Volume 13, Issue 7 , Pages 863-870, July 2007
Unrelated Donor Bone Marrow Transplants for Severe Aplastic Anemia with Conditioning Using Total Body Irradiation and Cyclophosphamide
Article Outline
Abstract
The outcome of unrelated donor bone marrow transplantation for aplastic anemia is inferior to that of sibling donor bone marrow transplantation because of a higher rate of transplant-related mortality (TRM), which is closely associated with the intensity of pretransplant conditioning to overcome graft rejection. We conducted a prospective trial with an intermediate to high dose of total body irradiation (TBI) in combination with a fixed dose of cyclophosphamide (120 mg/kg) to use for pretransplant conditioning for unrelated donor bone marrow transplantation in adult aplastic anemia. The number of patients who received doses of 1200, 1000, and 800 cGy of TBI were 5, 9, and 26, respectively. The corresponding probabilities of overall survival (OS) at 3 years were 40%, 44%, and 92%, respectively. The incidence of regimen-related toxicity with grade III-IV and graft rejection in the patients who received a dose of 800 cGy of TBI were 0 of 26 patients. The significant factors associated with OS were the TBI dose (800 cGy vs. ≥1000 cGy; P = .001), chronic graft-versus-host disease (less than or equal to limited vs. extensive; P = .013), the method of HLA typing for the donor-recipient matching (serologic typing vs. DNA-based typing; P = .006), and the transfusion amount before transplantation (≤90 vs. >90 units; P = .020).
Key Words: Aplastic anemia, Unrelated donor transplant, Total body irradiation, Cyclophosphamide
Introduction
Allogeneic bone marrow transplantation from an unrelated donor (u-BMT) is an alternative therapy for a patient with severe aplastic anemia who cannot acquire an adequate response to immunosuppressive therapy (IST) and does not have an HLA-identical sibling donor. Additionally, u-BMT can be a front-line therapy for very severe aplastic anemia when the patient can receive emergent u-BMT without IST. However, the success of this approach is limited by a higher incidence of transplant-related complications (TRC), such as graft rejection, graft-versus-host disease (GVHD), and various organ toxicities than is seen for bone marrow transplants from an HLA-identical sibling donor (s-BMT) [1, 2, 3, 4]. u-BMT recipients with aplastic anemia usually have the following unfavorable characteristics: a longer duration of disease, a higher iron deposit in tissues, and a higher chance to have a preformed alloimmunity because of multiple transfusions required before transplant, and a higher intensity of pretransplant conditioning required to overcome graft rejection [3, 4, 5, 6, 7]. As TRC are deeply influenced by the intensity of the conditioning regimens, it is necessary to determine the optimal intensity of conditioning regimens that can both overcome the risk of graft rejection and minimize regimen-related toxicities (RRT). The optimal type and optimal intensity of conditioning are difficult to determine because of a lack of prospective trials using unified regimens. Recently, a prospective trial of Deeg and colleagues [8] suggested that the combination of a low dose of total body irradiation (TBI) plus administration of 200 mg/kg of cyclophosphamide (CY) and 90 mg/kg of antithymocyte globulin (ATG) could be an optimal conditioning regimen for u-BMT in severe aplastic anemia. These investigators added low-dose TBI to the same conditioning regimens as those used for HLA-matched sibling donor transplantation; CY (200 mg/kg) plus ATG. From the beginning of 1998, we have been conducting a similar prospective trial to determine a safe and sufficient dose of TBI to use in combination with 120 mg/kg of CY as a conditioning regimen for u-BMT for aplastic anemia. In this trial, we have employed a high dose of TBI (from a dose of 1200 cGy to 800 cGy, stepwisely) and a lower dose of CY (120 mg/kg). ATG was not incorporated in this protocol.
Patients and Methods
Patients
The patients enrolled in the study were either those with severe aplastic anemia who could receive emergent transplants without preceding IST because the coordination period for u-BMT was short or those who had not responded to IST or had responded only transiently. Forty patients received u-BMT using TBI and CY from May 1998 to February 2006 at our institution. Informed consent was obtained from all patients. As of October 2006, the median follow-up duration period after transplant was 27 months (range: 1-100 months). Patients and transplant characteristics are summarized in Table 1. The median age of the patients was 27 years (range: 16-50 years). The median disease duration before transplant was 39 months (range: 2-192 months). Most patients were heavily transfused before transplant. The median amount of blood transfused was 81 units (range: 8-500 units). Eight patients with very severe aplastic anemia underwent u-BMT without preceding IST. Nineteen patients had received 1 course of conventional IST and 13 patients received more than 1 course of IST before transplant.
