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Prepublished online as a Blood First Edition Paper on June 21, 2002; DOI 10.1182/blood-2002-03-0984.
CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
From the Department of Adult Oncology and Department of
Biostatistical Science, Dana-Farber Cancer Institute, and the
Department of Medicine, Brigham and Women's Hospital, Boston, MA.
T-cell depletion (TCD) and immunosuppressive medications (ISTs) are
2 methods used for graft-versus-host disease (GVHD) prophylaxis in
unrelated donor (URD) transplantation. However, comparisons of the
clinical outcomes including quality of life and direct medical costs
associated with each type of procedure have not been reported. We
reviewed 48 TCD and 98 IST procedures performed from 1/1/97 to 12/31/99
at the Dana-Farber Cancer Institute, Boston, MA. With a median
follow-up of 1.5 years for survivors, no differences were seen in
relapse, acute GVHD, and overall survival between TCD and IST patients.
Multivariable Cox modeling showed that age of 50 years or less
(P = .002) and low-risk disease (P = .001) predicted survival, but method of GVHD prophylaxis
(P = .6) and degree of human leukocyte antigen (HLA)
matching (P = .8) did not. A subset of patients (53%)
completed quality of life surveys prior to and at 6 and 12 months after
transplantation; participation in the quality of
life study was not associated with clinical characteristics and
outcomes. No differences were seen in quality of life scores prior to
transplantation, and changes over time were similar between groups.
Costs ($113 000 vs $155 000, P < .0001) and total
hospital days (34 vs 46, P = .0006) were significantly lower for patients undergoing TCD procedures. As prospective, randomized studies comparing methods of GVHD prophylaxis are performed, assessment of quality of life and costs should be included to fully
understand the overall impact of each intervention.
(Blood. 2002;100:2697-2702) Almost 30 years after the first successful stem
cell transplantation from an unrelated donor, acute graft-versus-host
disease (GVHD) remains a major barrier to transplantation
success.1 Prophylaxis against acute GVHD is broadly
divided into 2 categories: reduction in T-cell type or number (T-cell
depletion [TCD]) and immunosuppressive medications (ISTs) that
interfere with T-cell function or survival. Observational studies of
unrelated donor (URD) marrow recipients suggest that long-term survival
and disease-free survival are similar using either TCD or IST
approaches to acute GVHD prophylaxis.2-6 However, many of
the same studies also show that TCD is associated with less acute and
chronic GVHD.2,3 Furthermore, TCD appears to be associated
with reduced peritransplantation complications such as hepatic
veno-occlusive disease and pulmonary dysfunction,6-8
suggesting that costs may be lower and quality of life better with TCD.
In the absence of a clear survival or clinical advantage, these
considerations may influence choice of GVHD prophylaxis. However, no
published studies thus far have compared the 2 major methods of GVHD
prophylaxis along these parameters.
We reviewed our experience with 146 URD transplants for hematologic
diseases performed over 3 years to compare clinical outcomes, quality
of life, and costs associated with TCD and IST approaches to acute GVHD prophylaxis.
Subjects
Choice of GVHD prophylaxis (TCD vs IST) was based on attending
physician recommendation and patient preferences after a discussion of
the risks and benefits of each method. Patients were treated on a
variety of clinical protocols. Human leukocyte antigen (HLA) matching
was performed using both serologic and molecular methods. Marrow was
harvested without growth factor treatment of donors. The day of marrow
infusion was designated day 0. Conditioning regimens consisted
primarily of cyclophosphamide (TCD 60 mg/kg per day × 2, IST 1800 mg/m2 per day × 2) and total body irradiation (14 Gy), although busulfan and cytoxan were delivered if radiation was
contraindicated by prior radiotherapy. In addition, TCD patients
received total lymphoid irradiation at a dose of 4.5 Gy or 7.5 Gy. TCD
was accomplished using an anti-CD6 antibody and rabbit complement
resulting in 1 to 2 logs depletion but sparing B and natural killer
cells.9 TCD patients received filgrastim (5 mcg/kg
starting day +1) after marrow infusion until engraftment but did not
receive any additional immunosuppressive medications unless they
required treatment for GVHD. GVHD prophylaxis for IST patients included
combinations of methotrexate (15 mg/m2 day 1, 10 mg/m2 on days +3, +6, +11) and cyclosporine (2.5 mg/kg
twice daily, starting day Routine clinical care for TCD and IST patients after transplantation
was delivered in the same outpatient facility using similar algorithms
for infectious disease prophylaxis and immune-suppressive medication
tapers. Our transplant program practices a primary physician outpatient
model so that all pretransplantation and posttransplantation care is
delivered by the same physician. Although the composition of individual
practices varied, all physicians cared for both TCD and IST patients.
