CMV IN HEMATOPOIETIC STEM CELL TRANSPLANTATION
Every year, roughly 84,000 patients receive a hematopoietic stem cell transplantation (HSCT).1 For many, it’s their last hope for fighting off an advanced or refractory disease.2 However, cytomegalovirus (CMV) viremia is still a risk, occurring in 30%-70% of recipients.3
Presentation: From Viremia to Disease
In HSCT recipients, insufficiently controlled CMV viremia remains a considerable risk even with CMV medication.4 Viremia can develop into CMV disease any time after transplant.5
CMV disease can cause multiorgan disease, including pneumonia, hepatitis, gastroenteritis, retinitis, and encephalitis, and the mortality rate attributed to CMV disease in HSCT recipients can be as high as 60%.5,6 CMV pneumonia is the most serious manifestation of CMV disease in HSCT recipients, and can manifest with fever, nonproductive cough, and hypoxia.7
Mortalityattributed to CMV disease in HSCT6
Risk Factors for Developing CMV Viremia
Serostatus is a significant risk factor for development of CMV in HSCT. Recipients who are seropositive for CMV (R+) are at the highest risk for developing CMV viremia. Donor positive, recipient negative (D+/R-) transplants are at intermediate risk, while D-/R- are at the lowest risk.8
Additional factors for developing CMV viremia include T-cell depletion, use of high-dose corticosteroids, and acute and chronic graft-vs-host-disease (GVHD).7
Late-onset CMV is a significant complication in HSCT.7 Those treated for CMV in the first 100 days after transplant are at risk for late-onset CMV. Cord blood transplant recipients who are CMV seropositive and those treated with corticosteroids or other immunosuppressive agents for GVHD are also at increased risk.9
The Persistent Challenge of Refractory/Resistant CMV
Viremia rates refuse to go down? CMV that is refractory or resistant to treatment can lead to high morbidity and mortality rates, particularly in high-risk HSCT recipients.10
In a study of 488 HSCT recipients, 51% experienced refractory CMV posttransplant.11 In a separate study, HSCT recipients with refractory CMV reactivation showed higher rates of CMV disease (11.9%) than those without refractory CMV (0.8%).10
3O%-7O% CMV Viremia rate IN HSCT3
refractory cmv rate n = 488 recipients11
Defining the Problem
Definitions for resistant and refractory CMV can vary between clinical practice and published literature. Clinical trials have historically used the following definitions10:
Antiviral drug resistance Viral genetic alteration—assessed by genotyping—that decreases susceptibility to one or more antiviral drugs.
Refractory CMV CMV viremia that increasesa after at least 2 weeks of appropriately dosed antiviral therapy.
aMore than 1 log10 increase in CMV DNA levels in blood or serum and determined by log10 change from the peak viral load within the first week to the peak viral load at ≥2 weeks as measured in the same laboratory with the same assay.
