Similar Outcome of Upfront Unrelated and Matched Sibling Donor Hematopoietic Stem Cell Transplantation in Idiopathic Aplastic Anaemia of Childhood and Adolescence: A Cohort Controlled Study on Behalf of the UK Paediatric BMT WP, of the PD WP and of the SAA WP of the EBMT

The classical treatment algorythm of idiopathic severe aplastic anemia (SAA) forsees, if a sibling donor is not available in the family, a first line option represented by immunosuppressive therapy (IST) with ATG and Cyclosporine A (CsA). IST provides a very good survival rate but a fairly high rate of failures (no response, relapse, need for transplant). This is particularly important in childhood and adolescence where faulty hematopoiesis represents a relevant limitation of quality of life. The option of haematopoietic stem cell transplantation (HSCT) from matched unrelated donor (MUD) as front line treatment with no prior failed IST, has never been investigated so far. This study provides for the first time the outcome analysis of 29 consecutive SAA patients who received an upfront unrelated donor HSCT without prior IST, in 9 UK Centres and compares each of these patient with 3 matched controls from the data base of the SAAWP of the EBMT who, in a similar time-span, underwent Matched Sibling Donor (MSD) HSCT. Twenty four patients received HLA-A,-B,-C,-DQ-,-DRB1 matched MUD HSCTs whilst 5 received single antigen/allele Mismatched Unrelated Donor (MMUD) grafts. The conditioning regimen was FCC (Fludarabine, Cyclophosphamide and Alemtuzumab) with the addition of low dose (3cGy) TBI for the MMUD HSCTs. GVHD prophylaxis was with CsA +-Mycophenolate. The primary endpoints were overall survival (OS) and event free survival (EFS). Events were death, disease recurrence, second HSCT, clinical PNH and post-transplant malignancies. Complete remission (CR) was defined as Hb > 10 g/dl, neutrophil count > 1x 10⁹/l and platelet count > 100x10⁹/l.

The 87 (3 for each MUD/MMUD HSCT) patients from the EBMT data base who underwent MSD HSCT as first line treatment were matched to the upfront MUD/MMUD cohort by age, gender, time from diagnosis to HSCT and source of stem cells. Their median follow-up was 1.6 years (range 0.01-9.39).

In the upfront MUD/MMUD cohort there were 12 males (41%) and 17 females (59%). Median age at HSCT was 8.46 years (range 1.73-19.11), 72% was aged below and 28% above 12 years; median interval from diagnosis to HSCT was 0.39 years (range 0.19-1.35) with 72 % receiving bone marrow and 28% peripheral blood stem cells. The median follow-up was 1.7 years (range 0.19-8.49). The median time to neutrophil recovery (>0.5 x 10⁹/l) was 18 days (range 9-29) and the median time to platelet recovery (>50 x 10⁹/l) was 19 days (range 10-40). The 100 day cumulative incidence (CI) of grade II-IV acute GVHD was 10 ± 6% ; there was only one case of grade III-IV acute GVHD (frequency of 3.5%). The 1 year CI of chronic GVHD was 19 ± 8%. There were 5/29 cases (frequency of 17,2 %), 4 in the MUD and 1 the MMUD subset. Chronic GVHD was limited in all cases and restricted to skin. There were only 2 events in this cohort; one primary graft failure following a HLA-A MMUD HSCT who has now successfully received a second HSCT and one death due to idiopathic pneumonia syndrome. No post-treatment malignancies occurred at last follow-up. The other 27 patients are in CR at last follow-up. The median interval diagnosis-neutrophil recovery was similar in MUD/MMUD (0.39 years; range 0.19-1.35) vs MSD transplants (0,31 years; range 0,1- 0,45) (p=0.93). The 2 year OS was 96%±4% in the upfront MUD/MMUD cohort vs 91%±3% of the MSD cohort (p=0.30). The 2 year EFS was 92%±5% in the upfront cohort vs 87%±4% in MSD (p=0.37) (Fig 1). The 2 year CI of rejection was 4%±4% in the MUD/MMUD vs .1%±1% in the MSD group (p=0.48).

This is the first controlled study indicating that in idiopathic SAA of childhood and adolecence upfront MUD/MMUD HSCT using FCC as conditioning regimen, has similar outcome to MSD HSCT. MUD HSCT may be considered a feasible and successful treatment option when children lack a MSD and a MUD is readily available.

Figure 1

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Figure 1

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Comparison of EFS between upfront MUD/MMUD and front-line MSD HSCT.

Events were: death, disease recurrence, second HSCT, clinical PNH and post-transplant- malignancies.