Qualitative and Quantitative

ORIGINAL ARTICLE

Neuromuscular complications after hematopoietic stem cell transplantation

Susanne Koeppen & Abhiyrahmi Thirugnanasambanthan & Michael Koldehoff

Received: 19 December 2013 /Accepted: 20 March 2014 /Published online: 29 March 2014 # Springer-Verlag Berlin Heidelberg 2014

Abstract Purpose The aim of this study was to analyze the occurrence of neuromuscular symptoms in recipients of allogeneic hema- topoietic stem cell transplantation (HSCT) for treatment of malignant hematopoietic disease. Methods Among 247 outpatients after allogeneic HSCT, we conducted a prospective non-interventional study between July 2011 and August 2013. During follow-up visits, clinical and electrophysiological findings were correlated to the pres- ence of autoantibodies/alloantibodies and to frequencies of lymphocyte subpopulations in peripheral blood. Results Resulting in an incidence of 8.1 %, 20 patients were diagnosed with neuromuscular complications at a median onset of 12 months post-transplant. Five patients (25 %) were identified with polyneuropathy (PNP), ten patients (50 %) with combined PNP and myopathy, four patients (20 %) with myopathy or polymyositis (PM), and one patient (5 %) with myasthenia gravis (MG). Immune-mediated sensorimotor PNP after HSCT is characterized by a predominantly axonal lesion and can be overlapping with neurotoxic side effects. The latency between HSCT and development of PM varied between 60 days and 72 months. In general, PM occurs parallel to graft-versus-host disease (GvHD) after tapering of immunosuppressive medication. Typical clinical features are proximal bilateral limb weakness with muscle atrophy. Auto- antibodies (Ab) were detected in 12 patients, myositis-specific Ab only in one patient. In patients with progressive

neurological symptoms, a decrease in the CD4/CD8 T cell ratio was observed. Conclusions GvHD-related myositis appeared similar to idi- opathic myositis regarding clinical and electromyographical findings. As outcome measure, sequential analysis of lympho- cyte subpopulations in peripheral blood seems to be more suitable than Ab measurements. Whereas peripheral neuropa- thies are commonly observed shortly after HSCT, MG is a rare complication in the late post-HSCT phase.

Keywords Allogeneic hematopoietic stem cell transplantation . Graft-versus-host disease . Polyneuropathy .

Polymyositis . Myasthenia gravis

Abbreviations AChR Ab Acetylcholine receptor antibody AL Acute leukemia ALL Acute lymphocytic leukemia ANA Antinuclear antibodies AML Acute myeloid leukemia Ab Autoantibodies CK-MB Creatine kinase-MB CLL Chronic lymphocytic leukemia CML Chronic myeloid leukemia GvHD Graft-versus-host disease HSCT Hematopoietic stem cell transplantation ND Not done MCL Mantle cell lymphoma MG Myasthenia gravis MM Multiple myeloma MPN Myeloproliferative neoplasm OMF Osteomyelofibrosis PM Polymyositis PNP Polyneuropathy

S. Koeppen (*): A. Thirugnanasambanthan Department of Neurology, Medical School, University of Duisburg-Essen, Hufelandstraße 55, 45122 Essen, Germany e-mail: [email protected]

M. Koldehoff Department of Bone Marrow Transplantation, West German Cancer Center, Medical School, University of Duisburg-Essen, Essen, Germany

Support Care Cancer (2014) 22:2337–2341 DOI 10.1007/s00520-014-2225-0

Introduction

Allogeneic hematopoietic stem cell transplantation (HSCT) has been shown to provide long-term disease-free survival for otherwise fatal malignant or non-malignant hematological disorders. With increasing survival rates due to toxicity- reduced HSCT methods and advanced graft-versus-host dis- ease (GvHD) management as well as improved antiinfectious therapy and prophylaxis, a distinct increment in late transplant-related complications can be observed. Early or delayed neurological complications usually associated with GvHD occur in 30–60 % of allogeneic HSCT recipients [1–3]. Acute GvHD and chronic GvHD remain the major causes of non-relapse mortality, and T cell alloreactivity has been established as the primary cause of GvHD. The extent of these complications can vary depending on the type of hema- tologic disease, stage of diagnosis, age of the transplant pa- tient, and whether the donor is major histocompatibility com- plex (MHC) matched or mismatched to the recipient [4, 5]. According to the National Institutes of Health (NIH) consen- sus criteria, neurological complications associated with GvHD affect the central or peripheral nervous system or the musculoskeletal system [6–10]. The most commonly recog- nized GvHD-related neuromuscular manifestations include polyneuropathy (PNP), less frequently myopathy, and myas- thenia gravis (MG) [11–14]. Autoimmune/alloimmune mech- anisms play a major role in the pathogenesis of neuromuscular symptoms in the context of GvHD. However, metabolic and drug-related factors may contribute to the neurologic impair- ment. The aim of this study was to investigate the incidence and clinical course of neuromuscular symptoms following allogeneic HSCT. We also investigated the relationship be- tween clinical features and laboratory findings.

