Dr Jurcic on the Evolution of Combination Therapies in the Management of Myelofibrosis

Joseph G. Jurcic, MD, professor, medicine, Columbia University Medical Center; director, Hematologic Malignancies Section, Division of Hematology/Oncology, Columbia University Herbert Irving Comprehensive Cancer Center, discusses the evolution of myelofibrosis treatment, emphasizing the potential of combination therapies in the management of this disease.

Jurcic mentions that the BET inhibitor pelabresib (CPI-0610) stands out, generating significant improvement in spleen response in combination with ruxolitinib in the phase 3 MANIFEST-2 trial (NCT04603495). Likewise, navitoclax , a BCL-2 inhibitor with BCL-xL inhibitory properties, exhibited promising results in the phase 3 TRANSFORM-1 trial (NCT04472598), particularly in enhancing spleen response, according to Jurcic .

Looking forward, Jurcic suggests the benefits of exploring combinations between JAK inhibitors and other agents, such as LSD1 inhibitors, XPO1 inhibitors, and PIN1 inhibitors. The first-in-class investigational LSD1 inhibitor bomedemstat (IMG-7289) elicited clinical activity and a tolerable safety profile as monotherapy in patients with advanced myelofibrosis, according to findings from a phase 2 study (NCT03136185) presented during the 2020 EHA Congress.

Additionally, the XPO1 inhibitor selinexor is under investigation as monotherapy and in combination with the JAK inhibitor ruxolitinib (Jakafi) in patients with JAK inhibitor–naive myelofibrosis and moderate thrombocytopenia in the phase 2 XPORT-MF-044/SENTRY-2 (NCT05980806) and phase 3 XPORT-MF-034/SENTRY (NCT04562389) trials, respectively.

Clinical trials incorporating JAK inhibitor–based combinations aim to target multiple disease abnormalities, thereby potentially resulting in symptom alleviation, spleen improvement, cytokine reduction, and allelic burden reduction, Jurcic says. These outcomes may serve as crucial surrogate end points for evaluating long-term survival, Jurcic notes.

The pursuit of combination therapies signifies a paradigm shift in myelofibrosis management, emphasizing a multifaceted approach to addressing the complexity of theis disease, Jurcic emphasizes. By targeting various pathways implicated in the pathogenesis of myelofibrosis, oncologists aim to optimize treatment outcomes and improve patients' quality of life, Jurcic explains.

Jurcic's insights underscore the importance of ongoing research and clinical trials in elucidating optimal therapeutic strategies for myelofibrosis. As new agents and combinations emerge, the field is moving toward a more personalized and effective approach to managing this challenging-to-treat hematologic malignancy, Jurcic concludes.