No accepted medical therapy exists for hereditary hemorrhagic telangiectasia (HHT), an autosomal dominant disorder that produces telangiectasias on mucocutaneous surfaces and arteriovenous malformations in visceral organs. Management includes treating complications, and many patients present with epistaxis and gastrointestinal (GI) bleeding, requiring iron supplementation and blood transfusion. However, preliminary results from an ongoing pilot study now demonstrate an efficacy signal with pomalidomide, a thalidomide derivative, for patients with HHT and refractory bleeding.
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Interim results of this phase I trial, begun in late 2015 and supported by Celgene, were presented at the 2016 American Society of Hematology Annual Meeting in San Diego. Cleveland Clinic Cancer Center hematologist Keith McCrae, MD, leads the study.
“The rationale for attempting pomalidomide in HHT is based on my personal experience with thalidomide and several reports in the literature suggesting that thalidomide may have activity in HHT,” Dr. McCrae says. “Pomalidomide likely shares mechanistic activity with thalidomide, but in clinical experience it seems to have less toxicity.”
The primary endpoint is a 50 percent reduction in the need for transfusion or parenteral iron therapy.
Significant responses to pomalidomide
Study subjects are adults with HHT and GI bleeding requiring at least four units of transfused blood or four doses of intravenous iron in the preceding four months, or those with epistaxis requiring two units transfusion or 500 mg of intravenous iron in the preceding four months, and with an epistaxis severity score (ESS) ≥ 4.
Treatment begins with a 1 mg/day dose of pomalidomide that increases by 1 mg every month if bleeding does not cease, up to a maximal dose of 5 mg/day. Once bleeding stops or the patient reaches a 5 mg daily dose, the maximum dose is maintained for four months before tapering off by 1 mg per month until discontinuation.
Seven subjects have been enrolled to date and the trial continues to accrue patients. “Three patients developed medical issues unrelated to the drug or to HHT and were taken off the study. “However, four patients have demonstrated significant responses to pomalidomide,” Dr. McCrae says.
Pomalidomide treatment has decreased the frequency of both iron infusions and nosebleeds in these participants. Patients who previously experienced daily severe nosebleeds may now experience just a few per week, and the nosebleeds seem to be much less severe, lasting less than two minutes. “As a result of these changes, patients’ quality of life has greatly improved,” he says.
For two participants with epistaxis, ESS scores decreased by two to three points within two months of treatment. One had previously required frequent blood transfusions and weekly iron infusions. In six months on the study, she has not required transfusion, and she has not needed iron infusion for more than three months. Improvements were also seen in two brothers with GI bleeding and epistaxis before they discontinued treatment for reasons unrelated to the study.
Safety data favorable
Side effects appear to be limited thus far. One patient left the study due to rash caused by pomalidomide, and another experienced cramps at the highest dose, but overall toxicity levels remained acceptable to continue treatment.
“Interestingly, when used for its FDA indication — malignant hematologic disorders such as multiple myeloma — pomalidomide has been associated with cytopenias, such as thrombocytopenia, as well as thrombosis,” Dr. McCrae notes., “However, we have not encountered these problems in our pilot study — likely because HHT patients have normal bone marrow function and do not have the predisposition to thrombosis often seen in patients with cancer.”
Ramping up testing
While more extensive study is planned, the trial’s preliminary findings show that HHT may be amenable to novel therapies, Dr. McCrae says, adding, “The findings were not entirely unexpected, but gratifying since this study uses a clinically available drug and applies it to a new disease. If the study continues to show success, this might lead to a new treatment for HHT in the near future.”
Investigators will continue to monitor participants for decreased bleeding and decreased need for blood transfusion or intravenous iron. They are also collecting blood samples for molecular analysis in order to determine the mechanisms by which pomalidomide may combat HHT.
In light of promising preliminary results, investigators are also working closely with the National Heart, Lung and Blood Institute as well as the HHT Foundation International to facilitate plans for a multicenter study that will attempt to provide definitive evidence of pomalidomide efficacy in 182 HHT patients.
“If pomalidomide shows efficacy in these studies, it might also be of interest to test it in patients with other HHT complications such as pulmonary and brain arteriovenous malformations,” Dr. McCrae says. “These results could lead to even more targeted and effective approaches in the future.”