The role of ibrutinib in COVID-19 hyperinflammation: A case report.

Immune modulation in COVID-19 is emerging as an important therapeutic strategy as increasing evidence suggests that inflammatory pathways are implicated in lung damage. Bruton tyrosine kinase inhibitors (BTKi), such as ibrutinib, are commonly used to treat indolent B-cell neoplasms and chronic graft-versus-host disease (GvHD). Given their potential to suppress pulmonary inflammatory cytokines and lessen acute lung injury, this could be applicable in the context of hospitalised COVID-19 patients. We describe an 81 year-old male receiving ibrutinib for Waldenstrom macroglobulinaemia (WM) who was hospitalised with COVID-19. On stopping the BTKi due to concerns of additional immunosuppression, he required non-invasive ventilation (NIV) in the intensive care unit (ICU) and demonstrated prompt clinical recovery when ibrutinib was reinstated. Continuing ibrutinib in patients with COVID-19 may be advantageous given its immunomodulatory properties and withdrawal of ibrutinib therapy may be detrimental. Further evidence is required to explore the potential therapeutic impact of BTKis and other immunomodulatory agents on the clinical course of COVID-19 as is currently being carried out in a number of clinical trials.

CANOMAD: a neurological monoclonal gammopathy of clinical significance that benefits from B-cell-targeted therapies.

CANOMAD (chronic ataxic neuropathy, ophthalmoplegia, immunoglobulin M [IgM] paraprotein, cold agglutinins, and disialosyl antibodies) is a rare syndrome characterized by chronic neuropathy with sensory ataxia, ocular, and/or bulbar motor weakness in the presence of a monoclonal IgM reacting against gangliosides containing disialosyl epitopes. Data regarding associated hematologic malignancies and effective therapies in CANOMAD are scarce. We conducted a French multicenter retrospective study that included 45 patients with serum IgM antibodies reacting against disialosyl epitopes in the context of evocating neurologic symptoms. The main clinical features were sensitive symptoms (ataxia, paresthesia, hypoesthesia; n = 45, 100%), motor weakness (n = 18, 40%), ophthalmoplegia (n = 20, 45%), and bulbar symptoms (n = 6, 13%). Forty-five percent of the cohort had moderate to severe disability (modified Rankin score, 3-5). Cold agglutinins were identified in 15 (34%) patients. Electrophysiologic studies showed a demyelinating or axonal pattern in, respectively, 60% and 27% of cases. All patients had serum monoclonal IgM gammopathy (median, 2.6 g/L; range, 0.1-40 g/L). Overt hematologic malignancies were diagnosed in 16 patients (36%), with the most frequent being Waldenström macroglobulinemia (n = 9, 20%). Forty-one patients (91%) required treatment of CANOMAD. Intravenous immunoglobulins (IVIg) and rituximab-based regimens were the most effective therapies with, respectively, 53% and 52% of partial or better clinical responses. Corticosteroids and immunosuppressive drugs were largely ineffective. Although more studies are warranted to better define the optimal therapeutic sequence, IVIg should be proposed as the standard of care for first-line treatment and rituximab-based regimens for second-line treatment. These compiled data argue for CANOMAD to be included in neurologic monoclonal gammopathy of clinical significance.

An evaluation of Ibrutinib for the treatment of Waldenstrom macroglobulinaemia.

INTRODUCTION: Waldenstrom Macroglobulinaemia (WM) is a heterogenous condition which poses a challenge to manage. Novel therapies such as Ibrutinib have been shown to be efficacious in treating WM. The landscape of Ibrutinib's role in treating WM is everchanging with new discoveries in disease genomics and evolution together as well as through new findings in clinical trials. AREAS COVERED: A systematic literature review was carried out using two databases 'Medline' and 'Embase' from 2009 to July 2019. Keywords used included 'Ibrutinib,' 'Waldenstrom Macroglobulinaemia,' and 'lymphoma.' There were four major clinical trials identified primarily describing outcomes of Ibrutinib in managing WM which this paper evaluates in detail. The authors present evidence of the role of Ibrutinib in the management of specific complications associated with WM. They also explore the recently discovered genomics of the disease affecting response to therapy. EXPERT OPINION: The evidence for the use of Ibrutinib as a treatment option for relapsed/refractory WM is compelling in MYD88 mutated WM with the response and survival rates potentially better than conventional salvage chemoimmunotherapy. There is also a case for it to be used in the frontline setting in patients unfit for conventional frontline chemoimmunotherapy.

