Abstract

Abstract 34

We performed randomized phase III study to compare the regimen related toxicities (RRT) of two different conditioning regimens, cyclophosphamide (CyATG) vs. cyclophosphamide plus fludarabine (CyFluATG) given in addition to anti-thymocyte globulin (ATG) for allogeneic hematopoietic cell transplantation (alloHSCT) for bone marrow failure syndrome including severe aplastic anemia (AA) and hypoplastic myelodysplastic syndrome (MDS).

CyATG consisted of Cyclophosphamide (Cy) 50 mg/kg (D –5 to –2). CyFluATG arm received fludarabine (Flu) 30 mg/m2 (D –6 to –2) and Cy 50 mg/kg (D –3 to –2). Thymoglobuline 3 mg/kg, lymphoglobulin 15 mg/kg on days -4 to -2 or alemtuzumab 20mg on day -4 were infused in both arms. Patients were stratified by stem cell donor (related vs. unrelated).

Total 83 patients (40 patients to Cy-ATG and 43 patients to Cy-Flu-ATG) were enrolled from February 2003. All patients except for one patient, who had assigned to Cy-Flu-ATG arm and died during conditioning, received full planed regimen and all planned patients were included in this analysis. Median age was 34 (15-60) years and male patients were 42/83 (50.6%). AA patients were 79 and MDS were 4. Matched sibling donors were 53 (63.9%). ATG was used in form of thymoglobulin (n=75, 90.4%), and some patients had received ALG (n=5, 6.0%) or alemtuzumab (n=3, 3.6%). Median duration from diagnosis to transplantation was 4.7 (0.2-177.7) months. Age, gender, donor type were not different in both arms (Table 1). Various TRT were similar between Cy-ATG and Cy-Flu-ATG (Table 2); granulocyte graft failure rate (p=0.959), platelet graft failure rate (p=0.625), acute GvHD (p=0.388), chronic GvHD (p=0.991), CMV antigenemia (p=0.550), hematuria (p=0.480). However, pulmonary complications (p=0.005) was significantly lower in CyFluATG arm. Infection rate (p=0.130) and sinusoidal obstruction syndrome (SOS, p=0.101) seemed lower in CyFluATG arm but were not statistically significant. Any RRTs were significantly higher in CyATG arm (80.0% vs. 39.5%; p<0.001) but any treatment-related toxicities were similar in both arms (85% vs. 79.1%; p=0.483). Figure 1 shows that 4-year survival rates (77.7% vs. 87.6%) were higher in CyFluATG arm without any statistical significance (p=0.265) and this trend was similar in MRD (81.9 vs. 92.1%; p=0.354) and AD (69.3 vs. 80.2%; p=0.442).

In conclusion, overall treatment-related complications and survival were similar between CyATG CyFluATG, however, CyFluATG seemed superior over CyATG in terms of pulmonary complications and RRT.
Table 1.

Characteristics of patients between Cy-ATG and Cy-Flu-ATG

Characteristics Cy-ATG Cy-Flu-ATG p-value 
Gender, n (%)   0.586 
Male 19 (47.5) 23 (53.5)  
Female 21 (52.5) 20 (46.5)  
Age, median (range) 34.5 (15±59) 34.0 (18±60) 0.365 
Months from diagnosis to SCT, median (range) 4.8 (0.2–147.2) 4.6 (0.9–177.7) 0.982 
Diagnosis, n (%)   0.617 
AA 39 (97.5) 40 (93.0)  
MDS 1 (1.9) 3 (7.0)  
Infused CD34+ cell dose (?106/kg), mean±SD 5.76±4.89 5.25±5.30 0.449 
ATG, n (%)   0.360 
Thymoglobulin 38 (95.0) 37 (86.0)  
ALG 1 (2.5) 4 (9.3)  
Alemtuzumab 1 (2.5) 2 (4.7)  
HLA-A, B, C and DR molecular matching, n (%)   0.699 
Full matched 30 (75.0) 30 (69.8)  
1 locus mismatched 3 (7.5) 3 (7.0)  
2 loci mismatched 3 (7.5) 2 (4.7)  
Not determined 4 (10.0) 8 (18.6)  
Donor, n (%)   0.834 
MSD 26 (65.0) 27 (62.8)  
AD 14 (35.0) 16 (37.2)  
Characteristics Cy-ATG Cy-Flu-ATG p-value 
Gender, n (%)   0.586 
Male 19 (47.5) 23 (53.5)  
Female 21 (52.5) 20 (46.5)  
Age, median (range) 34.5 (15±59) 34.0 (18±60) 0.365 
Months from diagnosis to SCT, median (range) 4.8 (0.2–147.2) 4.6 (0.9–177.7) 0.982 
Diagnosis, n (%)   0.617 
AA 39 (97.5) 40 (93.0)  
MDS 1 (1.9) 3 (7.0)  
Infused CD34+ cell dose (?106/kg), mean±SD 5.76±4.89 5.25±5.30 0.449 
ATG, n (%)   0.360 
Thymoglobulin 38 (95.0) 37 (86.0)  
ALG 1 (2.5) 4 (9.3)  
Alemtuzumab 1 (2.5) 2 (4.7)  
HLA-A, B, C and DR molecular matching, n (%)   0.699 
Full matched 30 (75.0) 30 (69.8)  
1 locus mismatched 3 (7.5) 3 (7.0)  
2 loci mismatched 3 (7.5) 2 (4.7)  
Not determined 4 (10.0) 8 (18.6)  
Donor, n (%)   0.834 
MSD 26 (65.0) 27 (62.8)  
AD 14 (35.0) 16 (37.2)  
Table 2.

