Antagonists against Graft-versus-Host Disease
Following Unrelated Donor Peripheral Blood Stem Cell
Basiliximab and daclizumab, two interleukin-2 receptor antagonists (IL-2RAs), prevent graft failure in renal transplantation, which also effectively treat steroid-refractory graft-versus-host disease (GVHD). However, only a few studies report that IL-2RAs prevent GVHD. Here we first retrospectively explored the prophy-lactic effects of basiliximab or daclizumab against GVHD in 82 patients with hematologic malignancies follow-ing unrelated donor-peripheral blood stem cell transplantation (URD-PBSCT). All recipients achieved engraftment. The rates of grade II-IV and III-IV acute GVHD (aGVHD) were 35.4% and 15.9%, respectively. Chronic GVHD (cGVHD) developed in 38.7% of evaluable patients. The transplantation-related mortality was 13.4%, while relapse rate was 8.5%. The 2-year overall survival (OS) reached 77.1% and disease-free survival (DFS) accumulated to 72.2%. The side effects of basiliximab and daclizumab were moderate and tolerable. There were no significant differences in aGVHD onset and survival between the daclizumab and basiliximab groups. However, basiliximab presented superior prophylactic effects on cGVHD than dacli-zumab. In conclusion, basiliximab or daclizumab prevents GVHD efficiently and feasibly following URD-PBSCT, and contributes to favorable outcome. Basiliximab has a similar effect on aGVHD but superior activity against cGVHD. Further prospective and randomized control studies are needed.
Biol Blood Marrow Transplant 18: 754-762 (2012)Ó 2012 American Society for Blood and Marrow Transplantation
KEY WORDS: Interleukin-2 receptor antagonists, Anti-CD25 monoclonal antibody, Peripheral blood stem cell transplantation, Unrelated donor, Graft-versus-host disease
Hematopoietic stem cell transplantation (HSCT) is the promising therapy for hematologic malignan-cies, but lack of suitable related donors restricts its
application. Fortunately, along with the development of data banks of hematopoietic stem cell donors, the Chinese patients have an increasing possibility of find-ing alternative unrelated donors (URDs). However, enhanced risk of graft-versus-host disease (GVHD) is one of the major critical barriers to successful URD-HSCT [1,2]. In the past decades, antithymocyte globulin (ATG) has been combined with standard GVHD prophylaxis regimens and significantly reduced GVHD in URD-HSCT[3-6]. Nevertheless, ATG targets multiple immunologic epitopes as a lymphocyte-depleting polyclonal antibody. Admin-istration of ATG pre- and peritransplantation not only simultaneously depletes host and donor T cells in vivo, but also affects additional cellular components including B cells, natural killer cells, and antigen-presenting cells. Thus, ATG is associated with side effects such as prolonged immune deficiency and increased incidence of infections, including cytomega-lovirus (CMV) disease and Epstein-Barr virus-associated posttransplant lympholiferative disease (PTLD), which abrogates its positive impacts[4,5,7]. Moreover administration of ATG raises the cost of
From the1Institute of Hematology, Union Hospital, Tongji Medi-cal College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; and 2Department of
Oncology, Taihe Hospital, Hubei University of Medicine, Shiyan, People’s Republic of China.
Financial disclosure: See Acknowledgments on page 761. * These two authors contributed equally to this work.
Correspondence and reprint requests: Prof. Linghui Xia, MD, Insti-tute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, People’s Republic of China (e-mail:
email@example.com) and Prof. Yu Hu, MD, PhD, Institute of Hematology, Union Hospital, Tongji Medical Col-lege, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, People’s Republic of China (e-mail:firstname.lastname@example.org).
Received May 18, 2011; accepted September 16, 2011
Ó 2012 American Society for Blood and Marrow Transplantation 1083-8791/$36.00
transplantation. Therefore, it is valuable to find alternative immunosuppressive agents for GVHD prophylaxis following URD-HSCT.
Both basiliximab and daclizumab are nonlympho-cyte-depleting monoclonal antibodies targeting the interleukin-2 receptor (IL-2R), which have been fre-quently used to induce immunosuppression in solid or-gan transplantation [8-10]. These interleukin-2 receptor antagonists (IL-2RAs) prevent acute rejection without increasing infections and malignancies in renal transplantation[9,11]. Compared with ATG, IL-2RAs have similar immunosuppressive efficacies but reduced adverse effects in standard-risk recipients of renal transplantation[9,11]. Furthermore, both daclizumab and basiliximab increase quality-adjusted life-years and decrease overall costs when assessing the cost-effectiveness of the newer renal immunosuppressants
[12,13]. Therefore, IL-2R blockade provides an attrac-tive option for the immunosuppression in solid organ transplantation.
Recent studies reveal that IL-2R can be the potential therapeutic target for GVHD . Thea-subunit of IL-2R (CD25) has been found predominantly on the surface of activated cytotoxic T cells. Specific binding of monoclonal antibody to CD25 blocks the IL-2-in-duced proliferation and provides selected immunosup-pression . Both basiliximab (chimeric anti-CD25 monoclonal antibody) and daclizumab (humanized anti-CD25 monoclonal antibody) have proven to be ef-fective treatments for refractory or steroid-resistant/ dependent acute GVHD (aGVHD), in particular, for cutaneous and low-moderate intestinal involvement
[14,16,17]. Moreover, few studies indicate that the IL-2R blockade with basiliximab or daclizumab con-tributes to GVHD prophylaxis in HSCT [18-22]. However, the documented cases are limited, and there is no published study on the prophylactic activity of basiliximab or daclizumab against GVHD following URD-HSCT.
