Chronic lymphocytic leukaemia (CLL) is the most common leukaemia worldwide, with 4.9 new cases per 100 000 per year in the UK (Milne et al, 2020). CLL is a lymphoproliferative disorder characterised by clonal proliferation and progressive accumulation of morphologically mature, monomorphic B lymphocytes in blood, bone marrow and lymphatic tissues (Burger 2020). In CLL, CD5+ B cells undergo malignant transformation and become continuously activated by the acquisition of mutations that lead to monoclonal B-cell lymphocytosis (MBL). Further accumulation of genetic abnormalities and subsequent oncogenic transformation of monoclonal B cells leads to CLL (Burger, 2020). CLL is considered identical to the indolent non-Hodgins lymphoma, small lymphocytic lymphoma (SLL). They both involve lymphocytes and are managed similarly. However, in CLL the disease is primarily found in blood and with SLL, it is primarily found in lymph nodes.
The exact aetiology of CLL is unknown. However, it is known that male sex and increasing age are identified epidemiological features of CLL (Call et al, 2014). CLL is more common in men with 6.8 cases per 100 000 per year vs 3.5 cases per 100 000 per year in women. This increased male incidence is also seen in all ethnic groups. Lifestyle and occupational factors may also influence risk, with those living or working on farms or or employed as hairdressers being identified as higher risk (Slager et al, 2014).
Presenting signs and symptoms of CLL may be absent at diagnosis, with many asymptomatic patients diagnosed incidentally. Symptoms may include lymphadenopathy, splenomegaly, hepatomegaly, early satiety and B symptoms (fever, night sweats and unintentional weight loss). More than 50% have lymphadenopathy, which can be localised or generalised. Splenomegaly and hepatomegaly are less common than lymphadenopathy. Skin involvement is rare (Burger, 2020).
The diagnosis of CLL requires the presence of lymphocytosis (>5000 lymphocytes per cubic millimeter) in the peripheral blood, sustained for at least 3 months. Bone marrow are not routinely required for a diagnosis of CLL, however, may be performed to assist assessment of cytopenias. Where a bone marrow examination is performed, the marrow often demonstrates >30% lymphocytes. Fluorescence in situ hybridisation (FISH) is used to identify chromosomal rearrangements, which can differentiate CLL from other conditions, such as mantle cell lymphoma. FISH is also important for disease stratification (Milne et al, 2020).
The clinical course of CLL is heterogeneous, ranging from a fairly asymptomatic disease that may even regress spontaneously to a progressive disease that eventually leads to a patient's death (Delgado et al, 2020). The disease may have a stable course but also may become aggressive, with frequent relapses. Staging is performed to define disease burden, predict median survival, and indicate prognosis. CLL is staged either using the Binet system (Stage A to C) or Rai system (Stage 0 to IV) (Burger, 2020). However, neither staging system is able to provide information regarding disease progression because of CLL heterogeneity.
Prognosis in CLL is influenced by the stage of disease as well as the presence of high-risk markers, del(17p), del(11q), or unmutated IGHV (Burger, 2020). The CLL International Prognostic Indicator (CLL-IPI) combines genetic, biochemical and clinical parameters to categorise patients into four prognostic risk groups using five independent prognostic factors and providing treatment recommendations by risk groups based on a point system (International CLL-IPI working group 2016) (Table 1). As outlined in Table 1, IgHV unmutated status is associated with a more aggressive CLL and high-risk cytogenetics results in higher scores, conferring a poor prognosis, thus indicating a greater need to treat (Condoluci et al, 2018). Patients scoring above four require treatment unless asymptomatic. In addition, patients with deletion or mutated genes score higher and do not benefit from non-chemo/chemo-immunotherapy regimes; experimental protocols are therefore indicated and more effective to overcome poor genetic features in patients scoring seven or more (Hallek, 2019).
Table 1. CLL-IPI scoring and when to treat
| Prognostic variable | CLL-IPI risk score |
|---|---|
| TP53 deleted or mutated | 4 |
| Unmutated IGHV | 2 |
| Serum beta-2 microglobulin concentration >3.5 mcg/mL | 2 |
| Rai Stage I-V or Binet Stage B-C | 1 |
| Patient's age > 65 years | 1 |
Treatment options
Many patients with CLL require surveillance only and have a normal life expectancy, with the majority of patients monitored with a watch and wait approach until the balance of risk and benefits favours treatment initiation (Milne et al, 2020). Clinical trials in early-stage CLL have failed to show survival benefit and therefore, by international guidelines treatment, in this patient cohort is not recommended. Ongoing randomised trials are evaluating the use of more modern therapies in early-stage disease and prognostic markers associated with worse clinical outcomes. However, until such time as treatment benefit is demonstrated, treating in this setting should be reserved for patients enrolled in these clinical trials (Rai and Stilgenbauer, 2020).
