In T-cell-depleted allogeneic bone marrow transplantation (TCD-BMT) using unrelated donors, the role of donor lymphocyte infusion (DLI) for survival and disease control has not been defined. In a study of 116 patients (92 matched, 24 mismatched) who received CD3+ T-cell-depleted marrow graft, sequential infusions of escalated doses of donor T lymphocytes up to 1×106 CD3+ cells/kg were prospectively investigated. T cells were administered while patients were on cyclosporine, provided ≥grade II acute graft-versus-host-disease (GVHD) had not occurred. Acute GVHD of ≥grade II occurred in 27 of 110 (25%) patients before DLI and in 39 of 79 (49%) patients after DLI. In total, 12 of 27 (44%) patients without DLI and 44 of 72 (61%) patients who received DLI developed chronic GVHD. A total of 19 patients died of GVHD, with 17 of acute and two of chronic GVHD. Overall survival (OS) and event-free survival (EFS) at 5 years were 27 and 21%, respectively. The 2-year incidence of relapse was 14%. In multivariate analysis, only chronic GVHD was a good prognostic factor for both OS: hazard ratio (HR) 1.4, P=0.04, and EFS: HR 1.6, P=0.01. Both acute and chronic GVHD were favorable prognostic factors for relapse probability: HR 1.9 for both, P=0.02, 0.01, respectively. The 1-year cumulative incidence of transplant-related mortality (TRM), excluding cases of GVHD, was 42%. The two most common causes of 1-year non-GVHD death were viral infection (9%) and idiopathic pneumonia syndrome (12%). Although the incidence of relapse was low, the study suggests that the current scheme of DLI in unrelated TCD-BMT would not improve survival unless TRM decreases significantly.
Long-term survival of recipients of bone marrow transplantation (BMT) using unrelated donors is associated with the degree of disparity of human leukocyte antigen (HLA), among other factors, and its high transplant-related mortality (TRM) is related to high rates of acute and chronic graft-versus-host-disease (GVHD).1,2,3 Depletion of marrow T lymphocytes has been shown to reduce both the incidence and severity of acute and chronic GVHD, although its role for survival remains uncertain.4,5,6,7 In both related and unrelated transplants of T-cell-depleted grafts, several factors such as the number of T lymphocytes in the graft, post-transplant immunosuppressive therapy and administration of additional T lymphocytes, are known to affect GVHD.8,9,10,11,12
In 1994, we initiated the current study to increase survival of both related and unrelated recipients by depleting graft T lymphocytes to <1×105 CD3+ cells/kg and giving delayed sequential infusions of up to 1–2×106 CD3+ cells/kg over 3 months post-transplant. The degree of graft T-cell depletion and the total number of T cells for delayed infusion were based on the threshold effect of 0.5–1×105 graft T cells/kg for GVHD and previous studies of TCD-BMT.13,14,15 T cells for donor lymphocyte infusion (DLI) were divided into three separate escalating doses to assess the dose–response relationship between GVHD and the T-cell dose in the range of 0.1–2×106 T cells/kg. Patients were grouped according to their risk for GVHD, defined by HLA disparity, related vs unrelated grafts and age.16,17,18 The first DLI was given at the time of transplant to the patients with a low risk for GVHD to prevent graft rejection in T-cell-depleted allotransplantation, and after engraftment to the patients with a high risk for GVHD to reduce severe acute GVHD in the early phase of engraftment. The initial analysis of 144 patients (related 90, unrelated 54), studied between 1994 and 1997, suggested a positive role of DLI in reducing the severity of GVHD in both related and unrelated transplants, thereby decreasing GVHD-related mortality.19 Further follow-up on the study, however, began to show a significant increase in TRM, especially of unrelated recipients, although the GVHD-related mortality remained relatively unchanged. The present report describes the clinical outcome of 116 unrelated recipients who participated in the study during the period between 1994 and 2000.
