Acute Leukaemia Allogeneic bone marrow transplantation for ... - Nature

7 downloads 79 Views 214KB Size Report
Allogeneic bone marrow transplantation for acute myeloblastic leukaemia in remission: risk factors for long-term morbidity and mortality. M Robin1, P Guardiola1 ...
Bone Marrow Transplantation (2003) 31, 877–887 & 2003 Nature Publishing Group All rights reserved 0268-3369/03 $25.00

www.nature.com/bmt

Acute Leukaemia Allogeneic bone marrow transplantation for acute myeloblastic leukaemia in remission: risk factors for long-term morbidity and mortality M Robin1, P Guardiola1, H Dombret2, A Baruchel3, H Esperou1, P Ribaud1, A Devergie1, E Gluckman1 and G Socie´1 1 Haematology Department, Bone Marrow Transplant Unit, Hospital Saint Louis, Paris, France; 2Haematology Department, Adult Haematology Unit, Bone marrow transplant unit Hospital Saint Louis, Paris, France; and 3Haematology Department, Pediatric Heamatology unit, Hospital Saint Louis, Paris, France

Summary: In this single-centre retrospective study, we analysed risk factors for nonrelapse long-term morbidity and mortality in patients with acute myeloblastic leukaemia (AML) who had undergone allogeneic transplantation. A total of 112 patients with de novo AML in first complete remission (CR1), n ¼ 90 or second complete remission (CR2, n ¼ 22) who received un-manipulated bone marrow grafts from human leukocyte antigen identical siblings between January 1985 and August 2000 were included. Of these, 97 patients alive and disease-free for at least 100 days after transplant were selected for the purpose of this longterm analysis. The use of an intensified conditioning regimen, Gram-negative bacteriaemia before transplantation, year of transplantation and number of pretransplant chemotherapy courses for patients in CR1 significantly affected the 7-year event-free survival which was 57%. 7-year transplant-related mortality TRM was 22%. Significant predictors for TRM were: bacterial infections before transplantation, major ABO blood group incompatibility, late severe bacterial infections, and chronic (graft-versus-host disease) GvHD. Predictive factors for late severe bacterial infections were infections before transplant, total body irradiation and GvHD. Incidence and risk factors for other late events including, chronic GvHD, late infections, osteonecrosis, cataract, endocrinecardiac- and lung-complications, cancer and performance status at last follow-up were also studied. The analysis strongly suggests that the combination of pretransplant factors such as chemotherapy and conditioning, and post transplant factors such as chronic GvHD had a major impact on late nonrelapse morbidity and mortality. Bone Marrow Transplantation (2003) 31, 877–887. doi:10.1038/sj.bmt.1704027 Keywords: AML; morbidity; transplanted related mortality; long-term results

Correspondence: Prof G Socie´, Service d’He´matologie, Greffe de Moelle, Hoˆpital Saint Louis Ap-Hp, 1 Avenue Claude Vellefaux, 75475, Paris Cedex 10, France The first two authors contributed equally to this study and both should be considered as first author Received 2 May 2002; accepted 17 September 2002

It has been shown in multicentre randomised trials that allogeneic stem cell transplantation (SCT) is the most effective strategy for preventing relapse in patients in first complete remission (CR) of acute myeloblastic leukaemia (AML).1–6 However, in adult patients, this benefit does not necessarily lead to a better disease-free survival, since allogeneic SCT is associated with significant transplantrelated mortality (TRM).2,7 In adults with good-risk AML, because chemotherapy alone or combined with differentiating agents can lead to sustained CR and cures, allogeneic SCT is usually indicated in second CR or first untreated relapse.8,9 In poor-risk AML, salvage rates are less predictable and the probability of reaching a second CR less certain; thus, allogeneic SCT is usually considered earlier, in first CR.10–12 Finally, age is also a determinant in the indication for allogeneic SCT.3,13 Constant improvements in the management of transplanted patients have resulted in increasing number of long-term survivors following allogeneic SCT.14,15 However, the mortality rate of these long-term survivors is still higher than that of an age-matched population.16–19 Information on late outcomes and identification of risk factors should help to improve treatment strategies aimed at reducing late transplant-induced morbidity. We assessed the long-term outcome of 97 patients who underwent allogeneic SCT for AML in first or second CR at Saint Louis Hospital.

Patients and methods Patient characteristics A total of 112 patients with de novo AML in first (n ¼ 90) or second CR (n ¼ 22) were transplanted, using unmanipulated bone marrow grafts from human leukocyte antigen (HLA) identical siblings from January 1985 to August 2000 at Saint Louis hospital. The median follow-up from the date of transplantation was 5.5 years (range: 7 months to 13.2 years), 24 patients being alive for at least 7 years from transplantation. Patient and disease characteristics are listed in Table 1. The 7-year TRM, event-free survival (EFS) and overall survival (OS) were 29, 47 and 55%, respectively.

Allogenic bone marrow transplantation for AML M Robin et al

878

From this group, 97 patients alive and disease-free for at least 100 days after transplant were selected for the purpose of this long-term analysis. The 15 deaths before day 100 post-transplantation were mainly transplant-related [acute graft-versus-host disease (GvHD) (n ¼ 8), haemorrhage (n ¼ 2), infection without GvHD (n ¼ 2), rejection (n ¼ 1)], while two patients died from early relapse. Cytogenetics were available in 67.9% of recipients. Patients were classified into three cytogenetics groups as good risk [t(15;17), inv(16), t(8;21)], poor risk [abn(5), abn(7), abn(11q), hypoploidy] and intermediate risk [all others] in 26, 14 and 36 patients, respectively. Patients were also classified as having normal, simple, or complex cytogenetics as summarised in Table 1. All patients had received a ‘cytarabine–anthracycline’ based induction regimen according to the ongoing protocols in use during the different time periods.13,20–22 Those less than 20 years old were more likely to be transplanted in first CR than the others (92 vs 75%, P ¼ 0.03). Patients transplanted in first CR received intermediate or high-dose cytarabine (HiDAC) less frequently (16% in the CR1 group vs 67% in the CR2 group, Po0.001). Chemotherapy regimens were not more intensive for the group of patients who had received more than three postremission chemotherapy courses (CTs): 24% HiDAC and 52% ambula-

Table 1

Patient and disease characteristics

Patients

Total 112

Children 41

Adults 71

P-value

Gender Male Female

61 (54.5) 51 (45.5)

28 (68.3) 13 (31.7)

33 (46.5) 38 (53.5)

0.03

Age (years) Median (range)

27 [2–53]

11 [2–18]

36 [19–53]

WBC at diagnosis Median (range) 9.7 [0.9–860] 71.5 [1–860] 27 [0.9–200] WBC >20  109/l 41 (36.6) 22 (53.7) 19 (26.8)

0.03 0.02

FAB classification Unclassified M0-M1-M2 M3 M4-M5 M4eosino M6-M7

4 61 15 24 3 5

(3.6) (54.5) (13.4) (13.4) (2.7) (4.5)

1 (2.4) 26 (63.4) 4 (9.8) 8 (19.3) 1 (2.4) 1 (2.4)

3 35 11 16 2 4

(4.2) (49.3) (15.5) (22.5) (2.8) (5.6)

NS

Cytogenetic Missing Normal Simple Complex

36 (32.1) 24 (21.4) 41 (36.6) 11 (9.8)

14 (34.1) 6 (14.6) 14 (34.1) 7 (16.6)

22 (31) 18 (25.4) 27 (38) 4 (5.6)

NS

Induction One course Two courses Pregraft HiDAC Postremission CTsa X3 cycles CR1

83 (74.1) 29 (25.1) 30 (27.5) 2 25 (28.7) 90 (80.4)

34 (82.9) 7 (17.1) 7 (17.1) 1.9 19 (25.7) 37 (90.2)

49 (69) 22 (31) 23 (33.8) 2 16 (30.8) 53 (74.6)

NS 0.06 NS NS 0.04

Percentages are in parentheses; WBC=white blood cell count; CR1=number of patients in first remission. a Number of postremission chemotherapy courses. Bone Marrow Transplantation

tory amsacrine plus cytarabine vs 19 and 40% for the others.

