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Blood, 1 January 2003, Vol. 101, No. 1, pp. 373-373
CORRESPONDENCE
To the editor:
Donor lymphocyte infusions as primary therapy for neoplasms
The recent article by Ballen et al1 offers the
opportunity for some considerations. The originality of this study
resides in the infusion either of nonmobilized pheresed lymphocytes
from HLA-identical siblings or of umbilical cord blood cells with
various degrees of HLA mismatches in patients with refractory cancer or hematologic malignancies. The immunosuppression consisted only of
100-cGy total body irradiation. Not surprisingly, given the low level of immunosuppression, all cancer patients rejected the lymphocytes and all cord blood transplants did not engraft. The only
patients evaluable for follow-up were the 11 patients who received
lymphocytes from their sibling donor. Nine of them had some level of
donor chimerism and 6 developed acute graft-versus-host disease
(aGVHD). In this context, characterized by the infusion of
allogeneic lymphocytes in an immunocompromised host without support of
stem cells, the subsequent aGVHD may be compared with the
transfusion-associated GVHD (TA-GVHD). TA-GVHD is a dramatic event with
the clinical features of classical aGVHD and a later development of
pancytopenia, with overwhelming infection as the most common cause of
death.2 In the Ballen et al1 study, 6 patients experienced neutropenia, in some cases with Gram-negative sepsis. Unfortunately, Ballen et al do not clarify the
correlation between neutropenia and aGVHD. However, it is
noteworthy that 2 of the patients who developed GVHD later
received an infusion of stem cells from their donors. It is reasonable
to assume that, at least in part, the same patients who had aGVHD later
developed neutropenia. In a similar study, Porter et al3 obtained the engraftment
of allogeneic lymphocytes in 4 of 16 patients, and the only patient who
developed grade 4 aGVHD subsequently had pancytopenia and died of
infection. We believe that these findings are convincing enough to
reconsider the rationale of clinical trials based on lymphocyte infusion without stem cell support, particularly in this era
of "mini-transplants." Further, the Ballen et al1 results highlight the unique susceptibility of
hematopoietic tissue to graft-versus-host effect because, in the
particular setting of this trial, the bone marrow damage is related
only to the graft-versus-host effect. Otherwise, in the
context of myeloablative and, at a lesser extent,
nonmyeloablative transplantation, the graft-versus-host-induced aplasia is masked by the cytotoxic effect of the conditioning regimen
and by the competition between recipient and donor stem cells. The high
immunogenicity of hematopoietic tissue can explain, at least in part,
the satisfactory clinical results obtained in the treatment of
hematologic malignancies with allogeneic stem cell
transplantation.4
Vittorio Montefusco
Correspondence: Vittorio Montefusco, Istituto Nazionale Tumori,
Milano, Italy; e-mail:
montefusco{at}istitutotumori.mi.it
References
1.
Ballen KK, Becker PS, Emmons RVB, et al.
Low-dose total body irradiation followed by allogeneic lymphocyte infusion may induce remission in patients with refractory hematologic malignancy.
Blood.
2002;100:442-450[Abstract/Free Full Text].
2.
Schroeder ML.
Transfusion-associated graft-versus-host disease.
Br J Haematol.
2002;117:275-287[Medline]
[Order article via Infotrieve].
3.
Porter DL, Connors JM, Van Deerlin VMD, et al.
Graft-versus-tumor induction with leukocyte infusions as primary therapy for patients with malignancies.
J Clin Oncol.
1999;17:1234-1243[Abstract/Free Full Text].
4.
Appelbaum FR.
Haematopoietic cell transplantation as immunotherapy.
Nature.
2001;411:385-389[CrossRef][Medline]
[Order article via Infotrieve].
Response:
Low-dose TBI for malignancy: cellular immune therapy
The authors appreciate the communication from Dr Montefusco.
