Emerging drugs for the treatment of Waldenström macroglobulinemia.

INTRODUCTION: Waldenström's Macroglobulinemia (WM) is an indolent lymphoma with uniquely distinct and heterogenous clinical and genomic profiles. Clonal lymphoplasmacytic cells secrete monoclonal IgM. More than 90% of patients harbor a mutation in MYD88 gene, leading to the constitutive activation of downstream pathways, involving BTK-mediated signaling. The use of BTK inhibitors has changed the treatment landscape of WM and has paved the way for new approaches to therapy. AREAS COVERED: WM is an orphan disease and ibrutinib is the only FDA/EMA approved agent. Currently established agent combinations will be reviewed with a focus on emerging therapeutic options. These include second generation inhibitors, agents that target other molecules in the BCR signaling pathway, CXCR4 inhibitors, proteasome inhibitors and anti-CD38 antibodies. The current research goal is to establish a combination that can induce deep and durable responses with minimal associated toxicity. In addition, agents that can overcome ibrutinib resistance or act in a synergistic manner with BTKi are under investigation. EXPERT OPINION: The optimal therapeutic approach for WM patients is not currently established. The question of whether a combinatory (or synergistic) regimen to overcome resistance and allow for fixed- duration treatment will allow for deep/durable responses is being addressed in ongoing clinical trials.

Bing-Neel syndrome revealing Waldenström's macroglobulinemia: a case report.

INTRODUCTION: Bing-Neel syndrome is a lympho-plasmocytic infiltration of the central nervous system. The Bing-Neel syndrome is a rare entity, which often occurs during the evolution of a Waldenström's macroglobulinemia but can in some cases be the revealing mode of it. OBSERVATION: We report the case of a 56-year-old patient with tumoral form of Bing-Neel syndrome revealing Waldentrom's macroglobulinemia. CONCLUSION: This observation describes a rare entity whose diagnosis and therapeutic management is complex.

Spectral-domain optical coherence tomography of retinal vessels in Waldenström's macroglobulinemia.

PURPOSE: To image retinal blood vessels in patients with Waldenström's macroglobulinemia using optical coherence tomography (OCT). METHODS: Retrospective case series examining fundus photographs and OCT scans of 16 eyes in eight patients with Waldenström's macroglobulinemia. Analyses included intravascular OCT reflectivity profiles and vessel diameters, and their relation to total immunoglobulin M (IgM) levels. RESULTS: In six out of eight patients, cross-sectional OCT scans of larger retinal vessels (diameter > 100 µm) showed normal intravascular reflectivity and retrovascular shadowing. In two patients with the highest total IgM > 60 g/l, altered intravascular reflectivity, distinct anterior and posterior vessel wall reflexes, and retrovascular hyposhadowing were seen. Normalization of the OCT reflectivity in these patients occurred after reduction of total IgM to < 17 g/l and was accompanied by decreasing venous tortuosity and disappearance of retinal haemorrhages and cotton wool spots. CONCLUSION: This study found that Waldenström's macroglobulinemia and total IgM > 60 g/l were associated with abnormal intravascular reflectivity and retrovascular shadowing on OCT. Awareness of these signs of hyperviscosity could potentially enable earlier detection of critical conditions in patients with Waldenström's macroglobulinemia and improve the assessment of severity and treatment effect.

Acquired C1-inhibitor deficiency presenting with nephrotic syndrome.

Acquired C1-inhibitor (C1-INH) deficiency is a rare and potentially life-threatening disorder, which presents with recurrent attacks of non-pitting oedema to the face, airway, limbs or gastrointestinal tract. It is often associated with underlying B-cell lymphoproliferative disorders. We describe a case of a 73-year-old man with acquired C1-INH deficiency who presented with nephrotic syndrome due to glomerular IgM deposition, secondary to an underlying secretory lymphoplasmacytic lymphoma. Both the acquired C1-INH deficiency and the nephrotic syndrome resolved when the underlying B-cell lymphoma was treated with rituximab and bendamustine, suggesting the underlying lymphoproliferative malignancy was driving both disorders.

Waldenstrom-associated anti-MAG paraprotein polyneuropathy with neurogenic tremor.

