Table 2.

Available results of clinical trials for PD-1/PD-L1 inhibitor in treatment of MDS/AML

Reference	Trial phase	Patient characteristics	Intervention	Target	Efficacy	Toxicity
Berger et al. [122]	I, single-arm	8 R/R AML (4 AML relapsed after allo-SCT) and 1 MDS	CT-011 (0.2–6 mg/kg)	PD-1	One AML patient achieved peripheral blasts reduction	50% AML patients experienced grade 3–4 AEs and died (due to fulminate resistant leukemia but not study drug)
Garcia-Manero et al. [127]	Ib, single-arm	28 HMA-failure MDS	Pembrolizumab 10 mg/kg, Q2weeks	PD-1	ORR 4%; CR 0% OS rate 49% at 24 weeks	Hypothyroidism (14%), fatigue (11%), 7% grade 3/4 treatment-related AEs: 1 gastroenteritis (grade 3) and 1 TLS (grade 4)
Garcia-Manero et al. [128]	II, multi-arms non-randomized	15 HMA-failure MDS	Nivolumab 3 mg/kg on day 1 and 15 Q4weeks	PD-1	ORR 35%; CR/CRp 15%; mOS NR	Skin rash (11%); fatigue (9%); pain (7%); infection (6%); FN (5%); pruritus (6%); diarrhea (5%); constipation (4%); nausea (4%); ALT elevations (3%); anorexia (3%); and cough (3%) One early mortality
		20 HMA-failure MDS	Ipilimumab 3 mg/kg Q3weeks	CTLA-4	ORR 13%; CR/CRp 0%; mOS 8 mos
		20 treatment-naïve MDS	Nivolumab 3 mg/kg on day 6 and 20, plus AZA 75 mg/m2 daily for 7 days Q4weeks	PD-1 + HMA	ORR 75%; CR/CRp 50%; mOS 12 mos
		21 treatment-naïve MDS	Ipilimumab 3 mg/kg on day 6, plus AZA 75 mg/m2 daily for 7 days Q4weeks	CTLA-4 + HMA	ORR 71%; CR/CRp 38%; mOS 8 mos
Chien et al. [132]	II, single arm	17 treatment-naïve MDS	Pembrolizumab 200 mg Q3weeks, plus AZA 75 mg/m2 daily for 7 days Q4weeks	PD-1 + HMA	ORR 76%; CR 3%; mOS NR	Arthralgias (40%), pneumonia (33%), nausea (27%). One patient died within first 60 days due to unrelated cause of ventricular fibrillation
		20 HMA-failure MDS	Pembrolizumab 200 mg Q3weeks, plus AZA 75 mg/m2 daily for 7 days Q4weeks	PD-1 + HMA	ORR 25%; CR 5%; mOS 5.8 mos	Pneumonia (32%), arthralgias (24%), constipation (24%). Two patients died within first 60 days
Daver et al. [131]	II, single arm	70 R/R AML (25 HMA-naïve and 45 HMA-failure)	Nivolumab 3 mg/kg on day 1 and day 14, plus AZA 75 mg/m2 daily for 7 days, Q4-6 weeks	PD- 1 + HMA	ORR 33% (58% in HMA-naïve,22% in HMA-failure patients); CR/CRi was 22%; mOS 6.3 mos	23% grade > 2 immune toxicities, 9 pneumonitis, 6 nephritis, 3 immune related skin rash, and 2 transaminitis
Gerds, et al. [129]	Ib, multi-arm non-randomized	10 HMA-failure MDS	Atezolizumab 1200 mg Q3weeks	PD-L1	ORR 0%; CR 0%; mOS 5.9 mos	10% grade > 3 FN; 0% died (10% occurred within 3 months)
		11 HMA-failure MDS	Atezolizumab 1200 mg Q3weeks plus AZA 75 mg/m2 daily for 7 days Q4weeks	PD-L1 + HMA	ORR 9%; CR 0%; mOS 10.7 mos	36% grade > 3 FN; 64% died (18% occurred within 3 months)
		21 treatment-naïve MDS	Atezolizumab 840 mg Q2weeks plus AZA 75 mg/m2 daily for 7 days Q4weeks	PD-L1 + HMA	ORR 62%; CRp 14%; mOS NR	33% grade > 3 FN; 29% died (all occurred within 3 months)
Zeidan, et al. [134]	II, multi-arms randomized controlled	42 treatment-naïve MDS	Durvalumab 1500 mg Q4weeks plus AZA 75 mg/m2 daily for 7 days Q4weeks	PD-L1 + HMA	ORR 61.9%; CR 7.1%; mOS 11.6 mos	Most common treatment-emergent AEs were hematologic and gastrointestinal toxicity. Immune-mediated AEs were observed in 7 MDS and 17 AML patients
		42 treatment-naïve MDS	AZA 75 mg/m2 daily for 7 days Q4weeks	HMA	ORR 47.6%; CR 9.5%; mOS 16.7 mos;
		64 treatment-naïve AML 1–7 every 4 weeks	Durvalumab 1500 mg Q4weeks plus AZA 75 mg/m2 daily for 7 days Q4weeks	PD-L1 + HMA	ORR 31.3%; CR 17.2%; mOS 13.0 mos
		65 treatment-naïve AML	AZA 75 mg/m2 daily for 7 days Q4weeks	HMA	ORR 35.4%; CR 21.5%; mOS 14.4 mos
Zeidner et al. [136]	II, single arm	37 R/R AML	HiDAC 1.5/2 gm/m2 daily for 5 days plus Pembrolizumab 200 mg on day 14. Responders were continued to receive pembrolizumab 200 mg Q3weeks	PD-1 +  chemotherapy	ORR 46%; CR 38%; mOS 8.9 mos	Most frequent grade > 3 pembrolizumab-related toxicities were ALT elevation (n = 1), AST elevation (n = 1), and grade > 3 maculopapular rash (n = 2). One patient did not survive due to disease progression within sixty days
Ravandi et al. [137]	II, single arm	44 treatment-naïve (42 AML and 2 high-risk MDS)	cytarabine 1.5 g/m2 daily for 4 days and idarubicin 12 mg/m2 daily for 3 days, plus Nivolumab 3 mg/kg on day 24 ± 2 and continued Q2weeks	PD-1 +  chemotherapy	ORR 80%; CR 78%; mOS 18.54 mos	6 patients had seven grade 3/4 IRAE with rash (n = 2), colitis (n = 2), transaminitis (n = 1), pancreatitis (n = 1) and cholecystitis (n = 1)

AE adverse events, AZA 5-azacytidine, CR complete response, CRp CR with incomplete platelet recovery, FN febrile neutropenia, HiDAC high dose cytarabine, IRAE immune-related adverse events, mOS median overall survival, NR not reached, ORR overall response rate, SAE serious adverse event, TLS tumor lysis syndrome