Leukemia Research 34 (2010) e154e156

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Leukemia Research
journal homepage: www.elsevier.com/locate/leukres

Letter to the Editor

GuillainBarr syndrome after use of alemtuzumab (Campath)
in a patient with T-cell prolymphocytic leukemia: A case report
and review of the literature
1. Introduction
Alemtuzumab (marketed as Campath, MabCampath or
Campath-1H) is a recombinant DNA-derived humanized monoclonal antibody that is directed against the 2128 kDa cell surface
glycoprotein, CD52. Binding of alemtuzumab to CD52 initiates
complement activation via the classical pathway [1]. The membrane attack complex that is formed in this way leads to lysis of
lymphocytes. Alemtuzumab is used in the treatment of chronic
lymphocytic leukemia (CLL) and T-cell lymphoma.
A major complication with alemtuzumab therapy is the
increased risk for opportunistic infections. In particular, reactivation of cytomegalovirus has been frequently reported. Although
alemtuzumab is a potent immunosuppressant, several groups have
described the paradoxical occurrence of autoimmune disease after
its use, including thyroid disorders and cytopenias [24]. Although
a direct causational association has not been established, patients
who received alemtuzumab in conditioning regimen for stem cell
transplantation have been reported to develop static peripheral
neuropathy of unknown pathogenesis [1]. GBS is an autoimmune
disorder in which the peripheral nervous system becomes the target of host-mediated immune destruction. We describe a report of a
73-year-old man with T-cell prolymphocytic leukemia, who developed GBS following treatment with alemtuzumab. No antecedent
infective etiology was identied. Although there are numerous
reports of autoimmune disease after treatment with alemtuzumab
and GBS after immunosuppressive treatment, we could nd only
one additional report of GBS after the use of alemtuzumab. We will
also discuss the occurrence of autoimmune disease after immunosuppressive treatment as a general phenomenon, and in particular
with alemtuzumab, and the possible mechanisms for this autoreactive T-cell dysregulation.
2. Case report
A 73-year-old male was found to have elevated white blood
cell count of 20.6 with differential showing lymphocytosis with
absolute lymphocyte count of 16.5. Other values were Hgb of 12.4
and platelet count of 244,000. Flow cytometry, T-cell receptor
gene rearrangement studies, and bone marrow biopsy established
the diagnosis of T-cell prolymphocytic leukemia (T-PLL). He was
treated with a course of intravenous alemtuzumab (1 dose of 3 mg,
2 doses of 10 mg and 12 doses of 30 mg in 34 days). He responded
well to the treatment and complete remission was achieved. He
came to the ED with 2-day history of falls and one week history
of numbness and tingling, 62 days after the completion of treatment. The patient had also experienced some mild diarrhea after
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the chemotherapy which ultimately resolved 57 days after his

prophylactic sulfamethoxazole/trimethoprim was stopped. At the
time of admission strength in all the extremities was MRC scale
of 4/5. Cranial nerve examination was normal, no facial asymmetry was noted. He did complain of some tingling sensation in his
feet and hands. He also described his legs as rubbery. The reexes
at the time of admission were 2+ in upper extremities and 1+ in
lower extremities. MRI of the brain did not reveal any abnormalities. Based on this clinical picture, a provisional clinical diagnosis
for GBS was made and the patient was admitted to the hospital. At
the time of admission his WBC count was 4.9, Hgb 11.6, hematocrit
33.8 and platelets were 199,000. In the next 48 h, he rapidly lost
additional strength rst in lower extremities, progressing rapidly to
involve upper extremities by the 4th day of admission. Electromyography and nerve conduction studies showed a generalized motor
and sensory polyneuropathy with mixed axonal and demyelinating
features consistent with diagnosis of GBS. CSF analysis showed clear
appearance with no color. Differential cell count of CSF showed
<1/l of nucleated cells. In CSF glucose level was 62 mg/dl and protein level was 99 mg/dl while at the same time glucose level in
blood was 100 mg/dl and protein level in blood was 5.2 g/dl. Further
CSF examination was also positive for abnormal albumin level with
albumin level in CSF of 48.2 mg/dl while it was 2.8 g/dl in blood. CSF
examination was also positive for oligoclonal bands and negative
for myelin basic protein and other myelin proteins CSF analysis
for VDRL, Indian Ink, CMV by PCR, EBV by PCR, Lyme western blot
titers and DNA, T. Gondii antibody test, Cryptococcal antigen test,
Enterovirus titers were all negative. Screening of blood for known
precipitants of GBS including Campylobacter jejuni, Giardia, Lyme
disease, VZV, HTLV and Mycoplasma were negative. ESR and CRP
remained within normal limits. GQ1b antibody was negative. Vitamin B12 was slightly below normal at 160 pg/ml but methylmalonic
acid was normal at 160 nmol/l. He was treated with plasmapheresis
for 1 day followed by 5 doses of 500 mg/kg (50 g/day) of IVIG which
improved his strength in upper extremities up to MRC scale of 2/5
and he also improved strength in his lower extremities from 0/5
MRC to 1/5 in the toe exors. But 7 days after his last IVIG dose, he
deteriorated again in strength in lower extremities to 0/5 MRC and
had difculty in breathing that required intubation for respiratory
protection and assisted ventilation. He remained intubated for 17
days. Following additional 5 days of plasmapheresis and inpatient
rehabilitation, his strength had improved in the lower extremity to
2/5 and upper extremity to 3/5 on the MRC scale. His latest physical examination approximately 2 months after discharge showed
improved strength in both upper and lower extremities to MRC
scale of 4/5.

