX1 was found in 26 patients.

Main pretreatment characteristics did not differ when considering the two induction arms or the different
postremission arms after the other randomizations.

Results of Induction

Results of induction therapy are summarized in Table 3. Six hundred sixty (72%) of all eligible patients achieved
CR after one course of chemotherapy, 35 (4%) died during the induction phase before their remission status could be
ascertained, and 227 failed to respond. CR proportions were 71% in the IDA arm and 72% in the DNR arm.
Treatment failure was observed in 24% of patients in the IDA arm and in 26% in the DNR arm. However,
significantly higher TRM was observed with IDA (5% v 2%; P = .01). There was no difference in terms of survival
between the two arms, but an advantage was observed for the IDA arm in terms of DFS in patients receiving only
chemotherapy (patients in group 1 and patients randomly assigned to the chemotherapy arm in group 2; median
DFS, 31.1 months with IDA v 18.2 months with DNR; P = .05; Fig 2).
Among the 210 patients re-treated after treatment failure, CR to salvage chemotherapy was 53% (111 patients).
Thirty-nine patients from group 1, who achieved CR in two courses, were then included and followed postremission
treatment in group 2. Eighty-eight patients failed to respond to salvage therapy, whereas 11 (5%) died during this
second course of induction therapy.

CR was achieved in 212 (89%) of 237 patients with T-lineage ALL (185 patients after one course and 27 patients
after two courses), and in 390 (86%) of 454 patients with (nonPh-positive) B-lineage ALL (349 patients after one
course and 41 patients after two courses).

Overall, 771 patients achieved CR (84%), whereas resistant patients represented 11%. In logistic regression analysis,
risk groups defined at diagnosis (P < .001) and response on day 8 (P < .001) were prognostic factors for achieving a
CR after induction and/or salvage therapy.

Toxicity of Induction Therapy

Most patients (911 patients) were assessable for toxicity during the first course of induction chemotherapy.
Neutrophils recovered to more than 0.5 10 9/L at a median of 21 days (range, 0 to 49 days) after initiation of
therapy (23 days with IDA and 19 days with DNR). Platelets recovered to more than 50 10 9/L at a median of 18
days (range, 0 to 66 days; 22 days with IDA and 12 days with DNR). The most frequent extrahematologic severe
(WHO grade 3) adverse effects were infection (19%), mucositis (15%), hepatotoxicity (15%), hemorrhage (12%),
gastrointestinal side effects (7%), and neurotoxicity (7%). Severe cardiac toxicity was observed in 3% of patients.
Severe extrahematologic toxicity was not significantly different between the two arms of first randomization, except
for mucositis (22% with IDA v 8% with DNR; P < .0001) and infections (27% with IDA v 11% with DNR; P <
.0001).

Severe adverse effects after salvage therapy (192 patients evaluated) were infection (31%), mucositis (15%),
hemorrhage (9%), hepatotoxicity (5%), neurotoxicity (4%), cardiac toxicity (1%), and gastrointestinal adverse
effects (1%).

The mortality rate after one or two courses of induction chemotherapy was 5%.

DFS and OS

Median OS was 23 months (Fig 3). Median DFS was 17.5 months, with 3-year DFS at 37% and 5-year DFS at 30%.
The estimated 3-year DFS rate was 35% and 43% for T- and (nonPh-positive) B-lineage ALL, respectively (Fig 4).

Outcome according to risk groups is summarized in Table 4. Only 706 patients were allocated to a risk group and
received postremission therapy according to the protocol regimen. Sixty-five patients (8%) were excluded from
additional randomizations. Reasons were medical decision (42%), severe toxicity during induction therapy resulting
in poor physical condition (38%), patient refusal (13%), and organizational reasons (7%). The cumulative incidence
of TRM and relapse is listed in Table 5.

Standard-risk ALL (group 1).

