Biological therapy in elderly patients with acute myeloid leukemia

Figures & data

Figure 1. All the main therapeutic strategies presented in the text are summarized in this image. Adoptive cell therapy such as allogeneic NK cells, CAR-T and CAR-NK are represented in gray as they are still in the earliest stages of clinical experimentation.

ADC: Antibody drug conjugate; BCL-2, B-cell leukemia/lymphoma-2; BiTE: Bispecific T-cell engager; DART: Dual-Affinity Re-Targeting; FLT3, FMS-like tyrosine kinase 3; GO, gemtuzumab ozogamicin; HMAs: hypomethylating agents; IDH, isocitrate dehydrogenase; MDM2: murine double minute 2; MHC-1, major histocompatibility complex; PD1, programmed cell death protein 1; PD-L1, programmed death-ligand 1; TCR: T-cell receptor; TriKE: Trispecifica Killer Engagers. Created by G Ciotti with BioRender.com.

Table 1. Monoclonal-antibodies with clinical activity in elderly AML. Toxicity was reported in order of frequency.

Target/Type	Study				Combination			Pop.	Efficacy/Outcome	Toxicity	Ref.
ADC anti-CD33
Gemtuzumab-ozogamicin^1	Phase 3				+ ‘3 + 7’			ND N = 139	No difference in response rate GO arm vs control: 2 yrs EFS: 41% vs 17% 2 yrs OS: 53% vs 42%	Persistent thrombocytopenia Prolonged myelosuppression Higher grade ≥3 AEs	[12]
	Phase 3				+ sCHT			ND N = 559	No difference in response rate GO arm vs control: 3 yrs RFS: 21% vs 16% 3 yrs OS: 25% v 20%	No additional toxicity Low rate of VOD (mostly arising during sepsis)	[13]
	Phase 2				+ AZA			ND N = 99	OS 11 mo, CR 35%-41%	Febrile neutropenia Consistent with AZA alone	[17]
	Phase 1/2				+ AZA			R/R N = 50	No advantage vs GO single-agent	Consistent with AZA alone No VOD events	[19,20]
	Phase 1/2				+ AZA + VORINOSTAT			R/R N = 52	ORR of 42% at the MTD	Febrile neutropenia Infections/Sepsis	[22]
Vadastuximab talirine	Phase 3				+ HMAs			ND N = 117	Terminated by Sponsor due safety issue	Higher rate of deaths, including fatal infection	[25]
Radioconjugate anti-CD33
Lintuzumab-Ac225	Phase 1				+ sCHT			R/R N = 15	cCR 67%	Febrile neutropenia Infection Maculopapular rash	[26]
	Phase 1/2				+ VEN			R/R	Still recruiting (data on the first 3 enrolled patients)	No DLT No non-hematologic AEs ≥2	[29]
BiTE – CD33xCD3
AMG-330	Phase 1				Alone			R/R N = 55	ORR 19%	CRS (reversible and dose-dependent)	[50,51]
Emerfetamab	Phase 1				Alone			R/R N = 30	Missing	Hematological toxicity Transaminitis CRS	[53]
Fusion protein anti-CD123
Tagrazofusp^2	Phase 1/2				Alone			R/R N = 45	Low efficacy Better results on low-burden leukemia	CLS Fever Transaminitis Hypoalbuminemia (all AEs mostly reversible)	[36]
ADC anti-CD123
Pivekimab sunirine	Phase 1/2				Alone			R/R N = 67	ORR 20%	Febrile neutropenia Diarrhea	[44]
	Phase 1/2				+ AZA + VEN			R/R N= 35	All: cCR of 40%; VEN naïve patients: cCR 60%; FLT3mut: cCR of 70%	Consistent with AZA+VEN	[45]
DART – CD123xCD3
Flotetuzumab	Phase 1/2				Alone			R/R N = 88	ORR: 13.6%; CR/CRi 30% in refractory/early relapsed In responders: OS of 10.2 mo	CRS IRR (grade 1–2)	[58,59]
Vibecotamab	Phase 1				Alone			R/R N = 104	ORR 14%	CRS No myelosuppression	[64]
BiTE – CLEC12AxCD3
Tepoditamab	Phase 1				Alone			R/R N = 50	Missing	No DLT Fever CRS Transaminitis (all AEs mostly reversible)	[68]

¹Approved by FDA and EMA in combination with daunorubicin and cytarabine and as a monotherapy for adult patients with ND, de-novo, CD33-positive AML.

