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Blood, Vol. 95 No. 4 (February 15), 2000:
pp. 1214-1221
CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
Treatment of relapsed leukemia after unrelated donor marrow
transplantation with unrelated donor leukocyte infusions
David L. Porter,
Robert H. Collins Jr,
Christine Hardy,
Nancy A. Kernan,
William R. Drobyski,
Sergio Giralt,
Mary E.D. Flowers,
James Casper,
Ann Leahey,
Pablo Parker,
Rosemarie Mick,
Bev Bate-Boyle,
Roberta King, and
Joseph H. Antin
From the Division of Hematology-Oncology, Department of Medicine,
and from the Department of Epidemiology and Biostatistics, University
of Pennsylvania Medical Center, Philadelphia, PA; Division of
Hematology/Oncology, University of Texas Southwestern Medical School,
and Baylor Sammons Cancer Center-Dallas, Dallas, TX; Memorial Sloan
Kettering Cancer Center, New York, NY; Division of Hematology-Oncology,
Department of Medicine, and from the Division of Pediatrics, Bone
Marrow Transplant Program, Medical College of Wisconsin, Milwaukee, WI;
Department of Hematology, University of Texas MD Anderson Cancer
Center, Houston, TX; Fred Hutchinson Cancer Research Center, University
of Washington, Seattle, WA; Division of Oncology, Children's Hospital
of Philadelphia, Philadelphia, PA; City of Hope Medical Center, Duarte,
CA; National Marrow Donor Program, Minneapolis, MN; and Department of
Adult Oncology, Dana-Farber/Partners Cancer Care and Department of
Medicine, Brigham and Women's Hospital and Harvard Medical School,
Boston, MA.
 |
Abstract |
The efficacy and toxicity of donor leukocyte infusions (DLI) after
unrelated donor bone marrow transplantation (BMT) is largely unknown.
We identified 58 recipients of unrelated DLI (UDLI) for the treatment
of relapsed disease from the National Marrow Donor Program database. A
retrospective analysis was performed to determine response, toxicity,
and survival after UDLI and to identify factors associated with
successful therapy. UDLI was administered for relapsed chronic
myelogenous leukemia (CML) (n = 25), acute myelogenous leukemia
(AML) (n = 23), acute lymphoblastic leukemia (ALL) (n = 7), and
other diseases (n = 3). Eight patients were in complete remission
(CR) before UDLI, and 50 were evaluable for response. Forty-two percent
(95% confidence interval [CI], 28%-56%) achieved CR, including 11 of 24 (46%; 95% CI, 26%-66%) with CML, 8 of 19 (42%; 95% CI,
20%-64%) with AML, and 2 of 4 (50%; 95% CI, 1%-99%) with ALL. The
estimated probability of disease-free survival (DFS) at 1 year after CR
was 65% (95% CI, 50%-79%) for CML, 23% (95% CI, 9%-38%) for
AML, and 30% (95% CI, 6%-54%) for ALL. Acute graft-versus-host disease (GVHD) complicated UDLI in 37% of patients (grade II-IV, 25%). A total of 13 of 32 evaluable patients (41%) developed chronic GVHD. There was no association between cell dose administered and
either response or toxicity. In a multivariable analysis, only a
longer interval from BMT to relapse and BMT to UDLI was associated with improved survival and DFS, respectively. UDLI is an
acceptable alternative to other treatment options for relapse after unrelated donor BMT.
(Blood. 2000;95:1214-1221)
© 2000 by The American Society of Hematology.
| |
Introduction |
Allogeneic donor leukocyte infusions (DLI) can
effectively induce complete remissions in patients with relapsed
leukemia after bone marrow transplantation (BMT). In 60% to 80% of
patients with chronic myelogenous leukemia (CML), DLI from a
histocompatible sibling will induce sustained complete cytogenetic or
molecular remissions.1-11 This therapy is less effective
for patients with other diseases who relapse after allogeneic
BMT.3,8,12,13 The toxicity of DLI from matched sibling
donors can be substantial. For patients with CML, treatment-related
mortality associated with DLI is as high as 20-30%,14 and
has been related to graft-vs-host disease (GVHD) and infectious
complications from marrow aplasia and/or immunosuppressive
therapy.3,14 DLI therapy would seem an acceptable
alternative to second allogeneic BMT, however, as the morbidity and
mortality of second BMT is high and prohibitive for many
patients.15,16
Patients who have relapsed after unrelated donor (URD) marrow grafting
may also benefit from DLI. However, there is limited data regarding the
efficacy and toxicity of DLI after unrelated donor BMT. Results in
several patients given unrelated donor leukocyte infusions (UDLI) have
been described in larger series of DLI, but too few patients were
reported to assess clinical outcomes.3,8 One study compared
matched sibling DLI to UDLI,17 but included only 12 recipients of unrelated DLI (UDLI) and was limited to patients with
relapsed CML. To determine the efficacy of UDLI and assess the toxicity
associated with this therapy, we analyzed data from 58 patients
identified by the National Marrow Donor Program (NMDP) who received
UDLI for relapse of their original disease.