A 71-year-old female patient presented with a 14-year history of slowly progressive distal limb numbness, paraesthesia and reduced vibration perception, ataxic gait and intentional tremor. Examination revealed with a length-dependent sensory neuropathy. Nerve conduction studies showed a chronic sensorimotor inflammatory demyelinating polyneuropathy. Intravenous immunoglobulin treatment (on two occasions) proved ineffective. Serum electrophoresis showed increased monoclonal IgM with kappa light chains. Anti-myelin-associated glycoprotein (MAG) levels were extremely elevated, >70 000 BTU. Bone marrow biopsy revealed 15%-20% small B cells and positive MYD88 mutation, indicative of Waldenstrom macroglobulinaemia. A diagnosis of Waldenstrom-associated anti-MAG paraprotein neuropathy with intentional (neurogenic) tremor was made. Repeat nerve conduction study showed a severe sensory demyelinating neuropathy with no axonal lesion. Treatment with rituximab was given for 1 month with minimal improvement. Repeat anti-MAG levels dropped to 53 670 BTU, with minimal clinical improvement.

Ixazomib: an investigational drug for the treatment of lymphoproliferative disorders.

INTRODUCTION: Ixazomib is a new, orally administered, reversible proteasome inhibitor which is under investigation for the treatment of refractory/relapsed multiple myeloma (MM), systemic light chain amyloidosis (AL) and Waldenström macroglobulinemia (WM). Areas covered: This article covers the mechanism of action, pharmacology and clinical trial results of ixazomib while under investigation for the treatment of various lymphoproliferative disorders. We examine the findings from several phase 3 clinical trials (i) the pivotal TOURMALINE-MM1 study investigating ixazomib versus placebo in combination with lenalidomide and dexamethasone; (ii) the TOURMALINE-MM3 study investigating ixazomib versus placebo as a maintenance therapy in newly diagnosed MM following induction therapy and autologous stem cell transplantation; (iii) the TOURMALINE-MM2 study investigating ixazomib versus placebo in combination with lenalidomide and dexamethasone in patients with newly diagnosed MM; and (iv) TOURMALINE-AL1 investigating ixazomib plus dexamethasone in patients with relapsed/refractory AL amyloidosis. Finally, we explore early phase clinical studies of this agent in Waldenström macroglobulinemia. Expert opinion: A key advantage of ixazomib is that it could allow an efficacious treatment approach to MM and other lymphoproliferative disorders through a convenient oral administration route. Ixazomib could soon be used in combination treatment regimens, but more work is necessary to define the place of this agent going forward.

Bortezomib-based chemotherapy can improve renal and tubular functions in patients with light chain-associated Fanconi syndrome.

Light chain-associated Fanconi syndrome (LCFS) is a disorder of renal proximal tubule due to immunoglobulin light chains. Cases of LCFS are rare and mostly sporadically reported, and treatment of this entity is still controversial. This single-center retrospective study included 22 patients diagnosed with LCFS in Peking Union Medical College Hospital. Monoclonal gammopathy of undetermined significance was diagnosed in 13 patients, and overt multiple myeloma in six patients, with two smoldering myeloma and one Waldenstrom macroglobulinemia. Light chain was mostly kappa type (90.9%). Baseline median estimated glomerular filtration rate was 66 (13-126) ml/min/1.73 m2, with one patient presented as end-stage renal disease. After a median follow-up of 37 months, three patients died. Twelve patients were treated with chemotherapy, including 7 with bortezomib-based regimens. Renal function was significantly improved in the group of patients who received chemotherapy (p = 0.026). Compared with other chemotherapy regimens, patients with bortezomib-based treatment had a better hematological response (p = 0.027) as well as a better proximal tubule outcome (p = 0.015). Chemotherapy likely outweighs supportive treatment in patients with LCFS. Bortezomib-based regimen seems to be a safe first-line therapy for management of those patients.

A safety profile of medications used to treat Waldenström's macroglobulinemia.

