Blood, 1 August 2002, Vol. 100, No. 3, pp. 741-741
G-CSF and monosomy 7 in marrow failure patients
Kojima and colleagues (page 786) report a correlation between
G-CSF treatment of children with aplastic anemia and evolution to
cytogenetic abnormalities and myelodysplasia. How strong is this
relationship and how generalizable the conclusions?
The Japanese investigators administered high G-CSF doses (close
to the adult equivalent of 10 µg/kg/d, later thrice weekly) for very long periods (in all patients for at least 3 months and in
nonresponders beyond, in some cases for years) and largely independent
of blood count values. This is far from the usual practice. G-CSF is
not recommended as first therapy in marrow failure; therapeutic trials
aim at elevating the neutrophil counts; and in those few patients who
respond, the dose is adjusted to maintain granulocytes above a safe
level. The Japanese protocol likely was based on earlier favorable
results from Europe, where G-CSF combined with immunosuppression in
producing excellent survival in aplastic anemia patients, but neither
later analysis of these data nor a formal randomized comparison could
confirm the specific value of the cytokine, even in protecting patients
from serious infection.
The results of Kojima et al must be balanced by other evidence. G-CSF
has passed long-term testing in many animal species. Its standard use
in cyclic neutropenia has been free of complications. In aplastic
anemia, G-CSF in the European trials has not been a risk factor for
evolution, and the overall rates of evolution to myelodysplasia there
and in our NIH experience, where G-CSF is used sparingly, are
comparable to those of Kojima et al. Most important: the protocol used
by Kojima et al dictated prolonged G-CSF exposure for nonresponders,
and poor clinical status is the major confounder of their
study, because evolution to monosomy 7 most frequently is seen
after failure of immunosuppressive therapy.
Chronic G-CSF therapy also has been associated with monosomy 7 in
children with Kostmann syndrome. In both constitutional neutropenia and
aplastic anemia, improved survival secondary to better supportive care
may allow manifestation of a latent malignant potential. That small
numbers of abnormal cells may reside quietly, even innocuously, in
failed bone marrows has become apparent only with the development of
increasingly sensitive techniques, as flow cytometry for paroxysmal
nocturnal hemoglobinuria and fluorescence in situ hybridization for
aneuploidy. Whether and how G-CSF might promote expansion of stem cells
lacking chromosome 7 is amenable to laboratory experimentation;
clarification of this relationship will have serious clinical
implications for marrow failure patients.
Neal S. Young
National Heart, Lung, and Blood Institute
