(Phase 3) Clinical Trial Data of Avatrombopag for the Treatment of Adults with Immune Thrombocytopenia

Laboratory test tube Avatrombopag is a thrombopoietin receptor agonist (TPO-RA), a class of drugs that helps the body produce new platelets, like eltrombopag (Promacta®/Revolade™) and romiplostim (Nplate®).

This study looked at whether patients with platelet counts greater than 50,000 µL ‘responded’ to avatrombopag based on the following characteristics: (1) age, (2) sex, (3) number of prior ITP therapies, (4) prior use of other TPO-RAs, (5) duration of ITP, (6) whether they were receiving multiple ITP medications at the start of the study, and (7) baseline platelet count. The researchers also assessed durability of response, which refers to how long a participant’s platelet counts remained greater than 50,000 while receiving avatrombopag.

In the first part of the trial, known as the core phase, 32 participants were enrolled in the avatrombopag group and 17 in the placebo group, meaning they did not receive the ITP medication.

In the core phase, almost all participants (29/32) in the avatrombopag group had a platelet response. Participants older than 49 years were more likely to respond to avatrombopag. However, the response of younger participants (under 49) lasted longer. Males had a longer duration of response compared to females. Participants who were not receiving multiple ITP medications and those who had a baseline platelet count greater than 15,000 at the start of the study were also more likely to respond to the treatment.

The researchers assessed the amount of time it took until there was a loss of response (LOR), which was defined as a platelet count less than 30,000 over two consecutive visits. On average, it took 119 days for participants in the avatrombopag group to experience a LOR, leave the study, or complete the study compared with 28 days for participants in the placebo group. Furthermore, 55.2% of patients in the avatrombopag group who showed a response did not experience an LOR throughout the trial.

The authors also report the findings from all the patients in the core and/or ‘extension phase’ (after the core phase) who received avatrombopag. The average time for a LOR to occur in this group was 182.6 days in this group, and 52.3% of participants did not experience an LOR at all. The subgroup analyses were similar for this group. Younger participants and males were again found to respond to avatrombopag for a longer period.

The number of previous ITP therapies or duration of ITP did not affect how long a participant responded to avatrombopag, but those who had fewer prior therapies and had ITP for a shorter period were less likely to experience an LOR. Lastly, participants who were not simultaneously receiving multiple ITP therapies and those who had a higher platelet count at the start of the study (greater than 15,000) had a longer response to avatrombopag and were less likely to experience an LOR. Whether or not a participant had previously received a different TPO-RA therapy did not influence the durability of response to avatrombopag.

Comments from PDSA Medical Advisors

The primary results of the Phase 3 trial, the Phase 2 trial (published in Blood in 2014) and other studies clearly demonstrate that avatrombopag is an effective and safe TPO agonist. This study is interesting but, overall, the numbers are too small in each category to give them too much weight, meaning we still can’t choose which subgroup of patients to treat with which agent. A small amount of additional data (six months) on longer use of avatrombopag is included which is valuable because there is still relatively little long-term data, especially when compared with romiplostim and eltrombopag.

Using an ITP Quality Improvement Tool to Improve Adherence to Treatment Guidelines

Man with laptop and notepad Hematologists do not always follow treatment guidelines for children with newly diagnosed immune thrombocytopenia (ITP). Therefore, researchers in this study created an ‘ITP quality improvement learning pathway’ to help care centers better follow national guidelines and standardize the provision of care.

Previously, researchers at Boston Children’s Hospital put together the first (2012-2014) and second (2014-2016) edition of this quality improvement tool. The quality improvement tool guides pediatric hematologists on how to evaluate bleeding and use national guidelines which recommend close observation of children with no or mild bleeding symptoms. When this tool was implemented at the hospital, the ‘observation rate’ of children with newly diagnosed ITP and no bleeding symptoms increased from 40% to 74% without any change in the rate of later hospitalizations, bleeding symptoms, or ITP resolution. This observational approach to care applies when a patient, rather than being given medication right away, is carefully observed by their physician to see if the ITP will start to resolve without the need for medication and risk of medication side effects.

In this study, the most recent data from the third edition (2016-2019) of the quality improvement tool were shown. Sixty-nine children with newly diagnosed ITP were managed using the third edition tool. Hematologists evaluated bleeding using a scale from 0-5 (0 being no bleeding and 5 being life-threatening) that was assessed by a hematologist. Most children had a bleeding score of either 1 or 2. Twenty-seven participants had a bleeding score of 3. After consulting with hematologists, most (60/69) participants were successfully managed through careful observation rather than medication.

Implementation of this quality improvement tool resulted in an increased number of children with newly diagnosed ITP being observed carefully (40% to 87%) and avoiding being treated with medication. Researchers also found that in five years of using this new ITP pathway tool, 24 children with newly diagnosed ITP who would have otherwise received ITP medication were instead treated through an observational approach. Importantly, there were no changes in health outcomes (hospitalizations, bleeding, or ITP resolution) when the ITP quality improvement tool was used even when fewer participants received ITP medication. The researchers also suggest that this approach may have reduced unnecessary hospital visits and the amount of side effects related to medication.

Comments from PDSA Medical Advisors

The primary aim of this study was to avoid unnecessary overtreatment of children with newly diagnosed ITP who likely will improve on their own. This pathway was an educational attempt to increase the chance that pediatric hematologists would refer to national ITP guidelines when managing children with ITP and, overall, it succeeded. Only one patient went on to develop more serious (grade 4) bleeding and was successfully managed with corticosteroids when that happened. Four others developed bleeding requiring management. The quality improvement pathway uses a modified bleeding scale that allows the difficult differentiation of types of bleeding. In this report, 27 patients had grade 3 bleeding, including low-risk moderate bleeding (18 people) and high-risk moderate bleeding (9 people). All patients with high-risk moderate bleeding were treated with medications whereas many with low-risk moderate bleeding were safely observed. Hospitalizations were minimal. The only other issue is not better knowing the long-term outcome: only 26/35 (74%) of patients were known to enter remission by six months. Presumably, many of the others were doing so well that they did not return for counts.