Decitabin (1) – Dacogen®

• Clinical trials
  • The assessment of the extent of the additional benefit of decitabine is based on the DACO-016 trial.
  • The DACO-016 trial is a phase III, multicentre, randomised, controlled, open-label comparative trial.
  • In the treatment arm, decitabine 20 mg/m² was administered as a one-hour intravenous infusion on five consecutive days (treatment cycle) every four weeks.
  • In the control arm, the patients’ treatment of choice (Treatment Choice, TC) was administered following medical consultation.

adult patients aged 65 years and over with newly diagnosed de novo or secondary acute myeloid leukaemia (AML) according to the World Health Organisation (WHO) classification, for whom standard induction therapy is not an option

• For adult patients aged 65 years and over with newly diagnosed de novo or secondary acute myeloid leukaemia (AML) according to the World Health Organisation (WHO) classification, for whom standard induction therapy is not an option, there is a minor additional benefit.
• The G-BA classifies the extent of the additional benefit of decitabine as minor, based on the criteria in Section 5(7) of the AM-NutzenV, taking into account the severity of the disease and the therapeutic objective in the treatment of the disease.
• In accordance with Section 5(7) in conjunction with Section 2(3) of the AM-NutzenV, this represents a moderate – and not merely minor – improvement in treatment-related benefit with regard to outcomes in the endpoint category of mortality/overall survival.
• mortality
  • In the DACO-016 study, ‘overall survival’ was assessed as the primary endpoint.
  • At the primary analysis date (CCO 2009), there was a trend towards a prolonged median overall survival (2.7 months) in the decitabine group compared with the TC group, which was not statistically significant (HR = 0.85; 95% CI [0.69; 1.04]).
  • For this supplementary analysis (CCO 2010), the results showed no change in median survival time; however, based on a log-rank test, they reached statistical significance.
  • The Kaplan–Meier curves intersect in this case, which makes it difficult to interpret the results.
  • The survival benefit of decitabine compared with the comparator therapy is almost exclusively observed in Eastern European patients (45.8% of the included patients), whilst no effect was observed in France, Spain, the United States of America, Australia, Canada and Taiwan.
  • The reasons for this difference are unclear; however, it cannot be ruled out that regional differences in supportive care and the management of patients with AML have contributed significantly to this, meaning that the applicability of the overall study data to the situation in Germany is limited and the median survival benefit observed in the overall study for patients in Germany could be less than 2.7 months.
  • For the endpoint of mortality, the G-BA therefore assesses the extent of the additional benefit as minor, even taking into account the severity of the disease.
  • The uncertainties in the statistical analysis and the questionable transferability of the overall study data to the German healthcare context suggest a potentially minor effect size in Germany, meaning that both the relative (HR) and the absolute (median survival benefit) advantages of decitabine over the comparator therapy may be minor compared to the overall study data.
  • A median overall survival benefit of up to a maximum of 2.7 months represents a moderate—and not merely minor—improvement in treatment-related benefit that has not been achieved to date.
• Morbidity – Complete remission (CR)
  • A complete remission (CR) associated with a noticeable reduction in disease symptoms for the patient is clinically relevant.
  • The endpoint ‘complete remission’ is an important prognostic factor and relevant to treatment decisions.
  • The operationalisation of CR in the DACO-016 study includes morphological criteria – primarily the blast count – as well as the criterion of being transfusion-independent for at least one week prior to the confirmation of complete remission.
  • The short period of just one week’s transfusion independence does not allow for an assessment of the patient-relevance of the CR endpoint.
  • No statistical comparison between the treatment arms was carried out for the CR endpoint.
  • Furthermore, data on the duration of CR are lacking.
  • The validity of the other response-related endpoints listed in the dossier is unclear.
  • Furthermore, no analyses are available for a high proportion of patients.
  • On the basis of the response-related endpoints (including CR), no conclusions can be drawn regarding morbidity and thus regarding the quantification of the extent of the patient-relevant additional benefit.
• Morbidity – Independence from transfusions
  • Transfusion independence is not a predefined endpoint of the study, but was routinely recorded at specified time points throughout the course of the study and evaluated post-hoc.
  • It is a criterion of the CR and is adequately taken into account by it.
  • This endpoint is therefore not taken into account for the present assessment.
• Quality of life – overall health status/quality of life (Global Health/Quality of Life Status) and fatigue
  • Data from the oncology-specific, cross-disease patient questionnaire EORTC QLQ-C30 are available for decitabine to assess the additional benefit in terms of quality of life.
  • The analyses available cover the ‘Overall Health/Quality of Life Status’ subscale (questions 29 and 30 of the EORTC questionnaire) and for the fatigue subscale (questions 10, 12 and 18 of the EORTC questionnaire).
  • At the defined assessment time point (day 1 of the third cycle), no statistically significant differences were observed between the treatment arms.
  • Due to the minor response rate for the questionnaires (69.1%), no valid conclusions can be drawn regarding the extent of the additional benefit for the ‘quality of life’ endpoint.
• Side effects
  • The positive effects of decitabine are offset by adverse events.
  • In the DACO-016 study, the proportion of patients who experienced at least one adverse event was largely comparable across the groups.
  • The proportions were also comparable for study discontinuations and deaths due to adverse events.
  • For serious adverse events, including in particular febrile neutropenia and pneumonia, the proportions were higher in the intervention arm.
  • Myelosuppression and adverse events associated with myelosuppression (in particular thrombocytopenia, anaemia and febrile neutropenia) are also typical of the untreated disease, but occur more frequently with decitabine.
  • Overall, the side effects are classified as significant for patients, but predominantly as manageable and treatable.
  • Particularly when taking into account the current severity of the disease and the lack of treatment options, these significant side effects do not, in the G-BA’s assessment, lead to a downgrading of the extent of the additional benefit.

Courtesy translation only, please refer to the German original.