No reactivation of JCV in bone marrow of follicular lymphoma patients treated front-line with rituximab plus 90y-ibritumomab tiuxetan

Treatment with the anti-CD20 monoclonal antibody rituximab has been associated with progressive multifocal leukoencephalopathy (PML) in rheumatological and nonHodgkin lymphoma patients and in solid organ transplant recipients [1]. PML is caused by reactivations of the polyomavirus JC (JCV), and early detection of JCV genome in peripheral blood has been suggested as a good surrogate marker for treatment interruption and increased surveillance for PML in kidney transplant recipients treated with rituximab and in multiple sclerosis patients treated with natalizumab [2, 3]. Moving from evidences of JCV replication in bone marrow plasma cells both after treatment with rituximab and in HIV-positive patients without PML, our group previously tested serial bone marrow samples of four PML cases and found that bone marrow JCV positivity preceded positivity in peripheral blood, cerebrospinal fluid, and brain biopsy [4]. Here, we systematically investigated the occurrence of JCV reactivations in follicular lymphoma patients treated with the murine anti-CD20 IgG1j mAb ibritumomab conjugated to the metal chelator tiuxetan for the retention of the b emitter yttrium (Y-IT). Informed consent was obtained from all patients for being included in the study. All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008. Twenty adult patients (enrolled in a phase I–II clinical trial of Y-IT therapy as standard initial treatment for advanced-stage follicular lymphoma [5]) received the single-agent Y-IT standard regimen as follows: a first rituximab 250 mg/m infusion was given alone on day 1. A second infusion of rituximab, administered 1 week later, on day 8 (±1), was followed immediately by 15 MBq/kg of Y-IT, given as a slow intravenous push over 10 min. Bone marrow aspiration samples were collected at diagnosis, and at restaging on months ?1, ?3, ?6, ?12 after treatment with Y-IT. Bone marrow DNA was tested by qualitative nested PCR (sensitivity: 1 copy per 35,000 cells, similar to that used by other investigators [2, 3]). We could not detect any reactivation in any patient at any time point. We have reported here for the first time the absence of JCV reactivations in bone marrow of lymphoma patients treated upfront with Y-IT. Although the study has a limited follow-up, the extremely high level of assay sensitivity provides clinicians reassurance on the risk of PML after treatment with Y-IT. Further studies are needed to confirm long-term safety of treatment with Y-IT in relapsed or refractory patients and of maintenance therapy. D. Focosi (&) M. Pistello Department of Translational Research, University of Pisa, via Paradisa 2, 56124 Pisa, Italy e-mail: daniele.focosi@gmail.com; d.focosi@ao-pisa.toscana.it