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Blood, Vol. 91 No. 6 (March 15), 1998:
pp. 1833-1844
REVIEW ARTICLE
By
From the Clinical Research Division, Fred Hutchinson Cancer Research
Center and University of Washington, Seattle, WA; and the Service
d'Hématologie-Greffe de Moelle and Unité de Recherche sur
la Biologie des Cellules Souches, Hôpital Saint Louis, Paris,
France.
ALTHOUGH MANY ASPECTS of the development
of malignant tumors are still incompletely understood, conditions have
been identified under which malignancies develop at a higher frequency
than in the population at large.1-3 These include, for
example, actinic exposure of the skin and the mutagenic effect of UV
light; genetic disorders such as Fanconi anemia, ataxia telangiectasia,
and immunodeficiency syndromes, which are associated with chromosome
fragility, defects of repair enzymes, or cellular immune defects; a
high incidence of malignancies has also been observed in patients
receiving immunosuppressive therapy after solid organ transplantation;
long-term studies in survivors of the atomic bomb explosions at
Hiroshima and Nagasaki have yielded a wealth of data on the effect of
various doses and qualities (gamma rays or neutrons) of radiation on
the development of malignancies, in particular of the blood-forming
organs.4 Similar observations have been made in patients
who received irradiation for medical indications, eg, acne, ankylosing
spondylitis, and other disorders.5-7 Secondary malignancies
are a well-recognized complication in patients with Hodgkin's disease
or non-Hodgkin's lymphoma treated with chemotherapy or combined
modality treatment.8-10 Certain viruses, such as
Epstein-Barr virus (EBV), which is used in the laboratory to
immortalize cell lines, can transform cells in vivo, which then may
show uncontrolled growth and evolve into malignancies.11-14
Experiments in the 1960s and 1970s in murine models suggested,
furthermore, that a graft-versus-host reaction after allogeneic spleen
cell transplantation could transform from an immunologic to a
neoplastic disorder, ie, the development of lymphoma.15
Finally, marrow transplant studies in rhesus monkeys and dogs in the
1970s and 1980s showed a significant increase in the incidence of
malignancies relative to controls in radiation chimeras, ie, in animals
irradiated with lethal doses of total body irradiation (TBI) and
infused with autologous or allogeneic marrow cells (reviewed in Deeg et
al,16 Broerse et al,17 and Kolb et
al18). Thus, it should not be surprising that new
malignancies occur in patients after hematopoietic stem cell
transplantation, in which one or several of these risk factors are
present. The potential overlapping effects of various factors are shown
schematically in Fig 1. The major
categories of posttransplant malignancies are listed in Table 1.
The majority of cases of PTLD after hematopoietic stem cell
transplantation have been observed in allogeneic (rather than autologous) recipients.19 Most of these PTLD are best
classified as B-cell PTLD rather than non-Hodgkin's
lymphoma.2,11,20-24 In addition, some T-cell PTLD have been
reported. Thirdly, lymphomas with clinical and biological
characteristics typical for non-Hodgkin's lymphoma or Hodgkin's
disease as seen in nontransplanted patients have occurred after stem
cell transplantation. Although lymphoproliferative disorders do not
represent a frequent posttransplant complication, important insights
have been gained into the pathophysiology and considerable progress has
been made in regards to treatment.
B-Cell PTLD
Incidence.
B-cell PTLD are clinically and morphologically heterogeneous; usually
they are associated with T-cell dysfunction and the presence of EBV.
B-cell PTLD have been observed with almost any organ
transplant.12,25-31 Cohen11 recently reviewed
100 well-documented cases, including 32 in marrow transplant
recipients. Additional cases have been described since then, bringing
the total number of PTLD after hematopoietic transplants to about 70 to
100.32-40 In Cohen's review,11 the mean
interval from transplantation to the development of B-cell PTLD was 5 months, with most being diagnosed within 3 months. It appears that
patients transplanted for congenital immunodeficiencies are at a
particularly high risk for PTLD, presumably due to the underlying
immunodeficiency and T-cell depletion of the donor graft generally used
for these diseases (see risk factors). Because the diagnostic criteria
may differ from study to study (eg, a nonlethal infectious
mononucleosis-like syndrome may resolve spontaneously, whereas
acute-onset extensive disease may be diagnosed only at autopsy), the
true incidence of B-cell PTLD after hematopoietic stem cell
transplantation is difficult to determine. In a large single-center
survey (1,400 allografted patients), the cumulative incidence of B-cell
PTLD reached a plateau of 1.6% by 4 years after transplantation; other published data range from 0.6% to 10%.41
Clinical features.
