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Blood, Vol. 91 No. 3 (February 1), 1998:
pp. 756-763
Nonmyeloablative Stem Cell Transplantation and Cell Therapy as an
Alternative to Conventional Bone Marrow Transplantation With Lethal
Cytoreduction for the Treatment of Malignant and Nonmalignant
Hematologic Diseases
By
Shimon Slavin,
Arnon Nagler,
Ella Naparstek,
Yossi Kapelushnik,
Memet Aker,
Gabriel Cividalli,
Gabor Varadi,
Mark Kirschbaum,
Aliza Ackerstein,
Simcha Samuel,
Avraham Amar,
Chaim Brautbar,
Ofira Ben-Tal,
Amiram Eldor, and
Reuven Or
From The Departments of Bone Marrow Transplantation and The Cancer
Immunotherapy & Immunobiology Research Center, Pediatrics, and Tissue
Typing Unit, Hadassah University Hospital, Jerusalem; and the Division
of Hematology, the Department of Medicine, Ichilov Hospital, Tel Aviv,
Israel.
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ABSTRACT |
Myeloablative conditioning associated with hazardous immediate and
late complications is considered as a mandatory first step in
preparation for allogeneic blood or marrow transplantation (allogeneic
BMT) for the treatment of malignant hematologic disorders and genetic
diseases. Immune-mediated graft-versus-leukemia (GVL) effects
constitute the major benefit of allogeneic BMT. Therefore, we have
introduced the use of relatively nonmyeloablative conditioning before
allogeneic BMT aiming for establishing host-versus-graft tolerance for
engraftment of donor immunohematopoietic cells for induction of GVL
effects to displace residual malignant or genetically abnormal host
cells. Our preliminary data in 26 patients with standard indications
for allogeneic BMT, including acute leukemia (n = 10); chronic
leukemia (n = 8), non-Hodgkin's lymphoma (n = 2), myelodysplastic syndrome (n = 1), multiple myeloma (n = 1),
and genetic diseases (n = 4) suggest that nonmyeloablative
conditioning including fludarabine, anti-T-lymphocyte globulin, and
low-dose busulfan (8 mg/kg) is extremely well tolerated, with no severe procedure-related toxicity. Granulocyte colony-stimulating factor mobilized blood stem cell transplantation with standard dose of cyclosporin A as the sole anti-graft-versus-host disease (GVHD) prophylaxis resulted in stable partial (n = 9) or complete
(n = 17) chimerism. In 9 patients absolute neutrophil count (ANC)
did not decrease to below 0.1 × 109/L whereas 2 patients
never experienced ANC <0.5 × 109/L. ANC  0.5 × 109/L was accomplished within 10 to 32 (median, 15) days.
Platelet counts did not decrease to below 20 × 109/L in 4 patients requiring no platelet support at all; overall platelet counts
>20 × 109/L were achieved within 0 to 35 (median 12)
days. Fourteen patients experienced no GVHD at all; severe GVHD (grades
3 and 4) was the single major complication and the cause of death in 4 patients, occurring after early discontinuation of cyclosporine A. Relapse was reversed by allogeneic cell therapy in 2/3 cases, currently with no residual host DNA (male) by cytogenetic analysis and polymerase chain reaction. To date, with an observation period extending over 1 year (median 8 months), 22 of 26 patients (85%) treated by allogeneic
nonmyeloablative stem cell transplantation are alive, and 21 (81%) are
disease-free. The actuarial probability of disease-free survival at 14 months is 77.5% (95% confidence interval, 53% to 90%). Successful
eradication of malignant and genetically abnormal host hematopoietic
cells by allogeneic nonmyeloablative stem cell transplantation
represents a potential new approach for safer treatment of a large
variety of clinical syndromes with an indication for allogeneic BMT.
Transient mixed chimerism which may protect the host from severe acute
GVHD may be successfully reversed postallogeneic BMT with graded
increments of donor lymphocyte infusions, thus resulting in eradication
of malignant or genetically abnormal progenitor cells of host origin.
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INTRODUCTION |
MYELOABLATIVE COMBINATIONS of high-dose
chemo-radiotherapy followed by rescue with autologous or allogeneic
bone marrow transplantation (BMT) blood or marrow-derived stem cell
transplantation are common modalities to treat various hematologic
malignancies resistant to conventional doses of chemotherapy. For
patients relapsing after conventional front-line chemotherapy protocols
or for patients that are considered at high risk to relapse as well as
for patients with genetic diseases, alloBMT is the treatment of choice.
The use of myeloablative doses of chemotherapy with or without total body irradiation (TBI) followed by rescue with allogeneic BMT offers an
important advantage in the form of alloreactivity against host leukemia
cells, the so-called graft-versus-leukemia (GVL) effects,1,2 and perhaps even graft-versus-tumor (GVT)
effects,3,4 which may be associated with undesirable
graft-versus-host disease (GVHD). For patients with underlying
malignancies, the transplant procedure is considered mostly as a rescue
procedure following myeloablative treatment to eradicate the basic
malignancy by the cytoreductive agents given within the short period of
conditioning before autologous or allogeneic BMT. In patients with
genetic disorders, myeloablative doses of cytoreductive agents are used to eradicate genetically abnormal stem cells before allogeneic BMT.
Attempts to improve the disease-free survival by increasing the
intensity of the conditioning regimen, thereby eradicating host-derived
stem cells more effectively, have resulted in unacceptable toxicity. It
seems unlikely that a substantial improvement in the treatment of
high-risk hematologic malignancies, which may require eradication of
all tumor cells, may be accomplished merely by increasing the intensity
of the conditioning based on the well known "log-dose"
relationship between the dose of cytoreductive agents and the degree of
tumor cell kill. Moreover, by comparing numerous protocols comprising a
wide range for intensities for each of the cytoreductive components
used for over 20,000 transplants reported to the International Bone
Marrow Transplant Registry, no difference or clear advantage could be
documented for different regimens administered as preparation for
autologous BMT or allogeneic BMT, including or excluding
TBI.5 The potential benefits of more intensive
chemo-radiotherapy may be further exploited in the future by using
targeted chemotherapy or targeted radiolabeled tumor-seeking compounds.
Over the years, the importance of immune reactions between
donor-derived immunocompetent T lymphocytes and host-type tumor cells
has been recognized to be of major therapeutic importance, accounting
for the significantly better antitumor effects induced by allogeneic
BMT compared with autologous BMT and transplants from an identical
twin.1,2 Moreover, we have shown in early 1987, as
confirmed in many transplant centers worldwide since, that relapse
after allogeneic BMT in patients considered incurable can be frequently
reversed by donor lymphocyte infusion (DLI).6-10 All this
indicates that the main therapeutic component of allogeneic BMT may be
ascribed to T-cell-mediated GVL effects rather than to physical
elimination of all tumor cells by high doses of cytoreductive agents
given as part of the conditioning before transplantation. The
possibility to completely eradicate tumor cells by adoptive allogeneic
cell therapy induced by DLI in patients failing all alternative
modalities suggests that alloreactive T lymphocytes of donor origin may
be the strongest tool available against tumor cells of hematopoietic
origin. Hence, the main role of the transplant procedure may be in the
induction of a state of host-versus-graft tolerance giving
donor-derived T lymphocytes the opportunity to recognize and eradicate
host-derived tumor cells or abnormal stem cells without
immunosuppressive treatment as anti-GVHD prophylaxis. This working
hypothesis prompted us to develop a new approach to the treatment of
diseases generally referred to conventional allogeneic BMT, focusing on
the use of donor T cells to eradicate both nonmalignant and malignant
cells of host origin, thus avoiding the need for myeloablative
conditioning, to improve the immediate and long-term outcome of the
patients. Our working hypothesis is based on experiments in animal
models of lymphocytic leukemia/lymphoma11-13 and acute
myeloid leukemia14 and on clinical observations over the
past 10 years, documenting that the efficacy of allogeneic cell therapy
induced by the allograft is the key element in accomplishing the
benefits the alloBMT procedure.8,9 A protocol was designed based on minimizing the intensity of the conditioning regimen to the
range of nonmyeloablative treatment, followed by infusion of
granulocyte colony-stimulating factor (G-CSF)-mobilized donor stem
cells enriched with circulating T lymphocytes collected by apheresis
using Baxter's CS 3000plus. The main focus is
on intensive short-term immunosuppression with fludarabine and
anti-T-lymphocyte globulin (ATG) with low-dose oral busulfan before
infusion of blood stem cells. GVL effects are mediated by the large
number of donor-derived immunocompetent T lymphocytes given together
with donor stem cells. GVL effects may be increased later on, by
allogeneic cell therapy with DLI on an outpatient basis. As will be
shown below, our preliminary experience seems promising and suggests
that allogeneic nonmyeloablative stem cells may result in complete
elimination of malignant or abnormal host cells with no or minimal
procedure-related toxicity. This approach may be safely offered to
patients of all age groups with low anticipated incidence of immediate
and long-term complications.
