Dr Gerds on Targeting CALR Mutations in Myeloproliferative Neoplasms

If you take myelofibrosis as a whole, [for example], not [all patients have] the same mutational profile. Some patients have CALR mutations. Some have JAK2 mutations. Some have MPL [mutations], and some have others. This is a big step forward into saying: What are the genetic underpinnings of a patient’s individual disease, and can we tailor therapy to meet that?

Aaron Gerds, MD, MS, a physician in the Department of Hematology and Medical Oncology at Cleveland Clinic, as well as an assistant professor in the Department of Medicine of the School of Medicine, deputy associate director for Clinical Research, and member of the Developmental Therapeutics Program at Case Comprehensive Cancer Center of Case Western Reserve University, discussed the rationale for targeting CALR mutations in the treatment of patients with myeloproliferative neoplasms (MPNs).

Gerds framed targeting CALR mutations as a meaningful precision medicine effort in the MPN field. For example, in the myelofibrosis patient population, underlying genetic profiles can vary by individual in terms of driver mutations, such as CALR, JAK2, or MPL. Developing targeted therapies directed at CALR mutations or other alterations could help inform therapeutic strategy and drive an individualized approach for each patient, Gerds said.

The biology of the CALR-mutant protein also adds to the rationale for exploring it as a therapeutic target, Gerds continued. Unlike JAK2 mutations, which occur intracellularly and are relatively difficult to target directly, CALR mutations are expressed on the cell surface, he said, allowing for monoclonal antibodies to bind directly and interrupt signaling, potentially starving malignant megakaryocytes critical for growth.

Cell surface expression also opens the door to immunotherapy approaches, including bispecific antibodies and engineered T-cell strategies, Gerds added. With immunotherapy approaches making inroads in other hematologic malignancies, targeting CALR mutations could allow for these types of agents to play a role in the MPN treatment paradigm, Gerds concluded.