Myelodysplastic syndrome and immunotherapy novel to next in-line treatments

Figures & data

Table 1. Select MDS studies with immune check-point inhibitors

Immune Checkpoint	Checkpoint Inhibitor	NCI Registration ID	Phase	Author, Year Reported	IPSS Prognostic Risk Category	Median Age (years)	Primary Outcome	HMA
PD-1	Pembrolizumab	NCT01953692	Ib	Garcia-Manero, 2016	Int-1 (36%) Int-2 (32%) High (25%)	73	ORR	Failure
		NCT03094637	II	Chien, 2019	Int-1 or higher	Not Repor	Safety ORR	Failure
						ted	OS	Naïve
	Nivolumab	**NCT02530463	II	Garcia-Manero, 2018	Low (4%) int-1(40%) int-2 (37%) High (15%)	71	Safety	Failure
								Naïve
		NCT01822509	I/Ib	Davids, 2020	Any	Not Reported	Safety MTD AE	Post-Transplant Relapse
PD-1 + CTLA4	Nivolumab + Ipilimumab	**NCT02530463	II	Garcia-Manero, 2018	Int-1 (29%) Int-2 (43%) High (29%)	69	Safety	Failure
								Naïve
CTLA4	Ipilimumab	NCT01757639	I/Ib	Zaidan, 2017	Int-1 (45%) Int-2/high risk (55%)	67	MTD Safety AE	Failure
		**NCT02530463	II	Garcia-Manero, 201	Low (4%) int-	71	Safety	Failure
				8	1(40%) int-2 (37%) High (15%)			Naïve
PD-L1	Durvalumab	NCT02775903	II	Zeidan, 201	✦Int,	Not Re	ORR	Naïve
				9	high, very high	ported
	Atezolizumab	NCT02935361	I/II	O’Connell, 2018	✦Int, high, very high	Not Reported	Safety Tolerability	Failure
TIM-3	MBG453	NCT03066648	I/Ib	Borate, 2020	✦ high, very	71	Safety Tolera	Naïve
					high		bility MTD Efficacy
CD-47	Magrolimab	NCT03248479	Ib	Sallman,	✦ Int, high	73	ORR, AE	Naïve
	(5F9)			2020	, very high			Failure
Immune Checkpoint	Intervention	Line Of Therapy	Number Of MDS Patients (n=)	**IWG CR & PR %(n=)	*IWG ORR ϕ	Median DOR/PFS/EFS	Median OS /Survival Probability (%)	Status	▵Adverse Events ≧ Grade 3
PD-1	PEM	Relapsed & Refractory	28	4% (1 PR)	14-25%	Not Reported	6 mo Survival 49% IPSS high: 29% int-2: 22% int-1 89%	Completed	7%
	PEM + AZA	Relapsed & Refractory	20	10% (2CR)	30%	Not reported	5.9 mo	Recruiting	None Reporte
		Frontline	10	20% (2CR)	70%		12.9 mo		d
	NIVO	Relapsed & Refractory	15	0	13%	EFS 7 mo	8 mo 1 yr survival 25%	Arm Closed	40%
	NIVO + AZA	Frontline	20	* 50% (10)	75%	EFS 10 mo	12mo 1 yr survival 50%	Completed	“27%
	NIVO	Relapsed & Refractory	7	43% (3PR)	43%	^1 year PFS 23%	^1 year OS 56%	Active Not Recruiting	21% ≧
PD-1 + CTLA4	NIVO + IPI	Relapsed & Refractory	8	1 CR	29%	Not Reported	8.4 mo	Recruiting	43%
	NIVO + IPI + AZA	Frontline	6	100% (3 CR)	50%	Not Reported	Not Reached	On Hold
CTLA4	IPI	Relapsed & Refractory	29	0	7%	Not Reported	9.8 mo	Completed	24%
	IPI	Relapsed & Refractory	20	*15% (3)	35%	EFS 6 mo	8 mo 1 yr suvival 45%	Completed	“33%
	IPI + AZA	Frontline	21	*38% (8)	71%	EFS Not Reached	OS Not Reached 1 yr survival 68%		Not reported
PD-L1	Durvalumab + AZA	Frontline	42	3CR (7%)	62%	8.7 mo	11.6 mo	Active Not	None Rep
	AZA		42	4CR (10%)	47%	8.6 mo	16.7 mo	Recruiting	orted
	ATEZO + G-DEC	Relapsed & Refractory	9	1CR (11%)	33%	Not Reported	Not Reached	Recruiting	17 total AE gr3 or higher
TIM-3	MBG453 + DEC	Frontline	19	26% (5 CR)	58%	Not Reported	Not Reported	Recruiting	40-50%
	MBG453 + AZA		13	10% (1PR)	70%	Not Reported
CD-47	Magrolimab + AZA	Frontline	39	45% (CR 14, 1 PR)	91%	DOR Not reached	5.8 mo survival 100%	Recruiting	Not reported
	Magrolimab	Relapsed & Refractory	4	Not reported	Not Reported	Not Reported	Not Reported

