516

CASE REPORT
A case of successful treatment with eltrombopag for severe
immune-related thrombocytopenia induced byatezolizumab : Case report
Saki Harada1, Takeshi Imakura1, Seidai Sato1, Hiroshi Nokihara1, and Yasuhiko Nishioka1, 2
Department of Respiratory Medicine and Rheumatology, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan,
Department of Community Medicine for Rheumatology, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan

1
2

Abstract : Immune checkpoint inhibitors (ICIs) have shown impressive anti-tumor effects against multiple typesof malignancies. Among the wide variety of immune-related adverse events (irAEs), immune-related thrombocytopenia (ITP) is relatively rare but often clinically significant and life-threatening. However, the appropriate
treatment for severe ITP has not been determined. We herein report an 82-year-old male patient with non-smallcell lung cancer who developed severe ITP three weeks after starting the third course of atezolizumab. The
initial combination therapy with high-dose prednisolone, intravenous immunoglobulin and platelet transfusion
was ineffective. However, additional treatment with eltrombopag, a thrombopoietin receptor agonist, resulted inremarkable improvement in the thrombocytopenia. J. Med. Invest. 70 : 516-520, August, 2023
Keywords : non-small-cell lung cancer, atezolizumab, immune-related thrombocytopenia, eltrombopag

INTRODUCTION
Immune checkpoint inhibitors (ICIs) are a promising therapeutic strategy for a wide variety of malignancies. These ICIs
are generally better tolerated than conventional cytotoxic chemotherapy. However, such treatment is often complicated withadverse events mimicking autoimmune and inflammatory diseases, known as immune-related adverse events (irAEs).
Hematological irAEs induced by ICIs reportedly account for
approximately 3.6% to 3.7% of all irAEs (1, 2). Immune-related thrombocytopenia (ITP) is one of the most common typesof hematological irAEs (1) and is potentially life-threatening.
Nevertheless, little has been reported on intractable ICI-induced
ITP after initial treatment fails. Only a few studies have reported that thrombopoietin receptor agonists (TPO-RAs) improvesevere ITP induced by ICIs targeting programmed cell death
1 (PD-1) in patients refractory to corticosteroids or intravenous
immunoglobulin (IVIG). Furthermore, no reports have explored
better approaches for treating severe and refractory ITP induced
by programmed cell death 1-ligand1 (PD-L1) inhibitors, such asatezolizumab.
We herein report the first case of a response to eltrombopag,
a TPO-RA, in the PD-L1 inhibitor atezolizumab-induced ITP.

CASE REPORTAn 82-year-old man was admitted to our hospital with dyspnea and purpura. He had been diagnosed with right lower lobe
lung adenocarcinoma (cT2aN0M0 stage IB) three years prior tothis admission. PD-L1 immunohistochemistry showed a tumor
proportion score of 0%. Because surgical resection was difficult
due to his poor pulmonary function, radiation monotherapy
Received for publication February 22, 2023 ; accepted August 1, 2023.
Address correspondence and reprint requests to Yasuhiko Nishioka,
MD, PhD, Department of Respiratory Medicine and Rheumatology,
Graduate School of Biomedical Sciences, Tokushima University, 3-1815, Kuramoto-cho, Tokushima 770-8503, Japan. E-mail : yasuhiko@
tokushima-u.ac.jp(60 Gy / 20 Fr) was performed according to the patient’s wishes.
One year after the radiation therapy, the cancer recurred, anda total of 13 courses of Tegafur / Gimeracil / Osteracil Potassium
monotherapy were administered. Two years later, the chemotherapy regimen was changed to atezolizumab (1200 mg / body,
every 3 weeks). Three weeks after starting the third course of
atezolizumab, the patient presented to our clinic with dyspnea
and purpura.
A physical examination revealed conjunctival pallor, diffuse
purpura on the extremities and decreased breath sounds inthe right lung field. His blood test showed severe thrombocytopenia (4000 / μL) with an elevated level of C-reactive protein(CRP ; 9.46 mg / dL). Platelet-associated IgG (PA-IgG) was abnormally elevated (11673.7 ng / 107cells), and the prothrombin
time-international normalized ratio (PT-INR), the activatedpartial thromboplastin time (APTT), fibrinogen, and D-dimer
values were mildly elevated (Table 1). Collagen disease-related
autoantibodies and antiplatelet antibody were negative (Table
1). (1,3)-β-D-glucan, IgG antibodies to Helicobacter pylori, IgM antibodies to viral capsid antigen (anti-VCA IgM) of Epstein-Barrvirus (EBV), and cytomegalovirus antigen / antibodies werealso negative (Table 1). Two sets of blood cultures were negative(Table 1).
Chest computed tomography (CT) revealed an increasing
tumor size of the right lower lobe, right pneumothorax, and rightpleural effusion. A bone marrow aspiration showed mild hyperplasia but no malignant invasion or megakaryocytopenia (Figure 1). Because there were no signs of infection or autoimmune
diseases causing secondary thrombocytopenia and no episodesof initiation of new drugs other than atezolizumab, we made adiagnosis of ITP induced by atezolizumab.
Following pulse corticosteroid therapy with 1000 mg of methylprednisolone (mPSL) for 3 days, we treated the patient with 60
mg / day (1 mg / kg) of prednisolone (PSL). In addition, we administered 24 g (400 mg / kg) of IVIG for 5 days plus platelet transfusions. However, despite these combination therapies, the platelet
counts only temporarily increased slightly. Given previous reports of the efficacy of TPO-RA in ICI-induced ITP (3, 4), oral
eltrombopag (12.5 mg daily) as a TPO-RA was started. Cyclosporine was also started to reduce the dose of PSL. Surprisingly,

