All content on this site is intended for healthcare professionals only. By acknowledging this message and accessing the information on this website you are confirming that you are a Healthcare Professional. If you are a patient or carer, please visit the MPN Advocates Network.

The MPN Hub uses cookies on this website. They help us give you the best online experience. By continuing to use our website without changing your cookie settings, you agree to our use of cookies in accordance with our updated Cookie Policy

Join our

Treatment sequencing for anemic myelofibrosis

with Jean-Jacques Kiladjian & Angela Fleischman

Monday, February 26, 2024 | 16:30 CET

This independent educational activity is supported by Bristol Myers Squibb. All content is developed independently by the faculty. The funder is allowed no influence on the content of this activity.


The MPN Hub website uses a third-party service provided by Google that dynamically translates web content. Translations are machine generated, so may not be an exact or complete translation, and the MPN Hub cannot guarantee the accuracy of translated content. The MPN Hub and its employees will not be liable for any direct, indirect, or consequential damages (even if foreseeable) resulting from use of the Google Translate feature. For further support with Google Translate, visit Google Translate Help.

Steering CommitteeAbout UsNewsletterContact
You're logged in! Click here any time to manage your account or log out.
You're logged in! Click here any time to manage your account or log out.

Current combination therapies in MPN

Dec 19, 2023
Learning objective: After reading this article, learners will be able to cite new combination therapies for the treatment of myeloproliferative neoplasms.

Bookmark this article

In recent years, combination approaches for the treatment of myeloproliferative neoplasms (MPN) have rapidly accelerated, with many late-phase clinical studies currently ongoing. These exciting treatment combinations offer the potential of previously unattainable disease modification and the possibility of new treatments in the near future.

During the 15th International Congress on MPN, John Mascarenhas presented the current status of combination therapies in the field of MPN. Here, we summarize the key points.

For more information on the current landscape of treatment options for patients with myelofibrosis (MF), check out our interview with John Mascarenhas and our review of current combination therapies for JAKi-naïve patients.

Bromodomain and extra-terminal motif inhibition

  • The combination of the bromodomain and extra-terminal inhibitor pelabresib, together with ruxolitinib, has shown potential for disease modification in MF
  • There has also been synergism reported in the treatment of blast phase disease
  • The combination therapy was recently investigated in the phase II MANIFEST trial (NCT02158858) for patients who were Janus kinase inhibitor (JAKi)-naïve
  • Key endpoints are shown in Table 1

Table 1. MANIFEST trial key results*

Trial endpoint

Patients (%)

SVR35 at Week 24


SVR35 at any time


TSS50 at Week 24


TSS50 at any time


SVR35, ≥35% reduction in spleen volume; TSS50, ≥50% reduction in Total Symptom Score.
*Adapted from Mascarenhas.1

  • Treatment-emergent adverse events that lead to treatment discontinuation were experienced by 14% of patients

B-cell lymphoma 2 inhibition

  • The B-cell lymphoma 2 inhibitor navitoclax, in combination with ruxolitinib, is currently under investigation for use in patients for whom ruxolitinib monotherapy did not yield an adequate response
  • In particular, arm three of the phase II REFINE study (NCT03222609) investigated the use of this combination in patients who were JAKi-naïve
  • Key results indicating potential disease modification are shown in Table 2

Table 2. REFINE trial arm three key results*

Trial endpoint, %


BMF reduction ≥Grade 1


Complete BMF resolution


Reduction in JAK2V617F VAF ≥20%


BMF, bone marrow fibrosis; JAK2, Janus kinase 2; VAF, variant allele frequency.
*Adapted from Mascarenhas.1
No differences from baseline to Week 12 or Week 24 in patients with or without high molecular risk mutations (47% vs 54%).

Exportin 1 inhibition

  • The exportin 1 inhibitor selinexor, in combination with ruxolitinib, is currently under investigation for the treatment of JAKi-naïve patients with MF.
  • Key results from the phase I XPORT-MF-034 study (NCT04562389) are shown in Table 3.

Table 3. XPORT-MF-034 study key results*

Trial endpoint at Week 24

Patients (%)

Selinexor 40 mg

Selinexor 60 mg

Efficacy evaluable














SVR35, ≥35% reduction in spleen volume; TSS50, ≥50% reduction in Total Symptom Score.
*Adapted from Mascarenhas.1

Treatment was generally tolerable, with a manageable safety profile even at the higher dose (60 mg).

Murine double minute 2 inhibition

  • The murine double minute 2 inhibitor navtemadlin, combined with ruxolitinib, was investigated in the phase Ib/II KRT-232-109 study (NCT04485260) for patients in whom ruxolitinib monotherapy yielded a suboptimal response
  • Key results from the trial are shown in Table 4

Table 4. Key results from the KRT-232-109 study*

Trial endpoint, %


SVR35 at Week 24


TSS50 at Week 24


BMF reduction ≥Grade 1 at Week 24


BMF, bone marrow fibrosis; SVR35, ≥35% reduction in spleen volume; TSS50, ≥50% reduction in Total Symptom Score.
*Adapted from Mascarenhas.1

The phase III BOREAS trial (NCT03662126) investigating this combination therapy is ongoing.

Telomerase inhibition

  • The combination of imetelstat and ruxolitinib for JAKi-naïve, intermediate/high-risk patients with MF is under investigation in the phase I/Ib MYF1001 study (NCT05371964)
  • The study places particular emphasis on both combination and sequential treatment of the two therapies


Several combination therapies for MPN are currently in late-stage development. Over the next 5 years, there is potential for a noticeable shift in the treatment paradigm, with combination therapies moving to the forefront of MPN treatment. Currently, there is a lack of data surrounding combination approaches after JAKi usage, emphasizing the need for further research into the feasibility of novel JAKi-based combinations.

  1. Mascarenhas J. Status of combination drug therapy in MPN. Session #6.1. 15th International Congress Myeloproliferative Neoplasms; Nov 2, 2023; New York, US.


Subscribe to get the best content related to MPN delivered to your inbox