The most frequent presentation of PTLD is with fever and
lymphadenopathy. Intra-abdominal lymphadenopathy, splenomegaly, or hepatomegaly may cause symptoms such as abdominal pain, vomiting, or
diarrhea. Extrahematopoietic organ involvement, including lungs, kidneys, and the central nervous system (CNS), is frequent. CNS involvement is of particular concern, because it has been associated with a dismal prognosis. The differential diagnosis in a symptomatic patient should include PTLD a priori in high-risk situations such as in
recipients of T-cell-depleted or HLA-nonidentical transplants. Early
diagnosis has become important since powerful therapeutic instruments
(see below) have been developed. Early diagnosis can be established and
the effect of therapy can now be monitored by semiquantitative
polymerase chain reaction (PCR) of the EBV DNA (see pathogenesis and
treatment).
Pathology.
B-cell PTLD occurring after allogeneic hematopoietic stem cell
transplantation are almost always of donor origin and associated with
EBV-genomic DNA integration. Biopsies show monomorphic or polymorphic,
diffuse large-cell lymphoma of B-cell origin. However, whereas the
morphology of B-cell PTLD occurring after solid organ transplantation
has been described extensively, few studies have examined in detail the
histologic features of PTLD in hematopoietic stem cell
recipients.37-39,42,43 Those reports show that, whereas some of these PTLD are histopathologically similar to the polymorphic PTLD described in solid organ transplant recipients, as many as half of
the cases after stem cell transplantation show aggressive features of
immunoblastic lymphoma.23 Also, in contrast to PTLD after
organ transplantation, most B-cell PTLD occurring after stem cell
transplantation are oligoclonal or monoclonal, as determined by
analysis of Ig gene rearrangements and fused termini of episomal EBV
DNA,13,23,44-46 although some discrepancies between these two methods (tumors appearing monoclonal on the basis of EBV genomic analysis and polyclonal by analysis of Ig gene rearrangement) have been
observed.44,47,48 PTLD express the full array of latent EBV
antigens, including EBNA-1, -2, -3, -4, -5, and -6 and
LMP1.14,23,49-52 Karyotypic analyses have identified
nonconsistent cytogenetic abnormalities, more frequently in monoclonal
lesions of more aggressive histology. However, with the exception of
two cases of B-cell PTLD developing in heart transplant
recipients,53 the characteristic translocation of
Burkitt's lymphoma has not been observed in lymphoproliferative
disorders developing after marrow (or solid organ) transplantation.
Risk factors.
B-cell PTLD were the first posttransplant malignancies for which risk
factors were identified.21,38,39,54 In 1989, Witherspoon et
al54 showed in multivariate analysis that treatment of
acute graft-versus-host disease (GVHD) with either antithymocyte
globulin or monoclonal anti-CD3 antibody, total body irradiation,
T-cell depletion of donor marrow, and HLA nonidentity between donor and recipient were risk factors for PTLD. A more recent survey by Bhatia et
al41 showed the following factors to be associated with an
increased risk of B-cell PTLD: T-cell depletion of the graft (relative
risk [RR] = 11.9), HLA mismatch (RR = 8.9), use of antithymocyte
globulin for acute GVHD prophylaxis (RR = 5.9) or in the preparative
regimen (RR = 3.1), and primary immune deficiency disease (RR = 2.5).