| |
Patients and methods |
Data collection
Patients were identified from the NMDP database. All centers that
requested donor leukocyte products through the NMDP for "relapse"
or "secondary malignancy" were contacted in writing; 19 of 20 centers contacted agreed to participate, accounting for 58 of 61 patients (95%) who received UDLI for relapse organized through the
NMDP. Questionnaires were sent to each center designed to assess
pretransplant characteristics and complications, relapse characteristics, and details of UDLI therapy. Most data were collected from individual centers, but some data, such as demographics and donor
information, were provided through NMDP records. Data collection included, but was not limited to, the following: (1)
Patient demographics: age and sex; (2) Pre-BMT characteristics:
diagnosis, cytogenetic abnormalities, pre-BMT therapy; (3) BMT
characteristics: time from diagnosis to BMT, disease status at BMT,
conditioning regimens, complications of BMT (including acute and
chronic graft-versus-host disease and other complications); (4) Disease
characteristics: disease status at relapse, time from BMT to relapse,
treatment for relapse other than UDLI; (5) UDLI characteristics:
indication for UDLI, time from relapse to UDLI, performance status,
chimerism analysis, use of chemotherapy before UDLI, cell dose
administered and number of infusions given, concurrent use of
cytokines, modification of donor leukocyte product; (6) Response to
UDLI: overall response, use of additional therapy (ie, cytokines),
toxicity including acute and chronic GVHD, pancytopenia and marrow
aplasia, infections, chimerism after UDLI, treatment and response of
GVHD, current disease status, date and cause of death.
UDLI was performed from October 1993 through February 1997; 58 patients received UDLI for relapsed disease, and 30 patients received
UDLI after a T-cell- depleted transplant. Patient
characteristics are summarized in Table 1.
Definitions
For patients with CML, a complete remission (CR) was defined as a
complete cytogenetic response. Responses were scored as partial
response (more than 50% reduction in abnormal cytogenetics), complete
cytogenetic response (no detectable cells containing the Philadelphia
chromosome on at least 1 occasion), and complete molecular response
(negative polymerase chain reaction [PCR] assay for bcr/abl
messenger RNA [mRNA]). For this analysis, 1 negative PCR test for
bcr/abl was considered a complete molecular response. Of 8 patients who were classified as achieving a molecular remission, more
than 1 negative PCR test was documented in 5 patients. Two patients
received UDLI while in a cytogenetic remission but with evidence of
disease by PCR (molecular relapse); CR in these patients was defined as
a "molecular remission." Early-phase relapse of CML included
patients with molecular, cytogenetic, or chronic phase relapse.
Patients were considered to have late-phase relapse of CML if they were
treated for accelerated or blast-phase CML. Patients with
accelerated-phase CML based on abnormal cytogenetics were initially
classified as having advanced-phase CML.
For patients with diseases other than CML, responses were scored as CR
(less than 5% blasts in bone marrow or no other evidence of disease)
or partial remission (more than 50% reduction in bone marrow or
peripheral blasts or more than 50% reduction in adenopathy). Patients
who received UDLI in conjunction with cytoreductive chemotherapy (n = 4) or after achieving remission from other therapy (n = 7) were considered not evaluable for a direct response to UDLI. The analysis was performed both including these patients (based on disease
status after UDLI regardless of pre-DLI therapy) and excluding these
patients, as noted below.
Based on data from other DLI series,1,3 a minimum follow-up
of 28 days after UDLI was required for patients to be considered evaluable for response, acute GVHD, or marrow aplasia. One patient with
grade IV acute GVHD 5 days after UDLI died on day 27 without a
response and was considered evaluable for acute GVHD but not response
or aplasia. No other patient who survived 28 days or fewer after UDLI
developed acute GVHD or marrow aplasia. A minimum follow-up of 100 days
after UDLI was required for patients to be evaluable for chronic GVHD.
HLA antigen matching was defined as matched versus mismatched according
to NMDP criteria. Mismatched patients include "minor" mismatches
(mismatches within cross-reactive antigen groups) and major mismatches
(non-cross-reactive antigen mismatches).
Statistical analysis
Data were analyzed either with the SAS statistical software (SAS
Institute, Cary, NC), or with Statview statistical software package
(Abacus Concepts, Berkeley, CA). Overall survival was calculated from
the time of first UDLI until death from any cause or last follow-up.
