Ibrutinib induces durable responses in CLL

Issue: December 10, 2015

NEW YORK — Single-agent ibrutinib induced rapid and durable responses in patients with chronic lymphocytic leukemia or small lymphocytic leukemia, according to study results presented at Lymphoma & Myeloma 2015.

Results showed 85% of patients with treatment-naive disease and 94% of patients with relapsed/refractory disease achieved investigator-assessed complete response, partial response or partial response with lymphocytosis.

“When you are talking to your patients about what they can expect, you can say with confidence it is very likely they are going to respond to treatment,” Steven Coutre, MD, of Stanford Cancer Center, said during a presentation.

Steven Coutre

Ibrutinib (Imbruvica; Pharmacyclics, Janssen) — an oral, once-daily Bruton’s tyrosine kinase inhibitor — is approved for the treatment of patients with previously treated CLL. It also is indicated for first-line treatment of patients with CLL who have deletion 17p.

In prior studies, ibrutinib demonstrated activity and an acceptable toxicity profile in patients with treatment-naive CLL or small lymphocytic leukemia (SLL).

In the current multicenter study, Coutre and colleagues evaluated the efficacy and safety of single-agent ibrutinib in patients with CLL or SLL. Investigators used International Workshop Group on CLL criteria to assess best overall response.

The analysis included 94 patients, of whom 27 were treatment naive and 67 had relapsed/refractory disease.

In the treatment-naive group, median age was 71 years (range, 65-84) and 74% were aged 70 years or older. In the relapsed/refractory group, median age was 66 years (range, 37-82) and 36% were aged 70 years or older.

All patients in the treatment-naive group and the majority (97%) of patients in the relapsed/refractory group had ECOG status of 0 or 1. The percentage of patients with Rai stage 0-II disease (41% vs. 45%) or Rai stage III-IV disease (56% vs. 51%) were comparable between treatment-naive and relapsed/refractory patients.

A considerably higher percentage of patients with relapsed/refractory disease had bulky nodes larger than 5 cm (52% vs. 11%).

Twenty-five patients — including two treatment-naive patients and 23 with relapsed/refractory disease — had deletion 17p. Twenty-two patients, all of whom had relapsed/refractory disease, had deletion 11q.

Patients with relapsed/refractory CLL had undergone a median four prior therapies (range, 1-12).

All study participants received ibrutinib 420 mg daily until disease progression or unacceptable toxicity.

Median time on treatment was 30.4 months (range, 1.3-44.2) for treatment-naive patients and 21.9 months (range, 0.3-44.6) for those with relapsed/refractory disease.

Researchers reported complete responses in 14% of the entire cohort, 26% of treatment-naive patients and 9% of patients with relapsed/refractory disease. They observed partial responses in 73% of the entire cohort, 52% of those with treatment-naive disease and 82% of those with relapsed/refractory disease.

Median time to initial response (1.9 months vs. 1.8 months), median time to best response (7.4 months vs. 7.4 months) and median time to complete response (15.6 months vs. 19.9 months) were comparable between the treatment-naive and relapsed/refractory groups.

Median duration of response had not been reached in either group. However, most patients (83.8% overall, 95.2% treatment naive, 79.1% relapsed/refractory) had sustained responses at 30 months.

“At the same time … platelet counts and hemoglobin rise early and continue to improve, indicating the efficacy of the drug and the lack of myelosuppression,” Coutre said.

Median PFS — the study’s primary endpoint — had not been reached in either group, although 95.8% (95% CI, 73.9-99.4) of treatment-naive patients and 75.9% (95% CI, 62.5-85.1) of those with relapsed/refractory disease remained progression free at 30 months.

PFS analysis by cytogenetics showed 59.6% (95% CI, 34.4-77.9) of patients with deletion 17p and 82.4% of those with deletion 11q remained progression free at 30 months. Median PFS was 32.4 months among those with deletion 17p; median PFS had not been reached in the deletion 11q group.

Median OS had not been reached in other group, but 96.2% (95% CI, 75.7-99.4) of treatment-naive patients and 87.1% (95% CI, 75.8-93.3) of those with relapsed/refractory disease remained alive at 30 months. OS analysis by cytogenetics showed a majority of patients with deletion 17p (81.3%; 95% CI, 57.6-92.6) and deletion 11q (88.2%; 95% CI, 60.6-96.9) were alive at 30 months.

In the entire cohort, the most frequently reported grade 3 or worse adverse events included hypertension (23%), pneumonia (15%), neutropenia (13%), atrial fibrillation (7%) and diarrhea (7%).

Coutre and colleagues reported higher rates of grade 3 or worse adverse events (any event, 82% vs. 63%; ibrutinib-related event, 37% vs. 22%), grade 3 or worse infections (48% vs. 11%), and grade 3 or worse serious adverse events (any event, 69% vs. 26%; ibrutinib-related event, 12% vs. 4%) among patients with relapsed/refractory disease.

Eight patients — one with treatment-naive disease and seven with relapsed/refractory disease — required a dose reduction due to adverse events.

Twelve patients — one with treatment-naive disease and 11 with relapsed/refractory disease — discontinued treatment due to adverse events. Twelve patients — three with treatment-naive disease and nine with relapsed/refractory disease — discontinued due to disease progression.

Eight patients — one with treatment-naive disease and seven with relapsed/refractory disease — died on study.

Fifty patients (53%) — including 22 (81%) of those who were treatment naive and 28 (42%) of those with relapsed/refractory disease — underwent treatment for more than 2 years. Sixty-six percent of patients — including 81% of treatment-naïve patients and 60% of those with relapsed/refractory disease — remain on treatment with single-agent ibrutinib.

“Continued use of ibrutinib leads to a rapid and durable response,” Coutre said. “[The drug] was well tolerated, allowing us to continue patients on treatment. This is particularly important for these types of drugs because we clearly see patients derive significant clinical benefit, despite the fact they still often have easily detectable disease, particularly in the bone marrow.” – by Mark Leiser

Reference:

Coutre S, et al. Abstract O2. Presented at: Lymphoma & Myeloma 2015: An International Congress on Hematologic Malignancies; Oct. 22-24, 2015; New York.

Disclosure: Coutre reports speakers honorarium from AbbVie, Celgene, Gilead, Janssen and Pharmacyclics. Please see the abstract for a list of all researchers’ relevant financial disclosures.