The genetics of Richter syndrome reveals disease heterogeneity and predicts survival after transformation.
Richter syndrome (RS) represents the development of diffuse large B-cell lymphoma in the context of chronic lymphocytic leukemia. The scarcity of biologic information about RS has hampered the identification of molecular predictors of RS outcome. We addressed this issue by performing a comprehensive molecular characterization of 86 pathologically proven RS. TP53 disruption (47.1%) and c-MYC abnormalities (26.2%) were the most frequent alterations, whereas common genetic lesions of de novo diffuse large B-cell lymphoma were rare or absent. By multivariate analysis, lack of TP53 disruption (hazard ratio, 0.43; P = .003) translated into significant survival advantage with 57% reduction in risk of death. An algorithm based on TP53 disruption, response to RS treatment, and Eastern Cooperative Oncology Group performance status had 80.9% probability of correctly discriminating RS survival (c-index = .809). RS that were clonally unrelated to the paired chronic lymphocytic leukemia phase were clinically and biologically different from clonally related RS because of significantly longer survival (median, 62.5 months vs 14.2 months; P = .017) and lower prevalence of TP53 disruption (23.1% vs 60.0%; P = .018) and B-cell receptor stereotypy (7.6% vs 50.0%; P = .009). The molecular dissection of RS into biologically distinct categories highlights the genetic heterogeneity of this disorder and provides clinically relevant information for refining the prognostic stratification of patients.
Division of Hematology, Department of Clinical and Experimental Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy. rossidav@med.unipmn.it
Davide
D
Rossi
Valeria
V
Spina
Clara
C
Deambrogi
Silvia
S
Rasi
Luca
L
Laurenti
Kostas
K
Stamatopoulos
Luca
L
Arcaini
Marco
M
Lucioni
Gabrielle B
GB
Rocque
Zijun Y
ZY
Xu-Monette
Carlo
C
Visco
Julie
J
Chang
Ekaterina
E
Chigrinova
Francesco
F
Forconi
Roberto
R
Marasca
Caroline
C
Besson
Theodora
T
Papadaki
Marco
M
Paulli
Luigi M
LM
Larocca
Stefano A
SA
Pileri
Valter
V
Gattei
Francesco
F
Bertoni
Robin
R
Foà
Ken H
KH
Young
Gianluca
G
Gaidano
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000465:Algorithms; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D016158:Genes, p53 / Q000235:genetics; D018740:Genetic Heterogeneity; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000150:complications / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality*; D008297:Male; D008875:Middle Aged; D025202:Molecular Diagnostic Techniques; D015337:Multicenter Studies as Topic; D009154:Mutation / Q000502:physiology; D011379:Prognosis; D016019:Survival Analysis