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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 94 No. 2 (July 15), 1999:
pp. 434-441
T-Cell Depletion Plus Salvage Immunotherapy With Donor Leukocyte
Infusions as a Strategy to Treat Chronic-Phase Chronic Myelogenous
Leukemia Patients Undergoing HLA-Identical Sibling Marrow
Transplantation
By
William R. Drobyski,
Martin J. Hessner,
John P. Klein,
Claudia Kabler-Babbitt,
David H. Vesole, and
Carolyn A. Keever-Taylor
From the Bone Marrow Transplant Program, Departments of Medicine and
Biostatistics, Medical College of Wisconsin, Milwaukee, WI; and the
Blood Center of Southeastern Wisconsin, Milwaukee, WI.
 |
ABSTRACT |
T-cell depletion (TCD) of the donor marrow graft has been shown to
reduce the severity of graft-versus-host disease (GVHD) in patients
with chronic-phase (CP) chronic myelogenous leukemia (CML) undergoing
HLA-identical sibling allogeneic marrow transplantation. However, there
has been a corresponding reduction in the graft-versus-leukemia effect
so that any decrease in GVHD-related mortality has been offset by an
increased rate of disease relapse. Therapy of recurrent disease with
donor leukocyte infusions (DLI) has been proven to be effective salvage
therapy for the majority of patients who relapse after allogeneic BMT
with CP CML. However, the overall impact of salvage DLI therapy on the
survival of CP CML patients initially transplanted with TCD marrow
grafts is not defined. To address this question, we have evaluated a
clinical strategy of TCD followed by targeted adoptive immunotherapy
with DLI in 25 CP CML patients undergoing allogeneic BMT from
HLA-identical siblings. All patients received a standardized
preparative regimen along with ex vivo TCD and posttransplant
cyclosporine as GVHD prophylaxis. Durable engraftment was observed in
all 25 patients. The incidence of grade II to IV acute GVHD was 8%.
The cumulative incidence of transplant-related mortality (TRM) was 4%,
and the 1-year probability of overall survival was 96%. The 3-year
cumulative relapse incidence was 49%. All relapsed patients received
DLI to reinduce remission. The total T-cell dose administered to these patients varied from 0.1 to 5.0 × 108 T cells/kg.
Complete responses were observed in 12 of 14 patients, with 1 additional patient still too early to evaluate. Three patients died of
GVHD after DLI, and 1 relapsed into blast crisis after a transient
cytogenetic remission. Of the remaining 10 patients, 8 are in molecular
remission, 1 is alive in relapse, and 1 is receiving DLI treatment. The
median follow-up after infusion of surviving DLI patients in remission
is 5.3 years. The probability of overall 5-year survival for the entire
population is 80%, with a median follow-up of 6.4 years. We conclude
that the clinical strategy of TCD followed by targeted adoptive
immunotherapy with DLI for those patients with evidence of recurrent
disease is a viable transplant strategy for CP CML, resulting in 80%
survival and a low risk of acute GVHD and transplant-related mortality.
© 1999 by The American Society of Hematology.
| |
INTRODUCTION |
T-CELL DEPLETION (TCD) has been shown to
reduce the severity of graft-versus-host disease (GVHD) in patients
undergoing HLA-identical sibling allogeneic bone marrow transplantation
(BMT) for chronic-phase (CP) chronic myelogenous leukemia
(CML).1-3 However, removal of donor T cells from the marrow
graft compromises the graft-versus-leukemia (GVL) effect that plays a
primary role in preventing disease recurrence.4,5 This has
resulted in increased relapse rates and an overall decrease in survival
when compared with patients transplanted with unmodified grafts. The decreased survival is attributable to the fact that benefits derived from a reduction in GVHD-associated mortality due to TCD is more than
offset by an increased rate of CML recurrence.
