Targeting CD123 in hematologic malignancies: identifying suitable patients for targeted therapy

Figures & data

Figure 1. The IL-3R system signaling pathway. AKT: protein kinase B; ERK: extracellular signal-regulated kinases; Grb2: growth factor receptor-bound protein 2; GTP: guanosine-5'-triphosphate; IL-3: interleukin 3; IL-3R: interleukin 3 receptor; JAK: Janus kinase; MAPK: mitogen-activated protein kinase; P: phosphate; PI3K: phosphoinositide 3-kinase; Shc: Src homology 2 domain-containing transforming protein; STAT: signal transducers and activators of transcription. Data from Martinez-Moczygemba and Huston, 2003 [24].

Figure 2. CD123 expression by immunohistochemistry in plasmacytoid dendritic cells in bone marrow biopsy of a patient with AML. Dual-color immunohistochemistry demonstrating membranous CD123 (brown) and nuclear TCF4 (red) staining; detailed section with ×20 magnification. AML: acute myeloid leukemia; TCF4: Transcription factor 4. Stemline Therapeutics, Inc. grants you non-exclusive permission to use the attached image in the article entitled ‘Targeting CD123 in hematologic malignancies: identifying suitable patients for targeted therapy’ authored by MM Patnaik, TI Mughal, C Brooks, R Lindsay, and N Pemmaraju and scheduled for publication in the journal entitled Leukemia & Lymphoma that is published by Informa Healthcare.

Figure 3. Phenotypic analysis of plasmacytoid dendritic cells by flow cytometry in bone marrow biopsy of a patient with BPDCN. pDCs expressing intermediate CD45 levels (top panels) are enriched for CD123 and CD303 expression (86.9%; bottom left panel). In this example, CD123+ CD303+ pDCs are characterized by co-expression of CD4, CD56, and TCL1 (bottom right panels). BPDCN: blastic plasmacytoid dendritic cell neoplasm; pDC: plasmacytoid dendritic cell; TCL1: T cell leukemia 1. Stemline Therapeutics, Inc. grants you non-exclusive permission to use the attached image in the article entitled ‘Targeting CD123 in hematologic malignancies: identifying suitable patients for targeted therapy’ authored by MM Patnaik, TI Mughal, C Brooks, R Lindsay, and N Pemmaraju and scheduled for publication in the journal entitled Leukemia & Lymphoma that is published by Informa Healthcare.

Table 1. CD123 expression in hematologic malignancies.

Hematologic malignancy	Frequency of CD123 expression in malignant cells
	FC	IHC
BPDCN	75–100% CD123+ pDCs [41,64]	75–100% CD123+ pDCs [38,39,41]
AML	55–97% [53,65] Among CD34+ cells: 78–93% [3,66,67] Among CD34+ CD38− cells: 82–100% [1,4,54]	29–55% [14,40,44]
ALL	B-ALL: 52–100% CD123 + [3,11,68,69] T-ALL: 0–43% CD123 + [3,11,69,70]
CLL	4–10% CD123 + [3,5,12]
CML	Among CD34+ CD38− cells: 88% [4] Chronic phase CML: 53% CD123 + [29] Blast crisis phase CML: 73% CD123 + [29]
CMML	BM: 20% CD123+ pDCs [71] PB: 10% CD123+ pDCs [71] Skin [72]: MMCT: 6% CD123+ pDCs MPDCP: 93.8% CD123+ pDCs	BM: 0–19% CD123+ pDCs in BM [73,74] Skin: 29.4% CD123+ pDCs [42]
Eosinophilic leukemia	PB: ≥90% CD123 + [60]
HCL	HCL: 86–100% CD123 + [3,5,12,75,76] HCLv: 40% CD123 + [12,76]
HL	HL cells: 59.3% [5]	HL cells: 22.5–100% [36,77,78] Tumor-associated macrophages are CD123+^a [36]
MDS	Total BM: 0.7% of CD34+ CD38− CD123 + [79] Among CD34+ CD38− BM cells: 40–100% CD123 + [4,6,10,79,80] Low-grade MDS: 43.7% CD34+ CD38− CD123+ cells [80] High-grade MDS: 53.4% CD34+ CD38− CD123 + [80]
MF	Idiopathic MF, among PB CD34+ cells: 3.9% CD123^high [81] Primary MF, among PB CD34+ CD38− cells: 54% CD123 + [60]
MM	BM: CD303+ CD123+ pDCs, 5%; PB: CD303+ CD123+ pDCs, 0.6% [63] PB: CD123+ pDCs, 4% in newly diagnosed MM; 3% in advanced MM [82]
NHL	LBCL: 2% [5] MCL: 33% [12] FL: 33% [12] Splenic MZL: 11–25% [12,76]	MGZL: 71% [77] PMBCL: 11% [77]
SM	Among CD34+ CD38− BM cells: 88.9% [4] Among CD117^high CD45^int BM cells: 38% [83] Total BM: 28–81%; PB: 33–91% [60]	BM: overall, 64%; 100% in aggressive SM; 61% in indolent SM; 57% in SM associated with hematologic neoplasm; 0% in mast cell leukemia [32]