The Journal of Medical Investigation Vol. 70 2023

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The Journal of Medical Investigation Vol. 70 August 2023
Table 1. Laboratory findings of the present case on admission.
【Hematology】
WBC【Biochemistry】
3600

/ μL

TP

6.8

g / dL

Neutro.

63

%

Alb

3

g / dL

Lympho.

13

%

AST

35

U/L

Mono.

23

%

ALT

35

U/L

Eosino.

1

%

T-Bil

0.8

mg / dL

Baso.

0

%

γ-GTP

17

U/L

RBC

316×104

/ μL

LDH

213

U/L

Hb

10.2

g / dL

BUN

21

mg / dL

Plt

4000

/ μL

Cre

0.85

mg / dLNa133

mEq / LK

3.7

mEq / LCa

8.4

mg / dL【Coagulation】
PT-INR

2.42

APTT

38

sec

KL-6

495

U / mLFib

637

mg / dLcasual blood glucose

355

mg / dL

D-dimer

3.7

μg / mL

HbA1c (NGSP)

6.5

%

CRP

9.46

mg / dL(1,3)-β-D-glucan< 6.0

pg / mL

ferritin332

ng / mL

CMV antigenemia

(-)

PAIgG

11673.7

ng / 107cells

EB-EA IgG (FA)< × 10

antiplatelet antibody(-)

EB-VCA IgM (FA)< × 10direct Coombs test

(1+)

EB-VCA IgG (FA)× 40

Anti-nuclear antibody< × 40EB-EBNA IgG (FA)

× 20

RF

10

human parvovirusB19 IgM(-)

【Immunology】【Microbiology】

IU / mL【Tumor markers】
CEA

2.7

ng / mL

CYFRA

8.5

ng / mL

HIV antigen / antibody(-) / (-)

Helicobacter pylori IgG

6blood cultures (2set)

negativeU / mLthe platelet count started to gradually increase after the start ofeltrombopag and stabilized at around 150,000 / µL. Even when
cyclosporine was discontinued and PSL was tapered, the platelet
count did not decrease. Eltrombopag was discontinued on day 52
after its initiation, with no recurrence of the thrombocytopenia.

DISCUSSION

Figure 1. A bone marrow aspiration in the present case before

treatment of ITP.
H&E stain of a bone marrow aspiration. The bone marrow showed
mild hyperplasia. The yellow arrows indicate that megakaryocytes
mildly increased. There were no atypical cells suggestive of cancerous
infiltration.

With the widespread use of ICIs showing excellent efficacy
against different types of cancer, various irAEs have also beenreported. Delanoy et al. reported that hematologic irAEs occurredin 3.7% (35 of 948) and ITP in 0.9% (9 of 948) of patients treatedwith PD-1 or PD-L1 inhibitors (1). Michot et al. also reported that
hematologic irAEs for all grades accounted for 3.6% (211 of 5923)
of all irAEs, while grade III-IV hematologic irAEs accounted
for 0.7% (41 of 5923) (2). In patients treated with atezolizumab,
hematologic irAEs of all grades occurred in 4.7% (27 of 577), andthose of grades III-IV occurred in 0.7% (4 of 577) (2, 5-7).
In general, patients with irAEs have been reported to respondbetter to ICIs than those without irAEs (8). In an analysis limited to PD-1 inhibitors in non-small-cell lung cancer (NSCLC)
patients, endocrine- and skin-related irAEs were reported toS. Harada, et al. TPO-RA improved ITP induced by atezolizumab

518

be associated with a higher overall response rate and longer
progression-free survival (PFS) than in patients who did notexperience endocrine- and skin-related irAEs (9). In addition,
endocrine-, skin-, and gastrointestinal-related irAEs were reported to be associated with a longer overall survival (OS) (9). A
previous analysis of ITP in patients treated with ICIs reported
that grade 1 thrombocytopenia is associated with a longer OS(10). By contrast, it has also been reported that grade ≥ 3 thrombocytopenia induced by ICIs is associated with a shorter OS (11).
Presumably, this is partly because severe thrombocytopenia
can potentially cause bleeding, which can be fatal, and thrombocytopenia makes it difficult to continue treatments for lungcancer. However, unlike the OS, there is no reported association
between the degree of thrombocytopenia and the PFS (10). It
is assumed that the effect of ICIs on solid tumors may not be
accurately evaluated due to pseudo-progression and other factors. In the present case, the anti-tumor effect of atezolizumab
was considered to be weak because the tumor was enlarged on

