Keywords
Cytomegalovirus - HyperCVAD - retinitis
Introduction
Primary cytomegalovirus (CMV) infection is usually asymptomatic in immunocompetent
individuals; however, in immunosuppressed hosts, the infection causes retinitis, gastroenteritis,
colitis, pneumonitis, and encephalitis and results in significant morbidity and mortality.
CMV produces a characteristic necrotizing retinitis which is a sight-threatening condition.
It occurs rarely in patients undergoing only chemotherapy. Few cases have been reported
during the maintenance phase of acute lymphoblastic leukemia (ALL) in children.[1] We report 2 patients on HyperCVAD chemotherapy developing CMV retinitis while on
treatment.
Case Reports
Patient 1
A 16-year-old boy was diagnosed with T-cell ALL and was started on HyperCVAD regimen.
He attained marrow remission after cycle IA and was continued till IV B, followed
by prophylactic cranial radiation and maintenance chemotherapy with oral 6-mercaptopurine
and methotrexate. One year later, he presented with decreased vision in the left eye.
Ophthalmologic examination showed granular variant of CMV retinitis [Figure 1]. His absolute CD4 count was 134 cells/μL and serum CMV quantitative polymerase chain
reaction (QPCR) was 63 IU/ml. He was started on intravenous ganciclovir 6 mg/kg/day
for 21 days followed by oral valganciclovir 900 mg twice daily for another 3 weeks.
He also received intravitreal ganciclovir injection, 2.25 mg at week 4. His CMV QPCR
became undetectable 2 weeks after starting therapy. The patient regained normal vision,
and an ophthalmology review after 5 weeks of therapy showed healed CMV retinitis.
His absolute CD4 count improved, and he completed 2 years of maintenance chemotherapy.
Ophthalmic examination after completion of treatment showed fresh CMV retinitis lesions
in the right eye and healed lesions in the left eye. He was restarted on weekly intravitreal
ganciclovir injection 2.25 mg for 2 doses along with oral valganciclovir for 2 months
following which his ocular lesions healed and he also underwent laser barrage of healed
left eye. Currently, he continues to be in complete remission of his leukemia and
his CMV retinitis at 60 months.
Figure 1: Retina of the left eye of patient 1 showing active granular cytomegalovirus
retinitis
Patient 2
A 32-year-old man was diagnosed with Burkitt’s lymphoma and started on HyperCVAD chemotherapy
along with Rituximab (R HyperCVAD). Following the cycle 4 A, he complained of defective
vision in the left eye. The ophthalmologic examination revealed bilateral acute retinitis;
left more than right [Figure 2]. His CMV IgG was positive, serum CMV QPCR was 1,20,150 IU/ml, and absolute CD4 count
was 45 cells/μL. He was given intravenous ganciclovir 6 mg/kg/day for 21 days followed
by oral valganciclovir. The CMV QPCR titers became normal after 3 weeks of therapy.
He also had profound myelosuppression during this period. A repeat ophthalmologic
evaluation showed good resolution of retinitis and vision was preserved. The CMV QPCR
became undetectable after 9 weeks, valganciclovir was discontinued after 15 weeks,
and he was kept on follow-up. After 3 months, the ophthalmologic evaluation showed
few hemorrhagic lesions in the right eye and oral valganciclovir was restarted at
900 mg once daily. He responded, ocular lesions healed, and the drug was stopped after
12 weeks. At present, he is in complete remission at 40 months. His CMV retinitis
also has completely resolved with preservation of normal vision.
Figure 2: Retina of the left eye of patient 2 showing active cytomegalovirus retinitis
Discussion
The incidence of CMV antigenemia in adults with lymphoid malignancies who did not
undergo stem cell transplant was reported as 13.6%.[2] The rate of CMV reactivation in patients with hematologic malignancies in the nontransplant
setting was highest for alemtuzumab therapy (50%), followed by 9.7% for HyperCVAD
regimen and 4.6% for fludarabine-based regimes.[3] The incidence of CMV retinitis affecting children with ALL in the nontransplant
setting was estimated as 3.6%, but no data is available in adults.[4] CMV retinitis presents as a necrotizing retinitis with a characteristic ophthalmoscopic
appearance, is usually unilateral, but may progress to opposite eye if inadequately
treated and may result in visual loss.
Both the patients in this report were on HyperCVAD chemotherapy when they developed
the CMV retinitis. There are only 3 other reports in world literature on patients
developing CMV retinitis while on HyperCVAD. A 39-year-old female with Burkitt’s lymphoma
on RHyperCVAD developed CMV retinitis and was treated with intravenous ganciclovir,
intravitreal ganciclovir, and intravenous foscarnet.[5] Another 50-year-old man with T-cell ALL developed CMV retinitis during 4th cycle
of R HyperCVAD and was treated with oral valganciclovir.[6] A 49-year-old man with ALL, on salvage chemotherapy with HyperCVAD, developed CMV
retinitis and was treated with intravenous ganciclovir with preservation of visual
acuity.[7]
There is profound immunosuppression during the maintenance phase of ALL. The reconstitution
of B-cell and natural killer cells occur early, whereas the T-helper and T-suppressor
cell recovery are delayed.[8] In addition, there is low absolute lymphocyte count, low CD4 T-cells, and immunoglobulins.
The addition of vincristine and dexamethasone pulses to 6-mercaptoputine and methotrexate
may affect cell-mediated immunity and increase the risk of CMV retinitis.[9]
In both patients in this report, CMV retinitis was diagnosed clinically along with
elevated plasma CMV DNA and reduced CD4 counts. Intraocular fluid sampling was not
done in view of the thrombocytopenia. Both responded to initial ganciclovir, however,
had asymptomatic relapse and were successfully treated with a second course of ganciclovir.
Currently, both patients are in complete remission of their primary disease as well
as the CMV status and have normal vision. The possible factors that predisposed our
patients to develop CMV retinitis could be the immunosuppression inherent to the disease
and to the intensive chemotherapy in addition to the high dose of steroids in HyperCVAD.
Early and prompt treatment for CMV retinitis is critical. Optimal treatment of CMV
retinitis includes intravenous ganciclovir, oral valganciclovir, intravitreal ganciclovir,
intravenous foscarnet, and cidofovir. Induction is usually given for 2–3 weeks followed
by maintenance. Although these antivirals provide effective treatment options, phenotypic
resistance to these has been reported in 5%–25%.[10] An ophthalmologist should also be included in the active management of CMV retinitis.
Indirect ophthalmoscopy should be performed at the time of diagnosis, 2 weeks after
initiating therapy, and monthly thereafter while patient on anti-CMV treatment to
evaluate efficacy of treatment and to detect complications such as retinal detachment.