In clinical practice, the suspicion of drug-resistant CMV infection is often based on suboptimal responses to antiviral agents, whether or not it is confirmed by laboratory testing and the identification of a known mutation by genotyping.10
When it comes to recognizing viremia and taking action, time is of the essence. One retrospective study of 174 allogeneic HSCT recipients found that faster clearance of CMV was associated with better survival.8
Risk Factors for Refractory/Resistant CMV
There are many factors which can contribute to resistant CMV in HSCT, including lower doses or longer duration of antiviral therapy, subtherapeutic CMV drug levels (due to inadequate drug absorption and bioavailability or oral prodrug conversion), poor patient compliance, active GVHD, rising CMV viral load, treatment with antithymocyte antibodies, and T-cell depletion.10
Refractory/Resistant CMV is a Threat to Survival
Refractory/resistant CMV corresponds with significant clinical challenges: protracted disease course, organ dysfunction, drug toxicities, recurrences, and a high mortality rate. In a recent study, recipients with refractory CMV reactivation showed a higher incidence of nonrelapse mortality (17.1%) than those without refractory CMV (8.3%). To make matters even more complex, second-line treatments for CMV often have significant toxicities. In one retrospective review of solid organ transplantations and HSCT with 39 patients, 51% of transplant recipients treated with a second-line antiviral experienced renal dysfunction.10,12
subtherapeutic drug levelsincrease risk of refractory/resistant CMV10
Refractory CMV reactivationIS ASSOCIATED WITH INCREASED NONRELAPSE MORTALITY10
3O%-7O% CMV Viremia rate IN HSCT3
Incidence of Neutropenia in HSCT patients who were treated with an antiviral therapy14
The Compounding Harm of Neutropenia
CMV is just one front in the battle against posttransplant infection, but it is not an isolated fight. Because of its role in influencing the production of various cytokines and T-cell responses, CMV makes it more difficult for the body to fight off additional infections.13 Neutropenia caused by antiviral therapy aggravates that effect, leaving the body more vulnerable to bacterial and fungal coinfections, potentially leading to worse outcomes and increased treatment costs.7,14
Neutropenia can occur in about 30% of HSCT patients treated with antiviral therapy.14
A threat to survival
Historically, neutropenia is associated with worse outcomes in HSCT. Specifically, it has been shown to negatively impact overall survival, event-free survival, and nonrelapse mortality.15
Neutropenia decreases overall survival15
The Menacing Risk of Graft-Vs-Host-Disease
GVHD continues to be a significant factor in HSCT, with acute GVHD being shown to occur in up to 40% of HSCT recipients with matched related donors and 60% of recipients with unrelated donors.16 GVHD is a major cause of mortality and morbidity, and has been associated with impaired posttransplant quality of life.14 In one study of 130 patients who experienced severe acute GVHD after HSCT, survival rates were 62%, 49%, and 47% at 1, 2, and 3 years respectively.17
While GVHD is a threat even in the absence of CMV, it has also been shown to be a significant risk factor for developing CMV viremia and disease.7,14 Additionally, CMV may play a role in the development of GVHD, creating a bidirectional relationship.14
a bidirectional relationship between CMV and GVHD
The immunosuppressive effects of GVHD and the corticosteroids used to treat it may allow for the reactivation of CMV.14
ANTIVIRAL DOSE ADJUSTMENT Refractory/ resistant viremia Increased viral load CMV disease Threat of renal dysfunction
The Precarious Threat of Renal Dysfunction
Acute and chronic kidney diseases are common following HSCT and can lead to long-term effects and negative impacts on mortality and morbidity. HSCT-associated kidney injury can be multifactorial, with causes including conditioning chemotherapy, radiation, nephrotoxic medications, and GVHD.18 To further complicate management, antiviral dose adjustments often have to be made for renal impairment.12,19 This creates the difficult balancing act of managing CMV with renal dysfunction.
A dangerous cycle that increases the risk of resistance
The nephrotoxicity balancing act is a tricky one, as renal function must be monitored and dose adjustments are often made for renal dysfunction.5 However, the same lowered dosage that can help protect kidneys is a risk factor for resistance, in turn making CMV infection more difficult to treat successfully.20
What's Your Next Move?
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- Niederwieser D, Baldomero H, Atsuta Y, et al. One and Half Million Hematopoietic Stem Cell Transplants (HSCT). Dissemination, Trends and Potential to Improve Activity By Telemedicine from the Worldwide Network for Blood and Marrow Transplantation (WBMT). Blood 2019;134(Supplement 1):2035.
- Haematopoietic Stem Cell Treatment HSCtx. World Health Organization. Accessed August 10, 2020. https://www.who.int/transplantation/hsctx/en/
- Cho S, Lee D, Kim H. Cytomegalovirus Infections after Hematopoietic Stem Cell Transplantation: Current Status and Future Immunotherapy. Int J Mol Sci. 2019;20(2666):1-17.
- Feuchtinger T, Opherk K, Bethge WA, et al. Adoptive transfer of pp65-specific T cells for the treatment of chemorefractory cytomegalovirus disease or reactivation after haploidentical and matched unrelated stem cell transplantation. Blood. 2010;116(20):4360-4367.
