In the early 1990s, 4 randomized studies compared conditioning regimens before transplantation for leukemia with either cyclophosphamide (CY) and total-body irradiation (TBI), or busulfan (Bu) and CY. This study analyzed the long-term outcomes for 316 patients with chronic myeloid leukemia (CML) and 172 patients with acute myeloid leukemia (AML) who participated in these 4 trials, now with a mean follow-up of more than 7 years. Among patients with CML, no statistically significant difference in survival or disease-free survival emerged from testing the 2 regimens. The projected 10-year survival estimates were 65% and 63% with Bu-CY versus CY-TBI, respectively. Among patients with AML, the projected 10-year survival estimates were 51% and 63% (95% CI, 52%-74%) with Bu-CY versus CY-TBI, respectively. At last follow-up, most surviving patients had unimpaired health and had returned to work, regardless of the conditioning regimen. Late complications were analyzed after adjustment for patient age and for acute and chronic graft-versus-host disease (GVHD). CML patients who received CY-TBI had an increased risk of cataract formation, and patients treated with Bu-CY had an increased risk of irreversible alopecia. Chronic GVHD was the primary risk factor for late pulmonary disease and avascular osteonecrosis. Thus, Bu-CY and CY-TBI provided similar probabilities of cure for patients with CML. In patients with AML, a nonsignificant 10% lower survival rate was observed after Bu-CY. Late complications occurred equally after both conditioning regimens (except for increased risk of cataract after CY-TBI and of alopecia with Bu-CY).

Since the 1970s, allogeneic stem cell transplantation after high-dose cyclophosphamide (CY) and total-body irradiation (TBI) has been used successfully to treat myeloid leukemia.1 Bone marrow transplantation (BMT) may fail because of relapse, graft failure, or transplantation-related complications. Studies of a busulfan (Bu) and CY regimen in the early 1980s2 were motivated by a desire to reduce toxicity and improve the probability of long-term remission.3-6Controversy concerning the optimal pretransplantation regimen for patients with myeloid malignancies still persists.

During the early 1990s, 4 randomized studies were carried out to address this controversy. For patients with acute myeloid leukemia (AML) in first remission, a French study compared these 2 regimens and found increased disease-free survival (DFS) and overall survival, and decreased relapse and transplantation-related mortality with CY-TBI.7 A second study from the Nordic group in patients with AML, chronic myelogenous leukemia (CML), or lymphoid malignancies, at different stages of the disease, also found better DFS and less toxicity with CY-TBI compared to Bu-CY,8 in patients with advanced diseases. In contrast, the Seattle group9 and a French multicenter trial10 found that outcome with the Bu-CY regimen was equivalent to CY-TBI with seemingly less early toxicity with Bu-CY for patients with CML. A meta-analysis of these 4 trials (and one other trial comparing Bu-CY with TBI-etoposide), examined 6 end points: survival, DFS, veno-occlusive disease, acute and chronic graft-versus-host disease (GVHD), and interstitial pneumonitis.11 Trends suggested that survival and DFS were better with TBI-based regimens than with Bu-CY, but the differences were not statistically significant. In that study, a power analysis suggested that Bu-CY was not likely to have a clinically relevant survival advantage, but the analysis could not exclude the possibility that such an advantage might exist for the TBI-based regimen.

The 4 studies comparing CT-TBI with Bu-CY were reported with follow-up ranging from 24 to 42 months.7-10 In light of the above-mentioned uncertainties, we decided to examine and update the long-term follow-up of these randomized trials. Patients with acute lymphoblastic leukemia or lymphoma (n = 42) included in the Nordic trial were excluded and only patients with AML and CML were studied. Our aims were to: (1) compare long-term survival, relapse, return to work/school, and general health status according to the conditioning regimens; and (2) estimate incidence rates and risk factors of late complications. This study included 316 patients with CML and 172 patients with AML. The mean follow-up for surviving patients is now more than 7 years after BMT.

Patients

Patients with lymphoid malignancies (acute lymphoblastic leukemia and lymphoma) were excluded for 2 reasons. First, only the trial from the Nordic group included these diagnoses. Second, a retrospective study from the International Bone Marrow Transplant Registry (IBMTR)12 and the recent update from the randomized Nordic study strongly suggest that Bu-CY conditioning is inferior in patients with lymphoid malignancies.13 

In the original trials 494 patients with myeloid malignancies were enrolled, and we were able to analyze the data for 488 patients (97.8% of the patients). The remaining 6 (2.2%) patients were enrolled in centers that declined to participate in this study. All patients received 120 mg/kg CY (60 mg/kg, on each of 2 consecutive days). For patients randomized in the Bu-CY regimen, 16 mg/kg Bu (1 mg/kg per dose orally every 6 hours over 4 consecutive days) was administered. TBI regimens varied in the different trials. In the Seattle study, all patients received 12 Gy TBI in a fractionated regimen. In the 2 French trials, most individuals (42 of 55 and 43 of 50 patients with CML and AML, respectively) were given TBI in a fractionated regimen for a mean total dose of 12 Gy. In the Nordic study, approximately two thirds of the TBI patients received fractionated irradiation.

