BTK Inhibitors in B-Cell Malignancies
INHIBITORS OF BRUTON TYROSINE KINASE (BTK) provide convenient, nonchemotherapeutic, orally dosed options for patients with B-cell malignancies such as chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL). However, careful management of toxicities and education of patients with a multidisciplinary approach is important to optimize response and outcomes, according to advanced practice nurses who participated in a virtual Oncology Nursing News® Scientific Interchange and Workshop on July 15, 2020. The session was moderated by Tara Lewis, NP, of the University of California, Los Angeles, Lymphoma Program.
B-CELL LYMPHOMAS AND BTK INHIBITORS
BTK is 1 of 5 members of the TEC family of nonreceptor kinases, and it plays an important role in the proliferation and survival of leukemic cells in B-cell malignancies. Specifically, BTK is essential for maintaining activation of pathways implicated in cell survival for CLL,1 and BTK inhibition attenuates the viability of MCL cells in a dose-dependent manner.2 The first-generation BTK inhibitor ibrutinib has changed the treatment paradigm for CLL and MCL, offering relatively durable responses from an orally dosed treatment that can be taken at home.
However, off-target toxicities are a major challenge with ibrutinib. The newer-generation BTK inhibitors acalabrutinib and zanubrutinib have shown clinical activity in CLL and MCL as well as greater selectivity than ibrutinib, which may contribute to improved tolerability for patients.3
Ibrutinib is a first-generation BTK inhibitor that irreversibly binds to the Cys481 residue in the active site of the ATP binding domain.4 Ibrutinib is currently approved for several indications, including CLL and small lymphocytic leukemia (SLL) with or without a chromosome 17p deletion and MCL that has progressed after receiving at least 1 prior therapy, although approved doses vary among malignancies. Ibrutinib is taken orally once daily at a dose of 420 mg for CLL/SLL and 560 mg for MCL, with dose reductions recommended for patients with mild tomoderate hepatic impairment.5
The first approval for ibrutinib came in 2017; it was for relapsed or refractory MCL, based on a single-arm phase 2 trial (NCT01236391). The trial results showed an overall response rate (ORR) of 68%, an estimated median duration of response (DOR) of 17.5 months among responders, and an estimated rate of overall survival (OS) of 58% at 18 months.6 The majority of adverse effects (AEs) were grade 1 or 2, and the most common nonhematologic AEs included diarrhea (50%), fatigue (41%), and nausea (31%).6
Results of the multicenter, open-label, phase 3 RESONATE trial (NCT01578707) showed that ibrutinib led to a 78% reduction in the risk for progression or death compared with ofatumumab (an anti-CD20 antibody) in patients with relapsed or refractory CLL or SLL.7 However, multiple AEs were observed, with grade 3 or higher diarrhea (4% vs 2%), all-grade bleeding-related AEs (44% vs 12%), and grade 3 or higher atrial fibrillation (AF; 3% vs 0%) occurring more frequently in the ibrutinib arm.7 A long-term follow-up analysis of the trial showed that the estimated rate of progression-free survival (PFS) at 3 years was 59% with ibrutinib and 3% with ofatumumab, with benefits observed across subgroups with high-risk features, such as chromosome 11q22.3 deletion and IGHV mutation.8 The OS at 3 years also tended to be longer for patients randomized to the ibrutinib arm, even though 68% of patients in the ofatumumab arm crossed over to receive ibrutinib after disease progression.8
Approval of ibrutinib was expanded to include treatment-naïve patients with CLL or SLL based in part on results from the phase 3 RESONATE-2 trial (NCT01722487). The study results showed that, compared with chlorambucil, ibrutinib was associated with an 84% reduction in the relative risk for progression or death, with improvements in PFS observed in subgroups with high-risk features, such as chromosome 11q22.3 deletion and IGHV mutations. 9
AEs in this trial were similar to those in other trials of ibrutinib: The most common nonhematologic AEs included diarrhea, fatigue, nausea, and cough, and hypertension and AF occurred in 14% and 6% of patients, respectively.9
Therapeutic combinations were also explored in clinical trials such as the international, open-label, randomized phase 3 iLLUMINATE trial (NCT02264574), which compared ibrutinib plus obinutuzumab with chlorambucil plus obinutuzumab in patients with treatment-naïve CLL or SLL. After a median follow-up of 31 months, the ibrutinib-containing regimen was associated with a 77% reduction in risk for progression or death, with rates of PFS of 79% and 31% in the ibrutinib plus obinutuzumab and chlorambucil plus obinutuzumab groups, respectively, at 30 months.10 The benefits of the ibrutinib regimen were also observed in the high-risk population, with an 85% reduction in risk for progression or death.10
However, some of the panelists have found ibrutinib’s toxicities, particularly the AF, to be difficult to manage. Susan C. Woodward, MSN, APRN, AOCNP, of Moffitt Cancer Center in Tampa, Florida, said that anecdotally, the incidence of AF with ibrutinib is higher in her practice than that reported in clinical trials, and the extensive management of cardiac toxicities required by her and her patients’ primary care doctors has prompted her practice to start with acalabrutinib in many patients. Similarly, Mary E. DiLorenzo, MSN, RN, FNP-BC, of the Novant Presbyterian Medical Center in Charlotte, North Carolina, added that her center does a stroke assessment to predict which patients are at high risk for AF and starts these patients on acalabrutinib instead of ibrutinib. The panelists also identified infections as a key issue with ibrutinib; although they are often manageable with intravenous immunoglobulin, Woodward identified 1 patient with severe paronychia on his toenails that resolved only after switching to acalabrutinib.