CT when grade 4 thrombocytopenia induced by atezolizumab
appeared. As in previous reports, there was no positive correlation between severe thrombocytopenia and antitumor efficacy.
When a situation such as the present case arises, not only should
ICIs be promptly discontinued, but effective thrombocytopenia
management should also be implemented.
We searched the literature concerning ICI-induced ITP published after 2012 and found 29 cases. The source of our literaturesearch was PubMed using the search items “thrombocytopenia”
and “nivolumab” or “pembrolizumab”, “ipilimumab”, “avelumab”,“atezolizumab”, “durvalumab” in the period of 2012 to 2022. We
excluded cases of thrombocytopenia due to drugs other than
ICIs or other diagnoses, such as thrombotic thrombocytopenia
or amegakaryocytic thrombocytopenia. The summarized characteristics of four atezolizumab-related cases are described inTable 2. In these four reports (12-15), two Chinese patients treated with recombinant human TPO for atezolizumab-induced ITP
were reported. However, one patient died without improvement

Table 2. A comparison of previous cases of atezolizumab-induced thrombocytopenia with the present case.
References

Age

Sex

Type ofcarcinoma

Treatment Efficacy
lineof ICI

Onset time Grade Treatment

12

57

Male

NSCLC(Ad)Third

No date4 days5

IL-11, corticosteroid, TPO, platelettransfusion

Died

13

76

Female NSCLC(Ad)SecondPR

15 days3

Corticosteroid

Resolved

14

57

Female NSCLC(Ad)Third

No date7 days4

Corticosteroid, IVIG, platelet apheresis

Resolved

4

IL-11, corticosteroid, TPO, IVIG, MMF,
platelet transfusion, tocilizumab

Resolved

4

Corticosteroid, IVIG, platelettransfusion, cyclosporin, eltrombopag

Resolved

15

76

Male

NSCLC(Ad)

First

PR

about
2 years
7 months

The present case

82

Male

NSCLC(Ad)

SecondPD

9 weeks

Median76

Outcome15 days

NSCLC : non-small-cell lung cancer, Ad : adenocarcinoma, PR : partial response, PD : progressive disease, IL-11 : interleukin-11,
TPO : thrombopoietin, IVIG : intravenous immunoglobulin, MMF : mycophenolate mofetil

Figure 2. The clinical course and laboratory data in the present case.

Thick and thin arrows for platelet transfusions indicate transfusions of 20 and 10 units, respectively ; IVIG arrows indicate 24 g (400 mg / kg) of
IVIG for 5 days. mPSL : methylprednisolone, PSL : prednisolone, IVIG : intravenous immunoglobulin, PA-IgG : platelet-associated IgG.

The Journal of Medical Investigation Vol. 70 August 2023
in thrombocytopenia, and the other did not improve with TPO
but did improve with an interleukin-6 inhibitor (12, 16). Although recombinant human TPO is not approved in Japan,
TPO-RA is approved for the treatment of ITP. The American Society of Clinical Oncology guidelines (17) and a literature review(1, 2) of hematologic irAEs recommend administering TPO-RA
or rituximab to patients with ICI-induced ITP refractory to corticosteroids and IVIG. There are previous reports that TPO-RA
was effective for pembrolizumab-induced ITP (3) and nivolumab-induced ITP (4) in patients with NSCLC. However, because
there have been no previous reports of the efficacy of TPO-RA
in atezolizumab-induced ITP, the present case is the first reportshowing its efficacy.
Thrombocytopenia in ITP is thought to be caused by reduced
platelet production in addition to platelet destruction (18). Therefore, in the treatment of ITP, it is important not only to suppress
platelet destruction by immunosuppression but also to stimulate
platelet production. Whether platelet destruction or decreased
platelet production has a greater impact on thrombocytopenia is
expected to vary from case to case. In the present case, the response to steroid treatment was weak, and only a mild increase
in megakaryocytes was seen compared to the severity of thrombocytopenia. These findings suggest that the reduction in theplatelet-producing capacity was more significant than platelet
destruction. Therefore, platelet recovery may be attributed primarily to the stimulation of platelet production by eltrombopag,
a TPO-RA, rather than to the suppression of platelet destruction
by immunosuppressive therapy. However, cyclosporine was also
used as immunosuppressive therapy to reduce the dose of PSL
after the start of eltrombopag administration. Therefore, it remains possible that cyclosporine also contributed to the improvement of thrombocytopenia. However, despite cyclosporine being
discontinued earlier than eltrombopag, the platelet counts did
not decrease after discontinuation. These results also suggestthat the restorative effect on platelet counts was mainly due tothe effect of eltrombopag rather than immunosuppressive therapies, including cyclosporine ; eltrombopag was therefore considered an effective treatment option in atezolizumab-induced ITP
with a reduced platelet-producing capacity.

CONCLUSION
We experienced the first case of a response to eltrombopag
in atezolizumab-induced ITP, suggesting that eltrombopag
may be an effective treatment option for severe ITP caused byatezolizumab.

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