Ibrutinib
The molecule ibrutinib was developed as an oral irreversible inhibitor of BTK, an intracytoplasmic enzyme in the BCR signaling pathway that is required for BCR activation of integrins and other molecules. Congenital mutations or absence of BTK in humans leads to profound deficiency of B lymphocytes due to arrest in B cell development with consequent agammaglobulinemia. In CLL, BCR signaling is aberrantly activated, promoting B cell proliferation and survival as well as modulating migration and homing of malignant cells. The anti-tumor activity of ibrutinib (Table
2) results from disruption of BCR signaling as well as targeting of toll-like receptor signaling and adhesion and migration pathways.
Table 2
Trials involving new agents
| 1b/2 | 85 | 4 | 71% | 2% | 75% at 26 months | n/a |
Ibrutinib vs. ofatumumab [ 37] | 3 | 391 | 3 | 42.6 vs. 4.1% | 2 vs. 1% | Not reached vs. 8.1 months |
p < 0.001 for ORR |
| 1b/2 | 101a
| 4 | 90% | 7% | 69% at 30 months | n/a |
Idelalisib + rituximab vs. placebo + rituximab [ 52] | 3 | 220 | Anti-CD20-based or ≥2 previous | 81 vs. 13% | 0% | Not reached vs. 5.5 months |
p < 0.001 for ORR |
| 1 | 56 | 4 | 84% | 21% CR/Cri
| n/a | n/a |
| 1 | 116 | 3 | 79% | 20% | 25 months | n/a |
| 2 | 107 | 2 | 79% | 8% | Not reached at 12.1 months | n/a |
Venetoclax + rituximab [ 62] | 1 | 49 | 2 | 84% | 41% CR/Cri
| n/a | n/a |
An initial phase 1b/2 clinical trial in relapsed/refractory CLL [
20] studied the safety, efficacy, and pharmacokinetics of ibrutinib. Eighty-five patients with a median of 4 (1–12) prior therapies, almost all exposed to a purine nucleoside and rituximab, were treated with ibrutinib at a dose of 420 mg (
n = 51) or 840 mg (
n = 34). Deletion 17p was present in 33% and del (11q) in 36%. The overall response rate (ORR) was 71% at both dose levels, and responses were independent of adverse cytogenetics. At 26 months, PFS for the entire cohort was 75% and OS 83%. The responses were predominantly partial with the observation of an early transient increase in lymphocytes, with frequent persistent peripheral lymphocytosis, despite regression of adenopathy and splenomegaly and improvement in other hematologic values. This phenomenon of an early rise in lymphocyte count has been attributed to dislodging of CLL cells from nodal compartments into the circulation. The recognition that persistent or increased lymphocytosis is not indicative of treatment failure with these agents has necessitated a revision of response criteria with the addition of partial response with lymphocytosis (PR
L) [
33]. Based on the results of these early phase studies, ibrutinib received FDA-accelerated approval in relapsed CLL in 2014 [
34], then was accepted as a breakthrough drug for CLL with 17p deletion the same year [
35]. This study established the 420-mg daily dose for subsequent trials with identical BTK occupancy at 96 to 99% for both the 420- and 840-mg doses [
36].
The efficacy of ibrutinib was confirmed in the RESONATE
™ trial, a phase 3 comparison of ibrutinib to ofatumumab in patients with relapsed or refractory CLL with PFS as the primary endpoint [
37]. Eligibility criteria included at least one prior therapy and ineligibility for purine analog treatment due to comorbidities, age over 70 years, presence of del (17p), or short duration of response after CIT. In this multicenter study, 391 patients were randomly allocated to receive ibrutinib 420 mg daily until disease progression (
n = 195) or ofatumumab at an initial dose of 300 mg, followed by 2000 mg weekly for 7 weeks, then every 4 weeks for 16 weeks (
n = 196). The baseline characteristics were well balanced with a median of 3 (1–12) prior therapies in the ibrutinib group and 2 (1–13) in the ofatumumab group; del (17p) and del (11q) were each detected in about 30% of patients in both arms. The study was terminated after a pre-planned interim analysis demonstrated markedly improved outcomes for the ibrutinib arm. With a median follow-up of 9.4 months, median PFS in the ofatumumab arm was 8.1 months and had not been reached in the ibrutinib arm with a HR for progression or death in the ibrutinib arm of 0.22 (
p < 0.001). A crossover design permitted patients progressing on ofatumumab to receive ibrutinib once the primary endpoint was reached, and at the time of analysis, 57 patients had crossed over to ibrutinib. Nonetheless, an OS advantage for the ibrutinib therapy was observed in both uncensored and censored for crossover groups (HR for death in ibrutinib arm 0.39 and 0.43, respectively, at 12 months; OS 90% in ibrutinib group and 81% in ofatumumab group). Improvement in PFS was observed across all subgroups regardless of age, clinical stage,
IGHV mutation status, or presence of del (17p).
