Practical management of chronic lymphocytic leukemia with acalabrutinib

Abstract

Treatment of chronic lymphocytic leukemia (CLL) has been transformed in the past two decades. The introduction of targeted therapies has improved patient outcomes and the deliverability of effective therapies. Making the best use of the next wave of Bruton’s tyrosine kinase (BTK) inhibitors requires an understanding of the nuances that separate the drugs in this class of agents. This paper reviews the newer BTK inhibitors and provides practical guidance on the management of CLL using acalabrutinib. Acalabrutinib is a safe and efficacious BTKi in the treatment of CLL. While some side effects appear to be an “on-target” effect of BTK inhibition, the selectivity of second-generation covalent BTK inhibitors such as acalabrutinib may result in a favorable safety profile due to less off-target kinase inhibition. Acalabrutinib represents a well-tolerated and effective alternative to ibrutinib in the management of CLL.

Keywords:

• Acalabrutinib
• chronic lymphocytic leukemia
• BTK inhibitors
• treatment

Introduction

Chronic lymphocytic leukemia (CLL) is one of the most common B-cell malignancies in adults in western countries [1]. There have been major advances in treatment over the past two decades which have greatly improved patient outcomes [2]. One such advance is the introduction of targeted therapies. Prior to their introduction, immuno-chemotherapy was the mainstay of treatment [2]. Unfortunately, the most effective combination of FCR (fludarabine, cyclophosphamide and rituximab) results in significant toxicity, particularly in those with comorbidities. The introduction of targeted therapies including Bruton’s tyrosine kinase inhibitors (BTKi) (ibrutinib, acalabrutinib, zanubrutinib), more potent CD20 monoclonal antibodies (obinutuzumab) and BCL2 inhibitors (venetoclax) are effective and in general, are better tolerated than immuno-chemotherapy [3–7]. Many of these agents are now available for treatment-naïve patients with CLL. BTK and BCL2 inhibitors are preferred options for patients with TP53 mutant CLL in any line of therapy [8–10].

The first-in-class BTKi ibrutinib has been in use since 2013 [2] and clinicians are now familiar with its safety profile and efficacy. Making the best use of the BTK inhibitors subsequently approved requires an understanding of some of the key points of differentiation from ibrutinib. The purpose of this paper is to briefly review the newer BTK inhibitors through this lens and provide practical guidance on the management of CLL using acalabrutinib.

The BTK inhibitors

BTK is a molecule that interconnects B-cell receptor (BCR) signaling, toll-like receptor (TLR) signaling and chemokine receptor signaling [2]. In CLL, constitutive phosphorylation of LYN, SYK, PKC-beta, BTK and PI3K and activation of NF-kappaB can initiate or maintain the survival, proliferation, or migration of CLL cells [2]. Most BTKi are irreversibly covalently bound to cysteine 481 (C481) in the adenosine triphosphate (ATP) binding pocket of BTK. The potency of inhibition depends on the agent, with ibrutinib the most potent BTKi, followed by zanubrutinib and then acalabrutinib [2]. Acalabrutinib has the lowest off-target rate, and the highest selectivity followed by tirabrutinib, zanubrutinib and ibrutinib [2,11]. These differences influence the effectiveness and tolerability of clinical practice [2]. Pirtobrutinib (previously LOXO-305) is the first reversible BTKi that has activity against BTK C481 substitutions that prevent irreversible BTK inactivation [12] and is now in a number of phase 3 clinical trials.

Ibrutinib

The first-in-class BTKi ibrutinib irreversibly inhibits BTK by binding with C481 in the BTK active site [13]. It is effective in treatment-naïve and relapsed refractory settings. With a median follow-up of 60 months, progression free survival and overall survival were significantly better in the ibrutinib arm over chlorambucil in first-line setting in RESONATE-2 with progression free survival (PFS) estimates at 6.5 years: 61% vs 9%; HR [95% CI]: 0.160 [0.111–0.230] [14]; OS estimates at 5 years: 83% vs 68%; HR [95% CI]: 0.450 [0.266–0.761] [15]. The PFS was 44.1 vs 8.1 months in ibrutinib vs ofatumumab arms in relapsed or refractory patients in the RESONATE study [8]. Both studies were criticized for the use of suboptimal comparator arms. Ibrutinib has an acceptable tolerability profile whether used as monotherapy [14–16] or in combination with bendamustine-rituximab [17]. However, it can be associated with significant gastrointestinal symptoms, with diarrhea present in 42% of patients in the first year. In addition, atrial fibrillation (5%) and hypertension (20%) were observed during the 5-year follow-up of RESONATE-2 [15].

