hATG+CsA vs hATG+CsA+Eltrombopag for SAA

This is a superiority trial aiming to increase the 3 month complete response rate. The sample size is calculated on the hypothesis that the experimental treatment will increase the 3 months response rate up to 21% (by 3 folds, based on the 7% reported in Scheinberg et al [17]). Under these assumptions, the sample size to reject the null hypothesis is n=96 patients for each treatment arm, increased by 4% for possibly not evaluable patients (total number of 200 patients, 100 each treatment arm). Statistical design for sample size calculation: increase from 7% (control arm) to 21% (investigational arm) in 3 month complete response rate (two-sided binomial test); alpha-error 0.05; power 0.8.

Inclusion criteria

• Diagnosis of severe or very severe aplastic anemia, defined by [29]:

• At least two of the following:

• 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
• Hypocellular bone marrow (<30% cellularity), without evidences of fibrosis or malignant cells
• Male or female age > 14 years;
• Written informed consent
• Willing and able to comply with all of the requirements and visits in the protocol
• Understands that they can be randomised to either treatment arm
• Negative pregnancy test for women of child bearing age
• Written acceptance to use contraception (hormonal or barrier method of birth control; abstinence) for the entire duration of study participation.

Exclusion criteria

• Prior immunosuppressive therapy with ATG (horse of rabbit) or any other lymphocyte depleting agent (i.e., alemtuzumab)
• Eligibility to a sibling allogeneic stem cell transplantation
• Evidence of a myelodysplastic syndrome, defined by the presence of myelodysplastic features, excess of blasts or karyotypic abnormalities typical of MDS (according to revised WHO 2008 criteria) [30],, as well as other primitive marrow disease. Patients with diagnosis of AA with cytogenetic abnormalities which are recurrent in MDS (according to revised WHO 2008 criteria) [30] should be included in this category, and are not eligible for the study; patients with del(20q), +8 and -Y are not included in this category, and thus are eligible for this study. The list of karyotypic abnormalities which qualifies for the diagnosis of MDS are listed in the Appendix.
• History or clinical suspect of constitutional aplastic anemia (i.e. Fanconi Anemia with positive DEB/MMC test or Dyskeratosis Congenita)
• History of malignant tumors with active disease within 5 years from enrollment, and/or previous chemo-radiotherapy
• Previous history of stem cell transplantation
• Treatment with cyclosporin A unless

• <4 weeks of cyclosporin A treatment before enrolement and
• wash out period of 2 weeks before enrollment
• CMV viremia, as defined by positive PCR or pp65 test
• WHO performance status ≥3
• Pregnant or breast feeding patients
• Patients with hepatic, renal or cardiac failure, or any other life- threatening concurrent disease
• Patients with HIV infection
• Patients without social health care assistance
• Participation in another clinical trial within 1 month before the start of this trial
• Patients and/or female partners of male patients not using highly effective method of birth control i.e. intrauterine device (IUD), hormonal (oral pill, injection, implants), tubal ligation or partner's vasectomy
• subjects with known hypersensitivity to any of the component medications

The presence of a Paroxysmal Nocturnal Hemoglobinuria clone is not an exclusion criterion.