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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 91 No. 10 (May 15), 1998:
pp. 3671-3680
Toxicity and Efficacy of Defined Doses of CD4+ Donor
Lymphocytes for Treatment of Relapse After Allogeneic Bone Marrow
Transplant
By
Edwin P. Alyea,
Robert J. Soiffer,
Christine Canning,
Donna Neuberg,
Robert Schlossman,
Christopher Pickett,
Heather Collins,
Yulan Wang,
Kenneth C. Anderson, and
Jerome Ritz
From the Divisions of Hematologic Malignancies and Biostatistics,
Dana-Farber Cancer Institute, Department of Medicine, Harvard Medical
School, Boston, MA.
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ABSTRACT |
Donor lymphocyte infusions (DLI) can induce remissions in patients
who have relapsed after allogeneic bone marrow transplantation (BMT).
However, DLI frequently also result in significant acute and/or
chronic graft-versus-host disease (GVHD). Several clinical and
experimental lines of evidence have suggested that CD8+ T
cells play a critical role in the pathogenesis of GVHD. To develop
methods to reduce the incidence of GVHD associated with DLI, we
administered defined numbers of CD4+ donor T cells after
ex vivo depletion of CD8+ lymphocytes to 40 patients with
relapsed hematologic malignancies after allogeneic BMT. Cohorts of
patients received 0.3, 1.0, or 1.5 × 108
CD4+ cells/kg. Overall, 12 of 38 patients (32%)
evaluable for toxicity developed acute or chronic GVHD. However, 6 of
27 patients (22%) receiving 0.3 × 108 CD4 cells/kg
developed GVHD compared with 6 of 11 patients (55%) who received
 1.0 × 108 CD4 cells/kg (P = .07).
Treatment-related mortality was low (3%), with 1 death related to
infection in the setting of immunosuppression for GVHD. Disease
responses after CD4+ DLI were documented in 15 of 19 patients (79%) with early-phase chronic myelogenous leukemia (CML)
relapse, 5 of 6 patients (83%) with relapsed multiple myeloma, and 1 patient with myelodysplasia. For patients with early-phase CML relapse,
the Kaplan-Meier probability of achieving complete cytogenetic
remission was 87% and the probability of complete molecular response
was 78% at 1 year after DLI. The median time to complete cytogenetic
response and molecular response in patients with CML was 13 weeks
(range, 9 to 30 weeks) and 34 weeks (range, 10 to 56 weeks),
respectively. The median time to response in patients with multiple
myeloma was 26 weeks (range, 15 to 62 weeks). All patients in this
trial who developed GVHD demonstrated tumor regression, but the
presence of GVHD was not required for patients to achieve a response,
because 48% of responding patients never developed evidence of GVHD.
Two patients with CML who did not respond at dose level 1 subsequently
achieved complete cytogenetic remission after a second infusion of
CD8-depleted cells at dose level 2. In patients with evidence of mixed
hematopoietic chimerism who achieved a complete remission after DLI,
cytogenetic analysis of marrow cells also demonstrated conversion to
complete donor hematopoiesis in all evaluable patients. These studies
suggest that relatively low numbers of CD8-depleted donor lymphocytes are effective in inducing complete remissions in patients with stable-phase CML and multiple myeloma who have relapsed after allogeneic BMT. Because of the relatively low risk of toxicity associated with the infusion of defined numbers of CD4+
donor cells, further studies can be undertaken in the setting of
persistent minimal residual disease to prevent relapse after allogeneic
BMT.
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INTRODUCTION |
DONOR LYMPHOCYTE infusions (DLI) have
emerged as an effective strategy for the treatment of patients with
chronic myelogenous leukemia (CML) who have relapsed after allogeneic
bone marrow transplantation (BMT).1-6 This therapy appears
to be most effective in patients with CML who have evidence of
cytogenetic relapse or who have relapsed into stable
phase.7-9 The use of DLI was initially envisioned as a
means to induce graft-versus-host disease (GVHD), which, in turn, could
eradicate recurrent leukemic cells by the induction of
graft-versus-leukemia (GVL) activity. Nevertheless, the success of DLI
has been limited to some extent by the morbidity and mortality
associated with GVHD. Although some investigators have linked the
induction of GVL activity following DLI to the induction of GVHD, there
have been reports of patients treated with DLI who obtain a complete
response in the absence of clinical GVHD. This finding suggests that
the GVL response may be independent of the clinical development of
GVHD.
T cells are presumed to be the principle mediators of GVHD in both
animal models and humans.10-16 T cells are also implicated as the mediators of GVL.17-21 Specific T-cell subsets and
T-cell number may both influence the incidence and severity of GVHD
after DLI. The distinction between specific T-cell subsets inducing GVL
and GVHD has been made in several preclinical
models.18,20-23 The T-cell subset responsible for GVL or
GVHD varies with the model.24 In humans, increased numbers
of circulating CD8+ T cells have been observed in patients
who develop GVHD after T-cell-depleted BMT compared with patients who
do not develop GVHD.25 A lower incidence of GVHD after
infusion of CD8-depleted bone marrow at the time of BMT compared with
non-T-cell-depleted BMT has been reported.26,27 Depletion
of CD8+ cells from the bone marrow may not be associated
with an increased risk of relapse in these patients as it is in
patients who receive pan-T-cell-depleted marrows. T-cell number is
also important in the development of GVHD, and investigators have shown
that increasing the number of T cells administered at the time of BMT
is associated with an increased incidence of GVHD.28
Infusion of increased numbers of T cells at the time of DLI may also be
correlated with an increased incidence of GVHD.29
Because both T-cell number and CD8+ T cells have been
implicated in the development of GVHD after BMT, we conducted a
clinical trial to examine the toxicity and clinical efficacy of the
infusion of defined numbers of selected T cells in patients with
hematologic malignancies who have relapsed after allogeneic BMT. Three
cohorts of patients received defined numbers of CD4+ T
cells in a dose escalation trial. To assess the role of selective lymphocyte subsets on toxicity and efficacy, the infused cells were
selectively depleted of CD8+ mononuclear cells ex vivo
before infusion. Patients were observed after selective
CD4+ DLI for the development of GVHD and for evidence of
tumor response.