In the present retrospective study, basiliximab or daclizumab was administrated in addition to standard GVHD prophylaxis regimens in 82 patients who received unrelated donor-peripheral blood stem cell transplantation (URD-PBSCT). The aims of this study were to evaluate hematologic recovery, GVHD, transplantation-related mortality (TRM), re-lapse, survival, and IL-2RAs-related toxicity. Our results first provided the evidence that basiliximab or daclizumab was effective and tolerable in preventing GVHD following URD-PBSCT.
DESIGN AND METHODS
Baseline Characteristics of Patients
Between July 2002 and January 2010, 82 consecu-tive patients with hematologic malignancies received
basiliximab or daclizumab in addition to standard GVHD prophylaxis regimens and underwent URD-PBSCT in the Union Hospital of the Huazhong University of Science and Technology. The data of these patients were retrospectively collected and ana-lyzed with approval of the Institutional Review Board on Medical Ethics at Huazhong University of Science and Technology. Baseline characteristics of patients are listed inTable 1.
Among all the 82 URDs, 66 were selected through the Chinese Marrow Donor Program and 16 were selected through the Buddhist Tzu Chi Stem Cells Center. Most of the donor human leukocyte antigen
Table 1. Patients’ Characteristics
Number of patients 82 Median age (range) 24 (12-53) Sex (male/female) 43/39 Diagnosis and the status at transplantation
High WBC when first diagnosed 5
Ph+ 4 CNS leukemia 1 1st remission 24 $2nd remission 4 Refractory 3 AML 26 1st remission 20 $2nd remission 4
Refractory or evolution from MDS 2
HAL 3 CML 17 CP 16 AP 1 MDS 2 NHL 3
Time from diagnosis to transplantation, months (range) 8 (3-72) Donor-recipient HLA type
6 of 6 matched on HLA-A, -B, and -DRB1 25 5 of 6 matched on HLA-A, -B, and -DRB1 37 #4/6 matched on HLA-A, -B, and -DRB1 20 Donor-recipient ABO blood type
Matched 27 Minor mismatched 25 Major mismatched 30 Conditioning regimen BUCY 43 TBI + CY 11 BUCY + IDA or VP16 19 BUCY + Ara-c 9 GVHD prophylaxis CsA + MTX + MMF + Anti-CD25 82 Median nucleated cell dose (108/kg) 7.2 (3.8-18.2)
Median CD34+cell dose (106/kg) 5.8 (3.2-15.6) Median follow-up time, months (range) 16.5 (2-72) ALL indicates acute lymphoblastic leukemia; WBC, white blood cell; Ph, Philadelphia chromosome; AML, acute myeloid leukemia; MDS, myelo-dysplastic syndrome; HA, hybrid acute leukemia; CML, chronic myeloid leukemia; CP, chronic phase; AP, accelerated phase; NHL, non-Hodgkin lymphoma; HLA, human leukocyte antigen; 6 of 6 matched, identical at allele or antigen level; 5 of 6 matched, single mismatch at allele level;#4 of 6 matched, 2 or more than 2 mismatches at allele level or single mis-match at antigen level; TBI, total body irradiation; IDA, idarubicin; VP-16, etoposide; Ara-C, cytarabine; MTX, methotrexate; MMF, mycopheno-late mofetil; Anti-CD25, anti-CD25 monoclonal antibody.
(HLA) typing results included data of HLA-A, -B, -C, -DRB1, and -DQB1, but a small part of the results be-tween 2002 and 2006 only contained data of HLA-A, -B, and -DRB1. Therefore, in this study, only HLA-A, -B, and -DRB1 data were collected to evaluate the HLA disparity between donor-recipient pairs.
Of 82 donor-recipient pairs, 25 were 6 of 6 identi-cal at allele or antigen level, 37 were 5 of 6 matched at allele level, and 20 were#4 of 6 matched at the allele level or single mismatch at the antigen level. Accord-ingly, we divided the patients into an HLA 6 of 6 matched group, an HLA 5 of 6 matched group, and an HLA #4 of 6 matched group when analyzing GVHD onset and survival.
Conditioning Regimen and Supportive Care The conditioning regimens included total body irradiation (8 Gy, on day26) and cyclophosphamide (Cy, 60 mg/kg/day i.v., from days23 to 22) in 11 pa-tients. Forty-three patients received busulfan (Bu, 3.2 mg/kg i.v. in divided doses daily, from days 26 to 24), Cy (1.8 g/m2/day i.v., from days23 to 22), and 4-Methyl derivative of chlorethyl cyclohexyl nitrosourea (Me-CCNU) (250 mg/m2) once on day 22. Nineteen patients had high-risk hematologic ma-lignancies. Those patients received a combination of BuCy and idarubicin (15 mg/m2/day, continuous infu-sion for more than 20 hours on days211 to 29) or eto-poside (VP16, 40 mg/kg/day, on day 21). High-risk hematological malignancies were defined as follows: for acute lymphoblastic leukemia (ALL), any patient with poor-risk cytogenetics [Ph, t(4;11), t(1;19)], age $ 35 years, white blood cell (WBC) count .30 109/L for B lineage and.100 109/L for T lineage at diagnosis, or the time to achieve complete remission .6 weeks; for acute myeloid leukemia (AML), any patient with delayed response to chemotherapy , unfavorable karyotype [25-27], or a history of preceding neoplasia and/or chemotherapy [28,29]; for myelodysplastic syndrome (MDS), any patient scored as Intermediate-2 or high-risk according to International Prognostic Score System (IPSS) . Additional high-risk diseases included the accelerated phase or blastic phase of chronic myeloid leukemia, progressive lymphoma, and hybrid acute leukemia.
