Ibrutinib for Relapsed/Refractory CLL
Ibrutinib is a first-in-class oral covalent BTK inhibitor. Its safety and efficacy were initially investigated in a pivotal phase Ib/II multicenter study (PCYC-1102 and PCYC-1103) including 101 patients with relapsed or refractory CLL (the study also included 31 patients with previously untreated CLL, discussed below) (N Engl J Med 2013;369(1):32-42). The most common (> 5%) grade > 3 events were neutropenia (15%), hypertension (5%), fever (5%), and sinusitis (5%). With extended treatment, the overall response rate (ORR) was 89 percent, complete remission (CR) rate 10 percent, and 7-year progression-free survival (PFS) rate 32 percent (26% for patients with deletion 17p) (Blood 2018;132(Suppl 1):3133-3133).
Sixteen patients with relapsed CLL were included in a small phase II trial investigating the activity of ibrutinib in patients carrying a TP53 mutation (the study also included 35 patients with treatment-naïve CLL, discussed below) (Lancet Oncol 2015;16(2):169-176). The ORR was 87 percent, and CR rate 7 percent, 5-year PFS 19.4 percent, and 5-year OS 54 percent (Blood 2018;131(21):2357-2366).
Similar findings were observed in a multi-center phase II study (RESONATE-17), the largest trial conducted in relapsed patients with CLL and deletion 17p (145 patients) (Lancet Oncol 2016;17(10):1409-1418). The ORR was 83 percent, CR rate 10 percent, 2-year PFS rate 63 percent, and 2-year OS rate 75 percent. In addition, a pooled analysis of trials investigating the activity of ibrutinib in 230 patients with relapsed CLL carrying deletion 17p showed an ORR of 85 percent, and a 30-month PFS and OS rate of 57 percent, establishing ibrutinib as the preferred agent for the treatment of patients with deletion 17p (Br J Haematol 2018;182(4):504-512). For additional trials performed in patients with relapsed CLL, see Table 1.
Ibrutinib for Treatment-Naïve CLL
The safety and efficacy of single agent ibrutinib as frontline therapy for patients with CLL was investigated in a phase Ib/II multicenter study (PCYC-1102 and PCYC-1103), including 31 patients aged > 65 years (Lancet Oncol 2014;15(1):48-58). The most common (> 5%) grade > 3 toxicities were diarrhea (13%) and hypertension (6%). The ORR was 89 percent, CR rate 26 percent, and 5-year PFS 92 percent (Blood 2015;125(16):2497-2506; Blood 2018;131(17): 1910-1919). A phase II study investigated the activity of ibrutinib in 35 patients with previously untreated CLL carrying a TP53 mutation (Lancet Oncol 2015;16(2):169-176). The ORR was 97 percent, CR rate 12 percent, 5-year PFS 74 percent, and 5-year OS 85 percent (Blood 2018;131(21):2357-2366).
In a phase III trial, RESONATE-2, 269 patients with previously untreated CLL were randomized to receive single agent ibrutinib or chlorambucil (N Engl J Med 2015;373(25):2425-2437). The study included only patients aged > 65 years and without deletion 17p and/or TP53 mutation. Patients treated with ibrutinib had a significantly higher ORR (86% vs. 35%, p<0.001), longer median PFS (not reached vs. 19 months, p<0.001), and higher 2-year OS rate (98% vs. 85%, p=0.001). A comparable rate of grade > 3 toxicities was observed (52% in both groups), the most frequent (> 5%) in the ibrutinib arm represented by neutropenia (10%) and anemia (6%). With extended follow-up, ORR to single ibrutinib increased to 92 percent, the CR rate from 7 percent to 18 percent, and the 2-year PFS rate was 89 percent (Haematologica 2018;103(9):1502-1510).
Recently, the activity of ibrutinib has been compared to chemoimmunotherapy in two randomized phase III trials. In one trial, 365 older patients with previously untreated CLL were randomized to receive either ibrutinib, ibrutinib and rituximab (IR), or bendamustine and rituximab (BR) (N Engl J Med 2018;379(26):2517-2528). Patients treated with ibrutinib had a higher ORR (93% vs. 81%) and a significantly higher 2-year PFS (87% vs. 74%, p<0.001) than those treated with BR. No difference in ORR and 2-year PFS was observed when comparing patients treated with ibrutinib to those treated with IR.
