Analysis of Prognostic Factors Predictive of Complete Response (CR) to Ibrutinib in Patients with CLL/SLL

Introduction: Chronic lymphocytic leukemia (CLL) has a heterogeneous clinical course, with many patients (pts) experiencing relapse after initial treatment. Ibrutinib is a first-in-class once-daily, oral, inhibitor of Bruton’s tyrosine kinase indicated for treatment of pts with CLL with ≥1 prior therapy and for pts with 17p deletion CLL. Extended follow-up of ibrutinib-treated pts has demonstrated an increase in complete response (CR) rate over time (Byrd, Blood 2015; Brown, Blood 2015). This ad hoc analysis examines baseline factors predictive of CR in pts with CLL/SLL treated with ibrutinib.

Methods: Univariate and multivariate analyses were performed on pooled data from studies of pts treated with either single-agent ibrutinib (PCYC-1102, PCYC-1112), or in combination with ofatumumab (PCYC-1109), to assess the prognostic value of various baseline factors on a CR to ibrutinib treatment in CLL/SLL. CR criteria were met per iwCLL parameters, including bone marrow confirmation, which was not mandated at any standard timepoint in any protocol. Both treatment-naive (TN) and previously treated (R/R) pts were included. Factors with P<0.15 in a univariate model were tested in a stepwise-selection logistic regression model. The multivariate model selected prognostic factors with P<0.05.

Results: Data from 398 pts with TN or R/R CLL/SLL were analyzed. Patients had a median age of 67 years (range, 30-86 years). At baseline, 238 (60%) pts had bulky disease ≥5 cm, 227 (57%) were Rai stage III-IV, and 230 (58%) had ECOG ≥1 status. At baseline 121 (30%) pts had del11q, 127 (32%) del17p, 242 (61%) unmutated IGHV, and 230 (58%) β-2-microglobulin levels ≥3.5 mg/L. A total of 31 (8%) pts were TN, with 38 (10%) having 1, 106 (27%) having 2, and 223 (56%) having had ≥3 prior lines of therapy, with a median of 3 prior therapies for R/R pts. Univariate analysis of prognostic factors showed that bulky disease, Rai stage at baseline, number of prior therapies, and β2-microglobulin levels at baseline had a significant effect on the odds of CR. The final multivariate model selected showed a significant effect for TN over R/R, and for bulky disease (<5 cm) (Table). The odds of a CR increased for TN pts vs. pts with ≥1 prior therapy (OR = 2.56, P=0.0488), while the odds of a CR increased without bulky disease (<5 cm vs. ≥5 cm [OR = 5.03, P=0.0002]). Univariate analysis excluding TN pts showed that bulky disease (<5 cm vs. ≥5 cm) and β2-microglobulin levels (≤3.5 vs. ≥3.5 mg/L) were the only baseline factors with significant effect on the odds of a CR (P=0.0001 and P=0.009, respectively). The final multivariate model for the R/R population selected only bulky disease as a significant factor (P=0.0001). The majority of pts for the R/R analysis received ibrutinib as third-line (29%) or beyond (61%), while 10% received ibrutinib after only 1 prior therapy. Of all pts treated with ibrutinib, 35/398 (9%) had a CR (PCYC-1102: R/R 12/101 [12%], TN 8/31 [26%]; PCYC-1109: 3/71 [4.2%]; PCYC-1112: 12/195 [6.2%]). 62% of all pts met iwCLL CR criteria for all hematological parameters (platelet, hemoglobin, ANC, and ALC), some pending bone marrow confirmation of CR. Median duration of response for all responders was not reached. The median time to CR among 35 CR pts was 13.7 months. The median time to first response (partial response with lymphocytosis [PR-L] or better) was 2.5 months.

Conclusions: Initial response to ibrutinib is achieved early, but the median time to CR is over one year. The rate of CR reported here with longer-term ibrutinib treatment is higher than in earlier reports (Byrd 2013, O’Brien 2014). Patients with treatment naive CLL and those without bulky lymphadenopathy have better odds of attaining a CR to treatment with ibrutinib.

Table. Analysis of baseline prognostic factors for all pts

Prognostic factors	Baseline factor effect
	Odds Ratio	P-value
Univariate model
ibrutinib vs. ibrutinib+anti-CD20 mAb	2.46	0.1459
<65 vs. ≥65 years	0.90	0.7816
Male vs. female	1.85	0.1578
ECOG 0 vs. >1	1.71	0.1334
Del11q negative vs. positive	1.05	0.9007
Del17p negative vs. positive	1.86	0.1569
IGHV mutated vs. unmutated	0.43	0.1268
Rai stage 0-II vs. III-IV	2.30	0.0251
Bulky disease <5 cm vs. ≥5 cm	5.84	<0.0001
Number of prior lines (0-1, 2, ≥3) 0-1  vs. 2 0-1  vs. 3 0 vs. ≥1 0 vs. ≥2	-0.61 1.49 3.54 4.38 4.42	0.0047 0.0481 0.0481 0.0012 0.0053
β2M <3.5 vs. ≥3.5 mg/L	3.05	0.0035
Multivariate model
Bulky disease <5 cm vs. ≥5 cm	5.03	0.0002
Prior lines 0 vs. ≥1	2.56	0.0488