Medline Plus has this to say about bone marrow transplants (here used interchangeably to refer to hematopoietic stem cell transplantation [HSCT]): “Bone marrow is the soft, fatty tissue inside your bones. The bone marrow produces blood cells. Stem cells are immature cells in the bone marrow that give rise to all of your different blood cells.” According to the literature, HSCT has become a standard of care for hematologic malignancies, congenital or acquired disorders of the hematopoietic system, and it is also applied as a therapeutic option in some of the solid tumors. Here, I have provided a brief overview of CMV, with a focus on HSCT recipients. DISCLAIMER: Extracted research data from ongoing clinical trials are subject to change. This is not a substitute for medical advice. Please consult your doctor for any medical condition.

1. Cytomegalovirus Infection:
Focus on HSCT recipients
Zeena Nackerdien

2. Why CMV is a health issue
• Human cytomegalovirus (HCMV) is an enveloped double-
stranded DNA virus that belongs to the herpesviridae family1
• HCMV is a common opportunistic infection among human
immunodeficiency virus (HIV)-infected individuals, a major source
of serious viral complications among organ-transplant recipients,
and a leading cause of hearing loss, vision loss, and mental
retardation among congenitally infected children. In fact, more
children suffer serious disabilities caused by congenital CMV than
by several better-known childhood maladies such as Down
syndrome or fetal alcohol syndrome2
Colugnati FA, Staras SA, Dollard SC, et
al. BMC Infect. Dis. 2007;7(1):71.

3. HCMV
Transmission
Th
HCMV = human cytomegalovirus
1. Radestad AF, Estekizadeh A, Cui HL, et al. Transl Oncol. 2018;11(6):1292-1300.

4. Who is the patient at risk
for CMV recurrence?
ANSWER
The highest risk
of CMV recurrence
and CMV disease is
reported for HSCT CMV-
seropositive recipients,
regardless of donor
serostatus
0.6 3.5 5
7
12
30
37
Median Rate of CMV Recurrence (%)

5. Basics of HSCT
• Hematopoietic cell transplantation is an important
and potentially curative treatment option for a wide
variety of malignant and nonmalignant diseases
• The multipotent hematopoietic stem cells (HSCs)
required for this procedure are usually obtained from
the bone marrow or peripheral blood of a related or
unrelated donor
• Umbilical cord blood, the blood remaining in the
umbilical cord and placenta following the birth of an
infant, has emerged as an established alternative
source of hematopoietic stem cells in allogeneic HSCT
MYELOABLATIVE TRANSPLANT:
• High doses of chemotherapy or radiation used
prior to transplantation with autologous or allogeneic
cells
NON-MYELOABLATIVE TRANSPLANT:
• Depending on age or other medical issues,
reduced-intensity transplantation may occur e.g., less
intensive chemo prior to transplantation with
allogeneic HSCT.
1. Negrin R. https://www.uptodate.com/contents/sources-of-hematopoietic-stem-
cells?search=hemapoietic%20stem%20cell%20transplant&source=search_result&selectedTitle=3~
150&usage_type=default&display_rank=3. Accessed September, 2018.

6. Types of
Diagnostic
Tests
1
Serology
2
Cell culture
3
Antigenemia
assay
4
Polymerase
Chain
Reaction
Amplification
5
Immunohisto
chemistry
6
Nucleic acid
sequence-
based
amplification
(NASBA)
7
Hybrid
capture assay
1. https://www.medgadget.com/2018/08/global-cytomegalovirus-diagnostics-market-
analysis-by-test-type-application-and-end-user-forecast-to-2023.html. Accessed Sep, 2018.