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MATERIALS AND METHODS |
Phase I/II clinical trial of DLI.
Forty patients with relapsed hematologic malignancies after allogeneic
BMT were entered on phase I and phase II clinical trials to examine the
toxicity and efficacy of different doses of CD4+ donor
lymphocytes. Patients with CML had evidence of clinical relapse or
greater than 10% Ph+ cells in the bone marrow when
analyzed by standard techniques. Patients with hematologic malignancies
other than CML had evidence of clinical relapse. Patients were required
to have a performance status of 0-1 and adequate renal and hepatic
function. All patients had HLA-identical sibling donors and were
documented to be nonreactive in mixed lymphocyte culture before DLI.
Patients were excluded if they had evidence of active grade II-IV acute
GVHD or extensive chronic GVHD or were receiving immune suppressive
medications to treat or prevent GVHD. In the initial phase I trial, 3 dose levels of cells were examined: (1) 0.3 × 108, (2) 1.0 × 108, and (3) 1.5 × 108 CD4+ cells per kilogram of patient weight.
No interferon or other immunomodulatory agents were administered
concurrently with or after DLI. After 5 to 7 patients were treated at
each dose level, 23 additional patients were treated at dose level 1 to
better define the toxicities and response at this dose level. These
studies were approved by the Human Subjects Protection Committee of the Dana-Farber Cancer Institute and written informed consent was obtained
from all patients and donors. Patient accrual was initiated in April
1994 and results were analyzed for all patients enrolled as of January
7, 1997.
Patient preparation.
All cytoreductive chemotherapy or immunotherapy was discontinued at
least 1 week before DLI. No interferon was administered in preparation
for DLI. No chemotherapy was administered after DLI; however,
hydroxyurea could be used to control white blood cell counts, if
needed, beginning 1 week after the infusion of donor cells. No
immunosuppressive medications for GVHD prophylaxis were administered
after DLI.
Collection and CD8 depletion of donor lymphocytes.
Using peripheral venous access, leukapheresis was performed for
approximately 3 hours per session on a Cobe-Spectra collection device (Cobe BCT Inc, Lakewood, CO) on the original bone
marrow donor. Mononuclear cells were isolated by density gradient
centrifugation using Ficoll-Hypaque. CD8+ cells were
depleted from the donor mononuclear cell fraction using anti-CD8
monoclonal antibody (MoAb; DFCI 2T8, IgG antibody) and rabbit
complement and techniques that have been described previously for
depletion of CD6+ T cells from bone
marrow.30,31 Two cycles of depletion with MoAb and
complement were performed on each pheresis product. Each cycle of ex
vivo treatment consisted of incubation of donor mononuclear cells (2 × 107 cells/mL) with anti-CD8 MoAb at room
temperature for 30 minutes followed by addition of baby rabbit
complement (Pel Freeze, Rogers, AR) and further incubation for 30 minutes at 37°C. Cells were washed three times with tissue culture
media (RPMI 1640; MediaTech, Herndon, VA) containing 2.5% human AB
serum after completion of all treatments. The viability of leukocytes
after depletion was confirmed by trypan blue dye exclusion. Aliquots of
mononuclear cells obtained before and after CD8 depletion were analyzed
for reactivity with directly fluorochrome-conjugated anti-CD4 and anti-CD8 MoAbs (Coulter Corp, Miami, FL) by flow cytometry (Coulter XL;
Coulter Corp). The total number of CD4+ and
CD8+ cells present after purging was calculated by
multiplying the percentage of cells reactive with anti-CD4 and anti-CD8
MoAbs by the total number of nucleated cells remaining after in vitro treatment. CD8-depleted donor lymphocytes were infused over 10 to 15 minutes through an intravenous catheter. Pheresis and ex vivo treatment
were repeated in a similar fashion at weekly intervals until the
targeted cell number was reached.
Evaluation of toxicity and response.
Patients were evaluated at weekly intervals by physical exam, complete
blood counts, and liver function tests for the first 12 weeks after
infusion and then based on clinical conditions. Bone marrow and
peripheral blood samples were obtained before the first infusion of
donor lymphocytes, at 3 months after infusion, and subsequently when
clinically indicated for analysis of morphologic, cytogenetic, and
molecular response. The presence of acute and chronic GVHD was graded
by standard criteria.32 Skin, liver, and bowel biopsies
were performed when indicated to confirm the diagnosis of GVHD.
Patients who developed GVHD were treated with prednisone. Cyclosporine
was added if response to prednisone was inadequate. Patients must have
been observed for greater than 8 weeks after DLI in the absence of
additional chemotherapy to be considered evaluable for toxicity.