Patients, materials, and methods
A total of 116 patients between 17 and 60 years of age were accrued to a study on T-lymphocyte depletion of the allograft and delayed prophylactic infusion of donor lymphocytes for hematological malignancies using unrelated donors, consecutively between December 1994 and December 2000, at the University of Iowa Hospitals and Clinics. The institutional review board of the College of Medicine at the University of Iowa approved the treatment protocol and an informed consent was obtained from all patients or their guardians.
Histocompatibility testing and donor selection
HLA typing was done as previously described.19 When identical at HLA A, B, and D/DRB1 loci, donor and patient pairs were considered matched. Donors were accepted if HLA class I antigens mismatched by a single split or single disparity in the same crossreactive group (n=22) or HLA class II by a single high-resolution DNA-DRB1 disparity (n=2).
Of the 70 patients with myeloid disorders, 27 patients received a regimen of cytosine arabinoside (ara-C) 18 g/m2 in six divided doses intravenously (i.v.) every 12 h days −8 to −3, cyclophosphamide 2.4 g/m2/day on days −6 and −5 and a total body irradiation (TBI) 1200 cGy in six fractions with lungs shielded to a dose of 800 cGy on days −2 to 0. A total of 43 patients received a similar regimen except that the second dose of cyclophosphamide was replaced by thiotepa 250 mg/m2 day on −5 to reduce cyclophosphamide cardiotoxicity. Patients with lymphoma (n=16), multiple myeloma (n=12) and chronic lymphocytic leukemia (n=4) received the same TBI on days −8 to −6, BCNU 300 mg/m2 on day −5, etoposide 600 mg/m2/day on days −3 and −2, ara-C 2 g/m2 every 12 h for four doses on days −4 to −2 and cyclophosphamide 3.6 g/m2 on day −2. Patients with acute lymphoblastic leukemia (ALL) (n=14) received TBI 1350 cGy in nine fractions with lungs shielded to a dose of 800 cGy on days −8 to −4 and 400 cGy testicular boost for male patients, etoposide 2.4 g/m2 on day −3, and cyclophosphamide 2.4 g/m2 on day −2.
GVHD prophylaxis and therapy
GVHD prophylaxis was done by ex vivo depletion of marrow T cells and cyclosporine. T cells were depleted by an anti-CD3 IgG2 monoclonal antibody (Muromonab-CD3: Ortho Biotec Inc., Raritan, NJ, USA) and newborn rabbit serum as a source of complement, as described previously.19 Intravenous cyclosporine 3 mg/kg/day was started on day −1 and later changed to oral administration if tolerated to maintain whole-blood trough levels between 150 and 350 ng/ml. Prophylactic cyclosporine was given throughout DLI. Patients who did not develop GVHD or whose GVHD became well controlled started cyclosporine taper in 4 weeks after the last T-cell infusion at a rate of 0.3–0.5 mg/kg every 2 weeks. Corticosteroids were added for initial therapy of acute GVHD of grade ≥II and chronic GVHD.
Patients were stratified for GVHD into a low-risk group (LR) if they were ⩽50 years and donors were matched, and a high-risk groups (HiR) if they were older than 50 years or had mismatched donors. Peripheral blood CD3+T lymphocytes were prepared for infusion as previously described.19 The first DLI was done on the day of transplantation for the LR (n=48), and after engraftment for the HiR (n=68). Subsequent DLI with escalating doses of T lymphocytes was administered 4–8 weeks after the previous DLI, as described in Table 1, provided ≥grade II of acute GVHD had not occurred and there were no concurrent serious transplant-related complications.
Supportive care was administered as previously described.19 Antibacterial, antifungal, and antiviral prophylaxes were done according to the institutional protocols, including broad-spectrum antibiotics and amphotericin-B during neutropenia, and sulfamethoxazole-trimethoprim and acyclovir post-transplant. Ganciclovir was used for cytomegalovirus (CMV) prophylaxis during the ablative phase and after engraftment for 6 months. CMV reactivations were monitored weekly for at least 6 months by CMV DNA hybrid capture on buffy coat samples. Granulocyte colony stimulating factor was administered at 300 μg beginning on day +7 and continued until two consecutive days of an absolute neutrophil count (ANC) >2×109/l.