An update of the initial phase 1b/2 trial reported 3-year follow-up of 31 treatment-naïve (TN) patients and 101 patients with relapsed/refractory CLL treated with single-agent ibrutinib [
38]. At a median of 30 and 23 months on study for TN and relapsed/refractory patients, 81 and 53%, respectively, remained on drug. Response quality improved with time; with extended follow-up, 94% of patients who achieved PR
L converted to CR or PR. Discontinuation due to disease progression was only 3% in the TN group but 21% in the relapsed/refractory group, whereas discontinuation due to drug intolerance was similar in both groups (10 and 12%, respectively). The estimated PFS at 30 months was 96 and 69% for the two groups but only 48% in patients with del (17p).
The toxicities observed with ibrutinib are modest, with the majority of reported adverse events (AEs) being grade 1–2. The most frequent nonhematologic AEs occurring in at least 20% of patients were diarrhea, bleeding, fatigue, pyrexia, and nausea. In the RESONATE study, AEs of grade 3 or higher in the ibrutinib arm included atrial fibrillation (AF) in 3%, although subsequent reports noted increasing AF prevalence with additional time on ibrutinib [
39]. Another study found that about 6% of all newly diagnosed CLL patients had a history of AF; in those without such a history, the background CLL population incidence of AF was about 1% per year [
40]. A recent systematic review and meta-analysis found that the pooled relative risk of AF associated with ibrutinib as compared to the comparator in randomized trials was 3.5 to 3.9, depending on the model used. The pooled rate of AF among ibrutinib recipients from all trials examined was 3.3 per 100 person-years [
41]. Arrhythmic symptoms or new-onset dyspnea in patients receiving ibrutinib should be evaluated clinically, with electrocardiography if appropriate. Ibrutinib therapy should be withheld in patients with new-onset or worsening grade 3 or 4 toxicities and reinitiated at the starting dose once symptoms have resolved [
42]. In the RESONATE, RESONATE-2, and HELIOS trials, most patients with AF were able to continue ibrutinib treatment and did not discontinue due to AF [
39,
43,
44].
Bleeding-related AEs, most commonly petechiae or ecchymoses, have also been reported with ibrutinib (44% with ibrutinib vs. 12% with ofatumumab in RESONATE), but major hemorrhage (grade 3 or higher or requiring red cell transfusion or hospitalization) occurred in only two patients in the ibrutinib group and three in the ofatumumab group. A study of single-agent ibrutinib in CLL found that the cumulative incidence of grade ≤2 bleeding-related AEs plateaued by 6 months, suggesting that the risk of bleeding decreases with continued therapy [
45]. Ibrutinib should be withheld for at least 3 to 7 days pre- and post-surgery depending on the type of surgery and the risk of bleeding, and vitamin K antagonists should not be administered concomitantly. If therapeutic anti-coagulation is required, consider temporarily withholding ibrutinib until stable anti-coagulation is achieved [
42].
As impaired humoral immunity and increased infection risk resulting from panhypogammaglobulinemia are characteristic of advanced CLL, the effect of BTK inhibition on normal B cell function in CLL may have clinical relevance. A study of 86 patients with previously untreated or relapsed/refractory CLL receiving ibrutinib for at least 12 months [
46] found a progressive decline in serum immunoglobulin G (IgG) levels, while immunoglobulin A (IgA) levels increased with treatment. In patients with a ≥50% increase in IgA level, the infection rate was decreased, suggesting partial immune recovery with ibrutinib therapy. Patients taking ibrutinib in RESONATE also experienced increased IgA levels, as well as sustained improvements in hemoglobin, platelet levels, and absolute neutrophil count (ANC) compared with patients taking ofatumumab [
47]. Another study found low rates of treatment-emergent autoimmune cytopenias (AICs) with ibrutinib treatment, and 19 of 22 patients receiving corticosteroids for autoimmune hemolytic anemia at the start of ibrutinib therapy were able to discontinue them with resolution of the hemolytic process [
48].