The cumulative risk of developing a B-cell PTLD in patients with
primary immune deficiency who received a T-cell-depleted
HLA-mismatched transplant was 64.8% ± 17.7% at 4 years, compared
with 0.9% ± 0.2% (P < .001) in patients who received an
HLA-matched transplant with no in vitro manipulation of the graft. The
role of HLA-mismatching in the pathogenesis of B-cell PTLD is not clear
but may consist in chronic antigenic stimulation or delayed immune
reconstitution. In unrelated transplants, the National Marrow Donor
Program (NMDP) reported an incidence of PTLD of 2% overall, 5% in
patients receiving a T-cell depleted marrow, and 1% for those
receiving a T-replete graft.55 However, available data
suggest that the risk is not uniform but depends on the method of
T-cell depletion and the type of additional immunosuppression used in
the posttransplantation period. Although in patients transplanted with
marrow depleted of T cells with specific monoclonal antibodies the
incidence of EBV-positive PTLD ranged from 11% to 25%, the incidence
was less than 1% with techniques removing both T and B lymphocytes
(eg, soybean agglutinin or Campath-1), possibly reflecting the 2 to 3 log reduction in B lymphocytes associated with these
procedures.23,56 However, when additional posttransplant immunosuppression with steroids and antithymocyte globulin was administered after HLA-matched or mismatched related transplants or
transplants from unrelated donors using soybean
agglutination/E-rosetting for T-cell depletion, the incidence of PTLD
increased to 6% to 18%.23 Finally, even in the absence of
in vitro T-cell depletion, the use of intensive in vivo
immunosuppressive prophylaxis or therapy of GVHD, especially with
anti-T-cell agents such as OKT3 antibody or antithymocyte globulin, is
associated with the development of B-cell PTLD.3,57
Pathogenesis.
B-cell PTLD are thought to develop because of depressed EBV-specific
cellular immunity and the inherent transforming capacities of EBV. EBV
is a ubiquitous herpes virus that infects 95% of individuals by
adulthood. The virus persists as a latent infection in certain epithelial cells, where reactivation and replication may occur intermittently, and in B lymphocytes.58 EBV type A and type B have been defined on the basis of sequence divergence in the EBNA-2
gene. In a recent series of 27 solid organ transplant recipients who
developed PTLD, type A EBV was present in 24 of 27 cases (89%) by PCR
amplification of EBNA-2 and EBNA-3c regions. In addition, there was
polymorphism at the EBER locus documenting the presence of four
different type A EBV strains. None of the 27 cases harbored type B
EBV.59 Whether the same applies to marrow transplant recipients remains to be determined.
Prophylaxis and treatment.
Because various recognized risk factors such as initial diagnosis
(primary immune deficiency syndrome) or type of donor
(HLA-nonidentical) cannot be changed and others (eg, GVHD prophylaxis)
are considered an integral part of the overall treatment regimen, it
has been proposed to use early identification of EBV-associated PTLD as an indication for therapy rather than apply true prophylaxis. The St
Jude group used both the outgrowth of transformed B lymphocytes ex vivo
and detection of EBV DNA by a PCR method as tools to detect EBV-associated lymphoproliferation before clinical disease
developed.68 A semiquantitative PCR assay is used to assist
in the detection of EBV DNA in peripheral blood and in monitoring the
effect of therapy.67,69-71
T-Cell Lymphoproliferative Disorders
Late-Onset Lymphoma
MDS and Acute Leukemia After Allogeneic Transplantation In the early 1970s, Fialkow et al95 and Thomas et al96 reported on two patients with acute lymphoblastic leukemia receiving TBI and transplanted with marrow from an HLA-identical sibling donor, who within 2 to 4 months experienced what appeared to be a relapse of their original disease. However, further studies using cytogenetic analysis showed that the leukemic cells were donor-derived. Both donors continued to be healthy. Several similar cases, including patients with acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and chronic myeloid leukemia (CML), were subsequently reported from other institutions (reviewed in Deeg et al97). Conditioning regimens in those patients consisted of chemotherapy only or chemotherapy plus TBI, and the diagnosis of recurrent leukemia in donor cells was made 6 months to more than 3 years after transplantation. Boyd et al98 estimated that as many as 3% to 5% of leukemia recurrences may in fact be new leukemias in donor cells. However, no molecular tools were used in that study.MDS and AML After Autologous Stem Cell Transplantation High-dose chemotherapy and autologous stem cell transplantation are used with increasing frequency in the treatment of non-Hodgkin's lymphoma, Hodgkin's disease, breast cancer, and other indications. Recent randomized trials have shown that this approach is more effective than conventional chemotherapy in patients with chemotherapy-sensitive relapse107 and in some patients with high-risk non-Hodgkin's lymphoma.108,109 Secondary MDS and AML have been observed after conventional chemotherapy and to a lesser extent radiotherapy for Hodgkin's disease and non-Hodgkin's lymphoma.8,110-113 Alkylating agents, epipodophylotoxins, combined modality therapy, and splenectomy have been implicated as risk factors.110 Clearly, therefore, this complication does occur in patients who have not been transplanted, and a thorough evaluation of all transplant candidates, particularly in regard to cytogenetic abnormalties, before autologous transplantation is mandatory.114
