Background: Anaplastic large cell lymphoma (ALCL) is an uncommon, aggressive CD30-positive T-cell lymphoma exhibiting or lacking chromosomal translocation involving the Anaplastic Lymphoma Kinase (ALK) gene and expression of ALK protein. ALK positive ALCL (ALK+-ALCL) typically has an improved prognosis compared with ALK-negative; however, patients often respond favorably to standard chemotherapy and CD30-directed immunoconjugates only to progress and are left with few treatment options. To help identify additional treatment options, we collected tumor tissue and established, characterized and evaluated in vivo an ALK+-ALCL patient-derived xenograft (PDX) model from a thirty one year old Caucasian female with relapsed ALCL following initial therapy with a pediatric S-phase specific regimen.
Methods: The ST2698 ALK+-ALCL model was established in CB17 SCID mice using tissue collected from a lymph node tumor biopsy. Clinical tissue, patient blood and the PDX model were subjected to WGS sequencing using an augmented and content-enhanced exome. The augmented exome is optimized to detect major cancer mutations by enhancing coverage over known sequencing gaps and GC-rich regions across >1300 cancer and 200 miRNA genes. We also performed whole-transcriptome sequencing on the PDX model. All data were analyzed using a cancer bioinformatics pipeline optimized for high accuracy detection of small variants and indels, somatic copy-number aberrations, gene expression and fusions. Drug sensitivity studies were performed evaluating sensitivity of the model to patient's current clinical treatment and relevant targeted therapies; study endpoints included tumor volume and time from treatment initiation with tumor growth inhibition, delay and regression reported at study completion.
Results: Exome analysis identified several variants which were confirmed by transcriptome data. Efficacy studies confirmed model sensitivity to the patient's current clinical course (CHOP). In addition, ST2698 was found moderately sensitive to the IMiD lenalidomide (T/C=47%). However, treatment with the ALK-inhibitors crizotinib or ceritinib resulted in tumor regressions including durable complete responses in some mice.
Conclusion: We have established and characterized a patient-derived ALK+-ALCL xenograft model using DNA and RNA-based analysis. In addition we evaluated the model in vivo and confirmed sensitivity to the patient's current clinical course and identified two ALK inhibitors as active, including reported complete tumor regressions.
Rasco:Celgene: Research Funding; Asana BioSciences, LLC: Research Funding. Tolcher:Asana BioSciences, LLC: Consultancy, Research Funding; AbbVie: Consultancy; ArQule: Consultancy; Bayer: Consultancy; BioMed Valley Discoveries: Research Funding; Janssen R&D: Consultancy.
Asterisk with author names denotes non-ASH members.