Abbreviations: ATEZO = Atezolizumab, PEM = Pembrolizumab, NIVO = Nivolumab, IPI = Ipilimumab, DEC = Decitabine, AZA = Azacitidine, G-DEC = Guadecitabine. IPSS = International Prognostic Scoring System, IWG = International Working Group, MDS = Myelodysplastic Syndrome, MTD = Maximum Tolerated Dose, ORR = Overall Response Rate, CR = Complete Response, PR = Partial Response, mCR = Marrow CR, HI = Hematologic improvement, gr = grade, mo = Months, OS = Overall Survival, DOR = Duration of Response, PFS = Progression Free Survival, EFS = Event Free Survival,

** all data are from the same trial with separate MDS cohorts

✦IPSS-R (Revised International Scoring System)

≁Last Reported Update (Year)

**IWG MDS: International Working Group (IWG) 2006 response criteria in myelodysplasia.

ϕORR: defined as CR, mCR, PR, or HI based on IWG 2006 response criteria

^PFS and OS for all study patients, including MDS (n = 28)

▵Highest grade reported for Adverse Events for all study patients

“ based on 2016 abstract with 12/35 patients reported gr3/4 AE:

Table 2. Select MDS studies with adoptive cellular therapies

	Native T-cell Receptor	Genetically Modified Construct	Antigen Specific Target	CAR-T Product	Phase NCT	Author, Year. Reported	Lymphodepleting CT Regimen**	Total No. Patients (n=)⍦	Line Of Therapy
CHIMERIC ANTIGEN RECEPTORS	NKG2D	NKG2D + CD3ζ		CYAD-01	I (THINK) NCT03248479	Sallman. 2019	No	25	Relapsed & Refractory
					I/II (DEPLETHINK) NCT03466320	Al-Homsi 2019	yes	9	Relapsed & Refractory
				CYAD-02	I (CYCLE-01) NCT04167696	TBD: ASH, 12/2020	yes	NA	Relapsed & Refractory
				CM-CS1		Baumeister 2019	No	11	Relapsed & Refractory
					NCT04167696
		Multi Leukemia Antigen Specific Targets		T- Cell Source	Phase NCT	Author, Year Reported⏆	Preconditioning Chemotherapy	Total No. Patients (n=)⍦	Line Of Therapy
DONOR LYMPHOCYTE INFUSION		WT1, PRAME, Survivin, NYESO1		Donor DERIVED	I (ADSPAM) NCT02494167	Lulla 2019	Yes	21	Post-HSCT adjuvant (n=12)
									Post-HSCT- Relapsed & Refractory (7)
Primary Outcome	Intervention (CAR-T cell Schedule):	INDUCTION Dosing Level Cohorts (T-cells/inf)	Number of treated MDS Patients (n=)	✦IPSS-R / WHO 2016 Classification	Hypomethylating Agent ℥	*ϕMDS Responses	Status	* ≧ Grade 3 AE	≧ Grade 3 CRS
DLT	CAR-T cell Every 2-weeks x 3	Two week intervals: DL1: 3x108 DL2: 1x109  DL3: 3x109	3	Intermediate (n=1)	Failure	1mCR	Recruiting	44%	24% (n=6)
	CAR-T cell dosed Every 1-week x 4	Dose Dense: DL2:1x109  DL3: 3x109		High/Very High (n=2)		0
Safety	CYFLU--> CAR-T cell dose x 1	DL1: 1x108	2	Very High (n=2)	Failure	not reported	Active. Not Recruiting	** 22%	*n=2 (22%)
	CYFLU--> CAR-T cell dose x 1 on Day 3	◦ DL2: 3x108	NA	NA	NA	NA	NA	None Reported
Safety	CYFLU--> CAR-T cell dose x 1 on Day 3	DL1 1x108 DL2: 3x108  DL3: 1x109	NA	Intermediate, High Very High	Failure	NA	Recruiting	TBD	TBD
MTD	CM-CS1 dose escalation	3×107 = MTD	6 MDS/AM	Higher Risk (RAEB)	Failure	0	Completed	0	0
	cohorts		L
Primary Outcome	Intervention	Dose Levels T-cells/m2 per infusion	Number of treated MDS Patients (n=)	✦IPSS-R / WHO 2016 Classification	Hypomethylating Agent ℥	*ϕMDS Responses	Status	▵ ≧ Grade 3 AE
DLT	HSCT-----> TAA--DLI day +30	DL1: 5 x 10e6 DL2: 1 x 10e7 DL 3: 2 x 10e7 DL4: 5 x 107 DL5 1 x 108	2	NA	NA	2 CR	Recruiting	0