Using genetic, biochemical, and clinical parameters analysed from patient data with early-stage CLL (n=4933), the International Prognostic score for early-stage CLL (IPS-E) was developed to predict time to first treatment (TTFT) in patients with early asymptomatic CLL at diagnosis into three risk groups (Condolusi et al, 2020) (Table 2). The three covariates found to correlate with TTFT are assigned one point each; these include unmutated immunoglobulin IGHV, absolute lymphocyte count higher than 15x10/L and palpable lymph nodes (Condolusi et al, 2020). Patients with a low IPS-E score of zero had a low five-year cumulative risk to start treatment in comparison to patients with a high score of 2-3, 8.4% vs 61.2% respectively (Condolusi et al, 2020) (Table 2).
Table 2. International Prognostic score for early stage CLL (IPS-E)
| Score | Risk category | 5 year cumulative risk to start treatment (%) |
|---|---|---|
| 0 | Low | 8.4 |
| 1 | Intermediate | 28.4 |
| 2-3 | High | 61.2 |
Significant advances in the understanding of CLL biology, molecular genetics, and new biomarkers have resulted in new more targeted therapies for patients needing treatment. Molecular assessment prior to every line of treatment is essential to avoid ineffective treatments. Moreover, treatment choice and aims should be made in collaboration with a patient's wishes, co-morbidities and potential drug side effects (Schuh et al, 2018).
Treating CLL involves managing the disease and treatment side effects. In addition, patients are living with a potentially relapsing, recurring cancer, thus assessment and interventions for psychosocial needs must be addressed. Moreover, because 90% of patients have one or more co-morbidities, a multidisciplinary approach involving patients and outlining the potential benefits and risks of treatment is important during the treatment decision-making process (Thurmes et al, 2008).
Previously, the mainstay of treatment was chemo-immunotherapy, but this is slowly declining because of significant toxicity and the availability of a number of novel agents (Burger, 2020). Chemoimmunotherapy offers only a brief duration response in patients with TP53 disruption defined by either deletion of chromosome 17p or mutation in the TP53 gene (Furman et al, 2014). The development of targeted agents (eg bruton tyrosine kinase (BTK) inhibitors, PI3-kinase inhibitors, BCL2 inhibitors, novel antibodies) and other investigational therapies (eg chimeric antigen receptor T cells) are changing the landscape of treatment options (Rai and Stilgenbauer, 2021). The introduction of these newer agents has significantly improved survival outcomes, including patients with high risk disease (NCCN, 2021).
Acalabrutinib
In response to the recognition of the unmet need for more effective targeted treatments for CLL, with fewer side effects and limited treatment options for patients with 17p deletion or TP53, the National institute for Health and Care Excellence (NICE) guidelines released in April 2021 recommended acalabrutinib as a monotherapy for treating adult patients with:
- A 17p deletion or TP53 mutation, or
- No 17p deletion or TP53 mutation, and fludarabine plus cyclophosphamide and Rituximab (FCR) or benamustine plus rituximab (BR) is unsuitable
- Previously treated CLL patients.
Approval of acalabrutinib by NICE also provides greater treatment choice and an alternative option for patients not suitable for Ibrutinib due to cardiovascular comorbidities. In addition, acalabrutinib is likely to be cost-saving compared to Ibrutinib (NICE, 2021).
Acalabrutinib is a potent next-generation selective inhibitor of bruton kinase inhibitor (BTK). Acalabrutinib binds covalently to BTK, thereby inhibiting its activity (Wu and Zhang, 2016). In B cells, BTK signalling results in activation of pathways necessary for B-cell proliferation, trafficking, chemotaxis and adhesion (Nam, 2017) and is critical for the survival of leukemic cells in various B cell malignancies (Pal Singh et al, 2018).