Acalabrutinib

More than 5,000 people have participated in the acalabrutinib clinical trial program. Of these, approximately 4,600 have undergone treatment with acalabrutinib as monotherapy or in combination with other agents (with the remainder being randomized to placebo or standard of care).

In the treatment-naïve setting, acalabrutinib ± obinutuzumab was compared to chlorambucil-obinutuzumab combinations in 535 patients (179, 179 and 177 patients) with CLL aged >65 or <65 and cumulative illness rating score of ≥6 or creatinine clearance 30–59ml/min [18,19]. After a median follow-up of 46.9 months, acalabrutinib (both monotherapy or with obinutuzumab) resulted in superior PFS relative to chlorambucil-obinutuzumab [19]. Grade ≥ 3 adverse events in more than 5% of patients in either acalabrutinib arm included neutropenia, anemia, and pneumonia [20].

The phase I/II ACE-CL-001 study [21–24] which included 99 patients with relapsed or refractory CLL or small lymphocytic lymphoma (SLL) provides the longest follow-up for acalabrutinib treated patients. Twice daily dosing with acalabrutinib resulted in near-complete BTK target occupancy over the dosing interval (200 mg once daily vs. 100 mg twice daily) and all patients were transitioned to 100 mg twice daily. After a median follow-up of 53 months, 85 patients remained on treatment; 14 patients discontinued treatment, with the most common reasons adverse events (AEs) (n = 6) and disease progression (n = 3). The overall response rate was 97% (90% partial response; 7% complete response) and was not lower in subgroups with higher biological risk with chemotherapy (TP53 mutation, IGHV unmutated). The most common adverse events were diarrhea (52%), headache (51%), upper respiratory tract infection, 37%; and fatigue, 34%). Grade 3 or worse events occurring in more than 5% of patients included neutropenia, pneumonia, hypertension, anemia, and diarrhea. Ten patients died due to adverse events with causes including pneumonia (n = 5), Candida infection, congestive cardiac failure, metastatic lung adenocarcinoma, metastatic prostate cancer, and respiratory failure (n = 1 each).

In the ELEVATE R/R study (ACE-CL-006, NCT02477696) 533 patients with previously treated CLL were randomized to acalabrutinib 100 mg twice daily or ibrutinib 420 mg once daily [25]. After a median follow-up of 40.9 months (range 0.0–59.1 months), acalabrutinib was non-inferior to ibrutinib in terms of independent review committee assessment of PFS (primary endpoint), with a median PFS of 38.4 months in both arms (HR 1.00; 95% CI 0.79–1.27) (Figure 1). The independent review committee assessed PFS, consistent across a range of pre-specified subgroups including age, sex, ECOG performance status, bulky disease, number of prior therapies, presence of del17 or del11, TP53 mutation, IGHV, and complex karyotype. However, the adverse event profile of acalabrutinib on balance favored ibrutinib (Table 1). The atrial fibrillation or flutter events of any grade were lower in patients treated with acalabrutinib (9% vs 16%, respectively, p = 0.02) leading to less treatment discontinuation (0 vs 7 instances). There were fewer ventricular arrhythmias or cardiac arrests (0.4% vs 1.9%) although these events were rare. Diarrhea (any grade, 46% vs 35%), arthralgia (23% vs 16%), hypertension (23% vs 9%), contusion (18% vs 12%), urine tract infection (14% vs 8%), back pain (13% vs 8%), muscle spasms (13% vs 6%) and dyspepsia (12% vs 4%) were all less frequent in the acalabrutinib treated patients. In contrast, headache (35% vs 20%) and cough (29% vs 21%) were more common in the acalabrutinib-treated patients. There were comparable incidences of Grade 3 or higher infections (31% vs 30%) and Richter’s transformation (4% vs 5%). Adverse events resulting in treatment discontinuation were less frequent with acalabrutinib than with ibrutinib (15% vs 21%, respectively). The non-inferior efficacy and improved toxicity profile are reasons to consider acalabrutinib over ibrutinib in this setting.

