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Therapeutic potential of new B cell-targeted agents in the treatment of elderly and unfit patients with chronic lymphocytic leukemia.

Rai KR - J Hematol Oncol (2015)

Bottom Line: Anti-CD20 monoclonal antibody therapy, which overall has improved response rates and survival in patients with CLL, has only recently been evaluated elderly and unfit patients.B cell-targeted agents such as the Bruton's tyrosine kinase inhibitor ibrutinib and the phosphatidylinositol 3-kinase inhibitor idelalisib are the first of a new generation of oral agents for CLL.Available clinical data suggest that these therapies have the potential to address the unmet need in elderly and unfit patients with CLL and result in clinical remission, and not merely symptom palliation and improved quality of life, which, by themselves, are also a reasonable goal.

View Article: PubMed Central - PubMed

Affiliation: Hofstra North Shore-LIJ School of Medicine and the North Shore-LIJ Cancer Institute, Lake Success, NY, USA. krai@nshs.edu.

ABSTRACT
Chronic lymphocytic leukemia (CLL), the most common adult leukemia in the Western world, is primarily a disease of the elderly, with most patients ≥65 years of age and having at least one major comorbidity. Aggressive chemoimmunotherapy regimens recommended to achieve remission and improve survival in young, fit patients are often poorly tolerated in elderly and/or less physiologically fit ("unfit") patients, necessitating alternative treatment options. Although patient age, fitness, and comorbidities are key considerations in the selection of a treatment regimen, historically, clinical trials have been limited to young, fit patients by virtue of the ethical concerns associated with potential end organ toxic effects that could worsen comorbidities. However, the availability of new therapies promises a shift to a research paradigm that encompasses the identification of optimal treatments for elderly and unfit patients. Anti-CD20 monoclonal antibody therapy, which overall has improved response rates and survival in patients with CLL, has only recently been evaluated elderly and unfit patients. B cell-targeted agents such as the Bruton's tyrosine kinase inhibitor ibrutinib and the phosphatidylinositol 3-kinase inhibitor idelalisib are the first of a new generation of oral agents for CLL. Available clinical data suggest that these therapies have the potential to address the unmet need in elderly and unfit patients with CLL and result in clinical remission, and not merely symptom palliation and improved quality of life, which, by themselves, are also a reasonable goal.

No MeSH data available.


Related in: MedlinePlus

BCR signaling cascades in the a absence and b presence of antigen. Protein kinases are shown in red and the lipid kinase PI3Kδ in blue [38]. BCR B-cell receptor, BTK Bruton’s tyrosine kinase, Ig immunoglobulin, IKK I kappa B kinase, NF nuclear factor, NFAT nuclear factor of activated T cells P phosphorylation, PI3Kδ phosphatidylinositol 3-kinase, PKC protein kinase C, PLC phospholipase C, SYK spleen tyrosine kinase. From [38]
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Fig3: BCR signaling cascades in the a absence and b presence of antigen. Protein kinases are shown in red and the lipid kinase PI3Kδ in blue [38]. BCR B-cell receptor, BTK Bruton’s tyrosine kinase, Ig immunoglobulin, IKK I kappa B kinase, NF nuclear factor, NFAT nuclear factor of activated T cells P phosphorylation, PI3Kδ phosphatidylinositol 3-kinase, PKC protein kinase C, PLC phospholipase C, SYK spleen tyrosine kinase. From [38]

Mentions: Therapy for CLL is evolving toward targeted approaches firmly grounded in an understanding of the disease pathophysiology [34, 35]. The B-cell receptor (BCR) regulates fundamental B-cell processes, including resting homeostasis, differentiation, proliferation, and survival [36]. Ablation of the BCR leads to rapid B-cell apoptosis, suggesting that it confers a survival signal to B cells [37]. These functions of the BCR are mediated by tonic and antigen-induced signals, which are transmitted by various kinases, including Lyn kinase, spleen tyrosine kinase (SYK), phosphatidylinositol 3-kinase (PI3K), and Bruton’s tyrosine kinase (BTK), via intracellular signaling cascades (Fig. 3) [38].Fig. 3


Therapeutic potential of new B cell-targeted agents in the treatment of elderly and unfit patients with chronic lymphocytic leukemia.