The combination of cyclosporine and short-course methotrexate was used for prevention of GVHD disease in all 4 trials.14 In addition, 17 patients with CML and 16 patients with AML received an anti–interleukin-2 receptor (p55) antibody.15 

Details of the original trials have been previously published: 2 trials enrolled patients with CML only, one with AML only, and one with both diseases (Table 1). Three of the 4 trials enrolled only patients with early-stage diseases (ie, AML in first complete remission or CML in first chronic phase).

Table 1.

Patient and disease characteristics in 4 randomized trials

DiseaseStageNo. of patients (original report)No. of patients with long-term follow-up (%)Median age at transplant, yFollow-up (original report, in mo)
Blaise et al AML First CR 101 100 32 23 ± 11  
Clift et al CML CP 147 96.5 37 Minimum 12  
Devergie et al CML CP 120 98.3 36 42  
Ringden et al CML/AML CP/CR1 46/51 98.4 33 1-50 
 CML/AML Advanced 11/19    
DiseaseStageNo. of patients (original report)No. of patients with long-term follow-up (%)Median age at transplant, yFollow-up (original report, in mo)
Blaise et al AML First CR 101 100 32 23 ± 11  
Clift et al CML CP 147 96.5 37 Minimum 12  
Devergie et al CML CP 120 98.3 36 42  
Ringden et al CML/AML CP/CR1 46/51 98.4 33 1-50 
 CML/AML Advanced 11/19    

CR indicates complete remission; CP, chronic phase.

Sex distribution was almost identical in the 4 trials (ratio of men to women close to 60%). The cohort showed no difference in patient selection or interval from diagnosis to transplantation in CML patients, or time from first complete remission to transplantation in patients with AML. In these early AML trials, no cytogenetic data were available, but the distribution of AML subtypes according to the French-American-British (FAB) classification did not differ according to the conditioning regimens. Details concerning patients enrolled in this study are summarized in Table 2.

Table 2.

Transplantation characteristics in the 4 randomized trials

AML (n = 172)
Bu-CY/CY-TBI
CML (n = 316) Bu-CY/CY-TBITotal (n = 488)
Trial    
 FHCRC — 73/69 142 
 SFGM-TC 55/49 65/53 222 
 Nordic group 37/31 30/26 124  
Age at transplantation, y (range) 35 (2.5-42)/33 (26.5-39.5) 38 (31-44)/36 (29-41) — 
GVHD prophylaxis MTX + CSA MTX + CSA 100%  
+ Anti–IL-2R 9:55/8:49 7:65/8:53 32:222 (14.4%) 
AML (n = 172)
Bu-CY/CY-TBI
CML (n = 316) Bu-CY/CY-TBITotal (n = 488)
Trial    
 FHCRC — 73/69 142 
 SFGM-TC 55/49 65/53 222 
 Nordic group 37/31 30/26 124  
Age at transplantation, y (range) 35 (2.5-42)/33 (26.5-39.5) 38 (31-44)/36 (29-41) — 
GVHD prophylaxis MTX + CSA MTX + CSA 100%  
+ Anti–IL-2R 9:55/8:49 7:65/8:53 32:222 (14.4%) 

IL-2R indicates interleukin-2 receptor; SFGM-TC, Société Française de Greffe de Moelle et de Therapie Cellulaire; MTX, methotrexate; CSA, cyclosporine.

Methods

Updated survival and DFS as well as occurrence of late complications were obtained through a questionnaire sent to each French and Nordic center. Updates from the Fred Hutchinson Cancer Research Center (FHCRC) were obtained through the database of the long-term follow-up program, as previously reported.16 Specific requests included the occurrence, and date if any, of cataract, thyroid abnormalities, persistent alopecia (either partial or total), avascular osteonecrosis, pulmonary diseases (including obstructive bronchiolitis), secondary malignancies, return to work or school, and functional status at last follow-up (as assessed by the World Health Organization [WHO] score). Additional data included demographic and posttransplantation information (including data on acute and chronic GVHD).

We encountered no difficulty in the definition of relapse for patients with AML. On the other hand, we found considerable difficulty in defining relapse for patients with CML, where hematologic, cytogenetic, or molecular criteria could be used.17 18 Furthermore, transient cytogenetic relapse has also been described after transplantation for CML. Differences in the definition of CML relapse could not be reconciled in this multi-institutional retrospective study. We therefore decided to take into account hematologic or cytogenetic relapses in CML as a binary variable (yes/no) according to referring center reports.