Patients were evaluated for engraftment, GVHD, relapse and death. The day of myeloid engraftment was defined as the first of three consecutive days of an ANC of more than 0.5×109/l. Platelet recovery was considered to have occurred when the platelet counts increased spontaneously to ≥50×109/l for 7 days. Acute and chronic GVHD were graded by the published criteria.20,21 Disease recurrence in patients with myelodysplastic syndrome or leukemia, including chronic myelogenous leukemia (CML), was defined by either morphologic evidence in the marrow, peripheral blood or extramedullary sites, or the reappearance of characteristic chromosomal abnormalities in marrow cells. Relapse of patients with lymphoma or myeloma was determined by published criteria.22,23 The variables analyzed were of HLA status, risk groups for GVHD, total number of T cells infused, maximum grade of acute GVHD, and maximum grade of chronic GVHD. Frequency analysis of categorical variables was done by Pearson's χ2 or Fisher's exact tests. Patients who had evidence of myeloid engraftment were evaluable for acute GVHD, and day 100 post-transplant was used as a landmark point for analysis of chronic GVHD. Events were defined as death of any cause and relapse. Cumulative incidence curves were used to calculate the probability of engraftment, acute and chronic GVHD, TRM, and relapse.24 Survival analyses were done by the product limit estimate of Kaplan–Meier and the log rank test was used for univariate analysis. For patients who received DLI, the day of last DLI was chosen as a landmark point for survival analysis. For multivariate analyses, variables with a P value of <0.1 in univariate analysis were entered into a stepwise multivariate regression by the Cox proportional hazard model.
In total, 30 patients had standard-risk and 43 had high-risk leukemia. High-risk leukemia was defined as acute myelogeneous leukemia (AML) (n=7) and acute lymphoblastic leukemia (ALL) (n=3) in refractory relapse or >second remission, secondary AML (n=6), AML (n=8) or ALL (n=6) with unfavorable cytogenetics, CML in accelerated or blastic phase (n=12), and chronic lymphocytic leukemia (CLL) with Richter's transformation (n=1). Other leukemia were classified as standard risk. Six patients with non-Hodgkin's lymphoma (NHL) were in partial remission (PR) and eight in less than PR at the time of transplantation, including three with primary refractory NHL. Eight patients with multiple myeloma (MM) were in PR and four in less than PR (Table 2).
The median number of mononuclear cells was 3.4 (range 1.0–9.8)×108/kg before, and 2.5 (range 1.0–9.6)×108/kg after T-cell depletion, with a recovery rate of 74%.
The median time to myeloid and platelet engraftment was 15 (range, 9–36) and 48 days (range, 24–168), respectively. An ANC ≥0.5×109/l was achieved in 92% of patients by day 28, and a platelet count >50×109/l in 78% by day 100. Graft failure occurred in three patients, and three additional patients died of transplant-related complications before engraftment. There was no increase in the incidence of platelet reconstitution of >50×109/l at day 100 by age ⩽35 (P=0.3), negative CMV status of recipient (P=0.18), graft mononuclear count >4×108/kg after T-cell depletion (P=0.3), or HLA-matched graft (P=0.4).
Graft T-cell depletion, DLI, and GVHD
The marrow CD3+ T cells were reduced by a median of 2.28 log to a median of 1.2 (range, 0.1–2.7)×105/kg, the CD2+ T cells by a 1.7 log to 1.6 (range, 0.4– 2.9)×105/kg, and the CD4+ CD8+ T cells by a 2.0 log to 1.3 (range, 0.3–2.1)×105/kg.
