Treatment of Acquired Severe Aplastic Anemia: Bone Marrow Transplantation Compared With Immunosuppressive Therapy-The European Group for Blood and Marrow Transplantation Experience

Andrea Bacigubpo, Ronald Brand, Rosi Oneto, Barbara Bmno, Gerard Socib, Jakob Passweg Anna Locaxiulli, Maria Teresa lhn Lint, Andre’ Ebelli, Shdun McCann, Judith Mmb, Per Ljunpnan, Jib? Hows, Pedro Marin, and Hubert Scbrezenmeier

Patients with severe aplastic anemia (SAA) can be successfully treated with bone marrow transplantation (BMT) or immunosuppressive therapy (IS). The current outcome using both forms of therapy among 3,669 patients treated in Europe between 1976 and 1998 is reviewed. Significant progress has been made and the overall risk of failure is now low, with survival rates greater than 80% for both treatments. Chronic graft-versus- host disease (GvHD) remains a problem for BMT patients, and carries a high risk of lethal complications. On the other hand, IS patients are exposed to late failure due to relapse or clonal/malignant diseases. First-line BMT from identical siblings is compared with IS therapy in an intent-to-treat analysis of 1,765 patients, regardless of subsequent transplant status. The outcome of SAA patients has improved considerably over time and is influenced by patient variables such as severity of the disease and age, but also by the choice of the initial treatment. Semin Hematol37:69-80. Copyright 0 2000 by W.B. Saunders Company.

B ONE MARROW TRANSPLANTATION (BMT) and immunosuppressive therapy are

accepted forms of therapy for patients with acquired severe aplastic anemia (SAp).47 While undergoing significant changes in the past 3 decades, they still retain some original features: cyclophosphamide (CY) 200 mg/kg is still the preferred conditioning regimen for human leukocyte antigen (HLA)-identical sibling transplants 30 years after Santos and Owens first described the regimen34 and Storb et al used it for SAA patients.42,43 Antilymphocyte glob&n (ALG) is the first choice agent for immunosuppressive pro- grams, more than 20 years after George Mathe and later Bruno Speck described its efficacy in the manage- ment of SAA.2G,41 The present report wi!.l update the data fi-om the large number patients reported to the Registry of the European Group for Blood and Marrow Transplantation (EBMT) Working Party on Severe Aplastic Anemia (WPSAA), treated either with BMT or immunosuppression. We discuss some outcome measures, including but not restricted to survival. A comparison of these 2 tream-rents is presented to assist the clinician in choosing first-line therapy.

Bone Marrow Transplantation BMT has been the treatment of choice for patients with aplastic anemia with a suitable donor in the family.7,“,‘4,32,42~5,47 We here report data on patients with acquired aplastic anemia from the WTSAA Registry of the EBMT (Fanconi’s anemia, Diamond- Blackfan syndrome, and paroxysmal nocturnal hemo- globinuria are excluded).

Between 1971 and 1998, 2077 patients under- went BMT A small number of syngeneic transplants

From the Working Pay, on Severe Aphtic Anemia of the European Blood and Mawow Traqktatibn Group; and the Medical StatisticaL Dtpartrnent, Universiy of lpi&a, L&den, The Netbmhd.

Supported by BIOMED EEC Grant No. 951031 to HS., an Azsochzione Italiana Ricercd contra il Ckncro (AIRC) M&ma grant to A.B., and b the Associazione Ricerca Trap&to M&l. Osseo (ARITMO), Geneva.

Address rtprint reqz~sts to A. Bacigahpo, MD, Department of Hbnatology, Ospedzle San Martino, Genova, Itab 16132.

CoBright 0 2000 4 WB. Sauna&s Company 0037-1963/00/3701-000G$10.00/0

Seminars in Hematology, Vo13Z No I (lanuavy), 2OOO:pp 69-80 69

70 Baczgalupo et al

were performed with excellent long-term survival (89%). The vast majority of patients received a graft from an HLA-identical sibling (n = 1,759), at a median interval from diagnosis of 3 months: 88% of these patients engrafted, 13% had severe acute graft- versus-host disease (GvHD), and 1,148 (65%) are alive. When compared with HIA-identical sibling grafts, patients who received alternative-donor trans- plants (n = 281) had a longer median interval horn diagnosis to BMT (10 months), as well as a greater risk of failure to engraft (26%) and of severe acute GvHD (28%), leading to a poorer overall outcome (37% survival). Among 37 patients who received grafts from an identical twin, the median interval from diagnosis to BMT was less than 3 months, 90% engrafted, none experienced GvHD, and the survival rate is 89%.

