SAN FRANCISCO—Combining the monoclonal antibody rituximab with oral dexamethasone is effective, perhaps optimum, therapy for idiopathic/immune thrombocytopenic purpura (ITP), according to the results of a Phase III multicenter randomized study of 101 patients reported as Abstract #1 at the Plenary Session of the ASH Annual Meeting here by Francesco Zaja, MD, Chair of Hematology at the University of Udine in Italy.
The combination should, indeed, become standard salvage therapy for patients whose disease is unresponsive to oral steroids, particularly in those for whom splenectomy carries higher risks, Dr. Zaja told conference attendees.
He also presented data showing that when used upfront to treat adults newly diagnosed with ITP, the immunotherapy/steroid combination nearly doubled sustained responses (63% vs 36%)—defined as reaching platelet counts of at least 50×109/L at six months—when compared with the use of dexamethasone alone, raising the suggestion that the antibody could be included for initial therapy in some patients.
In salvage therapy the combination was used if patients didn't achieve platelet counts above 20×109/L after 30 days with oral dexamethasone alone. Over half of these patients (56%) achieved sustained responses, which compares favorably with splenectomy, Dr. Zaja noted.
He explained that he and his colleagues decided to compare oral dexamethasone alone (40 mg on each of the first four days of treatment) with the same steroid regimen plus rituximab (375 mg/m2 iv on Days 7, 14, 21, and 28) for initial therapy in order to get a clear finding about the effect of adding the antibody.
The primary objective was to compare sustained response. Secondary objectives were to evaluate safety, initial response (defined as reaching platelet counts of at least 50×109/L at 30 days), the efficacy of the combination in patients not responding to steroids, and possible predictive factors of the response, and to explore pharmacokinetic mechanisms relating to response.
“We found that the experimental arm was more effective than dexamethasone monotherapy in initial and sustained response, and the difference was statistically significant for both,” he said.
The initial response rate on an Intention to Treat basis was 68% with the combination compared with 27% in patients receiving dexamethasone alone.
“We believe that on the basis of these results, from this—the first randomized Phase III study of its type to be conducted—steroids still represent the first-line treatment, but we believe that rituximab can be given earlier in the course of the disease, and in preference to splenectomy, in patients who are refractory to steroid therapy.”
Both treatments were well tolerated, with a small increase in the incidence of “any” adverse events in the experimental arm and no difference in the incidence of serious adverse events. Three patients had significant adverse events—two with supraventricular tachycardia or convulsion, which resolved, and one with interstitial pneumonia, which responded to antibiotics. There were no toxic or hemorrhagic deaths (Grade 5 toxicity).
No particular clinical, laboratory, or pharmacokinetic factors predictive of response were identified, however.
‘Nice, Carefully Done’
ASH's 2008 President, Kenneth Kaushansky, MD, the Helen M. Ranney Distinguished Professor and Chair of the Department of Medicine at the University of California, San Diego, who moderated a news conference at which Dr. Zaja discussed the study, noted that for the last several years, ever since rituximab has been available, it has been used in small, nonrandomized studies, with promising results.
“An occasional patient will have a remission of their ITP, or an improvement, only to relapse later. And this was done in a very uncontrolled fashion.
“Dr. Zaja's study is nice because it's a randomized, carefully done study, and shows that the addition of rituximab greatly improves the response rate of patients with severe refractory ITP.”
Mechanism of Action
Dr. Kaushansky told OT afterwards that rituximab is clearly depleting B cells—as it does in patients with lymphoma—which is how it works in other autoimmune diseases:
“Since B cells are producing the auto-antibody that's directed against the platelets, the simplest explanation is that rituximab reduces the auto-antibody production that is responsible for the platelet destruction,” he explained.
Important in Oncology
Asked for his opinion for this article, George Canellos, MD, the William Rosenberg Chair and Professor of Medicine at Harvard Medical School and a senior physician in the Department of Hematologic Oncology at Dana-Farber Cancer Institute, noted that optimizing therapy for auto-immune disease and ITP is crucial in hemato-oncology in general and that he wasn't greatly surprised by Dr. Zaja's results: “We've used rituximab for patients who have failed steroids, or gotten an inadequate job with steroids. And it works—we know that! We have bailed people out—with rituximab—of serious cytopenias that did not respond to steroids,” he said.
“But what Dr. Zaja did was to combine it upfront, and to ask the questions of whether or not the responses would be higher, and whether they would last longer—and indeed, that's what he showed.
“In cancer,” Dr. Canellos continued, “the major diseases that cause this are the small lymphocytic neoplastic disorders—for example, chronic lymphatic leukemia or small lymphocytic lymphoma, which are very closely related, but both have an association with other autoimmune phenomena. Although ITP may be the most common of these, patients can have autoimmune hemolytic anemia, or other autoimmune manifestations that are quite varied.
“And so, in the management of these people—some of them may be elderly, so a splenectomy is not an easy thing to contemplate—the value of rituximab is that it really has no acute toxicities of any severity, and you might bail somebody out of a serious thrombocytopenia with it.”
Dr. Canellos pointed out that the literature is filled with other immunosuppressants having beneficial effects on refractory ITP: “Most of these are antineoplastic agents and they are commonly used in practice, and can actually bail out patients with ITP.
“But rituximab has turned out to be the best one,” and Dr. Canellos said that his cautious approach in oncology practice, now confirmed by Dr. Zaja's Phase III findings, would be to start with steroids and use the combination if that approach failed.