Observations in animal models suggested that posttransplant (or
postirradiation) solid tumors occurred with considerable delay, ranging
from 7.5 to 15 years (median, 11.5 years) in x-irradiated and 4 to 15 years (median, 8 years) in rhesus monkeys irradiated with fission
neutrons.17 The time interval in Solid Tumors After Allogeneic Transplants Initial reports, generally on small numbers of patients who had undergone allogeneic (or syngeneic) marrow transplantation, documented the development of some adenocarcinomas of the rectum, brain tumors (glioblastomas) particularly in patients who had also received cranial irradiation (1,800 to 2,400 cGy) before transplantation, squamous cell carcinomas of the skin, and cancers of the oropharyngeal mucosa.97,130 In contrast to PTLD, which generally were diagnosed within 2 to 4 months of transplantation, these solid tumors were observed at 1 to 5 years.1-3
Solid Tumors After Autologous Transplants
Pathogenesis of Solid Posttransplant Tumors Much less is known about the pathogenesis of solid tumors than of PTLDs. However, the interaction of various factors, as shown in Fig 1, appears to apply to these malignancies as well. Using a PCR technique, Socié et al (unpublished observations) found evidence for involvement of human papilloma virus (HPV) 13, 15, or 16 in three of eight tumors examined; HHV8 was detected in one tumor. In addition, the pattern of p53 expression suggested mutations of this gene in all eight tumors studied. Mutations might be induced by cytotoxic therapy, and suppressed immunity would interfere with a normal surveillance. Clearly, considerable work is needed for a better understanding of those questions.Therapy Therapy of solid tumors after transplantation has followed the standards used in nontransplant patients. Experimental studies suggest that selective immunostimulation and measures aimed at scavenging free radicals may be beneficial in preventing tumor development.
The development of new malignancies has long been recognized as a potential complication of cytotoxic therapy, either with chemotherapeutic agents or irradiation. An increased incidence has been observed, eg, in patients treated for Hodgkin's disease, acute leukemia, or solid tumors in childhood. Intensive cytotoxic conditioning therapy is also used in preparation for stem cell transplantation to eradicate the underlying disease. Furthermore, in allogeneic transplants, the conditioning regimen provides immunosuppression, thereby assuring sustained engraftment of donor-derived cells. As a result, transplantation is followed by a period of severe immunodeficiency that is further enhanced, in allogeneic transplants, by immunosuppressive agents administered for prophylaxis or therapy of GVHD. These and other factors (including the primary disease and treatment administered pretransplant) contribute to the development of second malignancies after stem cell transplantation.
Hematopoietic stem cell transplantation offers curative therapy for many patients with otherwise incurable disease. Currently about 20,000 transplants are performed annually and most patients who do not experience a recurrence of their underlying disease within 1 or 2 years of transplantation do well and lead productive lives. However, some complications do occur, one of them being the development of a new malignancy. The incidence of posttransplant malignancies appears to be low overall, although some high-risk situations have been recognized, including an underlying diagnosis of immunodeficiency or other genetic defects, high-dose irradiation for conditioning, T-cell depletion of the marrow, HLA nonidentity of the donor, and chronic GVHD. Although we have begun to develop a good understanding of the mechanism involved in and the frequency of PTLD, information on hematopoietic disorders and solid tumors is much more rudimentary. The time course of development of the various malignancies varies (Fig 2), and longer observation is required before the full extent of the risk of solid tumors can be assessed. Thus, many questions remain. Nevertheless, available data provide a basis on which to develop approaches that may be associated with lower risks.