Table 1. Characteristics of 40 Patients with Aplastic Anemia Who Underwent Unrelated Donor Bone Marrow Transplantation with a Conditioning Regimen Composed of 800-1200 cGy of Total Body Irradiation Plus 120 mg/kg of Cyclophosphamide
| Characteristic | Median (Range) or No. of Patients (%) |
|---|---|
| Age, year | 27 years (16-50) |
| Sex (male:female) | 24(60%):16(40%) |
| Disease duration, month | 39 months(2-192) |
| Amount of blood transfused, units | 81 units(8-500) |
| Number of courses of immunosuppressive therapy | |
| 0 | 8(20%) |
| 1 | 19(48%) |
| >1 | 13(32%) |
| HLA typing method and HLA mismatch | |
| serological typing | 16(40%) |
| HLA-identical | 16 |
| HLA-nonidentical | 0 |
| DNA-based typing | 24(60%) |
| HLA-identical | 20 |
| HLA-nonidentical | 4⁎ |
| TBI dose | |
| 1200 cGy | 5(12%) |
| 1000 cGy | 9(23%) |
| 800 cGy | 26(65%) |
| GVHD prophylaxis | |
| CsA + MTX | 3(8%) |
| FK506 + MTX | 37(92%) |
| Cell dose infused | |
| MNC (×108/kg) | 1.0(0.3-5.4) |
| CD34+ (×106/kg) | 4.3(0.8-14.4) |
| CD3+ (×107/kg) | 5.0(1.2-21.8) |
⁎There were 4 HLA-nonidentical (antigen level in 1 and allele level in 3) transplants according to DNA-based typing. |
HLA Typing Method for Donor-Recipient Matching
The method of HLA typing for donor-recipient matching was determined by its availability at the time of enrollment into the study. For the first consecutive 16 patients, the donor-recipient was matched by serologic typing for HLA-A, -B, (-C), and -DR. For the remaining 24 patients, the donor-recipient were matched with DNA-based typing for HLA-A, -B, (-C), and -DRB1. During the use of serologic typing, HLA-nonidentical transplants were not performed, but there were 4 HLA-nonidentical (antigen level in 1 and allele level in 3) transplants during the use of DNA-based typing in this trial.
Pretransplant Conditioning and GVHD Prophylaxis
Administration of CY at a dose of 60 mg/kg/day for 2 days (120 mg/kg in total) was followed by TBI at a starting dose of 2 × 200 cGy fractions per day for 3 days (1200 cGy in total). The TBI dose was to be lowered by 200 cGy stepwisely according to the presence of graft rejection and other TRC after transplant. Patients were treated in groups of 5, with the first group receiving a dose of 1200 cGy of TBI (TBI 1200) and 120 mg/kg of CY (CY 120). If more than 1 patient of the group died of TRC other than graft rejection, the next cohort were to receive a reduced dose of TBI by 200 cGy, stepwise. If only 1 or none of the patients of the group died of TRCs other than graft rejection, the patients of the next group were to receive the same dose of TBI as the previous group. We de-escalated the TBI dose according to the presence of life-threatening TRC rather than RRT because infection and GVHD are the important TRC that are closely associated with conditioning intensity but are not included in the category of RRT [9]. For GVHD prophylaxis, the first 3 patients received cyclosporine and short course methotrexate [10]. The remaining 37 patients received tacrolimus and short-course methotrexate [11]. Cyclosporine (CSa) and tacrolimus were administered to patients until day 180, or more according, to the presence of GVHD.
Engraftment and TRC
Engraftment was defined as the first of 3 consecutive days with a neutrophil count that exceeded 0.5 × 109/L. Primary graft failure was defined as failure to achieve a neutrophil count of >0.5 × 109/L for 3 consecutive days at any time posttransplantation. Secondary graft failure was defined as the development of an absolute neutrophil count of <0.5 × 109/L after initial engraftment had been already achieved. RRT was graded by use of the Bearman score [9]. Acute GVHD (aGVHD) was graded as recommended by the aGVHD grading consensus conference [12]. Chronic GVHD (cGVHD) was assessed as none, limited, or extensive [13].