Because the development of any late complication clearly depends on the frequency and methods used in searching such late complications, adjustments were made by stratifying by trial in the final models. Statistical analysis was performed separately in each diagnosis group (AML, CML). Times to occurrence of relapse, death, cataract, hypothyroidism or hyperthyroidism, persistent alopecia, avascular osteonecrosis, or late pulmonary diseases were estimated using the Kaplan-Meier method.19 Multivariable Cox models, stratified on the original trial, were fit to evaluate the influence of conditioning regimen, adjusted for patient-, disease-, and transplantation-related variables.20 For categorical variables, a dummy variable for each but one category was created, taking on the value of 1 for patients in that category and 0 otherwise. The proportionality of hazards was tested by using time-varying coefficients. Estimated hazard ratios (HRs) with a 95% confidence interval (95% CI) were computed.

Finally, we evaluated the influence of conditioning regimen, adjusted for patient-, disease-, and transplantation-related variables (including chronic GVHD), with hair loss using multivariable (logistic) regression models. Estimated odds ratios (ORs) with 95% CI were given. All P values were 2-sided, with values of .05 or less indicating statistical significance. No correction was made for multiple comparisons. Statistical analysis used the SAS (SAS, Cary, NC) and S-Plus Software.

In patients with CML, no statistically significant differences in survival or DFS were detected between the use of Bu-CY versus CY-TBI before transplantation (Figure 1). The projected 10-year survival estimates were 65% (95% CI, 57%-74%) and 63% (95% CI, 54%-73%) with Bu-CY and CY-TBI, respectively. The corresponding estimates of DFS were 52% (95% CI, 43%-61%) and 46% (95% CI, 36%-56%) with Bu-CY and CY-TBI, respectively.

Fig. 1.

Survival and DFS of patients with CML receiving either Bu or TBI associated with CY as conditioning regimen before transplantation.

Fig. 1.

Survival and DFS of patients with CML receiving either Bu or TBI associated with CY as conditioning regimen before transplantation.

Close modal

In patients with AML, no statistically significant differences in survival or DFS were detected between the use of Bu-CY versus CY-TBI before transplantation (Figure 2). The projected 10-year survival estimates were 51% (95% CI, 41%-62%) and 63% (95% CI, 52%-74%) with Bu-CY and CY-TBI, respectively. The corresponding DFS estimates were 47% (95% CI, 36%-58%) and 57% (95% CI, 44%-70%) with Bu-CY versus CY-TBI, respectively. DFS rates were similar when the analysis was limited to patients with AML in first complete remission or CML patients in first chronic phase who did not receive the 33B3-1 antibody (data not shown).

Fig. 2.

Survival and DFS of patients with AML receiving either Bu or TBI associated with CY as conditioning regimen before transplantation.

Fig. 2.

Survival and DFS of patients with AML receiving either Bu or TBI associated with CY as conditioning regimen before transplantation.

Close modal

The 5-year cumulative incidence of clinical extensive chronic GVHD reached 20% and 19% among patients with AML, and in 37% and 39% among patients with CML, with Bu-CY versus CY-TBI, respectively.

The general health status was estimated through the WHO scale. Data concerning AML patients were available for only half the patients and were therefore not analyzed. In patients with CML, data on health status at last follow-up were available for more than 75% of the patients. More than 90% of these patients had normal health status or minimal impairment (WHO score 0 and 1), as assessed by their referring physician, without significant differences according to the conditioning regimen (P = .32; Table3).

Table 3.

Health, functional status, and return to work/school in the 4 randomized trials

AML Bu-CY/CY-TBICML Bu-CY/CY-TBI
WHO score: number of patients alive at last follow-up: N (%) 48 (52)/51 (64) 114 (68)/103 (69) 
WHO score: 0-1 number available (%) — 83:87 (95.4)/68:72 (94.4)  
Work: number available (not available for the FHCRC) 33/34 43/44  
Return to work/school: Yes;no (%) 29;33 (88)/34;40 (85) 31;43 (72)/36;44 (81) 
AML Bu-CY/CY-TBICML Bu-CY/CY-TBI
WHO score: number of patients alive at last follow-up: N (%) 48 (52)/51 (64) 114 (68)/103 (69) 
WHO score: 0-1 number available (%) — 83:87 (95.4)/68:72 (94.4)  
Work: number available (not available for the FHCRC) 33/34 43/44  
Return to work/school: Yes;no (%) 29;33 (88)/34;40 (85) 31;43 (72)/36;44 (81) 

Data concerning return to work were not recorded in the FHCRC data set. In the European studies, between 72% and 88% of the patients returned to school or work at date of last contact, without significant differences according to the conditioning regimen or according to the initial diagnosis (Table 3).

We analyzed the incidence of late complications in AML and CML patients with and without adjustment for age, acute GVHD, and chronic GVHD (Table 4). The 7-year cumulative incidence of cataracts reached 12.3% and 12.4% among patients with AML (P = .82), and 16% and 47% (P = .0003) among CML patients who received Bu-CY versus CY-TBI, respectively. After adjustment for patient age and for acute and chronic GVHD, the association between CY-TBI and cataracts among patients with CML remained statistically significant (HR = 2.3; 95% CI, 1.3-4.0;P = .004). The risk of cataracts was also associated with chronic GVHD (HR = 3.0; 95% CI, 1.6-5.4; P = .0003).

