Bendamustine debulking followed by ofatumumab and ibrutinib demonstrated an overall response rate of 92% in patients with chronic lymphocytic leukemia, meeting the primary end point of the phase II CLL2-BIO trial, and was well-tolerated with no new safety signals. Results from the study were published in Haematologica.
Bendamustine debulking followed by ofatumumab (Arzerra) and ibrutinib (Imbruvica) demonstrated an overall response rate (ORR) of 92% in patients with chronic lymphocytic leukemia (CLL), meeting the primary end point of the phase II CLL2-BIO trial (NCT02689141), and was well-tolerated with no new safety signals. Results from the study were published inHaematologica.
A total of 66 patients were enrolled in the study to receive bendamustine debulking followed by induction and maintenance therapy with ofatumumab and ibrutinib. The efficacy analysis excluded 1 patient who had less than 2 induction cycles in the first-line setting due to the predefined protocol, but the patients remained a part of the study population. At baseline, 32% of 65 patients had del(17p) or aTP53mutation (n = 21) and 65% of patients had an unmutatedIGHVstatus (n = 45). Sixty percent of patients were treatment naïve (n = 65), while the remaining 40% has relapsed/refractory CLL. Patients who were previously treated had received a median of 1.5 prior therapies (range, 1-5; interquartile range [IQR], 1-2). The most common prior therapies included bendamustine plus rituximab (Rituxan) and the triplet regimen of fludarabine, cyclophosphamide, and rituximab; however, there were 5 patients previously treated with novel agents.
One hundred percent of the 39 first-line patients with CLL responded to treatment following induction. In addition, 81% of patients with relapsed/refractory CLL responded to treatment. When tested against the null hypothesis of 75% ORR, the ORR observed in the mixed population of patients was 92% (95% CI, 83%-98%,P= .0013). Partial responses (PRs) were observed in 59 patients, including one PR with lymphocytosis. There were no complete responses (CRs) observed.
Investigators assessed minimal residual disease (MRD) in peripheral blood at the final restaging in 62 patients, and of those patients, 14% achieved MRD negativity (<10-4). In first-line patients the MRD negativity rate was 18% and for relapsed/refractory patients, the MRD negativity rate was 8%. MRD negativity was lower in patients with del(17p) and unmutatedIGHVstatus, at 0% and 9%, respectively. The ORR among patients with del(17p) and unmutatedIGHVstatus was 75% and 89%, respectively.
Following 2 cycles of bendamustine debulking, 59% of patients achieved a response (n = 30), which included 66% of the treatment-naïve patients (n = 23) and 44% of the relapsed/refractory patients (n = 16). Thirty-seven percent of patient in the study had stable disease and 4% progressed on therapy but continued with induction treatment.
In the subgroup of patients with del(17p) andTP53mutations, 11 of 21 patients received bendamustine debulking and of those patients, 6 achieved a response and 5 had stable disease. Among the previously treated group, 9 of 15 patients previously exposed to bendamustine received bendamustine debulking and 44% of those patients responded (n = 4).
Patient responses to treatment improved over time. Six months after restaging, the best response was observed as a CR/CRi (CR with incomplete marrow recovery) in 6% of patients (n = 4). Other responses included clinical CR/CRi without confirmatory CT scan and/or bone marrow biopsy, which occurred in 43% of patients (n = 28) and PRs occurred in 51% of patients (n = 33). A total of 12 patients stopped maintenance treatment due to either MRD-negative response (n = 5), progression (n = 4), adverse events ([AEs], n = 2), or death (n = 1).
Overall, 6 cases of progressive disease and 2 deaths were reported. All cases of disease progression occurred in patients with relapsed/refractory CLL. The 2 patients who died during the study were both 73 years old, one was on their 6th induction cycle and succumbed to sepsis, and the second patient was on the 2nd maintenance cycle and died due to complications associated with pneumonia.
In all 66 patients, a total of 959 AEs were reported. Sixty-three percent of the AEs occurred in the treatment-naïve group (n = 602), and 37% occurred in the relapsed/refractory group (n = 357). AEs showed up during different phases of treatment: During debulking, 16% of the AEs occurred, while the other 57% happened during induction treatment and 26% during maintenance therapy. Investigator assessment determined that 63% of the AEs observed were due to study treatment. Most of the AEs were grade 1 or 2.
The most common grade 1/2 toxicities observed with bendamustine debulking were nausea (27%), rash/exanthema (15%), and fatigue (13%). The most common grade 1/2toxicities seen with induction treatment were infusion-related reactions (36%), upper respiratory tract infections (30%), diarrhea (27%), muscle disorders (26%), fatigue (21%), and rash/exanthema (20%).
The prospective, open-label, multicenter investigator-initiated CLL2-BIO trial was conducted by the German CLL Study Group with the University of Cologne. The study was designed to follow the sequential triple-T concept. Patients in the study received debulking with bendamustine70 mg/m2on days 1 and 2, repeated after 28 days. Participants then received induction treatment with ofatumumab 300 mg was administered on day 1 and at1000 mg on days 8 and 15 of the first cycle and then every 4 weeks in cycles 2 to 6. Induction also included daily oral 420 mg of ibrutinib started on day 1 of the second cycle. Ibrutinib 420 mg was continued daily in the maintenance phase and ofatumumab was administered at 1000 mg every 3 months until unacceptable toxicity, progression, new CLL treatment, or for up to 24 months.
The study was open to adult patients with CLL who were treatment naïve or relapsed/refractory.
Cramer P, Tresckow J, Robrecht S, et al. Bendamustine, followed by ofatumumab and ibrutinibin chronic lymphocytic leukemia (CLL2-BIO): primary endpoint analysis of a multicentre, open-label phase-II trial [published online February 27. 2020].Haematologica. doi: 10.3324/haematol.2019.223693.