Pre-Emptive Rituximab for the Prevention of EBV-Related PTLD in Umbilical Cord Blood Transplantion Patients

We observed a high rate of Epstein-Barr virus (EBV) associated post-transplant lymphoproliferative disease (PTLD) in our umbilical cord blood transplantation (UCBT) patients. We retrospectively analyzed all UBCTs performed at our institution in order to 1) define risk factors for the development of PTLD and 2) assess whether pre-emptive therapy with rituximab (RTX) altered the incidence and outcomes of PTLD in patients with EBV viremia.

One hundred twenty-seven patients underwent UCBTs, with primarily double cord units, between March 2003 and April 2010. EBV viral loads were monitored by quantitative PCR. Viremia was defined as any detectable level of EBV DNA in peripheral blood. EBV events included all cases of isolated viremia, sustained viremia (≥ 2 positive viral loads on two separate dates), or biopsy/autopsy proven PTLD. One to four weekly doses of RTX (375mg/m²) were given pre-emptively to prevent PTLD in patients with sustained viremia. The frequency of monitoring, the decision to treat with RTX and the duration of treatment were at the clinician's discretion. Fisher's exact test and Cox modeling were used to evaluate the effect of clinical variables on the probability of developing PTLD.

Cohort Characteristics: Ninety-nine of 127 patients (77%) underwent reduced-intensity conditioning (RIC) transplantion. Eighty-five (86%) of those who received RIC transplants were conditioned with fludarabine, melphalan and anti-thymocyte globulin (ATG). Seventy-nine of the 99 patients (80%) who underwent RIC transplantation received ATG doses at 6mg/kg or greater.

PTLD rate and risk factors: Thirty-three patients (26%) had an EBV event. 9 patients (7%) had isolated viremia. No patient with isolated viremia was treated with RTX and none developed PTLD. 11 patients developed sustained viremia but not PTLD. Thirteen patients (10%) had biopsy-proven PTLD, a one-year cumulative probability of 12% (95% CI, 0.08–0.15). All patients who developed PTLD underwent RIC transplant and received at least 6mg/kg of ATG. ATG use was found to be a statistically significant risk factor for PTLD (p = 0.02) yet ATG use was not associated with decreased survival. Age, primary disease, degree of HLA match, graft-versus-host disease (GVHD) and type of GVHD prophylaxis were not identified as PTLD risk factors.

Effect of pre-emptive rituximab: 14 patients developed sustained viremia and did not have clinical evidence of PTLD at the time viremia was detected (12%). Twelve of these patients were treated pre-emptively with RTX. EBV DNA became undetectable in 9 of 12 (67%) of these patients, none of whom developed PTLD. EBV viremia resolved in 1 patient without RTX; this patient did not develop PTLD. One patient died of other causes before RTX could be given. Viremia initially cleared in one patient who later progressed to PTLD but achieved complete remission after treatment with virus-specific cytotoxic T-lymphocytes (CTL). Viremia did not resolve in 2 patients, both of whom developed PTLD. Despite treatment with virus-specific CTL both died of PTLD.

The adjusted hazard ratio (HR) for the development of PTLD among patients with sustained viremia was 230 (95% CI, 29–1856); the adjusted HR of pre-emptive rituximab was 0.24 (95% CI, 0.07 – 0.9).

ATG doses of 6mg/kg or greater were associated with PTLD in the UBCT population. Isolated EBV viremia was not a risk factor for the development of PTLD. Sustained EBV viremia conferred considerable risk. This risk of developing PTLD in patients with sustained viremia was reduced when RTX was given as pre-emptive therapy in this cohort. Further studies to better define the optimal duration of RTX therapy are needed. Prophylactic immune reconstitution with closely HLA-matched virus-specific CTL may also be an alternative option in this high-risk population.

No relevant conflicts of interest to declare.