Table 4.

Estimation of conditioning effect in each diagnostic group on each end point

End pointAML (n = 172)
(95% CI; P)
CML (n = 316)
(95% CI; P)
Cataract 11 events 66 events  
 BUCY vs CY-TBI 1.05 (0.32-3.44; .94) 2.67 (1.56-4.57; .0003
 Multivariable model   
  BUCY vs CY-TBI 1.05 (0.31-3.57; .94) 2.32 (1.32-4.07; .0035
  Acute GVHD 1.05 (0.30-3.69; .94) 1.37 (0.76-2.48; .30) 
  Chronic GVHD 0.27 (0.03-2.39; .24) 2.99 (1.64-5.44; .0003
  Age 1.02 (0.96-1.08; .51) 0.998 (0.975-1.023; .89) 
Pulmonary complications 9 events 46 events 
 BUCY vs CY-TBI 0.75 (0.20-2.80; .67) 0.80 (0.44-1.48; .48) 
 Multivariable model   
  BUCY vs CY-TBI 0.55 (0.14-2.11; .38) 0.70 (0.36-1.33; .27) 
  Acute GVHD 4.46 (0.85-23.5; .078) 1.32 (0.68-2.56; .41) 
  Chronic GVHD 1.60 (0.30-8.48; .58) 2.62 (1.31-5.27; .0067
  Age 0.995 (0.941-1.052; .86) 0.988 (0.958-1.019; .45
Avascular osteonecrosis 10 events 19 events 
 BUCY vs CY-TBI 1.04 (0.30-3.62; .95) 3.09 (1.11-8.57; .0307
 Multivariable model   
  BUCY vs CY-TBI 1.04 (0.30-3.64; .95) 2.52 (0.86-7.43; .094) 
  Acute GVHD 0.79 (0.21-3.03; .73) 1.33 (0.44-4.01; .61) 
  Chronic GVHD 3.18 (0.60-16.9; .17) 7.01 (1.85-26.5; .0041
  Age 0.972 (0.917-1.030; .34) 0.925 (0.880-0.972; .0021
Hair loss 58 events/86 66 events/98 
 BUCY vs CY-TBI 0.30 (0.12-0.80; .0160.61 (0.26-1.43; .25) 
 Multivariable model   
  BUCY vs CY-TBI 0.19 (0.06-0.58; .00350.79 (0.32-1.95; .61) 
  Acute GVHD 2.53 (0.81-7.91; .11) 1.08 (0.43-2.70; .87) 
  Chronic GVHD 2.74 (0.50-15.0; .25) 3.26 (1.11-9.59; .032
  Age 1.046 (1.001-1.094; .0461.027 (0.972-1.077; .37) 
End pointAML (n = 172)
(95% CI; P)
CML (n = 316)
(95% CI; P)
Cataract 11 events 66 events  
 BUCY vs CY-TBI 1.05 (0.32-3.44; .94) 2.67 (1.56-4.57; .0003
 Multivariable model   
  BUCY vs CY-TBI 1.05 (0.31-3.57; .94) 2.32 (1.32-4.07; .0035
  Acute GVHD 1.05 (0.30-3.69; .94) 1.37 (0.76-2.48; .30) 
  Chronic GVHD 0.27 (0.03-2.39; .24) 2.99 (1.64-5.44; .0003
  Age 1.02 (0.96-1.08; .51) 0.998 (0.975-1.023; .89) 
Pulmonary complications 9 events 46 events 
 BUCY vs CY-TBI 0.75 (0.20-2.80; .67) 0.80 (0.44-1.48; .48) 
 Multivariable model   
  BUCY vs CY-TBI 0.55 (0.14-2.11; .38) 0.70 (0.36-1.33; .27) 
  Acute GVHD 4.46 (0.85-23.5; .078) 1.32 (0.68-2.56; .41) 
  Chronic GVHD 1.60 (0.30-8.48; .58) 2.62 (1.31-5.27; .0067
  Age 0.995 (0.941-1.052; .86) 0.988 (0.958-1.019; .45
Avascular osteonecrosis 10 events 19 events 
 BUCY vs CY-TBI 1.04 (0.30-3.62; .95) 3.09 (1.11-8.57; .0307
 Multivariable model   
  BUCY vs CY-TBI 1.04 (0.30-3.64; .95) 2.52 (0.86-7.43; .094) 
  Acute GVHD 0.79 (0.21-3.03; .73) 1.33 (0.44-4.01; .61) 
  Chronic GVHD 3.18 (0.60-16.9; .17) 7.01 (1.85-26.5; .0041
  Age 0.972 (0.917-1.030; .34) 0.925 (0.880-0.972; .0021
Hair loss 58 events/86 66 events/98 
 BUCY vs CY-TBI 0.30 (0.12-0.80; .0160.61 (0.26-1.43; .25) 
 Multivariable model   
  BUCY vs CY-TBI 0.19 (0.06-0.58; .00350.79 (0.32-1.95; .61) 
  Acute GVHD 2.53 (0.81-7.91; .11) 1.08 (0.43-2.70; .87) 
  Chronic GVHD 2.74 (0.50-15.0; .25) 3.26 (1.11-9.59; .032
  Age 1.046 (1.001-1.094; .0461.027 (0.972-1.077; .37) 

