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CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
From the Institute of Hematology and Oncology,
Department of Hematology, Hospital Clínic, University of
Barcelona, Barcelona, Spain; Instituto Português de
Oncologia-Centro do Porto, Oporto, Portugal; Hospital Clínico,
Valencia, Spain; Hospital La Fe, Valencia, Spain; Hospital Sant Pau,
Barcelona, Spain; Hospital Ramón y Cajal, Madrid, Spain; Hospital
Duran i Reynals, Barcelona, Spain; Hospital Vall d'Hebron, Barcelona,
Spain; Hospital Clínico, Salamanca, Spain; Hospital Gregorio
Marañón, Madrid, Spain; and Hospital Virgen del
Rocío, Sevilla, Spain.
This study analyzed the characteristics of 257 HLA-identical
sibling transplants of granulocyte colony-stimulating factor-mobilized peripheral blood progenitor cells depleted of T cells by
CD34+ positive selection (allo-PBT/CD34+) for
their effect on the incidence of graft failure. Twenty-four patients
developed graft failure (actuarial probability, 11%; 95% confidence
interval, 7.1-14.9). Prognostic factors considered were sex and age of
donor and recipient, donor-recipient blood group compatibility,
diagnosis, disease status at transplant, conditioning regimen,
cytomegalovirus serology, number of CD34+ and
CD3+ cells infused, and cryopreservation. The major factor
associated with graft failure was the number of CD3+ cells
in the inoculum. Twenty-three of 155 patients receiving a T-cell dose
in the graft less than or equal to 0.2 × 106/kg
experienced graft failure, compared with only one of 102 patients receiving more than 0.2 × 106/kg (actuarial probability
18% vs 1%, respectively; P = .0001). The actuarial
probability of graft failure progressively increased as the number of
CD3+ cells in the graft decreased, which was determined by
grouping the number of CD3+ cells in quartiles (log-rank
P = .03; log-rank for trend P = .003). In
the multivariate analysis by the proportional hazard method, 2 covariates entered into regression at a significant level:
CD3+ cells less than or equal to
0.2 × 106/kg (risk ratio = 17;
P < .0001), and patients with chronic myelogenous leukemia (CML) conditioned with busulphan-based regimens (risk ratio = 4.8; P = .001). From these results it appears
that the number of CD3+ cells in the inoculum Allogeneic transplantation of hemopoietic stem
cells (allo-SCT) has gained widespread acceptance in the treatment of
hematologic malignancies.1 Graft-versus-host disease
(GVHD) is a major limitation to the success of allo-SCT. In fact, one
third of the patients submitted to allo-SCT require immunosuppressive
treatment due to this complication.2-4 Clinical and
experimental studies have shown that the presence of mature
immunocompetent T lymphocytes in the graft plays an important role in
the development of GVHD.3,5 Several clinical trials
indicate that the incidence and severity of GVHD in engrafted patients
are greatly reduced when the inoculum is T-cell depleted.6
Unfortunately, T-cell depletion (TCD) also results in a high incidence
of graft failure. The reported incidence of this complication among
recipients of TCD HLA-identical transplants ranges from 10% to
30%,7-11 in contrast to recipients of unmodified
HLA-identical marrow grafts, in which there is a 0.1% incidence of
graft failure.12 Graft failure is usually a fatal
complication.7,9
Multiple mechanisms have been reported to contribute to graft failure
after allo-SCT, such as primary disease,13 sex pairing between donor and recipient,7 conditioning
regimen,14,15 number of CD34+ cells
infused,16 and number of residual T cells in the
graft.17 The few studies in which factors related to graft
failure have been analyzed have been performed in
mice16,17 or in the context of bone marrow
transplant.7,13-15 No analyses have been conducted in the
growing setting of allogeneic transplantation of T-cell-depleted granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood progenitor cells (PBPCs).
We have investigated the characteristics of 257 allogeneic
transplants of G-CSF-mobilized PBPCs depleted of T cells by
CD34+ positive selection (allo-PBT/CD34+) for
their effect on the incidence of graft failure. In this series,
24 patients developed graft failure (actuarial probability, 11%; 95%
confidence interval [CI], 7.1-14.9); the most important factor
associated with this complication was the infusion to the patient
of a quantity of CD3+ cells more than or equal to
0.2 × 106/kg.