T lymphocytes were administered to 79 of 110 (72%) (48 LR, 31HiR), 28 of 79 (35%) (17 LR, 11 HiR) and four of 28 (14%) (three LR, one HiR) patients for the first, second and third DLI, respectively. For the first DLI, 31 patients became ineligible because of de novo acute GVHD of ≥grade II (n=27) and transplant-related complications (n=4). For the second and third DLI, 51 patients (21 acute GVHD; 30 transplant-related complications) and 24 (14 acute GVHD; 10 transplant-related complications) were ineligible, respectively. The LR patients received DLI on day 0 for the first, and a median of 32 (range 24–54) and 66 days post-transplant (range, 42–84) for the second and third infusions. For the HiR patients, DLI was given at a median of 21 (range, 12–35), 70 (range 44–84), and 91 days post-transplant, respectively, for the three consecutive infusions.
Acute GVHD ≥grade II occurred in 27 (25%) of 110 patients before the first DLI. A total of 21 patients developed ≥grade II acute GVHD after the first DLI, 14 after the second and four after the third DLI. Thus, the overall cumulative incidence of the 66 patients with ≥grade II acute GVHD was 69% (Figure 1a). Of these patients, 31 (29%) developed grade II and 35 (33%) patients grades III–IV. The median time to ≥de novo grade II acute GVHD of the 27 patients was 15 days (range 9–42) post-transplant. All cases of acute GVHD after each DLI occurred within six weeks following DLI, with a median time to ≥grade II acute GVHD of 21 (range 8–18), 14 (range, 6–28), and 21 (range, 14–37) days after the first, second and third DLI, respectively.
Of the 84 patients at risk for chronic GVHD, 24 (29%) developed limited and 32 (38%) patients extensive GVHD, with a 1-year cumulative incidence of 75% (Figure 1b). In all, 12 of 27 (44%) patients without DLI and 44 of 72 (61%) patients who received DLI developed chronic GVHD. Of all, 17 patients died of acute and two of chronic GVHD, respectively, with a 1-year cumulative incidence of mortality of 23% (Figure 1c, dotted line).
Of the factors affecting GVHD, only the HLA mismatch was associated with a higher incidence of ≥grade II acute GVHD and mortality owing to acute GVHD. A total of 18 of 20 (90%) mismatched and 53 of 86 (62%) matched recipients developed ⩾grade II GVHD (P=0.01), of whom nine (50%) mismatched and eight (15%) matched recipients died of acute GVHD (P=0.003). Neither the GVHD risk group nor the number of T cells infused was significant for acute GVHD. None of these three factors were significant for chronic GVHD.
In total, 23 (20%) patients died of causes not related to GVHD within 100 days post-transplant (median 37, range 0–89), including six deaths before engraftment. Between the day 100 and 1-year post-transplant at a median of 168 days (range 105–291) 22 additional patients died. Thus, the 1-year cumulative incidence of TRM was 42% (Figure 1c, solid line). The causes of death (n=23) in the 100 days post-transplant included graft failure (n=3), cyclophosphamide cardiomyopathy (n=3), veno-occlusive disorder (n=2), idiopathic pneumonia syndrome (IPS) (n=3), and infection (n=12). The etiologies of the infections included adenovirus (n=3), human herpes virus type 6 of the central nervous system (n=2), CMV (n=2), Klebsiella pneumoniae (n=1), Aspergillus spp (n=3) and Pseudellyescheria boydii (n=1). Between day 100 and 1-year post-transplant, the causes of death (n=22) were IPS (n=11), hemolytic uremic syndrome (n=4), aneurysmal rupture of abdominal aorta (n=1) and infection (n=6). The etiology of the infection ranged from CMV disease (n=2), parainfluenza virus type I (n=1), influenza virus A (n=1), Enterococcus faecalis (n=1), to Aspergillus flavus (n=1). Of the 18 patients with an infectious cause of death, 11 had received at least one DLI, and 14 of them had either grades II–III acute GVHD (n=10) or chronic GVHD (n=4).