Results show estimation of conditioning effect in each diagnostic group on each end point either unadjusted or adjusted on baseline covariates, stratified on trial, using Cox models with estimated HR (for cataracts, pulmonary complications, and avascular osteonecrosis) or logistic models with estimated OR (for hair loss). SignificantP values are in bold.

The 7-year cumulative incidence of late pulmonary disease was 6% among patients with AML and 15% among patients with CML, with no differences according to the conditioning regimen. Chronic GVHD was associated with pulmonary complications among patients with CML (HR = 2.6; 95% CI, 1.3-5.2; P = .007).

The 7-year cumulative incidence of avascular osteonecrosis was 6% and 7% among patients with AML (P = .95), and 3% and 10% among patients with CML (P = .03) who received Bu-CY versus CY-TBI, respectively. In multivariable analysis, the association between CY-TBI and osteonecrosis among patients with CML was not statistically significant (HR = 2.5; 95% CI, 0.8-7.4;P = .09). The risk of osteonecrosis was increased among patients with chronic GVHD (HR = 7.0; 95% CI, 1.8-26.5;P = .004) and decreased among older patients (HR = 0.93; 95% CI, 0.8-0.9; P = .002).

Hypothyroidism was reported in only 6 patients, and hyperthyroidism was reported in only 1 patient. No further analysis was done because the number of patients was too small.

Persistent impairment with hair regrowth was assessed in 194 patients (data not available from the FHCRC), representing 72% and 55% of the patients receiving Bu-CY and CY-TBI, respectively. The risk of alopecia was decreased in the CY-TBI group among patients with AML (OR = 0.3; 95% CI, 0.1-0.8; P = .02), but differences were not statistically significant among patients with CML (P = .25). The protective effect of CY-TBI remained statistically significant in the AML group after adjustment for age and for acute and chronic GVHD (HR = 0.19; 95% CI, 0.06-0.6;P = .004). The risk of persistent alopecia was increased among older patients with AML (OR = 1.04; 95% CI, 1.001-1.01;P = .05). In CML patients, chronic GVHD was associated with persistent alopecia (OR = 3.3; 95% CI, 1.1-9.6;P = .03).

Secondary solid malignancies were reported in 5 patients (epidermoid carcinoma, n = 2; gastric carcinoma, n = 1; malignant melanoma, n = 1; and adenocarcinoma of unknown primary site, n = 1). Three cases occurred among patients who received CY-TBI, and 2 occurred among patients who received Bu-CY.

No statistically significant differences were detected in the causes of death among patients who survived more than 2 years without relapse (data not shown).

Although the CY-TBI and Bu-CY regimens were introduced in the early 1980s as conditioning regimens before transplantation, it was only 10 years later that results of 4 randomized studies comparing both regimens were published.7-10 When reported, these studies had relatively short follow-up and even today, 20 years later, it was not clear if these 2 regimens could be used with similar efficacy in controlling leukemia and what was the spectrum of late complications that could be attributed to any of these regimens. This long-term follow-up examination of the 4 randomized studies provides more definitive answers in patients with CML but still cannot be definitive for patients with AML.

Our current results thus clearly confirm previous results published by Clift and coworkers9 and Devergie and colleagues10 and extends, in a larger group of patients, the updated Seattle results showing similar long-term survival and DFS rates with the use of Bu-CY compared to CY-TBI as the preparative regimen for patients with CML.21 

In patients with AML, prior results have been less clear. In the French study, Blaise and associates7 previously reported a statistically significant disadvantage in both the DFS and survival rates in the Bu-CY arm (a finding recently confirmed in an update of this French study22). A similar difference in the DFS rates among patients with AML has been found in a recent retrospective analysis of the IBMTR.23 In the Nordic study, the initial reports did not provide a separate analysis for patients with AML.8 In the updated results of this later study, Ringden and coworkers did not find a statistically significant difference in DFS between Bu-CY and CY-TBI regimens among patients with AML.13 In the current study, the advantage of the CY-TBI over Bu-CY was not statistically significant. In these early trials, no cytogenetic analysis was performed as a risk factor affecting the outcome of patients with AML.24,25 Furthermore, Bu plasma levels were not measured as a risk factor that strongly influences the risk of relapse after transplantation.26 These factors limit the interpretation of our results. The answer to this question could come from another trial with stratification on cytogenetic risk groups and with individually adjusted Bu levels, but it is very unlikely that such a trial will be done.

