Donor Lymphocyte Infusion: Beauty Is in the Eye of the Beholder


M.R. Bishop / Biol Blood Marrow Transplant 19 (2013) 847e850 849
Donor Lymphocyte Infusion: Beauty Is in the Eye of the
Beholder

Michael R. Bishop*

Section of Hematology/Oncology, University of Chicago, Chicago, Illinois
Article history:

Received 8 April 2013
Accepted 10 April 2013
In this issue of Biology Of Blood and Marrow Trans-
plantation, Bar et al. report on a retrospective analysis of the
effect of CD3þ cell dose in initial donor lymphocyte infusion
(DLI) on graft-versus-host disease (GVHD) and overall sur-
vival in 225 patients who received DLI for relapsed hema-
tologic malignancy, primarily at the Fred Hutchison Cancer
Research Center [1]. This article is important from several
perspectives, on which I will expound. However, the state-
ment that I enjoyed the most, and the primary focus of my
commentary, is in the first sentence of the discussion: “DLI is
an attractive salvage treatment option for patients with
persistent or relapsed hematologic malignancies.” Attrac-
tive? Now, this may be the first time I have heard of DLI being
described as attractive. I am sure that I will hear from
someone with far too much time on his or her hands of other
examples of this adjective to describe DLI, but it did make me
take pause. Based on our overall clinical experience with DLI,
"attractive" is probably one of the last words I personally
would use to describe it. I look at DLI more like having to take
your best friend to the prom because neither of you has
a date, and neither wants to go to the dance alone. Out of all
the other options, what do you do? Beauty is a very relative
and subjective term, and maybe it really is in the eye of the
beholder.

The report by Bar et al. provides wonderful background
for placing the “beauty” of DLI into perspective, reading like
a review of the history of DLI over the past 23 years. I would
actually argue that that this report should be required
reading for fellows during their transplantation rotation and
an excellent journal club article. It starts out with the
obligatory statement that “Allogeneic hematopoietic cell
transplantation has the potential to provide long-term
survival and even cure in patients with hematologic malig-
nancies,” which is tough to argue considering that I have
started approximately one-half of my own publications with
the same statement. This is followed by a statement of who
reported the first DLI, which is where it really starts to get
interesting, given that even this little 3-patient report has
been a repeated point of contention over the years [2,3]. The
article then moves on with the “Patients and Methods”
section to describe the 225 patients with a broad variety of
hematologic malignancies who were treated over an 18-year
Financial disclosure: See Acknowledgments on page 850.
* Correspondence and reprint requests: Michael R. Bishop, MD, Section of

Hematology/Oncology, University of Chicago, 5841 South Maryland Ave, MC
2115, Chicago, IL 60637.

E-mail address: mbishop@medicine.bsd.uchicago.edu.
1083-8791/$ e see front matter � 2013 American Society for Blood and
Marrow Transplantation.
http://dx.doi.org/10.1016/j.bbmt.2013.04.009
period, and then to how specifically DLI was used: with
and without chemotherapy or radiation, with adjuvant
cytokines (eg, IFN, IL-2), use of steady-state or “mobilized”
DLI, chimerism status and presence or absence of GVHD at
the time of DLI, and the use of immunosuppression to
prevent GVHD. Sound familiar? This is not a criticismdthese
are extremely relevant biologic and clinical issues that
investigators have attempted to address over the past 20
years [4-7].

The authors are self-depreciating when describing the
heterogeneity of their patient populations and treatment
approaches as a limitation of their study. However, I look at
this heterogeneity as a strength, placing the use of DLI in
a compact historical framework by a group of investigators
who have been at the forefront of translational and clinical
transplantation research since its inception. Possibly the
most informative (and somewhat comforting) aspect of this
report is that the authors’ results are very similar to what has
been previously reported and to general perceptions in the
transplantation community [8,9]. Consistent with previous
observations, Bar et al. found that CD3þ dose was correlated
with the risk of GVHD, and that higher CD3þ doses did not
decrease the risk of recurrence after successful DLI or
improve overall survival. At the same time, the results are
very disappointing relative to the lack of progress in DLI over
the last 25 years. The disease for which DLI has the best
results, chronic myelogenous leukemia, is today a relatively
rare indication for transplantation. We are still unsure as to
exactly when, how often, how much, precisely what, and
with what we should use DLI. Relative to when, there are no
established methods or guidelines for monitoring for disease
recurrence after transplantation, with the possible exception
of chronic myelogeous leukemia. Bar et al. addressed DLI
dose, but the optimal starting dose, whether the doses
should be escalated, and if so, how often remain unclear.
Maybe we should be giving relatively small (<1 � 106 CD3þ
cells/kg) on a more frequent (weekly?) basis. Other, possibly
even more important questions involve product content and
the need for cytoreduction to achieve a minimal residual
disease state and immunodepletion for creation of immu-
nologic “space” [10]. The correlation of success of DLI with
minimal residual disease is well established, and it is difficult
to expect DLI to be successful in the context of competing for
homeostatic and stimulatory cytokines in a immunologically
competent host with potentially inhibitory features (eg,
T regulatory cells). Relative to content, should they specifi-
cally be just CD3þ cells or subsets, natural killer cells, or some
combination?

Finally, should we just accept it as fact that no matter
what we attempt, the results with DLI will end up being the
same? It is my strong belief this is the not case; many of these
questions have been only partially addressed in an adequate
manner, and there are several new modalities, such as chi-
meric antigen receptors, that may enhance the efficacy
of DLI and merit further investigation in the allogeneic

http://dx.doi.org/10.1016/j.bbmt.2013.04.009
http://dx.doi.org/10.1016/j.bbmt.2013.04.009
mailto:mbishop@medicine.bsd.uchicago.edu


M.R. Bishop / Biol Blood Marrow Transplant 19 (2013) 847e850850
transplantation setting [11,12]. The key element is the design
and implementation of such studies in multi-institutional
settings, which was one the major recommendations from
the National Cancer Institute’s First International Workshop
on the Biology, Prevention, and Treatment of Relapse after
Allogeneic Hematopoietic Stem Cell Transplantation. Thus is
the only way that we are going to determine the optimal use
of DLI and to move the field forward [13].

So, as we step back and look across the dance floor, do we
really find ourdate,DLI,attractive? Maybe, ifviewedwithinthe
context of our other options for recurrent disease after allo-
geneic hematopoietic cell transplantation. However, I would
argue that maybe it is time for the transplantation community
to go the ophthalmologist to get our eyes examined.
ACKNOWLEDGMENTS
Financial disclosure: The authors have nothing to disclose.
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	Donor Lymphocyte Infusion: Beauty Is in the Eye of the Beholder
	Acknowledgments
	References