Identification of 2 DNA methylation subtypes of Waldenström macroglobulinemia with plasma and memory B-cell features.

Epigenetic changes during B-cell differentiation generate distinct DNA methylation signatures specific for B-cell subsets, including memory B cells (MBCs) and plasma cells (PCs). Waldenström macroglobulinemia (WM) is a B-cell malignancy uniquely comprising a mixture of lymphocytic and plasmacytic phenotypes. Here, we integrated genome-wide DNA methylation, transcriptome, mutation, and phenotypic features of tumor cells from 35 MYD88-mutated WM patients in relation to normal plasma and B-cell subsets. Patients naturally segregate into 2 groups according to DNA methylation patterns, related to normal MBC and PC profiles, and reminiscent of other memory and PC-derived malignancies. Concurrent analysis of DNA methylation changes in normal and WM development captured tumor-specific events, highlighting a selective reprogramming of enhancer regions in MBC-like WM and repressed and heterochromatic regions in PC-like WM. MBC-like WM hypomethylation was enriched in motifs belonging to PU.1, TCF3, and OCT2 transcription factors and involved elevated MYD88/TLR pathway activity. PC-like WM displayed marked global hypomethylation and selective overexpression of histone genes. Finally, WM subtypes exhibited differential genetic, phenotypic, and clinical features. MBC-like WM harbored significantly more clonal CXCR4 mutations (P = .015), deletion 13q (P = .006), splenomegaly (P = .02), and thrombocytopenia (P = .004), whereas PC-like WM harbored more deletion 6q (P = .012), gain 6p (P = .033), had increased frequencies of IGHV3 genes (P = .002), CD38 expression (P = 4.1e-5), and plasmacytic differentiation features (P = .008). Together, our findings illustrate a novel approach to subclassify WM patients using DNA methylation and reveal divergent molecular signatures among WM patients.

The Bruton tyrosine kinase inhibitor ibrutinib improves anti-MAG antibody polyneuropathy.

OBJECTIVE: To assess whether neuropathy with anti-myelin-associated glycoprotein (MAG) antibody may improve after treatment with ibrutinib, an oral inhibitor of Bruton tyrosine kinase, we prospectively treated with ibrutinib a cohort of 3 patients with anti-MAG neuropathy and Waldenström macroglobulinemia (WM). METHODS: All 3 patients underwent bone marrow biopsy showing WM, with MYD88 L265P mutated and CXCR4S338X wild type, and were started on ibrutinib 420 mg/die. Patients were assessed at baseline, at 3-6-9 months, and at 12 months in 2 patients with a longer follow-up, using Inflammatory Neuropathy Cause and Treatment (INCAT) Disability Score, INCAT sensory sum score, and Medical Research Council sum score. The modified International Cooperative Ataxia Rating Scale was performed in 2 patients, whereas it was not used in the patient with Parkinson disease as a major comorbidity. Responders were considered the patients improving by at least one point in 2 clinical scales. RESULTS: All the patients reported an early and subjective benefit, consistent with the objective improvement, especially of the sensory symptoms as shown by clinical scales. Treatment was well tolerated. CONCLUSION: These preliminary data point to a possible efficacy of ibrutinib in anti-MAG antibody neuropathy, which is the most common disabling paraproteinemic neuropathy, where active treatment is eagerly needed. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for patients with anti-MAG antibody neuropathy, ibrutinib improves neuropathy symptoms.

Ibrutinib monotherapy outside of clinical trial setting in Waldenström macroglobulinaemia: practice patterns, toxicities and outcomes.

