China
Africa
Explore chapters and articles related to this topic
The Contribution of Pets to Human and Veterinary Medicine
Published in Rebecca A. Krimins, Learning from Disease in Pets, 2020
Acalabrutinib is a Bruton’s tyrosine kinase inhibitor approved by the FDA in 2017 to treat mantle cell lymphoma and in 2019 received supplemental approval for the treatment of chronic lymphocytic leukemia and small lymphocytic leukemia in human patients. Studies performed in dogs with naturally occurring cancer supported research which aided the approval of this drug for human disease. Clinical benefit was observed in 30% (6/20) of dogs. These findings suggested that Acalabrutinib exhibited activity in canine B-cell lymphoma patients, was efficacious and supported the use of canine lymphoma as a relevant model for human non-Hodgkin lymphoma (NHL) (Harrington et al. 2016). Acalabrutinib was developed by Acerta Pharma which was acquired by AstraZeneca in 2016.
Leukemias
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
Following the success of ibrutinib and venetoclax inhibitors in high- and ultra-high-risk patients, particularly those with mutated TP53 clones, research is assessing not only the earlier use of these agents in an effort to prevent the emergence of chemorefractory disease but also their use in combination regimens; venetoclax is being tested in patients receiving bendamustine initially, followed by a combination of obinutuzumab and venetoclax. The interim results of this study are impressive, with an overall response rate of 97%, and 89% MRD negative. Studies are also assessing venetoclax-based combinations with other anti-CD20 antibodies and with/without ibrutinib. There is also renewed interest in navitoclax, another BCL2 inhibitor, which is more active against BCL-xL, as opposed to venetoclax, which is more potent against BCL2. Other candidate investigational approaches include acalabrutinib, a second-generation BTK inhibitor, alisertib (MLN8237), an aurora A kinase inhibitor, and several forms of immunotherapy. Acalabrutinib appears to have a better BTK occupancy compared with ibrutinib, and it will be of interest to determine whether this reduces the emergence of resistance. SYK inhibitors, such as fostamatinib and entospletinib, remain in clinical trials at present, with impressive results so far. The immunotherapy efforts include several monoclonal antibodies, such as lumiliximab (anti-CD23), epratuzumab (anti-CD22), and apolizumab (anti-HLA-DR), IDEC-114 (anti-CD80), immune-modulatory drugs, such as lenalidomide, and adoptive immunotherapy using CD19-specific CAR T-cells in patients who progress on ibrutinib. There has also been much interest in the use of immune checkpoint inhibitors, but the results of these Phase I/II studies have not been encouraging so far.
Leukaemias of Mature B- and T/NK-Cells
Published in Tariq I. Mughal, Precision Haematological Cancer Medicine, 2018
This has now changed with the deciphering of some of the underlying genetic complexity, and licensing of novel targeted drugs which have been tested against proteins in key pathways in B-cell lymphoid malignancies and found to be effective and safe. Much of this has been accomplished at an astonishing pace over the past 5 years, resulting in a fundamental change in the management and indeed outcome for CLL. Both ibrutinib, a potent BTK inhibitor and mediator of microenvironment, and idelalisib, a PI3Kδ inhibitor, are now licensed for the first-line treatment of patients considered to have ‘ultra-high-risk’ disease, as defined by the presence of del(17p) or TP53 mutation, and also for relapsed or refractory CLL (Figures 9.14 and 9.15). Sadly, despite the initial high responses observed, resistance is being increasingly reported. In this regard, it is important to recognize that both the critical role of the BCR signalling in the proliferation and survival of CLL cells through diverse protein kinases, such as BTK, PI3Kδ and spleen tyrosine kinase (SYK), as well as the precise mechanisms of acquired resistance remains an enigma (Figure 9.16). Unique toxicities are also being increasingly recognized. Ibrutinib can result in bleeding and atrial fibrillation, as a consequence of an off-target effect of inhibiting TEC kinase, and rash, as a result of EGFR inhibition. The next-generation BTK inhibitor, acalabrutinib, has been rationally designed to reduce such effects and ongoing studies confirm the drug’s efficacy in CLL; acalabrutinib is currently licensed for patients with mantle cell lymphoma, but not CLL. Both ibrutinib and acalabrutinib have also been found to have antithrombotic properties, whilst sparing haemostasis, and could potentially be useful in inhibiting atherosclerotic plaque–triggered thrombus. Another novel drug, venetoclax (ABT-199), a potent inhibitor of BCL2, which is considerably less thrombocytopenic, though more neutropenic, than navitoclax, a BCL2 and BCL-xL inhibitor, and has shown response rates of 71–79% and a 15-month rate of progression-free survival of 69% in a heavily pretreated high and ultra-high-risk group of patients with CLL, and in June 2018, was licensed for the treatment of patients with CLL or SLL with, or without, del(17p), following at least one prior line of treatment.