Transplantation procedure Transplant characteristics of the 97 patients who survived beyond day 100 are summarised in Table 2. In all, 79 patients received standard conditioning regimens (81%), that is, cyclophosphamide (Cy) 120 mg/kg plus TBI 12 Gy (n ¼ 34) or busulfan (Bu) 16 mg/kg plus Cy 120 or 150 mg/ kg (n ¼ 46). The remaining patients (n ¼ 17) received either Bu/Cy or Cy/TBI plus one of the following drugs: etoposide, melphalan, high-dose aracytine, or BCNU. These intensified conditioning regimens were more frequently used for patients in CR2 (8% in CR1 vs 61% in CR2, Po0.001). Nucleated cell dose infused per kilogram recipient body weight was lower when there was a major ABO blood group incompatibility (median: 1.1  108/kg with a major ABO incompatibility vs 3.5  108/kg without major incompatibility, Po0.001). Most patients received cyclosporine (CsA) and methotrexate (MTX) as GvHD prophylaxis.23,24 All patients were treated in laminar air flow rooms and received oral amoxicilline, ofloxacine, fluconazole, amphotericin B and acyclovir as prophylaxis. Fluconazole was stopped when patients had an absolute neutrophil count (ANC) above 1  109/l and were off corticosteroids. Amoxicilline was continued for at least 5 years post transplantation. Prophylaxis against Pneumocystis carinii and Toxoplasmosis was started after neutrophil recovery and continued for at least 6 months or until corticosteroids had been stopped.

Definitions End points were assessed on the date of last patient contact and analysed as of September 2001. Acute and chronic GvHD were graded according to the Seattle criteria.25,26 Analysis of chronic GvHD included patients who were alive with engraftment at day 100 post transplantation, cases being coded as absent, limited or extensive. Relapse was diagnosed according to cytological criteria. Deaths not attributable to disease – during continuous CR – were considered as events for the assessment of TRM. Second transplants for graft failure or rejection, relapse and death were considered as events to estimate EFS. OS was measured from the time of transplantation to the time of death. Patients not in CR at the time of death were considered to have died of relapse, even if this was not recorded as the immediate cause of death. Similarly, patients in CR with GvHD at the time of death were considered to have died of GvHD even if it was not the immediate cause of death. When analysing infectious complications arising after day 100, bacteriaemia, septic shock, pneumonia, intra-abdominal sepsis, acute pyelonephritis, meningitis, osteitis, arthritis, and empyema were considered as late severe bacterial infections (LSBI). Cytomegalovirus (CMV) infection and disease were defined according to standard criteria.27,28 Patients who relapsed or received a second transplant were censored at the time of relapse or second transplant when analysing incidence and predictors for late infections.

Allogenic bone marrow transplantation for AML M Robin et al

879 Table 2

Transplant characteristics of 97 patients surviving beyond day 100

Patients

Total 97

Children 38

Adults 59

P-value

5.6 [2–53] 56

4.8 [2–30] 27 (71.1)

6 [3–53] 27 (45.8)

0.02 0.01

3.4 [0.5–11] 35 (36.1) 92 (94.8)

2.7 [0.8–7.5] 20 (52.6) 36 (94.7)

3.8 [0.5–11] 15 (25.4) 56 (94.9)

0.1 0.02 NS

Year of transplant 1985–1989 1990–1994 1995–2000

30 (30.1) 42 (43.3) 33 (34)

13 (34.2) 13 (34.2) 12 (31.6)

15 (25.4) 22 (37.3) 22 (37.2)

NS

Conditioning regimen TBI Single dose Fractionated Cy-TBI Bu-cy Intensified

47 (48.5) 31 (32) 16 (16.5) 33 (34) 46 (47.4) 17 (18.6)

18 (47.4) 13 (34.2) 5 (13.2) 14 (36.8) 18 (47.4) 5 (13.2)

39 18 11 19 28 12

GvHD prophylaxis CsA+MTX CsA7other

86 (88.7) 5 (4.5)

31 (81.6) 7 (18.4)

57 (96.6) 2 (3.4)

0.02

2.5 [0.–13] 66 (68.1)

2.3 [0.7–7.9] 23 (60.5)

2.5 [0.6–13] 42 (72.4)

NS

15 (15.4) 15 (15.4)

5 (13.2) 6 (10.3)

10 (26.3) 9 (15.5)

NS

19 20

21 26

18 18

Recovery at day 100 ANC>0.5  109/l Platelets>20  109/l

97 (100) 80 (82.5)

38 (100) 32 (83)

59 (100) 81 (83.5)

Acute GvHD Grade I Grade II Grade III & IV

38 (39.2) 26 (26.8) 3 (3.1)

14 (36.8) 11 (28.9) 1 (2.6)

24 (40.7) 15 (25.2) 2 (3.4)

Time from diagnosis to SCT Median (range) o6 months

a

Time from last CR to SCTa Median (range) o3 months o6 months

(66.1) (30.5) (18.6) (32.2) (47.5) (20.4)

NS

NS

8

Nucleated cells (10 /kg) Median (range) X2 ABO incompatibility Minor Major Engraftment: Median time (days) to reach ANC >0.5  109/l Platelets>20  109/l

This table includes data on patients alive and in remission at day 100 after SCT. a Time in months. Percentages are in parentheses; 76 patients were transplanted in CR1 and 18 in CR2.

