MYD88 mutation + CXCR4 mutation

Testing for MYD88 mutations using AS-PCR or ddPCR in unsorted samples is viable for routine clinical practice. Under BTKi treatment, MYD88 and CXCR4 mutations hold greater prognostic importance than IPSSWM staging in WM.

Indolent T-cell lymphomas/lymphoproliferations of the GI tract are rare but must be differentiated from aggressive T-cell lymphomas. The WHO-HAEM5 also includes reactive/non-neoplastic lymph node lesions classified according to B or T cell predominance.

P1, N=13, Terminated, Dana-Farber Cancer Institute | Phase classification: P1/2 --> P1 | Active, not recruiting --> Terminated; Sponsor decision to end follow-up early

Regimens containing Bruton tyrosine kinase inhibitor (BTKi) were most widely recommended for both treatment-naïve and relapsed/refractory patients (94% for all patients, 95% for treatment-naïve patients, and 75% for relapsed/refractory patients), and most physicians recommended Ibrutinib (84% )...It systematically describes the issues that exist in WM diagnosis and treatment in China, such as a high rate of misdiagnosis, limited access to gene testing and new drugs, and poor patient adherence to treatment. Chinese doctors believe that improving doctors' and patients' understanding of WM is one of the most urgent issues that must be addressed right now.

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.

MYD88 mutation and underlying haemopathies are not predictive of a more severe disease. However, in cases of resistant and progressive neuropathy, they provide an opportunity to prescribe newly available drugs such as Bruton tyrosine kinase inhibitors.

In addition to tumor genotype and patient comorbidities, choice of therapy in WM should take into account these parameters. Results of ongoing and future clinical trials evaluating fixed-duration combinations with BTK inhibitors and novel agents are awaited.

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.

Novel transcripts identified by PacBio IsoSeq analysis drive expression of key genes including the important MAPK/ERK regulator DUSP22, and FC receptor FCRLB that promotes survival of B-lymphocytes. Other genes of interest included modulators of chromatic accessibility. Our findings demonstrate important new insights into isoform usage associated with WM subtype in WM and provide novel insights into the underlying biology of the disease.

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.

High-level evidence supports integration of monoclonal anti-CD20 antibody, rituximab, to the chemotherapy backbone to treat WM...Randomized trials comparing these two vastly divergent approaches are lacking. Recent studies demonstrating efficacy of B cell lymphoma-2 (BCL2) inhibitors and non-covalent BTK inhibitors in patients, previously exposed to a covalent BTK inhibitor, are a testament to the rapidly expanding options against WM.

Extramedullary solitary plasmacytoma of the breast is extremely rare. This case report seeks to educate clinicians about the rare possibility of extramedullary plasmacytoma in the breast, and it should be considered in the differential for a breast lump, especially in patients with autoimmune hepatitis and on azathioprine. Standard treatment for EMP consists of radiation due to high sensitivity and cure rate.

WM patients may benefit from chemotherapy regimens that include rituximab-based regimens, alkylating drugs, proteasome inhibitors, monoclonal antibodies, and drugs targeting Bruton tyrosine kinase inhibitors...Despite the rapidly developing therapeutic armament against WM, a lack of high-quality evidence from extensive phase 3 trials remains a significant challenge in the research. We believe clinical outcomes will keep improving when new medicines are introduced while preserving efficacy and minimizing toxicity.

Thus, there is a need to define genotypes before starting either standard treatment regimens or clinical trials. Here, we review the genomic profile of WM and its clinical implications while focusing on recent advances.

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.

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.

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.

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.

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.

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.

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.

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.

Head-to head comparative data to inform optimal approach are lacking, and a particularly vexing issue for the clinicians is choosing between fixed-duration bendamustine-rituximab (BR) therapy and an indefinite BTK inhibitor-based regimen, given that both approaches are well tolerated and effective, particularly for the patient population harboring MYD88 mutation. For the patients with MYD88 genotype, chemo-immunotherapy such as BR is preferred, although zanubrutinib, a potent second generation BTK inhibitor, with its reduced off target effects and greater BTK occupancy compared to its predecessor, ibrutinib, has also recently shown activity in MYD88 WM. This review summarizes the current literature pertaining to the diagnosis, prognosis, and the treatment of WM.