Figure 1. PFS, OS and EFS from ELEVATE R/R. Reproduced with permission from Byrd et al. [25]. PFS, OS, and EFS. (A) Kaplan-Meier curve of IRC-assessed PFS (primary endpoint). (B) Kaplan-Meier curve of OS (secondary endpoint). (C) Kaplan-Meier curve of IRC EFS. The Kaplan-Meier curves for IRC-assessed PFS cross at 33 months, indicating a violation of the proportional hazards assumption. A sensitivity analysis on the basis of RMST, which is valid under nonproportional hazards, confirmed that acalabrutinib was non-inferior to ibrutinib, with a difference in RMST (acalabrutinib-ibrutinib) of 1.1 months (95% CI: −2.17 to 4.36) over 55 months. The lower bound of the 95% CI was compared with an RMST noninferiority margin of −5.83 months, derived from the HR noninferiority margin of 1.429. For the PFS analysis, three ibrutinib-treated patients were censored because of PD or death immediately after missing two or more consecutive visits, and seven acalabrutinib and eight ibrutinib patients were censored at random assignment because of no baseline assessment and/or no adequate postbaseline assessment. EFS, event-free survival; HR, hazard ratio; IRC, Independent Review Committee; NE, not estimable; OS, overall survival; PD, progressive disease; PFS, progression-free survival; RMST, restricted mean survival time.

Table 1. Comparison of adverse events (AEs) from the randomized phase III ELEVATE R/R study.

	Acalabrutinib (N = 266)		Ibrutinib (n = 263)
Event	Any grade	Grade ≥ 3	Any grade	Grade ≥ 3
Diarrhea^a,b	92 (34.6)	3 (1.1)	121 (46.0)	13 (4.9)
Headache^a,b	92 (34.6)	4 (1.5)	53 (20.2)	0
Cough^a	77 (28.9)	2 (0.8)	56 (21.3)	1 (0.4)
Upper respiratory tract infection	71 (26.7)	5 (1.9)	65 (24.7)	1 (0.4)
Pyrexia	62 (23.3)	8 (3.0)	50 (19.0)	2 (0.8)
Anemia	58 (21.8)	31 (11.7)	49 (18.6)	34 (12.9)
Neutropenia	56 (21.1)	52 (19.5)	65 (24.7)	60 (22.8)
Fatigue^b	54 (20.3)	9 (3.4)	44 (16.7)	0
Arthralgia^a	42 (15.8)	0	60 (22.8)	2 (0.8)
Hypertension^a,b	23 (8.6)	11 (4.1)	60 (22.8)	23 (8.7)
Nausea	47 (17.7)	0	49 (18.6)	1 (0.4)
Pneumonia	47 (17.7)	28 (10.5)	43 (16.3)	23 (8.7)
Thrombocytopenia	40 (15)	26 (9.8)	35 (13.3)	18 (6.8)
Dyspnea	37 (13.9)	6 (2.3)	23 (8.7)	1 (0.4)
Bronchitis	34 (12.8)	3 (1.1)	23 (8.7)	2 (0.8)
Constipation	31 (11.7)	0	37 (14.1)	2 (0.8)
Contusion^a	31 (11.7)	0	48 (18.3)	1 (0.4)
Nasopharyngitis	29 (10.9)	0	27 (10.3)	0
Dizziness	28 (10.5)	0	26 (9.9)	0
Vomiting	28 (10.5)	1 (0.4)	36 (13.7)	3 (1.1)
Peripheral edema	26 (9.8)	0	38 (14.4)	1 (0.4)
Rash	26 (9.8)	2 (0.8)	33 (12.5)	0
Myalgia	25 (9.4)	2 (0.8)	27 (10.3)	1 (0.4)
Atrial fibrillation^a	24 (9.0)	12	41 (15.6)	9 (3.4)
Urinary tract infection^a	22 (8.3)	3	36 (13.7)	6 (2.3)
Back pain^a	20 (7.5)	0	34 (12.9)	2 (0.8)
Epistaxis	19 (7.1)	1	28 (10.6)	1 (0.4)
Muscle spasms^a	16 (6.0)	0	35 (13.3)	2 (0.8)
Dyspepsia^a	10 (3.8)	0	32 (12.2)	0

