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minimal residual disease (MRD) negativity and therefore a continuous treatment appears to be necessary to maintain responses.7-9 This prolonged treatment duration increases the risk of toxicities, non-compliance and selection of resistant clones, as well as inflating the costs of treatment.
We hypothesized that the combination of ibrutinib with the second-generation, fully humanized antibody ofatumumab10 might have the potential to increase the depth of responses and achieve CR and MRD negativity, i.e., eradicate the disease below the detection limit and thus enable treatment discontinuations without risk of immediate relapse. Several phase II and III studies are test- ing the combination of ibrutinib with the anti-CD20 anti- bodies rituximab,5,11,12 ofatumumab13 and obinutuzumab;4,14 the CLL2-BIO trial is evaluating ibrutinib with ofatumum- ab after an optional debulking with bendamustine.
Methods
The CLL2-BIO trial is a prospective, open-label, multicenter, investigator-initiated trial by the German CLL Study Group with the University of Cologne, Germany being the legal sponsor (par- ticipating sites are listed in the Online Supplementary Appendix, page 1). The design of this phase II trial is based on the previously published so-called “sequential triple-T concept” of a tailored and targeted treatment aiming at a total eradication of MRD.15,16 It is evaluating a sequential treatment consisting of two cycles of ben- damustine debulking, followed by six induction cycles and up to 24 months of maintenance treatment with ofatumumab and ibrutinib (Online Supplementary Appendix, Figure S1, page 5). The debulking (bendamustine 70 mg/m2 on days 1 and 2 repeated after 28 days) was recommended for patients with an absolute lymphocyte count ≥25,000/mL and/or lymph nodes with a diam- eter ≥5 cm, unless the patients had contraindications (e.g., refrac- toriness or known hypersensitivity to the drug). In the subse- quent induction treatment, 300 mg ofatumumab was adminis- tered on day 1 of the first cycle and 1,000 mg on days 8 and 15 of the first cycle and every 4 weeks in cycles 2 to 6. Daily oral intake of 420 mg ibrutinib started on day 1 of the second cycle. In the maintenance treatment, ibrutinib (420 mg) was continued daily and ofatumumab (1,000 mg) administered every 3 months until unacceptable toxicity, progression/new CLL treatment or for up to 24 months. Furthermore, treatment was stopped in the case of a CR and MRD negativity in peripheral blood in two assessments within an interval of 3 months.
The trial was designed for adult patients with treatment-naïve or relapsed/refractory CLL requiring treatment according to International Workshop on CLL (IWCLL) criteria;17 eligibility cri- teria are described in the Online Supplementary Appendix (pages 1- 3). All patients provided written informed consent. Responses were evaluated by the investigators according to IWCLL criteria17 and reviewed centrally. Computed or magnetic resonance tomography (CT/MRI), as well as a bone marrow aspirate were required for confirmation of a CR or CR with incomplete mar- row recovery (CRi). The response of patients fulfilling all IWCLL criteria of a CR/CRi (no evidence of lymphadenopathy, hepato- or splenomegaly on clinical examination and ultrasound or other imaging investigations, no disease-related symptoms and nor- malization of the hematologic parameters) but lacking one or both of these diagnostic modalities were termed “clinical CR” or “clinical CRi”, respectively, and graded as a partial response (PR).
Samples for detection of MRD, which were mostly peripheral blood and also bone marrow, were taken for the final restaging after the induction treatment onwards and were analyzed cen-
trally with four-color flow cytometry.18,19 Results were catego- rized into three different MRD levels: low (<10-4), intermediate (≥10-4 and <10-2) and high (≥10-2)20 and MRD "negativity" was defined as <10-4.
The primary endpoint of the CLL2-BIO trial was the overall response rate (ORR) after induction treatment. Further details on statistical analyses are provided in the Online Supplementary Appendix (page 4).
The study was approved by the health authorities and the insti- tutional review board of each participating site, was registered at clinicaltrials.gov (NCT02689141) and was conducted in accordance with the Declaration of Helsinki and International Conference on Harmonization-Good Clinical Practice.
Results
Between February 4 and October 4, 2016, 66 patients were enrolled. One patient treated first-line who received fewer than two induction cycles (treatment discontinuation due to a generalized seizure on day 4 of induction cycle 2) was excluded from the efficacy analysis as predefined by the protocol but remained in the safety population. The patients flow through the study is summarized in Figure 1.
The patients’ baseline characteristics are shown in Table 1. Of note, 21 of 65 patients (32%) had a del(17p) and/or TP53 mutation and 45 patients (69%) had unmutated IGHV.
Thirty-nine of the 65 patients (60%) were treatment- naïve and 26 patients (40%) had relapsed/refractory CLL with a median of 1.5 prior therapies (range, 1-5; interquar- tile range, 1-2). The prior therapies are presented in the Online Supplementary Appendix (page 6); most common therapies were bendamustine plus rituximab (15 times in 14 patients) and fludarabine, cyclophosphamide plus rit- uximab (8 times in 8 patients); five patients had received novel agents (3 idelalisib with rituximab and 2 veneto- clax).
Fifty-one of 65 patients (78%) received bendamustine debulking and 44 patients completed the planned two cycles; 14 patients (22%) started the induction therapy immediately. Sixty-three of 65 patients (97%) received all six induction cycles; two patients discontinued treatment in the fourth cycle, one due to bronchial carcinoma and one due to atrial fibrillation. The majority of patients received all eight ofatumumab infusions in the induction phase (62 of 65 patients, 95%) and the mean dose intensi- ty of ofatumumab was 99% of the planned dose. Regarding the daily oral intake of ibrutinib in the induc- tion phase, more than half of the patients had at least one dose reduction (40 patients, 62%) and/or treatment inter- ruption (37 patients, 57%). The median duration of the treatment interruptions was 1 day (range, 1-83 days); 19 patients (29%) had treatment interruptions lasting ≥7 days, which were mainly due to adverse events. The ibru- tinib dose was modified in 89 of the total of 384 treatment cycles (23%); this was due to adverse events in 42 cycles given to 24 patients. Despite these dose modifications, the mean dose intensity of ibrutinib in the induction treat- ment was 94% of the planned dose. The administration of debulking treatment with bendamustine appeared not to increase the rate of dose reductions and treatment inter- ruptions or to have an adverse impact on the dose intensi- ty (Online Supplementary Appendix, Table S5, page 8). Adverse events leading to dose modifications of ibrutinib and/or ofatumumab were mainly infusion-related reac-
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