e-ISSN 1941-5923

© Am J Case Rep, 2023; 24: e941789

DOI: 10.12659/AJCR.941789

Received:
Accepted:
2023.07.15
2023.10.04 Immune Checkpoint Inhibitor-Induced Pure Red
Available online:
Published:
2023.10.13
2023.11.14 Cell Aplasia: A Review of 2 Cases in Metastatic
Melanoma

Authors’ Contribution: ABCDEFG 1,2 Libardo Rueda Prada 1 Mayo Clinic College of Medicine and Science, Rochester, MN, USA
Study Design A ABCDE 1,2 Tatjana Gavrancic 2 Department of Hospital Medicine, Mayo Clinic, Jacksonville, FL, USA
Data Collection B 3 Department of Internal Medicine, Universidad Industrial de Santander,
Statistical Analysis C DF 3 Miguel O. Cadena Sanabria Bucaramanga, Santander, Colombia
Data Interpretation D CDE 1,4 Igor Dumic 4 Department of Hospital Medicine, Mayo Clinic Health System, Eau Claire, WI, USA
Manuscript Preparation E B 5 Kirk Bourgeois 5 Department of Pathology, Mayo Clinic, Jacksonville, FL, USA
Literature Search F 6 Division of Hemopathology, Mayo Clinic, Rochester, MN, USA
Funds Collection G B 6 Rebecca L. King 7 Division of Hematology and Medical Oncology, Mayo Clinic, Jacksonville, FL, USA
DEF 1,7 Yiyi Yan

Corresponding Author: Libardo Rueda Prada, e-mail: Prada.libardo@mayo.edu

Financial support: This study was supported by institutional funding from the Mayo Clinic
Conflict of interest: None declared

Case series
Patients: Female, 56-year-old • Female, 25-year-old
Final Diagnosis: Immune checkpoint inhibitor induced pure red cell aplasia
Symptoms: Anemia
Clinical Procedure: —
Specialty: Hematology • General and Internal Medicine • Oncolog

Objective: Rare disease

Background: Immunotherapy is a novel treatment offering an alternative to traditional chemotherapeutic agents for dif-
ferent malignancies. Hematologic adverse reactions (HARs) related to immune checkpoint inhibitors (ICIs) are
uncommon. Pure red cell aplasia (PRCA) is a rare hematologic complication of ICI therapy in metastatic mela-
noma with significant mortality risk despite treatment with steroids or immunosuppressive therapy. For unex-
plained acute anemia after exclusion of other causes, performing bone marrow biopsy is imperative to diag-
nose PRCA and rule out involvement of bone marrow by primary tumor. HARs can occur during ICI therapy or
even after ICI therapy is stopped. ICI rechallenge, even after the development of HARs, is considered in some
patients with good response to treatment of HARs from ICIs. Recurrence of HARs with the same or different
type of reaction is seen in some patients.
Case Reports: Two cases of ICI-induced PRCA were confirmed on bone marrow biopsy after dual ICI treatment with nivolum-
ab and ipilimumab in metastatic melanoma. In case 2, PRCA was successfully treated with steroids and later
rechallenged with single-agent nivolumab, causing mild ICI-induced immune thrombocytopenia, which did not
require treatment with steroids.
Conclusions: It is crucial to increase clinician awareness of the possibility of PRCA development not only during treatment
with ICI but also after finishing treatment with ICI; there is high mortality associated with missing an opportu-
nity to diagnose and treat PRCA on time with favorable results. ICI rechallenge can be considered in patients
who showed response to immunotherapy, especially those with limited alternative therapeutic options.

Keywords: Immune Checkpoint Inhibitors • Immunotherapy • Melanoma • Red-Cell Aplasia, Pure

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 Rueda Prada L. et al:
ICI-induced pure red cell aplasia in metastatic melanoma
© Am J Case Rep, 2023; 24: e941789

