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Case Report
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Figure 2. Clonal history of the two diseases. (A) Table of frequencies in bone marrow (BM) and skin biopsy: according to fluorescence in situ hybridization and next generation sequencing data. ND: not detected; y: years. (B) Sanger sequencing electrophoregram, showing mosaic UBA1 c.121A>C variant [NM_153280.3] in skin and successive three BM evaluations (BM1, 2, and 3). (C) Fish plot, representing clonal evolution upon BM evaluations (TET2 mutation is not displayed because of insufficient data in clonal evolution).
SF3B1, SH2B3, SMC1A, SMC3, SRSF2, STAG2, TET2, TP53, U2AF1, WT1, ZRSR2) was performed on the skin biopsy. Sequence analysis identified a DNMT3A p.R882H mutation (variant allele frequency [VAF] 22%) and a CALR type 1 mutation (VAF 6%). A monosomy of chro- mosome 7 was also identified by fluorescence in situ hybridization (FISH) in 30% of the cells of the biopsy (Figure 2A).
A concomitant bone marrow (BM) examination (BM1 after 10 years of evolution) showed evidence of megakaryocyte hyperplasia but neither signs of myelodysplasia nor blast excess. Using the same NGS panel, we found the same mutations of CALR (VAF 29 %) and DNMT3A (VAF 38 %), while FISH analysis detected only 2 % of cells with monosomy 7, suggestive of a clon- al relation between granulocytes in the BM and in the
skin lesions (Figure 2A). A thalidomide-based treatment was introduced, with an initial clinical improvement on skin lesions and a persistent normalization of platelet count, in spite of hydroxyurea progressive tapering and arrest. During this treatment, the patient progressively developed severe anemia, without efficacy of erythro- poietin support, and needed repeated blood transfusion. Serial BM evaluations (BM2 after 11 years, and BM3 after 11.5 years of evolution) were performed, which still showed no evidence of myelodysplastic changes, but a decreased number of typical ET-related megakaryocytes and a progressive profound erythroblastopenia. Interestingly, DNMT3A mutation persisted at similar fre- quency, whereas CALR allele burden dropped to 1%, and monosomy 7 became undetectable (Figure 2A).
After discontinuation of all therapies except aspirin,
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haematologica | 2021; 106(12)