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Anti-Cancer Drugs Acalabrutinib: Treatment For CLL/SLL/MCL
Anti-Cancer DrugsAcalabrutinib:Treatment For CLL/SLL/MCL.............................................................. 1 Acalabrutinib Backgroud................................................................................................................ 2 Acalabrutinib Reviews................................................................................................................... 3 Acalabrutinib Treatment(Used for).................................................................................................. 3 Acalabrutinib Mechanism Of Action................................................................................................4 What are the possible side effects ofAcalabrutinib?.........................................................................5 Acalabrutinib VS Ibrutinib............................................................................................................... 7 Research: Acalabrutinib On Treating Chronic lymphocytic leukemia (CLL) .....................................8 (1) Chronic lymphocytic leukemia (CLL)................................................................................. 8 (2) Preclinical Studies ofAcalabrutinib in CLL.......................................................................... 9 (3) Conclusions................................................................................................................... 10 Reference........................................................................................................................... 11
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Acalabrutinib Backgroud To date, acalabrutinib has been used in trials studying the treatment of B-All, Myelofibrosis, Ovarian Cancer, Multiple Myeloma, and Hodgkin Lymphoma, among others. As of October 31, 2017 the FDA approved Astra Zeneca’s orally administered Calquence (acalabrutinib). This Bruton Tyrosine Kinase (BTK) inhibitor indicated for the treatment of chronic lymphocytic leukemia, small lymphocytic lymphoma, and in adult patients with Mantle Cell Lymphoma (MCL) who have already received at least one prior therapy. Also known as ACP-196, acalabrutinib is also considered a second generation BTK inhibitor because it was rationally designed to be more potent and selective than ibrutinib, theoretically expected to demonstrate fewer adverse effects owing to minimized bystander effects on targets other than BTK. Nevertheless, acalabrutinib was approved under the FDA’s accelerated approval pathway, which is based upon overall response rate and faciliates earlier approval of medicines that treat serious conditions or/and that fill an unmet medical need based on a surrogate endpoint. Continued approval for acalabrutinib’s currently accepted indication may subsequently be contingent upon ongoing verification and description of clinical benefit in confimatory trials. Furthermore, the FDA granted this medication Priority Review and Breakthrough Therapy designations. It also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases. At this time, more than 35 clinical trials across 40 countries with more than 2500 patients are underway or have been completed with regards to further research 2
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into better understanding and expanding the therapeutic uses of acalabrutinib 5.
Acalabrutinib Reviews Acalabrutinib (CAS:1420477-60-6), which is marketed under the tradename of Calquence® in the U.S. and Canada, is a second-generation small molecule inhibitor of Bruton’s tyrosine kinase (BTK). Upon oral administration, acalabrutinib binds to and irreversibly inhibits the activity of BTK which prevents both B-cell activation and B-cell-mediated signaling. This action leads to an inhibition of the growth of malignant B cells that overexpress BTK. BTK is required for B-cell signaling, plays a key role in B-cell maturation, and is overexpressed in a number of B-cell malignancies, including CLL/SLL. The expression of BTK in tumor cells is associated with increased proliferation and survival. As a second-generation BTK inhibitor, acalabrutinib was designed to maximize the effect on BTK and minimize off-target activity on TEC (Tec Protein Tyrosine Kinase), EGFR (epidermal growth factor receptor), and ITK (interleukin-2-inducible T-cell kinase). The first generation BTK inhibitor, ibrutinib (Imbruvica), lacks this specificity which results in a higher incidence of adverse effects. In addition to CLL/SLL, acalabrutinib is approved for Mantle Cell Lymphoma (MCL). The National Cancer Center Network (NCCN) Guidelines list acalabrutinib with or without obinituzumab as first line therapy for CLL/SLL as well as appropriate for use in relapsed or refractory (R/R) CLL.
Acalabrutinib Treatment(Used for) Acalabrutinib is used to treat people with mantle cell lymphoma (MCL; a fast-growing cancer that begins in the cells of the immune system) who have already been treated with at least one other chemotherapy medication. 3
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Acalabrutinib is used alone or with obinutuzumab (Gazyva) to treat chronic lymphocytic leukemia (CLL; a type of cancer that begins in the white blood cells) and small lymphocytic lymphoma (SLL: a type of cancer that begins in the white blood cells). Acalabrutinib is in a class of medications called kinase inhibitors. It works by blocking the action of the abnormal protein that signals cancer cells to multiply. This helps stop the spread of cancer cells.
