Monoclonal antibodies: new chance in the management of B-cell acute lymphoblastic leukemia

Figures & data

Table 1. Studies using monoclonal antibodies in the management of acute lymphoblastic leukemia.

Study	Study type	Number of patients	Cohort	Treatment regimen	Results	Frequent grade 3/4 adverse events
MDACC [20]	Prospective randomized trial	282 adolescents and adults	Ph negative	Rituximab + hyper-CVAD	Higher 3-year CR duration rate (70%: 38%; P < 0.001); Longer 3-year OS rate (75%: 47%; P = 0.003)	Infection
GRAALL-2005/R [21]	RCT	209 adults	Newly-diagnosed Ph negative	Rituximab + chemotherapy	Longer EFS (HR 0.66; P = 0.04); Higher 2-year EFS rate (65%: 52%)	Infection; Laboratory abnormalities; Allergy
Jabbour et al. (2020) [26]	Phase 2	69 adults	Newly-diagnosed Ph negative	Ofatumumab + hyper-CVAD	CR rate 98%; 4-year EFS rate 59%; 4-year OS rate 68% (58–81)	Infection; Hyperglycaemia; Hypokalaemia
Topp et al. (2015) [36]	Phase 2	189 adults	R/R Ph negative	Single Blinatumomab	Median OS 6.1 months; Median RFS (6.9 months: 2.3 months); Median OS (11.5 months: 6.7 months)	Febrile neutropenia; Neutropenia; Anemia
TOWER (2017) [38]	Phase 3	405 adults	R/R Ph negative	Single Blinatumomab	Higher CR rate (34%:16%; P < 0.001); Longer median OS (7.7 months: 4.0 months; P = 0.01); Higher 6-month EFS rate (31%: 12%; P < 0.001)	Neutropenia; Infection; Elevated liver enzyme
BLAST (2017) [46]	Phase 2	116 adults	Hematologic CR MRD positive	Single Blinatumomab	Longer RFS (23.6 months: 5.7 months; P = 0.002); Longer OS (38.9 months: 12.5 months; P = 0.002)	Neutropenia; Pyrexia; Tremor
Martinelli (2017) [59]	Phase 2	45 adults	R/R Ph positive	Single Blinatumomab	CR/CRh rate 36%; Median RFS 6.7 months; Median OS 7.1 months	Pyrexia; Febrile neutropenia; Headache
Couturier et al. (2020) [61]	Retrospective study	26 adults	R/R Ph positive	Blinatumomab + Ponatinib	Molecular CR rate 88.5%; Median OS 20 months; Median EFS 15.3 months	Neurologic events; Cytokine release syndromes
INO-VATE (2016) [69], (2019) [70]	Phase 3	326 adults	R/R	Single-agent Inotuzumab Ozogamicin	Higher CR rate (80.7%: 29.4%, p < 0.001); Longer CR duration (4.6 months: 3.1 months, P = 0.03); Higher 2-year OS rate (22.8%: 10.0%; P = 0.0105)	Febrile neutropenia; Veno-occlusive disease
Bhojwani (2019) [75]	Retrospective study	51 children	R/R	Single-agent Inotuzumab Ozogamicin	CR/CRi rate 67%; MRD response 71%	Hepatic transaminitis; Hyperbilirubinemia; Infections
Jabbour (2017) [76]	Phase 2	59 adults	R/R	Inotuzumab Ozogamicin + mini-hyper-CVD	1-year RFS rate 40%; 1-year OS rate 46%	Prolonged thrombocytopenia; Infections; Hyperbilirubinemia Veno-occlusive disease
Kantarjian (2017) [77]	Phase 2	52 patients aged 60 years or older	Newly-diagnosed Ph negative	Inotuzumab Ozogamicin + mini-hyper-CVD	3-year EFS rate 49%; 3-year OS rate 56%	Prolonged thrombocytopenia; Infection; Increased aminotransferases; Hyperbilirubinaemia

