Patients with Relapsed/Refractory Myelofibrosis Achieve Responses to Single-Agent Tagraxofusp

September 5, 2019
Nichole Tucker

In an interview with&nbsp;<em>Targeted Oncology</em>,&nbsp;Naveen Pemmaraju, MD, discussed the results from the phase I/II trial of single-agent tagraxofusp used to treat patients with R/R myelofibrosis and&nbsp;examined novel agents and combination regimens that are being studied to potentially treat this patient population.<br /> <br /> &nbsp;

Naveen Pemmaraju, MD

Single-agent tagraxofusp-erzs (Elzonris) has demonstrated activity in patients with high-risk relapsed or refractory (R/R) myelofibrosis, based on recently reported phase II trial results (NCT02268253).

This study was conducted to address expression and overexpression of the interleukin-3 receptor (IL-3), CD123, in the leukemia stem cell, according to Naveen Pemmaraju, MD, associate professor, Department of Leukemia, The University of Texas MD Anderson Cancer Center. Even with the knowledge that CD123 expression and overexpression occurs, there is no FDA-approved agent that can target it in patients with myelofibrosis to date. The study, therefore, aimed to fulfill an unmet need of targeting CD123 expression and overexpression in patients with advanced, high-risk myeloproliferative neoplasms.

Thus far, 23 patients with R/R myelofibrosis have been treated with 2 stages of tagraxofusp dosing. Among the group, 57% of patients with baseline spleen size of ≥5 cm, along with 100% with monocytosis, showed a significant reduction in spleen size.

The most come adverse events were headache (22%), hypoalbuminemia (22%), alanine aminotransferase increase (17%), and thrombocytopenia (17%). The most common grade 3/4 treatment-related adverse event was thrombocytopenia in 2%. Capillary leak syndrome, a subgroup Pemmaraju identifies as an important group to watch in this study, occurred in one patient. The adverse events were expected with tagraxofusp, and the investigators considered all of the toxicities to be manageable.

The trial continues to enroll patients with R/R myelofibrosis who are intolerant to JAK inhibition. The primary objective of the study is to find the optimal dose of tagraxofusp and determine if the agent is safe and effective.

In an interview withTargeted Oncology,Pemmaraju discussed the results from the phase I/II trial of single-agent tagraxofusp used to treat patients with R/R myelofibrosis andexamined novel agents and combination regimens that are being studied to potentially treat this patient population.

TARGETED ONCOLOGY: Can you discuss the background for this trial?

Pemmaraju: At the 2019 ASCO Annual Meeting, we were excited to present the ongoing phase I/II results for a novel agent known as tagraxofusp or SL-401. The background is quite interesting. The concept is that tagraxofusp is the first-in-class FDA-approved agent that targets CD123, also known as the IL-3 receptor alpha.

Over 20 years ago, it was found that CD123 appears to be overexpressed in the so-called leukemia cell stem. But, over the last 10 to 15 years, there had been no approved agents in this class. I was recently able to lead a team of investigators to get this drug approved in another indication for a rare tumor known as blastic plasmacytoid dendritic cell neoplasm (BDPCN). In the course of that investigation, we and others have found that CD123, outside of BDPCN, appears to be expressed or even over-expressed in a number of different myeloid and lymphoid malignancies.

With that background in mind, we set out to investigate other urgent unmet medical needs and one of them appears to be myelofibrosis and chronic myelomonocytic leukemia (CMML). As in BDPCN, it does appear that in these diseases, CD123 is expressed or overexpressed in many of our patients. With that, we set out to do a phase I/II trial. The phase I is completed and has been presented before. What we presented were the updated phase II results, which include 23 patients treated so far, with a median age of 65 years. This represents what one would expect as a historical or real-world population of patients.

TARGETED ONCOLOGY: What were the findings of this study?

Pemmaraju: In this setting, approximately half of the patients so far have experienced spleen reduction, which is thought to be a meaningful indicator of clinical response in myelofibrosis. And, these are all patients who had at least 1 prior therapy.

The adverse effect profile is important with any novel agent. The CD123-directed agent is known to cause fluid retention and capillary leak syndrome, and we did see that at a significant level in one patient thus far in the study. Further, outside of this, the adverse effect profile was expected and manageable as we've seen with the other experiences.

In this phase II study that's ongoing, we continue to enroll patients. It's active and open at multiple sites and we will strive to continue to see which patients benefit.

