Discussion
PNS are mainly autoimmune. When the body tries to eliminate tumor cells, it launches an immune response, targeting normal neural tissues [11]. This could be mediated by antibodies or by T-cells. Antibodies targeted against an accessible membrane target is directly responsible for the disease, as in the case of acetylcholine receptor (AChR) antibodies in myasthenia gravis, P/Q type of voltage-gated calcium channels (VGCC) in Lambert Eaton Myasthenic syndrome (LEMS), and encephalitis associated with anti-NMDA receptor antibodies [10]. It has been documented that tumor outcome is better among patients with paraneoplastic syndromes [10]. Myasthenia gravis (MG) is a prototypical autoantibody-mediated disease. The autoantibodies in MG target structures within the neuromuscular junction (NMJ), thus affecting neuromuscular transmission. Immune mechanisms that describe both the B cell- and autoantibody-mediated pathogenesis by AChR and MuSK MG subtypes are highlighted in Figures 1 and 2. These figures are being reproduced with permission from frontiers in immunology [4]. It begins with naïve B cells in the bone marrow, which encounter self-antigens and receive T cell help in the thymus. Then they differentiate into autoantibody specific memory B cells, which are activated into antibody-secreting short-lived plasma-blasts or antibody-secreting long-lived plasma cells, which reside in the bone marrow and may also be present in the thymus. AChR autoantibodies are of IgG1, and MuSK are of IgG4 subclasses. They then migrate to the neuromuscular junction (NMJ) and produce various clinical features of MG [4].
Traditionally, there are many described differences between MG of AChR and MuSK subtypes. AChR MG has IgG1 and IgG3 autoantibodies and is mostly associated with thymic hyperplasia. CD20 negative plasma cells are responsible for auto-antibody production. In contrast, MuSK MG has IgG4 autoantibodies and is less likely to be associated with thymoma. CD20 positive plasmablasts are seen in them. Hence, AChR MG has a better chance of responding to thymectomy, and the MuSK subtype has a better chance of responding to rituximab [4].
MG is a recognized paraneoplastic syndrome in patients with thymoma (~15% of MG patients) [7], secondary to AChR/MuSK antibodies’ production from the thymic source. Only 31% had thymoma in our cohort, whereas 77% had positive AChR/ MuSK antibodies. In patients whose MG occurred after the diagnosis of MPN, it was considered secondary to the treatment. However, from figures 1 and 2, it is evident that alterations in bone marrow morphology can result in the production of AChR/MuSK antibodies causing MG. Considering that 10 out of the 13 patients in our cohort had positive auto-antibodies though only 4 of them had thymic hyperplasia, we hypothesize that the bone marrow proliferation was responsible for the production of autoantibodies in these patients. The authors of many reports had associated the onset of MG symptoms with the use of drugs to treat MPNs. Eg: TKI in [16], [17] and [18], busulfan in [24], [25] and [26], and interferon-alpha in [21]. However, there is no clarity in the mechanism of drug-induced MG in these reports. We assume that MG occurs as a neurologic paraneoplastic syndrome due to AChR/ MuSK auto-antibodies produced from abnormal bone marrow, which act at the NMJ, in patients with MPNs.
Among BCR-ABL1 negative MPNs (PV, ET, and PMF), survival is the longest in ET (median estimated at 20 years) and shortest in PMF (median estimated at six years). In the last 15 years, many MPN specific, mutually exclusive mutations were identified, namely JAK2 (chromosome 9p24), CALR (chromosome 19p13.2), and MPL (chromosome 1p34). JAK2 is the most frequent mutation with 98% in PV, 50% - 60% in ET, and 55%- 65% in PMF. CALR and MPL mutations are usually absent in PV but occur in ET and PMF. The frequency of CALR mutation in both ET and PMF is about 20%-25%. MPL mutations are the rarest of the three and occur in about 3% - 4% cases of ET and 6% - 7% cases of PMF [27]. Figure 3 is a flowchart showing the classification of MPNs based on chromosomal mutations. JAK2 and MPL mutations are believed to directly activate JAK-STAT and make myeloproliferation cytokine independent or hypersensitive. The precise mechanism of mutant CALR-induced myeloproliferation is less clear, but mouse models have suggested a primary effect on platelet production [28]. Targeted therapy with JAK inhibitors has so far failed to induce selective suppression of the disease clone in MPN [29]. The primary aim of treatment in PV and ET is to prevent thrombosis and alleviate symptoms. Randomized trials have shown the antithrombotic value of twice-daily aspirin in PV [30, 31], hydroxyurea in high-risk ET [32], and phlebotomy (hematocrit target <45%) in PV [33]. Aspirin therapy has also been shown to alleviate microvascular symptoms, such as erythromelalgia and headaches effectively, and possibly prevent vascular events in JAK2-mutated ET [34]. The only treatment in MF that can cure the disease or prolong survival is stem cell transplantation (SCT). As most patients with Philadelphia chromosome-negative MPNs have V617F mutation in Janus kinase 2 (JAK2), JAK inhibitor ruxolitinib is being used in myelofibrosis (MF) and hydroxyurea resistant or intolerant polycythemia vera (PV). However, there is no evidence that it reduces the malignant clone (measured by the allele frequency of JAK2 V617F in the bone marrow) or alters the natural history of PV (i.e., leukemic transformation, myelofibrosis).
Tyrosine Kinase Inhibitors (TKIs, E.g., Imatinib, Nilotinib, Dasatinib) are currently the mainstay of treatment in Philadelphia chromosome-negative MPNs. In the pre-Imatinib era, allogeneic stem cell transplantation was the therapy of choice for CML and remains the only proven curative treatment. IFN-α–based regimens were the pharmacologic treatment of choice in early phase CML [35]. Adding pegylated IFN-α (peg-IFN-α) at a dose of 50 to 90 μg weekly to imatinib resulted in statistically significant improvements in major metabolic response (MMR) and complete molecular remission (CMR) rates [36, 37]. TKIs cannot eliminate quiescent CML stem cells despite virtually complete inhibition of BCR-ABL1 kinase activity [38]. After TKI therapy initiation, BCR-ABL1 transcripts measured in blood or BM decline logarithmically but cannot be eliminated [39].