Primary Treatment of Acquired Aplastic Anemia: Outcomes with Bone Marrow Transplantation and Immunosuppressive Therapy

  1. Kristine Doney, MD;
  2. Wendy Leisenring, ScD;
  3. Rainer Storb, MD; and
  4. Frederick R. Appelbaum, MD
  1. For the Seattle Bone Marrow Transplant Team From the Fred Hutchinson Cancer Research Center, the University of Washington School of Medicine, and the Seattle Veterans Administration Medical Center, Seattle, Washington Acknowledgments: The authors thank the physicians, nurses, and support staff who comprise the Seattle Bone Marrow Transplant Team for their excellent patient care. They also thank the many physicians who referred their patients to the Fred Hutchinson Cancer Research Center. Grant Support: By Public Health Service grant HL36444 (awarded by the National Heart, Lung, and Blood Institute) and grants CA 18221, CA 15704, and CA 18029 (awarded by the National Cancer Institute). Requests for Reprints: Kristine Doney, MD, Fred Hutchinson Cancer Research Center, M-120, 1124 Columbia Street, Seattle, WA 98104. Current Author Addresses: Drs. Doney, Leisenring, Storb, and Appelbaum: Fred Hutchinson Cancer Research Center, Clinical Research Division, 1124 Columbia Street, Seattle, WA 98104.
     
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    Abstract

    Background: Both immunosuppressive therapy and bone marrow transplantation are accepted treatments for patients with aplastic anemia. Choosing one of these therapies for a given patient depends not only on donor availability but also on such factors as patient age.

    Objective: To compare survival rates and long-term complications after bone marrow transplantation or immuno-suppressive therapy in patients with acquired aplastic anemia and to identify prognostic factors associated with improved survival.

    Design: Center-based, retrospective analysis.

    Setting: Referral center for patients with aplastic anemia.

    Patients: 395 patients with acquired aplastic anemia.

    Intervention: Bone marrow transplant from an HLA-identical, related donor or immunosuppressive therapy.

    Measurements: Kaplan-Meier survival curves, results of log-rank tests, and cumulative incidence curves.

    Results: Of 168 bone marrow transplant recipients, 89% had sustained engraftment. Forty-six patients developed grade II to IV acute graft-versus-host disease, and 68 developed chronic graft-versus-host disease that required therapy. Of 227 patients who received immunosuppressive therapy, 44% achieved a complete, partial, or minimal response. Fifty-four percent died or had no response to therapy. Actuarial survival at 15 years was 69% for bone marrow transplant recipients and 38% for patients receiving immunosuppressive therapy (P < 0.001). Improved survival was associated with having bone marrow transplantation as primary therapy, being younger, having no transfusion before transplantation, and having a higher absolute neutrophil count. Disease duration, year of therapy, sex, refractoriness to platelet transfusions, and previous treatment with androgens or corticosteroids did not significantly affect survival.

    Conclusions: Data from this center suggest that bone marrow transplantation may be preferred for younger patients with acquired aplastic anemia who have matched, related donors. Long-term survival is excellent for patients who respond to either form of therapy.

    In the past 25 years, the role of bone marrow transplantation for the treatment of aplastic anemia has been established. In patients with severe aplasia who have genotypically or phenotypically HLA-identical, related donors, bone marrow transplantation is usually considered the treatment of choice. Because morbidity and mortality from bone marrow transplantation increase with patient age, many centers do not transplant bone marrow into patients older than 50 years of age. Thus, for older patients and for patients who do not have matched, related donors, immunosuppressive therapy is usually recommended as primary treatment. Since 1978, the Fred Hutchinson Cancer Research Center, Seattle, Washington, has offered either immunosuppressive therapy or bone marrow transplantation to patients with aplastic anemia on the basis of the availability of a bone marrow donor. In this analysis, we summarize the outcomes of each treatment and examine prognostic factors associated with survival after treatment.

