J Hematol

Journal of Hematology, ISSN 1927-1212 print, 1927-1220 online, Open Access

Article copyright, the authors; Journal compilation copyright, J Hematol and Elmer Press Inc

Journal website https://www.thejh.org

Case Report

Volume 11, Number 3, June 2022, pages 113-120

Spectrum of Immune Checkpoint Inhibitor Anemias: Results From a Single Center, Early-Phase Clinical Trials Case Series Experience

**Table 1.** Patient Demographics
Case	1	2	3	4
^aFrom last dose of ICI. ICI: immune checkpoint inhibitor; ICI-A: immune checkpoint inhibitor anemia; ECOG: Eastern Cooperative Oncology Group; CLL: chronic lymphocytic leukemia; heme-irAEs: hematological immune-related adverse events; PD-L1: programmed cell death ligand 1; PD-1: programmed cell death protein 1; PARP: poly-(ADP ribose) polymerase; ICOS: inducible T-cell co-stimulator; VEGF: vascular endothelial growth factor; IL: interleukin.
Age	69	68	65	68
ECOG	2	1	0	0
Sex	M	F	F	F
Cancer type	Non-small cell lung cancer	Gastroesophageal cancer	Esophageal cancer	Renal cell carcinoma
Histology	Adenocarcinoma	Adenocarcinoma	Adenocarcinoma	Clear cell carcinoma
Prior lines of therapy	1. cisplatin + pemetrexed 2. carboplatin + pemetrexed 3. single agent pemetrexed	1. mFOLFOX	1. mFOLFOX 2. paclitaxel + ramucirumab	1. sunitinib
Comorbidities	CLL	Hypothyroidism	Anxiety	Diabetes mellitus
Genomic alterations	KRAS_G12F KRAS_K167E ERBB4_R306C STK11_A241P TP53_R249S PDL1 0%	HER2 negative PDL1 10-20% MMR intact Germline BRCA2 mutation: (BRCA2):c.1813dup (p.Ile605fs)	EGFR_Q217K CDKN2A_M52V MMR intact PDL1 5% HER2 negative	N/A
Prior ICI exposure	No	No	No	No
Mechanism of action	STAT3 + anti-PD-L1 monoclonal antibody	PARP inhibitor + anti-PD-1 monoclonal antibody + VEGF inhibitor	ICOS agonist monoclonal antibody + anti-PD-1 monoclonal antibody	Pegylated recombinant IL-10 + anti-PD-1 monoclonal antibody
Time to ICI-A^a	4 weeks	6 weeks	3 weeks	2 weeks
Time to recovery	20 weeks	8 weeks	0 weeks	4 weeks
No. of cycle pre-ICI-A	11	21	2	4
No. of cycles post-ICI-A	0	14	0	0
Other heme-irAEs	Thrombocytopenia	No	Thrombocytopenia	Pancytopenia

Table 1. Patient Demographics

Case

^aFrom last dose of ICI. ICI: immune checkpoint inhibitor; ICI-A: immune checkpoint inhibitor anemia; ECOG: Eastern Cooperative Oncology Group; CLL: chronic lymphocytic leukemia; heme-irAEs: hematological immune-related adverse events; PD-L1: programmed cell death ligand 1; PD-1: programmed cell death protein 1; PARP: poly-(ADP ribose) polymerase; ICOS: inducible T-cell co-stimulator; VEGF: vascular endothelial growth factor; IL: interleukin.

Age

ECOG

Sex

Cancer type

Non-small cell lung cancer

Gastroesophageal cancer

Esophageal cancer

Renal cell carcinoma

Histology

Adenocarcinoma

Clear cell carcinoma

Prior lines of therapy

1. cisplatin + pemetrexed
2. carboplatin + pemetrexed
3. single agent pemetrexed

1. mFOLFOX

1. mFOLFOX
2. paclitaxel + ramucirumab

1. sunitinib

Comorbidities

CLL

Hypothyroidism

Anxiety

Diabetes mellitus

Genomic alterations

KRAS_G12F
KRAS_K167E
ERBB4_R306C
STK11_A241P
TP53_R249S
PDL1 0%

HER2 negative
PDL1 10-20%
MMR intact
Germline BRCA2 mutation: (BRCA2):c.1813dup (p.Ile605fs)