In a another randomized phase III trial, 529 younger patients with previously untreated CLL and without deletion 17p were randomized to receive IR or fludarabine, cyclophosphamide, and rituximab (FCR) (Blood 2018;132(Suppl 1):LBA-4-LBA-4). At an interim analysis, the hazard ratio (HR) for PFS favored ibrutinib over FCR (HR=0.35; p<0.0001). These trials have further established the use of single agent ibrutinib (without rituximab) as frontline treatment for all patients with CLL, irrespective of age. For additional trials performed in patients with previously untreated CLL, see Table 1.
Current Challenges Using Ibrutinib in CLL
Long-term toxicities. The three most concerning long-term toxicities associated with the use of ibrutinib are atrial fibrillation, bleeding risk, and hypertension (Haematologica 2018;103(5):874-879). Atrial fibrillation has been reported in up to 16 percent of patients, more commonly in older individuals with pre-existing cardiac conditions, and can be successfully managed with medical therapy (Haematologica 2017;102(10):1796-1805; Blood Adv 2017;1(20):1739-1748; J Hematol Oncol 2018;11(1):79). Minor bleeding is observed in almost half of patients, more commonly in the case of pre-existent platelet dysfunction or coagulation disorders (Haematologica 2015;100(12):1571-1578; Blood Adv 2017;1(12):772-778; Leukemia 2017;31(5):1117-1122). Cautious use of anticoagulants, along with ibrutinib discontinuation before and after major surgeries, are sufficient to limit the incidence of major bleedings (Br J Haematol 2019;184(4):558-569).Nearly 40 percent of CLL patients develop new onset hypertension within 12 months of ibrutinib exposure (J Clin Oncol 2017;35(15_suppl):7525-7525). Long-term follow-up is needed to better appreciate its influence on subsequent cardiovascular events.
Resistance to ibrutinib. Patients with CLL who develop resistance to ibrutinib and progress frequently have an acquired mutation in BTK (C481S) or PLCG2 (N Engl J Med 2014;370(24):2286-2294; Blood 2017;129(11):1469-1479; J Clin Oncol 2017;35(13):1437-1443; Leukemia 2017;31(7):1645-1647; Nat Commun 2016;7:11589; Nat Commun 2017;8(1):2185). Patients progressing during treatment with ibrutinib and in whom ibrutinib is discontinued abruptly experience an aggressive clinical course. As a consequence, overlapping with subsequent line of therapy, before full discontinuation, is recommended (Blood 2015;125(13):2062-2067; Am J Hematol 2019;94(5):554-562). PI3K inhibitors and venetoclax are alternate agents for patients intolerant to or progressing on ibrutinib, and allogeneic stem cell transplant should be discussed with eligible patients (Ann Oncol 2017;28(5):1050-1056; Lancet Oncol 2018;19(1):65-75).
Acalabrutinib for Relapsed/Refractory CLL
Acalabrutinib is an oral covalent inhibitor of BTK with pre-clinical evidence of high potency as well as greater selectivity for BTK than ibrutinib (Blood 2015;126(23).
Sixty-one patients with relapsed CLL were enrolled in a phase Ib/II multi-center study (ACE-CL-001) of single agent acalabrutinib: 30 in the escalation phase at doses of 100, 175, 250, and 400 mg daily, and 30 in the expansion cohort at the dose of 100 mg twice a day (N Engl J Med 2016;374(4):323-332). No dose-limiting toxicity was observed in the escalation phase, and the only grade > 3 toxicity observed in > 5 percent of patients was hypertension (7%). The ORR was 95 percent, with no CRs reported; response rates were also high in patients with deletion 17p; the 1-year PFS rate was 97 percent. An additional 73 (total 134) patients were subsequently enrolled in this trial (Blood 2017;130(Suppl 1):498-498). The most common (> 5%), grade > 3 toxicities were neutropenia (11%) and pneumonia (10%); grade > 3 hypertension and atrial fibrillation occurred in 3 percent and 2 percent of patients, while no severe bleeding was observed. The ORR was 98 percent, the CR rate 2 percent, and the 1.5-year PFS rate was 88 percent.
While this safety profile compares favorably with toxicity data reported with ibrutinib, it is important to note that information about baseline comorbidities, known to increase the incidence of BTKi-associated toxicities, are not clearly outlined in this study. In addition, extended follow-up and real-world data are missing and will be crucial to determine the precise incidence and type of long-term toxicities associated with the use of acalabrutinib. Of interest, in a subgroup analysis including 33 patients with ibrutinib-intolerant (but not refractory) CLL, the ORR was 76 percent, and 15 percent of ibrutinib-intolerant patients progressed after a median follow-up of 9 months, suggesting potential benefit for the use of acalabrutinib in patients unable to tolerate ibrutinib because of comorbid health conditions or toxicities (Blood 2016;128(22):638-638).