Disease-free survival (DFS) was calculated from the time CR was
documented until relapse, death, or last follow-up. Factors that were
examined for an association with these outcomes included age, sex,
donor-patient sex match, HLA-match grade, time from BMT to relapse,
time from relapse to UDLI, time from transplant to UDLI, acute and
chronic GVHD after transplant, T-cell-depleted graft for original BMT,
and indications for UDLI. The probabilities of overall
survival and DFS were calculated according to the method of Kaplan and
Meier.18 The effects of categorical variables on survival
and DFS were examined using the log-rank test,19 and the
effects of continuous variables were analyzed with a Cox proportional
hazards model.20 Optimal Cox models for survival and DFS
were developed using stepwise regression.21 Only factors
that were significant at the 0.05 level in the univariate analysis of
individual effects were considered in a multivariable analysis. Factors
associated with survival and DFS in the multivariable analysis were
corrected to adjust for a diagnosis of acute myelogenous leukemia (AML)
using Cox regression analysis. Other outcomes examined with a logistic
regression model22 included response and incidence and
severity of acute GVHD. For patient subsets with smaller sample sizes,
the Fisher exact test was used to evaluate associations.23
| |
Results |
Donor leukocyte infusions
In most cases, donor leukocytes were collected by leukapheresis and
procured through requests to the NMDP. In several cases, donor T-cells
were cryopreserved after T-cell depletion of the donor marrow at the
time of transplantation. Cell dose measurements were reported
differently by different centers. Cell dose was not reported for 4 patients. The total number of mononuclear cells (MNC) administered was
determined for 50 patients, and the CD3+ cell content of
the donor product was determined in 33 cases, as shown in Table 1. In
28 patients (48%), the cell dose was more than
1 × 108 MNC/kg, and in 24 patients (41%), the cell
dose was less than 1 × 108 MNC/kg. The donor
product was depleted of CD8+ cells in 5 patients, red cells
depleted in 4 patients, and gene insertion (herpes simplex virus
thymidine kinase) attempted in 1 donor product.
Donor cells were given in 1 infusion in 39 patients (67%), in 2 infusions in 12 patients (21%), and in 3 to 6 infusions in 7 patients
(12%). Of the 19 patients who received more than 1 UDLI, the dates of
subsequent infusions were available for 17 cases. UDLI was completed in
8 cases within 1 month and, in 15 cases, within 4 months. Although
subsequent infusions contained more than 2-fold higher cells than the
first infusion (dose escalation) in 8 patients, only 4 patients
received at least a 2-fold dose escalation over a period of more than 1 month, and none of these patients achieved a CR. The other patients who
received cells over more than 1 month received similar or even lower
cell doses.
Response and survival
Of the 58 patients treated with UDLI for relapsed disease, 8 were in
remission prior to UDLI. Of the 50 patients included in the response
analysis, 21 (42%; 95% confidence interval [CI], 28%-56%) were in
CR after UDLI, 4 patients (8%) achieved a partial remission (PR), and
22 (44%) had no response (Table 2).
Follow-up was insufficient to assess response in 3 patients.
Nineteen patients (33%) are alive (17 in CR), with a
median follow-up time from UDLI of 66 weeks (range, more than 9-180 weeks). Fifteen patients (26%) remain in remission more
than 9 to 155 weeks (median, 66 weeks) after documented
CR, 2 are in CR but have minimal residual disease detected only by PCR,
and 2 are alive with active disease. The probability of DFS for
patients with CML, AML, and acute lymphoblastic leukemia (ALL) who were in CR after UDLI is shown in Figure 1.
Seven patients who achieved a CR relapsed with their original disease
and subsequently died.
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| Fig 1.
Disease-free survival for patients with CML, AML, and ALL
who achieved a complete remission after UDLI.
Although 12 patients with AML were in CR after UDLI, the DFS is
determined for the 10 patients whose date of remission was
documented.
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Chronic myelogenous leukemia.
In prior analyses of family-member DLI, the treatment was
most effective for patients with CML. Similarly, in this series, 11 of
24 (46%; 95% CI, 26%-66%) recipients of UDLI for relapsed CML were
in remission after UDLI (1 additional patient was in CR prior to UDLI).
Eleven patients had no response, and 2 patients had a PR (Table 2). The
probability of DFS for the 12 patients in CR after UDLI is shown in
Figure 1; 8 of the 12 patients remain alive in CR more than 17 to 155 weeks (median, 67 weeks) after documented remission. The
median survival after UDLI for patients treated for relapsed CML was 42 weeks. Eleven patients (44%) remain alive more than 10-180 weeks
(median, 79 weeks) after UDLI. This includes 7 patients treated for
early-phase CML and 4 patients treated for advanced-phase CML.