Abbreviations: CAR = chimeric antigen receptor, cCAR = compound CAR CAR-T Chimeric Antigebn Receptor T-Cell,DL = Dosing Level, DLI = Donor Lymphocyte Infusion HSCT = Hematopoetic Stem Cell Transplant; NKG2D = Natural Killer Group 2D-R receptor, NKG2DL – Natural Killer Group 2D Ligand; IPSS = International Prognostic Scoring System, IWG = International Working Group, MDS = Myelodysplastic Syndrome, RAEB = Refractory Anemia Excess MTD = Maximum Tolerated Dose, ORR = Objective/Overall Response Rate, CR = Complete Response, PR = Partial Response, mCR = Marrow CR, HI = Hematologic improvement, gr = grade, mo = Months, OS = Overall Survival, DOR = Duration of Response, PFS = Progression Free Survival, CRS = Cytokine Release Syndrome, TBD = To be determined

* *Preconditioning Regimen Prior to CAR-T administration: CyFlu: Cyclophosphamide 300 mg/m²/day and fludarabine 30 mg/m²/day, daily for 3 days.

✦IPSS-R (Revised International Scoring System) Last Reported Update (Year)

℥ HMA Response prior to enrollment

⍦ Includes all patients on study with MDS and non-MDS hematologic cancer

*IWG MDS: International Working Group (IWG) 2006 response criteria in myelodysplasia.

ϕ ORR: defined as CR, PR, mCR or HI based on IWG 2006 response criteria (DL3: 1 × 109 no data yet)

◦No data on DL3 at the time of the report

℥ HMA response prior to enrollment

▵Highest reported Adverse Events of All Hematologic Cancers Enrolled and Treated (includes non-MDS)