For many patients who relapse with CML after BMT, donor leukocyte
infusions (DLI) are an effective salvage therapy.6-12
Because of the higher relapse rate associated with TCD, the vast
majority of patients treated with DLI have been previously transplanted with TCD marrow grafts. DLI is able to induce remissions in 70% to
80% of patients relapsing after a transplant for CP CML. Prior studies
have shown that a majority of patients have sustained molecular
remissions,7,8,10,12 indicating that these patients may in
fact be cured of their disease. However, this therapy has not been
without complications, because some patients develop fatal GVHD and/or
marrow aplasia attributable to the infusion of immunocompetent donor T
cells.6-12 Although these adverse effects have limited the
efficacy of DLI, the fact that the majority of relapsed patients can
achieve durable remissions has made this therapy a valuable adjunct to
the transplant management of CP CML. However, the overall impact of DLI
on the survival of CP CML patients initially transplanted with TCD
marrow grafts is unknown.
In this report, we describe the efficacy of a clinical strategy of TCD
marrow transplantation followed by targeted adoptive immunotherapy with
DLI in patients who relapse posttransplant. The goals of this study
were to define whether this approach would result in an overall
survival rate comparable to that observed in recipients of unmodified
marrow grafts. We also sought to determine the effect of this strategy
on transplant-related mortality after initial BMT, which is the major
obstacle preventing the application of allogeneic BMT to older patient populations.
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MATERIALS AND METHODS |
Patient population.
Twenty-five consecutive patients with first CP CML who received BMT
from HLA-identical sibling donors between January 1, 1988 and June 30, 1998 at Froedert Memorial Lutheran Hospital or the Children's Hospital
of Wisconsin were evaluated. The patient demographic data are shown in
Table 1. First chronic phase was defined
using previously published criteria.13 Each recipient and
donor candidate underwent serotyping for HLA-A and B alleles by
standard microcytotoxicity assays. HLA-DR and DQ disparities were
assessed by either microcytotoxicity assays or by oligonucleotide
genotyping.14,15 Informed consent was obtained from each
patient (or their guardians), and all treatment was administered under
protocols approved by the Institutional Review Committees of the
Medical College of Wisconsin.
Preparative regimen, GVHD prophylaxis, and supportive care.
All patients were treated in laminar air flow or HEPA-filtered rooms.
Pretransplant conditioning consisted of high-dose cytosine arabinoside
(3 g/m2 × 6, days  7 to 4),
cyclophosphamide (45 mg/kg × 2, days 6 and 5), and
methylprednisolone (1 g/m 2 × 4, days 2 to 0) followed by fractionated total body irradiation to a total dose of
either 13.32 or 14 Gy (days 2 to 0).16,17 GVHD
prophylaxis consisted of ex vivo T-cell depletion with the  
T-cell receptor antibody, T10 B9, and baby
rabbit complement plus posttransplant cyclosporine.18 All
patients received prophylactic antibiotics according to institutional
guidelines. Cytomegalovirus (CMV)-seronegative patients
received blood components from CMV-seronegative donors.
Assessment of engraftment, GVHD, and relapse.
The date of engraftment was defined as the first of 3 consecutive days
in which the absolute neutrophil count (ANC) was  500/µL. Trilineage
engraftment was documented by bone marrow examination in the majority
of patients 3 to 4 weeks after transplant. Follow-up marrow studies
were performed at 100 days, 6 months, 1 year, and at least yearly after
transplantation, whenever possible, to evaluate engraftment and disease
status. Durable engraftment was confirmed by cytogenetic analysis,
restriction fragment length polymorphism (RFLP) studies, or analysis of
variable number of tandem repeats (VNTRs) in blood or marrow samples to
distinguish donor from recipient cells. Acute GVHD was graded as 0 to
IV according to criteria of Glucksberg et al,19 whereas
chronic GVHD was defined as none, limited, or extensive.20
Patients who had evidence of engraftment were evaluable for acute GVHD,
whereas patients who engrafted and also survived more than 100 days
were evaluable for chronic GVHD. Transplant-related mortality was
defined as death resulting from any causes other than relapse.
