Editorial theme | The management of relapsed/refractory myelofibrosis: Part 4 – investigational combination approaches

The unmet clinical need in treating patients with relapsed or refractory myelofibrosis (R/R MF) is well acknowledged by investigators and experts in the field of myeloproliferative neoplasms (MPN). There are several clinical trials currently ongoing to offer new therapeutic options to improve treatment outcomes when the disease becomes difficult to manage with poor prognosis.

In the last few weeks, we touched upon challenges in case of failure or loss of response to Janus kinase (JAK) inhibitor (JAKi) ruxolitinib, novel approved or investigational JAKi, and phase II data on non-JAKi agents with different modes of action as part of our editorial series on R/R MF. In this final article, we will be looking at the treatment regimens under investigation in combination with, or as an add-on to, ruxolitinib.

Navitoclax + ruxolitinib

Navitoclax is a novel, orally available small molecule targeting several members of the antiapoptotic B-cell lymphoma 2 (BCL-2) family including BCL-X_L, BCL-2, and BCL-W. In preclinical studies, it was found that navitoclax enhances antitumor activity of JAK inhibitiors, and it is currently under evaluation in a phase II study (NCT03222609) either alone or in combination with ruxolitinib in patients with MF who experienced treatment failure with ruxolitinib.¹

First results presented recently demonstrated that at Week 24 the combination showed clinically meaningful outcomes such as spleen responses measured as ≥35% reduction in spleen volume (SVR₃₅), reductions in allelic burden, improvements in total symptom score (TSS) measured as ≥50% reduction in TSS (TSS₅₀), and reduced bone marrow fibrosis. The safety profile was manageable with thrombocytopenia, diarrhea, and fatigue being the most common treatment-emergent adverse events (TEAEs). 

The presence of high-molecular risk (HMR) mutations, defined as mutations in ASXL1, SRSF2, EZH2, U2AF1, and IDH1/2, or mutations in ≥3 genes, was found to have no impact on spleen response or improvement in TSS. Inflammatory biomarker analysis indicated that the combination may help to modulate MF-associated biomarker release.

We discussed the results with navitoclax and ruxolitinib in patients with R/R MF in an interview with Naveen Pemmaraju.

The phase III TRANSFORM-1 trial (NCT04472598) will investigate the combination of navitoclax and ruxolitinib versus placebo plus ruxolitinib in adult patients with primary or secondary MF who had no prior exposure to a JAKi. Primary endpoint is SVR₃₅ at Week 24. The study is currently recruiting.²

CPI-0610 + ruxolitinib

CPI-0610 is a unique, first-in-class, small molecule bromodomain and extraterminal domain (BET) inhibitor. BET proteins bind to chromatin to regulate the transcription of target genes associated with several profibrotic pathways. CPI-0610 is designed to exert disease-modifying activity via selective gene regulation of main oncogenic, fibrotic, and inflammatory factors.³

CPI-0610 is being evaluated as an add-on therapy in combination with ruxolitinib in patients with a suboptimal response to ruxolitinib, and patients with no prior exposure to JAKi, who were anemic (hemoglobin < 10 g/dL) and with intermediate-1 or higher risk disease in the phase II MANIFEST trial (NCT02158858). Latest results have been presented at the 62nd American Society of Hematology (ASH) Annual Meeting and Exposition.

The patients with suboptimal response to ruxolitinib were stratified into transfusion dependent (TD) and transfusion independent (TI) groups. The combination was associated with encouraging responses in terms of spleen volume reductions (SVR₃₅) and improvement in TSS (TSS₅₀).

• More patients in the TI group had SVR₃₅ versus the TD group, while the TSS₅₀ rate and median change in TSS were greater in the TD group
• The response rates were higher in JAKi-naïve patients compared with ruxolitinib-exposed patients
•  Improvement in bone marrow fibrosis was also reported in both cohorts
• The safety analysis demonstrated a good tolerability with low-grade TEAEs. The most common Grade 3 hematological TEAEs were anemia and thrombocytopenia

This combined approach will be further evaluated in the placebo-controlled phase III MANIFEST-2 trial (NCT04603495) in JAKi-naïve patients with MF. The study is also currently enrolling patients.³

To learn more about the MANIFEST trial, have a look at the interviews with Srdan Verstovsek and with the MPN Hub Steering Committee member Alessandro M. Vannucchi.

KRT-232 + ruxolitinib

KRT-232 is a murine double minute 2 (MDM2) inhibitor that demonstrated promising efficacy and manageable safety as monotherapy in the R/R MF setting. It has been suggested that ruxolitinib may enhance the clinical activity of KRT-232, and a prospective phase Ib/II study (NCT04485260) is currently ongoing to investigate the safety and efficacy of the combination of KRT-232 and ruxolitinib in patients with MF who have suboptimal response to ruxolitinib. The primary endpoint of this study is to establish a recommended phase II dose of KRT-232 in combination with ruxolitinib. Secondary outcomes include spleen volume reduction, change in TSS, duration of response, requirement for red blood cell transfusion, overall survival, progression- and leukemia-free survival, and safety and tolerability.

For more information on the study design, click here.

Conclusion

Novel drugs in combination with ruxolitinib are associated with encouraging responses and manageable safety profiles, and some of them are further investigated in phase III trials. A number of studies investigating combinations may offer suitable options for patients with R/R MF. To hear more about this topic, the MPN Hub spoke to Srdan Verstovsek about the effectiveness of JAKi combinations in treating MF, at the European School of Haematology (ESH) 2nd How to Diagnose and Treat CML / MPN conference.

The MPN is looking forward to providing extensive content on these trials in the future.