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Janus kinase inhibitor (JAKi) therapy has been the cornerstone of myelofibrosis (MF) treatment for the past decade. Identification of the key driver mutation in the JAK2 gene has facilitated a continuous improvement in survival rates and symptom responses for patients diagnosed with MF.
However, there remain challenges in optimizing response rates and managing the side effects of JAKi treatment; this has led to the investigation of combination therapies, as previously covered by the MPN Hub. The aim is to enhance the effects of initial JAKi treatment with a combined novel treatment, minimizing new toxicity signals and improving overall survival (OS) for patients with MF.
During the 2nd Myeloproliferative Neoplasms (MPN) Controversies and Debates, Pemmaraju presented current data on combination therapies in JAKi-naïve patients diagnosed with MF, highlighting recent results from clinical trials investigating combination treatments and outlining future directions in the field. Here, we summarize the key points.
Figure 1. Reasons for RUX discontinuation*
RUX, ruxolitinib.
*Adapted from Pemmaraju.1
The discontinuation rate highlights the need for therapeutic options beyond JAKis, such as the use of combination treatments and targeting new pathways, including:
Table 1. Ongoing global phase III studies investigating RUX combination therapies*
Combination |
Target |
Trial |
NCT |
---|---|---|---|
RUX + pelabresib |
BET inhibitor |
MANIFEST II |
|
RUX + navitoclax |
BCLXL inhibitor |
REFINE |
|
RUX + parsaclisib |
PI3K inhibitor |
LIMBER-304 |
|
BCLXL, B-cell lymphoma-extra-large; BET, bromodomain and extra terminal domain; PI3K, phosphoinositide 3-kinase; RUX, ruxolitinib. |
The addition of RUX to novel therapies has the potential to significantly impact the MF treatment landscape, enhancing treatment effects and improving clinical outcomes. Moreover, preliminary evidence suggests that some combination therapies such as RUX + navitoclax and RUX + pelabresib may lead to disease modification through BMF and variant allele reduction.
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