Gr& Failure and Graft Rejection Graft failure or rejection was one of the major problems in the early days of allogeneic BMT for SAA.10~28~2y~43~44 There is a clear donor effect on rejection: alternative-donor recipients (family matched, mismatched, and unrelated) had a significantly higher rate of graft failure/rejection compared with HLA- identical sibling transplants (26% zs 12%; P < .OOOOl). Alternative-donor transplant also has a greater likelihood of requiring a second BMT. For patients receiving HI&identical sibling grafts, there has been a modest reduction of graft failure over time: 18% before 1980, 12% horn 1980 to 1990, and 11% from 1991 to 1998 (P = .12). For clinical graft failure, we now have detailed information on mixed chimerism after BMT A considerable proportion of patients exhibit some degree of autologous reconstitu- tion after CY alone, which can be transient, persistent, or progressive and result in rejection.25 The major reduction in graft failure appeared at the time cyclo- sporine (CsA) was introduced in the early 1980s. For the last 10 years there remains a small proportion of patients, about lo%, who fail to engraft or reject a graft, especially if conditioned with CY alone. This number may be reduced with the addition of ALG to the conditioning regimen.

HLA-Identical Sibling Transplants When employing a Cox proportional hazards model for the 1,759 HLA-identical sibling transplants, 2 factors predict outcome: age of the patient (P <

.OOOl) and year of transplant (P < .OOOl). The severity of the disease, the interval between diagnosis and BMT, the presumed etiolou of the aplasia (idiopathic, posthepatitis, drug-induced), and the gender of the patient were not significant variables.

Donor and Year EEect Figure 1 outlines the actuarial survival for patients grafted from an HLA-identical sibling (A), a synge- neic twin (B), a phenotypically matched family donor (C), and an alternative donor (D, mismatched family + unrelated): there has been striing improve- ment for HLA-identical siblings (A) in the 2 treat- ment eras (</I 1990) from 56% to 71%, so that the difference with twin transplants is now relatively small. Alternative-donor and phenotypically matched family transplants have a much poorer outcome that has not improved over the past years. The large difference in the number of patients who have been grafted from a HLA-identical or an alternative-donor transplant reflects the reluctance of hematologists to undertake the latter procedure, especially because the ratio of patients with and without a HI&identical sibling is at least 1:4.

The Effect ofAge

The effect of age on HLA-identical sibling transplants also is clear: in the years 1976 to 1990, the actuarial survival for patients aged 16 years or less, 17 to 40, and greater than 40 years was 60%, 53%, and 27% (Fig 2)(P < .OOOl). In the years 1990 through 1998, survival was 77%, 68%, and 54%, respectively (P < .OOl). The age effect has persisted over time but the more recent outcomes are superior in all age groups.

The Role of Radiasion in the Gditioning Regimen

Of the 1,759 HLA-identical sibling transplants, 433 patients received radiation as part of their condition- ing regimen, in the form of total body irradiation, thoracoabdominal irradiation,ly or total lymphoid radiation. The actuarial 5-year survival rate of patients receiving radiation was 62% compared with 64% for patients prepared without radiation. The crude inci- dence of chronic GvHD in patients receiving radia- tion was 34% versus 22% (I) = .OOO2) and the crude rate of malignant disease, 4% versus 1% (P = .OOl). Therefore, there was no survival advantage for pa- tients receiving radiation, but there was an apparently

Transpbntation lh4s Immunosuppression 71

100

90

p 80 .- .g 70

jj 60

g 50

g 40

x 30 ‘ij 2 20 0

10

0

Figure 1.