Overall survival (OS), event-free survival (EFS) and relapse
The median survival of all patients was 8 months and the 1-year OS rate was 41%. OS at 5 years was 27% (CI: 23–31%) (Figure 2a, solid line). Of the 110 patients eligible for DLI, those who received DLI (n=79) had a median survival of 10 months (1-year survival 55%), compared to 7 months (1-year survival 38%) for patients without DLI (n=27) (P=0.09). Patients with chronic GVHD (n=56) had a median survival of 27 months (5-year survival 55%), compared to 12 months (5-year survival 25%) for patients without chronic GVHD (n=28) (P=0.01). Patients with ⩾grade II acute GVHD (n=66) had a median survival of 9 months (1-year survival 53%) vs 6 months (1-year survival 34%) for patients with no or grade I acute GVHD (n=27) (P=0.03). This discrepancy came from a high incidence of TRM (n=20) in the patients with no or grade I acute GVHD, compared with that of the other group (n=25) of patients, (P=0.02). The TRM of the patients with no or grade I acute GVHD comprised of IPS (n=10), bacterial sepsis (n=2), invasive fungal infection (n=2), and viral infection (n=6).
Median EFS was 8 months for all patients, with a 5-year EFS rate of 21% (Figure 2a, dotted line). A total of 34 patients are alive event free from 7 months to 6 years. Patients with ≥grade II acute GVHD (n=66) had a median EFS of 9 months (1-year survival 51%) vs 6 months (1-year survival 24%) for patients with no or grade I acute GVHD (n=27) (P=0.007). Patients with chronic GVHD (n=56) had a median survival of 23 months (5-year survival 50%), compared to 10 months (5-year survival 25%) for patients without chronic GVHD (n=28) (P=0.02). DLI was not a significant factor for EFS.
Disease relapse occurred in nine patients in a median of 6.5 months post-transplant (range, 3–14.5), with an incidence of relapse at 2 years of 14% (CI: 8–20%) for the 110 evaluable patients (Figure 2b). Patients with ≥grade II acute GVHD (n=66) had a 2-year relapse incidence of 6%, compared to 47% for patients with no or grade I acute GVHD (n=27) (P=0.005). Patients with chronic GVHD (n=56) had a 2-year relapse incidence of 10% vs 43% for patients without chronic GVHD (n=28) (P=0.005). Patients who received DLI (n=79) had a 2-year relapse incidence of 8%, compared with 23% for patients without DLI (n=27) (P=0.03).
In multivariate analysis (Table 3), only chronic GVHD was a good prognostic factor for both OS (HR 1.4, P=0.04) and EFS (HR 1.6, P=0.01). Both acute and chronic GVHD were favorable prognostic factors for relapse, with an HR of 1.9 for both, P=0.02 and 0.01, respectively.
The role of graft T-cell depletion for survival and disease control in transplants using unrelated donors has not been well defined albeit the risk for both acute and chronic GVHD has been shown to be lower than in T-cell nondepleted transplants in a number of studies.5,25,26,27,28 Furthermore, the role of DLI in unrelated recipients has not been addressed. The present study aimed to achieve a decrease in the incidence of GVHD by graft T-cell depletion, and to improve survival rates by a decrease in relapse through prophylactic DLI over 3 months post-transplant. The study was based on the hypothesis that the risk of GVHD in unrelated allotransplants would depend on the T-cell dose,13,14,15 HLA disparity,29,30,31 and a time-dependent process of graft vs host reactivity,32,33,34 similar to allotransplants using related donors.
