Tagraxofusp Appears Safe in Subgroup of Patients With Relapsed/Refractory Myelofibrosis

In an interview with Targeted Oncology, Naveen Pemmaraju, MD, an associate professor in the Department of Leukemia at The University of Texas MD Anderson Cancer Center, discussed the safety of SL-401 as a treatment in patients with MF following relapse or intolerance to JAK inhibition, based on data from an ongoing phase I/II clinical trial. He highlighted other research that also appear promising for this subgroup of patients with a poor prognosis.

Naveen Pemmaraju, MD

Tagraxofusp (SL-401; Elzonris) has demonstrated reductions in spleen size and monocytosis splenomegaly in intermediate- to high-risk patients with myelofibrosis (MF) who have relapsed on or became intolerant to JAK inhibitors, according to an ongoing phase I/II clinical trial presented at the 2019 ASCO Annual Meeting.

Patients that relapse on or become intolerant to JAK inhibitors have been associated with poor prognosis and have no approved therapies or consensus on a standard of care for subsequent treatment. Tagraxofusp, which previously received an FDA approval in December 2018 for the treatment of patients 2 years or older with blastic plasmacytoid dendritic cell neoplasm (BPDCN), is a novel targeted therapy that targets CD123; CD123-positive plasmacytoid dendritic cells are also expressed in the microenvironment of MF.

The multicenter, phase I/II trial is currently enrolling patients with MF that have relapsed or become refractory to or intolerant of JAK inhibitors. The objective of this trial is to determine the safety and efficacy of tagraxofusp in this patient population. Data from 27 patients were collected and analyzed.

As of the data cut-off, 6 patients received treatment for more than 6 months, and 9 patients were still on treatment. Overall, 100% of patients experienced reductions in the spleen size and monocytosis splenomegaly.

The most common treatment-related adverse events (TRAEs) included headaches, hypoalbuminemia, ALT increase, and thrombocytopenia, while the most common grade 3 TRAE was thrombocytopenia. Capillary leak syndrome also occurred in 1 patient.

In an interview withTargeted Oncology, Naveen Pemmaraju, MD, an associate professor in the Department of Leukemia at The University of Texas MD Anderson Cancer Center, discussed the safety of SL-401 as a treatment in patients with MF following relapse or intolerance to JAK inhibition, based on data from an ongoing phase I/II clinical trial. He highlighted other research that also appear promising for this subgroup of patients with a poor prognosis.

TARGETED ONCOLOGY: What challenges do oncologists face when treating a patient that has either failed or became intolerant to the JAK inhibitors?

Pemmaraju:The field of MF has been a difficult one for both patients and physicians. Still in 2019, the JAK inhibitor class of drugs is the only FDA-approved therapy or targeted therapy for intermediate- to high-risk MF. If a patient is intolerant, fails, or they can’t even go on a JAK inhibitor due to low platelets, for example, there are still no FDA-approved therapies. The difficulty is great. There are no widely available therapies or widely available consensus approach to treating these patients. Oftentimes, patients are older, in their 70s, 80s, or 90s, or are unfit for other therapies, so there is a real urgent unmet medical need here for targeted therapy that goes beyond a JAK inhibitor with new mechanisms of action.

TARGETED ONCOLOGY: What is the rationale for investigatingtagraxofuspin patients with MF who have failed or progressed on JAK inhibitors?

Pemmaraju:SL-401 is a novel drug. It is a drug that hits the target CD123, which is the interleukin-3 receptor-alfa. It’s been in development for a number of years. I had the privilege of leading a multicenter group and testing this agent in patients with a very rare myeloid neoplasm called BPDCN. In that phase I/II trial, which was published in theNew England Journal of Medicine2 months ago, we helped to put the data set together and lead this drug to FDA approval but for that rare subtype of disease. Because it hits CD123 and because this drug is now the first ever approved CD123-targeted agent, we and others have been interested in investigating this in other areas that may have diseases that overexpress CD123. Some of those may include chronic myelomonocytic leukemia (CMML), MF, acute myeloid leukemia, etc. That’s the rationale, that CD123 seems to be expressed in leukemia stem cells, possibly in the microenvironment of some of these myeloid malignancies, in the neoplastic clone itself. The target rationale itself is going beyond JAK inhibitor, are there other areas that can be targeted, and this was one that we hypothesized could be.

TARGETED ONCOLOGY: How is this trial designed?

Pemmaraju:As we tested the agent in BPDCN, we made some modifications in this next clinical trial as most patients with MF possibly present with more of a chronic disease state. One of the major parts of the design was it started out as a phase I clinical trial with 3+3 classic design at lower doses of 7, 9, 12 mcg/kg. No formal maximum-tolerated dose was established, but the dose of 12 mcg/kg was selected as the dose for these clinical trials. That established the safety, and it quickly moved into the phase II expansion phase.

The clinical trial design is 3 days IV dosing, and I want to contrast that with the 5 days that we did in the BPDCN study. Overall, [we started with] the phase I, dose-finding phase in MF and CMML, [then did the] phase II dose-expansion in those patients with MF and CMML.

TARGETED ONCOLOGY: Could you define the patient population analyzed in this trial?