Patients and donors
Positive selection of CD34+ cells
Evaluation and definitions Engraftment was documented by increasing neutrophil and platelet counts unsupported by transfusions. Time to neutrophil engraftment was assessed by determining the number of days after day 0 for patients to achieve more than 500/µL. Time to platelet engraftment was assessed by determining the number of days after day 0 to maintain an untransfused platelet count of 20 000/µL or greater. Kinetics of engraftment was analyzed, taking into consideration only those patients who did not receive G-CSF posttransplant. The diagnosis of graft failure was made if persistently falling peripheral blood counts and progressive bone marrow hypoplasia (< 25% cellularity) occurred after documented engraftment; occurred in the absence of leukemic relapse, drug toxicity, or infection; and persisted for at least 14 days. The day of graft failure was assigned to the day that the absolute neutrophil count (ANC) declined to less than 500/µL.Statistical methods Actuarial curves were obtained by the Kaplan-Meier method and statistically compared using the log-rank test. The characteristics considered in this study were donor sex, patient sex, sex pairing, donor age, patient age, donor-recipient blood group compatibility, diagnosis, disease status at transplant, conditioning regimen, pretransplant cytomegalovirus (CMV) serology of donor and recipient, number of CD34+ cells and of CD3+ cells infused with the inoculum (both analyzed by median, mean, and quartiles), and cryopreservation of the CD34+ positive fraction. All prognostic variables in the univariate analysis (Kaplan-Meier method) with a P value .2
(Table 2) were included for the
multivariate analysis, to eliminate the redundancy among highly
correlated characteristics, each of which may be individually
significant. This was performed, using the stepwise proportional hazard
Cox regression model. The proportional hazard assumption of the Cox
model was checked separately for each covariate before performing the
regression analysis. Such checking was done by a graphical and
analytical method. The graphs of loge
[ loge  (t)] versus loge (t) for each
dichotomous covariate were obtained to check that the curves were
roughly parallel. Additionally, for each covariate a time-dependent
covariate (covariate*t) was obtained and checked whether the
coefficient of the latter significantly differed from 0. The
proportional hazard assumption was not rejected for any one of the
covariates included in the Cox model. Statistical studies were
performed by means of SPSS 6.1 (1994; SPSS, Chicago, IL), SAS
6.1 (1997; SAS Institute, Cary, NC), or BMDP (1988; SPSS)
statistical software.
Engraftment and pattern of graft failure All patients reached an ANC of 500/µL and an untransfused platelet count of more than 20 000/µL. The median day to achieve an ANC more than 500/µL and an untransfused platelet count of more than 20 000/µL was 13 (range, 8-32) and 13 (range, 4-127), respectively. At a median of 65 days posttransplant (range, 20-270), 24 patients (9%) developed graft failure, for an actuarial probability of this complication of 11% (95% CI, 7.1-14.9). In the 24 cases peripheral blood neutrophil counts declined to 100/µL or less, all of them required platelet and red cell transfusions and developed marrow aplasia. Chimerism analysis at the time of graft failure was available in 17 (70.8%) of the 24 patients. In 5 cases (29.4%) peripheral blood cells were 100% host origin, and in 12 cases (70.6%) a mixed chimerism was found. In 4 of the 12 cases the study was also performed by separating peripheral blood neutrophils and T cells: in all of them, neutrophils were 100% of donor origin and a fraction of T cells were of host origin. None of the evaluable patients had a complete donor chimerism at the time of graft failure.Recipient and donor characteristics associated with graft failure In this analysis (Table 2), the most prominent finding was the association between the number of CD3+ cells in the inoculum and the probability of graft failure. Twenty-three (14.8%) of 155 patients receiving a T-cell dose in the graft less than or equal to 0.2 × 106/kg experienced graft failure, compared with only one of 102 patients (0.8%) receiving more than 0.2 × 106/kg, the actuarial probability being 18% and 1%, respectively (P = .0001). Of note, the actuarial probability of graft failure progressively increased as the number of CD3+ cells in the graft decreased, which was determined by grouping the number of CD3+ cells in quartiles. Thus, recipients of a dose of CD3+ cells (×106/kg) of less than or equal to 0.07, more than 0.07-0.12, more than 0.12-0.37, and more than 0.37 had an actuarial probability of graft failure of 18.5%, 16.1%, 8.3%, and 2.1%, respectively (log-rank P = .03; log-rank for trend P = .003) (Figure 1). In the univariate analysis (Table 2), 3 other factors were found to be associated with increased graft failure: CML patients (P = .007), conditioning regimen based on busulphan (P = .04), and cryopreservation of the graft (P = .03). Further analysis showed that the negative effect on engraftment of busulphan-based conditioning regimens only affected patients with CML. Thus, CML patients conditioned with busulphan had an actuarial probability of graft failure of 32% versus 7.5% for the other patients (P = .0008). Besides, CML patients conditioned with busulphan and receiving CD3+ cells more than or equal to 0.2 × 106/kg had an actuarial probability of graft failure of 50% compared to 12% in the remaining patients (Figure 2) (P = .00008). Likewise, when the analysis was restricted to CML cases, the actuarial probability of graft failure was 50% in those conditioned with busulphan-based regimens versus 12% in those conditioned with total body irradiation-based regimens (P = .04). In this series a trend for an association of female donor to male recipients with graft failure was also observed (P = .1). Finally, the age of the patients did not influence the probability of graft failure (P = .5).