Nine patients received a combination of BuCy and cytarabine. The conditioning regimen involved cytar-abine (2 g/m2on day28) followed by Bu (3.2 mg/kg i.v. in divided doses daily, on days 27 to 25), Cy (1.8 g/m2 on days 24 to 23), and oral Me-CCNU (250 mg/m2on day22).
To prevent seizures, phenytoin (100 mg) was administered orally 3 times daily beginning 24 hours before the first dose of Bu and continued until 24 hours after the last dose. Antimicrobial prophylaxis consisted of ganciclovir 5 mg/kg twice daily from day210 to 22,
ciprofloxacin 500 mg twice daily, and oral fluconazol from day 210 until day 175. Patients received cotrimoxazole twice daily from the time of neutrophil recovery to 6 months. CMV viral load was monitored by polymerase chain reaction at least weekly within 100 days posttransplantation. CMV reactivation was defined by positive CMV DNA detection in 2 consec-utive blood samples.
Collection of Hematopoietic Cells
Donor PBSCs were collected using standard mo-bilization protocols. Granulocyte colony stimulation factor (5-10 mg/kg once daily) was used to mobilize peripheral blood. The peripheral blood progenitor cells were harvested on day 4 and 5 after granulocyte colony stimulation factor. The harvested cells were in-fused without manipulation on the same day of leukapheresis collection.
Engraftment and Chimerism Assessment
Hematologic recovery, cytogenetic studies, bone marrow aspirate, and biopsy were used to assess the engraftment. Granulocyte engraftment was defined as an absolute neutrophil count of 0.5 109/L or more for 3 consecutive days, and the platelet count needed to be above 20 109/L without transfusion for 3 days. Chimerism was evaluated by polymerase chain reaction–based analyses of variable numbers of tandem repeats.
All patients received GVHD prophylaxis consist-ing of cyclosporine A (CsA), short-course methotrex-ate, mycophenolate mofetil, and IL-2AR (basiliximab, Simulect, Novartis Pharmaceuticals, East Hanover, NJ, or daclizumab, Zenapax, Roche Pharmaceuticals, Indianapolis, IN). Sixty recipients were given basilixi-mab intravenously at a dose of 20 mg by 30-minute i.v. infusion on day 0 (2 hours before transplantation) and day 14. The remaining 22 recipients were adminis-trated daclizumab intravenously at a dose of 1 mg/kg on day 0 (2 hours before transplantation) and day 14. CsA was orally or i.v administered twice daily starting on day21 to maintain blood levels between 150 and 250 ng/mL; the dosage was adjusted to blood levels and renal function. CsA was tapered by approx-imately 5% per week from day150 and discontinued on day1180 in the absence of grade II-IV aGVHD and extensive chronic GVHD (cGVHD). Methotrex-ate was given at a dose of 15 mg/m2i.v. on day 11, 10 mg/m2 on days 13, 16, and 111, and followed by folinic acid rescue. Mycophenolate mofetil was given at a dose of 7.5 mg/kg orally twice daily from days17 to 135. Acute GVHD was graded according
to Seattle criteria . Patients surviving more than 30 days were included in the analysis of aGVHD. Chronic GVHD was defined according to standard criteria . A minimum of 100 days of follow-up was the criterion evaluable for cGVHD.
IL-2RAs-related toxicities were evaluated accord-ing to the National Cancer Institute Common Toxic-ity Criteria Version 3.0. Organ damage because of GVHD and/or infectious complications was excluded.
Evaluations were based on data available by July 15, 2010. Demographic factors were summarized using percentage, median, and range value. Categoric vari-ables were compared using the chi-square test or Fisher exact test. Logistic regression was applied for multivar-iate analysis of risk factors for grade II-IV aGVHD and cGVHD. The cumulative probabilities of overall sur-vival (OS) and disease-free sursur-vival (DFS) were esti-mated by the Kaplan-Meier method. Differences between the curves were tested for statistical signifi-cance by the log-rank test. All tests were 2 tailed, and a P value of\.05 was considered to indicate statistical significance. Data was analyzed using SPSS software (version 16.0, SPSS Inc., Chicago, IL).
All recipients obtained hematologic recovery. The median time to neutrophil recovery was 12 days (range: 8-23), whereas the median time to platelet recovery was 14 days (range: 9-26). Analysis of chimerism indicated that all patients achieved full donor chimerism by day130 after URD-PBSCT. GVHD
Acute onset of GVHD occurred in 62.2% (51 of 82) patients; 22 patients (26.8%) developed grade I aGVHD and 16 patients (19.5%) suffered grade II aGVHD. The percentage of grade II-IV aGVHD and grade III-IV aGVHD were 35.4% (29 of 82) and 15.9% (13 of 82), respectively. Median onset time of aGVHD was 25 days posttransplantation (range: 10 to 88). Involved or-gans included skin in 21 patients, intestinal tract in 14 patients, liver in 10 patients, and multiple organs in 6 patients. Among 82 patients, 75 patients were evaluable for cGVHD. Limited cGVHD occurred in 13 patients (17.3%) and extensive cGVHD developed in 16 patients (21.4%). The median onset time of cGVHD was 145 days (range: 100-385) after transplantation.
