CMV Retinitis After Ruxolitinib Treatment: Case Report

Megan Brooks

January 20, 2016

What appears to be the first case of cytomegalovirus (CMV) retinitis in a patient with myelofibrosis treated with ruxolitinib (Jakafi/Jakavi, Incyte/Novartis) is reported in a letter to the editor in the January 21 issue of the New England Journal of Medicine.

"To my knowledge, there has been no previous reports on cytomegalovirus retinitis in these patients and no previous cases in my clinic," first author Joanna von Hofsten, MD, from Hallands   Hospital Halmstad, in Sweden, told Medscape Medical News.

She advises clinicians to "ask patients treated with ruxolitinib to report any symptoms of reduced or disturbed vision. If this is the case, the patient should undergo ophthalmological   examination."

Ruxolitinib is an oral JAK1 and JAK2 inhibitor. In 2011, it became the first drug treatment ever approved for myelofibrosis by the US   Food and Drug Administration (FDA). The drug was approved ahead of schedule under the FDA's priority review process for products that offer a significant advance over available therapies or that   provide a treatment when no adequate therapy exists.

Serious infections in patients who have received ruxolitinib have been previously reported, including disseminated herpes simplex virus infection. CMV retinitis should be added to the list, Dr   von Hofsten and colleagues say.

Medscape Medical News asked Srdan Verstovsek, MD, PhD, from the University of Texas MD Anderson Cancer Center, in Houston, for his thoughts on this case of CMV retinitis in a patient   treated with ruxolitinib. Dr Verstovsek was the principal investigator on one of the two pivotal trials that led to the FDA's approval of ruxolitinib.

"I am not sure what to tell you about this case; this is old news," he said. "It is well recognized that atypical infections can happen in patients on ruxolitinib," he added.

Details of the Case Report

In their letter to the New England Journal, they describe a 67-year-old man diagnosed in 2009 with primary myelofibrosis with extramedullary hematopoiesis and splenomegaly. In late 2013,   treatment with ruxolitinib (15 mg twice daily) was initiated. This produced a "palpable" reduction in spleen size.

About 6 months later, in June 2014, the patient presented to his ophthalmologist with unilateral anterior uveitis. He was started on mydriatic eyedrops and low-dose topical glucocorticoids but   failed to respond and developed signs of posterior involvement.

At this point, the patient was referred to Dr von Hofsten and colleagues, who noted a "slight vitritis and a few retinal hemorrhages." His vision was 20/200. They consulted with his   hematologist, who felt that an opportunistic infection was unlikely. The patient received intensified local treatment and oral glucocorticoids. The status of the eye suddenly deteriorated, with   vasculitis, optic-disk edema, and a small, whitish retinal infiltrate, prompting an anterior chamber tap. On real-time analysis with polymerase chain reaction, the aqueous humor was found to   bestrongly positive for CMV. No levels of CMV were detected in plasma. The patient was HIV negative.

The patient was started on valganciclovir (Valcyte, F. Hoffman-La Roche Ltd) 900 mg twice daily, but the affected eye became ischemic and amaurotic. The dose of ruxolitinib was   decreased, and valganciclovir was continued at a dose of 450 mg twice daily. The other eye subsequently became affected. Infection in the other eye was controlled with intravenous (and, later,   intravitreal) ganciclovir. Ruxolitinib was discontinued.

Check NK Cell Count Before Ruxolitinib?

Dr von Hofsten and colleagues note in their letter that a recent study showed a reduction in the number of natural killer (NK) cells in patients treated with ruxolitinib. This reduction was linked to clinically relevant infections. It has been shown that NK cells play a role in   controlling herpes infections (including CMV), especially when the number of T cells is low.

The clinicians note that when they initiated valganciclovir in their patient, the NK cell count (CD16 and CD56+) was 20 cells/mm3, which is below the normal range (80 - 570   cells/mm3). "Unfortunately, the levels before ruxolitinib treatment are not known. The CD4+ T-cell count was normal at 870 cells per cubic millimeter (normal range, 400 to 1200)," they   write.

Dr von Hofsten told Medscape Medical News that she thinks clinicians should "consider quantification of natural killer cells in patients before initiating treatment with ruxolitinib and   during follow-up. This is because of the previously reported higher risk of herpes infection (including CMV) in NK-deficient patients."

Company Responds

A Novartis spokesperson told Medscape Medical News by email that the company is "aware of the case" but added that "a causal relationship of the case of CMV retinitis with ruxolitinib   treatment has not been established at this time. Patient safety is a top priority for Novartis, and we are undertaking a comprehensive review to gather relevant information to more thoroughly   understand this isolated incident."

The company added, "Controlled clinical studies have validated the safety and efficacy of ruxolitinib as an important treatment for patients with MF, a debilitating blood cancer. No cases of   CMV retinitis have been identified in patients with myelofibrosis, polycythemia vera or other diseases treated with ruxolitinib in clinical trials or commercial use worldwide.

"An evaluation of the case will be submitted as part of the ruxolitinib Periodic Safety Update Report and Development Safety Update Report," the company said.

"Physicians should evaluate each patient on a case-by-case basis and refer to the Summary of Product Characteristics when prescribing ruxolitinib. It is also important that physicians determine   the benefit versus risk of ruxolitinib treatment for patients who may be at a greater risk for infections," Novartis said.

N Engl J Med. 2016;374:296-297. Full text


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