Blinatumomab (6) – Blincyto®

• Clinical trials
  • Study 20120215 is an ongoing, international, multicentre, randomised, controlled, open-label Phase III trial investigating the efficacy, safety and tolerability of blinatumomab as consolidation therapy compared with high-risk consolidation chemotherapy (HC) in paediatric patients with high-risk first relapse of Ph- CD19+ B-progenitor ALL.

paediatric patients aged 1 year or older with high-risk first relapse of Philadelphia chromosome-negative, CD19-positive B-progenitor ALL as part of consolidation therapy

• On balance, the G-BA concludes that, in particular due to the extent of the prolongation in survival and in view of the available findings on event-free survival and side effects, which overall support the additional benefit, for paediatric patients aged 1 year or older with high-risk first relapse of Philadelphia chromosome-negative, CD19-positive B-progenitor ALL, as part of consolidation therapy, there is a major additional benefit of blinatumomab compared with HC3.
• The certainty of evidence for the observed additional benefit is classified as an indication.
• mortality
  • Overall survival is a secondary endpoint of study 20120215 and is defined as the period from the time of randomisation until death from any cause.
  • For the endpoint of overall survival, the corresponding results from both data cuts show a statistically significant difference between the treatment arms in favour of blinatumomab.
  • The results show a statistically significant difference in overall survival in favour of blinatumomab compared with HC3, to an extent that is assessed as a very marked improvement.
• Morbidity – Event-Free Survival
  • Event-free survival (EFS) is the primary endpoint of study 20120215 and is defined as the time from randomisation until any cause of treatment failure, defined as: a relapse or the presence of an M2-type bone marrow status (≥ 5 % to < 25 % blasts in the bone marrow) following achievement of a CR, or failure to achieve a CR at the end of treatment, or a secondary tumour, or death from any cause, whichever occurred first.
  • The results for the EFS endpoint show a statistically significant advantage of blinatumomab compared with HC3.
  • Overall, based on the operationalisation and results for the EFS endpoint, and even taking into account the described uncertainty, sufficiently robust conclusions regarding patient-relevant therapeutic effects can be drawn.
• Morbidity – MRD remission
  • The MRD remission rate within a treatment cycle was determined by PCR analysis or flow cytometry, based on a reduction in leukaemia cells to < 10⁻⁴ (fewer than one leukaemia cell per 10,000 normal cells) at the end of treatment.
  • The endpoint ‘MRD negativity’ is classified as an endpoint of unclear relevance and is presented as supplementary information.
• quality of life
  • No data on health-related quality of life were collected in study 20120215.
• Side effects – Adverse events (AEs)
  • Overall, adverse events occurred in all patients in the blinatumomab arm and in 96.1% of patients in the HC3 arm.
  • The results for the endpoint ‘adverse events’ (AE) are presented as supplementary data.
• Side effects – Serious adverse events (SAE)
  • For serious adverse events, there is a statistically significant difference in favour of blinatumomab.
  • In detail, for SAEs, there was an increased risk for the SOC ‘Blood and Lymphatic System Disorders’ and the PT ‘Febrile Neutropenia’ under HC3 compared with blinatumomab.
• Side effects – Severe AEs (CTCAE grade ≥ 3)
  • With regard to severe adverse events with a CTCAE grade of ≥ 3, blinatumomab showed a statistically significant advantage over HC3.
  • Specifically, the severe AEs ‘Blood and lymphatic system disorders’ and ‘Gastrointestinal disorders’ occurred statistically significantly less frequently with blinatumomab than with HC3; the severe AEs ‘General disorders and administration site conditions’ occurred at a statistically significantly higher rate with blinatumomab.
• Side effects – discontinuation due to AEs
  • For the endpoint ‘discontinuation due to AEs’, only descriptive analyses are available.
  • Treatment with blinatumomab was discontinued in two patients due to AEs. The triggers for this were a nervous system disorder in one patient and the occurrence of seizures in another.
• Side effects – AEs of particular interest
  • In summary, with regard to AEs of particular interest, there was an increased risk of infusion reactions and neurological events with blinatumomab, whilst in the HC3 group there was an increased risk of neutropenia and elevated liver enzymes.
• Overall assessment / Conclusion
  • For the overall survival endpoint, there was a statistically significant difference in favour of blinatumomab compared with HC3, to an extent that is considered a very marked improvement.
  • The results for the EFS endpoint show a statistically significant advantage of blinatumomab compared with HC3.
  • No data were collected on health-related quality of life.
  • In the overall analysis of side effect endpoints, there is a statistically significant advantage for blinatumomab with regard to both severe adverse events (CTCAE grade ≥ 3) and severe unclassified events. In the category of side effects, a significant advantage of blinatumomab over HC3 is observed in the overall analysis.
  • In its overall assessment, the G-BA concludes that, particularly given the extent of the prolongation in survival and in view of the available results on event-free survival and side effects, which collectively support the additional benefit, for paediatric patients aged 1 year or older with high-risk first relapse of Philadelphia chromosome-negative, CD19-positive B-progenitor ALL, as part of consolidation therapy, a major additional benefit of blinatumomab over HC3 has been established.

Courtesy translation only, please refer to the German original.