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: mikihiro@tokushima-u.ac.jp

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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