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Messe Wien, site of EHA 2015

VIENNA—The immunotherapeutic agent PRM-151, when given alone or in combination with ruxolitinib, can reduce bone marrow fibrosis and improve platelet counts in patients with myelofibrosis (MF), results of a phase 2 trial suggest.

Using a novel assessment technique known as computer-assisted image analysis (CIA), researchers found that PRM-151, with or without ruxolitinib, prompted fibrosis responses in nearly three-quarters of patients studied.

And nearly 60% of thrombocytopenic patients saw improvements in their platelet counts.

“Thrombocytopenia remains a significant problem for many patients with myelofibrosis, and a new treatment that is not myelosuppressive and actually increases platelet counts would be of great benefit to patients,” said Srdan Verstovsek, MD, PhD, of the University of Texas MD Anderson Cancer Center in Houston.

He and his colleagues presented this research—the first part of a 2-stage study—at the 20th Congress of the European Hematology Association (abstract P677*). The trial is sponsored by Promedior, the company developing PRM-151.

Stage 1 of the study included 27 patients with a median age of 67 (range, 51-85). They had been diagnosed with primary MF, post-polycythemia vera MF, or post-essential thrombocythemia MF.

The patients received PRM-151 at 10 mg/kg IV dosed weekly (n=8) or monthly (n=7), or ruxolitinib plus PRM-151 at 10 mg/kg IV dosed weekly (n=6) or monthly (n=6). The patients who received ruxolitinib were already taking the drug, and doses varied. The mean duration of ruxolitinib treatment was 1.6 years (range, 0.6-3 years).

Patients were set to receive study treatment for 24 weeks but could continue beyond that if they experienced clinical improvement.

Response assessment: Using CIA

Hematopathologists who were blinded to the patient, treatment, and time point performed morphologic analysis on bone marrow specimens taken at baseline and at 12, 24, and 36 weeks (if available).

The pathologists also performed CIA on whole-slide scans from specimens taken at the same time points. The idea to use CIA came after morphologic analyses revealed some surprising findings.

“[The pathologists] were really struck by the fact that, in the patients who had reductions in fibrosis, there were other elements in the bone marrow that showed improvements,” said Beth Trehu, MD, Chief Medical Officer at Promedior. “There were trends toward normalization of the red cells and of the megakaryocytes.”

“They also remarked that, whereas the baseline samples were totally homogeneous—a grade 3 was a grade 3 throughout the bone marrow—after treatment, the samples became very heterogeneous. There were areas of grade 3, grade 2, grade 1, and 0, all in one sample.”

To solve this problem, the pathologists decided that a sample’s WHO grade would be defined as whatever grade was present in at least 50% of the sample. But the team still thought these grades weren’t accurately quantifying the effects of PRM-151.

So they turned to CIA, which allowed them to quantify the volume of collagen or reticulin fibers in the bone marrow.

Fibrosis and platelet responses

According to CIA, 73% of evaluable patients (19/26) experienced reductions in bone marrow fibrosis at any time during the trial.

Of the 23 evaluable patients who had grade 2 or 3 fibrosis at baseline, 11 patients had a reduction of 1 grade or more during the study period, according to morphologic analysis. Nine patients had a fibrosis response by morphology at the last time point they were assessed.

Reductions in fibrosis correlated with increased platelet counts in thrombocytopenic patients. Fifty-seven percent of thrombocytopenic patients (8/14) saw an improvement in platelet counts after treatment.

Results across treatment groups were as follows:

Treatment group (n) WHO fibrosis
at any time
CIA fibrosis
at any time
PRM-151 QW (7) 3 4 2
PRM-151 Q4W (7) 3 6 4
PRM-151 QW + RUX (6) 2 4 1
PRM-151 Q4W + RUX (6) 3 5 1

“The responses we saw with single-agent PRM-151, in particular, give us a lot of confidence that this drug is absolutely reversing fibrosis in the bone marrow,” Dr Trehu said. “And that is very nicely correlated with improvements in platelets, which are much harder to see in patients who are getting ruxolitinib because it’s a myelosuppressive agent.”

Dr Trehu added that these data suggest a monthly dose of PRM-151 is sufficient to treat MF patients, and there is a path forward for PRM-151 both alone and in combination with ruxolitinib.

Hemoglobin and spleen responses

The researchers also observed some improvements in hemoglobin levels and spleen size after treatment.

Of the 15 patients who had hemoglobin levels below 100 g/L at baseline, 3 met criteria for hemoglobin improvement. This included becoming transfusion independent, having a 50% reduction in the need for transfusion, or experiencing a 2 g/L increase in hemoglobin.

“Other patients had a nice trend toward hemoglobin improvement,” Dr Trehu noted.

Of the 20 patients with palpable spleen at baseline, reductions occurred in all but 1 patient. Four patients had a 50% or greater reduction in spleen size, but this response did not last beyond 12 weeks.

Adverse events

Forty-eight percent of patients (13/27) had at least 1 treatment-related adverse event (AE). Grade 1 AEs included diarrhea (n=3), fatigue (n=2), bruising at the infusion site (n=2), oral herpes (n=1), joint swelling (n=2), and headache (n=2). One patient had grade 2 oral herpes.

There were 5 serious AEs that were possibly treatment-related. Three events, from which patients recovered, were abdominal pain, sialadenitis, and pneumonia. The other 2 serious AEs were gastroenteritis and pneumonia, which resulted in death in an 85-year-old patient.

There were 2 deaths unrelated to treatment. One was due to pneumonia, and the other was a result of multi-organ failure and cardiac arrest. end hematology article

*Information in the abstract differs from that presented at the meeting.

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