Acute Leukemias - Republican Scientific Medical Library

Philadelphia Chromosome-Positive
Acute Lymphoblastic Leukemia
Olga Sala-Torra, Jerald P. Radich
Contents
14.1 Introduction ................... 177
14.2 Molecular Biology of the Ph Chromosome
........................ 177
14.2.1 Lineage Restriction of the Ph
Chromosome .............. 179
14.2.2 The Molecular and Cell Biology
of the Ph Chromosome ....... 179
14.2.3 The Biology of p190 Versus p210
BCR-ABL ................. 180
14.3 Treatment of Ph+ ALL ............ 180
14.3.1 Pediatric Ph+ ALL ........... 180
14.3.2 Adult Ph+ ALL ............. 181
14.3.3 Imatinib-based Therapy of Ph+ ALL 182
14.4 Hematopoietic Stem Cell
Transplantation ................. 183
14.5 The Detection of Minimal Residual
Disease ....................... 184
14.6 Conclusion .................... 184
References ......................... 184
14.1 Introduction
The Philadelphia chromosome (Ph) is the shortened
chromosome 22 resulting from the reciprocal translocation
between 5' part of the BCR gene from chromosome
22 combines with the 3' part of the ABL gene, resulting
in an chimeric BCR-ABL tyrosine kinase that is constitutively
activated and oncogenic. The Ph is the genetic
hallmark of chronic myeloid leukemia (CML), and it
is also the most frequent cytogenetic abnormality in
adult acute lymphoblastic leukemia (Ph+ ALL), where
it is present in roughly 25% of cases. The Ph occurs less
often in pediatric ALL, with a prevalence of < 5%. In
both age groups the Ph chromosome describes a subgroup
of ALL with a poor prognosis. Thus, patients with
Ph+ ALL are usually offered a hematopoietic stem cell
transplant if a suitable donor is available. The tyrosine
kinase inhibitor, imatinib mesylate, has been found to
block the activity of the BCR-ABL tyrosine kinase and
has made an impact in the short-term management of
Ph+ ALL. Unfortunately the effect of Imatinib monotherapy
tends to be short-lived in Ph+ ALL, and it is
by no means curative. Therefore, recent approaches
are investigating combinations of Imatinib with either
other small molecular inhibitors, chemotherapy, and
transplant regimens. Although the numbers of patients
reported are still small, the results suggest that these
combinations using Imatinib with other therapies may
improve clinical outcomes for this highly recalcitrant
malignancy.
14.2 Molecular Biology of the Ph Chromosome
The most common breakpoints of the BCR and ABL sequences
yield two fusion BCR-ABL genes in Ph+ ALL
(Fig. 14.1) [1–4]. These two different BCR-ABL variants
result from the different breakpoint locations in the
BCR gene, while the breakpoint in ABL occurs reliably
5' to ABL exon 2, except in rare circumstances. The typical
210 kD BCR-ABL fusion protein, found in CML and
Ph+ ALL, involves a break in the major breakpoint clus-