Brentuximab in Children, Adolescent and Young Adults with Relapsed/Refractory Anaplastic Large Cell Lymphoma

Abstract

Background: Anaplastic Large Cell Lymphoma (ALCL) is an aggressive malignancy characterized by strong expression of CD30. Multi-agent chemotherapy cures 65-90% of newly diagnosed patients, the rate of relapse approaching 30%. Targeted agents eventually followed by allogeneic stem cell transplantation (SCT) may represent a valuable salvage therapy in patients with relapsed/refractory ALCL. Brentuximab vedotin is a CD30-directed monoclonal antibody-drug conjugate (ADC) that comprises a monoclonal human/murine antibody linked to the microtubule-disrupting agent monomethyl auristatin E (MMAE) via a protease-cleavable linker. Design and methods: We retrospectively analyzed monocentric data of 20 patients with ALCL treated with Brentuximab from 2.10.2014 to 22.05.2022. Treatment was characterized by the intravenous infusion of 1.8 mg/kg Brentuximab in monotherapy or as part of a polychemotherapy regimen, in children with either relapsed disease or not fully responding to first-line treatment. More in detail, chemotherapy regimens administered in combination with the immunotherapy were: bendamustine, AM and BM blocks (ALCL99 Trial), or AA, BB and CC blocks (LNH97 Trial). Objective response rate (ORR) was assessed through computed tomography (CT)/FDG-PET scans. Results: Eight patients received Brentuximab for incomplete response to first-line treatment (2 of them had haemophagocytic lymphohistiocytosis at diagnosis, and underwent genetic testing that revealed the heterozygous variant c.1336C>T (p.Arg446Trp) in IKBKB gene and the hemizygous variant c.622T>C (p.Ala91Val) in IL2RG gene, respectively). In these patients, Brentuximab was mostly used in combination with the ALCL99 regimen. Three of these 8 patients experienced a subsequent relapse and were re-exposed to the drug after disease recurrence. Fifteen patients received Brentuximab at relapse. Median time between diagnosis and relapse was 10.3 months (range 3.4-34 months). The median number of Brentuximab infusions was 7 (range 2-25). The combination of Brentuximab 1.8 mg/kg/dose on Day 1 and Bendamustine 120 mg/m2/dose on Day 2 and 3, was the principal reinduction regimen in the relapsed cohort, having been infused in 9 patients with a median of 4 cycles (range 2 to 5). This drug combination was very well tolerated and showed a 100% complete response (CR) assessed by CT and FDG-PET scans, allowing to perform allogeneic SCT in all of them. Allogeneic SCT was performed in 15 patients (one of them was the child with haemophagocytic lymphohistiocytosis at diagnosis given Brentuximab during the first-line treatment because of incomplete response), while the remaining child, who had relapsed 34 months after the diagnosis, was treated with Brentuximab monotherapy and remains in CR. Nine patients received HLA-haploidentical SCT, while the remaining 6 were transplanted using either a matched sibling donor (3 patient) or an unrelated volunteer (3 patients) respectively. Sixteen out of the 20 patients (80%) are alive and disease free with a median follow-up of 28.6 months (range 3-78.7). Three patients died due to transplant related causes and 1 patient due to disease progression. Conclusions: Despite the limitations of a limited number of patients analyzed and the retrospective nature of the study, our data suggest that Brentuximab administered either in monotherapy or in combination with chemotherapy is a valuable salvage option and may represent a suitable bridge to allogeneic SCT.