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    Methods

    Patient Selection

    All patients who had a diagnosis of acquired aplastic anemia and were treated between January 1978 and December 1991 were included in our analysis. The records of 395 consecutive patients were reviewed. Before therapy, diagnoses were confirmed by aspirates and biopsies of bone marrow and by cytogenetic studies of unstimulated bone marrow cells. Severe aplastic anemia was defined according to the criteria of the International Aplastic Anemia Study Group [1]. These criteria include the presence of at least two of the following three peripheral blood findings: 1) a neutrophil count of less than 0.50 × 109/L, 2) a corrected reticulocyte count of less than 1%, and 3) a platelet count of less than 20 × 109/L. These criteria also stipulate that the bone marrow must be hypocellular, with lymphoid cells usually being predominant. For our study, patients with clonal cytogenetic abnormalities were considered to have a myelodysplastic syndrome and were excluded. Except for short-term androgen therapy or treatment with low-dose corticosteroids, bone marrow transplantation or immunosuppressive therapy was the primary treatment received. For the 168 patients having transplantation, bone marrow donors were either genotypically (n = 162) or phenotypically (n = 6) HLA-identical family members. Patients who received syngeneic transplants were excluded. Before therapy, informed consent was obtained using forms that had been approved by the Institutional Review Board of the Fred Hutchinson Cancer Research Center.

    Patient characteristics by treatment group are shown in Table 1. The groups did not differ in median age or in the duration and cause of aplasia. Most patients had recently received a diagnosis of idiopathic disease. The groups were also similar with regard to history of previous treatment with steroids, refractoriness to transfusion of platelets from randomly selected donors, not having transfusion before treatment, and absolute neutrophil count at hospital admission. All patients receiving transplants had severe aplastic anemia. Thirty-four (15%) of the patients who received immunosuppressive therapy did not fulfill all of the criteria for severe aplasia and were therefore classified as having moderate disease.

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    Table 1. Patient Characteristics by Treatment Group*

    Treatment Regimens

    All 168 patients who received a bone marrow transplant were conditioned with 200 mg of cyclophosphamide per kg of body weight, given over 4 days (Table 2). No patient received irradiation therapy. Seventy-eight patients also received unirradiated donor buffy-coat cells after the bone marrow infusion. Starting in 1988, 21 patients received horse antihuman thymocyte globulin (ATGAM, Upjohn Co., Kalamazoo, Michigan), 90 mg/kg, in addition to cyclophosphamide without buffy-coat cells [2, 3]. The primary prophylactic regimen for graft-versus-host disease was either a long course of methotrexate therapy or a short course of methotrexate plus cyclosporine therapy [4, 5]. The severity of acute and chronic graft-versus-host disease was assessed according to previously described criteria [6, 7]. Treatment of acute graft-versus-host disease varied with time depending on the active protocols; primary therapy included single-agent or combination therapy with corticosteroids, antithymocyte globulin, and cyclosporine [8-11]. Therapy for chronic graft-versus-host disease also varied with time and included corticosteroids, azathioprine, and cyclosporine, alone or in combination [12, 13].

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    Table 2. Conditioning Regimens and Engraftment Data of Bone Marrow Transplant Recipients (n = 168)*

    Table 3 shows the treatment regimens for the 227 patients who received immunosuppressive therapy. These regimens were defined by a sequential series of protocols that were used during the period of this analysis. Two hundred twenty-three patients received antithymocyte globulin, 15 mg/kg intravenously each day for 10 days, as the primary immunosuppressive agent [14-18]. Two patients received horse antihuman thoracic duct lymphocyte globulin (Swiss Serum Institute, Basel, Switzerland), and single patients who had positive reactions on skin tests to antithymocyte globulin received either cyclosporine or high-dose corticosteroid therapy [19]. All patients received corticosteroids during antithymocyte globulin therapy to reduce the side effects of antithymocyte globulin. Oxymetholone, 3 mg/kg per day orally, was administered for 3 months unless toxicity required discontinuation of therapy. Patients who had started therapy more recently also received granulocyte-macrophage colony-stimulating factor concurrently with immunosuppressive therapy.

