Jason Gotlib, MD, MS

2010-04-27

Dr. Gotlib indicated no relevant conflicts of interest.

Kantarjian H, Fenaux P, Sekeres MA, et al. Safety and efficacy of romiplostim in patients with lower-risk myelodysplastic syndrome and thrombocytopenia. J Clin Oncol. 2010;28:437-44.

In the field of supportive care for myelodysplastic syndromes (MDS), an anthropomorphic view would leave platelets feeling neglected. Erythropoiesis-stimulating agents and granulocyte colony-stimulating factors were already available for clinical use before the discovery of thrombopoietin and its receptor c-MPL in the mid 1990s. Development of first-generation thrombopoietins (e.g., recombinant human megakaryocyte growth and development factor, rHuMGDF) ultimately faltered because of the occasional appearance of neutralizing antibodies to endogenous thrombopoietin and thrombocytopenia in trials of healthy volunteers undergoing platelet donation. Other agents, such as interleukin-11, demonstrated modest benefit in MDS but never gained traction. Non-immunogenic thrombopoiesis-stimulating agents have now emerged, including the TPO nonpeptide mimetic eltrombopag, TPO antibody mimetics, and the peptibody romiplostim. Romiplostim and eltrombopag have demonstrated efficacy in short- and/or long-term studies of immune thrombocytopenic purpura¹ and are now FDA-approved for this condition.

Because of the presence of TPO receptors on early hematopoietic progenitors, and pre-clinical data demonstrating that TPO can stimulate myeloid blasts,² trepidation has surrounded the use of TPO receptor agonists in MDS. The initial foray of romiplostim in thrombocytopenic MDS patients is now reported by Kantarjian and colleagues. The study was conducted in subjects with lowerrisk disease having platelet counts <30,000/mm³, and treatments were done in dose cohorts of 300, 700, 1,000, and 1,500 mcg subcutaneously weekly. Increases in the median platelet count at the respective doses were to 60, 73, 38, and 58 x 103/mm³ at week 4. According to International Working Group (IWG), 2000 criteria, 45 percent of patients had complete or major platelet responses during the treatment phase, with a higher proportion of responses in patients with a platelet count >20,000/mm³ versus <20,000/mm³ (57 percent vs. 25 percent, respectively). There was no difference in platelet response rates among the dose cohorts. In the extension phase of 41 patients, 46 percent of patients experienced durable platelet responses and the median duration of treatment was 37 weeks. Bleeding events and platelet transfusions were less common among patients who achieved a durable platelet response compared to those who did not (4.3 vs. 39.3 per 100 patient-weeks). Regarding clinically relevant safety issues, four patients experienced transient increases in marrow blast counts, and two progressed to acute myeloid leukemia; these results were felt to be within the expected frequency of this MDS population. Of the 24 patients for whom pre- and post-treatment marrow reticulin studies were available, the reticulin grade was increased in seven, unchanged in 10, and decreased in seven. Neutralizing antibodies to either romiplostim or endogenous TPO were not identified, and no drug-attributable deaths occurred.

While romiplostim appears to be a feasible option for low/intermediate-1-risk MDS patients, several points merit consideration. Although 700 mcg weekly was selected for future studies, there was no dose-response relationship; therefore, evaluation of clinical efficacy at lower dose ranges is justified. In addition, as this trial was not designed to elucidate romiplostim’s impact on the rate of AML transformation, a randomized, placebo-controlled study with longer followup is needed. Because of the very low frequency of severe thrombocytopenia in de novo, untreated low/intermediate-1-risk patients,⁴ this study group may have limited applicability to the general MDS population. The greatest need for platelet-stimulating agents will be in patients with clinically significant bleeding and/or those requiring chronic platelet transfusions — features of higher-risk patients. Trials assessing romiplostin and similar agents in combination with lenalidomide and hypomethylating drugs are currently underway. Reducing therapy-related thrombocytopenia may allow preservation of dose intensity and frequency with the potential for optimizing the frequency and quality of remissions.

1. Bussel JB, Kuter DJ, Pullarkat V, et al. Safety and efficacy of long-term treatment with romiplostim in thrombocytopenic patients with chronic ITP. Blood. 2009;113:2161-71.
2. Bussel JB, Provan D, Shamsi T, et al. Effect of eltrombopag on platelet counts and bleeding during treatment of chronic idiopathic thrombocytopenic purpura: a randomised, double-blind, placebo-controlled trial. Lancet. 2009;373:641-8.
3. Corazza F, Hermans C, D’Hondt S, et al. Circulating thrombopoietin as an in vivo growth factor for blast cells in acute myeloid leukemia. Blood. 2006;107:2525-30.
4. Kao JM, McMillan A, Greenberg PL. International MDS risk analysis workshop (IMRAW)/IPSS reanalyzed: impact of cytopenias on clinical outcomes in myelodysplastic syndromes. Am J Hematol. 2008.83:765-70.

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