Of 12 patients treated for "early-phase" relapse, 7 (58%)
achieved a CR; CR was documented by PCR in 5 cases and by cytogenetics without PCR in 2 cases. The treatment characteristics and outcome for
these 12 patients according to disease status are summarized in Table
3.
Thirteen patients were treated for advanced-phase disease (accelerated
phase [n = 8] or blast crisis [n = 5]), including 2 patients
who relapsed with advanced disease but received chemotherapy before
UDLI. The median cell dose administered to these 13 patients was
0.9 × 108 MNC/kg (range,
0.17 × 108 to 5 × 108 MNC/kg).
Five of the 13 patients were in CR after UDLI; CR was documented by PCR
in 3 patients and cytogenetics in 2 patients. Four of these patients
had a direct response to UDLI, and 1 was in CR prior to UDLI. All 4 patients with a direct response to UDLI were treated for accelerated
phase and remain alive more than 48 to 155 weeks after documentation of
CR without a relapse. No patient with blast-crisis CML had a
direct response to UDLI with a minimum follow-up of 5 weeks, and all 5 patients died 5 to 17 weeks after UDLI from progressive disease
(n = 4) or infection (n = 1).
Because many patients who relapse after allogeneic BMT will have
complex karyotype abnormalities but have a clinical course typical for
chronic-phase CML, we analyzed response rates classifying patients with
accelerated-phase CML based only on cytogenetic abnormalities as
"early-phase relapse" and classified only patients with other
clinical findings of accelerated phase as "advanced-phase relapse." In this analysis, 10 of the 17 patients (59%) with
early-phase relapse were in CR after UDLI, and 2 of the 8 patients with
advanced-phase CML were in CR after UDLI. The overall survival appears
superior for recipients of UDLI for early-phase relapse of CML compared with patients with advanced-phase relapse (P = .02) (Figure
2) when these criteria are used for the
analysis.
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| Fig 2.
Survival after UDLI for CML according to disease state.
The solid line represents patients treated for early-phase relapse, and
the dashed line represents patients treated for advanced-phase
relapse. In this analysis, early-phase relapse includes patients
classified as "accelerated phase" based solely on abnormal
cytogenetic findings with no other clinical manifestations of
advanced phase disease. This analysis shows improved survival
for recipients of UDLI for early-phase relapse of CML.
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All 5 patients treated for relapsed CML (early-phase relapse
[n = 4]; advanced-phase relapse [n = 1]) who received donor
products depleted of CD8+ cells achieved a CR and remain in
remission 17 to 135 weeks after UDLI.
Acute myelogenous leukemia.
AML is less responsive to family-member DLI. Four patients
with AML were in CR before UDLI. Of 19 patients not in CR prior to
UDLI, 8 (42%; 95% CI, 20%-64%) were in CR after UDLI (Table 2).
Nine patients had no response, 1 patient had a PR, and follow-up was
insufficient in 1 patient. Four of the 12 patients in remission after
UDLI eventually relapsed 8 to 31 weeks after documentation of
remission; all 4 patients died from progressive disease. An additional
4 patients in CR after UDLI died from treatment-related complications
(GVHD [n = 1]; infection [n = 3]). Five patients (22%) are
alive in CR (n = 4) or with persistent cytogenetic evidence of
disease (n = 1) more than 9 to 102 weeks (median, 55 weeks) after
UDLI. The probability of DFS for patients who were in CR after UDLI is
shown in Figure 1, and the median survival after UDLI for relapsed AML
patients was 11 weeks.
Acute lymphoblastic leukemia.
DLI is typically the least effective in ALL. In this series, 3 patients
were in CR before UDLI: 1 relapsed and died of progressive disease, 1 died of GVHD, and 1 remains alive in CR 16 weeks
after UDLI. Of the remaining 4 patients, 2 (50%; 95% CI,
1%-99%) were in CR after UDLI (Table 2); 1 remains alive
158 weeks after UDLI, and 1 relapsed 14 weeks after UDLI
and died of progressive disease. The median survival after UDLI
for relapsed ALL patients was 35 weeks. One patient had no
response and died of progressive disease, and 1 patient died within
a week of UDLI with insufficient follow-up. The probability of
DFS for the 5 patients who were in CR after UDLI is shown in
Figure 1.
Other diseases.
Three patients with non-Hodgkin's lymphoma (n = 2) or chronic
myelomonocytic leukemia (n = 1) failed to achieve CR after UDLI (1 CR, 1 PR, and 1 with follow-up less than 28 days), with a follow-up of
2 to 24 weeks after UDLI. Two patients died from progressive disease,
while 1 remains alive with active disease 24 weeks after UDLI.
