Received: November 22, 2013
Accepted: November 23, 2013
Meditter J Hematol Infect Dis 2014, 6(1): e2014010, DOI 10.4084/MJHID.2014.010
This article is available on PDF format at:
Michele Baccarani1 and Fabrizio Pane2
1 University of Bologna and GIMEMA, Italy
2 University of Naples “Federico II” and CEINGE Biotecnologie Avanzate, Naples, Italy
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Editorials and Comments
The
history of chronic myeloid leukemia has marked one of the most
remarkable and exciting success of modern medicine, transforming an
almost always fatal cancer in a chronic conditions that can be
medically controlled, and opening space and hope for a cure in an
increasing number of patients.[1-6]
The discovery of
the molecular bases of CML and of a class of agents, the tyrosine
kinase inhibitors (TKIs), targeting the molecule that causes the
leukemic transformation of hemopoietic stem cells, has provided a
strongly positive support to the concept that cancer treatment must be
based on the knowledge of cancer biologic characteristics and on the
development of agents targeting specifically these characteristics.
Until this concept remained a chimera, for many years, the treatment of
cancer was necessarily based on cancer destruction exploiting the
subtle differences in sensitivity among normal and cancer cells. This
policy, a policy of “last cell kill”, gave positive results in many
cancers. Examples, in hematology, are lymphomas, particularly Hodgkin’s
lymphoma, and acute leukemia, particularly acute lymphoblastic leukemia
in children. TKIs in CML as well as transretinoic acid in acute
promyelocytic leukemia have at last shown that the concept of
cancer-specific treatment is no longer a chimera and can be applied to
clinical practice, in an increasing number of hematologic and
non-hematologic malignancies.
The way was neither easy nor rapid. CML was described in the 19th century and
was managed with radiation and chemotherapy until the end of the 20th
century, until the introduction and the wide application of allogeneic
stem cell transplantation (SCT) and of recombinant Interferon-alfa
(rIFNɑ).[1-6] SCT was in a sense
the sublimation of
the last cell kill theory, based on stem cell kill by radiation and
alkylating agents and on residual stem cell control by the transplanted
immune system. SCT is still the most important curative treatment of
CML, but in spite of progress, the mortality and the
morbidity
are still important and limiting the application.[6-8]
As a matter of fact, SCT does not fit the concept of cancer specific
treatment. rIFNɑ was a great success, and an unexpected one, but also
the benefit of rIFNɑ was limited, because less than 50% of patients had
a significant response, and side-effects were remarkable.[1,5,6,9]
Again, rIFNɑ was not specifically directed against Ph+ cells, and it is
intriguing to admit that after many years its mechanism of action is
poorly known. After radiation and conventional chemotherapy, after
allogeneic SCT, after rIFNɑ, the true breakthrough was made by
imatinib, the first of a class of small molecules inhibiting the TK.[10]
Soon after imatinib, other TKIs were rapidly developed and tested, and
other four TKIs are now available, though not yet in all countries, and
with different indications, dasatinib, nilotinib, bosutinib, and
ponatinib.[11-15] These compounds
are similar and
inhibit very effectively the kinase activity of BCR-ABL1, with a good
therapeutic response, but are not identical. There are differences, in
metabolism, pharmacokinetics and pharmacodynamics, there are
differences in the ability of inhibiting BCR-ABL1 and particularly the
mutated forms of BCR-ABL1, and there are differences in the inhibition
of other different TK, leading to some differences in efficacy and to
some differences in safety and side-effects. The major effect of the
availability of more TKIs has been the relief of patients from
dependence on only one drug, a condition that left too many patients at
risk of dying of leukemia, and that was a cause of fear also in the
responding patients. No more than 10 years ago, the big question was
how long will the response last, how long will survival be.[1] The early recognition of the
development of TKIs-resistant mutations was a cause of fear and
anxiety.[1,16]
We now know that with imatinib the responses are durable, that the risk
of developing mutations decreases with time, that the majority of the
patients who fail imatinib or are intolerant of imatinib can be rescue
with other TKIs, and that a stable and deep response to imatinib may
herald a treatment-free remission, a kind of clinical cure.[4,6,17,18]
However, the area of TKI and CML is still marked by a strong
competition among drugs and companies, a competition that has
comprehensible commercial bases, but has sound medical, ethical, and
social consequences.[19] Overall,
the availability of
more TKIs provides an unprecedented opportunity of designing the
treatment according to disease and patient, that is to say of
optimizing treatment, a goal that has not yet been reached because we
must still learn how to do the best and proper use of these drugs. Many
current treatment recommendations are based on efficacy, and the
evaluation of efficacy is based sometimes too much on the so-called
early surrogate markers of the outcome and sometimes too few on the
outcomes, that are progression-free survival, overall survival, and
treatment-free survival.[6] Since
the efficacy is
high, it is necessary to take into consideration more and more also the
safety and the tolerability, that affects so much the quality of life,
and also the compliance, that in turn is important for the efficacy.[20-22]
It is true that the TKIs are targeted against BCR-ABL1 and are much
less toxic and much better tolerated than most antileukemic and
anticancer agents. But even TKIs are not completely specific, can cause
important, and even life-threatening, clinical complications, as well
as minor chronic side-effects that in the long term can become hard to
tolerate.[20-26] A careful
monitoring of efficacy is
necessary, based primarily on quantitative molecular testing and in
case of failure also on mutational analysis, but also on cytogenetics,
whenever molecular monitoring is not available or is not standardized
according to the international scale.[6,27,28]
Monitoring is expensive, but the cost of careful monitoring is only a
small fraction of the cost of treatment, and allows to make a proper
use of any drug, from the clinical and also the financial point of
view. However, monitoring the efficacy is not sufficient. Monitoring
must be coupled with a careful attention to the patient, the
comorbidities, the age, the complaints, the style of life, and
ultimately the will of the patient.[20,26-29]
There is still a long and dedicated way to success. This issue of the
Mediterranean Journal of Hematology and Infectious Disease covers some
of the most important topics on the treatment of CML, to help health
care professionals to walk along this way and to improve the management
of CML patients.
]
References
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