Zulassungsstudien

TOWER study - In the randomised, open-label, phase 3 study the efficacy of Blinatumomab has been investigated against standard of care backbone-chemotherapy in patients with relapsed or refractory B-precursor-ALL (with >5% blasts in bone marrow and relapsed at one time after allogenic HSCT, untreated first relapse after a first remission phase of ≤12 months or refractory to last therapy).
Randomisation (2:1) was stratified by age (<35 yrs vs ≥35 yrs), prior salvage-theapies and prior HSCT. Overall survival (OS) was the 1° endpoint.
    Efficacy results (Kantarjan et al. N Eng J Med 2017):1
  • OS was significantly longer in the Blinatumomab group than in the SOC chemotherapy group. The median overall survival was 7.7 months in the Blinatumomab group and 4.0 months in the chemotherapy group (HR 0.71; 95% CI: 0.55, 0.93; P = 0.012).
  • Remission rates within 12 weeks after treatment initiation were significantly higher in the Blinatumomab group than in the chemotherapy group, both with respect to complete remission with full hematologic recovery (34% vs.16%, P<0.001) and with respect to complete remission with full, partial, or incomplete hematologic recovery (44% vs. 25%, P<0.001).
  • Higher complete remission rate in the Blinatumomab group than in the SOC group with full hematologic recovery (34% vs. 16%, P<0.001), resp. with incomplete hematologic recovery (44% vs. 25%, P<0.001).
  • Higher rate of event-free survival in the Blinotumomab arm compared to the SOC chemotherapy arm (31% vs. 12%; HR 0.55; 95% CI: 0.43, 0.71; P<0.001), and longer median duration of remission with Blinatumomab (7.3 vs. 4.6 months with SOC chemotherapy).
  • 76% of the responders achieved molecular remission in the Blinatumomab arm.
    Safety results (Kantarjan et al. N Eng J Med 2017):1
  • Serious Adverse Events (sAEs) were reported and included neurologic events, Cytokine Release Syndrome, events with administration.
  • There were a few AEs Grade ≥3 neutropenia and infections and similar frequent AEs of Grade ≥3 neurologic events with Blinatumomab.
  • Cytokine Release Syndrome in the Blinatumomab arm were reported as sAEs in 4%, and of Grade ≥3 in 5% of patients.
TOWER study
(Kantarjan et al. N Engl J Med 2017)

The additional benefit regarding OS and remission with Blinatumomab was independent of prior salvage therapy and was consistent over the various salvage stages. OS and remission

were in both arms better in the group without salvage therapy than in the salvage group. Patients with prior salvage therapy received more often an alloHSCT after Blinatumomab than after SOC. (Analysis by Dombret et al. EHA 2017)

TOWER by 1st salvage
(Dombret et al. EHA 2017)

Further analyses from TOWER:
TOWER by HSCT
(Gökbuget et al. EBMT Annual Meeting 2018)
Blinatumomab maintenance therapy after hematologic remission (Rambaldi et al. ASH 2017)
Quality of Life with Blinatumomab treatment (Topp et al. ASH 2017)
Baselines biomarkers on outcomes with Blinatumomab treatment (Wei et al. ASH 2017)
BLAST Study - Blinatumomab in adult patients with MRD positive B-cell-precursor ALL
Efficacy and safety of Blinatumomab were investigated in an open, single arm, multicentric study. Patients were ≥ 18 years, with a minimum of 3 blocks of standard-induction therapy against ALL, were in complete hematologic remission and had a molecular treatment failure or a molecluar relapse (defined as MRD ≥ 10-3).
1° Endpoint: MRD negativity after first cycle with Blinatumomab.
    2° Endpoints:
  • Hematologic Relapse Free Survival (RFS) at month 18; OS; time to hematologic relapse; duration of MRD-negativity
  • Incidence and seriousness of AEs
    Efficacy results (Gökbuget et al. Blood 2018):2
  • Complete MRD response after 1st cycle was 78% (88 of 113 patients).
  • Two more patients showed after 2 treatment cycles an MRD-response; there were no further responses after 3 or 4 treatment cycles.
  • Blinatumomab induced a high rate of MRD-negativity (80%).
  • RFS was 54% and the median RFS and OS were 18.9 months, resp. 36.5 months.
  • More patients with first CR (CR1) reached RFS with longer duration of response with a median of 24.6 months (18.7–NR) compared to patients with late CRs (11.0 mo (6.8–15.4)).
  • The transplant-rate was 67% in patients with continuous CR post Blinatumomab; the role of subsequent HSCT in this study is unclear.
  • A landmark analysis of the BLAST study showed that complete MRD responders had a significantly longer RFS and overall survival compared with MRD non-responders.
    Safety results: (Gökbuget et al. Blood 2018):2
  • Blinatumomab has been generally well tolerated, and the most (all grades) were pyrexia (89%), headache (38%), tremor (18%) and neutropenia (16%).
  • 10% and 3% of patients had grade 3 and 4 neurological AEs. 3% of patients had CRS (2 grade 1 cases, 2 grade 3 cases), all in the first cycle.
BLAST study
(Gökbuget et al. Blood 2018)

Blinatumomab pediatric study: von Stackelberg3

Phase 1/2 Maximum Tolerated Dose and Efficacy study of Blinatumomab in pediatric patients with relapsed/refractory ALL.
    Efficacy results:
  • Blinatumomab has anti-leukaemic activity in heavily pre-treated pediatric patients with r/r ALL, including ability to induce MRD-negative remissions
    - Most patients were refractory or had relapsed after HSCT; 71% of patients had relapsed within 6 months of the last salvage treatment
    - 39% of patients achieved CR, and 52% of these became MRD-negative
  • Blinatumomab has the potential to provide a bridge to HSCT
    - 48% of patients achieving CR went on to receive alloHSCT
    Safety results:
  • Adverse events associated with Blinatumomab treatment consistent with previous experience in this disease setting
  • Low incidence of severe CRS (any grade: 11% pts; ≥ grade 3: 6% pts) and neurological events (≤ grade 2: 20% pts; grade 3: 4% pts).
Blinatumomab pediatric study Von Stackelberg
For further information please contact MedInfo
Abbreviations: Overall Survival (OS); Month (Mo); Hazard Ratio (HR); versus (vs); Week (Wk); Standard of Care (SOC); Relapse Free Survival (RFS)

References:
  1. Kantarjian H, et al. N Engl J Med. 2017;376:836–47
  2. Gökbuget N, et al. Blood. 2018;131(14):1522-1531
  3. von Stackelberg A, et al. J Clin Oncol 2016;34:4381–9

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