Median OS was 37.8 months, with 3-year OS at 50% and 5-year OS at 44%. There were 307 patients who were
randomly assigned and received postinduction therapy: 153 were randomly assigned to early intensive
chemotherapy (arm A) and were randomly assigned 154 to chemotherapy without early intensification (arm B).
There were no differences in terms of DFS between the two arms (P = .78; Fig 5). Median OS was 32.6 months in
arm A and 39.5 months in arm B, with 5-year OS rates of 45% and 43%, respectively (P = .73).

High-risk ALL (group 2).

Median OS was 29 months with 3-year OS at 46% and 5-year OS at 38%. Eighty-two patients with a sibling donor
were scheduled for allogeneic SCT. In intention-to-treat analysis, autologous SCT (70 patients) and chemotherapy
(59 patients) produced comparable median DFS (15.2 v 11 months, respectively; P = .1; Fig 6). However, late
relapses were more frequent in the chemotherapy arm (3-year DFS rate, 39% v 24%; P = .08). Median OS was 28
months with 3-year OS at 44% and 5-year OS at 32% in the autologous SCT arm versus 26.1 months with 3-year
OS at 35% and 5-year OS at 21% in the chemotherapy arm. Of 70 patients randomly assigned in the autologous SCT
arm, 61 (87%) actually underwent transplantation. Seven patients did not receive autologous transplant but received
chemotherapy because of insufficient cell harvest (five patients), patient refusal (one patient), or poor physical
condition (one patient), and two patients underwent matched unrelated donor allogeneic SCT (medical decision). All
patients, except one who received matched unrelated donor allogeneic SCT, allocated to the chemotherapy arm
received their treatment. The median time between CR and autologous SCT was 2.9 months (range, 1.6 to 6.4
months). For patients who actually received autotransplantation, the median DFS was 13 months with a 5-year DFS
rate of 21%, whereas the median OS was 19.8 months with a 5-year OS rate of 29%. Only 52% of patients who
received autologous SCT were observed by maintenance therapy. In intention-to-treat, allogeneic SCT did better
than the other therapeutic strategies in terms of DFS in patients from groups 2 and 4 when using the results of the
HLA typing as a random allocation (P = .007; Fig 7). In the allogeneic SCT arm (82 patients in group 2 and 18
patients in group 4), 96 patients (96%) actually underwent transplantation. Four patients received chemotherapy
because of patient refusal (two patients), poor physical condition with hepatitis (one patient), or donor poor physical
condition (one patient). The median time between CR and transplantation was 2.3 months (range, 0.4 to 7.3 months).
The median DFS was 20.8 months with a 5-year DFS rate of 44%, whereas the median OS was not reached with a
5-year OS rate of 51%. Among these patients, 39 patients (40%) died, of whom 17 (44%) died as a result of
transplantation complications and the others as a result of leukemia.

Ph-positive and/or BCR-ABLpositive ALL (group 3).

A report on the first 154 patients with Ph-positive ALL has been detailed previously.14The updated series confirmed
a poor outcome with a median OS was 15.7 months with a 3-year OS rate of 28% and a 5-year OS rate of 24% (Fig
4). Median OS was 14.2 months for autografted patients and 21.5 months for allografted patients (including 10
matched unrelated donor SCT) with 3-year OS rates at 17% and 36%, respectively (P = .009). Median DFS values
were 6.5 and 15.5 months with 3-year DFS rates at 15% and 34%, respectively (P = .001).

CNS-positive ALL (group 4).

Median OS was 20.9 months with a 5-year OS rate of 36%. Eighteen patients with a sibling donor were allocated to
the allogeneic SCT arm, whereas 30 without any donor followed the autologous SCT arm. Median DFS values were
11.4 and 21.7 months with 3-year DFS rates at 40% and 47%, respectively (P = .65). Median OS values were 16 and
22.7 months with 3-year OS rates at 40% and 46%, respectively (P = .64). All patients allocated to the allogeneic
SCT arm followed treatment for their arm, whereas two patients randomly assigned in the autologous SCT arm did
not (one early relapse and one matched unrelated donor allogeneic SCT).

