Acute Leukemias - Republican Scientific Medical Library

a 14.4 · Hematopoietic Stem Cell Transplantation 183
with consolidation with high dose methotrexate and
Ara-C) and followed by maintenance with Imatinib
[80]. Remarkably, CR was achieved in 100% of patients
(93% after the first treatment course, compared to the
historical rate of 66% with hyper-CVAD alone), including
five patients with primary refractory disease. More
encouraging, of the 10 patients treated on protocol who
were not eligible for subsequent HSCT, five remained in
continuous CR with a median follow-up of 20 months,
while only two relapsed. The OS and DFS results with
the Imatinib/hyper-CVAD regimen appeared superior
to the historical results obtained with hyper-CVAD
alone [64]. Similarly, Imatinib has been administered
in conjunction with Linker-type chemotherapy, yielding
CR rates > 90% [82, 83].
Imatinib has also been used as a single agent during
the interim period between induction chemotherapy
and consolidation, and then later between consolidation
and HSCT. This strategy achieved a reduction BCR-ABL
mRNA of 0.77 and 0.34 logs after each cycle of therapy,
and was accompanied by a lower relapse rate (compared
to historical controls) in patients during consolidation
(4.3 vs. 40.7%); a higher rate of patients proceeded to
transplant in first CR (86.2 vs. 51.5%). The DFS after
transplant for patients successfully getting to transplant
at 3 years was 78% [84, 85].
Imatinib has been used as a treatment for minimal
residual disease (MRD) after transplantation in order
to abort relapse. In a prospective multicenter trial,
52% of patients became BCR-ABL negative after 1.5
months of treatment with Imatinib. Patients who became
PCR negativity early after the initiation of Imatinib
had a significantly higher DFS and OS at 1 year than
patients who did not become BCR-ABL negative (91%
and 100% vs. 23% and 13%, respectively) [86].
The effectiveness of Imatinib alone is limited by the
relatively frequent development of resistance [87]. Compared
to patients treated for chronic phase CML, the
rate of response to Imatinib in Ph+ ALL is not only substantially
lower but also much shorter. Progression on
Imatinib has been associated with the presence of point
mutations (either in the ATP binding domain or the activation
loop of Abl) that interferes with Imatinib binding
to Abl, or amplification of BCR-ABL [88]. The short
time span from response to relapse in Ph+ ALL suggests
the pre-existence of a mutated clone that expands under
the selective pressure of Imatinib. Indeed, the presence
of Abl point mutations affecting the ATP-binding pocket
have been described in Imatinib naïve patients [89, 90].
New strategies are being developed to overcome resistance
to Imatinib. First of all, as described above, Imatinib
is being incorporated in poly-chemotherapy regimens.
Secondly, new Abl inhibitors are being developed
and tested in clinical trials: AMN 107 has been found to
inhibit the proliferation of Imatinib-resistant BCR-ABL
expressing cells [91], and BMS-354825 [92], a small molecule
that inhibits kinases of the Src family as well as
Abl, is able to overcome most of the clinically relevant
described mutations. This last compound may be of
special interest in Ph+ ALL as Src kinases are involved
in the transformation of BCR-ABL induced B-ALL in the
murine model. Remarkably, the mutation T315I maintains
its resistance to both new Abl inhibitors. Other
approaches to overcome resistance include the delivery
of Imatinib at a much higher dose to specific cell types
therefore overcoming resistance and avoiding nonspecific
toxicity. For example, high-dose cell-specific Imatinib
distribution may be achieved by engineering Imatinib
encapsulated in liposomes that carry antibodies
specific for CD19 [93].
14.4 Hematopoietic Stem Cell Transplantation
Given the short remission duration of Ph+ ALL after
chemotherapy, allogeneic HSCT is considered the treatment
of choice in the setting of a suitable patient and
donor (Table 14.3). Results of HSCT are difficult to evaluate
and compare given the heterogeneity of transplant
regimens, patient cohorts, and merciful rarity of the
disease. But it is clear that allogeneic HSCT can achieve
a cure in a significant proportion of patients [94]. Reports
of autologous HSCT are few [42, 74, 95, 96]. The
data suggests that incidence of relapse is higher following
autologous transplant when compared to allogeneic
HSCT recipients [74]. The factors that are associated
most strongly with successful outcome after HSCT are
stage of disease (first remission being the most favorable),
and the occurrence of graft-versus-host disease
[41, 96–101]. In a review of 121 patients from three different
French adult and pediatric protocols, Esperou et
al. [97] found the disease status at the time of transplant
was the only independent factor predictor for survival
(estimated OS 4 years for patients undergoing HSCT
in first CR 42%, compared to 5% for patients transplanted
in more advanced disease stages), consistent
with previous reports [101, 102]. The type of donor
(HLA matched-related or matched-unrelated) does not