Given the low CR rate observed with the use of single agent acalabrutinib, combination strategies have been pursued. Twenty-six patients with relapsed or refractory CLL have been treated in a phase Ib/II study (ACE-CL-003) with the combination of acalabrutinib and obinutuzumab (Blood 2017;130(Suppl 1):432-432). The most common (> 5%) grade > 3 toxicities were neutropenia (24%), thrombocytopenia (9%), weight gain (7%), and syncope (7%). The ORR was 92 percent, CR rate 8 percent, and 1.5-year PFS rate was 92 percent. While these efficacy data do not differ significantly from what was observed with the combination of ibrutinib and anti-CD20 monoclonal antibodies, better results may be observed in less heavily pre-treated patients (see below) or with extended follow-up. This study, along with ACE-CL-002, investigating the safety and efficacy of acalabrutinib in combination with rituximab and venetoclax in patients with relapsed or refractory CLL, are ongoing.
While pre-clinical data show that acalabrutinib may be more potent than ibrutinib, clinical data of superior efficacy/greater durability of remissions are still lacking. A phase III registration trial comparing acalabrutinib to ibrutinib in patients with relapsed or refractory CLL is fully accrued (NCT02477696), and results are eagerly awaited. Recently, interim results of a randomized phase III study (ACE-CL-309) comparing acalabrutinib to the combination of rituximab and idelalisib or bendamustine in patients with relapsed or refractory CLL have been presented (EHA 2019). A total of 155 patients were randomized to each arm; the primary endpoint of superior PFS with acalabrutinib was met (median PFS: not reached for patients treated with acalabrutinib vs. 16.5 months for patients treated with rituximab and idelalisib or bendamustine, HR 0.31, 95% CI 0.20-0.49; p<0.001); superior PFS with the use of acalabrutinib was also observed in patients with high-risk cytogenetics. These data will likely support the FDA approval of acalabrutinib monotherapy for the treatment of patients with relapsed or refractory CLL. Acalabrutinib was approved by the FDA in 2017 for the treatment of patients with mantle cell lymphoma relapsed after at least one prior therapy. While it has not been approved yet for the treatment of patients with relapsed CLL, safety and efficacy data outlined above suggest that its off-label use may be considered for CLL patients intolerant (but not refractory) to ibrutinib, or in individuals with comorbid health conditions in whom ibrutinib may be more difficult to administer.
Acalabrutinib in Treatment-Naïve CLL
The safety and efficacy of single agent acalabrutinib has been investigated in a phase Ib/II multicenter study (ACE-CL-001) including 74 patients with previously untreated CLL (J Clin Oncol 2016;34(15_suppl):7521-7521; Haematologica 2016;101:151-151). Thirty-seven patients were treated at the dose of 200 mg daily, and 37 at the dose of 100 mg twice a day. Pharmacokinetic analysis showed that the twice-a-day dosing provided the most consistent level of BTK occupancy. Grade > 3 toxicities were rare, including syncope in two patients, hypertension in two, and pneumonia in one patient. The ORR was 96 percent, with no CRs reported, and 1-year PFS rate was 100 percent. Despite promising early data, larger datasets and more extended follow-up are needed before making any conclusion regarding long-term toxicities of acalabrutinib in patients with treatment-naïve CLL.
Nineteen patients with treatment-naïve CLL were included in a phase Ib/II multi-center study (ACE-CL-003) of acalabrutinib in combination with obinutuzumab (Blood 2017;130(Suppl 1):432-432). While pharmacokinetic and toxicity data have not yet been reported separately from those of relapsed/refractory patients also treated with the combination (see above), the ORR was 95 percent, CR rate 16 percent, and 1.5-year PFS was 89 percent; deeper responses may be observed with extended follow-up. Pre-clinical data show that acalabrutinib, unlike ibrutinib, does not affect antibody-dependent cellular cytotoxicity (ADCC), and may then benefit from the combination with an antibody (Haematologica 2017;102(10):e400-e403). Whether this will translate into higher clinical activity for the combination of an anti-CD20 antibody with acalabrutinib, as compared to ibrutinib, will require larger population samples and longer observation time.