Risk Factors for GVHD
As shown inTable 2, multivariate analysis was per-formed to evaluate risk factors for grade II-IV aGVHD
Table 2. Multivariate Analysis for Grade II-IV aGVHD and cGVHD following URD-PBSCT
aGVHD Grade II-IV cGVHD
OR 95% CI P OR 95% CI P Age (years) 30 or younger — — — — — — Older than 30 0.438 0.124-1.552 0.201 2.738 0.815-9.200 0.103 Diagnosis ALL — — — — — — AML 0.585 0.155-2.210 0.429 2.995 0.825-10.869 0.095 CML 0.359 0.074-1.731 0.202 2.127 0.504-8.985 0.305 Other 0.251 0.028-2.228 0.215 2.016 0.270-15.049 0.494 Donor-recipient ABO blood type — — — — — —
Matched — — — — — —
Minor mismatched 0.459 0.103-2.048 0.308 2.352 0.579-9.550 0.232 Major mismatched 2.767 0.745-10.274 0.128 0.947 0.248-3.615 0.937 Donor-recipient HLA type
6 of 6 matched — — — — — —
5 of 6 matched 1.073 0.307-3.744 0.912 2.613 0.766-8.917 0.125 #4 of 6 matched 5.233 1.174-23.324 0.030 0.909 0.189-4.383 0.906 Interval from diagnosis to PBSCT, months
#6 months — — — — — —
>6 months 1.779 0.541-5.846 0.343 1.059 0.350-3.202 0.920 The disease status before PBSCT
Standard risk — — — — — —
High risk 1.592 0.491-5.162 0.438 1.320 0.416-4.191 0.638 Grade II-IV aGVHD
No — — — — — —
Yes — — — 3.377 1.004-11.356 0.049
OR indicates odds ratio; ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; CML, chronic myeloid leukemia; HLA, human leukocyte antigen.
and cGVHD. Neither age, type of hematologic malig-nancy, donor-recipient ABO blood type disparity, interval from diagnosis to PBSCT, nor disease status before PBSCT is identified as the risk factor for grade II-IV aGVHD. However, if the donor-recipient HLA type disparity increases to 2 or more at the allele level, as well as single mismatch at antigen level on HLA-A, -B, and -DRB1, the risk of grade II-IV aGVHD signif-icantly enhances to 5.2-fold (P 5 .03). Furthermore, the onset of grade II-IV aGVHD is also associated with a 3.4-fold (P5 .049) risk of cGVHD.
Survival and Outcome
During a median follow-up of 16.5 months (range: 2-72), 66 patients survived and 16 patients died. In all, TRM was 13.4% (11 of 82) with a median onset time of 3 months posttransplantation (range; 2-23). The prin-cipal causes of TRM included aGVHD (n 5 5), cGVHD (n 5 2), invasive fungal infection (n 5 2), bacterial pneumonia (n 5 1), and hepatic veno-occlusive disease (n 5 1). Relapse occurred in 7 patients (8.5%) with a median onset time of 6 months posttransplantation (range: 2.5-14). Among those re-lapsed patients, 5 patients subsequently died of disease progression, 2 patients received combination chemo-therapy, and the remainder survived. As shown in
Figure 1, the estimated probabilities of 2-year OS and 2-year DFS are 77.1% (95% confidence interval [CI], 66.5%-87.7%) and 72.2% (95% CI, 59.9%-84.5%), respectively.
GVHD and Survival According to HLA Matching Status
Considering the different HLA matching status, grade II-IV aGVHD onset was only 28% in the HLA 6 of 6 matched group, 27% in the HLA 5 of 6 matched group, but significantly increased to 60% in the HLA #4 of 6 matched group (P 5 .031 and P5 .015, respectively). No significant difference was observed between the HLA 6 of 6 matched group and the HLA 5 of 6 matched group (P 5 .094). The occurrence of grade III-IV aGVHD in the HLA #4 of 6 matched group was 35%, which was higher than that in the 5 of 6 matched group (8%) and the HLA 6 of 6 matched group (12%). But only the differ-ence between the HLA#4 of 6 matched group and the HLA 5 of 6 matched group was significant (P5 .024).
Figure 1. Kaplan-Meier estimates of the cumulative probability of 2-year OS and DFS in all 82 patients following URD-PBSCT. OS indicates overall survival; DFS, disease-free survival; URD-PBSCT, unre-lated donor-peripheral blood stem cell transplantation; SCT, stem cell transplantation.
Figure 2. Kaplan-Meier estimates of the cumulative probability of 2-year OS (A) and DFS (B) in different HLA matching groups. (A) HLA 6/6 matched group versus HLA 5/6 matched group, P5.432; HLA 6 of 6 matched group versus HLA #4 of 6 matched group, P 5.835; HLA 5 of 6 matched group versus HLA#4 of 6 matched group, P 5.655. (B) HLA 6 of 6 matched group versus HLA 5 of 6 matched group, P 5.283; HLA 6 of 6 matched group versus HLA#4 of 6 matched group, P 5 .924; HLA 5 of 6 matched group versus HLA #4 of 6 matched group, P 5 .387. SCT indicates stem cell transplantation; 6 of 6 matched, HLA 6 of 6 matched; 5 of 6 matched, HLA 5 of 6 matched; 4 of 6 matched, HLA#4 of 6 matched; OS, overall survival; DFS, disease-free survival.
There was no statistical discrepancy in cGVHD rates among the 3 groups. As shown in Figure 2, the 2-year OS (A) and 2-2-year DFS (B) in 3 groups are not sig-nificantly different.
Forty patients experienced bacterial infection posttransplantation (48.8%), and 1 patient died of se-vere bacterial pneumonia. Ten patients developed probable or proven invasive fungal infection, and 2 pa-tients died. The rate of CMV reactivation was 47.6% (39 of 82). Only 1 patient suffered CMV pneumonia. The patient with CMV disease was treated with ganci-clovir 5 mg/kg twice daily for 21 days and then fol-lowed with ganciclovir 5 mg/kg daily until CMV DNA detection turned to negative, with a combination of intravenous immunoglobulin. The anti-CMV ther-apy was successful, thus CMV pneumonia was man-aged. Moreover, although Epstein-Barr virus was not monitored in those patients, there was no clinical evi-dence of PTLD.