Toxicity
Graft-versus-host disease.
Fifty-six patients were evaluable for GVHD with follow-up at least 28 days after UDLI, and these data are summarized in Table 2. Sixty-one
percent of patients had no GVHD, and grade II-IV acute GVHD developed
in 25% of patients. The incidence or severity of acute GVHD was not
related to the indication for UDLI, cell dose administered, or a prior
history of GVHD after BMT.
Of 32 patients surviving more than 100 days after UDLI, 13 (41%)
developed chronic GVHD. Limited chronic GVHD occurred in 3 patients,
and extensive chronic GVHD was seen in 10 patients. Seventeen (53%)
had no chronic GVHD with a median follow-up of 43 weeks (range, 16-180 weeks) after UDLI, and 2 patients were not evaluable for chronic GVHD.
The incidence of chronic GVHD was not associated with the indication
for UDLI, cell dose administered, or a history of GVHD after BMT. In
addition, acute GVHD after UDLI did not predict development of chronic
GVHD in patients surviving longer than 100 days from UDLI; 5 of 11 patients with acute GVHD developed chronic GVHD, whereas 8 of 21 patients without acute GVHD subsequently had clinical signs of chronic
GVHD (P = .7).
Aplasia from UDLI.
Four of 34 (12%) evaluable patients developed marrow aplasia
attributable to UDLI after receiving 0.1 × 108 to
2.2 × 108 MNC/kg. Aplasia was associated with a CR
in 1 patient with CML, 1 patient had a PR, and no response was noted in
2 patients. Two of these patients died from progressive disease, and 1 died from infection as a result of therapy.
Effect of pre-UDLI therapy
Many patients with AML and ALL received UDLI at the time of a
chemotherapy-induced nadir or after achieving remission with chemotherapy. To determine the effect of therapy prior to UDLI, patients with adequate follow-up who were evaluable for a direct response were analyzed separately from patients who received other therapy prior to UDLI.
Acute myelogenous leukemia.
Fifteen patients were evaluable for a direct response; a CR was
documented in 5 patients (33%) a median of 3 weeks (range, 1-57 weeks)
after UDLI. Two of these patients relapsed with AML 8 and 31 weeks
after a documented CR and died of progressive disease. Two additional
patients died of treatment-related complications (GVHD and infection),
and only 1 remains alive in remission more than 54 weeks
after achieving a CR.
Of the 7 patients in CR after UDLI who either received UDLI at the time
of a chemotherapy-induced nadir (n = 3) or after achieving a CR from
other therapy (n = 4), 2 ultimately relapsed 23 and 24 weeks after
UDLI and died of progressive disease. Two of the remaining 5 patients
died of infectious complications, and 3 remain alive in CR more than 9 to 66 weeks after UDLI; the time from UDLI to last
follow-up in 1 patient was over twice the time from BMT to relapse (66 weeks vs 25 weeks).
There was no significant difference in survival probability between the
patients evaluable for a direct response to UDLI and the patients
unevaluable for a direct response (P = .7).
Acute lymphoblastic leukemia.
Two of 3 patients evaluable for a direct response achieved a CR 3 weeks after UDLI. One patient relapsed with ALL 11 weeks after
achieving CR and died of progressive disease. The second patient
remains alive in CR more than 158 weeks after UDLI.
The patient with no response died of progressive disease.
Three patients received UDLI after chemotherapy-induced CR: 1 remains
alive in CR more than 16 weeks after UDLI, 1 patient died
of grade IV acute GVHD, and the third patient relapsed and died of
progressive disease within 26 weeks of UDLI. One patient died from
disease-related complications 1 week after UDLI and was not evaluable
for a response.
The use of pre-UDLI therapy does not appear to produce a noticeable
survival advantage when compared to patients who did not receive
pre-UDLI chemotherapy.
Effect of cell dose on outcome after UDLI
The MNC dose was reported for 50 of 58 patients. These 50 patients
received a median dose of 1 × 108 MNC/kg (range,
0.001 × 108 to 31.8 × 108
MNC/kg); CD3 counts were determined for 33 of these patients (median,
CD3+ cell dose, 0.4 × 108/kg; range,
0.01 × 108 to 5.5 × 108/kg).
There was no association between cell dose and achievement of CR,
presence or severity of acute GVHD (Figures
3 and 4), or chronic GVHD. Similarly, there was no association of MNC dose with
survival or DFS.
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| Fig 3.
Association of mononuclear cell dose with acute GVHD
after UDLI.