Most common AEs occurring in ≥10% (any grade) or ≥5% (grade 3 or higher) of patients in either treatment arm. Bold text indicates significant differences in event rates between the two arms. Reproduced with permission from Byrd et al. [25] under CC BY NC ND 4.0 (https://ascopubs.org/doi/full/10.1200/JCO.21.01210 and https://creativecommons.org/licenses/by/4.0/).

a. Descriptive two-sided P< .05 on the basis of Barnard's exact test without multiplicity adjustment for all-grade AEs

b. Descriptive two-sided P< .05 on the basis of Barnard's exact test without multiplicity adjustment for grade 3 or higher AEs

In the ASCEND study, patients with relapsed/refractory CLL were randomized 1:1 to either acalabrutinib 100 mg twice daily, investigator’s choice of bendamustine – rituximab or idelalisib-rituximab. There were 310 patients in the study, of whom 155 were randomized to the acalabrutinib arm. However, most patients on the standard arm received idelalisib/rituximab (119 vs. 36). Acalabrutinib arm resulted in longer PFS (median not reached versus 16.5 months, HR 0.31 (95%CI 0.20–0.49, p < 0.0001) (Figure 2), with 82% of patients receiving acalabrutinib being progression-free at 18 months compared with 48% in the control arm. Cross-study comparisons between ASCEND and RESONATE are challenging given the differences in patient characteristics (patients in RESONATE were more heavily treated and higher proportions with TP53 mutation) and control arms, the disparity in the length of follow-up (22 vs 65 months respectively) with these limitations in mind, the 18 month PFS rate was 82% for acalabrutinib vs 74% for ibrutinib. Acalabrutinib was approved by the FDA in 2019 [2].

Figure 2. Progression-free survival. The primary endpoint of progression-free survival is shown for (A) all patients and (B) for all patient's therapy received by the ASCEND intent-to-treat population. B-R, bendamustine plus rituximab; I-R, idelalisib plus rituximab; NR, not reached. Reproduced with permission from Ghia et al. [26].

Zanubrutinib

Zanubrutinib is a nonreversible covalent second-generation BTKi which exhibits less off-target inhibition of other tyrosine kinases including epidermal growth factor receptor (EGFR), Janus kinase 3 (JAK3), Tec family tyrosine-protein kinase (TEC) and interleukin-2 inducible T-cell kinase (ITK) compared to ibrutinib [27]. Treatment with zanubrutinib in patients with relapsed or refractory CLL/SLL results in a high ORR and median PFS of ∼22 months [28,29]. Activity in del(17p) CLL was demonstrated in the SEQUOIA trial in which 109 treatment naïve patients treated with zanubrutinib achieved an ORR of 94.5% (3.7% CR). The estimated 18-month PFS and OS were 88.6% and 95.1% respectively [30]. Zanubrutinib is not currently approved for CLL but was approved for mantle cell lymphoma (MCL) by the FDA in 2019 [2].