Statistical methods Chronic GvHD, late infections, TRM, cataracts, aseptic osteonecrosis, relapse incidence, EFS and OS incidence were estimated from the date of transplant. Analyses focused on projected probability of 7-year outcome. Groups were compared using the two-tailed log-rank test. In order to dichotomise continuous covariates, P-spline method and a penalised Cox model were used. The following covariates were analysed on univariate analysis: cytological subtype at diagnosis, cytogenetics, type of anthracycline regimen used during induction, dose of cytarabine used before transplantation, number of postremission chemotherapy courses before transplantation, time interval between diagnosis and transplantion, time interval between last remission and transplant, pretrans-

plant history of bacterial or fungal infections and organisms isolated, year of transplantation as a continuous covariate, recipient age at transplantation, recipient gender, recipient CMV serology, disease stage at transplantation, donor gender, donor–recipient sex match, number of nucleated cells infused, conditioning regimen, time to reach an ANC above 0.5  109 and 1.0  109/l, time required to reach an ANC of 1.0  109/l when it had reached 0.5  109/l, time to reach a platelet count above 20  109/l and above 50  109/l, grade II–IV acute GvHD, chronic GvHD, LSBI, and CMV reactivation before and after day 100, duration and maximum dose of corticosteroids used. Post-transplantation events occurring after day 100, that is, LSBI, viral infections, corticosteroid therapy, and chronic GvHD were analysed as time-dependent covariates. Covariates found significant at a P-value below 0.10 Bone Marrow Transplantation

Allogenic bone marrow transplantation for AML M Robin et al

880

were subsequently introduced in proportional hazards Cox models, and selected via a stepwise procedure. Departure from the proportional hazard assumption was assessed using a graphical approach and partial residuals. Timedependent or stratified Cox models were used when covariates did not meet the proportional hazard assumption. Potential interactions between the significant covariates were tested adding cross-product terms to the final models. When groups were compared according to continuous covariates, the Man–Whitney U test or Kruskal–Wallis one-way ANOVA on ranks test were used for difference in medians. According to the group sizes, w2 or Fisher’s exact tests were used to compare categorical covariates. S-PLUS 2000 Professional was used for all statistical analysis.

Results

(glioblastoma n ¼ 1, sinus carcinoma n ¼ 1). EFS was not statistically significant in patients grafted in CR1 or in CR2 (59 vs 48%, P ¼ NS), or between children and adults (63 vs 53%, P ¼ NS). Cox proportional hazard models were first built including patient – and transplant – characteristics affecting the 7-year EFS. For patients in CR1, Gramnegative bacteriaemia (RR: 3.11, 95% CI: 1.13–8.54, P ¼ 0.028), and number of postremission CT courses before transplantation (RR: 3.04, 95% CI: 1.29–7.16, P ¼ 0.011) were adverse factors (see Figure 1b). For patients in CR1 plus CR2, Gram-negative bacteriaemia before transplantation (relative risk (RR): 2.51; 95% CI: 1.02–6.18, P ¼ 0.046), year of transplantation (RR: 0.91, 95% CI: 0.84–0.99, P ¼ 0.043), and the use of an intensified conditioning regimen (RR: 3.53, 95% CI: 1.57–7.97, P ¼ 0.002) adversely affected 7-year EFS (Figure 1c, 1d). Finally, an extended Cox model including post-transplant covariates was fitted with the overall group of patients (Table 3).

EFS and relapse incidence Transplant-related mortality The 7-year TRM rate was 22% for the overall group (95% CI: 11–32%). It was 23% for patients grafted in CR1 (95% CI: 10–33%), and 18% for those in CR2 (95% CI: 0–35%). On multivariate analysis, a first Cox model stratified on recipient age (o20 years vs X20 years) excluding posttransplant covariates was fitted. In that model, multiple

1.0

1.0

0.8

0.8 Survival

Survival

The 7-year EFS and relapse incidence for the 97 patients surviving beyond day 100 post transplantation were 57% (95% CI: 47–70%), and 27% (95% CI: 15–37%), respectively (see Figure 1a). Main causes of death were chronic GvHD (n ¼ 13, of which seven patients had a concurrent infection), relapses (n ¼ 13), infections without chronic GvHD (n ¼ 3), and secondary solid cancers

0.6 0.4 0.2

0.0 0

2 4 6 Years post transplantation

1.0

1.0

0.8

0.8 Survival

Survival

0.4 0.2

0.0

0.6 0.4

0

2 4 6 Years post transplantation

0

2 4 6 Years post transplantation

0.6 0.4 0.2

0.2

0.0

0.0 0 Figure 1

0.6

2 4 6 Years post transplantation

(a) 7-year event-free survival. A 7-years EFS was estimated at 57% (95% CI: 47–70%). (b) Influence of number of postremission chemotherapy courses on 7-year EFS in patients transplanted in first remission. A total of 56 patients received less than three courses of postremission chemotherapy and 20 more than three courses; their 7-year leukaemia-free survival rates were 70% (95% CI: 58–85%) vs 27% (95% CI: 11–77%), respectively, P ¼ 0.005. Among the 20 patients receiving more than three postremission CTs, 11 died; causes of death included: GvHD (n ¼ 6), relapse (n ¼ 4), and late marrow failure (n ¼ 1); no difference was noted between the cause of death of these 11 patients and those of the 15 patients receiving less than three postremission CTs (data not shown). (c) Influence of conditioning regimen on 7-year EFS. In all, 17 patients received an intensified regimen and 80 received a standard regimen which led to an estimated KM rate for 7-years EFS of 39% (95% CI: 21–73%) vs 79% (95% CI: 50–75) respectively, P ¼ 0.005. (d) Influence of pretransplant Gramnegative bacteriaemia on 7-year EFS. Among nine patients who developed one or more episodes of Gram-negative bacteriaemia before SCT, the 7-year EFS was 18% (95% CI: 3–100%) whereas for patients who did not develop pretransplant infection, the 7-years EFS was 63% (95% CI: 52–76%), P ¼ 0.04. In all, 15 patients developed a severe pretransplant bacterial infection and nine developed two (N ¼ 6) or more (N ¼ 3) bacterial infections. Most infections were represented by bacteriaemias or sepsis (N ¼ 31) and responsible organisms were: Gram negative (Pseudomonas (N ¼ 9), Acinetobacter (N ¼ 2), Colibacillus (N ¼ 1)); Gram positive (Staphyloccoci (N ¼ 12), Streptococci (N ¼ 6), Enterococcus (N ¼ 1)).

Bone Marrow Transplantation

Allogenic bone marrow transplantation for AML M Robin et al

Table 3 Risk factors for TRM, GvHD, and LSBI in multivariate analysis including post-transplant and time-dependant covariates Relative risk

95% Interval

P-value

EFS Pregraft GN bacteriaemiaa Intensified cond. regimenb ANC 0.5 to 1  109/l >7 daysc Extensive GvHD LSBI

2.77 2.44 3.48 4.14 4.17

1.05–7.30 1.09–5.48 1.31–9.26 2.01–8.54 1.94–8.98

0.039 0.030 0.013 0.0001 0.0003

TRM Nb GN bacteriaemia oSCTa Intensified cond. regimen Extensive GvHD LSBI

2.62 5.21 16.79 14.67

1.28–5.36 1.26–21.52 4.62–61 3.5–61.42

0.008 0.023 o0.001 o0.001

Chronic GvHD Major ABO incompatibility 20  109/l Plt not reached at D100 Grade II–IV acute GvHD

2.61 2.25 2.68

1.17–5.83 1.03–4.93 1.32–5.44

0.019 0.043 0.006

Extensive chronic GvHD Major ABO incompatibility Positive CMV serology Grade II–IV acute GvHD

4.81 2.78 3.08

1.94–11.90 1.22–6.33 1.40–6.73

o0.001 0.015 0.005

LSBI GN bacteriaemia oSCTa TBI Extensive GvHD

2.48 3.45 2.23

1.04–5.84 1.39–8.55 1–4.94

0.039 0.0075 0.049

a

Gram-negative bacteriaemia before SCT or number of Gram-negative bacteriaemia before SCT. b Intensified conditioning regimen. c Time interval required to reach an absolute neutrophil count above 1.0  109/l from 0.5  109/l. plt=platelet rate.