Complications such as fatal GVHD resulting from DLI were attributable
to disease recurrence and therefore were not classified as
transplant-related mortality. Relapse was defined by either morphologic
evidence of CML in the peripheral blood, marrow, or extramedullary
sites or by the recurrence and sustained presence of the Philadelphia
chromosome on cytogenetic analysis. Patients whose sole evidence of
disease was positivity for the bcr/abl RNA transcipt by the polymerase
chain reaction (PCR) were not classified as having relapsed. Acute GVHD
occurring in patients treated with DLI was operationally defined as
that occurring within 100 days of infusion, whereas chronic GVHD was defined as that present after day 100 from infusion.
DLI therapy.
Patients with evidence of relapse were treated with DLI to reinduce
remission. Patients were taken off all immunosuppressive or cytotoxic
agents (eg, prednisone, cyclosporine, hydroxyurea, or interferon)
before the administration of leukocyte infusions. In no case did
discontinuation of immunosuppression result in a clinical antileukemic
effect or GVHD. Leukocyte collections from the original bone marrow
donors were performed using a Cobe spectra apheresis system (Cobe
Laboratories, Inc, Lakewood, CO), as previously described.7
Patients requiring multiple infusions received them every other day
immediately after collection from the donor. For donor/recipient pairs
who were ABO-compatible, leukocytes were infused directly into the
patient without further processing. Conversely, in patients who were
ABO-incompatible with the donor, Ficoll-hypaque density gradient
centrifugation was performed to remove red blood cells. No GVHD
prophylaxis was administered to any of the patients. The first 13 patients were infused with naïve unactivated donor T cells. The
most recent patient received activated donor T cells that had been
retrovirally transduced with the thymidine kinase gene.21
The percentage of lymphocytes in each apheresis product was determined
using an STKR Coulter Counter (Coulter Corp, Hialeah, FL). The
percentage of CD3+ T cells was calculated by flow
cytometric analysis. The total T-cell dose administered to patients was
calculated using the following formula: (total nucleated cell dose) × (% lymphocytes) × (% CD3+ T cells). The
first 9 patients treated with DLI received a total of approximately 2.5 to 5.0 × 108 T cells/kg (vide infra). Subsequent
patients received a lower dose of 0.1 to 1.0 × 108 T
cells/kg based on a study suggesting that this dose might reduce GVHD
without compromising antileukemic efficacy.22 Peripheral blood and bone marrow specimens were obtained from all patients at
least monthly for the first 3 months and then at 2-month intervals for
the next 4 months to assess disease status. Patients who received DLI
were classified as having attained complete remission if they had
documented cytogenetic remission by marrow examination at any time
after the administration of DLI. Patients were defined as being in
continuous complete remission if the most recent marrow examination
failed to show the presence of the Philadelphia chromosome.
PCR assay for detection of minimal residual disease.
Total cellular RNA was prepared from peripheral blood, peripheral blood
buffy coats, or peripheral blood mononuclear cells isolated by
Ficoll-hypaque, bone marrow, or cultured B cells (negative control) and
K562 (Philadelphia chromosome positive) cells. Peripheral blood and
marrow cells were used interchangeably based on previous data
demonstrating that both are equally sensitive for detecting residual
disease in CML patients.23 Cells were either viably frozen
or directly added to 4 mol/L guanidinium isothiocyanate. RNA was
prepared from 3 to 5 million cells. The conditions used for extraction
of RNA and PCR amplification have been previously detailed.17,24 All assays were performed in duplicate,
beginning with independent RNA isolations. Mock RNA preparations were
included in every assay as negative controls. The criteria used for
defining positive assay results have been previously
published.17 Assay sensitivity was monitored through the
addition and detection of 0.05 ng RNA from the Ph+ cell
line K562, mixed within a replicate assay for each unknown sample. This
quantity of RNA represents nucleic acid isolated from approximately
five K562 cells, which requires two rounds of nested primer PCR for
detection. Whenever possible, assays were performed at 6-month intervals.
Statistical analysis.
