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Case Report • Hematol., Transfus. Cell Ther. 46 (Suppl 2) • 2024 • https://doi.org/10.1016/j.htct.2024.02.027 linkcopy

Open-access The role of allogeneic stem cell transplantation in severe erythropoietic protoporphyria in adults and young adults: timing and modalities

AuthorshipSCIMAGO INSTITUTIONS RANKINGS

    Keywords
    Erythropoietic protoporphyria; Congenital erythropoietic porphyria; Hematopoietic stem cell transplantation; Liver transplantation

    Keywords
    Erythropoietic protoporphyria; Congenital erythropoietic porphyria; Hematopoietic stem cell transplantation; Liver transplantation

    Introduction

    Porphyrias are caused by enzymatic dysfunctions in the haem biosynthesis metabolic pathway.1

    Erythropoietic protoporphyria (EPP), the most common porphyria in children, that occurs in about 1 in 74,300 individuals, is an autosomal disorder, characterized by acute, severe, non-blistering phototoxicity within minutes of exposure by sunlight, and caused by pathogenic variants in the ferrochelatase (FECH) gene.2,3 The reduced enzyme activity results in the accumulation, during erythropoiesis, of protoporphyrin IX (PPIX), which activated by sunlight exposure, generates singlet oxygen and radical reactions, leading to tissue damage and excruciating pain.

    PPIX is excreted solely through the hepatobiliary route, and in case of accumulation can aggregate in hepatocytes and precipitate in bile canaliculi, causing severe hepatotoxicity, that may require liver transplantation (LT).4-6 However persistence of PPIX accumulation in the bone marrow causes the recurrence of liver disease in most patients, justifying sequential hematopoietic stem cell transplantation (HSCT) and LT to cure EPP-related hepatopathy.7,8

    Congenital erythropoietic porphyria (CEP) is a rare autosomal recessive disorder caused by a deficiency in uroporphyrinogen III synthase (UROS), leading to the accumulation of type I porphyrins during erythropoiesis. The prognosis is poor in severely affected patients due to the destruction of subcutaneous tissues and pancytopenia. Death often occurs early in adulthood.9,10 Since the 1990s, HSCTs have been the therapeutic choice for severe pediatric cases (Table 1).

    Thumbnail
    Table 1
    Individuals with EPP (erythropoietic protoporphyria) and CEP (congenital erythropoietic porphyria) treated using stem cell transplantation. Patients transplanted after 15 years old are presented in bold.

    Here, we present four patients with either EPP or CEP who underwent HSCT after the age of fifteen.

    Clinical cases

    Patient #1 was a 17-year-old EPP-patient who underwent a LT from his father in 2001, in the context of EPP-related hepatopathy. After five months, the patient underwent HSCT from the same haploidentical donor. The conditioning regimen was based on fludarabine and total body irradiation (TBI 2cGY). HSCT was complicated by primary graft failure. He continued transfusions and ferrochelating therapy to prevent hemochromatosis. He died 11 years later.

    Patient #2, a 32-year-old man diagnosed with EPP at the age of three, underwent a first LT in 2009 for liver cirrhosis. In the following years, he presented a progressive worsening of liver function and a liver biopsy in 2013 confirmed the recurrence of the initial disease (micro-nodular cirrhosis, with a very strong fibrotic component and pigment overload typical of PPIX deposition).

    He therefore underwent a second LT, followed by a HSCT, to prevent EPP recurrence on the graft. The patient underwent a non-myeloablative matched-unrelated transplant after conditioning with fludarabine, busulfan and thymoglobulin. He demonstrated excellent neutrophil engraftment on day +19. Peripheral blood donor chimerism was 100% by day +30. He did not have any signs of GvHD or infectious complications. His blood counts were normal. Free erythrocyte PPIX levels were normal and he did not experience any photosensitivity. Nine years after HSCT, he is alive but he underwent a third LT for arterial stenosis and severe infectious complications on second liver transplant.

    Patient #3 was a woman diagnosed with EPP at the age of five, which only presented regular mild episodes of photosensitivity. At the age of 40, she experienced a first severe cholestatic hepatitis episode and was treated with ursodeoxycholic acid for six months. The cholestasis resolved and PPIX levels dropped to pre-hepatitis levels.

    Eight months later, a second severe episode of cholestatic hepatitis occurred (bilirubin up to 500 μmol/L), requiring prolonged hospitalization in an intensive care unit. Hydroxycarbamide, red blood transfusions and plasma exchanges contributed to suppress endogenous hematopoiesis and the production of porphyrins, allowing full recovery. Liver biopsy showed a parenchyma of respected architecture, with portal fibrosis and discrete steatosis, and pigment overload typical of PPIX deposition.

    She was referred for an allogeneic HSCT from a 10/10 HLA-matched unrelated donor. Conditioning regimen, preceded by desensitization protocol by plasma exchanges, intravenous immunoglobulin and rituximab (donor specific antibody higher than 12,000 mean fluorescence intensity (MFI) by single antigen bead assay), consisted of fludarabine, busulfan and thymoglobulin.

    Neutrophil engraftment occurred on day +24 and peripheral blood donor chimerism was 94.2% by day +30 and 96% by day +100. There were no GvHD or infectious complications. Free erythrocyte protoporphyrin and the plasma-free protoporphyrin were repeated and dropped to normal levels at day 28 after HSCT (Figure 1). She had complete resolution of photosensitivity and she largely returned to a normal life. With 22 months of follow up, the patient is fine, with only mild persistent thrombocytopenia.

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    Figure 1
    Evolution of patient #3 total erythrocytes porphyrins level. Green area indicates the normal range. HSCT: hematopoietic stem cell transplantation.