Donor Type

< 1990; BMT > 1990. BMT I I I I I

12 24 36 48 60 12 24 36 48 60 Months from BMT Months from BMT

Actuarial survival at 5 years for patients undergoing BMT in Europe before 1990 (left, n = 1,030) and after 1990 (right, n = 1,047). Donors were (A) HLA-identical siblings (n = 915 [56% survival] before 1990; n = 844 [80% survival] after 1990); (B) syngeneic twins (n = 22 [95% survival] before 1990; n = 15 180% survival] after 1990); (C) HLA-phenotypic identical family donors (n = 27 [29% survival] before 1990; n = 46 [35% survival] after 1990); and (D) alternative donors, including family mismatched and unrelated donors (n = 66 [30% survival] before 1990; n = 142 [34% survival] after 1990). Significant progress in outcome is seen only in the H&identical setting.

higher incidence of late complications such as chronic GvHD and malignant disease.36

87% (consistent with the excellent results reported by Storb et a145).

CY alone as conditioning and CsA with or with- out methotrexate (MTX) for GvHD prophylaxis were given to 551 patients and their crude survival Graf-Versus-Host Disease

rate was 69%; ALG was added to the conditioning Acute grajhersus-host dikeme. Acute GvHD regimen in 28 patients, who had a survival rate of was recorded as grade 0 or I , II, and III or IV in 75%,

Age Effect 100

90 n

i? 80 .- .- ; 70

; 60

3 50

A

c 1990; BMT I I I I I

12 24 36 48 60 Months from BMT

21990; BMT

Ii 2i 3i 4i Months from BMT

6b

Figure 2. Effects of age and year of transplant before 1990 (left, n = 915) or after 1990 (right, n = 844) on outcome of BMT from HLA-identical siblings. (A) Age 516 years (n = 559 [60% survival] before 1990; n = 468 177% survival] after 1990); (B) age 540 years (n = 326 [53% survival] before 1990; n = 308 [68% survival] after 1990); (C) age >40 (n = 30 [27% survival] before 1990; n = 68 [54% survival] after 1990). Survival has improved in all age groups, but the effect of age remains.

72 Baczgahpo et al

1 l%, and 13% of patients. Grade III or IV acute GvHD was scored in 20% of cases before 1990 but in only 6% after 1990 (P < .OOOO 1). This improvement was mainly, but not exclusively, due to changes in the GvHD prophylaxis regimens employed: the inci- dence of severe (grade III or IV) acute GvHD was 26% for MTX prophylaxis, 11% for CsA , and 9% for CsA plus MTX (P < .OOOOl). Actuarial survival was profoundly influenced by acute GvHD: for grade 0 or I, II, and III or Iv, the actuarial 5-year survival rates were 60%, 55%, and 32% from 1976 through 1989 (I’ < .OOOOl) and 77%, 60%, and 33% from 1990 through 1998 (P < .OOO 1). It is interesting to note that improved survival was seen exclusively for patients with GvHD grade 0 or I, whereas the prognosis for patients with grade II and grade III or IV has not improved.

Chronic graft-versus-host disease. Chronic GvHD in patients surviving 100 days was recorded as absent in 77%, limited in 13%, and extensive in 10% of patients. As with acute GvHD, extensive chronic GvHD has been reduced from 15% before 1990 to 5% from 1990 through 1998 (J’ < .OOOOl). The overall actuarial 5-year survival rate for patients with no, limited, or extensive chronic GvHD was 89%, 84%, and 55% (I? < .OOOl). Survival beyond day 100 was not different before or after 1990 (Fig 3), suggesting that improved outcome is due to reduction of early deaths and that patients with extensive

chronic GvHD remain at risk of late death after transplant.

In conclusion, GvHD has a significant impact on survival. Because the risk of developing severe acute or chronic GvHD is significantly lower at present, survival of patients with SAA after HLA-identical sibling BMT has increased. However, our ability to treat GvHD once established has not improved much with time.ll

Immunosuppressive Therapy ALG was introduced in the late 1960s by Mathe et al as conditioning for marrow transplantation in aplastic anemia.26 Mathe and later Speck realized that ALG improved hematopoiesis in these patients by means of its immunosuppressive effect.38 AIG was then shown to be superior to supportive care in 2 prospective randomized trials8~9 (Table l).The clinical data were consistent with in vitro studies in which ALG in- creased colony formation of bone marrow cells de- rived from SAA patients1 and animal studies in which ALG improved hematopoiesis in benzene-induced aplasia. In addition to its immunosuppressive effect, ALG may also have a direct stimulating effect on progenitors cells, as first suggested by Faille et al. l5