[There is] one particular subset of patients that we would like to keep an eye on, which is patients with myelofibrosis and monocytosis. This an emerging, a newly recognized subset of patients who possibly may have a poorer prognosis than the other patients, independent of scoring systems. And in these patients with monocytosis myelofibrosis, early on, there appears to be some signal of activity that we need to continue to follow, watch out for, and see how it goes overtime.

TARGETED ONCOLOGY: What unanswered questions still exist with this agent?

Pemmaraju: For future directions for tagraxofusp in myelofibrosis, a number of questions are already emerging in our research. One major question is that the rate of capillary leak syndrome appears to be lower than what we saw in the BDPCN experience that we recently published. There may be a number of reasons for that. One particular aspect of this is that this drug is given intravenously 3 days per cycle, whereas, in the other experience, it was 5 days. They are different tumors with possibly different expression levels of markers. I would like us to actively investigate the lower rate of capillary leak syndrome thus far seen in this myelofibrosis/CMML clinical trial.

The second aspect, as with any novel agent, is exploring both in vitro and in vivo. What rational combinations may be applicable for this agent? Combining drugs in our field is a very common future direction and that will be something that will be of high interest to the field.

TARGETED ONCOLOGY: Do you foresee this type of agent having potential in combination with other types of therapies that are available for myelofibrosis?&nbsp;

Pemmaraju: A lot therapies, including the tagraxofusp, are actively being studied in the phase I and phase II settings [for after JAK inhibitor frontline therapy for patients with intermediate to high-risk myelofibrosis]. It does appear that there may be a number of rational combinations for a lot of these novel agents.

We do need to continue to investigate and explore a number of these different ideas and concepts over the next 3 to 5 years.

TARGETED ONCOLOGY: Aside from myelofibrosis, what other indications do you see the JAK inhibitor&nbsp;ruxolitinib (Jakafi)having benefit as a therapy?

Pemmaraju: This is a very emerging area of research. The initial indication for JAK inhibition included myelofibrosis, and then polycythemia vera in the advanced setting. Now, we're starting to see a number of clinical trials pop up. There was a recent FDA approval for acute graft versus host disease with the same molecule, the JAK inhibitor ruxolitinib. A number of different areas are in active investigation.

I think that the level of research for JAK inhibitors has gone in different ways. It's encouraging and we need to see how they go. One is single agent. For a number of different cancer types [both liquid and solid tumors], we and others are starting to do combination therapies with JAK inhibitors and other molecules in other subsets of diseases. For example, patients with myelofibrosis with what's called a suboptimal response, [these are patients that] are not quite failing and coming off the drug but remaining on the drug and then adding a second agent to that. I think that's the next area of active research and you'll see on and other websites that there are a number of trials like this popping up. I would like us to keep our eye on that field.

TARGETED ONCOLOGY: How can the risks of anemia be managed in patients who are prescribed ruxolitinib?

Pemmaraju: One of the most important, common, and challenging problems for our patients with myelofibrosis, that effects doctors, patients, and nurses, is the development of anemia. Low hemoglobin levels can occur at baseline because of the disease or later on in therapy either because of the therapies that we are giving or disease progression. This is a huge problem for our patients. Outside of the usual known supportive care measure such as blood transfusions and growth factor supplementations, we don't have many tools available to us. There are some older medications, such as danazol and other medicines that have been used to varying levels of effectiveness.

I think one exciting area of research here is coming up with other therapies, possibly chemotherapy or other agents, that may help to promote blood cell formation in different ways. One of these areas is the sotatercept/luspatercept story, which is being investigated in both myelodysplastic syndromes as well as in myelofibrosis. There was recent plenary session-level data presented for luspatercept in a subset of myelodysplastic syndrome and those trials are active and ongoing in our field of myelofibrosis. And then, other areas, again are combining older and newer drugs to either offset the JAK inhibition-causing anemia or the development of novel JAK inhibitors that may not cause as much anemia as the ones we have now in the clinic. These are all different areas of research and they pose new and important ways to address this issue.


Pemmaraju N, Ali H, Gupta V, et al. Results from ongoing phase 1/2 clinical trial of tagraxofusp (SL-401) in patients with intermediate or high risk relapsed/refractory myelofibrosis.J Clin Oncol. 2019;37(suppl; abstr 7058).