Ibrutinib Shows Strong PFS and OS Benefits in RESONATE Study Follow-Up


The BTK inhibitor ibrutinib continued to demonstrate sustained progression-free survival and overall survival in chronic lymphocytic leukemia, regardless of patients’ high-risk cytogenetic status.

John C. Byrd, MD

The BTK inhibitor ibrutinib (Imbruvica) continued to demonstrate sustained progression-free survival (PFS) and overall survival (OS) in chronic lymphocytic leukemia (CLL), regardless of patients’ high-risk cytogenetic status. With up to 4 years of follow-up from the international phase III RESONATE trial, the 3-year PFS rate was 59% and the 3-year OS rate was 74%, according to long-term efficacy and safety findings presented during the 2017 ASCO Annual Meeting.1

“These long-term results show that extended treatment with ibrutinib is tolerable and continues to show sustained PFS in previously treated patients with CLL regardless of high-risk cytogenetics, as the median PFS was not reached with up to 4 years of follow-up,” said lead investigator John C. Byrd, MD, the D. Warren Brown Chair of Leukemia Research, and director of hematologic malignancies at The Ohio State University Comprehensive Cancer Center. “Traditional poor prognostic factors for survival with chemoimmunotherapy, including del(17p) and del(11q), were not significant factors predictive of PFS outcomes with ibrutinib therapy.”

Full FDA approval for ibrutinib in CLL was based on data from the RESONATE study. It compared ibrutinib versus ofatumumab (Arzerra) in patients with relapsed or refractory CLL/small lymphocytic leukemia (SLL). Ibrutinib reduced the risk of progression by 78% and the risk of death by 57% in the primary analysis, and significantly improved survival.2

Key eligibility criteria were CLL/SLL diagnosis, at least 1 prior therapy, an ECOG performance status of 0 or 1, and measurable nodal disease. Patients were randomized 1:1 to receive either ibrutinib (n = 195) or ofatumumab (n = 196). The ibrutinib group received 420 mg once daily until progressive disease (PD) or unacceptable toxicity. The ofatumumab group received 300 mg initially followed by infusions of 2000 mg in 11 doses over 24 weeks.

At interim analysis (median 9 months of follow-up), the Data Monitoring Committee (DMC) found ibrutinib to be superior to ofatumumab for PFS and OS. The DMC recommended access to ibrutinib for all patients in the ofatumumab arm. An additional OS sensitivity analysis was performed to address the bias introduced by crossover to ibrutinib. Of 144 patients eligible for crossover, 133 chose to receive ibrutinib.

Baseline characteristics were comparable between the 2 groups, and genomic abnormalities were common. About one-third of patients had del(11q) in each arm. The same was true of del(17p), including 63 patients (32%) who received ibrutinib and 64 patients (33%) who received ofatumumab.

In the ibrutinib arm, 39 patients (25%) had a complex karyotype, as well as 33 (22%) of the ofatumumab patients. A majority of patients in both arms wereIGHVunmutated (73% vs 63% in the ofatumumab arm).

Analysis of the subgroups in the ibrutinib arm revealed several notable traits. Seventy-four percent of patients with del(11q) had extensive baseline bulky disease, defined as lymph nodes ≥5 cm. This compared with 59% of patients (n = 48) who had neither del(11q) nor del(17p).

The del(11q) patients on ibrutinib were also more likely to have unmutatedIGHV: 84% of patients (n = 27) compared with 69% (n = 37) with neither del(11q) nor del(17p) aberrations. In contrast, complex karyotype occurred more frequently among patients with del(17p): 42% of patients (n = 19) compared with only 15% of patients (n = 10) who had neither del(11q) nor del(17p).

PFS was significantly longer in patients receiving ibrutinib compared with ofatumumab at a median follow-up of 44 months (HR, 0.133; 95% CI, 0.099-0.178). The median PFS was 8.1 months for ofatumumab but had not been reached for ibrutinib. The 3-year PFS rate was 59% with ibrutinib vs 3% with ofatumumab.

