Abstract

Allogeneic transplantation in non- malignant inherited diseases is primarily performed to correct the basic defect by repleting stem cells capable of producing the deficient component. T cells in such situations are needed to facilitate engraftment and immunological reconstitution but, due to the non-malignant nature of the basic defect, no graft versus tumor effect is needed. Moderate T cell depletion - 105 T cells/kg- given in the setting of matched related transplant could abrogate GVHD, without negatively affecting engraftment. Presented herein is the long- term outcome and chimeric status of 18 children following allogeneic stem cell transplantation for non-malignant disorders using moderate T cell depletion with no post transplant immune suppression.

Patients and methods: 18 consecutive patients with non-malignant diseases were transplanted at the Rambam Medical Center, Haifa, Israel, for the following disorders: Six patients with thalassemia major, 3 with immunodeficiency, 3 with metabolic disorders (Hurler syndrome (2), San Felippo (1)), 2 with adreno-leuco-dystrophy (ALD), 2 with familial hemophagocytic lymphohistiocytosis (HLH), 1 with chronic granulomatous disease (CGD) and 1 with mitochondrial neuro-gastrointestinal encephalopathy (MNGIE) disease. Median age at transplantation was 22 months (range: 5 months–18 years). Peripheral blood stem cells were collected from matched related donor after priming with G-CSF. Conditioning regimen included busulphan 12–16mg/kg administrated over 4 days (days-9,-8,-7,-6), cyclophosphamide 120–200 mg/kg given over 4 days (days -5,-4,-3,-2), ATG (Fresenius) 25mg/kg given over 5 days (days-9,-8,-7,-6,-5), fludarabine 150–200mg/m2 administrated over 5 days (days -9,-8,-7,-6,-5), cyclosporine 1mg/kg only given for 9 days prior to transplantation during conditioning. T cell depletion was performed by positive selection of CD34 cells by immunomagnetic beads (CliniMACS). On day 0 high dose of CD34 cells were given, median CD34/kg- 10.5x 106 (range: 7.4–50x106). 105 T cells per kg were added. No prophylaxis for GVHD was given post transplant.

Results: All patients engrafted. Neutrophil engraftment occurred at a median of 10 days (range: 8–13 d), platelet transfusion independence occurred at a median of 20 d (range:11–34 d). Two out of 18 patients (11%) developed GVHD, 1 patient with thalassemia major who developed chronic GVHD and 1 with MNGIE disease who developed acute as well as chronic GVHD. Regarding chimeric status, 3 patients developed 100% donor chimerism, 2 of them experienced GVHD. 13 patients had >50% donor chimerism while 2 had < 50% donor chimerism. The chimeric status has remained steady with a median follow-up of 61 months (range: 27–114 mon). There were no graft rejections. All patients, those with complete donor chimerism as well as those with mixed donor chimerism, are alive and well each with very significant clinical improvement and without disease deterioration over the years.

Conclusion: Long term follow-up confirms the safety and efficacy of allogeneic SCT from matched family donors for patients with non malignant disorders using moderate T cell depletion and no post transplant immunosuppression. These data emphasize that in allogeneic transplantation of non-malignant disorders there is probably no need for full donor chimerism in order to achieve long term successful clinical outcome. Chimeric status, clinical outcome and GVHD with a median follow-up of >5 years.

Chimeric Status no.of Pts. Diagnosis Clinical outcome-all alive GVHD 
100% donor CGD, Thalassemia, MNGIE disease Correction of basic defect; transfusion independence 2/3 
>50% donor 13 Thalassemia (3)
 Immunodeficiency (3)
 Metabolic disease (3)
 ALD (2)
 HLH (2) Transfusion independence
 Resolved
 Major clinical response
 Major clinical response
 Resolved 0/13 
<50% donor Thalassemia (2) Transfusion independence 0/2 
Chimeric Status no.of Pts. Diagnosis Clinical outcome-all alive GVHD 
100% donor CGD, Thalassemia, MNGIE disease Correction of basic defect; transfusion independence 2/3 
>50% donor 13 Thalassemia (3)
 Immunodeficiency (3)
 Metabolic disease (3)
 ALD (2)
 HLH (2) Transfusion independence
 Resolved
 Major clinical response
 Major clinical response
 Resolved 0/13 
<50% donor Thalassemia (2) Transfusion independence 0/2 

Disclosures: No relevant conflicts of interest to declare.

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