Many of the toxicities associated with ibrutinib are related to its inhibitory effects on kinases other than BTK, which has prompted the search for BTK inhibitors with greater selectivity and potency.3 Preclinical data show that, compared with ibrutinib, acalabrutinib is a more selective inhibitor of BTK in vitro and is more potent in vivo.11 Acalabrutinib is currently approved for use in patients with CLL, SLL, or MCL who had received at least 1 prior therapy; it is taken orally in 100-mg doses twice daily (every 12 hours). Coadministration with cytochrome P450 (CYP) 3A inhibitors or inducers or proton pump inhibitors (PPIs) should be avoided, and acalabrutinib should not be taken within 2 hours of histamine-2 blockers or antacids.12
The global, multicenter, open-label phase 3 ELEVATE-TN trial (NCT02475681) randomized treatment-naïve patients with CLL to receive acalabrutinib monotherapy, acalabrutinib plus obinutuzumab, or obinutuzumab plus oral chlorambucil.13
At a median follow-up of 28 months, median PFS was longer in both acalabrutinib groups, with estimated rates of PFS at 24 months of 93%, 87%, and 47% in the acalabrutinib plus obinutuzumab, acalabrutinib monotherapy, and obinutuzumab plus chlorambucil groups, respectively.13 Neutropenia was the most common grade 3 or higher AE overall; Lewis pointed out during the workshop that the numerically higher neutropenia rates with acalabrutinib plus obinutuzumab (30%) and obinutuzumab plus chlorambucil (41%) than with acalabrutinib monotherapy (10%) may indicatethat combining therapies could increase risk for hematologic AEs.13
Results of the global, multicenter, open-label phase 3 ASCEND trial (NCT02970318), which randomized patients with relapsed or refractory CLL to receive acalabrutinib or investigator’s choice of therapy (rituximab + idelalisib or bendamustine), showed significantly longer PFS with acalabrutinib at a median follow-up of 16 months, with 12-month PFS rates of 88% with acalabrutinib and 68% with investigator’s choice of therapy. This improvement in PFS was observed across all subgroups, including those with chromosome 17p deletion, TP53 mutation, and Rai stage.14 AEs of interest included AF (5% with acalabrutinib vs 3% with investigator’s choice), bleeding AEs (26% vs 7%, respectively), grade 3 or higher infections (15% vs 24%), and second primary malignancies (6.5% vs 3%).14
Additionally, acalabrutinib received an accelerated FDA approval for relapsed or refractory MCL based on data from the multicenter, open-label, phase 2 trial ACE-LY-004 (NCT02213926), whose results showed an investigator-assessed ORR of 81% and a complete response (CR) rate of 40% at a median follow-up of 15 months.15 Updated results from a median follow-up of 26 months showed durable responses with acalabrutinib, with a median DOR of 26 months, a median PFS of 20 months, and an estimated 24-month PFS and OS of 49% and 72%, respectively.16
The most common AEs in the initial analysis were headache (38%), diarrhea (36%), fatigue (28%), and myalgia (21%).15 No cases of AF were reported in the initial report or the updated analysis, although the updated analysis showed that 13 patients (10%) had cardiac events and 33% of patients had bleeding events (including 3 grade 3 events).16 Grade 3 or 4 infections were reported in 15% of patients in the updated analysis,16 although the authors noted that the frequency of any-grade, grade 3 or higher, and serious infections decreased over time.16
The panelists agreed that headaches seem to be among the most prominent AEs associated with acalabrutinib in their practices. Woodward said that in her experience, the onset often occurs soon after starting treatment but resolves after a few weeks, and caffeine is often helpful for reducing severity. She noted that 1 patient she treats has had headaches for a year without resolution, despite trying multiple remedies, but is reluctant to discontinue acalabrutinib because she has had a good response from a disease perspective.
