Acalabrutinib in management of chronic lymphocytic leukemia: An Indian perspective

Abstract The treatment landscape of chronic lymphocytic leukemia (CLL) has witnessed immense changes in the past decade. Several newer target therapies and their combinations with anti‐CD 20 therapies have got approval for management of CLL in the treatment‐naïve and relapsed/refractory setting. Also, the availability of newer diagnostic techniques has helped differentiate the disease into high‐ and low‐risk CLL which acts not just as a prognostic marker but also helps decide the best drug management that can be administered to the patients. Targeted therapy has largely overtaken chemoimmunotherapy in the management of CLL, except for a small subset of the population (young and fit with IGHV mutation). However, with targeted therapy, there is also an issue of previously uncommon treatment‐emergent adverse events, the duration of therapy, and financial toxicity. The aim of this review article is to gather results from all landmark CLL trials and discuss the feasibility of incorporating Acalabrutinib in the CLL landscape from an Indian perspective.


INTRODUCTION
The CLL predominantly affects older individuals, the median age of diagnosis is 72 years old [1]. CLL rates are higher in Western Europe and North America compared to Asia, where the incidence is generally low.
The incidence of CLL in India is 0.41 per 100,000, approximately 10 times lower than the United States [2]. As per International Workshop on CLL (iwCLL) recommendations, diagnosing CLL requires the presence of ≥5 × 10 9 /L B-lymphocytes in the peripheral blood, sustained for at least 3 months. The clonality of these B-lymphocytes should be demonstrated by immunoglobulin light chain restriction using flow cytometry [3].
CLL is characterized by proliferation as well as accumulation of small, mature-appearing monoclonal CD5 + B cells that express CD5, CD19, CD23, and CD20 (low), and exhibit immunoglobulin light-chain restriction (kappa or lambda).
Patients with deletion of the short arm of chromosome 17, that is, del(17p), found in 5% to 8% of treatment naïve patients and in higher rates in relapsed/refractory patients, have shorter survival than patients with normal cytogenetics [4]. Del(17p) usually includes TP53, a prominent tumor suppressor gene, and is associated with poor response to chemotherapy-immunotherapy regimens [5].

FIRST-LINE CLL TREATMENT PARADIGM
In the 2000s, chemoimmunotherapies (CITs) transformed the CLL treatment landscape, becoming the preferred approach for the firstline treatment of CLL. However, individuals with TP53/del(17p) mutation do not respond well to chemotherapy-containing regimens leaving an unmet need in this and other high-risk populations (unmutated IGHV) defined in the chemotherapy era [11]. Therapies targeting PI3K, BTK, and BCL-2, alone and/or in combination with anti-CD20 antibodies, are driving innovations in the current landscape, providing increased efficacy and safety in the first-line treatment of high-risk patients. Results are shown in Table 2 (for chemotherapy) and Table 3 (for targeted therapy).

RELAPSED/REFRACTORY CLL TREATMENT PARADIGM
Relapsed/refractory CLL is more aggressive than the treatmentnaïve counterpart and more resistant to chemoimmunotherapy partly because of higher rates of del17p and other mutations due to clonal evolution [19]. It is therefore necessary for patients to be re-tested and check if the mutation profile has changed. In the past decade, manage- Combination regimens -Fludarabine, cyclophosphamide, and rituximab -Bendamustine and rituximab -Acalabrutinib and obinutuzumab -Venetoclax and obinutuzumab -Venetoclax and rituximab -Chlorambucil and obinutuzumab -Chlorambucil and rituximab -Ibrutinib and rituximab -Ibrutinib and obinutuzumab -Idelalisib and rituximab -High-dose methylprednisolone and rituximab -Fludarabine, cyclophosphamide, and ofatumumab -Lenalidomide a and rituximab Abbreviations: BTK, Bruton's tyrosine kinase; CD, cluster of differentiation; PI3K, phosphoinositide 3-kinase. a Classified as an immunomodulatory agent. ment of relapsed/refractory CLL has shifted to BTK inhibitors and BCL-2 inhibitors. Table 4 shows efficacy results for the two clinical trials in relapsed/refractory setting.