Novel drugs, including BTKi, continue to benefit patients with WM and improve their survival. It is worthwhile to further explore the positivity of MYD88 and CXCR4 mutations in the Chinese population and their sensitivity to BTKi.

Methods : Percentage changes in total peripheral WBC count, absolute neutrophil count (ANC), absolute lymphocyte count (ALC), and absolute monocyte count (AMC) from pretreatment levels were evaluated in the following settings: a phase 1/2 trial evaluating mavorixafor (200 mg twice daily or 400 mg once daily [QD]) in combination with axitinib (5 mg twice daily) in patients with advanced ccRCC who received ≥1 prior therapy; a phase 1b trial evaluating mavorixafor (400 mg QD) in combination with nivolumab (240 mg QD) in patients with metastatic ccRCC unresponsive to prior nivolumab monotherapy; a long-term extension of the aforementioned phase 2 trial evaluating mavorixafor 300 or 400 mg QD in patients with WHIM syndrome with pathogenic CXCR4 gain-of-function mutation and ANC ≤400/μL and/or ALC ≤650/μL; and an ongoing phase 1b trial evaluating mavorixafor (200 mg QD for 4 weeks, increased to 400 mg and 600 mg QD thereafter) in combination with ibrutinib (420 mg QD) in patients with WM with MYD88 and CXCR4 mutations. Mavorixafor alone or in combination with other therapies is the first oral treatment to either acutely or chronically increase total peripheral WBCs 1.5- to 3-fold and WBC subsets across all disease populations examined, in both the presence (WHIM syndrome and WM) and absence (ccRCC and healthy volunteers) of CXCR4 gain-of-function mutation. Increases in WBC subsets occurred rapidly and were sustained during chronic treatment, with a larger treatment effect in patients with pre-existing cytopenia (WHIM syndrome) compared to patients without cytopenia at baseline (ccRCC and WM). Co-occurring reduction in infection burden was observed in the phase 2 trial in WHIM syndrome.

Bendamustine rituximab (BR), cyclophosphamide, dexamethasone rituximab (CRD) and bortezomib dexamethasone rituximab (BDR) are currently considered frontline options. The Bruton tyrosine kinase inhibitor (BTKi) ibrutinib in combination with rituximab (IR) has recently shown efficacy in treatment naïve WM and has been approved for use in this setting...While chemo-immunotherapy remains a potent, fixed duration option for newly diagnosed WM, BTKi based regimens are a valid alternative for patients who prefer an oral treatment or who are unfit for cytotoxic therapy. With the expanding number of treatment options for WM, RCTs comparing BTKi/immunotherapy with chemo-immunotherapy regimens are called for.

Our findings as of June 2021 in patients with WM carrying both MYD88 and CXCR4 WHIM mutations show that mavorixafor in combination with ibrutinib is well tolerated. Mavorixafor and ibrutinib exposures were consistent with previous single-agent studies, suggesting no drug–drug interactions, and mavorixafor exposures tracked with increases in key WBC counts. All evaluable patients demonstrated at least a minor response.

It has shown favorable safety and tolerability profile with limited off-target adverse effects. It has the potential to be a promising treatment option for r/r WM patients.

In the final analysis of iNNOVATE with a median follow-up of 50 months, ibrutinib-rituximab showed ongoing superiority across clinical outcomes in patients with WM regardless of MYD88 or CXCR4 mutation status, prior treatment, and key patient characteristics.