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PATIENTS AND METHODS |
A cohort of 26 consecutive patients undergoing allogeneic
nonmyeloablative stem cell transplantation is presented, all of whom were given a combination of fludarabine and ATG. Patients' characteristics are described in Table 1.All patients would have been considered eligible candidates for
conventional myeloablative allogeneic BMT, including 6 with chronic
myelogenous leukemia in first chronic phase (CML/CP); 1 with CML in
accelerated phase (CML/AP); 1 with juvenile CML (JCML); 7 with acute
myelogenous leukemia (AML) in first complete remission (CR), 1 of whom
with secondary leukemia (AML, M5) 3 years after treatment for carcinoma of the ovary and 1 with AML in second CR; 1 with acute lymphoblastic leukemia (ALL) in first CR and 1 in second CR; 2 with non-Hodgkin's lymphoma (NHL) resistant to chemotherapy; 1 with myelodysplastic syndrome (MDS) with excess blasts; and 1 with multiple myeloma (MM).
The series also included 4 patients with nonmalignant disorders including 1 child with severe  -thalassemia major, 1 child with Fanconi's anemia, 1 child with Gaucher's disease, and 1 adult with
Blackfan Diamond syndrome (Table 1). Patient age ranged between 1 and
61 (median, 31) years. Conditioning before infusion of allogeneic stem
cells included immunosuppressive treatment with six daily infusions of
fludarabine (Fludara; Schering AG, Berlin, Germany) 30 mg/m2 (in adults the dose was adjusted to
ideal body weight) for 6 consecutive days (days  10 to 5); oral
busulfan 4 mg/kg/d for 2 consecutive days (days 6 to 5); and
anti-T-lymphocyte globulin (ATG-Fresenius AG, Munich, Germany) 10 mg/kg/d for 4 consecutive days (days 4 to 1). One patient (unique
patient number [UPN] 111 with Fanconi's anemia) received cytoxan 10 mg/kg instead of busulfan. G-CSF-mobilized blood stem cells were
collected once after 5 days of administration of G-CSF 10 µg/kg/d.
HLA-A,B,C,DR,DRB1 matched siblings were used as donors, with one
exception: UPN 1109 was grafted with A and C locus mismatches with
positive mixed lymphocyte reaction in the direction of
host-versus-donor. The total number of nucleated cells infused on day 0 ranged between 3.38 and 16.39 (mean, 8.60) × 108/kg.
Prophylaxis against GVHD included cyclosporine A (CSA) 1.5 mg/kg twice
daily intravenously starting on day 1, switching to an oral dose of
3 mg/kg twice daily as soon as the patients were off intravenous
therapy or as soon as they were discharged, with early tapering off,
starting as soon as engraftment with no GVHD was confirmed (around 4 to
6 weeks) and the patient's condition stabilized. Prophylaxis against
Pneumocistis carinii included trimethoprim/sulfamethoxazole (10 mg/kg/d trimethoprin) administered pretransplantation (days 10 to
1) and as soon as the absolute neutrophil counts (ANCs) exceeded
0.75 × 109/L (7 mg/kg/d trimethoprim) twice weekly.
Prophylaxis against Herpes simplex virus included low-dose oral
acyclovir 200 mg ×3/d starting on day 10 for 4 months.
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Table 1.
Characteristics of the First Cohort of Standard-Risk
Patients Undergoing Allogeneic Nonmyeloablative Stem Cell
Transplantation With Matched Related Donors
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Chimerism was assessed by standard cytogenetic analysis in male/female
donor-recipient combinations and in patients with CML, searching for
the proportion of Ph+ cells, to assess the actual
proportions of host and donor cells in marrow aspirates, representing
hematopoietic cells in mitosis. Residual male cells in female to male
chimeras were detected by the amelogenine gene method as previously
described in detail.15 In sex-matched donor-recipient
combinations, the various number of tandem repeats (VNTR)-polymerase
chain reaction (PCR) test with a sensitivity of detection
of 5% was used to assess the presence of residual host or donor cells
as previously described.16
Statistical evaluation.
The Kaplan-Meier method was used to calculate the probability of
disease-free survival as a function of time as well as for determining
the time to recovery of hematopoietic reconstitution.
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RESULTS |
The allogeneic nonmyeloablative stem cell transplantation protocol was
much better tolerated in comparison with the anticipated side effects
following a standard myeloablative regimen. As can be seen in Table
2, listing common procedure-related toxic
manifestations, following allogeneic nonmyeloablative stem cell
transplantation no grade 3 or 4 toxicity (World Health Organization
[WHO] criteria) were observed in any of the recipients. Grade 2 mucositis was documented in only 2 cases. All patients maintained oral
intake throughout the procedure, with 8 (31%) never requiring any
parenteral caloric supplements. Septic fever episodes with positive
blood cultures were observed in 4 cases, whereas 22 patients
experienced no evidence of severe culture-positive systemic infection.
Severe veno-occlusive disease (VOD) of the liver was observed in 2 cases whereas 11 developed mild to moderate manifestations of VOD and 13 patients showed no evidence of hepatic abnormality. No pulmonary toxicity was observed in this cohort of patients.
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Table 2.
Common Transplant Related Complications in the First
Cohort of Patients Undergoing Allogeneic Nonmyeloablative Stem Cell
Transplantation
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Additional important clinical parameters following allogeneic
nonmyeloablative stem cell transplantation in the first cohort of
patients who entered our study is shown in Table 3 and Fig 1. In 9 patients (34%) ANC did not decrease to below 0.1 × 109/L, and for the entire group it took a median of 10 days
for the ANC to drop below 0.1 × 109/L (Fig 1A). Two
patients never experienced ANC <0.5 × 109/L (Table 3).
The number of days with ANC <0.1 × 109/L in the
remaining 17 patients ranged between 0 and 20, with a median of 4 days.
ANC >0.5 × 109/L was accomplished within 10 to 32 (median, 15) days (Fig 1B). Platelet counts did not decrease to
below 20 × 109/L in 4 patients (Table 3), therefore
requiring no platelet support at all. Among the remaining 22 patients,
a decrease of platelet count to below 20 × 109/L was
observed after a median of 7 days, with 11% probability of remaining
with a low (<20 × 109/L) platelet count after day 11 (95% confidence interval of 3% to 27%) (Fig 1C). Spontaneous
platelet counts >20 × 109/L were achieved within 0 to
35 (median 12) days. Unsupported platelet counts >20 × 109/L was observed within 36 days in 85% of the patients
(95% confidence interval, 69% to 95%) (Fig 1D).
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Table 3.
Pertinent Clinical Data on the Outcome Following
Allogeneic Nonmyeloablative Stem Cell Transplantation, Including
Evidence for Engraftment, Acute and Chronic GVHD, Mixed Chimerism, and Outcome in Response to Allogeneic Cell-Mediated Immunotherapy
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| Fig 1.
Duration and degree of pancytopenia and engraftment of
HLA-identical G-CSF-mobilized blood stem cell allografts after
nonmyeloablative conditioning, expressed as cumulative percentage of
patients who never featured ANC < 0.1 × 109/L (A) or
ANC < 0.5 × 109/L; cumulative percentage of patients
with platelet counts below 20 × 109/L (C) and patients
with platelet counts never going below 20 × 109/L that
never required any platelet transfusion (D).
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GVHD grade 1 was observed in 12 of 26 patients (Table 3). Severe
GVHD (grades 3 and 4) was the single major complication, diagnosed in 6 cases (25%) and was the only cause of mortality in 4 patients, all of
whom developed the first signs of disease while off of CSA.
Interestingly, acute GVHD developed in only 4 patients while on regular
CSA maintenance therapy (only 1 patient with grade 3 GVHD, UPN 1109, currently alive and well). In 8 cases initiation of GVHD was observed
only following sudden discontinuation of CSA in an attempt to enhance
engraftment or displace residual host cells, documented by molecular or
cytogenetic analysis. The 4 patients who died from severe GVHD,
considered protocol failure, account for all the losses observed in the
entire series, with an observation period exceeding 1 year (median 8 months). In one of the patients (UPN 1093) who died of grade 4 GVHD,
which developed while she was off of CSA in a foreign country, access
to follow-up or further CSA treatment was denied; therefore, her death
may not be considered a protocol failure. The second patient (UPN 1124)
died of GVHD grade 4 that developed immediately after discontinuation of CSA and re-infusion of a second inoculum of mobilized stem cells
enriched with blood T cells given intentionally without CSA on day +22
in an attempt to enhance delayed granulocyte engraftment. Subsequently,
granulocyte counts increased within less than a week after the second
inoculum and reached ANC > 0.5 × 109/L on day +35,
suggesting that stem cell top-up may not only have been redundant, but
most likely may have contributed to the severity of GVHD, which could
be also due in part to the first BMT procedure, which resulted in
unavoidable fatal outcome. The third and forth patients with CML (UPNs
1131 and 1135) also developed grade 4 GVHD after sudden discontinuation
of CSA. All the other 8 patients who developed GVHD, of which only 3 manifested >grade 2 GVHD, responded to standard prednisone treatment
starting with 2 mg/kg with slow tapering off, as clinically indicated.
