Progressive multifocal leukoencephalopathy following fludarabine treatment in a chronic lymphocytic leukemia patient
Progressive multifocal leukoencephalopathy (PML) is a neurological disease caused by infection of the central nervous system (CNS) with the JC polyomavirus (JCV). JCV is endemic and infects a large proportion (70–90%) of healthy individuals worldwide, but infection is latent. JCV reactivation may oc...
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Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України
2011
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| Цитувати: | Progressive multifocal leukoencephalopathy following fludarabine treatment in a chronic lymphocytic leukemia patient / S. Lejniece, M. Murovska, S. Chapenko, B. Breiksa, Z. Jaunmuktane, L. Feldmane, I. Ziedlina, J. Gomez-Roman, M. Garcia-Cabeza, A. Lejnieks // Experimental Oncology. — 2011. — Т. 33, № 4. — С. 239-241. — Бібліогр.: 13 назв. — англ. |
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irk-123456789-1386662018-06-20T03:04:18Z Progressive multifocal leukoencephalopathy following fludarabine treatment in a chronic lymphocytic leukemia patient Lejniece, S. Murovska, M. Chapenko, S. Breiksa, B. Jaunmuktane, Z. Feldmane, L. Ziedlina, I. Gomez-Roman, J. Garcia-Cabeza, M. Lejnieks, A. Short communications Progressive multifocal leukoencephalopathy (PML) is a neurological disease caused by infection of the central nervous system (CNS) with the JC polyomavirus (JCV). JCV is endemic and infects a large proportion (70–90%) of healthy individuals worldwide, but infection is latent. JCV reactivation may occur, if the immune function is compromised. Aim: To present a PML case in a CLL patient after a long course of disease and treatment with fludarabine. JCV virus infection in this patient was proven both in brain biopsy material and blood. Methods: Patient with a nine-year history of CLL was hospitalized with the weakness in the right leg and left hand, tremors, speech difficulties. An MRI diagnosed infiltrative glial tumor of the left hemisphere, proliferating predominantly in the frontal lobe, more in the gyrus frontalis superior region. CNS tumor biopsy performed. Results: Morphology and immunoprofile of the lesion consistent with progressive multifocal leukoencephalopathy. The material from biopsy was diagnosed as positive for JCV DNA. JCV and HHV-7 genomic sequences were found in patient’s PBL DNA sample. In a plasma DNA sample, only genomic sequences were detected. Conclusion: The present case draws attention to the fact that the use of fludarabine and its combinations in CLL therapy increases the risk of JCV infection reactivation and development of serious complications like PML. 2011 Article Progressive multifocal leukoencephalopathy following fludarabine treatment in a chronic lymphocytic leukemia patient / S. Lejniece, M. Murovska, S. Chapenko, B. Breiksa, Z. Jaunmuktane, L. Feldmane, I. Ziedlina, J. Gomez-Roman, M. Garcia-Cabeza, A. Lejnieks // Experimental Oncology. — 2011. — Т. 33, № 4. — С. 239-241. — Бібліогр.: 13 назв. — англ. 1812-9269 http://dspace.nbuv.gov.ua/handle/123456789/138666 en Experimental Oncology Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України |
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Digital Library of Periodicals of National Academy of Sciences of Ukraine |
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DSpace DC |
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English |
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Short communications Short communications |
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Short communications Short communications Lejniece, S. Murovska, M. Chapenko, S. Breiksa, B. Jaunmuktane, Z. Feldmane, L. Ziedlina, I. Gomez-Roman, J. Garcia-Cabeza, M. Lejnieks, A. Progressive multifocal leukoencephalopathy following fludarabine treatment in a chronic lymphocytic leukemia patient Experimental Oncology |
| description |
Progressive multifocal leukoencephalopathy (PML) is a neurological disease caused by infection of the central nervous system (CNS) with the JC polyomavirus (JCV). JCV is endemic and infects a large proportion (70–90%) of healthy individuals worldwide, but infection is latent. JCV reactivation may occur, if the immune function is compromised. Aim: To present a PML case in a CLL patient after a long course of disease and treatment with fludarabine. JCV virus infection in this patient was proven both in brain biopsy material and blood. Methods: Patient with a nine-year history of CLL was hospitalized with the weakness in the right leg and left hand, tremors, speech difficulties. An MRI diagnosed infiltrative glial tumor of the left hemisphere, proliferating predominantly in the frontal lobe, more in the gyrus frontalis superior region. CNS tumor biopsy performed. Results: Morphology and immunoprofile of the lesion consistent with progressive multifocal leukoencephalopathy. The material from biopsy was diagnosed as positive for JCV DNA. JCV and HHV-7 genomic sequences were found in patient’s PBL DNA sample. In a plasma DNA sample, only genomic sequences were detected. Conclusion: The present case draws attention to the fact that the use of fludarabine and its combinations in CLL therapy increases the risk of JCV infection reactivation and development of serious complications like PML. |