3. Discussion
Alemtuzumab is an IgG monoclonal antibody directed against
the CD52 antigen. This antigen is mainly expressed on T lympho-

Letter to the Editor / Leukemia Research 34 (2010) e154e156

cytes, B lymphocytes [5] and monocytes [6]. Alemtuzumab has an

established role in the treatment of CLL and has become the treatment of choice for T-PLL [7]. Alemtuzumab induces rapid profound
lymphopenia that can last up to 18 months [8]. Alemtuzumab have
also been used as a conditioning agent for non-myeloablative bone
marrow transplantation and in the treatment of acute graft versus host disease [9,10]. The lymphopenia caused by alemtuzumab
is associated with profound immunosuppression. Opportunistic
infections with agents such as CMV frequently occur and patients
must be monitored for reactivation [11]. In addition to decreasing
effector immune cells, it also results in dysregulation of CD4CD25
regulatory T cells. These cells normally inhibit autoimmune activated cells and this indiscriminant dysregulation may predispose
to the development of autoimmunity. In addition, CD52 antigens are also expressed on monocyte-derived dendritic cells and
thus antigen presentation in the host is affected following alemtuzumab treatment [12,13] Immature peripheral dendritic cells
present antigen to T cells in a tolerogenic manner by silencing
activated T cells, activating and causing expansion of regulatory T
cells, and causing the differentiation of naive CD4 cells into regulatory T cells [1416]. The effect of alemtuzumab in depleting
these dendritic cells may also predispose to the development of
autoimmunity.
Furthermore, alemtuzumab has been shown to deplete natural killer cells; studies suggest these cells may play a role in both
exacerbating and protecting against autoimmune mechanisms
[12]. After the administration of alemtuzumab, B-cell recovery
tends to precede T-cell recovery, and the number of B cells may
exceed baseline values in some patients [17]. Autoimmune diseases
observed after the administration of alemtuzumab are predominantly antibody-mediated, and they respond to B-cell depletion
[18]. Autoreactive B cells can function without T-cell help [19].
Thus, the emergence of autoreactive B cells during the reconstitution of lymphocytes may also cause autoimmunity after treatment
with alemtuzumab.
In summary, treatment with alemtuzumab induces a wide range
of perturbations in the various components of the adaptive and
innate immune system, from which recovery and reconstitution
occur within different time frames and to different extents. These
immune dysregulations may set the stage for the development of
autoimmunity within the concurrent profound immunosuppressive environment created by this agent.
Similar immune dysregulations has also been described after the
use another monoclonal antibody rituximab. Rituximab is antiCD20
monoclonal antibody used in the treatment of many hematological malignancies. Various case reports have mentioned about the
correlation of rituximab use leading to GBS [20,21]. The mechanism of action in those cases is not clear but the hypothesis is
that CD20 down regulation during B-cell maturation and loss of
feedback mechanism may be the cause.
GuillainBarr syndrome (GBS) is a disorder in which the
bodys immune system attacks part of the peripheral nervous
system by destroying the myelin sheath that surrounds the
axons of many peripheral nerves, or even the axons themselves. It is believed to be caused by autoimmune mechanisms
that are predominantly T-cell mediated. It is a rare but recognized event after autologous and allogeneic bone marrow
transplantation, intensive conditioning regimens, and solid organ
transplantation. GBS is also well documented in conditions where
immune dysfunction is a feature, notably Hodgkin and nonHodgkin lymphoma, HIV infection, and numerous autoimmune
disorders such as chronic active hepatitis, hypothyroidism, sarcoidosis, Wegeners granulomatosis, and ulcerative colitis. It is
postulated that in these situations GBS may arise as a result of
viral infection/reactivation or as a result of the iatrogenic immune
dysregulation.