Prognostic factors for DFS.

In univariate analysis, WBC count less than 30 10 9/L (P < .0001), age younger than 35 years (P = .0001), and
early response on day 8 (P = .02) favorably affected DFS in the entire population. These covariates remained of
prognostic value in a multivariate model also including phenotype and arm of first randomization. The same analysis
was performed in the different risk groups as defined at time of diagnosis (Table 6) .

DISCUSSION

CR was achieved in 84% of patients, whereas the 5-year survival rate of the 922 patients was 33%. These results are
in the range of those published by most large cooperative groups. 2-7,15

Better results in terms of CR may be obtained by using more intensive induction chemotherapy and better supportive
care to reduce early deaths.16 In the LALA-87 trial, overall CR was achieved in 76% of patients (69% after one
course of induction chemotherapy) and toxic deaths occurred in 9% of patients. 3 Results were significantly
improved in the LALA-94 trial in which we did not find any period effect (data not shown). Better results in the
LALA-94 trial could be explained by reduced toxicity with fewer infections related to lower doses of
corticosteroids17 and the use of CSF in some centers, and by the introduction of the combination of MTZ with
IDaraC, instead of a combination of amsacrine with lower doses of araC as salvage therapy. We confirm here
previous reports about the efficacy of intensive- or high-dose araC combined with anthracyclines or other related
drugs in salvage therapy.16,18-21 This type of therapy seems particularly important for the most aggressive ALL. Early
intensified treatment may reduce the likelihood of the development of drug resistance, achieve sufficient drug levels
in sanctuary sites, and thus increase the proportion of long-term, disease-free survivors.
There is evidence that anthracyclines increase CR when added to other classic components of ALL therapy. 22 In our
trial, a comparison of DNR and IDA did not show any significant difference, except for an advantage for IDA in
terms of DFS in patients receiving only chemotherapy (predominantly patients in the standard-risk group and
therefore patients with T-lineage ALL, of whom approximately 75% followed group 1 after CR achievement). A
potential weakness is the uncertainty of anthracycline dose equivalence; that is, whether IDA 9 mg/m 2 on days 1, 2,
3, and 8 is equivalent to DNR 30 mg/m2 on days 1, 2, 3, 15, and 16. A potential benefit is further obscured by
different postremission strategies. In the chemotherapy-only arm, subgroup analysis suggested a benefit for
standard-risk patients. The higher infection rate with IDA may indicate nondose equivalence of the anthracyclines.
Our results tend to confirm that CR is obtained earlier with the use of high-dose anthracyclines and that the optimal
timing for anthracycline administration is probably the early phase of the disease. 23,24

The optimal consolidation therapy for adults with ALL in first CR remains unclear. The data for allogeneic SCT are
sparse, and few comparative trials exist. Results from retrospective studies suggest a benefit for allogeneic SCT
compared with standard chemotherapy. The lack of randomized studies limits our ability to infer a benefit of
allogeneic SCT. Trials evaluating allogeneic SCT have uniformly shown higher treatment-related mortality and
decreased disease relapse. In some studies, these effects offset one another and neutralize any benefit from
allogeneic SCT, resulting in centers favoring a conservative approach and recommending transplantation only for
patients younger than 30 years old with high-risk ALL.25,26 In the LALA-87 trial, we did not find any statistical
difference between allogeneic SCT and chemotherapy in the overall analysis. However, when the analysis was
retrospectively restricted to high-risk patients,27 survival rates were significantly higher in patients receiving
allogeneic SCT.8,9 This was confirmed prospectively by our present study, although Ph-positive ALL patients were
considered apart. To date, no traditionally randomized controlled study has been performed to test the efficacy of
allogeneic SCT in ALL. In the absence of true randomization, we must rely on genetic randomization.