Acalabrutinib Mechanism Of Action Mantle Cell Lymphoma (MCL) is a rare yet aggressive type of B-cell non-Hodgkin lymphoma (NHL) with poor prognosis. Subsequently, relapse is common in MCL patients and ultimately represents disease progression. Lymphoma occurs when immune system lymphocytes grow and multiply uncontrollably. Such cancerous lymphocytes may travel to many parts of the body, including the lymph nodes, spleen, bone marrow, blood, and other organs where they can multiply and form a mass(es) called a tumor. One of the main kinds of lymphocytes that can develop into cancerous lymphomas are the body’s own B-lymphocytes (B-cells). Bruton Tyrosine Kinase (BTK) is a signalling molecule of the B-cell antigen receptor and cytokine receptor pathways. Such BTK signaling causes the activation of pathways necessary for B-cell proliferation, trafficking, chemotaxis, and adhesion. Acalabrutinib is a small molecule inhibitor of BTK. Both acalabrutinib and its active metabolite, ACP-5862, act to form a covalent bond with a cysteine residue (Cys481) in the BTK active site, leading to inhibition of BTK enzymatic activity.As a result, acalabrutinib inhibits BTK-mediated activation of downstream signaling proteins CD86 and 4
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CD69, which ultimately inhibits malignant B-cell proliferation and survival. Whereas ibrutinib is typically recognized as the first-in-class BTK inhibitor,acalabrutinib is considered a second generation BTK inhibitor primarily because it demonstrates highter selectivity and inhibition of the targeted activity of BTK while having a much greater IC50 or otherwise virtually no inhibition on the kinase activities of ITK, EGFR, ERBB2, ERBB4, JAK3, BLK, FGR, FYN, HCK, LCK, LYN, SRC, and YES1. In effect, acalabrutinib was rationally designed to be more potent and selective than ibrutinib, all the while demonstrating fewer adverse effects – in theory – because of the drug’s minimized off target effects.
What are the possible side effects of Acalabrutinib? Acalabrutinib may cause serious side effects, including: Serious infections can happen during treatment with Acalabrutinib and may lead to death. Your healthcare provider may prescribe certain medicines if you have an increased risk of getting infections. Tell your healthcare provider right away if you have any signs or symptoms of an infection, including fever, chills, or flu-like symptoms. Bleeding problems (hemorrhage) can happen during treatment with Acalabrutinib and can be serious and may lead to death. Your risk of bleeding may increase if you are also taking a blood thinner medicine. Tell your healthcare provider if you have any signs or symptoms of bleeding, including blood in your stools or black stools (looks like tar), pink or brown urine, unexpected bleeding or bleeding that is severe or you cannot control, vomit blood or vomit that looks like coffee grounds, cough up blood or blood clots, dizziness, weakness, confusion, 5
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changes in your speech, headache that lasts a long time, or bruising or red or purple skin marks Decrease in blood cell counts. Decreased blood counts (white blood cells, platelets, and red blood cells) are common with Acalabrutinib, but can also be severe. Your healthcare provider should do blood tests to check your blood counts regularly during treatment with Acalabrutinib. Second primary cancers. New cancers have happened in people during treatment with Acalabrutinib, including cancers of the skin or other organs. Your healthcare provider will check you for skin cancers during treatment with Acalabrutinib. Use sun protection when you are outside in sunlight. Heart rhythm problems (atrial fibrillation and atrial flutter) have happened in people treated with Acalabrutinib. Tell your healthcare provider if you have any of the following signs or symptoms: fast or irregular heartbeat, dizziness, feeling faint, chest discomfort, or shortness of breath The most common side effects of Acalabrutinib include headache, diarrhea, muscle and joint pain, upper respiratory tract infection, and bruising. These are not all the possible side effects of Acalabrutinib. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
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Acalabrutinib VS Ibrutinib BTK plays a key role in the B-cell receptor signaling pathway; acalabrutinib binds irreversibly to BTK and inhibits its activity. The drug was designed as a potentially more selective BTK inhibitor, in an attempt to mitigate some of the treatment-limiting toxicities often seen with ibrutinib. According to Dr. Brown, “Acalabrutinib is the BTK inhibitor of choice for people with comorbidities, particularly cardiac issues.” The efficacy data look similar between acalabrutinib and ibrutinib, although follow-up is longer with ibrutinib, Dr. Brown continued. 7