However, we do not agree with the assertion that there was no stem cell
support. This is not the case and it has been known for decades that
nonmobilized peripheral blood contains stem cells. The procedure that
we have carried out is perhaps the most "mini" of
transplantations with only 100-cGy whole body irradiation and the infusion of relatively small numbers of stem cells with CD3 lymphocytes.1 The latter point is critical. We have shown
in extensive murine work in syngeneic systems that engraftment is determined by stem cell competition.2 In the allogeneic
setting either more ablation or some type of additional tolerization is necessary.3 It is clear, however, that a major determinant of engraftment and chimerism is stem cell competition. A quite small
number of stem cells will repopulate a host if the host has markedly
depleted stem cells, as was undoubtedly the case with our patients. It
has been shown in murine studies that a single stem cell can accomplish
this over time. In addition, it is important to understand that 100 cGy, while not being overtly myeloid toxic (ie, resulting in profound
decreases in peripheral blood counts), is profoundly stem cell toxic,
with decreases in marrow stem cells persisting for as long as
1 year after irradiation.4 Our patients were heavily
pretreated and then exposed to 100 cGy. There was also undoubtedly a
component of lymphocyte graft-versus-marrow effect. All of these influences served to produce patients with profound marrow
stem cell deficits, who were then repopulated with very low levels of
CD34+ cells, as low as 104/kg.
Admittedly, CD34+ cells are not stem cells but they do give
a possible surrogate marker for the presence of stem cells.
The fact that our patients became chimeric and in some cases showed
100% chimerism clearly illustrates the presence of stem cells in our
infused product. Therefore, our approach involves a combination of stem
cells and lymphocytes. Clearly, new approaches continue to be necessary in this clinical
arena. The mini-transplantations represent a relatively mini-advance with the most promising results seen in the indolent lymphomas. This is shown by the phenomena of
mini-transplantation creep, in which the transplants become
less and less "mini" and more and more toxic. Investigation of
different approaches involving infusion of lymphocyte
populations with hematopoietic stem cells, lymphocyte populations
alone, or other putative antitumor cell types should be pursued with
vigor. The bottom line in our studies is that some very gratifying
responses in refractory hematologic malignancies were obtained with
relatively little toxicity. Two of these patients remain free of
disease at 4 and 2-and-a-half years after transplantation.
Karen Ballen and Peter Quesenberry
Correspondence: Karen Ballen, Division of
Hematology/Oncology, Massachusetts General Hospital, 100 Blossom St,
Boston, MA 02114; e-mail: kballen{at}partners.org
References
1.
Ballen K, Becker P, Emmons R, et al.
Low-dose total body irradiation followed by allogeneic lymphocyte infusion may induce remission in patients with refractory hematologic malignancy.
Blood.
2002;100:442-450[Abstract/Free Full Text].
2.
Rao SS, Peters SO, Crittenden RB, Stewart FM, Ramshaw HS, Quesenberry PJ.
Stem cell transplantation in the normal nonmyeloablated host: relationship between cell dose, schedule, and engraftment.
Exp Hematol.
1997;25:114-121[Medline]
[Order article via Infotrieve].
3.
Quesenberry PJ, Zhong S, Wang H, Stewart FM.
Allogeneic chimerism with low-dose irradiation, antigen presensitization, and costimulator blockade in H-2 mismatched mice.
Blood.
2001;97:557-564[Abstract/Free Full Text].
4.
Stewart FM, Zhong S, Wuu J, Hsieh CC, Nilsson SK, Quesenberry PJ.
Lymphohematopoietic engraftment in minimally myeloablated hosts.
Blood.
1998;91:3681-3687[Abstract/Free Full Text].
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Related Article in Blood Online:
-
Low-dose total body irradiation followed by allogeneic lymphocyte infusion may induce remission in patients with refractory hematologic malignancy
- Karen K. Ballen, Pamela S. Becker, Robert V. B. Emmons, Thomas J. Fitzgerald, Chung C. Hsieh, Qin Liu, Christine Heyes, Yeteive Clark, William Levy, Jean Francois Lambert, Frank Chiafari, Irma Szymanski, Sarah Rososhansky, Mark A. Popovsky, F. Marc Stewart, and Peter J. Quesenberry
Blood 2002 100: 442-450.
[Abstract]
[Full Text]
[PDF]
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