ASH Annual Meeting

ImageATLANTA—Just as the use of erythropoiesis-stimulating agents (ESAs) in anemic patients with myelodysplastic syndromes (MDS) is based on baseline endogenous erythropoietin levels and red blood cell transfusion requirements, baseline endogenous thrombopoietin (TPO) levels and platelet transfusion requirements can likewise predict the response of thrombocytopenic MDS patients to treatment with romiplostim, a TPO receptor agonist. That was the conclusion of a study (Abstract 2801) reported here at the American Society of Hematology Annual Meeting by Mikkael A. Sekeres, MD, MS, Director of the Leukemia Program and Chair of the Hematology/Oncology Pharmacy and Therapeutics Committee at the Cleveland Clinic Taussig Cancer Institute. Recommendations for use of ESAs have been incorporated into quality-of-care treatment guidelines for anemic MDS patients based on the prediction of the likelihood of a response to treatment. “Similarly, we looked at baseline thrombopoeitin and platelet transfusion needs to predict response to romiplostim, and found that we were able to predict which patients are more likely to respond.” Sekeres, OT's Clinical Advisory Editor for Hematology/Oncology and Chair of the FDA's Oncologic Drugs Advisory Committee, explained that thrombocytopenia, which occurs in about 50 percent of patients with low- to intermediate-1 MDS, is associated with shortened survival and increased risk of acute myeloid leukemia (AML). Thrombocytopenia and abnormalities of platelet function in MDS contribute to an increased risk of bleeding. “Beyond disease-modifying therapies, platelet transfusions are the only treatment for thrombocytopenia in MDS,” he said. “No thrombopoietic agents are approved for use in MDS.” Romiplostim, a fusion protein analog of thrombopoietin, is approved for use in chronic idiopathic thrombocytopenic purpura (ITP), and there are now results from five MDS trials suggesting that romiplostim treatment improves thrombocytopenia in MDS patients, he said. The study reported at the ASH meeting included 250 MDS patients who received romiplostim monotherapy in a multicenter, placebo-controlled study; and the resulting model was then validated in a distinct population in a second study. Romiplostim was discontinued early, however, he said, due to concerns by the Data Monitoring Committee that the potential small benefit seen in the reduction of bleeding did not outweigh the potential risk for disease progression to AML, and that similarly, the transient increases in blast cell counts could put patients at risk for AML. Data Updates In 2011, use of romiplostim was stopped when the drug-treated group had increased, but reversible, peripheral blast counts as well as progression to AML. In another study at the ASH meeting, an update on all patients monitored over the last year, Hagop Kantarjian, MD, Chair of the Department of Leukemia at the University of Texas MD Anderson Cancer Center, reported that the hazard ratio for developing AML on romiplostim had decreased from 2.2 to 1.2 (Abstract #421). In his presentation of the 58-week update of the data, he noted that two other cases of AML had developed in the placebo arm that had not been recorded in time for the interim analysis in 2011. “If these two cases had been recorded correctly, the data review board may have considered the data in a different light,” he said. The updated data showed that the incidence of AML is six percent with romiplostim and 4.9 percent with placebo. “Most cases of peripheral blast increases resolved after discontinuation,” he said. “Most patient blast increases were transient and did not signify AML transformation. The number of platelet transfusions was significantly reduced in the group with less than 20,000 blasts. The patients in the group between 20,000 and 50,000 blasts showed reductions in clinically significant bleeding events. And in those with less than 10,000 blasts, the worst group of patients who are refractory to platelet transfusions, there was an increase in platelet counts in 30 percent of patients.” With longer follow-up, the increased rate of leukemic transformation is now the same in both arms, Sekeres noted. “What initially was a very concerning safety signal may have been abrogated with longer-term follow-up. Now we have longer-term follow-up data to support the safety of romiplostim in appropriately selected, lower-risk MDS patients and in choosing which patients are most likely to benefit from the drug.” Study Details In the study, hematologic improvement of platelets was defined as eight consecutive weeks of an absolute platelet increase of 30,000/L (for patients with baseline platelet counts more than 