bacterial infections during the pretransplant period (RR: 5.16, 95% CI: 1.27–20.91, P ¼ 0.022), time interval between last CR and transplantation (RR: 1.23, 95% CI: 1.00–1.52, P ¼ 0.05), an intensified conditioning regimen (RR: 3.42, 95% CI: 1.30–8.97, P ¼ 0.013), and a major ABO blood group incompatibility (RR: 3.64, 95% CI: 1.32–10.05, P ¼ 0.013) were significant predictors of late TRM (see also Figure 2a, 2c, 2d). In the first CR patients, multiple pretransplant bacterial infections (RR: 2.40, 95% CI: 1.20– 4.78, P ¼ 0.013), and number of postremission CT courses (RR: 4.14, 95% CI: 1.18–14.49, P ¼ 0.026) remained associated with 7-year TRM (see also Figure 2b). Results of the extended Cox model including the post-transplant covariates is summarised in Table 3.

Chronic GvHD In total, 35 patients developed chronic GvHD which was extensive in 27 cases. The 7-year incidence of overall and extensive chronic GvHD was 40% (95% CI: 29–50%) and 32% (95% CI: 21–41%), respectively. Progressive forms of chronic GvHD occurred in 12 cases while de novo chronic GvHD was observed in 23 patients. On a first multivariate Cox model stratified on recipient age, a major ABO blood group incompatibility (RR: 2.46, 95% CI: 1.11–5.43,

P ¼ 0.026) and intensified conditioning regimens (RR: 2.13, 95% CI: 0.99–4.60, P ¼ 0.054) were significant predictors for chronic GvHD. Results of the Cox models for chronic GvHD, and extensive chronic GvHD, stratified on age and including post-transplant covariates are summarised in Table 3. In the first CR patients, the number of postremission CT courses before transplantation (RR: 3.49, 95% CI: 1.47– 8.27, P ¼ 0.004), major ABO blood group incompatibility (RR: 3.00, 95% CI: 1.27–7.09, P ¼ 0.012), platelet count above 20  109 /l not reached by day 100 (RR: 2.54, 95% CI: 1.01–6.37, P ¼ 0.047), and grade II-IV acute GvHD (RR: 2.26, 95% CI: .96–5.35, P ¼ 0.06) were significantly associated with chronic GvHD.

881

Late infections Bacterial infections: In all, 24 patients developed one or more (n ¼ 5) late severe bacterial infections (Table 4), which occurred at a median of 7.5 months post transplantation (range: 4 months – 5 years). The 7-year probability of LSBI was 35% (95% CI: 26–46%) (Figure 3a). All cases of acute pyelonephritis were caused by E. coli; whereas, in most cases of pneumonia (83%), no bacterial documentation was obtained since antibiotics were started early after the onset of symptoms. Most of the bacteriaemias/septicaemias were observed during the first 6 months post transplantation (78%), whereas most pneumonias (83%) and all unusual infections (osteitis, meningitis, empyema) were observed after the first 6 months post transplant. Previous bacterial infection during the first 100 days post transplantation was not associated with an higher risk of LSBI. On multivariate analysis including pretransplant covariates, a previous history of Gram-negative bacteriaemia before transplantation (RR: 2.85, 95% CI: 0.94–8.60, P ¼ 0.063), and TBI (RR: 3.85, 95% CI: 1.50–9.86, P ¼ 0.005) were associated with a higher risk of LSBI, as confirmed in Figure 3b and 3c. In the final model in which post-transplant covariates were added, extensive GvHD also appeared also as a major risk factor (see Table 3, Figure 3d). Other infections. Late CMV reactivation occurred in nine cases (isolated blood antigenaemia n ¼ 6, gastroenteritis n ¼ 2, pneumoniae n ¼ 1), leading to a 7-year probability of CMV reactivation of 10% (95% CI: 6–16%). CMVreactivation occurred at a median of 5 months posttransplantation, without any reactivation after 1 year. Twothirds of these patients had already experienced CMV reactivation before day 100. In all, 24 patients developed nonlethal varicella zoster virus (VZV) infections, leading to a 7-year probability of VZV infection of 32% (95% CI: 20– 43%). These VZV infections occurred at a median of 12 months from transplantation (range: 5 months – 3.8 years). Other viral infections were post-transfusion viral hepatitis C (n ¼ 7), parvovirus B19-related erythroblastopenia (n ¼ 2), Epstein–Barr virus related lymphoproliferative disorder (n ¼ 1), and human immunodeficiency virus (n ¼ 1). With regard to fungal infections, nine patients developed invasive aspergillosis at a median of 5 months from transplantation (range: 3 – 6 months), and two patients developed candidaemia. Bone Marrow Transplantation

Allogenic bone marrow transplantation for AML M Robin et al

1.0

1.0

0.8

0.8

0.6

0.6

TRM

TRM

882

0.4 0.2

0.2

0.0

0.0 0

2 4 6 Years post transplantation

1.0

1.0

0.8

0.8 TRM

TRM

0.4

0.6 0.4

0

2 4 6 Years post transplantation

0

2 4 6 Years post transplantation

0.6 0.4 0.2

0.2

0.0

0.0 0

2 4 6 Years post transplantation

Figure 2

(a) Influence of pretransplant Gram-negative bacteriaemia on 7-year TRM. Patients with a history of pretransplant Gram-negative bacteriaemia had 7-year TRM KM estimate of 51% (95% CI: 0–80%) vs 18% (95% CI: 7–27%) for patients without, P ¼ 0.04. (b) Impact of number of postremission chemotherapy courses on 7-year TRM. Patients receiving two or less postremission CTs have an estimated 7-year TRM of 16% (95% CI: 3–28%) vs 40% (95% CI: 8–61%) for patients receiving more than two postremission CTs, P ¼ 0.03. (c) Impact of major ABO incompatibility on 7-year incidence TRM. Projected incidence at 7 years for TRM was 17% (95% CI: 28%) and 42% (95% CI: 13–62%) for major ABO incompatibility and others, P ¼ 0.002. 19 patients had a major ABO incompatibility and 77 patients had a minor ABO incompatibility or a standard ABO compatibility. (d) Impact of conditioning regimen on 7-years TRM. Patients conditioned with an intensified regimen had a 7-year TRM of 45% (95% CI: 8–67%) whereas patients conditioned with a standard regimen had a 7-year TRM of 18% (95% CI: 7–28%), P ¼ 0.06.

Table 4

In all, 30 late severe bacterial infections in 24 patients after SCT for AML

Organisms P. aeruginosa E. coli S. pneumonia S. aureus Othersa Unknown Time from SCT to LSBI o6 months 6—12 months 13–24 months >24 months Immunosuppressive treatment CsA alone Csb alone CsA+cs No treatment

Bacteriaemia (N=9)

Pneumonia (N=12)

Pyelo-nephritis (N=5)

Meningitis (N=2)

Empyema osteitis (N=2)

3 — — 1 1 4

— — 1 — 1 10

— 5 — — — —

— — 2 — — —

1 — — 1 — —

7 1 0 1

2 2 5 3

3 — 1 1

— — 1 1

— — 1 1

2 2 5 —

1 1 3 7

2 1 1 1

— 1 — 1

— — — 2

Five patients developed several late severe bacterial infections: three patients had two episodes of pneumonia, one patient had pneumonia and two episodes of bacteriaemia, one patient had pneumonia and pyelonephritis. a Others organisms were H. influenza, K. pneumoniae. b Cs=corticosteroid.