Engraftment was documented in all patients by increasing blood counts
as shown in Table 2, using either amelogenin-PCR for detection of
residual male cells in a female recipient (sensitivity of 1 male cell
in 106 female cells) as well as for detectio of mixed
chimerism on a semiquantitative basis in sex-mismatched host-donors,
because using this assay we could detect the presence of 1% to 30%
male cells compared with greater than 30% male cells.15
VNTR-PCR was used in sex-matched donor-recipient pairs with a
sensitivity of 1 in 20 cells. In 9 of 26 evaluable patients, a
transient stage of mixed chimerism was confirmed by documenting minimal
residual host cells by cytogenetic analysis, PCR, or disease-specific
reverse transcriptase (RT)-PCR (eg, bcr-abl in CML). In confirmed mixed chimeras with no GVHD CSA was rapidly discontinued, within 2 to 4 weeks.
No conclusive data can be given at this point to assess the total
incidence of chronic GVHD in allogeneic nonmyeloablative stem cell
transplantation-treated recipients because of the relatively short
observation period ranging from several months to over 1 year. As can
be seen in Table 3, chronic GVHD was diagnosed in 9 patients, in 2 of
which (UPNs 1073 and 1098) signs of GVHD appeared only after initiation
of allogeneic cell therapy.
Relapse was observed in 2 patients with acute leukemia (UPNs 1073 and
1080) whereas rapidly progressive residual disease was observed in 1 patient with NHL totally resistant to chemotherapy (UPN 1098).
Cytogenetic relapse with normal blood counts was diagnosed in 1 patient
with CML who developed no spontaneous GVHD even after discontinuation
of CSA. The patient is now under allogeneic cell therapy (UPN 1137).
Successful displacement of tumor cells by allogeneic cell therapy was
already accomplished in 2 cases (UPNs 1080 and 1098) while 1 patient is
still under treatment, too early for evaluation (Table 2). UPN 1080, a
male recipient originally treated for ALL in second CR, featured no
GVHD after allogeneic nonmyeloablative stem cell transplantation,
developed overt hematologic relapse at 4 months with the number of
blasts doubling within 1 to 2 days. The large tumor mass was
successfully debulked using a combination of cytosine arabinoside 3 g/m2/d in two split doses for 4 days and a single dose of
mitoxantron 12 mg/m2, followed by re-infusion of
lymphocyte-enriched donor (female) blood stem cells with no CSA.
Elimination of detectable male cells was confirmed by PCR analysis in
parallel with GVHD (grade 1-2) induced after DLI, with stable CR being
maintained to date with no further treatment. Because this patient
received chemotherapy for debulking of rapidly developing leukemia
cells before DLI, the data should be interpreted with some reservations
because chemotherapy, rather than allogeneic cell-mediated
immunotherapy, may have played a major role as well. In UPN 1098, an
elderly male patient with chemotherapy-resistant NHL, with rapidly
progressive malignant lymphoid infiltrate in the marrow and bone
neuralgia, with no spontaneous GVHD following allogeneic
nonmyeloablative stem cell transplantation, elimination of all disease
manifestations was confirmed after allogeneic cell therapy with DLI in
parallel with disappearance of host/male DNA by PCR and documentation
of 100% female karyotype, in parallel with onset of mild acute GVHD grade 2 that evolved to mild limited chronic GVHD. Another patient (UPN
1073) with AML in second CR relapsed 9 months following allogeneic nonmyeloablative stem cell transplantation. She is currently under combined treatment with chemotherapy and allogeneic cell therapy.
All 4 patients with nonmalignant indication for alloBMT are currently
alive and well, with a Karnofsky score of 100% with no evidence of the
basic disease, fully reconstituted with donor cells and no residual
host cells by male-specific PCR or VNTR-PCR.
To date, with an observation period extending over 1 year (median, 8 months), 22 of 26 patients (85%) treated by allogeneic nonmyeloablative stem cell transplantation are alive, 21 (81%) disease-free by all measurable criteria, including PCR, with excellent quality of life, and a Karnofsky score of 100%. It is too early to
assess the actuarial disease-free survival at the present time, but the
actual disease-free survival at a median follow-up of 8 months was
80.7% (at 14 months the actuarial disease-free survival was 77.5%
with a 95% confidence interval of 53% to 90%) (Fig
2). The data should be carefully
interpreted in view of the short observation period available.
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| Fig 2.
Kaplan-Meier actuarial disease-free survival at 14 months
of the entire group of 26 patients treated with allogeneic
nonmyeloablative stem cell transplantation.
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Mild and limited chronic GVHD developed in 9 of 25 patients with an
observation period greater than 100 days, but thus far none have
developed clinically significant disease manifestations.
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DISCUSSION |
Our study shows that elimination of malignant and genetically abnormal
hematopoietic cells of host origin can be achieved with a safe and
well-tolerated nonmyeloablative conditioning in patients with acute and
chronic leukemia, lymphoma, multiple myeloma, and nonmalignant diseases
including -thalassemia major, Blackfan Diamond anemia, Fanconi's
anemia, and Gaucher's disease. The principle behind the new allogeneic
nonmyeloablative stem cell transplantation protocol, presented here for
the first time, is to maximize transient immunosuppression with
nonmyeloablative agents rather to attempt to eradicate all tumor cells
or genetically abnormal stem cells which are expected to be eliminated
over time by alloreactive T cells of donor origin. Thus, we have chosen
a combination of fludarabine and anti-T-lymphocyte globulin raised in
rabbits against Jurkat cell line with reproducible and stable
expression of cell-surface proteins which induce more specific activity
against activated T lymphocytes. No procedure-related mortality was
reported thus far and all 4 deaths observed were due to acute GVHD,
which may have resulted in part from inadequate preventive measures
with CSA, including early withdrawal and a possibly redundant top-up with a second blood stem cell allograft with no CSA prophylaxis (UPN
1124). At least 2 of the 4 relapses observed, in patients with rapidly
progressive chemotherapy-resistant disease, responded to allogeneic
cell therapy, which further supports the important role and efficacy of
T-cell-mediated immunotherapy in recipients rendered tolerant to donor
cells without interference of immunosuppressive agents such as CSA. It
should be taken into consideration that early molecular or cytogenetic
relapse within 4 to 6 months of allogeneic nonmyeloablative stem cell
transplantation would not be considered a relapse at such an early
stage, even after lethal conditioning.17
Because of the short observation period and the relatively small cohort
of recipients, our data have to be carefully evaluated with no
over-interpretation. However, our working hypothesis, based on earlier
observations,6-10 seems to be supported by the encouraging
data. Until recently it was believed that the main goal of allogeneic
BMT and especially autologous BMT is to enable abrogation of
host-derived tumor cells or genetically abnormal hematopoietic cells by
administration of maximally tolerated doses of myeloablative
chemo-radiotherapy, while the transplant merely serves as a rescue
procedure. Hence, over the years the goal has been to maximize the
intensity of the conditioning, to kill all or as many tumor cells or
genetically abnormal host cells as possible. We suggest that the main
role of the transplant procedure is induction of donor-specific
unresponsiveness in the host that can be effectively induced by donor
stem cells, thereby enabling acceptance of donor-derived immune cells.
Development of host-versus-graft tolerance allows optimal secondary
adoptive immunotherapy with immunocompetent donor T lymphocytes in case
alloreactive donor T cells present in the graft leave tumor cells
behind. Although induction of GVL can be initially accomplished by
T-lymphocyte-enriched donor-derived stem cells, due to concomitant
administration of CSA as mandatory anti-GVHD prophylaxis some of the
GVL effect may be suppressed. After induction of donor-specific
transplantation tolerance by allogeneic nonmyeloablative stem cell
transplantation, pending absence of GVHD following discontinuation of
CSA or other immunosuppressive agents, immunocompetent T lymphocytes
obtained from the donor can be added in graded increments while
controlling for disappearance of tumor/host cells on the one hand and
signs of GVHD on the other.
Our working hypothesis is supported by many observations in rodents.
The use of allogeneic cell therapy for eradication of tumor cells in
tolerant recipients is well established.11-14 Likewise, Quesenberry et al18,19 have already documented the
feasibility of engraftment of BM cells with establishment of mixed
chimerism in nonmyeloablated recipients when no allogeneic barriers
exist, although with a much lower proportion of donor-derived cells. Furthermore, we have more than 10 years of clinical experience with
patients relapsing after allogeneic BMT, suggesting that allogeneic
cell therapy may displace and eradicate malignant and normal stem cells
of host origin, even in patients who were considered incurable until
recently.6,8,9 Many of these patients can now be rescued,
most probably cured, by DLI or more aggressive allogeneic cell therapy
program,9 provided that alloreactive immunocompetent
donor-type blood lymphocytes are given to chimeric, tolerant
recipients, sometimes even patients failing myeloablative doses of
common anti-cancer modalities who receive no immunosuppressive agents
such as CSA.6,8,9 The negative effects of CSA on GVL
effects were previously documented in experimental
animals20 and humans.21 The success rate of
allogeneic cell therapy increases if DLI is administered as soon as
relapse is apparent, preferably at the stage of minimal residual
disease (MRD).9 Because the use of DLI was accepted as a
standard rescue procedure6-10 in patients relapsing after
allogeneic BMT, it follows that relapse may not only be treated but be
more effectively prevented by DLI.22 Thus, prevention
rather than treatment of relapse can become the standard goal in
treating high-risk hematologic malignancies as soon as remission is
established. The present clinical study indicates that allogeneic
nonmyeloablative stem cell transplantation may become one of the
protocols to accomplish this goal, because treatment of MRD instead of
bulky disease is certainly easier, much more promising, and
cost-effective.