Whether or not a sibling is HLA matched depends on the random assortment of genes at fertilization. The intention-
to-treat analysis eliminates the time-to-treatment bias. However, there might be confounding factors due to the
limitations of genetic randomization. The probability of having an HLA-identical sibling donor depends of the size
of the sibship. Consequently, it is not equal for all patients. The physician and/or the patient may influence whether
a donor is identified and/or accepted. Trial enrollment or withdrawal may also be influenced by a protocol with
genetic randomization. Unfortunately, reports that include a donor analysis do not actually totally comply with the
intention-to-treat principle. The allogeneic SCT group generally includes appropriately all patients with a donor,
whereas the other two groups only include patients randomly assigned between autologous SCT and chemotherapy,
thereby introducing potential biases. It is possible that the inclusion of all no-donor patients would strengthen the
evidence in favor of allogeneic SCT. However, the apparent advantage for SCT in some subgroups was diminished
by the poor results of chemotherapy, resulting in a disappointingly low DFS overall despite to the risk-adapted
strategy employed. Allogeneic SCT appeared definitively of benefit to Ph-positive ALL14 and t(4;11) ALL.28 This
suggests the feasibility of using matched unrelated donor SCT in future clinical trials for those patients without a
sibling donor.

Many single-institution studies have evaluated autologous SCT in adults ALL. The best results report a DFS rate of
65%, but follow-up was only 16 months.29 However, the use of autologous SCT in first CR remains controversial
and is still an investigational treatment. A major objective of our study was to test the advantage of autologous SCT
compared with standard chemotherapy. Autologous SCT did not show superiority over chemotherapy in high-risk
ALL patients. However, in the chemotherapy arm, a continuous pattern of relapse beyond the third year was
observed. A different pattern of relapse was observed in the autologous SCT arm, with fewer late relapses. These
results confirm those reported by our previous trial in the global analysis 3 and in a subset analysis including only
patients with poor prognostic factors.9 However, there were some flaws in both LALA-87 and LALA-94 studies: the
number of patients in each arm was small, and some patients allocated to the transplantation group actually did not
undergo transplantation. Maintenance chemotherapy for 2 years was theoretically scheduled after transplantation,
given that this was postulated to be the reason for less relapses and improved DFS reported in a previous study, 30 but
was often not given or stopped early because of cytopenia or infections. To evaluate the effect of consolidation by
autologous SCT in a larger population of adult ALL patients, we recently performed a study reporting all patients
included in one of the last three successive trials from our group. 31 The results confirmed the absence of superiority
of autologous SCT over chemotherapy alone, and the use of autologous SCT in first CR was not advocated because
chemotherapy employed may not be optimal with regard to a standard therapy.

Few studies have evaluated comparatively more intensive versus standard therapy over short periods of
maintenance. Previous studies, comparing consolidation courses versus regular maintenance, did not find any
difference in terms of DFS.32,33 In our trial, the second randomization for standard-risk patients, comparing an early
intensive consolidation with no early intensification, showed no difference between the two arms of randomization.
Previous studies also demonstrated the absence of benefit of early intensification, but reported that the early block of
intensive treatment reduced the risk of relapse.2,27

