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The Evolution of Anticancer Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Two approved anticancer agents are claimed to have been discovered through a fragment-based approach. The first is vemurafenib (ZelborafTM) that received FDA approval for the treatment of late-stage melanoma in 2011, making it the first drug developed through a fragment-based lead discovery approach to gain regulatory approval. This agent recognizes and binds to the V600E-mutated B-RAF kinase protein, a member of the B-RAF/MEK/ERK pathway, although it also has efficacy against BRAF with the less common V600K mutation. The second example is venetoclax (VenclextaTM), which was approved by the FDA in 2016 for the treatment of CLL in patients with a 17p deletion on the chromosome 17 short arm, and who have been treated with at least one prior therapy. Venetoclax is a BH3-mimetic that blocks the antiapoptotic B-cell lymphoma-2 (Bcl-2) protein, leading to the programmed cell death of CLL cells.
Overview of Therapeutic Biomarkers in Cancer
Published in Sherry X. Yang, Janet E. Dancey, Handbook of Therapeutic Biomarkers in Cancer, 2021
Sherry X. Yang, Janet E. Dancey Treatment
CD20-directed therapy is active and approved for use by FDA for the treatment of non-Hodgkin’s lymphoma and chronic lymphocytic leukemia (CLL) with anti-CD20 monoclonal antibody rituximab and recently with obinutuzumab (Chapter 18). The latter is a third-generation, fully humanized IgG1 type II anti-CD20 antibody, which is indicated in combination with chlorambucil for the treatment of previously untreated CLL. Obinutuzumab in combination with bendamustine followed by the antibody monotherapy is recently ratified for follicular lymphoma patients who relapsed after, or are refractory to, a rituximab-containing regimen. Additionally, the FDA approved BCL-2 inhibitor, venetoclax, for the treatment of CLL or small lymphocytic lymphoma (SLL), with or without 17p deletion, following a least one prior therapy. Venetoclax is also indicated in combination with rituximab for CLL/SLL.
Leukemias
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
The 2018 iwCLL and the 2020 NCCN treatment recommendations suggest that good-risk patients can be managed successfully with a “watch and wait” policy, at intervals of 1 to 3 months, and therapy should be initiated for active disease (Table 28.16).160 The outcomes for those with intermediate-, high-, or ultra-high risk of the disease have had incremental benefit from a chemoimmunotherapy combination, and additional improvements are being observed with the approval of even more effective and relatively safe therapies, such as ibrutinib, a BTK inhibitor, and idelalisib, a PI3Kδ inhibitor, for high- and ultra-high-risk patients of all age groups.161,162 Venetoclax was approved in 2018 for the treatment of patients with CLL or SLL, with or without, del(17p), following at least one prior line of treatment.
Analysis and clinical characteristics of acute myeloid leukemia developing with prior or concurrent tumors in non cyto- or radiotherapy exposure patients in a single center
Published in Hematology, 2023
Yu Lian, Juanjuan Ti, Liangming Ma, Jia Wei, Zhilin Gao
However, we also noted that more patients received HMAs + VEN than IC (65.7% vs 31.4%). Patients receiving HMAs + VEN compared with IC-based regimens had slightly lower CR rates (56.5% vs 72.7%) but experienced a trend toward improved OS. Similar results were confirmed in several other studies, and the potential reason was that HMAs + VEN may be associated with lower early mortality, higher quality of life, and more time to undergo stem cell transplantation [10,26–29]. The recent approval of venetoclax in combination with HMAs is a welcome addition to the treatment approach for AML and has improved response rates [30,31]. Venetoclax is a selective small-molecule inhibitor of B-cell lymphoma 2 protein, which is overexpressed in leukemia stem cells. Its overexpression is positively correlated with drug resistance and poor prognosis in AML [32]. Studies have shown that leukemic cells are sensitive to venetoclax, both in vitro and in vivo. Additionally, azacitidine could inhibit another anti-apoptotic protein, MCL-1, which is vital for the survival of leukemic cells and may play a crucial role in the resistance to venetoclax [33,34]. Both clinical trials and real-world clinical practice demonstrated that venetoclax with HMAs had a high response rate (60-83.3%) in older patients and newly diagnosed unfit AML patients [31,35,36]. Even for relapsed or refractory AML patients, the regimen can achieve CR/CRi rates of 32-51%. A retrospective study reported that 60% of patients with t-AML achieved CR/CRi.
An update on the efficacy of Venetoclax for chronic lymphocytic leukemia
Published in Expert Opinion on Pharmacotherapy, 2023
Alexandra R. Lovell, Jacki Sawyers, Prithviraj Bose
Other side effects that have been commonly associated with venetoclax are myelosuppression and GI toxicity. As reported, venetoclax can induce significant neutropenia in patients on long-term therapy, and the dose/duration should be interrupted and/or reduced based on the grade of neutropenia. Although neutropenia rates of any grade are seen in up to 40% of the patients, grade 3 infections are reported at an exposure-adjusted rate of 2.1 per 100 patient-months. Patients should also be supported with growth factors and prophylactic antimicrobials, while neutrophil counts are low to reduce the risk of infection. GI toxicity is seen in approximately 75% of the patients taking venetoclax, with diarrhea and nausea being the most common. Usually, the GI side effects are seen during the ramp up period and decrease over time, rarely requiring dose reductions or interruptions [45,46].
Patent landscape of inhibitors and PROTACs of the anti-apoptotic BCL-2 family proteins
Published in Expert Opinion on Therapeutic Patents, 2022
Pratik Pal, Peiyi Zhang, Saikat K. Poddar, Guangrong Zheng
The impressive clinical success of venetoclax in leukemia treatment has triggered many follow-up drug discovery and development activities, resulting in a large number of patent disclosures and advancement of nine BCL-2 selective inhibitors into clinical trials. Despite its high molecular weight and very poor water solubility, venetoclax is orally bioavailable, which reflects the tremendous amount of medicinal chemistry efforts required to achieve these reasonable drug-like properties. However, the venetoclax oral tablets require a special formulation and have limited drug loading, a significant problem with patients who need high doses. To overcome this issue, AbbVie developed a phosphate prodrug of venetoclax, ABBV-167, which has significantly increased water solubility, reduced food effect, and enhanced bioavailability in healthy volunteers compared to venetoclax [157]. The issue may not be as big with some of the newly disclosed BCL-2 inhibitors that have improved PK properties and/or increased potency, which will lower the doses needed for the therapeutic effects.