Long-Term Outcome after Bone Marrow Transplantation for Aplastic Anemia Using Cyclophosphamide and Total Lymphoid Irradiation as Conditioning Regimen

Article Outline

• Abstract
• Introduction
• Patients and Methods
  • Patients
  • Conditioning Regimen, GVHD Prophylaxis, and Supportive Therapy
  • Statistical Analysis
• Results
  • Patient Characteristics
  • Engraftment
  • OS, Relapse, Mortality, and Cause of Death
  • GVHD
  • Other Transplantation-Related Complications
• Discussion
• References
• Copyright

Abstract 

We retrospectively studied 49 patients in a single institute to evaluate the long-term outcome of total lymphoid irradiation (TLI) conditioning for allogeneic stem cell transplantation (allo-SCT) to treat aplastic anemia (AA). Most of the patients had received transfusions and had undergone previous treatment, with 33 receiving related transplants and 16 receiving unrelated transplants. Conditioning consisted of cyclophosphamide (Cy; 200 mg/kg) plus TLI (750 cGy) for related transplantation and Cy plus total body irradiation (TBI; 500 cGy) and TLI (500 cGy) for unrelated transplantation. Antithymocyte globulin (ATG) was added for 6 of the unrelated transplantations. Graft-versus-host-disease (GVHD) prophylaxis consisted mainly of cyclosporine (CSA) and methotrexate (MTX). Graft failure developed in 2 patients (4.1%). With a median follow-up of 7 years, overall survival (OS) was 81% and was not statistically significantly different between the patients receiving related transplants and those receiving unrelated transplants. In multivariate analyses, a history of previous treatment with ATG was the sole factor associated with a worse survival rate, and the interval from diagnosis to treatment was not prognostic. The incidence of acute (grade II to IV) GVHD (aGVHD) was 23%, and that of chronic GVHD (cGVHD) was 29%. Female-to-male transplantation was the sole factor associated with chronic GVHD. B cell lymphoproliferative disorder developed only after the ATG-containing conditioning. No other secondary malignancies developed after long-term follow-up. Our findings suggest that TLI conditioning is feasible and effective for patients with AA.

Key Words: Aplastic anemia, Bone marrow transplantation, Secondary malignancy, Total lymphoid irradiation

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Introduction 

Allogeneic stem cell transplantation (allo-SCT) is a curative treatment strategy for patients with aplastic anemia (AA). A randomized prospective study showed that allo-SCT is the first choice of treatment for patients with severe AA who receive transplants from HLA-matched related donors [1]. Long-term complications, such as chronic graft-versus-host disease (-GVHD), secondary malignancies, and late infections, have been reported after allo-SCT 2, 3. Although the response rate and survival after immunosuppressive therapy are improving, problems remain, including incomplete response, clonal evolution, relapse, and cyclosporine (CsA) dependence [4].

A major problem with transplantation for AA has been graft failure [5]. The use of irradiation as part of the conditioning regimen has successfully reduced the failure rate, [6], although it may increase the risk of acute GVHD (aGVHD), secondary malignancies, and infertility 7, 8. Although encouraging results have been reported by the Seattle group using a novel conditioning regimen with cyclophosphamide (Cy) plus antithymocyte globulin (ATG) [9], other studies have reported that using ATG as part of the conditioning regimen increased graft failure, mixed chimerism, and B cell lymphoproliferative disorder (BLPD) 10, 11, 12.

Excellent results of a conditioning regimen with Cy plus total lymphoid irradiation (TLI) were reported in 1980 [13], and we began to use this regimen for related transplantation [14]. Considering the higher incidence of graft failure, the regimen was intensified with low-dose total body irradiation (TBI) for unrelated transplantation. To clarify the long-term outcome of TLI conditioning for AA, we conducted a retrospective study of 49 consecutive patients in a single institute. TLI conditioning proved to be a feasible and effective modality, with no secondary malignancies other than BLPD observed after long-term follow-up.