Combined immunosuppressive regimens have been shown to be superior to single-drug therapy (Table 1): the response rate (but not survival) was improved in

.p 80

.g 70

; 60

cGvHD Effect

IO_ < 1990; BMT z 1990; BMT 0 , I I I 1 I I I I 1

12 24 36 48 60 12 24 36 48 60 Months from BMT Months from BMT

Figure 3. Survival of patients after HLA-identical surviving at least 100 days and stratified by extent of chronic GvHD (cGvHD) and year of transplant before 1990 (left, n = 465) or after 1990 (right, n = 600). (A) No cGvHD (n = 219 [81% survival] before 1990; n = 502 [89% survival] after 1990); (B) limited cGvHD (n = 108 [87% survival] before 1990; n = 57 [84% survival] after 1990); (C) extensive cGvHD (n = 138 [64% survival] before 1990; n = 41[61% survival] after 1990). Survival is worse for patients with extensive cGvHD (P < .OOOl) and there was no improvement in outcome in the 2 transplant eras.

Transplantation l&w Immunosuppression 73

Table 1. Randomized Trials of Immunosuppressive Therapy

Author No. of

Patients Regimen Response

Rate 3-Year

P Survival P

Champlin, 1983g 21 1 = ALG 53% .0005 62% NS 21 2 = Control 0% 41%

Camitta, 19838 29 1 = ALG 69% .OOl 78% .002 13 2 = Control 23% 30%

Doney, 198512 13 1 = ALG 31% .19 78% .36 12 2 = Anti-T MoAb 8% 58%

Bacigalupo, 19933 69 1 = ALG + MPr + Andr 56% .04 71% .l 65 2 = vALG + MPr 40% 65%

Frickhofen, 199116 41 1 = ALG + MPr + CsA 65% .02 64% .l 43 2 = ALG + MPr 39% 58%

Marsh, 199gz5 54 1 = ALG + CsA 74% .02 91% .2 61 2 = ALG 46% 92%

Abbreviations: ALG, antilymphocyte globulin; Anti-T MoAb, anti-T-cell monoclonal antibody; MPr, methylprednisolone; Andr, androgen; CsA, cyclosporine; NS, not significant.

patients receiving ALG plus methylprednisolone and androgens compared with ALG plus methylpredniso- lone alone,3 in patients receiving ALG plus methyl- prednisolone and CsA compared with ALG plus methylprednisolone alone,‘” and recently in patients without severe disease receiving ALG plus CsA com- pared with CsA alone. 25 The addition of growth factors (particularly granulocyte colony-stimulating factor [G-CSF]) has produced encouraging results in a pilot study,4 b ut whether the combination ALG, CsA, and G-CSF is superior to the combination of ALG plus CsA still needs to be determined.

ALG remains the drug of first choice for patients with SAA who are not eligible for transplantation and, at present, combination with CsA is the best first-line therapy,33 Recently high-dose cyclophosphamide has been introduced for SAA patients, and clinical trials are ongoing.6a47

Immunosuppressive Regimens The Registry of the EBMT WPSAA contains 1,592 patients treated with immunosuppressive therapy between I974 and 1997, ofwhom 1,052 (66%) are alive. The median patient age was 25 years, with a range of 1 to 89 years. The median interval from diagnosis to treatment was 35 days, and the etiology was described as idiopathic in 1,065, related to hepatitis in 93, drug-induced in 156, and of other or unknown etiology in 278 patients. Patients under- went 1 (n = 1,208), 2 (n = 288), or 3 or more (n = 96) courses of treatment. Major immunosuppressive

regimens were as follows: ALG with or without anabolic steroids and corticosteroids; ALG and CSA; CsA alone; and ALG, CsA, and G-CSE The outcome of patients with a neutrophil count less than 0.5 X 1 OS/L who were treated on these regimens from 1976 through 1989 and from 1990 through 1998 are outlined in Fig 4. Improved survival was seen espe- cially with the combination ALG plus CsA, with or without growth factors; these results confirm the superiority of this combination over either ALG or GA alone.