Observation for at least 12 weeks without additional chemotherapy was
required for evaluation of response. Patients who demonstrated no
evidence of response or toxicity after 12 weeks of observation were
eligible to receive additional infusion of donor lymphocytes at the
next dose level. Results are analyzed as of October 1, 1997. Overall,
38 patients are evaluable for analysis of toxicity and 37 patients are
evaluable for response. Two patients, 1 with multiple myeloma and 1 with CML in blast crisis, were not evaluable for toxicity or response due to rapid disease progression and were removed from study at 3 and 6 weeks, respectively, after infusion. At the time of removal from the
study, neither patient had developed evidence of GVHD. One patient with
relapsed AML was treated while in complete remission and is evaluable
for toxicity but not response.
Cytogenetic and molecular studies.
Peripheral blood mononuclear cells (PBMC) and bone marrow cells were
obtained before DLI and at regular intervals after DLI for at least 12 weeks. Cytogenetic analysis was performed on bone marrow samples using
standard methods. In addition, mononuclear cells were obtained after
Ficoll-Hypaque density gradient sedimentation and cryopreserved in
media containing 10% dimethyl sulfoxide (DMSO) using
standard techniques. For patients with CML who had no detectable metaphases with the Ph chromosome, these cryopreserved samples were
used for detection of minimal residual disease. Cell samples were
thawed and RNA extracted using standard techniques.33
BCR-ABL transcripts were detected by a reverse
transcriptase-polymerase chain reaction (RT-PCR) method using a double
amplification method with nested primers as described
previously.34,35 Analysis of PCR-negative samples was
repeated three times to confirm a negative result.
Definitions of response.
Hematologic remission was defined as the return of normal blood counts
and bone marrow cellularity. Cytogenetic response for patients with CML
was defined as the absence of the Ph+ chromosome by routine
cytogenetic analysis of bone marrow samples after DLI. Molecular
remission for patients with CML was defined as the absence of
BCR-ABL transcripts by double amplification RT-PCR. In patients
with multiple myeloma, a decrease in disease-related Ig by greater than
50% was defined as a partial response and complete elimination of
monoclonal paraprotein with a normal bone marrow histology was defined
as a complete response. In patients with acute leukemia or lymphoma, a
complete response was defined as achievement of normal bone marrow
histology and no evidence of disease by routine evaluation including
appropriate x-rays or computer tomography (CT) scans.
Statistical methods.
Exact binomial confidence intervals are provided for the percentage of
patients developing GVHD or responding to therapy. Associations between
patient characteristics and outcome measures are assessed using the
Fisher exact test.36 Predictive models were developed
through univariate logistic regression. Odds ratios are calculated from
the coefficients in logistic regression. Time to GVHD, cytogenetic
response, and molecular response were calculated according to the
method of Kaplan and Meier.37
| |
RESULTS |
Patient characteristics.
The clinical characteristics of the 40 patients who received
CD4+ donor lymphocytes over a 38-month period are shown in
Table 1. Twenty-five patients had CML; 7 had multiple myeloma (MM); 4 had acute myelogenous leukemia (AML); 1 had Ph+ acute lymphocytic leukemia (ALL); 1 had
non-Hodgkin's lymphoma, diffuse large cell type (NHL); 1 had chronic
lymphocytic leukemia (CLL); and 1 had myelodysplastic syndrome (MDS).
CML was classified as being in stable phase, accelerated phase, or
blast crisis according to the criteria used by the International Bone
Marrow Transplant Registry.38 Thirty-nine patients had
previously received T-cell-depleted allogeneic marrow as the only form
of GVHD prophylaxis.30,39 One patient had received a
non-T-cell-depleted transplant with cyclosporine/methotrexate for
GVHD prophylaxis. The median length of time from transplantation to
relapse was 21 months (range, 2 to 62 months) and the median time from
relapse to cell infusion was 13 months (range, 1 to 75 months). Seven
patients had a history of grade 1 GVHD after transplant and 33 patients
had no prior history of GVHD. The median time on study of all evaluable
patients is 50 weeks (range, 8 to 129 weeks). In the initial phase of
the study, 17 patients were treated in a dose escalation schema to evaluate the toxicity of 3 doses of CD4+ donor lymphocytes
obtained after ex vivo CD8 depletion. Cohorts of 5 patients received
0.3 × 108 and 1.0 × 108
CD4+ cells/kg and 7 patients received 1.5 × 108 CD4+ cells/kg. To better define the
toxicity and efficacy of dose level 1, 23 additional patients received
infusions of 0.3 × 108 CD4+ cells/kg.
Composition of infused cells and efficacy of depletion of
CD8+ cells.
