Bone Marrow Transplantation in Congenital Erythropoietic Porphyria: Sustained Efficacy but Unexpected Liver Dysfunction

Abstract

Congenital erythropoietic porphyria (CEP) is a rare disease characterized by erosive photosensitivity and chronic hemolysis due to a defect of the enzyme uroporphyrinogen-III-synthase (UROS). To date, hematopoietic stem cell transplantation (HSCT) is the only curative therapy for the devastating early and severe form of the disease. We describe 6 patients with CEP treated with HSCT (3 of them twice after failure of a first graft) between 1994 and 2016 in our center, including 2 of the very first living patients treated more than 20 years ago. Four patients are doing well at 6 to 25 years post-HSCT, with near-normal biochemical parameters of porphyrin metabolism without the cutaneous or hematologic features of CEP. One patient died within the first year after HSCT from severe graft-versus-host disease (GVHD), and 1 child died of unexplained acute hepatic failure at 1 year after HSCT, despite full donor chimerism. Retrospectively, it appears that all but 1 child had increased transaminase activity with onset from the early postnatal period, which was significantly more marked in the child who died of liver failure. In contrast, liver function values progressively normalized after engraftment in all other children. Liver pathology before HSCT for 3 patients revealed varying degrees of portal, centrilobular, and perisinusoidal fibrosis; clarification of hepatocytes; and cytosolic porphyrin deposits. The liver porphyrin content in biopsy specimens was >60 times the normal values. Despite difficult engraftment, the long-term efficacy of HSCT in CEP appears to be favorable and reinforces its benefits for the severe form of CEP. Hepatic involvement requires careful evaluation before and after HSCT and further investigation into its pathophysiology and care.

Hematopoietic stem cell transplant for erythropoietic porphyrias in pediatric patients

“…There may be residual UROS or FECH deficiencies in other non‐erythropoietic sites, as suggested by mildly persistently elevated TUP or TPP levels, which is seen in our cohort and others, however patients remain asymptomatic 4 . At time of publication, over 20 patients with CEP and nine patients with EPP have been reported (including our cohort) in the literature to have successfully undergone HSCT, with no reports of symptom recurrence 4,6–8,11–14 …”

“…4 At time of publication, over 20 patients with CEP and nine patients with EPP have been reported (including our cohort) in the literature to have successfully undergone HSCT, with no reports of symptom recurrence. 4,[6][7][8][11][12][13][14] HSCT effectively corrects the defective bone marrow heme pathway in patients with erythropoietic porphyrias. The risks of HSCT have traditionally outweighed the benefits for the majority of patients with erythropoietic porphyrias, but contemporary strategies have made transplants safer.…”

Very Early Diagnosis and Management of Congenital Erythropoietic Porphyria

“…Unfortunately, CEP can be difficult to diagnose with a reported median age of diagnosis of 7 months with typical red urine, CEP skin lesions and hemolytic anemia appearing at median age of 1, 2, and 8 months, respectively. 21 Martinez Perinado et al 12 reported an early onset case of CEP who presented with severe post-delivery manifestations and underwent a matched unrelated HSCT at age 7 months. As CEP is a rare condition, a multidisciplinary evaluation led by the responsible pediatrician is necessary for early diagnosis and genetic testing.…”

“…Several case reports of successful HSCT in the treatment of CEP also described a similar situation, notably a recent study describing near-normal biological levels of porphyrins 25 years after HSCT. 21 The remaining elevated porphyrin levels, despite HSCT, might reflect the porphyrin production by nonerythroid tissues. Indeed, UROS deficiency is still present in nonerythroid tissues (i.e., liver cells) leading to a persistent accumulation of porphyrins despite full replacement of erythroid tissues with HSCT.…”

“…[10][11][12][13][14][15][16][17][18] A recent study presented 13 cases of HSCT in CEP, where 11 were still in remission 7 years after transplantation, and 2 died of infectious complications following HSCT. 19 Besnard et al 21 recently described the longterm complications post-HSCT of 6 patients during a maximum follow-up period of 25 years. Indeed, 4 patients had a favorable outcome with near-normal levels of porphyrins and no clinical manifestations of CEP while 1 died from severe GVHD and 1 from acute hepatic failure 1 year after HSCT.…”