ALL: acute lymphoblastic leukemia; AML: acute myeloid leukemia; BM: bone marrow; BPDCN: blastic plasmacytoid dendritic cell neoplasm; CLL: chronic lymphocytic leukemia; CML: chronic myeloid leukemia; CMML: chronic myelomonocytic leukemia; FL: follicular lymphoma; HCL: hairy cell leukemia; HCLv: variant hairy cell leukemia; HL: Hodgkin lymphoma; IHC: immunohistochemistry; LBCL: large B-cell lymphoma; MCL: mantle cell lymphoma; MDS: myelodysplastic syndromes; MF: myelofibrosis; MGZL: mediastinal gray zone lymphoma; MM: multiple myeloma; MMCT: myelomonocytic cell tumor; MPDCP: mature pDC proliferation; MZL: marginal zone lymphoma; NHL: non-Hodgkin lymphoma; PB: peripheral blood; pDC: plasmacytoid dendritic cell; PMBCL: primary mediastinal large B-cell lymphoma; RNA: ribonucleic acid; SM: systemic mastocytosis.

^aIHC and RNA.

Table 2. Clinical trials of CD123-targeting agents.

CD123-targeting agent	Mechanism of action	Disease	Study phase; no. of patients	Treatment	CT.gov identifier/ study status
Tagraxofusp (formerly SL-401, DT388IL3)	Diphtheria toxin/IL-3 fusion protein	R/R or poor-risk AML, HR MDS	Phase 1/2; N = 11	Tagraxofusp	NCT00397579 Completed
		BPDCN after HSCT	Phase 2; N = 20	Tagraxofusp	NCT04317781 Recruiting
		BPDCN	Phase 2; N = 40	Tagraxofusp plus venetoclax plus rituximab plus chemotherapy	NCT04216524 Recruiting
		MF, CMML	Phase 2; N = 130	Tagraxofusp	NCT02268253 Recruiting
		R/R MM	Phase 1/2; N = 9	Tagraxofusp plus pomalidomide plus dexamethasone	NCT02661022 Completed
		Adverse-risk AML in first CR and/or MRD in first CR	Phase 1/2; N = 16	Tagraxofusp as consolidation therapy	NCT02270463 Completed
		R/R AML, treatment-naive HR AML, HR MDS	Phase 1; N = 56	Tagraxofusp plus azacitidine or tagraxofusp plus azacitidine plus venetoclax	NCT03113643 Recruiting
		R/R AML, treatment-naive HR AML, BPDCN	Phase 1/2; N = 140	Tagraxofusp	NCT02113982 Completed
		R/R CD123+ or BPDCN-IF (CD123/CD4/CD56+) AML	Phase 2; N = 50	Tagraxofusp	NCT04342962 Not yet recruiting
Talacotuzumab (formerly CSL362)	Anti-CD123 mAb	AML and MDS after HMA failure	Phase 2; N = 25	Talacotuzumab	NCT02992860 Terminated
		AML	Phase 2/3; N = 326	Talacotuzumab plus decitabine, or decitabine	NCT02472145 Completed
		AML in CR or CRi at HR for relapse	Phase 1; N = 30	Talacotuzumab	NCT01632852 Completed
KHK2823	Humanized anti-CD123 mAb	AML, R/R MDS or not eligible for HMA therapy	Phase 1; N = 39	KHK2823	NCT02181699 Terminated
IMGN632	CD123-targeted ADC	R/R AML, BPDCN, ALL, other CD123+ hematologic malignancies, untreated BPDCN	Phase 1/2; N = 212	IMGN632	NCT03386513 Recruiting
		AML	Phase 1 b/2; N = 212	IMGN632, or IMGN632 plus azacitidine/venetoclax, or IMGN632 plus azacitidine plus venetoclax	NCT04086264 Recruiting
SGN-CD123A	CD123-targeted ADC	R/R AML	Phase 1; N = 17	SGN-CD123A	NCT02848248 Terminated
Flotetuzumab (formerly MGD006)	Anti-CD123 and -CD3 bispecific mAb	R/R CD123+ hematologic malignancies	Phase 2; N = 52	Flotetuzumab	NCT03739606 Withdrawn
		R/R AML, intermediate-2/HR MDS	Phase 1/2; N = 179	Flotetuzumab	NCT02152956 Recruiting
		R/R AML	Phase 1; N = 47	Flotetuzumab plus cytarabine	NCT04158739 Recruiting
		R/R advanced CD123+ hematologic malignancies^a	Phase 1; N = 40	Flotetuzumab	NCT04681105 Recruiting