Recently, we have shown that adoptive allogeneic cell therapy based on
DLI may also successfully displace residual hematopoietic cells of host
origin in patients undergoing allogeneic BMT for nonmalignant diseases
such as -thalassemia major23 and infantile osteopetrosis (M. Aker, S. Slavin, unpublished observations,
1995). Immunocompetent T lymphocytes, present in mobilized
blood stem cells, may also displace residual host-type genetically
abnormal hematopoietic cells following allogeneic nonmyeloablative stem cell transplantation. The proportion of donor cells may be increased by
allogeneic cell therapy if needed to further displace host-type hematopoietic cells and increase the proportion of donor stem cells.
Indeed, as shown here, allogeneic nonmyeloablative stem cell
transplantation was successful in all 4 cases attempted (Tables 1 and
3), suggesting that this approach may successfully replace the need for
aggressive conditioning, especially in infants and children, thus
possibly reducing late complications that are inevitable following
conventional myeloablative conditioning. Interestingly, as can be seen
in Table 3, severe GVHD was not an essential requirement for
replacement of all host with donor hematopoietic cells, suggesting that
in principle, successful allogeneic BMT may be accomplished with
reduced conditioning while avoiding severe GVHD. Attention must now be
given to improve the technology by careful prevention of GVHD by more
carefully controlling post-BMT immunosuppression, or alternatively by
improving the conditioning or the composition of the graft (ie,
reducing the T-cell number or inactivating their alloreactive
potential).
The protocol described here seems to be effective for all candidates
eligible for any standard allogeneic BMT procedure. Furthermore, allogeneic nonmyeloablative stem cell transplantation was well tolerated, certainly better than any standard myeloablative
conditioning, with no major procedure-related toxicity. Based on our
preliminary experience, that needs to be confirmed in a larger series
of patients observed for a longer time period, major advantages are to
be expected if it can be confirmed that allogeneic nonmyeloablative stem cell transplantation can safely replace allogeneic BMT. Because of
the patients' excellent general feeling throughout the procedure, independence of hyperalimentation and the low incidence of common immediate complications (mucositis; fever due to intercurrent infections with no or shorter period of agranulocytosis; shorter period
of platelet dependence; smaller risk of severe veno-occlusive disease
of the liver, interstitial pneumonitis, and multi-organ failure resulting from combination of some or all of the above) we
anticipate that allogeneic nonmyeloablative stem cell transplantation may eventually become an outpatient procedure. Perhaps even more important, the state of transient or stable mixed chimerism that results from allogeneic nonmyeloablative stem cell transplantation may
help design newer strategies for better control of GVHD.
The use of allogeneic nonmyeloablative stem cell transplantation may
also help bypass frequent late complications that result from the
combined effects of high-dose chemo-radiotherapy in addition to prior
conventional treatments, especially in the low- and high-age groups. In
the low-age group, in contrast to myeloablative allogeneic BMT,
allogeneic nonmyeloablative stem cell transplantation may reduce the
incidence of growth retardation and infertility due to the unique
sensitivity to chemoradiotherapy of the growth centers in the bones,
the gonads, and testicles. Indeed, early recovery of menstrual bleeding
observed in a 19-year-old woman (data not shown) was encouraging in
this regard. In elderly individuals, who normally may not be eligible
for a standard alloBMT, allogeneic nonmyeloablative stem cell
transplantation may permit a relatively safe clinical application of a
potentially curative procedure based primarily on adoptive
immunotherapy rather than high-dose chemo-radiotherapy.
In the long run, induction of a state of mixed chimerism, as shown in
Table 3, may help reduce the incidence and severity of GVHD. Based on
animal data, mixed chimerism seems to be a reliable recipe for
engraftment of allogeneic hematopoietic cells while avoiding GVHD, as
was previously shown by our earlier work24,25 and confirmed
by others.26,27 Apparently, as suggested by experimental data in mice, host hematopoietic cells can veto donor antihost alloreactivity while donor hematopoietic cells can veto residual alloreactive host cells, hence explaining why mixed chimeras can result
in bilateral transplantation tolerance.24-27
Following a similar rationale, the M.D. Anderson group has also
attempted the use of low-toxicity regimen, confirming the feasibility
to induce chimerism without the use of myeloablative regimen using
different compounds in the course of the conditioning.28 Their engraftment rate appears significantly lower, most likely due to
lack of use of anti-T-lymphocyte Ig, as done in the present series.
Availability of a relatively safe protocol for adoptive cell therapy
using matched allogeneic stem cells and T cells may offer treating
physicians another therapeutic tool that may be considered with fewer
hesitations for a larger number of patients in need at an optimal stage
of their disease. Many clinicians would agree that as far as using
chemotherapy and other available cytoreductive anticancer agents,
whatever cannot be achieved at an early stage of treatment is unlikely
to be accomplished later. In addition to preventing the development of
resistant tumor cell clones by continuous courses of conventional doses
of chemotherapy, clinical application of a final curative modality at
an earlier stage of disease may avoid the need for repeated courses of
chemotherapy with cumulative multi-organ toxicity, while preventing
development of platelet resistance induced by repeated sensitization
with blood products and development of resistant strains of various infective agents that frequently develops in the course of
antimicrobial protocols given for treatment of infections that are
unavoidable during repeated courses of conventional anticancer
modalities.
In summary, we propose that immunotherapy mediated by allogeneic
lymphocytes in tolerant hosts at an early stage of the disease, for
every patient with a fully matched sibling, may result in a significant
improvement of disease-free survival, quality of life, and
cost-effectiveness for candidates of allogeneic BMT. Once confirmed,
these observations may open new avenues for the treatment of
hematologic malignancies and genetic diseases at an earlier stage of
the disease, avoiding the need for repeated courses of chemotherapy or
alternative replacement therapy, respectively. Tumor cells or
genetically abnormal stem cells may be effectively eliminated by an
optimal combination of intense immunosuppression with relatively
low-dose chemotherapy, followed by infusion of donor stem cells
enriched with immunocompotent T cells, aiming for induction of
bilateral transplantation tolerance, thus enabling gradual elimination
of all host-type cells by donor T cells over time, while controlling
for GVHD. It remains to be seen whether a similar therapeutic approach
can be developed for patients with matched unrelated donor available
and whether a similar modality may be extrapolated for a large number
of malignancies other than those originating from hematopoietic stem
cells.
| |
FOOTNOTES |
Submitted September 15, 1997;
accepted October 31, 1997.
Supported by Schering AG.
Address reprint requests Shimon Slavin, MD, Department of Bone Marrow
Transplantation, Hadassah University Hospital, Jerusalem 91120, Israel.
The publication costs of this article were defrayed in part by page
charge payment. This article must therefore be here-by marked
"advertisement" in accordance with 18 U.S.C. section 1734 solely
to indicate this fact.
| |
ACKNOWLEDGMENT |
We thank Ryna and Melvin Cohen and Baxter International
Corporation and the Rich Foundation for supporting our ongoing basic and clinical research in cell therapy. The work was carried out in the
Max Moss Leukemia Research Laboratory established and supported by his
devoted wife Adi Moss.
| |
REFERENCES |
1.
Horowitz MM,
Gale RP,
Sondel PM,
Goldman JM,
Kersey J,
Kolb HJ,
Rimm AA,
Ringden O,
Rozman C,
Speck B:
Graft-versus-leukemia reactions after bone marrow transplantation.
Blood
75:555,
1990[Abstract/Free Full Text]
2.
Slavin S,
Ackerstein A,
Naparstek E,
Or R,
Weiss L:
The graft-versus-leukemia (GVL) phenomenon: Is GVL separable from GVHD?
Bone Marrow Transplant
6:155,
1990[Medline]
[Order article via Infotrieve]
3.
Moscovitch M,
Slavin S:
Anti-tumor effects of allogeneic bone marrow transplantation in (NZB × NZW) F1 hybrids with spontaneous lymphosarcoma.
J Immunol
132:997,
1984[Abstract]
4.
Ben-Yosef R,
Or R,
Nagler A,
Slavin S:
Graft vs tumor and graft vs leukemia in patients with concurrent breast cancer and acute myelocytic leukemia.
