An expert hematologist discusses important molecular targets in myelofibrosis, and when to consider transplant.
Stephen Oh, MD, PhD: As far as the molecular targets and pathways that are thought to be critical in myelofibrosis, both in terms of the disease biology and as far as relevant therapeutic targeting, we know that there are several key targets and pathways. Of course, the JAK-STAT signaling pathway, the JAK kinases, are essential for the disease biology. We know that patients typically have mutations in JAK2 or MPL or CALR. And these mutations all in some fashions do activate JAK-STAT signaling.
We additionally know that there are other related signaling pathways that are important and maybe differential activated across different types of patients. And one broad category that we are gaining greater appreciation for over the years is inflammatory signaling pathways. This includes the NF-kappa B pathway, which can be activated through several upstream mediators, including cytokines such as TNF. We also know that signaling through the IRAKs, including IRAK1, can mediate or activate NF-kappa B.
When we think about the potential for targeting some of these specific markers or pathways, the ramifications of the drugs that target these different pathways may relate to how they contribute to the disease biology. For instance, JAK2 and JAK-STAT signaling contributing to myeloproliferation and targeting that pathway then should result in reduction in the myeloproliferative phenotype. Many of the drugs that are currently available in this class of JAK inhibitors target JAK2 plus or minus JAK1. This may contribute to anti-inflammatory effects. They may contribute to effects on the blood counts in both positive and negative ways, such that depending on the potency of the effect on the JAK1 vs JAK2, this may have a different or distinctive effect on the cytopenias.
When we talk about inflammatory signaling pathways, drugs that have the capacity to target some of these relevant markers and pathways such as IRAKs, this could have a positive benefit in terms of inflammation. And then as far as CALR, we know that there's some degree of JAK-STAT activation mediated by CALR, but there are also emerging data that there are several other pathways that are modulated by CALR, and maybe these need to be targeted as well. Or as highlighted in the ASH [American Society of Hematology Meeting 2022] plenary session this year, more specific molecular targeting a mutant CALR may result in the most beneficial effect.
As far as patients or circumstances in which we might recommend transplantation for a patient with myelofibrosis, typically this would include patients who fall into the higher risk categories, depending on whichever prognostic scoring system one might be using. And given that if patients are in those higher risk categories, we know the prognosis is not great in conjunction with, is the patient a suitable candidate for transplantation? As most patients with myelofibrosis are diagnosed at older age, this plus other comorbidities may indicate that they are not an appropriate candidate for transplantation. However, if a patient is younger and, otherwise healthy, and they're in a higher risk category, this is where transplantation may be the best option for a patient with myelofibrosis. Those patients are the ones in general for whom I would recommend transplantation.
For patients who aren’t transplant candidates, the signals that may prompt initiation of systemic therapy relate in large part to symptoms and consideration of blood counts. For instance, if a patient has notable symptoms, if they have an enlarged spleen that's causing symptoms, these are things for which we know we have agents that can provide benefit. Whether we're talking about ruxolitinib or pacritinib or one of the other JAK inhibitors, these are agents that we know can provide benefit in that regard. This relates to a patient's blood counts as to which agent to use and how we might use them. The choice of the specific drug would certainly factor in as to when and how to initiate therapy.
Transcript edited for clarity.