Acute Leukemias - Republican Scientific Medical Library

180 Chapter 14 · Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia
to be indispensable for the transformation process induced
by BCR-ABL, at least in murine models, as lethally
irradiated mice deficient for STAT5 a/b and infected
with p210 or p190 leukemia develop myeloid
and B-cell tumors [31]. The p190 form of BCR-ABL
phosphorylates phospholipase gamma, and phosphatidylinositol
3' kinase [32], that in turn likely activate
proliferative pathways. In addition, there is evidence
that BCR-ABL acts to inhibit apoptotic pathways [33].
Moreover in CML, BCR-ABL appears to influence adhesion
to bone marrow stromal elements, thus releasing
immature cells into the periphery, as well as divorcing
the cell from adherence-mediated cell cycle control
[34, 35]. It is not known whether this occurs in
Ph+ ALL.
An interesting observation is the fact that the Src kinases
(Lyn, Hck and Fgr), while essential for the induction
of B-ALL by BCR-ABL in mouse models, are not required
for the induction of CML, and the inhibition of
Src kinases independent of the inhibition of BCR-ABL
(by CP76030) inhibits the lymphoid transformation
[36]. This again reinforces that the leukemogenesis of
p190 and p210 ALL and CML may be subtlety but fundamentally
different.
14.2.3 The Biology of p190 Versus p210 BCR-ABL
Several differences among the p190 and p210 fusion
genes have been described in different biological models.
The first characteristic that differentiates both transcripts
is the in vitro kinase activity. The kinase activity
of the chimeric BCR-ABL protein is higher in p190 BCR-
ABL than in the p210 variant (and p210 activity is greater
than the rare p230 BCR-ABL variant, caused by a
more downstream BCR break) [37, 38]. Li et al. uncovered
significant additional differences among the three
different BCR-ABL chimeric proteins [38]. The three
BCR-ABL types transformed in vitro murine myeloid
and lymphoid IL-3 dependent cells, but the transformation
of lymphoid cells (BA/F3) with p190 resulted in the
highest proliferative rate. Furthermore, in a bone marrow
transduction/transplantation system with marrow
enriched for myeloid precursor cells (with donors
treated with 5-FU), mice transplanted with precursors
transduced with any of the three fusion genes developed
a CML-like disease. On the other hand, when using untreated-donors,
a greater percentage of mice transplanted
with p190-transfected marrow developed B-
ALL, and they developed it faster than mice transplanted
with p210- or p230-transfected marrow. The activation
of STAT6, induced by p190 but not by p210, may
be involved in the preferred lymphoid transformation
by p190 BCR-ABL [39].
In addition, there are some clinical data that suggest
that patients with the p190 BCR-ABL do worse than
those with p210 after conventional chemotherapy [40].
Different prognostic value of the persistence of minimal
residual disease after transplant for the two breakpoints,
with p190 BCR-ABL having a worse prognosis [10, 41]
also favors that the different transcripts determine
somewhat different diseases.
14.3 Treatment of Ph+ ALL
Despite modern chemotherapy regimens having improved
the outcome of pediatric and adult ALL in the
last decades, the improved results in the aggregate have
not translated into an improvement in Ph+ ALL, where
treatment with chemotherapy alone still affords dismal
survival statistics [42, 43]. Newer strategies incorporating
Imatinib appear promising for short-term benefits,
but their impact in long-term survival remains to be
seen.
14.3.1 Pediatric Ph+ ALL
Childhood ALL is a paradigm of a malignancy curable
with chemotherapy alone. However, despite cure rates
exceeding 80% with current treatment protocols [44],
children with Ph+ ALL (Table 14.1) have an extremely
poor prognosis when compared to those with Ph-negative
ALL [45–49]. Although most (80–100%) Ph+ ALL
patients will obtain an initial complete remission (CR)
[42, 45–48, 50–55], their event-free survival (EFS) and
overall survival (OS) range from 28–50% and 40–50%
at 5 years. More recent studies incorporate related or
unrelated allogeneic hematopoietic stem cell transplantations
(HSCT) for first CR Ph+ ALL patients, preferring
to treat these patients with ablative regimens sooner
rather than later [42, 45–48, 54, 56, 57].
Despite the overall poor prognosis in Ph+ ALL, several
studies have defined prognostic subgroups among
pediatric patients with Ph+ ALL. In a meta-analysis of
ten different trials, Arico et al. [42] found that age
and initial WBC, included in the Rome/NCI criteria