Multivariate analysis In the first analysis, we tried to enter into regression all variables with a P value .2 (donor sex, sex-pairing
mismatch, female donor and male recipient, number of
CD3+ cells 0.2 × 106/kg,
cryopreservation, conditioning regimen, and CML). As shown in Table
3, only 2 variables entered into
regression at a significant level: a quantity of CD3+ cells
infused to the patients more than or equal to
0.2 × 106/kg and a diagnosis of CML. Because it was
evident from the univariate analysis that the busulphan conditioning
regimen acted adversely on the graft only in CML (Table 2), we
performed a second multivariate analysis (Table 3) with the same
covariates, adding the combined covariate of CML patients conditioned
with busulphan. From the coefficient, chi-square, P value,
and risk ratio, it was evident that this combined covariate contributed
more significantly to the regression, whereas the variable CML alone
lost its significance.
Results of secondary transplants Twenty-three of 24 patients with graft failure received a secondary transplant with unmanipulated G-CSF-mobilized PBPCs (22 cases) or marrow (1 case). The remaining patient showed autologous reconstitution and is currently alive and free of disease 3 years posttransplant. Seven cases (30.4%) received PBPCs as the only rescue procedure, and in 16 patients (69.6%) ATG was administered immediately before the hemopoietic progenitors, either alone (n = 9) or in association with cyclophosphamide (n = 4), nodal radiotherapy (n = 1), fludarabine (n = 1), or total body irradiation (n = 1). In 3 patients (13%) engraftment was not evaluable due to early death. In the remaining 20 patients, 11 (55%) engrafted and 9 (45%) did not engraft. Fifteen (62.5%) of 24 patients died, 12 due to severe pancytopenia and 3 due to GVHD; of these 3 cases, 2 had not received prophylaxis for GVHD after the apheresis product infusion, and the third patient developed GVHD after cyclosporine A was retired. Nine (37.5%) patients of the 24 remain alive, 8 with complete donor chimerism.
Graft failure is one of the most severe complications occurring after allo-SCT.7 In contrast to recipients of unmodified HLA-identical marrow grafts, in whom this complication is uncommon,10 allograft rejection is frequently observed in recipients of T-cell-depleted marrow.7-9,11,12 In many patients, secondary transplants cause unacceptable toxicity, and a considerable proportion of them do not reach a stable engraftment.7 In this series, graft failure developed in 24 of 257 patients (actuarial probability, 11%; 95% CI, 7.1-14.9) submitted to allo-SCT in which the leukapheresis product had been T-cell depleted by CD34+ positive selection (allo-PBT/CD34+). Following secondary transplants, 15 (62.5%) of the 24 patients died due to severe pancytopenia or to GVHD. Similar poor results have been obtained by other groups.7-9,20 Identification of risk factors associated with graft failure could be useful to recognize patients at high risk of developing this complication. Sex pairing between donor and recipient,7 intensity of conditioning regimen,8,14,15 marrow cell dose,16 and degree of TCD21 have been correlated with the risk of graft failure. However, these studies have been performed in the context of TCD of marrow graft and with a limited number of patients. No studies have yet been reported in the setting of TCD of G-CSF-mobilized PBPCs.22 The most relevant finding in our study was the strong correlation between the quantity of T cells in the graft and the engraftment. Thus, 23 (14.8%) of 155 patients receiving an amount of T cells less than or equal to 0.2 × 106/kg experienced graft failure, compared with only one of 102 patients (0.8%) receiving more than 0.2 × 106/kg, with the actuarial probability being 18% versus 1%, respectively (P = .0001). The effect of the T-cell dose on the engraftment was apparent in the univariate and in the multivariate analyses (Tables 2 and 3). This finding has not been previously reported in allo-SCT in humans and is in agreement with results in murine models, showing that rejection associated with TCD marrow is overcome by adding a small quantity of donor CD8+ cells17 or thymocytes to