Introduction
Mechanism of action for CD19-targeted BiTE therapy
Administration, dosing, and safety
Administration
Continuous intravenous infusion
Subcutaneous administration
Indication | Clinical study | Study phase | Study therapy | Completion year |
---|---|---|---|---|
BCP-ALL | Blinatumomab in Adult Patients With Minimal Residual Disease (MRD) of B-precursor Acute Lymphoblastic Leukemia (NCT03109093) | Phase 2 | Blinatumomab (AMG103) | Recruiting (2020) |
BCP-ALL | Treatment of Older Patients With B-precursor ALL With Sequential Dose Reduced Chemotherapy and Blinatumomab (EWALL-BOLD) (NCT03480438) | Phase 2 | Blinatumomab (AMG103) plus SOC chemotherapy | Recruiting (2020) |
BCP-ALL | Allogeneic Donor Lymphocyte Infusions Combined With Blinatumomab (DLI-TARGET) (NCT03982992) | Phase 2 | Blinatumomab (AMG103) in combination with donor lymphocyte infusion | Recruiting (2020) |
r/r B-cell NHL | A Phase II Study Of Blinatumomab For The Treatment Of Relapsed Or Refractory Indolent Non-Hodgkin Lymphoma (NCT02811679) | Phase 2 | Blinatumomab (AMG103), autologous stem cell transplant, Carmustine, Etoposide, Cytarabine, Melphalan | Recruiting (2020) |
R/R B-cell NHL | A Phase 1b Open-Label Study Investigating the Safety and Pharmacokinetics of Administration of Subcutaneous Blinatumomab for the Treatment of Relapsed/Refractory Indolent Non-Hodgkin's Lymphoma (NCT02961881) | Phase 1b | Blinatumomab (AMG103) | Recruiting (2020) |
DLBCL | Blinatumomab Consolidation Post Autologous Stem Cell Transplantation in Patients With Diffuse Large B-Cell Lymphoma (DLBCL) (NCT03072771) | Phase 1 | Blinatumomab (AMG103) | Recruiting (2020) |
Dosing
Safety
Impact of tumor burden
Efficacy of blinatumomab in BCP-ALL (Table 2)
Adults with BCP-ALL in CR with MRD
Pivotal study | Study population | Primary outcome | Other key outcomes |
---|---|---|---|
NCT02013167 (TOWER) [43] | R/R Ph– BCP-ALL (Adult) | Median OS: 7.7 months (95% CI, 5.6–9.6 months) | CR within 12 weeks of treatment initiation: 91/267 (34%) (95% CI, 28.0–39.5%; p < 0.001) CRh within 12 weeks of treatment initiation: 119/267 (44%) (95% CI, 37.9–50.0%; p < 0.001) EFS (6-month estimate): 31% MRD remission (defined as an MRD level below 0.0001): 76% Adverse events (grade ≥ 3): 231/267 (87%) |
NCT01466179 (Study MT103-211) [40] | R/R Ph– BCP-ALL (Adult) | CR or CRh: 81/189 (43%) (95% CI, 36–50%) within the first two cycles of treatment | Median RFS in patients with CR/CRh: 5.9 months (95% CI, 4.8–8.3 months) Median OS: 6.1 months (95% CI, 4.2–7.5 months) alloHSCT after blinatumomab-induced remission: 32/81 (40%) 100-day mortality following alloHSCT: 11% (95% CI, 0–23%) MRD response: 60/73 (82%) (95% CI, 72–90%) Adverse events (grade ≥ 3): 71 (38%) |
NCT01207388 (BLAST) [39] | MRD-positive BCP-ALL (Adult) | Complete MRD response: 88/113 (78%) patients after one cycle of treatment | Median OS: 36.5 months (95% CI, 19.8 months to not estimable) Median RFS: 18.9 months (95% CI, 12.3–35.2 months) Duration of hematologic remission: not reached |
NCT02000427 (ALCANTARA) [49] | R/R Ph+ BCP-ALL (Adult) | CR or CRh: 16/45 (36%) (95% CI, 22–51%) within the first two cycles of treatment | Complete MRD response: 14/16 (88%) (95% CI, 62–98%) during the first two cycles of treatment Median RFS: 6.7 months (95% CI, 4.4 months to not estimable) Median OS: 7.1 months (95% CI, 5.6 months to not estimable) alloHSCT after blinatumomab-induced remission: 4/16 (25%) (95% CI, 7–52%) Adverse events (grade ≥ 3): 37/45 (82%) |
NCT01471782 (Study MT103-205) [29] | R/R BCP-ALL (Pediatric) | Maximum-tolerated dosage: 15 mg/m2/day CR: 27/70 (39%) (95% CI, 27–51%) | Median RFS in responders (n = 27): 4.4 months (95% CI, 2.3–7.6 months) Median OS (n = 70): 7.5 months (95% CI, 4.0–11.8 months) alloHSCT after blinatumomab treatment: 24/70 (34%) Complete MRD response (< 10–4): 14/27 (52%) (95% CI, 32–71%) Adverse events (grade ≥ 3): 61 (87%) |