Results in standard-risk ALL (and therefore T-lineage ALL) were disappointing in comparison with the LALA-87
trial,3 suggesting a need for more intensive therapy. Indeed, T-cell phenotype is generally a favorable prognostic
factor.15,27,34,35Improvements in outcome for T-lineage ALL have been attributed to the introduction of araC, CPM,
and/or teniposide in consolidation regimens. In the LALA-87 trial, results in standard-risk ALL were similar for
allogeneic SCT and for chemotherapy or autologous SCT. We concluded that allogeneic SCT should only be
recommended for high-risk patients in first CR, and we therefore abandoned transplantation for this group of ALL
patients in the LALA-94 trial.8,9 A recent retrospective study showed particularly encouraging results of T-cell
lineage ALL after allografting in first CR, with 74% DFS at 3 years. 36 The poor outcomes, even among T-cell
lineage ALL in LALA-94 with chemotherapy alone, suggest studies examining allografts compared with more
intensive chemotherapy regimens, even for favorable subsets, are warranted.
Surprisingly, patients with CNS involvement showed a favorable outcome, with a median DFS of 19.2 months and
more than 44% survivors at more than 3 years. Although the presence of blasts in the CSF has been associated with
factors of poor outcome,37 and confers a high risk of CNS relapse if not treated intensively,38 large previous series
failed to show a significant impact of CNS involvement when treated intensively. 3,27 This appears to be confirmed
by our study and brings some justification for intensifying the treatment of this leukemia subtype.

On the basis of the results from the LALA-94 study, we are currently testing a pilot trial in which indications for
allogeneic SCT are increased in both nonPh-positive B-lineage ALL and T-lineage ALL depending on initial
prognostic factors and initial response to a prephase of corticosteroids and to initial chemotherapy evaluated on day
8; induction chemotherapy is intensified after day 15 for nonresponding patients; continuation therapy is intensified
in nonallografted patients with application of pediatric-like treatment with blocks of intensive chemotherapy and late
consolidation; autologous transplantation is withdrawn; and the therapeutic strategy is adapted to the evaluation of
minimal residual disease.

Appendix

The following hospitals participated in the LALA-94 trial: Groupe dEtude et de Traitement de la Leucmie Aigu
Lymphoblastique de lAdulte (GET-LALA Group) - Hpital Edouard Herriot, Lyon; Hpital Saint-Louis, Paris;
Hpital du Haut Levque, Pessac; Hpital Purpan, Toulouse; Hpital Henri Mondor, Crteil; Hpital Piti-
Salptrire, Paris; Institut Paoli Calmettes, Marseille; Hpital Cochin, Paris; Hpital de Hautepierre, Strasbourg;
Hpital de lArchet, Nice; Hpital Necker, Paris; Hpital Jean Bernard, Poitiers; Hpital Michallon, Grenoble;
Institut Gustave Roussy, Villejuif; Hpital du Bocage, Dijon; Hpital Saint-Antoine, Paris; Centre Hospitalier,
Caen; Hpital Pontchaillou, Rennes; Centre Hospitalier de la Cte Basque, Bayonne; Centre Hospitalier Lyon-Sud,
Pierre Bnite; HIA Percy, Clamart; Centre Hospitalier, Chambry; Hpital Dupuytren, Limoges; Centre Hospitalier,
Avignon; Hpital Louis Pasteur, Colmar; Centre Henri Becquerel, Rouen; Centre Hospitalier, Lille; Htel Dieu,
Clermont-Ferrand; Hpital Andr Mignot, Versailles; Hpital Beaujon, Clichy; Centre Hospitalier, Annecy; Centre
Hospitalier Lapeyronie, Montpellier; Centre Hospitalier, Aix en Provence; Hpital Jean Monod, Le Havre; Hpital
Lariboisire, Paris; Hpital Victor Dupouy, Argenteuil; Centre Hospitalier Dr Schaffner, Lens; Centre Antoine
Lacassagne, Nice; Centre Hospitalier, Meaux; Centre Hospitalier, Perpignan; Clinique St Vincent, Lille; Centre
Hospitalier, Nmes; Centre Hospitalier, Roubaix, France. Cliniques St Luc, Bruxelles; Centre Hospitalier Notre
Dame et Reine Fabiola, Charleroi; Cliniques de Mont Godinne, Yvoir; ASBL, Loverval; Hpital Saint Joseph, Gilly;
Hpital de Jolimont, Haine St Paul; Hpital St Joseph, Mons; Hpital de la Citadelle, Lige; Laboratoire de
Cytogntique, Leuven, Belgium. Swiss Group for Clinical Cancer Research (SAKK) Centre Hospitalier
Universitaire Vaudois, Lausanne; Kantonsspital, St Gallen; Universittsspital, Zrich; Hpital Cantonal
Universitaire, Genve; Kantonsspital, Basel; Inselspital, Bern; Kantonsspital, Winterthur; Kantonsspital, Luzern,
Switzerland. Australasian Leukemia and Lymphoma Group (ALLG)Westmead Hospital, Westmead; Adelaide
Hospital, Adelaide; Mater Misericordae Hospital, Newcastle; Alfred Hospital, Melbourne; Royal Adelaide Hospital,
Adelaide; Peter Mac Callum Cancer Centre Institute, Melbourne; Monash Medical Centre, Melbourne; Liverpool
Hospital, Sydney; St George Hospital, Sydney, Australia.