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Therefore, the key difference between the drugs lies in their side-effect profiles. Ibrutinib tends to be more poorly tolerated in older patients and is associated with high rates of atrial fibrillation and hypertension. “Acalabrutinib is much better-tolerated [than ibrutinib], so I use it preferentially, particularly in my older patients,” she said. The drug’s approval in CLL, granted in November 2019, was based on safety and efficacy data from interim analyses of the ELEVATE-TN trial of patients with previously untreated CLL and the ASCEND trial of patients with relapsed or refractory CLL.In both trials, acalabrutinib demonstrated superior progression-free survival compared with standard therapy, and a favorable tolerability profile. In the ELEVATE-TN trial, specifically, acalabrutinib combined with obinutuzumab and as monotherapy reduced the risk of disease progression or death by 90% and 80%, respectively. “Tolerability remains an issue in the current treatment landscape of CLL, which may require ongoing therapy for many years,” stated Jeff Sharman, MD, Director of Research at Willamette Valley Cancer Institute, Medical Director of Hematology Research for The US Oncology Network, and lead author of the ELEVATE-TN trial, in a press release. “In the ELEVATE-TN and ASCEND trials comparing [acalabrutinib] to commonly used treatment regimens, [acalabrutinib] demonstrated a clinically meaningful improvement in progression-free survival in patients across multiple settings, while maintaining its favorable tolerability and safety profile.”
Research: Acalabrutinib On Treating Chronic lymphocytic leukemia (CLL) (1) Chronic lymphocytic leukemia (CLL)
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Chronic lymphocytic leukemia (CLL), the most common adult leukemia, is a clonal neoplasm composed of monomorphic small mature B cells that coexpress CD5 and CD23. The landscape of treatment of CLL has changed dramatically in recent years. Drugs targeting proteins in the B cell antigen receptor (BCR) pathway, such as ibrutinib, have demonstrated improvement in progression free and overall survival, including in patients with high-risk disease. Although these drugs have revolutionized the treatment paradigm in patients with CLL, treatment exposure and intensity with ibrutinib can be limited due to the side-effect profile and treatment-related toxicities. Acalabrutinib, a second generation and more selective Bruton’s tyrosine kinase (BTK) inhibitor, was developed to maximize efficacy while minimizing ibrutinib-associated adverse events hypothesized to be secondary to ibrutinib’s off-target effects. This review will summarize the development, pre-clinical evaluation, and key clinical trials that have demonstrated acalabrutinib’s efficacy and toxicity profile in CLL.
(2) Preclinical Studies of Acalabrutinib in CLL
Several preclinical studies demonstrated the efficacy of acalabrutinib on BTK inhibition. When tested on human whole blood, acalabrutinib had equipotent BTK inhibition as compared to ibrutinib. Ibrutinib was found to cause increased apoptosis of CLL cells as compared to acalabrutinib, which could be explained by the off-target effects of ibrutinib. Acalabrutinib had less of an effect on healthy T cells likely due to its selectivity compared to ibrutinib. The anti-tumor effects of acalabrutinib were evaluated in two murine CLL models: a TCL1 adoptive transfer model and a xenografted human CLL model. Acalabrutinib was demonstrated to inhibit BCR signaling and treatment with acalabrutinib was associated with a significant increase in survival compared with untreated mice (median 81 days vs 59 days, p = 0.02). Acalabrutinib also caused a significant reduction in proliferating cells and total tumor burden in the spleen.
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Acalabrutinib’s interaction with anti-CD20 monoclonal antibodies has also been evaluated. Ibrutinib may interfere with several of the mechanisms of action of the anti-CD20 antibodies specifically inhibiting antibody-dependent cellular cytotoxicity and phagocytosis which may decrease their anti-tumor effect.Golay et al evaluated the effects of acalabrutinib on antibody-dependent cellular cytotoxicity and phagocytosis and found that it did not interfere with these processes, likely due to the minimal off-target effects of acalabrutinib.Although the combination of acalabrutinib with an anti-CD20 monoclonal antibody has not been study in an in vivo model, several phase 2 and phase 3 studies are ongoing or have been completed that demonstrate the efficacy of acalabrutinib in combination with an anti-CD20 monoclonal antibody. Other acalabrutinib combinations have been studied in both in vitro and in vivo models. Acalabrutinib was combined with a PI3Kdelta inhibitor (ACP-319) in a murine CLL model and demonstrated greater reduction in tumor proliferation, NF-KB signaling and expression of BCL-xL and MCL-1 as compared to monotherapy.Blood samples obtained from CLL patients not enrolled in a clinical trial were treated with acalabrutinib and venetoclax.This combination was demonstrated to have increased apoptosis when compared to either drug alone, suggesting a synergistic relationship similar to that seen with ibrutinib and venetoclax. A subsequent in vivo experiment demonstrated prolonged survival in mice treated with both acalabrutinib and venetoclax as compared to either drug alone.