MDACC, MD Anderson Cancer Center; GRAALL, Group for Research on Adult Acute Lymphoblastic Leukemia; Ph, Philadelphia chromosome; R/R, relapsed or refractory; MRD, minimal residual disease; hyper-CVAD, hyper-fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone; mini-hyper-CVD, a modified version of hyper-CVAD with 50% cyclophosphamide and dexamethasone, 25% methotrexate, no anthracycline; CR, complete remission; CRh, CR with incomplete hematologic recovery; CRi, CR with incomplete platelet recovery; OS, overall survival; EFS, event-free survival; RFS, relapse-free survival;

Table 2. Ongoing trials focus on the future direction of monoclonal antibodies.

Monoclonal antibody	Study type	Number of patients	Cohort	Primary outcome measures	Secondary outcome measures	NCT number
Combination with other medicine
Rituximab + Bortezomib	Phase 2	100	Relapsed Children	Remission rate	EFS rates; OS	NCT04224571 [85]
Blinatumomab + Nivolumab	Phase 2	550	Relapsed	1.MRD 2.Second remission rate	Dose-limiting toxicity; EFS post-induction	NCT04546399 [87]
Blinatumomab + Nivolumab ± Ipilimumab	Phase 1	30	CD19 positive R/R	1.Incidence of adverse events 2.Maximum tolerated dose	MRD; Anti-leukemia activity; CR; CRi; Progressive disease; DOR; OS	NCT02879695 [88]
Antibodies in treating MRD
Blinatumomab	Phase 2	40	MRD positive	RFS	EFS; OS; MRD negativity rate; MRD negativity rate after course 1; Incidence of toxicity	NCT02458014 [86]
Inotuzumab Ozogamicin	Phase 2	32	MRD positive CD22 positive children	1.Treatment response Cycle1 – count &percentage 2.Treatment Response Cycle 2 – count & percentage	Occurrence of death – count &percentage; Occurrence of Veno-occlusive disease – count & percentage	NCT03913559 [89]
Inotuzumab Ozogamicin	Phase 2	40	MRD positive	RFS	Incidence of adverse events; OS; MRD negativity rate	NCT03441061 [90]
Combination of two different antibodies
Blinatumomab + Inotuzumab Ozogamicin	Phase 2	64	CD22 positive	EFS	OS; RFS; EFS; CR rate; MRD	NCT03739814 [91]
Blinatumomab + Inotuzumab Ozogamicin	Phase 2	80	Newly diagnosed	RFS	OS; OR rate; MRD; Incidence of adverse events	NCT02877303 [92]
New medicine or antibody
ADCT-602 (antibody to CD20)	Phase 1/2	65	R/R	1.Maximum tolerated dose 2.Incidence of toxicity graded 3.Recommended phase II dose of ADCT-602 4.CR/CRi rate	ORR; OS; PFS; Measure the amount of ADCT-602 in the body at different time points; ADCT-602 exposure on QT interval	NCT03698552 [93]
GNR-084 (bispecific antibody to CD19/CD3)	Phase 1/2	36	R/R	GNR-084 safety and tolerability	The frequency of specific toxicity events; ORR; CR rate; Frequency of CRi; RFS; EFS; OS; MRD	NCT04601584 [94]
CNCT19 (antibody to CD19)	Phase 2	100	CD19 positive R/R	ORR	ORR; RFS; EFS; DOR; OS	NCT04684147 [95]
Flotetuzumab (antibody to CD123)	Phase 1	40	CD123 positive R/R	Incidence of adverse events	CR; MRD; DOR; Number/percent who bridge to allogeneic HCT; OS	NCT04681105 [96]

R/R, relapsed or refractory; CR, complete remission; CRi, CR with incomplete marrow recovery; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; RFS, relapse-free survival; EFS, event-free survival; MRD, minimal residual disease; DOR, duration of remission; HCT, hematopoietic cell transplantation; CRh, CR with incomplete hematologic recovery.

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