Chronic lymphocytic leukemia treatment algorithm 2022

Hampel, Paul J.

doi:10.1038/s41408-022-00756-9

Cited by 31 publications

(26 citation statements)

References 94 publications

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“…Notably, zanu and acalabrutinib have a similar incidence of all grade (RR, 1.12) and grade ≥3 (RR, 0.90) AEs [59]. Therefore, the choice between these two different second-generation BTKis is driven predominantly by specific toxicity profiles and safety in older patients with comorbid conditions and cardiovascular risk factors [60], keeping in mind that some comorbidities may amplify toxicities related to a given BTKi. For example, in patients with a significant history of headaches, therapy with acalabrutinib may be less preferable [61].…”

Section: Discussionmentioning

confidence: 99%

Advancements in the Treatment of CLL: The Rise of Zanubrutinib as a Preferred Therapeutic Option

Molica

Tam

Allsup

et al. 2023

Cancers

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Ibrutinib, the first-in-class Bruton’s tyrosine kinase inhibitor (BTKi), is a commonly deployed therapeutic option for previously untreated and relapsed/refractory (R/R) patients with chronic lymphocytic leukemia (CLL). The use of ibrutinib is, however, partially limited by off-target side effects. Zanubrutinib (zanu) is a second-generation BTKi with enhanced target selectivity and occupancy of the kinase binding site. The SEQUOIA study showed that zanu significantly prolonged progression-free survival (PFS) when compared to bendamustine–rituximab (BR) in treatment-naive CLL patients. More recently, data from the phase III ALPINE trial, which directly compared zanu with ibrutinib, demonstrated that zanu’s advantages include an improved safety profile as well as enhanced clinical efficacy. Based on the results of the SEQUOIA and ALPINE pivotal trials, the Food and Drug Administration (FDA) and European Medicines Agency (EMA) licensed zanu for the treatment of patients with CLL or small lymphocytic lymphoma (SLL) in January 2023. The updated (v2.2023) National Comprehensive Cancer Network (NCCN) guidelines and the most recent German CLL algorithm suggest that zanu may replace first-generation BTKis as a preferred therapeutic option for patients with CLL/SLL due to its increased selectivity for the kinase binding site, improved therapeutic efficacy, and favorable toxicity profile. Some drug class-related characteristics such as drug resistance, low complete remission (CR) rates, and indefinite treatment duration still remain with zanu, and the results from recently completed and ongoing fixed-duration clinical trials, combining zanu with an anti-BCL2 agent, are eagerly awaited with the possible promise of a reduced treatment duration and lower financial burden.

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Section: Discussionmentioning

confidence: 99%

Advancements in the Treatment of CLL: The Rise of Zanubrutinib as a Preferred Therapeutic Option

Molica

Tam

Allsup

et al. 2023

Cancers

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“…Chronic lymphocytic leukemia (CLL), as the least aggressive, if not progressing, does not require treatment immediately and a watch-and-wait approach is used in most cases based on the 2018 guidelines. 15 , 16 However, with a better understanding of the genomic landscape and the discovery of newer targeted therapies with fewer side effects, such as Bruton tyrosine kinase (BTK) inhibitors, there is an increasing number of clinical trials on early intervention strategies for CLL. 17 For acute lymphocytic leukemia (ALL), typical treatment starts with chemotherapy regimens of vincristine, dexamethasone, and an anthracycline like doxorubicin, with the possible inclusion of cyclophosphamide and pegaspargase and alternating high-dose methotrexate.…”

Section: Acute and Chronic Leukemiasmentioning

confidence: 99%

MNK Proteins as Therapeutic Targets in Leukemia

Mazewski¹,

Platanias²

2023

OTT

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In leukemia, resistance to therapy is a major concern for survival. MAPK-interacting kinases (MNKs) have been identified as important activators of oncogenic-related signaling and may be mediators of resistance. Recent studies in leukemia models, especially acute myeloid leukemia (AML), have focused on targeting MNKs together with other inhibitors or treating chemotherapy-resistant cells with MNK inhibitors. The preclinical demonstrations of the efficacy of MNK inhibitors in these combination formats would suggest a promising potential for use in clinical trials. Optimizing MNK inhibitors and testing in leukemia models is actively being pursued and may have important implications for the future. These studies are furthering the understanding of the mechanisms of MNKs in cancer which could translate to clinical studies.

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“…Chronic lymphocytic leukaemia (CLL) is a highly heterogeneous disease in terms of clinical presentation and course. 1 Metabolic rewiring is a critical hallmark of tumourigenesis and is essential for the development of cancer and its progression. 2 This process supports leukaemic cell growth and survival and has been linked to aggressive disease, drug resistance and relapse.…”

Section: Introductionmentioning

confidence: 99%

“…Chronic lymphocytic leukaemia (CLL) is a highly heterogeneous disease in terms of clinical presentation and course 1 . Metabolic rewiring is a critical hallmark of tumourigenesis and is essential for the development of cancer and its progression 2 .…”

Section: Introductionmentioning

confidence: 99%

Untargeted metabolomics identifies metabolic dysregulation of sphingolipids associated with aggressive chronic lymphocytic leukaemia and poor survival

Nguyen Van Long,

Valcourt‐Gendron,

Caron

et al. 2023

Clinical & Translational Med

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BackgroundMetabolic dependencies of chronic lymphocytic leukaemia (CLL) cells may represent new personalized treatment approaches in patients harbouring unfavourable features.MethodsHere, we used untargeted metabolomics and lipidomics analyses to isolate metabolomic features associated with aggressive CLL and poor survival outcomes. We initially focused on profiles associated with overexpression of the adverse metabolic marker glycosyltransferase (UGT2B17) associated with poor survival and drug resistance.ResultsLeukaemic B‐cell metabolomes indicated a significant perturbation in lipids, predominantly bio‐active sphingolipids. Expression of numerous enzyme‐encoding genes of sphingolipid biosynthesis pathways was significantly associated with shorter patient survival. Targeted metabolomics further exposed higher circulating levels of glucosylceramides (C16:0 GluCer) in CLL patients relative to healthy donors and an aggressive cancer biology. In multivariate analyses, C16:0 GluCer and sphinganine were independent prognostic markers and were inversely linked to treatment‐free survival. These two sphingolipid species function as antagonistic mediators, with sphinganine being pro‐apoptotic and GluCer being pro‐proliferative, tested in leukemic B‐CLL cell models. Blocking GluCer synthesis using ceramide glucosyltransferase inhibitors induced cell death and reduced the proliferative phenotype, which further sensitized a leukaemic B‐cell model to the anti‐leukaemics fludarabine and ibrutinib in vitro.ConclusionsSpecific sphingolipids may serve as prognostic markers in CLL, and inhibiting enzymatic pathways involved in their biosynthesis has potential as a therapaeutic approach.

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Chronic lymphocytic leukemia treatment algorithm 2022

Cited by 31 publications

References 94 publications

Advancements in the Treatment of CLL: The Rise of Zanubrutinib as a Preferred Therapeutic Option

Advancements in the Treatment of CLL: The Rise of Zanubrutinib as a Preferred Therapeutic Option

MNK Proteins as Therapeutic Targets in Leukemia

Untargeted metabolomics identifies metabolic dysregulation of sphingolipids associated with aggressive chronic lymphocytic leukaemia and poor survival

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