Severity of Disease and Outcome That patients with severe disease have a worse out- come is generally accepted.‘sJ24 A second analysis from the EBMT identified 3 subgroups of patients, classified by neutrophil count: 0 to 0.2 X 109/L (very severe), 0.21 to 0.5 X 109/1 (severe), and greater than 0.5 X lO”/L (not severe).2 The actuarial 5-year survival rates for patients treated before 1990 and stratified in these 3 risk groups were 46%, 61%, and 74%, and for patients treated from 1990 through 1998, 70%, 78%, and 77%. The effect of neutrophil count at the time of treatment on survival was analyzed in a Cox model adjusted for age and year of treatment: patients with a neutrophil count of 0.1 X 109/L had a lo-year survival rate of 50%, whereas patients with a neutrophil count of 1 X lO’/L have a projected survival of 90%. The difference in survival was greatest between 0.1 X 109/L (50%) and 0.5 X 109/L (74%), and less prominent at higher counts.

74 Bacigahpo et al

IS Regimen

F 80 .- .; 70

; 60 B

A

C

c 1990; IS i

L C

2 1990; IS

12 24 36 48 60 72 84 Months from treatment

12 24 36 48 80 72 84 Months from treatment

Figure 4. Survival of patients with neutrophil counts ~0.5 x log/L after immunosuppressive therapy, stratified by treatment given and year of treatment before 1990 (left, n = 585) or after 1990 (right, n = 317). (A) ALG (n = 523 150% survival] before 1990; n = 116 [83% survival] after 1990); (B) ALG + CsA (n = 56 164% survival] before 1990; n = 53 [83% survival] after 1990; (C) CsA (n = 6 125% survival1 before 1990: n = 22 132% survival] after 1990); (D) ALG + CsA + G-CSF (after 1990 only: n = 1%[85% survival]).

Age Effect

There was no linear effect of age on outcome for patients receiving immunosuppression as first-line therapy The actuarial 5-year survival rate for children (I 16 years) was 64%, for patients aged 17 to 40 years, 71%, and for patients older than 40 years, 59%.

Relapse Recurrence of original disease was at first believed to be unusual, but Schrezenmeier et al observed relapse in approximately one third of patients treated with immunosuppression35: the actuarial risk was 25% at 3 years before 1990 and 15% in the era 1990 through 1998 (the reduced risk in the latest cohort must be confirmed, as it may be due to the shorter follow-up).

Bone Marrow Transplantation Versus Immunosuppression

Published Studies The current standard approach is to offer BMT to young patients with a HLA-identical sibling and to reserve immunosuppression for older patients and those who lack a matched donor in the family. In actual practice, the process of clinical decision-making is often more complicated. Questions may arise on the treatment of a 4O-year-old patient with a donor: is

it better to start with immunosuppression and reserve BMT if there is no response? Or should the patient undergo an allogeneic BMT immediately? Is the outcome dependent on the severity of the disease? To answer these questions, the long-term results of treatment of large numbers of SAA patients who received immunosuppression or BMT as initial therapy must be analyzed. Information on survival but also long-term sequelae, causes of treatment failure, and quality of life are required.

Comparison of BMT with immunosuppression has been d&cult because aplastic anemia is rare and the number of patients in published reports has been relatively small (Table 2). In one of the first studies, reported by Speck et al, 18 patients underwent HLA-identical BMT,’ whereas 32 were treated with ALG39; survival was 44% and 69% in the 2 groups, respectively, but there were important differences noted: GvHD and rejection were the problems for transplant patients, whereas incomplete hematologic recovery and late complications such as relapse oc- curred in patients treated with ALG.39 These results were confirmed some years later on a larger number of patients?’ In pediatric patient populations, survival has usually been superior after BMT as compared with immunosuppression (Table 2).5,22,23 We pub- lished a study on 509 patients of whom 2 I8 received BMT and 291 were treated with immunosuppres-

Trdnspkantation V2mts Immunosuppression 75

Table 2. Summary of Published Trials Comparing BMT and lmmunosuppression

Author Population

Age Wr)

BMT (no. of

patients)

2-to 5-Year

Survival lmmunosuppression

(no. of patients)

2-to 5-Year Survival P

Speck, 19813g Bayever, 19845 Bacigalupo, 1988* Speck, 199040 Paquette, 199531 Locasciulli, 199023 Halperin, 198gz2 Doney, 199013 Fuhrer, 199817

Total

All ages l-25 I-50 All ages Adults Children Children All ages Children

18 44% 32 35 72% 22

218 63% 291 34 50% 111 55 72% 155

171 63% 133 14 79% 12

131 68% 139 26 84% 86

705 68% 958

69% 45% 61% 71% 45%

25% 52% 87%

52%

NS NS NS NS NS

,002 ?

