Publications by authors named "Zachary Hunter"
Article Synopsis
- A clinical trial was conducted to investigate the effects of combining two drugs, ibrutinib and venetoclax, for treating symptomatic, treatment-naïve patients with MYD88-mutated Waldenström macroglobulinemia (WM).
- Out of 45 patients enrolled, 42% achieved a very good partial response (VGPR), and the study noted significant adverse events, including a concerning rate of ventricular arrhythmia.
- After a median follow-up of 24.4 months, the study reported strong progression-free survival (76%) and overall survival (96%) rates, even though it was terminated early due to safety concerns.
Article Synopsis
- - Waldenström's macroglobulinemia (WM) is characterized as a type of lymphoma involving IgM monoclonal gammopathy and requires evidence of lymphoplasmacytic leukemia in the bone marrow for diagnosis.
- - Immunophenotyping and genotyping are crucial for accurately diagnosing WM and distinguishing it from similar diseases like marginal zone lymphoma and multiple myeloma.
- - The text emphasizes the need for standardized methodologies in mutational analysis for WM diagnosis and suggests exploring the diagnostic value of certain gene mutations that are not routinely assessed.
Article Synopsis
- Waldenström macroglobulinemia (WM) is a rare non-Hodgkin lymphoma marked by malignant lymphoplasmacytic cells in the bone marrow, where researchers studied the tumor microenvironment using mass cytometry (CyTOF).
- The study found a significant increase in specific B cell types and changes in immune cell populations, indicating that certain immune responses in the bone marrow are linked to better overall survival in WM patients.
- Results showed that immune checkpoints had a role in altering the immune landscape, and the effectiveness of the drug ibrutinib was connected to the levels of immature B cells and specific T cell subsets, highlighting CyTOF as a valuable tool for understanding WM and guiding treatments.
Article Synopsis
- * Researchers found that GPER1 is significantly increased in tumor cells of WM patients when compared to normal B cells.
- * The GPER1-selective agonist G-1 (Tespria) induces cell cycle arrest and apoptosis in cancer cells, activating the TP53 pathway and showing promise for further clinical development in WM treatment.
Article Synopsis
- The HCK family kinase is upregulated and activated by mutated MYD88 in specific types of lymphomas, triggering key signaling pathways like BTK, AKT, and ERK.
- In MYD88Mut lymphoma cells, HCK enhances SYK activation, while the SFK LYN plays a lesser role in certain lymphoma types, such as Waldenstrom macroglobulinemia.
- Overexpression of HCK leads to persistent activation of SYK, and inhibiting HCK reduces SYK activity, indicating that HCK could be a potential therapeutic target for treating MYD88Mut B-cell lymphomas.
Article Synopsis
- BTK inhibitors, like ibrutinib, are currently the only FDA-approved treatments for Waldenström macroglobulinemia (WM), but the factors affecting their effectiveness were not fully understood.
- In a study of 319 WM patients on ibrutinib, CXCR4 mutations and low platelet counts were linked to worse treatment responses and shorter progression-free survival, leading to a proposed scoring system based on these factors.
- The research found that older age (65+) greatly impacts overall survival and confirmed the significance of CXCR4 mutations as predictors for patient outcomes on ibrutinib.
Article Synopsis
- BCL2 is overexpressed in Waldenström macroglobulinemia (WM) cells, and venetoclax, a BCL2 inhibitor, shows potential for causing cell death in these cases, yet its effectiveness in WM needed further investigation.
- A phase II clinical trial demonstrated venetoclax's promising results in 32 treated patients, with overall response rates of 84%, and a median progression-free survival of 30 months.
- The treatment was generally well-tolerated, with neutropenia as the main side effect, and the presence of certain mutations did not influence the overall treatment outcomes.
Article Synopsis
- Immunoglobulin M (IgM) multiple myeloma (MM) is a rare condition that needs to be differentiated from other similar diseases, such as Waldenström macroglobulinemia, for effective treatment.
- The study involved analyzing genomic and transcriptomic data of IgM-MM samples through whole-genome and transcriptome sequencing, revealing shared characteristics with MM, but unique features like specific chromosomal translocations and deletions.
- Findings indicated that IgM-MM likely originates before the germinal center stage, highlighted by unique molecular signatures and elevated expression of potential therapeutic targets, such as CD20 and Bruton tyrosine kinase.
Article Synopsis
- - This study evaluated the effectiveness of ibrutinib, a daily treatment for 30 patients newly diagnosed with Waldenstrom macroglobulinemia (WM), showing promising response rates: 100% overall response, 87% major response, and 30% very good partial response (VGPR) after 50 months of follow-up.
- - Patients with CXCR4 mutations had lower VGPR rates (14% vs. 44%) and longer times to achieve major responses compared to those without mutations, indicating a possible impact of these mutations on treatment outcomes.
