Ibrutinib-induced chronic demyelinating polyneuropathy in a 65-year-old man with chronic lymphoid leucosis: a clinical case

Relevance. Most of oncological patients undergo chemotherapy, which has a wide range of various toxic reactions including polyneuropathy. Ibrutinib is a relatively new medicine with a few side effects associated with peripheral polyneuropathy. Demyelinating polyneuropathy induced by this drug is not yet defi ned in scientifi c literature. Methods. The paper describes the fi rst case of demyelinating polyneuropathy associated with ibrutinib in a 65-yearold man with chronic lymphoid leucosis. The authors carried out clinical assessment, laboratory and instrumental examinations. Results. Ibrutinib administration was followed by chronic sensorimotor distal polyneuropathy. The changes measured in nerve conduction studies (NCS) corresponded to chronic infl ammatory demyelinating polyneuropathy (CIDP) electrophysiological criteria (EFNS/PNS, 2010). The positive aspect of the described clinical case is that polyneuropathy regressed almost completely after a dose reduction and subsequent drug discontinuation. The second NCS made 5 months after a dose reduction showed an increase in compound motor action potential (CMAP) and nerve conduction velocities (NCV); however, normal values were not reached. Conclusion. This report on demyelinating neuropathy associated with ibrutinib requires further study of the drug effects. The below clinical description is of great interest since most of polyneuropathies associated with chemotherapy are axonal, but not demyelinating.


INTRODUCTION
Chemotherapy is a uniform method of treatment for a large number of oncological diseases, which form one of the main causes of morbidity and mortality in the world. However, along with high efficiency, this type of therapy has a wide range of side effects, which signifi cantly impair the patients' quality of life, demand correction of doses of the used drugs, delay the succession of courses or cease the treatment completely, involve additional costs for diagnostics and rehabilitation (1)(2)(3). Analysis and prevention of chemotherapy side effects is undoubtedly of great medical, social and economic importance; it is an obviously urgent problem in modern medical science.
This paper describes a case of demyelinating sensorimotor polyneuropathy in a patient with chronic lymphoid leucosis associated with ibrutinib administration.