Daclizumab versus Basiliximab
Among 82 recipients, 22 recipients received dacli-zumab, whereas 60 recipients received basiliximab. There was no significant difference in clinical charac-teristics in the patients between the basiliximab and da-clizumab groups (data not shown). The onset of grade II-IV aGVHD was not significantly different between the daclizumab and basiliximab groups (41% versus 33.3%, P5 .525); neither was the onset of grade III-IV aGVHD (13.6% versus 16.7%, P5 .74). Interest-ingly, the occurrence of cGVHD was significantly lower in the basiliximab group (30.4%) than that in the daclizumab group (63.2%, P5 .011), especially ex-tensive cGVHD (14.3% versus 42.1%, P5 .02). In all, TRM was 13.3% (8 of 60) in the basiliximab group, but 13.6% (3 of 22) in the daclizumab group (P5 .972). Relapse occurred in 2 of 60 recipients (3.3%) in the
basiliximab group, but 3 of 22 recipients (13.6%) in the daclizumab group (P 5 .117). As indicated in
Figure 3, the 2-year OS (A) and 2-year DFS (B) in the basiliximab group seem superior (77.3%, 95% CI, 63%-91%; 75.5%, 95% CI, 61.4%-89.6%) than those in the daclizumab group (72.7%, 95% CI, 54%-91%; 65.5%, 95% CI, 52%-79%), but the differ-ences are not significant (P 5 .336 and P 5 .296, respectively).
Side Effects of IL-2RAs
Either basiliximab or daclizumab was tolerable with moderate side effects. Nausea and vomiting occurred in 20 patients (24.4%), followed by diarrhea in 11 patients (13.4%) and constipation in 4 patients (4.9%). Those side effects were restricted to grade I-II. No related infection was observed. There were no other adverse effects developed as well, such as hema-tologic, cardiac, liver, nephro, and neurologic toxicity.
In the present study, we retrospectively analyzed the prophylactic effects of IL-2RAs against GVHD following URD-PBSCT. Our results first suggest that basiliximab or daclizumab effectively prevents GVHD in URD-PBSCT. According to the literature, the occurrence of aGVHD ranges from 30% to 80% postallogeneic HSCT. The risk of GVHD also in-creases in URD-HSCT. Grade II-IV aGVHD occurs in 43% to 70% of matched URD marrow transplanta-tions, and in 63% to 95% of HLA 1 antigen-mismatched URD transplantations . Moreover, cGVHD is reported in more than 55% of matched URD transplantion recipients and as many as 80% of HLA 1 antigen-mismatched URD transplantations
. Here we reported that grade II-IV and grade III-IV aGVHD were observed in 35.4% and 15.9% of patients post-URD-HSCT respectively, whereas
Figure 3. Kaplan-Meier estimates of the cumulative probability of 2-year OS (A) and DFS (B) in basiliximab or daclizumab group, P5.336 and P 5.296, respectively. SCT indicates stem cell transplantation; OS, overall survival; DFS, disease-free survival.
cGVHD only occurred in 38.7% of patients. Thus, these results indicate that IL-2RAs-intensified GVHD prophylaxis leads to adequate immunosup-pression following URD-HSCT, which coincides with the results from a previous study on haploidenti-cal bone marrow transplantation.
Because of the limitation of retrospective study, we found that only 11 patients did not receive IL-2RAs but received ATG for intensifying the GVHD prophylaxis regimen following URD-PBSCT when we collected data in our department. Moreover, there was a signifi-cant difference in clinical characteristics in the patients between the IL-2RAs and the no IR-2RAs (ATG) groups. Therefore, we considered that the collected data did not support providing a control group in the present study. However, we summarized the published literature that studied the ATG-intensified GVHD prophylaxis in URD-HSCT as a comparison. It has been reported that grade II-IV aGVHD occurs in 19%-51% patients receiving ATG-intensified GVHD prophylaxis regimens, while 11%-15% patients suffer grade III-IV aGVHD. The onset of cGVHD is 16%-44% in the ATG group, but up to 76% in the no-ATG group [3,4,6,35,36]. Considering our results mentioned above, it is suggested that basiliximab or daclizumab has comparable immunosuppressive activity with ATG as an intensifying agent to GVHD prophylaxis.
Moreover, our results also suggest that an IL-2R blockade does not increase the risk of infection when enhancing immunosuppression following URD-HSCT. In vivo T cell depletion with ATG decreases GVHD, but results in delayed immune reconstitution, leaving the recipient more susceptible to infections
[4,5,7,37]. However, daclizumab or basiliximab binds specifically to the IL-2R of activated T cells with high affinity and only selectively depletes the alloreac-tive donor lymphocytes, without affecting the resting T cells, which are important for preventing infectious complications [38,39]. Similarly, it is also addressed that daclizumab or basiliximab treatment has a lower incidence of infectious deaths than ATG treatment
. Bacigalupo et al.  reported that the rate of infectious death was 7% in 7.5 mg/kg ATG but 30% in the 15 mg/kg ATG group when ATG was adminis-tered to prevent GVHD. The CMV reactivation was similar in the ATG and non-ATG groups (67% versus 68%). Pidala et al. demonstrated that the rate of infectious death was 13.3% when 7.5 mg/kg ATG was administered to prevent GVHD. The overall cu-mulative incidence of CMV reactivation was 60%, and comfirmed CMV organ involvement was present in 15.6% (7 of 45) of patients. Here in our study, the rate of infectious death was only 3.7%. CMV reactiva-tion was observed in 47.6% of patients. Only 1 patient developed CMV disease and was cured with anti-CMV therapy. Moreover, no PTLD was observed in our
study. These results suggest that additional adminis-tration of daclizumab or basiliximab reinforces GVHD prophylaxis without increasing infections or infection-related deaths.
