Successful use of allogeneic bone marrow transplantation in a patient with myelodysplastic syndrome presenting with autoimmune manifestations

Myelodysplastic syndrome (MDS) is a clonal haematopoietic disorder, characterised by ineffective haematopoiesis and peripheral-blood cytopenias. There is a widely recognised association of MDS with autoimmune symptoms, with an incidence reported between 10 and 20%. Here, we discuss a patient presenting with multiple treatment-refractory autoimmune manifestations (AIMs), which preceded the diagnosis of MDS and culminated in the patient requiring an allogeneic bone marrow transplant (allo-BMT). A 56-year-old Caucasian male with no preceding history of autoimmune disease presented in April 2018, complaining of a widespread relapsing/remitting maculopapular rash, joint pain and proximal muscle weakness, associated with systemic symptoms (fever and lethargy). The rash appeared symmetrical and involved the face, torso, neck and proximal limbs (Fig 1A, B). Blood tests revealed a macrocytic anaemia [Hb 110 g/l, mean corpuscular volume (MCV 100 fl)], which had been present since May 2011. Initially diagnosed with erythema multiforme, he was commenced on oral prednisolone 40 mg daily. Despite initial improvement, over the next 12 months, he continued to experience intermittent rashes, low-grade pyrexia, lethargy, joint pain and progressive weight loss. By June 2018, he had developed worsening anaemia (Hb 80 g/l, MCV 106 fl), leukopenia of 2 8 9 10/l (neutrophils 1 68 9 10/l) and raised inflammatory markers. An autoimmune screen showed mildly reduced complement levels, C3 0 10 g/l (normal range 0 16-0 48 g/l) and C4 0 63 g/l (normal range 0 8–1.6 g/l), weak positive p-ANCA, mildly positive rheumatoid factor of 16 IU/ml (normal range 0–12 IU/ml) and anti-cardiolipin IgM antibody of 17 mplu/ml (normal range 0-12 mplu/ml). A computed tomography (CT) of chest–abdomen–pelvis was unremarkable. During this time, he was frequently requiring prednisolone (0.5 mg/kg) to control his symptoms. A bone marrow aspirate undertaken in July 2018 was hypercellular with features of erythroid and megakaryocytic dysplasia but no increase in blasts. A trephine biopsy was also hypercellular (80%) with architectural disarray, increased reticulin staining (grade 1–2) without significant para-trabecular fibrosis. Next generation myeloid sequencing (NGS; Illumina Myeloid Panel, Cambridge, UK) highlighted two pathogenic mutations: ASXL1 (NP_056153 2:p. Asp1032ValfsTer15) and SRSF2 (NP_003007 2:p. Pro95His), with variant allele frequencies of 49% and 37%, respectively. Based on these results, a diagnosis of primary MDS was established. IPSS-R score was 3, with an age-adjusted score of 2. He subsequently progressed to develop profound bilateral leg weakness and hip pain. Magnetic resonance imaging (MRI) showed foci of oedema-like signal within the thigh muscles, in keeping with myositis (Fig 1C). A rheumatology review concluded his symptoms were suggestive of atypical dermatomyositis, possibly attributable to the MDS. A skin biopsy was performed, which proved inconclusive. He remained anaemic and now occasionally required red cell transfusion support despite erythropoietin treatment (Fig 1D). Given his now chronic steroid dependence, he was treated with immunosuppression using anti-thymocyte globulin (ATG) and ciclosporin. However, there was again relapse of his constitutional, muscle and skin symptoms on reduction of prednisolone and persistence of his anaemia. In view of the severity and chronicity of his symptoms and the concurrent diagnosis of MDS requiring intermittent transfusion support, in a young fit patient, we elected to perform an allo-BMT. Tissue typing identified a 10/10 HLA (human leukocyte antigen) male sibling donor and he underwent a reduced intensity-conditioned haematopoietic stem cell transplant (HSCT) with fludarabine (30 mg/m/day on days 7 to 3), melphalan (140 mg/m on day 2) and alemtuzumab (20 mg/day on days 8 to 4 for in vivo T-cell depletion) in April 2019. His post-transplant course was complicated by persistent stage 2 chronic skin graft-versus-host-disease (GVHD), requiring extra-corporeal phototherapy. At three months post-transplant, peripheral blood showed 91% T-cell donor chimaerism. Post-transplant NGS showed no evidence of the prior pathogenic ASXL1 and SRSF2 mutations. He is currently transfusion-independent, has been weaned off steroid completely, does not require any analgesia and has no further systemic symptoms. He remains on mycophenolate mofetil and ciclosporin as treatment for chronic GVHD. Our case highlights several interesting points. Firstly, the true chronology of the autoimmune symptoms and the MDS diagnosis is difficult to establish. Our patient had a long history of AIMs prior to presentation, but he also had a ‘smouldering’ borderline MCV for at least six years. This is particularly significant as several observational studies suggest that chronic immune stimulation can promote the development of myeloid malignancies. AIMs can occur before, correspondence