Statistical Method
The differences of the categoric variables between the study groups were analyzed with the Pearson chi-square and Fisher’s exact tests. Survival curves were plotted using the Kaplan-Meier method. The differences of overall survival (OS) between the groups with respect to variables were analyzed with the log-rank test. The P-values reported were 2-sided and P < .05 was considered significant. All analyses were performed using the Statistical Package for the Social Sciences (SPSS) software, version 12.0 (SPSS 12.0 Inc., Chicago, IL).
Results
The transplantation outcomes are summarized in Table 2. Patients were followed for a median of 27 months (range: 1-100 months). The median follow-up period for surviving patients was 37 months (range: 7-100 months). Among the first 5 patients who received a dose of 1200 cGy of TBI (TBI 1200 group), 3 patients (60%) died of TRC, and therefore, the patients in the next group received a decreased dose of TBI of 1000 cGy (TBI 1000 group). Because the second group seemed to have an initially good outcome, we planned to give another 5 patients a dose of 1000 cGy of TBI. However, because 2 patients of the second group died of TRC during the third group trial, we de-escalated the TBI dose to 800 cGy beginning from the 15th patient on (TBI 800 group). The outcome of u-BMT using a dose of 800 cGy of TBI has been continuously satisfactory, and all remaining patients have received this dose.
Table 2. Outcomes of 40 Patients with Aplastic Anemia Who Underwent Bone Marrow Transplants from an Unrelated Donor Who Received Conditioning with Total Body Irradiation Plus Cyclophosphamide
| No. of Affected Patients (%) | P-Value | ||||
|---|---|---|---|---|---|
| Variable | TBI 1200 Group | TBI 1000 Group | TBI 800 Group | Overall | (TBI 1000-1200 vs. TBI 800) |
| Number | 5(12.5) | 9(22.5) | 26(65) | 40(100) | |
| Graft failure | .368 | ||||
| None | 5(100) | 8(89) | 25(96) | 38(95) | |
| Primary | 0 | 1⁎(11) | 0 | 1(2.5) | |
| Secondary | 0 | 0 | 1†(4) | 1(2.5) | |
| Regimen-related toxicity | .026 | ||||
| Maximal grade, 0-1 | 1(20) | 3(33) | 17(65) | 21(53) | |
| Maximal grade, 2 | 4(80) | 6(67) | 9(35) | 19(47) | |
| Maximal grade, 3-4 | 0 | 0 | 0 | 0 | |
| Acute GVHD | .198 | ||||
| Grade 0-1 | 2(40) | 8(89) | 18(69) | 28(70) | |
| Grade 2 | 3(60) | 1(11) | 8(31) | 12(30) | |
| Grade 3-4 | 0 | 0 | 0 | 0 | |
| Chronic GVHD‡ | .155 | ||||
| None | 2(40) | 4(80) | 15(69) | 21(62) | |
| Limited | 0 | 0 | 5(23) | 5(15) | |
| Extensive | 3(60) | 1(20) | 4(8) | 8(23) | |
| Survival | 2(40) | 4(44) | 24(92) | 30(75) | .001 |
⁎The cause of primary graft failure was graft rejection. |
†The cause of secondary graft failure was CMV infection and ganciclovir treatment. |
‡The numbers of evaluated patients for chronic GVHD were 5, 5, and 24 in the TBI 1200, TBI 1000, and TBI 800 groups, respectively. |
Engraftment
Thirty-eight (95%) out of 40 patients had sustained engraftment until the last follow-up. The median time to engraftment was 14 days (range: 9-24 days) and the median time to platelet recovery, defined as a platelet count >20 × 109/L without transfusional support, was 29 days (range: 10-200 days). One patient showed a delayed platelet recovery until 200 days posttransplant, but his platelet count rose slowly to the normal level thereafter. Two (5%) of 40 patients experienced graft failure. One patient who received a dose of 1000 cGy of TBI had primary graft failure because of graft rejection. The patient received a peripheral blood stem cell transplant from the same donor as a rescue, but died of infection without hematologic recovery. The other patient, who received a dose of 800 cGy of TBI, showed secondary graft failure at the 6th month after transplant. The cause of secondary graft failure may have resulted from cytomegalovirus (CMV) infection and ganciclovir treatment, rather than from graft rejection. The patient suffered from CMV antigenemia and received ganciclovir before the secondary graft failure occurred. The bone marrow chimerism of the patient was revealed as the donor type of 100% at the time of graft failure by polymerase chain reaction analysis of short tandem repeat sequences. The patient received a booster of bone marrow stem cells from the same donor on the 14th month after transplant and he recovered from cytopenia and is still alive with normal blood counts. The overall rate of graft rejection was 1 of 40 (2.5%).