The initial results of the study on the 54 recipients of unrelated grafts reported previously showed a 3-year OS of 57%, suggesting a potential benefit of this approach on the survival rates.19 Although the current study continues to show better survival and lower relapse in patients who developed GVHD, it fails to demonstrate an overall improvement in survival over the 6 years of follow-up, compared with the previously published data of unrelated allotransplants without T-cell depletion,35,36,37 mainly because of a high incidence of TRM. The loss of benefit in survival was most conspicuous in the patients with no or grade I acute GVHD, the majority of whom died of TRM despite their potential chances of better survival than patients with significant acute GVHD. In the study, the two most common causes of 1-year TRM were viral infection (9%) and IPS (12%). The incidence of TRM by viral infection appears to be related to immune deficiency exacerbated by allograft T-cell depletion and subsequent intense immunosuppression for GVHD. The viral infection shows no particular pattern except the absence of Epstein–Barr virus-related lymphoproliferative disorder. The incidence of IPS was high, and the clustering of the cases after the day 100 (median 125; range 105–291 days) requires further study. Since the risk of developing IPS may be related to the intensity of the conditioning regimen, and infusion of T lymphocytes,38,39,40 it remains to be seen whether a reduced radiation dose to the lungs, nonmyeloablative conditioning regimens, or changes in the scheme of DLI would decrease the incidence of the late-onset IPS. Of note, the high incidence of IPS in patients without ≥grade II acute GVHD, thereby requiring no steroids during the first 100 days, deserves further investigations on the role of steroids post-transplant after radiation-based myeloablative therapy.
In the present study, both DLI and GVHD were associated with improved OS and a decreased relapse rate in univariate analysis. DLI did not maintain significance in a subsequent multivariate analysis, suggesting that either the benefit of DLI may have been lost by the high incidence of TRM or DLI of the current methodology in unrelated allotransplants may not be as beneficial as in related allotransplants, probably because of the high rate of serious GVHD. Since the HLA-matching criteria of the study relied on serologically typed HLA A and B, and DNA DRB1, an unknown number of patients might have had mismatches in HLA Cw antigens that are known to be as important as DR antigens for GVHD,41 in addition to some patients with an apparent HLA match in A and B who may also have had molecular mismatches in these loci. In this regard, the absence of a dose–response relationship between the T-cell dose and the high incidence of both acute and chronic GVHD in the study indicates that DLI by the current methodology may not be safe without more refined HLA match criteria based on further molecular typing of HLA antigens. By the same token, it is obvious that patients who have an unrelated donor with an HLA mismatch in serologically defined A and B or in DNA DRB1 may not be a candidate for prophylactic DLI, owing to the high mortality rate of the patients in the study. Further refinement of DLI using the presence of persistent mixed chimerism or evidence of a remaining disease as criteria for prophylactic infusion may help reduce morbidity and mortality since some patients in the study, who may have been full donor chimera without evidence of remaining disease but had shown no or grade I acute GVHD, could have avoided DLI.
The current study shows limitations in the T-cell depletion for unrelated allotransplant and DLI based on the low-level HLA-matching criteria. In addition to the aforementioned molecular typing of HLA antigens, tests for alloreactivity of the donor T lymphocytes, such as limiting dilution analysis of donor-derived, host-reactive T-cell precursor frequency,29 or further DNA typing of multiple encoding loci of minor histocompatibility antigens42 may allow accurate assessment of alloreactivity of unrelated donor T lymphocytes for successful DLI. Selective depletion of alloreactive cells from allograft should be investigated further for clinical application that uses DLI.43,44 Novel therapeutic measures for infectious complications, including CMV- or EBV- specific cytotoxic T lymphocytes or Aspergillus- specific T lymphocytes, may potentially reduce TRM in similar studies.45,46
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We thank Colleen Chapleau for coordination for the Iowa Marrow Donor Program, Mary Dachtler for data management and all referring physicians for their dedication for the care of the patients.
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Lee, C., deMagalhaes-Silverman, M., Hohl, R. et al. Donor T-lymphocyte infusion for unrelated allogeneic bone marrow transplantation with CD3+ T-cell-depleted graft. Bone Marrow Transplant 31, 121–128 (2003) doi:10.1038/sj.bmt.1703803
- unrelated transplantation
- donor lymphocyte infusion
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