Background
• Acquired aplastic anemia – primary bone marrow failure with
pancytopenia (probable underlying autoimmune pathology)
• Standard of care – Anti Thymocyte globulin + cyclosporine (2/3
patients respond)
• Elthrombopag ( oral thrombopoetin receptor agonist) was shown to
increase efficacy of standard therapy in a phase 1-2 study.
Study design
• Randomized
• Phase 3 trial
• Open-label
• Multicentre
• Funding: Novartis, Pfizer, Alexion Pharma, Cancer Research UK, Bloodwise UK
Objective
• To investigate whether Eltrombopag added to standard
immunosuppressive treatment increases the rate of early (at three
months) complete response in untreated AA patient.
• Population: Newly diagnosed aplastic anemia
• Intervention: ATG + cyclosporine + Eltrombopag (150 mg OD from
Day 14-90)
• Control: ATG + cyclosporine
• Outcome: Haematological response at 3 months
• Time: 24 months
Was the study population clearly defined?
• Yes
Inclusion criteria
• Diagnosis of severe or very severe aplastic anemia, defined by :
At least two of the following:
1. – Absolute neutrophil counts <0.5 x 109/L (severe) or <0.2 x 109/L (very
severe)
– Platelet counts <20 x 109/L
– Reticulocyte counts <60 x 109/L
2. Hypocellular bone marrow (<30% cellularity), without evidences of fibrosis
or malignant cells
• Age ≥ 15 years;
• Written informed consent
Exclusion criteria
• Prior immunosuppression • Breast feeding
(ATG/alemtuzumab) • Hepatic/renal/cardiac failure
• Eligibility for sibling stem cell
• HIV
transplantation
• MDS • Without social health care assistance
• Fanconi anemia/Dyskeratosis congenita • Another clinical trial 1 month prior to
start of this trial
• h/o malignant tumors with chemo in
the last 5 years • Not on highly effective birth control
• h/o stem cell transplantation • Known hypersensitivity to trial drugs
• Cyclosporin < 2 weeks prior to • WHO performance score >3
enrollment • CMV viremia
Were the outcome measures clearly defined?
• Yes
Primary outcome
• Rate of Complete response (defined as Hb >10 g/dL, ANC > 1,000/μL
and Plt >100,000 μL) at 3 months since start of treatment in untreated
severe AA patients.
Secondary outcomes
• Time to first response • Cumulative incidence of clonal
• Time to best response evolution
• Time to complete response • Cumulative incidence of PNH
• Rates of response at 3,6,12,18 • Cumulative incidence of
and 24 months discontinuation of
immunosuppressive therapy
• Overall survival probability
• Need for transfusions
• Event free survival probability
• Need for supportive care
• Cumulative incidence of relapse
• Quality of life - EORTC QLQ C30
Were adequate number of people included in
the study?
• Hypothesis -> increase treatment response at 3 months by 21%
(expected -7%)
Power – 80%
Alpha – 0.05
Sample size – 96 in each arm
(4% loss to follow up)
100 in each arm
How serious was the risk of bias?
Did the intervention and control groups start with the
same prognosis?
Were the patients randomised?
• Yes
• 1:1
• Stratified based on age and disease severity
• Clinical Trials Management system
Was the allocation concealed?
• Yes
Were patients in the study groups similar with
respect to known prognostic factors?
Was prognostic balance maintained as the
study progressed?
To what extent was the study blinded?
• Open label
• Statistical analysis blinded
Were the groups prognostically balanced
at the study’s completion?
Was the follow up complete?
• Yes
Was the trial stopped early?
• No
Were the patients analysed in the groups to
which they were randomised?
• Yes
Validity of the study
•
Study population: well defined
•
Outcomes: well defined
•
Randomization: done
•
Allocation concealment: done
•
Blinding: open label
•
Sample size calculation: adequate
•
Intention to treat analysis: yes
•
Baseline characteristics: similar
Results
2 year survival
• Group A – 85%
• Group B – 90%
How large was the treatment effect and how
precise was the estimate of treatment effect?
3 month complete response 6 month complete response
How can I apply the results to patient care?
Were all clinically relevant outcomes
considered?
• Yes
Were the study patients similar to the patients
in my practice?
• Yes
Are the likely treatment benefits worth the
potential harm and costs?
• Eltrombopag – Rs 2170 for 50 mg ( Rs 6510 /day)
• Rs 4,94,760 for 3 months
• NNT – 8
(Rs. 39,58,080)
But no change in 2 year survival, no change in 6 month outcomes
Conclusion
• No change in survival, but may decrease need for transfusions in first
3 months
• Will not change practice
