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Blood, 15 January 2001, Vol. 97, No. 2, pp. 337-338
INSIDE BLOOD
High-dose therapy and ABMT for follicular
lymphoma
High-dose therapy and autologous hematopoietic stem
cell transplantation have become the accepted treatment for patients
with chemotherapy responsive diffuse large-cell lymphoma after a
relapse from initial remission. These observations have been the
stimulus to test autotransplantation as part of the primary therapy of patients with a diffuse large-cell lymphoma. At least one randomized study has suggested that the outcome in poor-risk patients can be
improved when an adjuvant transplantation is performed after initial
remission. For follicular lymphoma the place of autologous transplantation has been more controversial. Two case control studies
and one randomized trial from Europe have suggested an advantage in
disease-free survival, but in only one case control study of patients
undergoing transplantation in second remission was there a hint of an
increase in overall survival. Given that suggestive data, Horning et al
(page 404) performed this pilot study testing the hypothesis that
adjuvant autotransplantation performed in first remission at a time of
minimal disease could increase failure-free and overall survival in
young patients with a high-risk follicular lymphoma. Young patients
were chosen because in them the illness was most likely to
significantly shorten survival. The data from this trial are sufficiently exciting that it should
lead to further studies. Although this was not a randomized trial, the failure-free and overall survivals at 10 years (ie, 60% and
86%, respectively) are better than would be anticipated with
"standard" treatments. Although myelodysplasia / acute leukemia did occur as a complication in 5% of patients, a net benefit in survival was still suggested. One of the most provocative observations is that poor-risk patients seemed to benefit more from
autotransplantation than good-risk patients, with poor-risk
transplantation patients having an overall survival at 10 years of
approximately 80%, in contrast to 36% in historical controls. Given
these excellent results, it is probably time for a randomized trial of
adjuvant autotransplantation as part of the primary therapy for young
patients with follicular lymphoma who present with a high tumor burden.
 James O. Armitage
University of Nebraska Medical Center
Dynamic CD34 expression
Before the mouse gene was cloned, CD34 was the darling
of human hematopoietic stem cell biology. But the earliest experiments with the murine gene raised many questions that are now beginning to be
answered with more data. Matsuoka et al (see page 419) show that CD34
expression on murine hematopoietic stem cells (HSCs) is developmentally
regulated. By transplanting cells that were CD34 ,
CD34low, or CD34high from fetal
liver, neonatal, or aging adult mice, they clearly show by competitive
repopulation experiments that stem cells start out life expressing CD34
but that the level diminishes over time (for a picture worth a thousand
words, see Figure 3). Their data dramatically fill in a picture
that others have sketched, showing that early embryo HSCs express
CD34 but that adult bone marrow HSCs do not. Their observations seem consistent with the recent findings of Ogawa et
al, who showed that CD34 expression in adult mice correlates with
activation state. Rapid growth in early life may require expansion
(self-renewal) of the stem cell compartment, and therefore activation
of the HSCs, and high CD34 expression. In addition, their work could
explain some early conflicting reports, where some groups found that
adult murine HSCs express CD34 and others did not: Matsuoka et al see
big differences in CD34 expression over a period of a few weeks. Alas, the mouse is such a beautiful experimental system, but we are
still unfortunately limited in our ability to extend our conclusions to
the human with confidence. If we can extrapolate, we would guess that
stem cells in human cord blood, bone marrow from young donors, and
perhaps mobilized (activated) blood, would be predominantly
CD34high but that an increasing proportion of HSCs would be
found in a CD34 compartment with age. Now all we need is
more data to support this and, maybe someday, a function for CD34.
Margaret A. Goodell
Baylor College of Medicine
Autocrine IL-6 production by highly malignant
MM cells: prognostic and treatment implications
Frassanito et al (page 483) have demonstrated
increased numbers of multiple myeloma (MM) cells producing IL-6 in
patients with primary or refractory relapsed disease and
suggest that tumor progression in MM involves expansion of clones
growing in an autocrine IL-6 mediated fashion. These data are
consistent with and extend multiple prior studies. First, using freshly
isolated patient MM samples, this study further supports the central
role of IL-6 as a growth and survival factor in both an autocrine and
paracrine mechanism. Autocrine growth is suggested both by the presence of intracytoplasmic IL-6 in MM cells and by blockade of their spontaneous proliferation using anti-IL-6 antibodies (Abs). Paracrine growth is supported both by increased numbers of IL-6 producing non-MM
cells in the bone marrow and by IL-6 responsiveness of those MM cells
not secreting IL-6. Second, MM cells in the BM milieus, both by their
adherence to bone marrow stromal cells (BMSCs) and via secretion of
humoral factors such as TGF , VEGF, and TNF , trigger IL-6
transcription and secretion in BMSCs, thereby augmenting paracrine IL-6
mediated tumor cell growth. As disease progresses, MM cells are
no longer BMSC dependent and acquire genetic and cell cycle,
ie, RB, Ras, and p21, abnormalities that allow for constitutive
activation of growth signaling cascades independent of exogenous growth
factors. This study shows that chemosensitive MM cells do not produce
IL-6 and are responsive to exogenous IL-6, whereas MM cells in
progressive disease produce IL-6 and are no longer dependent on
exogenous IL-6 for their growth. Autocrine production of IL-6,
therefore, likely accounts for the high serum levels of IL-6 associated
with progressive disease. Third, the IL-6-producing MM cells in this
study were resistant to spontaneous and drug-induced apoptosis, which
is consistent with prior reports that IL-6 confers drug resistance by
protecting against dexamethasone-induced apoptosis. What are the clinical implications of these findings for diagnosis,
prognosis, and therapy of MM? With the advent of molecular profiling,
it will be possible to further characterize those MM cells producing
IL-6 versus those not producing it, define the mechanism whereby IL-6
is aberrantly regulated in MM cells, determine whether IL-6 production
is associated with drug resistance gene or other growth and apoptotic
genetic abnormalities, and define whether IL-6 production in MM
cells, either alone or together with other genetic abnormalities,
carries prognostic significance. These findings may also have important
treatment implications. Already strategies have utilized Abs to IL-6 or
IL-6 receptor, as well as IL-6 superantagonists, to inhibit IL-6
signaling. The current studies provide the framework for novel
therapeutics targeting those MM cells producing IL-6.
