Update on romiplostim therapy for immune thrombocytopenic purpura

Two cases of hematologic cancer were observed, consisting of lymphoma and myelodysplastic syndrome in one patient each in the standard-ofcare group. Bone marrow reticulin was found in one romiplostim-treated patient during 6 months posttreatment follow up, with the level being within the normal range (grade 2).

Thrombopoietin mimetics challenge the conventional wisdom about controlling ITP

Chronic immune thrombocytopenic purpura (ITP) affects 60,000 adults in the United States and is associated with the risk of life-threatening hemorrhage. For decades, the standard treatments included glucocorticoids and splenectomy. The advent and subsequent regulatory approval of the thrombopoietin mimetics romiplostim (Nplate) and eltrombopag (Promacta) have not only added to the therapeutic arsenal for this orphan disease but also successfully challenged the conventional wisdom that the key to controlling ITP is to reduce platelet destruction. Instead, these agents work by increasing intramedullary platelet production and are thus able to outpace the rate of peripheral destruction.

As reported by Kuter and colleagues last November in The New England Journal of Medicine, romiplostim is safe, well tolerated, and highly effective in the adult population with chronic ITP, including individuals with an intact spleen. Among the remaining questions regarding its use are: Where in the sequence of treatments for ITP do thrombopoietin mimetics belong? What is the long-term safety of these agents, given the changes to the bone marrow microenvironment that they induce? And, what will the cost impact be of a treatment that is designed for disease maintenance as opposed to providing a cure.

Thrombopoietin mimetics have not been widely tested for the treatment of pediatric ITP. Two small trials have shown that in children with disease that has been refractory to all standard approaches (with the exception of splenectomy), romiplostim is well tolerated, effective, and results in a meaningful reduction of clinically significant bleeding episodes. These data are preliminary but nevertheless provocative, and they offer the potential for new hope to children with chronic refractory ITP. Additional experience will be required to prove long-term safety and tolerability in the pediatric population before these new agents will be adopted into standard practice.

— David M.J. Hoffman, MD, FACP
Tower Hematology Oncology Medical Group
Beverly Hills, CA

Three deaths occurred during the study treatment period, including one death due to pneumonia in one romiplostim-treated patient and two deaths due to hepatic failure and cardiorespiratory arrest, respectively, in two patients in the standard-of-care group. Three additional deaths due to metastatic lung cancer, left ventricular failure, and hepatic neoplasm occurred in the standard-of-care group during the 6-month posttreatment follow up. None of the deaths was attributed to study treatment. No neutralizing antibodies to romiplostim or thrombopoietin were detected.

Quality of life

Quality of life was assessed by the ITP Patient Assessment Questionnaire, consisting of 44 ITP-specific items on each of 10 scales ranging from 0 to 100 points each (with higher scores indicating better quality of life). Scores on two scales (Women’s Reproductive Health and Work Quality of Life) could not be assessed due to inadequacies of the statistical model used in the analysis. Of the eight scales assessed, clinically significant increases of 8–15 points were observed for both treatment groups on all but the Fatigue scale. The romiplostim treatment group showed statistically greater improvements on the Symptoms (P = 0.01), Bother (P = 0.008), Activity (P = 0.02), Psychological (P = 0.049), Fear (P < 0.001), Social Quality of Life (P = 0.002), and Overall Quality of Life (P = 0.02) scales compared with the standard-of-care group, although the between-group differences of 2–8 points on these scales are of uncertain clinical significance.

Romiplostim in children with chronic refractory ITP

Few data exist on the effects of romiplostim therapy in pediatric ITP patients. In a recent single-blind, placebo-controlled trial,2 18 patients aged 2.5 to 16 years with chronic refractory ITP (baseline platelet count < 20 × 109/L) who had not undergone splenectomy were randomized to receive weekly SC injections of romiplostim (n = 12) or placebo (n = 6) for 12 weeks. Romiplostim was started at a dose of 1 μg/kg, escalated to 5 μg/kg at 5 weeks, and tapered afterward.

All patients had either no response or failed to maintain a response to at least two prior treatment modalities for ITP. All had received prior steroid treatment; 44% had received corticosteroids, IVIG, and anti-D immunogloblin in combination or sequentially; and 22% had received cytotoxic or immune-modulating agents. All such treatments were stopped 2 weeks prior to the study.

For patients in the romiplostim versus placebo group, mean age was 9.5 versus 7.0 years, 10 (83%) versus 3 (50%) were male, and median disease duration was 2.3 versus 3.0 years. Median baseline platelet counts were 10.5 × 109/L in both groups.