In this study, researchers investigated the combination of thrombopoietin receptor agonists (TPO-RAs) with immunosuppressive agents to treat refractory immune thrombocytopenia (ITP). TPO-RAs are medications that stimulate the body to produce platelets, whereas immunosuppressive medications suppress the body’s immune system from targeting platelets. They are both used to treat ITP. Participants were considered refractory if they failed rituximab, TPO-RAs, and splenectomy (or if splenectomy was declined). This means that they had already tried and failed at least one TPO-RA. It is worth noting that some of the information from this study was previously reported in another paper.
Thirty-nine participants were recruited for this study and the average length of their ITP was 57 months. Overall, participants had an average platelet count of 10,000/µl at the start of the study.
Participants received either romiplostim (Nplate®) or eltrombopag (Revolade®/Promacta®) as the TPO-RA, in addition to primarily mycophenolate mofetil but also azathioprine, cyclosporin, everolimus, or cyclophosphamide as the immunosuppressive drug.
Researchers considered a ‘response’ to therapy as achieving a platelet count greater than 30,000 and at least double the baseline platelet count for over three months. A ‘complete response’ occurred if the participant’s platelet count was greater than 100,000 for over three months.
Overall, 24/39 participants achieved a complete response, 6/39 achieved a response, and 9/39 failed to respond to the combination therapy. Within the group that responded to therapy, it took approximately 30 days after starting treatment to achieve a response, after which the platelet response continued for an average duration of 15 months.
After 21 months, 19 of the 30 participants who responded maintained their response, and 11 relapsed. During the follow-up period, seven participants experienced bleeding symptoms (four from the group that did not respond to treatment, and three from the group that initially responded but later relapsed). A total of 17/39 participants experienced at least one adverse event; 12 of whom had a serious adverse event, such as a blood clot.
Comments from PDSA Medical Advisors
In ITP, thrombocytopenia is the eventual outcome when platelet antibodies (step 1) lead to their rapid clearance in the spleen and elsewhere (step 2) that cannot be matched by platelet production (step 3). Immunosuppressive agents inhibit the first step, intravenous immune globulin and corticosteroids are examples of drugs that slow or stop step 2, and TPO-RAs act at step 3 to increase platelet production. This small study reemphasizes the principle that combining drugs that act on different steps in the process that leads to thrombocytopenia can be beneficial even when interfering with individual steps is ineffective. This combination of therapy was effective in the majority of patients but was not effective for all patients. More than half the patients had a significant adverse event (not necessarily due directly to treatment) which is a concern with combining medications. It is worth noting that there are other similar reports of combined treatment and, in general, using TPO-RAs as one of the agents, is important for optimal success. The success of additional immunosuppressive agents, which generally work primarily on T cells (in this case to block them from helping B cells and plasma cells to make antiplatelet antibodies) reinforces the important role of T cells in ITP, at least in difficult cases.
This study investigated the outcome for patients with ITP who received early second-line treatment (within three months of their first ITP treatment) compared to those who remained on first-line therapy. Second-line treatments included eltrombopag, romiplostim, rituximab, azathioprine, mycophenolate mofetil (MMF), splenectomy, or a combination of these. Platelet counts, bleeding, and the need for steroids were assessed in this study.
Health records of 8,268 patients with ITP were analyzed. Results showed that 88.6% of these patients did not receive second-line treatment within the first three months. Among those who did, 42.5% received rituximab, 43.6% received a TPO-RA, and 11.5% received any of multiple second-line therapies.
Overall, individuals who received early second-line treatment had a lower baseline platelet count (between 10,000-28,000) compared to those who received first-line treatment only (~67,000). The group that received multiple second-line therapies had the highest proportion of individuals who had at least one bleeding event within three months of treatment initiation.
After 3-6 months from starting treatment, all patients increased their platelet count from baseline, whether they received early second-line treatment or remained on first-line treatment. Similarly, there was a decrease in bleeding events in all groups. The largest decrease in the number of bleeding events was seen in those who received multiple second-line therapies, which was the group with the highest number of bleeding events at the start of treatment.
Only a small proportion of patients had follow-up data regarding their need for steroid use between 3-6 months. Nevertheless, the study found that 13/33 individuals (39%) who received early second-line treatment needed steroids in this timeframe, whereas for those who did not receive second-line therapy, 53/61 (87%) required steroids.
Comments from PDSA Medical Advisors
Guidelines and expert opinion concur that corticosteroids as the initial treatment for adults with ITP should be used for the shortest period possible, rarely more than 3-4 weeks. By then most individuals have received maximum benefit and protracted use increases toxicity without improving long-term outcomes. This small study affirms the feasibility of “early” introduction of second-line agents as a means to reduce exposure to corticosteroids.