Lancet
348:1242,
1996[Medline]
[Order article via Infotrieve]
5. Passweg JR, Rowlings PA, Armitage JO, Gale RP, Pelz CJ,
Sobocinski KA, Klein JP, Zhang M-J, Horowitz MM: Report from the
International Bone Marrow Transplant Registry and Autologous Blood and
Marrow Transplant Registry North America, in Cecka JM, Teraskaki PI
(eds): Clinical Transplants, 1995. Los Angeles, CA, UCLA Tissue Typing
Laboratory, 1996, p 117
6. (abstr, suppl 1)
Slavin S,
Or R,
Naparstek E,
Ackerstein A,
Weiss L:
Cellular-mediated immunotherapy of leukemia in conjunction with autologous and allogeneic bone marrow transplantation in experimental animals and man.
Blood
72:407a,
1988
7. (abstr, suppl 1)
Kolb HJ,
de Witte T,
Mittermuller J,
Hertenstein B,
Goldman JM,
Ljungman P,
Verdonck L,
Holler E,
Thalmaier K,
Bartram C:
Graft-versus-leukemia effect of donor buffy coat transfusions on recurrent leukemia after marrow transplantation.
Blood
82:214a,
1993
8.
Slavin S,
Naparstek E,
Nagler A,
Ackerstein A,
Kapelushnik Y,
Or R:
Allogeneic cell therapy for relapsed leukemia following bone marrow transplantation with donor peripheral blood lymphocytes.
Exp Hematol
23:1553,
1995[Medline]
[Order article via Infotrieve]
9.
Slavin S,
Naparstek E,
Nagler A,
Ackerstein A,
Samuel S,
Kapelushnik J,
Brautbar C,
Or R:
Allogeneic cell therapy with donor peripheral blood cells and recombinant human interleukin-2 to treat leukemia relapse post allogeneic bone marrow transplantation.
Blood
87:2195,
1996[Abstract/Free Full Text]
10.
Collins RH,
Shpilberg O,
Drobyski WR,
Porter DL,
Giralt S,
Champlin R,
Goodman SA,
Wolff SN,
Hu W,
Verfaillie C,
List A,
Dalton W,
Ognoskie N,
Chetrit A,
Antin JH,
Neumunaitis J:
Donor leukocyte infusions in 140 patients with relapsed malignancy after allogeneic bone marrow transplantation.
J Clin Oncol
15:433,
1997[Abstract/Free Full Text]
11.
Slavin S,
Weiss L,
Morecki S,
Weigensberg M:
Eradication of murine leukemia with histoincompatible marrow grafts in mice conditioned with total lymphoid irradiation (TLI).
Cancer Immunol Immunother
11:155,
1981
12.
Cohen P,
Vourka-Karussis U,
Weiss L,
Slavin S:
Spontaneous and IL-2 induced anti-leukemic and anti-host effects against tumor- and host-specific alloantigens.
J Immunol
151:4803,
1993[Abstract]
13.
Weiss L,
Lubin I,
Factorowich Y,
Lapidot Z,
Reich S,
Reisner Y,
Slavin S:
Effective graft vs leukemia effects independent of graft vs host disease after T-cell depleted allogeneic bone marrow transplantation in a murine model of B cell leukemia/lymphoma. Role of cell therapy and rIL-2.
Journal Immunol
153:2562,
1994[Abstract]
14.
Vourka-Karussis U,
Karussis D,
Ackerstein A,
Slavin S:
Enhancement of graft versus leukemia effect (GVL) with recombinant human interleukin 2 (rIL-2) following bone marrow transplantation in a murine model for acute myeloid leukemia in SJL/J mice.
Exp Hematol
23:196,
1995[Medline]
[Order article via Infotrieve]
15.
Pugatsch T,
Oppenheim A,
Slavin S:
Improved single step PCR assay for sex identification post allogeneic sex-mismatched BMT.
Bone Marrow Transplant
17:273,
1996[Medline]
[Order article via Infotrieve]
16.
Nakamura Y,
Leppert M,
O'Connell P,
Wolff R,
Holm T,
Culver M,
Martin C,
Fujimoto E,
Hoff M,
Kumlin E:
Variable number of tandem repeats (VNTR) markers for uman gene mapping.
Science
235:1616,
1987[Abstract/Free Full Text]
17.
Lin F,
Kirkland MA,
van Rhee FV,
Chase A,
Coulthard S,
Bungey J,
Goldman JM,
Cross NC:
Molecular analysis of transient cytogenetic relapse after allogeneic bone marrow transplantation for chronic myeloid leukaemia.
Bone Marrow Transplant
18:1147,
1996[Medline]
[Order article via Infotrieve]
18.
Nilsson SK,
Dooner MS,
Tiarks CY,
Weier HU,
Quesenberry PJ:
Potential and distribution of transplanted hematopoietic stem cells in a nonablated mouse model.
Blood
89:4013,
1997[Abstract/Free Full Text]
19.
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
25:114,
1997[Medline]
[Order article via Infotrieve]
20.
Weiss L,
Reich S,
Slavin S:
Effect of cyclosporine A and methylprednisolone on the GVL effect across major histocompatibility barriers in mice following allogeneic bone marrow transplantation.
Bone Marrow Transplant
6:229,
1990[Medline]
[Order article via Infotrieve]
21.
Bacigalupo A,
Van Lint MT,
Occhini D,
Gualandi F,
Lamparelli T,
Sogno G,
Tedone E,
Frassoni F,
Tong J,
Marmont AM:
Increased risk of leukemia relapse with high dose cyclosporine A after allogeneic marrow transplantation for acute leukemia.
Blood
77:1423,
1991[Abstract/Free Full Text]
22.
Naparstek E,
Or R,
Nagler A,
Cividalli G,
Engelhard D,
Aker M,
Gimon Z,
Manny N,
Sacks T,
Tochner Z,
Weiss L,
Samuel S,
Brautbar H,
Hale G,
Waldmann H,
Steinberg SM,
Slavin S:
T-cell-depleted allogeneic bone marrow transplantation for acute leukaemia using Campath-1 antibodies and post-transplant administration of donor's peripheral blood lymphocytes for prevention of relapse.
Br J Haematol
89:506,
1995[Medline]
[Order article via Infotrieve]
23.
Or R,
Kapelushnik J,
Naparstek E,
Nagler A,
Filon D,
Oppenheim A,
Amar A,
Aker M,
Samuel S,
Slavin S:
Second transplantation using allogeneic peripheral blood stem cells in a -thalassaemia major patient featuring stable mixed chimerism.
Br J Haematol
94:285,
1996[Medline]
[Order article via Infotrieve]
24.
Slavin S,
Strober S,
Fuks Z,
Kaplan HS:
Induction of specific tissue transplantation tolerance using fractionated total lymphoid irradiation in adult mice: Long-term survival of allogeneic bone marrow and skin grafts.
J Exp Med
146:34,
1977[Abstract/Free Full Text]
25.
Slavin S:
Total lymphoid irradiation (TLI).
Immunol Today
8:88,
1987
26.
Ildstad ST,
Sachs DH:
Reconstitution with syngeneic plus allogeneic or xenogeneic bone marrow leads to specific acceptance of allografts and xenografts.
Nature
307:168,
1984[Medline]
[Order article via Infotrieve]
27.
Sykes M,
Sachs DH:
Mixed allogeneic chimerism as an approach to transplantation tolerance.
Immunol Today
9:23,
1988[Medline]
[Order article via Infotrieve]
28.
Giralt S,
Estey E,
Albtar M,
van Besien K,
Rondon G,
Anderlini P,
O'Brien S,
Khouri I,
Gajewski J,
Mehra R,
Claxton D,
Andersson B,
Beran M,
Przepiorka D,
Koller C,
Kornblau S,
Korbling M,
Keating M,
Kantarjian H,
Champlin R:
Engraftment of allogeneic hematopoietic progenitor cells with purine analog-containing chemotherapy: Harnessing graft-versus-leukemia without myeloablative therapy.
Blood
89:4531,
1997[Abstract/Free Full Text]
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
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|
|
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|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
|
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178(10):
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|
|
|
|
|
|
|
S. Vigouroux, M. Michallet, R. Porcher, M. Attal, L. Ades, M. Bernard, D. Blaise, R. Tabrizi, F. Garban, J.-P. Cassuto, et al.
Long-term outcomes after reduced-intensity conditioning allogeneic stem cell transplantation for low-grade lymphoma: a survey by the French Society of Bone Marrow Graft Transplantation and Cellular Therapy (SFGM-TC)
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May 1, 2007;
92(5):
627 - 634.
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|
|
|
|
|
|
|
C. Crawley, S. Iacobelli, B. Bjorkstrand, J. F. Apperley, D. Niederwieser, G. Gahrton, and for the Chronic Leukaemia Working Party of the Eur
Reduced-intensity conditioning for myeloma: lower nonrelapse mortality but higher relapse rates compared with myeloablative conditioning
Blood,
April 15, 2007;
109(8):
3588 - 3594.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. A. Rizzieri, L. P. Koh, G. D. Long, C. Gasparetto, K. M. Sullivan, M. Horwitz, J. Chute, C. Smith, J. Z. Gong, A. Lagoo, et al.