Myalgias and arthralgias were also observed frequently by the panel, and DiLorenzo said that a short course of steroids (approximately 1 week followed by a quick taper) can help with management of these AEs in the early stages of therapy. “Once they’re a few cycles in—5, 6 months—the myalgias and arthralgias seem to lessen,” she said.
Zanubrutinib (BGB-3111) is a potent, specific, and irreversible BTK inhibitor that has been shown to have greater selectivity for BTK and less affinity for off-target kinases (eg, EGFR, ITK, and TEC) than ibrutinib in biochemical and cellular assays.17 Results of preclinical studies in animal models also showed that zanubrutinib has better oral bioavailability, with higher exposure and more complete target inhibition in the target tissues, than ibrutinib.17 Zanubrutinib received accelerated approval by the FDA for patients with relapsed or refractory MCL based on high ORRs observed in phase 1/2 and 2 trials.18
Initial safety and efficacy data from the multicenter, open-label, phase 2 BGB-3111-206 trial (NCT03206970) showed that zanubrutinib is well tolerated and has clinical activity in relapsed or refractory MCL. After a median follow-up of 36 weeks, the ORR assessed by independent review committee in 85 evaluable patients was 84%, with a CR reported in 59% of patients and an estimated PFS rate of 82% at 24 weeks.19
The most frequent treatment-emergent AEs (TEAEs) included decreased neutrophil count (31%), upper respiratory tract infection (29%), rash (29%), decreased platelet count (22%), and decreased white blood cell count (17%); the most frequent grade 3 or higher events were decreased neutrophil count (12%), lung infection (6%), anemia (5%), and decreased white blood cell count (3.5%).19 Additionally, grade 1 or 2 bleeding (including petechiae, purpura, contusion, and hematuria) was reported in 4 patients (5%), and major hemorrhage was reported in 1 patient (1%). No cases of AF or tumor lysis syndrome were reported.19
Early-stage trials of zanubrutinib have also shown clinical activity in CLL and SLL. A global, multicenter, open-label, phase 1/2 trial of 120 efficacy-evaluable patients with CLL or SLL (22 treatment-naïve, 98 relapsed/refractory) showed that zanubrutinib was generally well tolerated, with contusion (46%), upper respiratory tract infection (39%), diarrhea (30%), cough (28%), headache (23%), and fatigue (20%) as the most common any-grade AEs.20 AEs of interest included bleeding (including contusion, hematuria, petechiae, and purpura; 57%), diarrhea (30%), headache (23%), fatigue (20%), secondary malignancies (20%), arthralgia or myalgia (19%), neutropenia (decreased neutrophil count and febrile neutropenia; 19%), hypertension (8%), thrombocytopenia (6%), AF (3%), and major hemorrhage (2%).20
Zanubrutinib was associated with an ORR of 97%, a CR rate of 14%, and a PFS rate of 97% at 1 year and 89% at 2 years after a median follow-up of 25 months.20 Clinical activity was also observed in patients with CLL or SLL harboring a chromosome 17p deletion, which has an unfavorable prognosis and poor response to standard chemoimmunotherapy. In this subgroup, the ORR was 94%, the CR rate was 6%, and the PFS rate was 75% at 2 years.20 Considering the SEQUOIA study (BGB-3111-304), a global, multicenter, open-label, phase 3 trial (NCT03336333), and specifically, initial results from arm C, which was a nonrandomized arm of 109 patients with CLL or SLL harboring chromosome 17p deletion, outcomes showed that zanubrutinib was generally well tolerated and clinically active.