.09 NS

sion2 and there was no difference in survival (63% v 61%) when the overall patient population was ana- lyzed. However, BMT was superior to immunosup- pression (64% v 38%, P = .Ol) in patients younger than 20 years with neutrophil counts less than 0.2 X 1 09/L. The opposite result held in patients older than 20 years with neutrophil counts between 0.2 and 0.5 X 109/L (62% z, 82%, P = .002). A problem with this study was that the BMT arm contained patients who had not responded to immunosuppres- sion, and the outcome of transplantation may have been affected by inclusion of patients who had failed previous therapies. For patients who underwent BMT as first-line treatment, survival was 7 1 %, as compared with 49% for patients given BMT after failed immu- nosuppression and 47% for BMT patients who had not responded to androgen and prednisone.2

In I995 Paquette et al reported long-term fol- low-up data of 155 adults with SAA treated between 1977 and I988 with ALG and 55 patients who received a transplant31; again, there was no overall difference between the 2 treatments for patients aged I6 to 46 years (P = .6) However, survival for patients treated after 1994 improved significantly for those who underwent BMT (43% to 72%) but not for those undergoing immunosuppression (46% to 45%). Finally, a very recent study by the German Pediatric Group has shown encouraging results for 86 children receiving ALG (87% survival), as well as for children undergoing allogeneic BMT (84% survival) (Ta- ble 2).”

EBMT Analysis, 1998 We have recently completed an analysis of 1,765 patients with acquired aplastic anemia treated first

either with a BMT from a HLA-identical sibling (n = 583) or with immunosuppressive therapy (n = 1,182). The analysis was performed based on “inten- tion to treat,” so that patients who underwent pri- mary BMT were compared with patients initially given immunosuppression, whether or not they were subsequently transplanted.

Patients were aged 1 to 50 years, and all were diagnosed according to current criteria’; they were treated between 1974 and 1996 and reported to the WPSAA Registry by the European centers. First-line therapy was a HLA-identical sibling BMT in 583 patients (median age, 18 years) and immunosuppres- sion in 1,182 patients (median age, 23 years). Of the patients who received immunosuppression, 1 ,O 18 patients were never transplanted regardless of out- come of immunosuppressive therapy; 164 patients were considered immunosuppression failures and were later transplanted (129 patients with a median age of 21 years received a graft from a HLA-identical sibling at a median interval of 139 days from immu- nosuppression; 35 patients with a median age of 16 years were transplanted from alternative donors at a median interval of 131 days from immunosuppres- sion). The interval between diagnosis and treatment was not found to be a predictor of outcome and was not included in subsequent analyses.

Most of the analysis was performed using failure- free survival as an end point, with failure being defined as death for BMT patients and either death or a transplant for immunosuppression patients.

Multivariate statistical models were used to esti- mate treatment differences between comparable pa- tients (adjusting for age, calendar year, and neutrophil count). The stratified Cox proportional hazards model

BakgaLupo et al

was used to evaluate the sequelae of treatment deci- sions, adjusting for possibly confounding effects of calendar year, the age of the patient, and neutrophil count. Model fitting strategies included assessment of appropriateness of the Cox model with respect to treatment differences; determination of a proper model to predict survival probabilities; and computation of 95% confidence limits for differences in survival rates among the various subgroups to be compared, in any particular calendar year.

To verify the proportional hazards assumption, we used the Cox model with time-dependent covariates. Follow-up time was dichotomized into 2 categories, before or after the median time to a failure event. After fitting the intended model, we extended it with the interaction term “treatment X time,” where “time” was the dichotomy between early and late follow-up. The test of significance of the interaction between this time-dependent variable and the treat- ment variable is a test on proportionality of the hazards (testing whether the treatment efkct itself depends on follow-up time). The likelihood ratio test had a P value less than .OOl. Because we could not incorporate the treatment effect directly into a propor- tional hazards model as a main effect, we stratified by treatment, so that the baseline curves for the treat- ment categories were calculated independently (while the effects of the other covariates were estimated as a common effect in the entire study population).