Rai KR - J Hematol Oncol (2015)

BCR signaling cascades in the a absence and b presence of antigen. Protein kinases are shown in red and the lipid kinase PI3Kδ in blue [38]. BCR B-cell receptor, BTK Bruton’s tyrosine kinase, Ig immunoglobulin, IKK I kappa B kinase, NF nuclear factor, NFAT nuclear factor of activated T cells P phosphorylation, PI3Kδ phosphatidylinositol 3-kinase, PKC protein kinase C, PLC phospholipase C, SYK spleen tyrosine kinase. From [38]
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4522086&req=5

Fig3: BCR signaling cascades in the a absence and b presence of antigen. Protein kinases are shown in red and the lipid kinase PI3Kδ in blue [38]. BCR B-cell receptor, BTK Bruton’s tyrosine kinase, Ig immunoglobulin, IKK I kappa B kinase, NF nuclear factor, NFAT nuclear factor of activated T cells P phosphorylation, PI3Kδ phosphatidylinositol 3-kinase, PKC protein kinase C, PLC phospholipase C, SYK spleen tyrosine kinase. From [38]
Mentions: Therapy for CLL is evolving toward targeted approaches firmly grounded in an understanding of the disease pathophysiology [34, 35]. The B-cell receptor (BCR) regulates fundamental B-cell processes, including resting homeostasis, differentiation, proliferation, and survival [36]. Ablation of the BCR leads to rapid B-cell apoptosis, suggesting that it confers a survival signal to B cells [37]. These functions of the BCR are mediated by tonic and antigen-induced signals, which are transmitted by various kinases, including Lyn kinase, spleen tyrosine kinase (SYK), phosphatidylinositol 3-kinase (PI3K), and Bruton’s tyrosine kinase (BTK), via intracellular signaling cascades (Fig. 3) [38].Fig. 3

Bottom Line: Anti-CD20 monoclonal antibody therapy, which overall has improved response rates and survival in patients with CLL, has only recently been evaluated elderly and unfit patients.B cell-targeted agents such as the Bruton's tyrosine kinase inhibitor ibrutinib and the phosphatidylinositol 3-kinase inhibitor idelalisib are the first of a new generation of oral agents for CLL.Available clinical data suggest that these therapies have the potential to address the unmet need in elderly and unfit patients with CLL and result in clinical remission, and not merely symptom palliation and improved quality of life, which, by themselves, are also a reasonable goal.

View Article: PubMed Central - PubMed

Affiliation: Hofstra North Shore-LIJ School of Medicine and the North Shore-LIJ Cancer Institute, Lake Success, NY, USA. krai@nshs.edu.

ABSTRACT
Chronic lymphocytic leukemia (CLL), the most common adult leukemia in the Western world, is primarily a disease of the elderly, with most patients ≥65 years of age and having at least one major comorbidity. Aggressive chemoimmunotherapy regimens recommended to achieve remission and improve survival in young, fit patients are often poorly tolerated in elderly and/or less physiologically fit ("unfit") patients, necessitating alternative treatment options. Although patient age, fitness, and comorbidities are key considerations in the selection of a treatment regimen, historically, clinical trials have been limited to young, fit patients by virtue of the ethical concerns associated with potential end organ toxic effects that could worsen comorbidities. However, the availability of new therapies promises a shift to a research paradigm that encompasses the identification of optimal treatments for elderly and unfit patients. Anti-CD20 monoclonal antibody therapy, which overall has improved response rates and survival in patients with CLL, has only recently been evaluated elderly and unfit patients. B cell-targeted agents such as the Bruton's tyrosine kinase inhibitor ibrutinib and the phosphatidylinositol 3-kinase inhibitor idelalisib are the first of a new generation of oral agents for CLL. Available clinical data suggest that these therapies have the potential to address the unmet need in elderly and unfit patients with CLL and result in clinical remission, and not merely symptom palliation and improved quality of life, which, by themselves, are also a reasonable goal.

No MeSH data available.


Related in: MedlinePlus