Methods

Among patients with malignant hematologic disease who underwent allogeneic HSCT at the West German Cancer Center, University of Essen, Germany, between July 2011 and March 2013, 20 patients with GvHD-associated neuro- muscular symptoms were included in this prospective non- interventional study and followed until August 2013. The source population in this period included 429 allogeneic transplant patients, median age 54, and range 17–74 years. A total of 182 patients with active infectious diseases or malignancy relapse or who could not tolerate electrophysio- logical evaluation (n=2) were excluded. The IRB of the University of Essen approved the study, and written informed consent was obtained from each patient. Medical records were reviewed to determine diagnosis and treatment of the under- lying hematologic disease, any comorbidity, the patient’s con- dition prior to HSCT, and the clinical course until first

neurological evaluation. The neurological status was assessed using the total neuropathy score (TNS), the Medical Research Council (MRC) scale, hand grip strength measurements, fine motor activity, coordinative function, and balance tests. To assess symptoms of chemotherapy-induced peripheral neu- ropathy, the quality of life questionnaire of the European Organization for Research and Treatment of Cancer (EORTC) was used (QLQ-CIPN20). Patients were available for a neurological follow-up examination after a period of approximately 3 months. In parallel, blood samples were collected for serum creatine kinase (CK) measurement and immunological investigations including testing for autoanti- bodies (Ab) (ANA profile, ANCA-IFT, myositis profile, AChR Ab) and determination of lymphocyte subpopulations by flow cytometry. The antinuclear antibodies (ANA) were detected by immunofluorescence and by immunoblotting.

Statistical analysis

For individual values, we selected the median and the range. Continuous data are given as the mean with the standard deviation (SD). Variations in data between the different groups were tested either by a two-tailed unpaired t test or a Mann- Whitney U test using the SPSS 11.5 program (SPSS Inc., Chicago, IL, USA).

Results

Twenty patients presented with neuromuscular complications after allogeneic HSCT resulting in an incidence of 8.1 %. Patient characteristics and laboratory findings are summarized in the Table 1. The mean age of the patients was 50 years (49.9 ±9.6 years, range 27–64). The median interval between first evaluation and follow-up examination was 3 months. Due to GvHD, all patients received immunosuppressive treatment consisting of a calcineurin inhibitor and low-dose steroid medication. The median time from transplant to the onset of neuropathic symptoms was 12 months (range 2–120). The latency between HSCT and development of PM varied be- tween 60 days and 72 months. The most commonly reported motor symptoms were weakness in 65 % and muscle cramps in 55 % of the patients. The most frequent sensory symptoms were paresthesia (60 %) and numbness (45 %). The major clinical sign on neurologic examination was an impaired vibration sense detected in 70 % of the patients. The mean TNS score (range 0–36) was 8.97±4.5, the mean MRC sum score (range 0–60) was 54.3±7.9, and the mean value of the hand grip strength was 16.98±6.9 kp at baseline. Five patients (25 %) were identified with PNP, ten patients (50 %) with combined PNP and myopathy, four patients (20 %) with myopathy or PM, and one patient (5 %) with MG.

2338 Support Care Cancer (2014) 22:2337–2341

T ab

le 1

P at ie n t ch ar ac te ri st ic s an d la b o ra to ry

fi n d in g s

P at ie n t

A g e

A g e/ g en d er

D ia g n o si s

(t im

e o f)

O cc u rr en ce

o f

n eu ro m u sc u la r

co m p li ca ti o n s

af te r H S C T (m

o n th )

C li n ic al

p re se n ta ti o n

C re at in e k in as e

(U /l ) at b as el in e

an d at fo ll o w -u p

M y o g lo b in

(μ g /l ) at b as el in e

an d at fo ll o w -u p

A u to an ti b o d ie s

(t it er

le v el )

M y o si ti s p ro fi le

L y m p h o cy te

su b p op u la ti o n

C D 4 /C D 8 -r at io

at b as el in e an d

at fo ll ow

-u p

1 5 2

F em

al e

A M L (N

o v em

be r 2 0 0 7 )

