Highlights in MPN

In this video, Dr Nikki Granacher, haematologist at the Ziekenhuis aan de Stroom in Antwerp talks us through her highlights from ASH 2024 related to myeloproliferative neoplasms (MPN).

A first abstract that is discussed relates to risk stratification in MPN patients. In this study, Shivani Handa and colleagues evaluated the impact of TP53 mutations on disease outcomes in patients with MPN.1 This retrospective analysis included a total of 2,591 patients of whom 74 were found to harbour a TP53 mutation. Overall, 40 of these patients had a single hit TP53 mutation, while the remaining 34 had multi-hit mutations. Interestingly, multi-hit TP53 patients had a significantly higher risk for transformation to an accelerated or blast phase (AP/BP) than patients with a single-hit TP53 mutation (1-year rate: 34% vs. 15%; HR[95%CI]: 3.73[1.32-10.53]; p= 0.0194). Compared to patients with a high-molecular risk (HMR) mutation, multi-hit but not single-hit TP53-mutant MPN patients were found to have a significantly increased risk of MPN-AP/BP transformation. One-year OS rates were shown to be significantly worse for both multi-hit (55%) and single-hit (75%) TP53 mutant patients than for patients with an HMR mutation (99%, p< 0.0001 for both).1 The dismal prognostic impact of TP53 mutations was also shown in a second abstract presented by Tefferi et al. In this analysis, especially the presence of multi-hit TP53 mutations was shown to compromise overall survival (OS).2 While these findings require further validation, it seems wise to include the TP53 mutation status in the risk stratification of MPN patients and to consider multi-hit TP53 mutant MPN as a haematological emergency.

In a phase 1b study presented by Masarova et al., a treatment with CXCR4 enriched T regulatory cells (CK0804) was added to ruxolitinib in a cohort of 9 myelofibrosis (MF) patients with suboptimal disease control on ruxolitinib (i.e., palpable splenomegaly, symptoms, or grade 2 cytopenia). The treatment was very well tolerated with only one infusion reaction. While the impact on spleen volume was limited, the treatment did lead to a marked improvement in symptom control. This effect proved to be durable, with ongoing responses in all patients 6 months after the infusion.3 More intensive dosing schedules and other combinations with CK0804 will be explored in the years to come. As such, cellular therapy has now also entered the field of MF.

Also in MF patients, interesting data were presented with the MDM2 inhibitor navtemadlin. In the phase III BOREAS study, 183 patients with TP53 wildtype primary or secondary MF who were relapsed/refractory to a JAK inhibitor were randomized (2:1) to receive navtemadlin monotherapy or best available therapy, (BAT: hydroxyurea, PEG-interferon, immunomodulatory therapy, and/or supportive care).4 At week 24, 15% (18/123) of patients in the navtemadlin arm achieved a spleen volume reduction of 35% (SVR35) as compared to 5% in the BAT arm (p=0.08). Corresponding rates of total symptom score reduction ≥50% (TSS50) were reported at 24% and 12%, respectively.4 By using very strict prophylactic measurements, the navtemadlin treatment did not lead to high-grade gastro-intestinal toxicity, which is a typical side effect of MDM2 inhibition.4 In a second presentation on this study, navtemadlin was also shown to improve biomarkers of disease burden. Interestingly, changes in CD34-positive counts, driver allele burden, and serum inflammatory cytokine levels with navtemadlin treatment were significantly correlated with the magnitude of SVR. This shows a clear relation between navtemadlin-induced disease modification and SVR, a key clinical outcome predictive of quality of life and OS in MF.5

Another emerging agent in MF consists of nuvisertib or TP-3654, a selective PIM1 kinase inhibitor. At ASH 2024, updated results were presented of a phase 1/2 study evaluating nuvisertib as monotherapy in a cohort of 74 patients with relapsed/refractory MF. The treatment was well-tolerated across 5 dose levels, without any dose-limiting toxicity. Among the 18 patients who were eligible for SVR evaluating, an SVR25 rate of 22.2% was reported. In addition to this, the treatment has a significant impact on symptom control, with a TSS50 rate of 44.4%. Interestingly, the treatment had a minimal impact on blood counts, with a proportion of patients even experiencing a rise in the haemoglobin level and the platelet count. Finally, the drug also has disease-modifying potential, with about half of the evaluable patients showing an improvement in bone marrow fibrosis.6 As such, these findings support the further evaluation of nuvisertib, both as monotherapy and in combination with JAK inhibitors, in patients with MF.