Most patients are local and receive their posttransplantation care and
any necessary hospitalizations at our institution.
Data collection
Clinical data.
Clinical information on survival, relapse, acute and chronic GVHD,
veno-occlusive disease, organ toxicity, and causes of death were
obtained from the clinical transplant database. Relapse was diagnosed
based on hematologic parameters, tissue biopsy, bone marrow biopsy
findings, and cytogenetic or molecular methods according to particular
disease presentations. The consensus conference was used to grade acute
GVHD,10 and chronic GVHD was graded according to published
criteria.11 Patients' overall and event-free survival
follow-up information reflects data in the clinical database as of July
2001. Causes of death attributed to relapse, pulmonary complications
(including interstitial pneumonitis, diffuse alveolar hemorrhage, and
respiratory failure), infections, and all other causes were recorded.
All severe, life-threatening or fatal pulmonary, renal/bladder, and
infectious complications were collected.
Quality of life data.
Fifty-three percent of both TCD and IST patients participated in a
prospective quality of life study. Patients were surveyed by mail prior
to transplantation and at 6 and 12 months after the procedure using the
Medical Outcomes Study Short Form 36 (SF-36), the Quality of Life Index
(QLI), and a rating scale (RS) question. No patient was purposefully
excluded from the quality of life study. Nonparticipation resulted from
inability to contact the patient by telephone, failure to return the
baseline survey, or patient inability to communicate in English.
Cost data. Inpatient charges and total hospital days for the first year after transplantation were retrieved from the administrative database. Charges were converted to costs using departmental ratios of charges to costs, and adjusted to the year 2000 using the medical care component of the consumer price index.15 Professional charges (eg, attending billings) were not captured, but are expected to mirror direct inpatient costs. Outpatient direct medical costs (eg, clinic visits), patient time costs (eg, time spent in clinic), productivity costs (eg, time off work to recover from transplantation), and direct nonmedical costs (eg, transportation, local lodging) were not captured, but are expected to be low compared with direct medical inpatient costs.16 Biostatistical analysis Associations between categorical variables and method of GVHD prophylaxis (TCD vs IST) were assessed by a Fisher exact or chi-square test, as appropriate. The Wilcoxon rank-sum test was used for testing differences between continuous variables. No statistical adjustment was made for performing multiple tests, but a P value of more than .01 should be interpreted with care. All probability values are 2-sided.Patients' overall and event-free survival reflects follow-up information in the database as of July 2001. For event-free survival, relapses and deaths were considered events. The method of Kaplan and Meier was used to estimate survival curves and the log-rank test was used to compare the curves. Cumulative incidences of acute GVHD and relapse are reported separately with death as a competing risk. Cumulative incidence of extensive chronic GVHD is reported with both death and relapse as competing risks.17 We compared overall survival between the 2 GVHD prophylaxes, TCD and
IST, in a Cox regression analysis adjusting for patient age ( Quality of life scores were calculated using algorithms and guidelines for handling missing data recommended by the developers. Results are presented as medians, ranges, and where applicable, 25th to 75th percentiles. The Wilcoxon rank-sum test was used to compare baseline variables. A mixed model assuming a variance/covariance structure with constant variance and covariance was used to compare TCD and IST patients over time and at specific time points. A mixed model uses all available data while allowing for the correlation between observations attributable to within subject (time) and between subject (type of GVHD prophylaxis) factors.18 We analyzed heterogeneity of costs and length of stay between the 2 methods of GVHD prophylaxis by analysis of variance (ANOVA), adjusting
for patient age (
Patient characteristics Table 1 shows the patient characteristics. Briefly, 48 (33%) received TCD while 98 (67%) received IST. The groups were similar in age, patient-donor sex matching, patient-donor CMV status, and use of total body irradiation (TBI)-based conditioning. However, TCD patients were more likely to have better disease status (46% vs 24% low risk, respectively, P = .01) and less likely to have a mismatched donor (2% [one HLA-A mismatch] vs 16% [4 HLA-A, 8 HLA-B, 3 HLA-DR mismatches], P = .01). In addition, the spectrum of diseases differed with a higher proportion of acute leukemia in the TCD group, and more patients with chronic myelogenous leukemia and myelodysplastic syndrome in the IST group.