the grafts.23,24 Our results also support clinical studies in which "partial" TCD has been found to be associated with a lower risk of graft failure than "total" TCD.25-27 The finding, in some of our cases, of a proportion of recipient T cells at the moment of graft failure supports the concept that this complication is due to small numbers of host lymphoid cells surviving the conditioning regimen.11,27-29 The optimum number of T cells that should be left in the graft to allow reliable engraftment and to prevent GVHD is presently unknown. Of note, the actuarial probability of acute GVHD clinical grade II-IV in this series of 257 patients was very similar in the group of recipients receiving 0.2 × 106/kg or less CD3+ cells than in those receiving more than 0.2 × 106/kg CD3+ cells (13% vs 20%, respectively; P = NS) (data not shown). Taking these results into account, we are considering fixing the quantity of CD3+ cells in the graft at 0.3 × 106/kg for HLA-identical sibling allo-PBT/CD34+, adding to the positive fraction the necessary number of CD3+ cells to reach this quantity, and maintaining the use of cyclosporine as GVHD posttransplant prophylaxis. The number of CD34+ cells infused to the patient is also critical for a successful allografting16,30-32 and has been considered even more important than the number of donor lymphocytes when TCD is used.16,32 Our results, however, do not support that concept. Indeed, the manipulation of the graft can produce undesirable cell losses, thereby resulting in administering a low quantity of hemopoietic progenitor cells. The use of G-CSF-mobilized PBPCs circumvents this problem; thus, in our series the mean number of CD34+ cells infused to allo-PBT/CD34+ recipients was 4 × 106/kg (range, 0.6-15), much higher than that infused after allo-SCT using TCD marrow.22 The mean number (× 106/kg) of CD34+ cells infused to the patients developing graft failure was very similar to the group of patients not having this complication (3.6 vs 4, respectively; P = NS), and the number of CD34+ cells, analyzed by median, mean, and quartiles, were not associated with graft failure (Table 2). An additional observation in this study was that in the group of recipients of 0.2 × 106/kg or less CD3+ cells, the risk of graft failure was higher in CML patients conditioned with busulphan-based regimens than in those conditioned with total body irradiation-based regimens (actuarial probability of 50% vs 12%, respectively) (Tables 2 and 3; Figure 2). It could be speculated that, because CML patients are usually transplanted after having received less immunosuppressive treatment than patients with other forms of leukemia, they could have more host residual T cells surviving the conditioning regimen. However, several studies have stressed the importance of the irradiation in the conditioning regimen to reduce the incidence of graft failure following a T-cell-depleted transplant.14,15 It would seem, therefore, that the diagnosis of CML and the type of conditioning regimen are, together, a critical factor for graft failure when the number of T cells administered to the patients is below the threshold of 0.2 × 106/kg. To summarize, in this study a number of CD3+ cells equal to or less than 0.2 × 106/kg in the inoculum has been identified as the most critical factor to develop graft failure after allo-PBT/CD34+. In addition, our study also suggests that in patients with CML receiving 0.2 × 106/kg or less CD3+ cells, total body irradiation should be preferred to busulphan-based regimens.
Submitted June 12, 2000; accepted September 19, 2000.
Supported in part by grants FIJC-00/P-CR and FIJC-00/P-EM from the José Carreras International Foundation and grants FIS-98/0995 and FIS-98/0380 from the Fondo de Investigaciones Sanitarias de la Seguridad Social, Spanish Ministry of Health.
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: A. Urbano-Ispizua, Institute of Hematology and Oncology, Department of Hematology, Hospital Clínic, University of Barcelona, Villarroel 170, 08036 Barcelona, Spain; e-mail: aurbano{at}clinic.ub.es.
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Abstract
Introduction
with a
threshold of 0.2 × 106/kg or less
