Current combination therapies in MPN

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 15^th 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*

SVR35, ≥35% reduction in spleen volume; TSS50, ≥50% reduction in Total Symptom Score. *Adapted from Mascarenhas.1
Trial endpoint	Patients (%)
SVR35 at Week 24	68
SVR35 at any time	80
TSS50 at Week 24	56
TSS50 at any time	83

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

• A total of eight Grade 5 treatment-emergent adverse events were reported, but none were related to treatment
• Improvement in bone marrow fibrosis by ≥1 grade was experienced by 27% of patients at Week 24 and 40% of patients at any time
• A reduction in JAK2^V617F variant allele frequency ≥20% was experienced by 38% of patients
• Results from the phase III MANIFEST-2 trial (NCT04603495) will be presented at the 65th American Society of Hematology (ASH) Annual Meeting and Exposition.

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*

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%).
Trial endpoint, %	Patients
BMF reduction ≥Grade 1	28
Complete BMF resolution	22
Reduction in JAK2V617F VAF ≥20%	50†

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*

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

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*

BMF, bone marrow fibrosis; SVR35, ≥35% reduction in spleen volume; TSS50, ≥50% reduction in Total Symptom Score. *Adapted from Mascarenhas.1
Trial endpoint, %	Patients
SVR35 at Week 24	32
TSS50 at Week 24	32
BMF reduction ≥Grade 1 at Week 24	57

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.