INTRODUCTION: Waldenström's macroglobulinemia (WM) is a B-cell lymphoproliferative disease with serum IgM monoclonal component and bone marrow infiltration by lymphoplasmacytic lymphoma. Traditional therapy was based on that regimens used for closely related entities, such as chronic lymphocytic leukemia or multiple myeloma. This resulted in a lack of drugs specifically approved for WM, until the discovery of the Bruton Tyrosine Kinase (BTK) inhibitors. AREAS COVERED: Two main therapeutic attitudes are possible: (1) conventional therapies based on combinations with alkylating agents or proteasome inhibitors with steroids and anti-CD20 monoclonal antibodies or (2) new approaches with BTK inhibitors, usually alone. Other possibilities such as BCL2 inhibitors, PI3K/AKT inhibitors, and others are currently under evaluation, but we will focus the review on the most consolidated approaches that are available for patients with WM at different stages of the disease. PubMed, Web of Science, and clinicaltrials.gov were queried for the keywords 'Waldenstrom macroglobulinemia' and the different drugs here evaluated through 1 February 2018. EXPERT OPINION: Although WM has no many specific drugs, there are many possible therapies, including Ibrutinib, the first formally approved drug for this disorder.

Waldenström Macroglobulinemia: Review of Pathogenesis and Management.

Waldenström macroglobulinemia (WM) is a low-grade B-cell clonal disorder characterized by lymphoplasmacytic bone marrow involvement associated with monoclonal immunoglobulin M. Although WM remains to be an incurable disease with a heterogeneous clinical course, the recent discovery of mutations in the MYD88 and CXCR4 genes further enhanced our understanding of its pathogenesis. Development of new therapies including monoclonal antibodies, proteasome inhibitors, and Bruton tyrosine kinase inhibitors have made the management of WM increasingly complex. Treatment should be tailored to the individual patient while considering many clinical factors. The clinical outcomes are expected to continue to improve, given the emergence of novel therapeutics and better understanding of the underlying pathogenesis.

[How can we treat Waldenström's macroglobulinemia?] / Újdonságok a Waldenström-makroglobulinémia kezelésében.

Waldenström's macroglobulinemia is a rare, low-grade non-Hodgkin lymphoma of B cell origin, most common in elderly male patients with a median age of 64 years at diagnosis. It accounts for approximately 2% of hematologic malignancies. The disease is incurable now with a median overall survival of 6.2 years. In the past decade growing evidence suggests the role of the complex signaling pathways and microenvironment as a potential target of the therapy in the lymphoproliferative disorders as well as Waldenström's macroglobulinemia. In this review we try to highlight the importance of these novel targets and their possible role in the therapeutic strategies. We further summarize our knowledge about the pathophysiology, diagnostics and therapeutics standards of the disease.

Current treatment options and investigational drugs for Waldenstrom's Macroglobulinemia.

INTRODUCTION: Waldenström's Macroglobulinemia (WM) is a rare, indolent, incurable, low-grade B-cell lymphoplasmacytic neoplasm. This review article provides a modern clinical perspective of the individualized management of patients with symptomatic WM, in the context of the updated treatment guidelines and the currently available trial data. Areas covered: Rituximab-based regimens (such as the dexamethasone, rituximab and cyclophosphamide combination, DRC) are the most widely used in the management of both newly diagnosed and relapsed/refractory patients with WM. Recently, the Bruton's tyrosine kinase inhibitor ibrutinib has been licensed for use in WM with exciting results. Several investigational single agent and combination regimens are being evaluated for response, efficacy and tolerability in phase II clinical trials, including new generation monoclonal antibodies (ofatumumab), immunomodulatory agents (thalidomide and lenalidomide), proteasome inhibitors (bortezomib and carfilzomib), Bruton's tyrosine kinase inhibitors (ibrutinib and acalabrutinib), phosphoinositide 3-kinase/protein kinase B (Akt)/mammalian target of rapamycin pathway inhibitors (everolimus and perifosene), and histone deacetylase inhibitors (panobinostat) both in the setting of newly diagnosed and relapsed/refractory disease. Expert opinion: WM therapeutic approach should be individualized for each patient in accordance to the intensity of the disease characteristics, age, comorbidities, efficacy, tolerability and safety profile of each drug.

[Primary pleuropulmonary involvment in Waldenström's macroglobulinemia: an interdisciplinary issue]. / Manifestazioni bronco-pneumo-pleuriche della malattia di Waldenström: un lungo percorso interdisciplinare.

The incidence of pleuropulmonary manifestations in Waldenström's macroglobulinemia is low in haematological as well as pneumological international literature. The progressive decrease concerning these manifestations is due essentially to scant interdisciplinary attention for new issues correlated with this specific involvement, that is poorly understood and rarely object of dedicated publications.