Pasireotide Does Not Decrease Risk of GI Toxicity or Acute GVHD Following HSCT

Anthony D. Sung, MD

In patients who undergo allogeneic hematopoietic stem cell transplant (HSCT), the risks of developing gastrointestinal (GI) toxicity and acute graft-versus-host-disease (GVHD) are significant. In a phase II trial, investigators evaluated pasireotide, a long-acting synthetic somatostatin analog, in the peritransplant period as a method prevent the risk of this toxicity as well as acute GVHD.

However, according to the phase II data presented at the 2020 Transplantation and Cellular Therapies (TCT) Meetings, pasireotide was not associated with any effect on GI toxicity and acute GVHD following HSCT compared with historical controls matched by transplant diagnosis, donor, graft, GVHD prophylaxis, and conditioning regimen.

The rates of grade 3/4 GI toxicity in patients who received pasireotide were comparable with what was seen in those who did not receive the study drug. The agent also did not appear to impact the overall incidence of acute GVHD compared with the control arm.

Although these data were negative, investigators noted that a subset of patients who had Total Body Irradiation conditioning had less acute GVHD in the pasireotide arm compared with the control arm at 55% and 80%, respectively. However, the data were found to not be significant and require further study.

In an interview with OncLive during the 2020 TCT Meetings, Anthony D. Sung, MD, assistant professor of medicine at Duke University Medical Center, discussed the findings from the phase II trial of pasireotide as a method to prevent GI toxicity and acute GVHD in patients who undergo allogeneic HSCT.

OncLive: Could you provide some background to the phase II study of pasireotide?

Sung: [The GI toxicity and acute GVHD] is a part of the hematopoietic conditioning that is part of HSCT. Patients endure a lot of GI toxicity. The thought is that this is a direct effect from the chemotherapy and radiation that is administered, but also indirectly from the barrier that protects us from the harmful effects of pancreatic enzymes; these enzymes are made to digest proteins. The thought is that in the setting of this barrier [being] compromised, [pasireotide] can suppress pancreatic enzyme progression and therefore decrease GI toxicity.

What were the findings from your study?

Unfortunately, we did not see a significant result. We were very optimistic because there were data from some other studies that suggested that this agent could prevent GI toxicity and improve the histology and pathology. When we performed our trial, we actually saw no difference in GI toxicity. We also looked at other outcomes, such as GVHD, but we did not see a difference there either [with pasireotide].

Why do you think there was not an improvement in outcomes with pasireotide?

One possibility is that the GI toxicity associated with myeloablative conditioning is just too much. The effect of pasireotide is insufficient in that population. Another potential strategy in that setting is to use a reduced-intensity conditioning setting.

How would you define the safety profile for pasireotide?

Pasireotide is an FDA-approved drug for Cushing’s disease. In that population, adverse events include QT prolongation, as well as occasional nausea and GI discomfort. In our patients [who undergo HSCT], we didn’t see any major difference with pasireotide. However, the GI discomfort is always hard to tease out in regard to how much of that is due to the drug versus [how much is associated with] conditioning and transplant.

Are any next steps poised for pasireotide in this setting?

This study was [completed] in partnership with a sponsor. As we compile and finish up the results, we will discuss with them [what to do next]. I do think, given the negative results in the myeloablative setting, it has potential [to be used] in the reduced-intensity setting, but whether or not we will pursue it remains to be seen.

What other treatment options are available for this patient population?

This is a challenging space. There is a lot of interest previously with palifermin, which has had mixed results as well. Another area we are working on is the gut microbiome and how the microbiome may affect transplant outcomes. I am one of the associate directors of the Duke Microbiome Center, and a lot of our work is around different strategies to see what we can do in the microbiome setting to improve transplant outcomes.

Could your further discuss this research with the gut microbiome?

There have been a number of observational studies in transplantation that have been published showing that disruptions in the gut microbiome, whether it has less bacteria diversity or less particular organisms, is associated with increased infections, relapse, GVHD, and worse overall survival. Studies have shown that this is not just correlational, but if you disrupt the microbiome with antibiotics, you can worsen GVHD, survival, and other things.

What is the key takeaway from this research?

It is a very challenging space, but at the same time, it’s a very important one. We are constantly pursuing new strategies in hopes of improving outcomes in our patients.

Ramalingam S, Siamakpour-Reihani S, Bohannon L, et al. Phase II trial of pasireotide to prevent GI toxicity and acute GVHD in allogeneic HSCT. Presented at: 2020 Transplantation and Cellular Therapy Meetings; February 19-23, 2020; Orlando, FL. Abstract 64.