CXCR4 mutation

The recent advances in RNA-based gene targeting including CRISPR and short interfering RNA (siRNA), and the potential application to HPV infection are of great interest. An increased understanding of both the dysregulated immune responses in immunocompromised hosts and of viral persistence is essential for the design of next-generation therapies to eliminate HPV persistence and cancer development in the most at-risk populations.

Spleen tissue and peripheral blood samples from the patient were sequenced using a next-generation sequencing platform, and mutations possibly were detected in the CXCR4 and TRAF3 genes that may be related to the pathogenesis of the disease. This finding may provide insights into the molecular pathogenesis of SDRPL and assist in molecular diagnosis and targeted therapy for SDRPL.

Most mutations detected by NGS were subclonal following MYD88 L265P, although one non-IgM-type LPL patient harbored only CXCR4 S338X mutation. Our NGS analyses reveal genetic characteristics in LPL patients and suggest genetic similarities between these two subsets of LPL, WM and non-IgM-type.

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

Although associated with high rates of durable responses, unmet needs with BTK inhibitor therapy include indefinite duration therapy, high cost, scarcity of complete responses, and lower rates and shorter duration of response in patients with CXCR4 mutations. Herein, we review the data supporting the use of covalent BTK inhibitors, selected management issues, clinical trials with covalent BTK inhibitor combination regimens, and up-and-coming non-covalent BTK inhibitors.

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.

P2, N=80, Not yet recruiting, University of Ulm | Trial completion date: Dec 2029 --> Jun 2030 | Trial primary completion date: Dec 2024 --> Jun 2025

Bendamustine, Rituximab and Acalabrutinib front-line therapy for Waldenström's macroglobulinaemia is safe and well tolerated and initial clinical results show all 8 patients who completed 6 cycles of BR and Acalabrutinib to date have achieved a VGPR.

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.

This series of 2523 lymphoma samples represents a large collection of mutational data across different histologic subtypes. Despite MSK-IMPACT panels not being a discovery panel, the assay serves to describe identified somatic mutations across lymphoma subtypes. Individual mutations represent a smaller lymphoma population, however recurrent genetic alterations converge on common oncogenic pathways which cumulatively represent a larger lymphoma population.

In this largest multi-omic investigation undertaken into WM, we identified three distinct WM subtypes with distinct clinical and genomic features. Central these findings were the identification of BCL, PCL, and an earlier non-BCL/PCL evolving stage recognized through DPT modeling. The discovery of the DPT model for WM disease progression provides insight into the biology and targeting of WM progression.

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.

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.

Single cell sequencing techniques allow to characterize tumor heterogeneity and elucidate the order of appearance and co-dependency of alterations, which could shed light on the putative mechanisms leading to progression. WM evolution seems to be consistent with a branching model in which only clones containing MYD88 mutation give rise to more aggressive populations by acquiring new aberrations.

The combination of ibrutinib and venetoclax was associated with a major response rate of 93%, and a VGPR rate of 40% in previously untreated WM. However, there was a higher-than-expected rate of ventricular arrhythmia of 9%, which prompted stopping study therapy.

Orelabrutinib has shown good efficacy and manageable safety profiles in patients with R/R WM. InnoCare Pharma.

Due to better understanding of WM biology and the arrival of novel anti-lymphoma agents, the therapeutic options are increasing. Non-cytotoxic and fixed duration regimens, such as those explored in other indolent NHLs should be the focus of future clinical trials in WM.

In conclusion, the results highlight a potential diagnostic pitfall of LPL associated with marked plasmacytic differentiation and an IgG or IgA paraprotein that can resemble a plasma cell neoplasm. Useful features in favor of LPL against PCN include the characteristic immunophenotypic profile of the PCs in LPL, absence of CCND1::IGH and the presence of MYD88 and/or CXCR4 mutations.

Moreover, high BM mutation burden (≥8% MYD88 and ≥2% CXCR4) was associated with an increased risk of progression to symptomatic WM. We show the clinical applicability of ddPCR to assess MYD88 and CXCR4 in IgM MGUS and SWM and provide a molecular-based risk classification.

ASPEN is the largest phase 3 WM trial with head-to-head BTKi comparison. At a median follow-up of 43 months, zanubrutinib had higher CR+VGPR rates and clinically meaningful advantages in long-term safety/tolerability versus ibrutinib.

ASPEN is the largest phase 3 WM trial with head-to-head BTKi comparison. At a median follow-up of 43 months, zanubrutinib had higher CR+VGPR rates and clinically meaningful advantages in long-term safety/tolerability versus ibrutinib.

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.

P2, N=80, Not yet recruiting, University of Ulm | Initiation date: Jun 2022 --> Sep 2022

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.

In conclusion, MC density can be accurately measured in WM patients using a specific digital tool on well-outlined hematopoietic tissue surfaces. High MC density is associated with aggressive features and a poor clinical outcome, emphasizing the need for further investigation of the involvement of MCs in the pathophysiology of WM.

