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

Edgardo R. Parilla Castellar, Elaine S. Jaffe, Jonathan W. Said, Steven H. Swerdlow, Rhett P. Ketterling, Ryan A. Knudson, Jagmohan S. Sidhu, Eric D. Hsi, Shridevi Karikehalli, Liuyan Jiang, George Vasmatzis, Sarah E. Gibson, Sarah Ondrejka, Alina Nicolae, Karen L. Grogg, Cristine Allmer, Kay M. Ristow, Wyndham H. Wilson, William R. Macon, Mark E. Law, James R. Cerhan, Thomas M. Habermann, Stephen M. Ansell, Ahmet Dogan, Matthew J. Maurer and Andrew L. Feldman

Key points

  • 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, while other genetic subtypes have inferior outcomes.


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 three genetic markers (p<0.0001). 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 x 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.

  • Submitted April 21, 2014.
  • Accepted May 26, 2014.