Acute Leukemias - Republican Scientific Medical Library

152 Chapter 11 · Conventional Therapy in Adult Acute Lymphoblastic Leukemia: Review of the LALA Program
served after autologous SCT with fewer late relapses
[36]. The use of autologous SCT in first remission
was, however, not advocated.
11.9 Prognostic Factors
The majority of adults with ALL now achieve CR. Unfortunately,
despite these achievements, the majority of
these patients still relapse. One way of approaching this
challenge is to examine options for postremission therapy
based on the prognostic factors. Different classifications
have been proposed [13, 16, 37], identifying
roughly three risk groups: a standard-risk group that
contains patients with B- or T-lineage ALL who have
no adverse cytogenetics [absence of t(9;22)/BCR-ABL,
t(4;11)/MLL-AF4, or t(1;19)/E2A-PBX1], are under age
30, present with white blood cell counts of less than
30´10 9 /l, and achieve CR in less than 4 to 6 weeks; a
poor-risk group that contains patients with adverse cytogenetics,
present with WBC counts of more than
100 ´10 9 /l, or who achieve late CR, and patients aged
more than 60 years; and an intermediate-risk group
that contains patients with prognostic characteristics
of neither the standard-risk nor the poor-risk group.
These prognostic factors were also considered in the
LALA trials, in which other factors were identified. In
the LALA-87 trial, T-cell lineage ALL had a more favorable
outcome than B-cell lineage ALL [38]. T-ALL patients
had a significantly more favorable outcome than
favorable outcome than B-cell lineage ALL patients only
in the chemotherapy arm. A useful measure in risk assessment
could be the rate of clearance of leukemic cells
from the blood or bone marrow during the early phase
of therapy. Slow clearance of the cells has proved to be
an indicator of poor prognosis, requiring intensification
therapy [39].
Improved understanding of the molecular pathogenesis
of ALL, as well as the development of innovative
molecular monitoring techniques, is beginning to provide
both new prognostic information and insights into
future therapeutic strategies. The identification of new
molecular markers of disease may also increase our
ability to tailor treatment for specific risk groups in
ALL. Both T cell receptor (TCR) and genotypic stratification
have been shown to contribute to risk-adapted
management of adult T-cell lineage ALL [40]. Detection
of MRD is also beginning to provide important prognostic
information that may affect postremission strat-
egies. This was applied in the GRAALL-03 trial, in
which treatment decisions were based on the detection
and quantification of leukemia cells at different times
during postremission treatment [41]. Ultimately, the
goal of risk-stratification was to provide the rationale
for successful subset-specific therapeutic strategies to
improve outcome for all adults with ALL.
11.10 Treatment of Elderly Patients
A number of clinical and laboratory characteristics influence
the response to treatment and thus the survival
of patients with ALL. Among them, age is one of the
most important prognostic variables [7]. Only few reports
have been published on ALL in the elderly, but
all confirmed the poor prognosis in elderly patients
with ALL with survival rates of less than 10% at 5 years
[42]. This may be related to the biology of leukemia in
the elderly [7, 43] and/or could be related to an increase
in the number of early deaths during induction [44, 45].
Toxicity is probably not mainly hematologic since regeneration
after chemotherapy is not significantly delayed,
but mainly extrahematologic. This may lead to incomplete
application of a proposed treatment schedule,
which additionally worsens the outcome. Another major
reason for the poor outcome in elderly ALL patients is a
higher prevalence of disease refractory to standard chemotherapy
programs related to the higher incidence of
adverse risk factors, particularly the increasing frequency
of Philadelphia chromosome-positive ALL with
age.
The LALA group has developed special schedules for
elderly patients with ALL since 1992. The LALA group
initiated a study (LALAG-92) aimed at improving the
prognosis of ALL in older patients [46]. Induction therapy
was derived from the young adult protocol LALA-87
[15] with chemotherapy administered at lower dose and
tailored according to the response assessed on day 15. In
addition, the feasibility of maintenance with interferon
(IFN) combined with chemotherapy was assessed
(Fig. 11.6). The introduction of IFN in the treatment of
ALL was supported by anecdotal reports suggesting that
IFN may prove effective in some relapsing ALL [47, 48].
Moreover, in patients receiving IFN after bone marrow
transplantation, the risk for subsequent relapse was reduced
[49], and a hemizygous or homozygous deletion
of the IFN gene has been reported in 30% of ALL patients,
which led to the hypothesis that a functional or