Non infectious complications Aseptic osteonecrosis occurred in 14 cases, at a median of 12 months from transplantation (range: 10 – 84 months). The 7-year probability of developing this complication was 28%. Nine patients required surgery at a median of 8 Bone Marrow Transplantation

months from diagnosis (range: 10 days – 4 years). On multivariate analysis, factors associated with an increased risk of aseptic osteonecrosis were grade II–IV acute GvHD (RR: 2.91, 95% CI: 1.08–7.87, P ¼ 0.035), and a platelet count X20  109/l not reached by day 100 (RR: 5.00, 95% CI: 1.72–14.49, P ¼ 0.003).

Allogenic bone marrow transplantation for AML M Robin et al

1.0

0.8

0.8

0.6

0.6

LSBI

LSBI

883 1.0

0.4 0.2

0.2

0.0

0.0 0

2 4 6 Years post transplantation

1.0

1.0

0.8

0.8 LSBI

LSBI

0.4

0.6 0.4

0

2 4 6 Years post transplantation

0

2 4 6 Years post transplantation

0.6 0.4 0.2

0.2

0.0

0.0 0

2 4 6 Years post transplantation

Figure 3 (a) Incidence of late severe bacterial infection. A 7-year LSBI incidence was estimated at 35% (95% CI: 26–46%). (b) Impact of pretransplant Gram-negative bacterial infections on 7-years LSBI. Patients with history of pretransplant Gram-negative bacteriaemia had 7-year LSBI KM estimate of 70% (95% CI: 0–93%) vs 31% (95% CI: 18–42%), P ¼ 0.02. (c) Impact of total body irradiation on 7-year incidence of late severe bacterial infection. In all, 47 patients received a conditioning regimen including TBI and 50 patients received a conditioning regimen without TBI. A 7-years KM probability of LSBI was 52% (95% CI: 31–66%) for irradiated patients and 16% (95% CI: 4–26%) for nonirradiated patients, P ¼ 0.008. (d) Impact of GvHD on 7-year LSBI. Patients with extensive GvHD (N ¼ 27) had an estimated 7-year LSBI of 50% (95% CI: 12–70%) vs 30% (95% CI: 16–42%) for patients with limited GvHD or without GvHD P ¼ 0.14.

Cataracts were diagnosed in 18 cases at a median of 3 years post transplant (range: 13 months – 6 years), leading to a 7-year probability of 36%. Conditioning including single dose TBI was the only risk factor identified for this complication (Kaplan–Meier estimate: 73%, RR: 4.54, 95% CI: 1.72–12.00, P ¼ 0.002). In all, 14 patients, had thyroid insufficiency, of whom 12 had received a conditioning regimen including TBI. Nine out of 28 patients less than 16 years of age had growth retardation; four of them required growth hormone replacement. Growth retardation was only observed in children who were between 6 and 12 years of age at the time of SCT (Kaplan–Meier estimate: 57%), six of whom had been conditioned with TBI. No growth retardation was observed among children aged from 1 to 5 years at the time of SCT including one patient conditioned with TBI. In total, 16 children were assessable for puberty. Delayed puberty with gonadal insufficiency was observed in seven patients. Pulmonary restrictive syndromes were diagnosed in 11 patients. In addition, two patients had chronic bronchiolitis with interstitial and obstructive syndromes. Symptomatic cardiac failure requiring inotropic drugs and diuretics occurred in six patients. All these patients had received a cumulative dose of anthracycline below 300 mg/m2. Four patients developed second malignancies (glioblastoma, melanoma, breast cancer, and sinus cancer diagnosed 8, 4, 7, and 10 years after transplantation). These patients were 7, 12, 38, and 50 years old at SCT; all had received TBI during the conditioning regimen, but none had developed chronic GvHD. The woman who developed breast cancer also had severe dysplastic lesions of the cervix 6 months after SCT.

General health status and return to work or school Among 71 patients surviving more than a year following SCT, 75% had a good functional status (0-1 WHO scale). In total, 61% percent of the patients returned to work or school (children 90 vs 42% from adults, Po0.001). Of note, neuropsychological changes including overt depression requiring treatment were diagnosed in 14 patients.

Discussion We studied long-term morbidity and mortality in 97 consecutive recipients with AML in CR1 or CR2 with particular attention to pretransplant and post-transplant factors that could influence late morbidity. Among pretransplant parameters, prognostic factors such as age, hyperleukocytosis, disease status and cytogenetics at diagnosis29–33 had no significant impact on outcome in our series, as reported by others.34,35 The outcome of paediatric patients was not significantly better than that of adults although if they were less likely to develop GvHD. Similarly, no significant difference was observed between patients grafted in CR1, as compared to those grafted in CR2 for EFS, TRM, GvHD or late morbidity. However, the limited number of patients obviously precludes any definitive conclusions. Cytogenetics were assessable in only two thirds of patients. According to ongoing protocols, patients with favorable cytogenetics were first treated with chemotherapy only and were transplanted in CR2 if they relapsed. This therapeutic option thus leads to a statistical bias and can explain why cytogenetics data do not influence outcome in our study. Other Bone Marrow Transplantation

Allogenic bone marrow transplantation for AML M Robin et al

884

known cytogenetic classifications were no more relevant in our statistical models (data not shown) in showing any impact on outcome. Finally, when we analysed only patients in CR1, we failed to find any impact of cytogenetics on outcome but the small number of available karyotypes reduced the statistical power (data not shown). In our analysis, it appeared that the number of CT courses had a detrimental effect on both EFS and TRM. Intensive postremission therapy with intermediate or HiDAC has been proven to be better than conventional chemotherapy especially in young patients36 leading to an increased use of HiDAC. In two studies, the impact of HiDAC before transplant failed to result in any difference in patient outcome.37,38 In our study, long-term outcome of patients treated with HiDAC (mostly adults in CR2) was identical to that of those who did not receive HiDAC. In contrast, multiple chemotherapy courses seemed deleterious in our patients, as already suggested by others.39,40 However, there was a clear relation between the number of postremission CTs in CR1 patients and the interval between remission and SCT. Other authors have already described the favourable influence of early SCT on outcome of patients with AML.41 Chemotherapy-induced damage of epithelial cells triggering GvHD42,43 could be implicated in the deleterious impact of pretransplant chemotherapy courses. We analysed the pretransplant bacterial history and, in particular, gram-negative bacteriaemias which were most frequently nosocomial infections. Gram-negative bacteriaemia did not correlate with the number of postremission chemotherapy courses or pretransplant HiDAC, and was an independent risk factor for LSBI and EFS. These infections occurred mainly in patients in CR1 (88%). Total body irradiation was associated with the development of late complications including cataracts, avascular necrosis of bone, endocrine deficiencies and cancers as reported by others.44–47 Furthermore, in our series TBI was an independent risk factor for LSBI (RR: 3.45), confirming the results of a recent report.48 An intensified conditioning regimen which consisted of the combination of a standard conditioning regimen with another drug was used in 17 patients, of whom 11 were grafted in CR2. On multivariate analysis, intensified regimens had an impact on GvHD, TRM and EFS. Similarly, previous reports noted high rates of regimen-related toxicity in adult patients with advanced disease who received intensified conditioning.49,50 A randomised trial comparing the effectiveness of 12 with 15.75 Gy in patients with AML in CR1 concluded that the higher TBI dose resulted in a decreased relapse rate but in an increase in TRM, and therefore, had no positive impact on EFS.51 Major ABO incompatibility appeared as a risk factor for chronic GvHD and TRM on multivariate analysis. There is a relation between ABO incompatibility and the number of nucleated cells transplanted (poorer) as observed by others.52,53 Thus, necessary ex vivo manipulation of the graft impaired engraftment by decreasing the number of nucleated cells and by altering the composition of the graft.

