Serotherapy with Alemtuzumab but Not ATG Is Associated with Increased Adenovirus Infection in Pediatric Recipients of Cord Blood Grafts

Unrelated cord blood transplant (UCBT) is an established graft source for HSCT especially for minorities.  Use of serotherapy such as anti-thymocyte globulin (ATG) and alemtuzumab is associated with delayed immune reconstitution, leading to increased viral reactivation especially when the donors are virus naïve. Therefore, we studied the impact of serotherapy along with other factors on viral reactivation (EBV, CMV, adenovirus (ADV)), GVHD, and transplant-related mortality (TRM) at 100 days in pediatric patients after UCBT. Statistics used were chi-squared test, and Kaplan-Meier cumulative incidence (CI) with log-rank. For CI of viral reactivation, patients were censored if they died or reached day 100 before viral reactivation. All patients had weekly GVHD grading using Glucksberg criteria and weekly PCR for the 3 viruses. Reactivation was defined as blood viral PCR>1000 copies/ml. This retrospective study evaluated 47 consecutive UCBTs performed from 2006-2014. Median age was 3 years (range 0-17). Diagnoses: leukemia (19), immunodeficiency (10), hemoglobinopathy (7), bone marrow failure (6), metabolic disorder (3), and histiocytic disorder (2).  21 patients received myeloablative conditioning (MAC) and 26 reduced-intensity conditioning (RIC).  Median degree of HLA matching was 5/6 (4-6/6).   Pre-transplant serotherapy was used in 30 patients (15 alemtuzumab, 15 ATG) irrespective of HLA matching. Median cell dose was 6.15x10⁷(0.9–18.9x10⁷) TNC/kg. Among all variables evaluated, underlying diagnosis was the only one associated with development of ≥ grade 2 acute GVHD, occurring predominantly in leukemia patients(p=0.048). For viral reactivation, the conditioning regimen influenced CMV reactivation, with significantly more CMV reactivations in MAC recipients (p = 0.044), and more EBV reactivations in RIC recipients (p = 0.046). Conditioning regimen did not influence ADV reactivation.  For ADV, only the type of serotherapy had a strong association with reactivation, with more ADV infections in patients who received alemtuzumab (p = 0.044). No variable had a relationship with TRM.  We then explored the day 100 CI of viral reactivation, by type of serotherapy (Table 1). There was a trend towards higher CI of ADV reactivation in patients who received alemtuzumab. We conclude that in pediatric UCBT patients, while the impact of serotherapy on acute GVHD is unclear, it does have a major impact on viral reactivation. Specifically, alemtuzumab appears to have more impact on ADV reactivation than ATG. While further data will be collected on the morbidity and mortality associated with these infections, novel therapies to treat viruses in the context of serotherapy-treated UCBT recipients are needed.

	No serotherapy	ATG	Alemtuzumab	p value
ADV	5.8 (0-16.9)%	0 %	29.3 (5.1-53.5)%	0.056
CMV	5.8 (0-16.9)%	20 (0-44.8)%	34 (9.7-58.3)%	0.08
EBV	5.8 (0-16.9)%	18.2 (0-40.5)%	0%	.25