Submitted August 28, 1997;
accepted October 15, 1997.
The authors thank H.J. Kolb, R.P. Witherspoon, and R. Curtis for their continuing contributions; R. Storb and E. Gluckman for support; A. Fischer and A. Fillipovich for communication of yet unpublished results; B. Larson and H. Childs for typing the manuscript; and E.D. Thomas for providing critical comments.
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G. Socie, N. Salooja, A. Cohen, A. Rovelli, E. Carreras, A. Locasciulli, E. Korthof, J. Weis, V. Levy, and A. Tichelli Nonmalignant late effects after allogeneic stem cell transplantation Blood, May 1, 2003; 101(9): 3373 - 3385. [Full Text] [PDF]
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K. S. Baker, T. E. DeFor, L. J. Burns, N. K.C. Ramsay, J. P. Neglia, and L. L. Robison New Malignancies After Blood or Marrow Stem-Cell Transplantation in Children and Adults: Incidence and Risk Factors J. Clin. Oncol., April 1, 2003; 21(7): 1352 - 1358. [Abstract] [Full Text] [PDF]
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C. Metayer, R. E. Curtis, J. Vose, K. A. Sobocinski, M. M. Horowitz, S. Bhatia, J. W. Fay, C. O. Freytes, S. C. Goldstein, R. H. Herzig, et al. Myelodysplastic syndrome and acute myeloid leukemia after autotransplantation for lymphoma: a multicenter case-control study Blood, March 1, 2003; 101(5): 2015 - 2023. [Abstract] [Full Text] [PDF]
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G. Socie, R. A. Clift, D. Blaise, A. Devergie, O. Ringden, P. J. Martin, M. Remberger, H. J. Deeg, T. Ruutu, M. Michallet, et al. Busulfan plus cyclophosphamide compared with total-body irradiation plus cyclophosphamide before marrow transplantation for myeloid leukemia: long-term follow-up of 4 randomized studies Blood, December 15, 2001; 98(13): 3569 - 3574. [Abstract] [Full Text] [PDF]
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 K. D. Berg, N. K. Brinster, K. M. Huhn, M. G. Goggins, R. J. Jones, A. Makary, K. M. Murphy, C. A. Griffin, L. S. Rosenblum-Vos, M. J. Borowitz, et al. Transmission of a T-Cell Lymphoma by Allogeneic Bone Marrow Transplantation N. Engl. J. Med., November 15, 2001; 345(20): 1458 - 1463. [Full Text] [PDF]
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E. Chklovskaia, C. Nissen, L. Landmann, C. Rahner, O. Pfister, and A. Wodnar-Filipowicz Cell-surface trafficking and release of flt3 ligand from T lymphocytes is induced by common cytokine receptor {gamma}-chain signaling and inhibited by cyclosporin A Blood, February 15, 2001; 97(4): 1027 - 1034. [Abstract] [Full Text] [PDF]
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 H. C. Kluin-Nelemans, V. Zagonel, A. Anastasopoulou, D. Bron, K. J. Roozendaal, E. M. Noordijk, H. Musson, I. Teodorovic, B. Maes, A. Carbone, et al. Standard Chemotherapy With or Without High-Dose Chemotherapy for Aggressive Non-Hodgkin's Lymphoma: Randomized Phase III EORTC Study J Natl Cancer Inst, January 3, 2001; 93(1): 22 - 30. [Abstract] [Full Text] [PDF]
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J. Pedersen-Bjergaard, M. K. Andersen, and D. H. Christiansen Therapy-related acute myeloid leukemia and myelodysplasia after high-dose chemotherapy and autologous stem cell transplantation Blood, June 1, 2000; 95(11): 3273 - 3279. [Abstract] [Full Text] [PDF]
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I. N. M. Micallef, D. M. Lillington, J. Apostolidis, J. A. L. Amess, M. Neat, J. Matthews, T. Clark, J. M. Foran, A. Salam, T. A. Lister, et al. Therapy-Related Myelodysplasia and Secondary Acute Myelogenous Leukemia After High-Dose Therapy With Autologous Hematopoietic Progenitor-Cell Support for Lymphoid Malignancies J. Clin. Oncol., March 1, 2000; 18(5): 947 - 947. [Abstract] [Full Text] [PDF]