The ACE-CL-003 trial, along with the ACE-CL-002 trial investigating the safety and efficacy of acalabrutinib in combination with rituximab and venetoclax in patients with treatment-naïve CLL, are ongoing. A phase III registration trial comparing acalabrutinib and obinutuzumab to chlorambucil and obinutuzumab and to single agent obinutuzumab in patients with treatment-naïve CLL is fully accrued, but no results are available yet (NCT02475681). At this time, no studies comparing head-to-head acalabrutinib to ibrutinib for patients with previously untreated CLL are ongoing.
Single Agent Zanubrutinib for CLL
Zanubrutinib is an oral covalent inhibitor of BTK not yet marketed; pre-clinical evidence shows high potency as well as greater selectivity for BTK than observed with ibrutinib, with minimal off-target inhibition of kinases belonging to the TEC and EGFR-family (responsible for many of the toxicities observed with the use of less specific BTK inhibitors) (Cancer Res 2015;75; Thromb Haemost 2019;119(3):397-406; Eur J Haematol 2018; Jul 20). Advantageous pharmacokinetics and pharmacodynamics have been observed with the use of zanubrutinib. Complete and sustained BTK occupancy has been observed in peripheral blood mononuclear cells as was seen with ibrutinib. However, the trials with zanubrutinib also tested and were able to show complete occupancy in lymph nodes (Blood 2015;126(23).
In addition, based on drug interaction studies, the co-administration of a proton pump inhibitor does not affect zanubrutinib exposure, and patients have been allowed to receive warfarin and aspirin on the zanubrutinib trials (Hematological Oncology 2019;37(S2):45-46).
A total of 94 patients with CLL/SLL, including 72 (76.6%) with relapsed or refractory CLL and 22 (23.4%) with treatment-naïve CLL, have been treated with single agent zanubrutinib in a multicenter phase Ib study (Hematological Oncology 2017;35(S2):234-235; Blood 2017;130(Suppl 1):152-152). Six patients were treated in the escalation phase, at doses ranging from 40 to 320 mg daily, and 88 in the expansion phase, at doses of 320 mg or 160 mg twice a day. Grade 3/4 AEs reported in more than one patient were neutropenia (n=6), anemia (n=2), pneumonia (n=2), and hypertension (n=2). One patient had febrile neutropenia (grade 3) and one patient had disseminated herpes zoster infection (grade 3). Atrial fibrillation (grade 2) occurred in one patient with a history of hypertension and hyperlipidemia. Only one patient with CLL/SLL (receiving concomitant aspirin) experienced major hemorrhage (grade 3 subcutaneous hemorrhage). Concomitant antiplatelet (aspirin, clopidogrel, or nonsteroidal anti-inflammatory drugs) and anticoagulant (unfractionated or low molecular weight heparin, direct thrombin inhibitors, or warfarin) medications were used by 16.0 percent and 8.5 percent of patients, respectively. At a median follow-up of 13.7 months (range 0.4-30.5), the ORR was 96.2 percent (95% CI, 89.2-99.2), including 3 percent CR, 81 percent PR, and 13 percent PR with lymphocytosis (Blood 2019 Jul 24).
A phase II study, investigating the efficacy of zanubrutinib at the dose of 160 mg twice a day, has been performed in Chinese patients with relapsed or refractory CLL (BGB-3111-205) (Hematological Oncology 2019;37(S2):87-88). Ninety-one patients were included in the study: 79 percent were refractory to their most recent systemic therapy, 24 percent carried either TP53 mutation and/or deletion 17p by FISH, and 56 percent had unmutated IGHV. Safety and tolerability observed in Chinese patients was similar to that previously reported in CLL/SLL patients, serious adverse reports being reported in 33 percent of patients, and neutropenia being the only treatment-emergent adverse event observed in more than 10 percent of patients (grade 3 or higher in 43% of patients). ORR was 85 percent in all patients (CR rate 3%), 86 percent in patients with TP53 mutation and/or deletion 17p, and 82 percent in patients with unmutated IGHV; and the 1-year PFS rate was 87 percent. These data may bring approval of zanubrutinib monotherapy for the treatment of patients with relapsed or refractory CLL in China.
Single Agent Zanubrutinib Safety Profile
Safety data from six ongoing clinical trials of zanubrutinib monotherapy in 682 patients with CLL and other B-cell lymphoid malignancies (including mantle cell lymphoma, diffuse large B-cell lymphoma, and Waldenström macroglobulinemia) have been recently pooled and analyzed (HemaSphere 2019;3:526).