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Patients and Methods 

Patients 

Between 1984 and 2006, we evaluated a total of 49 consecutive allo-SCTs done for AA at the Japanese Red Cross Nagoya First Hospital. Three patients who had been conditioned with Cy alone before 1983 were not included. All patients provided written informed consent. The stem cell source was bone marrow in all patients.

Conditioning Regimen, GVHD Prophylaxis, and Supportive Therapy 

The Cy + TLI regimen for related transplantation consisted of Cy 50 mg/kg once daily intravenously (i.v.) from days −6 to −3 (total dose, 200 mg/kg) and TLI 750 cGy on day −1. The Cy + TBI + TLI regimen for unrelated transplantation consisted of Cy 50 mg/kg once daily i.v. from days −6 to −3 (total dose, 200 mg/kg), TBI 500 cGy divided into 2 fractions (6.5 cGy/min) on day −2 and TLI 500 cGy on day −1. (Initially, TLI was given in a single fraction at a dose rate of 26 cGy/min; however, since 1996, after radiation hepatitis developed in 1 patient [15], it has been divided into 2 fractions at the same dose rate.) ATG was added at a dose of 2.5 mg/kg once daily i.v. from days −5 to −2 (total dose, 10 mg/kg) for 6 patients who received unrelated transplants. However, the use of ATG has been proscribed since 2000 after BLPD developed in 3 consecutive patients. Donor-derived bone marrow was infused on day 0 without any manipulations. GVHD prophylaxis comprised CsA alone, CsA and methotrexate (MTX), or tacrolimus and MTX. Patients were treated in laminar airflow rooms. Antimicrobial prophylaxis included levofloxacin (since 1995), fluconazole (200 mg/day, since 1995), trimethroprim/sulfametoxasole, and acyclovir. Since 1990, monitoring for cytomegalovirus (CMV) antigenemia has been performed every week after engraftment up to day +100, with ganciclovir therapy instituted for positive assays. Since 1990, 42 patients have received granulocyte colony-stimulating factor (G-CSF) i.v. daily beginning on day +7 until an absolute neutrophil count (ANC) of > 1.5 × 10⁹/L for 3 consecutive days was achieved. One patient received granulocyte-macrophage colony-stimulating factor (GM-CSF) in 1989.

Statistical Analysis 

The aim of the present study was to evaluate the long-term efficacy, complications, and mortality of transplantation for AA with TLI conditioning. The engraftment, overall survival (OS), relapse rate, incidence of aGVHD and cGVHD, factors affecting OS and chronic GVHD, as well as secondary malignancies were evaluated. Engraftment was defined as ANC > 0.5 × 10⁹/L for 3 consecutive days. OS was calculated using the Kaplan-Meier method, and P values were calculated using the log-rank test. aGVHD was graded based on previously established criteria [16]. cGVHD was evaluated in patients surviving beyond day +100 and was classified as limited or extensive according to the Seattle criteria [17]. Cumulative incidences of aGVHD and cGVHD were estimated by Gray's method, with deaths not related to GVHD treated as competing risks. Univariate and multivariate analyses were performed using the Cox proportional hazard regression model. A 2-sided P value of < .05 was considered significant. Data analyses were completed as of January 2007.

