The use of checkpoint inhibitors in children with non-Hodgkin lymphomas
Authors: Kozlov A. V. , Kazantsev I. V. , Yukhta T. V. , Tolkunova P. S. , Gevorgyan A. G. , Lepik K. V. , Zvyagintseva D. A. , Golenkova M. S. , Shvetsov A. N. , Smykova O. G. , Baykov V. V. , Punanov Yu. A. , Morozova E. V. , Mikhailova M. B. , Zubarovskaya L. S. , Afanasyev B. V. 
Published: July 2020

The majority of children with NHL can be cured with first-line therapy but 10–25% of affected patients develop relapsed or refractory disease (R-R). The prognosis in these cases is unfavorable, no matter what form of modern treatment is adopted. New approaches to the treatment of this small, yet important, group of patients need to be introduced, including, first and foremost, targeted therapy and immunotherapy. As is known, PD-L1 is frequently expressed in non-Hodgkin lymphomas (NHL), which means that the use of checkpoint inhibitors (CPI) is theoretically justified. Objectives: to analyze the results of treatment with checkpoint inhibitors Nivolumab and Pembrolizumab in children with R-R NHL. The study was approved by the Independent Ethics Committee of the I.P. Pavlov First Saint-Petersburg State Medical University. We used CPIs in 8 children with R-R NHL undergoing treatment at the R.M. Gorbacheva Research Institute for Pediatric Oncology, Hematology and Transplantation. The median age was 12 (2–17) years. The distribution of the patients by diagnosis was as follows: primary mediastinal large B-cell lymphoma (PMBCL, n = 3), peripheral T-cell lymphoma (PTCL, n = 2), diffuse large B-cell lymphoma (n = 1), lymphoblastic lymphoma (n = 2). The median number of prior lines of therapy was 3 (1–5), and all patients had received at least 1 line of standard treatment. Refractory NHL was observed in 5 cases, and 3 patients had had multiple relapses (≥ 3). All patients had progression of their primary disease at the time of prescription of the CPI therapy. Nivolumab was administered at a dose of either 1 mg/kg (n = 4) or 3 mg/kg (n = 3) every 2 weeks, Pembrolizumab - at a dose of 2 mg/kg once every 3 weeks (n = 1). The median number of CPI doses received by the patients was 5.5 (2–12). In 5 patients, CPIs were administered as monotherapy, in 3 – in combination with cytostatic agents: FLAG, Gemcitabine and intrathecal triples (n = 1), Brentuximab vedotin (n = 1) and Bendamustine (n = 1). The efficacy of the treatment was evaluated in accordance with the LYRIC criteria. Once remission was achieved, we used hematopoietic stem cell transplantation and/or radiotherapy for consolidation. Response to the CPI therapy was observed in 4 out of 8 patients (complete response – in 2 patients). Interestingly, only patients with PMBCL and PTCL responded to the treatment. At the median follow-up of 368 (36–879) days, 5 patients were alive, with three of them remaining in long-term remission. During the follow-up period, there was only 1 clinically significant complication (cytopenia) that resolved after treatment with glucocorticosteroids. Finally, we would like to point out that this paper is one of the first reports on the successful use of CPIs in children with R-R NHL. PMBCL and PTCL turned out to be responsive to the treatment. This therapy can be used to achieve remission or possibly even cure in children whose only option would be palliative care if they were treated with standard approaches.