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International Journal of Myeloma vol. 10 no. 1 (2020)8
Successful treatment of progressive multifocal leukoencephalopathy with mirtazapine and mefloquine in refractory myeloma
Kengo UDAKA1, Shingen NAKAMURA1, Shiro FUJII1, Ryosuke MIYAMOTO2, Naoko MATSUI2, Shiyori KAWATA1, Taiki HORI1, Jumpei MURAI1, Ryohei SUMITANI1, Masahiro OURA1,
Kimiko SOGABE1, Mamiko TAKAHASHI1, Takeshi HARADA1, Kumiko KAGAWA1, Yuishin IZUMI2, Masahiro ABE1 and Hirokazu MIKI3
We herein describe a 52-year-old man with multiple myeloma (MM) who developed progressive multifocal leuko-
encephalopathy (PML). He was diagnosed with MM in December 20XY, and underwent high-dose chemotherapy
followed by autologous stem cell transplantation. He relapsed in October 20XY+2, and he was treated with the oral
administration of cyclophosphamide and prednisolone (CP). He developed apraxia and visual disturbance in March
20XY+4. Since PML was suspected, we stopped CP and mirtazapine was initiated; however, his neurological
symptoms did not improve. He was diagnosed with PML based on John Cunningham virus (JCV) DNA in his
cerebrospinal fluid (CSF). He was treated with therapy involving of mirtazapine, cytarabine, and high-dose
immunoglobulin; however, his neurological disorders did not improve despite the disappearance of JCV DNA
in his CSF. Therefore, we started combination therapy of mirtazapine and mefloquine, which resulted in the
significant improvement of both his neurological symptoms and MRI findings. Although we restarted the anti-MM
treatment, his neurological symptoms remained stable for more than 2 years with the continuation of this com-
bination therapy. The present case suggests that combination therapy of mirtazapine and mefloquine is effective
for patients with PML, particularly those requiring immunosuppressive chemotherapy.
Key words: progressive multifocal leukoencephalopathy, JC virus, multiple myeloma, mirtazapine, mefloquine
Introduction
Progressive multifocal leukoencephalopathy (PML) is a rare
demyelinating disease caused by John Cunningham virus
(JCV) infection in oligodendrocytes and astrocytes [1]. Neuro-
logical symptoms correspond to demyelinated lesions in the
brain, including sensory disorders, hemianopsia, cognitive
dysfunction, aphasia, and gait disturbance [1]. PML often
develops in patients with acquired immunodeficiency syn-
drome. PML has also been reported in human immuno-
deficiency virus (HIV)-negative patients with hematological dis-
ease, such as malignant lymphoma, and acute leukemia [2, 3].
Of note, PML is associated with immunosuppressive states
after treatments for against hematological malignancies, such
as rituximab therapy or stem cell transplantation [4].
PML progresses rapidly to death. Its median overall survival
without treatment was previously reported to be 3.5 months
[5]. However, recovery from immune suppression increases the
survival rate of PML with HIV [6]. There are currently no effec-
tive treatments for PML in HIV-negative immunosuppressive
patients.
Multiple myeloma (MM) remains an incurable disease, even
with the implementation of hematopoietic stem cell trans-
plantation and novel therapeutic modalities. Immunoparesis is
associated with MM; repeated treatment with anti-MM agents
including corticosteroids, strongly induces an immuno-
suppressive state in MM patients [7]. As a result, infection is
a major cause of morbidity and mortality in patients with MM
[8, 9].
International Journal of Myeloma 10(1): 8–12, 2020©Japanese Society of MyelomaCASE REPORT
Received: December 22, 2019, accepted: February 21, 20201Department of Hematology, Endocrinology and Metabolism, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan2Department of Clinical Neuroscience, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan3Division of Transfusion Medicine and Cell Therapy, Tokushima University Hospital, Tokushima, Japan
Corresponding author: Hirokazu MIKI, M.D., PhD.Division of Transfusion Medicine and Cell Therapy, Tokushima University Hospital, Tokushima, 2-50-1, Kuramoto-cho, Tokushima 770-8503, JapanE-mail: [email protected]
9International Journal of Myeloma vol. 10 no. 1 (2020)
Mirtazapine and mefloquine for PML
We herein report the efficacy of combination therapy of
mirtazapine and mefloquine for PML that developed in a
patient with MM after autologous peripheral blood stem cell
transplantation (ASCT) and the subsequent long-term oral
administration of cyclophosphamide and prednisolone (CP).
