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Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Idelalisib is also used in a Precision Medicine approach (see Chapter 11), as it has been found to benefit cancer patients with particular mutations in their tumor cells. For example, in the UK idelalisib is recommended by NICE for the treatment of CML in patients who have received at least one previous therapy, or as first-line treatment in combination with rituximab in the presence of a 17p deletion or TP53 mutation in patients not eligible for any other therapies. It is also recommended by NICE as a monotherapy for follicular lymphoma refractory to two previous lines of treatment.
Leukemias
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
For patients with CLL who relapse, it is important to establish whether they require treatment at the time of relapse for disease related symptoms or have active disease.160 For patients with an early relapse, defined as those who relapse within 24–36 months following treatment with chemoimmunotherapy, it is reasonable to consider ibrutunib, idelalisib, venetoclax, or duvelisib; for those who relapse after being in remission for 36 months or more, re-treatment with the initial therapy or any of the targeted drugs listed above is reasonable. The long-term efficacy of ibrutinib compared with ofatumab has now been well established.169 Idelalisib is approved for second-line therapy following at least one prior therapy. The drug is effective but associated with significant toxicities, including colitis, pneumonitis, and hepatitis (Figure 28.17). Venetoclax has been found to be remarkably effective in relapsed and/or refractory disease, with responses of about 80%, including 8% complete responses, and is now licensed for patients with relapsed disease and del(17p). The principal adverse effects are neutropenia and tumor lysis syndrome, which can be mitigated by a weekly ramp-up schedule starting at a very low dose. Duvelisib is also effective and approved for all patients with relapsed/refractory disease after they have received at least two lines of prior therapy. Ofatumumab was approved in 2016 to treat relapsed/refractory patients with CLL following two lines of prior therapy.
Enzyme Kinetics and Drugs as Enzyme Inhibitors
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Chronic lymphocytic leukemia (CLL) is a cancer of the blood forming cells in the bone marrow resulting in an overproduction of B-lymphocytes that proliferate uncontrolled and crowd out normal cells. If chromosome 17 or the tumor suppressor gene 53 (TP53) bear mutations (e.g., 17p deletions; for a TP53 gene mutation analysis see Minervini et al., 2016) the prognosis is particularly poor. B-cell receptor (BCR) signaling is essential for normal B-cell development but also plays a major role in both B-cell-mediated autoimmune inflammation and B-cell malignancies (Puri et al., 2013). Inhibitors of this pathway targeting the spleen tyrosine kinase (Syk), Bruton’s tyrosine kinase (Btk), and phosphatidylinositol 3-kinase isoform p110delta (PI3Kδ) are promising treatment options. Examples are Ibrutinib as monotherapy and Idelalisib in combination with Rituximab (next scheme). These inhibitors promote apoptosis, inhibit proliferation, and also prevent CLL cells from responding to survival stimuli provided by the microenvironment. Idelalisib is a second-line drug for patients with relapsed CLL, and is also approved for the treatment of follicular B-cell non-Hodgkin lymphoma and relapsed small lymphocytic lymphoma. Ibrutinib acts by interacting with Bruton’s tyrosine kinase, whereas Idelalisib inhibits PI3Kδ (Pongas and Cheson, 2016; Greenwell et al., 2017; Barrientos, 2016). First direct in vivo measurements demonstrating inhibition of CLL cell proliferation and promotion of high rates of CLL cell death by ibrutinib have been reported by Burger et al. (2017).
Investigational treatments for chronic lymphocytic leukemia: a focus on phase 1 and 2 clinical trials
Published in Expert Opinion on Investigational Drugs, 2020
Elżbieta Iskierka-Jażdżewska, Tadeusz Robak
Idelalisib is the first, and best-characterized, oral PI3 Kδ-isoform-selective inhibitor known to promote apoptosis in primary CLL cells. It inhibits CLL cell chemotaxis toward CXCL12 and CXCL13 and migration beneath stromal cells [45]. In addition, idelalisib reduces survival signals derived from BCR or nurse-like cells, and inhibits BCR-and chemokine-receptor-induced AKT and MAP kinase (ERK) activation. Idelalisib-mediated inhibition of PI3 Kδ allows abrogation of Akt phosphorylation in patient CLL cells and significantly reduces serum levels of CLL-related chemokines. During phase 2 and 3 studies, the most important observed serious AEs were immune complications (colitis, transaminitis and colitis) [46–48]. Its unsatisfactory safety profile has led to its reduced use in CLL, although the drug has some very useful features, in particular in controlling high risk disease [49–52]. However, the subsequent phases of clinical trials assessing the efficacy and safety of idelalsib in combinations with other drugs in RR CLL and in TN CLL are ongoing (NCT02332980, NCT02968563) (Table 3).
Minimizing and managing treatment-associated complications in patients with chronic lymphocytic leukemia
Published in Expert Review of Hematology, 2020
Elżbieta Iskierka-Jażdżewska, Tadeusz Robak
The use of budesonide results in a relatively shorter time to resolution (mean time 12.1 days with range 1‐ 35 days) [76] and should be continued until complete resolution of diarrhea; however, this drug should not be used for chronic suppression of symptoms associated with ongoing use of idelalisib, and probiotics can be used as additional support [72]. Duodenal biopsies in patients with idelalisib-induced diarrhea indicated villous blunting and increased intraepithelial lymphocytes; and in such cases, a lactose-free diet may be worth consideration [51]. More seriously, in the presence of bloody diarrhea and in cases unresponsive to treatment, colonoscopy and gastroenterological referrals are recommended [72]. In patients who have interrupted idelalisib, the drug may be resumed when the patient experiences a return to basal intestinal evacuation attitudes. In this case, idelalisib should be resumed at a lower dose than that used initially (e.g. 100 mg twice daily) [72].
Therapeutic potential of PI3K signaling in distinct entities of B-cell lymphoma
Published in Expert Review of Hematology, 2019
Ramona Wullenkord, Birte Friedrichs, Tabea Erdmann, Georg Lenz
In patients with MCL response rates with PI3K inhibitors were higher compared to other aggressive lymphoma entities. A dose-escalation phase I trial of idelalisib in patients with relapsed/refractory MCL enrolled 40 patients who had previously received a median of four prior therapies (range 1–14). The ORR of these patients was 40% with two patients achieving a CR. However, median PFS and median DOR were rather short with 3.7 and 2.7 months, respectively [99]. A phase II trial of buparlisib as monotherapy in patients with aggressive lymphoma included 22 patients with MCL. The ORR of these patients was 23% with one patient achieving a CR. The median PFS was 11.3 months and the median DOR was not reached in the MCL cohort [38]. The phase II study evaluating copanlisib monotherapy in relapsed/refractory lymphoma enrolled eleven patients with MCL and demonstrated an encouraging ORR of 64% in these patients with two patients achieving a CR [48]. In contrast, the ORR of the pan-PI3K/mTOR-inhibitor voxtalisib evaluated in a non-randomized phase II trial was inferior compared to other PI3K inhibitors with only 12% in MCL patients [83].