Background Case Reports

Pure red cell aplasia (PRCA) is a rare syndrome manifested by Case 1

marked reticulocytopenia, relative absence of erythroid pre-
cursors on bone marrow examination, and normocytic normo-
chromic anemia due to erythropoiesis failure [1-3]. Congenital
forms of PRCA are Diamond-Blackfan anemia and Pearson syn-
drome, but these forms are much less common than acquired
PRCA, which is further classified as primary or secondary [1-3].
Secondary acquired PRCA is the most common form, and its
etiologies vary, with infections, autoimmune conditions, solid
tumors, and medication-related adverse effects being the most
common. Multiple medications have been previously reported
to cause PRCA, and, for most of these, the exact mechanism
causing PRCA is unclear. Commonly used medications asso-
ciated with secondary PRCA include azathioprine, allopurinol,
carbamazepine, clopidogrel, linezolid, tacrolimus, valproic acid,
and trimethoprim-sulfamethoxazole [4-6]. Immune checkpoint
inhibitors (ICIs) are promising immunotherapy agents with ex-
panding indications for multiple cancers. Their association with
PRCA is established but remains rare [7,8]. Here we report 2
cases of PRCA related to immunotherapy for metastatic mel-
anoma and discuss differential diagnosis and management.
A 56-year-old woman presented to the Oncology Clinic for
evaluation of acute anemia. Her past medical history included
stage IV BRAF wild-type metastatic cutaneous melanoma to the
brain, lung, liver, and bones. She previously received pembro-
lizumab, experiencing disease progression, and recently com-
pleted the second cycle of dual immunotherapy with nivolum-
ab and ipilimumab 4 weeks before presentation. She had no
history of prior gastrointestinal bleeding.
Her initial vital signs were within normal limits. Physical exam-
ination was significant for a pale, alert patient. The remainder
of her physical examination was within normal limits, except
for a 3-cm sacral wound with mild surrounding redness, green-
ish discharge, and no bone exposure. Initial laboratory work-
up was remarkable for normocytic anemia, with a hemoglobin
level of 7.4 g/dL (baseline 13.1 g/dL, 3 weeks prior), chron-
ic hyponatremia, with a sodium level stable at 133 mmol/L,
creatinine level of 0.97 mg/dL (at baseline), albumin level of
3.3 g/dL, and mild chronic aspartate transaminase and alka-
line phosphatase elevation at 61 U/L and 181 U/L, respectively.

Table 1. Case 1. Summary of laboratory workup and timeline of hospital interventions.

2 units 1 unit Bone marrow biopsy
PRBC PRBC
Interventions

Time of First 1
Day 1 Day 2 Day 3 Day 4
presentation 24 h month

Hemoglobin (g/dL) 7.4 5.8 6.4 10.8 11.3 9.8 8.6

Platelet count (×109/L) 277 270 223 222 188 235 240

White blood cell count

4.9 5.2 5.7 4.4 4.0 3.6 3.5
(×109/L)

Reticulocyte (%) 0.32 0.81 0.36 0.31 0.25 6.38

Absolute reticulocytes 9.5 31.8 14.4 12.7 9.3 208.6

Iron 85 mcg/dL. Total iron binding capacity 188 mcg/dL. TSAT 45%. Ferritin 2307 mcg/L.
Additional anemia workup B12 level >1400 ng/L. Folate level 10.0 mcg/L. Fecal occult blood test negative. Normal peripheral
blood flow cytometric immunophenotyping. Parvovirus B19 serology and PCR negative

DIC workup D-dimer 2619 ng/mL. Fibrinogen 349 mg/dL. PT 13.9 sec. INR 1.3. aPTT 29 sec

No schistocytes seen in peripheral blood smear. LDH 794 U/L (chronically elevated 624-781 U/L
Hemolysis workup
over last year). Total bilirubin 0.6 mg/dL. Haptoglobin < 14 mg/dL. Direct Coombs negative

Reference ranges: Reticulocyte (%) 0.60-2.71. Absolute reticulocyte 30.4-110.9×109/L. Iron 35-145 mcg/dL. Total iron binding capacity
250-400 mcg/dL. TSAT 14-50%. Ferritin 11-307 mcg/L. B12 level 180-914 ng/L. Folate level ³4.0 mcg/L. D-dimer £500 ng/mL.
Fibrinogen 200-393 mg/dL. PT 9.4-12.5 sec. INR 0.9-1.1. aPTT 25-37 sec. LDH 122-222 U/L. Total bilirubin £1.2 mg/dL.
Haptoglobin 30-200 mg/dL.
DIC – disseminated intravascular coagulation; LDH – lactate dehydrogenase; PRBC – packed red blood cells; PT – prothrombin time;
aPTT – activated partial thromboplastin time; TSAT – transferrin saturation.