Endpoints were calculated at the date of last contact with the date of
latest follow-up being November 15, 1998. The median duration of
follow-up since BMT for the patient population was 77 months (range, 5 to 117 months). Cumulative actuarial probabilities of overall survival
and acute and chronic GVHD were calculated using the Kaplan-Meier
method.25 Cumulative incidence curves for relapse and
transplant-related mortality were computed as described by Pepe and
Motomi.26 Data for these two variables are presented as the
value ± the standard error. Patients were censored at the time of
death in the analysis of GVHD and relapse. Confidence limits for the
Kaplan-Meier estimate were based on the arcsine
transformation.27
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RESULTS |
Engraftment.
The mean bone marrow inoculum administered after TCD was 8.96 × 107 nucleated cells/kg (range, 1.43 to 19.3 × 107/kg). Limiting dilution assays were performed in the
last 15 patients in the cohort to determine the degree of TCD. In these
patients, the median log TCD was 1.90 (range, 1.15 to 3.26) and the
median T-cell dose was 3.4 × 105 T cells/kg (range,
0.044 to 31.5 × 105 T cells/kg). Sixteen patients
were treated with either granulocyte-macrophage colony-stimulating
factor (GM-CSF) or granulocyte colony-stimulating factor (G-CSF) to
accelerate myeloid engraftment after BMT. The median times to an ANC
500/µL and 1,000/µL for 3 consecutive days was 17 days (range,
11 to 29 days) and 21 days (range, 12 to 40 days), respectively. The
median time to a platelet count 20,000 was 25 days (range, 13 to 159 days). All patients had at least one marrow or peripheral blood sample
within the first 4 months posttransplant examined for the extent of
donor chimerism. Thirteen patients had greater than 90% donor cells by
either VNTR or RFLP analysis (median, 98%; range, 90% to 100%). Nine
recipients had complete donor chimerism on cytogenetic analysis using
either sex mismatching or informative polymorphisms to distinguish
donor from recipient cells. In 3 patients, chimerism studies were
uninformative, but these patients had sustained hematopoietic recovery.
No patient had evidence of marrow graft rejection.
GVHD.
All 25 patients were evaluable for the development of both acute and
chronic GVHD after BMT. The probability of developing grade II-IV acute
GVHD was 8% (95% confidence interval [CI], 2.3% to
28%). No patient developed grade III or grade IV acute GVHD. Limited
chronic GVHD occurred in 7 patients, whereas extensive chronic GVHD
developed in 3 patients. The overall probability of developing any
chronic GVHD and extensive chronic GVHD was 43% (95% CI, 29.9% to
60%) and 13% (95% CI, 4.8% to 33.6%), respectively. Surviving
patients not treated with DLI were tapered off immunosuppressive therapy at a median of 6 months (range, 2.5 to 24 months) posttransplant.
Treatment of relapsed patients with DLI.
The 3-year cumulative incidence of hematologic or sustained cytogenetic
relapse for the entire cohort was 49% (95% CI, 38.6% to 61.3%;
Fig 1). Fourteen relapses occurred in
patients transplanted with HLA-identical sibling marrow grafts. For
those patients who relapsed, the median time from BMT to relapse was
368 days (range, 187 to 1,494 days). Five patients who relapsed had a
history of both acute and chronic GVHD, 2 patients had acute GVHD only,
and 2 had chronic GVHD only. Five patients had no history of GVHD. All
14 patients with relapse subsequently received DLI to reinduce remission (Table 2). The median time from
relapse to DLI was 110 days (range, 45 to 2,022 days). Eight recipients
were in hematologic relapse and 6 were in cytogenetic relapse at the
time of DLI. None of the patients treated with DLI had GVHD at the time
of infusion or was on immunosuppressive therapy. Six patients developed acute GVHD, including 3 with grade I, 1 with grade II, and 2 with grade
IV. Three of these patients died of GVHD and 2 others progressed to
extensive chronic GVHD. Five patients with no or grade I acute GVHD
also subsequently developed extensive chronic GVHD. Marrow aplasia was
observed in 1 patient who required several marrow boosts from the
original donor before effective hematopoietic function was restored.