There was no association of cell dose with acute GVHD after UDLI.
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| Fig 4.
Association of mononuclear cell dose with response to
UDLI.
There was no association of cell dose with response to UDLI. CR
indicates complete remission; NR, no response; PR, partial remission;
NE, not evaluable.
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Mortality after UDLI
Thirty-nine of the 58 patients (67%) treated with UDLI had died at
the time of this analysis (Table 4). Thirteen patients (22%) died from direct treatment-related causes, including 5 patients (9%) who died from GVHD, 6 patients (10%) who died from infectious causes, and 2 patients (3%) who died from other treatment-related causes. Twenty-six of 58 patients (45%) died from progressive disease
or other disease-related complications.
Effect of pretreatment characteristics on outcome
We determined whether various pretreatment characteristics were
predictive for CR, acute GVHD, survival, and DFS. No factor could be
identified that was associated with response. In addition, as
summarized in Tables 5 and 6, no factor
was associated with GVHD after UDLI. However, in a univariate analysis,
several factors were identified that were associated with an improved
probability of survival and DFS, including a longer time interval
between BMT and relapse and between BMT and UDLI, the use of a
T-cell-depleted marrow graft at original BMT, and a diagnosis of CML.
When these factors were examined in a multivariable analysis, improved
survival was associated with an interval from BMT to relapse of more
than 1 year (P = .0015, hazard ratio 0.28, 95% CI,
0.13-0.61), and improved DFS was associated with an interval from BMT
to UDLI of more than 1 year (P = .002, hazard ratio 0.09, 95% CI, 0.02-0.40). More patients with AML relapsed and were treated
with UDLI within 1 year of BMT (21 of 23 AML patients) than patients
with CML (6 of 25 patients) or ALL (4 of 7 patients). When this
analysis was adjusted to account for the larger number of patients with
AML receiving UDLI within 1 year of BMT, a time interval from BMT to
relapse of more than 1 year remained the most significant predictor of
survival (P = .0033), and time from BMT to UDLI of more than 1 year remained the most significant predictor of DFS
(P = .003). These differences still may be due to more
disease-related deaths in patients treated within 1 year of BMT. In
these patients, there was no noticeable difference in treatment-related
mortality associated with UDLI given within 1 year of BMT.
When patients with CML were analyzed separately, no factor could
be identified that was predictive of response or acute GVHD. In a
univariate analysis, an interval from BMT to relapse of more than
1 year was associated with improved survival (P = .024) but not DFS (P = .24). The time from BMT to UDLI was also
associated with an improved probability of survival
(P = .01). In a multivariable analysis, the time from BMT to
UDLI remained predictive for improved survival (P = .009,
hazard ratio 0.98, 95% CI, 0.97-0.996) but was not associated with DFS
(P = .08). No other factor was identified that predicted
survival for CML patients other than CML phase at the time of UDLI, as
described above.
| |
Discussion |
For patients who relapse after matched sibling allogeneic BMT, DLI
has been used to induce a direct GVT reaction. However, this treatment
may be associated with potential morbidity and mortality.14
Applying this therapy after unrelated donor BMT might be expected to
have even greater risks of treatment-related toxicity, because of the
greater major and minor histocompatibility differences between
unrelated recipients and donors. Other series of DLI describe results
of UDLI in only small numbers of patients,3,8,17 and the
efficacy and toxicity of UDLI is largely unknown. Therefore, we have
compiled results from 58 of the 61 recipients of UDLI identified
through the NMDP database to determine the efficacy and toxicity of
this therapy and to determine factors that influence the success of UDLI.
Our analysis demonstrates that UDLI can successfully induce a direct
GVT effect for patients with relapsed leukemia. Approximately half of
the patients were in remission after UDLI, and most of these patients
had a direct response to UDLI without additional chemotherapy.
Unfortunately, outcome is limited by toxicity and relapse; only one
third of all patients remain alive, and 29% remain in remission;
however, 48% of patients who were in CR after UDLI remain alive in CR
more than 9 to 180 weeks after UDLI.
Patients with CML have the highest likelihood of response after
matched sibling DLI. Interestingly, when unrelated donors are
used, the response rate for relapsed CML is similar to the rate
expected with family-member DLI. Unfortunately, in neither situation is the treatment for blast-crisis relapse effective. For the
purpose of this analysis, a CR for patients with CML was defined as a
complete cytogenetic remission. Reversion to normal cytogenetics
was considered an appropriate definition of CR because the
significance of minimal residual disease detected by PCR alone is
of unclear significance in CML. However, the remission was further
documented in 8 of 12 patients by PCR analysis for the bcr/abl translocation. Although it is not known if all patients achieved a molecular remission, it is notable that in other series of
DLI, 95% to 100% of patients who were in cytogenetic remission had no
detectable bcr/abl RNA transcripts when studied by
PCR.1,3,8 It should be noted that patients were considered
to be in molecular CR if they had at least 1 negative PCR test for
bcr/abl, although the clinical significance of 1 negative test
is not well defined. After allogeneic BMT, sequential positive PCR
tests predict for clinical relapse, although some patients have
residual disease by PCR detection and do not relapse.24-27
Clearly, continued follow-up will be important to determine the
significance of positive PCR testing for bcr/abl after UDLI.