Clinical outcomes Table 2 summarizes clinical outcomes. TCD and IST patients were observed to have a similar cumulative incidence of relapse, grades II to IV acute GVHD and extensive chronic GVHD. The rate of grades III to IV GVHD (TCD 21% vs IST 17%), and overall and disease-free survival were similar. No differences could be detected in the incidence of severe, life-threatening, and fatal pulmonary, renal/bladder, and infectious complications, but the incidence of veno-occlusive disease was higher (22% vs 8%, P = .04) in the IST patients. The spectrum of contributory causes of death was similar between the groups. Median time to engraftment was much shorter for TCD patients (12 days [range, 9-45 days] vs 24 days [range, 15-41 days], P < .0001); these results exclude 8 IST patients who failed to engraft prior to death.
Figure 1 shows overall and disease-free
survival for 48 TCD and 98 IST patients. Modeling of survival
considering method of GVHD prophylaxis, patient age, patient-donor sex
matching, patient CMV serologic status, degree of HLA-matching, and
disease stage showed that age greater than 50 years (hazard ratio
[HR] 2.07, 95% CI 1.32-3.25, P = .002) and high risk
disease (HR 2.27, 95% CI 1.34-3.85, P = .002) were
significantly associated with a worse outcome. Method of GVHD
prophylaxis (TCD or IST) was not associated with survival (HR 0.88, 95% CI 0.54-1.44, P = .60). (Table
3).
Quality of life There were 25 (52%) TCD and 53 (54%) IST patients who filled out baseline quality of life surveys. Patients who did or did not provide quality of life data were similar regarding patient, disease, and treatment characteristics, and outcomes including survival, disease-free survival, acute GVHD, and relapse (P > .12). There was a trend for patients without quality of life data to be more likely mismatched (17% vs 7%, P = .06).Comparison of patients who did or did not provide quality of life data
within the TCD and IST populations showed that rates of relapse,
event-free survival, and overall survival were not different (data not
shown). For the patients who did return baseline surveys, quality of
life was not different between TCD and IST patients in any of the
domains of the SF-36, the utility calculated from the QLI scores, or
the rating scale. In Table 4, results of
the mixed model showed that quality of life changed over time, but both
TCD and IST groups reported similar changes as measured by the physical
and mental composite scales of the SF-36, the QLI-calculated utility,
and the rating scale.
There were 12 TCD and 33 IST surviving patients who responded to the
6-month survey (response rate 80% vs 97%). Similar scores were seen
on the physical composite SF-36 scale (32 vs 36, P=.60), mental composite SF-36 score (47 vs 54, P=.02), calculated utilities from the QLI (0.85 vs 0.85, P=.61) and the rating scales (70 vs 75, P=.10).
Reported rates of rehospitalization were similar (33% vs 38%,
P=.99) and 42% of TCD patients compared with 28% of IST patients reported very good or excellent health (P=.48).
There were 9 TCD and 24 IST survivors who responded to the 12-month survey (response rate 100% vs 90%). The raw SF-36 data are plotted in
Figure 2.
