Romiplostim is an Fc fusion protein that augments thrombopoi
Romiplostim is an Fc-fusion protein that augments thrombopoiesis by binding to and activating the thrombopoietin receptor. It is approved for the treatment of thrombocytopenia in patients with chronic immune thrombocytopenic purpura who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. Romiplostim is under investigation for thrombocytopenia in patients with International Prognostic Scoring System (IPSS) low-risk or intermediate 1-risk MDS who are not currently receiving disease-modifying treatment and in patients who have MDS with grade 3 or 4 treatment-related thrombocytopenia. Few phase II clinical trials have demonstrated the efficacy of romiplostim for increasing PLT levels and decreasing thrombocytopenic adverse events either alone or in combination with hypomethylating agents.
The novel nonpeptide thrombopoietin receptor agonist eltrombopag was approved also for treatment of patients with chronic idiopathic thrombocytopenic purpura (ITP) in the United States and in Europe. Eltrombopag has been shown to effectively elevate PLT numbers and reduce thrombocytopenia-related complications in patients with chronic ITP or hepatitis C. This drug is now under investigation for thrombocytopenia in low-risk MDS.
Valproic 7-Nitroindazole is another drug which has shown an antileukemic activity mainly when used in association and in high-risk MDS and AML.
Its current use in low-risk MDS is neither clear nor well established (Table 1 shows an overview of the published studies).
Case study A 51-years-old woman came to our attention on February 2010 for decreased PLT count (PLT 39×109/L) and an increase in the mean corpuscular volume (MCV) without anemia (Hb 12.6g/dL, MCV 104.3fL) or leukopenia (WBC 5.06×109/L, neutrophils 3.50×109/L) which were discovered by chance after a routine check of the complete blood cell (CBC) count. Anti-PLT I and D antibodies were absent. Physical examination did not show splenomegaly, showed a severe obesity (body mass index=33), the patient was previously diagnosed with a depression treated with risperidone. Since this was suggestive for a MDS, on 25th of February 2010 a bone marrow (BM) evaluation was performed; the BM aspirate was not evaluable, while the trephine showed a cellularity of 30%, an erythroid slow maturation with an increase of haemosiderin, small and medium size of the megakaryocytes precursors and no abnormality or maturation defects of the myeloid progenitors, myeloid blasts were less than 5%, no sign of bone marrow fibrosis. Cytogenetic was normal. The patient was eventually diagnosed with a IPSS low and WPSS very low risk MDS; considering her comorbidities, and the absence of a sibling donor she was considered noneligible for allogeneic stem cell transplantation; the patient also refused to be enrolled in a clinical trial for the use of eltrombopag in low risk MDS. As the patient never reported any bleeding, the final decision was to adopt a watch and wait strategy and the thrombocytopenia remained stable until May 2010 (40×109/L). On June 2010 PLT count started to decrease and we decided, after having properly informed the patient, to start valproic acid starting 200mg per day with a weekly assessment of serum valproic acid concentration (normal range in our laboratory: 50–100mcg/L); the decision to start from such a low valproic acid dosage was made based on our limited experience with this drug. There was a progressive increase in drug dosage up to 1200mg per day on November 2010 (with this dosage valproic acid serum concentration permanently raised up to 70mcg/L). The PLT count stayed stable around 20×109/L until December 2010. Since January 2011 the serum level of valproic acid moved to the upper normal limit (100mcg/L) and PLT increased up to 30×109/L in January and up to 40×109/L in April, 50×109/L in June, 60×109/L in September when she had to decrease the dosage down to 1000mg per day due to tremor and sleepiness. In November PLT count was 72×109/L. She is currently under treatment with valproic acid 1000mg per day and her PLT count is constantly higher than 90×109/L (Fig. 1 shows the trend of PLT count according to VA serum concentration).