MYD88 wild-type

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.

Analysis of the national registry for WM shows that ethnic minorities comprise 10% of WM/IgM MGCS, present with WM at a younger age, a lower M-protein and with a higher proportion of MYD88-wild type cases which may suggest different disease biology. There was no difference in overall survival in our cohort. Limitations include the retrospective analysis of real-world data and incomplete documentation of baseline data.

P=N/A, N=111, Recruiting, BeiGene | Not yet recruiting --> Recruiting | Initiation date: Sep 2023 --> Mar 2023

Predictors of cryoglobulinaemia-related treatment/death were hyperviscosity (HR: 73.01; 95% CI: 15.62-341.36, p < 0.0001) and cutaneous involvement (HR: 2.95; 95% CI: 1.13-7.71, p = 0.028). Type I IgM cryoglobulinaemia is more prevalent than previously described in IgM gammopathy and should be actively sought.

Additionally, DOCK8 depletion selectively decreases proximal BCR signaling, cellular proliferation and viability of DLBCLs with endogenous MYD88L265P/CD79BY196Falterations and increases the efficacy of BTK blockade in these lymphomas. Therefore, MYD88L265P/DOCK8-enhanced proximal BCR signaling is a likely mechanism for the increased sensitivity of MCD/ Cluster 5 DLBCLs to BTK blockade.

The most common frontline treatment is chemoimmunotherapy, such as R-CHOP. Central nervous system prophylaxis should be considered if feasible and consolidation with autologous transplant should be discussed in fit patients responding to chemoimmunotherapy.

The key recommendations from IWWM-11 CP4 included: (1) reaffirmation of IWWM-2 consensus panel recommendations that arbitrary values for laboratory parameters such as minimal IgM level or bone marrow infiltration should not be used to distinguish Waldenstrom's macroglobulinemia from IgM MGUS; (2) delineation of IgM MGUS into 2 subclasses including a subtype characterized by clonal plasma cells and MYD88 wild-type, and the other by presence of monotypic or monoclonal B cells which may carry the MYD88 mutation; and (3) recognition of "simplified" response assessments that use serum IgM only for determining partial and very good partial responses (simplified IWWM-6/new IWWM-11 response criteria). Guidance on response determination for suspected IgM flare and IgM rebound related to treatment, as well as extramedullary disease assessment was also updated and included in this report.

At survival analysis, the most important prognostic factors in PCDLBCL patients were age and MYD88 mutation, whereas relapse and high Ki67 expression were relevant in SCDLBCL patients. Our study comprehensively analyzed the clinico-pathological and molecular features of PCDLBCL LT, PCDLBCL-NOS, and SCDLBCL, underlining the differnces among them and the importance of properly identifying these entities at the time of diagnosis.

The higher incidence of second malignancies in the older subgroup could be related to inferior OS. However, we have registered no WM-related or unrelated (including "other neoplasia") features determining a worse OS outcome. Probably, the main causes of death in the very elderly subgroup of WM patients are due tocomorbidities not included in our analysis.

P2, N=42, Recruiting, Dana-Farber Cancer Institute | Not yet recruiting --> Recruiting | Initiation date: Aug 2023 --> May 2023

MYD88 variant has a high prevalence (66.7%) in anti-MAG antibody neuropathy representing a potential effective mutational target for Bruton tyrosine kinase inhibitors. MYD88 variant, however, does not seem to be a prognostic factor of neuropathy severity or response to rituximab. In patients not responding or becoming refractory to rituximab, a tailored therapy with new effective target therapies should be considered.

Initial clinical data with KT-413 demonstrate degradation of IRAK4 and Ikaros/Aiolos in PBMC and tumor. It is anticipated that higher doses will achieve the predicted degradation profile in tumors that may confer clinical benefit in MYD88-mutant patients. Dose escalation is ongoing, and analyses from additional patients will be presented at the meeting.

Here, we conducted a large cohort to further explore the incidence, clinical application and prognostic significance of MYD88 and CXCR4 mutation in Chinese WM/LPL. ASPCR and ddPCR exhibited the highest sensitivity in MYD88 mutation detection, and were effective and accurate enough for un-sorted low infiltrated WM specimens. And NGS was the most sensitive method to detect CXCR4 mutation.

P=N/A, N=111, Not yet recruiting, BeiGene | Initiation date: Dec 2022 --> Apr 2023

The MYD88 L265P mutation could also be detected using cell-free DNA derived from the cerebrospinal fluid of two PCNSL cases. Detection of the MYD88 L265P mutation using GeneSoC might not only improve the accuracy of intra-operative diagnosis of PCNSL but also help the future pre-operative diagnosis through liquid biopsy of cerebrospinal fluid.

P2, N=42, Not yet recruiting, Dana-Farber Cancer Institute

P=N/A, N=111, Not yet recruiting, BeiGene

Furthermore, based on new genetic classifications, co-mutations in MYD88 and CD79 (C5 and MCD subgroups) are associated with an inferior survival after standard R-CHOP. Enrollment in the Phase 1a portion of the KT413-DL-101 study is ongoing. NCT05233033.