But it remains arguable whether IL-2RAs affects graft-versus-leukemia effects. As previously reported, IL-2R monoclonal antibody (33B3.1), a rat antibody directed against IL-2R, significantly impairs leukemia-free survival mainly because of increasing late relapse . Nevertheless, inolimomab (BT563, Leucotac, Biotest, Piscataway, NJ), a murine mono-clonal antibody against CD25, does not enhance the 10-year leukemia-free survival after URD-bone mar-row transplantation . Furthermore, daclizumab or basiliximab administration results in low relapse rates during HSCT [17-20,43]. The discrepancy of CD25 monoclonal antibody types may account for the arguments. In our study, the relapse rate was only 8.5%, which was lower than that in the ATG group (18%-45%) according to published data
[3,4,6,35,36]. Thus, it is suggested that daclizumab or basiliximab does not affect graft-versus-leukemia as an intensifying GVHD prophylactic agent in HSCT. Moreover, daclizumab or basiliximab admin-istration results in favorable outcome. It has been reported that long-term OS and DFS achieves 56% and 51.6%, respectively, in the ATG group
[3,4,6,35,36]. In research on HLA-identical sibling transplantation, the 2-year OS is 72%, and ATG administration in addition to the standard GVHD prophylaxis regimen results in comparable outcome (2-year OS, 71%) post-HLA-mismatched related do-nor or haploidentical HSCT. Inspiringly, our re-sults showed that the 2-year OS and DFS also rose to 77.1% and 72.2%, respectively. The explanations for the favorable outcome can be the effective GVHD prophylaxis without increasing the risk of relapse, infections, and graft failure by IL-2RAs.
We evaluated the effects of IL-2RAs on GVHD in different HLA matching status. In the present study, the rate of grade II-IV aGVHD was similar in the HLA 6 of 6 matched group and the 5 of 6 matched group, but significantly higher in the#4 of 6 matched group. However, the 2-year OS and DFS were not sig-nificantly different among these 3 groups. These re-sults suggest that specific the IL-2R blockade effectively prevents aGVHD during URD-PBSCT, especially in HLA identical or only 1 allele mis-matched recipients. Furthermore, IL-2RAs benefits the outcome, even for those recipients with 2 or more HLA disparities.
We also evaluated the immunosuppressive effect of daclizumab versus basiliximab in HSCT because there was no published data. This type of comparable study has been performed in renal transplantation. Most studies suggest that there are no significant differences in acute rejection, graft function, survival, and safety
of induction therapy between basiliximab and daclizu-mab[45-48]. Only Lin et al.suggested that basilix-imab was more effective than daclizumab in preventing acute rejection following renal transplantation. In our study, basiliximab presented the same prophylactic ef-fects on aGVHD but superior prophylactic efef-fects on cGVHD than daclizumab. Nevertheless, the underly-ing mechanisms remain unclear. There are few hints. It is documented that 5 doses of daclizumab saturates the CD25 subunit for approximately 120 days after trans-plantation. The long-term immunosuppressive ef-fect of daclizumab may contribute to preventing cGVHD. In vitro study also indicates that daclizumab provides the synergistic activity of inhibiting T cell proliferation with CsA, whereas basiliximab shows only subadditive activity. Thus, it seems that da-clizumab has more advantages than basiliximab. How-ever, our results showed that daclizumab had equal effects on aGVHD prophylaxis but inferior effects on cGVHD than basiliximab. Therefore, further stud-ies are needed to explore the mechanisms underlying the different preventive activities against GVHD be-tween daclizumab and basiliximab.
On the whole, we provide the first evidence that an IL-2R blockade with daclizumab or basiliximab is efficient and safe in preventing GVHD following URD-PBSCT, and contributes to a favorable out-come. IL-2RAs can be the alternative immunosuppres-sive agents for intensifying GVHD prophylaxis in URD-HSCT. Basiliximab has similar effects on pre-venting aGVHD but superior activities against cGVHD than daclizumab. It should be noted that this study is retrospective; thus, further prospective and randomized control studies are needed.
Financial disclosure: There is no financial interest to disclose.
1. Schlenk RF, D€ohner K, Mack S, et al. Prospective evaluation of allogeneic hematopoietic stem-cell transplantation from matched related and matched unrelated donors in younger adults with high-risk acute myeloid leukemia: German-Austrian trial AMLHD98A. J Clin Oncol. 2010;28:4642-4648. 2. Gupta V, Tallman MS, Weisdorf DJ. Allogeneic hematopoietic
cell transplantation for adults with acute myeloid leukemia: myths, controversies, and unknowns. Blood. 2011;117:2307-2318. 3. Basara N, Baurmann H, Kolbe K, et al. Antithymocyte globulin for the prevention of graft-versus-host disease after unrelated hematopoietic stem cell transplantation for acute myeloid leuke-mia: results from the multicenter German cooperative study group. Bone Marrow Transplant. 2005;35:1011-1018.
4. Bacigalupo A, Lamparelli T, Bruzzi P, et al. Antithymocyte globulin for graft-versus-host disease prophylaxis in transplants from unrelated donors: 2 randomized studies from Gruppo Ital-iano Trapianti Midollo Osseo (GITMO). Blood. 2001;98: 2942-2947.