AEs of interest included infections (39%),bruising (25%), minor bleeding (18%), neutropenia (14%), arthralgia and myalgia (8%), diarrhea (8%), anemia (6%), hypertension (6%), thrombocytopenia (5.5%), fatigue (5.5%), headache (5%), petechiae (5%), second primary malignancy (3%), and major bleeding (3%).21 Among the 90 patients evaluable for efficacy, the ORR was 92% after a median follow-up of 7 months.21
The promising outcomes with zanubrutinib have also prompted the initiation of the global, open-label, phase 3 ALPINE trial (NCT03734016), which is randomizing patients (1:1 ratio) with relapsed or refractory CLL or SLL to receive zanubrutinib or ibrutinib to compare efficacy and safety between the BTK inhibitors. 22 The primary end point is ORR as determined by an independent review committee, and some of the key secondary end points include PFS, investigator-determined ORR, safety, DOR, OS, and patient-reported outcomes.22 The approved dose for zanubrutinib is 160 mg twice daily or 320 mg once daily, both orally, with dose reduction for hepatic impairment recommended in patients with severe hepatic impairment and in patients on moderate or strong CYP3A inhibitors; concomitant use should be avoided in patients taking moderate or strong CYP3A inducers.23
However, Lewis pointed out that unlike acalabrutinib, dose modification of zanubrutinib is not needed for patients taking PPIs, which could be an important consideration when choosing between the drugs.
Most of the panelists stated that they did not have much clinical experience with zanubrutinib, although Amy Sidorski, NP, of Rocky Mountain Cancer Centers in Aurora, Colorado, said that a patient of hers with MCL who had headaches and dizziness on acalabrutinib is tolerating zanubrutinib well. She added that the once-daily dosing option may be particularly beneficial for this patient because he often had difficulty remembering to take his second acalabrutinib dose of the day.
COMPARISON OF AE PROFILES
The panelists discussed the safety profiles of each BTK inhibitor, pointing out the longer list of toxicities with ibrutinib than with acalabrutinib and zanubrutinib. A retrospective analysis of 616 patients with CLL who received ibrutinib in a clinical trial or commercially in the United States showed that 41% of patients had discontinued ibrutinib at a median follow-up of 17 months, with a median time to discontinuation of 7 months.24
Toxicity was the most common reason for discontinuation and accounted for 63% and 50% of discontinuations in the frontline and relapsed/refractory settings, respectively.24 Arthralgia (42%), AF (25%), and rash (17%) were the most common toxicities leading to discontinuation in the frontline setting, and AF (12%), infection (11%), pneumonitis (10%), bleeding (9%), and diarrhea (7%) were the most common toxicities leading to discontinuation in the relapsed or refractory setting.24 However, the panelists said that the rates of discontinuation in this study seemed to be higher than those in their clinical experiences with ibrutinib.
“I wonder how many times maybe the drug was stopped for a moment and then dose-reduced, [and that counted as a discontinuation]. Or, were people just very fast to [stop] the drug?” said Victoria Alegria, ARNP, of Mayo Clinic of Jacksonville, Florida. “They also said over a 7-month period…sometimes some of those symptoms actually start to get better, so I would question that number. That high number of discontinuations, especially in that timeframe, has not been what we have seen in practice.”
Kara Saggiomo, MSN, RN, APN-C, AOCNP, of Rutgers Cancer Institute in New Brunswick, New Jersey, said that zanubrutinib appeared to be the “winner” among the 3 BTK inhibitors with respect to AE profile, but she added that persuading physicians to switch patients from ibrutinib or acalabrutinib may be difficult if the patient is responding and tolerating the drug they are currently taking. However, she said that switching to zanubrutinib may be considered for a patient with ongoing AEs, such as the patient on acalabrutinib in Woodward’s practice suffering from treatment-refractory headaches.
PATIENT EDUCATION AND ADHERENCE USING A MULTIDISCIPLINARY APPROACH
During the virtual workshop, the panelists discussed the ways their practices counsel, educate, and manage AEs for patients taking BTK inhibitors. Despite the BTK inhibitors’ efficacy and convenience, the lack of defined duration of therapy may present a challenge for patients in the clinic, although most panelists stated that their patients do not take them indefinitely. Alegria said that her treatment team generally limits ibrutinib therapy to 3 years in patients with CLL because of concerns about disease progression on ibrutinib, and they usually wait until repeat bone marrow biopsies show minimal residual disease negativity before stopping. “Most patients are aware that they will not be on it for life,” she said. “We can’t tell them exactly when [treatment will be over] based upon their disease.”