²Approved by FDA (for adults and pediatrics) and EMA (only adults) as monotherapy for the first-line treatment of blastic plasmacytoid dendritic cell neoplasm (BPDCN).

ADC: antibody-drug conjugate; AEs: adverse events; AZA: azacitidine; BiTE: Bispecific T-Cell Engager; CLS: capillary leak syndrome; CRS: cytokines release syndrome; CR/cCR: complete response/composite complete response; DART: dual-affinity re-targeting antibody; DLT: dose-limiting toxicities; EMA: European Medicines Agency; FDA: Food and Drugs Administraton; FLT3: FMS-like tyrosine kinase 3; FLT3i: FLT3 – inhibitor; HMAs: Hypomethylating agents; IRR: infusion-related reaction; MTD: maximum tolerated dose; N: number of patients; ND: newly diagnose; OS: overall survival; ORR: overall response rate; R/R: relapsed/refractory; sCHT: standard chemotherapy; VEN: venetoclax; VOD: veno-occlusive disease.

Table 2. Immune check-point inhibitors with promising clinical activity in elderly AML. Toxicity was reported in order of frequency.

Drug name	Study				Combination	Population	Efficacy/outcome	Toxicity	Ref.
mAb anti-PD1
Nivolumab	Phase 2				+ AZA	R/R N = 70	Global low survival advantage HMAs-naïve vs HMAs.exposed: ORR: 52% vs 33%; OS: of 6.3 mo vs 4.6 mo	Reversible immune-relate events (mostly pneumonitis)	[78]
	Phase 2				+ AZA + ipilimumab	R/R N = 31	CR/Cri: 36% OS: 10,5mo	Reversible immune-relate events (higher rate than NIVO+AZA)	[81]
Pembrolizumab	Phase 2				+ AZA	R/R & ND N = 37	Low efficacy in R/R ND: cCR:47%, OS 13 mo	Consistent with AZA alone	[84]
	Phase 1				+ DEC10d	R/R N = 6	ORR 66%	Hematological AEs Infections (pneumonia)	[85]
mAb anti-CD47
Magrolibab	Phase 2				+ AZA	ND p53mut N = 72	ORR: 48,6% (CR/CRi 41,6%) OS of 10.8mo	Febrile neutropenia Peripheral edema Anemia (manageable with priming-dose schedule)	[93]
	Phase 1/2				+ AZA + VEN	R/R & ND N = 38	ND: ORR 100% (CR/CRi 94%); R/R after VEN-failure: cCR 27%; R/R VEN-naïve: cCR 63%	Febrile neutropenia Pneumonia Anemia (as above)	[96]
mAb anti-TIM3
Sabatolimab	Phase 1				+ HMAs	ND N = 48	ORR: 40% (cCR 30%) High-risk: ORR 53,8% DOR: 12.6 mo	Consistent with HMAs alone	[101]
	Phase 2				+ AZA + VEN	ND N = 18	CR 72% (preliminary) Including high-risk MDS, and CMML	Febrile neutropenia Hematological toxicity	[103]

AEs: adverse events; AZA: azacitidine; CMML: chronic myelomonocytic leukemia; CR/cCR: complete response/composite complete response; DEC10d: decitabine for 10 days administration; DOR: duration of response; HMAs: Hypomethylating agents; mAb: monoclonal antibody; MDS: myelodysplastic syndrome; N = number of patients; ND: newly diagnose; ORR: overall response rate; OS: overall survival; R/R: relapsed/refractory; VEN: venetoclax;

Table 3. Small molecules with proven clinical activity in elderly AML patients and promising combination with standard treatments. Toxicity was reported in order of frequency/clinical relevance.

