Nivolumab As Salvage Therapy in Pediatric Patients with Relapsed and Refractory Lymphomas
Authors: Naumann-Bartsch Nora , Stachel Daniel , Chada Martin , Fritscher Torsten , Rompel Oliver , Haller Florian , Hartmann Arndt , Wößmann Wilhelm , Metzler Markus 
Published: October 2019

Abstract
The programmed death-1 (PD-1) inhibitor nivolumab has shown substantial activity in adults with relapsed or refractory Hodgkin's lymphoma (HL). Various clinical trials are currently ongoing to evaluate efficacy and safety of PD-1 blocking antibodies in other lymphoid malignancies as well. However, only limited experience has been obtained in children and adolescents so far. Here, we report the clinical course and striking response to nivolumab salvage therapy in 3 pediatric lymphoma patients.
Patients of age 11, 17, and 15 years were diagnosed with classical HL (#1), mediastinal gray-zone lymphoma (#2), and diffuse large B-cell lymphoma (#3), respectively. They underwent first-line therapies according to national pediatric standard treatment recommendations. All patients achieved initial remission, but #1 and #2 relapsed soon after, #3 already during first-line therapy. Relapse in #2 presented as classical HL. Second-line therapy resulted in remission in #1 but relapse occurred again shortly after high-dose chemotherapy followed by autologous stem cell transplantation and responded poorly to further treatment. Relapses in patients #2 and #3 were already refractory to extensive second-line regimens. All patients had very poor prognosis with fast progression of disseminated disease as confirmed by FDG-PET/CT imaging. High PD-ligand 1 expression in lymphoma specimens supported the decision to initiate off-label nivolumab therapy after obtaining informed consent. Nivolumab was administered at a dose of 3 mg/kg at weeks 1 and 4 followed by biweekly courses (Ansell et al., N Engl J Med, 2015). Already following the first infusion, a remarkable improvement of clinical symptoms was observed in all individuals. Rapid responses were proven by FDG-PET/CT in week 5 after only 2 applications, demonstrating metabolic partial remission in patient #1 and already complete remission (CR) in #2 and #3. Patient #1 eventually achieved CR after 8 nivolumab administrations. Therapy was continued and follow-up imaging confirmed durable CR status in all 3 individuals. Treatment has been well tolerated and no adverse events have occurred. Patient #1 proceeded to unrelated donor allogeneic hematopoietic stem cell transplantation (allo-HSCT) after a total of 11 nivolumab applications and remains in CR >4 months post allo-HSCT without significant side effects. Patients #2 and #3 are scheduled for allo-HSCT, having received 11 and 5 courses nivolumab to date.
The reported cases suggest that nivolumab can be highly effective and safe in children and adolescents with different relapsed lymphoma types, refractory to previous intensive chemo- and radiotherapy. Early and sustained CR status was achieved in all 3 patients following nivolumab initiation. Our observations may encourage further clinical studies and implementation of anti-PD-1 antibodies in therapy strategies for pediatric lymphomas.

Disclosures
No relevant conflicts of interest to declare.