Regimen-Related Toxicity
The incidence of a maximal RRT grade ≥II was significantly higher in the TBI 1000-1200 groups (10/14, 71%) than in the TBI 800 group (9/26, 35%) (P = .046). The most frequent RRT grade ≥II is stomatitis (n = 14) followed by gastrointestinal toxicity (n = 1), bladder toxicity (n = 1), renal toxicity (n = 1), hepatic toxicity (n = 1), and CNS toxicity (n = 1). There was no cardiac and pulmonary toxicity grade ≥II. However, none of the 40 patients experienced grade III or IV RRT, which suggested that the combination of a dose of 1200 cGy or less of TBI plus CY 120 was a generally tolerable regimen for u-BMT for aplastic anemia in terms of RRT.
aGVHD and cGVHD
The overall incidence of aGVHD was 18 of 40 (45%) but no patient had an aGVHD grade III-IV, which shows that the clinical manifestations of aGVHD in a u-BMT setting with these conditioning regimens for aplastic anemia were mild to moderate. There was a trend toward an increased incidence of aGVHD in the TBI 1200-1000 groups (57%) compared with the TBI 800 group (38%), but this trend was not statistically significant (P = .327). The incidence of cGVHD was 13 (38%) of 34 evaluated patients, and 8 (23%) patients had extensive cGVHD. The incidence of extensive cGVHD was higher in the TBI 1200-1000 groups (4 of 10; 40%) than in the TBI 800 group (4 of 20; 20%), but this was also not statistically significant (P = .195).
Cause of Death
The number of deaths was 10 (25%) of 40 patients. The causes of death are listed in Table 3. The causes of death of the patients who died before day 100 posttransplant were infection (n = 4), graft rejection (n = 1), and posttransplant thrombotic microangiopathy (n = 1). The causes of death of the patients who died after day 100 posttransplant were extensive cGVHD (n = 3) and hepatitis B (n = 1). Five of 6 patients who died in the early posttransplant period did not have aGVHD, and the remaining 1 patient had aGVHD grade I, which indicated that aGVHD was not an important cause of death in this study group. Meanwhile, extensive cGVHD was the main cause of death after 100 days posttransplant. There has been no posttransplant malignancies until the last follow-up, such as posttransplant lymphoproliferative disorder and solid tumors, which were reported in earlier reports [14, 15].
Table 3. Causes of Death in Unrelated Donor Bone Marrow Transplantation for Aplastic Anemia with a Conditioning Regimen of 800-1200 cGy of Total Body Irradiation Plus 120 mg/kg of Cyclophosphamide
| No. of Patients | ||
|---|---|---|
| Cause of Death | TBI=800cGy | TBI≥1000cGy |
| Chronic extensive GVHD | 0 | 3(6, 12,14)⁎ |
| CMV pneumonia | 0 | 1(2) |
| Fungal pneumonia | 0 | 1(2) |
| Mucormycosis | 0 | 1(3) |
| Graft rejection | 0 | 1(2) |
| Hepatitis B | 0 | 1(7) |
| Sepsis | 1(1) | 0 |
| Posttransplant thrombotic microangiopathy | 1(1) | 0 |
⁎The numbers in the parentheses indicate time (months) to death after transplant. |
Survival
As of October 2006, 30 (75%) of 40 patients are surviving with normal blood counts. The probabilities of OS at 3 years were 40%, 44%, and 92% in the TBI 1200, 1000, and 800 cGy groups, respectively. The patient who experienced secondary graft failure has also been showing normal blood counts after a booster with bone marrow stem cells from the same donor. The TBI dose (800 cGy vs. ≥1000 cGy), cGVHD (less than or equal to limited vs. extensive), the method of HLA typing (DNA-based vs. serologic), and the amount of blood transfusion before transplant (≤90 vs. >90 units) were the statistically significant factors influencing survival (P = .001, .013, .006, and .020, respectively; Figure 1). Age, the presence of an HLA mismatch, and the interval time from diagnosis to transplant were not significant factors based on statistical analysis.