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| Fig 1.
Actuarial probability of relapse for the entire patient
population. Tick marks represent patients currently alive in
remission.
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Twelve of 14 patients achieved cytogenetic remission at a median of 3 months (range, 1 to 8 months) after DLI. One of these 12 patients
relapsed 2 months later and eventually died of blast crisis CML. The 3 patients who died from GVHD were either in hematologic or cytogenetic
remission at the time of death. Two still had molecular evidence of
disease; 1 was in molecular remission (UPN 357). One patient has failed
to respond to DLI and is currently alive in relapse 7 months after DLI.
The last patient is too early to evaluate. Nine of 10 surviving
patients treated with DLI are off all immunosuppressive medications; 1 continues to have moderate oral GVHD 6 years after DLI and is on
treatment with topical steroids. The median follow-up after infusion of
surviving DLI patients in remission (n = 8) is 5.3 years (range, 2.2 to
6.7 years).
Remission status as assessed by PCR.
Serial PCR assays were performed in all 25 patients to more stringently
define the remission status of recipients after TCD allogeneic BMT with
or without adjunctive DLI. A total of 267 RNA samples (19 pretransplantation and 248 posttransplantation) were evaluable using
previously published criteria.17 Pretransplantation samples
were obtained in 19 patients and all were positive for the bcr/abl RNA
transcript. In 6 patients, no pretransplant sample was available. One
hundred fifty-eight of 248 posttransplant samples were collected from
the bone marrow and 90 from the peripheral blood. Positive assays were
observed in 44 of 90 (49%) of peripheral blood samples and in 93 of
158 (59%) of bone marrow samples. The average number of posttransplant
samples assayed per patient was 9.9 (range, 2 to 17).
Serial molecular assays performed in patients who did not require
treatment with DLI for relapsed disease are shown in
Fig 2A, whereas those conducted in the 14 patients who required DLI are shown in Fig 2B. Nine of 11 cytogenetic
responders to DLI also achieved molecular remission. The remaining 2 patients died of GVHD before molecular remission could be documented.
No relapses have been observed in patients achieving molecular
remission. Eleven patients who have not received DLI are currently
alive in cytogenetic remission. Eight of these 11 patients are also in
molecular remission at the time of last analysis, whereas 3 patients
are positive for the bcr/abl RNA transcript. The bcr/abl signal was
detectable only after two rounds of PCR amplification in these
patients, indicative of a leukemic burden of between 1 in
103 and 1 in 106 cells,24 which is
below the level of detection of cytogenetic analysis. When all patients
in the study are combined, 15 of 20 (75%) surviving patients are
currently in molecular remission.
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| Fig 2.
Serial PCR analysis for patients who received
HLA-identical sibling marrow grafts for the treatment of CP CML. (A)
Patients who have not relapsed and therefore have not been treated with
DLI. (B) Patients who were treated with DLI for relapsed disease. ( )
Patients testing positive for the presence of the bcr/abl RNA
transcript. ( ) Patients testing negative for the presence of the
bcr/abl RNA transcript. Arrows indicate time of relapse posttransplant.
(i) Denotes the time of first donor leukocyte
infusion.
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Transplant-related mortality and survival.
One patient died from transplant-related toxicity. This death was
attributable to a gastrointestinal hemorrhage (UPN 848) in a patient
who was receiving immunosuppressive therapy for GVHD at the time of
demise. Overall transplant-related mortality after BMT was 4% (95%
CI, 1% to 24%) for the entire patient population (Fig 3). No deaths attributable to relapse
or DLI therapy occurred within the first year of transplant, resulting
in a 1-year probability of survival of 96%. The probability of overall
survival for the entire population at 5 years is 80% (95% CI, 58.9%
to 91.5%), with a median follow-up of 6.4 years (range, 0.4 to 9.8 years; Fig 4). The median Karnofsky score
of surviving patients is 100 (range, 70 to 100).
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| Fig 3.
Actuarial probability of transplant-related mortality for
patients transplanted with HLA-identical sibling marrow grafts.