e155

Our patient had symptoms of mild diarrhea preceding the onset

of GBS. It is possible that an underlying infection might have
elicited an immune response leading to GBS, although investigations failed to detect viral or bacterial infection. Even T-cell
lymphoma in theory can lead to GBS but in our patient his last
bone marrow biopsy showed that he was in remission at that time.
Castelli et al. previously described a similar case of GBS occurring in a patient with CLL who was treated with alemtuzumab
[22]. These two cases collectively suggest that the immunosuppressive state induced by alemtuzumab may predispose patients
to GBS. Molecular mimicry is another theory in which the antibodies produced by bodys immune system to alemtuzumab cross
react to a host epitope leading to GBS. We postulate that alemtuzumab like other immunosuppressive agents may predispose
patients to develop GBS putatively via an autoimmune mechanism
resulting from indiscriminate dysregulation of regulatory T cells or
via molecular mimicry. Clinicians should be vigilant in monitoring
for the development of GBS in patients treated with alemtuzumab
and similar agents.
Conict of interest
None.
Acknowledgments
Contributions: K.K.S.A. provided the conception and design of
the case report, along with acquisition of data analysis and interpretation of data. S.M.R. helped in nding articles and references
for the case report. J.S. helped in understanding the pharmacogenic
mechanism of action. S.T. provided the understanding of the basic
cause and effect relation of the drug and disease. T.L. provided
active input and feedback for the case report, who diagnosed and
treated the leukemia helped in the understanding of the initial
presentation of the patient and approved the nal version. J.J.D.
helped in drafting the article and revised it critically for important
intellectual content.
References
[1] Laros-van Gorkom BAP, Huisman CAM, Wijermans PW, Schipperus MR. Schipperus Experience with alemtuzumab in treatment of chronic lymphocytic
leukaemia in The Netherlands. Neth J Med 2007;65(9):3337.
[2] Kirk AD, Hale DA, Swanson SJ, Mannon RB. Autoimmune thyroid Disease after
renal transplantation using depletional induction with alemtuzumab. Am J
Transplant 2006;6:10845.
[3] Loh Y, Oyama Y, Statkute L, Quigley K, Yaung K, Gonda E, et al. Development of
a secondary autoimmune disorder after hematopoietic stem cell transplantation for autoimmune diseases: role of conditioning regimen used. Blood
2007;109:26433548.
[4] Elimelakh M, Dayton V, Park KS, Gruessner AC, Sutherland D, Howe RB, et al. Red
cell aplasia and autoimmune hemolytic anemia following immunosuppression
with alemtuzumab, mycophenolate, and daclizumab in pancreas transplant
recipients. Haematologica 2007;92:102936.
[5] Ginaldi L, De Martinis M, Matutes E, Farahat N, Morilla R, Dyer MJ, et al. Levels
of expression of CD52 in normal and leukemic Band T cells: correlation with in
vivo therapeutic responses to Campath-1H. Leuk Res 1998;22:18591.
[6] Hale G, Xia MQ, Tighe HP, Dyer MJ, Waldmann H. The CAMPATH-1 antigen
(CDw52). Tissue Antigens 1990;35:11827.
[7] Dungarwalla m, Matutes E, Dearden C. E Prolymphocytic leukemia of B and T
cell subtypea state of the art paper. Eur J Hematol 2008;80(June (6)):46976.
[8] Brett S, Baxter G, Cooper H, Johnston JM, Tite J, Rapson N. Repopulation of
blood lymphocyte sub-populations in rheumatoid arthritis patients treated
with the depleting humanized monoclonal antibody, CAMPATH-1H. Immunology 1996;88:139.
[9] Prez-Simn JA, Kottaridis PD, Martino R, Craddock C, Caballero D, Chopra R,
et al. Nonmyeloablative transplantation with or without alemtuzumab: comparison between 2 prospective studies in patients with lymphoproliferative
disorders. Blood 2002;100:31217.
[10] Carella CCAM, Beltrami G, Scalzulli PR, Carella Jr AM, Corsetti MT. Alemtuzumab can successfully treat steroid-refractory acute graft-versus-host
disease (aGVHD). Bone Marrow Transplant 2004;33:1312.
[11] Laurenti L, Piccioni P, Cattani P, Cingolani A, Efremov D, Chiusolo P, et
al. Cytomegalovirus reactivation during alemtuzumab therapy for chronic