CLINICAL CASE
A 65-year-old patient, a retired man, referred to the outpatient department of the Research Center of Neurology (Moscow, Russia) in July 2016 complaining of weakness in feet and awkwardness in wrists, numbness in fi ngers, shins and feet, and lack of confi dence when walking.
The patient's anamnesis showed that since 2008 he was followed up by oncohematologist for the diagnosis "chronic lymphocytic leukemia, stage B, the state after a course of leukeran and fl udarabine (LF) therapy, 5 courses of chemotherapy with fl udarabine, cyclophosphamide and rituximab (FCR), 10 courses of rituximab and bortezomib (RB) therapy, remission". In 2008-2009 within a course of chemotherapy, the patient received leukeran and fl udarabine. In 2010-2011 he underwent 5 courses according to FCR scheme. This treatment was followed by a 1-year remission. A recurrence of chronic lymphocytic leukemia was detected in 2012; additional 10 courses of chemotherapy, which were carried out according to the RB treatment regimen in 2012-2014, led to stabilization. The patient had no any neurological complaints against the background of the above chemotherapeutic cycles, his state was satisfactory. At the end of 2015 (on 16.12.2015), it was decided to switch to ibrutinib 420 mg per day. In May 2016 (i.e. 5 months after the beginning of ibrutinib administration), the patient began to feel slow steady increase of polyneuritic sensitive and motor disturbances. He was diagnosed with toxic polyneuropathy at the place of his residence and prescribed neurometabolic therapy, which was ineffective. In June 2016 (6 months of ibrutinib therapy, 1 month after the beginning of neurologic disorders), the oncohematologist reduced the dose of ibrutinib to 280 mg a day, taking into account the progressive character of polyneuropathy.
The patient was examined at our site one month after the drug dose reduction, which helped to stabilize his state. The patient denied alcohol intake, aggravated hereditary anamnesis, and accompanying diabetes mellitus.
The results of the general examination were as follows: normosthenic constitution (weight -75 kg, height -170 cm), no symptoms of edema, no rash and other skin lesions, no bone deformations.
The neurological presentation in July 2016: the patient was alert, attentive and oriented; the speech was clear and fl uent with good repetition, comprehension and naming; there were no meningeal signs. Cranial nerves were intact. Examination revealed distant symmetric peripheral quadriparesis with a decrease in strength in the ulnar group of arm muscles to Grade 4 of Medical Research Coun-cil (MRC) scale (the right side was slightly worse), in extensors and fl exors of the feet and toes -to Grade 3 of MRC scale. In other groups of muscles (the muscles of the shoulder girdle, the extensors of wrists and fi ngers, the median group of arm muscles, the muscles of shin fl exors and extensors) the strength was suffi cient. The patient stood on his toes and heels with diffi culty; at the same time, he squatted down and stood up quite satisfactory. Muscle bulk was normal, muscle tone was decreased. Fasciculations were absent. Tendon refl exes were symmetric: m. biceps brachii -brisk, styloradial -low, knee -brisk, ankles -absent. There were no pathological refl exes and tension symptoms. Coordination tests were uncertain. In Romberg's test with open eyes, the patient stood steadily, with closed eyes -reeled (sensitive ataxia). There was a painful hyposthesia of the distal polyneuritic type. The position and vibration senses were lowered in toes. The light touch sense was reduced in the distal parts of legs. Thermoesthesia was not changed. Pelvic organ functions were not disturbed. There was symmetric steppage gait when walking, but the man walked without support. The higher cortical functions corresponded to the functions of his age.
The additional examinations and their results were the following: -Electrophoresis of serum and urine protein with immunofi xation: no pathological monoclonal secretion was revealed; -Antibodies to GM1 gangliosides: GM2-GM3-GM4; GD1a, GD1b, GD2-GD3, GT1a, GT1b, GQ1b, sulfatides were negative; -Electrophysiological study included needle electromyography and nerve conduction studies (NCS). NCS revealed rough generalized minimum asymmetric sensorimotor neural level of lesion of initially demyelinating character; it was much more expressed in the lower extremities. In studying the motor nerve fi bers of arms, we registered conduction blocks of different degree of manifestation in the areas atypical for compression. In studying the motor and sensory nerves of legs, there were no registered responses of compound motor action potential (CMAP) and compound sensory action potential (CSAP). In studying the distal muscle of the leg (m.tibialis anterior dex.) by a needle electrode at rest, single denervation activity of muscle fi bers  Note: m.Abductor digiti minimi -the muscle abducting the little fi nger; m.Abductor pollicis brevis -the short muscle abducting the thumb; n.Ulnaris -ulnar nerve; n.Medianus -median nerve.
was registered; the analysis of parameters of motor unit potentials showed signs of re-innervation ( Fig. 1, Table 1).
-Ultrasonography of nerves (spinal C5-Th1, branches of the brachial plexus, median and elbow nerves) did not show any change of the cross-section area at all the levels of the study.  Thus, the neurological examination of the patient revealed clinical signs of sensorimotor distal polyneuropathy. The neurophysiological examina-tion confi rmed the generalized sensorimotor neural level of lesion and specifi ed the nature of the lesion as initially demyelinating. Anamnestic data showed convincing interrelation between the beginning of ibrutinib administration and development of polyneuropathy. The patient was diagnosed "Ibrutinib-associated chronic demyelinating polyneuropathy". Recommendations included dynamic observation and a rehabilitation course (including kinesiotherapy, wearing of orthoses).
At the re-examination conducted at the end of November 2016 (4 months after the initial examination, 5 months after ibrutinib dose reduction), the patient felt stronger in wrists, mentioned insignificant reduction of sensitive disturbances and improvement of stability when walking. The second NCS showed positive dynamics as compared with the previous examination: -In examining the right ulnar nerve, there was a reduction of conduction block on to the forearm and an increase in motor conduction velocity (CV) at this level from 22 to 34 m/s was noted (the norm is more than 50 m/s); -In examining the left ulnar nerve, we registered a signifi cant increase in distal CMAP -from 4.7 to 6.35 mV (the norm is more than 6), a reduction of conduction block from 68% to 42% (not registered in the norm), and an increase in sensor CV from 30 to 44 m/s (the norm more than 50 m/s); -In examining the right deep fi bular nerve (a branch of the tibialis anterior muscle), there was an increase in the M-response -from 1.03 to 2.24 mV, an increase in sensor CV at the level of the knee from 32 to 40 m/s (the norm is more than 40 m/s); -Other parameters, including intensity of muscle fi ber denervation activity in the distal muscle of the leg, were unchanged ( Fig. 1, Table 2).