Approved and emerging Bruton’s tyrosine kinase inhibitors for the treatment of chronic lymphocytic leukemia
Published in Expert Opinion on Pharmacotherapy, 2022
Alycia Hatashima, Mehdi Karami, Mazyar Shadman
Headache is a notable adverse effect commonly associated with acalabrutinib. Pooled safety data of patients treated with acalabrutinib monotherapy revealed that 38% of patients experienced headaches, of which 97% were grade 1 or 2 [56]. Low rates of grade ≥3 headaches were also reported in the ELEVATE-RR trial at less than 2% [49]. Phase II and III trials of acalabrutinib in CLL patients reported any grade headaches in 51%, 37%, and 35% of patients, respectively [22,49,57]. Patients most often experience headaches during the first 3 weeks of treatment which subsequently resolve with continuation of therapy. The etiology of acalabrutinib-induced headaches is not well understood but may be related to agonism of calcitonin gene-related peptide, a target of a new class of migraine medications [56].
Identifying aggressive subsets within diffuse large B-cell lymphoma: implications for treatment approach
Published in Expert Review of Anticancer Therapy, 2022
Timothy J Voorhees, Narendranath Epperla
Despite negative studies evaluating ibrutinib + R-CHOP in front-line treatment of DLBCL, some signal for potential clinical benefit remained in those less than 60 years which has led some to speculate that cardiovascular toxicity of ibrutinib may have limited a potential clinical benefit. Acalabrutinib, a second generation BTKi with more favorable safety profile compared to ibrutinib, is being studied in combination with R-CHOP in a randomized phase II study of patients with DLBCL (REMoDL-A, NCT04546620). Tumor samples will be molecularly characterized, but treatment will not be dependent on molecular findings. Similarly, zanubrutinib is also being studied in combination with R-CHOP for front-line therapy of DLBCL in a phase Ib design (NCT04850495). Additionally, a modified approach is currently under investigation in which an 14 day treatment window of daily acalabrutinib prior to R-chemotherapy. Any patients who have ≥25% reduction of the target lesions with acalabrutinib therapy proceed to rituximab based chemoimmunotherapy with concurrent acalabrutinib on days 1–10 of the 21 day cycle (NCT04002947). All patients with <25% reduction of target lesions move on to chemoimmunotherapy alone [78].
Drug repurposing strategies and key challenges for COVID-19 management
Published in Journal of Drug Targeting, 2022
Shubham Mule, Ajit Singh, Khaled Greish, Amirhossein Sahebkar, Prashant Kesharwani, Rahul Shukla
Acalabrutinib is a commonly prescribed oral immunosuppressant for non-Hodgkin lymphoma. Acalabrutinib suppresses cytokine storm by blocking’Bruton's tyrosine kinase stimulation pathway; therefore, a drop in IL-6 and C-reactive protein, along with increased neutrophils, results in an anti-inflammatory response against COVID-19 [149]. ’straZeneca's Calquence (acalabrutinib) was evaluated on 19 COVID-19 patients. It was primarily intended to treat severe lymphocytic mantle cell lymphoma (MCL) and cell lymphoma leukaemia (CLL). The CT indicated that the medication had a major part in improving the breathing problems of patients with SARS-CoV 2 without any undesirable profile, while on a 10–14 days dosage regimen of acalabrutinib, 82% of patient’s demonstrated deletion of artificial ventilation and supporting oxygen.