David B. Miklos, MD, PhD
Ibrutinib (Imbruvica) showed promising activity in heavily pretreated, relapsed/refractory chronic lymphocytic leukemia (CLL) after allogeneic stem cell transplantation (ASCT), according to data presented at the American Society for Blood and Marrow Transplantation 2015 BMT Tandem Meeting.
“These data support that Imbruvica may be an effective treatment option for relapsed posttransplant CLL patients, and are consistent with findings from clinical studies in the overall high-risk CLL population,” said Danelle James, MD, head of Oncology at Pharmacyclics, which codevelops ibrutinib with Janssen Biotech.
In one session, David B. Miklos, MD, PhD, assistant professor of Medicine at Stanford University, reviewed data from 16 patients across four phase II/III studies of ibrutinib. The patients all had heavily pretreated, posttransplant, relapsed/refractory, high-risk CLL and received ibrutinib monotherapy or in combination with ofatumumab (Arzerra).
Ten of the 16 patients had high-risk CLL and 75% (n =12) had received ≥4 previous therapies. The endpoints of the four studies included overall survival (OS), progression-free survival (PFS), overall response rate (ORR), and duration of response.
At a median follow-up of 23.3 months, OS, PFS, and duration of response had not been reached. Patients received ibrutinib for a median of 18 months (range, 0.4-38.8 months), and 11 patients (69%) continued on study treatment.
ORR in the 16 patients was 88% and the PFS rate at 2 years was 76.6%.
In the four studies Miklos reviewed, ibrutinib was well tolerated in patients with prior ASCT, with a toxicity profile that was comparable to adverse event (AE) reports in the trials’ overall relapsed/refractory CLL populations.
Five of the 16 patients (31%) discontinued treatment, two following disease progression, two related to pneumonia, and one patient withdrew voluntarily. Infections, which were reported in 6 patients, were the treatment-related grade 3/4 AE with the highest frequency.
In a separate presentation at the BMT meeting, Christine E. Ryan, of the Stanford University School of Medicine, discussed data for five patients with high-risk CLL who relapsed following ASCT. Ibrutinib was administered at 420 mg/daily starting at 1 month to 2 years post-relapse.
Treatment with ibrutinib showed sustained disease response. In two patients receiving ibrutinib monotherapy, undetectable CLL minimal residual disease (MRD) was achieved after 8 and 39 months, respectively. One of these patients achieved complete donor CD3 chimerism after 12 months of ibrutinib, and maintained undetectable CLL MRD 10 months post-treatment.
Four patients with abnormal lymph nodes had a 68% reduction in their lymph node size after 3 months of ibrutinib therapy.
Also of note, after 6 months of ibrutinib treatment, one patient reached resolution of GVHD.
“These data provide supportive safety information as we evaluate Imbruvica in post allo-transplant patients who are suffering from chronic GVHD," said James.
The ongoing phase Ib/II PCYC 1129 study is examining ibrutinib in patients with steroid-dependent or refractory chronic GVHD (NCT02195869). Phase Ib of the open-label, multicenter study was completed with no dose-limiting toxicities. Patient accrual is ongoing for phase II of the study, in which patients will receive ibrutinib at the recommended 420-mg dose.
Ibrutinib was initially granted accelerated approval by the FDA in CLL in February 2014 for the treatment of patients who had received at least one previous therapy. The decision was based on data from 48 patients enrolled in the single-arm phase Ib/II PCYC-1102-CA study. At a median 15.6-month follow-up for this group, single-agent ibrutinib produced an ORR of 58.3% (all partial responses) with a duration of response of up to 24.2 months.
In July 2014, ibrutinib received a full approval from the FDA in CLL and the approval was also expanded to include patients who harbor a 17p deletion. The action was based on data from the phase III RESONATE study.
RESONATE examined single-agent ibrutinib in patients with relapsed/refractory CLL. In the study, ibrutinib dramatically increased PFS by nearly 80% and significantly extended OS by 57% compared with ofatumumab. Additionally, ibrutinib lowered the risk of progression by 75% in patients who harbored a 17p deletion.
Ibrutinib also has approved indication for the treatment of patients with mantle cell lymphoma.
According to Pharmacyclics, 13 phase III studies of ibrutinib have been launched, and 58 trials are registered on www.clinicaltrials.gov.