All patients were treated with ≥1 dose of oral zanubrutinib at doses of 40 to 320 mg once daily, and almost all received either 320 mg daily or 160 mg twice daily. Median age was 64 years, 68 percent of patients were men, 15 percent were aged ≥ 75 years and 91 percent had relapsed or refractory disease. After a median exposure to zanubrutinib of 13 months and a median relative dose intensity of 99 percent across all studies, 38 percent of patients discontinued treatment: 25 percent because of progressive disease (most from DLBCL and other NHL), 9 percent because of adverse events.
Ninety-seven percent of patients reported adverse events, but primarily grade 1-2; the most common grade ≥ 3 adverse events were neutrophil count decreased (14%), anemia (8%), neutropenia (7%), pneumonia (4%), platelet count decreased (4%), lung infection (4%), and hypertension (3%). Serious adverse events were reported in 36 percent of patients and were treatment-related in 12 percent; the most common serious adverse events were pneumonia (5%), lung infection (3%), urinary tract infection (2%), fever (2%), cellulitis (1%), pleural effusion (1%), and anemia (1%); the only treatment-related serious adverse event reported in >1 percent of patients was pneumonia (2%).
Adverse events of interest were infrequent. Atrial fibrillation occurred in 1.9 percent of patients, in 77 percent of cases within the first 12 months of treatment, and mostly in individuals with predisposing risk factors (such as prior atrial fibrillation, hypertension or concomitant infection). Major hemorrhage was observed in 2.5 percent of patients, all with predisposing risk factors, such as gastro-intestinal disease, trauma, or concomitant use of anticoagulants. While these represent very encouraging safety data, longer follow-up and CLL-specific real-world data will be needed to validate these findings.
Zanubrutinib-Based Combinations in CLL
Given its lack of influence on ADCC, (Haematologica 2019 Jan 24) the combination of zanubrutinib and obinutuzumab has been investigated in a multicenter phase Ib trial, including 20 patients with treatment-naïve and 25 patients with relapsed refractory CLL (Blood 2017;130(Suppl 1):1745-1745; Hematological Oncology 2017;35(S2):113-113; ICML 2019). The only grade > 3 toxicities observed in > 5 percent of patients were neutropenia (31%), pneumonia (8.9%), and thrombocytopenia (6.7%). There were no cases of major hemorrhage or atrial fibrillation/flutter. The ORR for TN and R/R CLL/SLL was 100 percent (20/20) and 92 percent (23/25), CR rates 30 percent 6/20) and 28 percent (7/25), and 1-year PFS rate 100 percent and 92 percent, and 2-year PFS rate 95 percent and 83 percent, respectively. Larger studies and extended follow-up will better define the durability of these high response rates over time.
A phase II study adding venetoclax to this combination in patients with previously untreated CLL is ongoing (NCT03824483). In addition, a phase III randomized trial comparing the efficacy of single agent zanubrutinib to chemoimmunotherapy in patients with treatment-naïve CLL (BGB-3111-304; NCT03336333), and a phase III randomized trial comparing the efficacy of single agent zanubrutinib to single agent ibrutinib in patients with relapsed/refractory CLL are ongoing (BGB-3111-305; NCT03734016).
Zanubrutinib has recently received FDA breakthrough designation for the treatment of patients with relapsed mantle cell lymphoma. Ongoing randomized phase III trials will help understanding whether the pre-clinical data of higher potency will translate into greater clinical efficacy as compared to that seen with ibrutinib. Further investigation regarding the safety and activity of zanubrutinib in patients intolerant (but not refractory) to ibrutinib or in individuals with significant comorbid health conditions is warranted. In addition, in light of its lack of activity on ITK, its combination with anti-CD20 monoclonal antibodies may produce deeper and more durable responses than that observed with ibrutinib-based combinations.
Conclusions & Future Directions
The introduction of ibrutinib has revolutionized the treatment of patients with CLL (N Engl J Med 2018;379(26):2517-2528). More selective and less toxic BTKi, such as acalabrutinib and zanubrutinib, may be more suitable for the treatment of individuals with relevant comorbid conditions, the latter being very common in patients affected by CLL, as the median age at the time of diagnosis is 72 years (Br J Haematol 2017;178(3):394-402). Ongoing trials investigating the safety and efficacy of these agents in combination with anti-CD20 monoclonal antibodies and other targeted agents, such as venetoclax, may result in deeper responses and potentially eradication of minimal residual disease.
PAOLO STRATI, MD, is in the Department of Lymphoma and Myeloma at the The University of Texas MD Anderson Cancer Center. SUSAN M. O'BRIEN, MD, is at the Chao Family Comprehensive Cancer Center, University of California, Irvine, Orange, Calif.
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