ALK-negative anaplastic large cell lymphoma is a genetically heterogeneous disease with widely disparate clinical outcomes

• Published in: Blood 2014-08, Vol.124 (9), p.1473-1480
• Main Authors: Parrilla Castellar, Edgardo R., Jaffe, Elaine S., Said, Jonathan W., Swerdlow, Steven H., Ketterling, Rhett P., Knudson, Ryan A., Sidhu, Jagmohan S., Hsi, Eric D., Karikehalli, Shridevi, Jiang, Liuyan, Vasmatzis, George, Gibson, Sarah E., Ondrejka, Sarah, Nicolae, Alina, Grogg, Karen L., Allmer, Cristine, Ristow, Kay M., Wilson, Wyndham H., Macon, William R., Law, Mark E., Cerhan, James R., Habermann, Thomas M., Ansell, Stephen M., Dogan, Ahmet, Maurer, Matthew J., Feldman, Andrew L.
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Aged; Aged, 80 and over; Anaplastic Lymphoma Kinase; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Child; Dual-Specificity Phosphatases - genetics; Female; Gene Rearrangement; Humans; Immunohistochemistry; In Situ Hybridization, Fluorescence; Interferon Regulatory Factors - genetics; Kaplan-Meier Estimate; Lymphoid Neoplasia; Lymphoma, Large-Cell, Anaplastic - genetics; Lymphoma, Large-Cell, Anaplastic - metabolism; Lymphoma, Large-Cell, Anaplastic - pathology; Male; Middle Aged; Mitogen-Activated Protein Kinase Phosphatases - genetics; Prognosis; Receptor Protein-Tyrosine Kinases - genetics; Receptor Protein-Tyrosine Kinases - metabolism; Transcription Factors - genetics; Tumor Suppressor Proteins - genetics; Young Adult
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2014-04-571091

Anaplastic lymphoma kinase (ALK)-negative anaplastic large cell lymphoma (ALCL) is a CD30-positive T-cell non-Hodgkin lymphoma that morphologically resembles ALK-positive ALCL but lacks chromosomal rearrangements of the ALK gene. The genetic and clinical heterogeneity of ALK-negative ALCL has not been delineated. We performed immunohistochemistry and fluorescence in situ hybridization on 73 ALK-negative ALCLs and 32 ALK-positive ALCLs and evaluated the associations among pathology, genetics, and clinical outcome. Chromosomal rearrangements of DUSP22 and TP63 were identified in 30% and 8% of ALK-negative ALCLs, respectively. These rearrangements were mutually exclusive and were absent in ALK-positive ALCLs. Five-year overall survival rates were 85% for ALK-positive ALCLs, 90% for DUSP22-rearranged ALCLs, 17% for TP63-rearranged ALCLs, and 42% for cases lacking all 3 genetic markers (P < .0001). Hazard ratios for death in these 4 groups after adjusting for International Prognostic Index and age were 1.0 (reference group), 0.58, 8.63, and 4.16, respectively (P = 7.10 × 10−5). These results were similar when restricted to patients receiving anthracycline-based chemotherapy, as well as to patients not receiving stem cell transplantation. Thus, ALK-negative ALCL is a genetically heterogeneous disease with widely disparate outcomes following standard therapy. DUSP22 and TP63 rearrangements may serve as predictive biomarkers to help guide patient management. •ALK-negative ALCLs have chromosomal rearrangements of DUSP22 or TP63 in 30% and 8% of cases, respectively.•DUSP22-rearranged cases have favorable outcomes similar to ALK-positive ALCLs, whereas other genetic subtypes have inferior outcomes.