Acute Leukemias - Republican Scientific Medical Library

a 19.2 · New Chemotherapy Agents 241
free survival and overall survival [31]. Use of hypomethylating
agents such as 5-aza-2'-deoxycytidine
(decitabine) or 5-azacytidine may thus provide therapeutic
benefit for patients with a defined methylator
phenotype. Although experience with these agents in
ALL remains sparse, understanding defined genetic
and epigenetic changes in adult ALL may offer another
dominant molecular mechanism whose targeting
may lead to risk-adapted therapies.
19.2.4 Signal Transduction Inhibitors
Ph-positive ALL is the most common subtype in adult
ALL and has historically been associated with one of
the worst outcomes to even intense-dose multiagent
chemotherapy regimens [32]. Ph-positive leukemic
blasts are characterized by expression of BCR-ABL tyrosine
kinases of either 210 kD (p210) or 190 kD (190)
as a consequence of the reciprocal translocation between
the long arms of chromosomes 9 (harboring
the ABL gene) and 22 (BCR). Whereas p210 occurs most
commonly in chronic myeloid leukemia (CML), p190 is
more frequently expressed in Ph-positive acute leukemias
and is also a more active tyrosine kinase activity
than p210. Imatinib mesylate (Gleevec) is a small molecule
with potent antiproliferative activity against BCR-
ABL cell lines in vitro at submicromolar concentrations
that are easily achievable clinically. Although imatinib
has made its biggest impact in the treatment of patients
with CML, p190- and p210-expressing cells are equally
sensitive, making Ph-positive ALL a suitable target as
well.
Although single-agent imatinib is active in Ph-positive
ALL, almost all patients will eventually relapse
and progress so that major efforts are being invested
in combination programs of imatinib with dose-intensive
chemotherapy to increase response rates and improve
durability of responses. Thomas et al. were the
first to combine imatinib with the ALL induction
regimen hyper-CVAD (cyclophosphamide, vincristine,
doxorubicin, dexamethasone alternating with highdose
methotrexate and cytarabine) [33]. In a recent
update, 25 of 26 patients (96%) with active disease at
study entry achieved CR at a median time to response
of 21 days [34]. Thirteen of the patients were able to
proceed with allogeneic stem cell transplant within a
median of 3 months from start of therapy. Molecular
responses as assessed by RT-PCR for BCR-ABL oc-
curred in nine of 19 patients. Two-year DFS was 87%
with the hyper-CVAD imatinib combination compared
with 28% with hyper-CVAD alone in this group of patients.
Similar results have been reported by the Japan
Adult Leukemia Study Group (JALSG) by Towatari et
al. [35]. Of 24 patients with Ph-positive ALL, all but
one (96%) achieved CR after a single course of induction
therapy. PCR testing was negative in almost 80%
of patients during follow up. Fifteen patients (63%)
were able to proceed to an allogeneic stem cell transplant.
Ottmann et al. compared the efficacy of imatinib
in Ph-positive ALL when given either intermittently
between chemotherapy courses or concurrently
[36]. Concurrent administration achieved higher CR
rates (96 vs. 58%) and more profound decreases of
BCR-ABL levels by PCR testing.
More potent second-generation tyrosine kinase inhibitors
such as nilotinib and dasatinib have recently
entered clinical trials [37]. Both agents proved more potent
in proliferation assays than imatinib and also
showed activity against imatinib-resistant cell lines.
The role of new kinase inhibitors in Ph-positive ALL
is currently investigated in clinical trials.
19.2.5 Monoclonal Antibody Therapy
Monoclonal antibody therapy has emerged as one of
the most effective additions to the therapy of hematologic
malignancies including the acute leukemias. The
attraction of monoclonal antibodies is based on two
characteristics: (1) selectivity of the tumor target by
virtue of expression of more or less tumor-specific cell
surface antigens; and (2) different mechanisms of actions
compared to more traditional cytotoxic chemotherapy
involving elements of the complement system,
human effector functions, and most likely intracellular
signaling pathways leading to apoptotic cell
death. ALL blasts express several antigens that can
serve as therapeutic targets including CD19, CD20,
CD33, or CD52 [38].
Rituximab is an anti-CD20 directed chimeric monoclonal
antibody that has been developed for the therapy
of relapsed and refractory indolent NHL. Expression of
CD20 is detected in 35% of adult ALL, particularly in elderly
patients and has been associated with a worse
prognosis [39]. Expression is higher in ALL subsets;
up to 55% in Ph-positive ALL and almost ubiquitous
in mature B ALL (Burkitt). Combination of rituximab