The comparison of treatment-related toxicities between Cy-ATG and Cy-Flu-ATG

Factors Cy-ATG Cy-Flu-ATG p-value 
Graft failure, n (%) 5 (12.5) 7 (16.3) 0.625 
Granulocyte 1 (2.5) 1 (2.3) 0.959 
Platelet 5 (12.6) 7 (16.3) 0.625 
Acute GvHD, n (%)    
Any grades 6 (15.0) 10 (23.3) 0.388 
Grade 3/4 2 (5.0) 1 (2.3) 0.514 
Chronic GvHD, n (%)    
Any 5 (12.5) 5 (11.6) 0.991 
Extensive 4 (10.0) 3 (7.0) 0.369 
CMV antigenemia, n (%) 24 (60.0) 23 (53.5) 0.550 
Infection, n (%) 32 (80.0) 28 (65.1) 0.130 
Interstitial pneumonitis, n (%) 0 (0.0) 0 (0.0) – 
Pulmonary complications, n (%) 14 (35.0) 4 (9.3) 0.005 
SOS, n (%) 5 (12.5) 1 (2.3) 0.101 
Hematuria, n (%) 10 (8.7) 8 (29.6) 0.480 
Any regimen-related toxicities, n (%) 32 (80.0) 17 (39.5) <0.001 
Any treatment-related toxicities, n (%) 34 (85.0) 34 (79.1) 0.483 
Factors Cy-ATG Cy-Flu-ATG p-value 
Graft failure, n (%) 5 (12.5) 7 (16.3) 0.625 
Granulocyte 1 (2.5) 1 (2.3) 0.959 
Platelet 5 (12.6) 7 (16.3) 0.625 
Acute GvHD, n (%)    
Any grades 6 (15.0) 10 (23.3) 0.388 
Grade 3/4 2 (5.0) 1 (2.3) 0.514 
Chronic GvHD, n (%)    
Any 5 (12.5) 5 (11.6) 0.991 
Extensive 4 (10.0) 3 (7.0) 0.369 
CMV antigenemia, n (%) 24 (60.0) 23 (53.5) 0.550 
Infection, n (%) 32 (80.0) 28 (65.1) 0.130 
Interstitial pneumonitis, n (%) 0 (0.0) 0 (0.0) – 
Pulmonary complications, n (%) 14 (35.0) 4 (9.3) 0.005 
SOS, n (%) 5 (12.5) 1 (2.3) 0.101 
Hematuria, n (%) 10 (8.7) 8 (29.6) 0.480 
Any regimen-related toxicities, n (%) 32 (80.0) 17 (39.5) <0.001 
Any treatment-related toxicities, n (%) 34 (85.0) 34 (79.1) 0.483 
Figure 1.

Overall survival

Figure 1.

Overall survival

Disclosures:

Off Label Use: Cyclophosphamide, Fludarabine and thymoglobulin were used in conditioning regimens of this phase III clinical trial.

Author notes

*

Asterisk with author names denotes non-ASH members.