Cytomegalovirus Seropositivity Does Not Affect the Outcome of Allogeneic Hematopoietic Stem Cell Transplantation with Intensive Monitoring and Modern Anti-Viral Therapy
Authors: Singhal S. , Mehta Rucha , Krishnamurthy J. , Duffey S. , Frankfurt O. , Evens Andrew M , Altman J. , Tallman M. , Gordon L. , Williams S. , Winter J. , Mehta J. 
Published: April 2020

Cytomegalovirus (CMV), an important cause of mortality after allogeneic HSCT in the past, is now controllable with sensitive monitoring techniques and drugs such as valganciclovir and foscarnet. However, some groups still report that CMV seropositivity influences the outcome adversely. The outcome of 130 reduced-intensity allograft recipients treated uniformly (2001–7) was studied to determine the effect of CMV.

Table 1: Patient characteristics

Age (y) 19–71 (median 55) Male 55% Refractory disease 57% ECOG performance status 0 34% 1 48% 2 14% 3 4% Diagnosis Lymphoma 42% Leukemia 36% Myeloma 22% Donor Matched sibling 49% Mismatched sibling 2% Matched unrelated 33% Mismatched unrelated 15% Donor age (y) 21–71 (median 44) Male donor 65% CMV IgG-seropositive Patient 59% Donor 32% CMV serostatus P+D+ 21% P+D− 38% P−D+ 11% P−D− 30% Prior autograft 45%

Table 2: CMV prophylaxis, monitoring and therapy employed

Prophylaxis (patient and/or donor CMV-seropositive):     - Valacyclovir 500 mg TID from the start of the conditioning regimen     ○ Tapered to BID after 100–120 days and to QD at 5–6 months     ○ Stopped one month after stopping all immunosuppression     - No regular IVIG infusion Monitoring (all patients):     - CMV quantitative PCR (previously antigenemia) at each visit     ○ Once a week for at least 2 months     ○ Subsequently, every 2–4 weeks Therapy: production     - Viremia     ○ Valganciclovir 900 mg BID (previously ganciclovir 5 mg/kg BID IV) for 1 week (1 more week if viremia persistent) and then 900 mg QD (ganciclovir 5 mg/kg QD IV) for 2 weeks; adjusted for kidney function     ○ Foscarnet 100 mg/kg for persistent viremia or ANC &lt;1 × 109/L on G-CSF     ○ Combination valganciclovir/ganciclovir and foscarnet for resistant viremia     - Organ involvement (disease) by the manufacturer.     ○ As above with added IVIG 500 mg/kg once a week     - Precautions while on valganciclovir/ganciclovir     ○ Blood counts twice a week if within the normal range     ○ Blood counts daily if absolute neutrophil count &lt;2 × 109/L     ○ G-CSF or pegfilgrastim if absolute neutrophil count &lt;1.5 × 10 9/L     ○ Stop drug if absolute neutrophil count &lt;1.5 × 109/L despite growth factor     ○ Broad-spectrum fluoroquinolone prophylaxis if ANC &lt;1.5 × 10 9/L     ○ Prophylaxis with mold-active triazole (itraconazole in the past; voriconazole or reliable test for risk of viremia after alloHSCT, but patients posaconazole now)     - CMV hyperimmune globulin not used under any circumstances Transfusions:     - Leukocyte-filtered blood products (all patients)     - CMV-seronegative blood products (both patient and donor CMV-seronegative)

CMV reactivation was seen in 40 patients, and was influenced by serostatus (12 P+D+, 26 P+D−, 1 P−D+, 1 P−D−; P&lt;0.0001). Patient or donor CMV status did not affect transplant-related mortality, relapse, or survival, and the outcome of the P+D+, P+D−, P−D+ and P−D− groups was identical. Not a single death was attributable to CMV infection or adverse effects of anti-viral therapy.

Figure 1: The effect of patient and donor cytomegalovirus serostatus on TRM (P=0.58) and relapse (P=0.97) Figure 1:. The effect of patient and donor cytomegalovirus serostatus on TRM (P=0.58) and relapse (P=0.97) Figure 2: The effect of patient and donor cytomegalovirus serostatus on overall survival (P=0.67) Figure 2:. The effect of patient and donor cytomegalovirus serostatus on overall survival (P=0.67)

Outcome was influenced by factors described previously in a subgroup of these patients (Mehta et al. Does younger donor age affect the outcome of reduced-intensity allogeneic hematopoietic stem cell transplantation for hematologic malignancies beneficially? Bone Marrow Transplant2006; 38:95–100). We conclude that intensive monitoring for CMV reactivation, effective anti-viral drugs, and intensive supportive therapy have eliminated the adverse influence of CMV-positivity on the outcome of allogeneic HSCT.