Table 2 Clinical advances of blinatumomab in the treatment of B-cell malignancies

GMALL (original study NCT00198991, follow-up study NCT00198978)

2

Adults (≥18 years) with MRD-positive B- ALL

21 (20 evaluable for response)

Continuous IV infusion at a dose of 15 μg/m² /d

MRD-negative response rate: 80% (16/20) 5-year RFS rate: 50% (10/20) Median RFS: 19.1 months in 16 MRD responders; 3.2 months in 4 nonresponders CR in HSCT patients: 5/9 CR in non-HSCT patients: 5/11

Grade ≥ 3 AEs: 81% Grade 3 CNS AEs: 19%

[32,33,34]

BLAST (NCT01207388).

2

Adults with MRD-positive B-ALL

116 (113 evaluable for response)

Continuous IV infusion at a dose of 15 μg/m² /d

MRD-negative response rate: 78% (88/113) 18 months RFS rate: 54% Median RFS: 18.9 months Median OS: 36.5 months 25% patients without HSCT after blinatumomab remained in continuous CR 49% with HSCT remained in continuous CR

Grade ≥ 3 AEs: 60% Any grade CRS: 3%

Grade ≥ 3 CRS: 2% Any grade CNS AEs: 53% Grade ≥ 3 CNS AEs: 13%

[35, 36]

NCT02412306

1/2

Japanese adults with R/R Ph-negative B-ALL

26

Continuous IV infusion at a dose of 9 μg/m² /d for the first 7 days and 28 μg/m² /d thereafter

Phase 1b:

CR/CRh rate: 80% (4/5)

MRD-negative response rate in responders: 100% (4/4)

Phase 2:

CR/CRh rate: 38% (8/21)

MRD-negative response rate in responders: 38% (3/8)

Median RFS: 5 months

Grade ≥ 3 AEs: 96%

Any grade CRS: 46%

Grade ≥ 3 CRS: 4%

Any grade CNS AEs: 46% Grade ≥ 3 CNS AEs: 5%

[37]

NCT01209286

2

Adults with R/R Ph-negative B-ALL

36

Continuous IV infusion at a dose of 5–30 μg/m² /d

CR/CRh rate: 69%(25/36) MRD-negative response rate in responders: 88% (22/25) Median OS: 9.8 months Median RFS: 7.6 months

CNS AEs requiring intervention: 17%

Grade ≥ 3 CRS: 6%

[38]

NCT01466179

2

Adults (≥18 years) with R/R Ph-negative B-ALL

189

Continuous IV infusion from 9 to 28 μg/m²/d

CR/CRh rate: 43%(81/189) MRD-negative response rate in responders: 82% (60/73) Median OS: 6.1 months Median RFS: 5.9 months

Grade ≥ 3 AEs: 83% Grade ≥ 3 CRS: 2%

Any grade CNS AEs: 52% Grade ≥ 3 CNS AEs: 13%

[39]

TOWER (NCT02013167)

3

Adults (≥18 years) with R/R Ph-negative B-ALL

405 (271 for blinatumomab, 134 for chemotherapy)

Continuous IV infusion from 9 to 28 μg/m²/d

Median OS: 7.7 vs. 4.0 months CR rate: 34% vs. 16%; CR/CRh/CRi rate: 44% vs. 25% 6-month EFS: 31% vs. 12% Median DOR: 7.3 vs. 4.6 months

Grade ≥ 3 AEs: 87% vs. 92% Grade ≥ 3 CNS AEs: 9.4% vs.8.3%

Grade ≥ 3 CRS: 4.9% vs. 0% (blinatumomab vs. chemotherapy)

[40]

RIALTO (NCT02187354)

Expanded Access

Children (≤17 years) with R/R B-ALL

110 (98 evaluable for response)

≤ 25% blasts: 15 μg/m²/d

> 25% blasts: 5 μg/m²/d for first 7 days, 15 μg/m²/d thereafter,

CR rate: 59% (58/98)

MRD-negative response rate in responders: 79% (46/58)

Median OS:13.1 months

Median RFS: 8.5 months 62% (36/58) proceeded to HSCT after achieving CR

Grade ≥ 3 AEs: 65%

Grade ≥ 3 CRS: 3%

Any grade CNS AEs: 42%

Grade ≥ 3 CNS AEs: 5.5%

[41]

MT103–205 (NCT01471782)

1/2

Children (≤17 years) with R/R B-ALL

94 (70 evaluable for response)

Continuous IV infusion from 5 to 15 μg/m²/d

CR rate: 39% (27/70) MRD-negative response rate in responders: 52% (14/27) 48% (13/27) proceeded to HSCT after achieving CR

Grade ≥ 3 AEs: 87%

Any grade CRS: 11%

Grade ≥ 3 CRS: 6%

Any grade CNS AEs: 24%

Grade ≥ 3 CNS AEs: 4%

[42]

NCT02000427

2

Adults (≥18 years) with R/R Ph-positive B-ALL

45

Continuous IV infusion from 9 to 28 μg/m²/d

CR/CRh rate: 36%(16/45) MRD-negative response rate in responders: 88% (14/16) Median OS: 7.1 months Median RFS: 6.7 months 44% (7/16) proceeded to HSCT after achieving CR

Grade ≥ 3 AEs: 82%

Any grade CRS: 7%

Grade ≥ 3 CNS AEs: 7%

[43]

MT103–104 (NCT00274742)

1

Adults (≥18 years) with R/R B-NHL

76

Dose-escalation: 0.5–90 μg/m²/d Dose-expansion: 60 μg/m²/d

Patients with dose of 60 μg/m2/d: ORR: 69% across NHL subtypes and 55% for DLBCL

Median DOR: 404 days Median OS in overall population: 4.6 years Median OS in responders: 7.7 years Median OS in nonresponders: 1.1 years

Grade 3, 4, and 5 AEs: 90, 66, and 4%, respectively

Any grade CNS AEs: 71% Grade 3 CNS AEs: 22%

[44, 45]

NCT02910063

2

Adults with R/R B-NHL

41

Continuous IV infusion from 9 to 28 to 112 μg/d

ORR: 37% (15/41) including CMR: 22% (9/41) and PMR: 15% (6/41)

HSCT was performed in 53.3% (8/15) responders.

Grade ≥ 3 AEs: 71%

Grade ≥ 3 CRS: 2%

Any grade CNS AEs: 56% Grade ≥ 3 CNS AEs.: 24%

[46]

NCT01741792

2

Adults with R/R B-DLBCL

25 (21 evaluable for response)

Cohort I + III: Stepwise dose 9 to 28 to 112 μg/d

Cohort II: Flat dose 112 μg/d

Patients with dose of 112 μg/d at least 1 week:

ORR: 43% (9/21)

CR rate: 19% (4/21)

Cohort I: n = 23 Grade ≥ 3 AEs: 95.7%

Any grade CRS: 0% Grade ≥ 3 CNS AEs: 22%

Cohort II: n = 2 Grade ≥ 3 CNS AEs: 100%

[47]