From pathogenesis to personalized treatments of neuropathies in hematological malignancies

Abstract

The peripheral nervous system may be involved at any stage in the course of several hematological diseases, the most common being monoclonal gammopathies (of undetermined significance or malignant) or lymphomas. The underlying pathogenic mechanisms are different and therapies aim at targeting the dangerous either B‐cell or plasma cell clones. Recently, high‐throughput technologies, and next‐generation sequencing have increased our knowledge of hematological diseases pathogenesis by the identification of somatic mutation affecting pivotal signaling pathways. Accordingly, new target therapies are used that may also be borrowed for treatment of neuropathies in hematological diseases.

Ibrutinib-induced acute kidney injury via interstitial nephritis

“…Such early onset of palpable purpuriform lesions may suggest more severe disease and may require discontinuation of treatment, glucocorticoid therapy, and could recur upon repeated administration of the drug [16]. Peripheral neuropathies due to various pathomechanisms are not uncommon in hematologic malignancies [17]. Ibrutinib may ameliorate anti-myelinassociated glycoprotein mediated form but can also provoke it [11,17] by an unknown mechanism.…”

“…Peripheral neuropathies due to various pathomechanisms are not uncommon in hematologic malignancies [17]. Ibrutinib may ameliorate anti-myelinassociated glycoprotein mediated form but can also provoke it [11,17] by an unknown mechanism. In our case, its simultaneous appearance with skin and kidney symptoms raised the possibility of vasculitis.…”

Mechanisms of Nerve Damage in Neuropathies Associated with Hematological Diseases: Lesson from Nerve Biopsies

“…• pathological studies of sural nerves show deposits of IgM and complement in myelin sheets, suggesting the need for complement activation in the demyelination process [19]; • IgM recognize NCAM (Neural Cell Adhesion Molecules) and are seen in correspondence of MAG in demyelinated areas [13]; in skin biopsies of the same patients there is a concurrent localization of IgM, C3d complement, and MAG in the dermal myelinated fibers, leading to the loss of nerve fibers [20]; • feline nerves injected with the serum of patients with anti-MAG/SGPG IgM supplemented with additional complement, develop complement-mediated demyelination and conduction block within 2-9 days [21]; • systemic transfusion of chickens with anti-MAG IgM produces segmental demyelination with IgM deposits on external myelin sheets and consequent widening of myelin lamellae as observed in human pathology [22]; • cats immunized with purified SGPG develop an ataxic neuropathy with the involvement of dorsal root ganglia, similar to anti-MAG antibody neuropathy [23]; • patients with anti-MAG antibody neuropathy respond to immunomodulant therapies, especially monoclonal antibodies (i.e., rituximab, obinutuzumab, ibrutinib) [24][25][26], and therapy response seems to correlate with the reduction of anti-MAG antibodies titers [27][28][29].…”

“…26], and therapy response seems to correlate with the reduction of anti-MAG antibodies titers [27][28][29].…”

“…Cryoglobulins usually clump together below 37 • C, activate the complement cascade, and recruit acute phase blood cells inflating and damaging capillaries of the extremities but also of the skin, the glomerulum and vasa nervorum. In the context of hematological diseases, both type I (monoclonal IgMs or IgGs, rarely IgA) and type II cryoglobulinemia (mixed forms, usually associated with HCV infections or connective tissue diseases occur in MGUS, or B cells malignancies (WM, chronic lymphocytic leukemia, CLL), with a predominance of type II cryoglobulinemia in WM [29,30]. Type III cryoglobulinemia caused by polyclonal IgM and IgG is seen predominantly in chronic infections (mainly hepatitis C virus, HCV) and also connective tissue diseases (in particular Sjogren syndrome) [31][32][33].…”