Partially Matched, Nonmyeloablative Allogeneic Transplantation: Clinical Outcomes and Immune Reconstitution
J. Clin. Oncol.,
February 20, 2007;
25(6):
690 - 697.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Eto, M. Harano, K. Tatsugami, M. Harada, Y. Kamiryo, K. Kiyoshima, M. Hamaguchi, M. Tsuneyoshi, Y. Yoshikai, and S. Naito
Cyclophosphamide-Using Nonmyeloablative Allogeneic Cell Therapy against Renal Cancer with a Reduced Risk of Graft-versus-Host Disease
Clin. Cancer Res.,
February 1, 2007;
13(3):
1029 - 1035.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. H. Antin
Reduced-Intensity Stem Cell Transplantation: "...whereof a little More than a little is by much too much." King Henry IV, part 1, I, 2
Hematology,
January 1, 2007;
2007(1):
47 - 54.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Martino, R. Parody, T. Fukuda, J. Maertens, K. Theunissen, A. Ho, G. J. Mufti, N. Kroger, A. R. Zander, D. Heim, et al.
Impact of the intensity of the pretransplantation conditioning regimen in patients with prior invasive aspergillosis undergoing allogeneic hematopoietic stem cell transplantation: a retrospective survey of the Infectious Diseases Working Party of the European Group for Blood and Marrow Transplantation
Blood,
November 1, 2006;
108(9):
2928 - 2936.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Aschan
Allogeneic haematopoietic stem cell transplantation: current status and future outlook
Br. Med. Bull.,
October 5, 2006;
(2006)
ldl005v2.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N.-C. Gorin, M. Labopin, J.-M. Boiron, N. Theorin, T. Littlewood, S. Slavin, H. Greinix, J. Y. Cahn, E. P. Alessandrino, A. Rambaldi, et al.
Results of Genoidentical Hemopoietic Stem Cell Transplantation With Reduced Intensity Conditioning for Acute Myelocytic Leukemia: Higher Doses of Stem Cells Infused Benefit Patients Receiving Transplants in Second Remission or Beyond--The Acute Leukemia Working Party of the European Cooperative Group for Blood and Marrow Transplantation
J. Clin. Oncol.,
August 20, 2006;
24(24):
3959 - 3966.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Schmid, M. Schleuning, R. Schwerdtfeger, B. Hertenstein, E. Mischak-Weissinger, D. Bunjes, S. v. Harsdorf, C. Scheid, U. Holtick, H. Greinix, et al.
Long-term survival in refractory acute myeloid leukemia after sequential treatment with chemotherapy and reduced-intensity conditioning for allogeneic stem cell transplantation
Blood,
August 1, 2006;
108(3):
1092 - 1099.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. J. Shaughnessy, C. Bachier, C. F. LeMaistre, C. Akay, B. H. Pollock, and Y. Gazitt
Granulocyte Colony-Stimulating Factor Mobilizes More Dendritic Cell Subsets Than Granulocyte-Macrophage Colony-Stimulating Factor with No Polarization of Dendritic Cell Subsets in Normal Donors
Stem Cells,
July 1, 2006;
24(7):
1789 - 1797.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Barkholt, M. Bregni, M. Remberger, D. Blaise, J. Peccatori, G. Massenkeil, P. Pedrazzoli, A. Zambelli, J.-O. Bay, S. Francois, et al.
Allogeneic haematopoietic stem cell transplantation for metastatic renal carcinoma in Europe
Ann. Onc.,
July 1, 2006;
17(7):
1134 - 1140.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. Garban, M. Attal, M. Michallet, C. Hulin, J. H. Bourhis, I. Yakoub-Agha, T. Lamy, G. Marit, F. Maloisel, C. Berthou, et al.
Prospective comparison of autologous stem cell transplantation followed by dose-reduced allograft (IFM99-03 trial) with tandem autologous stem cell transplantation (IFM99-04 trial) in high-risk de novo multiple myeloma
Blood,
May 1, 2006;
107(9):
3474 - 3480.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. Carnevale-Schianca, A. Cignetti, A. Capaldi, K. Vitaggio, A. Vallario, A. Ricchiardi, E. Sperti, R. Ferraris, M. Gatti, G. Grignani, et al.
Allogeneic nonmyeloablative hematopoietic cell transplantation in metastatic colon cancer: tumor-specific T cells directed to a tumor-associated antigen are generated in vivo during GVHD
Blood,
May 1, 2006;
107(9):
3795 - 3803.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. B. Bachli, D. J. Schaer, R. B. Walter, J. Fehr, and G. Schoedon
Functional expression of the CD163 scavenger receptor on acute myeloid leukemia cells of monocytic lineage
J. Leukoc. Biol.,
February 1, 2006;
79(2):
312 - 318.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. J. Jabbour, E. Estey, and H. M. Kantarjian
Adult Acute Myeloid Leukemia
Mayo Clin. Proc.,
February 1, 2006;
81(2):
247 - 260.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
U. Hegenbart, D. Niederwieser, B. M. Sandmaier, M. B. Maris, J. A. Shizuru, H. Greinix, C. Cordonnier, B. Rio, A. Gratwohl, T. Lange, et al.
Treatment for Acute Myelogenous Leukemia by Low-Dose, Total-Body, Irradiation-Based Conditioning and Hematopoietic Cell Transplantation From Related and Unrelated Donors
J. Clin. Oncol.,
January 20, 2006;
24(3):
444 - 453.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Rzepecki, T. Sarosiek, and C. Szczylik
Alemtuzumab, Fludarabine and Melphalan as a Conditioning Therapy in Severe Aplastic Anemia and Hypoplastic Myelodysplastic Syndrome--Single Center Experience
Jpn. J. Clin. Oncol.,
January 1, 2006;
36(1):
46 - 49.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. F. Apperley
Managing the Patient with Chronic Myeloid Leukemia Through and After Allogeneic Stem Cell Transplantation
Hematology,
January 1, 2006;
2006(1):
226 - 232.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. L. Scott and B. M. Sandmaier
Outcomes with Myeloid Malignancies
Hematology,
January 1, 2006;
2006(1):
381 - 389.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. Locatelli
Reduced-Intensity Regimens in Allogeneic Hematopoietic Stem Cell Transplantation for Hemoglobinopathies
Hematology,
January 1, 2006;
2006(1):
398 - 401.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. L. Abbott
Chronic Lymphocytic Leukemia: Recent Advances in Diagnosis and Treatment
Oncologist,
January 1, 2006;
11(1):
21 - 30.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Mohty, D. Blaise, C. Faucher, N. Vey, R. Bouabdallah, A.-M. Stoppa, F. Viret, G. Gravis, D. Olive, and B. Gaugler
Inflammatory cytokines and acute graft-versus-host disease after reduced-intensity conditioning allogeneic stem cell transplantation
Blood,
December 15, 2005;
106(13):
4407 - 4411.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. J. Wu, L. Krishnamurti, J. L. Kutok, M. Biernacki, S. Rogers, W. Zhang, J. H. Antin, and J. Ritz
Evidence for ineffective erythropoiesis in severe sickle cell disease
Blood,
November 15, 2005;
106(10):
3639 - 3645.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
I. Yung, L. Weiss, A. Abdul-Hai, J. Kasir, S. Reich, and S. Slavin
Induction of Early Post-Transplant Graft-versus-Leukemia Effects Using Intentionally Mismatched Donor Lymphocytes and Elimination of Alloantigen-Primed Donor Lymphocytes for Prevention of Graft-versus-Host Disease
Cancer Res.,
November 1, 2005;
65(21):
9735 - 9740.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Harano, M. Eto, T. Iwai, K. Tatsugami, K. Kiyoshima, Y. Kamiryo, M. Tsuneyoshi, Y. Yoshikai, and S. Naito
Renal Cancer Treatment with Low Levels of Mixed Chimerism Induced by Nonmyeloablative Regimen Using Cyclophosphamide in Mice
Cancer Res.,
November 1, 2005;
65(21):
10032 - 10040.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Crawley, R. Szydlo, M. Lalancette, A. Bacigalupo, A. Lange, M. Brune, G. Juliusson, A. Nagler, A. Gratwohl, J. Passweg, et al.
Outcomes of reduced-intensity transplantation for chronic myeloid leukemia: an analysis of prognostic factors from the Chronic Leukemia Working Party of the EBMT
Blood,
November 1, 2005;
106(9):
2969 - 2976.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Stelljes, M. Bornhauser, M. Kroger, J. Beyer, M. C. Sauerland, A. Heinecke, B. Berning, C. Scheffold, G. Silling, T. Buchner, et al.
Conditioning with 8-Gy total body irradiation and fludarabine for allogeneic hematopoietic stem cell transplantation in acute myeloid leukemia
Blood,
November 1, 2005;
106(9):
3314 - 3321.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Lowsky, T. Takahashi, Y. P. Liu, S. Dejbakhsh-Jones, F. C. Grumet, J. A. Shizuru, G. G. Laport, K. E. Stockerl-Goldstein, L. J. Johnston, R. T. Hoppe, et al.