| format |
Article |
| author |
Lejniece, S. Murovska, M. Chapenko, S. Breiksa, B. Jaunmuktane, Z. Feldmane, L. Ziedlina, I. Gomez-Roman, J. Garcia-Cabeza, M. Lejnieks, A. |
| author_facet |
Lejniece, S. Murovska, M. Chapenko, S. Breiksa, B. Jaunmuktane, Z. Feldmane, L. Ziedlina, I. Gomez-Roman, J. Garcia-Cabeza, M. Lejnieks, A. |
| author_sort |
Lejniece, S. |
| title |
Progressive multifocal leukoencephalopathy following fludarabine treatment in a chronic lymphocytic leukemia patient |
| title_short |
Progressive multifocal leukoencephalopathy following fludarabine treatment in a chronic lymphocytic leukemia patient |
| title_full |
Progressive multifocal leukoencephalopathy following fludarabine treatment in a chronic lymphocytic leukemia patient |
| title_fullStr |
Progressive multifocal leukoencephalopathy following fludarabine treatment in a chronic lymphocytic leukemia patient |
| title_full_unstemmed |
Progressive multifocal leukoencephalopathy following fludarabine treatment in a chronic lymphocytic leukemia patient |
| title_sort |
progressive multifocal leukoencephalopathy following fludarabine treatment in a chronic lymphocytic leukemia patient |
| publisher |
Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України |
| publishDate |
2011 |
| topic_facet |
Short communications |
| url |
http://dspace.nbuv.gov.ua/handle/123456789/138666 |
| citation_txt |
Progressive multifocal leukoencephalopathy following fludarabine treatment in a chronic lymphocytic leukemia patient / S. Lejniece, M. Murovska, S. Chapenko, B. Breiksa, Z. Jaunmuktane, L. Feldmane, I. Ziedlina, J. Gomez-Roman, M. Garcia-Cabeza, A. Lejnieks // Experimental Oncology. — 2011. — Т. 33, № 4. — С. 239-241. — Бібліогр.: 13 назв. — англ. |
| series |
Experimental Oncology |
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2025-07-10T06:19:20Z |
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2025-07-10T06:19:20Z |
| _version_ |
1837239752161492992 |
| fulltext |
Experimental Oncology ��� �������� ���� ��ecem�er���� �������� ���� ��ecem�er� ��ecem�er� ���
PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY FOLLOWING
FLUDARABINE TREATMENT IN A CHRONIC LYMPHOCYTIC LEUKEMIA
PATIENT
S. Lejniece1,2,*, M. Murovska3, S. Chapenko3, B. Breikša2, Z. Jaunmuktane1,
L. Feldmane1, I. Ziediņa2, J. Gomez-Roman4, M. Garcia-Cabeza5, A. Lejnieks1,2
1Riga Stradins University, Riga LV1039, Latvia
2Riga Eastern Clinical University Hospital, Riga LV1006, Latvia
3A. Kirchenstein Institute of Microbiology and Virology, Riga Stradins University, LV1054, Latvia
4Department of Anatomic Pathology, “Marques de Valdecilla” University Hospital, Santander 39001, Spain
5Service of Pathology, “Principe de Asturias” University Hospital, Alcala de Henares 28801, Spain
Progressive multifocal leukoencephalopathy (PML) is a neurological disease caused by infection of the central nervous system
(CNS) with the JC polyomavirus (JCV). JCV is endemic and infects a large proportion (70–90%) of healthy individuals worldwide,
but infection is latent. JCV reactivation may occur, if the immune function is compromised. Aim: To present a PML case in a CLL
patient after a long course of disease and treatment with fludarabine. JCV virus infection in this patient was proven both in brain
biopsy material and blood. Methods: Patient with a nine-year history of CLL was hospitalized with the weakness in the right leg
and left hand, tremors, speech difficulties. An MRI diagnosed infiltrative glial tumor of the left hemisphere, proliferating pre-
dominantly in the frontal lobe, more in the gyrus frontalis superior region. CNS tumor biopsy performed. Results: Morphology and
immunoprofile of the lesion consistent with progressive multifocal leukoencephalopathy. The material from biopsy was diagnosed
as positive for JCV DNA. JCV and HHV-7 genomic sequences were found in patient’s PBL DNA sample. In a plasma DNA sample,
only genomic sequences were detected. Conclusion: The present case draws attention to the fact that the use of fludarabine and its
combinations in CLL therapy increases the risk of JCV infection reactivation and development of serious complications like PML.