DISCUSSION
Chemotherapy-induced polyneuropathy is a subacute (within 4-8 weeks) or chronic (for more than 8 weeks) polyneuritic disorders that develop during or 3-6 months after a chemotherapy course with predominance of symptoms refl ecting involvement of sensory and autonomic fi bers (Table 3). Their specifi c feature is dose-and chemotherapeutic agent-dependence, alleviation of symptoms after discontinuation of the drug that induces the disease (2,3).
The group of chemotherapeutic agents with high and moderate degree of neurotoxicity is currently defi ned (Table 4) (4).
The exact mechanism of chemotherapy-induced types of polyneuropathy is still unclear. Nevertheless, considering various action spectrums of drugs and results of a number of pilot studies, scientists suggest the following main pathogenic drivers: disturbance of DNA cellular structure, mitochondrion and microtubules damage, axonal transport disturbance, oxidizing processes and apoptosis activation, neurotransmitter ion channel function change, etc. The result of these processes is formation of vicious mutually activating pathophysiological circles. The specifi ed changes inevitably lead to dorsal ganglia damage, development of neuronopathy and disturbance of axon microtubular architectonics, which fi nally results in axonal nerve fi bers degeneration (Fig. 2) (5,6). Chemotherapy-induced sensory, autonomic and sensorimotor polyneuropathies are common in the practice of clinical neurologists; the great majority of them are axonal (2)(3)(4)20). The demyelinating pattern of changes is much less often revealed in the NCS of this category of patients.
Scientifi c literature covers few cases of development of demyelinating polyneuropathies caused by chemotherapy. In all the described cases, the cause of the complication is bortezomib ( Table 4) (8)(9)(10)(11)(12). It is assumed that demyelinating polyneuropathies associated with bortezomib are caused by immunе-mediated mechanisms. That was confi rmed by morphological, neuroimaging and neurophysiological studies, as well as by clear neurologic improvement after administration of high-dosage intravenous immunoglobulin (9,10,13). Development of demyelinating polyneuropathy after ibrutinib administration has not been described in scientifi c literature.
Ibrutinib (Imbruvica, PCI-32765) is a new-generation drug in the treatment of malignant B-lymphoproliferative diseases. It is a covalent selective inhibitor of Bruton thyroxikinase, which plays an  Banach M. et al. 2016 (4), with alterations).

Preparati on
Cases of administrati on Mechanism of acti on Neurotoxicity Plati num-based drugs: cisplati n, carboplati n, oxaliplati n Lung, ovarian, bladder, colorectal cancer, etc.
The preparati ons bifuncti onally alkylate DNA strands, inhibit biosynthesis of nucleic acids, and cause cell death. At the f rst stage, they inhibit the synthesis of DNA, RNA and protein; on the second stage, they form metabolic products, which aff ect only DNA synthesis.
These drugs have a cytotoxic anti mitoti c eff ect, induce anomalous bundle-like arrangement of microtubules throughout the enti re cell cycle.  important role in maintenance of malignant cells viability. In 2014, it was approved by the U.S. Food and Drug Administration for treatment of patients with chronic lymphocytic leucosis (14). The official instruction to the drug (the part concerning side effects) mentions development of sensory axonal neuropathy in up to 40% of cases (15).
The interrelation between ibrutinib administration and polyneuritic disturbances in our patient was evident; it was also confi rmed by spontaneous improvement after the daily dose reduction. This case was characterized by the presence of the motor disturbances, which were not described previously. There were also interesting electrophysiological fi ndings, requiring specifi cation of the disease etiology: either toxic or dysimmune.
As other causes of demyelinating polyneuropathy (idiopathic, hereditary, paraproteinemic ones) were excluded in the course of examination and the ultrasonography of peripheral nerves did not reveal any changes in their structure that could be typical for an infl ammatory process (16)(17)(18), toxic genesis was obvious. This allowed choosing the best tactics for the patient managing (dynamic observation after the permissible ibrutinib dose reduction) and proved the refusal from immunotherapy by intravenous immunoglobulins.
The main tactics for managing the patients with the polyneuropathies of toxic genesis after chemotherapy consists in the most possible reduction in the dose of the chemotherapeutic drug and symptomatic therapy: correction of autonomic disturbances, treatment of neuropathic pain syndrome by drugs and methods with a proved effi ciency (tricyclic antidepressants, duloxetine/venlafaxine, pregabalin/gabapentin, cognitive behavioural therapy, transcranial magnetic stimulation, etc.), prescription of non-drug treatment-and-rehabilitation actions (kinesiotherapy, transdermal electroneuroand myostimulation) (21)(22)(23). Persistence or increase of neurologic disorders and considerable motor defi ciency limiting self-care may require complete cancellation of chemotherapy. There is no pathogenic treatment for toxic polyneuropathies, and neurometabolic drugs showed no convincing effi ciency in test trials (4,21,22).
Another tactics should be used in the cases of progressing demyelinating chemotherapy-induced polyneuropathies with proven dysimmune genesis, in which it is possible to conduct a disease-modifying treatment with steroid drugs or intravenous immunoglobulin (9,10,24,25). Dysimmune genesis of polyneuropathy can be clarifi ed by means of laboratory tests (blood test for antibodies to gangliosides, electrophoresis of serum proteins and urine with immunofi xation, liquor analysis for oligoclonal antibodies, etc.), instrumental examination (ultrasonography of nerves, magnetic resonance imaging of plexus with a contrast intensifi er) and morphological examinations (sural nerve biopsy) tests (16)(17)(18)(19).

CONCLUSION
The present paper is the fi rst description of chronic demyelinating polyneuropathy developed after ibrutinib administration. It shows the differentiated approach to specify the causes of neurologic disorders in the patients undergoing chemotherapy.