Acute Leukemias - Republican Scientific Medical Library

a 22.4 · CNS Relapsed in Adult Acute Lymphoblastic Leukemia 277
fer from both treatment-related mortality and a significant
rate of relapse. Ultimately, few patients are longterm
disease-free survivors. A major cause of this high
degree of relapse is related to the modest “graft-versusleukemia”
effect associated with treating ALL. Graft-versus-leukemia
is the process by which the transplanted
(donor) immune system eliminates residual leukemic
cells and as such is a type of graft-versus-host reaction.
Graft-versus-leukemia appears to be less active in ALL
than in AML or CML. Supporting this concept are data
from the International Bone Marrow Transplant Registry
that compared identical twin (syngeneic) transplants
to HLA-identical sibling transplants [16]. Graftversus-leukemia
should be more pronounced in the allogeneic
transplants as compared with the syngeneic
transplants, and in this study there was a significantly
higher relapse rate in the syngeneic transplants for
AML and CML, but not for ALL. This implies that
graft-versus-leukemia is less important in ALL. A second
indication that graft-versus-leukemia is less active
in ALL comes from an analysis of studies of donor T-cell
infusions used to treat leukemia that has relapsed after
allogeneic bone marrow transplant. In this study, donor
lymphocyte infusions produced complete responses in
73% of patients with CML, 29% of patients with AML,
and 0% of patients with ALL [17]. There is however, a
mild graft-versus-leukemia effect in ALL and a report
of 1132 patients with ALL demonstrated that acute and
chronic graft-versus-host disease are associated with
lower overall rates of relapse compared to those patients
without graft-versus host disease [18].
There is significant controversy over the use and
timing of allogeneic transplant in adult ALL. The results
of 192 adults with ALL transplanted at the Fred Hutchinson
Cancer Center report a 5-year disease-free survival
of only 15% for patients transplanted in second CR or
beyond [19]. Another study suggested more favorable
results, but this is difficult to interpret as the results
combined both pediatric and adult patients, or patients
in first CR (who may already be cured) with higher-risk
patients [20]. As only a small subset of patients with relapsed
disease are cured with allogeneic transplant,
many investigators have chosen to evaluate this modality
in patients in first CR. However, two large comparisons
of allogeneic transplant versus standard chemotherapy
for patients in first CR have failed to demonstrate
an improved survival for the transplant arm [21,
22]. In one of these studies, subset analysis suggests a
benefit for certain high-risk patients [21]. However, this
benefit was not confirmed in the other study [22]. Thus,
currently the only patients for whom allogeneic transplant
in first CR can be routinely recommended are in
patients with t(9;22) and t(4;11). For other adult patients,
we recommend that allogeneic transplant be reserved
for second CR.
Autologous transplant for adult ALL is even less effective
than allogeneic transplant [23]. The extremely
poor results in patients in second CR led to testing this
modality in patients in first CR. However, both a nonrandomized
[24] and randomized trial [25] have shown
no benefit to autologous transplant compared with
maintenance chemotherapy in patients in first CR. This
modality should therefore be considered investigational
at this time and not routinely performed in patients in
first CR.
22.3 Philadelphia Chromosome-Positive Adult
Acute Lymphoblastic Leukemia
Philadelphia-chromosome positive (Ph+) disease carries
a very poor prognosis, and long-term survival, even
with high-dose chemotherapy, is rare. Thus, for patients
with Ph+ disease, allogeneic transplant in first CR is
commonly recommended and may be curative in a minority
of patients [26, 27]. The development of imatinib
(Gleevec®, formerly STI-571), a tyrosine kinase inhibitor
with relative specificity for bcr-abl, has dramatically
changed the treatment and outcome of patients with
CML [28]. This agent also has activity in Ph+ ALL
[29]. In this setting, however, it is less active than it is
in CML with only 29% of relapsed or refractory patients
achieving a CR [29]. Unfortunately, the median time to
progression is only 2.2 months, demonstrating the development
of resistance to imatinib in this patient group
[30, 31]. Currently, many investigators are assessing
combination therapy with imatinib and chemotherapy
in both the initial treatment [32] or in the relapsed setting
[33].
22.4 CNS Relapsed in Adult Acute
Lymphoblastic Leukemia
CNS relapse occurs in approximately 10% of patients
who have received appropriate prophylaxis. In the majority
of these patients, simultaneous bone marrow relapse
can be documented. In occasional patients, CNS