Abstract
Cytomegalovirus retinitis (CMVR) following hematopoietic stem cell
transplantation
(HCT) for a primary immunodeficiency is a rare but highly morbid
condition with potential irreversible consequences despite optimal
antiviral pharmacotherapy. Viral-specific T cells (VSTs) pose a
promising and safe approach eradicating intractable viral disease. We
describe the case of a 21-month-old male with Wiskott-Aldrich syndrome
(WAS) and CMVR post-HCT with sustained long-term virologic and clinical
response after CMV-specific T cell therapy. This case highlights the
need to consider VSTs as an adjunct upfront strategy in refractory CMVR
and for routine ophthalmologic screening and surveillance in high-risk
patients post-HCT.
Introduction
Wiskott-Aldrich syndrome (WAS) is an X-linked disease caused by
mutations in the WAS gene leading to thrombocytopenia, eczema,
recurrent infections, autoimmune disease, and
malignancy1. If transplanted prior to 5 years of age,
hematopoietic stem cell transplantation (HCT) offers a curative outcome
with a survival of >94%2. Despite
excellent survival outcomes, infections due to delayed immune recovery
remain a source of morbidity.
Disseminated CMV viremia post-HCT occurs in 60-85% of patients with CMV
seropositive status, especially in the setting of a T cell-depleted
graft3. CMV retinitis (CMVR) after HCT is rare, but
can cause potential devastating visual consequences. The median onset of
CMV following HCT is Day +34, and the median time of diagnosis of CMVR
is Day+ 251 post-HCT4,5. The minimal symptoms in the
early stages of CMVR and its suboptimal response to systemic and
intra-vitreal antiviral therapy, make CMVR a very challenging condition
to diagnose and treat.4 Recently, virus-specific T
lymphocytes (VSTs) have been used to treat systemic CMV, as they were
found to be effective in 83% of subjects treated for CMV
infection6.
In this report, we describe the successful case of an infant that
received CMV-specific T cells after developing persistent CMV viremia
and retinitis following a TCRαβ/CD19 B cell-depleted haploidentical HCT
despite standard antiviral therapy, achieving full donor chimerism,
CD3+ T cell recovery (>1000 cells/µL),
and normal phytohemagglutinin (PHA)-induced blastogenesis.
Case Report
A 7-month-old Asian male was diagnosed with WAS after he presented with
gastrointestinal bleeding and thrombocytopenia with a gene mutation in
the WAS gene (WAS 665del, p/Pro222Ginfs). The patient underwent a
paternal (CMV+)
TCRαβ/CD19
B cell-depleted HCT following conditioning chemotherapy with busulfan,
fludarabine, thiotepa, and rituximab. A cell dose of 38 x
106 CD34+ cells/kg was infused with
an αβ T cell dose of 0.49 x105 cells/kg. The patient
achieved neutrophil and platelet engraftment on Days +17 and +13,
respectively. Donor chimerism was 100% at Day +30 and remained at the
same level 2 years post-HCT. Post-HCT complications included maximum
grade 2 skin and GI acute graft-versus-host disease (aGvHD), which
resolved after a short course of systemic corticosteroids. On routine
surveillance, CMV reactivated on Day +49 with a maximum viral load of 53
060 IU/mL occurring on Day +78 (Fig. 1). At the time of CMV
reactivation, absolute CD3+ T cells were
65/µL
and CD4+ T cells 36/µL. Serial eye exams following CMV
diagnosis were unremarkable. He received induction dosing with
foscarnet followed by treatment
dosing with ganciclovir (GCV). Of note, CMV resistance testing was
negative.
On Day +158, he presented with a 1-week history of rotary bilateral
nystagmus and a CMV viral load of 520 IU/mL. CD3+ T
cells were 1 488/µL and CD4+ T cells were 233/µL.
Brain MRI showed right optic nerve enhancement (Fig. 2A) and an exam
under anesthesia (EUA) revealed bilateral granular CMVR with retinal
vasculitis and severe cystoid macular edema concerning for concomitant
immune recovery uveitis (IRU) (Fig. 2B). The aqueous humor was positive
for CMV bilaterally. The patient received both systemic and
intra-vitreal foscarnet and GCV with anterior chamber paracentesis
bilaterally. After the second intra-vitreal injection, the aqueous humor
was culture-negative for CMV. Systemic and single sub-tenons
corticosteroid injections were given to each eye for superimposed IRU.