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Rueda Prada L. et al:
ICI-induced pure red cell aplasia in metastatic melanoma
© Am J Case Rep, 2023; 24: e941789
A D
B E
C
The urinalysis results were suggestive of infection. Additional
laboratory workup is summarized in Table 1. No leukopenia or
thrombocytopenia was observed. There was persistent reticu-
locytopenia, which improved approximately 1 month after the
ICI was stopped. Despite an elevated D-dimer level, disseminat-
ed intravascular coagulation was considered less likely given
a fibrinogen level >100 mg/dL, absence of thrombocytopenia,
minimally elevated prothrombin time/international normalized
ratio, normal activated partial prothrombin time, and absence
of clinical signs of bleeding or thrombosis. Hemolysis seemed
less likely given the chronic lactate dehydrogenase elevation
in the setting of liver metastasis, absence of hyperbilirubine-
mia, negative Coombs test, and absence of schistocytes on
peripheral blood smear. The low haptoglobin level could have
been related to metastatic liver disease.
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Figure 1. Bone marrow biopsy revealed a hypercellular
marrow with trilineage hematopoiesis. (A)
Hematoxylin and eosin staining (magnification ×10).
Immunohistochemistry studies show (B) decreased
erythrocytosis by CD71 (×10) that are primarily
erythrocyte precursors by (C) E-cadherin (×10),
indicating minimal maturing erythroid lineage present
beyond erythrocyte precursors. No evidence of
melanoma by (D) Melan-A (×10), and (E) SOX10 (×10).
Intravenous (i.v.) ceftriaxone, vancomycin, and flagyl were ini-
tiated to cover for a possible infected sacral wound and uri-
nary tract infection. Her hemoglobin level dropped in the first
24 h, to 5.8 g/dL. Her hemoglobin level improved after a to-
tal of 3 units of packed red blood cells. Her reticulocyte count
was persistently low. The urine culture result was positive for
pan-sensitive E. coli. Her sacral ulcer improved with wound
care measures. There were no signs of abscess. Antibiotics
were deescalated to i.v. ceftriaxone, and 7 days of treatment
were completed. The Hematology Department was consult-
ed for suspected PRCA related to immunotherapy. Bone mar-
row biopsy results showed slight hypercellularity (60%) with
markedly decreased erythroid precursors (<5% of total) with
minimal erythroid maturation, consistent with PRCA, while
morphology and immunohistochemistry showed no evidence
of involvement of metastatic melanoma (Figure 1). However,
additional bone marrow studies (chromosome karyotype and
Next-GeneSequencing) were both abnormal yet inconclusive
as to the etiology from myelodysplastic syndrome/clonal cy-
topenia of undetermined significance and/or melanoma. PRCA
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 Rueda Prada L. et al:
ICI-induced pure red cell aplasia in metastatic melanoma
© Am J Case Rep, 2023; 24: e941789

diagnosis was considered based on the bone marrow findings
mentioned, and no other conclusive alternative etiology was
found on further testing. An immunotherapy rechallenge was
not considered, given the rapid disease progression, poor per-
formance status, and concern of anemia relapse. Her hemoglo-
bin level remained stable, with no new transfusions required.
She was not a candidate for further systemic therapy or clini-
cal trial, given her decreased performance status. The patient
transitioned her care to hospice.
Case 2
A 25-year-old woman presented to the Oncology Clinic for eval-
uation of fever and fatigue. She was diagnosed with BRAF wild-
type metastatic mucosal melanoma in the anus 3 months ear-
lier and had an excision of the anal mass 10 days after initial
diagnosis. Since then, she had received frontline dual immuno-
therapy with nivolumab (1 mg/kg) and ipilimumab (3 mg/kg).
She had completed 3 cycles of immunotherapy, with the most
recent one 5 days before presentation. Two days after her last
treatment, she developed fatigue and a right-sided facial droop
and was evaluated in the Emergency Department. At that time,
her hemoglobin level was 6.9 g/dL (baseline 9.3 g/dL), and she
received 2 units of packed red blood cells. The computed to-
mography (CT) scan of the head and magnetic resonance im-
aging (MRI) of the brain were within normal limits. Possible
Bell’s palsy was diagnosed.
During the clinic visit, her vital signs were remarkable for a
temperature of 39.3 °C. The rest of her vital signs were with-
in normal limits. At the physical examination, she was in no
acute distress. The rest of her physical examination was with-
in normal limits, except for an erythematous macular rash on
both cheeks, sparing the nasolabial folds, and neurologic ex-
amination with no signs of focalization, except for right-sided
peripheral VII cranial nerve palsy.
Initial laboratory workup was significant for normocytic ane-
mia, with a hemoglobin level of 7.1 g/dL, unremarkable chem-
istry panel, with creatinine level of 0.85 mg/dL, and normal

Table 2. Case 2. Summary of laboratory workup and timeline of hospital interventions.