Table 3. Select MDS studies with vaccines

	Vaccine	Antigen Specific Target	HLA Epitopes	Adjuvant/Delivery	NCI Registration ID	Phase	Author, Year Reported	Line Of Therapy	Primary Outcome
WT1	WT4869	WT1	HLA-A*24;02	Not Reported	Japanese trial	I	Suzuki, 2015	Relapsed and Refractory	Safety
	DSP-7888	WT1	HLA-A*02:01/06 HLA-A*24:02 HLA-DRβ1	Not Reported	NCT02436252	I/II	Miyakoshi, 2016	Relapsed and Refractory	Safety & OS
	WT-1 peptide vaccine	WT1-A1 WT1-122A1long WT1-427long WT1-331long	HLA‐A*02:01 HLA-DR.B1	Montanide ISA51VG + GM-GCSF	NCT00665002	I	Brayer, 2015	Relapsed and Refractory	Safety Tolerance Immunogenicity
PR-1	proteinase 3. PR1 peptide	PR-1	HLA-A2	Montanide ISA51VG + GM-GCSF	NCT00004918	I/II	Qazilbash. 2017	Relapsed and Refractory	Toxicity and immunogenicity
PR1 + WT1	PR1	PR1:169-177 WT1:126-134	HLA-A*0201	Montanide ISA51VG + GM-GCSF	NCT00270452	I	Rezvani, 2008	Treatment Naïve	Safety Toxicity
	PR-1	PR1:169-177 WT1:126-134	HLA-A*0201		NCT00499772	II	Rezvani, 2011	Relapsed	Immunogeniity
NY-ESO-1	DEC205 mAb + NY-ESO-1 fusion protein (CDX-1401)	NY-ESO-1	HLA-unrestricted	poly-ICLC adjuvant	NCT01834248	I	Griffiths, 2018	Treatment naïve	Toxicity
	Vaccine Dosing Interventions:	MDS Patients (n=)	✦IPSS-R/IPSS risk/ or WHO Classification^ (n=)	Median Age (years)	Hypomethylating Agent ℥	*IWG CR & PR	*IWG ORR ϕ	Median OS /Survival Probability (%)	Status	* ≧ Grade 3 AE
WT1	5 up to 1,200 µg/body q 2 weeks	26	HR MDS (17) LR-MDS (9)	Not Reported	Failure	0	18.2%,	13 mo**	Completed	0
	3.5-10.5 mg/body,Id every 2-4 weeks	12	HR-MDS (7) LR-MDS (5)⌑	Not Reported	Failure	0	17%	7.3-10.8 mo**	Active Not Recruiting	□ 50%.
	Vaccine q 2 weeks x 6	2	Int2/High risk	74	Failure	0	0	Not Reported	Completed	6%
PR-1	Vaccine Dose every 3 weeks x 6	11	RAEB I, RAEB II, RA, RA	69	Failure	1 PR	36%	Not Reported	Completed	0
PR1 + WT1	single dose	2	RA & RARS	41	Naïve	0	0	Not Reached	Completed	0
	Vaccine x 2 weeks x 6	2	RA & RARS	41	Naïve	0	0	Not Reached	Completed	0
NY-ESO-1	Vaccine x1 alone cycle1, Vaccine C2day 15 + Decitabine d 1-5 x 4 cycles	7	Very High (4) High (1) Intermediate(2)	65 yo (56-79)	Naïve	3	71%	Not Reported	Completed	⍜ 66%

Abbreviations: CHLA = Human Leukocyte Antigen; IPSS = International Prognostic Scoring System, IWG = International Working Group, MDS = Myelodysplastic Syndrome, RAEB = Refractory Anemia Excess MTD = Maximum Tolerated Dose, ORR = Objective/Overall Response Rate, CR = Complete Response, PR = Partial Response, mCR = Marrow CR, HI = Hematologic improvement, gr = grade, mo = Months, OS = Overall Survival, DOR = Duration of Response, PFS = Progression Free Survival

≁ Last Reported Update (Year)

✦IPSS-R (Revised International Scoring System)

^WHO 2016 classification: RA = Refractory Anemia, RAEB = Refractory Anemia with Excess Blasts I and II, RARS = Refractory Anemia with Ringed Sideroblasts

*IWG MDS: International Working Group (IWG) 2006 response criteria in myelodysplasia

ϕORR: defined as CR, PR, mCR or HI based on IWG 2006 response criteria

□lower risk MDS but transfusion dependent

℥ prior HMA use and/or response in HR-MDS

℥HMA response prior to enrollment

**med OS i higher risk patients

▵Highest reported Adverse Events of All Hematologic Cancers Enrolled and Treated (includes non-MDS)

□ (most injection site reactions) ⍜Most were hematologic toxicities