Adults with R/R BCP-ALL
Children and adolescents with R/R BCP-ALL
BCP-ALL subtypes
Combination and sequential therapies
Study | Study phase | Indication | Other study drug | Class of other study drug |
---|---|---|---|---|
D-ALBA Frontline Sequential Dasatinib and Blinatumomab in Adult Philadelphia Positive Acute Lymphoblastic Leukemia [61] | Phase 2 | (Ph+) BCP-ALL, (Ph-like BCP-ALL) | Dasatinib | TKI |
Blinatumomab and Combination Chemotherapy or Dasatinib, Prednisone, and Blinatumomab in Treating Older Patients With Acute Lymphoblastic Leukemia | Phase 2 | (R/R Ph+ and Ph−) BCP-ALL | Dasatinib, prednisone, vincristine, methotrexate, 6-mercaptopurine | TKI plus chemotherapy |
Relapsed Philadelphia chromosome-positive pre-B-ALL after CD19-directed CAR-T cell therapy successfully treated with combination of blinatumomab and ponatinib | N/A | (R/R Ph+) BCP-ALL | Ponatinib | TKI |
Chemoimmunotherapy with inotuzumab ozogamicin combined with mini-hyper-CVD, with or without blinatumomab in patients with Philadelphia chromosome-negative acute lymphoblastic leukemia in first salvage | N/A | R/R (Ph−) ALL | Inotuzumab ozogamicin | Monoclonal antibody |
Blinatumomab in combination with immune checkpoint inhibitors of PD-1 and CTLA-4 in adult patients with relapsed/refractory (R/R) CD19 positive B-cell acute lymphoblastic leukemia (ALL) [57] | Phase 1 | R/R BCP-ALL | Nivolumab/ipilimumab | Monoclonal antibody (checkpoint inhibitors) |
A phase I/II study of blinatumomab in combination with pembrolizumab for adults with relapsed refractory B-lineage acute lymphoblastic leukemia: University of California Hematologic Malignancies Consortium Study 1504 [58] | Phase 1/2 | R/R BCP-ALL | Pembrolizumab | Humanized antibody (checkpoint inhibitor) |
Treatment Protocol for Children and Adolescents With Acute Lymphoblastic Leukemia - AIEOP-BFM ALL 2017 (NCT03643276) | Phase 3 | BCP-ALL | Multiple | Chemotherapy/other |
Blinatumomab plus PD-1 and CTLA-4 inhibitors in R/R BCP-ALL
Blinatumomab plus TKIs in Ph+ R/R BCP-ALL
Blinatumomab use in frontline BCP-ALL therapy in older patients
Blinatumomab use in first-salvage, mini-HCVD, and inotuzumab in BCP-ALL therapy
Efficacy of CD19-targeted BiTE molecules in B cell NHL
Blinatumomab
Modes of resistance with CD19-directed therapies
Antigen escape
Dysregulated immune checkpoint pathways and T cell exhaustion
Lineage switch
Health economics and outcomes of CD19 therapies
BiTE (bispecific T cell engager) technology | Chimeric antigen replacement (CAR) T cell therapy | |
---|---|---|
Structure | A recombinant protein comprising two linked single-chain variable fragment capable of binding to the specified tumor antigen and CD3 on T cell | A construct encoding an scFv against the specified tumor antigen (i.e., CD19 and co-stimulatory domain) |
Availability | “Off-the-shelf” product; available immediately to any patient | Requires manufacturing per each individual ~ 4 weeks [84] |
Persistence | One infusion, expansion in vivo, may persist for years | |
Clinical use | Pretreatment with dexamethasone or prednisone required to manage CRS [17] | Pretreatment lymphodepleting regimen required to enhance CAR T-cell expansion and efficacy and tocilizumab must be available to manage CRS [32] |
Efficacy | BCP-ALL: see Table 2 R/R DLBCL: ORR, 43% (9/21); median PFS, 3.7 months (95% CI, 1.4–7.7); CR rate, 19% (4/21) [24] R/R NHL: CMR, 22% (9/41); ORR, 37% (15/41) [30] | Tisagenlecleucel R/R BCP-ALL (pediatric to young adult): overall remission rate, 81% (61/75); 66% on an intention-to-treat analysis [35] R/R DLBCL: ORR, 52% (48/93) [34] Axicabtagene ciloleucel R/R DLBCL: ORR, 82% (63/77) [33] |
Toxicity | CRS, neurotoxicity | CRS, neurotoxicity, HLH |