Acute Leukemias - Republican Scientific Medical Library

154 Chapter 11 · Conventional Therapy in Adult Acute Lymphoblastic Leukemia: Review of the LALA Program
Fig. 11.7. Comparison of Philadelphia-positive ALL patients treated
in the elderly with imatinib mesylate and chemotherapy (AFR09)
with those treated according to our previous protocol (LALAG-97).
replaced, in all patients with WHO performance status
< 3, by therapeutic schedules either similar to those administered
to adults under 60 years of age, or specifically
design for elderly patients. However, “age-adapted”
therapies did not show any advantage in terms of
DFS. Higher toxicity of “young adult-like” therapy was
contrabalanced by a higher relapse rate after “ageadapted”
therapy probably related to lighter maintenance
therapy [52].
Prognosis of Philadelphia-positive elderly ALL
could be transformed by the introduction of imatinib
mesylate [53] and could become even better than that
of the other subtypes of ALL in the elderly. This
prompted the GRAALL to treat apart Philadelphia-positive
and Philadelphia-negative ALL and to implement a
treatment protocol alternating chemotherapy and imatinib
in previously untreated elderly patients with Philadelphia-positive
ALL (AFR09 trial) (Fig. 11.6). Our first
results showed very encouraging data with a projected 1year
event-free survival (EFS) at 57% for patients treated
with imatinib and a 1-year OS at 71% (Fig. 11.7) [54].
11.11 GRAALL Trials (2003–Present)
Despite improvements in outcome of adult patients with
ALL, several questions were still open. Is the current
stratification using standard-risk and high-risk ALL absolutely
adequate in adults? Although risk models have
been proposed, the prevailing view was that the vast majority
of affected adults should be considered having a
high risk of recurrence and that all adult ALL patients
should be treated with intensive protocols. Encouraging
results of T-cell lineage ALL after allografting in a recent
retrospective study [55], together with the poor
outcomes observed in the LALA-94 trial with chemotherapy
alone [24] and the identification of T-cell
lineage subtypes associated with a poor outcome [39],
suggested further studies examining allografts compared
with more intensive chemotherapy regimens.
The use of more intensive chemotherapy regimens
was supported by a retrospective study comparing the
characteristics and outcome of 100 adolescents treated
in the French adult LALA-94 trial and 77 adolescents
treated during the same period in the French pediatric
FRALLE (French Acute Lymphoblastic Leukemia)-93
trial [56]. In this study, the comparison pointed out that
adolescents treated in the pediatric protocol had a significantly
better outcome in terms of CR achievement
and EFS. Such a more favorable evolution was not explained
by a difference in patients characteristics, and
was already remarkable after the induction course, suggesting
the major role of drugs and global treating attitude
disparities between pediatric and adults departments.
These results incited not only treatment of adolescents
using pediatric protocols but also the design of
new trials inspired by pediatric protocols to treat young
adults over 20 years. Disparity was particularly observed
in patients with B-cell lineage ALL, but was also
present in patients with T-cell ALL. Differences in induction
courses, which could underlie this gain in CR
rates, were essentially the continuous administration
of higher doses of prednisone and the use of L-asparaginase
in the FRALLE-93 protocol. Higher doses of major
drugs in the treatment of ALL were used in the pediatric
protocol within a shorter period of time. The
3-time daily administration schedule of steroids has
early been demonstrated superior to more spaced administration
in children ALL [57]. Moreover, a recent
study of the Dana-Farber Cancer Institute demonstrated
improved response to increased steroids dose in pediatric
patients [58]. Children aged 9–18 years have been
shown to benefit from higher doses of L-asparaginase
despite an increased related toxicity, and repeated doses
of L-asparaginase during early treatment significantly
improved outcome in pediatric patients with T-ALL
[59]. Moreover, the pediatric delayed intensifications appeared
to contribute to an improve outcome. This strategy,
initially proposed by the Berlin-Frankfurt-Munster
study group [60], has been demonstrated in children
older than 10 years [61], with increased benefit of an