Protective conditioning for acute graft-versus-host disease.
N. Engl. J. Med.,
September 29, 2005;
353(13):
1321 - 1331.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Corradini, F. Zallio, J. Mariotti, L. Farina, M. Bregni, P. Valagussa, F. Ciceri, A. Bacigalupo, A. Dodero, M. Lucesole, et al.
Effect of Age and Previous Autologous Transplantation on Nonrelapse Mortality and Survival in Patients Treated With Reduced-Intensity Conditioning and Allografting for Advanced Hematologic Malignancies
J. Clin. Oncol.,
September 20, 2005;
23(27):
6690 - 6698.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. van Besien, A. Artz, S. Smith, D. Cao, S. Rich, L. Godley, D. Jones, P. Del Cerro, D. Bennett, B. Casey, et al.
Fludarabine, Melphalan, and Alemtuzumab Conditioning in Adults With Standard-Risk Advanced Acute Myeloid Leukemia and Myelodysplastic Syndrome
J. Clin. Oncol.,
August 20, 2005;
23(24):
5728 - 5738.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M.-T. Rubio, T. I. Saito, K. Kattleman, G. Zhao, J. Buchli, and M. Sykes
Mechanisms of the Antitumor Responses and Host-versus-Graft Reactions Induced by Recipient Leukocyte Infusions in Mixed Chimeras Prepared with Nonmyeloablative Conditioning: A Critical Role for Recipient CD4+ T Cells and Recipient Leukocyte Infusion-Derived IFN-{gamma}-Producing CD8+ T Cells
J. Immunol.,
July 15, 2005;
175(2):
665 - 676.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Crawley, M. Lalancette, R. Szydlo, M. Gilleece, K. Peggs, S. Mackinnon, G. Juliusson, L. Ahlberg, A. Nagler, A. Shimoni, et al.
Outcomes for reduced-intensity allogeneic transplantation for multiple myeloma: an analysis of prognostic factors from the Chronic Leukaemia Working Party of the EBMT
Blood,
June 1, 2005;
105(11):
4532 - 4539.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Okamura, A. Utsunomiya, R. Tanosaki, N. Uike, S. Sonoda, M. Kannagi, M. Tomonaga, M. Harada, N. Kimura, M. Masuda, et al.
Allogeneic stem-cell transplantation with reduced conditioning intensity as a novel immunotherapy and antiviral therapy for adult T-cell leukemia/lymphoma
Blood,
May 15, 2005;
105(10):
4143 - 4145.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. Baron, M. B. Maris, B. M. Sandmaier, B. E. Storer, M. Sorror, R. Diaconescu, A. E. Woolfrey, T. R. Chauncey, M. E.D. Flowers, M. Mielcarek, et al.
Graft-Versus-Tumor Effects After Allogeneic Hematopoietic Cell Transplantation With Nonmyeloablative Conditioning
J. Clin. Oncol.,
March 20, 2005;
23(9):
1993 - 2003.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Ivanov, T. Aarts, S. Hol, A. Doornenbal, A. Hagenbeek, E. Petersen, and S. Ebeling
Identification of a 40S Ribosomal Protein S4-Derived H-Y Epitope Able to Elicit a Lymphoblast-Specific Cytotoxic T Lymphocyte Response
Clin. Cancer Res.,
March 1, 2005;
11(5):
1694 - 1703.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. P. Alyea, H. T. Kim, V. Ho, C. Cutler, J. Gribben, D. J. DeAngelo, S. J. Lee, S. Windawi, J. Ritz, R. M. Stone, et al.
Comparative outcome of nonmyeloablative and myeloablative allogeneic hematopoietic cell transplantation for patients older than 50 years of age
Blood,
February 15, 2005;
105(4):
1810 - 1814.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Rao, P. J. Amrolia, A. Jones, C. M. Cale, P. Naik, D. King, G. E. Davies, H. B. Gaspar, and P. A. Veys
Improved survival after unrelated donor bone marrow transplantation in children with primary immunodeficiency using a reduced-intensity conditioning regimen
Blood,
January 15, 2005;
105(2):
879 - 885.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. J. Cornelissen and B. Lowenberg
Role of Allogeneic Stem Cell Transplantation in Current Treatment of Acute Myeloid Leukemia
Hematology,
January 1, 2005;
2005(1):
151 - 155.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Giralt
Reduced-Intensity Conditioning Regimens for Hematologic Malignancies: What Have We Learned over the Last 10 Years?
Hematology,
January 1, 2005;
2005(1):
384 - 389.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Kami, A. Makimoto, Y. Heike, and Y. Takaue
Reduced-intensity Hematopoietic Stem Cell Transplantation (RIST) for Solid Malignancies
Jpn. J. Clin. Oncol.,
December 1, 2004;
34(12):
707 - 716.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Kosaka, K. Koh, N. Kinukawa, Y. Wakazono, K. Isoyama, T. Oda, Y. Hayashi, S. Ohta, H. Moritake, M. Oda, et al.
Infant acute lymphoblastic leukemia with MLL gene rearrangements: outcome following intensive chemotherapy and hematopoietic stem cell transplantation
Blood,
December 1, 2004;
104(12):
3527 - 3534.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. O. Freytes, F. R. Loberiza, J. D. Rizzo, A. Bashey, C. N. Bredeson, M. S. Cairo, R. P. Gale, M. M. Horowitz, T. R. Klumpp, R. Martino, et al.
Myeloablative allogeneic hematopoietic stem cell transplantation in patients who experience relapse after autologous stem cell transplantation for lymphoma: a report of the International Bone Marrow Transplant Registry
Blood,
December 1, 2004;
104(12):
3797 - 3803.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. F. Freeman, D. A. Jacobsohn, S. T. Shulman, W. J. Bellini, P. Jaggi, G. d. Leon, G. F. Keating, F. Kim, L. M. Pachman, M. Kletzel, et al.
A New Complication of Stem Cell Transplantation: Measles Inclusion Body Encephalitis
Pediatrics,
November 1, 2004;
114(5):
e657 - e660.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. Baron, J. E. Baker, R. Storb, T. A. Gooley, B. M. Sandmaier, M. B. Maris, D. G. Maloney, S. Heimfeld, D. Oparin, E. Zellmer, et al.
Kinetics of engraftment in patients with hematologic malignancies given allogeneic hematopoietic cell transplantation after nonmyeloablative conditioning
Blood,
October 15, 2004;
104(8):
2254 - 2262.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. P. Rettig, J. K. Ritchey, J. L. Prior, J. S. Haug, D. Piwnica-Worms, and J. F. DiPersio
Kinetics of In Vivo Elimination of Suicide Gene-Expressing T Cells Affects Engraftment, Graft-versus-Host Disease, and Graft-versus-Leukemia after Allogeneic Bone Marrow Transplantation
J. Immunol.,
September 15, 2004;
173(6):
3620 - 3630.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Takahashi and R. W. Childs
Nonmyeloablative Transplantation: An Allogeneic-Based Immunotherapy for Renal Cell Carcinoma
Clin. Cancer Res.,
September 15, 2004;
10(18):
6353S - 6359S.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Y. L. Ho, A. Pagliuca, M. Kenyon, J. E. Parker, A. Mijovic, S. Devereux, and G. J. Mufti
Reduced-intensity allogeneic hematopoietic stem cell transplantation for myelodysplastic syndrome and acute myeloid leukemia with multilineage dysplasia using fludarabine, busulphan, and alemtuzumab (FBC) conditioning
Blood,
September 15, 2004;
104(6):
1616 - 1623.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. L. Abbott
Do "minitransplantations" have "minitoxicity"?
Blood,
September 1, 2004;
104(5):
1239 - 1240.
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Diaconescu, C. R. Flowers, B. Storer, M. L. Sorror, M. B. Maris, D. G. Maloney, B. M. Sandmaier, and R. Storb
Morbidity and mortality with nonmyeloablative compared with myeloablative conditioning before hematopoietic cell transplantation from HLA-matched related donors
Blood,
September 1, 2004;
104(5):
1550 - 1558.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Stelljes, R. Strothotte, H.-G. Pauels, C. Poremba, M. Milse, C. Specht, J. Albring, G. Bisping, C. Scheffold, T. Kammertoens, et al.
Graft-versus-host disease after allogeneic hematopoietic stem cell transplantation induces a CD8+ T cell-mediated graft-versus-tumor effect that is independent of the recognition of alloantigenic tumor targets
Blood,
August 15, 2004;
104(4):
1210 - 1216.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. de Lima, D. Couriel, P. F. Thall, X. Wang, T. Madden, R. Jones, E. J. Shpall, M. Shahjahan, B. Pierre, S. Giralt, et al.
Once-daily intravenous busulfan and fludarabine: clinical and pharmacokinetic results of a myeloablative, reduced-toxicity conditioning regimen for allogeneic stem cell transplantation in AML and MDS
Blood,
August 1, 2004;
104(3):
857 - 864.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. de Lima, A. Anagnostopoulos, M. Munsell, M. Shahjahan, N. Ueno, C. Ippoliti, B. S. Andersson, J. Gajewski, D. Couriel, J. Cortes, et al.