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Results 

Patient Characteristics 

Patient characteristics are summarized in Table 1. The causes of AA were idiopathic (n = 47) and hepatitis (n = 2). The severity of disease at transplantation was moderate (n = 8) and severe (n = 41), according to Camitta's criteria [1]. All patients in the moderate group were transfusion-dependent. Most patients had received some form of treatment before transplantation (ie, ATG, CsA, androgens, steroids, G-CSF, or combinations thereof). The interval from diagnosis to transplantation ranged from 1 month to 36 years (median, 21 months). It was significantly longer after unrelated transplantation than after related transplantation (11 months to 28 years [median, 14 years] vs 1 month to 36 years [median, 11 months]; P = .0003, Mann-Whitney U test). The 2 patients who underwent transplantation 28 and 36 years after diagnosis were observed without therapy in childhood. They received immunosuppressive therapy because of progressive pancytopenia 20 years after diagnosis, but it was not effective. They decided to undergo allo-SCT after becoming transfusion-dependent. Thirty-three patients received HLA-matched related transplants (30 from siblings, 2 from fathers, and 1 from a son). Sixteen patients received unrelated transplants, including 10 HLA-matched transplants and 6 HLA-mismatched (2 HLA-A allele mismatch, 2 HLA-DRB1 allele mismatch, and 2 HLA-DR serologic mismatch) transplants. Twenty-eight patients were conditioned with Cy + TLI for related transplants, and 14 were conditioned with Cy + TBI + TLI for unrelated transplants. Five patients with high risk for graft failure who received related transplants were conditioned with the same regimen used for unrelated transplants; 1 of these patients had received heavy transfusions, 1 patient had a high titer of anti-D antibody, and 3 patients had received a transplant from a father or a son. Two patients who received unrelated transplants were conditioned with Cy (200 mg/kg) + TLI (750 cGy) + ATG (10 mg/kg).

Table 1. Patient characteristics

Number of patients	49
Median age, years (range)	24 (16 to 47)
Etiology of aplastic anemia
Idiopathic	47
Hepatitis	2
Severity
Moderate	8
Severe	41
Previous treatment
None	2
Corticosteroid	29
ATG	16
CsA	21
Anabolic steroid	22
G-CSF, erythropoietin	10
Median units of previous transfusions
Red blood cell	44
Platelet	90
Donor and HLA matching
Related match	33
Unrelated match	10
Unrelated mismatch	6
Median BM cells harvested, ×108/kg (range)	3.2 (1.8 to 6.9)
Conditioning regimen for related transplantation
Cy + TLI 7.5Gy	28
Cy + TBI 5Gy + TLI 5Gy	5
Conditioning regimen for unrelated transplantation
Cy + TBI 5Gy + TLI 5Gy	10
Cy + TBI 5Gy + TLI 5Gy + ATG	4
Cy + TLI 7.5Gy + ATG	2
GVHD prophylaxis
CsA + MTX	37
Tacrolimus + MTX	10
CsA	2
ABO compatibility
Match	31
Major mismatch	5
Minor mismatch	9
Major-minor mismatch	4

Engraftment 

Graft failure developed in 2 of the 49 patients (4.1%). One patient who experienced primary graft failure after receiving an HLA-matched unrelated transplant with conditioning with Cy + TLI + ATG received a second CD34-purified transplantation from his haploidentical brother and achieved sustained engraftment, but subsequently died of CMV infection and heart failure 37 days after the second transplantation. Another patient experienced late graft failure 161 days after receiving an HLA-matched related transplant with conditioning with Cy + TLI. He received a second transplant from the same donor and achieved sustained engraftment, but died of idiopathic interstitial pneumonia 64 days after the second transplantation. Sustained engraftment was achieved in all of the other evaluable patients.

OS, Relapse, Mortality, and Cause of Death 

Currently, 41 patients are alive with a median follow-up of 7 years (range, 7 months to 23 years). The estimated overall 7-year OS was 81% (Figure 1). It was not statistically significantly different between those receiving related transplants and those receiving unrelated transplants (82% vs 81%; P = .65) (Figure 2). None of the patients experienced recurrence of AA.

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• Figure 1 

  OS was 81% at 7 years.

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• Figure 2 

  OS was not significantly different between related and unrelated transplantation (82% vs. 81%; P = .65).

In univariate analyses, a history of previous treatment with ATG was the sole significant factor associated with lower survival rates (relative risk [RR] = 17; 95% confidence interval [CI] = 2.1-140). There was a trend toward lower survival rates in patients with more than 2 years from diagnosis to transplantation (RR = 4.0; 95% CI = 0.80-20). None of the other factors listed in Table 2 were prognostic. In multivariate analyses, a history of previous treatment with ATG remained a significant factor, and the interval from diagnosis to transplantation was not prognostic.