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    Table 3. Treatment Regimens and Responses to Therapy in Patients Receiving Immunosuppressive Therapy (n = 227)

    Supportive Care

    All patients who received immunosuppressive therapy and 58 patients who had transplantation were treated in private, nonsterile rooms. One hundred ten transplant recipients were treated in rooms with laminar air flow isolation. Patients who had an absolute neutrophil count less than 0.5 × 109/L and whose body temperature exceeded 38.5 °C were empirically treated with broad-spectrum antibiotics. Patients received transfusions with irradiated red blood cells when the hematocrit was 0.25 or less, and they received transfusions with irradiated platelets when the platelet count was 20 × 109/L or less. Patients who had transplantation received care at the transplantation center for 3 months after bone marrow grafting; when clinically stable, patients receiving immunosuppressive therapy were discharged to the care of their referring physicians.

    Criteria for Response to Immunosuppressive Therapy

    Response to immunosuppressive therapy was initially evaluated 75 days after the start of treatment. We defined nonresponders as patients in whom peripheral blood counts did not improve and patients who died before day 75. For responders, degree of response was assessed when the maximum improvement in peripheral blood counts occurred. We used the following functional definitions of response: 1) Complete responders attained a normal hematocrit, an absolute neutrophil count of 1.0 × 109/L or greater, and a platelet count of 100 × 109/L or greater without transfusion; 2) partial responders had improvement in all three cell lines, with an absolute neutrophil count of 0.5 × 109/L or greater, no infections, and no transfusion requirement; and 3) minimal responders had an increase in the absolute neutrophil count of 0.5 × 109/L or more but remained dependent on transfusion.

    Statistical Analysis

    Survival probabilities were estimated using the Kaplan-Meier method, and comparisons between curves were based on the log-rank statistic [20]. All P values are two sided. Survival data were censored as of the date of last contact. Cumulative incidence curves are presented as estimates of the probability of certain events (such as relapse) when a competing event (such as death) occurred that would eliminate the possibility of observing the event of interest. These methods and their advantage over the Kaplan-Meier method in this setting have been described elsewhere [21].

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    Results

    Bone Marrow Transplantation

    Results in the transplant recipients are shown in Table 2. These patients reached an absolute neutrophil count of 0.20 × 109/L a median of 17 days after transplantation and reached a count of 1.00 × 109/L 26 days after transplantation. The median time to independence from platelet transfusion was 22 days.

    In 18 patients (11%), bone marrow grafts were rejected; median time to rejection was 141 days after bone marrow infusion. Sixteen of these 18 patients had a second transplantation; 12 of the 16 received transplanted cells from the same donor; and 4 received transplants from other family donors. Ten of the 16 had sustained engraftment; 6 had poor or no engraftment. Eight patients survive, and 8 died. The primary cause of death was chronic, extensive graft-versus-host disease. One patient refused a second transplantation, received immunosuppressive therapy, did not respond, and died. One patient had three transplantations with cells from the same donor before achieving sustained engraftment. This patient is a long-term survivor.

    Forty-six of the 150 patients (31%) who had sustained engraftment after the first transplantation developed grade II to IV acute graft-versus-host disease. Twenty-six of these patients developed chronic extensive graft-versus-host disease that required therapy. Currently, 23 of the 46 patients are alive, with a median Karnofsky score of 90% (range, 80% to 100%). An additional 42 patients with no or grade I acute graft-versus-host disease developed chronic extensive graft-versus-host disease that required therapy. Of these 42 patients, 31 are alive. The surviving patients have a median Karnofsky score of 100% (range, 80% to 100%). A secondary malignant condition developed in three patients: Squamous-cell carcinoma developed in two of these patients 43 and 103 months after transplantation, respectively, and acute lymphocytic leukemia developed in the third patient 7 months after bone marrow grafting. No transplant recipient developed a myelodysplastic syndrome. The top panel of Figure 1 shows the cumulative incidence of graft rejection or development of a secondary malignant condition in transplant recipients.

    Figure 1. Cumulative incidence of rejection or evolution of a secondary malignant condition in patients having bone marrow transplantation. Cumulative incidence of evolution of a myelodysplastic syndrome or acute leukemia, paroxysmal nocturnal hemoglobinuria (PNH) or recurrent aplasia after immunosuppressive therapy.
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    Figure 1. Cumulative incidence of rejection or evolution of a secondary malignant condition in patients having bone marrow transplantation. Cumulative incidence of evolution of a myelodysplastic syndrome or acute leukemia, paroxysmal nocturnal hemoglobinuria (PNH) or recurrent aplasia after immunosuppressive therapy. Cumulative incidence of long-term complications. Top.Bottom.