CD8 depletion was performed on 67 pheresis products for the 40 patients
on this study. A median of 1 (range, 1 to 5) leukopheresis session was
required to achieve the targeted cell dose. An increasing number of
leukopheresis sessions were required for increasing cell doses. At dose
level 1, 24 patients required a single donor pheresis and 4 patients
required 2 pheresis sessions to reach the targeted cell number. In 56 of the 67 depletions, no CD8+ cells were detected by direct
immunofluorescence assay above background levels after ex vivo
depletion. Eleven pheresis products contained small numbers of
CD8+ cells detected by direct immunofluorescence after ex
vivo depletion. These 11 products contained a median of 1 × 106 CD8+ cells/kg (range, 0.3 to 1.7 × 106 CD8+ cells/kg) after depletion. Eleven
patients received single infusions with detectable CD8+
cells (7 patients at dose level 1, 2 at dose level 2, and 2 at dose
level 3). After CD8 depletion, the median composition of the infused
cells in the 67 pheresis products included 51% CD3+ T
cells (range, 31% to 80%), 23% CD14+ monocytes (range,
3% to 47%), 6% CD56+ natural killer cells (range, 0% to
21%), and 5% CD20+ B cells (range, 0% to 19%). The
absolute median number of CD3+, CD4+,
CD8+, CD56+, and CD20+ cells
infused at each dose level is summarized in
Table 2. Before depletion,
CD8+ cells represented a median of 21% (range, 6% to
38%) of the mononuclear cells in the pheresis product.
Incidence of GVDH after DLI.
Overall, 12 of 38 evaluable patients (32%; 90% confidence interval
[CI], 19% to 46%) developed evidence of acute or chronic GVHD after
CD8-depleted DLI. As shown in Table 3, 6 patients developed acute GVHD (4 had grade II and 2 had grade III).
Three patients developed de novo extensive chronic GVHD, as
manifested by mucocutaneous involvement and liver function test
abnormalities. Three patients developed GVHD with simultaneous
characteristics of both acute (liver and bowel) and chronic
(mucocutaneous) GVHD. One patient treated at dose level 3 developed
grade 3 acute GVHD and died of infectious complications related to
immunosuppression. This was the only death in this patient population
attributable to any cause other than disease relapse.
Although limited numbers of patients in the phase I study were treated
at dose levels 2 and 3, the incidence of GVHD appeared to be higher in
patients who received larger numbers of donor cells (P = .07).
Six of 27 patients (22%) who received 0.3 × 108
CD4+ cells/kg (dose level 1) developed acute or chronic
GVHD, whereas 6 of 11 patients (55%) who received 1.0 × 108 CD4+ cells/kg (dose levels 2 and 3)
developed GVHD. The median time to onset of GVHD in all patients who
developed GVHD was 11 weeks (range, 7 to 42 weeks). There was no
difference in the time to onset of GVHD in patients treated at
different dose levels. The presence of detectable residual
CD8+ cells after ex vivo treatment was not associated with
subsequent GVHD.
Cytopenia after CD4+ DLI.
Peripheral cytopenias (absolute neutrophil count <500/µL or
platelet count <20,000/µL) not related to disease progression were
noted in 7 patients (Table 3). Six patients developed both neutropenia
and thrombocytopenia related to DLI, and 1 patient developed
thrombocytopenia alone. Only patients who demonstrated responses to DLI
developed cytopenias related to lymphocyte infusion. Cytopenias related
to DLI occurred in patients with and without evidence of GVHD.
The median time to the development of neutropenia and thrombocytopenia
related to DLI was 12 weeks (neutropenia range, 8 to 62 weeks; thrombocytopenia range, 7 to 61 weeks). Of those
patients evaluable for the development of cytopenia, 4 of 22 patients
(18%) treated at dose level 1 and 3 of 11 patients (27%) treated at dose levels 2 and 3 developed neutropenia secondary to DLI. Three of 22 (14%) patients treated at dose level 1 and 3 of 10 (30%) patients
treated at dose levels 2 and 3 developed thrombocytopenia after DLI. In
all but 1 case, episodes of neutropenia and thrombocytopenia were
transient after DLI. One patient with relapsed stable-phase CML treated
at dose level 1 had prolonged pancytopenia. This patient received an
infusion of CD6 T-cell-depleted marrow30 from the same
donor without additional chemotherapy or radiotherapy conditioning and
subsequently demonstrated engraftment with normal blood counts. No
infectious or hemorrhagic complications related to neutropenia or
thrombocytopenia were noted in any of these patients.
Response to CD4+ DLI.
Thirty-seven patients treated on this study are evaluable for response
(Table 4). Follow-up for at least 12 weeks
after DLI and measurable evidence of disease at the time of cell
infusion were both required criteria for evaluable response. Patients
evaluable for response after initial DLI included 24 with CML, 6 with
multiple myeloma, 3 with AML, and 1 each with ALL, NHL, CLL, and MDS.
Overall, 21 responses were noted (57%; 90% CI, 42% to 71%).
Responses occurred frequently in patients with stable-phase or
cytogenetic CML relapse (79%; 90% CI, 58% to 92%) and multiple
myeloma (83%; 90% CI, 42% to 99%), but only 14% (90% CI, 1% to
52%) of patients with other hematologic malignancies responded to DLI.
None of the 5 patients with accelerated phase or blastic phase CML
responded to initial DLI.
Cytogenetic and molecular remissions after CD4+ DLI
in patients with CML.
The probabilities of complete cytogenetic or molecular response for 19 patients with either cytogenetic relapse or stable phase CML relapse
are shown in Fig 1. At 6 months after a
single treatment course of donor lymphocytes, the Kaplan-Meier
probability of complete cytogenetic response was 74% and complete
molecular response was 28%. At 1 year after DLI, the probability of
complete cytogenetic response was 87% and the probability of complete
molecular response was 78%. Although the overall response rate was
very high for patients with cytogenetic or stable-phase CML relapse, the median time to both cytogenetic and molecular response was prolonged. As shown in Fig 1, the median time to cytogenetic response from the time of first CD4+ DLI was 13 weeks (range, 9 to
30 weeks), whereas the median time to elimination of the
BCR-ABL transcript detectable by PCR was 34 weeks (range, 11 to
56 weeks). No patient who has obtained a cytogenetic remission has
relapsed with a median of 72 weeks (range, 25 to 127 weeks) of
follow-up after obtaining cytogenetic remission. No patient who has
obtained a molecular remission has had any subsequent blood or marrow
samples positive for BCR-ABL transcript by PCR.