EGFR_Q217K
CDKN2A_M52V
MMR intact
PDL1 5%
HER2 negative

N/A

Prior ICI exposure

Mechanism of action

STAT3 + anti-PD-L1 monoclonal antibody

PARP inhibitor + anti-PD-1 monoclonal antibody + VEGF inhibitor

ICOS agonist monoclonal antibody + anti-PD-1 monoclonal antibody

Pegylated recombinant IL-10 + anti-PD-1 monoclonal antibody

Time to ICI-A^a

4 weeks

6 weeks

3 weeks

2 weeks

Time to recovery

20 weeks

8 weeks

0 weeks

4 weeks

No. of cycle pre-ICI-A

No. of cycles post-ICI-A

Other heme-irAEs

Thrombocytopenia

Pancytopenia

**Table 2.** Laboratory Features of ICI-A
Case	1	2	3	4
ICI-A: immune checkpoint inhibitor anemia; DAT: direct antiglobulin test; LDH: lactate dehydrogenase: N/A: not available; IgG: immunoglobulin G.
Hemoglobin	Pre	8.9	11.8	13.5	13.9
	Nadir	4.6	7.8	5.9	7.7
	Post	10.2	10.8	N/A	13
LDH	Pre	319	206	499	346
	Nadir	439	259	7,175	4,896
	Post	315	228	N/A	424
Reticulocyte count, %	Pre	N/A	N/A	N/A	1.1
	Nadir	1.2	1.9	14.4	3.9
	Post	1.2	N/A	N/A	2.4
Haptoglobin	Pre	131	N/A	N/A	N/A
	Nadir	< 3	16	< 3	< 3
	Post	176	38	N/A	< 3
Total bilirubin	Pre	0.8	0.3	0.7	0.2
	Nadir	1.3	0.6	7.1	1
	Post	0.3	0.3	N/A	0.5
Ferritin	Pre	N/A	N/A	N/A	N/A
	Nadir	1,074	770	1,031	32,110
	Post	N/A	N/A	N/A	750
Spherocytes	No	No	Yes	Yes
DAT	IgG^- C3⁺	IgG^- C3^-	IgG^- C3^-	IgG⁺ C3^-

Table 2. Laboratory Features of ICI-A

Case

ICI-A: immune checkpoint inhibitor anemia; DAT: direct antiglobulin test; LDH: lactate dehydrogenase: N/A: not available; IgG: immunoglobulin G.

Hemoglobin

Pre

8.9

11.8

13.5

13.9

Nadir

4.6

7.8

5.9

7.7

Post

10.2

10.8

N/A

LDH

Pre

319

206

499

346

Nadir

439

259

7,175

4,896

Post

315

228

N/A

424

Reticulocyte count, %

Pre

N/A

1.1

Nadir

1.2

1.9

14.4

3.9

Post

1.2

N/A

2.4

Haptoglobin

Pre

131

N/A

Nadir

< 3

Post

176

N/A

< 3

Total bilirubin

Pre

0.8

0.3

0.7

0.2

Nadir

1.3

0.6

7.1

Post

0.3

N/A

0.5

Ferritin

Pre

N/A

Nadir

1,074

770

1,031

32,110

Post

N/A

750

Spherocytes

Yes

DAT

IgG^- C3⁺

IgG^- C3^-

IgG⁺ C3^-

**Table 3.** Treatment and Outcomes
Case	Immunosuppressive agent	PRBC use	Rechallenge with ICI	ICI-A recurrence	Best response	PFS	OS	Further lines of therapy
^aThe patient withdrew consent while in PR after 34 cycles and lost to follow-up. ^bAlive currently. QD: once a day; QW: once a week; QM: once a month; PO: orally; Q12H: every 12 h; Q3D: every 3 days; BID: twice a day; MP: methylprednisolone; PRBC: packed red blood cell; ICI-A: immune checkpoint inhibitor anemia; ICI: immune checkpoint inhibitor; PFS: progression-free survival; OS: overall survival; SD: stable disease; PR: partial response; N/A: not available.
1	Cyclosporine 200 mg QD × 30 weeks	20 units	No	N/A	SD (-1%)	46 weeks	79 weeks	Afatinib
	Rituximab 1 g QW × 4 weeks
	IVIG 1 g QM × 18 weeks
	MP 100 - 200 mg IV × 4 doses, prednisone 60 mg PO QD tapered over 25 weeks
2	None	6 units	Yes	No	PR (-46%)	N/A^a	N/A^a	N/A
3	MP 1 mg/kg Q12H × 5 days	5 units	No	N/A	N/A	6 weeks	6 weeks	None
4	Etoposide 100 mg/m² Q3D × 3 doses + dexamethasone 10 mg BID tapered over 1 month + 1 dose of tocilizumab 4 mg/kg	3 units	No	N/A	SD (0%)	52 weeks	N/A^b	Axitinib

Table 3. Treatment and Outcomes

Case

Immunosuppressive agent

PRBC use

Rechallenge with ICI

ICI-A recurrence

Best response

PFS

Further lines of therapy

^aThe patient withdrew consent while in PR after 34 cycles and lost to follow-up. ^bAlive currently. QD: once a day; QW: once a week; QM: once a month; PO: orally; Q12H: every 12 h; Q3D: every 3 days; BID: twice a day; MP: methylprednisolone; PRBC: packed red blood cell; ICI-A: immune checkpoint inhibitor anemia; ICI: immune checkpoint inhibitor; PFS: progression-free survival; OS: overall survival; SD: stable disease; PR: partial response; N/A: not available.

Cyclosporine 200 mg QD × 30 weeks

20 units

N/A

SD (-1%)

46 weeks

79 weeks

Afatinib

Rituximab 1 g QW × 4 weeks

IVIG 1 g QM × 18 weeks

MP 100 - 200 mg IV × 4 doses, prednisone 60 mg PO QD tapered over 25 weeks

None

6 units

Yes

PR (-46%)

N/A^a

N/A

MP 1 mg/kg Q12H × 5 days

5 units

N/A

6 weeks

None

Etoposide 100 mg/m² Q3D × 3 doses + dexamethasone 10 mg BID tapered over 1 month + 1 dose of tocilizumab 4 mg/kg

3 units

N/A

SD (0%)

52 weeks

N/A^b

Axitinib