Observational REVEAL Study Highlights Potential Risk Factors for Disease Transformation in Polycythemia Vera

A history of thrombosis is currently one of the factors for stratifying the risk for future thrombosis for patients with polycythemia vera (PV); however, a history of thrombosis could also serve as a potential factor in identifying patients in this population who are at higher risk of experiencing disease transformation, according to Michael R. Grunwald, MD.

“Having a history of thrombosis is not only a risk factor for future thrombosis; it is also a risk factor for disease progression to myelofibrosis or acute myeloid leukemia [AML]. That lends some insight into the biology of [PV], and perhaps, in the future, to introducing disease-modifying agents earlier in a patient's [disease] course,” Grunwald said in an interview with OncLive®.

Findings from the real-world, observational REVEAL study (NCT02252159) presented at the 2024 EHA Congress showed that at a median follow-up of 3.7 years, 6.7% of evaluable patients with PV (n = 2023) progressed to myelofibrosis. A univariate analysis of patients with vs without progression demonstrated that significant covariates associated with progression included disease duration, history of thrombosis, white blood cell count, hematocrit level, and variant allele frequency.

In the interview, Grunwald detailed the need to better identify risk factors associated with progression in patients with PV, elucidated findings from this real-world study, and expanded on the implications of the data.

Grunwald serves as the chief of the Leukemia Division and director of the Transplantation and Cellular Therapy Program at Atrium Health’s Levine Cancer Institute in Charlotte, North Carolina. He is also a clinical professor of hematology and oncology at Wake Forest University School of Medicine, Bowman Gray Center for Medical Education, in Winston-Salem, North Carolina.

OncLive: What limitations currently exist in PV risk models? What knowledge gaps did this study aim to address?

Grunwald: [Current] risk models attempt to stratify patients for the risk of thrombosis. There are 2 known risk factors for thrombosis: age greater than 60 [years] and a history of thrombosis, whether it be arterial or venous thrombosis. We know that patients with 1 of those 2 features—or both—are high risk for future thrombosis.

However, we do not have validated risk factors for the transformation [of PV] to more severe diseases, namely post-PV myelofibrosis and AML. That being the case, we sought to identify risk factors for transformation to myelofibrosis or AML in [patients with] PV.

What were the key characteristics of the patient population included in this observational study? What methodologies were employed?

This was the largest prospective, observational cohort of patients with PV [to date]. Not all patients were enrolled at diagnosis; patients could be enrolled at any point during their disease course. There were a total of 2510 patients observed on this study, and 2023 had a confirmed diagnosis of PV where we were certain that these patients had PV. The [remaining] balance of patients may or may not ultimately have had PV.

We examined that subset of 2023 patients…and looked to see which patients had signs of progression to myelofibrosis. Looking at the characteristics of those 2 groups—the [myelofibrosis] transformed group and the non-transformed group—we noticed that [patients in the] group that had transformed [to myelofibrosis] had a longer duration between diagnosis and enrollment on the study.

What other key results from the study were presented at the 2024 EHA Congress?

We were able to identify 5 risk factors that seemed to separate the transformed group from the non-transformed group. One [risk factor] was elevated white blood cell count; the second was a history of thrombosis; the third was elevated variant allele frequency for the JAK2 mutation; [the fourth] was time between diagnosis and enrollment, which was a little bit different between the groups; and finally, we identified that hematocrit [level] less than or equal to 45% was a risk factor for progression.

We do believe that the lower hematocrit [risk factor] is a variable that was confounded by a few other features. Many of those patients with lower hematocrit [levels] were on cytoreductive therapy, and they had a longer duration from diagnosis to enrollment. This is just a hypothesis, but some of those patients may have already been on their way to myelofibrosis at the point when they entered the study.

Based on these findings, what are the clinical implications for the monitoring of patients with PV, particularly in regard to these risk factors?

If a patient has a history of thrombosis and we discover that a certain type of therapy might be able to help that at-risk population have a lower chance of [PV] transforming [into myelofibrosis], it stands to reason that more of these patients should be treated with that therapy, whatever that therapy is. That basic understanding is helpful [for informing future research and treatment].

Some of the other risk factors that we identified have been suggested in previous work, [such as] the elevated white blood cell count and the higher variant allele frequency. It's almost intuitive that the duration of time from diagnosis to starting on the study—essentially the amount of time [a patient has had PV]—would be a risk factor, given that it takes time to progress.

How could these findings inform future studies?

We presented a molecular analysis in a small subset of patients who were transformed vs non-transformed, and we're trying to identify whether there are molecular features that can prognosticate for transformation. We have that in myelofibrosis, where we know that there are certain high-risk mutations. However, this remains unknown in PV.

Now, we're looking at a larger cohort of patients on the REVEAL study, including some whose disease transformed and some whose disease did not transform. We are seeing whether if we can identify molecular differences in these larger groups of patients.

Reference

Grunwald MR, Zwicker JI, Gerds AT, et al. A real-world evaluation of risk factors for disease progression in patients with polycythemia vera (PV) enrolled in REVEAL. Presented at: 2024 EHA Congress; June 13-16, 2024; Madrid, Spain. Abstract P1047.