Interpreting Data From the REFINE Study: Ruxolitinib + Navitoclax in Myelofibrosis


Expert perspectives on specific subsets of the REFINE study, which combined ruxolitinib with navitoclax in patients diagnosed with myelofibrosis.


Naveen Pemmaraju, MD: At the ASH [American Society of Hematology] December 2022 meeting, my colleagues were able to provide an ongoing update of the so-called REFINE multiarm cohort study. This particular arm is being led by my colleague [Francesco] Passamonti, [MD,] of Italy. Dr Passamonti showed an update of one of the cohort arms of the REFINE study, which very specifically is ruxolitinib plus navitoclax, so that’s BCL-XL inhibition, but in frontline, untreated patients with myelofibrosis. Claire Harrison, [MD, FRCP,] and I had shown in earlier data sets a different cohort, a different arm of the REFINE study, which focused on ruxolitinib plus navitoclax in what you would call a suboptimal or add-on approach. In those earlier studies, we showed the feasibility, safety, and efficacy of the combination, so now the combination is being moved up in the untreated frontline setting. So, what Professor Passamonti nicely showed in this group of patients, approximately 30-plus patients, is continued not only safety, which is always important to establish in these new combinations, no new or unexpected adverse effects. We already know that some patients will have thrombocytopenia, and some patients will have mild diarrhea. But more importantly, it showed a very nice, encouraging but early efficacy signal.

This efficacy signal was manifested in at least a couple of different ways. This group of patients is showing a very nice spleen size reduction overall, and symptom burden improvement, but also starting to correlate with early signs of disease modification. A subset of these patients also had bone marrow fibrosis reduction quite early. Some had VAF, variant allele fraction [reduction], early. Of course, the cohort will be followed long term to help understand factors such as overall survival. What I think we can get out of this early phase 2 REFINE combination approach of ruxolitinib and navitoclax is that inhibition with BCL-XL in combination with a JAK inhibitor continues to be a very safe, efficacious approach. It needs a bit longer follow-up in duration time, continued monitoring, as already built in the protocol for safety.

I think it will be wonderful for all of these combinations to show this disease modification signal, which is the combination of spleen and symptoms, overall survival improvement, and ultimately, some correlation with the biochemical markers including fibrosis, VAF reduction, and cytokines in a subset of patients. It is important to really understand and examine that subset more. So, we look forward to more updates for these REFINE cohorts, which has already led to a phase 3 experience known as TRANSFORM-1 and TRANSFORM-2 which on a larger scale, aims to investigate ruxolitinib and navitoclax in more patients with myelofibrosis. In the case of T1, TRANSFORM-1, this is in the frontline setting, and T2 in the relapsed setting.

Transcript edited for clarity.

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