Next-generation ALK inhibitors are highly active in ALK-positive large B-cell lymphoma

Abstract

Anaplastic lymphoma kinase (ALK)-positive large B-cell lymphoma is a rare large B-cell lymphoma subtype that is characterized by a plasmablastic phenotype and an ALK gene fusion. ALK-positive large B-cell lymphoma is resistant to the first-generation ALK inhibitor crizotinib and uniformly fatal with few if any complete responses in the relapsed setting, where no long-term survivors have been reported in the literature. No standard therapies exist for patients with relapsed or refractory disease, and its rarity and lethality have precluded prospective clinical research. Herein, we report the generation of the first ALK-positive large B-cell lymphoma patient-derived xenograft model, in which we show that next-generation ALK inhibitors are therapeutically active. On this basis, we administered the next-generation ALK inhibitor alectinib to four consecutive patients (three crizotinib-refractory). All four responded (two complete responses), one in ongoing remission after allogeneic transplantation >15 months. One with progressive disease was treated with lorlatinib and achieved complete response. These data support use of alectinib and lorlatinib as off-label therapeutic options for patients with relapsed or refractory ALK-positive large B-cell lymphoma.

TFG::ALK fusion in ALK positive large B-cell lymphoma: a case report and review of literature

“…This driver effect is important to consider as it indicates that inhibition of this central fusion gene and associated pathways could potentially reduce tumor growth. Importantly, studies have shown that ALK translocated tumors are highly sensitive to targeted ALK inhibitor therapies ( 10 , 16 , 29 ). Presently, crizotinib is the most well studied ALK inhibitor in ALK+ LBCL and it induces a transient improvement in lymphadenopathy and serum LDH levels, though this has been followed by rapid progression and a survival time of less than 6 months ( 5 ).…”

“…Soumerai et al evaluated the therapeutic potential of higher potency ALK inhibitors alectinib and lorlatinib in patientderived xenograft models. They hypothesize that crizotinib resistance in ALK+LBCL may be overcome by these higher potency ALK inhibitors via upregulation of bypass signalling pathways possibly engaged by the tumor microenvironment (29).…”

Diverse and reprogrammable mechanisms of malignant cell transformation in lymphocytes: pathogenetic insights and translational implications

“…ALK inhibition already has, or could be, combined with either standard chemotherapy ( 45 ), CD30 antibody-toxin conjugate ( 46 ), or, preferably, agents targeting pathways playing a role in ALK-driven lymphomas ( 35 ). Similar to NPM1::ALK, another form of chimeric ALK involving clathrin (CLTC::ALK) which is expressed in a distinct subtype of B-cell lymphoma displaying plasmablastic cell morphology and immunophenotype, is also highly responsive to the next generation ALK inhibitors ( 47 ), further highlighting the potent oncogenic role of chimeric ALK, regardless of the T- vs. B-cell lineage of the transformed lymphocytes ( Figures 1 , 2 ).…”

Case report: A patient with ALK-positive large B-cell lymphoma benefited from myeloma-like treatment combined with the ALK inhibitor lorlatinib

“…Therefore, novel therapeutic approaches should be evaluated specifically for this patient group. ALK inhibitors are reported effective against ALK + lymphomas, including ALCL, ALK-positive non-small-cell lung cancer (NSCLC) and ALK + LBCL (4)(5)(6). Here, we reported that a patient with ALK + LBCL achieved durable complete remission using myeloma-like treatment combined with the thirdgeneration ALK inhibitor, lorlatinib.…”