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| Fig 1.
Probability of complete cytogenetic response and
molecular remission after CD4+ DLI in patients with
relapsed early-phase CML. Nineteen patients with cytogenetic or
stable-phase CML relapse were evaluable for response. Three
nonresponders received second infusions of CD4+ donor
lymphocytes and were censored at the time of second infusion.
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Response to CD4+ DLI in patients with MM.
Seven patients with MM received CD4+ DLI. Three patients
had IgG, 2 patients had IgA, and 2 patients had light chain disease. One patient died 3 weeks after lymphocyte infusion related to rapidly
progressive disease and was not evaluable for response. Six patients
with MM are evaluable for response (Table 4). Five of 6 patients
demonstrated decreasing numbers of plasma cells in the bone marrow
associated with decreased numbers of monotypic Ig staining plasma
cells. Three patients, 2 with light chain disease and 1 with IgG
myeloma, achieved complete responses after DLI documented by complete
elimination of detectable monoclonal plasma cells in marrow biopsies as
well as complete elimination of detectable paraprotein in blood and
urine. Two patients achieved a partial response with a reduction in
myeloma-associated protein by greater than 50%. At the time of maximal
response in these 2 patients, bone marrow biopsies continued to
demonstrate persistent involvement with MM. Three of the 5 patients who
responded had an initial increase in paraprotein level 4 weeks after
DLI. Subsequent measurements demonstrated progressively decreasing
levels of paraprotein. The median time to maximal response in patients
with relapsed MM was 26 weeks (range, 18 to 62 weeks). In contrast to
patients with CML, in whom responses have been durable in all patients
thus far, 3 patients with MM who responded to DLI subsequently
demonstrated progression. Two patients have remained in complete
remission 12 and 28 months after CD4+ DLI.
Response to DLI in patients with acute leukemia and lymphoma.
Four patients with AML and 1 each with ALL, NHL, CLL, and MDS (RAEBT)
received infusions of CD4+ donor lymphocytes. Seven of 8 patients with acute leukemia or lymphoma had evidence of active disease
at the time of DLI. Six of 7 patients with active disease at the time
of DLI had progression of their disease after DLI. The single patient
with MDS was in hematologic relapse with 20% myeloblasts in the marrow
at the time of DLI and achieved a complete remission 10 weeks after
DLI. One patient with AML who had relapsed after allogeneic BMT had received one cycle of salvage chemotherapy and was in complete remission at the time of DLI. This patient remains in remission 48 weeks after DLI and has no evidence of GVHD.
CD4+ cell dose escalation for patients without
evidence of response or toxicity.
Nine patients who were treated at the first dose level and did not
develop toxicity or evidence of response received a second infusion of
CD4+ donor cells at dose level 2. These included 3 patients
with stable-phase CML, 3 patients with advanced CML, and 1 patient each
with AML, CLL, and MM. The median time from the first infusion to the
second infusion in these patients was 21 weeks (range, 12 to 28 weeks). Three patients with CML responded to the second infusion of
CD4+ donor cells. None of these patients was classified as
a responder for the previous analysis summarized in Table 4. One
patient with stable-phase CML relapse demonstrated a complete
cytogenetic response 26 weeks after the second infusion but has not
achieved a molecular response. One patient with accelerated phase CML
demonstrated a complete cytogenetic response after the addition of
interferon 50 weeks after the second DLI. This patient achieved a
complete molecular response with no detection of the BCR-ABL
transcript by PCR 68 weeks after the second infusion and remains in
remission 30 months after the second infusion. This patient also
developed extensive chronic GVHD 70 weeks after the second infusion.
One patient with CML in accelerated phase developed a complete
hematologic response after the addition of interferon 30 weeks after a
second DLI. No other patients who received a second infusion of donor cells developed evidence of GVHD. Two patients with stable-phase CML
have not shown evidence of response 7 and 9 months after a second DLI.
Relationship of GVHD to response after CD4+
DLI.
All 12 patients who developed GVHD demonstrated a response to DLI. This
included 8 patients with CML, 3 patients with MM, and 1 patient with
MDS. Although the development of GVHD was strongly associated with
response (P = .0004), responses were also noted in 9 patients
without the development of either acute or chronic GVHD. Seven complete
cytogenetic responses occurred in patients with early phase CML in the
absence of GVHD. Two patients with MM also demonstrated responses,
including 1 complete response, in the absence of GVHD.
To better define the relationship between GVHD and response, we
compared the time to response in patients who developed GVHD with
patients that did not develop GVHD (Fig 2).
This comparison included all 25 evaluable patients with cytogenetic or
stable-phase CML relapse or MM. As shown in Fig 2, the probability of
response was 100% in patients who developed GVHD compared with 72% in
patients without GVHD. This difference was not significantly different (P = .75). The analysis shown in Fig 2 also demonstrates that the time required to achieve a response was very similar in patients who either developed or did not develop GVHD.
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| Fig 2.