Pirtobrutinib (formerly LOXO-305)

In contrast to ibrutinib, acalabrutinib and zanubrutinib which are nonreversible, covalent BTK inhibitors, pirtobrutinib is a reversible non-covalent BTK inhibitor with low nM potency against both wild type and C481 mutated BTK, 300-fold selectivity for BTK relative to 98% of other kinases [31]. The first-in-human phase I/II trial included 323 patients with relapsed/refractory B-cell malignancies. Among the 170 with CLL/SLL, patients had received a median of 3 (range 2–5) prior lines of therapy, 86% were exposed to a prior BTK inhibitor and 71% had discontinued the prior BTK inhibitor due to disease progression. Treatment was well tolerated with few adverse events of grade 3 or higher. Atrial fibrillation was seen in <1% of patients, grade 3 bleeding in one patient (following trauma) and bruising was seen in 16% suggesting a safety profile differing from covalent BTK inhibitors. Among 139 efficacy evaluable CLL/SLL patients, the overall response rate (ORR) was 63% (all partial response [PR] or partial response with lymphocytosis [PR-L]), with similar efficacy in patients treated with prior BTK inhibitors or C481S mutation [31]. Pirtobrutinib appears likely to be a safe and effective treatment for patients who experience covalent BTK inhibitor treatment failure.

Practical management of patients with CLL receiving acalabrutinib

Case 1  

A 52-year-old woman presents with bulky adenopathy and symptomatic splenomegaly of 17 cm by computed tomography (CT) scan. Hb 117 g/L; lymphocyte count 42.99 x 10⁹/L; platelets 197 x 10⁹/L. The immunoglobulin heavy chain variable region gene (IGHV) is unmutated, with del(11q) detected on fluorescence in-situ hybridization (FISH) as the only FISH abnormality. TP53 mutation was not detected. She has comorbidities including recurrent respiratory infections, ulcerative colitis (which required a total colectomy), and inflammatory arthropathy. She suffers from anxiety and depression. Her renal function is normal. She is hypogammaglobulinemia.

This is a young patient with disease biology predicting inferior outcomes following chemo-immunotherapy (IGHV unmutated) although TP53 is unmutated and has some comorbidities. Treatment options depend on regional drug availability. Potential options to consider include FCR; bendamustine-rituximab (BR); a BTKi ± obinutuzumab or rituximab; venetoclax-obinutuzumab.

Given the unmutated IGHV status, this patient is likely to have a median PFS of less than four years with minimal chance of long-term remission with chemo-immunotherapy and given the comorbidities toxicity may be a concern [32]. Relative to FCR, ibrutinib and rituximab was shown to result in both improved survival and lower grade 3 infections in the E1912 trial [33]. However, at the time of writing, in many regions of the world, it is not currently possible to use BTKi in treatment-naïve patients outside of the clinical trials due to drug access limitations.

There are also favorable efficacy data for acalabrutinib monotherapy in treatment-naïve patients, albeit less mature than FCR or ibrutinib monotherapy and long-term outcomes and tolerability studies are awaited [18].

Case 1 continued

The patient underwent bone marrow assessment and was found to have 90% marrow involvement; del(11q) on FISH and single nucleotide polymorphism (SNP) array showed other clonal chromosomal abnormalities suggestive of DNA instability associated with dysfunction of DNA repair mechanisms. The patient received acalabrutinib as single-agent therapy by compassionate access. She demonstrated a rapid reduction in bulky adenopathy with a sustained lymphocytosis for 3 months and gradual improvement in anemia. She remains in ongoing clinical remission 20 months later but with persistent hypogammaglobulinemia requiring monthly IVIG.

Patients with del(11q) predominantly have unmutated IGHV. These patients experience shorter responses to FCR and have a high risk of clonal evolution on relapse. In some respects, clonal evolution appears inevitable with FCR due to the DNA damage caused by alkylating agents and purine analogs.

In comparison, BTKi responses appear independent of del(11q)/IGHV mutation status, with ibrutinib demonstrating a possible response advantage in del(11q) patients [34] and acalabrutinib demonstrating effectiveness in patients with del(11q) who were intolerant of ibrutinib [22]. Venetoclax or PI3K inhibitor therapy also provides efficacy in the relapsed refractory setting, even in high-risk CLL [23]. However, with bulky adenopathy and rising lymphocytosis, the risk of tumor lysis is significant and may require inpatient management repeatedly over the ramp-up period. Dual novel agent therapy (ibrutinib for 3 months followed by addition of venetoclax as in the PCYC1142 study) may significantly reduce the risk of tumor lysis but is currently unavailable outside of clinical trial [35].