A stratified Cox proportional hazards model was used to estimate the effects of calendar year, age and neutrophil count on failure-free survival in both treatment groups. For easier clinical interpretation, difkrences of survival curves are used to describe treatment effects over the entire follow-up period.

IS as inltlal treatment

Graphics describe the di&erences between immuno- suppression and BMT with confidence limits and cut-off points to aid in decision-making. The Cox models were fitted using SPSS for Windows (~6.1.3). Backward elimination at the 10% significance level was used to remove interaction terms. Interaction between treatment (the stratification variable) and the covariates was incorporated by computing the appro- priate terms as additional variables. In addition, we evaluated the effect of model misspecification on the clinical interpretation of the results; the effect was substantial. A Cox model was used to fit the data separately for immunosuppression and BMT patients with year, age and neutrophil count as covariates. Such a model yields estimates of the average effect of calendar year over the entire time period (adjusted for patient characteristics) expressed in terms of a hazard ratio, as well as an estimated overall survival percent- age for a specific calendar year for an average patient, as for example a patient having an age and neutrophil count equal to the average in that treatment group.

Outcome

The outcome of both BMT and immunosuppression has improved significantly over time, with an average reduction in mortality rate of 6% per year in immuno- suppression and 8% annually in BMT between 1974 and 1996. The estimated 5-year survival for the typical patient receiving immunosuppression has im- proved from 58% in 198 1 to 75% in 1991 and for BMT from 54% to 77% (Fig 5).

Immunosuppressbn compared with BMT. Im- munosuppression was compared with BMT in pa- tients stratified by age (10 or 50 years) and by

BMT as initial treatment

100

so

80

70

60

50

40

30

20

IO

0 0 1 2 3 4 6 0 I 2 3 4 5

Figure 5. Probability of sur- vival for patients receiving im- munosuppression (IS) or EMT as initial treatment in 1981 and in 1991. The death rate has been reduced by a factor 0.53: the hazards ratio for IS and BMT (0.53 and 0.43) do not diier significantly (P = .15).

Trxzmphtation V?~G Immunosuppression 77

PMN = 0.1x1 0*9/l DIFFERENCE IN FF SURVIVAL

B PMN = 0.5x10*9/f

point of no difference 0

DIFFERENCE IN FF SURVIVAL

0 365 730 1095 1460 1825 0 365 730 1095 1460 1825

days since start initial treatment days since start initial treatment

Figure 6. Differences in failure-free (FF) survival for patients aged 10 or 50 years first treated with immunosuppression (IS) or BMT. (A) Patients with neutrophil (PMN) counts of 0.1 X log/L; (B) patients with PMN counts ~0.5 X log/L. The 2 curves represent differences in FF survival between BMT and IS. (A) An advantage is shown for BMT over IS in young patients with low PMN counts; 95% confidence intervals are well above 1. (B) Advantage is for IS over BMT for older patients with high PMN counts.

neutrophil count (0.1 or 0.5 X 109/L). Figure 6A depicts data for patients with a neutrophil count of 0.1 X 109/L. The figure shows the d8erence in survival between immunosuppression and BMT em- bedded in 95% confidence bands. The dividing line (point of no difference) is where immunosuppression and BMT are comparable; above the line there is an advantage for BMT, below for immunosuppression. For lo-year-old patients, BMT shows a 10% advan- tage in the first year, increasing to 19% at 5 years. This result indicates nonproportionality (and therefore the nonapplicability of the unstratified Cox model): the difference between BMT and immunosuppression is

until 5 years posttreatment. At age 50 years, results are better (by 150/) f o or immunosuppression and remain so at 5 years.