		AML	Expanded access program	Flotetuzumab	NCT04678466 Recruiting
APVO436	CD123 and CD3ε bispecific antibody	R/R AML or MDS	Phase 1; N = 108	APVO436	NCT03647800 Recruiting
JNJ-63709178	Humanized anti-CD123 and anti-CD3 bispecific antibody	R/R AML	Phase 1; N = 120	JNJ-63709178	NCT02715011 Recruiting
XmAb14045 antibody with XmAb^® Fc domain	Anti-CD123 and anti-CD3 bispecific mAb	R/R AML, B-cell ALL, BPDCN, blast-phase CML	Phase 1; N = 145	XmAb14045	NCT02730312 Recruiting
CD123-targeted CAR T cells	IM23 CAR T: T cells expressing CD123-specific CAR	R/R AML	Phase 1; N = 15	IM23 CAR T: CD123-targeted CAR T cells	NCT03585517 Unknown
	UCART123: T cells expressing CD123-specific CAR	R/R AML	Phase 1; N = 59	UCART123: Allogeneic CD123-targeted CAR T cells	NCT03190278 Recruiting
	UCART123: T cells expressing CD123-specific CAR	BPDCN	Phase 1; N = 1	UCART123: Allogeneic CD123-targeted CAR T cells	NCT03203369 Terminated
	T cells expressing CD123-specific CAR	R/R AML	Phase 1/2; N = 40	CD123-targeted CAR T cells	NCT04272125 Recruiting
	T cells expressing CD123-specific CAR	R/R AML	Phase 1/2; N = 10	CD123-targeted CAR T cells	NCT03556982Unknown
	T cells expressing CD123-specific CAR	R/R AML	Phase 1/2; N = 45	CD123-targeted CAR T cells	NCT04265963 Recruiting
	T cells expressing CD123-specific CAR	R/R AML	Phase 1; N = 15	CD123-targeted CAR T cells	NCT03796390 Recruiting
	T cells expressing CD123-specific CAR	R/R AML	Phase 1; N = 32	CD123-targeted CAR T cells	NCT04318678 Recruiting
	T cells expressing CD123-specific CAR	CD123-expressing R/R myeloid malignancy	Phase 1/2; N = 45	CD123-targeted CAR T cells	NCT02937103 Recruiting
	T cells expressing CD123-specific CAR	R/R AML/ALL	Phase 1; N = 2	CD123-targeted CAR T cells	NCT03672851 Terminated
	T cells expressing CD123-specific CAR	R/R AML	Phase 1; N = 12	CD123-targeted CAR T cells	NCT03766126 Active, not recruiting
	T cells expressing CD123 CAR with CD137 and CD28 costimulatory domains	R/R AML	Phase 1; N = 50	CD123-targeted CAR T cells	NCT04014881 Recruiting
	T cells expressing CD123 CAR with TCRζ and 4-1BB costimulatory domains	Pediatric patients with R/R AML	Phase 1; N = 12	CD123-targeted CAR T cells	NCT04678336 Recruiting
	MB-102: T cells expressing CD123-specific, hinge-optimized CD28 co-stimulatory CAR and a EGFRt (CD123CAR-CD28-CD3ζ-EGFRt)	R/R AML, persistent/recurrent BPDCN	Phase 1; N = 42	Autologous/allogeneic MB-102	NCT02159495 Recruiting
	MB-102: T cells expressing CD123-specific, hinge-optimized CD28 co-stimulatory CAR and EGFRt (CD123CAR-CD28-CD3ζ-EGFRt)	R/R BPDCN, AML, HR MDS	Phase 1/2; N = 126	Autologous/allogeneic MB-102	NCT04109482 Recruiting
	T cells expressing CD123-specific linked to TCR and 4-1BB signaling domains CAR	R/R AML	Phase 1; N = 7	Autologous CD123CAR-TCR/4-1BB–expressing T-cell infusion	NCT02623582 Terminated
	T cells expressing CD123CAR-4-1BB-CD3ζ-EGFRt	Recurrent AML after HSCT	Phase 1; N = 20	Allogeneic CD123CAR-4-1BB-CD3ζ-EGFRt–expressing T cells	NCT03114670 Unknown
	CD123- and CD33-specific CARs expressed on a T cell	R/R or HR hematologic malignancies	Phase 1; N = 20	CD123-CD33 compound CAR T cells	NCT04156256 Unknown
