Immunotargeting relapsed or refractory precursor B-cell acute lymphoblastic leukemia – role of blinatumomab

Figures & data

Figure 1 Blinatumomab: structure and mode of action.

Notes: (A) Blinatumomab contains the variable domains (V_H and V_L) of two different IgG molecules. It is constructed out of two scFv, each formed by a pair of the V_H and V_L from two IgG molecules binding CD3 and CD19. The two scFv proteins are connected with a flexible, nonimmunogenic linker made of 25 amino acids. (B) Blinatumomab in the presence of CD3- and CD19-positive cells leads to a very close linkage with multiple connections between the two different cell types. This close contact zone forms a cytolytic synapse mediating TCR activation: granzymes and perforin are exocytosed into the CD19 positive target cell inducing its apoptosis.
Abbreviations: scFv, single chain variable fragment; TCR, T-cell receptor.

Table 1 Published clinical trials on blinatumomab

Study indication, phase, clinical trial identifier, sponsor	Patient characteristics	Blinatumomab dosing	Outcome data	Rate of cytokine-release syndrome and neurotoxic events
Adult R/R B-ALL, randomized controlled (blinatumomab vs chemotherapy), multicenter international, Phase III, TOWER, NCT02013167, Amgen^Citation30	405 patients, blinatumomab =271 patients, chemotherapy =134 patients • Relapse within 12 mo after CR1 or allogenic HSCT or nonresponse to first salvage therapy or ≥2 relapse • Bone marrow ≥5% blasts • Only Ph-neg. patients • No active CNS disease • 140/403 (35%) patients had previous allogenic HSCT • Mean age 40.9 years	Blinatumomab: • Continuous infusion with 9 µg/d for 1 week followed by 28 µg/d for 3 weeks, next cycle after 2 weeks off starting with 28 µg/d (for 4 weeks) • Prior dexamethasone Both groups: • Up to 5 cycles/blocks blinatumomab/chemotherapy for induction and consolidation, maintenance therapy when indicated	Primary outcome for blinatumomab vs chemotherapy: • Median OS 7.7 mo vs 4.0 mo after median follow-up of 11.7 mo, P=0.01 Secondary outcomes for blinatumomab vs chemotherapy: • CR/CRh in 44% vs 25%, P<0.001 • 33% vs 12% became MRD negative • Median RFS 7.3 mo vs 4.6 mo • 6 mo EFS 31% vs 12% • In both groups, 24% of the patients proceeded to allogenic HSCT • OS curves are separating within 3 mo with longer survival for blinatumomab and are converging again after 15 mo	Blinatumomab vs chemotherapy: • All AEs > grade (°)II=87% vs 92% • CRS >°II=13/267 (5%) vs 0/109 • Neurotoxicity >°II=25/267 (9%) vs 9/109 (8%)
Adult R/R B-ALL, single arm, multicenter international, Phase II, NCT01466179, NCT02003612, Amgen^Citation28,Citation29	189 patients • Relapse within 12 mo after CR1 or allogenic HSCT or nonresponse to first salvage therapy or ≥2nd relapse • Bone marrow ≥10% blasts • Only Ph-neg. patients • No previous/active CNS disease • 64/189 (34%) patients had previous allogenic HSCT • Median age of 39 years	Continuous infusion with 9 µg/d for 1 week followed by 28 µg/d for 3 weeks, next cycle after 2 weeks off starting with 28 µg/d (for 4 weeks) In case of high leukemic burden prior dexamethasone	Primary outcome: • 81/189 (43%) patients achieved CR/CRh within 2 treatment cycles Secondary outcomes: • 60/181 (33%) patients became MRD negative within 2 treatment cycles (59 after the first, 1 patient after the second cycle) • 32/81 (40%) patients with CR/CRh proceeded to allogenic HSCT After follow-up of a median of 8.9 mo: • In 81 patients with CR/CRh, median RFS was 5.9 mo with 6.9 mo for MRD responders vs 2.3 mo for MRD nonresponders • Median OS for all 189 patients: 6.1 mo with a median follow-up of 9.8 mo	• CRS >°II=2/189 (2%) • Neurotoxicity >°II=20/189 (11%); 87% of neurological events occurred in first cycle
Pediatric R/R B-ALL, single arm, multicenter international, Phase I/II, NCT01471782, Amgen^Citation7	46 Phase I, 44 patients Phase II • Bone marrow ≥25% blasts • <18 years • 70 patients received final dosing = eligible for response evaluation  ○ Median age of 8 years	Phase I: escalating dosing; Phase II: continuous infusion with 5 µg/m^2/d for 1 week followed by 15 µg/m^2/d for 3 weeks, second cycle after 2 weeks off starting with 15 µg/m^2/d (for 4 weeks) Prior dexamethasone	Primary outcome Phase I: • 4 DLT: 3 CRS °IV, 1 respiratory failure Primary outcome for the 70 patients who received final dosing: • 27/70 (39%) patients achieved CR within two cycles Secondary outcomes: • 14/70 (20%) became MRD negative within two cycles After follow-up of a median of 23.1 mo: • Median RFS =4.4 mo in the CR group • Median RFS =7.3 mo in MRD response group • 2/3 patients with Ph+ ALL achieved CR • Median OS =7.5 mo	Phase I: • CRS >°II=3/49 (6%) Phase II: • CRS >°II=5/70 (7%) • Neurotoxicity >°II=0/70 • 2 patients (3%) with II° seizure
Adult R/R B-ALL, single arm, multicenter in Germany (GMALL group), Phase I/II, NCT01209286, Amgen^Citation37,Citation53	36 patients evaluable • M2/3 bone marrow with >5% blasts • Only Ph-neg. patients • No previous/active CNS disease • 15/36 (42%) patients had previous allogenic HSCT • Median age of 32 years	Phase I: escalating dosing; Phase II: continuous infusion with 5 µg/m^2/d for 1 week followed by 15 µg/m^2/d for 3 weeks, next cycle after 2 weeks off starting with 15 µg/m^2/d (for 4 weeks) Phase II: prior dexamethasone	Primary outcome: • 25/36 (69%) patients achieved CR/CRh • 8 of 15 (52%) patients achieved CR/CRh after allogeneic HSCT Secondary outcomes: • 22/36 (61%) patients became MRD negative • 13/25 (52%) responders underwent allogeneic HSCT (2 relapses afterwards, 6 TRM) • 12/25 (48%) responders did not proceed to allogeneic HSCT (8 relapses) After follow-up of a median of 28.9 mo: • 12 patients in CR, resulting in an estimated RFS of 61% • Of 9 patients after allogenic HSCT, 6 were in CR, 2 had relapsed, 1 died due to TRM	CRS >°II=2/36 (6%) Neurotoxicity >°II=5/36 (14%); 4/5 within the first treatment week • 3 encephalopathy (tremor, aphasia, confusion) • 2 seizures • 1 patient with II° seizure • All events were reversible
Adult B-ALL with CR but persisting/relapsing MRD, single arm, multicenter in Germany (GMALL group), Phase II, NCT00198991, NCT00198978, Amgen^Citation26,Citation42,Citation54	20/21 patients evaluable • 15 with persisting MRD • 5 with relapsed MRD • Including 5 cases of Ph+ ALL nonresponding to TKI • No prior HSCT • Median age of 47 years	15 µg/m^2/d for 4 weeks, next cycle after 2 weeks off, up to 4 cycles 4 initial cycles, followed by up to 3 additional cycles No prior dexamethasone	Primary outcome: • 16/20 (80%) patients became MRD negative, all within the first treatment cycle • 3/5 patients with Ph+ ALL responded • 9 patients underwent allogenic HSCT After follow-up of a median of 50.8 mo: • 10 patients in CR, resulting in long-term RFS of 50% • Of 9 patients after allogenic HSCT, 5 were in CR, 3 had relapsed, 1 died due to TRM • Of 11 patients w/o allogenic HSCT, 5 were in CR, 5 had relapsed, 1 withdrew from trial • In 2/6 relapses patients the ALL became CD19 neg. • 2/6 relapses were extramedullary (CD19+)	CRS >°II=0 Neurotoxicity >°II=1 (generalized seizure, completely reversible)

