MYD88 wild-type

However, compared to MyD88wt counterparts, MyD88D162E BMDMs had increased oxidative stress and dysfunctional mitochondria, along with reduced prosurvival Bcl-xL and BTK expression, rendering cells more prone to apoptosis, exacerbated by ibrutinib treatment...These findings underscore the importance of MyD88wt signaling for NF-κB activation, protecting against macrophage premature apoptosis at resting state. Targeting MyD88 quantity rather than just its signaling could be a promising strategy for MyD88-driven lymphoma treatment.

The findings of the RAINBOW trial (NCT046152), comparing the dexamethasone, rituximab, and cyclophosphamide (DRC) regimen to the first-generation, ibrutinib are awaited, but more studies are needed to draw definitive conclusions on the comparative efficacy of chemoimmunotherapy and BTKi. Complete response is elusive with BTKi, and combination regimens to improve upon the efficacy and limit the treatment duration are also under evaluation in WM.

Finally, gene expression analysis showed common transcriptional features between patients compared to the healthy control but also differentially expressed genes between MYD88 L265P and MYD88 WT patients involved in distinct pathways, including NFκΒ, BCL2, and BTK. Overall, our data highlight the intra-tumor clonal heterogeneity in WM with potential prognostic and therapeutic implications.

In TP53MUT, compared to ibrutinib, zanubrutinib-treated patients had higher VGPR+CR (34.6% vs 13.6%, P<0.05), numerically improved MRR (80.8% vs 63.6%, P=0.11), and longer PFS (not reached vs 44.2 months, HR=0.66, P=0.37). Collectively, WM patients with CXCR4MUT or TP53MUT had worse prognosis compared to patients with WT alleles and zanubrutinib led to better clinical outcomes.

The cBTK-i zanubrutinib shows greater response activity and/or improved PFS in wild-type MYD88, mutated CXCR4, or altered TP53 patients...For patients with acquired resistance to c-BTKi, newer options include the non-covalent BTK-inhibitor pirtobrutinib or the BCL2 antagonist venetoclax. Combinations of BTK-inhibitors with chemoimmunotherapy, CXCR4 and BCL2 antagonists have advanced and are discussed. Algorithms for positioning BTK-inhibitors in treatment-naïve and previously treated WM patients based on genomics, disease characteristics, and co-morbidities are presented.

NGS was the most sensitive method for detecting CXCR4 mutation. MYD88 mutation had prognostic significance in BTKi-based therapy, while CXCR4 mutation indicated higher tumor burden and inferior survival in BTKi-based therapy.

Background and Significance: Zanubrutinib, a next-generation, selective BTKi, is approved for treatment of WM based on data from the phase 3 ASPEN study (NCT03053440), in which zanubrutinib showed a favorable benefit-risk profile vs ibrutinib, a first-generation BTKi, in patients with symptomatic WM (Tam CS, et al. MRR, VGPR+ rate, and ORR will be presented with 95% CIs, and median DOR will be estimated with the Kaplan-Meier method. The study is currently open for enrollment.

This is the first independent validation of our previously reported multi-omic driven WM subtype classification. The studies underscore that epigenetic differences underlie the biology of WM subclassification and support a strong role for epigenetic changes driving WM evolution.

We also validated MSS-WM using competing risk analysis (p=0.001) and in the cohort of rituximab treated patients (p<0.0001)... Our proposed model, MSS-WM, is a simple, clinically useful, externally validated model that reliably risk stratifies previously untreated patients with active WM into four groups that have distinct outcomes based on the composite scores derived from the patients' age, serum albumin and serum LDH at diagnosis.

Patients received the 28-day cycle of Rituximab (375 mg/m2 IV on day 1), Bortezomib (1.3 mg/m2 SC on day 1, 8, 15), Lenalidomide (15 mg per oral day 1-21) and dexamethasone (20 mg iv or oral day 1-4). R-VRD regiment could be helpful for MYD88 mutation negative or CXCR4 mutation positive patients. BTK inhibitors show superior response and survival outcomes for patients with MYD88 mutation positive and CXCR4 mutation negative. So, we are supposed that R-VRD could be optional treatment for patients who are not suitable for BTK inhibitors.