	T cells expressing CD123-specific CAR	R/R AML	Phase 2/3; N = 20	CAR T cells targeting CD123 and CLL1	NCT03631576 Recruiting
	T cells expressing CD123-specific CAR	R/R AML	Not applicable; N = 50	Single or double CAR T cells targeting CD33, CD38, CD56, CD123, CD117, CD133, CD34, or Muc1	NCT03473457 Recruiting
	T cells expressing CD123-specific CAR	R/R AML	Phase 1/2; N = 10	Multiple CAR T cells targeting Muc1, CLL1, CD33, CD38, CD56, and CD123	NCT03222674 Unknown
	Fourth-generation CAR T cells targeting CD123 (4SCAR-CD123)	R/R B-ALL CD19− or relapsed after CD19-targeted CAR T	Phase 1/2; N = 100	CAR T cells targeting CD22, CD123, CD38, CD10, CD20, and TSLPR	NCT04016129 Recruiting
	Fourth-generation CAR T cells targeting CD19 and CD123 (4SCAR19/123)	R/R B-cell malignancies	Phase 1/2; N = 100	CAR T cells targeting CD19 and CD20, CD22, CD30, CD38, CD70, and CD123	NCT03125577 Recruiting
	Fourth-generation CAR T cells targeting CD22, CD123, CD38, CD10, and CD20 (4SCAR)	CD19− R/R B-ALL	Phase 1/2; N = 100	CAR T cells targeting CD22, CD123, CD38, CD10, and CD20	NCT04430530 Recruiting
	Fourth-generation CAR T cells targeting CD19, CD22, CD123, and CD38 (4SCAR)	R/R B-ALL	Phase 1; N = 30	Single or combinations of CAR T cells targeting CD19, CD22, CD123, and CD38	NCT02968472 Unknown
	T cells expressing CD123-specific CAR	R/R AML	Phase 1/2; N = 10	CAR T cells targeting CLL1, CD33, and/or CD123	NCT04010877 Recruiting
	T cells expressing CD123-specific CAR	R/R ALL, AML, MDS	Phase 1; N = 30	CD123-targeted CAR T cells alone or combined with Eps or WT1 peptide-specific dendritic cells	NCT03291444 Recruiting
UniCAR02-T–CD123	Anti-CD123 recombinant antibody (TM123)	CD123+ R/R AML, B-ALL, BPDCN	Phase 1; N = 45	T cells carrying universal CARs (UniCAR02-T) in combination with anti-CD123 recombinant antibody	NCT04230265 Recruiting
		CD123+ adverse high-risk AML	Phase 1; N, not specified	T cells carrying universal CARs (UniCAR02-T) in combination with anti-CD123 recombinant antibody	NCT04106076 Withdrawn
IL-3-targeted CAR T cells	T cells expressing IL-3–specific CAR	CD123+ R/R AML	Phase 1; N = 36	IL-3–targeted CAR T cells	NCT04599543 Recruiting

ADC: antibody-drug conjugate; ALL: acute lymphoblastic leukemia; AML: acute myeloid leukemia; BPDCN: blastic plasmacytoid dendritic cell neoplasm; CAR: chimeric antigen receptor; CLL1: C-type lectin-like molecule 1; CML: chronic myeloid leukemia; CMML: chronic myelomonocytic leukemia; CR: complete response; CRi: CR with incomplete platelet recovery; EGFRt: truncated form of epidermal growth factor receptor; Eps: exopolysaccharide; HMA: hypomethylating agent; HR: high-risk; HSCT: hematopoietic stem cell transplantation; IL-3: interleukin 3; mAb: monoclonal antibody; MDS: myelodysplastic syndromes; MF: myelofibrosis; MM: multiple myeloma; MRD: minimal residual disease; Muc1: mucin 1; R/R: relapsed/refractory; TCR: T-cell receptor; TSLPR: thymic stromal lymphopoietin receptor; WT1: Wilms tumor 1.

^aIncludes R/R acute leukemia, R/R ALL, R/R BPDCN, R/R CML (Philadelphia chromosome [BCR-ABL1] positive), R/R hairy cell leukemia, R/R Hodgkin lymphoma, R/R T-ALL, systemic mastocytosis.

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