The first BTK inhibiting therapy, ibrutinib, showed great efficacy in treating WM...Another Phase 1/2 study has been conducted with just zanubrutinib in WM showcasing high efficacy with few toxicities as well. Even though zanubrutinib has been the third and last BTK inhibitor to currently penetrate the market for B-cell lymphoproliferative malignancies, we highlight the emergence of zanubrutinib as a key player in the forefront of the therapeutic landscape in WM.

Meanwhile, we found that De Novo CD5-positive DLBCL had BCL-6(9/46,19.6%), C-MYC (4/46, 8.7%) and IRF4 (2/19, 10.5%) rearrangement, but without BCL-2 rearrangement, there were no significantly associations with prognosis. In summary, our research explored the gene alterations of De Novo CD5-positive DLBCL in a relatively large scale for the first time, the most common gene mutation was MYD88 which was also a potential prognostic factor, providing a potential therapeutic target for the patients of De Novo CD5-positive DLBCL.

Treatment included chemotherapy(containing nitrogen mustard phenylbutyrate, fludarabine, cyclophosphamide), proteasome inhibitor regimens, rituximab regimens and immunomodulator regimens. Conclusion These results demonstrate that zanubrutinib and dexamethasone are quickly effective in the treatment of WM, with more deeper response and less toxicity.

Between 1984 and 2021 the three most popular treatments received at L1 were: Dexamethasone-Rituximab-Cyclophosphamide (DRC) 20.1% (144/690), R-Bendamustine (BR) 15.2% (105/690), Fludarabine based (±Cyclophosphamide, Rituximab) 9.0% (62/690) [Figure 1]...The most received treatments from 2020 at: Ibrutinib 31.1% (60/193), R-Bendamustine 12.4% (24/193), DRC 10.4% (20/193)...As targeted therapies have become available, there is a paradigm shift towards their use; however there is still much to learn about the optimal selection and sequencing of therapies in WM patients whose diseases are heterogenous by nature. Patient-related outcome studies are underway to complement ongoing follow-up of clinically meaningful remission duration and tolerance.

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.

Methods WM cells (MWCL-1 cell line, MYD88 L265P CXCR4 WT ) pretreated with mavorixafor and B-cell targeted therapies (BTK antagonists: ibrutinib, zanubrutinib, evobrutinib, pirtobrutinib, nemtabrutinib; or BCL2 inhibitor venetoclax) were co-cultured with established BMSCs (HS27a cells). Conclusion Our studies provide preliminary evidence for the potential use of mavorixafor in disrupting the interaction of WM cells with the BMSC-based microenvironment, enhancing the efficacy of B-cell targeted therapies in the treatment of WM and potentially other lymphomas. Further studies using additional WM cell lines and/or primary patient cells are warranted to support these findings.

A statistically significant difference in CXCR4 MUT level was observed between patients treated at the time of enrollment and those still in WW. However, a longer FU is needed to better clarify the clinical implications of CXCR4 mutations in our series.

P2, N=33, Completed, Dana-Farber Cancer Institute | Active, not recruiting --> Completed

In the absence of head-to-head comparison between chemoimmunotherapy and Bruton's tyrosine kinase inhibitors in otherwise fit patients with a MYD88 mutation, our preference is fixed duration therapy with four to six cycles of chemoimmunotherapy with bendamustine-rituximab. In this review, we discuss the role of MYD88 and CXCR4 mutation in treatment selection, and current data for frontline and salvage treatment options in patients with WM.

P2, N=50, Active, not recruiting, Dana-Farber Cancer Institute | Recruiting --> Active, not recruiting

P2, N=36, Recruiting, Shayna Sarosiek, MD | Not yet recruiting --> Recruiting | Initiation date: Jun 2022 --> Feb 2022

P2, N=80, Not yet recruiting, University of Ulm | Initiation date: Dec 2021 --> Jun 2022

WM cells (MWCL-1 cell line, MYD88L265PCXCR4WT) pretreated with mavorixafor and BTK inhibitors (ibrutinib, zanubrutinib, evobrutinib, LOXO-305, ARQ 531) were co-cultured with established BMSCs (HS27a cells). Mavorixafor addition enhanced the efficacy of not only ibrutinib but the other BTK inhibitors tested, supporting the greater potential of this combination therapeutic strategy in WM patients with or without CXCR4WHIM mutations. Further studies using additional WM cell lines and/or primary patient cells are warranted to support these findings.

The detection of MYD88 mutation is important for a correct therapeutic strategy, since a Brutons tyrosine kinase inhibitor, ibrutinib, is most effective in patients with mutated MYD88 and wt CXCR4. The therapy is started when first symptoms occur. The aim of this study is to summarize current knowledge about this disease, its dia-g-nostics, molecular basis and treatment.