Clonal evolution frequently seen with relapsed/refractory disease following primary immunochemotherapy, is not restricted to this treatment modality. While the mechanism of clonal evolution following newer agents is incompletely understood [32,36–38], BTK mutations have been detected following ibrutinib and acalabrutinib therapy and BCL2 mutations have been described in venetoclax-resistant patients [39]. BTK mutations were detected in 6 of 9 (67%) patients with relapsed/refractory CLL tested at the time of acalabrutinib treatment failure, although the sample size was small [23]. Mutations in BTK and PLCG2 are found in approximately 80% of CLL patients with acquired resistance to ibrutinib, and PLCG2 mutations appear to drive BCR pathway signaling in the presence of BTKi [40]. Reversible, non-covalent inhibitors of C481S have been shown to retain activity in patients with CLL refractory to covalent BTKi irrespective of the presence of C481S mutations [12,41].

Case 2  

A 72-year-old man with comorbidities including gout (for which he is taking allopurinol) and gastroesophageal reflux disease (GORD) on pantoprazole presents with CLL in need of treatment due to anemia and thrombocytopenia. Molecular testing reveals IGHV mutated disease with no (no del(17p) or TP53 mutation). His Cumulative Illness Rating Scale (CIRS) score is 7. The patient is treated with acalabrutinib 100 mg twice daily. He complains of mild headache and diarrhea during the first few weeks on acalabrutinib.

Byrd et al. reported long-term safety data from the initial phase I/II study of acalabrutinib in 135 patients with relapsed/refractory CLL/SLL [23]. The most common adverse events (AEs) were diarrhea (52%) headache (51%), URTI (37%) and fatigue (34%). These events were mainly self-limiting, with only 1% discontinuing due to diarrhea, and 5% requiring dose interruption. The toxicity profile was similar among treatment-naïve patients [42].

Practice points:  

Headache is common during the early phase of treatment with acalabrutinib. It does not appear to be migrainous and does not necessitate cessation of therapy or dose reduction. Hydration and simple analgesia are all that are generally required for most patients. There are some anecdotal reports of dramatic responses to caffeine. The headache abates usually after a few weeks. It is important to counsel the patient regarding this effect at treatment commencement to avoid unnecessary anxiety.

The diarrhea, similarly, responds to hydration and inhibitors of peristalsis and does not require dose alteration in most patients. This also improves with time and persistent diarrhea is unusual.

GORD is a common comorbidity. If proton pump inhibitors cannot be avoided, they should be taken 2–4 h after acalabrutinib. More pharmacokinetic studies are required to define optimal dosing interval in this situation.

Case 3  

An 82-year-old male with IGHV mutated, TP53 wild type CLL presents with anemia (Hb 80 g/L), thrombocytopenia (platelets 50 × 10⁹/L) and lymphocyte count of 250 × 10⁹/L. He is an ex-smoker with significant chronic obstructive pulmonary disease, chronic renal impairment (glomerular filtration rate 45 mL/min), atrial fibrillation (AF), hypertension and type 2 diabetes.

Practice point  

We recommend that strong inhibitors of CYP3A4 are avoided and that dose reductions are considered for moderate inhibitors.

Renal impairment and the risk of tumor lysis in an elderly CLL population remain immediate clinical concerns with venetoclax and potentially the other emerging BCL2 inhibitors. However, another issue frequently arising in the management of elderly patients with CLL is the cardiovascular risks of BTK inhibitors. The increased selectivity of the newer BTK inhibitors appears to translate to an improved toxicity profile. AF occurs in 4–16% of patients treated with ibrutinib, with an incidence of 5.77 per 100 person-years, substantially higher than the estimated population background rate (0.55 per 100 person-years) [43]. The estimated rate of AF in CLL patients treated with first-line acalabrutinib is 3–5% [20,44]. Notably, no new AF events were reported by Wang et al. in 124 patients with mantle cell lymphoma treated with acalabrutinib monotherapy after a median follow-up period of 26 months [45]. A randomized trial comparing acalabrutinib with ibrutinib in patients with previously treated CLL has reported that AF is less frequently observed in acalabrutinib than ibrutinib treated patients [25]. At the time of writing, one patient has experienced a Grade 4 ventricular fibrillation on day 1,322 of treatment (0.1% in the pooled analysis of 1,040 patients) [46].