Nonablative versus reduced-intensity conditioning regimens in the treatment of acute myeloid leukemia and high-risk myelodysplastic syndrome: dose is relevant for long-term disease control after allogeneic hematopoietic stem cell transplantation
Blood,
August 1, 2004;
104(3):
865 - 872.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. M. Kotloff, V. N. Ahya, and S. W. Crawford
Pulmonary Complications of Solid Organ and Hematopoietic Stem Cell Transplantation
Am. J. Respir. Crit. Care Med.,
July 1, 2004;
170(1):
22 - 48.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Miyakoshi, K. Yuji, M. Kami, E. Kusumi, Y. Kishi, K. Kobayashi, N. Murashige, T. Hamaki, S.-W. Kim, J.-i. Ueyama, et al.
Successful Engraftment After Reduced-Intensity Umbilical Cord Blood Transplantation for Adult Patients with Advanced Hematological Diseases
Clin. Cancer Res.,
June 1, 2004;
10(11):
3586 - 3592.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. V. Besien, S. Smith, J. Anastasi, R. Larson, M. Thirman, T. Odenike, and W. Stock
Irreversible myelosuppression after fludarabine-melphalan conditioning: observations in patients with graft rejection
Blood,
June 1, 2004;
103(11):
4373 - 4374.
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. Kroger, G. Schilling, H. Einsele, P. Liebisch, A. Shimoni, A. Nagler, J. A. Perez-Simon, J. F. San Miguel, M. Kiehl, A. Fauser, et al.
Deletion of chromosome band 13q14 as detected by fluorescence in situ hybridization is a prognostic factor in patients with multiple myeloma who are receiving allogeneic dose-reduced stem cell transplantation
Blood,
June 1, 2004;
103(11):
4056 - 4061.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
O. Y. Jones, A. Steele, J. M. Jones, Y. Marikar, Y. Chang, A. Feliz, R. A. Cahill, and R. A. Good
Nonmyeloablative Bone Marrow Transplantation of BXSB Lupus Mice Using Fully Matched Allogeneic Donor Cells from Green Fluorescent Protein Transgenic Mice
J. Immunol.,
May 1, 2004;
172(9):
5415 - 5419.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Y. Mapara and M. Sykes
Tolerance and Cancer: Mechanisms of Tumor Evasion and Strategies for Breaking Tolerance
J. Clin. Oncol.,
March 15, 2004;
22(6):
1136 - 1151.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
U. Schuler
Reduced intensity conditioning before allografting: moderate enthusiasm may be more appropriate
Eur. Respir. J.,
March 1, 2004;
23(3):
357 - 358.
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Nusair, R. Breuer, M.Y. Shapira, N. Berkman, and R. Or
Low incidence of pulmonary complications following nonmyeloablative stem cell transplantation
Eur. Respir. J.,
March 1, 2004;
23(3):
440 - 445.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Carvallo, N. Geller, R. Kurlander, R. Srinivasan, O. Mena, T. Igarashi, L. M. Griffith, W. M. Linehan, and R. W. Childs
Prior chemotherapy and allograft CD34+ dose impact donor engraftment following nonmyeloablative allogeneic stem cell transplantation in patients with solid tumors
Blood,
February 15, 2004;
103(4):
1560 - 1563.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. A. Jacobsohn, K. M. Emerick, P. Scholl, H. Melin-Aldana, M. O'Gorman, R. Duerst, and M. Kletzel
Nonmyeloablative Hematopoietic Stem Cell Transplant for X-Linked Hyper-Immunoglobulin M Syndrome With Cholangiopathy
Pediatrics,
February 1, 2004;
113(2):
e122 - 127.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. D. Faulkner, C. Craddock, J. L. Byrne, P. Mahendra, A. P. Haynes, H. G. Prentice, M. Potter, A. Pagliuca, A. Ho, S. Devereux, et al.
BEAM-alemtuzumab reduced-intensity allogeneic stem cell transplantation for lymphoproliferative diseases: GVHD, toxicity, and survival in 65 patients
Blood,
January 15, 2004;
103(2):
428 - 434.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. Blaise, J. O. Bay, C. Faucher, M. Michallet, J.-M. Boiron, B. Choufi, J.-Y. Cahn, N. Gratecos, J.-J. Sotto, S. Francois, et al.
Reduced-intensity preparative regimen and allogeneic stem cell transplantation for advanced solid tumors
Blood,
January 15, 2004;
103(2):
435 - 441.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Casper, W. Knauf, T. Kiefer, D. Wolff, B. Steiner, U. Hammer, R. Wegener, H.-D. Kleine, S. Wilhelm, A. Knopp, et al.
Treosulfan and fludarabine: a new toxicity-reduced conditioning regimen for allogeneic hematopoietic stem cell transplantation
Blood,
January 15, 2004;
103(2):
725 - 731.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Zoller
Tumor Vaccination after Allogeneic Bone Marrow Cell Reconstitution of the Nonmyeloablatively Conditioned Tumor-Bearing Murine Host
J. Immunol.,
December 15, 2003;
171(12):
6941 - 6953.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. T. Ueno, Y. C. Cheng, G. Rondon, N. M. Tannir, J. L. Gajewski, D. R. Couriel, C. Hosing, M. J. de Lima, P. Anderlini, I. F. Khouri, et al.
Rapid induction of complete donor chimerism by the use of a reduced-intensity conditioning regimen composed of fludarabine and melphalan in allogeneic stem cell transplantation for metastatic solid tumors
Blood,
November 15, 2003;
102(10):
3829 - 3836.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. A. Lister
High-Dose Therapy for Follicular Lymphoma Revisited: Not If, but When?
J. Clin. Oncol.,
November 1, 2003;
21(21):
3894 - 3896.
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. K. Strair, D. Schaar, D. Medina, M. B. Todd, J. Aisner, R. S. DiPaola, J. Manago, B. Knox, A. Jenkinson, R. Senzon, et al.
Antineoplastic Effects of Partially HLA-Matched Irradiated Blood Mononuclear Cells in Patients With Renal Cell Carcinoma
J. Clin. Oncol.,
October 15, 2003;
21(20):
3785 - 3791.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Fukuda, R. C. Hackman, K. A. Guthrie, B. M. Sandmaier, M. Boeckh, M. B. Maris, D. G. Maloney, H. J. Deeg, P. J. Martin, R. F. Storb, et al.
Risks and outcomes of idiopathic pneumonia syndrome after nonmyeloablative and conventional conditioning regimens for allogeneic hematopoietic stem cell transplantation
Blood,
October 15, 2003;
102(8):
2777 - 2785.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Wong, S. A. Giralt, T. Martin, D. R. Couriel, A. Anagnostopoulos, C. Hosing, B. S. Andersson, P. Cano, M. Shahjahan, C. Ippoliti, et al.
Reduced-intensity conditioning for unrelated donor hematopoietic stem cell transplantation as treatment for myeloid malignancies in patients older than 55 years
Blood,
October 15, 2003;
102(8):
3052 - 3059.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. Bachar-Lustig, S. Reich-Zeliger, and Y. Reisner
Anti-third-party veto CTLs overcome rejection of hematopoietic allografts: synergism with rapamycin and BM cell dose
Blood,
September 15, 2003;
102(6):
1943 - 1950.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M.-T. Rubio, Y.-M. Kim, T. Sachs, M. Mapara, G. Zhao, and M. Sykes
Antitumor effect of donor marrow graft rejection induced by recipient leukocyte infusions in mixed chimeras prepared with nonmyeloablative conditioning: critical role for recipient-derived IFN-{gamma}
Blood,
September 15, 2003;
102(6):
2300 - 2307.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. N. Barker, D. J. Weisdorf, T. E. DeFor, B. R. Blazar, J. S. Miller, and J. E. Wagner
Rapid and complete donor chimerism in adult recipients of unrelated donor umbilical cord blood transplantation after reduced-intensity conditioning
Blood,
September 1, 2003;
102(5):
1915 - 1919.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. H. Antin
A 41-Year-Old Woman With Chronic Myelogenous Leukemia
JAMA,
August 27, 2003;
290(8):
1083 - 1090.
[Full Text]
[PDF]
|
|
|
|
|
|
|
D.C. Taussig, A.J. Davies, J.D. Cavenagh, H. Oakervee, D. Syndercombe-Court, S. Kelsey, J.A.L. Amess, A.Z.S. Rohatiner, T.A. Lister, and M.J. Barnett
Durable Remissions of Myelodysplastic Syndrome and Acute Myeloid Leukemia After Reduced-Intensity Allografting
J. Clin. Oncol.,
August 15, 2003;
21(16):
3060 - 3065.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Renga, P. Pedrazzoli, and S. Siena
Present results and perspectives of allogeneic non-myeloablative hematopoietic stem cell transplantation for treatment of human solid tumors
Ann. Onc.,
August 1, 2003;
14(8):
1177 - 1184.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
Abstract
Introduction
Abstract