5. Koreth J, Antin JH. Current and future approaches for control of graft-versus-host disease. Expert Rev Hematol. 2008;1:111. 6. Bacigalupo A, Lamparelli T, Gualandi F, et al. Prophylactic
an-tithymocyte globulin reduces the risk of chronic graft-versus-host disease in alternative-donor bone marrow transplants. Biol Blood Marrow Transplant. 2002;8:656-661.
7. Bacigalupo A. Antithymocyte globulin for prevention of graft-versus-host disease. Curr Opin Hematol. 2005;12:457-462. 8. Brennan DC, Daller JA, Lake KD, et al. Thymoglobulin
Induc-tion Study Group. Rabbit antithymocyte globulin versus basilix-imab in renal transplantation. N Engl J Med. 2006;355: 1967-1977.
9. Sageshima J, Ciancio G, Chen L, Burke GW 3rd. Anti-interleu-kin-2 receptor antibodies-basiliximab and daclizumab-for the prevention of acute rejection in renal transplantation. Biologics. 2009;3:319-336.
10. Mattei MF, Redonnet M, Gandjbakhch I, et al. Lower risk of in-fectious deaths in cardiac transplant patients receiving basilixi-mab versus anti-thymocyte globulin as induction therapy. J Heart Lung Transplant. 2007;26:693-699.
11. McKeage K, McCormack PL. Basiliximab: a review of its use as induction therapy in renal transplantation. BioDrugs. 2010;24: 55-76.
12. Yao G, Albon E, Adi Y, et al. A systematic review and economic model of the clinical and cost-effectiveness of immunosuppres-sive therapy for renal transplantation in children. Health Technol Assess. 2006;10: iii-iv, ix-xi, 1-157.
13. Chapman TM, Keating GM. Basiliximab: a review of its use as induction therapy in renal transplantation. Drugs. 2003;63: 2803-2835.
14. Berger M, Biasin E, Saglio F, Fagioli F. Innovative approaches to treat steroid-resistant or steroid refractory GVHD. Bone Mar-row Transplant. 2008;42:S101-S105.
15. Depper JM, Leonard WJ, Robb RJ, Waldmann TA, Greene WC. Blockade of the interleukin-2 receptor by anti-Tac antibody: inhibition of human lymphocyte activation. J Im-munol. 1983;131:690-696.
16. Miano M, Cuzzubbo D, Terranova P, et al. Daclizumab as use-ful treatment in refractory acute GVHD: a paediatric experi-ence. Bone Marrow Transplant. 2009;43:423-427.
17. Funke VA, de Medeiros CR, Setubal DC, et al. Therapy for se-vere refractory acute graft-versus-host disease with basiliximab, a selective interleukin-2 receptor antagonist. Bone Marrow Transplant. 2006;37:961-965.
18. Wawer A, Laws HJ, Dilloo D, G€obel U, Burdach S. Long-time survival after unrelated bone marrow transplantation in children and adolescents and targeted therapy with CD25 blockade to prevent GVHD. Klin Padiatr. 2004;216:169-175.
19. Ji SQ, Chen HR, Yan HM, et al. Anti-CD25 monoclonal anti-body (basiliximab) for prevention of graft-versus-host disease af-ter haploidentical bone marrow transplantation for hematological malignancies. Bone Marrow Transplant. 2005;36:349-354. 20. Shamsi TS, Irfan M, Farzana T, et al. Allogeneic peripheral
blood stem cell transplant (PBSCT) using anti-IL2 receptor an-tibody Daclizumab for the prevention of acute graft versus host disease in steroid refractory Diamond Blackfan anaemia: a case report. J Pak Med Assoc. 2005;55:454-455.
21. Chen HR, Ji SQ, Wang HX, et al. Humanized anti-CD25 monoclonal antibody for prophylaxis of graft-vs-host disease (GVHD) in haploidentical bone marrow transplantation with-out ex vivo T-cell depletion. Exp Hematol. 2003;31:1019-1025. 22. Maschan AA, Trakhtman PE, Balashov DN, et al. Fludarabine,
low-dose busulfan and antithymocyte globulin as conditioning for Fanconi anemia patients receiving bone marrow transplanta-tion from HLA-compatible related donors. Bone Marrow Trans-plant. 2004;34:305-307.
23. Shigematsu A, Kondo T, Yamamoto S, et al. Excellent outcome of allogeneic hematopoietic stem cell transplantation using a con-ditioning regimen with medium-dose VP-16, cyclophosphamide and total-body irradiation for adult patients with acute lympho-blastic leukemia. Biol Blood Marrow Transplant. 2008;14:568-575. 24. Kern W, Haferlach T, Schoch C, et al. Early blast clearance by remission induction chemotherapy is a major independent prog-nostic factor for both achievement of complete remission and long-term outcome in acute myeloid leukemia: data from the German AML cooperative group (AMLCG) 1992 trial. Blood. 2003;101:64-70.
25. Grimwade D, Walker H, Oliver F, et al. The importance of di-agnostic cytogenetics on outcome in AML: analysis of 1,612 pa-tients entered into the MRCAML10 trial—The Medical Research Council Adult and Children’s Leukaemia Working Parties. Blood. 1998;92:2322-2333.
26. Slovak ML, Kopecky KJ, Cassileth PA, et al. Karyotypic analysis predicts outcome of preremission and postremission therapy in adult acute myeloid leukemia: A Southwest Oncology Group/ Eastern Cooperative Oncology Group Study. Blood. 2000;96: 4075-4083.
