ANTI-CMV Immunoglobulins in Association with ANTI-CMV Drugs in Patients with Hematological Malignancies Submitted to Allogeneic STEM CELL Transplantation: A MULTI-Center Retrospective Experience
Authors: Malagola Michele , Peccatori Jacopo , Greco Raffaella , Serio Francesca , Santarone Stella , Iori Anna Paola , Quatrocchi Luisa , Barbieri Walter , Abruzzese Antonella , Leotta Salvatore , Carotti Alessandra , Pierini Antonio , Rambaldi Benedetta , Morello Enrico , Polverelli Nicola , Turra Alessandro , Cattina Federica , Gandolfi Lisa , Di Bartolomeo Paolo , Milone Giuseppe , Velardi Andrea , Foà Robin , Ciceri Fabio , Russo Domenico 
Published: October 2019

Abstract
CMV represents one of the most serious life-threatening complications of allogeneic stem cell transplantaion (allo-SCT). Pre-emptive treatment with anti-CMV drugs is highly effective, but toxicity and repetitive reactivation of CMV represent a major challenge in the clinical practice. The use of anti-CMV specific immunoglobulins (Megalotect) is controversial.
We retrospectively collected data on 539 patients with hematological malignancies submitted to allo-SCT in 6 Italian Bone Marrow Transplant Units between 2016 and 2017. Two hundred and forty two of the 539 patients (45%) developed at least one CMV reactivation. In 94/242 cases (39%) Megalotect was used according to internal guidelines. This report focuses on this group of 94 patient. Megalotect was used as prophylaxis in 15/94 cases (16%) and as pre-emptive therapy together with a specific anti-CMV drug in 79/94 cases (84%). Fifty-six out of 94 cases (60%) received 50 UI/Kg weekly, 33/94 cases (35%) received 50 U/Kg every 2-3 weeks (the remaining patients received different doses and schedule according to the Center policy). Megalotect was used because all the 94 patients were considered at high risk of developing repetitive CMV reactivation. In the prophylaxis setting these risk factors were: haploidentical and cord blood transplantation in 5 cases and unfavorable CMV sireology combiation in 14 cases. In the pre-emptive setting, the risk factors were: haploidentical transplantation in 30 cases, aGVHD requiring high-dose steroids in 37 cases and unfavourable CMV serology combination (D-/R- in 44 cases, D+/R- in 1 case). In the pre-emptive setting the following anti-CMV drugs were used first-line: gancyclovir (31 cases), foscarnet (19 cases), valgancyclovir (14 cases), different combinations (15 cases).
Overall, the treatment was well tolerated, with no reported infusion reactions nor other adverse events. Megalotect was administered for a median of 2 doses (range 1-9) and 3 doses (range 1-33) in patients treated prophylactically or pre-emptively. None of the 15 cases treated with Megalotect as prophylaxis developed CMV reactivation. Focusing on the 79 cases treated with Megalotect pre-emptively, 59 patients (75%) achieved at least one CMV viremia negativity during tratment. Median time to first negativity was 19 days (range 3-190). In 30/79 cases (38%) a subsequent CMV reactivation was observed during the follow up, which was treated with a second-line anti-CMV specific drug. Interestingly, only 6/94 cases (6%) developed CMV disease: gut localization in 4 cases and other site in 2 cases.Overall 24/94 patients died (25%) and no death was CMV-related
Our preliminary experience with Megalotect suggests that it is safe and well tolerated both in the pre-emptive and prophylaxis setting. We have no conclusive data regarding the efficacy of this treatment in reducing the cumulative dose of anti-CMV specific drugs. Interestingly, when used as prophylaxis, no CMV reactivation was recorded. In the pre-emptive setting, the combination of Megalotect and anti-CMV specific drug was able to induce negativity of CMV viremia in a relatively short time (median 19 days) and 38% of these high-risk patients only developed further CMV reactivation during follow up. Further prospective trials are warrented to address the most appropriate use of Megalotec (preophylaxis vs pre-emptive) and to identify the best setting of patients who can benefit from Megalotect alone or in addition to anti-CMV specific drugs.

Disclosures
Foà: ABBVIE: Other: ADVISORY BOARD, Speakers Bureau; JANSSEN: Other: ADVISORY BOARD, Speakers Bureau; AMGEN: Other: ADVISORY BOARD; GILEAD: Speakers Bureau; CELGENE: Other: ADVISORY BOARD, Speakers Bureau; INCYTE: Other: ADVISORY BOARD; NOVARTIS: Speakers Bureau; CELTRION: Other: ADVISORY BOARD; ROCHE: Other: ADVISORY BOARD, Speakers Bureau.