ACALABRUTINIB
BTK is a non-receptor protein tyrosine kinase that plays a critical role in B-cell development, differentiation, signaling, proliferation, and survival. It is a key component of the BCR signaling pathway and also functions in the TLR, G protein-coupled chemokine receptor, B-cell adhesion, and migration signaling pathways ( Figure 1) [23].
Acalabrutinib and its active metabolite, ACP-5862, inhibit BTK enzymatic activity irreversibly by covalently binding a cysteine residue in the BT active site. This inhibits BTK-mediated activation of downstream signaling proteins CD86 and CD 69 as well as malignant Bcell proliferation and survival. Acalabrutinib has been shown to be more selective than ibrutinib and is hence considered a safer option for patients requiring treatment in CLL [24]. In an in vivo IC 50 kinase inhibition study [25], the affinity for BTK was highest among the enzymes tested in the panel (Table 5). Acalabrutinib IC 50 concentrations for ITK (tyrosine-protein kinase) and EGFR (epidermal growth factor receptor) were more than 200-fold higher (less inhibition) than for BTK. in prespecified subgroups (including high-risk) was improved with acalabrutinib monotherapy. Even though the median duration of exposure was longest in the acalabrutinib arm, adverse events (including serious adverse events were reported more frequently in the I-R treatment arm than acalabrutinib monotherapy or B-R treatment arm. A retrospective analysis (January 2013 to October 2015) of 447 adult patients on CLL on ibrutinib revealed high rates of drug discontinuation [28]. At a median follow-up of 20 months, roughly 50% of the study population had discontinued ibrutinib. Twenty-three percent discontinued ibrutinib due to toxicity, the remaining discontinuing due to disease progression, death, or other reasons.
At a median follow-up of 23 months, there were still 48 patients on study. Although all patients discontinued prior ibrutinib due to adverse events, only 12% discontinued acalabrutinib due to adverse events after 23 months of follow-up. An overall response rate of 72% (5% CR rate) was observed in this population. Acalabrutinib, therefore, is a viable option for patients who discontinue ibrutinib due to its toxicity.
In a phase I/II study of acalabrutinib in relapsed/refractory CLL, at 42 months of follow-up, adverse events of all grades occurring in ≥10% of patients receiving acalabrutinib; generally, these were diarrhea (52%), headache (51%), upper respiratory tract infection (37%), and fatigue (34%). The adverse events were mostly mild to moderate in severity and mostly self-limiting [30].

INDIAN PERSPECTIVE
From the above data, it is evident that the majority of CLL patients ben-  Cardiac toxicity is a major problem with first-generation BTK inhibitor.
In LMIC, there is an increasing trend of developing life-style diseases and in fact cardiovascular diseases are even now more numerous in India and China than in all the economically developed countries in the world put together. Therefore, second-generation BTK inhibitors may have a bigger role to play in these countries.

CONCLUSION
In this review article, we have discussed in detail the pathophysiology of CLL, the clinical staging systems, the key studies that have helped shape the treatment paradigm of CLL in the treatment-naïve and relapsed/refractory setting. For more than half a century, chemotherapy was the treatment of choice for all CLL patients with an active disease. With the introduction of newer agents, the use of chemotherapy has declined significantly, except in the small proportion of young and fit patients with low-risk CLL (IGHV mutated) where FCR regimen has shown remissions of 10 years or more. Newer and more selective agents have drastically improved the quality of life in patients with CLL, especially those with high-risk CLL. Even though the BTK inhibitors (ibrutinib and acalabrutinib) generally do not induce a deep remission early on, significant survival advantage especially in terms of progression-free has been noted when compared to the standard of treatment when they are continued till disease progression or development of treatment-related adverse events. Although there have been no head-to-head trials, acalabrutinib, being a more selective inhibitor of BTK is considered safer and might lead to lesser adverse events and fewer discontinuations over the long term. In the two landmark trials of Acalabrutinib in the first-line and relapsed/refractory setting (ELEVATE-TN and ASCEND), it was observed to be more efficacious and safer than comparators as a monotherapy or in combination with an anti-CD 20 inhibitor. Finite therapy has been established by the addition of venetoclax in combination with anti-CD 20 antibody. However, more mature data is needed to know whether finite treatment with BCL-2 inhibitor or indefinite treatment with BTK inhibitors is advantageous in terms of long-term survival. Finally, we discussed how to implement acalabrutinib in an Indian setting.

CONFLICT OF INTEREST
Pranav Sopory is an employee of AstraZeneca Pharma India Ltd.