Temozolomide Demonstrates High Response in Older Patients With Primary Vitreoretinal Lymphoma

Temozolomide demonstrated a high overall response rate in a study of patients with primary vitreoretinal lymphoma (PVRL) who were either considered ineligible for intensive firstline treatment or whose PVRL relapsed after or was refractory to such treatment.

PVRL is a rare non-Hodgkin lymphoma with a generally poor prognosis, in part due to the high risk of central nervous system involvement. The study, published in Blood, suggests temozolomide may be an important alternative treatment strategy in patients with PVRL who present with contraindications to intensive chemotherapy or are failed by such therapy.

“There are few available data about elderly patients with relapsed/refractory PVRL, and our study is one of the largest,” said lead study author Marine Baron, MD, of Pitié-Salpêtrière University Hospital in Paris. In young and fit patients, she said, autologous hematopoietic cell transplantation (AHCT) is a treatment option with high response rates, but AHCT is too toxic for many elderly or frailer patients. “In elderly patients, local treatment of PVRL, such as ocular radiotherapy or intravitreal methotrexate, could be considered, but they don’t protect from cerebral relapse,” she said.

Dr. Baron and investigators conducted a retrospective, multicenter analysis of 21 adults (median age = 75 years; range = 35-90) with PVRL.

At baseline, 1 patient had associated brain involvement and 19 patients had received at least 1 prior treatment. A total of 14 patients had received high-dose methotrexate, whereas 5 patients had received either high-dose cytarabine (n=3) or intravitreous methotrexate injections (n=2). Prior to treatment with temozolomide, 2 patients received AHCT and 1 patient received cerebral radiotherapy.

Treatment consisted of oral temozolomide 150 or 200 mg/m2, administered 5 days per month. Responses to therapy were assessed by ophthalmologic examination and gadolinium contrast-enhanced magnetic resonance imaging.

Over a median follow-up of 42 months (range = 9-115), the mean duration of temozolomide treatment was 5.2 months (range = 1-40). The overall response rate (ORR) was 81%:

  • 2 patients (10%) achieved a partial response
  • 15 patients (71%) achieved a complete response (CR)
  • 4 patients (19%) had progressive disease

The authors also noted that 1 patient with both ocular and cerebral involvement achieved CR during treatment.

The median duration of response was 10.9 months (range = 3-109). At last follow-up, 6 patients remained in CR – all but one of whom had stopped temozolomide treatment. One patient who received an AHCT prior to temozolomide has maintained a CR for a total of 115 months following treatment initiation.

Six deaths occurred during study follow-up, 5 of which were due to cerebral progression. The researchers reported a median progression-free survival (PFS) of 12 months (range = 8 months to not reached) and a 2-year PFS rate of 30%. The median overall survival was not reached at the time of the study’s publication.

Grade 3 toxicities, including anemia and vomiting, were reported in 3 patients, while 1 patient experienced grade 4 neutropenia and thrombocytopenia. Another patient reported worsening memory and asked to discontinue treatment; this patient had neurologic dysfunction prior to temozolomide initiation. “No unusual toxicity was observed and, compared with [intensive] chemotherapy, radiotherapy, lenalidomide, or ibrutinib, temozolomide seems to be better tolerated,” the investigators wrote.

They also observed that in patients who responded to temozolomide, levels of cytokines used to diagnose and monitor PVRL decreased. In 9 responders who were tested, the course of interleukin 10 (IL-10) assays on the vitreous and/or the aqueous humour decreased, while the course of IL-10 assays increased for 1 patient with progressive disease.

Future directions for evaluating this drug would be to test its efficacy and safety in a larger randomized cohort, said Dr. Baron. “We would like to address temozolomide efficacy in a larger population and to compare temozolomide with drugs such as lenalidomide and ibrutinib in a prospective study,” she explained. Dr. Baron also hopes to examine the efficacy of temozolomide in the frontline setting “given the high rates of relapses after frontline therapy with methotrexate and aracytin.”

In addition to temozolomide’s high ORR, the authors suggest the drug may offer an economic advantage over other therapies used in similar clinical contexts. However, additional cost-to-benefit ratio analyses are needed to identify the economic feasibility of temozolomide in the older population with PVRL, and cost depends on the country and context of patients treated.

Limitations of the study included the small sample size, retrospective design, as well as the lack of central pathologic confirmation.

The authors report no relevant conflicts of interest.

Reference

Baron M, Belin L, Cassoux N, et al. Temozolomide is effective and well tolerated in patients with primary vitreoretinal lymphoma. Blood. 2020 March 2. [Epub ahead of print]