Abstract

Background: Allogeneic hematopoietic cell transplantation (aHCT) is curative for a number of pediatric nonmalignant disorders. Toxicities related to conditioning, failure of engraftment, and GVHD remain obstacles to successful transplantation for these patients. Since 2000, our institution has prospectively studied busulfan/fludarabine (Bu/Flu)-based conditioning regimens with a goal to reduce complications associated with myeloablative conditioning while maintaining adequate, stable donor-derived hematopoiesis. While overall survival has remained excellent, graft failure rates remain high. Therefore, we performed a retrospective analysis to identify risk factors for graft failure in patients receiving Bu/Flu-based conditioning. In addition, we report results for second aHCTs following graft failure.

Methods: Since 2000, our institution has performed 74 aHCTs with Bu/Flu-based conditioning for nonmalignant disorders. The most common diagnoses include Wiskott-Aldrich syndrome (n = 10), thalassemia (n = 9), Hurler syndrome (n = 7), hemophagocytic lymphohistiocytosis (HLH) (n = 6), sickle cell disease (n = 5), and aplastic anemia (n = 5). Three aHCTs were excluded due to relapse of the underlying disease (e.g. HLH) despite > 90% donor chimerism. Conditioning included a backbone of busulfan and fludarabine as previously described (Law J, et al, Biol Blood Marrow Transplant, 2012). Starting in 2012, four doses of clofarabine 10 mg/m2 (0.33 mg/kg for patients < 12 kg) were added for recipients of mismatched unrelated donors (MMUD). In addition, conditioning included either rabbit antithymocyte globulin (rATG) or alemtuzumab.

Results: Twelve graft failures (17%) occurred between day +18 and +445 (median +66). Of the variables analyzed, only donor chimerism for whole blood and the CD3 subset were significantly correlated with graft failure (CD14/15 and CD19 subsets were not). Cord blood aHCTs were excluded from conditioning analysis since these transplantations exclusively used rATG rather than alemtuzumab.

Table 1:

Risk Factors for Graft Failure

 Durable Engraftment Graft Failure Odds Ratio (95% CI) P-value 
HLA Match 
Matched 45 --  
Mismatched 14 2.30 (0.63 to 8.38) 0.28 
Donor 
Related 22 --  
Unrelated 37 10 2.97 (0.60 to 14.84) 0.20 
Conditioning 
Bu/Flu/rATG (+/–Clo) 14 --  
Bu/Flu/alemtuzumab (+/–Clo) 40 0.28 (0.07 to 1.19) 0.11 
Source 
Marrow 41 --  
Peripheral Blood 13 0.39 (0.04 to 3.46) 0.67 
Cord Blood 3.08 (0.61 to 15.54) 0.17 
CMV Reactivation (Prior to Graft Failure) 
No 42 --  
Yes 12 2.80 (0.65 to 12.10) 0.21 
Whole Blood Donor Chimerism (Day +30) 
> 90% 48 --  
< 90% 6.40 (1.60 to 25.55) 0.01 
CD3 Donor Chimerism (Day +30) 
> 50% 32 --  
< 50% 11.43 (1.83 to 71.45) 0.009 
 Durable Engraftment Graft Failure Odds Ratio (95% CI) P-value 
HLA Match 
Matched 45 --  
Mismatched 14 2.30 (0.63 to 8.38) 0.28 
Donor 
Related 22 --  
Unrelated 37 10 2.97 (0.60 to 14.84) 0.20 
Conditioning 
Bu/Flu/rATG (+/–Clo) 14 --  
Bu/Flu/alemtuzumab (+/–Clo) 40 0.28 (0.07 to 1.19) 0.11 
Source 
Marrow 41 --  
Peripheral Blood 13 0.39 (0.04 to 3.46) 0.67 
Cord Blood 3.08 (0.61 to 15.54) 0.17 
CMV Reactivation (Prior to Graft Failure) 
No 42 --  
Yes 12 2.80 (0.65 to 12.10) 0.21 
Whole Blood Donor Chimerism (Day +30) 
> 90% 48 --  
< 90% 6.40 (1.60 to 25.55) 0.01 
CD3 Donor Chimerism (Day +30) 
> 50% 32 --  
< 50% 11.43 (1.83 to 71.45) 0.009 

Among the 12 patients with aHCTs that resulted in graft failure, 7 were successfully rescued with a second transplantation, 1 declined a second transplantation, 1 is awaiting a second transplantation, and 3 died due to sequelae of graft failure despite a second transplantation.

Table 2:

Second Transplantations

 Conditioning First Donor Second Donor Diagnosis 
Durable Engraftments 
 Cy 120, TBI 200, hATG 90 MUD CB MUD PB Hurler 
 Cy 120, TBI 200, hATG 90 MUD BM MUD PB Hurler 
 Cy 120, TBI 1200, hATG 90 MMUD BM Same Mannosidosis 
 Cy 120, TBI 1200, hATG 90 MUD BM MUD PB Aplastic anemia 
 Mel 140, Flu 90, hATG 90 MRD CB Same BM/PB Thalassemia 
 Mel 140, TT 10, alemtuzumab MUD BM Same Wiskott-Aldrich 
 Mel 140, TT 10, hATG 90 MRD BM Same ZAP-70 combined immunodeficiency 
Second Graft Failures 
 Cy 120, TBI 200, hATG 90 MMUD BM MMUD PB Congenital neutropenia 
 Cy 180, TT 10, rATG 8 MMUD BM Haplo PB Porphyria 
 Cy 120, alemtuzumab MUD PB Same Adrenoleukodystrophy 
 Conditioning First Donor Second Donor Diagnosis 
Durable Engraftments 
 Cy 120, TBI 200, hATG 90 MUD CB MUD PB Hurler 
 Cy 120, TBI 200, hATG 90 MUD BM MUD PB Hurler 
 Cy 120, TBI 1200, hATG 90 MMUD BM Same Mannosidosis 
 Cy 120, TBI 1200, hATG 90 MUD BM MUD PB Aplastic anemia 
 Mel 140, Flu 90, hATG 90 MRD CB Same BM/PB Thalassemia 
 Mel 140, TT 10, alemtuzumab MUD BM Same Wiskott-Aldrich 
 Mel 140, TT 10, hATG 90 MRD BM Same ZAP-70 combined immunodeficiency 
Second Graft Failures 
 Cy 120, TBI 200, hATG 90 MMUD BM MMUD PB Congenital neutropenia 
 Cy 180, TT 10, rATG 8 MMUD BM Haplo PB Porphyria 
 Cy 120, alemtuzumab MUD PB Same Adrenoleukodystrophy 

MRD = matched related donor, MUD = matched unrelated donor

Conclusions: We have previously shown that reduced toxicity conditioning with busulfan, fludarabine, and either rATG or alemtuzumab is well tolerated with low rates of transplant-related morbidity and mortality. In our cohort, low early donor chimerism was significantly correlated with increased graft failure. Close monitoring and early interventions may benefit patients at high risk for graft failure. Notably, there was a trend towards reduction in graft failure with alemtuzumab (9%) compared to rATG (26%), which did not reach statistical significance possibly due to insufficient power. While graft failure remains an issue with Bu/Flu-based conditioning, rescue with second transplantation is feasible with a reasonable chance for success.

Disclosures

No relevant conflicts of interest to declare.

Author notes

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