Abbreviations: AE, adverse event; ALL, acute lymphoblastic leukemia; CNS, central nervous system; CR, complete remission; CRh, complete remission with incomplete hematological recovery; CRS, cytokine-release syndrome; DLT, dose limiting toxicity; EFS, event-free survival; GMALL, German Multicenter Study Group for Adult ALL; HSCT, hematopoietic stem cell transplantation; mo, months; MRD, minimal residual disease; OS, overall survival; Ph, Philadelphia chromosome; RFS, relapse-free survival; R/R ALL, relapsed or refractory acute lymphoblastic leukemia; TKI, tyrosine kinase inhibitors (imatinib and/or dasatinib); TRM, therapy-related mortality.

Figure 2 PD-L1 expression is a possible escape mechanism for the action of blinatumomab.

Notes: (A) An in vitro study observed a higher expression of the T-cell exhaustion marker PD-1 in ALL patients compared to healthy controls. PD-1/PD-L1-mediated T-cell suppression could lead to resistance to blinatumomab therapy. (B) With the simultaneous application of a specific PD-1 inhibitor, the PD-1/PD-L1-mediated T-cell suppression could be abrogated restoring the activity of blinatumomab.
Abbreviation: ALL, acute lymphoblastic leukemia.

Table 2 Clinical trials in ALL that are currently recruiting

Phase	Sponsor	Clinical trial identifier	Condition	Concomitant medication	Primary end point
I/II	Amgen	NCT02412306	Japanese adults with R/R ALL		Phase I: DLT, II: CR
II	M.D. Anderson cancer center	NCT02877303	Primary diagnosed Ph-neg. ALL ≥14 years	Sequentially with Hyper-CVAD	RFS
II	M.D. Anderson cancer center	NCT02458014	Adult patients in CR1 or CR2 with MRD nonresponse or relapse	None	RFS
II	M.D. Anderson cancer center	NCT02807883	Maintenance after allogeneic HSCT in adults	None	Toxicity, GvHD, graft failure
II	National Cancer Institute	NCT02143414	Primary diagnosed patients ≥65 years ± Ph+	Combination chemotherapy or dasatinib + prednisone	DLT, OS
III	Amgen	NCT02393859	Pediatric patients with 1. High risk relapse	Comparison with standard combination chemotherapy	EFS
III III	National Cancer Institute National Cancer Institute	NCT02101853 NCT02003222	Patients from 1 to 30 years with relapsed ALL Primary diagnosed Ph-neg. adults	Comparison with standard combination chemotherapy ± HSCT ± standard combination chemotherapy	DFS OS

Abbreviations: CR, complete remission; CVAD, course A: cyclophosphamide, vincristine, dexamethasone, course B: methotrexate, cytarabine; DLT, dose limiting toxicity; EFS, event-free survival; GvHD, graft vs host disease; HSCT, hematopoietic stem cell transplantation; MRD, minimal residual disease; OS, overall survival; Ph, Philadelphia chromosome; RFS, relapse-free survival; R/R ALL, relapsed or refractory acute lymphoblastic leukemia.

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