Authors Disclosures of Potential Conflicts of Interest

The authors indicated no potential conflicts of interest.

Fig 1.Schema of LALA-94 trial. IDA, idarubicin; DNR, daunorubicin; ALL, acute lymphoblastic leukemia; CR,
complete remission; MTZ, mitoxantrone; IDaraC, intermediate-dose cytarabine; Ph+, presence of Philadelphia
chromosome; CPM, cyclophosphamide; araC, cytarabine; MP, mercaptopurine; Allo, allogeneic; SCT, stem-cell
transplantation; Auto, autologous; MTX, methotrexate.

Fig 2.Disease-free survival (DFS) according to first randomization for patients receiving only chemotherapy (307
patients in group 1 and 59 patients randomly assigned in the chemotherapy arm in group 2). CR, complete
remission.

Fig 3.Overall survival (OS) of the entire cohort (922 patients). DFS, disease-free survival.

Fig 4.Disease-free survival (DFS) according to immunophenotype (390 patients with nonPhiladelphia[Ph] -positive
B-linage acute lymphoblastic leukemia [ALL] and 212 patients with T-lineage ALL) as compared with Ph-positive
ALL (140 patients). CR, complete remission.
Fig 5.Disease-free survival (DFS) according to second randomization for patients in group 1 (154 patients in the not
intensive arm and 153 patients in the intensive arm). MTZ, mitoxantrone; IDaraC, intermediate-dose cytarabine; NS,
not significant.

Fig 6.Disease-free survival (DFS) according to second randomization for patients in group 2 (70 patients in the
autologous stem-cell transplantation [SCT] arm and 59 patients in the chemotherapy arm). CR, complete remission.

Fig 7.Disease-free survival (DFS) according to genetic randomization. For this analysis, patients from group 2 (211
patients) and those from group 4 (48 patients) were pooled. The group with a sibling donor comprised 100 patients,
whereas that with no sibling donor included 159 patients. CR, complete remission.

Table 1. Chemotherapy Regimen for ALL Patients

Administration
Chemotherapy Dose Day Number Route
Induction chemotherapy
Idarubicin 9 mg/m2 1, 2, 3, 8 IV
or
Daunorubicin 30 mg/m2 1-3, 15, 16 IV
Vincristine 2 mg TD 1, 8, 15, 22 IV
2
Cyclophosphamide 750 mg/m 1, 8 IV
2
Prednisone 60 mg/m 1-7, 15-21 IV or PO
Postinduction chemotherapy
Arm A (between days 28 and 35; MTZ/IDaraC)
Cytarabine 1 g/m2 bid 1, 2, 3, 4 IV
Mitoxantrone 10 mg/m2 3, 4, 5 IV
or
Arm B (between days 28 and 35; CPM/araC/MP)
 Administration
Chemotherapy Dose Day Number Route
Cyclophosphamide 1 g/m2 1, 15, 29 IV
2
Cytarabine 75 mg/m 3-6, 10-13, 17-20 IV
2
Mercaptopurine 60 mg/m 1-28 PO
Maintenance chemotherapy
MTX/Aspa (on days 75, 90, 220, 304, 388, and months 16,
20, 24, 28)
Methotrexate* 1,500 mg/m2 1 IV
L-asparaginase 10,000 U/m2 2 IV
CPM/araC (on days 105, 262, 346, and months 14, 18, 22,
26, 30)
Cyclophosphamide 1 g/m2 1 IV
2
Cytarabine 500 mg/m 1 IV
RT/MP (from day 130 to 145)
Cranial irradiation 18 Gy
Mercaptopurine 60 mg/m2/d 1-15 PO
VAD (on days 160 and 190)
Vincristine 0.4 mg 1, 2, 3, 4 IV
2
Doxorubicin 12 mg/m 1, 2, 3, 4 IV
Dexamethasone 40 mg 1, 2, 3, 4 IV
MP/MTX (between maintenance courses from day 220 to
month 30)
Mercaptopurine 60 mg/m2/d PO
2
Methotrexate 15 mg/m /wk IM