The findings from two significant phase 3 trials, ELEVATE-TN (Sharman et al, 2020) and ASCEND (Ghia et al, 2020) in patients with previously untreated CLL and relapsed or refractory CLL respectively, have demonstrated similar efficacy but fewer adverse events with acalabrutinib compared with ibrutinib. For instance, in trials involving CLL patients with relapsed or refractory disease, infection Grade 3 was reported in 30% (n= 59) of patients on ibrutinib in the RESONATE study (Barrientos et al, 2018; Brown et al, 2018) and Grade 3 infections were reported in 20% (n=30) of patients in the ASCEND study (Ghia et al, 2020). In addition, it was reported in a nonrandomised study that a group of patients with CLL (n=33) who discontinued ibrutinib due to intolerance could tolerate acalabrutinib (Awan et al, 2019).
The results of the ongoing phase III trial ELEVATE-RR (ACE-CL-006, NCT02477696) (Clinicaltrials. gov, 2015) will offer clinicians further data on the frequency of atrial fibrillation with acalabrutinib versus ibrutinib among previously treated CLL patients, with the possible option of potent selective BCL2 inhibitor, venetoclax, for patients at risk for cardiac arrhythmias (Burger, 2020). Venetoclax is an attractive alternative if BTK inhibitors have unacceptable side effects or where patients prefer a limited duration treatment. Venetoclax is also an option for CLL patients previously treated unsuccessfully with the phosphatidylinositol 3-Kinase (PI3K) inhibitor, idelalisib (Bosch and Hallek, 2018). Idelalisib is not the first-choice kinase inhibitor for CLL therapy because of its autoimmune side effects (eg autoimmune hepatitis) but it does offer an alternative to BTK inhibitors for patients who experience severe side effects (Burger, 2020).
In summary, acalabrutinib is a more selective BKTi than ibrutinib with higher potency and fewer off-target effects. As a result, acalabrutinib is associated with fewer grade 3 and higher toxicities (Burger, 2020), is the treatment of choice for people with comorbidities, particularly cardiac issues (Brown and Dean, 2020), is better tolerated in the elderly and is associated with less cardiac toxicity, lower thrombocytopenia and bleeding risk and lower grade irritating side effects. Of note, both acalabrutinib and ibrutinib are continuous therapies until disease progression or the emergence of unacceptable side effects with the key difference between both is daily (ibrutinib) versus twice daily (acalabrutinib) dosing.
Dose and administration
Acalabrutinib is a self-administered oral hard capsule (100 mg) taken twice daily, 12 hours apart, with rapid absorption (peak plasma levels are reached after 0.6-1.1 hour) and a short half-life (approximately 1 hour) (Byrd et al, 2016). The dose may be reduced to 100 mg daily where drug interaction or dose modification as a result of toxicity is indicated.
Patients are advised to swallow the capsule whole with a glass of water, with or without food, and not to break, open or chew capsules. Patients are also advised that if they miss a dose by more than 3 hours, to skip and take the next scheduled dose (SPC, 2021). No special storage is required, however, the drug should be stored safely away from children.
No data on the effects of acalabrutinib on fertility are currently available and animal studies suggest a risk to the fetus from exposure during pregnancy. Therefore, acalabrutinib should be avoided during pregnancy, and women of childbearing potential on acalabrutinib should be advised to avoid becoming pregnant and use effective contraception. If a patient becomes pregnant while on the treatment they must immediately contact their haematology consultant for advice and instruction (SPC, 2021).
Patient education and adherence
Patient education is central to therapeutic adherence to oral anti-cancer drugs, and nurses are ideally positioned to educate and support patients with CLL in collaboration with pharmacy colleagues (Mawhinney et al, 2019). An ideal tool to assist nurse prescribers in patient education is the Multinational Association of Supportive Care in Cancer (MASCC) Teaching Tool for Patients Receiving Oral Agents for Cancer (Rittenberg, 2012). The tool comprises four sections that help guide the education process. Section one assesses the patient's knowledge of the treatment plan, current medications and their ability to take the prescribed anti-cancer oral agent. Section two comprises education on storage, handling, disposal, etc, of the anti-cancer agent. Section three focuses on specific information on the drug, such as dose, adverse effects and potential interactions. Finally, section four allows the prescriber to review the information provided with the patient and their understanding (Kav et al, 2010). Questions to focus on include the name of the agent, its indication, the dose, frequency and time schedule, and the management of common adverse events (Neuss et al, 2013).