In the European studies, 72% to 88% of the patients went back to school or work without significant differences according to the conditioning regimen or the initial diagnosis.

Only the Nordic study has previously evaluated the incidence of late complications among patients who received Bu-CY as compared to those who received CY-TBI.13 These authors found that Bu-CY was associated with an increased risk of chronic GVHD, obstructive lung disease, and alopecia. In our analysis, the pretransplantation conditioning regimen did not influence the incidence of chronic GVHD. We found that late obstructive lung disease was associated with chronic GVHD27-30 but not with the use of Bu-CY as described in the Nordic study.13 The reason for the association between chronic GVHD and obstructive lung disease among patients with CML but not among patients with AML remains unclear. Only 9 patients with AML developed late pulmonary diseases, thus preventing any meaningful statistical analysis. Some patients with CML may have received Bu, an agent known to induce pulmonary fibrosis, before the transplantation, but data concerning the type and duration of pretransplantation treatment were not available for our study. We found an increased risk of alopecia in AML patients who received Bu-CY, similar to results of the Nordic study.13 Chronic GVHD was associated with alopecia in CML patients. Hair follicles are targets of GVHD, and alopecia has been associated with the sclerodermatous form of chronic GVHD.31 Although alopecia is not life-threatening, this complication does affect quality of life. In 7 patients who all received Bu-CY, alopecia was total and permanent. Cataract formation has long been described as a late complication of TBI.32The 47% incidence rate of cataract after the use of TBI in our study fits with the incidence rate reported by Tichelli et al and that published by the FHCRC group.33,34 Cataract formation was also associated with chronic GVHD as described previously.33 This association most likely occurs through the effects of corticosteroids used to treat chronic GVHD.34 Associations between avascular osteonecrosis and younger age, prolonged steroid therapy, and TBI have also been described previously both in French and FHCRC retrospective studies.35,36 Hypothyroidism has been associated with the use of TBI32 and Bu-CY,37 but the number of cases was too small for meaningful analysis in our study.

We found very few cases of late cancers, but the median follow-up was only 7 years. Because cancer incidence rates do not begin to increase until more than 6 years BMT,38 39 it is probably too soon to draw any conclusions about the risk of cancer after Bu-CY as compared with CY-TBI. It is already clear, however, that late cancers can occur after Bu-CY conditioning. For this reason, these patients should have close monitoring for second cancers after the transplantation.

How can these findings be relevant to new paradigms for allogeneic transplantation conditioning regimens (nonmyeloablative conditioning),40-42 and in the era of STI571 (the bcr-abl inhibitor)43,44? Both use of nonmyeloablative conditioning regimen and of STI571 have led to highly encouraging results in phase I and II trials. This would probably lead to an extended role of allogeneic transplantation for older patients after nonmyeloablative conditioning regimen, and to reduced (or delayed) indication of transplantation in patients with CML. However, both of these new treatment modalities have only been recently introduced and follow-up is clearly lacking, as yet. Long-term results, such as those presented in this study, are therefore important as a referent treatment modality before results of phase III trials (comparing nonmyeloablative conditioning regimen versus standard Bu-CY or CY-TBI, or STI571 versus transplantation) will become available. On the other hand, these new therapeutic modalities may prove to be useful for the treatment of leukemia relapse. STI571 may be used as an alternative to donor lymphocyte infusion in patients with CML who relapse after transplantation. Nonmyeloablative conditioning followed by peripheral blood stem cell transplantation would probably reduced transplantation-related mortality in patients with AML who relapse after a first transplantation in which a conventional therapy has been used.

In conclusion, Bu-CY and CY-TBI lead to similar long-term outcomes in patients with myeloid malignancies (although TBI provides slightly better long-term survival in patients with AML). Long-term complications, general health status, and return to work were mostly influenced by chronic GVHD and rarely by the conditioning regimens.

The authors thank Gary Schoch for providing the computerized data from the FHCRC, and all French physicians who sent updated information on patients included in the 2 randomized studies of the SFGM-TC: Dominique Maraninchi, Josy Reiffers, Jean Pierre Jouet, Noël Milpied, Michel Attal, Jean Jacques Sotto, Mathieu Kuentz, Norbert Ifrah, Pierre Bordigoni, Nicole Gratecos, François Guilhot, Denis Guyotat, Eliane Gluckman, and Jean Paul Vernant.

The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked “advertisement” in accordance with 18 U.S.C. section 1734.