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| Fig 4.
Actuarial probability of survival for the entire patient
population. Tick marks represent patients currently alive.
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DISCUSSION |
Allogeneic BMT using HLA-identical sibling donors has proven to be
effective therapy for patients with CP CML, with long-term survival
rates of 50% to 80%.1-3,28,29 In most clinical series, patients have been transplanted with unmodified marrow grafts due to
the concern about the increased relapse rate associated with TCD that
has counterbalanced any salutory effects from a reduction in GVHD. In
that regard, data reported to the International Bone Marrow Transplant
Registry indicate that, of a total of 3,141 CP CML patients undergoing
HLA-identical sibling marrow grafts between 1992 and 1997, 94% were
transplanted with non-TCD grafts (M. Horowitz, personal
communication, December 1998). The 1-year transplant-related mortality in this population was 26%, indicating that a substantial number of patients die of this complication. Studies
from single institutions and cooperative groups have reported 1-year
mortality rates of between 10% and 40% in the same patient population.29-31 The divergent problems inherent in each
transplant approach prompted us to consider an alternative strategy
whereby TCD could be used to decrease transplant-related mortality and DLI would then be used as needed to address the problem of increased relapse. This approach viewed the initial transplant as one element in
a multistep strategy designed to achieve engraftment without collateral
life-threatening toxicity from GVHD and then to target adjunctive
immunotherapy to those patients who had evidence of recurrent disease.
The current study demonstrated that use of this clinical strategy
resulted in durable engraftment in all patients with only modest
toxicity from GVHD. Transplant-related mortality occurred in only 1 of
25 recipients. The probability of survival at 1 year was 96%, with
only one death observed within the first 6 months posttransplant,
indicating that the regimen was well tolerated in a cohort in which
approximately 50% of patients were greater than 40 years of age. As
expected, relapse was substantial, with a probability of disease
recurrence of 49% at 3 years. However, approximately 60% of relapsed
patients have achieved durable remissions with DLI therapy, and all
surviving remitters remain in molecular remission with a median
follow-up of 5.3 years. The resulting overall 5-year survival rate of
80% therefore compares favorably to results using unmodified marrow grafts.
Schattenberg et al32 have reported similar results with
this approach, although in their study, not all relapsed patients were
treated with DLI and several additional recipients received non-TCD
second marrow transplants for graft failure. The potential role of DLI
was therefore not evaluable in all patients. Moreover, the median
follow-up of more than 6 years in the present study is substantially
longer and provides more conclusive proof of the durability of both
DLI-induced remissions and remissions in patients not requiring salvage immunotherapy.
The major problem with the use of DLI in this clinical setting is the
toxicity attributable to the infusion of donor leukocytes, specifically
that due to GVHD and marrow aplasia, which has limited the overall
efficacy of this therapy. Both of these complications have contributed
to and resulted in the death of patients who were otherwise in
remission. Improvements in overall survival using this clinical
strategy are therefore contingent upon alternative approaches designed
to reduce the severity of these specific problems. With respect to
marrow aplasia, studies indicate that the incidence of this
complication is inversely proportional to the extent of residual donor
hematopoiesis.33 Prior studies7,10 support the
premise that treating patients in early relapse when there is still
evidence of donor hematopoiesis essentially eliminates this
complication. In CML, this goal can usually be accomplished, because
relapse can often be detected before it is clinically evident and
patients have reverted back to complete recipient chimerism by using
cytogenetic and molecular assays.