Idelalisib
Idelalisib (Table
2) is an orally bioavailable inhibitor of the delta isoform of PI3K, the predominant PI3K isoform in B cells. PI3K has limited expression in other hematopoietic cells, and thus, PI3K inhibition acts as a targeted B cell therapy. As an inhibitor of PI3K signaling downstream from the BCR in CLL cells, this drug also interrupts BCR signaling pathways. However, idelalisib may also disrupt the protective effect of the CLL microenvironment [
49] by interfering with chemokine networks, including CXCR4, CD40, and CD49d effects on multiple signaling pathways [
50]. It was approved by the FDA in 2014 for the treatment of relapsed CLL in combination with rituximab [
51].
In phase 1 studies, idelalisib was investigated as a single agent and in combination with many other chemoimmunotherapeutic agents in relapsed or refractory CLL patients. The clinical activity and acceptable toxicity led to a pivotal phase 3 randomized trial of idelalisib plus rituximab vs. rituximab plus placebo [
52]. Patients were eligible if they had progressed within 24 months of their last treatment (which must have included an anti-CD20-based therapy or at least two prior cytotoxic regimens) and were not candidates for cytotoxic drugs due to impaired marrow reserve as a consequence of prior myelosuppressive therapy, or a creatinine clearance <60 mL/min, or a CIRS score >6. Of the patients, 222 were allocated to treatment with rituximab 375 mg/m
2 as an initial dose, followed by 500 mg/m
2 every 2 weeks for four doses then every 4 weeks for three doses (for a total of eight infusions) in combination with either idelalisib 150 mg or placebo twice daily. Patients (median age 71 years) were stratified by
IGHV mutation status and the presence of del (17p) or
TP53 mutation (present in 40%). Baseline characteristics, including hematologic values, CIRS scores, and number and type of prior therapies, were well balanced. At 24 weeks, 93% of patients in the rituximab-idelalisib group were progression-free compared to 46% in the rituximab-placebo arm, and the study was stopped at this pre-specified point. Median PFS in the rituximab-placebo arm was 5.5 months and had not been reached in the idelalisib with rituximab cohort (HR for progression or death in the idelalisib arm, 0.15; 95% confidence interval 0.08 to 0.28;
p < 0.001). This clinical benefit for the combination was observed in all pre-specified subgroups including high-risk patients with del (17p) and/or
TP53 mutation. Updated results of this study [
53] reported a median PFS of 16.6 months in the latter group and 20.3 months in patients without either abnormality.
In this study, the most frequently observed grade 3 or higher adverse events attributed to idelalisib were diarrhea (5%) and increases in hepatic transaminases (8%) [
53]. Adverse events of any grade included neutropenia (60%), transaminase elevation (40%), anemia (29%), thrombocytopenia (19%), bleeding (14%), pneumonia (10%), rash (10%), and pneumonitis (6%). Diarrhea/colitis of any grade occurred in 21% of patients on idelalisib and was managed by drug interruption, corticosteroids, and symptom management. The incidence of diarrhea/colitis is underrepresented in the early publications due to limited time on therapy for most patients at the time of analysis. Later reports with longer follow-up report a higher incidence of diarrhea/colitis, an adverse event that requires careful monitoring and rapid treatment [
54]. The distinct late-onset diarrhea occurs with a median onset of more than 6 months of therapy and may be associated with colitis with lymphocytic infiltration on biopsy [
55]. This adverse event requires drug interruption and typically requires steroid therapy for rapid resolution. Either prednisone or nonabsorbable corticosteroids (e.g., budesonide) are generally effective in ameliorating this condition. Once the diarrhea resolves, the patient can often be successfully rechallenged with idelalisib and the steroids tapered off. Hepatic enzyme elevations were reversible by withholding drug, and idelalisib could be restarted in most patients without recurrence. Pneumonitis has also been reported with idelalisib in other studies, including fatal cases, without identifiable pathogens and with no defined mechanism. A 2015 consensus paper summarizes experience in the management of these more concerning toxicities of idelalisib [
56]. During safety monitoring of several trials of idelalisib in untreated CLL and relapsed low-grade lymphoma, an increased incidence of serious infection was observed and these trials were terminated. Health care professionals were advised of these results by the manufacturer (Gilead Sciences), and prophylaxis for
Pneumocystis carinii and monitoring for cytomegalovirus reactivation have consequently been mandated during idelalisib treatment [
57].