Abbreviations: ALL, acute lymphoblastic leukemia; IV, intravenously; TD, total dose; PO, orally; MTZ,
mitoxantrone; IDaraC, intermediate-dose cytarabine; CMP, cyclophosphamide; MP, mercaptopurine; araC,
cytarabine; RT, radiation therapy; MTX, methotrexate; Aspa, L-asparaginase; VAD, vincristine, doxorubicin, and
dexamethasone; IM, intramuscularly.

*Administered over 30 minutes.

Table 2. Clinical and Biologic Characteristics of the 922 Patients at Diagnosis

Characteristic No. of Patients %

Age, years
Median 33
Range 15-55
Sex
Male 596
Female 326
Characteristic No. of Patients %
Mediastinal mass
Yes 165 18
No 740
Organomegaly
Yes 613 67
No 307
CNS involvement
Yes 62 7
No 860
Bleeding
Yes 231 25
No 680
Fever 38.5C
Yes 269 30
No 639
WHO performance status
0 264
1 456
2 136
3 36
4 8
ND 22
Hemoglobin, g/L (n = 909)
Median 97
Range 30-174
< 100 471 52
100-120 199 22
120 239 26
9
WBC count, 10 /L (n = 922)
Median 14.4
Range 0.2-920
<4 203 22
4-10 185 20
10-30 188 20
30 346 38
9
Platelet count, 10 /L (n = 919)
Median 55
Range 2-621
< 50 422 46
50-100 225 24
Characteristic No. of Patients %
100-200 160 17
200 112 13
Peripheral-blood blast cells, %
Median 57
Range 0-100
Bone marrow blast cells, %
Median 91
Range 20-100
FAB classification*
L1 346
L2 301
L3 0
Unclassifiable 59
Immunophenotype
B lineage 647 72
T lineage 239 26
Undifferentiated 16 2
Karyotype and/or molecular biology
t(4;11)/MLL-AF4 36 4
Ph+/BCR-ABL 198 23
t(1;19)/E2A-PBX 26 3

Abbreviations: ND, not determined; FAB, French-American-British classification; Ph+, presence of Philadelphia
chromosome.

*Determined in 706 patients.

Determined in 902 patients.

Determined in 863 patients.

Table 3. Results of Induction Chemotherapy According to Risk Groups

Group 1 (standard Group 2 (high Group 3 (Ph- Group 4 (CNS- All

Outcome risk) risk) positive) positive) Patients
First induction
No. of patients 430* 238 198 56 922
CR rate, % 83 66 53 73 72
Failure, % 15 28 45 16 25
Death, % 2 6 2 11 3
 Group 1 (standard Group 2 (high Group 3 (Ph- Group 4 (CNS- All
Outcome risk) risk) positive) positive) Patients
Salvage
therapy
No. of patients 58* 61 82 9 210
CR rate, % 67 48 44 78 53
Failure, % 28 44 52 22 42
Death, % 5 8 4 0 5

Abbreviations: Ph+, presence of Philadelphia chromosome; CR, complete remission; SCT, stem-cell transplantation.