    Immunosuppressive Therapy

    The clinical response to immunosuppressive therapy is shown in Table 3. Seventy-eight patients (34%) achieved a complete or partial response. An additional 23 patients (10%) had a minimal response. One hundred twenty-two patients (54%) did not respond to therapy; 29 of these patients died on or before day 75.

    Long-term complications of immunosuppressive therapy included recurrent aplasia in 25 patients, evolution to a myelodysplastic syndrome or acute leukemia in 20 patients, and appearance of paroxysmal nocturnal hemoglobinuria in 5 patients. The difference in the probability of developing a myelodysplastic syndrome after immunosuppressive therapy (20 of 227 patients) or bone marrow transplantation (0 of 168 patients) is significant (P < 0.001; Fisher exact test). The bottom panel of Figure 1 shows the cumulative incidence of these complications after immunosuppressive therapy.

    Survival

    The actuarial survival of each treatment group is shown in (Figure 2). At 15 years, the survival rate was 69% for the transplantation group and 38% for the immunosuppressive therapy group (P < 0.001). In the immunosuppressive therapy group, survival correlated with response: At 15 years, the survival rates for complete, partial, and minimal responders were 75%, 64%, and 55%, respectively. The survival rate for nonresponders was 13%. The primary causes of death in the transplantation group were infection and chronic graft-versus-host disease (40% and 28% of deaths, respectively). For patients receiving immunosuppressive therapy, hemorrhage and infection contributed equally to mortality (37% and 38% of deaths, respectively). Causes of death for all patients are listed in Table 2 and Table 3.

    Figure 2. Survival of 168 patients who had bone marrow transplantation. Survival of 227 patients who received immunosuppressive therapy. Tick marks denote censoring times of surviving patients. The difference in actuarial survival between patients who had transplantation and those who received immunosuppressive therapy was statistically significant ( < 0.001; log-rank test).
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    Figure 2. Survival of 168 patients who had bone marrow transplantation. Survival of 227 patients who received immunosuppressive therapy. Tick marks denote censoring times of surviving patients. The difference in actuarial survival between patients who had transplantation and those who received immunosuppressive therapy was statistically significant ( < 0.001; log-rank test). Actuarial survival after therapy for acquired aplastic anemia. Top.Bottom.P

    Prognostic Factors

    According to univariate analysis, the factors associated with improved survival included having bone marrow transplantation as primary therapy, being younger, having no transfusion before treatment, and having a higher absolute neutrophil count at hospital admission. Factors found not to be significantly associated with improved survival included disease duration, year of therapy, sex, refractoriness to transfusion of platelets from randomly selected donors, and previous exposure to corticosteroids or androgens.

    The survival advantage for patients having bone marrow transplantation decreased with increasing patient age (Figure 3). At 15 years, the survival rate was 100% for the 12 patients younger than 6 years of age who received transplants and 51% for the 25 patients younger than 6 years of age who received immunosuppressive therapy (P = 0.006). Among patients 6 to 19 years of age and 20 to 39 years of age, survival was also significantly better for transplant recipients than for patients who received immunosuppressive therapy (P = 0.001 and P = 0.04, respectively). For patients older than 40 years of age, survival did not differ between treatment groups (P > 0.2). The number of transplant recipients in this subgroup was small (n = 11), however, because patients older than 55 years of age were excluded from transplantation protocols during the study period.

