Cytomegalovirus (CMV) Resistance Associated Mutations (RAM) after ex vivo T-Cell Depleted (TCD) Hematopoietic Cell Transplant (HCT)

Background: More than 70% of CMV R+ recipients of TCD allografts experience CMV reactivation early post HCT. Viremia is often prolonged despite preemptive therapy. We report rates of CMV resistance-associated mutations (RAM) in a cohort of adult HCT recipients of ex vivo TCD allografts by CD34⁺ selection.

Methods: 220 adult CMV seropositive recipients of TCD allografts (Miltenyi Biotec, Gladbach, Germany) for hematologic malignancies at MSKCC were retrospectively analyzed. Routine CMV monitoring was performed by a quantitative PCR assay from day +14 to +180 post HCT. High grade CMV viremia was defined as >5x 10³ copies or IU/mL for ≥ 2 consecutive measurements more than 7 days apart. Genotypic test was performed (Viracor IBT, Lenexa, Kansas) at physicians’ discretion for rising viral load on treatment or rebound viremia after suppression. All patients (pts) were treated preemptively for CMV viremia.

Results: Of 220 pts, 161 (73%) developed CMV viremia at a median 28 days post HCT (IQR 23-34). Forty seven pts (29% of pts with CMV viremia) were tested, and CMV RAM was confirmed in 20 pts (42.6% of tested pts; 12.4% of viremic pts). Time from HCT to RAM detection was at median 152 days (IQR 105-189). Nineteen pts had > 5x 10³ copies or IU/mL for a median of 6 weeks (IQR 3-9). Among the 20 pts with CMV RAM, UL97 mutations were found in 12 (60%) pts, conferring resistance to gancivlovir (GCV) alone. The remaining 8 (40%) pts had UL54 ± UL97 mutations, conferring resistance to several combinations of ganciclovir, foscarnet and cidofovir (Table 1). The time of GCV treatment before RAM detection was at median 73 days (IQR: 97 – 115) among patients had UL97 single mutations. Of 20 pts with RAM, 11 (55%) had CMV disease.

Conclusion: 1) 29 % of TCD HCT with CMV viremia was tested for CMV RAM to guide clinical management. 2) RAM were confirmed in 12.4% of TCD HCT with CMV viremia. 3) Among 20 pts with confirmed RAM, 12 (60%) conferred resistance to ganciclovir (GCV) alone. Genotyping resistance is warranted in pts with prolonged and high grade viremia. Novel treatment modalities are needed.

Table 1: Types of CMV RAM detected

Gene	Resistance	N (%)
UL97
	GCV	12 (60%)
UL54 ± UL97
	GCV + FOS	3 (15%)
	GCV + CDV	3 (15%)
	FOS	1 (5%)
	GCV + FOS + CDV	1 (5%)
TOTAL		20

Abbreviations: GCV (val)ganciclovir; FOS foscarnet; CDV cidofovir

Seong Jin Kim, MPH¹, Julia Foldi, MD., PhD.¹, Genovefa Papanicolaou, MD^1,2 and Yao-Ting Huang, PhD, MPH¹, (1)Infectious Disease Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, (2)Weill Cornell Medical College, Cornell University, New York, NY

Disclosures:

S. J. Kim, None

J. Foldi, None

G. Papanicolaou, Chimerix, Inc.: Consultant , Investigator and Scientific Advisor , Honoraria
Merck: Grant Investigator , Research grant

Y. T. Huang, None

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