Combined #ect of age and mutropbil counts. Table 3 presents the estimated differences in 5-year failure-free survival between the 2 initial treatment options, immunosuppression and BMT, as a function of age and neutrophil counts. Negative values indicate a survival disadvantage of BMT compared with

Table 3. Difference Between BMT and lmmunosuppression in 5Year Failure-Free Survival (%) After Initial Treatment

not constant. Age Wr)

In contrast, immunosuppression provided an early

I

advantage

confidence limits showed a significant advantage for

(15%) for a 5O-year-old patient, but

immunosuppression only up to 3 years posttreat-

the advant&e decreased to 7% at 5 Gears; the 95%

ment, indicating that the long-term treatment failure

Neutrophil Count

(X109/L) 10 20 30 40 50

0 0.1

24* 20 14 19

6 14

-2 8 1 -7

0.2 14 9 3 -4 -11 0.3 10 5 -1 -7 -14 0.4 6 1 -4 -10 -16

rate after immunosuppression is greater than that for BMT

0.5 3 -2 -7 -12 -17t

Figure 6B shows results in patients with a neutro- phil count of 0.5 X 109/L. At age 10 years, results are equivalent and run along the line of no difference

NOTE. Positive values: advantage BMT (*24% 5-yr failure- free survival difference in favor of BMT); negative values: advantage immunosuppression (tl7% difference in favor of immunosuppression).

78 Ba&ahpo et al

immunosuppression, while positive values indicate a survival advantage for BMT. Clearly, combinations of young age and low neutrophil counts favor BMT, while older age plus high neutrophil counts favor the use of immunosuppression. (The effect of neutro- phil counts and age on outcome for an individual patient can be queried interactively at the Internet address htp://ebmt. clinicahesearcb. nVebmt/models/ses_ init. bei.)

Age, neutropbd count and c-r yeax To assess whether the predictive value of neutrophil count and age changed with calendar year at treat- ment initiation, the corresponding interaction terms were added to the final Cox models. There was no indication that the effect of neutrophil count and age on survival had changed over time.

Selecting Optimal First Treatment

We have confirmed that neutrophil counts at the time of treatment and patient age are important predictors of outcome 2J6J9,24,32,44. We can identify 3 groups of patients: (1) patients in whom BMT was clearly superior, including children regardless of neutrophil count and adults up to the age of 40 with low neutrophil counts (2 0.3 X 109/L); (2) patients in whom immunosuppression was clearly superior, com- prising adults above age 40; and (3) patients in whom differences between therapy were not well delineated, as in patients age 10 to 40 years with neutrophil counts exceeding 0.3 X 1 OS/L, in whom either BMT or immunosuppression would be appropriate.

The dif&rence in projected survival between pa- tients treated with BMT and immunosuppression is not linear but increases with time in favor of BMT. For young patients, for example, with low neutrophil counts, a 10% advantage at 1 year becomes a 19% advantage at 5 years in favor of BMT These data confirm a higher risk of late death in patients treated with immunosuppression, due to complications such as relapse of the original disease and evolution to leukemia or myelodysplasia.37 For these patients, immunosuppressive therapy may only “postpone the inevitable.“30 Therefore, since the advantage for BMT is projected to increase in the long term, we would favor first-line marrow transplantation in patients for whom there is no clear difference in likely outcome for the 2 forms of therapy.

Conclusions The outcome of SAA patients has considerably im- proved over time and is influenced by severity of the disease and age at onset, but also by the choice of the initial treatment. BMT from a HLA-identical sibling is always superior in young patients (5 20 years) for any neutrophil count. Immunosuppression is a better choice in older patients (41 to 50 years) when the neutrophil count is greater than 0.5 X 109/L. In the age group 21 to 40, the differences are less clear, with BMT equal to or superior to immunosuppression when the neutrophil count is less than 0.2 X 109/L. In all age groups there is a larger number of late failures in the, immunosuppression-treated patients. The long-term outcome is increasingly important. It is unfortunate that we lack systematic studies exatnin- ing the comparative quality of life of survivors. The impact of complications such as chronic GvHD, tram&ion-dependence, relapse, and late evolution of malignant disease need to be carefUy evaluated.

We did not examine immunosuppressive therapy in comparison to alternative-donor BMT, as the results of the latter procedure are so inferior to outcomes using HLA-identical siblings. Candidates for alternative-donor transplants would be children with very severe aplasia, once thought to be at high risk of failing immunosuppression treatment, but intensive immunosuppression and growth factors may be quite successll also in this patient popula- tion. Alternative-donor transplants are improving rapidly and we may expect to rescue in the near future the small proportion of patients who either do not have a HLA-identical sibling or have failed immuno- suppressive therapy (see chapter by Margolis) .

Acknowledgment The authors are grateful to all European centers that have contributed data.

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