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
(ATG/alemtuzumab)
• Eligibility for sibling stem cell
transplantation
• MDS
• Fanconi anemia/Dyskeratosis congenita
• h/o malignant tumors with chemo in
the last 5 years
• h/o stem cell transplantation
• Cyclosporin < 2 weeks prior to
enrollment
• Breast feeding
• Hepatic/renal/cardiac failure
• HIV
• Without social health care assistance
• Another clinical trial 1 month prior to
start of this trial
• Not on highly effective birth control
• Known hypersensitivity to trial drugs
• WHO performance score >3
• 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
• Time to best response
• Time to complete response
• Rates of response at 3,6,12,18
and 24 months
• Overall survival probability
• Event free survival probability
• Cumulative incidence of relapse
• Cumulative incidence of clonal
evolution
• Cumulative incidence of PNH
• Cumulative incidence of
discontinuation of
immunosuppressive therapy
• Need for transfusions
• Need for supportive care
• 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