New era for myelofibrosis treatment with novel agents beyond Janus kinase‐inhibitor monotherapy: Focus on clinical development of BCL‐X_L/BCL‐2 inhibition with navitoclax

Abstract

Myelofibrosis is a heterogeneous myeloproliferative neoplasm characterized by chronic inflammation, progressive bone marrow failure, and hepatosplenic extramedullary hematopoiesis. Treatments like Janus kinase inhibitor monotherapy (e.g., ruxolitinib) provide significant spleen and symptom relief but demonstrate limited ability to lead to a durable disease modification. There is an urgent unmet medical need for treatments with a novel mechanism of action that can modify the underlying pathophysiology and affect the disease course of myelofibrosis. This review highlights the role of B‐cell lymphoma (BCL) protein BCL‐extra large (BCL‐XL) in disease pathogenesis and the potential role that navitoclax, a BCL‐extra large/BCL‐2 inhibitor, may have in myelofibrosis treatment.

Molecular Genetic Profile of Myelofibrosis: Implications in the Diagnosis, Prognosis, and Treatment Advancements

“…Multiple clinical trials have suggested that a >20% reduction in VAF is associated with a higher rate of spleen response, symptomatic improvement, decreased fibrosis level, and longer overall survival [125]. Overall, ruxolitinib as a single agent in frontline therapy has not demonstrated a consistent biological effect in reducing the mutation burden [126]; the improvement in survival is significant in MF patients with a high mutation burden [124], but overall still controversial [125,127]. Discontinuation due to failed response, disease progression, or intolerance is up to 60% of patients within 3 years [121,128,129].…”

“…The BCL2 and BCL-xL inhibitor ABT-737 worked synergistically with a JAK inhibitor and effectively overcame acquired ruxolitinib resistance in an animal experiment [158]. Clinical trials of combination therapy with BCL2, BCL-xL, and BCL-W inhibitor navitoclax showed promising results in most patients, with significant symptomatic alleviation, decrease of spleen size, improvement in anemia, lowering of blood cytokine levels, reduction of fibrosis burden (at least 1-grade reduction, with some achieving complete resolution), and at least half of the cases achieving >20% JAK2 or CALR mutant allele reduction (reviewed by Pemmaraju et al [125]). The combination achieved a good response in approximately 30% of the patients with relapsed or refractory MF.…”