Venetoclax
Venetoclax (Table
2), a BH3 mimetic, is an orally administered small molecule that potently inhibits the anti-apoptotic BCL-2 protein with limited effect on BCLX
L, a related anti-apoptotic protein important for platelet survival. Venetoclax induces rapid onset apoptosis of CLL cells, apparently independently of
TP53 function. Analysis of both in vivo and in vitro results from a phase 1 trial showed that the depth of clinical responses to venetoclax were also independent of chromosome 17p deletion,
TP53 mutation, and
TP53 function [
58]. This agent has recently been approved by the FDA for the treatment of previously treated CLL with 17p deletion in the USA [
59] and is currently being studied in phase 2 and 3 trials.
In an initial phase 1 trial [
60], 56 patients with relapsed/refractory CLL or small lymphocytic lymphoma (SLL), including 17 with del (17p), were treated with single-agent venetoclax. The ORR was 84% (82% in del [17p]) including rates of 20% CR or CR with incomplete marrow recovery (Cr
i). Tumor lysis syndrome (TLS) developed in five patients, leading to the suspension of the trial to reassess dosing of the drug. The trial was restarted with a weekly stepwise dosing schedule with no subsequent observed TLS.
Roberts reported the results of a phase 1 study of venetoclax in combination with rituximab in 49 patients with relapsed/refractory CLL [
61]. A CR/Cr
i rate of 41% was observed, including MRD negativity in 65% (13/20) of these patients (49% [24/49] overall). These responses were sustained in six patients achieving CR/CR
i for up to 21 months after discontinuing treatment. The most frequent grade 3 or higher AEs were neutropenia (51%), thrombocytopenia (16%), and anemia (14%), and there was one death due to TLS.
The updated results of the initial phase 1 dose-escalation study of daily oral venetoclax, including an expansion cohort of 60 additional patients, have recently been reported [
62]. In the dose-escalation phase, 56 patients with relapsed/refractory CLL or SLL received daily venetoclax in doses ranging from 150 to 1200 mg. In an expansion cohort of 60 additional patients, venetoclax was escalated in weekly stepwise increments to 400 mg daily. Patients enrolled in this study had received a median of three prior lines of therapy although none with prior ibrutinib or idelalisib. Patients with autoimmune cytopenias were excluded. Pooled ORRs of 71 to 79% were observed in subgroups with adverse prognostic features including fludarabine resistance, del (17p), and unmutated
IGHV. Complete remissions were observed in 20% of the patients in both cohorts, and 5% had undetectable MRD by flow cytometry. With a median follow-up of 17 months in the cohort treated at 400 mg daily, the median PFS could not be reliably estimated, but the rate of PFS was estimated to be 66% at 15 months with the likelihood that the CR rate would increase with longer observation. In the expansion cohort following dose-escalation adjustments, no cases of clinical tumor lysis were observed.
A multicenter, phase 2, single-arm study examined venetoclax monotherapy (using a stepped-dose schedule) in relapsed or refractory del (17p) CLL [
63]. At a median follow-up of 12.1 months, an ORR of 79% was achieved (85 of 107 patients), with a CR/Cr
i of 8%, a nodular PR of 8%, and a PR of 69%. MRD in peripheral blood was not detectable in 18 of 45 assessed patients. The most common grade 3–4 adverse events were neutropenia (40%), infection (20%), anemia (18%), and thrombocytopenia (15%). Serious adverse events occurred in 55% of patients, irrespective of their relationship to treatment, with pyrexia, autoimmune hemolytic anemia, pneumonia, and febrile neutropenia seen most commonly. Laboratory TLS was reported in five patients during the ramp-up period (four within the first 2 days of treatment and one at week 3) but resolved without clinical sequelae.
Despite the lack of clinical TLS after the institution of the slow stepwise increase in dose of venetoclax, it remains important to monitor for laboratory abnormalities indicating TLS, particularly in patients considered at higher risk because of a significantly elevated blood lymphocyte count (>25 Gi/L) or those with bulky adenopathy (>5 cm). In appropriate cases, hospitalization for dose escalations of venetoclax is required.