Single Agent Ibrutinib in CLL/SLL Patients with and without Deletion 17p
Authors: Farooqui Mohammed , Valdez Janet , Soto Susan , Stetler-Stevenson Maryalice , Yuan Constance M. , Thomas Francine , Tian Xin , Maric Irina , Wiestner Adrian 
Published: October 2019

Abstract
INTRODUCTION: Ibrutinib is FDA approved for patients (pts) with CLL who are previously treated or have deletion (del) 17p. Data on depth and durability of response beyond the first 2 years of therapy are limited. Here we compare the response of pts with and without del17p with long follow-up(f/u).
PATIENTS AND METHODS: This investigator-initiated phase II trial (NCT01500733) enrolled 86 pts (Cohort 1: no del17p, n=35; Cohort 2: del17p n=51). Both treatment (tx) naïve (TN) and relapsed refractory (R/R) pts with active disease were eligible. Response was assessed by computed tomography (CT), physical exam, bone marrow (BM) biopsy, and routine clinical and laboratory studies. Spleen volume (SV) was calculated from CT scans using a General Electric Advanced Workstation Server. Eight color flow cytometry (FC) on peripheral blood (PB) and BM was performed at yearly intervals. Wilcoxon rank-sum test was used to examine the differences between the two cohorts.
RESULTS: Median f/u for all pts currently on study was 36 months (mo). Among pts with no del17p 24 (69%) pts completed 2 years(y) and 12 (34%) pts completed 3y. 33 (65%) pts with del17p completed 2y and 18 (35%) pts completed 3y. Median age was 66y (33-85) and 70% had Rai stage III/IV. Most adverse events were grade ≤2, most commonly (>25%) diarrhea, nail ridging, arthralgias, rash, bruising, and cramps. Tx-related non hematologic toxicities grade ≥3 occurred in <15%, and grade ≥3 infections or cytopenias were reported <25% of pts.
The estimated progression free survival and overall survival at 36 mo is 82% and 88%. A total of 81 pts (n=33 (no del17p), n=48 (del17p)) were evaluable for response (2 enrollment deviations, 1 malignancy, 2 deaths before 6 mo). 5 (6%) deaths occurred on study (4 infections not tx-related, 1 possibly tx-related sudden death). 2 (2%) pts were primary refractory and 7 (8%) pts had progressive disease (PD) after initial response (3 CLL, 2 PLL, 2 Richter's transformation). Best response was complete response (CR) in 17 (21%) pts, partial response (PR) in 60 (74%), and stable disease (SD) and progressive disease (PD) each in 2 (2%) pts. Median time to best response was 2y. Responses for TN vs R/R pts were: 20 vs 23% CR, 78% vs 68% PR, 0% vs 6% SD, 2% vs 3% PD, and for no del17p vs del17p: 21% vs 21% CR, 73% vs 75% PR, 3% vs 2% each with SD and PD. There were no statistically significant differences in response rates by prior tx or del17p status.
Disease control in all evaluable tissue sites were compared between the two cohorts based on del17p status (no del17p vs del17p) (Table): median reduction in lymphadenopathy 89% (59-100) vs 82% (22-100), median reduction in SV 94% (26-100) vs 98% (37-100), median reduction in tumor infiltration in the BM was 90% (11-99) vs 88% (28-100), and ALC response showed a median reduction of 97% (range: +44% to -99%) and 95% (range: +119% to -99%).
Table. Median tumor reduction at best response. Compartment All pts NO DEL17p DEL 17p P Nodal 85% (n=79) 89% (n=32) 82% (n=47) 0.01 Spleen 98% (n=67) 94% (n=28) 98% (n=39) 0.3 BM 89% (n=73) 90% (n=31) 88% (n=42) 0.6 ALC 96% (n=81) 97% (n=33) 95% (n=48) 0.16
We quantified depth of response by measuring the degree of flow cytometric minimal residual disease (MRD) (CLL % of leukocytes). The median MRD at 1y (n=51), 2y (n=46), and 3y (n=24) in PB was 41%, 12%, and 8% respectively. Median MRD values at 1y (n=17), 2y (n=32), and 3y (n=15) in BM was 12%, 8%, and 7%. There was no significant difference in MRD levels in pts by prior tx status. However, pts with no del17p tended to have less residual disease measured by FC than pts with del17p. For example, at 2y MRD levels in PB were 6.4% vs 16% and in BM 4.7% vs 11.1%, respectively (P =0.02). At 3y one patient with no del17p achieved near MRD negativity in PB at 0.018%, and MRD negativity in the BM at 0.007%.
CONCLUSION: With continued therapy 95% of pts achieved a response by iwCLL criteria and the depth of response improved with 21% CRs irrespective of the presence of del17p. However, all patients remained MRDpositive. With a median f/u of 36 mo, responses were durable in the majority of pts, with secondary resistance developing in 8% of pts.
Research supported by the Intramural Research Program of NHLBI. We thank our patients for participation. We acknowledge Pharmacyclics for providing study drug.

Disclosures
Off Label Use: Ibrutinib is approved for CLL patients with relapsed refractory disease and patients with deletion 17p CLL. Some of the patients on this abstract from this clinical trial are treatment naive CLL patients without 17p deletion. . Wiestner:Pharmacyclics: Research Funding.