Ibrutinib-Based Regimens for Patients with Relapsed/Refractory CLL: Impact of Complex Karyotype
Ibrutinib has shown efficacy and tolerability in patients with relapsed/refractory CLL, including in patients with del17p, although patients with del17p remain a high-risk group with shorter PFS and a pattern of continuous relapses (Byrd JC, et al. N Engl J Med. 2013;369:32-42, 1278-1279; O’Brien SM, et al. J Clin Oncol.2014;32[15 suppl]. Abstract 7014). Because del17p CLL is frequently associated with a complex metaphase karyotype (CKT), defined as ?3 distinct chromosomal abnormalities, and treatment-naïve patients or patients with relapsed/refractory CLL with CKT generally have inferior outcomes (Woyach JA, et al. N Engl J Med. 2014;370:2286-2294), Thompson and colleagues evaluated the prognostic significance of CKT in patients with CLL who are treated with ibrutinib (Thompson PA, et al. Blood.2014;124. Abstract 22).
A total of 100 patients with relapsed/refractory CLL were reviewed; 50 received ibrutinib monotherapy, 36 received ibrutinib plus rituximab, and 14 received ibrutinib plus bendamustine and rituximab; 49% of these patients had del17p and 36% had CKT, with 85% of the patients with CKT having del17p. At a median follow-up of 27 months, the overall response rate (ORR) for the entire population was 95%, with 16% achieving a complete remission.
On univariate analyses, a negative impact on event-free survival (EFS) was observed in patients with CLL who were refractory to fludarabine (median EFS, 27 months vs not reached; P = .015), those with del17p (27 months vs not reached; P = .014), and patients with CKT (16 months vs 39 months; P <.001). However, there was no association between del17p and EFS when the patients with CKT were excluded. On multivariate analysis, the presence of CKT with the deletion in chromosome 11q (del11q) or del17p and the presence of fludarabine-refractory disease were significantly associated with inferior OS.
Thus, the presence of CKT appears to be independently associated with inferior EFS and OS in patients with relapsed/refractory CLL who are treated with ibrutinib, and is a much more important predictor of outcome than del17p. Because of the association of CKT with del17p, it may be a key determinant of responsiveness to ibrutinib in patients with del17p, and this could dictate therapy: patients with relapsed/refractory CLL and del17p without CKT could be managed with ibrutinib alone, whereas those patients with CKT would be candidates for treatment intensification strategies after ibrutinib-based therapy, either with novel drug combinations or allogeneic stem-cell transplant (SCT).