In elderly patients with chronic lymphocytic leukemia, complex karyotype abnormalities, certain KRAS and POT1 mutations, and newly discovered mutations in genes involved in the DNA damage response were found to predict a poor response to chlorambucil-based chemotherapy or chemoimmunotherapy and poor survival, according to a report in Blood.
These findings are from what the investigators described as the first comprehensive prospective analysis of chromosomal aberrations (including complex karyotype abnormalities), gene mutations, and clinical and biological features in elderly CLL patients who had multiple comorbidities. This patient population is generally considered ineligible for aggressive first-line agents such as fludarabine and cyclophosphamide, said Carmen Diana Herling, MD, of the Laboratory of Functional Genomics in Lymphoid Malignancies, University of Cologne (Germany), and her associates.
For their analysis, investigators studied 161 such patients enrolled in a clinical trial in which all were treated with chlorambucil alone, chlorambucil plus obinutuzumab, or chlorambucil plus rituximab. The median patient age was 75 years. Comprehensive genetic analyses were performed using peripheral blood drawn before the patients underwent treatment.
Karyotyping detected chromosomal aberrations in 68.68% of patients, while 31.2% carried translocations and 19.5% showed complex karyotypes. Gene sequencing detected 198 missense/nonsense mutations and other abnormalities in 76.4% of patients.
Dr. Herling and her associates found that complex karyotype abnormalities independently predicted poor response to chlorambucil and poor survival. “Thus, global karyotyping (i.e., by chromosome banding analysis) seems to substantially contribute to the identification of CLL patients with most adverse prognoses and should be considered a standard assessment in future CLL trials,” they said (Blood. 2016;128:395-404).
In addition, KRAS mutations correlated with a poor treatment response, particularly to rituximab. Targeting such patients for MEK, BRAF, or ERK inhibitors “might offer personalized treatment strategies to be investigated in such cases.”
Mutations in the POT1 gene also correlated with shorter survival after chlorambucil treatment. And finally, poor treatment response also correlated with previously unknown mutations in genes involved with the response to DNA damage. This “might contribute to the accumulation of genomic alterations and clonal evolution of CLL,” Dr. Herling and her associates said.