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, Amgen30 | 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, Amgen28,29 | 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, Amgen7 | 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/m2/d for 1 week followed by 15 µg/m2/d for 3 weeks, second cycle after 2 weeks off starting with 15 µg/m2/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, Amgen37,53 | 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/m2/d for 1 week followed by 15 µg/m2/d for 3 weeks, next cycle after 2 weeks off starting with 15 µg/m2/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, Amgen26,42,54 | 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/m2/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.