Additional PFS analysis in the ibrutinib arm revealed several key findings. Patients in the del(11q) subgroup tended to have a more favorable outcome. PFS outcomes were not statistically different for patients with del(17p), del(11q), or in those without cytogenetic abnormalities. The PFS rate at 3 years was 53% for patients with del(17p), 66% for del(11q), and 58% for patients without these abnormalities.

PFS was comparable between patients with unmutatedIGHVstatus and those with mutatedIGHVstatus. The 3-year PFS was 63% versus 66%, respectively. Among the patients with unmutatedIGHVstatus, 3-year PFS was 55% for patients with del(17p), 70% for del(11q), and 63% for patients without either abnormality.

Patients withoutTP53mutations tended to have a longer PFS than those withTP53mutations (median PFS not reached compared to 40.7 months), although this difference was not deemed to be statistically significant. Patients who had not been heavily pretreated (2 or fewer previous therapies) had improved PFS compared to those who had more than 2 prior therapies (median PFS not reached versus 35.1 months). The investigators also determined that the significant PFS benefit with ibrutinib was consistent across baseline disease and patient characteristics.

Median OS was not reached for either arm, although OS was longer for ibrutinib than ofatumumab. A sensitivity analysis, adjusting for crossover, also showed OS benefit with ibrutinib compared to ofatumumab (HR, 0.37; 95% CI, 0.22-0.62).

The overall response rate (ORR) for ibrutinib was 91%. The complete response (CR)/complete response with incomplete marrow recovery (CRi) rate was 9% with current follow-up and has increased over time.

The median treatment duration was 41 months with ibrutinib and 5 months with

ofatumumab. At the time of analysis, 46% of patients randomized to the ibrutinib arm continued ibrutinib therapy with median follow-up of 44 months. Ninety patients (46%) were still on ibrutinib at the time of analysis.

Of 105 patients (54%) who discontinued ibrutinib, the most common reason was PD (27%). Fourteen of these patients experienced transformation; 9 transformed to diffuse large B-cell lymphoma, 3 to Hodgkin’s disease, and 2 to prolymphocytic lymphoma. Among 23 patients (12%) who discontinued ibrutinib treatment due to adverse events (AEs), the most frequent AEs were pneumonia (n = 3), anemia, thrombocytopenia, diarrhea, and anal incontinence (n = 2 each).

The most common AEs of any grade were consistent with prior reports of ibrutinib and include diarrhea, fatigue, cough, and upper respiratory infection. The most common grade ≥3 hematologic AEs included neutropenia (23%), anemia (8%) and thrombocytopenia (8%). The most common grade ≥3 non-hematologic AEs included pneumonia (17%), hypertension (8%), urinary tract infection (6%), and diarrhea (6%).

The prevalence of grade ≥3 AEs has generally declined over time, with incidence the highest during the first year. Rates of most grade ≥3 AEs decreased from year 1 to years 2-3, including neutropenia (18% vs 8%), pneumonia (11% vs 4%), and atrial fibrillation (4% vs 2%).

The prevalence of any-grade atrial fibrillation remained consistent over time with reported rates of 6%, 5%, 8%, and 8% over years 0-1, 1-2, 2-3, and >3, respectively. Rates of hypertension, however, increased over time, rising from 8% in year 0-1 to 22% in year >3.

AEs leading to discontinuation were varied, but decreased over time from 6% in year 0-1 to 4% in year 2-3. AEs that occurred in more than 1 patient were pneumonia (n = 3) and diarrhea (n = 2). AEs leading to dose reduction remained consistent over time, occurring in 6%, 9%, 4%, and 7% over years 0-1, 1-2, 2-3, and >3, respectively.


  1. Byrd JC, Hillmen P, O’Brien SM, et al. Long-term efficacy and safety with ibrutinib (ibr) in previously treated chronic lymphocytic leukemia (CLL): Up to four years follow-up of the RESONATE study.J Clin Oncol35, 2017 (suppl: abstr 7510).
  2. Byrd JC, Brown JR, O'Brien SM, et al. Ibrutinib versus ofatumumab in previouslytreated chronic lymphoid leukemia.N Engl J Med. 2014;371:213-223.
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