Table 2. Relative risk of death after transplantation

UE indicates unevaluable.

Four patients (8%) died within 100 days after transplantation, from brain hemorrhage, GM-CSF–induced acute respiratory distress syndrome, primary graft failure, and pneumonia after BLPD. Four others (8%) died more than 100 days after transplantation, from different causes, including late graft failure, hypoglycemia, Staphylococcus pneumoniae sepsis, and Pseudomonas aeruginosa sepsis during immunosuppressive treatment for scleroderma. The latter 2 patients had extensive cGVHD. The patient who died of hypoglycemia received insulin injections for diabetes resulting from transfusion-induced hemochromatosis.

GVHD 

Grade II-IV aGVHD developed in 11 patients, for a cumulative incidence of 23% (Figure 3A). This incidence was not statistically significant between related and unrelated transplant recipients (18% vs 31%; P = .26). Grade III aGVHD developed in only 1 patient after related transplantation, and no patients developed grade IV aGVHD.

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• Figure 3 

  Cumulative incidence of GVHD: (A) grade II-IV aGVHD, 23%; (B) cGVHD, 29%.

Chronic GVHD developed in 14 of 44 evaluable patients, for a cumulative incidence of 29% (Figure 3B); the difference in incidence between related and unrelated transplant recipients was not statistically significant (28% vs 32%; P = .68). Of the 14 patients with cGVHD, 1 had the limited type and 13 had the extensive type, whereas 5 had previous aGVHD. Female-to-male transplantation was the sole significant factor associated with cGVHD (RR = 3.1; 95% CI = 1.1-8.9) (Table 3).

Table 3. Relative risk of chronic GVHD after transplantation in the 44 evaluable patients

UE indicates unevaluable.

Other Transplantation-Related Complications 

Fifteen patients (31%) experienced a total of 16 episodes of other transplantation-related complications, including BLPD (n = 3), Cy-induced hemorrhagic cystitis (n = 2), adenovirus-induced hemorrhagic cystitis (n = 1), capillary leak syndrome (n = 1), radiation pneumonia (n = 1), radiation hepatitis (n = 1), osteonecrosis (n = 1), pericardial effusion (n = 1), pure red cell aplasia (n = 1), bronchiolitis obliterance organizing pneumonia (BOOP; n = 1), syndrome of inappropriate antidiuretic hormone secretion (n = 1), idiopathic thrombocytopenic purpura (ITP; n = 1), and engraftment syndrome (n = 1). All but 3 patients (those with BLPD, osteonecrosis, and ITP) recovered from their complications. No secondary malignancies other than BLPD developed in any patient.

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Discussion 

Conditioning with Cy alone was the initial regimen used for AA, but this has been associated with a high incidence of graft rejection (9%-19%) 8, 18, particularly in patients receiving transfusions. The addition of TLI was used to reduce graft rejection, and favorable results were reported in small numbers of patients 13, 14, 19, 20. Novitzky et al. [21] reported that radiation-containing conditioning led to universal engraftment despite T cell depletion. The present study demonstrated satisfactory results and long-term efficacy in a larger number of transfused patients. Moreover, a further addition of low-dose (5 Gy) TBI was feasible and effective for engraftment after unrelated transplantation, whereas the incidence of graft rejection was reportedly higher for this population 22, 23, 24. Although ATG is widely used for unrelated transplantation 25, 26, our results show that it likely is not useful for engraftment if radiation-containing conditioning is used. A recently randomized study conducted by the International Bone Marrow Transplant Registry failed to show the advantage of ATG + Cy over Cy alone [27]. Of note, the rate of graft failure was as high as 16%-18%, significantly higher than that found in our study (P = .026). Although novel conditioning regimens without irradiation, including fludarabine or Campath-1H, are being investigated for AA 28, 29, 30, their impact on infectious complications, GVHD, and long-term outcomes is not yet well known. ATG may be useful in association with these regimens without irradiation. Furthermore, results may vary depending on the type and dose of ATG used.