1 2

P o ly n eu ro p at h y

1 0 3 , 1 6 6

5 1, 6 8

– –

0 .8 , 1 .1

2 5 5

M al e

C M L (A

p ri l 2 0 0 6 )

1 2

M y o p at h y /

p o ly n eu ro p at h y

11 5 , 2 2 0 C K -

M B 17

4 0, 6 2

A N A + , (1 :6 4 0 )

– 0 .7 , 1 .9

3 5 1

F em

al e

C M L (N

o v em

b er

2 0 0 5 )

6 P o ly n eu ro p at h y

4 7 5 , C K -M

B 5 , 7 7

9 2, 4 4

– –

0 , 0 .2

4 6 4

M al e

B ip h en ot y p ic A L

(N o v em

b er

2 0 0 7 )

1 2

M y o p at h y /

p o ly n eu ro p at h y

3 0 , 5 2

1 9, 2 1

– –

0 .1 , 0 .2

5 4 6

M al e

C M L (F eb ru ar y 1 9 9 8 )

1 2 0

M y o p at h y /

p o ly n eu ro p at h y

9 6 , 11 0

3 5, 3 4

– –

0 .4 , 0 .3

6 5 3

M al e

C L L (2 0 0 9 )

5 M y o p at h y /

p o ly n eu ro p at h y

2 7 , 2 1

6 2, 6 0

– –

1 , 1 .4

7 2 7

F em

al e

A L L (M

ar ch

2 0 1 0 )

5 M y o p at h y

9 0 , 1 2 9

4 0, 7 8

A N A + , (1 :6 4 0 )

– 0 .6 , 0 .6

8 4 9

M al e

C M L (F eb ru ar y 2 0 0 0 )

6 0

M y as th en ia g ra v is

1 2 4

5 7

A N A + , (1 :1 6 0 )

– 2 .2 , 2 .6

9 4 3

M al e

A M L (M

ay 2 0 0 1 )

2 4

P o ly n eu ro p at h y

4 2

6 2

A N A + , (1 :8 0 )

– 0 .3 , 0 .1

1 0

5 9

M al e

A L L (M

ay 2 0 11 )

2 P o ly n eu ro p at h y

7 2 , 2 0

7 9, 9 9

– –

0 .7 , 0 .7

11 5 6

M al e

M M

(S ep te m b er

2 0 0 5 )

3 P o ly n eu ro p at h y

4 4

4 5

A N A + , (1 :2 5 6 0 )

– 1 , 1

1 2

4 2

F em

al e

A L L (N

o v em

be r 2 0 0 6 )

2 4

M y o p at h y /

p o ly n eu ro p at h y

7 1

3 9

A N A + , (1 :2 5 6 0 )

A n ti -P M -S cl +

1 .9 , 1 .6

1 3

6 4

M al e

A M L (F eb ru ar y 2 0 0 6 )

9 M y o p at h y

4 4

3 5

A N A + , (1 :2 5 6 0 )

– 1 .2 , 1

1 4

4 4

M al e

A M L (J u n e 2 0 06 )

1 2

M y o p at h y /

p o ly n eu ro p at h y

6 6 , 4 1

9 0, 4 6

A N A + , (1 :3 2 0 )

– 2 .1 , 1 .5

1 5

4 6

F em

al e

S ec o n d ar y O M F

(O ct o b er

1 9 9 6 )

7 2

M y o p at h y

7 9 , 5 9

5 7, 6 0

A N A + , (1 :8 0 )

– 0 .7 9, 0 .5

1 6

3 2

F em

al e

A L L (J an u ar y 11 )

1 4

M y o p at h y

5 7 , 3 1

3 5, 2 8

– N D

0 .1 , 0 .5

1 7

5 1

F em

al e

O M F (D

ec em

b er

2 0 0 9 )

2 4

M y o p at h y /

p o ly n eu ro p at h y

7 0 , 6 5

2 2, 3 1

A N A + , (1 :1 2 8 0 )

– 0 .4 , 0 .7

1 8

5 5

F em

al e

O M F (N

o v em

b er

1 9 9 2 )

2 M y o p at h y /

p o ly n eu ro p at h y

5 0

N D

N D

– 0 .6 , 0 .3

1 9

6 4

M al e

M P N (O

ct o b er

2 0 0 9 )

2 4

M y o p at h y /

p o ly n eu ro p at h y

11 9

5 8

A N A + , (1 :3 2 0 )

– 0 .1 3, 0 .2

2 0

4 4

M al e

M C L (J u ly

2 0 0 7 )