Among the SCDLBCL, only relapse and high expression of Ki67 are associated with shorter OS (Tab1).Discussion Our study emphasizes the clinico-pathological, cytogenetic and molecular similarities and differences between PCDLBCL and SCDLBCL, underlying the importance of properly staging CDLBCL pts at time of diagnosis . In the PCDLBCL setting, we confirmed the independent pathological entity of the NOS category highlighting the better prognostic outcome of this subtype.

In November 2021, zanubrutinib became the first of these agents to be approved by the European Medicines Agency for the treatment of WM...Acalabrutinib, which is pre-approval in WM, appears to offer similar advantages over ibrutinib in terms of its safety profile...In the future, BTKis may be increasingly utilized within combination regimens. Several ongoing trials in WM are investigating the potential for BTKi use in combination with established and novel targeted agents.

In summary, WGS analysis in WM allows the demonstration of sustained germinal center activity over time and allows the reconstruction of the temporal evolution of specific genomic features. In addition, our data suggests that, while MYD88-mutations are central to WM clone establishment and can be observed in precursor disease, CNA may contribute to later phases, and may be used as a biomarker for progression risk from precursor conditions to symptomatic disease.

However, some patients (pts) have experienced toxicities to BTK inhibitors ibrutinib (ibr) and acalabrutinib (acala), which lead to dose reduction or treatment discontinuation. Exploratory analysis results confirmed that cell cycle, DNA damage, and NOTCH1 pathway genes were frequently mutated in pts with B-cell malignancies on study BGB-3111-215 (pts intolerant to ibr and/or acala). Pts with mutations associated with poor prognosis at baseline were more likely to develop PD.

Background: Based on new genetic classifications, co-mutations in MYD88 and CD79B (C5 and MCD subgroups) are associated with an inferior survival after standard R-CHOP. Preclinical studies highlight the potential of IRAKIMiDs as a therapeutic approach for the treatment of MYD88MT DLBCL. KTX-582 demonstrates preferential activity in MYD88MT ABC-DLBCL. Single agent venetoclax demonstrated varying potency in ABC-DLBCL cell lines, irrespective of MYD88 mutational status.

This is the largest reported series describing the characteristics of IgM-associated type I cryoglobulinaemia. It is common amongst patients with monoclonal IgM disorders and approximately half of patients may be symptomatic. Distinct clonal populations are present in which type I cryoglobulinaemia may develop including an MYD88L265P WM clone and MYD88-wild type CAD/anti-MAG clone.

Eight patients received ibrutinib, and 6 chemo-immunotherapy. Conclusion This study demonstrates that the BR regimen is efficient in treatment naïve WM pts, yielding long-term responses. The occurrence of secondary cancers, including TRMN, should be closely monitored in these patients.

Therefore, and based on the above, BTK inhibitor monotherapy is preferred in patients with MYD88MUT/CXCR4WT disease, while the addition of rituximab to ibrutinib or zanubrutinib can be considered in patients with MYD88MUT/CXCR4MUT or MYD88MUT/ CXCR4WT disease. Rituximab-containing regimens such as bendamustine and rituximab, or bortezomib, dexamethasone and rituximab are safe and highly effective options in WM patients regardless of MYD88 or CXCR4 mutational status13,14. The BCL2 antagonist venetoclax is another option in the relapsed setting...Ongoing clinical trials are investigating triple, fi xed-duration BTK inhibitors-containing regimens as well as non-covalent BTK inhibitors and immunotherapeutic agents such as the phospholipiddrug conjugate CLR-131, the anti-CD19 antibody-drug conjugate loncastuximab, and chimeric antigen receptor T-cells. It would be of great interest to investigate the impact that the genomic profi le of patients WM might have on these novel agents. Also, additional research is needed to standardize MYD88 and CXCR4 mutational testing to further optimize the applicability of genomic profi le in the management of patients with WM.

Fixed duration BR is a highly effective primary therapy for WM, irrespective of the pts’ MYD88L265P mutation status. Progression of disease within 2 years (POD24) of initiation of BR is associated with inferior OS. Our preliminary analysis, suggesting that CXCR4WHIM mutation confers resistance to BR, warrants confirmation in prospective studies.

ASPEN is the largest phase 3 trial with head-to-head BTKi comparison in WM. At a median follow-up of 43 mo, ZANU was associated with a higher VGPR+CR rate and clinically meaningful advantages in long-term safety and tolerability vs IBR.

The first patient with anti-MAG neuropathy treated with venetoclax-rituximab shows encouraging results.

Patients with IGHV4, especially IGHV4-34, had higher levels of lactate dehydrogenase, and IGHV4 was a predictive marker of shorter progression-free survival. These results showed for the first time that the IGHV repertoire has clinical relevance in LPL/WM.

The first patient with anti-MAG neuropathy treated with venetoclax-rituximab shows encouraging results.

Conclusion Fixed-duration BR is a highly effective regimen for pts with previously untreated symptomatic WM, irrespective of the MYD88 L265P mutation status, although early POD, within 2 years of initiation of BR, is associated with inferior subsequent survival. Our preliminary analysis, suggesting that the presence of CXCR4 mutation confers resistance to BR, warrants confirmation in prospective studies.