Pb1998: azacytidine and allogenous stem cell transplantation in late-onset erythropoietic protoporphyria

Topic: 10. Myelodysplastic syndromes - Clinical Background: Late-onset erythropoietic protoporphyria (EPP) is a condition that has been reported in less than 25 patients. Late-onset EPP is an acquired condition caused by mutations or epigenetic hits in adult patients who harbors a heterozygous ferrochelatase (FECH) mutation or a low-expression allele. The more common primary form of EPP is caused by compound heterozygous or homozygous mutations in the FECH gene, or hemizygous mutations in the X-linked ALAS2 gene, with symptoms starting in childhood. The symptoms of EPP, in particular skin blistering and pain when exposed to sunlight, are due to accumulation of protoporphyrin IX (PPIX). EPP symptoms may be debilitating and it predisposes to severe acute cholestatic hepatitis. We report the clinical course of two unrelated patients from a single institution encountered over a one-year period, both were treated with azacitidine (Aza) and allogeneic bone marrow transplantation (alloBMT). Aims: To describe the phenotype of late-onset EPP patients, and the response to treatment. Methods: Case reports and review of literature Results: Case 1: a 48-year old female presented with skin blistering and edema in the sunlight exposed areas. After a protracted workup-period, she was diagnosed with EPP, based on elevated PPIX levels (25 umol/L; N:0-0.5 umol/L). A germline heterozygous FECH mutation was identified. She was moderately cytopenic. A bone marrow biopsy was without overt myelodysplasia but showed clonal cytopenia of unknown significance, with ETV6, IDH2 and SRSF2 mutations (Variant allele frequencies (VAF) ranging from 6 to 17%). Three months later she developed cytogenetic abnormalities (+8 and +19). We initiated monthly Aza 100 mg/m2/5days which normalized her karyotype, skin symptoms, and PPIX levels after three series (Fig 1). Following this surprising depth of response treatment was stopped. Nine months later, she relapsed with both symptoms, increasing PPIX levels (48.6 umol/L), and karyotypical changes. Three additional Aza series were administered and an alloBMT with an unrelated donor was performed. The conditioning regimen was Fludarabin 30 mg/m2/5 days and Treosulfan 10 mg/m2/3 days and the follow-up immunosuppression was tacrolimus and methotrexate. She was still in remission 9 months post-transplant (Fig 1). Case 2: a 54-year old male with slight cytopenia was diagnosed with myelodysplastic syndrome (MDS-RS-SLD). The histopathological changes were modest and his karyotype was normal. The IPSS-R score indicated “very low risk” disease. But he had mutations in the DNMT3A, IDH2, SRSF2 and SF3B1 genes (VAF from 7 to 40%), consistent with genetic instability. As he had light-induced skin symptoms and swelling of his face we measured a PPIX level (elevated at 18.1 umol/L) and verified the presence of a heterozygous germline FECH mutation. Aza treatment quickly resulted in symptom relief and had fully normalized PPIX levels after 3 series. An alloBMT with an unrelated donor was performed after seven series of Aza. By day 118 he developed MDS relapse and recently received a second transplant. Summary/Conclusion:Late-onset EPP could be underreported in literature. The symptomatic impact of EPP can be substantial and indicate treatment by itself. We saw rapid normalization of PPIX levels and a relief of photosensitivity post-Aza – suggesting normalization of aberrant methylation of the patients´ normal FECH allele. A fludarabin-treosulfan based alloBMT conditioning regimen was well tolerated without hepatic adverse events – a major concern in EPP patients. One patient suffered a MDS relapse and in future transplants an increased intensity regimen could be considered.Keywords: MDS, Azacitidine, Genetic instability