Case Report
A 52-year-old man was diagnosed with MM (IgA-λ type,
International Staging System: 2) in December 20XY. He
received induction chemotherapy consisting of vincristine,
doxorubicin, and dexamethasone for three cycles, and
achieved a partial response (PR). He received high-dose
chemotherapy (melphalan: 200 mg/m2) followed by ASCT
(CD34 positive cells 2.4 × 106 cells/kg) in February 20XY+2,
and achieved very good PR. However, he relapsed in October
20XY+2, and was treated with CP. His disease status remained
stable without progression with continuous CP; however, he
developed apraxia in March 20XY+4, followed by dysmnesia,
visual disturbance, weakness in the right arm, and aphasia. He
was admitted to our hospital in May 20XY+4 (835 days after
ASCT).
On admission, his body temperature was 36.8°C, blood
pressure 125/89 mmHg, pulse rate 68/minute, and oxygen
saturation 99% on room air. He had severe memory impair-
ment (Mini-Mental State Examination score of 5/30), moderate
apraxia, moderate visual agnosia, moderate left-right disori-
entation, mild motor-dominant aphasia, and forced-grasping.
A visual field defect, ataxia, and nuchal rigidity were not
detected. Mild right arm weakness with a positive Barre’s sign
was noted. The snout reflex was positive, deep tendon reflexes
were normal in the upper and lower limbs, and Babinski’s sign
was negative.
Laboratory data on admission in May 20XY+4 were listed in
Table 1. Pancytopenia (hemoglobin: 8.3 g/dL, white blood
cells: 2,200/μL, and platelets: 113 × 103/μL) with a marked
decrease in CD4-positive lymphocytes (24/μL) was observed in
the peripheral blood. His serum IgA level was elevated with a
monoclonal spike (695 mg/dL, normal range: 110–410 mg/dL),
while IgG decreased (597 mg/dL, normal range: 870–1,700
mg/dL) and β2-microglobulin (4.37 mg/L, normal range
<2.2 mg/L) increased. Magnetic resonance imaging (MRI) of
the brain showed a white matter lesion involving the left
parietal and occipital lobes, exhibiting hyperintense signals on
T2- weighted images and fluid attenuated inversion recovery
(FLAIR) images (Fig. 1B, 1C). Lesions were observed as hypo-
intense signals on T1-weighted images and hyperintense
signals on diffusion-weighted images, and were not enhanced
by gadolinium (Fig. 1D, 1E). PML was strongly suspected based
on MRI findings. A cerebrospinal fluid (CSF) examination
showed a normal opening pressure (12 cmH2O), a normal cell
count (1/3 mm3), and normal levels of protein (46 mg/dL) and
Table 1. Results of laboratory examination in May 20XY+4 (at diagnosis of PML)
Blood cell count Blood chemistry Serological test
WBC 2,200/μL GOT 22 U/L CRP 1.18 mg/dL
band 0.0% GPT 18 U/L IgG 597 mg/dL
seg 75.0% T-Bil 0.5 mg/dL IgA 695 mg/dL
baso 0.0% ALP 154 U/L IgM 20 mg/dL
eosino 0.0% LDH 238 U/L sIL-2R 110 U/mL
mono 15.0% BUN 10.0 mg/dL β2MG 4.37 mg/L
lymph 10.0% Cre 0.58 mg/dL HIV (Ag/Ab) (–)
CD4+ 24/μL Na 142 mEq/L Vitamin B1 11 ng/mL
CD8+ 133/μL K 3.9 mEq/L Vitamin B12 >1500 pg/mL
RBC 2.4 × 106/μL Cl 108 mEq/L Aspergillus antigen 0.2
Hb 8.3 g/dL Ca 8.1 mg/dL 1-3 β-D-glucan <4.8 pg/mL
Hct 25.7% TP 5.6 g/dL
MCV 107.1 fL Alb 2.9 g/dL Cerebrospinal fluid
PLT 113 × 103/μL Glucose 123 mg/dL Opening pressure 12 cmH2O
Cell count 1/3 mm3
Hemostatic test Protein 46 mg/dL
PT 11.0 sec Glucose 50 mg/dL
PT-INR 0.93 Cl 123 mEq/L
APTT 29.5 sec
Fib 483 mg/dL
International Journal of Myeloma vol. 10 no. 1 (2020)10
UDAKA et al.
glucose (50 mg/dL). A polymerase chain reaction (PCR) analy-
sis for JCV in CSF showed positive results (JCV-DNA 1.39 × 102
copies/mL) and the HIV antibody test was negative (Table 1).
Therefore, he was diagnosed with HIV-negative PML. We
stopped CP and started mirtazapine (15 mg/day) with the
continuous infusion of cytarabine (100 mg/day for 5 days)
and high-dose intravenous immunoglobulin. After this combi-
nation therapy, the PCR test for JCV in CSF became negative
with the recovery of CD4-positive lymphocyte counts (176/μL).