2 units PRBC Intravenous 2 units Bone marrow IVIG Cyclosporine
(ER evaluation) Solu-Medrol PRBC biopsy Prednisone
Interventions

Time of First 1
Day 1 Day 2 Day 3 Day 4
presentation 24 h month

Hemoglobin (g/dL) 7.1 7.2 5.4 6.9 9.5 8.6 12.8

Platelet count (×109/L) 134 140 93 102 134 119 173

White blood cell count

5.1 4.3 1.7 5.0 8.6 7.4 13.2
(×109/L)

Reticulocyte (%) <0.31 0.39 <0.31 <0.31 <0.31 <0.31 3.10

Absolute reticulocytes 8.8 11.1 8.8 8.8 8.8 8.8 354

Two months before this admission: Iron 18 mcg/dL. Total iron binding capacity 297 mcg/dL.
TSAT 6%. Ferritin 14. B12 level 320 ng/L. Folate level 7.3 mcg/L. Iron studies during this
Anemia workup​
admission: Iron 2-3 mcg/dL. Total iron binding capacity 192 mcg/dL. TSAT >90%. Ferritin 642.
Folate level and B12 level was not repeated

DIC workup​ D-dimer 555 ng/mL. Fibrinogen 111 mg/dL. PT 11.6 sec. INR 1.1. aPTT 32 sec

No schistocytes on peripheral blood smear. LDH 877 U/L. Total bilirubin 1.7 mg/dL
Hemolysis workup​ (indirect 1.3 mg/dL). Haptoglobin < 14 mg/dL. Direct Coombs negative. G6PD normal.
ANA normal. Paroxysmal nocturnal hemoglobinuria antigen normal​
Parvovirus B19 serology and PCR negative. Hepatitis A, B, C serology was negative for active
Infectious workup​
infection. HSV 1 and 2 PCR negative. HIV antigen and antibody screen negative

Reference ranges: Reticulocyte (%) 0.60-2.71. Absolute reticulocyte 30.4-110.9×109/L. Iron 35-145 mcg/dL. Total iron binding capacity
250-400 mcg/dL. TSAT 14-50%. Ferritin 11-307 mcg/L. B12 level 180-914 ng/L. Folate level ³4.0 mcg/L. D-dimer £500 ng/mL.
Fibrinogen 200-393 mg/dL. PT 9.4-12.5 sec. INR 0.9-1.1. aPTT 25-37 sec. LDH 122-222 U/L. Total bilirubin £1.2 mg/dL.
Haptoglobin 30-200 mg/dL.
ANA – antinuclear antibody; DIC – disseminated intravascular coagulation; LDH – lactate dehydrogenase; HSV – herpes simplex virus;
PRBC – packed red blood cells; PT – prothrombin time; aPTT – activated partial thromboplastin time; TSAT – transferrin saturation.