Key Words: progressive multifocal leukoencephalopathy, JC polyomavirus, chronic lymphocytic leukemia, fludarabine, immuno-
suppression.
Progressive multifocal leukoencephalopathy �PML�
is a neurological disease caused �y infection of the
central nervous system �CNS� with the JC polyomavi-
rus �JCV�. JCV was discovered in ��7� and is a type
of human polyomavirus genetically similar to the
BK virus. JCV is endemic and infects a large proportion
�7����%� of healthy individuals worldwide [�]� �ut
infection is latent. Following primary infection� the virus
esta�lishes a latent infection which may persist in a la-
tent state for an extended period� even in immuno-
competent individuals. JCV reactivation� however� may
occur� if the immune function is compromised� for
example� in HIV-infected patients� patients receiving
�one marrow or renal transplants and patients receiv-
ing chemotherapy [�]. �uring the course of AI�S�
up to �% of patients may develop PML. For hemato-
logical patients the risk of developing PML is lower and
incidence of PML in previously descri�ed chronic
lymphocytic leukemia �CLL� patients is �.5�% [�]. Ir-
radiation of the CNS� intrathecal application of metho-
trexate� and severe immunosuppression are risk-in-
creasing factors. If JCV activation occurs� the virus can
cause demyelinization� �eginning in the deeper �rain
structures and progressing rapidly [�]. PML clinical
features are fatigue� disorientation� dementia� depres-
sion� seizures� hemiparalysis� and other focal neuro-
logical signs. In most cases� the disease has a fatal
course within weeks or months.
Immunosuppression also develops in cases
of CLL� especially following fludara�ine therapy. Here�
we present a PML case in a CLL patient after a long
course of disease and treatment with fludara�ine. JCV
virus infection in this patient was proven �oth in �rain
�iopsy material and �lood.
MATERIALS AND METHODS
In March ����� a 5�-year-old man was diagnosed
with CLL. He himself detected enlarged lymphatic
nodes in the neck and consulted his family doctor.
At that stage: WBC — ��.� × ���/l� HGB — ��� g/l�
RBC — �.�5 × ����/l� lym — ��.� × ���/l� PLT —
�66 × ���/l� small peripheral lymphadenopathy� CLL
stage II diagnosed according to Binet. For eight years
he received chloram�ucil and prednisolone therapy
as out-patient� without achieving hematological remis-
sion. Because of disease progression received � cy-
cles of COP �cyclophosphani� vincristini� prednisoloni��
followed �y 7 cycles FM� �fludara�ine� mitoxantrone�
dexamethasone�.
In Fe�ruary ���8� patient with a nine-year history
of CLL was hospitalized in a surgical ward for an unre-
lated condition and reported a three week history of the
weakness in the right leg and left hand� tremors. The
patient also experienced speech difficulties� including
Received: September 27, 2011.
*Correspondence: E-mail: lejniece@latnet.lv
Fax: +37167821154
Abbreviations used: CLL — chronic lymphocytic leukemia; CNS —
central nervous system; JCV — JC polyomavirus; LPD — lympho-
proliferative disorders; PBL — peripheral blood leukocytes; PML —
progressive multifocal leukoencephalopathy.
Exp Oncol ����
��� �� �������
SHORT COMMUNICATIONS
��� Experimental Oncology ��� �������� ���� ��ecem�er�
clumsiness and a slight slur. The neurologist’s final
conclusion was cortinuclear failure of the right side with
central paresis of the left arm with tremor� central paresis
of the right leg� and motor aphasia. An MRI diagnosed
infiltrative glial tumor of the left hemisphere� proliferat-
ing predominantly in the frontal lo�e� more in the gyrus
frontalis superior region. The process was spreading
to the frontal part of corpus callosum and putamen� and
also the temporal lo�e of the same hemisphere. Se-
veral tiny periventricular and hyperintense su�cortical
vascular foci of the same nature in �oth hemispheres.
Blood count: WBC — �.� × ���/l� HGB — ��� g/L� RBC —
�.5� × ����/l� PLT — ��� × ���/l� lym — �.�� × ���/l.
Biochemical analyses without pathology� only L�H and
�eta�-microglo�ulin increased. Additional tests: Anti
HIV�/� — negative� EBV �NA — negative� CMV �NA
qualitatively — negative� Aspergillus Ag quantitatively —
negative� Cryptococcus Ag — negative.
