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2023-12-19T15:51:16.000Z

Current combination therapies in MPN

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

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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

68

SVR35 at any time

80

TSS50 at Week 24

56

TSS50 at any time

83

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, %

Patients

BMF reduction ≥Grade 1

28

Complete BMF resolution

22

Reduction in JAK2V617F VAF ≥20%

50

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

50

91.7

TSS50

57.1

77.8

Intent-to-treat

SVR35

40

78.6

TSS50

40

58.3

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, %

Patients

SVR35 at Week 24

32

TSS50 at Week 24

32

BMF reduction ≥Grade 1 at Week 24

57

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

Conclusion

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.

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