Hypertension was a late safety signal for patients treated with ibrutinib. Dickerson et al. reported that the overall incidence of patients on ibrutinib developing new or worsening hypertension over a median of 30 months was 78.3% [47]. New hypertension was reported in 71.6%, with a time to 50% cumulative incidence of 4.2 months [23]. Severe hypertension (BP >160/100 mm Hg) was reported in 17.7% [47]. Rates of incident hypertension, or exacerbation of existing hypertension in patients treated with acalabrutinib likely range between 7 and 22% [23].

Infection, particularly pneumonia, remains a constant reminder of the inherent immunosuppression experienced by patients with CLL. In terms of infection prophylaxis with novel agents, no clear international guideline exists. Opportunistic infections, such as Pneumocystis jirovecii pneumonia (PJP), have been reported in CLL patients treated with ibrutinib, and are an important consideration of causes of morbidity and mortality.

Ryan et al. described the prevalence of PJP among 212 patients with CLL with ibrutinib or acalabrutinib in Boston. 125 (59%) received PJP prophylaxis (either trimethoprim-sulfamethoxazole (74%) or atovaquone (26%)) [20]. Among patients not receiving prophylaxis, the incidence of PJP was 3.4%: specifically in those on BTKi monotherapy and not on prophylaxis it was 2.4%. Among 130 patients receiving PJP prophylaxis, there were no cases of PJP observed. The authors suggested that given the relatively low incidence of PJP, particularly in patients receiving BTKi monotherapy, routine antimicrobial prophylaxis was not routinely required, however, could be considered for individual patients considered at higher risk. Current guidelines do recommend prophylaxis against hepatitis B reactivation in at-risk individuals receiving BTK inhibitor monotherapy [48].

The elderly patient described in Case 3 with renal and cardiac impairment and infection risk has several clinical features which make chemo-immunotherapy, ibrutinib and venetoclax-based therapy less appealing and acalabrutinib may be preferred given these considerations. Despite his renal impairment with his cardiac and respiratory comorbidities we consider him at increased risk of adverse outcomes in the event of PJP infection and would recommend prophylaxis with trimethoprim and sulfamethoxazole.

Practical management of adverse events in patients treated with acalabrutinib

Clinical experience has shown that adverse events experienced by patients prescribed acalabrutinib are generally mild and reduce over time with the most common diarrhea, headache, upper respiratory tract infection, arthralgia and contusion [42]. Discontinuation of therapy due to serious adverse events is infrequent. As stated previously headache and diarrhea are transient and are best managed symptomatically without cessation of the drug. Arthralgias can be persistent and may be difficult to treat, but are usually low-grade and self-limiting. Symptomatic treatment with paracetamol, prednisolone and light physical exercise can benefit some patients [49] (Table 2).

Table 2. Adverse events of interest were reported in the ACE-CL-001 study (NCT02029443).

Events of interest in acalabrutinib study	All treated patients (N = 99), n (%)
	All grades	Grade ≥3
Cardiac events	20 (20)	4 (4)
Atrial fibrillation	5 (5)	2 (2)
Ventricular tachyarrhythmias	0	0
Anemia	8 (8)	2 (2)
Leukopenia	9 (9)	9 (9)
Neutropenia	9 (9)	9 (9)
Other leukopenia	1 (1)	1 (1)
Thrombocytopenia	3 (3)	1 (1)
Hemorrhage	65 (66)	3 (3)
Major hemorrhage	4 (4)	3 (3)
Hepatotoxicity	4 (4)	2 (2)
Hypertension	22 (22)	11 (11)
Infections	83 (84)	15 (15)
Interstitial lung disease/pneumonitis	1 (1)	0
Second primary malignancies	26 (26)	5 (5)
Second primary malignancies, excluding non-melanoma skin	11 (11)	5 (5)
Tumor lysis syndrome	0	0

Reproduced from Dolan et al. [50] under CC BY 4.0 (https://www.mdpi.com/1718-7729/27/4/7009 and https://creativecommons.org/licenses/by/4.0/).

