Current status of phosphoinotiside-3 kinase inhibitors in blood cancers

Shouse, Geoffrey; Danilova, Olga V.; Danilov, Alexey V.

doi:10.1097/cco.0000000000000871

Cited by 10 publications

(4 citation statements)

References 43 publications

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“…PI3K inhibitors inhibit the δ isoform of PI3K, an effective treatment strategy for patients with indolent B-cell lymphomas. Idelalisib (a δ isoform inhibitor) and duvelisib (a δ and γ isoform inhibitor) are approved for the treatment of CLL . PI3K inhibitors are associated with higher rates of all infections and several immune-mediated adverse events.…”

Section: Discussionmentioning

confidence: 99%

“…Idelalisib (a δ isoform inhibitor) and duvelisib (a δ and γ isoform inhibitor) are approvedforthetreatmentofCLL. 59 PI3Kinhibitorsareassociatedwith higher rates of all infections and several immune-mediated adverse events. Patients taking idelalisib should be monitored every month for elevated liver enzyme levels (39%), pneumonitis (cough, dyspnea, and hypoxemia)(5.5%),diarrhea(29%),andcolitis(4.5%).…”

Section: Inhibitors Of the Bcr Pathwaymentioning

confidence: 99%

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Diagnosis and Treatment of Chronic Lymphocytic Leukemia

Shadman

2023

JAMA

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ImportanceChronic lymphocytic leukemia (CLL), defined by a minimum of 5 × 109/L monoclonal B cells in the blood, affects more than 200 000 people and is associated with approximately 4410 deaths in the US annually. CLL is associated with an immunocompromised state and an increased rate of complications from infections.ObservationsAt the time of diagnosis, the median age of patients with CLL is 70 years, and an estimated 95% of patients have at least 1 medical comorbidity. Approximately 70% to 80% of patients with CLL are asymptomatic at the time of diagnosis, and one-third will never require treatment for CLL. Prognostic models have been developed to estimate the time to first treatment and the overall survival, but for patients who are asymptomatic, irrespective of disease risk category, clinical observation is the standard of care. Patients with symptomatic disease who have bulky or progressive lymphadenopathy or hepatosplenomegaly and those with a low neutrophil count, anemia, or thrombocytopenia and/or symptoms of fever, drenching night sweats, and weight loss (B symptoms) should be offered treatment. For these patients, first-line treatment consists of a regimen containing either a covalent Bruton tyrosine kinase (BTK) inhibitor (acalabrutinib, zanubrutinib, or ibrutinib) or a B-cell leukemia/lymphoma 2 (BCL2) inhibitor (venetoclax). There is no evidence that starting either class before the other improves outcomes. The covalent BTK inhibitors are typically used indefinitely. Survival rates are approximately 88% at 4 years for acalabrutinib, 94% at 2 years for zanubrutinib, and 78% at 7 years for ibrutinib. Venetoclax is prescribed in combination with obinutuzumab, a monoclonal anti-CD20 antibody, in first-line treatment for 1 year (overall survival, 82% at 5-year follow-up). A noncovalent BTK inhibitor, pitobrutinib, has shown an overall response rate of more than 70% after failure of covalent BTK inhibitors and venetoclax. Phosphoinositide 3′-kinase (PI3K) inhibitors (idelalisib and duvelisib) can be prescribed for disease that progresses with BTK inhibitors and venetoclax, but patients require close monitoring for adverse events such as autoimmune conditions and infections. In patients with multiple relapses, chimeric antigen receptor T-cell (CAR-T) therapy with lisocabtagene maraleucel was associated with a 45% complete response rate. The only potential cure for CLL is allogeneic hematopoietic cell transplant, which remains an option after use of targeted agents.Conclusions and RelevanceMore than 200 000 people in the US are living with a CLL diagnosis, and CLL causes approximately 4410 deaths each year in the US. Approximately two-thirds of patients eventually need treatment. Highly effective novel targeted agents include BTK inhibitors such as acalabrutinib, zanubrutinib, ibrutinib, and pirtobrutinib or BCL2 inhibitors such as venetoclax.