Data from a retrospective review of 63 patients, with known CXCR4 mutational status in 49 patients, treated with bortezomib and rituximab showed no significant difference in PFS or OS when comparing patients with or without CXCR4 mutations.6 A prospective study of 69 patients treated with bendamustine plus rituximab showed no difference in disease response or survival outcomes based on the CXCR4 mutational status.7 Similar results were also reported in a pooled analysis of patients treated with bortezomib, carfilzomib, or ixazomib in the frontline setting.8 No difference in response rates, PFS or OS after frontline treatment initiation was noted between patients with and without CXCR4 mutations...Patients with MYD88WT and CXCR4WT disease, which constitute 5–10% of patients with WM, have specific clinical characteristics, such as shorter overall survival (OS) and increased risk of transformation to aggressive lymphoma.10–12 Bendamustine plus rituximab should be considered an option given reported efficacy in a retrospective study.13 However, a prospective study suggested a shorter PFS in the six MYD88WT patients.2 Lower response rates to single agent ibrutinib were reported in a study using an allele-specific polymerase chain reaction (AS-PCR) assay in CD19-selected bone marrow cells to assess MYD88 mutational status.14 In the INNOVATE study, the combination of ibrutinib plus rituximab was associated with an ORR of 81%, a major response rate of 63%, a VGPR rate or 27% and a 30-month PFS rate of 80% in patients with MYD88WT and CXCR4WT disease.9 In this study, however, the MYD88 mutational status was assessed in 136 patients using next-generation sequencing (NGS) in unselected bone marrow cells...In the acalabrutinib study, 50 of 106 (47%) of the participants were genotyped and 14 (28%) had MYD88WT disease...Zanubrutinib therapy was associated with an ORR, major response rate and VGPR rate of 80%, 50% and 27%, with an 18-month PFS rate of 68%. Genomic profiling has emerged as a potential approach to tailoring treatment options in patients with WM.

During study participation extensive neurological testing and serum IgM and anti MAG testing will be performed. In total 40 patients will be included and the MAGNAZ study expects to start in Q4 2021.

For patients with MYD88 and CXCR4 mutations or without MYD88 or CXCR4 mutations, chemoimmunotherapy or proteasome inhibitor-based regimens are favored, but efficacy data with ibrutinib in combination with rituximab and with novel covalent BTK inhibitors are emerging. Participation in clinical trials is positively encouraged in WM patients in frontline and relapsed settings. Agents of interest include the BCL2 antagonist venetoclax, the CXCR4 inhibitor mavorixafor, and the non-covalent BTK inhibitors pirtobrutinib and ARQ-531.

The study demonstrates the feasibility of combining a CXCR4-antagonist with ibrutinib, and provides support for the development of CXCR4-antagonists for CXCR4Mut WM. www.clinicaltrials.gov (NCT03225716).

Both MYD88 and CXCR4 were identified with high sensitivity and specificity in cfDNA derived from the plasma of WM patients, including previously treated patients. The use of cfDNA represents a non-invasive, convenient, and potentially cost-effective method for genotyping patients with WM.

Our findings to date in patients with WM carrying both MYD88 and CXCR4 mutations show that mavorixafor in combination with ibrutinib is well tolerated at doses ≤400 mg QD. Unaltered mavorixafor and ibrutinib exposures suggest no apparent drug–drug interaction, and mavorixafor exposures tracked with increased WBC counts. Combination of mavorixafor with ibrutinib led to rapid and clinically meaningful decrease in IgM, suggesting mavorixafor may sensitize CXCR4WHIM-expressing cells to BTKi.

P1/2, N=13, Active, not recruiting, Dana-Farber Cancer Institute | Trial primary completion date: Jan 2021 --> Jan 2023

Mavorixafor and ibrutinib exposures were consistent with previous single-agent studies, suggesting no drug–drug interactions, and mavorixafor exposures tracked with increases in key WBC counts. Combination of mavorixafor with ibrutinib led to rapid and clinically meaningful decrease in IgM levels, suggesting that mavorixafor may sensitize CXCR4WHIM-expressing cells to BTKi.

FCM exploration of both B-cells and PC led to identify a CD138 expression continuum as an objective marker of ongoing PC differentiation of WM tumor cells and was strongly associated with increased IgM peak levels and MYD88 mutations. This approach could contribute to place FCM at the forefront of WM diagnosis.