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Rueda Prada L. et al:
ICI-induced pure red cell aplasia in metastatic melanoma
© Am J Case Rep, 2023; 24: e941789
A B
Figure 2. (A) Bone marrow aspirate and (B) core biopsy show hypercellular bone marrow with markedly decreased and left shifted
erythropoiesis. Only rare scattered pronormoblasts were identified on the aspirate, and the biopsy showed inconspicuous
erythroid islands with virtually no maturation. There was background megakaryocytic and granulocytic hyperplasia.
(A) Wright Giemsa, 600× oil. (B) Hematoxylin and eosin, 200×.
liver enzyme and alkaline phosphatase levels. The remaining
laboratory results are summarized in Table 2. CT of the chest/
abdomen/pelvis with i.v. contrast showed progression of the
metastatic lymphadenopathy in the pelvis and progressive en-
largement of a metastatic lesion in the right ilium. Blood cul-
ture results were negative. Antibiotics were not initiated, ow-
ing to a low suspicion for infection. Disseminated intravascular
coagulation was considered less likely. Hemolysis was consid-
ered in the differential diagnosis, based on additional test re-
sults (see Table 2).
The patient was treated with i.v. Solu-Medrol 1 g daily for 5
days for probable immunotherapy-induced PRCA, with a com-
ponent of possible autoimmune hemolytic anemia. Her he-
moglobin level dropped in the first day to 5.4 g/dL. She re-
ceived a transfusion with 2 units of packed red blood cells.
Her hemoglobin level improved to 6.9 g/dL on day 2 and to
9.5 g/dL on day 3, without additional transfusion needed. A
bone marrow aspirate and biopsy (Figure 2) showed a slight-
ly hypercellular marrow for age (90%), with decreased and
markedly left-shifted erythropoiesis and increased granulo-
poiesis and megakaryocytes. There was marked anisopoi-
kilocytosis with occasional microcytic cells and slight ellipto-
cytes, white blood cells without cytologic abnormalities, and
platelets without cytologic abnormalities. The myeloid: ery-
throid ratio was >10: 1. Erythroid precursors quantity was de-
creased, left shifted maturation with predominantly pronor-
moblasts. Myeloid precursors quantity was increased, normal
maturation. Iron staining was done, showing storage iron was
normal, sideroblasts were absent, and ring sideroblasts were
not seen. There was no involvement by metastatic melano-
ma. Parvovirus B19 staining was negative. Solu-Medrol i.v.
was followed by 5 days of i.v. immune globulin (IVIG), cyclo-
sporine 100 mg twice daily, and prednisone. Ipilimumab and
nivolumab were discontinued.
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Four months later, while being off treatment, she was noticed
to have new multifocal lytic bone lesions and a new lung nod-
ule, so she was re-started on single-agent nivolumab. After 2
cycles, she developed acute thrombocytopenia (platelet count
of 66×109/L, which resolved after a course of prednisone), sug-
gestive of mild immune thrombocytopenia secondary to ICI;
however, her hemoglobin level remained stable, and therefore
treatment was continued. Four months after having been on
nivolumab, MRI of the femur suggested new metastatic dis-
ease, and nivolumab was stopped. Carboplatin, paclitaxel, and
pembrolizumab were then initiated as salvage therapy. She
had a partial response after 3 cycles of salvage chemo-immu-
notherapy. Unfortunately, she experienced thrombocytopenia
and therefore continued treatment with carboplatin, reduced
to AUC 4. After 6 cycles, the patient had a positive response
with no new metastatic disease and was placed on a treatment
holiday per her preference. Chemo-immunotherapy was rein-
itiated 3 months later because of symptomatic disease pro-
gression. She was able to tolerate the treatment for the next
6 months, until she was found to have cerebral metastatic dis-
ease, for which she received radiation therapy, followed by ad-
missions for rectal bleeding and lumbar spine pathologic frac-
ture, causing cauda equina. She died 6 months later.
Discussion
Our immune system plays an important role in the battle against
cancer. Immune checkpoints are crucial self-tolerance path-
ways that prevent the immune system from attacking healthy
cells. Cancer cells downregulate the immune system by multi-
ple mechanisms, including production of immunosuppressive
cytokines that stimulate inhibitory immune checkpoints [9].
Immunotherapy is a revolutionary therapy that enhances a
patient’s immune system to destroy tumor cells. With the
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introduction of ipilimumab in 2011, followed by pembrolizum-
ab in 2014, ICIs have transformed cancer management, offering
a usually more tolerable alternative to the systemic cytotox-
ic therapy. The use of ICIs has shown benefits in the treat-
ment of different types of malignancies, including melanoma,
Hodgkin’s lymphoma, and lung, bladder, and renal cancer [10].
Unfortunately, immunotherapy can cause immune-related