Opportunistic infections

Prophylaxis against Hepatitis B reactivation is recommended [48]. PJP prophylaxis is not uniformly recommended for patients receiving acalabrutinib monotherapy but may be considered on a case-by-case basis [51].

Bruising and bleeding

There are potentially differential effects of acalabrutinib and ibrutinib on platelets [52]. In an in vitro model of platelet aggregation in response to collagen, acalabrutinib did not affect maximal collagen-induced platelet aggregation in an ‘ibrutinib low-sensitive’ group [52]. In CLL patients, acalabrutinib inhibited maximal platelet aggregation and delayed aggregation only in the ibrutinib high-sensitive group. The authors suggested that a switch from ibrutinib to acalabrutinib therapy in CLL patients who demonstrate bleeding and bruising clinically with ibrutinib may be insufficient to prevent further bleeding. Results from clinical trials show that although no grade 3 bleeding was observed in relapsed CLL patients on acalabrutinib, mild hemorrhages occurred in a comparable proportion of patients treated with ibrutinib [53].

In patients requiring anticoagulation or antiplatelet agents we recommend that while single antiplatelet agent use in association with BTKi may be acceptable, dual antiplatelet agents plus BTKi are to be avoided [53]. Cessation of acalabrutinib 7 days prior to major surgical intervention is recommended, resuming 3 days after. It should be held for 3 days prior to and after minor surgery, for example, tooth extraction. Vitamin K antagonists are not recommended to be used with BTKi. In the case of direct-acting oral anticoagulant (DOAC) use, rivaroxaban and apixaban undergo CYP3A4-mediated metabolism (33% and 25%, respectively), while dabigatran does not. Despite this, apixaban with twice-daily dosing, switching to half dose after six months of therapy may decrease the overall bleeding risk. It must be noted however that individual patient risk factors must be considered, and the impact of recurrent drug interruption is not known [53].

Drug-drug interactions

Drug-drug interactions with acalabrutinib have been modeled using a physiologically-based pharmacokinetic approach [26]. This study has recommended doses of acalabrutinib of 100 mg once per day are recommended with moderate CYP3A4 inhibitors, and doses of 200 mg twice daily with strong CYP3A4 inducers [26]. There were no clinically relevant effects on sensitive CYP3A4 or CYP2C8 substrates. The authors noted that CYP3A4 modulator effects may be less significant when the total active component is considered. Further research into potential drug-drug interactions with acalabrutinib is required.

Conclusion

Acalabrutinib is a safe and efficacious BTKi in the treatment of CLL. While some side effects appear to be an “on-target” effect of BTK inhibition, the selectivity of second-generation covalent BTK inhibitors such as acalabrutinib may result in a favorable safety profile due to less off-target kinase inhibition. Acalabrutinib represents a well-tolerated and effective alternative to ibrutinib in the management of CLL.

Acknowledgment

The authors thank Belinda Butcher BSc (Hons) MBiostat Ph.D. CMPP AStat of WriteSource Medical Pty Ltd, Sydney, Australia, for providing medical writing support.

Disclosure statement

BJK reports consulting/advisory/honoraria: Roche, Janssen, MSD, Gilead, AstraZeneca, Loxo Oncology, Abbvie. WSH reports consulting/advisory/honoraria – Merck & Co. Inc., Bristol Myers Squibb, Pfizer, Roche, Abbvie, Novartis, Bayer Ag, Taiho. CYC reports consulting/advisory/honoraria – Roche, Janssen, MSD, Gilead, Ascentage Pharma, AstraZeneca, Loxo Oncology, TG therapeutics; research funding – Celgene, Roche, Abbvie. MSD; travel expenses – Roche.

Additional information

Funding

The medical writing support was funded by AstraZeneca, Sydney, Australia in accordance with Good Publication Practice (GPP3) guidelines (http://www.ismpp.org/gpp3).