Response rates in patients with acute leukemia to matched sibling DLI
have generally been poor; only 10% to 20% of patients treated for
relapsed AML or ALL achieve CR. In contrast, 42% of patients with AML
were in CR after UDLI, and 2 of 4 evaluable patients treated for ALL
who were evaluable for a response achieved a CR. The small numbers of
patients treated in each group preclude comparisons among disease
categories or to matched sibling DLI and are insufficient to allow
detailed analysis of factors predictive for response and outcome;
however, these response rates are favorable compared with anticipated
outcomes for alternative therapy such as second unrelated donor
BMT.15,28,29 Although UDLI may be an attractive alternative
to second unrelated donor BMT, long-term outcome in either case is
unsatisfactory, demonstrating the need to develop newer, more effective
approaches to relapse of acute leukemia.
Morbidity and mortality remain significant after UDLI. However, the
incidence of acute or chronic GVHD and marrow aplasia may be acceptable
compared with other potential treatment options such as second marrow
transplantation. The treatment-related mortality rate was 22% in our
series, mostly related to GVHD and infections. Although it is difficult
to compare results from this retrospective analysis to results from
HLA-matched sibling DLI, the incidence and severity of acute and
chronic GVHD did not appear to be higher after UDLI compared with large
retrospective analyses of DLI from matched siblings.3,8 The
incidence of acute GVHD after UDLI was 38% compared with 60% after
sibling DLI.3,8 Similarly, the incidence of chronic GVHD
was 41% compared with 61% reported after matched sibling
DLI.3 However, patients who relapse after unrelated donor
BMT may be a selected group with a lower risk of GVHD. The most
susceptible patients to severe GVHD may have died or developed severe
GVHD after BMT and may have been considered inappropriate candidates
for UDLI. Moreover, the graft-versus-leukemia (GVL) effects after
unrelated donor BMT may be greater than after matched sibling BMT, even
when the marrow graft is T-cell depleted.30 Thus, patients
who do relapse may represent a selective population with the lowest
risk of GVHD.
Although toxicity after UDLI seems acceptable, strategies to minimize
treatment-related morbidity and mortality will be useful. For instance,
10% of patients died of infectious complications directly related to
therapy, including marrow aplasia. After matched sibling DLI, the
administration of additional donor marrow has successfully reversed
marrow aplasia1,4; the early administration of additional
donor stem cells, or the use of granulocyte colony-stimulating factor-mobilized donor MNC products, may serve to limit complications related to neutropenia. Several patients received manipulated donor
products in an effort to reduce GVHD. All 5 recipients of CD8+ cell-depleted products for relapsed CML achieved
remissions, similar to results noted after CD8+
cell-depleted matched sibling DLI.31,32 One of these
patients developed grade II acute GVHD, and 2 patients developed
chronic GVHD; given the small numbers of patients, the value of
this manipulation is unknown.
We were unable to identify any factors that were associated with either
response or GVHD after UDLI. Interestingly, in contrast to studies by
Mackinnon et al in family-member DLI,9 there was no association of cell dose with response, survival, or toxicity. No patient had a CR after receiving cell doses below
0.1 × 108 MNC/kg, while many patients failed to
respond to doses above 1 × 108 MNC/kg. Because
there was no association between cell dose and GVHD, it is reasonable
to administer 0.1 × 108 to
1 × 108 MNC/kg unrelated donor leukocytes for
relapsed disease. In 33 cases, CD3+ cell doses were known,
and there was a similar lack of association with CD3+ cell
dose and response, toxicity, and survival. A threshold dose of effector
cells may be required for GVHD and GVL activity, and doses above this
threshold may not result in quantitative differences in GVHD or GVL
activity. Given the lack of association between MNC dose and toxicity,
it is also unclear that lower cell doses will result in safer therapy.
