Single Agent Ibrutinib (PCI-32765) Achieves Equally Good and Durable Responses In Chronic Lymphocytic Leukemia (CLL) Patients With and Without Deletion 17p
Authors: Farooqui Mohammed , Aue Georg , Valdez Janet , Martyr Sabrina , Jones Jade , Soto Susan , Stetler-Stevenson Maryalice , Yuan Constance , Arthur Diane C , Thomas Francine , Tian Xin , Liu Delong , Maric Irina , Wiestner Adrian 
Published: October 2019

Abstract

Introduction
Chemoimmunotherapy has markedly improved the outcomes of patients (pts) with CLL. However, pts having deletion of the short arm of chromosome 17 (DEL 17p) have inferior outcomes with current standard treatments (with the possible exception of allogeneic stem cell transplantation), and elderly pts are in need of less toxic regimens. Bruton’s tyrosine kinase (BTK) is essential for B cell receptor (BCR) signaling, which has emerged as a key driver of CLL pathogenesis and progression. Ibrutinib (PCI-32765) is a covalent inhibitor of BTK with significant antitumor activity in CLL (Advani et al, JCO 2013, Byrd et al NEJM 2013).

Patients and methods
This investigator-initiated phase II, single-center trial of ibrutinib monotherapy prospectively addressed the possible role of ibrutinib in DEL 17p CLL irrespective of the pts’ prior treatment history (NCT01500733). Elderly pts without a chromosomal deletion at 17p (normal (NL) 17p) were concurrently enrolled into a second cohort. The primary endpoint of the study is response after 6 months (mo) assessed by computed tomography (CT), bone marrow (BM) biopsy, and routine clinical and laboratory studies. The spleen volume was calculated from CT scans using a General Electric Advanced Workstation Server. Del 17p was assessed by interphase fluorescence in situ hybridization (FISH). Differences in response rates were calculated by a proportional test.

Results
We report on the first 53 patients (n=24 (NL 17p); n=29 (DEL 17p)) with a median follow up of 14 months (mo). Median age was 66 yrs (33-85) and 70% had Rai stage III/IV. Most adverse events were grade ≤2, most commonly diarrhea, fatigue, arthralgias/myalgias, and rash. Treatment related non hematologic toxicities grade ≥3 occurred in < 5%, grade ≥3 infections or cytopenias were uncommon and reported in 15% of pts regardless of causality. Four deaths on study were not treatment related. A total of 47 pts were restaged at 6 mo (6 patients did not reach this endpoint; 2 unrelated deaths, 3 unrelated secondary malignancies, and 1 progressive disease due to presumed transformation at 2 weeks in a pt with DEL 17p). The estimated event free survival at 14 mo is 93%. At 6 months, 31(66%) pts had a partial response (PR by IWCLL criteria), and 13 (28%) pts a PR with lymphocytosis (PRL), i.e. pts fulfill criteria of PR except for the absolute lymphocyte count. Responses by treatment cohort (Table 1) were for NL 17p vs DEL 17p: 81% vs 53% PR and 9% vs 43% PRL. The apparent difference in response rates is due to slower clearance of the treatment-induced lymphocytosis in DEL 17p. However, clinical benefit and disease control in all tissue sites was equal for NL 17 and DEL 17p (Table 2): nodal response was 100% in both cohorts (median tumor reduction 75% in NL 17p and 70% on DEL 17p), reduction in spleen volumes of 269 ml (40%, range 30-1079 ml) vs 446 ml (46%, range 44-1716 ml), and reduction in tumor infiltration in the bone marrow by 76% and 84%, respectively. Median ALC decreased from 79 k/µl (0.5–402) to 30 k/µl (0-167) for a median reduction of 71% and 60%, respectively.
To obtain a direct measure of the relative impact of ibrutinib on tumor cells carrying a DEL 17p, we repeated FISH testing at 6 mo (n=20). In the individual pts, DEL 17p was present in 12-97% of the tumor cells pre treatment and in 0-92% at 6 months. Interestingly, in 80% of pts the relative size of the DEL 17p subclone decreased (n = 20, median reduction 34%; P< 0.02); 4 pts (20%) had no evidence of 17p after 6 mo.

Conclusion
Ibrutinib as a single agent appears to be equally effective against CLL with or without DEL 17p. This conclusion is based on a comparison of responses in two concomitantly treated CLL cohorts and supported by the absence of a treatment-related increase in the 17p clone in individual patients.
Research supported by the Intramural Research Program of NHLBI. We thank our patients for participation and their willingness to have additional research studies done. We acknowledge Pharmacyclics for providing study drug.

Disclosures:
Off Label Use: Ibrutinib not FDA approved for CLL.