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Post-Transplant Cyclophosphamide, Mycophenolate Mofetil May Increase CMV Reactivation and Disease in Seropositive Patients

March 14, 2023

April 2023

Katie Robinson

Katie Robinson is a medical writer based in New York.

In patients who are seropositive for cytomegalovirus (CMV), the type of post-transplantation prophylaxis for graft-versus-host disease (GVHD) may affect CMV recurrence and disease, according to study results published in Blood Advances.1 Post-transplant cyclophosphamide (PTCy) was associated with a higher risk of early CMV reactivation (i.e., within 100 days) but a comparable one-year viral burden and CMV disease compared to methotrexate (MTX) prophylaxis. Researchers also found that in patients receiving mycophenolate mofetil (MMF), the CMV viral burden over the first post-transplant year was significantly higher versus MTX prophylaxis.

“Our results show that CMV seropositive patients receiving PTCy or MMF after [human leukocyte antigen (HLA)]-matched peripheral blood stem cell transplantation have a higher risk of CMV reactivation compared to patients receiving MTX-based GVHD prophylaxis,” said corresponding author Masumi Ueda Oshima, MD, of Fred Hutchinson Cancer Center in Seattle. “Thus, patients receiving PTCy or MMF should be vigilantly monitored for CMV, and letermovir prophylaxis should be strongly considered.”

Dr. Ueda Oshima and colleagues retrospectively compared CMV reactivation and disease in 780 seropositive patients who underwent HLA-matched peripheral blood stem cell grafts for hematologic malignancies between July 2007 and September 2018. All participants received a calcineurin inhibitor plus either PTCy (n=44), MMF (n=414), or MTX (n=322).

After multivariable adjustment, PTCy and MMF were associated with an increased risk of CMV reactivation (≥250 IU/mL) on or before day 100 post-transplant (PTCy vs. MTX: hazard ratio [HR] = 1.64, 95% CI 1.03-2.61; p=0.039; MMF vs. MTX: HR=1.50, 95% CI 0.97-2.32; p=0.067).

“The risk appears to be limited to the early post-transplant period after PTCy, and overall viral burden in the first-year post-transplant appears to be low. CMV viral immunity may be compromised early on after PTCy, but the risk appears to be mitigated later on, likely related to the effective prevention of chronic GVHD and lower cumulative immunosuppressive treatment,” Dr. Ueda Oshima said.

Spline curves were fit over average daily viral load, and areas under the curve (AUC) within one-year were calculated. MMF was associated with higher risk of early CMV reactivation at higher thresholds (≥1,000 IU/mL), late CMV reactivation, and one-year viral load AUC (mean difference = 0.125 units vs. MTX, 95% CI 0.061-0.189; p<.001). The AUC was similar between PTCy and MTX (mean difference = 0.016 units vs. MTX; 95% CI -0.126-0.158; p=0.827). The risk of CMV disease was not significantly different among the GVHD prophylaxis regimens.

According to the authors, the study results related to PTCy are consistent with data from the Center for International Blood and Marrow Transplant Research, which includes HLA-matched sibling transplantation, but extend the findings to recipients of HLA-matched unrelated donor transplants.2,3

The authors concluded that early post-transplant CMV anti-viral immunity may be compromised by the use of PTCy, but it later spares the use of immunosuppressive treatment, potentially providing an advantage in restoring viral immunity and “resulting in the effective prevention of progression to higher viral load levels and CMV disease.”

Limitations of the trial include the relatively low number of patients in the PTCy group.

“This study looked at a time period before the routine use of letermovir prophylaxis, so it would be interesting to see if our findings apply to a more contemporary cohort of patients who receive letermovir,” Dr. Ueda Oshima said.

Any conflicts of interest declared by the authors can be found in the original article.

Katie Robinson is a medical writer based in New York.

References

  1. Ueda Oshima M, Xie H, Zamora D, et al. Impact of GVHD prophylaxis on CMV reactivation and disease after HLA-matched peripheral blood stem cell transplantation [published online ahead of print, 2023 Jan 3]. Blood Adv. doi: 10.1182/bloodadvances.2022009112.
  2. Goldsmith SR, Abid MB, Auletta JJ, et al. Posttransplant cyclophosphamide is associated with increased cytomegalovirus infection: a CIBMTR analysis. Blood. 2021;137(23):3291-3305.
  3. Singh A, Dandoy CE, Chen M, et al. Post-transplantation cyclophosphamide is associated with an increase in non-cytomegalovirus herpesvirus infections in patients with acute leukemia and myelodysplastic syndrome.Transplant Cell Ther. 2022;28(1):48.e1-48.e10.

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