Bone Marrow Transplantation

Time to reach platelets 420  109/l was a risk factor for chronic GvHD independent of acute GvHD indicating that delayed platelet reconstitution is predictive for subsequent chronic GvHD. Kinetics of engraftment measured by the time between 0.5  109/l and above 1.0  109/l ANC was an independent risk factor for EFS on multivariate analysis, including post-transplant and time-dependant covariates. Late complications were dominated by chronic GvHD and LSBI which occurred, respectively, in 40 and 36% of the patients. Both remained major risk factors for TRM. On multivariate analysis, risk factors for chronic GvHD were all related to pretransplant or early post-transplant factors, that is, number of postremission CTs, intensified regimens, major ABO incompatibility, engraftment and acute GvHD. Extensive chronic GvHD, a major risk factor for late infections,48,54 was a risk factor for LSBI on multivariate analysis, whereas limited GvHD was not. Steroid treatment is also a well-known risk factor for other infections such as invasive aspergillosis55–57 and for other complications including diabetes, growth hormone deficiency or cataract.58–61 Aspergillosis and CMV occurred in about 10% of the patients, thus precluding any meaningful analysis of risk factors. Delayed CMV infections were not explained by ganciclovir prophylaxis in our series in contrast to Nguyen,62 but most patients received high-dose intravenous acyclovir until engraftment which is reported to decrease CMV infection rate.63,64 Late onset of VZV infections were frequent but rarely disseminated as already reported65 and we observed low rates of VZV-related mortality in contrast to older series66–69 most probably linked to the success of systematic prophylaxis with acyclovir.65,70 Thyroid hormone insufficiency occurred in 14 patients. One-third of assessable children had delayed growth, half of whom had low growth hormone levels. This mainly concerned children between 6 and 12 years of age. Michel et al 58 have already reported a greater height loss in patients transplanted within puberty. The incidence of growth retardation reported here is in keeping with that reported in the literature where TBI was the major risk factor.44,61,71 Cardiac failure occurred in six patients including one very late case, 8 years after SCT. Although rarely reported after SCT this complication is increasingly described in long-term survivors of childhood cancers including leukaemia.58,72,73 Thus, the cumulative effects of pretransplant chemotherapy with post-transplant complications such as the X-syndrome74 may increase the risk of late vascular complications which should be amenable to early detection and even prevention. Four patients, all of whom had received irradiation with the conditioning regimen, developed solid tumours and two of them died from their tumour 4 and 10 years post-transplant. Since cancer incidence increases over time, high-risk situations must be recognised especially in children who are prone to second cancers.45,75 In conclusion, this retrospective analysis strongly suggests that pregraft factors such as chemotherapy, bacterial infections, conditioning regimen and graft characteristics have a major impact on late morbidity and mortality.

Allogenic bone marrow transplantation for AML M Robin et al

References 1 Zittoun RA, Mandelli F, Willemze R et al. Autologous or allogeneic bone marrow transplantation compared with intensive chemotherapy in acute myelogenous leukemia. European Organization for Research and Treatment of Cancer (EORTC) and the Gruppo Italiano Malattie Ematologiche Maligne dell’Adulto (GIMEMA) Leukemia Cooperative Groups. N Engl J Med 1995; 332: 217–223. 2 Harousseau JL, Cahn JY, Pignon B et al. Comparison of autologous bone marrow transplantation and intensive chemotherapy as postremission therapy in adult acute myeloid leukemia. The Groupe Ouest Est Leucemies Aigues Myeloblastiques (GOELAM). Blood 1997; 90: 2978–2986. 3 Burnett AK, Goldstone AH, Stevens RM et al. Randomised comparison of addition of autologous bone-marrow transplantation to intensive chemotherapy for acute myeloid leukaemia in first remission: results of MRC AML 10 trial. UK Medical Research Council Adult and Children’s Leukaemia Working Parties. Lancet 1998; 351: 700–708. 4 Ravindranath Y, Yeager AM, Chang MN et al. Autologous bone marrow transplantation versus intensive consolidation chemotherapy for acute myeloid leukemia in childhood. Pediatric Oncology Group. N Engl J Med 1996; 334: 1428–1434. 5 Amadori S, Testi AM, Arico M et al. Prospective comparative study of bone marrow transplantation and postremission chemotherapy for childhood acute myelogenous leukemia. The Associazione Italiana Ematologia ed Oncologia Pediatrica Cooperative Group. J Clin Oncol 1993; 11: 1046–1054. 6 Woods WG, Neudorf S, Gold S et al. A comparison of allogeneic bone marrow transplantation, autologous bone marrow transplantation, and aggressive chemotherapy in children with acute myeloid leukemia in remission: a report from the Children’s cancer group. Blood 2001; 97: 56–62. 7 Cassileth PA, Harrington DP, Appelbaum FR et al. Chemotherapy compared with autologous or allogeneic bone marrow transplantation in the management of acute myeloid leukemia in first remission [see comments]. N Engl J Med 1998; 339: 1649–1656. 8 Fenaux P, Chevret S, Guerci A et al. Long-term follow-up confirms the benefit of all-trans retinoic acid in acute promyelocytic leukemia. European APL group. Leukemia 2000; 14: 1371–1377. 9 Anderlini P, Ghaddar HM, Smith TL et al. Factors predicting complete remission and subsequent disease-free survival after a second course of induction therapy in patients with acute myelogenous leukemia resistant to the first. Leukemia 1996; 10: 964–996. 10 Kantarjian HM, Keating MJ, Walters RS et al. The characteristics and outcome of patients with late relapse acute myelogenous leukemia. J Clin Oncol 1988; 6: 232–238. 11 Gale RP, Horowitz MM, Weiner RS et al. Impact of cytogenetic abnormalities on outcome of bone marrow transplants in acute myelogenous leukemia in first remission. Bone Marrow Transplant 1995; 16: 203–208. 12 Creutzig U, Ritter J, Schellong G. Identification of two risk groups in childhood acute myelogenous leukemia after therapy intensification in study AML-BFM-83 as compared with study AML-BFM-78. AML-BFM Study Group. Blood 1990; 75: 1932–1940. 13 Michel G, Leverger G, Leblanc T et al. Allogeneic bone marrow transplantation vs aggressive post-remission chemotherapy for children with acute myeloid leukemia in first complete remission. A prospective study from the French Society of Pediatric Hematology and Immunology (SHIP). Bone Marrow Transplant 1996; 17: 191–196.