27. Schoch C, Haferlach T, Haase D, et al. Patients with denovo acute myeloid leukaemia and complex karyotype aberrations show a poor prognosis despite intensive treatment: a study of 90 patients. Br J Haematol. 2001;112:118-126.
28. Appelbaum FR. Who should be transplanted for AML? Leuke-mia. 2001;15:680-682.
29. Schoch C, Kern W, Schnittger S, Hiddemann W, Haferlach T. Karyotype is an independent prognostic parameter in therapy-related acute myeloid leukemia (t-AML): an analysis of 93 pa-tients with t-AML in comparison to 1092 papa-tients with de novo AML. Leukemia. 2004;18:120-125.
30. Greenberg P, Cox C, Le Beau MM, et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood. 1997;89:2079-2088.
31. Antin JH, Childs R, Filipovich AH, et al. Establishment of com-plete and mixed donor chimerism after allogeneic lymphohemato-poietic transplantation: recommendations from a workshop at the 2001 Tandem Meetings of the International Bone Marrow Trans-plant Registry and the American Society of Blood and Marrow Transplantation. Biol Blood Marrow Transplant. 2001;7:473-485. 32. Przepiorka D, Weisdorf D, Martin P, et al. 1994 Consensus
Conference on Acute GVHD Grading. Bone Marrow Transplant. 1995;15:825-828.
33. Sullivan KM. Graft-versus-host disease. In: Thomas ED, Blume KG, Forman SJ, editors. Hematopoietic Cell Transplanta-tion. London, Oxford: Blackwell Scientific; 1999. pp. 515-536. 34. Grewal SS, Barker JN, Davies SM, Wagner JE. Unrelated donor
hematopoietic cell transplantation: marrow or umbilical cord blood? Blood. 2003;101:4233-4244.
35. Duggan P, Booth K, Chaudhry A, et al. Unrelated donor BMT recipients given pretransplant low-dose antithymocyte globulin have outcomes equivalent to matched sibling BMT: a matched pair analysis. Bone Marrow Transplant. 2002;30:681-686. 36. Finke J, Bethge WA, Schmoor C, et al. Standard
graft-versus-host disease prophylaxis with or without anti-T-cell globulin in haematopoietic cell transplantation from matched unrelated
donors: a randomised, open-label, multicentre phase 3 trial. Lancet Oncol. 2009;10:855-864.
37. Seggewiss R, Einsele H. Immune reconstitution after allogeneic transplantation and expanding options for immunomodulation: an update. Blood. 2010;115:3861-3868.
38. Campara M, Tzvetanov IG, Oberholzer J. Interleukin-2 re-ceptor blockade with humanized monoclonal antibody for solid organ transplantation. Expert Opin Biol Ther. 2010;10: 959-969.
39. Couriel D, Caldera H, Champlin R, Komanduri K. Acute graft-versus-host disease: pathophysiology, clinical manifestations, and management. Cancer. 2004;101:1936-1946.
40. Salvana EM, Salata RA. Infectious complications associated with monoclonal antibodies and related small molecules. Clin Micro-biol Rev. 2009;22:274-290.
41. Pidala J, Tomblyn M, Nishihori T, et al. ATG prevents severe acute graft-versus-host disease in mismatched unrelated donor hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2011 Jan 6 [Epub ahead of print].
42. Blaise D, Olive D, Michallet M, Marit G, Leblond V, Maraninchi D. Impairment of leukaemia-free survival by addi-tion of interleukin-2-receptor antibody to standard graft-versus-host prophylaxis. Lancet. 1995;345:1144-1146.
43. Schmidt-Hieber M, Fietz T, Knauf W, et al. Efficacy of the interleukin-2 receptor antagonist basiliximab in steroid-refractory acute graft-versus-host disease. Br J Haematol. 2005; 130:568-574.
44. Lu DP, Dong L, Wu T, et al. Conditioning including antithy-mocyte globulin followed by unmanipulated HLA-mismatched/haploidentical blood and marrow transplantation can achieve comparable outcomes with HLA-identical sibling transplantation. Blood. 2006;107:3065-3073.
45. Kandus A, Arnol M, Omahen K, et al. Basiliximab versus dacli-zumab combined with triple immunosuppression in deceased donor renal transplantation: a prospective, randomized study. Transplantation. 2010;89:1022-1027.
46. Naderi GH, Mehraban D, Ganji MR, Jafarpouriani M, Latif AH. The outcome of induction therapy with monoclonal antibodies in kidney transplantation among Iranian patients: a prospective study. Transplant Proc. 2009;41:2768-2771. 47. Vega O, Cardenas G, Correa-Rotter R, Alberu J,
Morales-Buenrostro LE. Basiliximab vs. limited-dose daclizumab (2 mg/kg) administered in single or two separated doses in kid-ney transplantation. Rev Invest Clin. 2008;60:82-86.
48. Pham K, Kraft K, Thielke J, et al. Limited-dose Daclizumab ver-sus Basiliximab: a comparison of cost and efficacy in preventing acute rejection. Transplant Proc. 2005;37:899-902.
49. Lin M, Ming A, Zhao M. Two-dose basiliximab compared with two-dose daclizumab in renal transplantation: a clinical study. Clin Transplant. 2006;20:325-329.
50. Hershberger RE, Starling RC, Eisen HJ, et al. Daclizumab to prevent rejection after cardiac transplantation. N Engl J Med. 2005;352:2705-2713.
51. Kircher B, Latzer K, Gastl G, Nachbaur D. Comparative in vitro study of the immunomodulatory activity of humanized and chi-meric anti-CD25 monoclonal antibodies. Clin Exp Immunol. 2003;134:426-430.