Setting	Combination		Study			Population	Efficacy/Outcome	Toxicity	Ref.
FLT3-mutated
Gilteritinib (both ITD/TKD)	Alone^1		Phase 3			R/R	CR 34%, OS 9.8 mo in GILTE arm	Lower than salvage CHT	[131,132]
	+ VEN		Phase 2			R/R	cCR 83.8% Also effective in pts already treated with FLT3i	Febrile neutropenia Myelosuppression	[133]
	+ AZA		Phase 3			ND	No advantage in CR and OS	Consistent with AZA alone	[134]
	+ AZA + VEN		Phase 1/2			R/R and ND	CR 73% in ND, ORR 67% in R/R	Febrile neutropenia Prolonged myelosuppression Infections	[142]
Quizartinib (only ITD)	Alone^2		Phase 3			R/R	OS: 6.2 mo in the experimental arm Survival advantage only vs LDSC	Febrile neutropenia Sepsis QT-prolongation Nausea	[135]
	+ LDAC or AZA		Phase 1/2			R/R and ND	cCR 87% in ND, 64% in R/R Better survival in QUIZ/AZA arm	Febrile neutropenia Pneumonia Infections	[136]
	+ DEC + VEN		Phase 1/2			R/R	cCR 90%, OS at 6mo 86%	Febrile neutropenia	[137]
	+ ‘3 + 7’^3		Phase 3			ND Up to 75 yrs	Median OS: 31.9 mo with QUIZ vs 15.1 mo with PBO*	Consistent with ‘3 + 7’+ PBO QT-prolongation Higher rate of G3 neutropenia	[138]
Crenolanib (including D835)	+ ‘3 + 7’		Phase 2			ND Up to 75 yrs	(34%) pts were >60 yrs CR 86% after 2 cycles, OS 20.2 mo	Febrile neutropenia Diarrhea	[139, 140]
IDH-mutated
Enasidenib (IDH2-inhibitor)	+ AZA		Phase 1/2			ND	ORR 74% Modest OS advantage	Consistent with AZA alone	[145]
Ivosidenib (IDH1-inhibitor)	+ AZA^4		Phase 3			ND	Experimental arm: OS 24 mo, CR 47%	Consistent with AZA alone	[146]
	+ VEN ± AZA		Phase 1/2			R/R and ND	cCR 87%, OS 42 mo	Febrile neutropenia Pneumonia	[147]
NPM1-mutated/MRD eradication
Glasdegib (hedgehog-inhibitor)	+ LDAC^1		Phase 2			ND	Modest OS advantage vs LDAC alone: 59,8% at 1-years vs 38,2%	Consistent with LDAC alone	[148]
Mutated-TP53
Idasanutlin (MDM2-inhibitor)	+ VEN		Phase 1/2			R/R	Only modest efficacy cCR 26%, OS 5.1 mo	Diarrhea and vomiting Febrile neutropenia Infections (sepsi, pneumonia)	[150]
Pevonedistat (NEDD8-inhibitor)	+ AZA		Phase 3			ND - low blast	No advantage in CR rate and OS vs AZA alone	Consistent with AZA alone No increased toxicities	[152]
	+ AZA + VEN		Phase 1/2			ND ≥75 yrs 43%	cCR 64% OS: 8.9 mo in TP53mut vs 18 mo	Consistent with AZA+VEN Hypophosphatemia	[153]
Eprenetapopt	+ AZA		Phase 2			ND – Low blast	ORR 69% (including MDS patients)	Consistent with AZA aloneAtaxia (reversible)	[155]
KMT2Ar & NPM1-mut
Revumenib (Menin – inhibitors)	Alone		Phase 1/2			R/R	AML n = 56/68 pts cCR 38% with DOR 9.1 mo	QT-prolong (asymptomatic) Differentiation syndrome	[160]
Ziftomenib (Menin – inhibitors)	Alone		Phase 1/2			R/R	Dosage 600 mg (12pts) cCR 33%	Febrile neutropenia Cytopenias Differentiation syndrome	[61]
RARα- overexpressed
Tamibarotene (RARα agonist)	+ AZA		Phase 2			ND	ORR 67%, CR/CRi 61% OS 8.4 mo (18 mo in CR/Cri pts) High rate of transfusion independence	Consistent with AZA alone Hypertriglyceridemia (G ≥ 3)	[163]

*Sub-analysis on patients > 60 years: not available.

¹Approved by FDA and EMA.

²Only approved in Japan.

³Priority review by FDA.ss

⁴Approved by FDA, not by EMA.

AZA: azacitidine; CR/cCR: complete response/composite complete response; DEC: decitabine; DOR: duration of response; FDA: Food and Drugs Administraton; FLT3: FMS-like tyrosine kinase 3; FLT3i: FLT3 – inhibitor; EMA: European Medicines Agency HMAs: Hypomethylating agents; IDH: Isocitrate dehydrogenase; KMT2Ar: Lysine Methyltransferase 2A gene rearrangements; LDAC: low-dose cytarabine; LDSC: low-dose standard chemotherapy; mo: months; MRD: minimal residual disease; ND: newly diagnose; NPM1: nucleophosmin 1; OS: overall survival; ORR: overall response rate; PBO: placebo; R/R: relapsed/refractory; VEN: venetoclax.

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