adverse events (irAEs) and compromise almost any organ or
system. The skin, digestive, pulmonary, renal, and endocrine
systems are the most affected [11]. Hematologic adverse reac-
tions (HARs) to immunotherapy are not common and include
thrombocytopenia, pancytopenia or immune aplastic anemia,
neutropenia, hemolytic anemia, cytokine release syndrome
with hemophagocytic syndrome, bicytopenia, and PRCA [12].
Immune-mediated thrombocytopenia and hemolytic anemia
are among the most common HARs seen, usually involving the
use of the ICIs nivolumab and pembrolizumab [13]. Ipilimumab
has shown the shortest time from therapy initiation to on-
set of HARs [13]. It is important to keep monitoring blood cell
counts even after discontinuation of treatment, given that
HAR recurrence has been seen in approximately 8.9% of cas-
es [13]. The mortality from HARs related to ICIs is variable and
dependent on the type of disturbance, with the highest seen
being aplastic anemia at 54.5%, and average mortality for all
adverse reactions between 12% and 15.5% [13,14]. Hence, it
is important to increase clinician awareness of this condition
to provide prompt treatment and avoid significant mortality.
There are reports of nivolumab-induced autoimmune hemolyt-
ic anemia [15,16], some which are associated with PRCA [17].
Rare cases of PRCA have been reported without hemolysis,
such as the case reported by Yuki et al of a patient with car-
diac metastatic melanoma who developed PRCA at 21 months
of being on nivolumab [18]. There are several case reports of
aplastic anemia in patients with metastatic melanoma and oth-
er malignancies treated with dual immunotherapy [13,19-21].
However, cases of PRCA with dual immunotherapy in patients
with metastatic melanoma have been rarely reported. A case
series review of 15 cases of new-onset PRCA related to immu-
notherapy from the Food and Drug Administration’s Adverse
Event Reporting System from 2011 to 2022 reported 9 cases
related to metastatic melanoma, among which 6 were relat-
ed to single immunotherapy either with pembrolizumab, ipili-
mumab or nivolumab, and only 3 were related to dual immu-
notherapy with ipilimumab and nivolumab [7].
PRCA is rare and usually presents as a normocytic, normochro-
mic anemia with a persistent low reticulocyte count and sig-
nificant decreased or absent red blood cell precursors in bone
marrow (< 1% erythroblasts or few proerythroblasts and/or
basophilic erythroblasts not exceeding 5% of the marrow dif-
ferential count). Iron stains are usually normal. PRCA can be
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Rueda Prada L. et al:
ICI-induced pure red cell aplasia in metastatic melanoma
© Am J Case Rep, 2023; 24: e941789
congenital or acquired. Acquired PRCA can be caused by au-
toimmune diseases, neoplasms invading bone marrow, medi-
cations, such as azathioprine and procainamide, or can be re-
lated to infections, such as parvovirus B19.
Our patients did not have a history of a pre-existing autoim-
mune disease, which if present and active may have increased
their risk of developing severe irAEs with the use of ICIs. A
multicenter study of a small cohort of patients with meta-
static melanoma treated with ipilimumab who had a pre-ex-
isting autoimmune diseases showed a higher incidence of
irAEs and autoimmune disorder flare-up [22]. These concerns
led to exclude patients with autoimmune diseases from clin-
ical trials. Further studies were done to clarify the risk-bene-
fit ratio of ICIs in patients with cancer and pre-existing auto-
immune diseases. These studies indicated that the use of ICIs
may be safe in this patient population and is not an absolute
indication to discontinue ICI therapy. However, there may be
still a risk of severe and fatal disease [23,24]. A more recent
study showed similar efficacy and safety with ICI use in pa-
tients with cancer without and with pre-existing autoimmune
disease. However, impaired T-cell activation in patients with
active pre-existing autoimmune disease predisposes them to
worse outcomes during ICI therapy. On the contrary, the de-
velopment of immune irAEs in patients with autoimmune dis-
ease, which was found to be usually mild, may be a sign of
T-cell activation, which is associated with superior immuno-
therapy efficacy and better outcomes [25].
Neurological irAEs are seen in <1% of patients on ICIs [26]. Bell’s
palsy, as seen in case 2, has been rarely reported in patients on
immunotherapy [26-28]. A single-center retrospective study of
353 patients treated with immunotherapy between 2015 and
2018 found 5 cases of Bell’s palsy, from which 3 cases were
related to dual immunotherapy in patients with metastatic
melanoma [27]. In some cases, it is difficult to differentiate a
paraneoplastic syndrome manifestation related to underlying
malignancy from neurological irAEs secondary to ICIs.
Anemia observed in oncologic patients can be multifactorial.
Hence, bone marrow biopsy is important to confirm the diag-
nosis of PRCA and is critical to rule out direct tumor involve-