7. Approaches
To Prevent CMV-
Related
Outcomes
UNIVERSAL PROPHYLAXIS1
1. Although universal
prophylaxis was effective in
preventing CMV primary
infection and reactivation
after transplantation in some
trials, the overall benefit of
prophylactic agents has been
difficult to assess
2. Universal prophylaxis has
been associated with
toxicities particularly
detrimental after HCT,
including clinically significant
myelosuppression
associated with ganciclovir
and valganciclovir use, which
may increase nonrelapse
mortality
PREEMPTIVE THERAPY1
1. Antiviral treatment
triggered by early
detection of active CMV
infection, before clinical
disease occurs
2. Specifically, patients
undergo blood CMV
surveillance with viral DNA
or antigen detection, and
antiviral therapy is initiated
above a certain detection
threshold
1. Chen K, Cheng MP, Hammond SP, et al. Blood Adv.
2018;2(16):2159-2175; 2. Kotton CN, Kumar D, Caliendo AM, et
al. Transplant. 2018;102(6):900-931.
HYBRID APPROACH2
1. The sequential approach of a
short course prophylaxis
followed by viral load
surveillance, previously
designated the “hybrid
approach,” limits the
duration of prophylaxis to
the period of most intense
immunosuppression.

8. Allogeneic
HSCT: Effects
of Antivirals
1. Chen K, Cheng MP, Hammond SP, Einsele H, et al. Blood Adv. 2018;2(16):2159-2175.
Antiviral Number of Studies
(Participants)
Median Treatment
Duration (Days)
Results
Acyclovir 8 (1347) 102 Although delay in onset of CMV
reactivation, the drug showed
nonsignificant efficacy in preventing
CMV.
Ganciclovir 5(647) 101 Effective in ↓ CMV infection and CMV
disease after allo-HSCT, but not
associated with ↓all-cause mortality
Maribavir 2(792) 84 No statistically significant effect on
mortality; well-tolerated
Brincidofovir 2(682) 71 Did not improve CMV-related
outcomes; Low completion rate in
Phase 3 trial (38%)
Letermovir 2(686) 122.5 Significantly ↓CMV reactivation, use of
pre-emptive anti-CMV therapy, and all-
cause mortality; Improved adverse
event profile; High treatment
completion rate (71%)

9. CMV
Reactivation is
Leading
Infectious
Complication in
HSCT Recipients
Allogeneic hematopoietic
stem cell transplantation
(HSCT) has curative
properties for many
hematologic disorders
Early post-HSCT, both innate and
adaptive immunity are impaired, due
to immunosuppression associated
with the procedure
CMV reactivation primarily
occurs within the first 100
days post-HCT, in more than
one third of CMV-
seropositive patients, the
group at highest risk for
CMV reactivation
Due to early CMV reactivation post-
HCT and enhanced risk of severe end-
organ disease, CMV positive
serology, either of the donor or the
recipient remains associated with
higher non-relapse mortality and
poorer overall survival
Current antiviral therapy
effectively limits viremia,
however its use is associated
with systemic and organ
toxicity, which besides
adding to the cost of HCT,
creates delays in immune
reconstitution, increases
fungal/bacterial infections,
breakthrough
gastrointestinal CMV
disease, and risk of late-
onset CMV disease
1. Nakamura R, La Rosa C, Longmate J, et al. The Lancet
Haematology. 2016;3(2):e87-e98.

10. Future Developments
CMV infection can fail to respond, with or without the presence of genotypic mutation(s) known to be associated with
resistance to these therapies. Refractory or resistant CMV infection in transplant recipients remains challenging due to a
limited number of available antiviral drugs, their associated serious toxicities, and an increased number of vulnerable patients.
The lack of consistent definitions for “resistant/refractory CMV” in clinical practice and the literature hampers assessment of
clinical trial results. Consistent criteria have been developed to aid clinical trials of investigational anti-CMV agents.
1. Chemaly RF, Chou S, Einsele H, et al. Clin Infect Dis. 2018 (e-pub).

11. Refractory CMV Viremia Definitions for
Clinical Trials (Transplant Recipients)
Refractory CMV infection is defined as CMV
viremia (DNAemia or antigenemia) that increases
(i.e., >1 log10 increase in CMV DNA levels in blood
or serum between peak viral load within the first
week and the peak viral load at 2 weeks or more as
measured in the same laboratory with the same
assay) after at least 2 weeks of appropriately dosed
antiviral therapy,
To increase the sensitivity of this definition, it is
important to emphasize that CMV viral load
monitoring should be done regularly and not less
than once per week. On the other hand, a modest
quantitative increase in viral load (as defined above
but a < 1 log10 increase) during the first 2 weeks of
anti-CMV therapy may occur in some patients, and
it may not be an indication of refractoriness or
resistance unless it persists at the same level or
higher at 2 weeks or more
Probable refractory CMV infection is defined as a
persistent viral load (CMV viral load at the same
level or higher than the peak viral load within 1
week but < 1 log10 increase in CMV DNA titers
done in the same laboratory and with the same
assay) after at least 2 weeks of appropriately dosed
antiviral therapy.
Persistent CMV DNA titers below 1000 IU/mL, and
in particular detected but not quantifiable (<137
IU/mL), should not be considered refractory CMV
infection.
1. Chemaly RF, Chou S, Einsele H, et al. Clin Infect Dis. 2018 (e-
pub).