To maximise the safety and long-term tolerability of BTKis, patients' clinical history must be carefully considered, including drug allergies and current medications (Lipsky and Lamanna, 2020). The prescriber also assesses the patient's ability to self-administer and involves family members/carers in education sessions where appropriate. It is important to check for drug interactions when prescribing acalabrutinib. Acalabrutinib is metabolised in the liver, and concomitant use of CYP3A inhibitors or inducers should be avoided; strong or moderate CYP3A inhibitors may increase plasma concentrations of acalabrutinib, which may increase the risk of toxicity and strong or moderate CYP3A inducers may decrease plasma concentration. In addition, patients on gastric-reducing agents require specific advice. It is necessary to avoid co-administration with gastric acid-reducing agents. Acalabrutinib needs an acidic environment to be absorbed and reduced absorption and plasma levels may be seen with concurrent use of a proton pump inhibitor (eg omeprazole) (Nam, 2017). Moreover, as a result of to the long-lasting effect of proton pump inhibitors, separation of doses with PPI may not eliminate the interaction (SPC, 2021). If a gastric reducing agent is required, an antacid (eg calcium carbonate) or H2 receptor antagonist (eg rantadine) should be given in a staggered dose, generally 2 hours before or ten hours after (SPC, 2021).
Adherence is considered the ‘most important issue with oral oncology agents’, and includes not only taking the prescribed oral agent but also taking the correct dose at the correct time, correct storage and appropriate reporting of side effects (Ritterberg, 2012). It is known that education can improve adherence among lymphoma patients prescribed acalabrutinib (Badillo et al, 2020). As part of the education process with oral chemotherapy, nurses report that they remain alert for the questions patients ask and the patient's attitude, which provide them with intuitive clues on the patient's level of adherence (Tolotti et al, 2021). Factors associated with higher levels of adherence include adequate social support, appropriate perception of their illness and its management, a high perceived necessity for their medication and self-efficacy in taking their oral chemotherapy (Kaptein et al, 2021).
Attitudes of concern suggesting poor adherence include a patient's lack of motivation to learn about their prescribed medication. Additional clues to possible low adherence include not collecting their prescription on time, not being able to name the medication, when to take it, and its common side effects. Other ‘red flags’ include not being aware of which foods to avoid and who to contact if side effects are experienced. In addition, patients who have not established a routine for taking their medication (eg reminders) are at risk of non-adherence (Dowling et al, 2019).
Contacting patients assessed to be at ‘high risk’ a few days following the education session is advised (Mawhinney et al, 2019). ‘High risk’ patients can be identified using the World Health Organization (2003) five dimensions of adherence. These five dimensions include socioeconomic (eg living alone), patient-related (eg anxiety), clinical condition (eg comorbidities), therapy-related (eg complexity of dosing, polypharmacy), and healthcare system-related factors (eg lack of continuity in care with different healthcare professionals involved in a patient's follow-up). These five dimensions of adherence are considered extremely valuable because they approach patient adherence from a wider perspective than the individual patient (Kaptein et al, 2021).
In addition, nurses also appreciate the importance of ‘knowing their patients as much as possible, as well as their patient's history and daily life habits’ (Tolotti et al, 2021). Patients' desire to survive is a driving force for adherence with non-curative oral chemotherapy (Dowling et al, 2019). Signs of depression and lower quality of life are associated with lower patient adherence to oral chemotherapy (Kaptein et al, 2021). Other identified barriers to adherence include high levels of distress and anxiety, low perceived behavioural control and fear of side effects (Kaptein et al, 2021). Identifying and responding sensitively to patients who are stressed is essential. Nurses describe how they ensure dedicated time for patient education and show their care and concern by appropriate body language (Tolotti et al, 2021).
Other considerations to promote adherence in this chronic patient group include patient diaries, pill diaries, patient apps and telephone follow-ups. In addition, mobile health platforms such as smartphone apps offer another tool for patients to increase their learning about treatment and monitor their adherence and side effects (Kongshaug et al, 2021). It is anticipated that in the near future, evidence-based mHealth apps will be routinely used to improve patient outcomes from treatment, improve communication with healthcare professionals and empower patients to manage their illness (Rowland et al, 2020).