Days of hospitalization and costs Days of hospitalization and costs were available for 47 TCD and 98 IST patients. One patient was excluded from the cost analysis due to research administrative error. Hospital days and costs were correlated (r2 = 0.39) as expected. Univariate comparisons are shown in Table 2. TCD patients had fewer days of hospitalization (34 vs 46, P = .0006) and lower costs ($113 000 vs $155 000, P < .0001) during the first year after transplantation. This was primarily due to the initial hospitalization, as there was no difference in length of stay and costs in subsequent hospitalizations between the 2 groups.Results from the separate ANOVA analyses modeling the natural logarithm
of costs and length of stay are presented in Table 5. The model provides estimates of the
differences in means on the log scale; transformation back to the
original scales results in ratios with the standard interpretation. For
example, a ratio of 1.22 for costs corresponds to a 22%
increase in costs when patients with high-risk disease are compared
with those with low-risk disease, controlling for all other
characteristics. Our data show that after controlling for patient age,
patient-donor sex matching, patient CMV serologic status, degree of HLA
matching, and disease stage, costs were significantly lower for TCD
patients ($125 000 vs $173 000, ratio 0.73, 95% CI 0.63-0.84, P < .0001) and significantly higher for high-risk
patients (ratio 1.2, 95% CI 1.1-1.4, P = .01). When time
to engraftment was included in the model, an effect of TCD on overall
costs was still detectable (P = .02). Length of stay was
also longer for IST patients (49 vs 40 days, ratio 1.2, 95% CI
1.1-1.4, P = .004) adjusting for all other patient characteristics. Thus, TCD patients have approximately 9 fewer days of
hospitalization and cost $48 000 less than IST patients after
adjusting for age, disease stage, patient-donor sex matching, degree of
HLA matching, and patient CMV status.
We report the costs, quality of life, and clinical outcomes of 48 TCD and 98 IST recipients of URD bone marrow transplants for hematologic diseases. Although the IST group had a higher percentage of mismatched and high-risk patients, their clinical outcomes were remarkably similar to the TCD group. Specifically, rates of engraftment, acute GVHD, extensive chronic GVHD, relapse, and survival were similar. This is consistent with other observational reports in the literature for URD transplantation,2,5 and contrasts with findings in related donor transplantation in which TCD is associated with less acute and chronic GVHD but more relapse.20 Approximately half (53%) of patients participated in a longitudinal quality of life study. Comparison of participants and nonparticipants suggests that the studied population is clinically representative of the entire cohort. TCD and IST patients reported similar pretransplantation quality of life, but contrary to our hypothesis, changes in quality of life were similar over time between the 2 groups and may be due to the comparable GVHD and complication rates. However, total days of hospitalization within the first year and costs were lower for patients undergoing TCD procedures. This finding is largely attributable to the initial period of hospitalization. Subsequent admissions for TCD and IST patients were of similar length and cost. There was a high degree of correlation between time to engraftment and length of initial hospitalization, which in turn drove some of the cost difference. Some supportive care measures were protocol specific, such as filgrastim in the TCD procedures or methotrexate in the IST procedures, and may have contributed to differences in time to engraftment and thus costs. However, an independent effect of TCD on costs was detected despite adjustment for time to engraftment (P = .02). We note a few caveats to our conclusions. First, this is a single-institution, observational study with a median follow-up of 1.5 years for survivors. Patients undergoing TCD procedures were more likely to be HLA matched while patients undergoing IST procedures had more advanced disease. Although conclusions were similar even after adjustment for these differences, residual selection bias may be obscuring significant differences. In addition, late relapses and transplant complications could still result in clinical, quality of life, or cost differences between TCD and IST patients. Second, due to the participation of only half the patients in the quality of life study, the power to detect statistically meaningful differences may be limited and selection bias might be important. However, we believe that factors associated with nonresponse are likely to apply equally to TCD and IST patients. Finally, different methods of TCD and different stem cell products have their own profile of complications and clinical outcomes. Our results may only apply to TCD of marrow accomplished through anti-CD6 (a narrow specificity antibody) and complement.21 In summary, we observed similar clinical outcomes and quality of life following TCD and IST URD bone marrow transplantation. However, days of hospitalization and costs were significantly lower with TCD procedures even after adjustment for clinical characteristics in the population. Longer follow-up of this cohort and additional randomized clinical trials may help address the relative merits of different GVHD prophylaxis regimens. A large, prospective, multicenter, randomized study comparing TCD against IST in URD marrow transplantation is being supported by the National Heart, Lung and Blood Institute (NHLBI) with quality of life and costs as secondary endpoints. Enrollment is complete and follow-up is ongoing. However, multiple strategies for TCD are represented in the NHLBI trial, and results will not be available for some time. We strongly support attention to quality of life and costs in evaluating GVHD prophylaxis regimens. Allogeneic hematopoietic stem cell transplantation is a costly procedure with long-term health consequences, and these data are important to help society and individual patients choose which approach offers the best outcomes.
