Cytomegalovirus Reactivation in Children with Hemoglobinopathies Who Undergo Hematopoietic Cell Transplantation with Distal Alemtuzumab

Abstract

Introduction Cytomegalovirus (CMV) viremia after allogeneic hematopoietic cell transplant (HCT) is associated with substantial morbidity. In vivo T cell depletion with alemtuzumab is a known risk factor for CMV reactivation. After observing very early CMV viremia in patients who received distal alemutuzumab in preparation for HCT for hemoglobinopathies, we implemented a quality improvement project to decrease the burden of CMV in this population. Objective To describe patterns of CMV reactivation before and after changing our CMV prophylaxis and surveillance strategies. Methods We reviewed medical records of children undergoing HCT for sickle cell disease (SCD) or beta thalassemia at Children`s Hospital of Philadelphia between 2007-2018, who received distal alemtuzumab containing conditioning regimens. Patients received alemtuzumab (48 mg, starting ∼22 days before transplant) with fludarabine and melphalan. Beginning in February 2014, CMV seropositive (CMV+) patients received prophylaxis with valganciclovir from completion of alemtuzumab through day -1 and foscarnet starting on day 0, as well as weekly CMV surveillance beginning with alemtuzumab administration. Rates of CMV reactivation, as well as balancing metrics [time to engraftment and rate of acute kidney injury (AKI) within 100 days post-HCT] were evaluated before and after implementation of this preventive approach. Results Twenty-nine children were included in the analysis. The median age was 11.1 (range: 3.1 to 17.3) years at HCT; 22 (75.9%) patients had SCD and 8 (24.1%) had beta thalassemia. All patients received bone marrow grafts, 22 (75.9%) from HLA-identical siblings and 7 (24.1%) from unrelated donors. Prior to HCT, 13 patients were CMV+. Of those, 11 (84.6%) developed CMV reactivation (7/7 pre-intervention and 4/6 post-intervention). Time from alemtuzumab start to CMV reactivation, regardless of prophylactic strategy, is shown in Figure 1. CMV reactivation occurred at a median of 4 (range: -11 to +13) days after planned HCT. During the post-intervention period, CMV reactivation was identified in 2 patients prior to the start of the proximal cytotoxic phase of conditioning and HCT was delayed until viremia cleared. One CMV seronegative patient developed CMV viremia 47 days post-HCT. Median time to engraftment was similar before and after the intervention (12.5 versus 13 days), as was the proportion of patients with AKI (3/7 versus 1/6). Conclusion In this cohort, rates of CMV viremia were high and CMV reactivation often occurred very early in the transplant course. In two cases, CMV reactivation was identified prior to transplant day, necessitating a delay in HCT. Consideration should be given to implementing a program of screening or prophylaxis beginning as early as the start of alemtuzumab administration in CMV+ patients. Further research is needed to determine the optimal prophylactic strategy.