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CLL With Akiva Diamond, MD

Oncology / Hematology

Dr. Diamond is a lymphoma specialist, a malignant hematologist, and an assistant professor of medicine at Baylor College of Medicine and the Dan L. Duncan Comprehensive Cancer Center in Houston, Texas.

New Insights on Venetoclax Resistance and Karyotype Complexity in CLL

Hey Everyone,

I hope you’re all doing well. I wanted to share some exciting findings from recent studies shedding light on venetoclax resistance in CLL. In one study, researchers analyzed 11 patients with disease progression on venetoclax and found that acquired loss(8p) and gain (1q21.2-21.3) were key contributors to resistance, suggesting potential combination therapies. Gene expression analysis revealed upregulated BCR signaling and MAPK pathway activation in progression samples.

In another study, the impact of complex karyotypes in CLL patients receiving venetoclax-based treatments was explored. Complex karyotypes (≥3 chromosomal aberrations) and highly complex karyotypes (≥5 CAs) were associated with adverse outcomes. Notably, highly complex karyotypes and specific translocations were identified as independent adverse prognosticators for progression-free survival in venetoclax-treated patients. These findings emphasize the importance of karyotyping in CLL diagnosis to improve prognostication.

For more details, check out the full articles linked below. Please continue reading for additional articles and selections for the month!

Warm regards,

Akiva

Articles
  • Mashup Score: 5
    NCCN Guidelines Update: Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma - 1 year(s) ago

    Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is characterized by the accumulation of abnormal lymphocytes in the blood, bone marrow, and lymphoid tissues, leading to a weakened immune system and an increased risk of infections for patients. The NCCN Guidelines for CLL/SLL underscore the need for a comprehensive evaluation of multiple factors to determine the most appropriate…

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      akivadiamond

      Here is a nice summary of a presentation given by Dr. Stephens on the recent updates and guidance on selecting front line treatment.

  • Mashup Score: 1
    Pirtobrutinib after a Covalent BTK Inhibitor in Chronic Lymphocytic Leukemia - PubMed - 1 year(s) ago

    In this trial, pirtobrutinib showed efficacy in patients with heavily pretreated CLL or SLL who had received a covalent BTK inhibitor. The most common adverse events were infections, bleeding, and neutropenia. (Funded by Loxo Oncology; BRUIN ClinicalTrials.gov number, NCT03740529.).

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      akivadiamond

      This month we saw the publication of the long awaited BRUIN trial. A Phase 1-2 trial of pirtobrutinib in relapsed and refractory CLL. 40.5% of patients had prior BCL2i treatment. ORR was 73% with a median PFS of 19.6 months.

  • Mashup Score: 1
    High karyotypic complexity is an independent prognostic factor in patients with CLL treated with venetoclax combinations - 1 year(s) ago

    Key Points. hCKTs (≥5 CAs) and translocations are independent prognostic factors for inferior PFS in patients with TP53-intact CLL treated with venetoclax-based

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      akivadiamond

      Interesting research showing that high karyotypic complexity is a negative prognostic factor in venetoclax treated patients. They also demonstrated that chemotherapy treatment (FCR and BR), but not ven-based treatment, was associated with an increase in karyotypic complexity. Although prognostic, further research will be needed to see if this karyotype can help with treatment selection.

  • Mashup Score: 0
    Genetic events associated with venetoclax resistance in CLL identified by whole-exome sequencing of patient samples - 1 year(s) ago

    Key Points. Clonal evolution on venetoclax selects for 8p deletion, which leads to increased venetoclax resistance in vitro.Elevated Erk signaling and constitut

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      akivadiamond

      BCL2 mutations is a well described late event for patients on venetoclax. In this study investigators describe several other mechanisms of acquired resistance to venetoclax in 11 CLL patients. The majority of the patients had prior chemoimmunotherapy, and there was a high percent with P53 and SF3B1 mutations. Upregulated MAPK signaling were identified suggesting MEK as a potential therapeutic target. As many newly diagnosed patients are no longer exposed to chemotherapy, and may only have fixed duration exposure to venetoclax, it will be important to continue to study resistance mechanisms with our newer treatment algorithms.

  • Mashup Score: 0
    Real-world comparative effectiveness of acalabrutinib and ibrutinib in patients with chronic lymphocytic leukemia - 1 year(s) ago

    Key Points. First comparative effectiveness study of acalabrutinib and ibrutinib in real-world patients with chronic lymphocytic leukemia.Acalabrutinib demonstr

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      akivadiamond

      In a retrospective analysis of 2509 patients with CLL treated with acalabrutinib vs ibrutinib using the Flatiron Health database time to discontinuation was significantly longer in the acalabrutinib treated patients (in a weighted analysis). The median age of patients treated in this analysis was 71, compared to 66 in the ELEVATE-RR trial. This highlights that the improved tolerability of newer BTK inhibitors may be even more pronounced than that seen in the phase 3 trials when used in older patients outside of a clinical trial.

  • Mashup Score: 3
    Sustained remissions in CLL after frontline FCR treatment with very long-term follow-up - 1 year(s) ago

    Key Points. Patients (pts) with mutated IGHV (IGHV-M) have favorable very long-term PFS after FCR, although late relapse (>10 years) rarely occursCumulative

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      akivadiamond

      With a median of 19 years of follow up, patients with IGVH-mutated CLL continue to have excellent responses to FCR. However, 6.3% had therapy related myeloid neoplasms. Relapses after 10 years were uncommon. This data highlights the curative potential of FCR in IGVH mutated patients and can still be considered as a curative, limited duration approach in younger fit IGVH mutated patients.