e156

[12]

[13]

[14]
[15]

[16]
[17]

[18]
[19]

[20]

[21]

[22]

Letter to the Editor / Leukemia Research 34 (2010) e154e156

lymphocytic leukemia: incidence and treatment with oral ganciclovir. Haematologica 2004;89:124852.
Ratzinger G, Reagan JL, Heller G, Busam KJ, Young JW. Differential CD52
expression by distinct myeloid dendritic cell subsets: implications for alemtuzumab activity at the level of antigen presentation in allogeneic grafthost
interactions in transplantation. Blood 2003;101:14229 [Erratum in: Blood
2005;105:3018].
Buggins AGS, Mufti GJ, Salisbury J, Codd J, Westwood N, Arno M, et al. Peripheral
blood but not tissue dendritic cells express CD52 and are depleted by treatment
with alemtuzumab. Blood 2002;100:171520.
Rutella S, Lemoli RM. Regulatory T cells and tolerogenic dendritic cells: from
basicbiology to clinical applications. Immunol Lett 2004;94:1126.
Kubach J, Becker C, Schmitt E, Steinbrink K, Huter E, Tuettenberg A, et
al. Dendritic cells: sentinels of immunity and tolerance. Int J Hematol
2005;81:197203.
Johansson S, Berg L, Hall H, Hoglund P. NK cells: elusive players in autoimmunity. Trends Immunol 2005;26:6138.
Cox AL, Thompson SA, Jones JL, Robertson VH, Hale G, Waldmann H, et al. Lymphocyte homeostasis following therapeutic lymphocyte depletion in multiple
sclerosis. Eur J Immunol 2005;35:333242.
Clatworthy MR, Jayne DR. Acquired hemophilia in association with ANCAassociated vasculitis: response to rituximab. Am J Kidney Dis 2006;47:6802.
Groom JR, Fletcher CA, Walters SN, Grey ST, Watt SV, Sweet MJ, et al. BAFF and
MyD88 signals promote a lupuslike disease independent of T cells. J Exp Med
2007;204:195971.
Carmona A, Alonso JD, de las Heras M, Navarrete A. GuillainBarr syndrome
in a patient with diffuse large B-cell lymphoma, and rituximab maintenance therapy. An association beyond anecdotal evidence? Clin Transl Oncol
2006;8:7646.
Jaso R, Sierra M, Calleja J, Valero C. PascualGuillainBarr Julio syndrome
after rituximab in a patient with idiopathic thombocytopenic purpura: a causal
association? J Neurol 2009;(November).
Castelli R, Moreo G, Panli B, Cogiamanian F, Reda G, Cortelezzi A, et al.
GuillainBarr syndrome in a chronic lymphocytic leukaemia (CLL) patient
after subcutaneous alemtuzumab and high dose of prednisone therapy. J
Peripher Nerv Syst 2009;14(Supplement):128.

Kamal K.S. Abbi

Syed M. Rizvi
Department of Internal Medicine Residency Program,
Penn State Milton S Hershey Medical Center,
500 University Drive, Hershey, PA 17033-0850, USA
Jeffrey Sivik
Department of Pharmacy,
Penn State Milton S Hershey Medical Center,
Hershey, PA, USA
Subramanian Thyagarajan
Department of Neurology,
Penn State Milton S Hershey Medical Center,
Hershey, PA, USA
Thomas Loughran
Joseph J. Drabick
Division of Hematology and Oncology,
Penn State Milton S Hershey Medical Center,
Hershey, PA, USA
Corresponding

author. Tel.: +1 717 531 8521;

fax: +1 717 531 2034.
E-mail address: kabbi@hmc.psu.edu
(K.K.S. Abbi)
20 October 2009
Available online 2 April 2010