EHA 2026 | Primary analysis of INDEPENDENCE: luspatercept in transfusion-dependent patients with MF on a JAKi

Okay, first of all, the INDEPENDENCE study is in the setting of patients with myelofibrosis who are transfusion-dependent. Transfusion dependency in general is a very high-risk condition with median survival of around two years from the start of transfusions. And the INDEPENDENCE study randomized patients who received a diagnosis of myelofibrosis, of course, intermediate 1, 2, or high risk, receiving transfusion of 4 to 12 units in the last 12 weeks. All these patients must be on a stable dose of ruxolitinib for more than 32 weeks. And these patients were randomized to receive 2:1 luspatercept or placebo. The primary endpoint of the study was RBC-TI, so red blood cell transfusion independence, for more than 12 consecutive weeks, starting within the first 24 weeks. And then other additional key secondary points that are RBC-TI-16, the reduction of transfusion, and so on. 

And I have to say that the population of patients enrolled in the INDEPENDENCE study was composed of a cohort of old patients with very advanced disease. So the median duration of myelofibrosis was about four years, with a long history of transfusion dependence of about two years, and on a JAK inhibitor. And the vast majority of these patients were on ruxolitinib. And this cohort of patients were on a high-transfusion burden, remember that 70% of the patients were on high-level transfusion burden, so more or equal to or more than six units in the last 12 of the weeks. 

And if we look at the primary endpoint result, this has been achieved in 23.1% of the patients on luspatercept. So this means that one out of four patients in this setting, so on ruxolitinib and requiring transfusions, achieved the primary endpoint. So one out of four became transfusion-independent. And however, the statistical endpoint was not met because the threshold for statistical significance was 0.044. And we did further evaluation just to understand why this happened. And I think that is of interest the evaluation that we did according to the regions. And we found that in different regions, such as Europe, Indo-East, Africa, Latin America, and North America, there was a great difference between response in the luspatercept cohort and in placebo cohort. And so this is in line with what we expect in the management of patients with myelofibrosis. But in the Asian Pacific area, there is a very high and very unexpected rate of patients receiving placebo who achieved the primary endpoint. 

And so we also did another analysis comparing mainland China that composed the 42% of the population of the Asian Pacific area. And we found that these patients, despite a very low level of hemoglobin at baseline, received in the 12 weeks before enrollment the same number of transfusions than the rest of the world population. And you also study what happened in terms of pre-transfusion during the prospective part of the study. So during the first 24 weeks of treatment, we found that the mean hemoglobin level for transfusion was 5.1 versus 7.4 in the rest of the world. So basically, the unexpected high rate of RBC-TI-12 achieved with placebo was done due to the more conservative approach in terms of transfusion that is according also to the guidelines in China. 

We did also post-hoc analysis that we perform on a mandatory blinded investigator response assessment at day 169, and basically excluding one single patient who was considered a responder because not receiving transfusion for a long period of time due to a regional blood shortage, not considered this patient as a non-responder, the final P-value was 0.039. So theoretically, it would be significant. 

Then the other second key point was all in favor of luspatercept, and these are RBC-TI-16, RBC-TI-12, plus a more hemoglobin increase of one gram per deciliter, and also the transfusion burden reduction was at 50%. And concerning safety, we have to say that overall the drug was generally manageable. And all the adverse events were consistent with the Phase 2 MF001 study. So basically, the information that we have from the INDEPENDENCE study was basically the RBC-TI-12 has been achieving 23.1% of the patients. And this is absolutely similar to the result obtained in the phase two study. And that the reduction in transfusion burden more than 50% has been achieving from 40% to 52% of the patients. And overall, the drug is safe. So I think that this is the final message for doctors treating patients with myelofibrosis. And further analysis will come after with a longer follow-up evaluation of other parameters such as the mutation relationship and so on.

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