However, Saggiomo said that she focuses on educating patients on the chronic nature of their illness and the need for ongoing therapy as long as it is beneficial, tolerable, and affordable. “If they’re able to maintain it and do well with it, we do try to encourage treatment to last as long as we can,” she said. Mary A. Timberg, MSN, NP, RN, of the Hackensack University Medical Center in New Jersey, added that the dosing of ibrutinib (and other BTK inhibitors) as an oral pill that can be taken at home, as opposed to the intravenous dosing of chemotherapy, is also attractive for many patients, particularly in the coronavirus disease 2019 era.
Several panelists added that educating patients on when they need to hold doses before minor procedures, such as colonoscopies and procedures to remove skin growths, is important to prevent excessive postoperative bleeding. “I had a patient tell me, ‘Oh, they’re just taking some [little growth] off, no big deal,’” said Alegria. “[Afterward], he came in with 50 stitches on his hand after Mohs surgery.”
The panelists said that counseling patients on the risks and signs of serious TEAEs is important before starting patients on BTK inhibitors. “The resources out there are great,” said Coleen Bejot, APN, RN, NP-C, also of Hackensack University Medical Center. “We have excellent pamphlets for almost all the B-cell malignancies—Waldenström, CLL, mantle cell, etc—so we go through the packet with them. I feel as if we educate them pretty well.”
The panelists said that online resources can also help with counseling patients on adherence and proper medication use. Christine Smith, MSN, APRN, FNP-C, of the University of Kansas Cancer Center in Kansas City, said that her practice uses resources from Oral Chemotherapy Education (created by the National Community Oncology Dispensing Association and available at oralchemoedsheets.com), along with their hematology pharmacist, to counsel patients who are starting any treatment regimen. Several panelists said they use chemocare.com, an online resource that provides information on drugs and their AEs, cancer wellness, and links to additional resources and organizations, as well as free booklets from the Leukemia & Lymphoma Society.
Bejot added that frequent telephone check-ins from the oncology nurse navigators in her practice provide additional education and reassurance for patients. “They feel very confident knowing that somebody is looking after them, and I think that helps,” she said. Several panelists also mentioned that when a patient has cardiac comorbidities, which may put them at high risk for AF or stroke if they take ibrutinib, there is value of having both a cardio-oncologist and the patient’s primary care doctor as partners. The first can monitor for early signs of cardiac AEs, and the second can ensure that the patient’s blood pressure remains well controlled. Saggiomo also emphasized the importance of educating patients about the symptoms of AF and ensuring that they have a low threshold to notify providers if they become symptomatic.
The panelists added that all patients taking a BTK inhibitor should receive frequent telephone follow-ups in the first few months of therapy. Saggiomo said that the pharmacist in her practice who works with oral medications follows up with the patient during the first 2 weeks of therapy to assess drug tolerance. Similarly, Smith said that the oral chemotherapy pharmacist in her practice performs check-ins at 2 weeks, 1 month, and monthly for a few months, after which the check-ins decrease in frequency if the patient is stable. “Phone-call follow-ups seem to help catch any toxicities that they might be having and bring them in sooner,” said Smith.
The panelists added that frequent monitoring of cytopenias with blood panels is a key part of their practices, particularly in a patient’s first few months after beginning treatment. Amy A. Esposito, MS, APRN, FNP-C, OCN, also of Rocky Mountain Cancer Centers, said that her practice performs blood panels every 1 to 2 weeks in the first month, followed by blood panels monthly and eventually every 3 months. Woodward said that she obtains blood panels every week for the first month because her practice does not have nurse navigators, followed by less frequent monitoring if the patient remains stable. “I just want to make sure that they’re well established and stable on [ibrutinib] before we turn them loose,” said Woodward.
The panelists concluded the workshop by saying that most of the physicians they work with are willing to try the newergeneration BTK inhibitors if data support their efficacy and safety. They added, however, that covering the costs of treatment with BTK inhibitors continues to be the main barrier, particularly because many patients with B-cell malignancies are older adults with limited incomes. Alegria said that some patients in her practice have needed to use different therapies because they cannot afford the out-of-pocket costs of ibrutinib, whereas other patients have had difficulties with high co-pays but do not qualify for financial assistance, highlighting the continued need for improved access to BTK inhibitors.
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