We wish to thank our colleagues at the Dana-Farber Cancer Institute and Brigham and Women's Hospital for the excellent care of the patients who participated in the study. We especially thank our patients for participating in this research and sharing their experiences with us.
Submitted March 29, 2002; accepted May 21, 2002.
Prepublished online as Blood First Edition Paper, June 21, 2002; DOI 10.1182/blood-2002-03-0984.
Supported in part by National Institutes of Health grant nos. CA75267-01 and AI 29530, the Amy Strelzer-Manasevit Scholars Program, and the Leukemia and Lymphoma Society of America.
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.
Reprints: Stephanie Lee, Center for Outcomes and Policy Research, Dana-Farber Cancer Institute, 44 Binney St, Boston, MA 02115; e-mail: stephanie_lee{at}dfci.harvard.edu.
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© 2002 by The American Society of Hematology.
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  J. R. Fann, C. M. Alfano, S. Roth-Roemer, W. J. Katon, and K. L. Syrjala Impact of Delirium on Cognition, Distress, and Health-Related Quality of Life After Hematopoietic Stem-Cell Transplantation J. Clin. Oncol., April 1, 2007; 25(10): 1223 - 1231. [Abstract] [Full Text] [PDF]
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 Y-B Yu, J-P Gau, J-Y You, H-H Chern, W-K Chau, C-H Tzeng, C-H Ho, and H-C Hsu Cost-effectiveness of postremission intensive therapy in patients with acute leukemia Ann. Onc., March 1, 2007; 18(3): 529 - 534. [Abstract] [Full Text] [PDF]
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 C. S. Cutler, S. J. Lee, P. Greenberg, H. J. Deeg, W. S. Perez, C. Anasetti, B. J. Bolwell, M. S. Cairo, R. P. Gale, J. P. Klein, et al. A decision analysis of allogeneic bone marrow transplantation for the myelodysplastic syndromes: delayed transplantation for low-risk myelodysplasia is associated with improved outcome Blood, July 15, 2004; 104(2): 579 - 585. [Abstract] [Full Text] [PDF]
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F. M. Marty, S. J. Lee, M. M. Fahey, E. P. Alyea, R. J. Soiffer, J. H. Antin, and L. R. Baden Infliximab use in patients with severe graft-versus-host disease and other emerging risk factors of non-Candida invasive fungal infections in allogeneic hematopoietic stem cell transplant recipients: a cohort study Blood, October 15, 2003; 102(8): 2768 - 2776. [Abstract] [Full Text] [PDF]
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Top
Abstract
Introduction
3) or tacrolimus (0.02 mg/kg 4 times a day,
24 hours by continuous infusion).
50 years vs > 50 years), sex matching (female donor and male patient
vs all other combinations), degree of HLA match (matched vs
mismatched), patient cytomegalovirus (CMV) serostatus (seronegative vs
seropositive), and disease risk (low risk vs high risk). The estimates
of relative risks and 95% confidence intervals (CIs) are reported at a
median follow-up of 18 months.
