Transformation of MDS/MPN‐RS‐T to AML: Trisomy 13, resistant thrombocytosis and transient disease control with oral busulfan therapy
Authors: Aisling Barrett, Mark Catherwood, Patrick Thornton, Philip Murphy, John Quinn
Journal: American Journal of Hematology (2017)

We read with great interest the paper published by Patnaik et al.—“Refractory anemia with ring sideroblasts (RARS) and RARS with thrombocytosis (RARS-T): 2017 update on diagnosis, risk-stratification, and management1”—and report on a case of what is now known as myelodysplastic syndrome (MDS)/myeloproliferative neoplasm (MPN) with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T) which involved the rare complication of transformation to acute myeloid leukemia. A 68-year-old gentleman presented in 2014 with fatigue on a background of radical retropubic prostatectomy (RRP) for prostate cancer seven years prior. His hemoglobin (Hb) on presentation was 10 g/dL with a platelet count of 592 × 109/L. Bone marrow aspirate revealed hypercellularity with dysplastic megakaryocytes, dyserythropoiesis and increased numbers of ring sideroblasts (>15%) in keeping with a diagnosis of MDS/MPN-RS-T. Molecular analysis confirmed the presence of the SF3B1 mutation, known to be present in approximately 90% of MDS-RS cases and the majority of MDS/MPN-RS-T cases.2 Baseline karyotype was normal and the JAK2 mutation was not present. He was managed with erythropoietin (EPO) injections prior to representation in July of 2016 with worsening fatigue; he was found to have a white cell count (WCC) of 30 × 109/L and a platelet count of 1153 × 109/L with bone marrow sampling showing transformation to acute myeloid leukemia (AML) with 35% blasts. Karyotype confirmed the acquisition of trisomy 13 but there was no FLT3-ITD mutation identified by molecular analysis. There was no response to hydroxyurea and he received two cycles of azacytidine but failed to respond, with a rising white cell count, and then was treated with daunorubicin and cytarabine (DA). Bone marrow aspirate following this cycle of chemotherapy revealed 60% blasts and, at this point, the options of palliative management or further chemotherapy were discussed. Intravenous fludarabine, cytarabine and idarubicin (FLAG-Ida) chemotherapy was then commenced; however again there was no response with a rapidly rising WCC and platelet count. At this point, the patient was started on oral busulfan 4–6 mg daily which had led to a swift reduction in the WCC and platelet count and a stable period of four months of maintenance as an outpatient, as demonstrated in Figure 1. Subsequent deterioration required intermittent doses of mitoxantrone to control the WCC before the patient died from progressive disease. Change in WCC and platelet count over time The hybrid nature of MDS/MPN-RS-T has been reflected in the 2016 World Health Organization (WHO) revision of the classification of myeloid neoplasms and acute leukemia, where it is now classified as an MDS/MPN overlap disorder.3 It is a rare crossover disorder comprising 2–3% of MDS diagnoses. Diagnosis involves the following criteria: thrombocytosis >450 × 109/L, refractory anemia, bone marrow dyserythropoiesis, ring sideroblasts accounting for greater than 15% of bone marrow progenitors and abnormal megakaryocytes. MDS/MPN-RS-T has a number of recognized genetic associations, most commonly the SF3B1 mutation which is seen in 90% of cases; other less commonly associated gene mutations, which are associated with the pathology of myeloproliferative disease, include JAK-2 (43–57%), CALR (3%) and MPL (3%). Interestingly, it has been hypothesized that MDS with ring sideroblasts (MDS-RS) can transform into MDS/MPN-RS-T with acquisition of the JAK-2 mutation.2 Poor prognostic factors in MDS/MPN-RS-T include older age (>80), low Hb (<8 g/dl), abnormal cytogenetics, the presence of SETBP-1 or ASXL-1 mutations and the absence of SF3B1 or JAK-2 mutations.4 It is interesting to compare outcomes and variables between MDS/MPN-RS-T and its sister conditions MDS-RS and essential thrombocythemia (ET). A recent study has shown that survival in MDS/MPN-RS-T significantly exceeds that of MDS-RS (76 months versus 63 months) and compares poorly with survival in ET (115 months).2 Thrombotic events in MDS/MPN-RS-T and ET were shown to exceed those of MDS-RS, which may be expected considering the disease characteristics. Rates of transformation to AML were similar in the two MDS subtypes but lower in ET, the myeloproliferative counterpart. This case is noteworthy as MDS/MPN-RS-T has a relatively low transformation rate to AML, with a leukemic transformation rate per 100 years of 1.82. A recent paper described two cases; both were patients who were aged greater than 70 years and had been diagnosed with MDS/MPN-RS-T at least two years prior to transformation.4 One patient had cytogenetics exhibiting clonal evolution, with 7q deletion detected in the marrow following transformation, and died from neutropenic sepsis with chemotherapy; the second did not have clonal evolution and was undergoing chemotherapy at the time of publication. Another case report involved a 70-year-old patient who died from AML transformed from MDS/MPN-RS-T; this case involved the development of a monosomy 7 clone in the leukemic marrow.5 The refractoriness of the transformed AML in our case to multiple lines of chemotherapy also serves to highlight the aggressive nature of the disease. In summary, we describe a case of MDS/MPN-RS-T with transformation to treatment-refractory AML highlighted by the presence of trisomy 13 and resistant thrombocytosis. Although transient, our patient's relative “response” to oral busulfan was unexpected but does suggest that this therapy may be clinically useful in similar cases.