    Figure 3. Tick marks denote censoring times of surviving patients. A. Patient age, younger than 6 years; 12 patients had transplantation and 25 patients received immunosuppressive therapy ( = 0.006). B. Patient age, 6 to 19 years; 63 patients had transplantation and 62 patients received immunosuppressive therapy ( = 0.001). C. Patient age, 20 to 39 years; 82 patients had transplantation and 73 patients received immunosuppressive therapy ( = 0.04). D. Patient age, 40 years or older; 11 patients had transplantation and 67 patients received immunosuppressive therapy ( > 0.2).
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    Figure 3. Tick marks denote censoring times of surviving patients. A. Patient age, younger than 6 years; 12 patients had transplantation and 25 patients received immunosuppressive therapy ( = 0.006). B. Patient age, 6 to 19 years; 63 patients had transplantation and 62 patients received immunosuppressive therapy ( = 0.001). C. Patient age, 20 to 39 years; 82 patients had transplantation and 73 patients received immunosuppressive therapy ( = 0.04). D. Patient age, 40 years or older; 11 patients had transplantation and 67 patients received immunosuppressive therapy ( > 0.2). Effect of patient age on actuarial survival by treatment group.PPPP

    Although the actuarial survival in both treatment groups was higher in patients who had not previously received transfusion than in patients who had received transfusion, this effect was statistically significant only in the group that had transplantation (Figure 4). At 15 years, actuarial survival was 81% for the 53 transplant recipients who did not receive transfusion and 63% for the 115 transplant recipients who did (P = 0.04). Among patients in the immunosuppressive therapy group, the survival rate at 15 years was 39% for the 41 patients who did not receive transfusion and 37% for the 174 patients who did (P = 0.11).

    Figure 4. Survival of 53 transplant recipients who did not receive transfusion and 115 transplant recipients who received transfusion ( = 0.04; log-rank test). Survival of 41 patients who received immunosuppressive therapy and did not receive transfusion and 174 patients who received immunosuppressive therapy and transfusion ( = 0.11; log-rank test). Tick marks denote censoring times of surviving patients.
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    Figure 4. Survival of 53 transplant recipients who did not receive transfusion and 115 transplant recipients who received transfusion ( = 0.04; log-rank test). Survival of 41 patients who received immunosuppressive therapy and did not receive transfusion and 174 patients who received immunosuppressive therapy and transfusion ( = 0.11; log-rank test). Tick marks denote censoring times of surviving patients. Effect of transfusion status on actuarial survival by treatment group. Top.PBottom.P

    Conversely, the effect on survival of a higher absolute neutrophil count before therapy was significant only in patients who received immunosuppressive therapy (survival rate at 15 years, 27% in the 89 patients with an absolute neutrophil count < 0.20 × 109/L and 47% in the 138 patients with an absolute neutrophil count > 0.20 × 109/L; P = 0.002) (Figure 5). Survival did not significantly differ between the transplant recipients with high granulocyte counts and those with low granulocyte counts (P > 0.2).

    Figure 5. Tick marks denote censoring times of surviving patients. > 0.2 for the bone marrow transplantation group and = 0.002 for the immunosuppressive therapy group. In the bone marrow transplantation group, 98 patients had an absolute neutrophil count greater than 2.0 × 10 /L and 70 had a count less than 2.0 × 10 /L. In the immunosuppressive therapy group, 133 patients had an absolute neutrophil count greater than 2.0 × 10 /L and 94 had a count less than 2.0 × 10 /L.
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    Figure 5. Tick marks denote censoring times of surviving patients. > 0.2 for the bone marrow transplantation group and = 0.002 for the immunosuppressive therapy group. In the bone marrow transplantation group, 98 patients had an absolute neutrophil count greater than 2.0 × 10 /L and 70 had a count less than 2.0 × 10 /L. In the immunosuppressive therapy group, 133 patients had an absolute neutrophil count greater than 2.0 × 10 /L and 94 had a count less than 2.0 × 10 /L. Effect of the absolute neutrophil count (ANC) before therapy on actuarial survival by treatment group.PP9999
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    Discussion

    The 395 patients described in our study were all referred to a single center that focuses on bone marrow transplantation for the treatment of malignant and nonmalignant diseases. During the study period, we offered bone marrow transplantation to patients with severe aplastic anemia who were younger than 55 years of age and had HLA-identical, related donors. Patients without such donors who had moderate or severe aplasia received immunosuppressive therapy with an antithymocyte globulin-based or antilymphocyte globulin-based regimen.

    Supportive care differed between the two groups. Transplant recipients were treated in laminar air flow rooms if such rooms were available, and they received medical care at the transplantation center for a longer period. The age range also differed between groups because there was no upper age restriction for patients receiving immunosuppressive therapy. Thirty-two patients who received immunosuppressive therapy were older than 55 years of age.