    Patient #4 was diagnosed with CEP at the age of two, mostly with skin involvement. At four years old, he underwent a first matched-unrelated allogeneic HSCT after a myeloablative conditioning regimen. Post-transplantation, his blood count was normal, he did not show any signs of GvHD or infectious complications and he showed a marked improvement in skin lesions. However, after 10 years, he presented with moderate cytopenia, new erosive, bullous skin lesions with scleroderma areas and functional joint impotence. Erythrocyte porphyrins increased to a very high level (24 µmol/L) in red blood cells (n <1.9). Peripheral blood chimerism was 76% recipient.

    At the age of 22, he underwent a second HSCT from a matched-unrelated donor after a reduce intensity conditioning regimen. He achieved neutrophil engraftment on day +18 and a full donor chimerism. No acute GvHD occurred. Two years after HSCT, the patient leads a normal life, with normal protoporphyrin levels.

    Discussion and conclusions

    EPP and CEP have great clinical variability related to heterogenous residual enzymatic activities; while numerous therapies have been applied, HSCT is the only curative treatment for severe forms of the diseases. From 1991, when the first HSCT was performed for CEP, there have been about thirty reports of, mainly pediatric, patients (Table 1).

    The four cases we present may expand the already known experience about HSCT in porphyrias, to young adults and adults. Two patients presented the resolution of disease manifestations achieving normal protoporphyrin levels, one had primary graft failure (conditioning regimen was retrospectively not sufficient for engraftment) and the last experienced late secondary graft failure but was rescued by thae second transplant. None experienced acute nor chronic GvHD.

    HSCT is certainly feasible, from any stem cell source or any type of donor, when the disease is severe. In the past, a myeloablative conditioning regimen was preferred, however engraftment seems to not be lower with non-myeloablative conditioning and minimization of toxicity is a priority in patients with liver failure and non-malignant disease. Hepatic involvement requires careful pre-transplant evaluation, including liver biopsy.

    From a metabolic point of view, the efficacy of HSCT depends on the initial level of toxic porphyrin production and on the level of myeloid chimerism reached, i.e., the higher the initial porphyrin production, the lower the level of residual native erythropoietic cells must be for the patient to be asymptomatic. In patient #4, a 76% recipient chimerism was associated with sufficient erythrocyte porphyrins production (3.529 nmol/mmol creatinine) to induce severe symptomatology. It is therefore important to target full myeloid chimerism and normal erythrocyte porphyrins, especially in CEP patients.

    In conclusion, HSCT should be evaluated for high-risk adults and young adult patients, with EPP and liver involvement. If possible HSCT must be perform before LT to prevent long-term complications inherent to solid organ transplantation; after LT it is necessary to prevent the inevitable relapse of the disease.

    Acknowledgments

    The authors would like to thank Juliette Villemonteix, Pauline Houssel-Debry, Olivier Roux, Juliette Delforge, Anne Brignier, Nathalie Parquet, Régis Peffault De Latour, Gerard Socie and Laurent Gouya for their contribution and help in data collection.

    References

    • 1 Dawe R. An overview of the cutaneous porphyrias. F1000Res. 2017 30;6:1906. doi: 10.12688/f1000research.10101.1. PMID: 29152226; PMCID: PMC5664971.
      » https://doi.org/10.12688/f1000research.10101.1.
    • 2 APF. Erythropoietic protoporphyria (EPP) and X-Linked Porphyria (XLP). American Porphyria Foundation (APF). Accessed October 14, 2022.
    • 3 Balwani M. Erythropoietic protoporphyria and X-linked protoporphyria: pathophysiology, genetics, clinical manifestations, and management. Mol Genet Metab. 2019;128(3):298-303. doi:10.1016/j.ymgme.2019.01.020. Epub 2019 Jan 24. PMID: 30704898; PMCID: PMC6656624.
      » https://doi.org/10.1016/j.ymgme.2019.01.020.
    • 4 Bloomer JR (1988). The liver in protoporphyria. Hepatology 8, 402-407. [PubMed: 3281889]
    • 5 Bloomer JR (1997). Hepatic protoporphyrin metabolism in patients with advanced protoporphyric liver disease. Yale J Biol Med 70, 323-330. [PubMed: 9626752]
    • 6 Wahlin S, Aschan J, Bjornstedt M, Broome U, Harper P. Curative bone marrow transplantation in erythropoietic protoporphyria after reversal of severe cholestasis. J Hepatol 2007; 46: 174-179.
    • 7 McGuire BM, Bonkovsky HL, Carithers Jr RL, Chung RT, Goldstein LI, Lake JR et al. Liver transplantation for erythropoietic protoporphyria liver disease. Liver Transpl 2005; 11: 1590-1596.
    • 8 Wahlin S, and Harper P (2010). The role for BMT in erythropoietic protoporphyria. Bone Marrow Transplant 45, 393-394. [PubMed: 19525986]
    • 9 Dupuis-Girod S, Akkari V, Ged C, et al. Successful match-unrelated donor bone marrow transplantation for congenital erythropoietic porphyria Gunther disease. Eur J Pediatr. 2005;164:104-107.
    • 10 Harada FA, Shwayder TA, Desnick RJ, Lim HW. Treatment of severe congenital erythropoietic porphyria by bone marrow transplantation. J Am Acad Dermatol. 2001;45:279-282.

    Publication Dates

    • Publication in this collection
      20 Jan 2025
    • Date of issue
      2024

    History

    • Received
      22 Aug 2023
    • Accepted
      27 Feb 2024
    • Published
      18 Apr 2024
    Creative Common - by-nc-nd 4.0
    This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivative License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium provided the original work is properly cited and the work is not changed in any way.
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