Philip A. Thompson, MBBS, University of Texas MD Anderson Cancer Center, Houston, Texas, USA, reported that complex metaphase karyotype (CKT), defined as ≥ 3 unrelated abnormalities, rather than del(17p), is linked with inferior outcomes in patients with chronic lymphocytic leukemia (CLL) treated with ibrutinib who relapse or are fludarabine-refractory.

Ibrutinib has robustly increased progression-free survival (PFS) in CLL [Byrd JC et al. N Engl J Med. 2013], although patients with deletions in the short arm of chromosome 17 remain a high-risk group. In CLL, del(17p) is often associated with CKT involving multiple unrelated abnormalities [Haferlach T et al. Leukemia. 2007]. Genes conferring treatment resistance exist in patients with del(17p) and/or CKT [Woyach JA et al. N Engl J Med. 2014]. The significance of CKT in the outcome of ibrutinib treatment of CLL is unclear.

This study analyzed 100 CLL patients (median age 65 years) treated a median of twice with ibrutinib-based regimens from mid-2010 to mid-2013. The majority of patients (60%) were Rai stage III-IV and lacked immunoglobulin heavy chain variable mutations (81%). A minority (19%) were refractory to fludarabine therapy. Use of fluorescence in-situ hybridization (FISH) revealed prevalence of del(17p), del(11q), CKT, and other mutations in 48%, 28%, 42%, and 24% of patients, respectively. Of the 32 patients with del(17p) and 33 with no del(17p) for whom metaphase karyotype data were available, 23 and 4, respectively, harbored CKT.

The median follow-up was 27 months (range, 11 to 48 months). Eight patients who underwent planned allogeneic stem cell transplant were censored for event-free survival (EFS) analysis. In 36 patients treated with ibrutinib + rituximab, complete response rate (CRR) was 8%. In 14 patients treated with ibrutinib + bendamustine + rituximab, CRR was 50% (P = .001), and the significance remained in multivariable analysis. Overall rates and CRRs did not differ significantly between patients with or without del(17p), del(11q), and other mutations, or those with or without CKT. The presence of del(17p) was associated with significantly worse EFS.

EFS was also significantly worse for patients with CKT vs no complex karyotype (12/27 vs 31/38; P < .0001) and in patients with del(17p) and CKT vs those with del(17p) alone (11/23 vs 7/9; P = .047). In the absence of CKT, patients with del(17p) or del(11q) had similar EFS (7/9 vs 9/10; P = .516). Multivariable analysis revealed the significant association of CKT with EFS (HR, 5.3; 95% CI, 1.5 to 19.2; P = .011).

The most frequent event was progression of CLL (n = 10), followed by death (n = 8), and Richter transformation (n = 5). In 27 patients with CKT and 38 patients without CKT, CLL progression was evident in 5 and 1 patients, respectively. Overall survival in all patients was not significantly different.

Patients refractory to fludarabine had significantly worse overall survival (10 of 19 died) than those not refractory to fludarabine (19 of 81 died) (P = .009). Multivariable analysis revealed significant association of fludarabine-refractory disease with worse overall survival (HR, 6.4; 95% CI, 1.8 to 22.8; P = .004).

The data implicate CKT as a more important predictor of outcome than del(17p). Absence of CKT is associated with less frequent disease progression. When progression occurs, it tends to occur > 12 months after ibrutinib treatment, with death soon after.

The researchers concluded that patients with CKT are an ideal group in which to study novel treatments.