Novel Targeted Therapies for Chronic Lymphocytic Leukemia in Elderly Patients: A Systematic Review

Farooqui, Arafat Ali; Ashraf, Aqsa; Farooq, Talha Bin; Anjum, Ahmad; Rehman, Saif Ur; Akbar, Arshia; Kanate, Abraham S.; Dean, Robert M.; Ahmed, Malik Qistas; Tariq, Muhammad Junaid; Nabeel, Shaha; Faisal, Muhammad Salman; Anwer, Faiz

doi:10.1016/j.clml.2020.02.013

Cited by 6 publications

(5 citation statements)

References 46 publications

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“…Venetoclax is a selective BCL-2 inhibitor that has been approved for the treatment of first-line and relapsed/refractory CLL [ 6 ]. Monotherapy with venetoclax facilitates a rapid reduction in the disease burden with a high overall response of about 80% and a complete response of 6–20% in patients with relapsed or refractory CLL, including those with poor prognosis [ 39 ]. However, the resistance to venetoclax can be found in some CLL patients with mechanisms not fully uncovered [ 38 ].…”

Section: Discussionmentioning

confidence: 99%

Aberrantly expressed Wnt5a in nurse-like cells drives resistance to Venetoclax in chronic lymphocytic leukemia

et al. 2022

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Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of neoplastic B lymphocytes with high levels of Wnt5a in the plasma. Currently, the cell source of Wnt5a remains controversial. The receptor of Wnt5a is ROR1, whose expression is associated with disease progression and resistance to venetoclax, a BCL-2 inhibitor approved for the treatment of CLL. In this study, we found that the levels of Wnt5a in the plasma of CLL patients were positively correlated with absolute monocyte counts, but not lymphocyte counts. We cultured monocyte-derived nurse-like cells (NLCs) from patients with CLL, and detected Wnt5a expressed in NLCs. Flow cytometry and transwell assays showed that the antibody neutralizing Wnt5a inhibited the enhanced survival and migration in CLL cells co-cultured with NLCs. Furthermore, we performed a drug screening with CLL cells cultured with or without NLCs with a library containing 133 FDA-approved oncology drugs by using high-throughput flow cytometry. We observed a significant resistance to venetoclax in CLL cells co-cultured with NLCs. Immunoblot revealed the activation of NF-κB with enhanced expression of MCL-1 and BCL-XL in CLL cells co-cultured with NLCs. Neutralizing Wnt5a or blocking NF-κB pathway significantly decreased the expression of MCL-1 and BCL-XL, which leads to enhanced sensitivity to venetoclax in CLL cells co-cultured with NLCs. In conclusion, our data showed that NLCs could be one of the sources of Wnt5a detected in patients with CLL, and Wnt5a-induced NF-κB activation in the CLL microenvironment results in resistance to venetoclax in CLL cells.

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Section: Discussionmentioning

confidence: 99%

Aberrantly expressed Wnt5a in nurse-like cells drives resistance to Venetoclax in chronic lymphocytic leukemia

et al. 2022

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“…12,19,29,53,71 Further studies are needed to evaluate the possible oncogenic role of classical CLL treatments and recent drugs such as BTK inhibitors, PI3K inhibitors, and BH3-mimetics. 74 In this systematic review, we also included articles reporting the simultaneous diagnosis of cSCC and CLL. 17,31,32,38,40,49,56,67,70 In these studies, the presence of a dense tumor-associated lymphocytic infiltrate in patients with no history of leukemia represented a clue to the prompt evaluation for the underlying hematologic malignancy.…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

“…Existing data suggest that chemoimmunotherapeutic agents, such as fludarabine, chlorambucil, cyclophosphamide, and rituximab, increase the susceptibility to second cancer 12,19,29,53,71 . Further studies are needed to evaluate the possible oncogenic role of classical CLL treatments and recent drugs such as BTK inhibitors, PI3K inhibitors, and BH3‐mimetics 74 …”

Section: Discussionmentioning

confidence: 99%

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Cutaneous squamous cell carcinoma in patients with chronic lymphocytic leukemia: a systematic review of the literature

et al. 2021

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The continuous improvement of life expectancy of patients with chronic lymphocytic leukemia (CLL) has resulted in increased risk of second primary malignancy that potentially may affect survival and quality of life of CLL patients. We performed a systematic review to assess the risk and the clinical‐pathological features and prognosis of cutaneous squamous cell carcinoma (cSCC) in patients with CLL. We searched PubMed, Embase, and Cochrane Central Register of Control Trials databases for articles published from database inception to December 31, 2019. English‐language studies reporting original data on patients with a specific diagnosis of CLL and cSCC were included. Data were extracted using a standardized extraction form, and any discordance was resolved by consensus. Descriptive data were generated by pooling patients from eligible studies. Of the 4588 non‐duplicate records identified, 55 articles met our inclusion criteria. These studies reported that CLL patients have a 3.2% prevalence of cSCC, with an 11.5% cSCC‐related lethality and an overall risk of metastasis of 5.7% (7.3% for regional lymph node involvement and 3.8% for distant metastasis). The quality of evidence was limited by the high heterogeneity in the design, populations, and objectives of the included studies. This systematic review suggests that cSCC in CLL patients tends to behave less aggressively compared with the solid organ transplant recipients but has a higher morbidity and mortality than in the general population. Future prospective studies are needed to increase the quality of evidence and to determine the best treatment modalities and screening intervals for these patients.

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“…The economic burden of AEs in patients receiving CLL therapy was reported to be substantial in a retrospective insurance database study [18]. Because of the toxicity associated with continuous long-term targeted therapy, consideration should be given to the use of limited-duration combination therapies when appropriate [19].…”

Section: Consideration Of Health-related Quality Of Lifementioning

confidence: 99%

Current and future treatment strategies in chronic lymphocytic leukemia

Patel

Pagel

2021

J Hematol Oncol

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Treatment decisions for patients with chronic lymphocytic leukemia (CLL) are dependent on symptoms and classification into high-, medium-, or low-risk categories. The prognosis for CLL hinges, in part, on the presence or absence of less-favorable genetic aberrations, including del(17p), del(11q), TP53 dysfunction, and IGHV mutations, as these markers are associated with worse treatment response. Promising results from multiple clinical trials show emerging therapies targeting Burton tyrosine kinase, B-cell leukemia/lymphoma 2, and phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta result in better outcomes and prolonged progression-free survival for patients both with and without certain high-risk aberrations. Favorable outcomes using these novel oral targeted therapies, either alone or in combination with other treatments such as anti-CD20 antibodies, has led to their use almost entirely supplanting chemoimmunotherapy in the treatment of CLL. In this narrative review, we summarize the current clinical evidence for the use of targeted mono- and combination therapies for CLL, discuss new and next-generation treatment approaches currently in development, and provide insight into areas of unmet need for the treatment of patients with CLL.

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Novel Targeted Therapies for Chronic Lymphocytic Leukemia in Elderly Patients: A Systematic Review

Cited by 6 publications

References 46 publications

Aberrantly expressed Wnt5a in nurse-like cells drives resistance to Venetoclax in chronic lymphocytic leukemia

Aberrantly expressed Wnt5a in nurse-like cells drives resistance to Venetoclax in chronic lymphocytic leukemia

Cutaneous squamous cell carcinoma in patients with chronic lymphocytic leukemia: a systematic review of the literature

Current and future treatment strategies in chronic lymphocytic leukemia

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