    The two factors most significantly associated with improved survival were younger patient age and type of treatment (that is, bone marrow transplantation). Bone marrow transplantation was superior in patients younger than 20 years of age, and survival was significantly better for patients who were 20 to 40 years of age when they had transplantation. No survival difference was seen in patients older than 40 years of age, although the number of transplant recipients in this age group was small.

    Transplant recipients who did not receive transfusion before therapy survived significantly longer than did those who received transfusion. This observation was noted previously in a sample of transplant recipients in which an “untransfused” patient was defined as a patient whose first transfusion was given within 72 hours of the start of the preparative regimen with cyclophosphamide [22]. In this subgroup of patients, a decreased incidence of graft rejection was ascribed to decreased sensitization to the donor's non-HLA antigens resulting from blood transfusions [22].

    In contrast, the association between a higher absolute neutrophil count before treatment and improved survival is seen only in the patients who received immunosuppressive therapy. In previous studies, a higher absolute neutrophil count has been correlated with both an increased rate of response to immunosuppressive therapy and an increased survival rate [15, 23]. For patients receiving immunosuppressive therapy, a higher absolute neutrophil count may indicate that the bone marrow has a reversible stem-cell injury and thus is capable of autologous recovery.

    On examination of the distribution of transfusion status and absolute neutrophil counts within the different age groups, it is of interest that in the youngest age group (persons <6 years of age), 58% of transplant recipients had not received transfusion. In each of the older age groups, approximately 30% of transplant recipients had not received transfusion. This distribution of patients who did not receive transfusion may partially explain why the youngest patient group had significantly better survival after transplantation.

    Factors associated with improved survival in our study are consistent with those found in an analysis of 509 patients with severe aplastic anemia reported by the European Bone Marrow Transplant Registry [24]. Two hundred eighteen patients received transplanted cells from matched, related donors, and 291 received immunosuppressive therapy with an anti-lymphocyte globulin-based regimen. Both a low neutrophil count and increasing age were associated with worse survival. Transfusion status was not included in that analysis. Compared with our results, actuarial survival in the European Bone Marrow Transplant Registry for patients who had transplantation was lower (63% at 6 years) and survival for patients who received immunosuppressive therapy was higher (61% at 6 years).

    In a recent summary of long-term outcome of adults (≥ 16 years of age) with aplastic anemia, investigators from the University of California, Los Angeles, compared 56 patients who had severe aplastic anemia and received antithymocyte globulin therapy with 55 similar patients who had allogeneic marrow transplantation [25]. Actuarial survival at 6 years did not differ between the groups (49% for patients who received antithymocyte globulin and 52% for patients who had transplantation). Survival according to type of therapy was not significantly associated with patient age. Year of treatment did not affect survival in patients receiving antithymocyte globulin; however, the 18 patients who had transplantation after 1983 had a 6-year survival rate of 72%, whereas the 37 patients who had transplantation before 1983 had a survival rate of 43%. This improved survival in patients who had had transplantation more recently is thought to be related to more effective prophylaxis of graft-versus-host disease with methotrexate and cyclosporine.

    Only one small study [26] has reported using bone marrow transplantation as salvage therapy for patients in whom two courses of immunosuppressive therapy failed or life-threatening infections developed. For the nine patients described, actuarial survival at 5 years was 80%. Because of the small sample size, however, these results must be interpreted with caution.

    Continued monitoring of patients with aplastic anemia who have received bone marrow transplants or immunosuppressive therapy has identified long-term complications unique to each form of treatment. In our transplant recipients, late graft rejection (≥ 100 days after transplantation) occurred in 4.8% of patients, and extensive chronic graft-versus-host disease developed in 40%. Secondary malignant conditions have been diagnosed in only three patients. Because a myelodysplastic syndrome did not develop in transplant recipients, it is possible that some patients with aplastic anemia had a clonal or premalignant condition at diagnosis and that a conditioning regimen of cyclophosphamide followed by allogeneic bone marrow transplantation is sufficient to eradicate the abnormal clone.

