Blood, 15 May 2002, Vol. 99, No. 10, pp. 3491-3492
CML yields a few more clues
The popular, though not necessarily correct, interpretation of
molecular events in chronic myeloid leukemia (CML) assumes that the
acquisition of a BCR-ABL fusion gene is the critical event in
generating chronic phase (CP) disease and that other genetic events
then occur that underlie disease progression. Thus interferon-alfa,
until recently the agent most active in inducing cytogenetic remissions
in CML in chronic phase, has little activity in advanced phase disease.
If then the new kinase inhibitor imatinib (STI571, Gleevec) targets
mainly the Abl kinase activity of the Bcr-Abl oncoprotein, it should
have little or no activity in advanced phase disease. It came therefore
as something of a surprise that the compound was active in CML cell
lines, all derived from patients with CML in transformation, and in
treating patients with blastic phase disease. The papers by Sawyers et
al
(p 3530) and Kantarjian et al (p 3547) in this issue of
Blood confirm this impressive clinical activity. There are
only 2 logical explanations: either BCR-ABL continues to play a
major role in at least some patients with advanced phase disease, or
imatinib also inhibits other kinases not yet identified that are
involved in blastic transformation. Some extra support for the notion
that Bbl-Abl is no benign bystander in advanced phase disease comes
from the observations reported recently that imatinib-resistant cell
lines over-express Bcr-Abl and patients who respond and then become resistant to imatinib may have acquired mutations in the Abl ATP binding domain that interfere with imatinib binding. One feels however
that this cannot be the whole story, and non-Bcr-Abl mechanisms must be playing a role in other cases of primary or secondary resistance to imatinib. In the past lymphoid transformations have been
more amenable to treatment than myeloid transformations, though the
reverse seems to apply with imatinib. Overall median survivals are 6 to
8 months, which seems no great improvement on results achieved in the
pre-imatinib era. What does seem important is that hematologic and
indeed cytogenetic responses can be achieved frequently with a
relatively nontoxic oral agent, which can then set the scene for more
intensive chemotherapy or allogeneic stem cell transplantation. Both
papers end their summaries with reference to the future use of imatinib
in combination with other agents, and here indeed lies the best hope
for substantial prolongation of life for CML patients unfortunate
enough to proceed to blastic transformation.
John Goldman
Hammersmith Hospital/ Imperial College, London