Probability of response after CD4+ DLI in
25 patients with relapsed early-phase CML or MM. Time to response is
compared in patients who developed GVHD (n = 11) and patients who did
not develop GVHD (n = 14).
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Factors associated with the development of GVHD and response after
CD4 DLI.
A variety of clinical factors listed in
Table 5 were examined for possible
association with either GVHD or response after DLI. Each variable was
analyzed by Fisher exact tests in the 38 patients evaluable for
toxicity (GVHD) or in the 37 patients evaluable for response. Factors
such as patient gender, age at DLI, time from transplant to DLI, prior
interferon, and GVHD after BMT were not associated with the development
of GVHD or response after DLI. Six patients (3 stable-phase CML and 3 advanced CML) received hydroxyurea to control increasing peripheral
blood counts after DLI. Only 1 of these patients with stable-phase
relapse responded to the initial course of DLI. Two additional patients
who received hydroxyurea responded to a second infusion of
CD4+ DLI. The number of cells infused and sex of the donor
may influence the likelihood of developing GVHD. When analyzed
together, infusion of cells at dose levels 2 or 3 from a female donor
was significantly associated with the development of GVHD (P = .006). In addition to the development of GVHD, the only clinical
variables associated with response were a diagnosis of CML or MM. There
was no significant association of response with the dose of
CD4+ cells infused.
Cytogenetic abnormalities in residual host nonleukemic cells.
In 9 patients with early-phase CML relapse, cells with cytogenetic
abnormalities in the absence of the Ph chromosome were noted before the
time of DLI. Presumably, these represented residual recipient cells
with radiation- or chemotherapy-induced cytogenetic abnormalities that
were unrelated to the malignant clone. Five of these patients had
sex-mismatched transplants that definitively identified the abnormal
metaphases as being derived from residual recipient cells. Two
additional patients who received sex-mismatched transplants also had
residual recipient metaphases with normal karyotypes detected by
cytogenetic evaluation after BMT. Ten of these 11 patients achieved a
complete cytogenetic remission after DLI with elimination of all
metaphases containing the Ph chromosome. At the time of cytogenetic
remission, both abnormal and normal cells unrelated to the
Ph+ leukemic clone were also eliminated in every patient
and were no longer detected on subsequent analysis.
| |
DISCUSSION |
Specific T-cell populations and the number of cells infused have both
been implicated in the development of GVHD after BMT and after DLI. The
primary objectives of the current phase 1 study were to identify the
toxicities associated with infusion of CD4+ donor
lymphocytes and to determine an appropriate dose of CD4+
donor cells for use in future clinical trials of adoptive cellular therapy after allogeneic BMT. To accomplish these aims, cohorts of
patients received defined numbers of CD4+ donor lymphocytes
after ex vivo depletion of CD8+ cells. No patients received
additional immune-stimulating or immune-suppressive agents, and no
further cellular therapy was administered for at least 6 months after
the initial course of therapy. As a result, we were able to evaluate
both the role of selective lymphocyte populations and cell number and
the risk of GVHD after DLI. The overall incidence of GVHD was
relatively low, with only 12 of 38 (32%) patients developing acute or
chronic GVHD. In a previous clinical trial of CD8-depleted DLI in 10 patients with relapsed CML, Giralt et al40 reported that
only 3 patients developed acute or chronic GVHD after infusion of a
mean of 0.9 × 108 mononuclear cells/kg. These results
compare favorably with results of unfractionated DLI in 140 patients
reported by Collins et al.9 In this large experience
compiled from 25 transplant centers in North America, 76% of patients
developed acute or chronic GVHD. However, the majority of patients in
that report received unmanipulated infusions of more than 1 × 108 T cells/kg. By reducing the total number of T cells
infused and removal of CD8+ cells, the overall incidence of
GVHD appears to be reduced in the two trials of CD8-depleted
DLI. The relative contributions of limiting the number of
T cells infused or CD8+ depletion in the reduction in GVHD
cannot be adequately assessed in the current phase I study. Further
studies will be necessary to define the importance of these two factors
in the development of GVHD after DLI.
Lowering the incidence of GVHD after DLI may have important clinical
implications for the use of this treatment modality in larger numbers
of patients after allogeneic BMT. With a relatively low incidence of
GVHD in our study, we noted that treatment-related mortality associated
with DLI was only 3%. In contrast, Collins et al9 reported
that the probability of mortality not related to hematologic malignancy
was 14% at 1 year and 18% at 2 years in recipients of unfractionated
DLI. The lower incidence of treatment-related mortality in patients
receiving CD8-depleted DLI is likely due to the finding that only 18%
of patients developed severe acute GVHD (grade 3-4) or extensive
chronic GVHD, and therefore very few patients required intensive
immune-suppressive therapy for prolonged periods after CD8-depleted
DLI. This relatively low incidence of severe toxicity associated with
CD8-depleted DLI may be very helpful in planning future studies to
evaluate the routine use of DLI in larger patient populations at high
risk for relapse after allogeneic rather than in relatively small
numbers of patients who have already demonstrated definitive evidence of relapse.41
In contrast to its effect on GVHD, CD8 depletion of donor lymphocytes
does not appear to compromise the GVL effect in patients with
early-stage CML relapse. In our study, the probabilities of achieving a
complete cytogenetic and complete molecular response were 87% and
78%, respectively, at 1 year after DLI. These results are similar to
the large multicenter experience reported by Collins et al9
in which 74% of patients with early-stage CML relapse achieved
complete cytogenetic remission after infusion of unfractionated donor
lymphocytes. However, 90% of patients in the experience reported by
Collins et al9 had morphologic evidence of relapse, compared with only 47% in the current study. Thus, despite the high
response rate demonstrated after infusion of CD8-depleted cells,
further studies may be necessary to directly compare the efficacy of
CD8-depleted cells with unfractionated DLI. Of note, the cytogenetic
and molecular remissions noted in our study also appear durable, with
no recurrence of disease noted in any of these patients. As with
unmanipulated infusions, patients with advanced-phase CML relapse did
not respond well to CD8-depleted DLI. In our study, no responses were
noted after a single course of therapy and only 2 patients with
accelerated CML subsequently responded to a second infusion of
CD8-depleted cells.
