David Bowen

Safety and efficacy of romiplostim in patients with lower-risk myelodysplastic syndrome and thrombocytopenia.

PURPOSE To assess the safety and efficacy of romiplostim, a peptibody that increases platelet production, for treatment of thrombocytopenic patients with myelodysplastic syndromes (MDS). PATIENTS AND METHODS Eligible patients had lower-risk MDS (International Prognostic Scoring System low or intermediate 1), a mean baseline platelet count <or= 50 x 10(9)/L, and were only receiving supportive care. Patients received three injections of 300, 700, 1,000, or 1,500 microg romiplostim at weekly intervals. After evaluation of platelet response at week 4, patients could continue to receive romiplostim in a treatment extension phase for up to 1 year. RESULTS All 44 patients who enrolled completed the treatment phase; 41 patients continued into the extension phase. Median platelet counts increased throughout the study, from fewer than 30 x 10(9)/L at baseline to 60, 73, 38, and 58 x 10(9)/L at week 4 for the 300-, 700-, 1,000-, and 1,500 -microg dose cohorts, respectively. A durable platelet response (per International Working Group 2000 criteria for 8 consecutive weeks independent of platelet transfusions) was achieved by 19 patients (46%). The incidence of bleeding events and platelet transfusions was less common among patients who achieved a durable platelet response than those who did not (4.3 v 39.3 per 100 patient-weeks). Forty-three patients (98%) reported one or more adverse events. Treatment-related serious adverse events were reported in five patients (11%), all of whom were in the 1,500-microg dose cohort. Two patients progressed to acute myeloid leukemia during the study. No neutralizing antibodies to either romiplostim or endogenous thrombopoietin were seen. CONCLUSION Romiplostim appeared well-tolerated in this study and may be a useful treatment for patients with MDS and thrombocytopenia.

Analysis of mitochondrial DNA in 104 patients with myelodysplastic syndromes

OBJECTIVE To determine the frequency and spectrum of somatic mutations of mitochondrial DNA (mtDNA) in bone marrow of patients with myelodysplastic syndrome (MDS). MATERIALS AND METHODS Analysis included 104 patients with MDS (24 refractory anemia, 32 refractory anemia with ringed sideroblasts, 34 refractory anemia with excess of blasts, 7 refractory anemia with excess of blasts in transformation to acute leukemia, and 7 chronic myelo-monocytic leukemia), 3 patients with acute myeloid leukemia from MDS, and 36 patients with myeloproliferative disease (23 chronic myeloid leukemia, 9 polycythemia vera, 4 idiopathic myelofibrosis). Mutation scanning was performed using heteroduplex analysis with denaturing high-performance liquid chromatography (dHPLC). The entire mitochondrial genome was amplified in 67 overlapping polymerase chain reaction fragments carefully optimized regarding DNA melting profiles. Abnormal dHPLC findings were confirmed by DNA sequencing. RESULTS Heteroplasmic mtDNA mutations, mostly transitions, were identified in 56% of MDS and 44% of myeloproliferative disorders patients. In MDS, mutation frequency increased with age and more-advanced disease. Mutational spectra showed no hot spots and were similar in different types of MDS. Heteroplasmic mutations generally did not represent known polymorphisms, and about half of them affected conserved amino acids or nucleotides. Mutations were less frequent in protein encoding genes (50 per 10(6) base pairs) than other mitochondrial genes (transfer RNAs, ribosomal RNAs, and control region; about 80 per 10(6) base pairs). CONCLUSIONS As mitochondria often show ultrastructural abnormalities in MDS, including pathological iron accumulation, mitochondrial dysfunction may contribute to MDS pathology. We found a high frequency of acquired mtDNA mutations in MDS. However, their functional importance remains unclear, considering that genotype correlates poorly with phenotype in mitochondrial diseases. The clonally expanded mtDNA mutations in MDS support the concept of age-related damage to mtDNA in hematopoietic stem cells.

Management of Low-Risk MDS

The majority of MDS patients have “low-risk” disease. Although many patients require no interventional therapy initially, the goal for those with symptomatic cytopenias is usually an improvement in quality of life with optimizing overall survival. A small proportion of predominantly younger patients may be considered for allogeneic stem cell transplantation. For the majority of symptomatic patients, therapy is directed at improving anemia. Erythropoiesis-stimulating agents will improve hemoglobin concentration in up to 60–90 % of carefully selected patients, specifically those with low transfusion burden or absent transfusion requirement and low baseline serum erythropoietin concentration. Emerging data indicates a potential survival advantage for ESA therapy in MDS patients. Younger patients with normal karyotype and non-sideroblastic low-risk MDS may respond to immunosuppressive therapy. Lenalidomide induces high-frequency red cell transfusion independence in patients with del(5q) MDS.