    For patients receiving immunosuppressive therapy, the cumulative incidence of developing a hematologic malignant condition was 10.6%. An additional 3.9% of patients are known to have developed paroxysmal nocturnal hemoglobinuria (this is probably an underestimate, however, because routine screening has not been done in all long-term survivors). Aplasia recurred in an additional 8.4% of patients who did not have transplantation (24% of patients who achieved a complete, partial, or minimal response).

    The incidence of long-term complications in patients who did and those who did not have transplantation varies among centers. For patients having transplantation at our center, the incidence of early and late graft rejection has decreased to less than 5% with current preparative regimens. Secondary malignant conditions have developed with a much lower frequency than that reported for patients who received conditioning regimens that included radiation [27]. Between 75% and 80% of the patients in our study who developed chronic graft-versus-host disease have been successfully treated, and their quality of life (as assessed by Karnofsky scores) is excellent.

    In patients receiving immunosuppressive therapy, the risk for paroxysmal nocturnal hemoglobinuria or a malignant condition has been reported to be as high as 57% at 8 years [28]. In a more recent update of European Bone Marrow Transplantation Registry data on 860 patients who received immunosuppressive therapy [29], the 10-year Kaplan-Meier probability of developing a hematologic malignant condition (n = 44) or a solid tumor (n = 7) was 18.8%.

    Our analysis has at least two limitations: Ours was not a randomized study, and the treatment regimens in the two patient groups were heterogeneous. Although the two groups were comparable with respect to several factors, including age, duration and cause of aplasia, and history of transfusion, maximum comparability could have been achieved only with a prospective, randomized trial.

    We also could not control for changes in treatment regimens with time. Within the population of transplant recipients, refinement of both the preparative regimen and the prophylactic therapy used for graft-versus-host disease has decreased the incidence of rejection and the incidence and severity of graft-versus-host disease, respectively. Similarly, immunosuppressive therapy regimens have included various combinations of antithymocyte or antilymphocyte globulin, corticosteroids, and growth factors in an attempt to increase the sustained complete response rate associated with this therapy. Each of these changes could have significantly affected the survival rate of subsets within a treatment group and subsequently affected the overall outcome of the entire group. Caution should therefore be used in attempts to draw strict conclusions about the relative merits of bone marrow transplantation and immunosuppressive therapy.

    Our results suggest that for patients with severe aplastic anemia who are 40 years of age or younger and have an HLA-identical, related donor, bone marrow transplantation can be associated with significantly improved survival compared with survival in patients receiving certain immunosuppressive therapy regimens. For patients older than 40 years of age, survival does not differ between patients who have transplantation and those who receive immunosuppressive therapy. Long-term complications can occur and are unique to each type of therapy. Treatment that is started soon after diagnosis can affect survival if patients do not have transfusion before transplantation or if they have a high absolute neutrophil count before immunosuppressive therapy.

    Our data must be interpreted in light of the different results among centers as well as the preliminary results of new treatment regimens for both bone marrow transplantation and immunosuppressive therapy. Because we wanted to assess long-term survival and complications, we analyzed a patient sample that has been followed for at least 5 years. The effect of more recent changes in both therapeutic approaches is not yet known. For example, cyclosporine was not considered to be a standard component of immunosuppressive therapy during the period of our analysis. Currently, however, most centers (including ours) have added cyclosporine to the treatment regimen and have abandoned the use of androgenic steroids. Recent results from the European Bone Marrow Transplantation Registry for patients with severe aplastic anemia treated with growth factors, antilymphocyte globulin, corticosteroids, and cyclosporine suggest a survival rate of 92% at 3 years [30]. Similarly, in our recent series of patients with severe aplasia who received transplants from matched, related donors, we are routinely using antithymocyte globulin and cyclosporine as the preparative regimen and methotrexate and cyclosporine as prophylaxis for graft-versus-host disease. Even though the age limit for eligibility for transplantation has been extended to 65 years, the actuarial survival at 4 years for eligible patients is now 92%. If these results are sustained after longer follow-up and are confirmed by other centers, recommendations for the treatment of aplastic anemia will continue to be redefined.

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    1. Ann Intern Med January 15, 1997 vol. 126 no. 2 107-115
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