Two patients in this study had rapidly progressive disease and were not
considered evaluable for toxicity or response. If these 2 patients are
included in the analysis of toxicity, the overall incidence of GVHD in
the study is 30%, compared with 32% if these patients are included.
The incidence of GVHD at dose level 1 is also not significantly
affected by the addition of these patients. With respect to response, 1 patient had CML in blast crisis and the other had MM. Inclusion of the
patient with MM in our analysis of response would result in a response
rate of 71% in this patient population. No significant changes are noted in the factors associated with either the development of GVHD or
response by the addition of these 2 patients to the analysis.
Reports of previous clinical trials have noted that the time to
complete cytogenetic response after DLI in patients with CML can be
prolonged. However, the time required to achieve response has been
difficult to define in previous studies, because many patients received
additional infusions of donor cells weeks to months after the initial
infusion. Moreover, many patients in other studies have also received
additional immune stimulating therapy with interferon- or other
agents in conjunction with DLI. In our study, no patients with
stable-phase CML relapse received a second infusion of donor cells less
than 6 months after the initial infusion, and none received any other
immune modulating therapy within the first year after DLI. As shown in
Fig 1, the vast majority of cytogenetic responses occurred by 6 months
after DLI in patients with early stage CML relapse. Occasional patients required longer than 6 months, with the probability of cytogenetic complete response increasing slightly from 74% at 6 months to 87% at
1 year after DLI. In contrast, molecular responses are achieved much
more slowly, with only a 28% probability of patients being PCR
negative by 6 months, compared with 78% by 12 months after DLI. These
results suggest that patients with clinically stable CML relapse should
be observed for evidence of a cytogenetic response without additional
treatment for at least 6 months after DLI. Other treatment options,
including retreatment with donor lymphocytes at a similar or increased
dose of cells, addition of interferon- or interleukin-2
(IL-2),42 or a second BMT may play an important role in
patients who fail to respond to initial DLI. However, these additional
treatments should not be considered until sufficient time has elapsed
for adequate evaluation of their initial therapy.
Patients with relapsed MM were also noted to have a high response rate
(83%) to DLI, comparable to patients with early-stage CML.43 However, unlike patients with CML, the response in
patients with MM was not always complete or durable. Three patients
developed complete responses to DLI and 2 others demonstrated partial
responses. Although 2 patients remain in a complete remission, several
patients who responded subsequently developed evidence of progressive
disease. Interestingly, progressive disease in 2 patients occurred with the development of plasmacytomas that were noted while the bone marrow
and serum paraprotein continued to show evidence of a response. This
finding may suggest that the DLI reaction in patients with myeloma is
primarily bone marrow directed and that extramedullary sites may remain
sanctuary sites of disease. As with patients with CML, the time to
response in patients with myeloma can be prolonged, and an initial
increase in Ig after DLI should not be viewed as a failure to respond
to DLI.
The results of this study demonstrate that the clinical development of
GVHD is not required for GVL. Overall, 43% of patients in this study
responded to CD8-depleted DLI without clinical evidence of GVHD. Of
patients with early stage CML, 46% achieved a complete response
without GVHD, whereas 40% of patients with myeloma had evidence of a
response without GVHD. The time to response in patients who developed
GVHD and those who did not was similar. Moreover, except for infusion
of larger numbers of cells from female donors, there were no pre-DLI
clinical characteristics identified that predicted for an increased
risk of GVHD after DLI.
Although responses can occur in the absence of GVHD, the development of
GVHD is nevertheless highly associated with response. This close
relationship between GVHD and GVL has been noted in prior studies.
Collins et al9 reported that 42 of 45 patients (93%) who
developed a complete response also developed GVHD. In our study, GVHD
was noted only in patients who developed a response after DLI. In fact,
there were no patients in our study who developed GVHD and did not
respond. This is in contrast to results of unmanipulated lymphocyte
infusions, in which GVHD can occur in some patients in the absence of a
response. This observation suggests that one possible effect of CD8
depletion may be the selective removal of those alloreactive T cells
that may be responsible for GVHD in the absence of a GVL effect.
Although Fig 2 shows that the achievement of clinical response is not
dependent on the development of GVHD, evidence of the GVL reaction is
often noted in patients before the clinical development of GVHD.
