Publications by authors named "Kofides A"
Article Synopsis
- Covalent Bruton's tyrosine kinase-inhibitors (cBTK-i) are effective in treating MYD88-mutated Waldenstrom's macroglobulinaemia by inhibiting key signaling pathways that promote tumor growth.* -
- BTK mutations can lead to treatment resistance by reactivating ERK1/2, which causes increased inflammatory cytokine production and helps BTK wild-type tumor cells survive.* -
- Pirtobrutinib, a non-covalent BTK-inhibitor, has been shown to successfully block damaging ERK1/2 activity and can overcome resistance in MYD88 lymphoma cells with mutated BTK.*
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
- 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
- - 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
- * 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
- - 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
- * 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
Article Synopsis
- * A study analyzed the differences in clinical characteristics and treatment outcomes between WM patients receiving ibrutinib on clinical trials (ON trial) and those off trials (OFF trial), finding similar response rates and survival outcomes.
- * Both treatment-naïve and previously treated patients showed effectiveness of ibrutinib; the study validates its efficacy compared to previous clinical trial results.
Article Synopsis
- Ibrutinib is an effective treatment for Waldenström macroglobulinaemia (WM), but some patients develop resistance due to mutations in the BTK target or the PLCG2 protein.
- A study using whole-exome sequencing aimed to discover other molecular reasons for this resistance beyond the known mutations.
- Key findings included deletions on chromosomes 6q and 8p affecting important cellular processes, as well as mutations in genes related to ubiquitin ligases and immune signaling pathways in resistant WM patients.
Article Synopsis
- * Patients with mutated WM face better survival rates compared to those with wild-type WM, who are at higher risk for transformation into more aggressive forms like diffuse large B-cell lymphoma.
- * The understanding of specific mutations has led to targeted drug development for WM, particularly with drugs like BTK inhibitors (e.g., ibrutinib), allowing for more personalized treatment strategies based on mutation status.
Article Synopsis
- - Activating mutations in MYD88 enhance pro-survival signaling in certain lymphoma cells through BTK and HCK, both of which are affected by the drug ibrutinib; however, complete responses to this treatment remain infrequent.
- - The research identified the activation of SYK, a key component of B-cell receptor (BCR) signaling, alongside MYD88 in mutated lymphoma cells, suggesting novel pathways of resistance to ibrutinib.
- - Combining SYK inhibitors with ibrutinib in MYD88-mutated lymphoma cells leads to improved cell death, proposing a new therapeutic strategy that combines these two treatments for better clinical outcomes.
Article Synopsis
- The study analyzed 31 cases of non-IgM lymphoplasmacytic lymphoma (LPL) and compared them with 93 cases of Waldenström macroglobulinemia (WM), matching participants by age, sex, and diagnosis year.
- Non-IgM LPL cases exhibited fewer mutations and shorter times to treatment compared to WM controls, but had higher chances of extramedullary disease.
- Despite these differences in clinical features and treatment options, both groups had similar response rates and overall survival outcomes.
Hematopoietic cell kinase (HCK) is an SRC family member that is aberrantly upregulated in B-cell neoplasms dependent on MYD88-activating mutations and supports their growth and survival. We showed herein that activation of Toll-like receptor (TLR) signaling in MYD88 wild-type B cells also triggered HCK expression, denoting on path regulatory function for HCK by MYD88. To clarify the signaling cascades responsible for aberrant HCK expression in MYD88-mutated B-cell lymphomas, we performed promoter-binding transcription factor (TF) profiling, PROMO weighted TF consensus binding motif analysis, and chromatin immunoprecipitation studies.
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- Rituximab-based treatments are frequently used as initial therapy for patients with symptomatic Waldenström macroglobulinemia (WM), and a study found that some patients show improvement in their response even after finishing treatment.
- Out of 178 patients analyzed, 38% who received maintenance therapy and 31% who were observed experienced a significant drop (≥25%) in serum IgM levels several months or years after completing their regimen.
- Factors such as lower baseline hemoglobin, high bone marrow involvement, CXCR4 mutations, and elevated serum IgM levels were linked to a lower chance of improved response, which was associated with better progression-free survival and overall survival rates in WM patients.
MYD88 L265P is the most common mutation in lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (LPL/WM) and one of the most frequent in poor-prognosis subtypes of diffuse large B-cell lymphoma (DLBCL). Although inhibition of the mutated MYD88 pathway has an adverse impact on LPL/WM and DLBCL cell survival, its role in lymphoma initiation remains to be clarified. We show that in mice, human MYD88L265P promotes development of a non-clonal, low-grade B-cell lymphoproliferative disorder with several clinicopathologic features that resemble human LPL/WM, including expansion of lymphoplasmacytoid cells, increased serum immunoglobulin M (IgM) concentration, rouleaux formation, increased number of mast cells in the bone marrow, and proinflammatory signaling that progresses sporadically to clonal, high-grade DLBCL.
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