High Dose Valaciclovir As CMV Prophylaxis in Allogeneic Hematopoietic Stem Cell Recipients at High Risk of CMV Reactivation

Background

Cytomegalovirus (CMV) is a common, potentially devastating complication of allogeneic haematopoietic stem cell transplantation (alloHSCT). Universal antiviral prophylaxis strategies including letermovir are effective, but unsubsidised in Australia. Prophylactic ganciclovir or valganciclovir are challenging due to myelotoxicity. Valaciclovir demonstrates anti-CMV activity in high doses, but little current data explore prophylaxis in the alloHSCT setting, particularly in haploidentical transplantation. We aimed to evaluate the clinical efficacy and tolerability of high dose valaciclovir (high dose VALA) as CMV prophylaxis in high risk patients undergoing alloHSCT.

Methods

This study was completed at the Royal Melbourne Hospital, Melbourne Australia. We performed a retrospective analysis of alloHSCT recipients at high risk of CMV reactivation (defined as recipient and/or donor CMV seropositivity, and undergoing T-cell depletion, haploidentical or umbilical cord stem cell transplantation). Patients transplanted between July 2018 – June 2019, treated with high dose VALA (2g TDS) from day +7 to +100 and beyond were compared to a historical cohort (transplanted between July 2017 - June 2018) on standard dose valaciclovir (std dose VALA) (500mg BD until engraftment then 500mg daily). We compared the rates and time to reach a CMV threshold of 400 IU/ml, at which point pre-emptive CMV therapy was commenced. Tolerability was also evaluated.

Results

Patient demographics are described in Table 1. Of the standard dose VALA cohort, (median follow-up 259 days), 23/31 (74%) developed a viral load >400 IU/mL, requiring pre-emptive CMV therapy. None had CMV disease. Median time to viral load >400 IU/mL was 39 days (range 13 – 68).

Of the high dose VALA cohort (median follow-up 209 days), 11/25 (44%) developed a viral load >400 IU/mL, requiring pre-emptive CMV therapy. Of these 11 cases, 7 patients had viral load >400 IU/mL while on high dose VALA prior to D+100, 3 patients had ceased high dose VALA prior to D+100 due to intolerance and in 1 patient this occurred post D+100 while on high dose VALA. One patient developed CMV (gut) disease following early cessation of high dose VALA, whilst on standard dose VALA. Median time to reactivation >400 IU/mL was 64 days (range 26-170).

Time to reactivation >400 IU/ml was significantly different between the standard vs high dose VALA cohorts (mean ± SEM; 37.9 ± 2.7 vs 67.8 ± 11.3 days, **p=0.0015).

Median duration of high dose VALA prophylaxis was 50 days (range 11-288). Seven (28%) patients continued high dose VALA to day +100 and beyond. Intolerance led to early cessation in 10 (40%) patients (acute kidney injury, n=6; cytopenia, n=3; both, n=1). Other patients ceased due to requirement for definitive CMV therapy (n=6) and unclear reasons (n=2).

Conclusions

In high risk alloHSCT recipients, high dose VALA is an effective CMV prophylactic strategy resulting in lower CMV reactivation rates, and delays CMV reactivation. This may reduce requirements for myelotoxic CMV treatment during the early post-engraftment period and need for inpatient admission. CMV infection following high dose VALA cessation remains a risk, particularly when dose reductions have occurred due to toxicity, and intolerance and ongoing monitoring is required. Treatment tolerability remains a limitation.