Human Heme-Oxygenase-1 Deficiency Treated Successfully by Matched Sibling Donor Allogeneic Stem Cell Transplant

Abstract

Background and aim: Previously only three cases of human Heme Oxygenase-1 (HO-1) deficiency have been reported. All three had tetrad of asplenia, inflammation, hemolysis & nephritis and died of intracranial bleed. In HO-1 deficient mice, it has been shown that macrophages engaged in recycling of red cells were depleted from the tissues, which resulted in intravascular hemolysis and severe damage to the endothelial system, kidneys, and other organs. Same group reported that subablative allogeneic stem cell transplant (SCT) has a curative effect for disease in HO-1 deficient mice by providing HO-1 expressing wild-type macrophages. We describe here the first and only successful allogeneic SCT from a matched sibling donor (MSD) performed for a child diagnosed with HO-1 deficiency. Methods: A 10-yr-old-boy presented with complaints of fever, pallor and severe hypertension. He had short stature, abnormal facies but normal development. Hemoglobin 5 g/dl, urine for haemoglobin was positive, platelets 1600,000/ul, ferritin 15,000 mcg/L and urine albumin 4+. Ultrasound abdomen showed asplenia. A diagnosis of HO-1 deficiency was suspected. Mutation analysis showed homozygous missense mutations in exon2 (R44X) on chromosome 22q12, which would result in the absence of the functional protein, HO-1. We managed him over next 4-years with good disease control with prednisolone, hydroxyurea and mycophenolate mofetil (MMF). We did HLA-typing and found elder healthy 24-yr-old sister to be a fully matched donor. After discussing with the family and taking informed consent we offered MSD SCT with a non-myeloabalative conditioning. We conditioned him with Campath-.6 mg/kg, Fludarabine-160 mg/m2, Cyclophospamide-29 mg/kg and Total body irradiation-2Gray. We infused 11 million/kg CD34+ cells from the sister. Graft-versus-Host disease (GVHD) prophylaxis consisted of tacrolimus & MMF. Results: Child tolerated procedure very well. Had no fever throughout post-SCT phase and lowest platelets were 70,000/ul. His blood pressure normalised with appearance of monocytes in his blood. His proteinuria decreased from 4+ to nil by day+8. His neutrophils engrafted on day+12 and he was discharged on day+16. His reddish urine color suddenly cleared by day+8. He had no GVHD. Post-discharge, his chimerism on day+22 showed 86.7% donor cells but dropped to 64% on stopping MMF by day+40. MMF was restarted on day+70 after he achieved stable mixed chimerism between 50-60% donor cells over next 12 months. Now he is day+490 post-SCT with 51% donor cells and doing well. He has no evidence of hemolysis, proteinuria, hypertension, fever. He has normal ferritin and platelets. He has gained 10 cm height and 12 kg weight in last 15-months. Conclusion: Non-myeoablative allogeneic MSD SCT is a feasible treatment option for patients suffering from auto-inflammatory disorder due to HO-1 deficiency. Although mixed chimerism is a concern.