Ibrutinib-related data in Waldenström macroglobulinaemia (WM) remain sparse, particularly outside of trials. We report on 80 patients [previously treated, n = 67 (84%), treatment-naïve, n = 13 (16%)] with WM, evaluated consecutively at Mayo Clinic, who received ibrutinib off-study after its approval in 2015 for WM. Overall response rate (ORR) was 91%; major-response rate (MRR) was 78%. The median time to first response and best response was 2·9 [95% confidence interval (CI): 2-4] and 5·7 (95% CI: 4-12) months, respectively. The median follow-up was 19 (95% CI: 14-21) months; 18-month progression-free survival (PFS) was 82%. The median time on therapy was 12·5 (95% CI: 9·3-16·7) months, and the median duration-of-response was 32 (range: 23-32) months. Twenty-five patients (31%) had discontinued therapy at last follow-up (68% due to treatment-related toxicities) and 18% of patients required dose reduction. Fatigue (12%) and atrial-fibrillation (11%) were common non-haematological toxicities. IgM rebound occurred in 36% of patients who abruptly discontinued ibrutinib. Following ibrutinib discontinuation, 84% of patients received subsequent treatment, achieving an ORR of 57% and MRR of 50%. The median PFS from commencement of subsequent salvage therapy was 18 months. Ibrutinib therapy, outside of clinical trials, is effective in WM, but is associated with toxicities and challenges, including IgM rebound and a high drug discontinuation rate for reasons other than disease progression.

Treatment of Bing-Neel syndrome with first line sequential chemoimmunotherapy: A case report.

RATIONALE: Bing-Neel syndrome (BNS) is a rare manifestation of Waldenström macroglobulinemia (WM) with <200 cases reported in the literature. Herein, we describe a case of newly diagnosed BNS treated with a novel therapeutic strategy. PATIENT CONCERNS: A 67-year-old woman diagnosed with asymptomatic WM 3 years ago presented with gradual vision deterioration the past 3 months. Ophthalmologic examination revealed bilateral reduction in visual acuity (7/10) and bilateral optic disc swelling which was more prominent in the left eye. DIAGNOSES: Brain imaging revealed bilateral swelling of optic nerves extending from the retina to the optic chiasm and swelling of the left optic tract. Patchy enhancement of optic nerves was also shown upon intravenous contrast administration. Flow cytometry of the cerebrospinal fluid (CSF) revealed the presence of κ-light chain restricted, monoclonal B-lymphocytes. CSF protein electrophoresis showed a monoclonal band in the gamma region and immunofixation was positive for immunoglobulin M and kappa light chain. Thus, the diagnosis of BNS was established. INTERVENTIONS: The patient was initially treated with intrathecal methotrexate and systemic chemotherapy. Following 2 intrathecal methotrexate infusions, CSF flow cytometry did not detect any cells, whereas the patient reported improvement in visual acuity. Therefore, we opted to start maintenance treatment with IV rituximab and per os ibrutinib. OUTCOMES: Following 1 year posttreatment initiation, visual problems have resolved completely and the patient remains on hematologic and imaging complete response. LESSONS: We propose a novel sequential chemoimmunotherapy approach for BNS treatment aiming both at rapid disease control and deep and durable remission with minimization of induced toxicity.

CXCR4 mutations affect presentation and outcomes in patients with Waldenström macroglobulinemia: A systematic review.

Introduction: The genomic landscape of Waldenström macroglobulinemia (WM) is characterized by recurrent MYD88 (MYD88L265P) and CXCR4 mutations (CXCR4MUT), detected in 90% and 30% of cases, respectively. The role of CXCR4MUT in clinical features and outcomes to therapy in WM patients is evolving. Areas covered: We performed a systematic review aimed at evaluating the prevalence of CXCR4MUT in WM patients, and at assessing differences in clinical features and outcomes to therapy between WM patients with and without CXCR4MUT. Seventeen studies were included in our analysis. The pooled prevalence of CXCR4MUT in WM patients was 31%; 34% in MYD88L265P and 5% in MYD88WT patients. CXCR4MUT were associated with higher serum IgM levels and higher risk of hyperviscosity than CXCR4WT patients. Very good partial response (VGPR) and progression-free survival (PFS) rates to ibrutinib, with and without rituximab, appeared lower in CXCR4MUT than in CXCR4WT patients. Response and PFS rates were not affected by CXCR4MUT status on patients treated with proteasome inhibitors. Expert opinion: Our systematic review shows that WM patients with CXCR4MUT have specific clinical features and have lower response and PFS rates to BTK inhibitors. Our findings support standardization of CXCR4 testing and development of CXCR4-directed therapy.

Neuropathies and paraproteins.