- - Despite some treatment-related side effects, including fatigue and atrial fibrillation in 20% of patients, the study concluded that ibrutinib
Article Synopsis
- MYD88 and CXCR4 mutations are frequently found in Waldenström macroglobulinemia (WM) and the CXCR4 mutation can affect patient response to BTK inhibitors.
- A phase 1 trial tested the CXCR4-antagonist ulocuplumab combined with ibrutinib, enrolling 13 symptomatic patients, which resulted in significant declines in median immunoglobulin M levels and bone marrow disease.
- The study achieved high response rates, with a 2-year progression-free survival of 90%, while showing that combining the two treatments is feasible and well-tolerated, despite some adverse events.
Ibrutinib is highly active and produces long-term responses in patients with Waldenström macroglobulinemia (WM), but acquired resistance can occur with prolonged treatment. We therefore evaluated the natural history and treatment outcomes in 51 WM patients with acquired resistance to ibrutinib monotherapy. The median time between ibrutinib initiation and discontinuation was 2 years (range, 0.
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- Activating mutations in MYD88 lead to increased cell growth in malignancies via HCK-dependent activation of BTK, with ibrutinib being effective in cases of MYD88 mutations but facing resistance due to BTK mutations like BTKCys481Ser.* -
- KIN-8194 is a new dual inhibitor of HCK and BTK that effectively kills MYD88-mutated lymphoma cells, including those resistant to ibrutinib, showing strong efficacy and good tolerance in rodent studies.* -
- KIN-8194 demonstrated improved survival rates compared to ibrutinib in mouse models and its combination with the BCL_2 inhibitor venetoclax further enhanced tumor-killing effects,
Article Synopsis
- * Different testing methods for detecting the CXCR4 S338X variant may lead to inconsistent results in clinical trials, complicating treatment strategies.
- * The study found that while targeted next-generation sequencing often missed CXCR4 mutations, combining allele-specific PCR with CD19 cell selection greatly improved detection accuracy, although sensitivity was reduced in cases with low bone marrow involvement and varied mutation presence.
Article Synopsis
- * EPI-X4 is a natural antagonist of CXCR4 that inhibits cancer cell migration and invasion by blocking CXCL12 signaling, demonstrating potential as a therapeutic agent against WM.
- * Enhanced versions of EPI-X4, designed to better bind CXCR4, could improve its effectiveness in curbing the growth-promoting effects of CXCR4 signaling in WM patients.
Article Synopsis
- Cancer research aims to understand tumor growth mechanisms and translate findings into better diagnostics and treatments, ultimately improving patient care.
- Waldenström's Macroglobulinemia (WM) is a B-cell cancer characterized by high levels of monoclonal IgM and mutations in the MYD88 and CXCR4 genes, which play a vital role in disease development.
- The identification of these mutations has enhanced understanding of WM and enabled the prediction of treatment responses to the BTK inhibitor ibrutinib, suggesting potential therapeutic strategies for related CXCR4-positive diseases.
Article Synopsis
- * Analysis of two patient groups treated with ibrutinib found that around 64%-71% achieved a partial response or better within six months, with significantly better three-year PFS rates for those who did.
- * Results suggest that achieving at least a partial response at six months is linked to improved PFS, indicating it could serve as a valuable marker in future clinical trials for Bruton tyrosine kinase inhibitors in treating WM.
Article Synopsis
- Daratumumab showed a 23% overall response rate in previously treated patients with Waldenström's macroglobulinemia (WM).* -
- Patients treated with daratumumab had a median progression-free survival (PFS) of 2 months.* -
- The two patients who had a partial response to the treatment had higher baseline levels of CD38 fluorescent intensity in their plasma cells.*
Article Synopsis
- - Single-cell whole-genome amplification helps researchers explore the genetic structure of Waldenström’s macroglobulinemia, a type of cancer.
- - The genetic mutations found in the cells may be linked to changes in genes responsible for DNA repair and tumor suppression.
- - Understanding these mutations can provide insights into the disease's progression and potential treatment strategies.
Article Synopsis
- A multicenter trial assessed the long-term effectiveness of ibrutinib monotherapy in 63 previously treated patients with Waldenström macroglobulinemia (WM), revealing high overall (90.5%) and major response rates (79.4%) after a median follow-up of 59 months.
- The treatment significantly reduced serum immunoglobulin M levels and bone marrow disease involvement, with notable differences in response rates and progression-free survival linked to mutations in certain genes.
- Ibrutinib demonstrated a good safety profile, with an 87% overall survival rate at five years, though some patients experienced serious side effects like neutropenia and atrial arrhythmias.
Article Synopsis
- * Patients showed significant response rates with a median time to response of 2 months and a 96% overall response rate, while mutations in CXCR4 influenced the timelines of response slightly.
- * The treatment was well-tolerated with no severe side effects, and demonstrated promising long-term outcomes, including a median progression-free survival of 40 months, indicating IDR is a safe and effective first-line option for symptomatic WM