Figure 1.
A, OS of unrelated bone marrow transplantation in severe aplastic anemia by TBI dose; B, HLA typing method; C, cGVHD; and D, transfusion amount before transplant. P-values were determined by the log-rank test.
Discussion
Until now, only a few prospective trials had been conducted to find the optimal intensity and optimal type of conditioning regimens for bone marrow transplantation from an u-BMT for aplastic anemia [8, 16, 17]. Recently, the prospective trial of Deeg and colleagues [8] has suggested that the combination of low-dose TBI (200 cGy) and CY (200 mg/kg) and ATG (90 mg/kg) is an optimal regimen. These investigators added low-dose TBI to the same conditioning regimens as those used for S-BMT. The OS of the patients who received TBI 200 plus CY 200 plus ATG for conditioning were 23 of 35 (66%) for the HLA matched u-BMT and 5 of 11 (45%) for the HLA-mismatched u-BMT.
In 1998, we planned a prospective trial to determine an optimal conditioning regimen using TBI and CY. In a previous pilot study of 5 patients who received u-BMT following CY/ATG conditioning when used for recipients of HLA-identical unrelated donor marrow, 3 patients experienced graft failure and only 1 patient survived long term [17]. Therefore, we thought that, to overcome the graft failure, the use of a more intensive conditioning regimen could eradicate both the abnormal hematopoietic stem cells and abnormal immune cells of the recipient that are suggested to be the causes of the development of aplastic anemia and the use of TBI and CY, so-called traditional standard conditioning regimens that had been the most widely used in the transplantation field, were chosen for this trial.
Our results show that the combination of TBI 800 plus CY 120 was sufficient and safe for conditioning of u-BMT for aplastic anemia. No graft rejection was seen for patients in the TBI 800 group. Although 1 patient who received a dose of 800 cGy of TBI had secondary graft failure, it was not from the graft rejection, and he continues to survive with a normal blood count after a booster with bone marrow stem cells from the same donor. The OS was 24 of 26 (92%) in this group, which is comparable to a previously reported outcome of sibling donor transplant for aplastic anemia [18, 19, 20]. In addition, no grade III-IV RRT was seen in the TBI 800 group in contrast to earlier trials where the incidence of life-threatening RRT in the high dose TBI (1200 cGy or more) group was high [8, 21]. The incidence of RRT grade ≥III for low-dose TBI plus CY 200 plus ATG in the trial of Deeg and colleagues [8] was 21%, which seems to be higher than that of our study group (0%) despite the lower dose of TBI employed than in the present trial, which suggests the higher dose of the chemotherapy (CY 200 mg/kg) might affect RRT, rather than the additional radiation. The low incidence of aGVHD also might reduce the risk of severe RRT in our group of patients because aGVHD is a systemic alloimmune disease that is mediated by multiple complex cytokines and can influence RRT, including lung toxicity and posttransplant thrombotic microangiopathy [22, 23, 24], even though its grade is determined only using the skin, liver, and gut.