1
Thomas
ED
Stem cell transplantation: past, present and future.
Stem Cells.
12
1994
539
544
2
Santos
GW
Tutschka
PJ
Brookmeyer
R
et al
Marrow transplantation for acute non-lymphocytic leukemia after treatment with busulfan and cyclophosphamide.
N Engl J Med.
309
1983
1347
1353
3
Geller
RB
Saral
R
Piantadosi
S
et al
Allogeneic bone marrow transplantation after high dose busulfan and cyclophosphamide in patients with acute nonlymphocytic leukemia.
Blood.
73
1989
2209
2218
4
Biggs
JC
Szer
J
Crilley
P
et al
Treatment of chronic myeloid leukemia with allogeneic bone marrow transplantation after preparation with BuCy2.
Blood.
80
1992
1352
1357
5
Copelan
EA
Biggs
JC
Szer
J
et al
Allogeneic bone marrow transplantation for acute myelogenous leukemia, acute lymphocytic leukemia, and multiple myeloma following preparation with busulfan and cyclophosphamide (Bucy2).
Semin Oncol.
20
1993
33
38
6
Copelan
EA
Biggs
JC
Thompson
JM
et al
Treatment for acute myelocytic leukemia with allogeneic bone marrow transplantation following preparation with BuCy2.
Blood.
78
1991
838
843
7
Blaise
D
Maraninchi
D
Archimbaud
E
et al
Allogeneic bone marrow transplantation for acute myeloid leukemia in first remission: a randomized trial of a busulfan-cytoxan versus cytoxan-total body irradiation as preparative regimen: a report from the Groupe d' Etudes de la Greffe de Moelle Osseuse.
Blood.
79
1992
2578
2582
8
Ringden
O
Ruutu
T
Remberger
M
et al
A randomized trial comparing busulfan with total body irradiation as conditioning in allogeneic marrow transplant recipients with leukemia—a report from the Nordic Bone Marrow Transplantation Group.
Blood.
83
1994
2723
2730
9
Clift
RA
Buckner
CD
Thomas
ED
et al
Marrow transplantation for chronic myeloid leukemia: a randomized study comparing cyclophosphamide and total body irradiation with busulfan and cyclophosphamide.
Blood.
84
1994
2036
2043
10
Devergie
A
Blaise
D
Attal
M
et al
Allogeneic bone marrow transplantation for chronic myeloid leukemia in first chronic phase: a randomized trial of busulfan-cytoxan versus cytoxan-total body irradiation as preparative regimen: a report from the French Society of Bone Marrow Graft (SFGM).
Blood.
85
1995
2263
2268
11
Hartman
AR
Williams
S
Dillon
JJ
Survival, disease-free survival and adverse effects of conditioning for allogeneic bone marrow transplantation with busulfan/cyclophosphamide vs total body irradiation: a meta-analysis.
Bone Marrow Transplant.
22
1998
439
443
12
Davies
SM
Ramsay
NKC
Klein
JP
et al
Comparison of preparative regimens in transplants for children with acute lymphoblastic leukemia.
J Clin Oncol.
18
2000
340
347
13
Ringden
O
Remberger
M
Ruutu
T
et al
Increased risk of chronic graft-versus-host disease, obstructive bronchiolitis, and alopecia with busulfan versus total body irradiation: long-term results of a randomized trial in allogeneic marrow recipients with leukemia.
Blood.
93
1999
2196
2201
14
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.
73
1989
1729
1734
15
Blaise
D
Olive
D
Michallet
M
Marit
G
Leblond
V
Maraninchi
D
Impairment of leukaemia-free survival by addition of interleukin-2-receptor antibody to standard graft-versus-host prophylaxis.
Lancet.
345
1995
1144
1146
16
Sullivan
KM
Siadak
M
Stem cell transplantation.
Cancer Patients Follow-up.
Johnson
FE
Virgo
KS
1997
490
518
Mosby
St Louis, MO
17
Guglielmi
C
Arcese
W
Hermans
J
et al
Risk assessment in patients with Ph+ chronic myelogenous leukemia at first relapse after allogeneic stem cell transplant: an EBMT retrospective analysis.
Blood.
95
2000
3328
3334
18
Craddock
C
Szydio
RM
Klein
JP
et al
Estimating leukemia-free survival after allografting for chronic myeloid leukemia: a new method that takes into account patients who relapse and are restored to complete remission.
Blood.
96
2000
86
90
19
Kaplan
EL
Meier
P
Non parametric estimation from incomplete observations.
J Am Stat Assoc.
53
1958
457
481
20
Cox
DR
Regression models and life-tables (with discussions), series B.
J R Stat Soc.
34
1972
184
192
21
Clift
RA
Radich
J
Appelbaum
FR
et al
Long-term follow-up of a randomized study comparing cyclophosphamide and total body irradiation with busulfan and cyclophosphamide for patients receiving allogeneic marrow transplants during chronic phase of chronic myeloid leukemia.
Blood.
94
1999
3960
3962
22
Blaise
D
