Lenalidomide induces long-lasting responses in elderly patients with chronic lymphocytic leukemia

Strati, Paolo; Keating, Michael J.; Wierda, William G.; Badoux, Xavier C.; Calin, Steliana; Reuben, James M.; O’Brien, Susan; Kornblau, Steven M.; Kantarjian, Hagop M.; Gao, Hui; Ferrajoli, Alessandra

doi:10.1182/blood-2013-04-495341

Cited by 71 publications

(40 citation statements)

References 17 publications

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“…To date, success in therapeutically enhancing cell-mediated immunity in CLL has been limited. Lenalidomide has favorable immune-modulating properties in T cells in CLL patients via downregulation of the lymphoid transcription factor IKZF1 through a cereblon-dependent mechanism, and can promote durable, sustained complete remissions in 50% or more of patients receiving this treatment (16). However, lenalidomide in this setting also can produce significant morbidity and sometimes fatal outcome from early-onset tumor flare.…”

Section: Ibrutinib Treatment Increases Numbers Of Both Cd4mentioning

confidence: 97%

Ibrutinib treatment improves T cell number and function in CLL patients

Long

Beckwith

et al. 2017

Journal of Clinical Investigation

307

343

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BACKGROUND.Ibrutinib has been shown to have immunomodulatory effects by inhibiting Bruton's tyrosine kinase (BTK) and IL-2-inducible T cell kinase (ITK). The relative importance of inhibiting these 2 kinases has not been examined despite its relevance to immune-based therapies. METHODS.Peripheral blood mononuclear cells from chronic lymphocytic leukemia (CLL) patients on clinical trials of ibrutinib (BTK/ITK inhibitor; n = 19) or acalabrutinib (selective BTK inhibitor; n = 13) were collected serially. T cell phenotype, immune function, and CLL cell immunosuppressive capacity were evaluated. RESULTS. Ibrutinib markedly increased CD4+ and CD8 + T cell numbers in CLL patients. This effect was more prominent in effector/effector memory subsets and was not observed with acalabrutinib. Ex vivo studies demonstrated that this may be due to diminished activation-induced cell death through ITK inhibition. PD-1 and CTLA-4 expression was significantly markedly reduced in T cells by both agents. While the number of Treg cells remained unchanged, the ratio of these to conventional CD4 + T cells was reduced with ibrutinib, but not acalabrutinib. Both agents reduced expression of the immunosuppressive molecules CD200 and BTLA as well as IL-10 production by CLL cells. CONCLUSIONS. Ibrutinib treatment increased the in vivo persistence of activated T cells, decreased the Treg/CD4+ T cell ratio, and diminished the immune-suppressive properties of CLL cells through BTK-dependent and -independent mechanisms. These features provide a strong rationale for combination immunotherapy approaches with ibrutinib in CLL and other cancers. TRIAL REGISTRATION. ClinicalTrials.gov NCT01589302 and NCT02029443. Samples described here were collected per OSU-0025.

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Section: Ibrutinib Treatment Increases Numbers Of Both Cd4mentioning

confidence: 97%

Ibrutinib treatment improves T cell number and function in CLL patients

Long

Beckwith

et al. 2017

Journal of Clinical Investigation

307

343

View full text Add to dashboard Cite

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“…This experience is in contrast to a trial reporting long-lasting efficacy with lenalidomide monotherapy 25 and highlights the safety and toxicity challenges associated with trial management. Clinical experience suggests an individual component to how CLL patients tolerate lenalidomide, and identifying predictive pretreatment factors requires future research.…”

Section: How To Manage Safety and Toxicity?mentioning

confidence: 66%

“…[23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41] When used as monotherapy, overall response rates (ORRs) have been up to 72% (mostly partial responses) for first-line therapy and 25% to 30% for fludarabine-refractory CLL. Lenalidomide has shown clinical activity in patients with high-risk features such as del(17p) (31%-38% ORR).…”

Section: Clinical Experience With Lenalidomidementioning

confidence: 99%

How does lenalidomide target the chronic lymphocytic leukemia microenvironment?

Kater

Tonino

Egle

et al. 2014

Blood

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Immunotherapy has emerged as a viable clinical strategy to harness endogenous antitumor T-cell immunity. Lenalidomide is an oral immunomodulatory drug that repairs antitumor T-cell function and is showing efficacy in ongoing chronic lymphocytic leukemia (CLL) and lymphoma clinical trials. This article focuses on advances in our understanding of its mechanism of action in the tumor microenvironment and provides a clinical update in CLL. Challenges associated with this drug and its potential use in the targeted drug treatment era are discussed.

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“…Among 60 patients aged ≥65, the ORR was 65% (CR 10%) and the estimated 2-year PFS was 60%. Interestingly, response lasted >36 months in 58% of patients, and at a median follow-up of 4 years, time-to-treatment failure was not reached [87].…”

Section: Immunomodulatory Drugsmentioning

confidence: 99%

Magic pills: new oral drugs to treat chronic lymphocytic leukemia

Vitale

Griggio

Todaro

et al. 2017

Expert Opinion on Pharmacotherapy

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Introduction: A deeper understanding of chronic lymphocytic leukemia (CLL) biology has led to the identification of new promising therapeutic targets. Different classes of molecules are currently under investigation and novel oral drugs have recently been approved or are in a late stage of clinical development. Areas covered: We present biological data illustrating the heterogeneous mechanisms of action of new oral drugs in CLL. Moreover, we provide clinical data from phase I to III studies, and discuss efficacy and side effects profile of these new therapies. Data are derived from peer-reviewed articles indexed in PubMed and from abstracts presented at major international meetings. Expert opinion: Novel oral drugs represent a valuable alternative to chemo-immunotherapy for patients with CLL, especially when high-risk disease features are present and when age or comorbidities preclude the use of standard treatments. Based on data from ongoing clinical trials, the indications of already approved agents will most likely be expanded and new options will soon be available. Moreover, treatment combinations will broaden the therapeutic armamentarium of physicians treating CLL. The availability of multiple choices is of benefit for patients with CLL, but also represents a challenge for the need of choosing the right drug for each patient. ARTICLE HISTORY

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Lenalidomide induces long-lasting responses in elderly patients with chronic lymphocytic leukemia

Cited by 71 publications

References 17 publications

Ibrutinib treatment improves T cell number and function in CLL patients

Ibrutinib treatment improves T cell number and function in CLL patients

How does lenalidomide target the chronic lymphocytic leukemia microenvironment?

Magic pills: new oral drugs to treat chronic lymphocytic leukemia

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