- Boeckh M, Ljungman P. How I treat cytomegalovirus in hematopoietic cell transplant Recipients. Blood. 2009;113(23):5711-5719.
- Camargo JF, Komanduri KV. Emerging concepts in cytomegalovirus infection following hematopoietic stem cell transplantation. Hematol Oncol Stem Cell Ther. 2017;10(4):233-238.
- Ljungman P, Hakki M, Boeckh M. Cytomegalovirus in Hematopoietic Stem Cell Transplant Recipients. Hematol Oncol Stem Cell Ther. 2011;25(1):151-169.
- Camargo JF, Kimble E, Rosa R, et al. Impact of Cytomegalovirus Viral Load on Probability of Spontaneous Clearance and Response to Preemptive Therapy in Allogeneic Stem Cell Transplantation Recipients. Biol Blood Marrow Transplant. 2018;24(4):806-814.
- Bar M, Flowers MED. Special Considerations for Long-Term Survivors After Hematopoietic Stem Cell Transplantation. In Ljungman P, Snydman D, Boeckh M. Transplant Infections. Springer International Publishing Switzerland; 2016:951-962.
- Chemaly RF, Chou S, Einsele H, et al. Definitions of Resistant and Refractory Cytomegalovirus Infection and Disease in Transplant Recipients for Use in Clinical Trials. Clin Infect Dis. 2019;68(8):1420-1426.
- Liu J, Kong J, Chang YJ, et al. Patients with refractory cytomegalovirus (CMV) infection following allogeneic haematopoietic stem cell transplantation are at high risk for CMV disease and non-relapse mortality. Clin Microbiol Infect. 2015;21(12):1121.e9-15.
- Avery RK, Arav-Boger R, Marr KA, et al. Outcomes in Transplant Recipients Treated With Foscarnet for Ganciclovir-Resistant or Refractory Cytomegalovirus Infection. Transplantation. 2016;100(10):e74-e80.
- Solak Y, Biyik Z, Cizmecioglu A, et al. Cytomegalovirus and Aspergillus spp. coinfection in organ transplantation: a case report and review of the literature. CEN Case Rep. 2013;2(1):59-67.
- Chan ST, Logan AC. The clinical impact of cytomegalovirus infection following allogeneic hematopoietic cell transplantation: Why the quest for meaningful prophylaxis still matters. Blood Rev. 2017;31(3):173-183.
- Salzberger B, Bowden RA, Hackman RC, Davis C, Boeckh M. Neutropenia in Allogeneic Marrow Transplant Recipients Receiving Ganciclovir for Prevention of Cytomegalovirus Disease: Risk Factors and Outcome. Blood. 1997;90(6):2502-2508.
- Gooptu M, Koreth J. Better acute graft-versus-host disease outcomes for allogeneic transplant recipients in the modern era: a tacrolimus effect? Haematologica. 2017;102(5):806-808.
- Bashley A, Zhang X, Morris L, et al. Improved Survival of Patients Diagnosed with Severe (Grade3-4) Acute GVHD or Severe NIH Grade Chronic GVHD in the Current Era Compared to. Historic Controls. Blood. 2019;134(Supplement 1):2006.
- Angelo JR, Hingorani S. Chapter 9: Hematopoietic Stem Cell Transplant—Related Kidney Disease. In Perazella MA. Onco-Nephrology Curriculum. American Society of Nephrology; 2016:1-7. Accessed August 12, 2020. https://www.asn-online.org/education/distancelearning/curricula/onco/
- Kotton CN, Kumar D, Caliendo AM, et al. The Third International Consensus Guidelines on the Management of Cytomegalovirus in Solid-organ Transplantation. Transplantation. 2018;102(6):900-931.
- Drew WL. Cytomegalovirus Resistance Testing: Pitfalls and Problems for the Clinician. Clin Infect Dis. 2010;50(5):733-6.