Since the first evaluation of ibrutinib in a phase 1 trial in a wide setting of B cell malignancies, it was demonstrated that this orally administered molecule was well tolerated and induced clinical objective responses (60 %) across B cell histologies, with highest response rate in MCL and CLL patients [
2]. Ibrutinib treatment was then investigated in relapsed CLL patients in a phase 1b/2 multicenter clinical trial conducted on 85 patients (33 % with 17p13 deletion), reporting an overall response rate (ORR) of 71 %, with two complete responses (CR), and further 18 % with partial response (PR) with lymphocytosis. At 26 months, the progression-free survival (PFS) was 75 % [
3]. The response to ibrutinib did not vary according to traditional high-risk prognostic factors, with 68 % of response in 17p13-deleted setting, even if most events associated with disease progression occurred in patients with high-risk cytogenetics (PFS = 57 %) (Table
1). The most common adverse events were diarrhea, fatigue and upper respiratory tract infections. The events of infection mainly occurred in the early phase of treatment, but collectively, the incidence of grade 3 infections did not result increased as compared to rates reported after traditional therapies. It was also reported that the levels of IgG and IgM remained relatively stable, whereas IgA increased throughout treatment [
3]. The efficacy of ibrutinib in previously treated CLL was also confirmed in a phase 3 multicenter study in which 391 patients were randomized to receive ibrutinib or anti-CD20 antibody ofatumumab [
4]. The ORR was 43 % (all partial responses) with additional 20 % PR with lymphocytosis in ibrutinib-treated patients as compared to only 4 % in the ofatumumab arm. Ibrutinib in comparison to ofatumumab significantly prolonged the duration of PFS and the rate of OS, regardless of high-risk features. The frequencies of any grade or grade >3 infections in the ibrutinib group were 70 and 24 %, respectively [
4]. Very recently, Byrd and colleagues reported updated observations indicating that ibrutinib treatment is well tolerated in CLL patients for an extended period (3-year follow-up) and responses are durable and improves in quality (median time to CR, 21 months), being disease progression uncommon, and primarily occurring in the high-risk patient settings with 17p or 11q deletions in leukemic clone [
5]. Ibrutinib is currently investigated in combination with both chemotherapy and monoclonal antibodies to reduce the extent of lymphocytosis and to achieve higher frequencies of complete responses. Burger and colleagues reported the results of a phase 2 study conducted on 40 high-risk CLL patients treated with ibrutinib plus rituximab [
6]. The ORR was 95 %, with 87 % PR and 8 % CR, and the PFS at 18 months was 78 % for all patients and 72 % for 17p-deleted/mutated patients. Infections were the most common adverse effects. Overall, the combination strategy was associated with a shorter duration of lymphocytes redistribution as compared to ibrutinib alone, and complete remissions were achieved in more patients. A randomized study comparing ibrutinib versus ibrutinib plus rituximab is ongoing (NCT02007044). As first-line monotherapy, a phase 1b/2 multicenter trial conducted on 29 elderly symptomatic CLL patients reported encouraging results with 71 % ORR (13 % CR) and rare hematological toxicity and infections, indicating that ibrutinib treatment is well tolerated and effective in elderly setting. Median serum levels of IgA increased during treatment, no changes in IgM and IgG over time [
7]. As upfront strategy, two phase 3 trials are ongoing comparing the efficacy of chlorambucil or ibrutinib in elderly CLL (RESONATE-2, NCT01722487) and the efficacy of bendamustine-rituximab versus ibrutinib-rituximab versus ibrutinib (NCT01886872). In a very recent phase 1b study evaluating the safety and efficacy of ibrutinib in combination with chemoimmunotherapy (CIT) (bendamustine, rituximab (BR); fludarabine, cyclophosphamide and rituximab (FCR)) in patients with relapsed/refractory CLL, the ORR in the BR-ibrutinib group was 93 % with 40 % CR with an expected toxicity profile and PFS 70 % at 36 months; all three patients receiving FCR-ibrutinib achieved CR. The treatment-related lymphocytosis was reduced, but not completely absent when ibrutinib was combined to BR [
8]. A phase 3 randomized trial combining ibrutinib with BR in relapsed/refractory CLL/SLL (NCT01611090) and a phase 2 study combining ibrutinib with FCR in untreated, young CLL patients (NCT02251548) are ongoing. Another recent report of a phase 2 study conducted on 51 treatment naïve and relapsed/refractory CLL patient harboring TP53 aberrations reported activity of single-agent ibrutinib in this high-risk subset with ORR at 24 weeks of 92 % (50 % PR and 42 % PR with lymphocytosis) and PFS at 24 months of 82 % [
9]. Rapid disease control was achieved in all tissue compartments and durable responses were reported, but deep remissions were rare, even in previously untreated patients. Noteworthy, subclones carrying 17p13 deletion seemed equally sensitive to ibrutinib as those without the deletion [
9].
Table 1
Clinical trials with ibrutinib and idelalisib in CLL patients
| | | | | | All cases | All cases | | TP53 subset | TP53 subset |
| Relapsed | 1b/2 | 85 | 66 (37–82) | Ibru mono | 71 + 18a (2 %) | 75 % at 26 ms | 33 % | 68 % (4 %) | 57 % at 26 ms |
O’Brian, Lancet Oncol 2014 [ 7] | First line | 1b/2 | 29 | 71 (65–84) | Ibru mono | 71 + 13 %a (13 %) | 96 % at 24 ms | 6 % | NA | NA |
Farooqui, lancet Oncol 2015 [ 9] | Treated or untreated with TP53 aberrations | 2 | 51 | 62 (33–82) | Ibru mono | - | - | 100 % | 50 + 42 %a
| 82 % at 24 ms |
| Relapsed/refractory | 3 | 391 | 67 (30–86)b
| Ibru vs. Ofa | 43 + 20 %a (0 %) | 88 % at 6 ms | 32 % | NA | 83 % at 6 ms |
Burger, Lancet Oncol 2014 [ 6] | High-risk previously treated or untreated | 2 | 40 | 63 (35–82) | Ibru + RTX | 95 % (8 %) | 78 % at 18 ms | 50 % | 100 % (10 %) | 72 % at 18 ms |
| Relapsed/refractory | 1 | 54 | 63 (37–82) | Ide mono | 39 + 33 %a (0 %) | 50 % at 16 ms | 24 % | 54 % (0 %) | 50 % at 3 ms |
| Relapsed | 3 | 220 | 71 (48–90)b
| Ide + RTX vs. placebo | 81 % (0 %) | 93 % at 6 ms | 38 % | NA | NA |
Ibrutinib also showed antitumor activity in several types of NHL as single agent or in combination [
2,
10]. Wang et al. reported the results of a phase 2 study conducted on 111 patients with relapsed or refractory MCL treated with a daily dose of 560 mg of single-agent ibrutinib. The treatment showed durable efficacy with ORR of 68 % (21 % CR) and PFS of 14 months [
11]. There was an increase of MCL cells in blood 10 days after treatment initiation in 34 % of patients, with a subsequent decline in these cells to near baseline by day 28 [
11]. In patients with relapsed DLBCL, ibrutinib showed preferential activity against tumors with the activated B cell-like (ABC) subtype with a response of 40 % [
12]. In a phase 1b study, 32 patients with B-NHL received ibrutinib plus rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), showing promising results, also in the subset of DLBCL, and acceptable safety profile with known toxicities associated with R-CHOP treatment [
13]. A phase 3 clinical trial (NCT01855750) to assess the clinical outcome of ibrutinib plus R-CHOP in patients with ABC-DLBCL lymphoma is ongoing.