Pemmaraju:Overall, the findings that we showed updated at both ASCO and EHA now covers 27 patients treated with MF. The median age reflects a historical expectation for patients with MF, so 69 years old with an upwards range of 81 years. There was a good distribution of patients with bone marrow and spleen involvement, but the median platelets was only 59 with a range down to 13. Again, this is a group of patients with an urgent medical need. Among those patients with low platelet, 37% have platelets below 50.

Among these patients, all of them had prior therapies that you’d expect such as JAK inhibitors (70%), 2 patients remarkably had a prior transplant before coming on this study, and there was a good mix of people with primary MF, post-essential thrombocytopenia or -polycythemia vera MF. Finally, a lot of these patients were high-risk patients by the DIPPS Plus score, so that’s 33%.

TARGETED ONCOLOGY: What were the findings from the phase I and phase II?

Pemmaraju:Overall, the results showed that in terms of safety, especially in the phase I, it was an overall well-tolerated drug, and it did have an increase in the liver function tests. Several patients had headaches, hypoalbuminemia, anemia, and thrombocytopenia. The most important risk to look out for with this drug is capillary leak syndrome (CLS), which was reported on in the BPDCN study and theNew England Journal of Medicinestudy. Here, there was 1 case of CLS, but it was only grade 3; there were no deaths associated with this phenomenon.

Overall, what we are seeing here is that among patients treated so far, there were several patients with spleen reductions and symptom burden improvement. We need to further quantify those and standardize them across the IWG criteria. Interestingly, there was some early signal with patients with monocytosis and splenomegaly that had some reduction based on splenomegaly, so this is an area that we want to further analyze and look into to see if there is more information that can be had.

Five patients had a treatment duration of a year or longer. This is an IV drug. Sometimes you’ll find a hospital for patients to be administered, so that’s notable. Quality of life did show improvement in several patients, so that needs to be quantified. Overall, you have several patients in a durable setting with an IV drug, some a year out, several responses that have been seen that need to be categorized now by IWG now that the data are maturing, and several patients with quality-of-life improvement as well.

TARGETED ONCOLOGY: What are the next steps planned for this trial?

Pemmaraju:Next steps are very important. It is an ongoing, enrolling phase II clinical trial, so it has not yet met its accrual. That’s the first step, to finish that, which would likely be done by 2019 or the first part of 2020. The second aspect of it would be to further investigate this monocytosis in patients with MF. Our colleagues at the Mayo Clinic and other groups are finding this may represent a higher-risk group of patients with MF independent of some of the other scoring systems. Monocytosis highly expresses CD123, so the hypothesis would be to see if this drug program has activity in this subgroup of poor-prognosis patients. That needs to be further investigated with more patients, more analysis.

Other steps would be to see about combinations with CD123 and other agents of either the JAK inhibitor class or other agents. That would be very interesting to pursue further in the coming years.

TARGETED ONCOLOGY: What other research is ongoing for patients with MF who fail on or become intolerant to JAK inhibitors?

Pemmaraju:Outside of this CD123 class of drugs, there are several other active areas that are emerging now in MF, [that were presented]both at ASCO and EHA. They roughly divide into promoters of apoptosis—that includes drugs like SMAC mimetics, Bcl-xl inhibition, or targeting of the hemopoietic stem cell microenvironment. As we mentioned CD123 inhibition, there is also heat shock 90 protein inhibition. All of these are in active clinical trials.

Outside of this is modulation of the P53 pathway and MPN2 inhibition; these are in multiple clinical trials. There is another aspect which is targeting fibrosis cytokines and other kinds of pathways, like PRM-151, the pentraxin pathway, TGF-beta modulation, sotatercept, luspatercept, aurora kinase A inhibition with the alisertib drug, bromodomain inhibition, LSD-1 inhibition, and telomerase inhibition, just to name a few.

Over the last few years, an emerging area of research in preclinical and now clinical phase I and II trials looking beyond JAK inhibitors that we are looking forward to seeing at the major meetings in the coming years. We’re waiting to see the single-agent and in combination, adding back to ruxolitinib (Jakafi) and JAK inhibitors, or in the post-JAK inhibitor failure setting.

TARGETED ONCOLOGY: What advice would you give to a community oncologist faced with a patient that relapsed or has became intolerant to the JAK inhibitors?

Pemmaraju:This is a very important question, and one that I am getting calls about more and more frequently. The first situation would be to see what is available in that person’s community setting. I always encourage, not just because I’m in academic, but I always suggest referral to clinical trials because there are no approved therapies in that setting.

Second, [I advise] keeping track of all the developments that are happening. Other JAK inhibitors may be available in clinical trials and then maybe these non-JAK inhibitors that we just discussed. The most important thing I can recommend is that we and others have shown that overall survival may be significantly lower in patients once they have failed the JAK inhibitor. I think referral to a clinical trial center is the most important advice I can give to doctors out there in this setting.

TARGETED ONCOLOGY: Is there anything else in myelofibrosis you would like to highlight?

Pemmaraju:As we are here in 2019, I want to remind everyone that allogenic stem cell transplant is still the only curative option for many of the patients with MF. We want to make sure to mention that for the appropriate patient.

Lastly, social media and the internet have been great resources for patients, particularly #MPNSM on social media, used by me and other colleagues. It has been a great resource for people to get to know the field, thought leaders, discussions, particularly at the major meetings.

I really wanted to highlight that; allogenic stem cell transplant still is an important means for the appropriate patients, and social media [is useful] in a rare blood cancer field.


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 15; abstr 7058).