Although some patients developed evidence of GVHD simultaneously with
response, there were no instances in our study in which development of
GVHD preceeded a response. Evidence of the GVL reaction includes the
decrease in white blood cell counts as well as decreasing numbers of
Ph+ cells in the bone marrow that often occur before
obtaining a complete cytogenetic response. In some cases, cytogenetic
responses in patients with CML preceded the development of GVHD by
weeks to months. A similar pattern has been noted in patients with MM, with a decrease in monoclonal protein often noted before development of
GVHD. Taken together with the observation that GVHD was noted only in
responding patients, these clinical findings suggest the possibility
that GVL may induce GVHD, an association that has often been viewed in
reverse.6,44,45 Although the potential mechanisms whereby
this may occur in vivo are highly speculative, it is possible that GVL
in vivo may generalize from a disease-specific or
hematopoietic-restricted alloantigen-specific response to a more
nonspecific reaction such as GVHD. As further experiments define the
mechanism of GVL in vivo, it may be possible to begin to examine this
hypothesis.
A previous report by Mackinnon et al29 suggested that
infusion of increasing numbers of cells at the time of DLI was
associated with an increased incidence of GVHD. However, the results of
this study were somewhat difficult to interpret, because patients were eligible to receive additional infusions of donor cells 4 weeks after a
previous infusion if there was no evidence of toxicity at that time.
Although our study was not designed to have adequate power to detect
differences in GVHD incidence between dose levels, a suggestion of an
increased incidence of GVHD was noted in patients treated with 1.0 × 108 CD4+ cells/kg compared with
patients treated with 0.3 × 108 CD4+
cells/kg (55% v 22%). However, two large registry reports did not find a relationship between the number of cells infused and the
risk of GVHD.8,9 These studies examined patients receiving greater than 3 or 4 × 108 mononuclear cells/kg
compared with patients receiving fewer cells. The data presented in
this study and others29,46 suggest that the cell number
threshold for the development of significant GVHD may be well below the
levels examined in these reports. With these conflicting results, the
optimal dose of cells to be infused at the time of DLI has yet to be
determined. The single infusion of 1 × 107
CD3+ cells/kg reported by Mackinnon et al29 and
3 × 107 CD4+ cells/kg reported
in our study appear to be associated with a relatively low incidence of
GVHD. In future studies, the efficacy of lower doses of cells should be
explored recognizing the often prolonged time to the development of
GVHD as well as disease response after a single infusion of cells.
Whereas significant responses were noted in patients with early-stage
CML and multiple myeloma, no significant responses were noted in
patients with advanced CML or acute leukemia after a single course of
cell infusion. The reason for this lack of response is not known. One
possible explanation is the rapid progression of disease in patients
with acute leukemia. As noted previously, the time to response after
DLI is often prolonged and the GVL reaction may not have sufficient
time to develop in patients with rapidly progressive disease. An
alternative hypothesis is that acute leukemia cells do not
contain suitable target antigens or may not be capable of
proper antigen presentation at the cell surface. Interestingly, no
evidence of GVHD was noted in these patients as well. Future studies to
improve the efficacy of response in patients with advanced CML or acute
leukemia may include the treatment of these patients while in a minimal
disease state or the addition of cytokines, such as IL-2, which may
lead to the activation of specific T-cell populations, promote proper
presentation of target antigens, or amplify the GVL response in these
patients.
The mechanism and specificity of the DLI reaction remains uncertain. T
cells are believed to the primary mediators of GVL. Whereas almost all
detectable CD8+ T cells were removed by the depletion,
their participation in the GVL reaction after DLI cannot be excluded.
Phenotypic analysis of circulating lymphocytes did not demonstrate the
expansion of any specific effector population. In other studies, the
analysis of T-cell repertoire in CML patients treated with CD8-depleted DLI demonstrates the clonal expansion of specific T-cell populations that coincide with the development of cytogenetic
response.47 The identification of the expanded T cells,
their CD4 or CD8 subtype, and the specificity of these cells has yet to
be determined.
Whether DLI represents a disease-specific or allo-specific response is
unclear. In sex-mismatched donor-recipient pairs, all patients who
responded to DLI had cytogenetic conversion to donor hematopoiesis.
This finding is consistent with others who have also demonstrated a
conversion from a mixed chimeric state before infusion to complete
donor hematopoiesis after infusion.6,29,48 In our study, we
noted that radiation-induced cytogenetic abnormalities in residual host
cells were also eliminated at the time of response. Taken together,
these observations suggest that the DLI reaction is likely to be
directed against allo-specific antigens rather than disease-specific
targets.49 Minor HLA antigens represent possible examples
of allo-antigens expressed on hematopoietic stem cells that may be
targets of the GVL response,50,51 but other unrecognized
targets may also exist. The restricted expression of minor
histocompatibility antigens may also function to limit the toxicity of
this treatment and limit the extent and severity of GVHD. The
effectiveness of DLI in CML and MM may be due to the derivation of
these tumors from hematopoietic stem cells or to their ability to
express the GVL target antigens at relatively high levels compared with
other cells. As further studies begin to identify the target antigens
of the GVL response in patients with different hematologic
malignancies, it may be possible to develop new clinical strategies to
selectively amplify the antileukemia effects of treatment with donor
cells.
| |
FOOTNOTES |
Submitted July 23, 1997;
accepted January 12, 1998.
Supported by National Institutes of Health Grants No. AI29530 and
CA01730 and the Leonard Frankel Foundation for Leukemia.
Address reprint requests to Edwin P. Alyea, MD, Division of Hematologic
Malignancies, Dana-Farber Cancer Institute, 44 Binney St, Boston, MA
02115; e-mail: edwin_alyea{at}dfci.harvard.edu.
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.
| |
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Abstract
Introduction
Abstract