(3) Conclusions
In summary, the studies described demonstrate that acalabrutinib has significant efficacy in treatment of CLL, both treatment naïve and relapsed refractory. It is unclear whether the efficacy is equivalent or superior to ibrutinib and studies are ongoing in an attempt to further compare these agents. Although classic BTK-associated toxicities such as bleeding or atrial fibrillation events are relatively infrequent events, acalabrutinib does have a unique AE profile, particularly headache, which require careful monitoring and expertise in management. Data from ongoing studies evaluating combinations 10
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with acalabrutinib will help to further define its role in the management of CLL. Finally, with FDA approval, real-world experience with acalabrutinib will help to further define the toxicity profile.
Reference [1] U.S. Food and Drug Administration. Project Orbis: FDA approves acalabrutinib for CLL and SLL. Available at https://www.fda.gov/drugs/resources-information-approved-drugs/proj ect-orbis-fda-approves-acalabrutinib-cll-and-sll. Accessed April 29, 2020. [2] Sharman JP, Banerji V, Fogliatto LM, et al. ELEVATE-TN: Phase 3 study of acalabrutinib combined with obinutuzumab or alone vs obinutuzumab plus chlorambucil in patients with treatment-naive chronic lymphocytic leukemia. Blood 2019;134(suppl 1):31. [3] AstraZeneca Press Release. Calquence approved in the US for adult patients with chronic lymphocytic leukaemia. Available at https://www.astrazeneca.com/media-centre/press-releases/2019/calq uence-approved-in-the-us-for-adult-patients-with-chronic-lymphocytic -leukaemia-21112019.html. Accessed April 29, 2020. [4] Goede V, Fischer K, Busch R, et al. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med. 2014;370(12):1101–1110. doi:10.1056/NEJMoa1313984. [5] Parikh SA, Muchtar E, Laplant B, et al. A randomized phase 2 study comparing acalabrutinib with or without obinutuzumab in the treatment of early stage high risk patients with Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL). Blood. 2019;134(Supplement_1):4306. doi:10.1182/blood-2019-123824. [6] Covey T, Gulranjani M, Cheung J, et al. Pharmacodynamic evaluation of acalabrutinib in relapsed/refractory and treatment-naive 11
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patients with Chronic Lymphocytic Leukemia (CLL) in the phase 1/2 ACE-CL-001 Study. Blood. 2017;130(Supplement1):1741. doi:10.1182/blood.V130.Suppl_1.1741.1741. [7] Byrd JC, Brown JR, O’Brien S, et al. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med. 2014;371(3):213–223. doi:10.1056/NEJMoa1400376. [8] Woyach JA, Bojnik E, Ruppert AS, et al. Bruton’s tyrosine kinase (BTK) function is important to the development and expansion of chronic lymphocytic leukemia (CLL). Blood. 2014;123(8):1207–1213. doi:10.1182/blood-2013-07-515361. [9] Chiorazzi N, Rai KR, Ferrarini M. Chronic lymphocytic leukemia. N Engl J Med. 2005;352(8):804–815. doi:10.1056/NEJMra041720. [10] Barr PM, Robak T, Owen C, et al. Sustained efficacy and detailed clinical follow-up of first-line ibrutinib treatment in older patients with chronic lymphocytic leukemia: extended phase 3 results from RESONATE-2. Haematologica. 2018;103(9):1502–1510. doi:10.3324/haematol.2018.192328. [11] Herman SEM, Montraveta A, Niemann CU, et al. The Bruton Tyrosine Kinase (BTK) inhibitor ACP-196 demonstrates clinical activity in two mouse models of chronic lymphocytic leukemia. Blood. 2015;126(23):2920. doi:10.1182/blood.V126.23.2920.2920.
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