Pediatric patients with idiopathic aplastic anemia (AA) respond better than adults to immunosuppressive therapy (IST) but the long-term risks of relapse, ciclosporine dependence, and clonal evolution are high. UK investigators reported a 5-year estimated failure-free survival (FFS) after IST of 13.3%. In contrast, in 44 successive children who received a matched unrelated donor (MUD), hematopoietic stem cell transplantation (HSCT), there was an excellent estimated 5-year FFS of 95%. Forty of these children had previously failed IST. Because of those excellent results, up-front fully matched unrelated donor (MUD) hematopoietic stem cell transplantation (HSCT) became an attractive first-line option. In 2005 to 2014, a UK cohort of 29 children with idiopathic AA thus received MUD HSCTs as first-line therapy (they did not receive IST prior to HSCT). Results were excellent, with low Graft versus Host Disease rates and only 1 death (idiopathic pneumonia). This cohort was then compared with historical matched controls, transplanted or not. Outcomes for the up-front unrelated cohort HSCT were similar to Matched Related Donor HSCT and superior to IST and unrelated HSCT post-IST failure. Since then, many investigators are offering up-front MUD HSCT in pediatric patients worldwide. However, those results should be treated with extreme caution: 1) the design is retrospective; 2) the excellent up-front MUD HSCT may arise from the use of alemtuzumab in the conditioning regimen (alemtuzumab is not easily available worldwide) and 3) there was no formal quality-of-life assessment. Moreover, this strategy is highly dependent on donor identification (Caucasian patients have the highest likelihood of having a MUD) and donor not eventually receive HSCT because of the risk of infections/complications caused by unexpected donor delays or cancellation. Prospective trials are thus urgently needed to address the feasibility of such procedure, in term of timing (delay to offer MUD HSCT) and conditioning regimen (nothing is known of the use of other regimens, non alemtuzumab-based, in this setting).
The main objective of this Two-Stage Phase 2 multicenter study is to realize up-front HSCT within 2 months once a MUD has been identified.
age<18years old
Pediatric patients aged less than 18 years with idiopathic aplastic anemia and an indication for treatment (severe aplastic anemia or moderate aplastic anemia requiring transfusions)
With a good probability to have a HLA-10/10 matched unrelated donor available (the patient needs to have at least 3 MUD identified within the book BMDW (Bone Marrow Donors Worldwide) or using the easy match software to be included)
Lansky >70% for those below 16 years and Karnofsky > 70% for those above 16 years
With a matched related donor available
With uncontrolled infection
With seropositivity for HIV or HTLV-1 or active hepatitis B or C defined by a positive PCR HBV or HCV and associated hepatic cytolysis
Renal failure with creatinine clearance below 70% of higher normal values for age
Single group
HSCT Arm group
Other interventionConditioning regimen Stem cell source Only Bone Marrow With a minimal target dose of 4x108 nucleated cells/kg recipient ideal body weight. If the graft is less rich than the minimum target dose, it can be administered at the discretion to the physician. GVHD Prophylaxis Prevention of EBV reactivation : Rituximab 150mg/m2 IV at Day+5 post HSCT.
Proportion of patients with upfront matched unrelated donor (MUD) hematopoietic stem cell transplantation (HSCT) effectively performed
Proportion of patients with upfront matched unrelated donor (MUD) hematopoietic stem cell transplantation (HSCT) effectively performed in the first two months after unrelated donor search.
Graft failure incidence
Neutrophils engraftment
Neutrophils engraftment will be defined as first day of 3 consecutive days with neutrophils \>0.5 G/L
Platelets engraftment
Platelets engraftment will be defined as first day of 7 consecutive days with platelets \>20 G/L
Absolute number of neutrophils
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