Maraninchi
D
Michallet
M
et al
Long-term follow-up of a randomized trial comparing the combination of cyclophosphamide with total body irradiation or busulfan as conditioning regimen for patients receiving HLA-identical marrow grafts for acute myeloblastic leukemia in first complete remission.
Blood.
97
2001
3669
3671
23
Litzow
MR
Bolwell
BJ
Camitta
BM
et al
Comparison of allogeneic bone marrow transplantation with cyclophosphamide-total body irradiation versus busulfan-cyclophosphamide conditioning regimens for acute myelogenous leukemia in first remission [abstract].
Blood.
96
2000
480a
24
Slovak
ML
Kopecky
KJ
Cassileth
PA
et al
Karyotypic analysis predicts outcome of pre-remission and postremission therapy in adult acute myeloid leukemia: a Southwest Oncology Group/Eastern Cooperative Oncology Group study.
Blood.
96
2000
4075
4083
25
Grimwade
D
Walker
H
Oliver
F
et al
The importance of diagnostic cytogenetics on outcome in AML: analysis of 1,612 patients entered into the MRC AML 10 trial.
Blood.
92
1998
2322
2333
26
Slattery
JT
Clift
RA
Buckner
CD
et al
Marrow transplantation for chronic myeloid leukemia: the influence of plasma busulfan levels on the outcome of transplantation.
Blood.
89
1997
3055
3060
27
Folz
RJ
Mechanisms of lung injury after bone marrow transplantation.
Am J Respir Cell Mol Biol.
20
1999
1097
1099
28
Crawford
SW
Noninfectious lung disease in the immunocompromised host.
Respiration.
66
1999
385
395
29
Kantrow
SP
Hackman
RC
Boeckh
M
Myerson
D
Crawford
SW
Idiopathic pneumonia syndrome—changing spectrum of lung injury after marrow transplantation.
Transplantation.
63
1997
1079
1086
30
Quabeck
K
The lung as a critical organ in marrow transplantation.
Bone Marrow Transplant.
14
1994
S19
S28
31
Socie
G
Cahn
JY
Acute graft-versus-host disease.
The Clinical Practice of Stem-Cell Transplantation.
Barrett
AJ
Treleaven
J
2
1998
595
618
Isis Medical Media
Oxford, United Kingdom
32
Sullivan
KM
Agura
E
Anasetti
C
et al
Chronic graft-versus-host disease and other late complications of bone marrow transplantation.
Semin Hematol.
28
1991
250
259
33
Benyunes
MC
Sullivan
KM
Deeg
HJ
et al
Cataracts after bone marrow transplantation: long-term follow-up of adults treated with fractionated total body irradiation.
Int J Radiat Oncol Biol Phys.
32
1995
661
670
34
Tichelli
A
Gratwohl
A
Egger
T
et al
Cataract formation after bone marrow transplantation.
Ann Intern Med.
119
1993
1175
1180
35
Fink
JC
Leisenring
WM
Sullivan
KM
Sherrard
DJ
Weiss
NS
Avascular necrosis following bone marrow transplantation: a case-control study.
Bone.
22
1998
67
71
36
Socie
G
Cahn
JY
Carmelo
J
et al
Avascular necrosis of bone after allogeneic bone marrow transplantation: analysis of risk factors for 4388 patients by the Societe Francaise de Greffe de Moelle (SFGM).
Br J Haematol.
97
1997
865
870
37
Toubert
ME
Socie
G
Gluckman
E
et al
Short- and long-term follow-up of thyroid dysfunction after allogeneic bone marrow transplantation without the use of preparative total body irradiation.
Br J Haematol.
98
1997
453
457
38
Curtis
RE
Rowlings
PA
Deeg
HJ
et al
Solid cancers after bone marrow transplantation.
N Engl J Med.
336
1997
897
904
39
Deeg
HJ
Socie
G
Malignancies after hematopoietic stem cell transplantation: many questions, some answers.
Blood.
91
1998
1833
1844
40
McSweeney
PA
Niederwieser
D
Shizuru
JA
et al
Hematopoietic cell transplantation in older patients with hematologic malignancies: replacing high-dose cytotoxic therapy with graft-versus- tumor effects.
Blood.
97
2001
3390
3400
41
Barrett
J
Childs
R
Non-myeloablative stem cell transplants.
Br J Haematol.
111
2000
6
17
42
Giralt
S
Thall
PF
Khouri
I
et al
Melphalan and purine analog-containing preparative regimens: reduced-intensity conditioning for patients with hematologic malignancies undergoing allogeneic progenitor cell transplantation.
Blood.
97
2001
631
637
43
Druker
BJ
Sawyers
CL
Kantarjian
H
et al
Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome.
N Engl J Med.
344
2001
1038
1042
44
Druker
BJ
Talpaz
M
Resta
DJ
et al
Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia.
N Engl J Med.
344
2001
1031
1037

Author notes

Gérard Socié, Service d'Hématologie, Greffe de Moelle, Hôpital Saint Louis, 1 Ave Claude Vellefaux, 75475, Paris Cedex 10, France; e-mail:gsocie@chu-stlouis.fr.

Sign in via your Institution