SOHO 2024 | Challenges and unmet needs in MPNs: transplant decision-making and the management of MPN-AP/BP

It’s a very exciting time in the field of MPNs, lots of novel drug discoveries, developments. And with that, I think the management of MPNs is becoming increasingly complex. Two specific scenarios that stand out to me in terms of challenging scenarios are how to incorporate molecular mutations into transplant decision making for patients with myelofibrosis and the management of accelerated and blast-phase MPNs. To the first point, historically, we’ve used risk scores with cytogenetic and clinical information such as the DIPSS and the DIPSS Plus to stratify our patients with myelofibrosis into lower-risk versus higher-risk disease. Nowadays, really for the last six or seven years, we’ve had molecular risk scores. We know that those better refine our prognostic tools. They may upstage patients from intermediate-risk to high-risk, particularly if several high-risk mutations are found. Where things are muddy, however, is what do you do for patients who have low-risk disease clinically, but when you factor in those high-risk mutations, they all of a sudden have high-risk disease using a molecular score. Many of these patients, if they’re transplant-eligible, we typically will refer and have them assessed by our transplant colleagues. There have been retrospective studies to tease out what, if any, molecular mutations have a post-transplant impact or may particularly benefit from transplantation as a curative modality. And unfortunately, the results across these various retrospective studies are quite heterogeneous, they don’t really add up nicely. I’d say the one big takeaway is patients with multi-hit TP53 involvement tend to do poorly post-transplant with a long-term survival of about 20 to 25%. But patients with single-hit TP53 mutations, other high-risk mutations, if they’re transplant eligible, even if they have low-risk disease, in my mind, I would strongly consider allo-transplant workup and then ultimately proceeding if that is aligned with the patient’s interests and an appropriate donor, et cetera. Now, to think about accelerated and blast-phase MPNs, I’d say this is an area of high unmet need in the MPN landscape. Currently, there’s no standard approach to how we treat these diseases. We oftentimes will borrow from AML treatments, whether it be intensive chemo, hypomethylating agents or hypomethylating agents plus venetoclax. Unfortunately, even with these various treatment approaches, median overall survival is less than a year. We are trying to get a sense of whether targeted therapies such as IDH inhibitors could be a promising approach for those that have the appropriate mutations. And then there’s some targets pre-clinically, such as BCL-xL, LSD1, and others that merit prospective evaluation, specifically in accelerated and blast-phase MPNs. So I think much work needs to be done to move the needle forward. Thankfully, trials are either underway or under design to look at some of these novel pathways that can be targeted and hopefully improve outcomes for this patient population.