The overall incidences of grade II-IV aGVHD and cGVHD in this trial were 30% and 38%, respectively, which are similar to those seen in an earlier large study from Japan where 29% of patients experienced grade II-IV aGVHD and 30% of the patients had cGVHD [5]. However, these values are smaller than those reported earlier by Deeg and colleagues [8], where the incidences of grade II-IV aGVHD and cGVHD were 69%-77% and 52%-57%. The low incidence of GVHD, particularly of severe aGVHD, might in part be related to a more limited gene pool in the Korean population than exists in European and North American populations. According to recently analyzed data in our institution, the incidence of aGVHD in acute myelogenous leukemia (AML) patients who underwent an unrelated donor transplant using TBI and CY was also low (36%, unpublished data). The differences in the incidence of GVHD also make it difficult to compare the outcome of this trial with those of the other earlier trials using a different conditioning regimen because GVHD can affect the outcome of transplantation. This trial found no statistically significant difference in the incidence of aGVHD and extensive cGVHD between the TBI 1200-1000 groups and the TBI 800 group, but showed a trend toward an increased incidence of GVHD in the higher TBI group (P = .198 and .195, respectively). Life-threatening infection and GVHD, main causes of death in our study subjects, are not defined as RRT but are known to be related with the intensity of conditioning [25, 26]. This may be why patients in the TBI 1200-1000 groups did not show a good outcome like those in the TBI 800 group despite a low incidence of life-threatening RRT.
We matched donor and recipient with either serologic or DNA-based HLA typing according to the availability of the HLA typing method at the time of transplant. Therefore, the early-trial groups (TBI 1000-1200 groups) used serologic HLA typing and the late-trial group (TBI 800 group) used mainly DNA-based HLA typing for the matching program. All patients who received TBI 1000-1200 (n = 14) were matched with serologic typing. Only 2 patients (14%) of the TBI 800 group were matched with the serologic method, and 24 patients (86%) of the TBI 800 group were matched with donors by DNA-based typing. DNA-based HLA typing is now widely used in the stem cell transplantation field because many clinical studies have confirmed a better outcome in transplantation with the high-resolution HLA typing not only for aplastic anemia but also for other hematologic malignant diseases [5, 27, 28, 29, 30]. Kojima and colleagues [5] have examined the HLA of serologically identical unrelated donor transplantation with the DNA-based typing method retrospectively, and found that even for a serologically identical donor, HLA-identical transplantation by DNA-based typing showed a more favorable outcome than HLA-nonidentical transplantation by DNA-based typing for aplastic anemia. The HLA typing method is a confounding factor that made it difficult to interpret the independent effect of the TBI dose for our results. Because the method of HLA typing is also a significant factor for outcome (P = .031) in this trial as determined by univariate analysis, the improved outcome of the TBI 800 group (P = .008) cannot be explained by the TBI dose independently from the HLA typing method, statistically. Because of this confounding factor and the small number of subjects in this trial, multivariate analysis did not indicate any significant independent prognostic factors. However, all patients who underwent u-BMT with an HLA-matched donor determined by serologic typing (n = 2) and with an HLA-mismatched donor determined by DNA-based typing (n = 4) in the TBI 800 group are surviving long term, and none of them had RRT grade III-IV. This suggests the combination of TBI 800 and CY 120 can be an acceptable conditioning regimen even in a transplant from an HLA-mismatched unrelated donor based on DNA-based typing if the degree of mismatch is low.
This trial indicates a large amount of transfused blood before transplant is an unfavorable prognostic factor but the time interval from diagnosis to transplant is not a significant prognostic factor, which might suggest that the degree of exposure to alloantigen and the amount of transfused blood are more important than the disease duration. This may be because the preformed alloimmunity from the previous transfusion can affect graft rejection and the higher iron overload can affect the incidence of RRT and infection [6, 7, 31, 32, 33]. The age of the patient at transplant is also known to be an important factor for the outcome of transplant for aplastic anemia [5, 8, 34]. However, the analysis of this trial was not consistent with previous findings, possibly because this study population confined the adult and range of the age of the patients (from 16-50 years; median: 27 years) was narrower compared to earlier reports, and the study population was too small to determine the influence of these factors.
A comparison between the use of TBI 800/CY 120 and other conditioning regimens used in the other study groups is difficult to make because of the small number of subjects in this trial and different characteristics of the patients from other prior trials. However, the present results indicate that an intermediate dose of TBI (800 cGy) used in combination with CY 120 can also be a considerable conditioning regimen for unrelated donor transplant for aplastic anemia, especially in conjunction with the use of high-resolution HLA typing, which is not only sufficient to overcome graft rejection and sustain engraftment, but is also safe in terms of other TRC.
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PII: S1083-8791(07)00237-6
doi:10.1016/j.bbmt.2007.03.013
© 2007 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.
Volume 13, Issue 7 , Pages 863-870, July 2007