ment of the bone marrow to determine the potential cause
of PRCA and to guide further treatment. In case 1, infection
was unlikely to be the major cause for the profound anemia,
since the laboratory findings were not compatible with infec-
tious hemolytic anemia and there were no signs of severe sys-
temic infection. In addition, our patients were not on other
medications that could have explained their anemia, and oth-
er etiologies, such as disseminated intravascular coagulation,
and infections, such as parvovirus B19 infection, were ruled
out. Hemolysis was considered unlikely in case 1 but likely in
case 2, based on hemolysis workup. Although haptoglobin is
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Rueda Prada L. et al:
ICI-induced pure red cell aplasia in metastatic melanoma
© Am J Case Rep, 2023; 24: e941789
commonly used as one of the markers for hemolysis, its val-
ue should be interpreted in conjunction with other hemato-
logic evaluations to establish the diagnosis of hemolysis. In
addition, an abnormal haptoglobin level can be seen in oth-
er conditions, such as metastatic carcinomas or cirrhosis, in
the absence of hemolysis [29]. Low haptoglobin in case 1 was
considered possibly related to liver dysfunction from metastat-
ic disease. The patient in case 1 had chronic elevated lactate
dehydrogenase possible secondary to metastatic disease and
had no acute change during this hospital admission.
The patient in case 1 did not require any additional interven-
tion more than supportive blood transfusions. But in other cas-
es, such as case 2, treatment with high-dose steroid, IVIG, and
chronic immunosuppressant is required, and it is important to
consider rechallenge with immunotherapy after clinical recovery.
Final management decisions are individualized and made based
on initial workup, severity, and clinical course, despite the initial
similar diagnosis of PRCA. Other types of HARs could be seen
with ICI rechallenge, such as the one seen in case 2, in which the
patient developed mild immune thrombocytopenia with a single
immunotherapy rechallenge after having recovered from PRCA.
The exact mechanism of PRCA related to immunotherapy is
unknown, but like other irAEs, it is presumed to be related to
widespread activation of cytotoxic T cells, production of anti-
red blood cell (or erythroid precursors) antibodies, and direct
damage to erythroblasts [30]. In fact, activated CD8+ lympho-
cytes seen in bone marrow specimens of patients with PRCA
support this theory [31]. Other studies have suggested a pos-
sible production of red blood cell antibodies against erythroid
precursors or erythropoietin, especially with ipilimumab [16,32].
Because of the rarity of PRCA related to immunotherapy, it is
unclear whether PRCA is more likely to occur in certain patient
populations, such as according to sex, age, and other comor-
bidities. In addition, the immunotherapy regimens used that
are associated with PRCA also need to be evaluated in further
studies, especially given the introduction of a newer genera-
tion of ICIs over the past few years.
Treatment of PRCA related to immunotherapy includes cortico-
steroids, supportive management with transfusions as need-
ed, and the addition of cyclosporine in refractory cases. Other
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HARs may require additional treatments, such as IVIG, ritux-
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rechallenge is considered when indicated after a patient has
recovered. This represents a risk for HAR recurrence, which has
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the immunotherapy rechallenge. Additional studies are need-
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Conclusions
Immunotherapy is a novel and revolutionary treatment being
widely used for different types of malignancies. There is a sig-
nificant risk of irAEs with the use of immunotherapy. HARs to
immunotherapy are not common and carry a significant mor-
tality risk. PRCA secondary to immunotherapy in metastatic
melanoma is rare and carries significant mortality risk, despite
treatment with steroids or immunosuppressive therapy. Bone
marrow biopsy is crucial for diagnosis and for performing ad-
ditional studies to rule out other etiologies, such as direct tu-
mor invasion to the bone marrow. Patients with PRCA relat-
ed to immunotherapy are at risk of developing other types of
HARs. It is important to increase clinician awareness of this
risk in order to provide prompt initial treatment and to con-
tinue monitoring patients for any other HARs during immu-
notherapy rechallenge, particularly in patients who are candi-
dates and have no other options for treatment.
Declaration of Figures’ Authenticity
All figures submitted have been created by the authors who
confirm that the images are original with no duplication and
have not been previously published in whole or in part.
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