In March ���8� he was transferred to the neuro-
surgery ward. Patient was recum�ent� partial aphasia�
hemisyndrome of the left side. Frontal lo�e cere�rot-
omy was performed and tissue samples taken for his-
tological examination. CNS tumor �iopsy performed.
RESULTS
Morphology and immunoprofile of the lesion con-
sistent with progressive multifocal leukoencephalopa-
thy �Figure�.
Figure. Scattered throughout the hypercellular lesion with nu-
merous foamy macrophages and reactive astrocytes there are
homogenous intranuclear inclusions in oligodendrocytes with
simultaneous ground glass appearance of nuclei �H&E × ���
The material was additionally examined to detect
JCV �NA. �NA was extracted from ��7 µm-thick
sections o�tained from formalin-fixed and paraffin
em�edded �rain tissue. Sections were digested with
protease K and �NA was purified on silica columns
�Qiagen Gm�H� Germany� according to the manu-
facturer’s protocol. The technique consisted of ge-
nomic amplification �nested PCR with JC�/JC� primers
in external amplification and PEP�/PEP� in internal
amplification� followed �y restriction fragment length
polymorphism with the enzyme BamH�. Beta-glo�in
gene was used as a control for the integrity of the
genome of the sample. After amplification with the
primers� a �7� �p fragment of the JCV genome was
o�tained. This fragment was digested with the enzyme
BamH�. The reaction mixture was electrophoresed
on a �% agarose gel. The viral su�type was determined
according to the digestion �ands as descri�ed previ-
ously [��.]. After digestion with the enzyme BamH� the
�7� p� �and disappeared and the case was diagnosed
as positive for JCV �NA.
JCV was detected in the patient’s �lood. The
nested polymerase chain reaction �nPCR� was used
for the detection of viral sequences in �NA isolated
from peripheral �lood leukocytes �PBL� and plasma
�markers of latent/persistent and active infection�
respectively�. JCV and HHV-7 genomic sequences
were found in patient’s PBL �NA sample. In a plasma
�NA sample� only genomic sequences were detected.
JCV causing PML in the patient was confirmed
�oth in �rain �iopsy and �lood. Motor aphasia� hemi-
syndrome of the left side progressed. Patient received
symptomatic therapy and died a month after opera-
tion� in April ���8. Post-mortem examination was not
performed.
DISCUSSION
PML was first descri�ed in patients with CLL and
Hodgkin lymphoma in ��58 [6]. Association �etween
purine nucleoside analogues and PML has �een
explored in a systematic study of evaluation the clini-
cal characteristics of HIV-negative patients affected
�y lymphoproliferative disorders �LP�� who develop
PML [�]. In this study B-cell CLL was the most frequent
underlying LP� and the most frequent treatment re-
ceived was purine analogues.
In the majority of previously descri�ed CLL cases
PML diagnosis was confirmed with JCV detection
in �rain �iopsy [�� 7� 8]� in some cases JCV was de-
tected in spinal fluid [�� ��]. In most of reported cases�
similarly to the patient descri�ed �y us� PML developed
following fludara�ine therapy [�� 8� �� ��]� therefore
it is considered that the immunosuppressive effect
of this therapy may cause JCV activation. Moreover�
the case of PML development in 6�-year-old male with
CLL after 6 months of fludara�ine therapy and without
JCV infection is previously reported and authors sug-
gested the possi�le role of fludara�ine in producing
PML-like lesions in patients with CLL [��]. Another
investigation suggests that immunosuppression
caused �y chronic lymphoproliferative malignancies
alone may �e a factor in the development of PML and
chemotherapy with fludara�ine may act as an addi-
tional trigger [�]� �esides some reported cases date
�ack to the time �efore fludara�ine was accessi�le for
treatment [��� ��].
The present case� in addition to the previously re-
ported� draws attention to the fact that the use of fluda-
ra�ine and its com�inations in CLL therapy increases
the risk of JCV infection reactivation and development
of serious complications like PML. Because devel-
opment of PML is tightly linked to suppression and/
or modulation of the immune system as in develop-
ment of hematological malignancies as in monoclonal
Experimental Oncology ��� �������� ���� ��ecem�er���� �������� ���� ��ecem�er� ��ecem�er� ���
anti�ody treatments� further scrutiny of the course
of JCV infection in immune cells will �e essential to our
understanding of development of PML and identifi-
cation of new therapeutic targets [��]. The present
case� in addition to a few previously reported� draws
attention to the fact that the use of fludara�ine and its
com�inations in CLL therapy increases the risk of seri-
ous infection complications like PML.
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