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A. Gustafsson, V. Levitsky, J.-Z. Zou, T. Frisan, T. Dalianis, P. Ljungman, O. Ringden, J. Winiarski, I. Ernberg, and M. G. Masucci Epstein-Barr virus (EBV) load in bone marrow transplant recipients at risk to develop posttransplant lymphoproliferative disease: prophylactic infusion of EBV-specific cytotoxic T cells Blood, February 1, 2000; 95(3): 807 - 814. [Abstract] [Full Text] [PDF]
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G. Socie, R. E. Curtis, H. J. Deeg, K. A. Sobocinski, A. H. Filipovich, L. B. Travis, K. M. Sullivan, P. A. Rowlings, D. W. Kingma, P. M. Banks, et al. New Malignant Diseases After Allogeneic Marrow Transplantation for Childhood Acute Leukemia J. Clin. Oncol., January 14, 2000; 18(2): 348 - 348. [Abstract] [Full Text] [PDF]
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L. I. Gordon, M. Young, E. Weller, T. M. Habermann, J. N. Winter, J. Glick, C. Ghosh, P. Flynn, and P. A. Cassileth A Phase II Trial of 200% ProMACE-CytaBOM in Patients With Previously Untreated Aggressive Lymphomas: Analysis of Response, Toxicity, and Dose Intensity Blood, November 15, 1999; 94(10): 3307 - 3314. [Abstract] [Full Text] [PDF]
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P. A. Rowlings, R. E. Curtis, J. R. Passweg, H. J. Deeg, G. Socie, L. B. Travis, D. W. Kingma, E. S. Jaffe, K. A. Sobocinski, and M. M. Horowitz Increased Incidence of Hodgkin's Disease After Allogeneic Bone Marrow Transplantation J. Clin. Oncol., October 1, 1999; 17(10): 3122 - 3127. [Abstract] [Full Text] [PDF]
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R. E. Curtis, L. B. Travis, P. A. Rowlings, G. Socie, D. W. Kingma, P. M. Banks, E. S. Jaffe, G. E. Sale, M. M. Horowitz, R. P. Witherspoon, et al. Risk of Lymphoproliferative Disorders After Bone Marrow Transplantation: A Multi-Institutional Study Blood, October 1, 1999; 94(7): 2208 - 2216. [Abstract] [Full Text] [PDF]
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M. Subklewe, A. Chahroudi, A. Schmaljohn, M. G. Kurilla, N. Bhardwaj, and R. M. Steinman Induction of Epstein-Barr Virus-Specific Cytotoxic T-Lymphocyte Responses Using Dendritic Cells Pulsed With EBNA-3A Peptides or UV-Inactivated, Recombinant EBNA-3A Vaccinia Virus Blood, August 15, 1999; 94(4): 1372 - 1381. [Abstract] [Full Text] [PDF]
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Introduction
References
end of the LMP-1 gene, in a region that
affects the half-life of the LMP-1 protein, have been reported in some
EBV-related lymphoproliferative disorders60,61; B-cell PTLD
after marrow or stem cell transplantation have not been analyzed yet.
interferon, B-cell-specific monoclonal antibodies, and cellular therapy. A combination of 
unless we postulate that TBI modifies the microenvironment in a
way that enhances the risk of leukemogenesis. However, if the
development of MDS/AML is related to the transplant procedure, we need
to ask the following questions. Is it the procedure itself or, eg, the
status of immunoincompetence following the transplant that contributes
to the development of MDS? Do peripheral blood stem cells modify the
milieu in a way different from marrow? Investigations into the function
of growth factor mobilized peripheral blood stem cells show indeed
cellular function (T cells and monocytes) and cytokine patterns
different from marrow.
-irradiated dogs was
1.6 to 10.5 years (median, 8 years).
Introduction