Ibrutinib Shows Survival Benefit in Previously Treated CLL/SLL Patients with High-Risk Disease

Longer-term data from the phase III RESONATE trial – a head-to-head comparison of ibrutinib and ofatumumab – continue to demonstrate ibrutinib’s efficacy in patients with previously treated chronic lymphocytic leukemia (CLL), according to data presented at the 2016 ASH Meeting on Lymphoma Biology. The benefits also appear to extend to patients with high-risk genetic mutations and poorer prognoses.

Historically, CLL with p53 dysfunction or del17p has been difficult to treat, with few available therapeutic options, according to Jennifer R. Brown, MD, PhD, director of the CLL Center at Dana-Farber Cancer Center and associate professor of medicine at Harvard Medical School, and first author of the study.

With the advent of novel inhibitors, this may be changing. “These targeted therapies appear to be more effective against CLL with p53 mutation and del17p, which is the highest risk group [of patients],” Dr. Brown told ASH Clinical News, “but there is still a question as to whether they completely reverse that adverse prognosis.”

To this end, Dr. Brown and her team examined two-year progression-free survival (PFS), overall survival (OS), and overall response rate (ORR) among patients with these high-risk gene mutations enrolled in the RESONATE trial. They also included patients who had NOTCH1, BIRC3, and SF3B1 mutations – newly identified mutations also associated with worse survival in CLL.

RESONATE included 391 patients with relapsed or refractory CLL or small lymphocytic leukemia (SLL) who received at least one previous anti-cancer therapy. Patients were randomized to receive oral ibrutinib 420 mg (n=142) or intravenous ofatumumab (n=196) for up to 24 weeks.

At 18-months of follow-up, 76 percent of ibrutinib-treated patients had not experienced disease progression, compared with eight percent in the ofatumumab-treated group. ORR was also higher with ibrutinib compared with ofatumumab (90% vs. 25%; p value not reported), regardless of baseline genetic mutations (TABLE 1). Additionally, patients who received one prior therapy fared significantly better on ibrutinib than those who were more heavily pre-treated, with longer PFS (p=0.035) and OS (p=0.028).

In subgroup analyses, PFS among ibrutinib-treated patients was similar regardless of a patients’ specific genetic mutations at baseline and whether or not they had del17p deletion or p53 mutation, suggesting that these mutations do not confer a worse outcome in these patients (TABLE 2).

While just five to 10 percent of newly diagnosed patients with CLL can be expected to carry these high-risk mutations, the numbers are much higher in patients who received multiple lines of therapy, Dr. Brown explained, though it is unknown whether the mutations are pre-existing or due to chemotherapy exposure. In this study, roughly half of relapsed patients had a p53 mutation and about one-third had del17p, del11q, or NOTCH1; fewer expressed BIRC3 (10-15%) and ATM mutations (20-22%).

“These findings contribute to our understanding that perhaps some of the new targeted therapies can overcome high-risk mutations and may also ultimately help to risk-stratify patients being treated with ibrutinib,” Dr. Brown said.

Ibrutinib was “generally well tolerated,” she noted. Adverse events (AEs) leading to discontinuation among ibrutinib-treated patients were most frequent during the first six months of follow-up and, at the time of analysis, 74 percent of ibrutinib-treated patients remained on study treatment. The most common grade 3/4 adverse events in the ibrutinib group were neutropenia (19%), pneumonia (10%) thrombocytopenia, anemia, and hypertension (6% each). Atrial fibrillation occurred in 13 (7%) of patients.


Reference

Brown JR, Hillmen P, O’Brien S, et al. Efficacy of ibrutinib by baseline high-risk genetic features, including novel gene mutations, and safety with longer follow-up from the phase 3 RESONATETM trial in previously treated CLL/SLL. Abstract #88509. Presented at the 2016 ASH Meeting on Lymphoma Biology, June 20, 2016; Colorado Springs, CO.

TABLE 1. Progression-Free Survival and Overall Response Rate by Subgroup
18-Month Progression-Free Survival Overall Response Rate
Ibrutinib (n=195) Ofatumumab (n=196) Ibrutinib (n=195) Ofatumumab (n=196)
Overall 76% 8% 90% 25%
Prior therapy
1 91% 11% 35/35 (100%) 14/53 (26%)
2 76% 0 141/160 (88%) 35/143 (24%)
≥3 71% 4%
Del11q
Yes 83% 0 57/63 (90%) 7/59 (12%)
No 73% 10% 114/127 (90%) 42/132 (32%)
Del17p
Yes 71% 7% 56/63 (89%) 13/64 (20%)
No 79% 8% 120/132 (91%) 36/132 (27%)
IGHV
Unmutated 77% 0 90/98 (92%) 22/83 (27%)
Mutated 74% 15% 32/36 (89%) 12/49 (24%)

TABLE 2. Progression-Free Survival and Overall Response Rate Among Patients with Novel Genetic Mutations
18-Month Progression-Free Survival Overall Response Rate
Ibrutinib (n=142) Ofatumumab (n=149) Ibrutinib (n=142) Ofatumumab (n=149)
ATM
Mutated 77% 0 26/28 (93%) 8/33 (24%)
Not mutated 77% 8% 106/114 (93%) 32/116 (28%)
NOTCH1
Mutated 77% 0 37/40 (93%) 13/45 (29%)
Not mutated 77% 11% 95/102 (93%) 27/104 (26%)
SF3B1
Mutated 65% 10% 42/43 (98%) 10/44 (23%)
Not mutated 83% 0 90/99 (91%) 30/105 (29%)
TP53
Mutated 73% 0 67/72 (93%) 13/68 (19%)
Not mutated 82% 9% 65/70 (93%) 27/81 (33%)
MYD88
Mutated 0 0 2/3 (67%) 1/3 (33%)
Not mutated 77% 8% 130/139 (93%) 39/146 (27%)
BIRC3
Mutated 81% 0 20/21 (95%) 4/15 (27%)
Not mutated 76% 9% 112/121 (93%) 36/134 (27%)

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