Panobinostat Combo Shows Early Promise in Myelofibrosis and Polycythemia Vera

The combination of panobinostat (Farydak) and ruxolitinib (Jakafi) demonstrated efficacy and a tolerable safety profile as a treatment for patients with primary myelofibrosis (PMF) and post-polycythemia vera—related myelofibrosis (post-PV MF), and post-essential thrombocythemia–related myelofibrosis (post-ET MF), according to results of a phase I dose-escalation study that were published in Leukemia Research.

In the 14 patients who were evaluable for clinical responses, 40% achieved a clinical improvement (CI; n = 6) with the combination, and 53% had stable disease (SD; n = 8). CIs were caused by spleen improvement in 5 patients and in 1 patient, an improvement in hemoglobin led to the CI. Of those who had a CI, 83% were JAK2V617F positive (n = 5), and 83% were ruxolitinib-naïve (n = 5). No patients who experienced a CI had favorable cytogenic abnormalities, and there was no significance between clinical activity between patients who were ruxolitinib-naïve and those who had prior treatment with ruxolitinib was observed.

In the open-label, single-institution study, investigators followed a 3 + 3 design in the phase I stage to determine the maximum-tolerated dose (MTD) of panobinostat plus ruxolitinib. The cohorts received either ruxolitinib at 10 mg plus panobinostat at 10 mg, ruxolitinib at 10 mg with panobinostat at 15 mg, ruxolitinib at 10 mg plus panobinostat at 20 mg, or ruxolitinib at 10 mg plus panobinostat 10 mg. Individuals were eligible to enroll in the study if they had intermediate-2 and higher by International Working Group-Myeloproliferative Neoplasms Research and Treatment Post PV/ET MF, and PM with an ECOG performance status of 3 or lower and met the extensive criteria for laboratory values.

A total 15 patients were included in the study. At the start of the study, it was determined that 40% of patients had PMF (n = 6), 47% had post-ET MF (n = 7), and 13% had post-PV MF (n = 2). At the start of the study, 67% of the patients had JAK2V617F positivity (n = 10). When the study commenced, 13% of patients were red blood cell (RBC) transfusion-dependent and 87% had palpable spleen, with a median size of 13 cm (range, 0-18 cm ).

The primary endpoint was to determine the toxicity profile and identify the MTD of the combination to be used in phase II of the study. Secondary endpoints included response, change in spleen size at weeks 12 and 24, and symptom response on cycle 6 day 29.

Among patients who achieved a CI, the median percent change in spleen from baseline was -43% (-61% to 4%), and the median percent change in spleen length was -91.7 cm (-100.0). Five patients achieved either a 35% spleen volume response and/or 50% reduction in spleen length.

Investigators performed a bone marrow morphologic analysis during the study. Seven patients demonstrated improved degree of fibrosis with 5 patients improving from MF3 to MF2, 1 patient improving from MF3 to MF1, and 1 showing improvement from MF2 to MF1. Additionally, 6 patients had improved cellularity of at least 20% compared with their original biopsy.

An analysis to understand how gene mutation correlates with response was also conducted in this study, which was determined by next-generation sequencing of peripheral blood granulocytes. This analysis showed no correlation between clinical responses and the mutational status observed.

Regarding safety, the most common treatment-emergent hematologic toxicity observed in the study was worsening anemia (47%). As far as non-hematologic toxicities, gastrointestinal (GI) toxicity was the most prevalent, with 67% of patients having experienced diarrhea. The other GI toxicities included nausea (27%), flatulence (27%), and abdominal bloating (13%). None of the GI toxicities were above grade 2. The notable grade 3/4 toxicities included hypertension (21%), vertigo (7%), oral ulcers (7%), and fatigue (7%).

The investigators concluded that the combination of panobinostat and ruxolitinib was feasible in the patient population. Multiple combination trials were initiated during the time period that this trial was launched, limiting patient enrollment for this trial, wrote the authors. Overall, the investigators emphasized that the combination was safe and tolerable with limited toxicity.

Mascarennhas J, Marcellino BK, Lu M, et al. A phase I study of panobinostat and ruxolitinib in patients with primary myelofibrosis (PMF) and post-­polycythemia vera/essential thrombocythemia myelofibrosis (post-­PV/ET MF). Leukemia Research. 2020;88:106272. doi: 10.1016/j.leukres.2019.106272.