Cancer Science and Therapy

CLL has a variable clinical course and prognostic factors are vital. Metaphase cytogenetics have been minimally informative as CLL cells do not respond to traditional mitogens. CpG stimulates CLL cells to divide in <80% cases. Investigation of karyotypic abnormalities within one year of diagnosis in untreated CLL patients using CpG-stimulation identified complex karyotype (CK) (>3 unrelated abnormalities) that predicted a shorter time to first treatment (TFT) compared to non-CK (NCK, 12 months estimates 45% and 15%, respectively, p=0.0005). Despite a strong correlation of del(17p) with CK, CK predicted TFT independent of del(17p), a known poor prognosticator. Additionally, in patients with either balanced or unbalanced translocation, the good prognosis of mutated IGHV was negated (mutated IGHV translocation present vs absent, HR 3.59, p<0.001; unmutated IGHV translocation present vs absent, HR 1.03, p=0.92, interaction p=0.002). Independent of IGHV and translocation, CK (HR 1.70, p=0.037) remained statistically significant. Patients with Richter’s transformation (RT), an aggressive lymphoma in some CLL patients, exhibited higher risk for death with CK (HR 2.72, p=0.025) than in patients with NCK after R-EPOCH treatment. CK was independently associated with ibrutinib discontinuation due to progression. Although a low percentage of patients treated with ibrutinib experience RT, 6/9 patients with near-tetraploidy detected prior to ibrutinib treatment developed RT. In a multivariable model, both near-tetraploidy (HR 8.66, p<0.0001) and CK (HR 4.78, p=0.01) were independent risk factors for discontinuing ibrutinib due to transformation. In conclusion, CpG-stimulated karyotypes should be performed in CLL patients to identify karyotypic abnormalities that are significant for prognostication.