In the current study, our results after unrelated transplantation were comparable to those after related transplantation, despite the longer interval from diagnosis to transplantation. Survival rates after unrelated transplantation were reported to range from 20% to 61% 22, 23, 24, 31, 32, and Kojima et al. [33] concluded that ATG as part of the conditioning regimen improved survival rates. However, the use of ATG in conditioning regimens was not associated with OS in the current study. Our survival rate of 81% was satisfactory even though most of our patients did not receive ATG, and it is noteworthy that BLPD developed only after ATG conditioning. Therefore, we conclude that ATG is not necessary in conditioning for AA if radiation-containing conditioning is used. Another recent report also failed to show any advantage of ATG on outcome [27].

Many studies have identified the interval from diagnosis to transplantation as a risk factor for survival 8, 33, 34. However, this interval was not found to be a significant factor affecting OS in the current study. Even when transplantation was performed after 2 years from diagnosis, the OS rate at 7 years was 70%. TLI conditioning is promising for adult patients with AA. A history of previous treatment with ATG may decrease OS when combined with TLI conditioning. Interestingly, all 10 patients who received tacrolimus and MTX as GVHD prophylaxis are alive. Although these patients constitute a relatively small group, the efficacy of tacrolimus is a promising subject for future investigation.

The TLI conditioning was well tolerated in the current study. Two patients developed irradiation-related pneumonia and hepatitis, but they recovered with no medication therapy. Deeg et al. [32] recently reported that the optimal dose of TBI for unrelated bone marrow transplantation was 200 cGy and that a higher dose could increase pulmonary toxicity. However, such toxicity was not common in the present study. We believe that radiation dose and dosimetry are almost optimal if radiation is given in fractions. Reducing the radiation dose to the lungs is an important and interesting issue, but in the present study, the cumulative lung dose was about 6 Gy even with the TBI + TLI regimen. A dose of 6 Gy is lower than the safe dose of 9 Gy recently reported by Soule et al. [35]. Thus, reducing the radiation dose may not be necessary, considering the increased risk of graft rejection. Our mortality rate of 8% on day 100 was relatively high, but any association between the irradiation conditioning and cause of death was unlikely. Most of the early deaths were related to patients' background factors, including ATG as part of the conditioning and GM-CSF. Although cataracts and endocrine dysfunction have been reported after TBI conditioning [36], these complications were not found in the current study. Of note, 2 patients with extensive cGVHD died from sepsis (Staphylococcus and Pseudomonas) more than 3 years after transplantation. Therefore, the long-term prevention of infection is of great importance to reduce long-term mortality, particularly in patients with cGVHD.

Although the use of irradiation as part of the conditioning regimen has been reported to increase aGVHD (35%-53%) 8, 34, the incidence of aGVHD was as low as 23% in the present study. TLI may play a role in protecting against aGVHD; recent investigations have found that the increased percentage of host natural killer (NK) T cells after TLI could reduce aGVHD [37]. Tissue damage after a conditioning regimen is hypothesized to increase aGVHD. TLI is less likely to cause tissue damage. cGVHD is considered a main cause of death after long-term follow-up of allo-SCT among patients with AA [2]. In the current study, the incidence of cGVHD was as low as 29%, lower than the 60% reported in previous studies 34, 38. Because univariate analyses showed that female-to-male transplantation was the sole factor affecting cGVHD, sex matching as well as HLA matching is important.

Several studies have reported an increased risk of secondary malignancies after irradiation conditioning 3, 34, 38, 39. In the current study, however, malignancies other than BLPD failed to develop after long-term follow-up. One reason for this is the limited field of irradiation; another is the low incidence of cGVHD. Interestingly, an Italian group reported no secondary malignancies after Cy + TLI conditioning, and their incidence of cGVHD was as low as 35% [19]. Our data demonstrate that limited field irradiation does not induce secondary malignancies.

In summary, our findings indicate that TLI conditioning is feasible and effective for adult patients with AA.

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