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].