PURPOSE OF REVIEW: There is an increasingly recognized association between haematological and neurological disease. This is especially true in the peripheral nervous system in which, to an extent, proof of a link is easier to achieve. The most sensitive low level paraprotein detection methods should always be employed in which a paraprotein is suspected. Peripheral nerves can be damaged not only by the immunological targeting of the myelin by the paraprotein, but by deposition (light chain amyloid and cryoglobulins) or direct infiltration (neurolymphomatosis). This has resulted in other defined paraprotein-related disease pathogeneses. RECENT FINDINGS: Our opportunities for treating these patients are greater not only through better recognition of disease but also treatments introduced from haematological research. Beyond rituximab, combination therapies, proteasome inhibition and novel biological treatments are being described in haematological practice with early efficacy in neurology. Important developments here should be exploited in neurology to improve outcomes. SUMMARY: This review of the current literature focuses not only on the long-term outcome studies in anti-myelin-associated glycoprotein neuropathy, but developments in the diagnosis and treatment of monoclonal gammopathy of undetermined significance and Waldenström's Macroglobulinaemia.

Progression Risk Stratification of Asymptomatic Waldenström Macroglobulinemia.

BACKGROUND: Waldenström macroglobulinemia (WM) is preceded by asymptomatic WM (AWM), for which the risk of progression to overt disease is not well defined. METHODS: We studied 439 patients with AWM, who were diagnosed and observed at Dana-Farber Cancer Institute between 1992 and 2014. RESULTS: During the 23-year study period, with a median follow-up of 7.8 years, 317 patients progressed to symptomatic WM (72%). Immunoglobulin M 4,500 mg/dL or greater, bone marrow lymphoplasmacytic infiltration 70% or greater, ß2-microglobulin 4.0 mg/dL or greater, and albumin 3.5 g/dL or less were all identified as independent predictors of disease progression. To assess progression risk in patients with AWM, we trained and cross-validated a proportional hazards model using bone marrow infiltration, immunoglobulin M, albumin, and beta-2 microglobulin values as continuous measures. The model divided the cohort into three distinct risk groups: a high-risk group with a median time to progression (TTP) of 1.8 years, an intermediate-risk group with a median TTP of 4.8 years, and a low-risk group with a median TTP of 9.3 years. We validated this model in two external cohorts, demonstrating robustness and generalizability. For clinical applicability, we made the model available as a Web page application ( www.awmrisk.com ). By combining two cohorts, we were powered to identify wild type MYD88 as an independent predictor of progression (hazard ratio, 2.7). CONCLUSION: This classification system is positioned to inform patient monitoring and care and, for the first time to our knowledge, to identify patients with high-risk AWM who may need closer follow-up or benefit from early intervention.

AL amyloidosis with a localized B cell neoplasia.

Immunoglobulin light chain-derived (AL) amyloidosis may occur as a systemic disease usually with dismal prognosis and a localized variant with favorable outcome. We report 29 patients with AL amyloidosis and associated lymphoplasmacytic infiltrate spatially related to amyloid deposits. In 17 cases, the amyloid deposits were classified as ALλ and 12 as ALκ Histopathology in all cases showed relatively sparse plasma cells and B cells without tumor or sheet formation by the lymphoplasmacytic infiltrate. The B cells predominantly showed an immunophenotype of the marginal zone. In situ, hybridization revealed 17 cases with λ- and 10 with κ light chain restricted plasma cells, which was concordant with the AL subtype in each case. Clonal immunoglobulin heavy variable gene (IGHV) or κ light chain rearrangement was found in 23/29 interpretable cases. A single case harbored a MYD88L265P-mutation. Taken together, we detected 27 (93%) cases of AL amyloidosis with an associated light chain restricted and predominantly molecularly clonal plasma cell population. Clinical data were available in 18 patients. Five patients suffered from systemic lymphoma and two from systemic AL amyloidosis. The remaining cases were classified as localized with regard to both, the AL amyloidosis and the light chain restricted plasma cell population. To the best of our knowledge, we herein present the largest cohort of AL amyloidosis associated with a light chain restricted and predominantly molecularly clonal plasma cell population, which we designate as a distinct disease entity: "AL amyloidosis with a localized B cell neoplasia of undetermined significance".