*Patients allocated in the standard-risk group based on criteria defined at time of diagnosis. Patients in CR after
salvage therapy will enter the high-risk group and follow first the genetic randomization and, in absence of sibling
donor, the randomization between autologous SCT and chemotherapy.

Table 4. DFS According to Risk Groups

Risk Group No. of Patients Median DFS (months) 3-Year DFS (%) 5-Year DFS (%)
Group 1 (standard-risk ALL) 307 23.8 41 35
Group 2 (high-risk ALL) 211 15.6 38 30
Group 3 (Ph-positive ALL) 140 8.7 24 20
Group 4 (CNS-positive ALL) 48 19.2 44 41
All patients 771* 17.5 37 30

Abbreviations: DFS, disease-free survival; ALL, acute lymphoblastic leukemia; Ph, Philadelphia; CR, complete
remission.

*Among the 771 patients who achieved CR, 65 (8%) were not allocated to a postremission group of treatment.

Table 5. Cumulative Incidence of TRM and Relapse According to Treatment Modality

3-Year Cumulative 5-Year Cumulative 3-Year Cumulative 5-Year Cumulative

Treatment No. of Incidence of TRM Incidence of TRM Incidence of Incidence of
Modality* Patients (%) (%) P Relapse (%) Relapse (%) P
Group 1
Intensive arm 153 3 5 NS 49 53 NS
Not-intensive 154 4 9 46 53
arm
Group 2
Chemotherapy 59 0 28 NS 67 70 NS
Autologous 70 7 17 54 60
SCT
 3-Year Cumulative 5-Year Cumulative 3-Year Cumulative 5-Year Cumulative
Treatment No. of Incidence of TRM Incidence of TRM Incidence of Incidence of
Modality* Patients (%) (%) P Relapse (%) Relapse (%) P
Groups 2 + 4
Sibling donor 100 18 18 .01 34 36 .001
No sibling 159 7 18 58 62
donor
Group 3
Allogeneic SCT 75 22 22 NS 53 58 .003
Autologous 65 26 26 77 90
SCT

Abbreviations: TRM, treatment-related mortality; NS, not significant; SCT, stem-cell transplantation.

*Allocation on an intention-to-treat basis.

Table 6. Prognostic Factors for Disease-Free Survival

Multivariate Analysis
Univariate Analysis
Group P P RR 95% CI
All patients
WBC count < .0001 .05 1.32 1.01 to 1.73
Age .0001 .01 1.55 1.18 to 2.03
Response on day 8 .02 .02 1.43 1.06 to 1.92
Standard-risk ALL (group 1)
WBC count .003 .01 1.46 1.09 to 1.95
Arm of first randomization .04 .003 1.48 1.13 to 1.92
Response on day 8 .01 .03 1.52 1.01 to 2.28
Time to CR achievement .01
High-risk ALL (group 2)
WBC count .03 .001 2.06 1.30 to 3.25
Age .02 .003 1.86 1.24 to 2.79
Ph-positive ALL (group 3)
WBC count .02 .002 1.97 1.29 to 3.01
Time to CR achievement .01
Age .01 1.80 1.09 to 2.99
CNS-positive ALL (group 4)
Response on day 8 .04
Time to CR achievement < .0001
NOTE. Favorable prognostic factors are WBC count < 30 10 9/L, age < 35 years, early response, one course of
induction therapy for CR achievement, and idarubicin arm during the first induction therapy.

Abbreviations: RR, relative risk; ALL, acute lymphoblastic leukemia; CR, complete remission; Ph-positive,
presence of Philadelphia chromosome.

Supported in part by PHRC No. 94-95-97.02, Ministre de lEmploi et de la Solidarit, France.

Authors disclosures of potential conflicts of interest are found at the end of this article.

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