Historically, outcomes after alternative donor (AD)-HCT for FA have been strikingly inferior to those observed in recipients of HLA-matched sibling donor (MSD) hematopoietic stem cells (HSC) with excessive rates of graft failure, graft-versus-host-disease (GVHD), regimen related toxicity and infection, resulting in poor survival rates. Between 2006-2013, 44 FA patients with marrow aplasia and good organ function underwent AD-HCT after total body irradiation 300 cGy (single fraction) with thymic shielding, fludarabine (FLU) 140 mg/m2, cyclophosphamide (CY) 40 mg/kg and antithymocyte globulin (ATG). Outcomes were compared to those transplanted with HSC from an HLA matched sibling donor (n=24) after FLU 175 mg/m2, CY 20 mg/kg and ATG conditioning (1999-2013). GVHD preventative measures were identical with all recipients of marrow having the graft T cell depleted by CD34 selection (regardless of donor type) prior to infusion in addition to cyclosporine A and methylprednisolone or mycophenolate mofetil. Recipients of umbilical cord blood had no additional graft processing.

Except for higher use of pre-HCT G-CSF in recipients of AD-HCT, patient characteristics were similar between the 2 groups. Probabilities of neutrophil recovery, acute and chronic GVHD were similar between the groups (Table 1). Most notably, probability of survival at 3 years was the same between the two groups (Figure 1).

Table 1

Patient Characteristics and HCT Outcomes

MSD-HCTAD-HCT
N 24 44 
Patient Characteristics   
Age - years, median (range) 8 (3-43) 8 (3-34) 
Male sex - no. (%) 12 (50%) 25 (57%) 
<3 malformations - no. (%) 13 (54%) 23 (52%) 
≥1 transfusion prior to HCT- no. (%) 15 (63%) 18 (41%) 
G-CSF prior to HCT – no. (%) 3 (13%) 21 (50%)* 
Clonal abnormality prior to HCT – no. (%) 4 (17%) 9 (20%) 
Positive CMV serostatus 12 (50%) 27 (61%) 
HCT Outcomes   
Neutrophil Recovery 100% 93% 
- median time (range) days 11 (9-41) 12 (9-40) 
Grade II-IV acute GVHD 4% 9% 
Grade III-IV acute GVHD 4% 0% 
Chronic GVHD 8% 2% 
Follow-up - years, median (range) 5.4 (2-11) 3.3 (1-6) 
MSD-HCTAD-HCT
N 24 44 
Patient Characteristics   
Age - years, median (range) 8 (3-43) 8 (3-34) 
Male sex - no. (%) 12 (50%) 25 (57%) 
<3 malformations - no. (%) 13 (54%) 23 (52%) 
≥1 transfusion prior to HCT- no. (%) 15 (63%) 18 (41%) 
G-CSF prior to HCT – no. (%) 3 (13%) 21 (50%)* 
Clonal abnormality prior to HCT – no. (%) 4 (17%) 9 (20%) 
Positive CMV serostatus 12 (50%) 27 (61%) 
HCT Outcomes   
Neutrophil Recovery 100% 93% 
- median time (range) days 11 (9-41) 12 (9-40) 
Grade II-IV acute GVHD 4% 9% 
Grade III-IV acute GVHD 4% 0% 
Chronic GVHD 8% 2% 
Follow-up - years, median (range) 5.4 (2-11) 3.3 (1-6) 
*

p value <0.01

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Figure 1
Figure 1.
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To our knowledge, this is the first demonstration of comparable outcomes after AD-HCT and MSD HCT for FA patients with marrow aplasia. These findings have three important implications: 1) timing for HCT need not be delayed if the patient lacks an HLA matched sibling donor, 2) potentially reduced enthusiasm for in vitro fertilization and preimplantation genetic diagnosis to have a 'savior sibling' and 3) ineligibility of FA young patients with a suitable AD (HLA matched adult volunteer or 5-6/6 matched UCB) and good organ function for high risk trials, including gene modified HSC.

Disclosures:

Wagner:Novartis: Research Funding.

Topics:
antithymoglobulin, cd34 antigens, congenital abnormality, cyclophosphamide, cyclosporine, cytomegalovirus, donors, fanconi anemia, fertilization in vitro, fludarabine

Author notes

*

Asterisk with author names denotes non-ASH members.

This icon denotes a clinically relevant abstract

© 2013 by The American Society of Hematology
2013
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