Although 19 patients received more than 1 donor cell infusion, a
"dose escalation" strategy was unlikely to be an important factor
in this analysis. Subsequent infusions were completed within 1 month in
8 patients, and dates of subsequent infusions were not available for 2 patients. Eight of the remaining 9 patients received infusions within 5 months, and 1 patient received an additional UDLI 1 year later. Only 3 patients who received multiple doses of UDLI more than a month apart
eventually achieved a CR; in these 3 patients it is difficult to
know the cell dose responsible for remission induction. For instance, a
response may have occurred from the first infusion if sufficient
time was given before subsequent infusions. It is notable, however,
that in these 3 patients subsequent doses were similar to the
original dose. Given the limited number of patients who received dose
escalations over more than 1 month, there is insufficient data to
determine a dose-response relationship by this strategy, as has been
observed after escalating doses of matched sibling DLI.9
Intervals from BMT to relapse and BMT to UDLI were the
only factors predictive of improved survival and DFS in both a
univariate and multivariable analysis of UDLI. There was no significant
difference in treatment-related death in the recipients of UDLI within
1 year of BMT, implying that the difference in survival and DFS is not
due to excessive toxicity of UDLI when given within a year of BMT. The
differences were largely accounted for by an increased incidence in
disease-related death in the group of patients treated within 1 year of
BMT. Notably, many more patients with AML relapsed and received UDLI
within 1 year of BMT than patients with CML or other diseases, which
could partially account for the worse prognosis in this group of
patients. It is also probable that patients who relapse within 1 year
of BMT have more aggressive disease and are least likely to respond to
GVL induction. However, given the excessive toxicity anticipated from
second BMT within 1 year of the initial transplant, a trial of UDLI or
other investigational therapy seems warranted.
In the matched sibling setting, low doses of DLI (for
instance, used in the treatment of posttransplant EBV-related
lymphoproliferative disorders are felt to minimize the risk of GVHD and
aplasia. However, even lower doses of T cells may precipitate GVHD when
the histocompatibility disparity between donor and recipient is higher,
such as in the unrelated donor transplant setting. In this series,
clinically important acute GVHD occurred with low doses of donor
lymphocytes, and there was no correlation of cell dose with toxicity.
It is therefore possible that even lower doses of MNC will be necessary to further minimize GVHD. It should be noted, however, that factors other than cell dose may have a significant impact on development of
GVHD. The degree of minor histocompatibility antigen disparity is
likely to influence GVHD. In addition, the timing of DLI may be
critical, and infusions given shortly after BMT may result in
significantly more GVHD than infusions given with a greater delay after
BMT.33,34
There are several limitations to this study. It is a retrospective
analysis of data collected from 19 transplant centers. Treatment
strategies differed among institutions, and methods and timing of
follow-up testing were not standardized. Both the timing of cytogenetic
or PCR testing and the sensitivity of the assays may have varied among
laboratories. Reporting bias is also a common concern in this type of
analysis, but it is important to note that data were available for 95%
of all patients who received UDLI identified through the NMDP database,
and it is therefore likely that this study includes a representative
population of UDLI recipients. Despite these limitations, it is
unlikely that a prospective study will be done soon to address these
issues. This study gives a reliable estimate of the value of UDLI and highlights its limitations and areas for future investigation.
| |
Acknowledgments |
The following centers contributed to this study by submitting
data: MD Anderson Cancer Center, Houston, TX;
Memorial Sloan Kettering Cancer Center, New York,
NY; Fred Hutchinson Cancer Research Center, Seattle, WA; Baylor
University Medical Center, Dallas, TX; Medical College of Wisconsin,
Milwaukee, WI; City of Hope Medical Center, Duarte, CA; Children's
Hospital of Philadelphia, Philadelphia, PA; Fairview University Medical
Center, Minneapolis, MN; Brigham and Women's Hospital, Boston, MA;
Emory University, Atlanta, GA; St. Jude Children's Research Center,
Memphis, TN; Methodist Hospital of Indiana, Indianapolis, IN;
Children's National Medical Center, Washington, DC; University of
Iowa, Iowa City, IA; University of Arkansas, Little Rock, AK;
Children's Hospital of Orange County, Orange, CA; Medical
College of Virginia, Richmond, VA; Mount Sinai Medical Center, New
York, NY; and University of Rochester, Rochester, NY. RHC acknowledges
support from the Leukemia Association of North Central Texas.
| |
Footnotes |
Submitted April 21, 1999; accepted October 15, 1999.
Reprints: David L. Porter, Division of Hematology-Oncology, 16 Penn Tower, 3400 Spruce St, University of Pennsylvania Medical Center,
Philadelphia, PA 19104; e-mail: dlporter{at}mail.med.upenn.edu.
The publication costs of this
article were defrayed in part by
page charge payment. Therefore,
and solely to indicate this fact,
this article is hereby marked
"advertisement"
in accordance with 18 U.S.C.
section 1734.
| |
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Abstract
Introduction