Successful Use of Brigatinib Followed By Allogeneic Stem Cell Transplantation in Primary Refractory Anaplastic Lymphoma-Kinase Positive Large B Cell Lymphoma

Abstract

Anaplastic lymphoma-kinase (ALK) positive large B cell lymphoma (LBCL) is a rare, aggressive lymphoma with high relapse rates and poor response to standard cytotoxic therapy. Brigatinib, a next-generation multi-kinase inhibitor that blocks signal transduction associated with the ALK mutational re-arrangement, has shown substantial efficacy in patients with ALK-positive non-small cell lung cancer. We present a unique and successful case of a young patient with primary refractory ALK-positive LBCL who received salvage chemotherapy plus brigatinib followed by allogeneic stem cell transplantation. A 26 year-old previously healthy male presented with weight loss, night sweats, and abdominal pain. Exam was notable for a large abdominal mass. PET/CT scan revealed a large, FDG-avid heterogeneous peripherally enhancing pelvic mass, ascites, and diffuse abdominal lymphadenopathy. Testicular ultrasound was unremarkable. Large atypical plasmablastic cells with amphophilic cytoplasm and prominent nucleoli were noted within areas of necrosis. The abnormal cells were negative for CD19, CD20, PAX5, CD30, and CD117. They were positive for CD138 and granular, cytoplasmic ALK-1. Genomic testing revealed RANBP2-ALK fusion. The patient was diagnosed with ALK-positive LBCL. CSF cytology revealed no malignant cells and bone marrow biopsy revealed normal hematopoiesis. Therapy with cyclophosphamide, doxorubicin, vincristine, etoposide, and methylprednisolone (CHOEP) was initiated. Interval PET/CT revealed primary refractory disease with an enlarging abdominal mass and resultant hydronephrosis. He had worsening leukocytosis and liver dysfunction. Salvage therapy with dexamethasone, cytarabine, cisplatin (DHAP) plus brigatinib was initiated after a risk and benefit discussion regarding the off-label use of brigatinib. He achieved a complete metabolic response and subsequently underwent an umbilical cord blood stem cell transplant with a cyclophosphamide, fludarabine, and total body irradiation-based conditioning regimen followed by tacrolimus and mycophenolate mofetil for graft-versus-host-disease (GVHD) prophylaxis. Maintenance brigatinib was initiated post-transplant. The patient remains in complete remission over a year post-transplant with no unexpected toxicities and no GVHD. ALK-positive LBCL carries a poor prognosis with no standard therapeutic options. This case demonstrates safety and efficacy with the novel use of brigatinib. ALK inhibitors may represent a successful therapeutic strategy and further investigation in a clinical trial setting is warranted.