885 14 Frassoni F, Labopin M, Gluckman E et al. Results of allogeneic bone marrow transplantation for acute leukemia have improved in Europe with time—a report of the acute leukemia working party of the European group for blood and marrow transplantation (EBMT). Bone Marrow Transplant 1996; 17: 13–18. 15 Bortin MM, Horowitz MM, Gale RP et al. Changing trends in allogeneic bone marrow transplantation for leukemia in the 1980s. JAMA 1992; 268: 607–612. 16 Sullivan KM, Agura E, Anasetti C et al. Chronic graft-versushost disease and other late complications of bone marrow transplantation. Semin Hematol 1991; 28: 250–259. 17 Tabbara IA. Allogeneic bone marrow transplantation: acute and late complications. Anticancer Res 1996; 16: 1019–1026. 18 Deeg HJ. Early and late complications of bone marrow transplantation. Curr Opin Oncol 1990; 2: 297–307. 19 Socie G, Stone JV, Wingard JR et al. Long-term survival and late deaths after allogeneic bone marrow transplantation. Late Effects Working Committee of the International Bone Marrow Transplant Registry. N Engl J Med 1999; 341: 14–21. 20 Castaigne S, Chevret S, Lepage E et al. Prognostic factors of acute non lymphoblastic leukemia in children and adults. Results from two multicentric trials (705 patients). Nouv Rev Fr Hematol 1990; 32: 297–300. 21 Castaigne S, Archimbaud E, Fenaux P et al. Role of double induction in the treatment of acute myeloblastic leukemia in the adult: intermediate results of protocol LAM90. Nouv Rev Fr Hematol 1994; 36: S139–S140. 22 Michel G, Baruchel A, Tabone MD et al. Induction chemotherapy followed by allogeneic bone marrow transplantation or aggressive consolidation chemotherapy in childhood acute myeloblastic leukemia. A prospective study from the French Society of Pediatric Hematology and Immunology (SHIP). Hematol Cell Ther 1996; 38: 169–176. 23 Storb R, Deeg HJ, Pepe M et al. Graft-versus-host disease prevention by methotrexate combined with cyclosporin compared to methotrexate alone in patients given marrow grafts for severe aplastic anaemia: long-term follow-up of a controlled trial [see comments]. Br J Haematol 1989; 72: 567–572. 24 Storb R, Deeg HJ, Pepe M et al. Methotrexate and cyclosporine versus cyclosporine alone for prophylaxis of graft-versus-host disease in patients given HLA-identical marrow grafts for leukemia: long-term follow-up of a controlled trial. Blood 1989; 73: 1729–1734. 25 Shulman HM, Sullivan KM, Weiden PL et al. Chronic graftversus-host syndrome in man. A long-term clinicopathologic study of 20 Seattle patients. Am J Med 1980; 69: 204–217. 26 Glucksberg H, Storb R, Fefer A et al. Clinical manifestations of graft-versus-host disease in human recipients of marrow from HL-A-matched sibling donors. Transplantation 1974; 18: 295–304. 27 Boeckh M, Gooley TA, Myerson D et al. Cytomegalovirus pp65 antigenemia-guided early treatment with ganciclovir versus ganciclovir at engraftment after allogeneic marrow transplantation: a randomized double-blind study. Blood 1996; 88: 4063–4071. 28 Meyers JD, Flournoy N, Thomas ED. Risk factors for cytomegalovirus infection after human marrow transplantation. J Infect Dis 1986; 153: 478–488. 29 Clift RA, Buckner CD, Thomas ED et al. The treatment of acute non-lymphoblastic leukemia by allogeneic marrow transplantation. Bone Marrow Transplant 1987; 2: 243–258. 30 Ferrant A, Labopin M, Frassoni F et al. Karyotype in acute myeloblastic leukemia: prognostic significance for bone marrow transplantation in first remission: a European Group for Blood and Marrow Transplantation study. Acute Leukemia Bone Marrow Transplantation

Allogenic bone marrow transplantation for AML M Robin et al

886 31

32

33

34

35

36

37

38

39

40

41

42

43 44 45

46

47

Working Party of the European Group for Blood and Marrow Transplantation (EBMT). Blood 1997; 90: 2931–2938. Woods WG, Kobrinsky N, Buckley J et al. Intensively timed induction therapy followed by autologous or allogeneic bone marrow transplantation for children with acute myeloid leukemia or myelodysplastic syndrome: a Childrens Cancer Group pilot study. J Clin Oncol 1993; 11: 1448–1457. Keating MJ, Smith TL, Kantarjian H et al. Cytogenetic pattern in acute myelogenous leukemia: a major reproducible determinant of outcome. Leukemia 1988; 2: 403–412. McGlave PB, Haake RJ, Bostrom BC et al. Allogeneic bone marrow transplantation for acute nonlymphocytic leukemia in first remission. Blood 1988; 72: 1512–1517. Keating S, Suciu S, de Witte T et al. Prognostic factors of patients with acute myeloid leukemia (AML) allografted in first complete remission: an analysis of the EORTC- GIMEMA AML 8A trial. The European Organization for Research and Treatment of Cancer (EORTC) and the Gruppo Italiano Malattie Ematologiche Maligne dell’ Adulto (GIMEMA) Leukemia Cooperative Groups. Bone Marrow Transplant 1996; 17: 993–1001. Tallman MS, Kopecky KJ, Amos D et al. Analysis of prognostic factors for the outcome of marrow transplantation or further chemotherapy for patients with acute nonlymphocytic leukemia in first remission. J Clin Oncol 1989; 7: 326–337. Mayer RJ, Davis RB, Schiffer CA et al. Intensive postremission chemotherapy in adults with acute myeloid leukemia. Cancer and Leukemia Group B [see comments]. N Engl J Med 1994; 331: 896–903. Tallman MS, Rowlings PA, Milone G et al. Effect of postremission chemotherapy before human leukocyte antigenidentical sibling transplantation for acute myelogenous leukemia in first complete remission. Blood 2000; 96: 1254–1258. Cahn JY, Labopin M, Sierra J et al. No impact of high-dose cytarabine on the outcome of patients transplanted for acute myeloblastic leukaemia in first remission. Acute Leukaemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT). Br J Haematol 2000; 110: 308–314. Fopp M, Fey MF, Bacchi M et al. Post-remission therapy of adult acute myeloid leukaemia: one cycle of high-dose versus standard-dose cytarabine. Leukaemia Project Group of the Swiss Group for Clinical Cancer Research (SAKK). Ann Oncol 1997; 8: 251–257. Cassileth PA, Lynch E, Hines JD et al. Varying intensity of postremission therapy in acute myeloid leukemia. Blood 1992; 79: 1924–1930. Jourdan E, Maraninchi D, Reiffers J et al. Early allogeneic transplantation favorably influences the outcome of adult patients suffering from acute myeloid leukemia. Societe Francaise de Greffe de Moelle (SFGM). Bone Marrow Transplant 1997; 19: 875–881. Hill GR, Krenger W, Ferrara JL. The role of cytokines in acute graft-versus-host disease. Cytokines Cell Mol Ther 1997; 3: 257–266. Krenger W, Hill GR, Ferrara JL. Cytokine cascades in acute graft-versus-host disease. Transplantation 1997; 64: 553–558. Sanders JE. Bone marrow transplantation for pediatric leukemia. Pediatr Ann 1991; 20: 671–676. Curtis RE, Rowlings PA, Deeg HJ et al. Solid cancers after bone marrow transplantation [see comments]. N Engl J Med 1997; 336: 897–904. Deeg HJ, Leisenring W, Storb R et al. Long-term outcome after marrow transplantation for severe aplastic anemia. Blood 1998; 91: 3637–3645. Bhatia S, Ramsay NK, Steinbuch M et al. Malignant neoplasms following bone marrow transplantation. Blood 1996; 87: 3633–3639.

