Bone Marrow Transplantation Arrests Cerebrovascular Disease Progression and Improves Psychometric Outcomes in Children with Sickle Cell Disease

Abstract 11

Stem cell transplantation (SCT) is currently the only curative option for sickle cell disease. Cerebrovascular disease (CVD) is one of the main indications to undertake this procedure as even with best conventional approaches there is a significant risk of recurrence or progression and there is evidence that SCT arrests disease progression, though more detailed study of outcomes is awaited. Early studies of SCT in sickle cell disease showed a high rate of neurological complications that led to the optimization of protocols.

We conducted a retrospective analysis of related SCT in children with severe SCD between 2001 and 2010 at our institution to study the effect of transplantation. 20 patients (11 male, 9 female) received a BMT for sickle CVD (n=11) or recurrent vaso-occlusive crises (n=9). One patient with CVD was a second procedure following primary graft failure in a previous sibling transplant. CVD was investigated with clinical history and examination, transcranial Doppler ultrasound, magnetic resonance imaging/magnetic resonance angiography and psychometric testing using WISC-IV: 7 patients had no evidence of CVD, 5 had silent infarcts, 6 ischaemic stroke and 2 Moya-Moya disease. The median age at transplantation was 136 months (range 34 – 210 months). Donor source was HLA-matched siblings in 18 patients, one 9/10 mismatched sibling and HLA-matched relative in another. Bone marrow was used in all (n=19) but one patient who received combined bone marrow and umbilical cord. All patients (n=18) but two received conditioning with oral busulfan 14 mg/kg, cyclophosphamide 200 mg/kg and alemtuzumab 0.3 mg/kg; 1 patient received fludarabine 160 mg/m², treosulfan 42 mg/m², thiotepa 10mg/kg and ATG (Thymoglobulin) 11.25 mg/kg and 1 patient received oral busulfan 16mg/kg, cyclophosphamide 200 mg/kg and antilymphocyte globulin (45 mg/kg). GvHD prophylaxis was provided with ciclosporin and short course methotrexate (n=18), ciclosporin and MMF (n=1) and ciclosporin alone (n=1). Mean cell dose was 3.70 × 10⁸ TNC/kg (range 1.45 – 6.16 × 10⁸ TNC/kg). Neutrophil engrafment (>0.5 × 10⁹/L) occurred at a median of 19.5 days (range 12 – 28 days) and platelet engrafment (>50 × 10⁹/L) at median of 26 days (range 21 – 52 days). The median follow up is 974 days (range 270 – 3622 days). 18 patients achieved stable donor haemopoiesis, one patient suffered secondary graft failure due to Parvovirus B19 infection and one patient died on day +21 post-transplant due to sepsis and multi-organ failure.

No significant sickle related neurological events occurred during these transplants. All 18 patients with long-term engraftment achieved radiological stabilization of the underlying CVD. Imaging performed at least 12 months post SCT showed no further changes from pre-transplant images. There were no clinical neurological events after SCT. Psychometric testing demonstrated improvements in all areas in patients transplanted for silent infarcts, particularly those affecting processing speed. In summary, SCT appears safe even in patients with severe CVD, arrests further progression and shows functional improvement.