The most significant complication of DLI therapy was GVHD, which was
the cause of death in 3 of the patients in the present study and has
been reported to be fatal in 10% to 20% of patients.6-12 Although conventional pharmacologic approaches are successful in the
majority of patients with GVHD after DLI, not all respond to this
approach. The optimal strategy for the amelioration of GVHD in DLI
patients has yet to be defined, although several alternative approaches
are currently being explored that offer the potential to reduce
GVHD-related toxicity. Mackinnon et al22 have shown that
the use of limiting T-cell doses (1 × 107/kg) may be
superior to the administration of higher T-cell doses for the treatment
of CML in cytogenetic or molecular relapse. In their study, 8 patients
treated at this cell dose achieved remission, whereas only 1 had
evidence of GVHD. This strategy appears to be dependent on treatment in
early (cytogenetic/molecular v hematologic) relapse and will
require confirmatory studies to ascertain whether GVHD can indeed be
abrogated without compromising antileukemic reactivity. An alternative
strategy is the incorporation of a suicide gene into T cells in an
effort to more precisely modulate GVH/GVL reactivity. The gene that is
currently being used in clinical trials is the herpes simplex thymidine
kinase gene, which allows for the selective elimination of transduced donor T cells after ganciclovir administration.34 Finally,
the use of specific T-cell subsets (eg, CD4+ T cells) as
opposed to unfractionated DLI is an approach that may have utility in
increasing the therapeutic index.35,36 Given that a
majority of patients who die of GVHD after DLI are in remission at the
time of death, the ability to mitigate GVHD-related toxicity offers the
potential to improve overall survival in this patient population.
However, there are several potential disadvantages with this clinical
strategy that need to be considered. One pertains to the possibility
that a patient who is transplanted in the CP will subsequently relapse
with accelerated phase or blast crisis disease. In such instances, DLI
has been shown to be much less effective; therefore, these patients
might not be salvageable with immunotherapy. Although
reported,37 this was not observed in this series and appears to be a very uncommon occurrence, because the vast majority of
such patients relapse in the CP of their disease.28,38 A second concern pertains to the responsiveness of relapsed patients to
DLI therapy even when they are treated in the early phase of their
disease. Prior studies have shown that 70% to 80% of patients who
relapse into CP CML respond to treatment, but a minority either fail to
respond or relapse after initial therapy.39 The reason that
some patients do not respond to DLI is unknown, but appears to be due
to an inability of donor T cells to recognize target antigens on the
leukemia cell surface and eradicate disease. Two patients in the
current study who were in hematological relapse ultimately relapsed
after a transient DLI-induced remission. A potential solution to this
problem is to administer DLI when patients are in cytogenetic relapse.
Studies have shown that CML patients treated in cytogenetic or
molecular relapse have a significantly better response rate than
patients treated in hematologic relapse,40,41 presumably
due to the presence of a minimal disease burden. The administration of
DLI in cytogenetic relapse might be advantageous from the standpoint
that this approach would avoid treating patients in molecular relapse
who, as observed in this study, may not manifest any further disease
progression for a prolonged period of time. Patients could then still
be captured for treatment before there were any overt clinical signs of recurrence.
In summary, this study demonstrates that ex vivo TCD of the donor
marrow graft to reduce GVHD followed by adjunctive immunotherapy with
DLI for the treatment of disease relapse is a viable strategy for the
therapy of CP CML with HLA-identical sibling donors. Transplant-related mortality is low with this approach and survival rates are comparable or superior to those observed in recipients of unmodified marrow grafts. This strategy may be particularly beneficial in older recipients, who comprise the majority of patients with CML and are at
greatest risk from complications of GVHD and transplant-related mortality. Another advantage of this approach is that patients who are
not destined to relapse are not exposed to the same degree of GVHD risk
that derives from a non-TCD graft. We conclude that the use of TCD in
this patient population should be reassessed in light of the emerging
clinical approaches that are currently being explored for the therapy
of relapsed disease posttransplant. These refinements offer the
potential to augment the therapeutic index of posttransplant
immunotherapy with the goal of further improving survival in these
patients and even extending the age of viable candidates for allogeneic BMT.
| |
FOOTNOTES |
Submitted December 28, 1998; accepted March 10, 1999.
The publication costs of this
article were defrayed in part by
page charge payment. This article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
Address reprint requests to William R. Drobyski, MD, Bone Marrow
Transplant Program, Froedert Memorial Lutheran Hospital, 9200 W
Wisconsin Ave, Milwaukee, WI 53226.
| |
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ABSTRACT
INTRODUCTION
