The National Comprehensive Cancer Network (NCCN) has updated its clinical practice guidelines for myeloproliferative neoplasms (MPNs), prioritizing clinical trials and incorporating new drug approvals. These updates, released in August 2024, signify increased activity and evolving treatment paradigms in the management of MPNs, a group of blood cancers characterized by excessive blood cell production in the bone marrow.
Emphasis on Clinical Trials
According to Dr. Aaron Gerds, chair of the NCCN panel handling MPN updates, the guidelines now emphasize clinical trials as a preferred option, even in the frontline setting. This recommendation stems from the recognition that current therapies, while transformative, still leave significant room for improvement. "The available therapies are not good enough...we need to do better, and we continue to do better. So, trials, even the frontline setting, we feel are incredibly important to emphasize," Dr. Gerds stated.
This shift reflects the growing number of ongoing clinical trials evaluating novel therapies and combinations for MPNs, particularly myelofibrosis. Many of these trials involve adding a new agent to the standard of care, such as ruxolitinib, offering patients access to potentially more effective treatments while still receiving established therapies.
Role of Next-Generation Sequencing
The updated NCCN guidelines also highlight the critical role of next-generation sequencing (NGS) in evaluating patients with MPNs, especially those at higher risk. NGS provides valuable information about the genetic mutations driving the disease, which can inform prognosis and treatment decisions. Identifying mutations beyond the JAK/STAT pathway is particularly important for accurate risk stratification using models like the MIPS score.
However, challenges remain in ensuring adequate reimbursement for NGS testing. Dr. Gerds acknowledged the tension between clinicians and third-party payers regarding the cost of advanced diagnostics and therapies. Despite these challenges, the NCCN guidelines underscore the clinical value of NGS in optimizing MPN management.
Refining Disease Terminology
Another key update involves refining the terminology used to describe accelerated/blast phase MPN. The revised guidelines aim to distinguish this advanced stage of MPN from de novo acute myeloid leukemia (AML), as these conditions have distinct prognoses and responses to chemotherapy. This clarification is intended to improve treatment considerations and clinical trial design.
Considerations for JAK Inhibitor Selection
With four FDA-approved JAK inhibitors now available for myelofibrosis—ruxolitinib (Jakafi), pacritinib (Vonjo), momelotinib (Ojjaara), and fedratinib (Inrebic)—clinicians face the challenge of selecting the most appropriate agent for individual patients. While all four drugs inhibit JAK2, they differ in their selectivity for other targets and their clinical trial inclusion criteria.
Ruxolitinib remains a strong choice for patients with splenomegaly and preserved platelet counts, while pacritinib is particularly useful in cytopenic patients with thrombocytopenia. Momelotinib has demonstrated efficacy in patients with baseline anemia, and fedratinib has shown promise in patients previously treated with ruxolitinib. The NCCN guidelines provide an algorithm to aid in this selection process, but clinicians must also consider the nuances of each patient's disease and treatment history.
Promising Therapies in the Pipeline
Several phase 3 trials are underway evaluating novel therapies for myelofibrosis. The MANIFEST-2 trial is assessing the combination of ruxolitinib and pelabresib in frontline patients, while the TRANSFORM-1 study is evaluating ruxolitinib plus navitoclax versus ruxolitinib alone. Additionally, a phase 3 trial is investigating imetelstat (Rytelo) in patients with relapsed or refractory myelofibrosis.
These ongoing trials, along with studies of other agents like selinexor (Xpovio) and navtemadlin, offer hope for improved outcomes in MPN patients. The rapid pace of research in this field suggests that the NCCN guidelines will continue to evolve as new data emerge.