Adverse events
Informing patients of possible adverse events is central to educating patients on acalabrutinib. Headache is a unique adverse event with acalabrutinib, with grade 1 or 2 headaches reported by 70% of patients, usually during the first cycles (Byrd et al, 2020; Sharman et al, 2020). Headaches typically occur within 30 min of dosing, often do not require treatment and can be easily managed with analgesia or caffeine, while avoiding non-steroidal anti-inflammatory drugs (NSAIDs). Patients should be encouraged to increase their fluid intake and be reassured that headaches are usually self-limiting and abate over a period of up to 4 weeks (Sharman et al, 2020).
Diarrhoea is reported to be the most common adverse events among patients on BTKi therapy with reported rates on acalabrutinib of 18-39% similar to those with ibrutinib (all grades 42%) (Byrd et al, 2020; SPC, 2021). However, it appears not to be drug-related and resolves quickly with limited use of anti-diarrheal medication (eg loperamide) (O'Brien et al, 2021). Immunosuppression is another risk with infections (of any grade) occurring in >50% of patients on BTKis with those early in their treatment and R/R patients at greatest risk.
Table 3 provides an overview of the frequency of adverse events in landmark studies of acalabrutinib (Lipsky and Lamanna, 2020). While the incidence of atrial fibrillation is low, it is imperative that patients are monitored and managed effectively with an oral anticoagulant.
Table 3. Frequency of adverse events in landmark studies of acalabrutinib
| ELEVATE STUDY (Sharman et al, 2020) Treatment naïve’ patients n=179Follow-up 28.3 months | ASCEND Study (Ghia et al, 2020) Relapsed or Refractory patients n=154Follow-up 22 months | |
|---|---|---|
| Atrial FibrillationAll gradesGrade ≥3 | 7 (3.6)Not reported in original publication | 9 (6)2 (1) |
| BleedingAll gradesGrade ≥3 | 70 (39)4 (2) | 44 (29)4 (3) |
| Hypertension | ||
| All gradesGrade ≥3 | 9 (5)4 (2) | 7 (5)4 (3) |
| ArthralgiaAll gradesGrade ≥3 | 28 (16)1 (0.6) | 23 (15) (Reported at 16.1 months)2 (1) (Reported at 16.1 months) |
| DiarrhoeaAll gradesGrade ≥3 | 62(35)1 (0.6) | 30 (20)3 (2) |
(Adapted from Lipsky and Lamanna (2020))
Acalabrutinib should only be discontinued if atrial fibrillation is not medically controlled. Pre initiation ECG and close monitoring are essential. Patient education on the importance of reporting symptoms promptly will also assist management and ensure patients are maintained on acalabrutinib (Bassan et al, 2014).
An increasing understanding of the common adverse effects associated with acalabrutinib has resulted from numerous trials (Byrd et al, 2021). In the results of a recent trial of treatment-naive CLL patients (n=99 patients), the most common AEs (20% of all grades) reported included diarrhoea (all grades 51%; grade 35%), headache (all grades 51%; grade 3, 5%), headache (all grades 45%; grade 3, 5%), upper respiratory tract infection (all grades 44%; grade 3, 1%), contusion (all grades 42%; grade 3, 0%), arthralgia (all grades 42%; grade 3, 1%), weight increase (all grades 32%; grade 3, 1%), nausea (all grades 31%; grade 3, 4%), cough (all grades 30%; grade 3, 0%), vomiting (all grades 22%; grade 3, 2%), hypertension (all grades 21%; grade 3, 10%) and sinusitis (all grades 21%; grade 3, 2%) (Byrd et al, 2021). Thirty-eight patients reported serious AEs, the most common being pneumonia (n=4) and sepsis (n=3) (Byrd et al, 2021).
On average, 11% of patients discontinue treatment because of unacceptable side effects of acalabrutinib (SPC, 2021). Therefore management of toxicities requires careful consideration. To maximise the safety and long-term tolerability of BTKi's, prior to commencing therapy, each patient's clinical history should be carefully reviewed. Experience with ibrutinib has shown patient-specific risk factors such as advanced age and comorbidities can increase the likelihood of adverse events. During treatment, careful attention and follow-up to patient-reported symptoms are essential.