12. Refractory CMV Viremia Definitions for
Clinical Trials (Transplant Recipients)
Refractory CMV end-organ disease
is defined by a worsening in signs
and symptoms or progression into
end-organ disease after at least 2
weeks of appropriately dosed
antiviral therapy
Signs and symptoms of CMV end-organ disease
may be difficult to discern and reporting
symptoms is often subjective and varies with
patient and provider. Certain CMV end-organ
diseases (e.g. CMV retinitis and gastrointestinal
diseases) are not always associated with
measurable viral loads in serum or whole
blood; in these cases, CMV may be replicating
locally at tissue sites and may not be recovered
for resistance testing
Probable refractory CMV end-organ
disease is defined by the lack of
improvement in signs and
symptoms after at least 2 weeks of
appropriately dosed antiviral
therapy
Signs and symptoms of CMV end-organ disease
may be difficult to discern and reporting
symptoms is often subjective and varies with
patient and provider. In addition, other factors
have to be weighed into the determination of
probable refractory CMV end-organ disease
such as the site (i.e. gastrointestinal tract vs.
retina) and the presence of other contributing
causes to the signs and symptoms such as
GVHD
GVHD = graft-versus-host-disease
1. Chemaly RF, Chou S, Einsele H, et al. Clin Infect Dis. 2018 (e-pub).

13. Resistance/Susceptibility Definitions for Clinical
Trials (CMV Treatment in Transplant Recipients)
Antiviral drug resistance is commonly defined as a
viral genetic alteration that decreases susceptibility
to one or more antiviral drugs. The alteration
typically involves genes involved in antiviral drug
anabolism (e.g. UL97-mediated phosphorylation of
ganciclovir, the antiviral drug target (e.g. UL54,
UL97, UL56/89/51), or compensation for antiviral
inhibition of biological function (e.g. UL27)
Decreased susceptibility is
defined by assay of the
drug concentration
required to reduce viral
growth in cell culture by
50% (EC50).
1. Chemaly RF, Chou S, Einsele H, et al. Clin Infect Dis. 2018 (e-
pub).

14. Predictors of
Increased Risk
for Post-
Transplant
CMV Disease
Immune monitoring of CMV-specific T-cell responses can
predict individuals at increased risk of CMV disease
posttransplant and may be useful in guiding prophylaxis
and preemptive therapies
In addition to IFN-γ, other markers, including IL-2, TNF-α,
CD107, programmed death-1 (PD-1), and CD154 have been
used to correlate CMV-specific T-cell responses with the
risk of CMV infection
Moreover, a negative test before transplantation may aid in
predicting viremia in the posttransplant period or the
dynamics of T-cell responses may be used as a monitoring
tool in a preemptive setting
Various commercial assays are also predictive of CMV
viremia and CMV disease

15. Takeaways
Patients at increased risk for
primary CMV reactivation and
CMV disease are most likely to
benefit from anti-CMV
prophylaxis.
Additional research is warranted to
further refine which HCT populations
would benefit most from prophylaxis in
a rapidly evolving landscape. Further
research is also warranted to study the
impact of CMV surveillance after the
prophylactic period, the optimal threshold
at which to initiate preemptive therapy
after prophylaxis, and the role of
CMV-specific immune monitoring for
guiding prophylactic and preemptive
CMV strategies. These parameters will
remain fluid and are likely to change in
the future with the incorporation of
CMV immunotherapies and CMV vaccines.
1. Chen K, Cheng MP, Hammond SP, et al.Blood Adv.
2018;2(16):2159-2175.