Immune Thrombocytopenia: Impact of the EXTEND Trial

James B. Bussel, MD:Both romiplostim and eltrombopag have had long-term studies of hundreds of patients followed out to at least 6 years of treatment. The eltrombopag data that were the final results of the EXTEND trial, which was the long-term trial for eltrombopag, were just published in late 2017. In that trial, people had had to be on a previous eltrombopag trial, so there was a tendency for people who didn’t respond in the previous study not to enter the EXTEND trial. On the other hand, there were patients who had been on placebo in the earlier trial who were receiving treatment in EXTEND with eltrombopag for the first time.

The trial showed a very high response rate in that more than 80% of the patients had at least 1 platelet count greater than 50,000 and 40% or so of the patients had every count in the first 6 months greater than 50,000. And 60% to 70% of the patients entering the trial had every count greater than 30,000 in the first 6 months, and, in many cases, the responses lasted longer than that. So, the efficacy, which was in patients who may have been slightly preselected, was very, very good. Similarly, toxicity was relatively not high.

Overall, in multiple different studies with eltrombopag, including studies in children, about 3% of patients cannot tolerate it because of effects on the liver. But other patients who have transient increases in the transaminases will have them go back to normal with or without an interruption in dosing. Thrombosis is probably the most significant, the fact it could happen. And in both the long-term romiplostim study as well as EXTEND, the long-term eltrombopag study, there was about a 6% rate of thromboembolic events, more venous than arterial. But in both studies, both occurred.

The eltrombopag EXTEND study showed that almost all of those, a great majority, occurred in the first year. And it’s also true that in both studies, no new side effects seemed to appear. Initially, there had been great concern about the development of bone marrow reticulin fibrosis, but with studies done with EXTEND, with specific bone marrow studies with both agents, and with studies that we did at our center, it seemed clear that while there might be a minor increase in fibrosis, having this increase in fibrosis have any impact at all on the hematological outcome or response to treatment or long-term effects appeared to be totally negligible. And as a result, after a number of years of monitoring, we’ve totally stopped doing bone marrows to see whether there is fibrosis. Whether or not parenthetically to do bone marrows in patients for use of a TPO-RA, for example, prior to initiating treatment, is another question that’s unresolved and that’s up to the individual practitioner. My impression has been that more and more people do not do that anymore.

Transcript edited for clarity.

Case: A 48-year-old woman presenting with unusual bruising

October 2017

• A 48-year-old woman presents with complaints of bruising after minor bumps, bleeding gums despite regular tooth cleaning, and a recent spontaneous bloody nose; symptom onset about 1 year ago
• Physical evaluation reveals a woman of normal weight and average height, afebrile, no splenomegaly
• No personal or family history of cancer, autoimmune disease; no recent viral illnesses; no bone pain or night sweats
• Current medications: ibuprofen as needed, generic hydrochlorothiazide (HCTZ)
• Laboratory findings:
  • CBC reveals platelets 28 X 10⁹/L
  • WBCs within normal
  • Renal and hepatic function within normal
• Diagnosis: idiopathic thrombocytopenic purpura
• Patient started on a course of prednisone 1 mg/kg for 21 days, then tapered off
  • Platelets: 29 X 10⁹/L
  • Second course of prednisone 1 mg/kg for 21 days

April 2018

• After 2 courses of prednisone, patient’s platelets have not recovered
  • CBC shows platelets at 28 X 10⁹/L
• Symptoms of easy bruising and bleeding from gums continue
• After discussion with patient, she is started on the thrombopoietin receptor agonist (TPO-RA) eltrombopag (PROMACTA), at a dose of 50 mg/day
  • Dose increased to 75 mg/day; last platelet count, 65 X 10⁹/L