3 M y o p at h y /

p o ly n eu ro p at h y

3 2 , 11 1

3 7

A N A + , (1 :3 2 0 )

– 0 .6 5, 1 .2

Support Care Cancer (2014) 22:2337–2341 2339

Electrophysiological testing including nerve conduction stud- ies and electromyography, if possible, revealed an axonal motor neuropathy of the peroneal nerve in 12 patients and a sural nerve axonopathy in 6 patients. The maximum CK serum concentration observed was 475 U/l. Ab were detected in 12 patients, myositis-specific Ab only in one patient. Nine- teen patients had hematopoietic full chimerism, and one pa- tient had mixed chimerism. At the time of onset of neuromus- cular symptoms, a coincidence with a decrease of CD4 T cells and increase of CD8 T cells was observed in 17 and 12 patients, respectively.

Discussion

Improved survival of patients undergoing allogeneic HSCT shifts the focus of neurologic involvement towards long-term sequelae. Because of different new conditioning protocols of allogeneic HSCT and immunosuppression, the nature of neu- rologic complications has changed over time. In this study, post-HSCT PNP in combination with myopathy appeared to be more common than isolated myopathy or peripheral neu- ropathy. Prior to the onset of PM, the immunosuppressive medication had been tapered in all patients. PM following HSCT has been reported to occur in approximately 3.4– 7.7 % of patients usually along with other manifestations of GvHD [15]. In general, the onset is insidious, although it can be acute especially after donor lymphocyte infusion (DLI) [16]. Typical clinical features of PM are proximal bilateral limb weakness and muscle atrophy, similar to idiopathic PM [17]. The presence of Ab may correlate with the severity of chronic GvHD [18]. In most cases, GvHD-related PM shows a prompt treatment response to corticosteroids and cyclospor- ine resulting in complete and sustained remission [19]. Nor- mal or slightly elevated serum CK-levels in our patients are compatible with clinical stability described in most cases. Myositis-specific Ab were found in only one patient. This is corresponding to previous reports [20]. MG has been de- scribed as rare manifestation of chronic GvHD in the late post-HSCT phase [21, 22]. However, circulating Ab directed against muscle acetylcholine receptor (AChR Ab) are detect- able in about 20 % of patients with chronic GvHD [23]. In our patient with MG following HSCT, the onset of clinically overt MG was associated with elevated AChR Ab and titin Ab. It is noteworthy that titin Ab in the context of post-HSCT MG have not been reported before. A considerable number of patients in the present study complained of neuropathic symp- toms correlated with other GvHD manifestations. However, the pathogenesis of peripheral neuropathies following alloge- neic HSCT is often multifactorial [24, 25]. Compared to prior studies, the onset of PNP after HSCT showed a higher vari- ability in our patients. Electrophysiological studies revealed a predominantly axonal lesion of the peripheral nervous system

and chronic neurogenic or myogenic changes of the affected muscles. None of our patients met the diagnostic criteria for chronic inflammatory demyelinating polyneuropathy (CIDP). The majority of patients were in stable clinical condition during the observation period. Accordingly, laboratory testing gave only little evidence of disease activity. Immunosuppres- sive treatment was continued. However, our study has some limitations. First, patients were not neurologically evaluated prior to HSCT. Therefore, chemotherapy-induced PNP under- lying a later developing GvHD-related affection of the periph- eral nervous system cannot be excluded despite negative history of neuropathic symptoms prior to HSCT. Second, steroid myopathy might be a contributing factor of the motor deficit in some patients because corticosteroids are the first- line therapy of GvHD. In a retrospective analysis of patients with acute myeloid leukemia or myelodysplastic syndrome treated with high-dose steroid for acute GvHD following allogeneic HSCT, steroid myopathy was identified in 41 % of the patients [26]. Third, the small number of patients and lack of a control group requires confirmation of the results in a larger controlled prospective study. Despite these limitations, it can be concluded from the results of this study based on the partly longitudinal character of neurological evaluation that the neuromuscular system seems to be affected more frequent- ly than reported so far in patients with GvHD after allogeneic HSCT. The immunological findings suggest that sequential analyses of lymphocyte subpopulations in peripheral blood might be helpful during the immunosuppressive dose reduc- tion period in order to prevent GvHD-related clinical deterio- ration. However, only further research studies can determine whether it is possible to prevent those complications by adapting the immunosuppressive regimen based on the lym- phocyte subpopulation findings in the peripheral blood.

Conflict of interest The authors declare no conflict of interest. They also state that they have full control of primary data and that they agree to allow the journal to review their data if requested.

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