However, his neurological symptoms worsened, and the
hyperintense lesion on the FLAIR image expanded to the left
frontal and right parietal lobes (Fig. 2B). After obtaining
informed consent from the patient and his wife under the
approval of the Ethics Committee/Internal Review Board of the
Tokushima University Hospital (permission # 1012), oral admin-
istration of mefloquine (275 mg/week) was initiated 3 months
after the diagnosis of PML. His neurological symptoms
gradually improved after the combination of mefloquine and
mirtazapine without apparent adverse events, and he was
discharged in August 20XY+4 (940 days after ASCT). Unfor-
tunately, a laboratory examination showed an increase in
M- protein, and an anti-MM treatment, involving CP, thalido-
mide, and high-dose dexamethasone, was started along with
mirtazapine and mefloquine in October 20XY+4. His neuro-
logical symptoms remained stable without progression,
and MRI showed a marked reduction in white matter lesions
(Fig. 2C, 2D). He died due to MM progression in August
20XY+6 (Fig. 3).
Discussion
The present case demonstrated that PML may occur in
immunocompromised MM patients after ASCT. PML must be
considered in immunodeficient patients after ASCT with
neurological symptoms, and relevant diagnostic examinations
need to be performed. In addition to the discontinuation
of immunosuppressive therapy, several drugs have been
attempted in the treatment of HIV-negative PML. However,
no specific antiviral treatment for JCV has been established.
Cytarabine, a chemotherapeutic drug, has been demonstrated
Figure 1. Brain MRI findings of the patient at the diagnosis of PML. A: T1-weighted image (T1WI). Note that the lesion basically demonstrates hypointense signals but there is subtle hyper intense signals in the advancing edge. B: T2-weighted image (T2WI). C: Fluid attenuated inver-sion recovery (FLAIR) image. D: Diffusion-weighted image (DWI). E: T1-weighted image of the brain after the gadolinium injection (Gd-T1).
11International Journal of Myeloma vol. 10 no. 1 (2020)
Mirtazapine and mefloquine for PML
Figure 2. Follow-up brain MRI imaging of the patient (FLAIR). A: MRI of the brain in May 20XY+4 (at the diagnosis of PML). B: MRI in June 20XY+4. C: MRI in May 20XY+5. D: MRI in April 20XY+6.
Figure 3. Clinical course of the patient. IVIG: intravenous immunoglobulin. HD-Mel: high-dose melphalan. ASCT: autologous peripheral blood stem cell transplantation. Thal: thalidomide. CPA: cyclophosphamide. PSL: prednisolone. DEX: dexamethasone. CSF: cerebrospinal fluid. PB: peripheral blood.
International Journal of Myeloma vol. 10 no. 1 (2020)12
UDAKA et al.
to exert in vitro anti-viral activities against JCV [1, 10]. It inhibits
both DNA and RNA polymerases and nucleotide reductase
enzymes, which confers anti-viral activity [6, 10]. Aksamit et al.
reported that five out of 19 HIV-negative PML patients treated
with cytarabine showed neurological improvement [11].
Mirtazapine is an α-2-adrenergic, 5HT2A, and 5HT3-receptor
antagonist that crosses the blood-brain barrier. It functions as
is an antidepressant; that binds to 5HT2A, a cellular receptor
for JCV, and may prevent the spread of JCV infection to adja-
cent glial cells [12]. Mefloquine, an anti-malarial drug, is able
to enter the CSF and is expected to inhibit JCV replication in
vitro [13]. Epperla et al. reported that combination therapy
with mefloquine and mirtazapine achieved a clinical response
for PML in a patient with chronic lymphocytic leukemia [14].
Yoshida et al. also showed that combination therapy of
mefloquine and mirtazapine induced significant clinical
improvements in PML after allogenic peripheral blood cell
transplantation with continuing immunosuppressive therapy
for severe acute graft-versus-host disease [15]. The present
case was also simultaneously treated with anti-MM and anti-
JCV therapies. However, optimal dosages for these drugs
should be established.
Anderson et al. found only 9 case reports of PML in patients
with MM in the literature [16]. Five out of 9 MM patients devel-
oped PML after ASCT and two after bortezomib-combined
therapy [16]. However, limited information is currently avail-
able on PML in MM patients. The association of novel anti-MM
agents, such as proteasome inhibitors and immunomodula-
tory drugs, with PML development and progression remains
largely unknown. Although restoration of the immune
response is integral to the management of PML [16], discontin-
uation of immunosuppressive anti-MM therapy often causes
regrowth and progression of MM. The present case suggests
that combination therapy of mirtazapine and mefloquine is
effective with the long-term suppression of PML, even in
patients receiving immunosuppressive chemotherapy. Because
PML is a fatal complication in severe immunosuppressive
states, the efficacy of this combination treatment for HIV-
negative PML patients on immunosuppressive treatment
should be warranted in well-designed clinical studies.
Conflicts of Interest
The authors state that they have no Conflicts of Interest
(COI).
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