CMV PCR became undetectable in the blood on Day +216 and the patient’s
nystagmus improved but did not resolve. An EUA showed improved macular
edema and inactive retinitis bilaterally but the patient developed
uveitis due to the corticosteroid injections, for which IV tocilizumab
for a total of 4 monthly doses was provided. Surveillance EUA on Day
+295 showed recurrent CMVR in the right eye despite negative CMV serum
titers in both blood and aqueous humor (Fig. 1). CD3+T cells were 94/µL and CD4+ T cells were 30/µL, which
was attributed to tocilizumab since T cell engraftment remained 100%.
The patient was subsequently enrolled on a phase II clinical trial
(NCT02532452) for the use of third-party quadrivalent
VSTs7. The patient, then 21-months-old, received 3
doses of CMV-specific T cells over 3.5 months spaced 4-6 weeks apart.
Following the first dose, CD3+ T cells increased from
994/µL to 3
372/µL
and CD4+ T cells increased from 284/µL to 1
389/µL. After the third infusion,
retinitis resolved and both the aqueous humor and blood remained
negative for CMV. As of this manuscript’s submission date, the patient
is 11-months post the first infusion of CMV-specific T cells, remains
without evidence of CMVR, has normal immune reconstitution
(CD3+ T cells 3 440/µL; CD4+ T cells
1 583/µL) and a normal mitogen stimulation test (PHA).
Discussion
Despite the curative potential of HCT for patients with WAS, post HCT
infectious complications such as disseminated CMV infection occur in
60-85% of patients with CMV seropositive status, especially in the
setting of a T cell depleted graft8. CMVR, occurring
in up to 5.6% of cases, can be visually devastating9.
This case highlights the importance of thorough and regular examinations
of the eyes in patients with CMV viremia. Although this particular
patient had early examinations that did not detect CMVR, it is important
to continue long-term monitoring if CMV is refractory.
HCT graft manipulation strategies such as
TCRαβ/CD19-depletion significantly
mitigate the risk of aGvHD, which is important for non-malignant
diseases such as WAS10. However, the consequent delay
in immune reconstitution increases the risk of opportunistic infections
as B cell and CD8+ T cell numbers don’t normalize
until 100-180 days and thymic-dependent CD4+ T cells
until 6-9 months post-HCT11. The risk of viremia for
CMV seropositive HCT recipients is inversely correlated with the
frequency of graft-derived CMV-specific T cells and the timing of
CMV-specific T cell immune reconstitution after HCT12.
In this patient, the rapid increase in CD4+ T cells
following VST infusion was key to CMVR resolution.
Although CMVR improves in the majority of affected
patients13, this patient had persistent CMVR despite
months of intravitreal and systemic antiviral therapy, negative
resistance testing, and a reconstituting immune system. The adoptive
transfer of VSTs offers a promising alternative to conventional therapy
in treating viral infections such as CMV, adenovirus, BK, and JC
virus3,14,15. Studies have shown resolution of CMV
viremia after one to two doses of VSTs in approximately 85% of
patients16. Gupta et al. treated seven patients, aged
26-68 years, who had CMVR with VST with a 90% resolution of the disease
with a median follow-up of 33 months17. Additionally,
there is one case report of a 3-year-old who also achieved remission of
CMVR following VSTs18. Our patient was 21 months of
age at the time of CMV-specific T cell infusion.
There are many advantages for using VST early, especially for young
children. First, serial intra-vitreal injections of foscarnet and GCV
require frequent examinations under anesthesia. Repeat episodes of
general anesthesia have been correlated with an increased risk of
neurodevelopmental delay19. Second, intra-vitreal
injections carry risk of systemic and ocular morbidity, including
endophthalmitis, intraocular inflammation, retinal detachment and
intraocular pressure elevation. Any of these can result in permanent
vision loss17,20.
In conclusion, ongoing ophthalmologic evaluations of children with
persistent CMV viremia are needed to detect CMVR early. Initiation of
treatment with CMV-specific T cells should be considered early for the
treatment of patients with CMVR as an adjunct therapy in children who
have resistant CMV disease.