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Section: Discussionmentioning

confidence: 99%

Section: Inhibitors Of the Bcr Pathwaymentioning

confidence: 99%

Diagnosis and Treatment of Chronic Lymphocytic Leukemia

Shadman

2023

JAMA

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“…Hypertension does not appear to be class effect of all PI3Ki. 131,137 Isoform specificity of certain PI3K inhibitors, such as idelaslisib, umbralisib, duvelisib, parsaclisib, 138 and dactolisib, 139 have resulted in a different adverse effect profile with lower overall rates of hypertension, 131 compared with pan-PI3Ki copanlisib. 140,141 This difference may also be in part attributed to drug delivery method (intermittent intravenous infusion opposed to regular oral dosing).…”

Section: Clinical and Epidemiological Evidence For Pi3ki-induced Hype...mentioning

confidence: 99%

Established and Emerging Cancer Therapies and Cardiovascular System: Focus on Hypertension—Mechanisms and Mitigation

et al. 2023

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Cardiovascular disease and cancer are 2 of the leading causes of death worldwide. Although improvements in outcomes have been noted for both disease entities, the success of cancer therapies has come at the cost of at times very impactful adverse events such as cardiovascular events. Hypertension has been noted as both, a side effect as well as a risk factor for the cardiotoxicity of cancer therapies. Some of these dynamics are in keeping with the role of hypertension as a cardiovascular risk factor not only for heart failure, but also for the development of coronary and cerebrovascular disease, and kidney disease and its association with a higher morbidity and mortality overall. Other aspects such as the molecular mechanisms underlying the amplification of acute and long-term cardiotoxicity risk of anthracyclines and increase in blood pressure with various cancer therapeutics remain to be elucidated. In this review, we cover the latest clinical data regarding the risk of hypertension across a spectrum of novel anticancer therapies as well as the underlying known or postulated pathophysiological mechanisms. Furthermore, we review the acute and long-term implications for the amplification of the development of cardiotoxicity with drugs not commonly associated with hypertension such as anthracyclines. An outline of management strategies, including pharmacological and lifestyle interventions as well as models of care aimed to facilitate early detection and more timely management of hypertension in patients with cancer and survivors concludes this review, which overall aims to improve both cardiovascular and cancer-specific outcomes.

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“…This is why targeting the PI3K pathway has promise in treating B cell malignancies. At present, two PI3K inhibitors are used in routine clinical practice for the treatment of patients with CLL and FL: idelalisib (an orally administered PI3Kδ inhibitor) and copanlisib (an intravenously administered pan-PI3K inhibitor) [ 162 , 163 ] ( Figure 2 a and Table 2 ). As the first-in-class PI3Kδ inhibitor, idelalisib showed efficacy in patients with a 17p deletion and p53 mutation, unmutated IGHV status, and R/R CLL [ 161 ].…”

Section: Current Treatments and Clinical Trials Of B Cell Malignancie...mentioning

confidence: 99%

Current Status of Novel Agents for the Treatment of B Cell Malignancies: What’s Coming Next?

Tannoury

Garnier

Susin

et al. 2022

Cancers

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Resistance to death is one of the hallmarks of human B cell malignancies and often contributes to the lack of a lasting response to today’s commonly used treatments. Drug discovery approaches designed to activate the death machinery have generated a large number of inhibitors of anti-apoptotic proteins from the B-cell lymphoma/leukemia 2 family and the B-cell receptor (BCR) signaling pathway. Orally administered small-molecule inhibitors of Bcl-2 protein and BCR partners (e.g., Bruton’s tyrosine kinase and phosphatidylinositol-3 kinase) have already been included (as monotherapies or combination therapies) in the standard of care for selected B cell malignancies. Agonistic monoclonal antibodies and their derivatives (antibody–drug conjugates, antibody–radioisotope conjugates, bispecific T cell engagers, and chimeric antigen receptor-modified T cells) targeting tumor-associated antigens (TAAs, such as CD19, CD20, CD22, and CD38) are indicated for treatment (as monotherapies or combination therapies) of patients with B cell tumors. However, given that some patients are either refractory to current therapies or relapse after treatment, novel therapeutic strategies are needed. Here, we review current strategies for managing B cell malignancies, with a focus on the ongoing clinical development of more effective, selective drugs targeting these molecules, as well as other TAAs and signaling proteins. The observed impact of metabolic reprogramming on B cell pathophysiology highlights the promise of targeting metabolic checkpoints in the treatment of these disorders.

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Current status of phosphoinotiside-3 kinase inhibitors in blood cancers

Cited by 10 publications

References 43 publications

Diagnosis and Treatment of Chronic Lymphocytic Leukemia

Diagnosis and Treatment of Chronic Lymphocytic Leukemia

Established and Emerging Cancer Therapies and Cardiovascular System: Focus on Hypertension—Mechanisms and Mitigation

Current Status of Novel Agents for the Treatment of B Cell Malignancies: What’s Coming Next?

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