Kenneth C. Anderson
Dana-Farber Cancer Institute
"Stealth" red cells
The red cell membrane contains diverse surface
molecules carrying polymorphic epitopes that are recognized
serologically as blood group antigens and that can stimulate alloimmune
responses following red blood cell transfusion or during pregnancy.
Alloimmunization is particularly problematic in patient groups
receiving multiple transfusions. For example, up to 30% of chronically
transfused sickle cell patients are alloimmunized. Furthermore,
microrganisms such as Parvovirus B19, Plasmodium
vivax, and Plasmodium falciparum use distinct red cell
surface proteins to invade erythroid cells and cause disease pathology.
Thus there has been a great deal of interest in developing strategies
to sterically mask antigenic epitopes and create "Stealth red
cells" that could be used to prevent alloimminization. Blackall et al
(page 551) have documented that glycophorin A epitopes responsible for
alloantibody and P falciparum binding are effectively
blocked by coating red cells with polythylene glycol (PEG). The
modified red cells are also resistant to parasite invasion. These
findings raise the possibility that the modified red cells could be
used to prevent alloimmunization. They could also be used for exchange
transfusion, as a supportive measure in managing clinically
overwhelming malaria infections. While the in vitro studies outlined
are convincing and indeed very promising, many difficult hurdles must
be overcome before such modified red cells could be used in clinical
practice. It is important to ascertain that the PEG coating results in
complete masking of all clinically relevant antigens because any
residual antigenic activity is likely to induce an immune response. The PEG-coated red cells must be shown to be functionally effective, stably
coated, and safe for use in humans. Although it is difficult to
foresee widespread use of these modified red cells, they could be
very useful in the management of selected patients for whom compatible red cell products are hard to find. Although many
significant and major hurdles need to be overcome before a practical
blood product for use in humans will be forthcoming, the developments reported by Blackall et al are exciting and warrant further careful exploration.
Narla Mohandas
Lawrence Berkeley National Laboratory
Signal transduction in regulatory T cells:
toward prevention of GVHD?
Previous studies showed that the addition of IL-10 and
TGF to the allogeneic mixed lymphocyte reaction yielded populations of murine CD4+ T cells incapable of inducing
graft-versus-host disease (GVHD) after in vivo transfer to
histoincompatible recipients. In this issue, Boussiotis et al (page
565) have investigated the biochemical status of alloantigen-stimulated
T cells rendered tolerant by in vitro culture in medium containing
IL-10 and TGF. The populations of tolerant T cells had an altered
pattern of signal transduction, including impaired activation of the
protein tyrosine kinase ZAP-70 and the ras pathway. Similar alterations
in signal-transduction pathways have been observed by other authors in
anergic T cells following costimulation blockade. In addition to the
thorough analysis of proximal signal transduction pathways, Boussiotis et al found that the populations of tolerant T cells were blocked in
the G1 phase of the cell cycle. A biochemical correlate of the
cell-cycle block was impaired downregulation of the p27kip1
cdk inhibitor. A paradox raised by the findings was that the reported biochemical
alterations were detected in bulk populations of cells containing an
unknown, but presumably low, frequency of alloreactive T cells. One
would have predicted that the altered signal transduction would only be
detected at the single-cell level if the signaling alternations were
restricted to the tolerant T cells. It is possible that the findings
reflect a biochemical equivalent of "infectious tolerance," a
previously reported phenomena where unresponsive antigen-specific T
cells were found to be capable of inhibiting the response of T cells
with different antigenic specificities. The report by Boussitotis et al
is important and timely in light of the resurgence of interest in
regulatory T cells. In addition to extending the understanding of
signal transduction in antigen-unresponsive T cells, the present
results are important, as there are clinical implications from the
findings. Given the massive increase in allogeneic immunotherapy that
has arisen as a consequence of nonmyeloablative stem-cell
transplantation, there is an ever-increasing need to develop a means to
prevent acute and chronic GVHD.
Carl H. June
University of Pennsylvania
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A. Lister, L. E. Abrey, and J. T. Sandlund
Central Nervous System Lymphoma
Hematology,
January 1, 2002;
2002(1):
283 - 296.
[Abstract]
[Full Text]
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