Acute Leukemias - Republican Scientific Medical Library

Novel Therapies in Acute Lymphoblastic Leukemia
Stefan H. Faderl, Hagop Kantarjian
Contents
19.1 Introduction ................... 237
19.2 New Chemotherapy Agents ....... 238
19.2.1 Liposomal Preparations ....... 238
19.2.2 Nucleoside Analogs .......... 239
19.2.3 Epigenetic Therapy .......... 240
19.2.4 Signal Transduction Inhibitors . . 241
19.2.5 Monoclonal Antibody Therapy . . 241
19.2.6 Other Agents .............. 242
19.2.6.1 Pegylated Asparaginase . 242
19.2.6.2 Forodesine (BCX-1777) . . 242
19.3 Getting to Know Chemotherapy:
The Role of Pharmacogenetics and
Mechanisms of Drug Resistance .... 243
19.4 Conclusion .................... 244
References ......................... 244
19.1 Introduction
Although prognosis of adult ALL has improved over the
last few decades, still only 30–40% of patients achieve
long-term, disease-free survival and can be considered
cured [1, 2]. The remainder will eventually relapse and
die from disease progression or other ALL-related consequences.
New strategies, refinements of old ones, and
novel agents are therefore needed. How modifications of
induction regimens can positively impact the outcome
in subsets of the disease is exemplified in mature B-cell
ALL where short, dose-intensive chemotherapy leads to
survival of 50–70% of the patients and T-cell ALL in
which addition of cyclophosphamide, high-dose methotrexate
and cytarabine in the induction and consolidation
sequence is associated with similar survival rates
[3]. Other subgroups such as Philadelphia chromosome-(Ph)
positive ALL are still largely incurable
with chemotherapy alone although the combination of
BCR-ABL tyrosine kinase inhibitors with intensive chemotherapy
is showing promising leads in this group of
patients as well.
Several paths to better treatment strategies can be
pursued and must not be seen isolated from each other:
(1) continuous modification of current therapy programs
in light of a better understanding of disease subtypes
and regimen-specific components; (2) development
of new drugs targeted against identifiable cytogenetic-molecular
abnormalities; and (3) appreciation of
the role of pharmacogenetics in ALL and developing
mechanisms to overcome drug resistance. Successful
implementation of any of those strategies ultimately requires
a more profound understanding of the biological
characteristics of ALL taking into account the heterogeneity
of ALL. Given the complexity of ALL treatment
programs, it can hardly be expected that there is a single
new agent that will stand out on its own so that progress
in ALL will require not only integration of new agents
into treatment algorithms, but also to learn how to better
use the armamentarium of currently available agents
and combinations (Table 19.1) [4].