Nurses play a key role in empowering patients to overcome the challenges of their chronic disease and treatment side effects. It is also vital that caregivers are involved in patient education and familiar with the management of BTKi-emergent toxicities because this drug group is likely to remain a mainstay of treatment alone or in combination for some time (Lipsky and Lamanna, 2020). Prompt recognition of side effects and early management is essential to improving patients' quality of life and assisting with treatment adherence. For instance, management of bleeding risk with careful consideration to the risk and benefits of concurrent anticoagulant or anti-platelet therapy. A risk-benefit analysis in consultation with the multidisciplinary team and patients is essential. Avoiding NSAIDs is also recommended as it may exacerbate bleeding risk.
Importantly, many of the side effects of treatment are manageable and self-limiting with early intervention. As outlined above, management of grade 1/2 diarrhoea with loperamide. In addition, hydration and caffeine for headaches will alleviate symptoms and mitigate against dose reductions or discontinuation of acalabrutinib. Furthermore, a short steroid course and cautious use of anti-inflammatory drugs may be useful for arthralgia and myalgia (Lipsky and Lamanna, 2020).
Patients receiving BTK inhibitors are immunocompromised and are at risk of infectious complications despite receiving effective therapy. Infections (of any grade) occur in >50% of patients on BTKis, particularly during the early period after starting treatment, with relapsed refractory patients at greater risk (Lipsky and Lamanna, 2020). Prompt recognition and early intervention are therefore vital. Early interventions include pre-treatment initiation with vaccines, and intravenous immunoglobulin for recurrent infections, and known hypogammaglobulinemia. Careful consideration is advised for prophylaxis in patients deemed high risk of opportunistic infection (eg R/R or heavily pre-treated patients) or patients with a prior history of infection (Lipsky and Lamanna, 2020).
The growing number of patients on novel CLL drugs requires new thinking in meeting the increasing follow-up care of these patients. Continuity of patient care and promotion of adherence and compliance is essential, particularly in light of the indefinite treatment duration. Dedicated nurse/pharmacy-led oral anticancer medication clinics are evolving as a direct consequence of the evolution of oral treatment developments in cancer care (Mawhinney et al, 2019). Benefits of nurse/pharmacy-led oral therapy clinics include continuity of care, consistency in information provision, efficient use of time with patients, improved therapeutic relationships and an enhanced patient and carer experience. A key aspect of these clinics is the reiteration of education on adverse events. Emphasis on early reporting and intervention is central to effective education in light of the indefinite use of BTKis (as long as they are effective). Careful assessment and monitoring through nurse/pharmacy lead oral anti-cancer medication clinics assists with early recognition and management of adverse events, thereby impacting on patients' quality of life.
Conclusion
In summary, the choice of first-line treatment for CLL should be based on disease stage, presence or absence of del (17p) or TP53 mutation, IGHV mutation status, patient's age, performance status, comorbid conditions and drug toxicity profile (NCCN, 2021). As per NCCN guidance and informed by the trials mentioned earlier, Ibrutinib and acalabrutinib +/- obinutuzumab is the preferred first-line treatment options for all patients including high-risk groups. Venetoclax and obinutuzumab is an effective fixed duration chemotherapy-free approach for all patients including del (17p) and TP53 mutation. Idelalisib is not indicated as a first-line treatment. Finally, fludarabine, cyclophosphamide, rituximab chemoimmunotherapy is preferred for patients younger than 65 years with untreated IGHV-mutated CLL as it offers a defined treatment course, and the majority of patients are expected to have more than 10 years of progression-free survival and potentially may be cured (NCCN, 2021).
In relapsed/refractory disease, many effective treatment options exist including ibrutinib, idelalisib (+/- rituximab), acalabrutinib, duvelisib and venetoclax +/- rituximab. Zanubrutinib may be an appropriate option for patients with contraindications or intolerance to other BTKi, including patients with del (17p) CLL (NCCN, 2021). Moreover, in patients with relapsed/refractory disease, the option of the BCL2 antagonist, venetoclax, is also available after BTK inhibitor treatment (Burger, 2020).
It is estimated that 2395 patients in the UK will be eligible for treatment with acalabrutinib each year (NICE, 2021). Approval of acalabrutinib by NICE provides greater treatment choice offering an alternative treatment with increased years of disease control. Acalabrutinib is well tolerated in patients who discontinue ibrutinib because of side effects and is also shown to be effective in patients who progressed on ibrutinib. Moreover, discontinuation rates appear to be lower with acalabrutinib when compared to ibrutinib (Lipsy and Lammana, 2020). This advancement heralds an exciting era in the management of CLL.