Describe a rapid clonal evolution to AML with monossomy 7 in an aplastic anemia (AA) patient.

A 17-year-old patient was diagnosed with severe aplastic anemia after a history of fatigue, mucocutaneous bleeding and pancytopenia. Bone marrow (BM) aspirate was hypocellular and had no dysplastic changes. Trephine biopsy confirmed 5% cellularity and absence of increased immature progenitors; reticulin fibrosis was not observed. Conventional cytogenetics showed a 46, XY karyotype; a small paroxysmal nocturnal hemoglobinuria (PNH) clone was present in red cells, neutrophils and monocytes. Chromosome breakage analysis for Fanconi anemia was unremarkable, and telomere length was within the normal range. The patient had no HLA-matched donor, and once hATG was discontinued in Brazil and eltrombopag was unavailable, he was included in a group of patients treated with upfront immunosuppressive therapy (IST) with subcutaneous alemtuzumab and cyclosporine; The patient achieved a partial response after 3 months of treatment. Cyclosporine was gradually tapered and was completely stopped after a year of treatment. This patient was lost to follow-up visits for six months and returned after four years of IST, complaining about worsening of fatigue and gingival bleeding. Complete blood count was notable for a loss of the achieved PR, and the presence of a small population of dysplastic monocytes. Revaluation of BM showed a hypercellular smear, and the presence of 60% of immature myeloid cells composed by myeloblasts and monocytes precursors. BM immunophenotyping was compatible with acute myelomonocytic leukemia. Conventional cytogenetics detected a monosomy of chromosome 7 and a trisomy of chromosome 21. Molecular studies for FLT3 and NPM1 mutations, and RUNX1-RUNX1T1 and CBFB-MYH11 fusion genes were negative. The PNH clone size remained stable. The patient was started on standard AML chemotherapy with cytarabine and daunorubicin. An hematologic complete remission with a negative minimal residual disease was achieved. Due to an acute appendicitis during AML induction, the patient awaits consolidation therapy with an haploidentical hematopoietic stem-cell transplant (HSCT) from his brother.

Frontline therapy for severe aplastic anemia patients younger than 40 years who have an HLA-matched sibling donor is HSCT. Triple IST with eltrombopag, hATG and cyclosporine is now considered the standard frontline therapy for patients older than 40 years and those who lack a suitable HLA-matched donor. Once hATG was discontinued in many countries, previous studies have reported outcomes of replacing hATG with rabbit ATG, cyclophosphamide, or alemtuzumab. Clonal evolution to myeloid neoplasms is a recognized complication of IST and patients with AA may develop secondary MDS/AML, with the main associated factors being longer disease duration, presence of mutations with an adverse prognosis, a short telomeric length and the development of cytogenetic abnormalities (CAs). The most recurrent CAs include total or partial loss of chromosome 7, trisomy 8 and 13q deletion, and, less frequently, trisomy 6, trisomy 15 and trisomy 21.

T-cell-mediated autoimmune diseases, such as AA, have a higher risk of progression to AML/MDS dur to development of somatic mutations and CAs. Monosomy 7 independently represents a poor prognostic factor due to the high rate of progression to acute leukemia, such as occurred with the patient reported.