Bone Marrow Transplantation

48 Kulkarni S, Powles R, Treleaven J et al. Chronic graft versus host disease is associated with long-term risk for pneumococcal infections in recipients of bone marrow transplants. Blood 2000; 95: 3683–3686. 49 Giralt SA, LeMaistre CF, Vriesendorp HM et al. Etoposide, cyclophosphamide, total-body irradiation, and allogeneic bone marrow transplantation for hematologic malignancies. J Clin Oncol 1994; 12: 1923–1930. 50 Yau JC, LeMaistre CF, Andersson BS et al. Allogeneic bone marrow transplantation for hematological malignancies following etoposide, cyclophosphamide, and fractionated total body irradiation. Am J Hematol 1992; 41: 40–44. 51 Clift RA, Buckner CD, Appelbaum FR et al. Allogeneic marrow transplantation in patients with acute myeloid leukemia in first remission: a randomized trial of two irradiation regimens. Blood 1990; 76: 1867–1871. 52 Bacigalupo A, Van Lint MT, Occhini D et al. ABO compatibility and acute graft-versus-host disease following allogeneic bone marrow transplantation. Transplantation 1988; 45: 1091–1094. 53 Mehta J, Powles R, Treleaven J et al. Long-term follow-up of patients undergoing allogeneic bone marrow transplantation for acute myeloid leukemia in first complete remission after cyclophosphamide-total body irradiation and cyclosporine. Bone Marrow Transplant 1996; 18: 741–746. 54 Winston DJ, Ho WG, Champlin RE. Current approaches to management of infections in bone marrow transplants. Eur J Cancer Clin Oncol 19892; 5 (Suppl. 2): S25–S35. 55 Wald A, Leisenring W, van Burik JA, Bowden RA. Epidemiology of Aspergillus infections in a large cohort of patients undergoing bone marrow transplantation [see comments]. J Infect Dis 1997; 175: 1459–1466. 56 McWhinney PH, Kibbler CC, Hamon MD et al. Progress in the diagnosis and management of aspergillosis in bone marrow transplantation: 13 years’ experience. Clin Infect Dis 1993; 17: 397–404. 57 Wingard JR, Beals SU, Santos GW et al. Aspergillus infections in bone marrow transplant recipients. Bone Marrow Transplant 1987; 2: 175–181. 58 Michel G, Socie G, Gebhard F et al. Late effects of allogeneic bone marrow transplantation for children with acute myeloblastic leukemia in first complete remission: the impact of conditioning regimen without total-body irradiation—a report from the Societe Francaise de Greffe de Moelle. J Clin Oncol 1997; 15: 2238–2246. 59 Sanders JE, Pritchard S, Mahoney P et al. Growth and development following marrow transplantation for leukemia. Blood 1986; 68: 1129–1135. 60 Cohen A, Duell T, Socie G et al. Nutritional status and growth after bone marrow transplantation (BMT) during childhood: EBMT Late-Effects Working Party retrospective data. European Group for Blood and Marrow Transplantation. Bone Marrow Transplant 1999; 23: 1043–1047. 61 Cohen A, Rovelli A, Bakker B et al. Final height of patients who underwent bone marrow transplantation for hematological disorders during childhood: a study by the Working Party for Late Effects-EBMT. Blood 1999; 93: 4109–4115. 62 Nguyen Q, Champlin R, Giralt S et al. Late cytomegalovirus pneumonia in adult allogeneic blood and marrow transplant recipients. Clin Infect Dis 1999; 28: 618–623. 63 Prentice HG, Gluckman E, Powles RL et al. Impact of longterm acyclovir on cytomegalovirus infection and survival after allogeneic bone marrow transplantation. European Acyclovir for CMV Prophylaxis Study Group. Lancet 1994; 343: 749–753. 64 Prentice HG, Gluckman E, Powles RL et al. Long-term survival in allogeneic bone marrow transplant recipients

Allogenic bone marrow transplantation for AML M Robin et al

887

65

66

67

68

69

following acyclovir prophylaxis for CMV infection. The European Acyclovir for CMV Prophylaxis Study Group. Bone Marrow Transplant 1997; 19: 129–133. Steer CB, Szer J, Sasadeusz J et al. Varicella-zoster infection after allogeneic bone marrow transplantation: incidence, risk factors and prevention with low-dose aciclovir and ganciclovir. Bone Marrow Transplant 2000; 25: 657–664. Han CS, Miller W, Haake R, Weisdorf D. Varicella zoster infection after bone marrow transplantation: incidence, risk factors and complications. Bone Marrow Transplant 1994; 13: 277–283. Atkinson K, Meyers JD, Storb R et al. Varicella-zoster virus infection after marrow transplantation for aplastic anemia or leukemia. Transplantation 1980; 29: 47–50. Locksley RM, Flournoy N, Sullivan KM, Meyers JD. Infection with varicella-zoster virus after marrow transplantation. J Infect Dis 1985; 152: 1172–1181. Deeg HJ, Storb R, Thomas ED. Bone marrow transplantation: a review of delayed complications. Br J Haematol 1984; 57: 185–208.

70 Selby PJ, Powles RL, Easton D et al. The prophylactic role of intravenous and long-term oral acyclovir after allogeneic bone marrow transplantation. Br J Cancer 1989; 59: 434–438. 71 Huma Z, Boulad F, Black P et al. Growth in children after bone marrow transplantation for acute leukemia. Blood 1995; 86: 819–824. 72 Uderzo C, Biagi E, Rovelli A et al. Bone marrow transplantation for childhood hematological disorders: a global pediatric approach in a twelve year single center experience. Pediatr Med Chir 2000; 21: 157–163. 73 Leahey AM, Teunissen H, Friedman DL et al. Late effects of chemotherapy compared to bone marrow transplantation in the treatment of pediatric acute myeloid leukemia and myelodysplasia. Med Pediatr Oncol 1999; 32: 163–169. 74 Socie G. Is syndrome ‘X’ another late complication of bone-marrow transplantation?. Lancet 2000; 356: 957–958. 75 Socie G, Curtis RE, Deeg HJ et al. New malignant diseases after allogeneic marrow transplantation for childhood acute leukemia. J Clin Oncol 2000; 18: 348–357.

Bone Marrow Transplantation