20,000/L) or an increase from less than 20,000/L to more than 20,000/L and by at least 100 percent (for patients with baseline platelet counts less than 20,000/L). The rates of hematologic improvement of platelets were significantly higher with use of romiplostim (36.5%) compared with placebo (3.6%), as were the median platelet counts from Week 4 on, Sekeres noted. Data from the trial were used to examine the relationship between baseline TPO levels and platelet transfusion needs and outcomes. Platelet response was defined as meeting the same criteria, but for one week as opposed to for eight consecutive weeks. “As with the ESA model, we developed a TPO model to obtain predictive scores,” he said, and this TPO model was validated using data from a previous Phase 1/2 study of romiplostim in lower risk thrombocytopenic MDS patients. Among the 167 romiplostim-treated patients, those with hematologic improvement of platelets had lower median baseline TPO levels and lower mean baseline TPO levels, and were less likely to have had six or more platelet units transfused in the past year. For those with a platelet response during 50 percent or more of the study weeks, median baseline TPO levels were lower, as were mean baseline TPO levels and the likelihood of having had six or more platelet units transfused in the past year. A history of prior platelet transfusion (less than six vs six or more units in the past year) was a better predictor of platelet response than baseline platelet counts, the researchers found. The model was then validated in a second independent study, showing a similar pattern of response rates associated with baseline TPO levels and the presence of past platelet transfusions. “For thrombocytopenic patients with lower-risk MDS, lower baseline TPO levels and limited platelet transfusion history—less than six units in the past year—predict a greater likelihood that a patient will have a platelet response when treated with romiplostim.” Elaborating in an interview, Sekeres said, “This is a drug that is effective in treating lower-risk MDS patients who have thrombocytopenia. We now have a model to predict who is most likely to respond in this patient population. If romiplostim were approved by FDA for lower-risk MDS, we would be able to predict which patients are likely to respond to the drug, just as we now are able to make predictions for ESA use.” For MDS patients with excess blasts, though, the drug should be used only with extreme caution, he stressed. ‘Great Model, Now Validated, but Still Experimental’ Asked for her opinion, Rena Buckstein, MD, Head of the Hematology Psychology Group and Myelodysplastic Syndrome Program at the University of Toronto, said, “This is a great model that has been validated. The numbers are consistent. The prognostic score is similar in concept to the score for erythropoietin levels and number of cells transfused. A patient who has low TPO levels and has not had many platelet transfusions is more likely to respond to romiplostim. The biology is plausible. But, the point remains that using this in thrombocytopenia and MDS is still experimental. This study won't change my practice now, but it might in the future if romiplostim is indicated for MDS… I might measure TPO levels with a now commercially available test if I was thinking of putting a patient on romiplostim. It would be good to know the likelihood of response.” She added that she might test for TPO levels if she was using the small molecule agonist eltrombopag, which also has been shown to be effective in ITP and is now in clinical trials in MDS. “If I see there is no increase in leukemia in the romiplostim clinical trials, this would be an interesting prognostic scoring system to validate in other drugs as well,” she said. Safety Still Being Evaluated Kantarjian noted that romiplostim was effective in increasing platelet counts, decreasing bleeding and the need for platelet transfusions in some patients, and improving erythroid and neutrophil lineages in addition to platelets. “The safety of romiplostim is still being evaluated, and studies with the drug will be re-initiated,” he said. “My belief is that now we are ready in go with future therapies that address combinations of hypomethylating agents and romiplostim in MDS, in the same way we have done with hypomethylating agents and granulocyte-colony stimulating factor and EPO. “We should also investigate romiplostim in patients with the highest risk of bleeding and cytopenia complications. These are patients who have failed hypomethylating agents and have MDS with significant cytopenia, rather than ones who have transformed to AML.”

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